New Drug Approvals All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, OPEN SUPER

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New Drug Approvals All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, OPEN SUPERSTAR Helping millions, 10 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 27 lakh plus VIEWS on this blog in 221 countries, 7 CONTINENTS The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent, USE CTRL AND+ KEY TO ENLARGE BLOG VIEW A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, I have lot to acheiveJoin me on LinkedinJoin me on ResearchgateJoin me on FacebookFACEBOOK...................................................................Join me on twitter..................................................................Join me on google plusGoogleplus MYSELF DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 Follow Blog via Email Enter your email address to follow this blog and receive notifications of new posts by email. Join 2,538 other followers Email Address: DR ANTHONY MELVIN CRASTO Ph.D DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug moleculesand implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etcCetuximab Sarotalocan Sodium is an antibody-drug-conjugate (molecular weight: 156,000-158,000) consisting of tetrasodium salt of Sarotalocan (6-({[3-({(OC-6-13)-bis({3-[bis(3-sulfopropyl)(3-sulfonatopropyl)azaniumyl]propyl}dimethylsilanolato-κO,κO )[(phtalocyaninato(2-)κN29,κN30,κN31,κN32)-1-yl]silicon}oxy)propoxy]carbonyl}amino)hexanoyl (C70H96N11O24S6Si3; molecular weight: 1,752.22)) attached to an average of 2-3 Lys residues of Cetuximab.[2166339-33-7 , Cetuximab sarotalocan]Originator Japan TobaccoDeveloper Japan Tobacco; JW PharmaceuticalClass Acetic acids; Amides; Antianaemics; Pyridones; Small molecules; TriazolesMechanism of Action Hypoxia-inducible factor-proline dioxygenase inhibitors27 Dec 2019 Japan Tobacco and SalubrisBio enter into a development and marketing agreement for enarodustat (JTZ 951) in China, Hong Kong, Macau and Taiwan for Anaemia29 Nov 2019 Preregistration for Anaemia in Japan (PO)31 Oct 2019 Phase I development in Anaemia is ongoing in USAEnarodustat is a potent and orally activefactor prolyl hydroxylaseinhibitor, with anEC50of 0.22 μM. Enarodustat has the potential for renal anemia treatmentInhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π–π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells andin vivoby improving cell permeability led to the discovery of JTZ-951 (compound14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound14was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound14was selected as a clinical candidate.To a solution of SI-5 (2.28 g, 6.19 mmol) in EtOH (9.1 mL) was added 2N NaOH aq. (12.4 mL, 24.8 mmol) at room temperature. After stirring at 90 °C for 2 h, 6N HCl aq. (4.1 mL, 24.6 mmol). This was allowed to gradually cool with stirring and crystals were precipitated. The crystals were collected by filtration to give the title compound 14 (2.16 g, 103% yield). 1H NMR (400 MHz, DMSO-D6) δ: 14.22 (s, 1H), 12.98 (br s, 1H), 9.84 (t, J = 5.6 Hz, 1H), 8.58 (s, 1H), 7.33– 7.18 (m, 5H), 6.80 (s, 1H), 4.22 (d, J = 5.6 Hz, 2H), 3.40 (t, J = 7.7 Hz, 2H), 3.12 (t, J = 7.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ: 170.28, 167.70, 165.32, 152.95, 148.53, 146.49, 140.05, 128.33, 128.20, 126.17, 106.72, 95.56, 41.00, 31.95, 31.72. HRMS m/z: [M+H]+ calcd for C17H17N4O4, 341.1244; found, 341.1243. Anal. (C17H16N4O4) calcd C 59.99%, H 4.74%, N 16.46%; found C 60.02%, H, 4.78%, N, 16.42%. Melting point: 186 °C Purity: 100.0%./////////////Enarodustat, 2020 APPROVALS, JAPAN 2020,エナロデュスタット ,JTZ 951, ENAROY, 2020 APPROVALS,Sofpironium Bromide1-ambo-(3R)-3-{[(R)-(Cyclopentyl)hydroxy(phenyl)acetyl]oxy}-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidinium bromideC22H32BrNO5 : 470.4[1628106-94-4]SYNPATENTWO 2018026869https://patents.google.com/patent/WO2018026869A1/enCertain glycopyrronium salts and related compounds, as well as processes for making and methods of using these glycopyrronium salts and related compounds, are known. See, for example, US Patent No. 8,558,008, which issued to assignee Dermira, Inc. See also, for example, US Patent No. 2,956,062, which issued to assignee Robins Co Inc. A H. See also, for example, International Patent Application Publication Nos. WO 98/00132 Al and WO 2009/00109A1, both of which list applicant Sepracor, Inc., as well as US Patent Nos. 6,063,808 and 6,204,285, both of which issued to assignee Sepracor, Inc. Certain methods of treating hyperhidrosis using glycopyrronium salts and related compounds are known. See, for example GB 1,080,960. Certain forms of applying glycopyrrolate compounds to a subject are known. See, for example US Patent Nos. 6,433,003 and 8,618,160, both of which issued to assignee Rose U; also US Patent Nos. 7,060,289; 8,252,316; and 8,679,524, which issued to PurePharm, Inc.[0004] One glycopyrronium salt which is useful in certain medical applications is the following compound:[0005] As illustrated above, the absolute configuration at the three asymmetric chiral positions is 2R3 R1 RS. This means that the carbon indicated with the number, 2, has the stereochemical R configuration. The carbon indicated with the number, 3 , also has the stereochemical R configuration. The quatemary ammonium nitrogen atom, indicated with a positive charge, may have either the R or the S stereochemical configuration. As drawn, the compound above is a mixture of two diastereoisomers.[0006] Certain processes for making glycopyrronium salts are known. However, these processes are not as safe, efficient, stereospecific, or stereoselective as the new processes disclosed herein, for example with respect to large-scale manufacturing processes. Certain publications show that higher anticholinergic activity is attributed to the 2R3 R configuration. However, to date, processes for making the 2R3 R isomers, as well as the 2R3 R1 R isomers are low yielding, involve too many reaction steps to be economically feasible, use toxic materials, and/or are not sufficiently stereospecific or stereoselective with respect to the products formed.EXAMPLE 2[0179] The below synthetic description refers to the numbered compounds illustrated in FIG. 2. Numbers which refer to these compounds in FIG. 2 are bolded and underlined in this Example.[0180] Synthesis of R(-)-Cyclopentylmandelic acid (4)[0181] R(-)-cyclopentylmandelic acid (compound 4) can be synthesized starting withR(-)-mandelic acid (compound 1) according to Example 1.[0182] Step 1 : Making Compound 2.[0183] R(-)-mandelic acid (1) was suspended in hexane and mixed with pivaldehyde and a catalytic amount of trifluoromethanesulfonic acid at room temperature to form a mixture. The mixture was warmed to 36 °C and then allowed to react for about 5 hours. The mixture was then cooled to room temperature and treated with 8% aqueous sodium bicarbonate. The aqueous layer was removed and the organic layer dried over anhydrous sodium sulfate. After filtration and removal of the solvent under vacuum, the crude product was recrystallized to give (5R)-2-(tert-butyl)-5-phenyl-l,3-dioxolan-4-one (compound 2) in 88% yield (per S-enantiomer yield).[0184] Step 2: Making Compound 3.[0185] Compound 2 was reacted with lithium hexamethyl disilazide (LiHMDS) in hexane at -78 °C under stirring for one hour. Next, cyclopentyl bromide was added to the reaction mixture including compound 2 and LiHMDS . The reaction was kept cool for about four (4) hours and then slowly warmed to room temperature and allowed to react for at least twelve (12) more hours. The resulting mixture was then treated with 10% aqueous ammonium chloride. The aqueous layer was discarded and the organic layer dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue recrystallized from hexane to give pure product (5R)-2-(tert-butyl)-5-cyclopentyl-5-phenyl- l,3-dioxolan-4-one (3) in 63% yield (per S-enantiomer yield).[0186] Step 3: Making Compound 4.[0187] R(-)-cyclopentylmandelic acid (compound 4) was prepared by providing compound 3 in aqueous methanolic potassium hydroxide at 65 °C for four hours. After cooling this mixture to room temperature and removing the methanol under vacuum, the aqueous solution was acidified with aqueous hydrochloric acid. The aqueous solution was then extracted twice with ethyl acetate and the organic phase dried with anhydrous sodium sulfate. After removing the solvent and performing a recrystallization, pure R(-)- cyclopentylmandelic acid (compound 4) was obtained in 62% yield (based on S-enantiomer yield).[0188] Next, a racemic mixture of l -methyl-3-pyrridinol (20) was provided:[0189] Synthesis of 2R3 R-glycopyrrolate base (8)[0190] Step 4: Making Compound 8.[0191] Enantiomerically pure R(-)-cyclopentylmandelic acid (4) was coupled to racemic l-methyl-3-pyrridinol (20) using 1, 1 -carbonyldiimideazole (CDI) activated esterification to make an enantiomerically pure mixture of the following erythro- and threo- glycopyrrolate bases (compounds 8 and 21, respectively):[0192] The 2R3 R-glycopyrrolate base (compound 8) was then resolved using the 5- nitroisophthalate salt procedure in Finnish Patent 49713, to provide enantiomerically pure 2R3 Έ. {erythro) as well as pure 2R3 S {threo). In this example, the 2R3 S {threo) was discarded. The 2R3 Έ. {erythro) was separated as stereomerically pure compound 8.[0193] Step 6: Making Compound 9.[0194] The glycopyrrolate base, compound 8, was treated in dry acetonitrile with methyl bromoacetate at room temperature under stirring for three (3) hours. The crude product was dissolved in a small volume of methylene chloride and poured into dry ethyl ether to obtain a precipitate. This procedure was repeated three times to provide (3R)-3-((R)- 2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-l -(2-ethoxy-2-oxoethyl)-l-methylpyrrolidin-l ium bromide, also known as 3 (R)-[R-Cyclopentylphenylhydroxyacetoy]- -ethyl- l methoxycarbonylpyrrolidinium bromide (compound 9) in 89% yield. Compound 9 included the following stereoisomers:EUS-2019161443-A1Processes for making, and methods of using, glycopyrronium compounds2016-08-02NCT02058264A Safety, Tolerability and Preliminary Efficacy Study of BBI-4000 in Subjects With Axillary HyperhidrosisPhase 1Completed2014-09-11JapicCTI-184249A repeatedly applied study of BBI-4000 in patients with primary hyperhidrosiscomplete2018-12-13JapicCTI-184003A long term safety study of BBI-4000 gel in patients with primary axillary hyperhidrosiscomplete2018-06-15JapicCTI-183948A confirmatory study of BBI-4000 gel in patients with primary axillary hyperhidrosiscomplete2018-05-07UMIN000020546A skin irritation study of BBI-4000 in healthy adult males (phase 1)Complete: follow-up complete2016-01-18 Tetrahydrobiopterin, September 29, 2020 5:58 am / Leave a comment SapropterinSapropterin dihydrochloride, Dapropterin dihydrochloride, R-THBP, 6R-BH4, SUN-0588, Phenoptin, Biopten, Biobuden, BiptenApproval:US: Dec’07, EU: Dec’08Approval:US: Dec’07, EU: Dec’08IUPAC Name(6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-3,4,5,6,7,8-hexahydropteridin-4-oneSMILES[H][C@@]1(CNC2=C(N1)C(=O)NC(N)=N2)[C@@H](O)[C@H](C)Oсапроптерин [Russian] [INN]سابروبتيرين [INN]沙丙蝶呤 [Chinese] [INN]17528-72-227070-47-9Sun 0588CAS Registry Number: 62989-33-7CAS Name: (6R)-2-Amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinoneAdditional Names: (6R)-L-erythro-tetrahydrobiopterin; dapropterin; R-THBP; 6R-BH4Molecular Formula: C9H15N5O3Molecular Weight: 241.25Percent Composition: C 44.81%, H 6.27%, N 29.03%, O 19.90%Literature References: Natural cofactor of the aromatic amino acid hydroxylases required for catecholamine and serotonin biosynthesis. Identification of cofactor activity: S. Kaufman, Proc. Natl. Acad. Sci. USA 50, 1085 (1963). Prepn of (6R,S)-BH4: B. Schircks et al., Helv. Chim. Acta 61, 2731 (1978). Chromatographic separation of diastereoisomers: S. W. Bailey, J. E. Ayling, J. Biol. Chem. 253, 1598 (1978). Absolute configuration of natural isomer: W. L. F. Armarego et al., Aust. J. Chem. 35, 785 (1982). Stereospecific synthesis: S. Matsuura et al., Heterocycles 23, 3115 (1985); H. Sakai, T. Kanai, EP 191335; eidem, US 4713454 (1986, 1987 both to Shiratori; Suntory). Bioavailability: G. Kapatos, S. Kaufman, Science 212, 955 (1981). Effect on neurotransmitter monoamine biosynthesis: S. Miwa et al., Arch. Biochem. Biophys. 239, 234 (1985). LC determn in biological samples: Y. Tani, T. Ishihara, Life Sci. 46, 373 (1990). Therapeutic potential in hyperphenylalaninemia: S. Kaufman, J. Nutr. Sci. Vitaminol, Suppl., 601 (1992).Properties: pK¢ 5.05. uv max (0.1 N HCl): 265 nm (e 14000).pKa: pK¢ 5.05Absorption maximum: uv max (0.1 N HCl): 265 nm (e 14000)Derivative Type: DihydrochlorideCAS Registry Number: 69056-38-8Manufacturers Codes: SUN-0588Trademarks: Biopten (Maruho)Molecular Formula: C9H15N5O3.2HClMolecular Weight: 314.17Percent Composition: C 34.41%, H 5.45%, N 22.29%, O 15.28%, Cl 22.57%Properties: Crystals from HCl, mp 245-246° (dec). [a]D25 -6.81° (c = 0.665 in 0.1 M HCl). uv max (2 M HCl): 264 nm (e 16770).Melting point: mp 245-246° (dec)Optical Rotation: [a]D25 -6.81° (c = 0.665 in 0.1 M HCl)Absorption maximum: uv max (2 M HCl): 264 nm (e 16770)Therap-Cat: In treatment of hyperphenylalaninemia.Keywords: Enzyme CofactorSapropterin (tetrahydrobiopterin or BH4) is a cofactor in the synthesis of nitric oxide. It is also essential in the conversion of phenylalanine to tyrosine by the enzyme phenylalanine-4-hydroxylase; the conversion of tyrosine to L-dopa by the enzyme tyrosine hydroxylase; and conversion of tryptophan to 5-hydroxytryptophan via tryptophan hydroxylase.Sapropterin commonly known as tetrahydrobiopterin (THB or BH4) developed by BioMarin and marketed as Sapropterin dihydrochloride under the brand name of KUVAN®. It is indicated for the treatment of phenylketonuria (PKU) and tetrahydrobiopterin deficiencies. Sapropterin dihydrochloride is chemically known as (6R)-2-amino-6-[(lR, 2S)-1, 2- dihydroxypropyl]-5,6,7,8-tetrahydro-4(lH)-pteridinone dihydrochloride and structurally represented as below.Sapropterin dihydrochlorideDue to its vital role in the conversion of L-tyrosine into L-DOPA, which is the precursor for dopamine, a deficiency in tetrahydrobiopterin can cause severe neurological disorders unrelated to toxic build-up of L-phenylalanine; dopamine is a crucial neurotransmitter, and is the precursor of norepinephrine and epinephrine. Thus, a deficiency of tetrahydrobiopterin can result in phenylketonuria (PKU) from L-phenylalanine concentrations or hyperphenylalaninemia (HP A), as well as monoamine and nitric oxide neurotransmitter deficiency or chemical imbalance. The chronic presence of PKU can result in severe brain damage, including symptoms of mental retardation, speech impediments like stuttering, slurring, seizures or convulsions and behavioural abnormalities.In an article published in Bio Chem J 347 (1): 1-16, tetrahydrobiopterin is reported to be biosynthesized from guanosine triphosphate (GTP) by three chemical reactions mediated by the enzymes GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR).Preparation of Sapropterin is reported with a mixture of R S isomers in Helv. Chim. Acta, 60, 1977, 211-214, by catalytic reduction of L-biopterin of formula (2). Similar process with slight modifications is also published in Hel. Chim. Acta, 61, 1978, 2731- 2738.(2)In another publication reported in Helv. Chim. Acta, 62, 1979, 2577-2580, separation of the diastereomers (6R) and (6S)-5,6,7,8-tetrahydro-L-biopterin is reported by fractional crystallization of corresponding tetraacetyl derivative followed by hydrolysis using aq. HC1.In another process published in Heterocycles, 23(12), 1985, 3115-3120, Sapropterin dihydrochloride of formula (1) is prepared by catalytic hydrogenation of L- biopterin of formula (2) in the presence of Pt02 under latm hydrogen pressure in 0.1 M potassium phosphate buffer at pH 11.8 for 18hr followed by filtration and recrystallization from 8M HC1. With slight modifications in the above reaction conditions like using platinum black, aq. base solutions like tetraethylammonium hydroxide or triethylamine etc. under 100 Kg/cm2 hydrogen pressure / 0° C / pH 12.0 / 1000 rpm / 20h/3N HCl-EtOH with 85% yield is disclosed in US4713454. In another process disclosed in US4595752, L-biopterin of formula (2) is catalytically reduced in the presence of platinum oxide in aq. base / acid solutions like (10% aq. potassium carbonate, aq. sodium carbonate, aq. potassium acetate and 0.1 N aq. HCl) under bubbling of hydrogen gas for 5-30hr at room temperature followed by filtration and isolated as HCl salt of formula (1) using aq. HCl and ethanol to obtain Sapropterin dihydrochloride.In another approach disclosed in WO2005049614, racemic isomers of Sapropterin dihydrochloride are prepared from L-neopterin.In another process disclosed in WO2009088979, the diacetyl biopterin is hydrolysed in the presence of aq. diethyl amine-n-butanol mixture at 40°C for 16hr at pH 11.5 followed by hydrogenation in the presence of platinum black using 50 bar hydrogen pressure at 25 °C. Product of formula (1) isolated as HCl salt from ethanol or butanol.In another process disclosed in US20130197222, Sapropterin dihydrochloride of formula (1) is prepared starting from condensation of crotonoic acid.The process for preparation of key intermediate, L-biopterin of formula (2) is cited in the following references.In an article published in J. Am. Chem. Soc, 1955, 77, 3167-3168, L-biopterin of formula (2) is reported to be first isolated from human urine. The melting point reported to be 250-280°C. In another article published in J. Am. Chem. Soc, 1956, 78, 5868-5871, L-biopterin of formula (2) is prepared starting from L-rhamnose. A slight modification in the reaction conditions mentioned above is disclosed in US3505329.In the article published in Helv. Chim. Acta, 1969, 52, 1225-1228, L-biopterin of formula (2) along with 7-biopterin is synthesized by condensing 2, 4, 5-triamino-6-oxo-l, 6-dihydropyrimidine dihydrochloride with (1 -benzyl- l-phenyl-hydrazino)-5-desoxy-L- ribulose followed by oxidation of the tetrahydro derivative.Later in the year 1974, in an article, J. Am. Chem. Soc, 1974, 96, 6781-6782, L-biopterin is reported to be prepared starting from L-rhamnose. In another approach published in Bull. Chem. Soc. Jpn., 1975, 48(12), 3767-3768, L- biopterin of formula (2) is prepared from 2, 4, 5-triamino-6-hydroxypyrimidine dihydrochloride is reacted with hydrazone derivative in aq. methanol at reflux temperature.In another process disclosed in US5043446 (1989), L-biopterin process is claimed to be synthesized starting from D-ribose. Similar approach with slight variations in the process, later published in Liebigs Ann. Chem., 1989, 1267-1269.In another approach published in Agric. Biol. Chem., 1989, 53, 2095-2100, L-biopterin is synthesized starting from (S)-ethyl lactate. Prior to this publication the methodology is claimed by the same authors in JP01-221380 (1989).In another approach disclosed in US5037981 (1990), L-biopterin is synthesized from 2- methylfuran.In the article, Synthesis, 1992, 303-308, L-biopterin is synthesized from (4S)-4(3P- Acetoxy-5-androsten-17P-ylcarbonyloxy)-2-pentynol.In the approach published in J. Org. Chem., 1996, 61, 8698-8700, L-biopterin is synthesized from L-tartaric acid.In the patent US7361759 (2005), L-biopterin of formula (2) is made from L-rhamnose diethyl mercaptal.US 20120157671 application discloses the preparation of compound of formula (4a) is by reacting D-ribose of formula (3) with acetone in the presence of sulphuric acid at room temperature followed by neutralization with sodium carbonate and concentrated under vacuum.https://www.mdpi.com/1999-4923/12/4/323/htmSynthesis ReferenceSteven S. Gross, Blocking utilization of tetrahydrobiopterin to block induction of nitric oxide synthesis. U.S. Patent US5502050, issued October, 1984.US5502050SYNSYNSynthetic ReferenceHong, Hao; Gage, James; Chen, Chaoyong; Lu, Jiangping; Zhou, Yan; Liu, Shuangyong. Method for synthesizing sapropterin dihydrochloride. Assignee Asymchem Laboratories (Tianjin) Co., Ltd., Peop. Rep. China; Asymchem Life Science (Tianjin) Co., Ltd.; Tianjin Asymchem Pharmaceutical Co., Ltd.; Asymchem Laboratories (Fuxin) Co., Ltd.; Jilin Asymchem Laboratories Co., Ltd. WO 2013152609. (2013).syn 1EP 0191335. Aust J Chem 1984,37(2),355-66, Chem Lett 1984,5(5),735-8Helv Chim Acta 1979,62(8),2577-80This compound can be prepared in two related ways: 1) The catalytic hydrogenation of biopterin (I) with H2 over PtO2 aqueous K2HPO4 at pH 11.4 or aq. (Et)4NOH at pH 12 yields a solution which is acidified with HCl. After evaporation, the residue is crystallized in ethanol HCl. 2) The acetylation of biopterin (I) with refluxing acetic anhydride gives the triacetyl derivative (II), which is hydrogenated with H2 over PtO2 in trifluoroacetic acid, yielding the (6RS)-mixture of triacetyl derivatives (III). Acetylation of (III) with refluxing acetic anhydride affords the tetracetyl (6RS)-derivative (IV), which by fractional crystallization or column chromatography of the dihydrochloride in methanol gives the desired compound as pure (6R)-isomer.PATENThttps://patents.google.com/patent/WO2016189542A1/enformula 1).The present invention is shown in below scheme- 1Experimental Section: Example-1: Preparation of (6R)-2-amino-6-[(lR, 2S)-1, 2-dihydroxypropyl]-5,6,7,8- tetrahydro-4(lH)-pteridinone dihydrochloride of formula (1):Step (i): Preparation of 2, 3-O-isopropylidene-D-ribose of formula (4a)Into a 5L, 4 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer socket, and a condenser, were charged acetone (3.0 L), D-ribose (300.0 gm, 2.0 mole) and p-toluene sulfonic acid (11.5 gm). The solution was stirred and maintained at 20-25°C for 2.5-3.0hrs. After completion of reaction, the reaction mixture was neutralized with aq. base solution and filtered. The filtrate was evaporated to dryness to get 375.0 gm (98.8% by theory) of 2, 3-O-isopropylidene-D-ribose of formula (4a) as light brown colour oily residue. Purity: 95% by GC. Step (ii): Preparation of l-deoxy-3, 4-O-isopropylidene-D-allitol of formula (5a)Into a 5L, 4 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer socket, and a condenser, was charged, 2.0L, 3M methyl magnesium chloride and cooled to 10° C. To this stirred solution, a solution of 200gm of 2,3-0- isopropylidene-D-ribose of formula (4a) dissolved in 200 mL tetrahydrofuran was added. After completion of reaction, the reaction mixture was quenched with ammonium chloride, extracted with ethyl acetate and separated. The solvent was evaporated to dryness under vacuum to get 185gm of l-deoxy-3, 4-O-isopropylidene-D-allitol of formula (5a) as dark brown colour oily residue. The crude product was purified by crystallization from ethyl acetate/hexane mixture to get 130g (60% by theory) as white crystalline solid. Purity: 98% by GC.JR (λ Cm-1, KBr disc): 3317.64, 2993.69-2976.90, 2926.08, 2873.26 (m) -CH3, 1074.35; 1 HNMR (400 MHz, DMSO-d6, EDl®j ¾ : (H2¾H3, J=6.8Hz, 3H),1.148 (s, CH3, 3H), 1.290 (s,CH3), 3.415-3.357 (m, CH, 1H), 3.652-3.571 (m, CH2, 2H), 3.812-3.803 (d, 2 X CH, 2H), 4.00-3.969 (q, CH, 1H), 4.504-4.476 (t, ΟΗ, ΙΗ), 4.504- 4.476 (d, OH, 1H), 5.381-5.371 (d, OH, 1H): 13 CNMR (100 MHz, DMSO-d6, □ (ppm): 20.59, 25.35, 27.73, 63.18, 64.61 , 69.77, 76.82, 81.40, 107.31 ; Mass: 206.42 [M], 205.41 [M-l]. DSC (° C): 77.58° C Step (iii): Preparation of 5-deoxy-2, 3-O-isopropylidene-D-ribose of formula (6a)Into a 5L 4 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer socket, and a condenser, were charged, 1.6 L of water and 270 gm of sodium meta periodate. The solution was cooled to 10-20°C. To the stirred solution, a solution of 200 gm of l-deoxy-3, 4-O-isopropylidene-D-allitol of formula (5a) dissolved in 1.4 L of isopropyl ether at 25°C. After addition, the reaction mixture was maintained at 25-30° C for l-2h. After completion of reaction, the layers were separated and the organic layer was washed with water, aq. sodium bicarbonate and separated. The excess solvent was removed by distillation under vacuum to get 145 gm (85.4% by theory) of 5- deoxy-2, 3-O-isopropylidene-D-ribose of formula (6a) as yellow oil. Purity: 98% by GC.Step (iv v): Preparation of 5-deoxy-L-ribose phenyl hydrazone of formula (8) a) Step (iv): Preparation of 5-deoxy-L-ribose of formula (7)Into a 2L 4 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer socket, and a condenser, were charged 600ml of water and 200gm of 5- deoxy-2, 3-O-isopropylidene-D-ribose of formula (6a). To the stirred reaction mixture, 180gm of resin was charged and stirred for 8-10 h at 10-15° C. After completion of reaction, the resin was recovered and the filtrate was clarified by activated charcoal and filtered. The filtrate was distilled off under vacuum and the resulting 5-deoxy-L-ribose of formula (7) present water was directly used in the next step without further isolation and purification. The purity of 5-deoxy-L-ribose of formula (7) present in water was above 95% by TLC.b) Step (v): Preparation of 5-deoxy-L-ribose phenyl hydrazone of formula (8)Into a 2L 4 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer socket, and a condenser, were charged the above aq. solution of 5-deoxy-L- ribose of formula (7), 5.0 mL of acetic acid. To the stirred solution, 125g of phenyl hydrazine was charged and stirred the reaction mixture for l-2h at 25-35° C. After completion of reaction, the reaction product was filtered and washed with isopropyl ether. The wet product was dried to get 190g (73.9% by theory) of 5-deoxy-L-ribose phenyl hydrazone of formula (8) as yellow colour crystalline powder. Purity: 99.0% by HPLC. Step (VI toX): Preparation of L-erythro-biopterin of formula (2)a) Step (vi): Preparation of triacetoxy-5-deoxy-L-ribose phenylhydrazone of formula (9)Into a 10L 4 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer socket, and a guard tube, were charged 5L of ethyl acetate, 500g of 5- deoxy-L-ribose phenyl hydrazone of formula (8) and 54gm of 4-dimethylaminopyridine. The reaction mixture was cooled to 25-30° C and was added 730gm of acetic anhydride drop wise. The reaction mixture was maintained under stirring for 2-3h. After completion of reaction, the reaction mixture was washed with water, aq. sodium carbonate and water, and separated. The organic layer was used in the next stage without further isolation and purification.b) Step (vii): Preparation of 1,2-diacetyl-biopterin of formula (10)Into a 20L 4 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer socket, addition funnel, and a condenser, were charged, the above organic layer containing triacetoxy-5-deoxy-phenyl hydrazone of formula (9) obtained in step (vi), 3.0 L methanol and 4-hydroxy-2,5,6-triaminopyrimidine base (generated from 600 gm of corresponding sulphate salt) and salt (generated from 350 gm of tetra butyl ammonium bromide and 154g of 70% perchloric acid) and 5.3L water under stirring and heated and maintained at 35-40°C for 6-8h. The reaction mixture was then cooled to 20- 25°C and added 1.0 Kg 35% aq. hydrogen peroxide drop wise. The reaction mixture was maintained for 36-40h under stirring at 25-30°C and resulting product was filtered under suction. The wet product was washed with water and utilized in the next step without further purification.c) Step (viii): Preparation oi -erythro biopterin of formula (2)Into a 10L 4-necked round-bottomed flask equipped with a mechanical stirrer, condenser, thermometer socket, and addition funnel, were charged 1.35 L of aq. potassium hydroxide and the above wet product obtained from step (vii). The reaction mixture was heated to 45-50° C and maintained form 2-3h and filtered. The pH of the filtrate was adjusted to neutral and the resulting product was filtered and dried to get 205 g of crude L-erythro-biopterin of formula (2) as dark brown solid. Purity: 90% by HPLCd) Step (ix): Preparation of potassium salt oi -erythro biopterin of formula (11a) Into a 10L 4 necked round-bottomed flask equipped with a mechanical stirrer, thermometer socket, and a glass stopper, were charged 650 mL water followed by HOg of potassium hydroxide and dissolved under stirring. The potassium hydroxide solution was cooled to 25-30° C and the above crude L-erythro-biopterin of formula (2) was charged under stirring. The resulting solution was then clarified using activated carbon and filtered. The potassium salt was regenerated from the solution by the addition of 8.5L of isopropyl alcohol. The resulting salt was filtered and washed with isopropyl alcohol. The wet product of formula (11a) was utilized in the next step without further purification.e) Step (x): Preparation of pure L-er thro biopterin of formula (2) from potassium salt of L-erythro biopterin of formula (2)Into a 5L 4 necked round-bottomed flask equipped with mechanical stirrer, thermometer socket, and addition funnel, were charged 3.2 L of water and the above wet potassium salt of formula (11a). The reaction mixture was stirred to dissolve completely. The resulting solution was clarified using activated carbon and filtered. The pH of the filtrate was adjusted to 6.0-7.0 to get pure L-erythro-biopterin of formula (2). The product was filtered and washed with water followed by isopropyl alcohol followed by isopropyl ether to get 130g of highly pure L-erythro biopterin of formula (2) with 98% HPLC purity Appearance: pale brown coloured solid.1H NMR (3N DC1) 5(ppm): 1.569-1.585(d, 3H), 4.596-4.657(p, 1H), 5.325-5.337(d, 1H), 9.355(s, 1H); Mass: 238.29(M+1), 239.22(M+2).Step (xi): Preparation of Sapropterin dihydrochloride of formula (1)Into a 5L 4 necked round-bottomed flask equipped with mechanical stirrer, and thermometer socket, were charged 1.8L of water, 250g of L-erythro-biopterin of formula (2) followed by 800mL of 20% aq. potassium carbonate solution under stirring. The solution was then added 90g of platinum oxide catalyst. The reaction mixture was then transferred into an autoclave and pressurized with 40 bar hydrogen gas and hydrogenated at room temperature for 24-30h under stirring. After completion of reaction, the catalyst was filtered off and the pH of the filtrate was acidified with concentrated hydrochloric acid. The water was evaporated under vacuum and the resulting crude Sapropterin dihydrochloride of formula (1) was isolated as pale yellow colour solid by addition of isopropanol/l-pentanol mixture. The product was dried in a vacuum oven to get 250g of crude Sapropterin dihydrochloride of formula (1). Step (xii): Purification of Sapropterin dihydrochloride of formula (1)Into a 2L 4 necked round-bottomed flask equipped with a mechanical stirrer, thermometer socket, and reflux condenser, were charged 1L water and 250g of Sapropterin dihydrochloride of formula (1). The contents were stirred to dissolve completely. The clear solution was treated with activated charcoal and filtered. The filtrate was distilled off completely under vacuum to afford pale yellow solid. The product was isolated from isopropanol/l-pentanol mixture to get 225.0 g (90%) pure Sapropterin dihydrochloride of formula (1) as pale yellow to off-white solid. HPLC purity is 99.9%.Example 2: Preparation of triacetoxy-5-deoxy-L-ribose phenylhydrazone of formula(9)Into a 10L 4 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer socket, and a guard tube, were charged 50mL of ethyl acetate, 5.0g of 5- deoxy-L-ribose phenyl hydrazone of formula (8) and 0.54g of N, N-dimethylamino pyridine. The reaction mixture was cooled to 15-20°C and was added 7.2gm of acetic anhydride drop wise. The reaction mixture was maintained under stirring for 6-8h. After completion of reaction, the reaction mixture was washed with water, aq. sodium carbonate and water, and separated. The organic layer was distilled under reduced pressure and product was isolated from n-hexane to get 6.2g of triacetoxy-5 -deoxy-L- ribose phenylhydrazone of formula (9) 79.4% yield.Appearance: Orange coloured solid.Melting point: 70-75 °C.1HNMR (CDC13): 1.275-1.29 l(d, 3H), 2.039(s, 3H), 2.085-2.095(d, 6H), 5.083-5.144(m, 1H), 5.390-5.416(t, 1H), 5.589-5.619(t, 1H), 6.849-6.886(t, 1H), 6.922-6.937(t, 1H), 6.966-6.987(d, 2H), 7.221-7.242(d, 2H), 7.563(s, 1H(D20 exchangeable).13CNMR (CDC13): 15.325, 20.816-21.053, 68.482, 71.717, 73.043, 112.759, 120.510, 129.212, 132.105, 144.049, 169.496, 169.948. Example 3: Preparation of potassium salt of L-erythro biopterin of formula (11)Into a 1.0L 4 necked round-bottomed flask equipped with a mechanical stirrer, thermometer socket, and a glass stopper, were charged 75 mL water followed by 3.7g of potassium hydroxide and dissolved under stirring. The potassium hydroxide solution was cooled to 25-30° C and 15.0g of crude L-erythro-biopterin of formula (2) was charged under stirring. The resulting solution was then clarified using activated carbon and filtered. The potassium salt was regenerated from the solution by the addition of 500mL of ethanol. The resulting salt was filtered and washed with ethanol and dried to get 9.1g of potassium salt of L-erythro biopterin of formula (11) with 52.3% yield. HPLC 98% Appearance: Brown coloured solid.1H NMR (D20): 1.187-1.203(d, 3H), 4.158-4.220(p, 1H), 4.731-4.745(d, 1H), 8.623(s, 1H).13C NMR (D20): 18.198, 70.645, 76.703, 128.811, 147.875, 149.410, 156.504, 164.774, 173.731.Mass: 276.23(M+1), 277.21(M+2), 238.29(M-K+1); DSC (° C): 313.12°Example 4: Preparation of Sapropterin dihydrochloride of formula (1)Into a 5L 4 necked round-bottomed flask equipped with mechanical stirrer, and thermometer socket, were charged 1.8L of water, 250g of L-erythro-biopterin of formula (2) followed by 800ml of 20% aq. potassium hydroxide solution under stirring. The solution was then added 90gm of platinum oxide catalyst. The reaction mixture was then transferred into an autoclave and pressurized with 50 bar hydrogen gas and hydrogenated at room temperature for 24-30h under stirring. After completion of reaction, the catalyst was recovered by filtration and the filtrate was acidified with concentrated hydrochloric acid. The water was evaporated under vacuum and the resulting crude Sapropterin dihydrochloride of formula (1) was isolated as pale yellow colour solid by addition of ethanol- 1 -pentanol mixture. The product was dried in a vacuum oven to get 250g of crude Sapropterin dihydrochloride of formula (1). Example 5: Purification of Sapropterin dihydrochloride of formula (1)Into a 2L 4 necked round-bottomed flask equipped with a mechanical stirrer, thermometer socket, and reflux condenser, were charged 1L water and 250g of Sapropterin dihydrochloride of formula (1). The contents were stirred to dissolve completely and the clear solution was treated with activated charcoal and filtered. The filtrate was distilled off completely under vacuum to afford pale yellow solid. The product 225.0 g (90%) was isolated ethanol- 1 -pentanol mixture as pure Sapropterin dihydrochloride of formula (1) as pale yellow to off-white solid. HPLC purity is 99.9%.syn   PATENThttps://patents.google.com/patent/WO2016101211A1/enwas developed by Merck and was launched in the United States and the European Union in 2007 and 2008 under the trade name Kuvan. This product can be used to treat hyperphenylalaninemia (HPA) caused by tetrahydrobiopterin (BH4) deficiency. The structure is as follows:The chemical name is: (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-fluorenone Dihydrochloride.The oxaprozin hydrochloride can be obtained by hydrogenation of L-erythrobiopterin. The literature Liebigs Ann. Chem. 1989, 1267-1269 reports the preparation of L-erythrobiopterin starting from L-ribose. The preparation route is as follows:Although the method is simple and easy to perform, it is a better preparation route, but the disadvantage is that the starting material L-ribose price is higher, thus causing the cost of sapropium hydrochloride to be high.The literature for the preparation of L-erythrobiopteris is reported by the documents Helv. Chim. Acta, 1985, 1639-1643, US2011218339A, etc. The product of the acetylation reaction of the steroid compound 6 with 2,4,5-triaminopyrimidinone Cyclization in a methanol/water/pyridine system followed by aromatization with an iodine reagent to give an acetylated L- Red-type biopterin, followed by hydrolysis and deacetylation to obtain L-erythrobiopterin. The reaction equation is as follows:Among them, compound 6 is used as a key intermediate, and many methods for its preparation are reported. The method reported in J. Am. Chem. Soc. 1974, 6781-6782, J. Am. Chem. Soc. 1976, 2301-2307, etc., uses L-rhamnose as a raw material, and reacts with ethanethiol to form a corresponding shrinkage. Sulfuraldehyde, oxidizing thiol to sulfone with an oxidizing agent, removing a carbon under alkaline conditions to obtain 5-deoxy-L-arabinose, and reacting 5-deoxy-L-arabinose with phenylhydrazine to obtain a key intermediate formula 6 . The synthetic route is as follows:Although this method has been improved and improved many times, the ethanethiol used has a special malodor and requires the use of a deodorizing device, and its lower boiling point also causes inconvenience to the production.Document J. Org. Chem. 1996, 8699-8700 reports that L-tartaric acid is used as a starting material, which is protected by hydroxyl group, carboxyl group, reduction, addition, deprotection to obtain 5-deoxy-L-ribose, 5-deoxy- The condensation of L-arabinose with phenylhydrazine gives key intermediates. The synthetic route is as follows:The reducing agent used in the route of the acid chloride to reduce the aldehyde is bis(triphenylphosphine) copper borohydride (I), which has a high price and is not favorable for the control of industrialization cost. The reaction temperature of the format reagent with carbonyl addition and lactone reduction is -78 ° C, and the energy consumption in industrial production is high. In addition, the post-treatment of the multi-step reaction uses silica gel column color The spectrum is purified and it is difficult to achieve industrialization. Therefore, this route has great disadvantages in terms of cost and operability in industrial production.Document CN201010151443.2 reports the use of L-arabinose as a starting material to obtain L-erythrobioptery through a multi-step reaction. The preparation route is as follows:In reproducing the preparation method, we have found that the intermediate 2 is directly subjected to reduction and desulfonation reaction to prepare the intermediate 2, which has the disadvantages of low yield, low product purity, and difficulty in purification of the product. Therefore, it is necessary to find a simple, feasible and low-cost preparation route. scheme synthetic route includes the following steps:Example 1: Preparation of Product 1To the reaction flask was added 10 L of anhydrous methanol, and 1.5 kg of the starting material L-arabinose was added under mechanical stirring. 250 g of concentrated sulfuric acid was added dropwise under a water bath, and the reaction was stirred for 20-24 hours. The reaction was monitored by TLC, and 350 g of sodium carbonate was added to the reaction system. Stir until pH = 7-8 and filter. The filtrate was concentrated under reduced pressure at 35 ° C to 40 ° C to dryness to yield 1.64 kg of oil, yield -100%.Example 2: Preparation of product 2The product 1, 4 L of pyridine and 5 L of acetonitrile were added to the reaction flask and dissolved by mechanical stirring. The mixture was cooled by stirring, and a solution of 1.8 kg of p-toluenesulfonyl 5 L acetonitrile was added dropwise at a temperature of 0 to 5 ° C. After completion of the dropwise addition, the reaction was stirred at room temperature 20-25 ° C for 4 hours. The TLC monitors the reaction.After concentration, 12 L of ethyl acetate and 5 L of water were added to the concentrated residue, and the layers were stirred. The organic layer was washed with 1 mol/L hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine and dried. Filtration and concentration of the filtrate gave 1.7 kg of pale yellow oil, yield 56.3%.Example 3: Preparation of product 31.2 kg of product 2 was added to a 10 L reaction flask, dissolved with 6 L of methyl ethyl ketone, and 840 g of sodium iodide was added with stirring. After the addition, the temperature was refluxed for 12 hours, and the reaction was completed by TLC. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated. It was dissolved in ethyl acetate, washed with water, and the aqueous layer was evaporated. The combined organic layers were washed with EtOAc EtOAc m.Example 4: Preparation of product 4To a 20 L reaction flask was added 900 g of product 3, 332 g of triethylamine dissolved in 9 L of methanol, 45 g of 10% Pd/C, vacuumed, hydrogenated twice, and hydrogenated at a constant temperature of 25-30 ° C for 16 hours. The reaction was completed by TLC, filtered, and the filtrate was concentrated under reduced pressure to give a residue. 4 L of ethyl acetate was added to the residue to precipitate a white solid. The mixture was stirred at 0 ° C for 30 min, and filtered. The filtrate was added to 2 L of a 0.4 mol/L sulfuric acid solution and the layers were separated. The aqueous layer was washed once with 50 mL of ethyl acetate to give an aqueous solution of product 4 (approximately 250 g).Example 5: Preparation of product 5The aqueous solution of product 4 was added to the reaction flask, and the reaction was heated at 75 ° C for 3 hours, and the reaction was completed by TLC (DCM: MeOH = 10:1). After cooling to room temperature, it was washed with 100 mL of ethyl acetate, and the aqueous layer was separated to give the product 5, i.e., about 213 g of aqueous solution of 5-deoxy-L-arabinose, which was directly reacted in the next step.Example 6: Preparation of product 6To the reaction flask, 2.5 L of ethyl acetate and 170 g of phenylhydrazine were added under nitrogen, and an aqueous solution of the product 5 was added dropwise with stirring at a temperature of 5 to 10 ° C (protected from light). The reaction was kept for 1 hour, and then the temperature was raised to 20-25 ° C for 30 min. The reaction was completed by TLC and the layers were separated. The aqueous layer was extracted with ethyl acetate and organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and filtered.The ethyl acetate solution of product 6 was added to the reaction flask under nitrogen, and 8 L of petroleum ether was slowly added with stirring. After the addition was completed, the mixture was cooled to -5 10 ° C and stirred for 1 hour, and filtered to give a beige solid. Drying under reduced pressure at 30-35 ° C gave a dry product of about 250 g, yield 71.4%.Example 7: Preparation of product 7To the reaction flask was added 2.5 L of ethyl acetate and 250 g of product 6. 30 g of DMAP was added with stirring. 400 ml of acetic anhydride was added dropwise at a temperature of 15 ° C, and the reaction was stirred at a temperature of 20-25 ° C for 3 hours. The reaction was monitored by TLC, and a hydrochloric acid solution was added at a temperature of 15 ° C to separate the layers. The organic layer was washed with saturated hydrochloric acid and saturated sodium hydrogen sulfate. The organic phase was separated, dried and filtered to give 371 g, m.Example 8: Preparation of product 9To the reaction flask was added 220 g of product 8, 2.2 L of purified water. Under stirring, 500 g of a product 7 in 5 L of methanol and 150 g of anhydrous lithium perchlorate dissolved in 1.5 L of water were added. After the addition was completed, the reaction was stirred at a temperature of 30 to 32 ° C for 20 hours. The reaction is completed and filtered. The filtrate was temperature-controlled at 15 ° C to 20 ° C, and 1 L of 30% hydrogen peroxide was added dropwise. After the addition, the reaction was kept at 20 ° C for 6 hours, and the solid was precipitated, filtered, and dried by blasting at 35-40 ° C to obtain 215 g of a brownish yellow product 9 in a yield of 47%.Example 9: Preparation of product 10To the reaction flask, 80 g of product 9, 400 ml of purified water, 300 ml of n-butanol, and 80 ml of diethylamine were added, and the mixture was stirred and heated to 45-50 ° C for 16 hours. After the TLC reaction is completed, the layers are separated, and the aqueous layer is separated to obtain an aqueous solution of the product 10, which is directly reacted in the next step.Example 10: Preparation of Product IAn aqueous solution of product 10 was added to the autoclave, and 50 ml of triethylamine and 2 g of platinum dioxide were added thereto with stirring. The pressure was evacuated, the hydrogen was replaced three times, the pressure was controlled to 1.5 MPa, and the reaction was stirred at 35 ° C for 20 hours. After filtration, the filtrate was added to 30 ml of n-butanol for 5 min, and the mixture was allowed to stand to give an aqueous solution of product I. 200 ml of concentrated hydrochloric acid was added dropwise at a temperature of 10 ° C, and the aqueous solution was concentrated under reduced pressure to dryness. 500 ml of 95% ethanol was added to the crude product, and the mixture was heated to 55-60 ° C for 1 hour, then cooled to 35 ° C for 2 hours, filtered, and the filter cake was dried to give the product I35 g.Example 11: Preparation of product 9 To the reaction flask was added 1.25 L of ethyl acetate and 125 g of product 9. 15 g of DMAP was added with stirring. 200 ml of acetic anhydride was added dropwise at a temperature of 15 ° C, and the reaction was stirred at a temperature of 20-25 ° C for 3 hours. The reaction was monitored by TLC, and a hydrochloric acid solution was added at a temperature of 15 ° C to separate the layers. The organic layer was washed with saturated hydrochloric acid and saturated sodium hydrogen sulfate. The organic phase was separated, dried and concentrated to give 12,5 g of oil.Example 12: Preparation of product 10The product 9 prepared in Example 11 was added to the reaction flask, 600 ml of purified water, 450 ml of n-butanol, and 120 ml of diethylamine were added, and the mixture was stirred and heated to 45-50 ° C for 16 hours. After the TLC reaction is completed, the layers are separated, and the aqueous layer is separated to obtain an aqueous solution of the product 10, which is directly reacted in the next step.Example 13: Preparation of Product IAn aqueous solution of the product 10 prepared in Example 12 was added to the hydrogenation vessel, and 80 ml of triethylamine, 3 g of platinum dioxide was added thereto with stirring, and vacuum was applied thereto, and the pressure was controlled to 1.5 MPa, and the reaction was stirred at 35 ° C for 20 hours. After filtration, the filtrate was added to 45 ml of n-butanol for 5 min, and the mixture was allowed to stand to give an aqueous solution of product I. After cooling at 10 ° C, 300 ml of concentrated hydrochloric acid was added dropwise, and the aqueous solution was concentrated under reduced pressure to dryness. 750 ml of 95% ethanol was added to the crude product, and the mixture was heated to 55-60 ° C for 1 hour, then cooled to 35 ° C for 2 hours, filtered, and the filter cake was dried to give the product I 48.9 g.///////////https://patents.google.com/patent/US9365573B2/enSapropterin dihydrochloride, chemical name (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinone dihydrochloride, molecular formula C9H15N5O3.2HCl, and CAS registry number 69056-38-28, is a synthetic product of tetrahydrobiopterin (BH4) dihydrochloride. BH4 is a cofactor of Phenylalanine Hydroxylase (PAH). Tyrosine is acquired from Phenylalanine (Phe) through hydroxylation under the action of PAH which is low in activity or even inactive in PKU patients, while BH4 is able to activate PAH, promote normal oxidative metabolism of Phe in the bodies of the patients, and reduce the Phe levels in the bodies of some patients. On Dec. 16, 2007, the sapropterin dihydrochloride tablets produced by BioMarin Pharmaceutical Inc. in USA were approved by the Food and Drug Administration (FDA) for marketing for treatment of PKU. Because of the effective activity of sapropterin dihydrochloride, it is extremely necessary to select a route applicable to industrial production with high product purity.At present, BH4 is mainly synthesized by the following methods reported in literatures:1. Preparation using 4-hydroxy-2,5,6-triaminopyrimidine (TAP) and 5-deoxy-L-arabinose as raw materials, please see literature E. L. Patterson et al., J. Am. Chem. Soc. 78, 5868(1956).2. Preparation using TAP and 5-deoxy-L-arabinose phenylhydrazone as raw materials, please see literature Matsuura et al., Bull. Chem. Soc. Jpn., 48,3767 (1975);3. Preparation by reaction of raw materials hydroxyl-protected TAP and 4-acetyl-2,3-epoxypentanal through oxidation of iodine and a dehydroxylation protecting group, please see literature Matsuura et al., Chemistry of Organic Synthesis, MI/g. 46. No. 6, P570(1988).These traditional methods for preparing BH4 have the following major disadvantages: raw materials are expensive, arabinose which can be hardly acquired is used as a carbon atom radical for asymmetric synthesis; there are multiple steps in reactions with low yield, and low product purity, 5-deoxy-L-arabinose is easily degraded in a reaction solution, and products of the synthesis routes above have low stereoselectivity. To sum up, the traditional synthesis methods are not applicable to mass industrial production. Therefore, a synthesis route, which is applicable to industrial production with high product purity, high yield and high stereoselectivity, needs to be searched urgently.tep 10: add 0.7 kg (0.05 g/g) of palladium 5% on carbon in the presence of the methanol solution containing 1.5 kg of acetylamino-7,8-dihydropteridineobtained in Step 9, introduce hydrogen until the pressure of the reaction kettle is 0.8±0.05 MPa, control the temperature of the system at 25±5° C. and the pressure at 0.8±0.05 MPa, react for 82 hours, after reacting thoroughly, perform quenching in 31.9 kg (9 eq) of dilute hydrochloric acid having a concentration of 15%, and perform suction filtration and drying to the system to obtain a target product, i.e. a crude product of sapropterin dihydrochloriderecrystallize and purify the crude product by 29 L (20 ml/g) of methanol at 35±5° C. to obtain 0.8 kg of a pure product, with a yield of 45%, a purity of 98.3% and an enantiomeric excess of 99.1%.Embodiment 5: main raw material:and X═OStep 1: add 836 kg (0.3 eq) of a tetrahydrofuran solution contaning a samarium catalyst having a concentration of 4%, 29.2 kg (0.3 eq) of (R)-(+)-1,1′-bi-2-naphthol, 28.4 kg (0.3 eq) of triphenylphosphine oxide, and 600 kg (10 kg/kg) of a 4 A molecular sieve to a 3000 L reaction kettle, after stirring uniformly, control the system temperature at 20±5° C., add 117.4 kg (2 eq) of meta-chloroperoxybenzoic acid, add 60 kg (1 eq) of benzyl crotonateto the system after adding meta-chloroperoxybenzoic acid, react for 32 hours while preserving the temperature, add 19.6 kg (0.3 eq) of citric acid to the system to stop the reaction, and perform centrifugation, concentration and rectification to the system to obtain 40.5 kg of (2S,3R)-2,3-epoxy-benzyl butyratewith a yield of 62%;Step 2: add 36.8 kg (3 eq) of acetone, and 5.4 kg (0.6 eq) of lithium chloride to a 500 L enamel vessel, control the temperature at 15±5° C., add 40.5 kg (1 eq) of (2S,3R)-2,3-epoxy-benzyl butyratereact for 7 hours while preserving the temperature, add 422 kg (2 eq) of a potassium bicarbonate aqueous solution having a concentration of 10%, and perform liquid separation, extraction and concentration to the system to obtain 44 kg of (4S,5S)-2,2,5-trimethyl-acetonide-benzyl butyratewith a yield of 82%;Step 3: add 352 L (8 ml/g) of ethanol, and 44 kg (1 eq) of (4S,5S)-2,2,5-trimethyl-2,3-acetonide-benzyl butyrateto a 1000 L reaction kettle, increase the temperature to 37±5° C., add 4.8 kg (1.5 eq) of pure water and 53.2 kg (1.5 eq) of a sodium hydroxide aqueous solution having a concentration of 20%, react for 6 hours while preserving the temperature, perform centrifugation, dissolve a filter cake in 352 L (8 ml/g) of ethanol, add 71.0 kg (3 eq) of L-α-amphetamine, preserve the temperature at 22±5° C. for 4 hours, and perform centrifugation and drying to obtain 32.4 kg of (4S,5S)-2,2,5-trimethyl-2,3-acetonide-phenylacetylamino butyratewith a yield of 62%;Step 4: add 48 L (6 ml/g) of 1,4-dioxane, 8 kg (1 eq) of (4S,5S)-2,2,5-trimethyl-2,3-acetonide-phenylacetylamino butyrateto a 72 L reaction bottle, then add a dilute sulphuric acid aqueous solution having a concentration of 10% to the system to regulate the pH at 2.5±0.5, control the temperature at −5±5° C., react for 1 hour, perform liquid separation to obtain an organic phase, add 7.0 kg of (2.0 eq) N,N-diisopropylethylamine to the organic phase, and concentrate the system to obtain 4.1 kg of (4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-methanoic acidwith a yield of 93.5%;Step 5: add 49 L (12 ml/g) of 2-methyltetrahydrofuran, 4.1 kg of 1,3-dioxolan-4-methanoic acidand 13.1 kg (4 eq) of N,N-diisopropylethylamine to a 100 L reaction bottle, reduce the temperature to −22±5° C., add 5.5 kg (2.0 eq) of ethyl chloroformate, react for 1.8 hours while preserving the temperature, introduce a diazomethane gas for 1.8 hours, add 18.5 kg (4.5 eq) of a hydrochloride ethanol solution having a concentration of 20%, react for 1.8 hours, add potassium bicarbonate to regulate the pH value to 8.5±0.5, and perform extraction, liquid separation and concentration to obtain 4.1 kg of (4S,5S)-2,2,5-trimethyl-5-chloroacetyl-1,3-dioxolanewith a yield of 83.7%;Step 6: add 49 L (12 ml/g) of acetone, 4.1 kg of (4S,5S)-2,2,5-trimethyl-5-chloroacetyl-1,3-dioxolane3.4 kg (2.5 eq) of sodium azide, and 1.8 kg (0.5 eq) of potassium iodide to a 72 L bottle, react the system for 26 hours while preserving the temperature at 34±5° C., perform filtering and concentration to obtain an acetone solution containing 3.9 kg of (4S,5S)-2,2,5-trimethyl-5-(2-azidoacetyl)-1,3-dioxolanewith a yield of 91.5%;Step 7: add 46.4 L (12 ml/g) of methyl tert-butyl ether and 1.2 kg (0.3 g/g) of Raney nickel to a 100 L reaction kettle, introduce hydrogen until the system pressure is 0.8±0.1 MPa, regulate the pH of the system to 3±0.5 with concentrated sulfuric acid, add an acetonitrile solution containing 3.9 kg (1 eq) of (4S,5S)-2,2,5-trimethyl-5-(2-azidoacetyl)-1,3-dioxolanereact at 27±5° C. for 8.5 hours, perform suction filtration and concentration to obtain 2.3 kg of (3S,4S)-1-amino-3,4-dihydroxy-2-pentanonewith a yield of 89%;Step 8: add 23 L (10 ml/g) of propanol, 6.9 L (3 ml/g) of pure water, 0.9 kg of (0.3 eq) of potassium iodide, 4.8 kg (1.2 eq) of compound A (2-amino-6-chloro-5-nitro-3H-pyrimidin-4-one), 2.3 kg (1 eq) of (3S,4S)-1-amino-3,4-dihydroxy-2-pentanoneand 10.5 kg (6 eq) of diisopropylamine to a 50 L reaction bottle, react the system for 7 hours while preserving the temperature at 72±5° C., then add a potassium dihydrogen phosphate-dipotassium phosphate aqueous solution to regulate the pH of the system to 7.5±0.5; and filter the system to obtain 2.5 kg of 2-acetylamino-5-nitro-6-((3S,4S)-3,3-dihydroxy-2-oxo-pentylamino)-pyrimidin-4-onewith a yield of 44%;Step 9: add 1.25 kg (1 eq) of 2-acetylamino-5-nitro-6((3S,4S)-3,3-dihydroxy-2-oxo-pentylamino)-pyrimidin-4-one50 L (40 ml/g) of ethanol and 0.5 kg (0.4 g/g) of 10% palladium on carbon to a 100 L autoclave, introduce hydrogen until the reaction system pressure is 0.8±0.05 MPa, control the temperature of the system at 27±5° C. and the pressure at 0.8±0.05 MPa, react for 24 hours, filter the system, and regulate the pH to 11±0.5 to obtain an ethanol solution containing 1.1 kg of acetylamino-7,8-dihydropteridinewhich is used directly in the next step;Step 10: add 0.44 kg (0.4 g/g) of palladium 10% on carbon in the presence of the ethanol solution containing 1.1 kg of acetylamino-7,8-dihydropteridineobtained in Step 9, introduce hydrogen until the pressure of the reaction kettle is 0.8±0.05 MPa, control the temperature of the system at 25±5° C. and the pressure at 0.8±0.05 MPa, react for 80 hours, after reacting thoroughly, perform quenching in 20 kg (8 eq) of dilute hydrochloric acid having a concentration of 15%, and perform suction filtration and drying to the system to obtain a target product, i.e. a crude product of sapropterin dihydrochloriderecrystallize and purify the crude product by 21.4 L (20 ml/g) of ethanol at 35±5° C. to obtain 0.4 kg of a pure product, with a yield of 46.2%, a purity of 98.5% and an enantiomeric excess of 99.2%.Embodiment 6: main raw material:and X═NStep 1: add 522 kg (0.05 eq) of a tetrahydrofuran solution containing a samarium catalyst having a concentration of 2%, 9.1 kg (0.05 eq) of (R)-(+)-1,1′-bi-2-naphthol, 8.9 kg (0.05 eq) of triphenylphosphine oxide, and 567 kg (7 kg/kg) of a 4 A molecular sieve to a 3000 L reaction kettle, after stirring uniformly, control the system temperature at 8±5° C., add 57.4 kg (0.eq) of a tert-butyl hydroperoxide toluene solution having a concentration of 50%, add 81.1 kg (1 eq) of (E)-N-isopropylbut-2-enamideto the system after adding the tert-butyl hydroperoxide toluene solution, react for 34 hours while preserving the temperature, add 6.1 kg (0.05 eq) of citric acid to the system to stop the reaction, and perform centrifugation, concentration and rectification to the system to obtain 56.1 kg of (2S,3R)-2,3-epoxy-diisopropylamido butyratewith a yield of 61.5%;Step 2: add 11.4 kg (0.5 eq) of acetone, and 8.8 kg (0.1 eq) of zinc bromide to a 500 L enamel vessel, control the temperature at 20±5° C., add 56.1 kg (1 eq) of (2S,3R)-2,3-epoxy-diisopropylamido butyratereact for 8.5 hours while preserving the temperature, add 329 kg (2 eq) of a sodium bicarbonate aqueous solution having a concentration of 10%, and perform liquid separation, extraction and concentration to the system to obtain 64.7 kg of (4S,5S)-2,2,5-trimethyl-2,3-acetonide-diisopropylamido butyratewith a yield of 82%;Step 3: add 259 L (4 ml/g) of tetrahydrofuran, and 64.7 kg (1 eq) of (4S,5S)-2,2,5-trimethyl-2,3-acetonide-diisopropylamido butyrateto a 1000 L reaction kettle, increase the temperature to 27±5° C., add 2.9 kg (0.5 eq) of pure water and 29.9 kg (0.5 eq) of a methanol solution of sodium methoxide having a concentration of 29.9%, react for 4 hours while preserving the temperature, perform centrifugation, dissolve a filter cake in 194 L (3 ml/g) of tetrahydrofuran, add 39 kg (1 eq) of L-α-phenylethylamine, preserve the temperature at 18±5° C. for 3.5 hours, and perform centrifugation and drying to obtain 54.3 kg of 1-phenyltehanamine (4S,5S)-2,2,5-trimethyl-1,3-dioxolane-4-carboxylatewith a yield of 60%;Step 4: add 30 L (3 ml/g) of 2-methyltetrahydrofuran, 10 kg (1 eq) of 1-phenyltehanamine (4S,5S)-2,2,5-trimethyl-1,3-dioxolane-4-carboxylateto a 72 L reaction bottle, then add a dilute phosphoric acid aqueous solution having a concentration of 10% to the system to regulate the pH at 1.5±0.5, control the temperature at −5±5° C., react for 1 hour, perform liquid separation to obtain an organic phase, add 3.7 kg of (0.8 eq) N,N-diisopropylethylamine to the organic phase, and concentrate the system to obtain 5.3 kg of (4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-methanoic acidwith a yield of 92.5%;Step 5: add 42 L (8 ml/g) of 1,4-dioxane, 5.3 kg of 1,3-dioxolan-4-methanoic acidand 8.5 kg (2 eq) of N,N-diisopropylethylamine to a 100 L reaction bottle, reduce the temperature to −10±5° C., add 4 kg (21.0 eq) of propyl chloroformate, react for 2 hours while preserving the temperature, introduce a diazomethane gas for 2 hours, add 12 kg (2 eq) of a hydrochloride ethanol solution having a concentration of 20%, react for 2 hours, add sodium hydroxide to regulate the pH value to 7.5±0.5, and perform extraction, liquid separation and concentration to obtain 5.1 kg of (4S,5S)-2,2,5-trimethyl-5-chloroacetyl-1,3-dioxolanewith a yield of 81%; Step 6: add 41 L (8 ml/g) of tetrahydrofuran, 5.1 kg of (4S,5S)-2,2,5-trimethyl-5-chloroacetyl-1,3-dioxolane3.1 kg (1 eq) of azidotrimethylsilane, and 0.5 kg (0.1 eq) of sodium iodide to a 72 L bottle, react the system for 30 hours while preserving the temperature at 12±5° C., perform filtering and concentration to obtain an acetone solution containing 4.6 kg of (4S,5S)-2,2,5-trimethyl-5-(2-azidoacetyl)-1,3-dioxolanewith a yield of 87.5%;Step 7: add 28 L (6 ml/g) of 1,4-dioxane and 0.23 kg (0.05 g/g) of palladium 10% on carbon to a 50 L reaction kettle, introduce hydrogen until the system pressure is 0.8±0.1 MPa, regulate the pH of the system to 3±0.5 with acetic acid, add an acetonitrile solution containing 4.6 kg (1 eq) of (4S,5S)-2,2,5-trimethyl-5-(2-azidoacetyl)-1,3-dioxolanereact at 27±5° C. for 8.5 hours, react for 8.5 hours, perform suction filtration and concentration to obtain 2.7 kg of (3S,4S)-1-amino-3,4-dihydroxy-2-pentanonewith a yield of 87.7%;Step 8: add 16.3 L (6 ml/g) of isopropanol, 2.7 L (1 g/g) of pure water, 0.4 kg of (0.1 eq) of sodium iodide, 4.8 kg (1.0 eq) of compound A (2-amino-6-chloro-5-nitro-3H-pyrimidin-4-one), 2.7 kg (1 eq) of (3S,4S)-1-amino-3,4-dihydroxy-2-pentanoneand 8.7 kg (4 eq) of sodium carbonate to a 50 L reaction bottle, react the system for 7 hours while preserving the temperature at 45±5° C., then add an ammonium formate-ammonia aqueous solution to regulate the pH of the system to 6.5±0.5; and filter the system to obtain 2.85 kg of 2-acetylamino-5-nitro-6((3S,4S)-3,3-dihydroxy-2-oxo-pentylamino)-pyrimidin-4-onewith a yield of 42.5%;Step 9: add 2 kg (1 eq) of 2-acetylamino-5-nitro-6-((3S,4S)-3,3-dihydroxy-2-oxo-pentylamino)-pyrimidin-4-one60 L (30 ml/g) of ethanol and 0.2 kg (0.1 g/g) of platinum dioxide to a 100 L autoclave, introduce hydrogen until the reaction system pressure is 0.6±0.05 MPa, control the temperature of the system at 20±5° C. and the pressure at 0.6±0.05 MPa, react for 20 hours, filter the system, and regulate the pH to 11±0.5 to obtain an ethanol solution containing 1.7 kg of acetylamino-7,8-dihydropteridinewhich is used directly in the next step;Step 10: add 0.2 kg (0.1 g/g) of platinum dioxide in the presence of the ethanol solution containing 1.7 kg of acetylamino-7,8-dihydropteridineobtained in Step 9, introduce hydrogen until the pressure of the reaction kettle is 0.6±0.05 MPa, control the temperature of the system at 15±5° C. and the pressure at 0.6±0.05 MPa, react for 75 hours, after reacting thoroughly, perform quenching in 30 kg (5 eq) of dilute hydrochloric acid having a concentration of 10%, and perform suction filtration and drying to the system to obtain a target product, i.e. a crude product of sapropterin dihydrochloriderecrystallize and purify the crude product by 17 L (10 ml/g) of butanone at 15±5° C. to obtain 0.6 kg of a pure product, with a yield of 43%, a purity of 98.4% and an enantiomeric excess of 98.9%.Thus, it can be seen that synthesis of a sapropterin dihydrochloride compound and an intermediate thereof disclosed in a method of the present disclosure can obtain a target product with a high purity, a high enantiomeric excess, and a high yield. The synthesis method uses readily-available raw materials, significantly reduces a synthesis route of sapropterin dihydrochloride. The technological conditions are stable, and there is less pollution in the whole operation process, hence providing an effective scheme for mass industrial production of sapropterin dihydrochloride.The above are only preferred embodiments of the present disclosure and should not be used to limit the present disclosure. For those skilled in the art, the present disclosure may have various modifications and changes. Any modifications, equivalent replacements, improvements and the like within the spirit and principle of the present disclosure shall fall within the scope of protection of the present disclosure.///////^ Jump up to:a b  Sapropterin (Kuvan) Use During Pregnancy . Drugs.com. 17 May 2019. Retrieved 4 March 2020.^  Sapropterin . Drugs.com. 28 February 2020. Retrieved 4 March 2020.^  International Non-proprietary Names for Pharmaceutical Substances (INN) . Fimea. Retrieved 4 March 2020.^ Jump up to:a b Kappock TJ, Caradonna JP (November 1996). Pterin-Dependent Amino Acid Hydroxylases . Chemical Reviews. 96 (7): 2659–2756. doi:10.1021/CR9402034. PMID 11848840.^ Całka J (2006).  The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons . Folia Histochemica et Cytobiologica. 44 (1): 3–12. PMID 16584085.^ Bhagavan, N. V. (2015). Essentials of Medical Biochemistry With Clinical Cases, 2nd Edition. USA: Elsevier. p. 256. ISBN 978-0-12-416687-5.^ Schaub J, Däumling S, Curtius HC, Niederwieser A, Bartholomé K, Viscontini M, et al. (August 1978).  Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis . Archives of Disease in Childhood. 53 (8): 674–6. doi:10.1136/adc.53.8.674. PMC 1545051. PMID 708106.^ Jump up to:a b  Kuvan- sapropterin dihydrochloride tablet Kuvan- sapropterin dihydrochloride powder, for solution Kuvan- sapropterin dihydrochloride powder, for solution . DailyMed. 13 December 2019. Retrieved 4 March 2020.^ Jump up to:a b c  Kuvan EPAR . European Medicines Agency (EMA). 4 March 2020. Retrieved 4 March 2020.^  Drug Approval Package: Kuvan (Sapropterin Dihydrochloride) NDA #022181 . U.S. Food and Drug Administration (FDA). 24 March 2008. Retrieved 4 March 2020. Lay summary (PDF).^ Jump up to:a b c d e  Kuvan (sapropterin dihydrochloride) Tablets and Powder for Oral Solution for PKU . BioMarin. Retrieved 4 March 2020.^  Drug Approval Package: Kuvan Powder for Oral Solution (Sapropterin Dihydrochloride) NDA #205065 . U.S. Food and Drug Administration (FDA). 28 February 2014. Retrieved 4 March 2020. Lay summary (PDF).^ Herper M (28 July 2016).  How Focusing On Obscure Diseases Made BioMarin A $15 Billion Company . Forbes. Retrieved 9 October 2017.^  BioMarin Announces Kuvan (sapropterin dihydrochloride) Patent Challenge Settlement . BioMarin Pharmaceutical Inc. 13 April 2017. Retrieved 9 October 2017 – via PR Newswire.^  Tetrahydrobiopterin Deficiency . National Organization for Rare Disorders (NORD). Retrieved 9 October 2017.^  What are common treatments for phenylketonuria (PKU)? . NICHD. 23 August 2013. Retrieved 12 September 2016.^ Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, et al. (June 2014).  Phenylketonuria Scientific Review Conference: state of the science and future research needs . Molecular Genetics and Metabolism. 112 (2): 87–122. doi:10.1016/j.ymgme.2014.02.013. PMID 24667081.^ Jump up to:a b Haberfeld, H, ed. (1 March 2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Kuvan 100 mg-Tabletten.^  Genetics Home Reference: GCH1 . National Institutes of Health.^ Wu G, Meininger CJ (2009). Nitric oxide and vascular insulin resistance . BioFactors. 35(1): 21–7. doi:10.1002/biof.3. PMID 19319842. S2CID 29828656.^ Kaufman S (February 1958).  A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine . The Journal of Biological Chemistry. 230 (2): 931–9. PMID 13525410.^ Thöny B, Auerbach G, Blau N (April 2000).  Tetrahydrobiopterin biosynthesis, regeneration and functions . The Biochemical Journal. 347 Pt 1: 1–16. doi:10.1042/0264-6021:3470001. PMC 1220924. PMID 10727395.^ Kuzkaya N, Weissmann N, Harrison DG, Dikalov S (June 2003).  Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase . The Journal of Biological Chemistry. 278 (25): 22546–54. doi:10.1074/jbc.M302227200. PMID 12692136.^ Muller-Delp JM (November 2009).  Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability . Cardiovascular Research. 84 (2): 178–9. doi:10.1093/cvr/cvp307. PMID 19744948.^ Gori T, Burstein JM, Ahmed S, Miner SE, Al-Hesayen A, Kelly S, Parker JD (September 2001).  Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study . Circulation. 104 (10): 1119–23. doi:10.1161/hc3501.095358. PMID 11535566.^  Search results for Kuvan . ClinicalTrials.gov. U.S. National Library of Medicine.^  BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric Symptoms in Subjects with PKU . BioMarin Pharmaceutical Inc. 17 August 2010.^ Burton B, Grant M, Feigenbaum A, Singh R, Hendren R, Siriwardena K, et al. (March 2015).  A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria . Molecular Genetics and Metabolism. 114 (3): 415–24. doi:10.1016/j.ymgme.2014.11.011. PMID 25533024.^ Fernell E, Watanabe Y, Adolfsson I, Tani Y, Bergström M, Hartvig P, et al. (May 1997). Possible effects of tetrahydrobiopterin treatment in six children with autism clinical and positron emission tomography data: a pilot study . Developmental Medicine and Child Neurology. 39 (5): 313–8. doi:10.1111/j.1469-8749.1997.tb07437.x. PMID 9236697. S2CID 12761124.^ Frye RE, Huffman LC, Elliott GR (July 2010).  Tetrahydrobiopterin as a novel therapeutic intervention for autism . Neurotherapeutics. 7 (3): 241–9. doi:10.1016/j.nurt.2010.05.004. PMC 2908599. PMID 20643376.^ Channon KM (November 2004). Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease . Trends in Cardiovascular Medicine. 14 (8): 323–7. doi:10.1016/j.tcm.2004.10.003. PMID 15596110.^ Alp NJ, Mussa S, Khoo J, Cai S, Guzik T, Jefferson A, et al. (September 2003).  Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression . The Journal of Clinical Investigation. 112 (5): 725–35. doi:10.1172/JCI17786. PMC 182196. PMID 12952921.^ Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, et al. (April 2005).  Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension . Circulation. 111 (16): 2126–33. doi:10.1161/01.CIR.0000162470.26840.89. PMID 15824200.^ Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, et al. (March 2012).  Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease . Circulation. 125 (11): 1356–66. doi:10.1161/CIRCULATIONAHA.111.038919. PMC 5238935. PMID 22315282.^ Romanowicz J, Leonetti C, Dhari Z, Korotcova L, Ramachandra SD, Saric N, et al. (August 2019).  Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease . Journal of the American Heart Association. 8 (15): e012711. doi:10.1161/JAHA.119.012711. PMC 6761654. PMID 31331224.^ Kraft VA, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, et al. (January 2020).  GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling . ACS Central Science. 6 (1): 41–53. doi:10.1021/acscentsci.9b01063. PMC 6978838. PMID 31989025. Sapropterin . Drug Information Portal. U.S. National Library of Medicine.InChI=1S/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1 DeveloperDr Reddys Laboratories; HatchtechClassAntiparasitics; Heterocyclic compounds; Pyridines; Small moleculesMechanism of ActionChelating agents; Metalloprotease inhibitors27 Jul 2020Registered for Pediculosis (In adolescents, In children, In infants, In adults) in USA (Topical)18 Jun 2020FDA assigns PDUFA action date of 12/08/2020 for Abametapir for Pediculosis (Dr Reddy s Laboratories website, June 2020)31 Mar 2019Abametapir is still in preregistration phase for Pediculosis in USAAbametapir is a novel pediculicidal metalloproteinase inhibitor used to treat infestations of head lice.4 The life cycle of head lice (Pediculus capitis) is approximately 30 days, seven to twelve of which are spent as eggs laid on hair shafts near the scalp.2 Topical pediculicides generally lack adequate ovicidal activity,2 including standard-of-care treatments such as permethrin, and many require a second administration 7-10 days following the first to kill newly hatched lice that resisted the initial treatment. The necessity for follow-up treatment may lead to challenges with patient adherence, and resistance to agents like permethrin and pyrethrins/piperonyl butoxide may be significant in some areas.3Investigations into novel ovicidal treatments revealed that several metalloproteinase enzymes were critical to the egg hatching and survival of head lice, and these enzymes were therefore identified as a potential therapeutic target.1 Abemetapir is an inhibitor of these metalloproteinase enzymes, and the first topical pediculicide to take advantage of this novel target. The improved ovicidal activity (90-100% in vitro) of abemetapir allows for a single administration, in contrast to many other topical treatments, and its novel and relatively non-specific mechanism may help to curb the development of resistance to this agent.1Abametapir was first approved for use in the United States under the brand name Xeglyze on July 27, 2020.6Abametapir, sold under the brand name Xeglyze, is a medication used for the treatment of head lice infestation in people six months of age and older.[1][2]The most common side effects include skin redness, rash, skin burning sensation, skin inflammation, vomiting, eye irritation, skin itching, and hair color changes.[2]Abametapir is a metalloproteinase inhibitor.[1] Abametapir was approved for medical use in the United States in July 2020.[1][3]Medical usesAbametapir is indicated for the topical treatment of head lice infestation in people six months of age and older.[1][2]HistoryThe U.S. Food and Drug Administration (FDA) approved abametapir based on evidence from two identical clinical trials of 699 participants with head lice.[2] The trials were conducted at fourteen sites in the United States.[2]The benefit and side effects of abametapir were evaluated in two clinical trials that enrolled participants with head lice who were at least six months old.[2]About half of all enrolled participants was randomly assigned to abametapir and the other half to placebo.[2] Abametapir lotion or placebo lotion were applied once as a ten-minute treatment to infested hair.[2] The benefit of abametapir in comparison to placebo was assessed after 1, 7 and 14 days by comparing the counts of participants in each group who were free of live lice.[2]SYNRonald Harding, Lewis David Schulz, Vernon Morrison Bowles, Pediculicidal composition. WIPO Patent WO2015107384A2, published July, 2015.References Bulevirtide acetate September 26, 2020 2:24 am / Leave a comment Bulevirtide acetate(N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt.molecular formula C248H355N65O72,molecular mass is 5398.9 g/molブレビルチド酢酸塩;APROVED 2020/7/31, EU, HepcludexMYR GmbHBulevirtide is a 47-amino acid peptide with a fatty acid, a myristoyl residue, at the N-terminus and an amidated C-terminus. The active substance is available as acetate salt. The counter ion acetate is bound in ionic form to basic groups of the peptide molecule and is present in a non-stoichiometric ratio. The chemical name of bulevirtide is (N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt. It corresponds to the molecular formula C248H355N65O72, its relative molecular mass is 5398.9 g/molBulevirtide appears as a white or off-white hygroscopic powder. It is practically insoluble in water and soluble at concentrations of 1 mg/ml in 50% acetic acid and about 7 mg/ml in carbonate buffer solution at pH 8.8, respectively. The structure of the active substance (AS) was elucidated by a combination of infrared spectroscopy (IR), mass spectrometry (MS), amino acid analysis and sequence analysis Other characteristics studied included ultraviolet (UV) spectrum, higher order structure (1D- and 2D- nuclear magnetic resonance spectroscopy (NMR)) and aggregation (Dynamic Light Scattering). Neither tertiary structure nor aggregation states of bulevirtide have been identified. With regard to enantiomeric purity, all amino acids are used in L-configuration except glycine, which is achiral by nature. Two batches of bulevirtide acetate were evaluated for enanatiomeric purity and no relevant change in configuration during synthesis was detected.Bulevirtide is manufactured by a single manufacturer. It is a chemically synthesised linear peptide containing only naturally occurring amino acids. The manufacturing of this peptide is achieved using standard solidphase peptide synthesis (SPPS) on a 4-methylbenzhydrylamine resin (MBHA resin) derivatised with Rink amide linker in order to obtain a crude peptide mixture. This crude mixture is purified through a series of washing and preparative chromatography steps. Finally, the purified peptide is freeze-dried prior to final packaging and storage. The process involves further four main steps: synthesis of the protected peptide on the resin while side-chain functional groups are protected as applicable; cleavage of the peptide from the resin, together with the removal of the side chain protecting groups to obtain the crude peptide; purification; and lyophilisation. Two chromatographic systems are used for purification. No design space is claimed. Resin, Linker Fmoc protected amino acids and myristic acid are starting materials in line with ICH Q11. Sufficient information is provided on the source and the synthetic route of the starting materials. The active substance is obtained as a nonsterile, lyophilised powder. All critical steps and parameters were presented and clearly indicated in the description of the manufacturing process. The process description includes also sufficient information on the type of equipment for the SPPS, in-process controls (IPCs). The circumstances under which reprocessing might be performed were clearly presented. No holding times are proposed. Overall the process is sufficiently described.The finished product is a white to off white lyophilised powder for solution for injection supplied in single-use vials. Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide. The composition of the finished product was presented. The powder is intended to be dissolved in 1 ml of water for injection per vial. After reconstitution the concentration of bulevirtide net peptide solution in the vial is 2 mg/ml. The components of the formulation were selected by literature review and knowledge of compositions of similar products available on the market at that time, containing HCl, water, mannitol, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. All excipients are normally used in the manufacture of lyophilisates. The quality of the excipients complies with their respective Ph. Eur monographs. The intrinsic properties of the active substance and the compounding formulation do not support microbiological growth as demonstrated by the stability data. No additional preservatives are therefore needed.https://www.ema.europa.eu/en/documents/assessment-report/hepcludex-epar-public-assessment-report_en.pdfHepcludex is an antiviral medicine used to treat chronic (long-term) hepatitis delta virus (HDV) infection in adults with compensated liver disease (when the liver is damaged but is still able to work), when the presence of viral RNA (genetic material) has been confirmed by blood tests.HDV is an incomplete virus, because it cannot replicate in cells without the help of another virus, the hepatitis B virus. Because of this, patients infected with the virus always also have hepatitis B.HDV infection is rare, and Hepcludex was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 19 June 2015. For further information on the orphan designation, see EU/3/15/1500.Hepcludex contains the active substance bulevirtide.Bulevirtide, sold under the brand name Hepcludex, is an antiviral medication for the treatment of chronic hepatitis D (in the presence of hepatitis B).[2]The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.[2]Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells.[2] By blocking the entry of the virus into the cells, it limits the ability of HDV to replicate and its effects in the body, reducing symptoms of the disease.[2]Bulevirtide was approved for medical use in the European Union in July 2020.[2]Medical usesBulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.[2][3]PharmacologyMechanism of actionBulevirtide binds and inactivates the sodium/bile acid cotransporter, blocking both viruses from entering hepatocytes.[4]The hepatitis B virus uses its surface lipopeptide pre-S1 for docking to mature liver cells via their sodium/bile acid cotransporter (NTCP) and subsequently entering the cells. Myrcludex B is a synthetic N-acylated pre-S1[5][6] that can also dock to NTCP, blocking the virus s entry mechanism.[7]The drug is also effective against hepatitis D because the hepatitis D virus is only infective in the presence of a hepatitis B virus infection.[7]References Bulevirtide . Drug Information Portal. U.S. National Library of Medicine.IUPAC Name3-methyl-4-[(E)-[(5-nitrofuran-2-yl)methylidene]amino]-1lambda6-thiomorpholine-1,1-dioneSMILESCC1CS(=O)(=O)CCN1\N=C\C1=CC=C(O1)[N+]([O-])=ODanong Chen, Glenn Rice. 2013. Novel formulations of nitrofurans including nifurtimox with enhanced activity with lower toxicity.US20150140089A1OriginatorBayerClassAntiprotozoals; Nitrofurans; Small molecules; Thiamorpholines; ThiazinesMechanism of ActionDNA damage modulators07 Aug 2020Registered for Chagas disease (In adolescents, In children, In infants) in USA (PO)31 Jan 2020Preregistration for Chagas disease (In infants, In children, In adolescents) in USA (PO)29 Jan 2020Bayer completes a phase I trial in Chagas disease in Argentina (PO) (NCT03334838)Title: NifurtimoxCAS Registry Number: 23256-30-6CAS Name: 3-Methyl-N-[(5-nitro-2-furanyl)methylene]-4-thiomorpholinamine 1,1-dioxideAdditional Names: 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide; tetrahydro-3-methyl-4-[(5-nitrofurfurylidene)amino]-2H-1,4-thiazine 1,1-dioxide; 1-[(5-nitrofurfurylidene)amino]-2-methyltetrahydro-1,4-thiazine 4,4-dioxideManufacturers Codes: Bay 2502Trademarks: Lampit (Bayer)Molecular Formula: C10H13N3O5SMolecular Weight: 287.29Percent Composition: C 41.81%, H 4.56%, N 14.63%, O 27.85%, S 11.16%Literature References: Prepn from 5-nitrofurfural and 4-amino-3-methyltetrahydro-1,4-thiazine 1,1-dioxide: Herlinger et al., DE 1170957 corresp to US 3262930 (1964 and 1966 to Bayer). Series of articles on pharmacology and clinical findings: Arzneim.-Forsch. 22, 1563-1642 (1972). Toxicity data: K. Hoffmann, ibid. 1590.Properties: Orange-red crystals from dil acetic acid, mp 180-182°. LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann).Melting point: mp 180-182°Toxicity data: LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann)Therap-Cat: Antiprotozoal (Trypanosoma).Keywords: Antiprotozoal (Trypanosoma).Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness.[1][4] For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment.[4] In Chagas disease it is a second-line option to benznidazole.[5] It is given by mouth.[1]Common side effects include abdominal pain, headache, nausea, and weight loss.[1] There are concerns from animal studies that it may increase the risk of cancer but these concerns have not be found in human trials.[5] Nifurtimox is not recommended in pregnancy or in those with significant kidney or liver problems.[5] It is a type of nitrofuran.[5]Nifurtimox came into medication use in 1965.[5] It is on the World Health Organization s List of Essential Medicines.[4] It is not available commercially in Canada.[1] It was approved for medical use in the United States in August 2020.[3] In regions of the world where the disease is common nifurtimox is provided for free by the World Health Organization (WHO).[6]Chagas disease, caused by a parasite known as Trypanosoma cruzi (T.cruzi), is a vector-transmitted disease affecting animals and humans in the Americas. It is commonly known as American Trypanosomiasis.11The CDC estimates that approximately 8 million people in Central America, South America, and Mexico are infected with T. cruzi, without symptoms. If Chagas disease is left untreated, life-threatening sequelae may result.11Nifurtimox, developed by Bayer, is a nitrofuran antiprotozoal drug used in the treatment of Chagas disease. On August 6 2020, accelerated FDA approval was granted for its use in pediatric patients in response to promising results from phase III clinical trials. Continued approval will be contingent upon confirmatory data.10 A convenient feature of Bayer s formulation is the ability to divide the scored tablets manually without the need for pill-cutting devices.10Medical usesNifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days.[7][8] However, long-term use of nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects.[8][9] Due to the low tolerance and completion rate of nifurtimox, benznidazole is now being more considered for those who have Chagas disease and require long-term treatment.[5][9]In the United States nifurtimox is indicated in children and adolescents (birth to less than 18 years of age and weighing at least 2.5 kilograms (5.5 lb) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi.[2]Nifurtimox has also been used to treat African trypanosomiasis (sleeping sickness), and is active in the second stage of the disease (central nervous system involvement). When nifurtimox is given on its own, about half of all patients will relapse,[10] but the combination of melarsoprol with nifurtimox appears to be efficacious.[11] Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.[12]Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second-stage African trypanosomiasis.[13]Pregnancy and breastfeedingUse of nifurtimox should be avoided in pregnant women due to limited use.[5][8][14] There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants.[15] Other authors do not consider breastfeeding a contraindication during nifurtimox use.[15]Side effectsSide effects occur following chronic administration, particularly in elderly people. Major toxicities include immediate hypersensitivity such as anaphylaxis and delayed hypersensitivity reaction involving icterus and dermatitis. Central nervous system disturbances and peripheral neuropathy may also occur.[8]ContraindicationsNifurtimox is contraindicated in people with severe liver or kidney disease, as well as people with a background of neurological or psychiatric disorders.[5][16][20]Mechanism of actionNifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant breakdown of DNA.[8] Its mechanism is similar to that proposed for the antibacterial action of metronidazole. Nifurtimox undergoes reduction and creates oxygen radicals such as superoxide. These radicals are toxic to T. cruzi. Mammalian cells are protected by presence of catalase, glutathione, peroxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death.[8]Manufacturing and availabilityNifurtimox is sold under the brand name Lampit by Bayer.[3] It was previously known as Bayer 2502.Nifurtimox is only licensed for use in Argentina and Germany,[citation needed] where it is sold as 120-mg tablets. It was approved for medical use in the United States in August 2020.[3]ResearchNifurtimox is in a phase-II clinical trial for the treatment of pediatric neuroblastoma and medulloblastoma.[21]SYNNifurtimoxSynthesis of Essential Drugs2006, Pages 559-582Nifurtimox, 1,1-dioxide 4-[(5-nitrofuryliden)amino]-3-methylthiomorpholine (37.4.7), is made by the following scheme. Interaction of 2-mercaptoethanol with propylene oxide in the presence of potassium hydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsul-fide) (37.4.3), which undergoes intramolecular dehydration using potassium bisulfate to make 2-methyl-1,4-oxithiane (37.4.4). Oxidation of this using hydrogen peroxide gives 2-methyl-1,4-oxithian-4,4-dioxide (37.4.5), which when reacted with hydrazine transforms to 4-amino-3-methyltetrahydro-1,4-thiazin-1,1-dioxide (37.4.6). Reacting this with 5-nitrofurfurol gives the corresponding hydrazone—the desired nifurtimox [58,59].58. H. Herlinger, K.H. Heinz, S. Petersen, M.Bock, Ger. Pat. 1.170.957 (1964).59. H. Herlinger, K.H. Heinz, S. Petersen, M. Bock, U.S. Pat. 3.262.930 (1966)References^ Jump up to:a b c d e f  Nifurtimox (Systemic) . Drugs.com. 1995. Archived from the original on 20 December 2016. Retrieved 3 December 2016.^ Jump up to:a b  Lampit (nifurtimox) tablets, for oral use  (PDF). U.S. Food and Drug Administration(FDA). Bayer HealthCare Pharmaceuticals Inc. Retrieved 6 August 2020.^ Jump up to:a b c d  Lampit: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA). Retrieved 6 August 2020.^ Jump up to:a b c World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.^ Jump up to:a b c d e f g h Bern, Caryn; Montgomery, Susan P.; Herwaldt, Barbara L.; Rassi, Anis; Marin-Neto, Jose Antonio; Dantas, Roberto O.; Maguire, James H.; Acquatella, Harry; Morillo, Carlos (2007-11-14).  Evaluation and Treatment of Chagas Disease in the United States . JAMA. 298 (18): 2171–81. doi:10.1001/jama.298.18.2171. ISSN 0098-7484. PMID 18000201.^  Trypanosomiasis, human African (sleeping sickness) . World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December2016.^ Coura JR, de Castro SL (2002).  A critical review of Chagas disease chemotherapy . Mem Inst Oswaldo Cruz. 97 (1): 3–24. doi:10.1590/S0074-02762002000100001. PMID 11992141.^ Jump up to:a b c d e f g h  Nifurtimox Drug Information, Professional . http://www.drugs.com. Archivedfrom the original on 2016-11-08. Retrieved 2016-11-09.^ Jump up to:a b Jackson, Yves; Alirol, Emilie; Getaz, Laurent; Wolff, Hans; Combescure, Christophe; Chappuis, François (2010-11-15).  Tolerance and Safety of Nifurtimox in Patients with Chronic Chagas Disease . Clinical Infectious Diseases. 51 (10): e69–e75. doi:10.1086/656917. ISSN 1058-4838. PMID 20932171.^ Pepin J, Milord F, Mpia B, et al. (1989). An open clinical trial of nifurtimox for arseno-resistant T. b. gambiense sleeping sickness in central Zaire . Trans R Soc Trop Med Hyg. 83(4): 514–7. doi:10.1016/0035-9203(89)90270-8. PMID 2694491.^ Bisser S, N Siesi FX, Lejon V, et al. (2007).  Equivalence Trial of Melarsoprol and Nifurtimox Monotherapy and Combination Therapy for the Treatment of Second-Stage Trypanosoma brucei gambiense Sleeping Sickness . J Infect Dis. 195 (3): 322–329. doi:10.1086/510534. PMID 17205469.^ Pepin J (2007).  Combination Therapy for Sleeping Sickness: A Wake-Up Call . J Infect Dis. 195 (3): 311–13. doi:10.1086/510540. PMID 17205466.^ Priotto G, Kasparian S, Mutombo W, et al. (July 2009). Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiensetrypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial . Lancet. 374(9683): 56–64. doi:10.1016/S0140-6736(09)61117-X. hdl:10144/72797. PMID 19559476.^ Schaefer, Christof; Peters, Paul W. J.; Miller, Richard K. (2014-09-17). Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment. Academic Press. ISBN 9780124079014. Archived from the original on 2017-09-08.^ Jump up to:a b  Nifurtimox use while Breastfeeding | Drugs.com . http://www.drugs.com. Archived from the original on 2016-11-08. Retrieved 2016-11-07.^ Jump up to:a b c  Parasites American Trypanosomiasis (also known as Chagas Disease) . U.S. Centers for Disease Control and Prevention (CDC). Archived from the original on 2016-11-06. Retrieved 2016-11-09.^ Jump up to:a b Forsyth, Colin J.; Hernandez, Salvador; Olmedo, Wilman; Abuhamidah, Adieb; Traina, Mahmoud I.; Sanchez, Daniel R.; Soverow, Jonathan; Meymandi, Sheba K. (2016-10-15).  Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States . Clinical Infectious Diseases. 63 (8): 1056–1062. doi:10.1093/cid/ciw477. ISSN 1537-6591. PMC 5036918. PMID 27432838.^ Castro, José A.; de Mecca, Maria Montalto; Bartel, Laura C. (2006-08-01). Toxic side effects of drugs used to treat Chagas disease (American trypanosomiasis) . Human Experimental Toxicology. 25 (8): 471–479. doi:10.1191/0960327106het653oa. ISSN 0960-3271. PMID 16937919.^ Jump up to:a b Estani, Sergio Sosa; Segura, Elsa Leonor (1999-09-01).  Treatment of Trypanosoma cruzi infection in the undetermined phase. Experience and current guidelines of treatment in Argentina . Memórias do Instituto Oswaldo Cruz. 94: 363–365. doi:10.1590/S0074-02761999000700070. ISSN 0074-0276. PMID 10677756.^  Chagas disease . World Health Organization. Archived from the original on 2014-02-27. Retrieved 2016-11-08.^ Clinical trial number NCT00601003 for Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma at ClinicalTrials.gov. Retrieved on July 10, 2009. Nifurtimox . Drug Information Portal. U.S. National Library of Medicine.InChI=1S/C10H13N3O5S/c1-8-7-19(16,17)5-4-12(8)11-6-9-2-3-10(18-9)13(14)15/h2-3,6,8H,4-5,7H2,1H3  Imlifidase September 22, 2020 2:24 am / Leave a comment MDSFSANQEI RYSEVTPYHV TSVWTKGVTP PANFTQGEDV FHAPYVANQG WYDITKTFNGKDDLLCGAAT AGNMLHWWFD QNKDQIKRYL EEHPEKQKIN FNGEQMFDVK EAIDTKNHQLDSKLFEYFKE KAFPYLSTKH LGVFPDHVID MFINGYRLSL TNHGPTPVKE GSKDPRGGIFDAVFTRGDQS KLLTSRHDFK EKNLKEISDL IKKELTEGKA LGLSHTYANV RINHVINLWGADFDSNGNLK AIYVTDSDSN ASIGMKKYFV GVNSAGKVAI SAKEIKEDNI GAQVLGLFTLSTGQDSWNQT NImlifidaseイムリフィダーゼ;EMA APPROVED, 2020/8/25, IdefirixPre-transplant treatment to make patients with donor specific IgG eligible for kidney transplantationImmunosuppressant, Immunoglobulin modulator (enzyme)Imlifidase is under investigation in clinical trial NCT02854059 (IdeS in Asymptomatic Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients).Imlifidase, brand name Idefirix, is a medication for the desensitization of highly sensitized adults needing kidney transplantation, but unlikely to receive a compatible transplant.[1]Imlifidase is a cysteine protease derived from the immunoglobulin G (IgG)‑degrading enzyme of Streptococcus pyogenes.[1] It cleaves the heavy chains of all human IgG subclasses (but no other immunoglobulins), eliminating Fc-dependent effector functions, including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC).[1] Thus, imlifidase reduces the level of donor specific antibodies, enabling transplantation.[1]The benefits with imlifidase are its ability to convert a positive crossmatch to a negative one in highly sensitized people to allow renal transplantation.[1] The most common side effects are infections and infusion related reactions.[1]In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of Imlifidase.[1][2]Medical usesPer the CHMP recommendation, imlifidase will be indicated for desensitization treatment of highly sensitized adult kidney transplant people with positive crossmatch against an available deceased donor.[1] The use of imlifidase should be reserved for people unlikely to be transplanted under the available kidney allocation system including prioritization programmes for highly sensitized people.[1]HistoryImlifidase was granted orphan drug designations by the European Commission in January 2017, and November 2018,[3][4] and by the U.S. Food and Drug Administration (FDA) in both February and July 2018.[5][6]In February 2019, Hansa Medical AB changed its name to Hansa Biopharma AB.[4]Cyclohexanecarboxamide, N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-, cis 2097132-94-8 [RN]BLU-667BS-15942Other Namescis-N-[(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]cyclohexanecarboxamideBLU 123244BLU 667PralsetinibX 581238cis-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamideN-[(1S)-1-[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamideFDA APPROVED GAVRETO, 2020/9/4Pralsetinib, sold under the brand name Gavreto, is a medication for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC).[1] Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.[1]The most common adverse reactions include increased aspartate aminotransferase (AST), decreased hemoglobin, decreased lymphocytes, decreased neutrophils, increased alanine aminotransferase (ALT), increased creatinine, increased alkaline phosphatase, fatigue, constipation, musculoskeletal pain, decreased calcium, hypertension, decreased sodium, decreased phosphate, and decreased platelets.[1]Pralsetinib was approved for medical use in the United States in September 2020.[1][2][3][4]Medical usesPralsetinib is indicated for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.[1][4]HistoryEfficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385) with 220 participants aged 26-87 whose tumors had RET alterations.[1][4] Identification of RET gene alterations was prospectively determined in local laboratories using either next generation sequencing, fluorescence in situ hybridization, or other tests.[1] The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1.[1] The trial was conducted at sites in the United States, Europe and Asia.[4]Efficacy for RET fusion-positive NSCLC was evaluated in 87 participants previously treated with platinum chemotherapy.[1] The ORR was 57% (95% CI: 46%, 68%); 80% of responding participants had responses lasting 6 months or longer.[1] Efficacy was also evaluated in 27 participants who never received systemic treatment.[1] The ORR for these participants was 70% (95% CI: 50%, 86%); 58% of responding participants had responses lasting 6 months or longer.[1]The US Food and Drug Administration (FDA) granted the application for pralsetinib priority review, orphan drug, and breakthrough therapy designations[1]and granted approval of Gavreto to Blueprint Medicines.[1]PATENTUS 20170121312https://patents.google.com/patent/US20170121312A1/enStep 7: Synthesis of (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (Compound 129) and (1S,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (Compound 130)[0194][0195]The title compounds were prepared from methyl 1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (192 mg, 0.53 mmol) using the same two-step procedure (hydrolysis and amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (190 mg), which was then dissolved in 6 mL methanol and purified by SFC (ChiralPak AD-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 2.5 mL injections, 70 mL/min). Peak 1 was concentrated to give (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (29 mg, 10%) as a white solid. Peak 2 was concentrated to give (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (130 mg, 46%) as a white solid.Example 6. Synthesis of Compound 149Step 1: Synthesis of Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate[0197]Methyl 4-iodo-1-methoxycyclohexanecarboxylate (3.37 g, 11.3 mmol) was dissolved in dimethylacetamide (38 mL) in a pressure vessel under a stream of N2. Rieke Zinc (17.7 mL of a 50 mg/mL suspension in THF, 13.6 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes. The vessel was opened under a stream of N2 and 2,4-dichloro-6-methylpyrimidine (1.84 g, 11.3 mmol) was added followed by PdCl2dppf (826 mg, 1.13 mmol). The vessel was capped and heated to 80° C. for one hour, then cooled to room temperature. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H2O (3×), brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 50% EtOAc-hexanes) to give methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (74 mg, 2.2%) as a colorless oil. MS (ES+) C14H19ClN2O3 requires: 298, found: 299 [M+H]+.Step 2: Synthesis of tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate[0199]Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (70.5 mg, 0.236 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (69.8 mg, 0.354 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (20.0 mg, 0.2 equiv.), Pd2(dba)3 (21.6 mg, 0.1 equiv.), and potassium acetate (70 mg, 0.71 mmol) were combined in a vial under nitrogen and 0.98 mL dioxane was added. The reaction mixture was heated to 115° C. for 2 h, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, filtered through celite, concentrated onto silica gel, and the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-hexanes) to give tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (48 mg, 44%) as a yellow oil. MS (ES+) C23H33N5O5 requires: 459, found: 460 [M+H]+.Step 3: Synthesis of 1-Methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid[0201]Lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added to a solution of tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (47.7 mg, 0.104 mmol) in THF/MeOH/H2O (17:1:1, 1.8 mL). The reaction mixture was heated to 60° C. and stirred for 16 h. The reaction mixture was then cooled to ambient temperature and concentrated to give crude 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, crude) which was used in the subsequent amide coupling without any further purification. MS (ES+) C17H23N5O3 requires: 345, found: 346 [M+H]+.Step 4: Synthesis of (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (Compound 149)[0203]The title compound was prepared from 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, 0.104 mmol) using the same procedured (amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (36 mg), which was then dissolved in 6 mL methanol-DCM (1:1) and purified by SFC (ChiralPak IC-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 1.0 mL injections, 70 mL/min). Peak 1 was an undesired isomer, and Peak 2 was concentrated to give (1 s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (13.4 mg, 24%) as a white solid.Synthesis of IntermediatesExample 7. Synthesis of Ketone and Boronate IntermediatesA. Methyl 1-methoxy-4-oxocyclohexane-1-carboxylate[0207]A solution of 1,4-dioxaspiro[4.5]decan-8-one (20.0 g, 128 mmol) in CHBr3 (3234 g, 1280 mmol) was cooled to 0° C. and potassium hydroxide (57.5 g, 1024 mmol) in EtOH (300 mL) was added dropwise over 2.5 hrs. After stirring the mixture for 23 h, the mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product, which was purified by flash column chromatography on silica gel (gradient elution, PE:EA=15:1 to 10:1) to obtain the title compound (18.0 g).[0208]To a solution of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g, 43 mmol) in 1,4-dioxane (250 mL) was added aqueous HCl (6 M, 92.5 mL), and the mixture was stirred for 23 h at ambient temperature. The mixture was then diluted with H2O and extracted with EtOAc.[0209]The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (PE:EA=15:1) to obtain the product (8.0 g). 1H NMR (400 MHz, DMSO) δ 4.20-4.13 (m, 2H), 3.43 (q, J=6.9 Hz, 1H), 2.48-2.39 (m, 1H), 2.24-2.12 (m, 2H), 2.10-2.01 (m, 1H), 1.22 (t, J=7.1 Hz, 2H), 1.17 (t, J=7.0 Hz, 2H).C. Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate[0211]A solution of methylmagnesium bromide (3M, 109.8 mL, 329.4 mmol) was added dropwise to a suspension of CuCN (14.75 g, 164.7 mmol) in diethyl ether (50 mL) at 0° C. The mixture was stirred for 30 min at 0° C. and then cooled to −78° C. The solution of ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate (10 g, 54.9 mmol) in diethyl ether (10 mL) was then added dropwise. The mixture was stirred between −40° C. to −20° C. for 2 h, then was warmed to ambient temperature for 16 h. The reaction mixture was carefully added to a saturated solution of ammonium chloride. The aqueous layer was extracted twice with diethyl ether, and the organic layers were combined. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (PE:EA=10:1) to give ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g).Step 2: Synthesis of ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate[0212]Ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g, 5.85 mmol) and DIPEA (3.03 g, 23.4 mmol) were dissolved in dry toluene (2 mL) and heated at 45° C. for 10 minutes. Trifluoromethanesulfonic anhydride (6.61 g, 23.4 mmol) in DCM (20 mL) was added dropwise over 10 min and the mixture was heated at 45° C. for 2 h. The mixture was allowed to cool to room temperature, concentrated, diluted with water (60 mL) and extracted with DCM (2×40 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (1 g).Step 3: Synthesis of ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate[0213]Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1 g, 3.03 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.15 g, 4.54 mmol), Pd(dppf)Cl2 (73.5 mg, 0.09 mmol) and potassium acetate (891 mg, 9.08 mmol) were suspended in 1,4-dioxane (20 mL). The reaction mixture was flushed with nitrogen, then heated to 100° C. for 2 h. The mixture was cooled to room temperature, filtered, and concentrated, and the resulting brown oil was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (618 mg).D. Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate[0215]Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate was prepared using the same synthetic protocol as described above using ethyl 2-methyl-4-oxocyclohexane-1-carboxylate as the starting material.[0217]A mixture of acrylaldehyde (120 g, 2.14 mol), methyl methacrylate (200 g, 2.00 mol) and hydroquinone (2.2 g, 20 mmol) were heated in a sealed steel vessel at 180° C. for one h. The mixture was then cooled to ambient temperature and concentrated. The residue was purified by silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=100:1 to 80:1) to give methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (70 g, 22% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 6.38 (d, J=6.4 Hz, 1H), 4.73-4.70 (m, 1H), 3.76 (s, 3H), 2.25-2.22 (m, 1H), 1.99-1.96 (m, 2H), 1.79-1.77 (m, 1H), 1.49 (s, 3H).[0218]To a solution of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (20.0 g, 128 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane (67 mL, 1 M in tetrahydrofuran) dropwise at −5° C. The reaction mixture was stirred at 0° C. for 3 hours. This reaction was monitored by TLC. The mixture was quenched by a solution of sodium acetate (10.5 g, 128 mmol) in water (15 mL). Then the mixture was treated with 30% hydrogen peroxide solution (23.6 g, 208.2 mmol) slowly at 0° C. and stirred at 30° C. for 3 h. The mixture was then partitioned between saturated sodium sulfite solution and tetrahydrofuran. The aqueous layer was further extracted with tetrahydrofuran (2×). The combined organic layers were washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=10:1 to 1:1) to give crude methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18 g, crude) as a pale yellow oil, which used directly for next step.[0219]To a solution of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18.0 g, 103 mmol) in anhydrous dichloromethane (200 mL) was added PCC (45.0 g, 209 mmol) in portions. The reaction mixture was stirred at ambient temperature until TLC indicated the reaction was completed. Petroleum ether (500 mL) was then added and the mixture was filtered. The filter cake was washed with petroleum ether (100 mL), and the filtrate was concentrated under vacuum to give methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate (15 g, 84% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 4.25 (d, J=17.6 Hz, 1H), 4.07 (d, J=17.6 Hz, 1H), 3.81 (s, 3H), 2.52-2.44 (m, 3H), 2.11-2.04 (m, 1H), 1.53 (s, 3H).Example 8. Synthesis of Iodide IntermediatesA. Methyl 1-methoxy-4-iodocyclohexane-1-carboxylate[0221]Methyl 1-methoxy-4-oxocyclohexanecarboxylate (4.00 g, 21.5 mmol) was dissolved in methanol (100 mL) and the solution was cooled to 0° C. Sodium borohydride (2.03 g, 53.7 mmol) was added in portions over 20 min. The reaction mixture was stirred for 30 min, then was quenched by addition of aqueous saturated NH4Cl solution. The quenched reaction mixture was evaporated to remove the MeOH, then the aqueous suspension was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a residue that was purified by flash-column chromatography on silica gel (gradient elution, 5% to 100% ethyl acetate-hexanes) to afford methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 49.5%) as a colorless oil. MS (ES+) C9H16O4 requires: 188, found: 211 [M+Na]+.[0222]Methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 10.6 mmol) was dissolved in THF (20 mL) and imidazole (723 mg, 10.6 mmol) and triphenylphosphine (3.34 g, 12.8 mmol) were added. The mixture was cooled to 0° C., and then a solution of iodine (3.24 g, 12.8 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction mixture was allowed to warm to ambient temperature and was then stirred for 2 days, after which it was poured over saturated sodium thiosulfate solution and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was triturated with hexane (40 mL, stir for 20 min). The mixture was filtered, and the filtrate was evaporated to provide a residue that was purified by flash-column chromatography on silica gel (gradient elution, 0 to 30% ethyl acetate-hexanes) to give the title compound (2.37 g, 75%) as a pale yellow oil. MS (ES+) C9H15IO3 requires: 298, found: 299 [M+H]+.[0224]The title compound was prepared as described above using ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate as a starting material. C11H19IO3 requires: 326, found: 327 [M+H]−.Example 9. Synthesis of Amine IntermediatesA. (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine[0226]4-Fluoro-1H-pyrazole (4.73 g, 55 mmol) and potassium carbonate (17.27 g, 125 mmol) were combined and stirred in N,N-dimethylformamide (41.7 mL) for 10 minutes in an open sealed tube before addition of 2-bromo-5-acetylpyridine (10 g, 50 mmol). The reaction tube was sealed and stirred for 20 hours at 100° C. The reaction mixture was then cooled to room temperature and poured into water (˜700 mL). The mixture was sonicated and stirred for 20 minutes, after which a beige solid was isolated by filtration, washed with small amounts of water, and dried to yield 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.81 g, 96% yield). MS: M+1=206.0.Step 2: Synthesis of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide[0227]To a stirred room temperature solution of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.806 g, 47.8 mmol) in THF (96 mL) was added (R)-(+)-t-Butylsulfinamide (5.79 g, 47.8 mmol) followed by titanium (IV) ethoxide (21.8 g, 96 mmol). The solution was stirred at 75° C. on an oil bath for 15 hours. The reaction solution was cooled to room temperature and then to −78° C. (external temperature) before the next step. To the −78° C. solution was added dropwise over nearly 55 minutes L-Selectride (143 mL of 1N in THF, 143 mmol). During addition, some bubbling was observed. The reaction was then stirred after the addition was completed for 15 minutes at −78° C. before warming to room temperature. LC-MS of sample taken during removal from cold bath showed reaction was completed. The reaction was cooled to −50° C. and quenched slowly with methanol (˜10 mL), then poured into water (600 mL) and stirred. An off-white precipitate was removed by filtration, with ethyl acetate used for washes. The filtrate was diluted with ethyl acetate (800 mL), the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography to yield (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.5 g, 99% purity, 70.3% yield) as a light yellow solid. MS: M+1=311.1.Step 3: Synthesis of (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine[0228]A solution of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.53 g, 33.9 mmol)) in methanol (79 mmol) and 4N HCl/dioxane (85 mL, 339 mmol) was stirred for 2.5 hours, at which point LC-MS showed reaction was complete. The reaction solution was poured into diethyl ether (300 mL) and a sticky solid was formed. The mixture was treated with ethyl acetate (200 mL) and sonicated. The solvents were decanted, and the sticky solid was treated with more ethyl acetate (˜200 mL), sonicated and stirred. The bulk of the sticky solid was converted to a suspension. A light yellow solid was isolated by filtration, washed with smaller amounts of ethyl acetate, and dried to yield (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine (7.419 g, 78% yield). LC-MS confirmed desired product in high purity. MS: M+1=207.1.InChI=1S/C27H32FN9O2/c1-16-11-22(33-23-12-17(2)35-36-23)34-25(31-16)19-7-9-27(39-4,10-8-19)26(38)32-18(3)20-5-6-24(29-13-20)37-15-21(28)14-30-37/h5-6,11-15,18-19H,7-10H2,1-4H3,(H,32,38)(H2,31,33,34,35,36)/t18-,19?,27?/m0/s1Roche buys into Blueprint’s RET inhibitorThe deal positions pralsetinib to compete against Lilly’s Retevmoby Lisa M. JarvisJULY 18, 2020 | APPEARED IN VOLUME 98, ISSUE 28Roche is investing $775 million in cash and equity for access to Blueprint Medicines’ oncology drug candidate pralsetinib, which is under review by the US Food and Drug Administration.Pralsetinib is a small-molecule inhibitor of RET alterations—rare genetic fusions or mutations that occur at low levels across lung, thyroid, and many other cancers.The drug will go up against Eli Lilly and Company’s Retevmo, an RET inhibitor that received FDA approval in May for certain lung and thyroid cancers. Lilly acquired Retevmo in its $8 billion purchase of Loxo Oncology in 2019, a deal to obtain Loxo’s pipeline of small molecules for genetically defined tumors.But SVB Leerink analyst Andrew Berens points out that Retevmo has side effects: it can cause an irregular heart rhythm called QT prolongation and hemorrhagic events. That leaves room for pralsetinib, which Roche will be better able to get in front of oncologists, Berens argues. In addition to a vast commercial network, Roche brings diagnostic tools to help identify cancer patients whose tumors feature RET alterations.The FDA has a deadline of Nov. 23 to decide on approving the drug for lung cancer.Roche’s move lowers the likelihood of a takeover of Blueprint, which had appeared on many investors’ short lists of acquisition targets. “We were surprised by the profuse language framing this deal as ensuring Blueprint’s independence,” Piper Sandler stock analyst Christopher J. Raymond told investors in a note.Anti-acne, Androgen receptor antagonistClascoterone, sold under the brand name Winlevi, is an antiandrogen medication which is used topically in the treatment of acne.[1][2][3] It is also under development for the treatment of androgen-dependent scalp hair loss.[2] The medication is used as a cream by application to the skin, for instance the face and scalp.[3]Clascoterone is an antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone.[4][5] It shows no systemic absorption when applied to skin.[3]The medication, developed by Cassiopea and Intrepid Therapeutics,[2] was approved by the US Food and Drug Administration (FDA) for acne in August 2020.[6][7]Medical usesClascoterone is indicated for the topical treatment of acne vulgaris in females and males age 12 years and older.[1][8] It is applied to the affected skin area in a dose of 1 mg cream (or 10 mg clascoterone) twice per day, once in the morning and once in the evening.[1] The medication should not be used ophthalmically, orally, or vaginally.[1]Available formsClascoterone is available in the form of a 1% (10 mg/g) cream for topical use.[1]ContraindicationsClascoterone has no contraindications.[1]Side effectsThe incidences of local skin reactions with clascoterone were similar to placebo in two large phase 3 randomized controlled trials.[1][9] Suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) may occur during clascoterone therapy in some individuals due to its cortexolone metabolite.[1][8] HPA axis suppression as measured by the cosyntropin stimulation test was observed to occur in 3 of 42 (7%) of adolescents and adults using clascoterone for acne.[1][8] HPA axis function returned to normal within 4 weeks following discontinuation of clascoterone.[1][8] Hyperkalemia (elevated potassium levels) occurred in 5% of clascoterone-treated individuals and 4% of placebo-treated individuals.[1]PharmacologyPharmacodynamicsClascoterone is an steroidal antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone (DHT).[1][4][5] In a bioassay, the topical potency of the medication was greater than that of progesterone, flutamide, and finasteride and was equivalent to that of cyproterone acetate.[10] Likewise, it is significantly more efficacious as an antiandrogen than other AR antagonists such as enzalutamide and spironolactone in scalp dermal papilla cells and sebocytes in vitro.[5]\PharmacokineticsSteady-state levels of clascoterone occur within 5 days of twice daily administration.[1] At a dosage of 6 g clascoterone cream applied twice daily, maximal circulating levels of clascoterone were 4.5 ± 2.9 ng/mL, area-under-the-curve levels over the dosing interval were 37.1 ± 22.3 h*ng/mL, and average circulating levels of clascoterone were 3.1 ± 1.9 ng/mL.[1] In rodents, clascoterone has been found to possess strong local antiandrogenic activity, but negligible systemic antiandrogenic activity when administered via subcutaneous injection.[10] Along these lines, the medication is not progonadotropic in animals.[10]The plasma protein binding of clascoterone is 84 to 89% regardless of concentration.[1]Clascoterone is rapidly hydrolyzed into cortexolone (11-deoxycortisol) and this compound is a possible primary metabolite of clascoterone based on in-vitro studies in human liver cells.[1][8] During treatment with clascoterone, cortexolone levels were detectable and generally below or near the low limit of quantification (0.5 ng/mL).[1] Clascoterone may also produce other metabolites, including conjugates.[1]The elimination of clascoterone has not been fully characterized in humans.[1]ChemistrySee also: List of steroidal antiandrogens § Cortisol derivativesClascoterone, also known as cortexolone 17α-propionate or 11-deoxycortisol 17α-propionate, as well as 17α,21-dihydroxyprogesterone 17α-propionate or 17α,21-dihydroxypregn-4-en-3,20-dione 17α-propionate, is a synthetic pregnane steroid and a derivative of progesterone and 11-deoxycortisol (cortexolone).[11] It is specifically the C17α propionate ester of 11-deoxycortisol.[10]An analogue of clascoterone is 9,11-dehydrocortexolone 17α-butyrate (CB-03-04).[12]HistoryC17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogenic activity.[10] Clascoterone, also known as cortexolone 17α-propionate, was selected for development based on its optimal drug profile.[10] The medication was approved by the US Food and Drug Administration (FDA) for the treatment of acne in August 2020.[6]Two large phase 3 randomized controlled trials evaluated the effectiveness of clascoterone for the treatment of acne over a period of 12 weeks.[1][8][9] Clascoterone decreased acne symptoms by about 8 to 18% more than placebo.[1][9] The defined treatment success endpoint was achieved in about 18 to 20% of individuals with clascoterone relative to about 7 to 9% of individuals with placebo.[1][8][9] The comparative effectiveness of clascoterone between males and females was not described.[1][9]A small pilot randomized controlled trial in 2011, found that clascoterone cream decreased acne symptoms to a similar or significantly greater extent than tretinoin 0.05% cream.[8][13] No active comparator was used in the phase III clinical trials of clascoterone for acne.[8] Hence, it s unclear how clascoterone compares to other therapies used in the treatment of acne.[8]The FDA approved clascoterone based on evidence from two clinical trials (Trial 1/NCT02608450 and Trial 2/NCT02608476) of 1440 participants 9 to 58 years of age with acne vulgaris.[14] The trials were conducted at 99 sites in the United States, Poland, Romania, Bulgaria, Ukraine, Georgia, and Serbia.[14]Participants applied clascoterone or vehicle (placebo) cream twice daily for 12 weeks.[14] Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed.[14] The benefit of clascoterone in comparison to placebo was assessed after 12 weeks of treatment using the Investigator s Global Assessment (IGA) score that measures the severity of disease (on a scale from 0 to 4) and a decrease in the number of acne lesions.[14]Society and cultureNamesClascoterone is the generic name of the drug and its INN and USAN.[11][15]ResearchClascoterone has been suggested as a possible treatment for hidradenitis suppurativa (acne inversa), an androgen-dependent skin condition.[16]PATENThttps://patents.google.com/patent/EP2503005B1/enCortexolone derivatives in which the hydroxyl group at position C-17α is esterified with short chain aliphatic or aromatic acids and the derivatives of the corresponding 9,11-dehydro derivative, are known to have an antiandrogenic effect.[0002]EP 1421099 describes cortexolone 17α-propionate and 9,11-dehydro-cortexolone-17-α-butanoate regarding a high antiandrogenic biological activity demonstrated both in vitro and in vivo on the animal.[0003]US3530038 discloses the preparation of a crystalline form of cortexolone-17α-propionate having a melting point of 126-129 °C and an IR spectrum with bands at (cm-1): 3500, 1732, 1713, 1655 and 1617.[0004]A method for obtaining the above mentioned derivatives is described by Gardi et al. (Gazz. Chim. It. 63, 43 1,1963) and in the United States patent US3152154 providing for the transformation of cortexolone, or transformation of 9,11-dehydrocortexolone, in the intermediate orthoester using orthoesters available in the market as a mixture of aprotic solvents such as cyclohexane and DMF, in presence of acid catalysis (ex. PTSA.H20). The intermediate orthoester thus obtained can be used as is or upon purification by suspension in a solvent capable of solubilising impurities, preferably in alcohols. The subsequent hydrolysis in a hydroalcoholic solution, buffered to pH 4-5 preferably in acetate buffer, provides the desired monoester.[0005]Such synthesis is indicated in the diagram 1 below[0006]However, the monoesters thus obtained were, in the reaction conditions, unstable and, consequently hard to manipulate and isolate (R. Gardi et al Tetrahedron Letters, 448, 1961). The instability is above all due to the secondary reaction of migration of the esterifying acyl group from position 17 to position 21.[0007]It is thus known that in order to obtain the above mentioned monoesters with a chemical purity in such a manner to be able to proceed to the biological tests, it is necessary to use, at the end of the synthesis, a purification process which is generally performed by means of column chromatography.[0008]Furthermore, US3152154 describes how the hydrolysis of the diester in a basic environment is not convenient due to the formation of a mixture of 17α,21-diol, of 17- and 21 -monoesters, alongside the initial non-reacted product.[0009]Now, it has been surprisingly discovered that an alcoholysis reaction using a lipase from Candida as a biocatalyst can be usefully applied during the preparation of 17α monoesters of cortexolone, or its 9,11-dehydroderivatives.[0010]As a matter of fact, it has been discovered that such enzymatic alcoholysis of the 17,21-diester of the cortexolone, or of its derivative 9,11-dehydro, selectively occurs in position 21 moving to the corresponding monoester in position 17, as shown in diagram 2 below:[0011]The chemoselectivity of the special enzymatic reaction in alcoholysis conditions, according to the present invention, opens new perspectives for preparation, at industrial level with higher yields, of 17α-monoesters with respect to the methods already indicated in literature.[0012]The diesters serving as a substrate for the reaction of the invention can be prepared according to the prior art, for example following the one described in B.Turner, (Journal of American Chemical Society, 75, 3489, 1953) which provides for the esterification of corticosteroids with a linear carboxylic acid in presence of its anhydride and PTSA monohydrate.[0055]Add butanol (0.4g, 5.45 mmoles) and CCL (17.4g, 3.86 U/mg, FLUKA) to a solution of cortexolone-17α,21-dipropionate (0.5g, 1.09 mmoles) in toluene (50ml). Maintain the mixture under stirring, at 30 °C, following the progress of the reaction in TLC (Toluene/ethyl acetate 6/4) until the initial material is dissolved (24h). Remove the enzyme by means of filtration using a Celite layer. Recover the cortexolone 17α-propionate (0.437, 99%) after evaporation under low pressure. Through crystallisation, from diisopropyl ether you obtain a product with a purity 99% in HPLC.[0056]1H-NMR (500MHz, CDCl3) relevant signals δ (ppm) 5.78 (br s, 1 H, H-4), 4.32 (dd, 1 H, H-21), 4.25 (dd, 1H, H-21), 1.22 (s, 3H, CH3-19), 1.17 (t, 3H, CH3), 0.72 (s, 3H, CH3-18). P.f. 114 °C[0057]According to the method described in example 1 prepare cortexolone-17α-butanoate.[0058]1H-NMR relevant signals δ (ppm) 5.78 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.23 (s, 3H, CH3-19), 0.97 (t, 3H, CH3), 0.73 (s, 3H. CH3-18). P.F. 134-136 °CExample 3 (comparative)According to the method described in the example prepare cortexolone-17α-valerate.[0059]1H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.22 (s, 3H, CH3-19), 0.95 (t, 3H, CH3), 0.72 (s, 3H, CH3-18). P.f. 114 °C (diisopropyl ether).Example 4 (comparative)According to the method described in the example prepare 9, 11-dehydro-cortexolone-17α-butanoate.[0060]1H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 5.54 (m, 1H, H-9), 4.29 (dd, 1H, H-21), 4.24 (dd, 1H, H-21), 1.32 (s, 3H, CH3-19), 0.94(t, 3H, CH3), 0.68 (s, 3H, CH3-18). P.f. 135-136 °C (acetone/hexane).[0061]Dissolve cortexolone, 17α, 2-dipropionate (0.5g, 1.09 mmoles) in acetonitrile (40ml), add CALB (2.3g, 2.5 U/mg Fluka) and octanol (0.875ml). Leave the mixture under stirring, at 30 °C, for 76 hrs. Remove the enzyme by means of filtration using a paper filter. Once the solvents evaporate, recover a solid (0.4758) which upon analysis 1H-NMR shall appear made up of cortexolone-17α-propionate at 91%.[0062]Add the solvent (t-butylmethylether or diisopropylether) to the sample according to the ratios indicated in Table 3. Heat the mixture to the boiling temperature of the solvent, under stirring, until the sample dissolves completely. Cool to room temperature and leave it at this temperature, under stirring, for 6 hours. Filter using a buchner funnel and maintain the solid obtained, under low pressure, at a room temperature for 15 hours and then, at 40°C, for 5 hours.[0063]Disslove the sample in the suitable solvent (dichloromethane, acetone, ethyl acetate or ethanol) according to the ratios indicated in table 3 and then add the solvent, hexane or water, according to the ratios indicated in table 3, maintaining the mixture, under stirring, at room temperature. Recover the precipitate by filtration using a buchner funnel and desiccate as in example 6.Example 8.Obtaining a pharmaceutical form containing the medication in a defined crystalline form.[0064]Prepare a fluid cream containing 2 % cetylic alcohol, 16% glyceryl monostearate, 10% vaseline oil, 13 % propylene glycol, 10% polyethylenglycol with low polymerization 1.5% polysorbate 80 and 47.5 % purified water. Add 1 g of cortexolone 17α-propionate of crystalline form III to 100 g of this cream and subject the mixture to homogenisation by means of a turbine agitator until you obtain homogeneity. You obtain a cream containing a fraction of an active ingredient dissolved in the formulation vehicle and a non-dissolved fraction of an active ingredient, present as a crystal of crystalline form III. This preparation is suitable for use as a formulation vehicle for skin penetration tests on Franz cells, where a coefficient of penetration in the range of 0.04 to 0.03 cm/h is observed on the preparation.^ Jump up to:a b c d e f g h i j k l m n o p q r s t u v w  Winlevi (clascoterone) cream, for topical use (PDF). Cassiopea. Retrieved 9 September 2020.^ Jump up to:a b c http://adisinsight.springer.com/drugs/800026561^ Jump up to:a b c Kircik LH (July 2019).  What s new in the management of acne vulgaris . Cutis. 104(1): 48–52. PMID 31487336.^ Jump up to:a b Rosette C, Rosette N, Mazzetti A, Moro L, Gerloni M (February 2019). Cortexolone 17α-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro . J Drugs Dermatol. 18 (2): 197–201. PMID 30811143.^ Jump up to:a b c Rosette C, Agan FJ, Mazzetti A, Moro L, Gerloni M (May 2019). Cortexolone 17α-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro . J Drugs Dermatol. 18 (5): 412–418. PMID 31141847.^ Jump up to:a b  Cassiopea Receives FDA Approval for Winlevi (clascoterone cream 1%), First-in-Class Topical Acne Treatment Targeting the Androgen Receptor . Cassiopea (Press release). Retrieved 2020-08-30.^  Winlevi: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA). Retrieved 9 September 2020.^ Jump up to:a b c d e f g h i j Barbieri, John S. (2020). A New Class of Topical Acne Treatment Addressing the Hormonal Pathogenesis of Acne . JAMA Dermatology. 156 (6): 619–620. doi:10.1001/jamadermatol.2020.0464. ISSN 2168-6068. PMID 32320045.^ Jump up to:a b c d e Hebert A, Thiboutot D, Stein Gold L, Cartwright M, Gerloni M, Fragasso E, Mazzetti A (April 2020).  Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials . JAMA Dermatol. 156 (6): 621–630. doi:10.1001/jamadermatol.2020.0465. PMC 7177662. PMID 32320027.^ Jump up to:a b c d e f Celasco G, Moro L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, Nicoletti F (2004). Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist . Arzneimittelforschung. 54 (12): 881–6. doi:10.1055/s-0031-1297043. PMID 15646372.^ Jump up to:a b https://chem.nlm.nih.gov/chemidplus/rn/19608-29-8^ Celasco G, Moroa L, Bozzella R, Ferraboschi P, Bartorelli L, Di Marco R, Quattrocchi C, Nicoletti F (2005). Pharmacological profile of 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04), a new androgen antagonist with antigonadotropic activity . Arzneimittelforschung. 55 (10): 581–7. doi:10.1055/s-0031-1296908. PMID 16294504.^ Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G (2011). Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0·05% cream . Br. J. Dermatol. 165 (1): 177–83. doi:10.1111/j.1365-2133.2011.10332.x. PMID 21428978. S2CID 38404925.^ Jump up to:a b c d e  Drug Trial Snapshot: Winlevi . U.S. Food and Drug Administration (FDA). 26 August 2020. Retrieved 10 September 2020.  This article incorporates text from this source, which is in the public domain.^ World Health Organization (2019). International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82 . WHO Drug Information. 33 (3): 106. hdl:10665/330879.^ Der Sarkissian SA, Sun HY, Sebaratnam DF (August 2020). Cortexolone 17 α-proprionate for hidradenitis suppurativa . Dermatol Ther: e14142. doi:10.1111/dth.14142. PMID 32761708. Clascoterone . Drug Information Portal. U.S. National Library of Medicine.Clinical trial number NCT02608450 for A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (25) at ClinicalTrials.govClinical trial number NCT02608476 for A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (26) at ClinicalTrials.govOther namesCB-03-01; Breezula; 11-Deoxycortisol 17α-propionate; 17α-(Propionyloxy)-deoxycorticosterone; 21-Hydroxy-3,20-dioxopregn-4-en-17-yl propionateInChI=1S/C24H34O5/c1-4-21(28)29-24(20(27)14-25)12-9-19-17-6-5-15-13-16(26)7-10-22(15,2)18(17)8-11-23(19,24)3/h13,17-19,25H,4-12,14H2,1-3H3/t17-,18+,19+,22+,23+,24+/m1/s1 Enter your email address to follow this blog and receive notifications of new posts by email. Join 2,538 other followers Email Address: Cetuximab sarotalocan sodiumCetuximab Sarotalocan Sodium (Genetical Recombination) Cetuximab Sarotalocan Sodium is an antibody-drug-conjugate (molecular weight: 156,000-158,000) consisting of tetrasodium salt of Sarotalocan (6-({[3-({(OC-6-13)-bis({3-[bis(3-sulfopropyl)(3-sulfonatopropyl)azaniumyl]propyl}dimethylsilanolato-κO,κO )[(phtalocyaninato(2-)κN29,κN30,κN31,κN32)-1-yl]silicon}oxy)propoxy]carbonyl}amino)hexanoyl (C70H96N11O24S6Si3; molecular weight: 1,752.22)) EnarodustatEnarodustat エナロデュスタット JTZ 951 Formula C17H16N4O4 CAS 1262132-81-9 Mol weight 340.3333 PMDA2020/9/25 APPROVED ENAROY Anti-anemic, Hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitor Originator Japan TobaccoDeveloper Japan Sofpironium bromideSofpironium bromide ソフピロニウム臭化物 BBI 4000 [(3R)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidin-1-ium-3-yl] (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetate;bromide Formula C22H32NO5. Br CAS 1628106-94-4 BASE 1628251-49-9 Mol weight 470.3972 PMDA APPROVED JAPAN 2020/9/25, Ecclock Anhidrotic Sofpironium Bromide 1-ambo-(3R)-3-{[(R)-(Cyclopentyl)hydroxy(phenyl)acetyl]oxy}-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidinium bromide C22H32BrNO5 : 470.4 Tetrahydrobiopterin,Sapropterin Sapropterin dihydrochloride, Dapropterin dihydrochloride, R-THBP, 6R-BH4, SUN-0588, Phenoptin, Biopten, Biobuden, Bipten Approval:US: Dec’07, EU: Dec’08 Approval:US: Dec’07, EU: Dec’08 IUPAC Name (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-3,4,5,6,7,8-hexahydropteridin-4-one SMILES [H][C@@]1(CNC2=C(N1)C(=O)NC(N)=N2)[C@@H](O)[C@H](C)O сапроптерин [Russian] [INN] سابروبتيرين [INN] Abametapir アバメタピル , абаметапир , أباميتابير , 阿巴甲吡 ,Abametapir アバアバメタピル , абаметапир , أباميتابير , 阿巴甲吡 , 5,5 -dimethyl-2,2 -bipyridine, 6,6 -Bi-3-picoline BRN 0123183 HA 44 HA-44 HA44 Formula C12H12N2 CAS 1762-34-1 Mol weight 184.2371 Xeglyze, FD APPROVED 24/7/2020 Pediculicide, Metalloproteinase inhibitor Bulevirtide acetateBulevirtide acetate (N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt. molecular formula C248H355N65O72, molecular mass is 5398.9 g/mol ブレビルチド酢酸塩; APROVED 2020/7/31, EU, Hepcludex MYR GmbH Antiviral, Entry inhibitor   Disease Hepatitis delta virus NifurtimoxNifurtimox Formula C10H13N3O5S CAS 23256-30-6 Mol weight 287.2923 FDA APPROVED, 2020/8/6, LAMPIT Antiprotozoal   Disease Chagas disease IUPAC Name 3-methyl-4-[(E)-[(5-nitrofuran-2-yl)methylidene]amino]-1lambda6-thiomorpholine-1,1-dione SMILES CC1CS(=O)(=O)CCN1\N=C\C1=CC=C(O1)[N+]([O-])=O SYN Danong Chen, Glenn Rice. ImlifidaseMDSFSANQEI RYSEVTPYHV TSVWTKGVTP PANFTQGEDV FHAPYVANQG WYDITKTFNG KDDLLCGAAT AGNMLHWWFD QNKDQIKRYL EEHPEKQKIN FNGEQMFDVK EAIDTKNHQL DSKLFEYFKE KAFPYLSTKH LGVFPDHVID MFINGYRLSL TNHGPTPVKE GSKDPRGGIF DAVFTRGDQS KLLTSRHDFK EKNLKEISDL IKKELTEGKA LGLSHTYANV RINHVINLWG ADFDSNGNLK PralsetinibPralsetinib Formula C27H32FN9O2 CAS 2097132-94-8 Mol weight 533.6005 Cyclohexanecarboxamide, N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-, cis 2097132-94-8 [RN] BLU-667 BS-15942 Other Names cis-N-[(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]cyclohexanecarboxamide BLU 123244 BLU 667 Pralsetinib X 581238 cis-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide FDA ClascoteroneClascoterone (1R,3aS,3bR,9aR,9bS,11aS)-1-(2-hydroxyacetyl)-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl propanoate Formula C24H34O5 CAS 19608-29-8 Mol weight 402.5238 FDA APPROVED, 2020/8/26, Winlevi クラスコステロン; Anti-acne, Androgen receptor antagonist Clascoterone, sold under the brand name Winlevi, is

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