[go: up one dir, main page]

WO2009057136A2 - Épimérisation par synthèse stéréosélective d'analogues de la vitamine d - Google Patents

Épimérisation par synthèse stéréosélective d'analogues de la vitamine d Download PDF

Info

Publication number
WO2009057136A2
WO2009057136A2 PCT/IN2008/000480 IN2008000480W WO2009057136A2 WO 2009057136 A2 WO2009057136 A2 WO 2009057136A2 IN 2008000480 W IN2008000480 W IN 2008000480W WO 2009057136 A2 WO2009057136 A2 WO 2009057136A2
Authority
WO
WIPO (PCT)
Prior art keywords
borane
ilia
general structure
compound
reducing agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2008/000480
Other languages
English (en)
Other versions
WO2009057136A3 (fr
Inventor
Mubeen Khan
Gangadhar Patil Dayaghan
Baluram Wagh Ghanshyam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glenmark Generics Ltd
Original Assignee
Glenmark Generics Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Generics Ltd filed Critical Glenmark Generics Ltd
Publication of WO2009057136A2 publication Critical patent/WO2009057136A2/fr
Anticipated expiration legal-status Critical
Publication of WO2009057136A3 publication Critical patent/WO2009057136A3/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane

Definitions

  • the present invention relates to novel epimerization process of C-24 ketones to desired C-24 alcohols by stereo selective reduction using chiral borane reducing agents for the preparation of calcipotriene.
  • Calcipotriol or calcipotriene shows a strong activity in inhibiting undesirable proliferation of epidermal keratinocytes [F. A. CM. Castelijins, M. J. Gerritsen, I. M. J. J. van Vlijmen-Willems, P. J. van Eip, P. C. M. van de Kerkhof; Acta Derm. Venereol. 79, 11, 1999].
  • the efficiency of calcipotriol in the treatment of psoriasis was shown in a number of clinical trials [D. M. Ashcroft et al.; Brit. Med. J. 320, 963-67, 2000] and calcipotriol is currently used in several commercial drug formulations.
  • WO 2003/060094 disclosed method of selectively enzymatically esterifying and selectively enzymatically solvolyzing epimers at C-24 analogs of vitamin D and esters using enzymes.
  • the enzymatic esterification synthesis is not commercially favourable since it requires costly enzymes and depending on the selectivity of enzyme requires additional reaction steps involved.
  • WO 2005/087719 disclosed a process for preparation of diastereomerically enriched C-24 hydroxyl epimers of calcipotriene derivatives by stereo selective reduction of labile triene system which is protected as sulfur dioxide adduct. This process gives 1 : 1 or more of desired 24 (S)-hydroxyl epimer. This process requires protection of C-24 keto triene compound by sulfur dioxide and deprotection of sulfur dioxide adducts of C-24 (S) and C-24 (R) hydroxyl mixtures followed by separation of desired (S)-epimer from the formed epimer mixtures. This would results in reduced yields, impure products and tedious work-up procedures, especially on large scale.
  • Ri and R 2 may be the same or different and represent hydrogen or a hydroxy protecting group, in an inert solvent with a borane reducing agent in the presence of a chiral auxiliary, wherein the chiral auxiliary is (R)-2-methyl-CBS-oxazaborolidine to give a mixture of compounds of general structure Ilia and UIb,
  • a process for preparing calcipotriene comprises the following steps a. reducing a compound of general structure II,
  • Rj and R 2 may be the same or different and represent hydrogen or a hydroxy protecting group, in an inert solvent with a borane reducing agent in the presence of a chiral auxiliary, wherein the chiral auxiliary is (R)-2-methyl-CBS-oxazaborolidine to give a mixture of compounds of general structure Ilia and HIb,
  • Ilia HIb which is enriched with Ilia, wherein Ri and R 2 are as defined above. b. isolating the compound of formula-IIIa and converted to calcipotriene.
  • a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and calcipotriene obtained through the process of the present invention.
  • hydroxy protecting group is any group which forms a derivative that is stable to the projected reactions wherein said hydroxy protecting group can be selectively removed by reagents that do not attack the regenerated hydroxy group.
  • Silyl derivatives such as tert-butyldimethylsilyl forming silyl ethers are examples of hydroxy protecting groups;
  • Silyl chlorides such as tert-butyldimethylsilyl chloride (TBSCI), trimethylsilylchloride, triethylsilylchloride, diphenylmethylsilylchloride, triisopropylsilylchloride, and tert-butyldiphenylsilylchloride are examples of hydroxy protecting agents.
  • Ethers or esters are also used as hydroxy protecting groups for example ethers such as tetrahydropyranyl (THP) ether, alkoxyalkyl ethers (acetals) such as methoxymethyl (MOM) ether; esters such as chloroacetate ester, trimethylacetate, acetate or benzoate ester.
  • ethers such as tetrahydropyranyl (THP) ether, alkoxyalkyl ethers (acetals) such as methoxymethyl (MOM) ether
  • esters such as chloroacetate ester, trimethylacetate, acetate or benzoate ester.
  • borane reducing agent is a borane containing compound which is capable of enantioselectively or diastereoselectively reducing the C24 keto group of formula-II to alcohol of formula-IIIa and IHb.
  • chiral auxiliary means any chiral compound or optically active catalyst, e.g. a compound comprising asymmetrically substituted carbon atoms or axially chiral compounds, or mixtures of chiral compounds and/or optically active catalysts, which will improve the yield of a compound of general structure Ilia with respect to its epimer (increase the molar ratio IHa: IHb) in the reduction of a compound of general formula II with the reducing agent.
  • a mixture of compounds of general structure IHa and HIb 5 which is enriched with IHa means a mixture, were the molar ratio (diastereomer ratio) of IIIa/HIb is one (50: 50) or larger than one, thus that the mixture contains at least 50% of the compound of general structure HIa (containing 50% or less of the compound of general structure IHb).
  • compound of general structure Ilia means C24 (S)-hydroxy epimer of calcipotriene intermediate
  • general structure IHb means C24 (R)-hydroxy epimer of calcipotriene intermediate.
  • separating a compound means the purification and/or isolation of a compound more than 90% purity, such as at least 95% purity. It also means increasing the concentration of required isomer in a mixture of compounds.
  • the process for preparing compounds of formula-IIIa and/or HIb includes
  • Rj and R 2 may be the same or different and represent hydrogen, or a hydroxy protecting group, with a borane reducing agent in the presence of a chiral auxiliary in an inert solvent to form a compounds of Formula-IIIa and IIIb
  • Ilia IIIb wherein Ri and R 2 may be the same or different and represent hydrogen, or a hydroxy protecting group, preferably Rj and R 2 are both tert-butyl dimethyl silyl group.
  • the compound of Formula II is known in the art and can be prepared by any known method, for example, a compound of Formula II can be synthesized by the process mentioned in US 4866048 and "MJ Calverley, tetrahedron 43(20), 4609-4619, 1987, the contents of each of which are incorporated herein by reference.
  • a suitable inert solvent for use herein may be, for example any organic solvent compatible with said reducing agent under the reaction conditions employed, or mixtures of such solvents.
  • suitable inert solvents include hydrocarbons, such as toluene, xylenes and the like; and ethers, such as tert-butyl methyl ether, diisopropyl ether or tetrahydrofuran and the like and mixtures thereof; halogenated hydrocarbon solvent such as methylene chloride, ethylene chloride and the like; acetates such ethyl acetate and the like.
  • the solvent is toluene, tetrahydrofuran or mixtures thereof, preferably mixture of toluene and tetrahydrofuran.
  • the reduction reaction of a prochiral ketone is usually carried out in a temperature interval between about -50 and 5O 0 C, preferably between about -20 and 20 0 C, more preferably between about -10 and 10 0 C, most preferably between 0 and 5°C.
  • the temperature of the reduction reaction will depend on the specific reaction conditions, reagents and solvents used.
  • the reducing agent may be added to the compound of general structure II optionally dissolved or mixed with an inert solvent, e.g. under an inert atmosphere, such as nitrogen.
  • the compound of general structure II optionally dissolved or mixed with an inert solvent, may be added to the reducing agent, optionally dissolved or mixed with an inert solvent.
  • the sequence of addition of reducing agent and/or compound of general structure II is not particularly critical.
  • borane reducing agent for use herein may be, for example borane or any borane derivatives, such as borane complexes with amines or ethers.
  • borane reducing agents e.g. include but are not limited to N, N-diethylaniline-borane, borane-tetrahydrofuran, 9-borabicyclononane (9-BBN) 5 or borane dimethylsulfide.
  • the borane reducing agent is borane dimethylsulfide or N, N- diethylaniline-borane.
  • the borane reducing agent is N, N- diethylaniline-borane.
  • the "chiral auxiliary" for use herein may be, for example chiral oxazaborolidine reagents selected from but are not limited to (lR,2S)-cis-l-amino-2-indanol, (lS,2R)-cis-l- amino-2-indanol, (S)-prolinol, (R)-prolinol, B-(3-pinanyl)-9-borabicyclo [3.3.2] nonane (alpine-borane), 5,5-diphenyl-2-methyl-3,4-propano-l ,3,2-oxazaborolidine, (S)-2-methyl- CBS-oxazaborolidine, (R)-2-methyl-CBS-oxazaborolidine.
  • the chiral auxiliary is (R)-2-methyl-CBS-oxazaborolidine.
  • the reducing agent may be used about 2.0 to 3.5 mol equivalents to the starting prochiral ketone compound of formula-II, preferably 2.2 to 2.6 mol equivalents and most preferably 2.4 mol equivalents.
  • the chiral auxiliary may be present in catalytic amounts, such as substoichiometric, or equimolar or in molar excess referring to a prochiral ketone compound of formula-II.
  • the ratio of chiral auxiliary and prochiral ketone compound of formula-II may be 1 :1.5 mol equivalents, preferably 1 :1.1 mol equivalents.
  • any byproducts formed in reaction for example N,N-diethyI aniline can be removed by conventional techniques for example extraction of reaction mixture with aqueous acid solution.
  • Aqueous acids are selected from acetic acid, hydrochloric acid, hydrobromic acid and the like and mixtures thereof, preferably hydrochloric acid can be used.
  • the compound of formula-IIIa and HIb present in crude reaction mixture may be with the ratio of about 60:40, preferably with the ratio of about 65:35.
  • the separation, isolation and/or purification methods for separating Ilia and IHb include, but are not limited to solvent crystallization, distillation, chromatography method such as adsorption chromatography (including column chromatography and simulated moving bed (SMB)). The separation, isolation and purification methods may be used subsequently and in combination.
  • compounds Ilia and IHb thus obtained may be purified by dissolving the crude mixture in an organic solvent selected from the group consisting of Cj -4 alcohols, ethers and mixtures thereof to form a solution.
  • Ethers are selected but are not limited to diisopropyl ether, diethyl ether, and methyl tert-butyl ether.
  • Ci -4 alcohols are selected but are not limited to methanol, ethanol, propanol, isopropanol, and butanol.
  • the organic solvent is methanol, diisopropyl ether and mixtures thereof, most preferably the organic solvent is mixture of methanol and diisopropyl ether.
  • the solution may be heated to dissolve the compounds of general structure Ilia and IHb.
  • the temperature suitable for dissolving the compounds of general structure Ilia and IHb depends on the solvent used and the amount of the compounds of general structure IHa and IHb in the solution.
  • the compounds of general structure Ilia and IHb solution is heated at a temperature of at least about 35 0 C to about 55 0 C.
  • the solution is heated at about 40 0 C to about 50 0 C and more preferably at about 40 0 C to about 45 0 C.
  • the compound of general structure Ilia can be recovered from the solution by any known method for example concentration under vacuum to obtain the residue or cooling the resultant solution to -20 to 20 0 C, preferably from 5 to 15 0 C.
  • the resulting solid can then be filtered and washed with an organic solvent such as methanol, diisopropyl ether or mixtures thereof.
  • an organic solvent such as methanol, diisopropyl ether or mixtures thereof.
  • the isolated crystals can then be dried. If, desired repeat the purification step by one or more times to achieve the desired purity.
  • the process of the present invention advantageously provides compound Ilia in relatively high chiral purity, e.g., a purity of greater than or equal to about 90%, preferably greater than or equal to about 95%, and more preferably greater than or equal to about 97.5%.
  • compounds of general structure IHa and IHb 5 which is enriched with general structure Ilia for example having the ratio of about 97.5:2.5 may be converted into calcipotriene by any known methods, for example isomerization of general structure Ilia and when Ri and R 2 are not hydrogen, removing the hydroxyl protecting groups by reaction conditions as disclosed in US 4866048 and "MJ Calverley, tetrahedron 43(20), 4609-4619, 1987, the contents of each of which are incorporated herein by reference.
  • Example 1 Preparation of (l ⁇ ,3 ⁇ ,5E,7E,20R)-l,3-bis-(tert-butyldimethylsiloxy)-20-(- cyclopropyl-3S-hydroxy-prop-lE-enyl )-9, lO-Secopregna-5, 7, 10(19), triene (Structure HIa, wherein Ri & R 2 are tert- butyl dimethyl silyl) and (l ⁇ ,3 ⁇ ,5E,7E,20R)-l,3-bis-(tert- butyldimethylsiloxy)-20-(-cycIopropyl-3R-hydroxy-prop-lE-enyl)-9, 10-Secopregna-5, 7, 10(19), triene (Structure HIb, where in Ri & R 2 are tert- butyl dimethyl silyl).
  • the organic phase was dried with over anhydrous sodium sulfate and concentrated under vacuum at below 4O 0 C to give the oily residue of structural formula-Ilia and IHb (Ratio of HIa and HIb by HPLC purity: 65:35).
  • the obtained oily residue (mixture of Ilia and UIb) was purified by passing through short path column to remove the unwanted impurities to give the pure compound.
  • Example 2 Purification of compound formula-IIIa and HIb (where in Ri & R 2 are tert- butyl dimethyl silyl).
  • the tert-butyl dimethyl silyl protected calcipotriene was dissolved in 400 ml of Tetrahydrofuran (THF) and tetra-butyl ammonium fluoride (24 gm). The resulting mixture was heated at 60-65°C for 2 hours.. Quenched the reaction mass into 2% sodium bicarbonate solution (1200 ml) and ethyl acetate (1200 ml) and stir for 15 minutes. Separated the ethyl acetate layer and washed with water followed by organic phase was dried over sodium sulfate. Evaporating the organic phase under vacuum at below 4O 0 C to give the calcipotrien as an oily residue. The calcipotriene residue was passed through short path of column and eluted by ethyl acetate. The fractions were concentrated and crystallized from methyl formate to give pure calcipotriene.
  • THF Tetrahydrofuran

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé d'épimérisation de cétones C-24 vers l'alcool C-24 souhaité par réduction stéréosélective à l'aide d'agents réducteurs de borane chiral, en présence d'un auxiliaire chiral tel que (R)-2-méthyle-CBS-oxazaborolidine, pour la préparation d'intermédiaires du calcipotriène et leur traitement pour obtenir du calcipotriène.
PCT/IN2008/000480 2007-08-03 2008-07-30 Épimérisation par synthèse stéréosélective d'analogues de la vitamine d Ceased WO2009057136A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1507MU2007 2007-08-03
IN1507/MUM/2007 2007-08-03

Publications (2)

Publication Number Publication Date
WO2009057136A2 true WO2009057136A2 (fr) 2009-05-07
WO2009057136A3 WO2009057136A3 (fr) 2010-11-11

Family

ID=40591604

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000480 Ceased WO2009057136A2 (fr) 2007-08-03 2008-07-30 Épimérisation par synthèse stéréosélective d'analogues de la vitamine d

Country Status (1)

Country Link
WO (1) WO2009057136A2 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
US8298515B2 (en) 2005-06-01 2012-10-30 Stiefel Research Australia Pty Ltd. Vitamin formulation
CN103159657A (zh) * 2011-12-08 2013-06-19 重庆华邦胜凯制药有限公司 一种定向合成不饱和共轭醇的方法
CN103694156A (zh) * 2014-01-07 2014-04-02 成都医路康医学技术服务有限公司 一种银屑病治疗药物钙泊三醇的制备方法
CN105624215A (zh) * 2014-10-27 2016-06-01 天津金耀集团有限公司 一种卡泊三醇合成新方法
ES2674336A1 (es) * 2016-12-28 2018-06-28 Laboratorios Viñas S.A. Procedimiento para reducir derivados carbonílicos de vitamina d y uso correspondiente
CN116947912A (zh) * 2023-06-09 2023-10-27 湖北恒安芙林药业股份有限公司 一种卡泊三醇中间体的制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106188122B (zh) * 2015-05-05 2019-05-14 上海医药工业研究院 一种手性烯丙醇类化合物的差向异构化方法
CN106908524B (zh) * 2015-12-23 2021-05-04 重庆华邦胜凯制药有限公司 卡泊三醇中间体l及其潜在基因毒性杂质的分离与测定方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8362287B2 (en) * 2004-03-18 2013-01-29 Leo Pharma A/S Stereoselective synthesis of vitamin D analogues
KR20070056001A (ko) * 2004-04-02 2007-05-31 레오 파마 에이/에스 비타민 ｄ 동족체의 합성에 유용한 중간체의 신규한제조방법

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
US8298515B2 (en) 2005-06-01 2012-10-30 Stiefel Research Australia Pty Ltd. Vitamin formulation
US8629128B2 (en) 2005-06-01 2014-01-14 Stiefel West Coast, Llc Vitamin formulation
CN103159657A (zh) * 2011-12-08 2013-06-19 重庆华邦胜凯制药有限公司 一种定向合成不饱和共轭醇的方法
CN103159657B (zh) * 2011-12-08 2016-06-29 重庆华邦胜凯制药有限公司 一种定向合成不饱和共轭醇的方法
CN103694156A (zh) * 2014-01-07 2014-04-02 成都医路康医学技术服务有限公司 一种银屑病治疗药物钙泊三醇的制备方法
CN103694156B (zh) * 2014-01-07 2015-09-02 成都医路康医学技术服务有限公司 一种银屑病治疗药物钙泊三醇的制备方法
CN105624215A (zh) * 2014-10-27 2016-06-01 天津金耀集团有限公司 一种卡泊三醇合成新方法
CN105624215B (zh) * 2014-10-27 2020-10-27 天津金耀集团有限公司 一种卡泊三醇合成新方法
ES2674336A1 (es) * 2016-12-28 2018-06-28 Laboratorios Viñas S.A. Procedimiento para reducir derivados carbonílicos de vitamina d y uso correspondiente
CN116947912A (zh) * 2023-06-09 2023-10-27 湖北恒安芙林药业股份有限公司 一种卡泊三醇中间体的制备方法

Also Published As

Publication number Publication date
WO2009057136A3 (fr) 2010-11-11

Similar Documents

Publication Publication Date Title
WO2009057136A2 (fr) Épimérisation par synthèse stéréosélective d'analogues de la vitamine d
EP3383844B1 (fr) Procédé permettant la préparation de carboprost et de son sel de trométhamine
CN113754665A (zh) 一种核苷类化合物的制备方法
CN112645861A (zh) 一种分离卡前列素15位异构体的方法
US8759555B2 (en) Stereoselective synthesis of vitamin D analogues
US7205420B2 (en) Epimerization of analogs of vitamin D
EP2909225A1 (fr) Procédé de purification d'acétate d'abiratérone
US9296780B2 (en) Process for alkynylating 16-substituted-17-keto steroids
EP1730108B1 (fr) Synthese stereoselective d'analogues de vitamine d
EP1789384B1 (fr) Epimerisation d'alcools allyliques
CN115010692A (zh) 一类新颖大环内酯的设计、制备及其应用
EP4606813A1 (fr) Intermédiaire de médicament et son procédé de préparation
JP5704763B2 (ja) トランス−４−アミノシクロペンタ−２−エン−１−カルボン酸誘導体の製造
CN114685511A (zh) 一种瑞德西韦中间体的纯化方法
EP1951654B1 (fr) Procede ameliore de fabrication de phosphate d oseltamivir
ZA200100875B (en) Enantioselective synthesis
MXPA06009372A (en) Stereoselective synthesis of vitamin d analogues
HK1098122B (en) Stereoselective synthesis of vitamin d analogues
HK1254507A1 (en) Process for the preparation of carboprost and its tromethamine salt
HK1254507B (en) Process for the preparation of carboprost and its tromethamine salt
JPH11147868A (ja) １１−トランスビタミンａ類の製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08845620

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08845620

Country of ref document: EP

Kind code of ref document: A2