WO2017118928A1 - Procédé servant à la séparation de diastéréomères de ténofovir alafénamide - Google Patents

Procédé servant à la séparation de diastéréomères de ténofovir alafénamide Download PDF

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Publication number
WO2017118928A1
WO2017118928A1 PCT/IB2017/050032 IB2017050032W WO2017118928A1 WO 2017118928 A1 WO2017118928 A1 WO 2017118928A1 IB 2017050032 W IB2017050032 W IB 2017050032W WO 2017118928 A1 WO2017118928 A1 WO 2017118928A1
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ethyl
solution
adenine
propyl
isopropoxycarbonyl
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Ceased
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PCT/IB2017/050032
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WO2017118928A9 (fr
Inventor
Dinesh Dnyaneswar DIXIT
Manoj Kunjabihari AGARWAL
Narotham Venkata Maddireddy
Himanshu Madhav Godbole
Girij Pal Singh
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Lupin Ltd
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Lupin Ltd
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Publication of WO2017118928A9 publication Critical patent/WO2017118928A9/fr
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    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention is relates to an effective process for the separation of diastereomers of Tenofovir alafenamide or its intermediate.
  • the process comprises the steps of resolving a Tenofovir alafenamide or its intermediate raceme by taking Proline or Phenylalanine compound as a resolving agent to obtain a diastereomeric salt; separation of isomers and desaltification of salt to obtain diastereomerically pure Tenofovir alafenamide or its intermediate.
  • the preparation process of diastereomerically pure Tenofovir alafenamide or its intermediate is simple and feasible to operate and cheap in required reagent; the resolving agent is easily available and non-toxic and easy to recycle; the preparation process is applicable to industrial production. Background of the invention:
  • Tenofovir alafenamide is chemically known as 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl]adenine, an isopropylalaninyl monoamidate phenyl monoester prodrug of tenofovir.
  • Tenofovir alafenamide has the structure shown in Formula-I:
  • PCT Publication No. WO2002008241 which is hereby incorporated by reference, discloses prodrugs of phosphonate nucleotide analogues, including tenofovir alafenamide, as well as methods for diasteriomeric separation by the use of chromatography.
  • the chromatography techniques described are batch elution chromatography, simulated bed chromatography.
  • WO2013052094 describes crystallization techniques for the diastereomeric separation of 9-[(R)-2-[[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]- phenoxyphosphinyl] methoxy] propyl] adenine to give 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy]propyl] adenine.
  • chiral resolving agents Numerous chiral resolving agents have been available and are known. However, as mentioned previously, useful chiral resolving agents for crystallization on an industrial scale have particular requirements. For example, they should be relatively inexpensive and of a high state of optical purity. They should react easily with the desired target enantiomer and form a diastereomeric complex with physical properties sufficiently different from other associative complexes in the solution so as to precipitate relatively exclusively, and in a state free from the other associative complexes. Precipitation in such degree of relative exclusivity is necessary in order to achieve a high degree of optical purity of the enantiomeric target compound. Additionally, good resolving agents should be recyclable, that is, recoverable from the solution in significant quantitative yield.
  • the present invention thus provides a simple, effective and industrial feasible process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine or its intermediate. Summary of the invention:
  • the present invention relates to a process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]- phenoxyphosphinyl] methoxy] propyl] adenine.
  • the present invention relates to a process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]- phenoxyphosphinyl] methoxy] propyl] adenine by using a Proline compound as a resolving agent.
  • the present invention relates to a process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]- phenoxyphosphinyl] methoxy] propyl] adenine by using a Phenylalanine compound as a resolving agent.
  • the present invention relates to a process for the separation of diastereomers of intermediate compound of formula II by using Proline or Phenylalanine compounds as resolving agents.
  • the notation OR indicates a bond which protrudes back from the plane of the paper; the notation " OR " indicates a bond which protrudes forward from the plane of the paper; and the notation TM " OR ⁇ indicates a bond for which the stereochemistry is not designated (a racemic).
  • chiral resolving agent or “optically active resolving agent” refers to either the dextro or levo rotatory optical isomer of the following compounds: Proline and Phenylalanine i.e., D or L- isomer.
  • salt or “diastereomeric salt” has the general meaning imputed to the term by the art. For example, it can refer to the associative complex which results when the anionic element of an acidic chiral resolving agent associates with the cationic portion of the desired enantiomer of a basic racemic target compound (enantiomer) which results from one or more points of interaction due to one or more weak attractive forces.
  • the present invention provides a preparation of 9-[(R)-2-[[(S)- [ [(S)- 1 - (isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy]propyl] adenine comprising the steps of:
  • step (b) heating the solution of step (a) to an elevated temperature to form a solution of a diastereomeric salt of the optically active resolving agent and 9-[(R)-2-[[(R,S)- [ [(S)- 1 -(isopropoxycarbonyl)ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine;
  • step (b) cooling the solution from step (b) for a period of time to precipitate the diastereomeric salt
  • step (b) heating the solution of step (a) to an elevated temperature to form a solution of a diastereomeric salt of the optically active resolving agent and the 9-[(R)-2- [[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy] propyl] adenine;
  • step (b) cooling the solution from step (b) for a period of time to precipitate the diastereomeric salt
  • step a) of a process of the present invention a diastereomeric salt of 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl] adenine with L- Proline or L- Phenylalanine is obtained in a solid form, while the filtrate contains the other diastereomer (RRS) salt.
  • a diastereomeric salt of 9-[(R)-2-[[(R)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine with D- Proline or D-Phenylalanine is obtained in a solid form, while the filtrate contains the other diastereomer (RSS) salt.
  • the starting material used in the first step (step a), 9-[(R)-2-[[(R,S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine can be taken from previous reaction step as an in-situ or as an isolated form.
  • the "suitable organic solvent” refers to any polar organic solvent in which the interactive complex formed between the chiral resolving agent and the compound. Exemplary the organic solvent selected from but not limited to methanol, ethanol, ethyl acetate, acetone, 2-butanone, acetonitrile, dioxane or mixtures thereof.
  • the "elevated temperature" facilitating formation of the interactive complex may be any temperature at which the complex is soluble, but is typically in the range of about 50° C. to about 100° C. When the organic solvent is ethyl acetate the range is about 65° C. to about 70° C.
  • the temperature to which the solution is cooled can be any temperature lower than the temperature at which the interactive complex begins to precipitate, but is typically between -20° C. and 45° C. Preferably, it is -10° C. to 35° C. and most preferably it is 5° C. to 30° C.
  • the period of time for which the solution is cooled is a time period sufficient for the diastereomeric salt in the solution to precipitate. It can vary depending upon temperature and degree of agitation during the crystallization period.
  • the filtrate is further treated in order to recover the diastereomer which was not previously removed by precipitation.
  • the further treatment involves the conversion of the salt in the filtrate to its base using ammonia, or other similar bases, in water, followed by extraction and isolation of the base.
  • (isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine may be converted to the corresponding salt by reacting with a suitable acid, such as fumaric acid, lactic acid, malic acid, succinic acid, malonic acid, oxalic acid and the like.
  • a suitable acid such as fumaric acid, lactic acid, malic acid, succinic acid, malonic acid, oxalic acid and the like.
  • the acid used is fumaric acid.
  • a pharmaceutical composition comprising 9- [(R)-2- [ [(R)- [[(S)- 1 -(isopropoxycarbonyl)ethyl] amino]phenoxy- phosphinyljmethoxy] propyl] adenine or a pharmaceutically acceptable salt thereof OR 9- [(R)-2- [[(S)- [ [(S)- 1 - (isopropoxycarbonyl)ethyl] amino]phenoxyphosphinyl] methoxy] propyl] adenine or a pharmaceutically acceptable salt thereof, prepared according to the process of the present invention, and one or more pharmaceutically acceptable excipients.
  • the present invention provides for the preparation of an intermediate compound of formula III comprising the steps of:
  • step b) heating the solution from step a) to an elevated temperature to form a solution of a diastereomeric salt of the optically active resolving agent and the compound of formula II;
  • step c) cooling the solution from step b) for a period of time to precipitate the diastereomeric salt
  • step b) heating the solution from step a) to an elevated temperature to form a solution of a diastereomeric salt of the optically active resolving agent and the compound of formula
  • step c) cooling the solution from step b) for a period of time to precipitate the diastereomeric salt
  • suitable organic solvent refers to any polar organic solvent in which the interactive complex formed between the chiral resolving agent and the compound.
  • organic solvent selected from but not limited to methanol, ethanol, ethyl acetate, acetone, 2-butanone, acetonitrile, dioxane or mixtures thereof.
  • reaction mixture was heated to 25-30°C and washed with 20% aq. sodium dihydrogenphosphate solution (5 L) at 25 °C. Stirred the reaction mass and separated the layers. The organic layer was distilled under vacuum. Ethyl acetate (5000 ml) and L-Proline (0.31 kg) was added to the residue, contents heated to 65- 70°C, cooled and filtered to obtain 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy] propyl] adenine L- Proline.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé et des sels diastéréomères qui permettent la résolution optique de la 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)éthyl]amino]-phénoxyphosphinyl] méthoxy]propyl]adénine et les intermédiaires correspondants. Le procédé consiste à placer en solution un agent de résolution chiral, soit L/D-Proline soit L/D-Phénylalanine, à précipiter le sel diastéréoisomère obtenu entre l'agent de résolution chiral et l'énantiomère cible et à séparer l'énantiomère.
PCT/IB2017/050032 2016-01-06 2017-01-05 Procédé servant à la séparation de diastéréomères de ténofovir alafénamide Ceased WO2017118928A1 (fr)

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IN201621000509 2016-01-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107522743A (zh) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 一种半富马酸替诺福韦艾拉酚胺工业化连续生产方法
CN110283208A (zh) * 2018-06-22 2019-09-27 南京济群医药科技股份有限公司 一种替诺福韦艾拉酚胺的手性拆分方法
CN111189947A (zh) * 2020-03-30 2020-05-22 济南新科医药科技有限公司 一种分离检测富马酸丙酚替诺福韦异构体的分析方法
CN114804989A (zh) * 2022-05-06 2022-07-29 华中科技大学 卡巴拉汀关键手性中间体的纯化方法与外消旋化回收利用

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WO2002008241A2 (fr) 2000-07-21 2002-01-31 Gilead Sciences, Inc. Promedicaments a base d"analogues nucleotidiques de phosphonate et leurs methodes de selection et d"elaboration
WO2013052094A2 (fr) 2011-10-07 2013-04-11 Gilead Sciences, Inc. Procédés de préparation d'analogues de nucléotides antiviraux
WO2014195724A1 (fr) 2013-06-07 2014-12-11 Cipla Limited Procédé efficace pour séparer les diastéréomères de la 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)éthyl]amino]phénoxyphosphinyl]méthoxy]propyl]-adénine
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WO2002008241A2 (fr) 2000-07-21 2002-01-31 Gilead Sciences, Inc. Promedicaments a base d"analogues nucleotidiques de phosphonate et leurs methodes de selection et d"elaboration
WO2013052094A2 (fr) 2011-10-07 2013-04-11 Gilead Sciences, Inc. Procédés de préparation d'analogues de nucléotides antiviraux
WO2014195724A1 (fr) 2013-06-07 2014-12-11 Cipla Limited Procédé efficace pour séparer les diastéréomères de la 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)éthyl]amino]phénoxyphosphinyl]méthoxy]propyl]-adénine
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RALPH STEPHANI ET AL: "In the Laboratory Resolution of Racemic Phenylsuccinic Acid Using (-)-Proline as a Resolving Agent An Introductory Organic Chemistry Experiment", JOURNAL OF CHEMICAL EDUCATION @BULLET, vol. 74, no. 10, 1 October 1997 (1997-10-01), pages 1226, XP055371127 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107522743A (zh) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 一种半富马酸替诺福韦艾拉酚胺工业化连续生产方法
CN110283208A (zh) * 2018-06-22 2019-09-27 南京济群医药科技股份有限公司 一种替诺福韦艾拉酚胺的手性拆分方法
CN110283208B (zh) * 2018-06-22 2022-07-08 南京济群医药科技股份有限公司 一种替诺福韦艾拉酚胺的手性拆分方法
CN111189947A (zh) * 2020-03-30 2020-05-22 济南新科医药科技有限公司 一种分离检测富马酸丙酚替诺福韦异构体的分析方法
CN111189947B (zh) * 2020-03-30 2022-06-17 济南新科医药科技有限公司 一种分离检测富马酸丙酚替诺福韦异构体的分析方法
CN114804989A (zh) * 2022-05-06 2022-07-29 华中科技大学 卡巴拉汀关键手性中间体的纯化方法与外消旋化回收利用
CN114804989B (zh) * 2022-05-06 2023-12-26 华中科技大学 卡巴拉汀关键手性中间体的纯化方法与外消旋化回收利用

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