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WO2011095990A2 - Procédé pour la purification de prostaglandines et analogues de celles-ci - Google Patents

Procédé pour la purification de prostaglandines et analogues de celles-ci Download PDF

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Publication number
WO2011095990A2
WO2011095990A2 PCT/IN2011/000076 IN2011000076W WO2011095990A2 WO 2011095990 A2 WO2011095990 A2 WO 2011095990A2 IN 2011000076 W IN2011000076 W IN 2011000076W WO 2011095990 A2 WO2011095990 A2 WO 2011095990A2
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WO
WIPO (PCT)
Prior art keywords
prostaglandins
water
purification process
formula
purification
Prior art date
Application number
PCT/IN2011/000076
Other languages
English (en)
Other versions
WO2011095990A3 (fr
Inventor
Mohan Anand Chandavarkar
Ramakrishnan Ramachandran Iyer
Vikas Vasant Nawathye
Gajanan Jalindar Chavan
Sandeep Laxman Nawale
Original Assignee
Fdc Limited
Chachad, Kalpesh, Chintamani
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 Fdc Limited, Chachad, Kalpesh, Chintamani filed Critical Fdc Limited
Publication of WO2011095990A2 publication Critical patent/WO2011095990A2/fr
Publication of WO2011095990A3 publication Critical patent/WO2011095990A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a process for purification of prostaglandins of formula 1 into enantiomerically pure isomer of formula 2 by reverse phase preparative HPLC, and converting said isomer into prostaglandin derivatives of formula 3.
  • Prostaglandin derivatives in this invention relates to PGF 2a analogues.
  • R ⁇ is selected from benzyl or phenoxy group substituted with alkyl, halo or haloalkyl
  • R 2 is selected from branched or linear chain alkoxy and alkylamino, preferably R 2 is selected from group consisting of Ci to C 6 alkoxy groups and C ⁇ to C 6 alkylamino and represents either single or double bond.
  • Prostaglandin! ⁇ (PGF 2a ) is known to be a very potent vasoconstrictor and oxytoxic agent.
  • a prostaglandin is a member of a group of lipid compounds which are derived enzymatically from fatty acids and have important functions in the animal body.
  • Prostaglandin is characterized by the substituents on the cyclopentyl ring. They are mediators and have a variety of strong physiological effects, such as regulating the contraction and relaxation of smooth muscle tissue.
  • Prostaglandin analogues such as Latanoprost, Bimatoprost and Travoprost have been used in the management of open-angle glaucoma. They reduce intra-ocular pressure by enhancing uveoscleral outflow, and may also have some effect on the trabecular meshwork as well.
  • US 5422368 discloses preparation of prostaglandins and their analogues by oxidation of protected-Corey lactone, followed by Emmons condensation reaction, reduction, deprotection, DIBAL reduction, Wittig reaction and esterification. Further, prostaglandins were purified by column chromatography on silica gel-60 using ethyl acetate as eluant.
  • US 7498458 discloses process for the synthesis and purification of prostaglandins and analogues especially analogues of PGF 2a .
  • the synthesis of prostaglandin analogues involves oxidation of protected-Corey lactone, followed by modified Homer- Wadsworth- Emmons reaction to yield the desired enone. Reduction followed by deprotection, and hydrogenation gives the corresponding diol which is protected as its silyl ether. Reduction of the lactone along with Wittig reaction, esterification and deprotection provided the desired Latanoprost
  • This patent specifically discloses purification of Latanoprost by normal phase HPLC.
  • US 7166730 discloses process for the preparation of prostaglandins wherein it involves stereoselective reduction of the carbonyl group of a substituted Corey lactone followed by isolation. The undesired isomer formed during the reduction was oxidized back to the substituted Corey lactone. The desired isomer was further processed to form respective prostaglandin derivative, where the penultimate intermediate of prostaglandin derivative was purified by column chromatography on silica gel.
  • US 3962312 discloses purification of 9a-hydroxy-l l a, 15 a-ditetrahydropyranyloxy- prost-cis-5-enoic acid by column chromatography on silica gel.
  • US 6689901 discloses preparation of 15(S)-prostaglandin intermediates by contacting corresponding enone with (-)-chlorodiisopinocampheylborane at -50 to 0°C, followed by reacting with a boron complexing agent.
  • the said intermediate is used to prepare Latanoprost that is purified by column chromatography on silica gel.
  • EP1891005 discloses process for preparation of prostaglandins especially Latanoprost, by anion generation from sulfone, followed by alkylation, reductive desulfonation, hydroxyl group deprotection, conversion and esterification.
  • Latanoprost was purified by chromatography on LiChroprep column, followed by preparative HPLC.
  • the present invention provides a process for purification of penultimate intermediate of prostaglandin derivative by reverse phase preparative HPLC that reduces the purification time by providing easy separation of impurities of the prostaglandins.
  • the primary objective of the present invention is to provide a process for purification of prostaglandins of formula 1 using reverse phase preparative HPLC.
  • Another objective of the present invention is to provide a process for purification of prostaglandins of formula 1 using inexpensive and non-hazardous eluant system, which will not only make the purification process cost effective, but will also increase the efficiency of purification.
  • Yet another objective of the present invention is to provide easy and excellent separation of prostaglandins from undesired trans-impurity.
  • the present invention discloses a process for purification, of prostaglandins of formula 1 into enantiomerically pure isomer of formula 2 by reverse phase preparative HPLC, and converting said isomer into prostaglandin derivative of formula 3.
  • the prostaglandin derivative in this invention relates to PGF 2a analogues.
  • Ri is selected from benzyl or phenoxy group substituted with alkyl, halo or haloalkyl
  • R 2 is selected from branched or linear chain alkoxy and alkylamino, preferably R 2 is selected from a group consisting to C 6 alkoxy groups and Ci to C 6 alkylamino and represents either single or double bond.
  • RP-HPLC refers to reverse phase HPLC, which is a well developed method for separating substances on the basis of hydrophobicity.
  • NP-HPLC normal phase
  • RP-HPLC reverse-phase
  • polarities of the stationary and mobile phases are reversed, allowing only hydrophobic interactions with the analytes.
  • Polar analytes elute first followed by non-polar.
  • hydrophobic packings such as octadecyl- or octylsilane phases bonded to silica or neutral polymeric beads are used, and the mobile phase used is usually water and a water-miscible organic solvent.
  • the present invention provides the process for purification of prostaglandins of formula 1 into enantiomerically pure isomer of formula 2 by RP-HPLC (reverse phase preparative HPLC), and converting the said isomers into prostaglandin derivative of formula 3.
  • Prostaglandin derivatives in this invention relate to PGF 2a analogues including Latanoprost, Travoprost and Bimatoprost. To illustrate the process of the invention, the detailed description is provided herein as depicted below in Scheme 1.
  • R ⁇ is selected from benzyl or phenoxy group substituted with alkyl, halo or haloalkyl
  • R 2 is selected from branched or linear chain alkoxy and alkylamino, preferably R 2 is selected from group consisting of Q to C 6 alkoxy groups and Q to C 6 alkylamino; and represents single or double bond.
  • Starting prostaglandin of formula 1 is riot only racemic at 15-position but also has 5-trans as a geometrical isomeric impurity present in it. This prostaglandin is produced by general processes known in the art.
  • the present invention discloses purification process " of penultimate intermediate of prostaglandin derivatives using reverse phase HPLC in order to separate the undesired trans-impurity from the desired prostaglandin.
  • the reverse phase HPLC is performed using a non-chiral preparative HPLC column and an eluant system.
  • the non-chiral preparative HPLC column is selected from C4, C8 and CI 8 columns and the eluant system comprises a mixture of inexpensive and non- hazardous solvents out of which one solvent is water whose pH has been adjusted between 2.0-5.0 using trifluoro acetic acid.
  • the water as used above is selected from plain water, 0.0 IM ammonium formate in water, 0.0 IM ammonium acetate in water or 0.01M D-tartaric acid in water, whose pH has been adjusted between 2.0-5.0 using trifluoro acetic acid.
  • 'water' is referred to as 'water whose pH has been adjusted between 2.0-5.0 using trifluoro acetic acid'.
  • the water as used above is selected from plain water, 0.0 IM ammonium formate in water, 0.0 IM ammonium acetate in water or 0.0 IM D-tartaric acid in water.
  • the eluant system comprises of water and at least one organic solvent selected from acetonitrile, alcohol and THF.
  • the said alcohol is selected from a group consisting of methanol, ethanol, propan-l-ol, propan-2-ol, butan-l-ol, butan-2-ol, tert-butanol, 3-methyl-l-butanoI, 2-methyl-l- propanol, 2-methoxyethanoI and 2-ethoxyethanol.
  • the ratio of water in the mobile phase of the eluant system ranges from 30% to 80% and the ratio of other solvent (s) ranges from 18% to 70%.
  • substantially free of the undesired trans-isomer refers to less than 1%, preferably less than 0.5%, more preferably less than 0.3% and even more preferably less than 0.2% of the trans-isomer impurity.
  • the desired cis-isomer is greater than 98.5 %.
  • the trans-isomer impurity is less than 0.5 %.
  • prostaglandin of formula 2 as obtained according to the process of present invention is converted into corresponding prostaglandin derivative of formula 3 by processes known in the prior art.
  • HPLC separation of Latanoprost acid was carried out using a C-18 column.
  • the isocratic eluant system comprises of water (adjusted with trifluoro acetic acid to a pH of 3): acetonitrile : ethanol in the volume percent ratio of 65% : 30% : 5%.
  • HPLC separation of Latanoprost acid was carried out using a C-18 column.
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 3) : acetonitrile : isopropanol in the volume percent ratios of 65%: 30%: 5%.
  • HPLC separation of Latanoprost acid was carried out using a C-18 column.
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 3) : acetonitrile : tetrahydrofuran in the volume percent ratios of 65%: 30%: 5%.
  • HPLC separation of Latanoprost acid was carried out using a C-18 column.
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 3) : acetonitrile in the volume percent ratios of 65%: 35%
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 3) : isopropanol in the volume percent ratios of 70%:30%
  • HPLC separation of Latanoprost acid was carried out using a C-18 column.
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 2): acetonitrile : ethanol in the volume percent ratios of 65%: 30%: 5%.
  • HPLC separation of Latanoprost acid was carried out using a C-18 column.
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 5): acetonitrile : ethanol in the volume percent ratios of 65%: 30%: 5%.
  • HPLC separation of Latanoprost acid was carried out using a C-18 column.
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 3): acetonitrile : tetrahydrofuran : isopropanol in the volume percent ratios of 70%: 10%: 15%: 5%.
  • HPLC separation of Latanoprost acid was carried out using a C-8 column.
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 3):acetonitrile : ethanol : isopropanol in the volume percent ratios of 60%: 30%: 5%: 5%.
  • HPLC separation of Latanoprost acid was carried out using a C-4 column.
  • the isocratic eluant system comprises water (adjusted with trifluoro acetic acid to a pH of 3): acetonitrile : ethanol in the volume percent ratios of 65%: 30%: 5%.
  • HPLC separation of Latanoprost acid was carried out using a C-18 column.
  • the isocratic eluant system comprises 0.01 M ammonium formate in water (adjusted with trifluoro acetic acid to a pH of 3) : acetonitrile : ethanol in the volume percent ratios of 65%: 30%: 5%
  • the pure Lantanoprost acid thus obtained is converted into Lantanoprost by conventional methods.
  • the other prostaglandins of formula I such as Travoprost acid and Bimatoprost acids are purified by adopting the reverse phase preparative HPLC by employing the non-chiral columns and eluent systems as exemplified above to obtain desired cis-isomers that are substantially free from its 'trans-isomer'. These acids are subsequently converted into Travoprost and Bimatoprost.

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

Abstract

La présente invention concerne un procédé pour la purification de prostaglandines de formule (1) en isomère énantiomériquement pur de formule (2) par CLHP préparative en phase inverse, et la conversion dudit isomère en dérivé de prostaglandine de formule (3). Le dérivé de prostaglandine dans cette invention est apparenté à des analogues de PGF2α.
PCT/IN2011/000076 2010-02-03 2011-02-02 Procédé pour la purification de prostaglandines et analogues de celles-ci WO2011095990A2 (fr)

Applications Claiming Priority (2)

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IN283/MUM/2010 2010-02-03
IN283MU2010 2010-02-03

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WO2011095990A2 true WO2011095990A2 (fr) 2011-08-11
WO2011095990A3 WO2011095990A3 (fr) 2012-01-12

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103543216A (zh) * 2012-07-17 2014-01-29 上海信谊药厂有限公司 拉坦前列素滴眼液中杂质测定的方法
CN103588692A (zh) * 2012-08-15 2014-02-19 台湾永光化学工业股份有限公司 使用制备型高效液相层析仪纯化含氟的前列腺素的方法
CN104297352A (zh) * 2013-07-16 2015-01-21 天津金耀集团有限公司 一种曲伏前列素含量及有关物质的分析方法
WO2015136317A1 (fr) 2014-03-13 2015-09-17 CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. Nouveau procédé pour la préparation de prostaglandines de haute pureté
US20160016883A1 (en) * 2013-08-15 2016-01-21 Chirogate International Inc. Processes and intermediates for the preparations of isomer free prostaglandins
CN112209863A (zh) * 2020-07-07 2021-01-12 浙江尖峰药业有限公司 一种他氟前列素规模化制备的方法
WO2022138586A1 (fr) 2020-12-23 2022-06-30 協和ファーマケミカル株式会社 Procédé de séparation d'isomère géométrique

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3962312A (en) 1972-09-21 1976-06-08 Ono Pharmaceutical Company 9,11,15-Trihydroxy prost-5-enoic acid analogues
US5422368A (en) 1988-09-06 1995-06-06 Kabi Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US6689901B2 (en) 2001-07-17 2004-02-10 Pharmacia & Upjohn Company Process and intermediates to prepare latanoprost
US7166730B2 (en) 2000-01-27 2007-01-23 Fine Tech Laboratories, Ltd Process for the preparation of prostaglandin derivatives
EP1891005A2 (fr) 2005-04-18 2008-02-27 Instytut Farmaceutyczny Procede de preparation de derives de 13,14-dihydro-pgf2 alpha
US7498458B2 (en) 2001-05-24 2009-03-03 Resolution Chemicals Limited Process for the preparation of prostaglandins and analogues thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1990450A (zh) * 2005-12-30 2007-07-04 明德国际仓储贸易(上海)有限公司 前列腺素f型衍生物的制造方法及新颖中间体
US20100041912A1 (en) * 2007-01-05 2010-02-18 Astra Zeneca Method for the wittig reaction in the preparation of carboprost

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3962312A (en) 1972-09-21 1976-06-08 Ono Pharmaceutical Company 9,11,15-Trihydroxy prost-5-enoic acid analogues
US5422368A (en) 1988-09-06 1995-06-06 Kabi Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US7166730B2 (en) 2000-01-27 2007-01-23 Fine Tech Laboratories, Ltd Process for the preparation of prostaglandin derivatives
US7498458B2 (en) 2001-05-24 2009-03-03 Resolution Chemicals Limited Process for the preparation of prostaglandins and analogues thereof
US6689901B2 (en) 2001-07-17 2004-02-10 Pharmacia & Upjohn Company Process and intermediates to prepare latanoprost
EP1891005A2 (fr) 2005-04-18 2008-02-27 Instytut Farmaceutyczny Procede de preparation de derives de 13,14-dihydro-pgf2 alpha

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103543216A (zh) * 2012-07-17 2014-01-29 上海信谊药厂有限公司 拉坦前列素滴眼液中杂质测定的方法
CN103588692A (zh) * 2012-08-15 2014-02-19 台湾永光化学工业股份有限公司 使用制备型高效液相层析仪纯化含氟的前列腺素的方法
CN104297352A (zh) * 2013-07-16 2015-01-21 天津金耀集团有限公司 一种曲伏前列素含量及有关物质的分析方法
JP2020164527A (ja) * 2013-08-15 2020-10-08 チャイロゲート インターナショナル インク．Ｃｈｉｒｏｇａｔｅ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃ． 異性体を含まないプロスタグランジンを製造するための方法及び中間体
US20160016883A1 (en) * 2013-08-15 2016-01-21 Chirogate International Inc. Processes and intermediates for the preparations of isomer free prostaglandins
JP2016193930A (ja) * 2013-08-15 2016-11-17 チャイロゲート インターナショナル インク．Ｃｈｉｒｏｇａｔｅ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃ． 異性体を含まないプロスタグランジンを製造するための方法及び中間体
US9994543B2 (en) * 2013-08-15 2018-06-12 Chirogate International Inc. Processes and intermediates for the preparations of isomer free prostaglandins
CN106103409A (zh) * 2014-03-13 2016-11-09 奇诺因药物和化学工厂私人有限公司 用于制备高纯度前列腺素类的新颖方法
US10501410B2 (en) 2014-03-13 2019-12-10 CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. Pocess for the preparation of high purity prostaglandins
WO2015136317A1 (fr) 2014-03-13 2015-09-17 CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. Nouveau procédé pour la préparation de prostaglandines de haute pureté
CN112209863A (zh) * 2020-07-07 2021-01-12 浙江尖峰药业有限公司 一种他氟前列素规模化制备的方法
WO2022138586A1 (fr) 2020-12-23 2022-06-30 協和ファーマケミカル株式会社 Procédé de séparation d'isomère géométrique
CN116583500A (zh) * 2020-12-23 2023-08-11 协和医药化工股份有限公司 几何异构体的分离方法
EP4261206A4 (fr) * 2020-12-23 2024-10-30 Kyowa Pharma Chemical Co., Ltd. Procédé de séparation d'isomère géométrique

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