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WO2015051900A1 - Procédé de préparation d'entécavir au moyen de nouveaux intermédiaires - Google Patents

Procédé de préparation d'entécavir au moyen de nouveaux intermédiaires Download PDF

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Publication number
WO2015051900A1
WO2015051900A1 PCT/EP2014/002704 EP2014002704W WO2015051900A1 WO 2015051900 A1 WO2015051900 A1 WO 2015051900A1 EP 2014002704 W EP2014002704 W EP 2014002704W WO 2015051900 A1 WO2015051900 A1 WO 2015051900A1
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WIPO (PCT)
Prior art keywords
compound
formula
entecavir
preparation
hydroxyl
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/EP2014/002704
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English (en)
Inventor
Theocharis V. KOFTIS
Efstratios Neokosmidis
Efi GIOTI
Stefanos KOTOULAS
Thanos Andreou
Anastasia - Aikaterini VARVOGLI
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.)
Pharmathen SA
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Pharmathen SA
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Publication date
Application filed by Pharmathen SA filed Critical Pharmathen SA
Publication of WO2015051900A1 publication Critical patent/WO2015051900A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • 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
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the present invention relates to a novel process for the antiviral drug compound Entecavir.
  • Entecavir (Formula I) is an antiviral drug used for the treatment of chronic hepatitis B.
  • the chemical name of Entecavir is 2-amino-9-[(lS, 3R, 4S)-4-hydroxy-3- (hydroxymethyl)-2-methylidenecyclopentyl]-6,9-dihydro-3H-purin-6-one.
  • the trade name is Baraclude ® and it is marketed as monohydrate by Bristol-Myers Squibb.
  • Entecavir being a nucleoside analog, acts as an inhibitor of reverse transcription, DNA replication and transcription in the viral process.
  • Entecavir begins with the cyclopentadienyl anion.
  • the carbocyclic core is built up to the point where all the oxygen substituents are protected and then, the coupling with the guanine base is accomplished via epoxide ring opening.
  • the exocyclic methylene moiety may be formed under standard olefination conditions. The synthesis is completed with two deprotection steps.
  • This process lines up a number of well-known synthetic transformations in an efficient way to reach the suitably protected cyclopentanone, as a key intermediate.
  • What follows is an olefination reaction, coupling with a guanine derivative under Mitsunobu conditions and a two-step deprotection sequence.
  • the process suffers from low yields at these crucial steps.
  • the olefination reaction performed with the use of Nysted reagent, affords, according to the experimental data provided in said application, the exomethylene product in 35% w/w yield.
  • the Mitsunobu reaction proceeds also with a yield particularly low for a coupling reaction, namely 82% w/w.
  • the present invention encompasses a process for the preparation of compound of formula II and its use for the preparation of Entecavir (formula I).
  • the illustrated process holds a number of features suitable for industrial purposes, including high yields, efficient purification methods and reagents and conditions that are easy to use in an industrial process.
  • R ⁇ and R 2 are independently selected from hydrogen or a hydroxyl-protecting group or R ⁇ and R 2 may together form a cyclic hydroxyl- protecting group and R 3 is selected from hydrogen or a hydroxyl-protecting group.
  • the invention also provides a process for the preparation of Entecavir (Formula I) from compounds of formula II, said process comprising:
  • Entecavir is prepared according to the above process, from compound of formula II, wherein R ⁇ and R 2 are t- butyldimethylsilyl.
  • the invention also provides a process for the preparation of compound of formula
  • Rj and R 2 are independently selected from hydrogen or a hydroxyl-protecting group or Ri and R 2 may together form a cyclic hydroxyl- protecting group and R3 is selected from hydrogen or a hydroxyl-protecting group.
  • the invention further provides a process for the preparation of Entecavir (Formula I) from compounds of formula III, said process comprising: a) subjecting compound of formula III to reaction with trimethylsilylmethylmagnesium halide (TMSCH 2 MgX, wherein X is halogen) or trimethylsilylmethyl lithium, to form compound of formula IV;
  • TMSCH 2 MgX trimethylsilylmethylmagnesium halide
  • hydroxyl protecting group refers to protecting groups known in the art and exemplified such as in Greene's Protective Groups on Organic Synthesis 4 th Edition, John Wiley & Son, Peter G. M. Wuts, Theodora W. Greene, Print ISBN: 9780471697541.
  • Preferred hydroxyl protecting groups are alkyl and aryl ethers, silyl ethers, esters, carbonates, sulfonates.
  • More preferred hydroxyl protecting groups are allyl (All), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl (THP), 2,4-dinitrobenzyl, diphenylmethyl (DPM), trityl (Tr), p-methoxyphenyldiphenylmethyl (MMTr), benzyl (Bn), naphthyl (NAP), p- methoxybenzyl (PMB), p-nitrobenzyl, formyl, acyl (Ac), chloroacyl, methoxyacyl, pivaloyl (Piv), benzoyl (Bz), p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, p- phenylbenzoyl, trimethylsily
  • cyclic hydroxyl-protecting group refers, also to hydroxyl protecting groups exemplified in the textbook mentioned above.
  • Preferred cyclic hydroxyl protecting groups are cyclic acetals, cyclic ketals, cyclic ortho esters, cyclic carbonate, silyl derivatives.
  • More preferred cyclic hydroxyl-protecting group are isopropylidene, pentylidene, hexylidene, benzylidene, p-methoxybenzylidene, naphthylidene, 4- phenylbenzylidene, methoxymethylene, ethoxymethylene, cyclic carbonate, 1,3- (1,1 ,3,3-tetraisopropyl)disiloxanediyl (TIPDS).
  • TIPDS 1,3- (1,1 ,3,3-tetraisopropyl)disiloxanediyl
  • amine protecting group refers, also to protecting groups exemplified in the textbook mentioned above. Preferred amine protecting groups are carbamates, amides, N-alkyl, N-aryl, N-silyl amino and N-sulfonyl derivatives.
  • More preferred amine protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), 2,2,2-trichloroethyl carbonate (Troc), formyl, acetyl, trifluoroacetyl, benzyl (Bn), allyl (All), trityl (Tr), trimethoxyphenylmethylene, trimethylsilyl (TMS), tert-butyldimethylsilyl, (TBS), p- methoxybenzyl (PMB), p-halo-benzyl, diphenylmethyl, naphthylmethyl, benzenesulfonate, tosylate.
  • Boc tert-butoxycarbonyl
  • allyloxycarbonyl (Alloc)
  • amine base may refer to compounds of formula NR 4 R 5 R ⁇ 5, wherein R4, R 5 and 3 ⁇ 4 are selected from hydrogen, alkyl or substituted alkyl groups, aminoacids, heterocyclic bases, such as monocyclic, bicyclic or tricyclic amine bases, protected or unprotected DNA bases and their derivatives;
  • a process for the preparation of entecavir from compound of formula III characterized by an elimination reaction of compound of formula II or compound of formula IV.
  • the present invention provides a process for the preparation of compounds of formula II comprising: a) subjecting compound of formula III to reaction with trimethylsilyl methyl magnesium halide (TMSCH 2 MgX, wherein X is a halogen) or trimethylsilyl methyl lithium (TMSCH 2 Li) to form compound of formula IV;
  • TMSCH 2 MgX trimethylsilyl methyl magnesium halide
  • X is a halogen
  • TMSCH 2 Li trimethylsilyl methyl lithium
  • R l 5 R 2 and R 3 are defined as above and
  • Step a) may be performed in a polar aprotic solvent or a non-polar solvent.
  • Preferred solvents are halogenated hydrocarbons, ethers, ketones and aromatic hydrocarbons.
  • the reaction may be performed at temperatures that range from -20 °C to the boiling point of the solvent used in the reaction. Preferred temperature range is from
  • Step b) is a typical deprotection reaction. The step may be performed according to methods described in Greene's Protective Groups on Organic Synthesis 4 th Edition mentioned above.
  • Step c) is a recrystallization procedure that may be performed in an organic solvent.
  • Preferred solvents are alcohols, ketones, esters, ethers, aromatic and aliphatic hydrocarbons or mixtures thereof. More preferred solvents are methanol, ethanol, 2- propanol, dichloromethane, chloroform, tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, acetone, methyl isobutyl ketone.
  • Ri, R 2 and R 3 are representing hydroxyl protecting groups, or Ri and R 2 together form a cyclic hydroxyl protecting group and R 3 represents a hydroxyl protecting groups, wherein the hydroxyl protecting groups are preferably selected from alkyl and aryl ethers, silyl ethers, esters and carbonates.
  • More preferred hydroxyl protecting groups are allyl (All), methoxymethyl (MOM), 2- methoxyethoxymethyl (MEM), methylthiomethyl (MTM), benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl (THP), 2,4-dinitrobenzyl, diphenylmethyl (DPM), trityl (Tr), p-methoxyphenyldiphenylmethyl (MMTr), benzyl (Bn), naphthyl (NAP), p-methoxybenzyl (PMB), p-nitrobenzyl, formyl, acyl (Ac), chloroacyl, methoxyacyl, pivaloyl (Piv), benzoyl (Bz), p-nitrobenzoyl, p- methoxybenzoyl, p-bromobenzoyl, p-phenylbenzoyl, trimethylsilyl
  • hydroxyl protecting groups are allyl (All), methoxymethyl (MOM), tetrahydropyranyl (THP), diphenylmethyl (DPM), trityl (Tr), p- methoxyphenyldiphenylmethyl (MMTr), benzyl (Bn), p-methoxybenzyl (PMB), acetyl (Ac) pivaloyl (Piv), benzoyl (Bz), p-nitrobenzoyl, p-phenylbenzoyl, triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert- butyldiphenylsilyl (TBDPS).
  • Step a) may be performed in a polar aprotic solvent.
  • Preferred solvents are defined as above.
  • the reaction may be performed at temperatures that range from -20 °C to the boiling point of the solvent used in the reaction. Preferred temperature range is from
  • Step b) is a typical deprotection reaction.
  • the cleavage of the benzyl group may be achieved according to procedures described in Greene's Protective Groups on Organic Synthesis 4 th Edition.
  • Preferred conditions for this step are catalytic hydrogenation conditions. More preferred conditions are a palladium-based catalyst and a hydrogen source.
  • Step c) is a recrystallization procedure that may be performed in an organic solvent or a mixture of organic solvents, as described above.
  • Ri and R 2 are defined as above.
  • Ri and R 2 are preferably alkyl and aryl ethers, silyl ethers, esters, carbonates, or Ki and R 2 together form a cyclic hydroxyl protecting group. More preferably, Ri and R 2 are silyl ethers, esters, alkyl and aryl esters. Even more preferably, Ri and R 2 are silyl protecting groups.
  • R 1 ; R 2 and R 3 are defined as above.
  • R ⁇ and R 2 are preferably alkyl and aryl ethers, silyl ethers, esters, carbonates, or R ⁇ and R 2 together form a cyclic hydroxyl protecting group. More preferably, R ⁇ and R 2 are silyl ethers, esters, alkyl and aryl esters.
  • R 3 is preferably a hydroxyl protecting group that can be cleaved in the presence of hydroxyl protecting groups R ⁇ and R 2 .
  • Rj, R 2 and R 3 represent hydroxyl protecting groups, or Ri and R 2 together form a cyclic hydroxyl protecting group and R 3 represents a hydroxyl protecting group, wherein the hydroxyl protecting groups are selected from alkyl and aryl ethers, silyl ethers, esters, carbonates.
  • a process for the preparation of Entecavir from compound of formula II comprising: a) elimination reaction and Mitsunobu coupling with compound of formula VI, to yield compound of formula V, wherein R ⁇ and R 2 are defined as above, X may be a halogen, OH or OBn and, R and R' are independently selected from amine protecting groups or hydrogen, as defined above;
  • Step a) comprises of a Mitsunobu reaction and an elimination reaction in one chemical step.
  • the skilled person can perform this step by following procedures exemplified in prior art.
  • Mitsunobu reactions are performed in the presence of a phosphine and an azo-based compound.
  • phosphines are trialkyl and triarylphosphines and their polymer-supported analogues. More preferred phosphines are triphenylphosphine, trimethylphosphine, tributylphosphine.
  • Preferred azo-based compounds are diethylazodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD), di-t-butylazodicarboxylate, 2- (phenylazo)pyridine, di-/?-chlorobenzylazodicarboxylate (DCAD), 1,1 '- (azodicarboxyl)dipepidine.
  • DEAD diethylazodicarboxylate
  • DIAD diisopropylazodicarboxylate
  • DCAD di-t-butylazodicarboxylate
  • DCAD di-/?-chlorobenzylazodicarboxylate
  • 1,1 '- (azodicarboxyl)dipepidine 1,1 '- (azodicarboxyl)dipepidine.
  • Mitsunobu reactions are also carried out with the employment of phosphorane ylides.
  • Preferred phosphorane ylides are (cyanomethylene)trimethylphosphoran
  • Base catalyzed conditions may refer to organic or inorganic bases.
  • Organic bases may be amine bases, hydrocarbon or alkoxide alkali metal salts or alkali metal amine salts.
  • Inorganic bases may be alkali metal hydrides, alkali metal hydroxides, salts thereof or quaternary ammonium salts or non-nucleophilic bases such as silyl amides.
  • Acid catalyzed conditions may refer to strong inorganic acids, Lewis acids or organic acids. By combining the conditions required for the performance of these two reactions, step a) may be performed in a single chemical step.
  • Step b) is performed with respect to the protecting groups present on intermediate V.
  • the person skilled in the art is enabled to perform this step by referring to textbooks such as Greene's Protective Groups on Organic Synthesis 4 th Edition.
  • X is halogen
  • the conversion to the free guanine moiety involves a hydrolysis reaction under acidic conditions, which also leads to deprotection of acid labile protecting groups. More specific examples can also be found in prior art, such as WO2010074534 or EP0481754.
  • Entecavir may be prepared according to the above described process, wherein Ri and R 2 are representing hydroxyl protecting groups, or Ri and R 2 together form a cyclic hydroxyl protecting group, wherein the hydroxyl protecting groups are selected from silyl ethers, esters, alkyl and aryl ethers, carbonates.
  • Entecavir may be prepared according to the above described process, wherein R ⁇ and R 2 are t-butyldimethyl silyl, X is halogen, R is t-butoxycarbonyl (Boc) and R' is H.
  • Entecavir may be prepared according to the above described process, wherein Ri and R 2 are t-butyldimethylsilyl, X is halogen and R and R' are H.
  • step b) should be interpreted as a deprotection step with respect to all the protecting groups. It can be performed as a global deprotection step, or a suitable sequence of deprotection reactions can be selected. The person skilled in the art can perform this step according to procedures described in Greene's Protective Groups on Organic Synthesis 4 th Edition.
  • R] and R 2 are independently selected from hydrogen, hydroxyl-protecting group or Ri and R 2 may together form a cyclic hydroxyl-protecting group and R 3 is a hydroxyl protecting group.
  • Steps a)-c) may be performed as already described above. According to another aspect of the present invention there is provided a process for the preparation of entecavir, comprising the following steps:
  • Steps a)-f) may be performed as already described above.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation du composé de médicament antiviral entécavir, au moyen de nouveaux intermédiaires.
PCT/EP2014/002704 2013-10-08 2014-10-06 Procédé de préparation d'entécavir au moyen de nouveaux intermédiaires Ceased WO2015051900A1 (fr)

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EPPCT/EP2013/003016 2013-10-08
EP2013003016 2013-10-08

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037363A (zh) * 2015-07-13 2015-11-11 山东罗欣药业集团股份有限公司 一种恩替卡韦化合物的新合成方法
CN109293508A (zh) * 2018-10-30 2019-02-01 常州博海威医药科技股份有限公司 一种恩替卡韦中间体的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0481754A2 (fr) 1990-10-18 1992-04-22 E.R. Squibb & Sons, Inc. Hydroxymethyl(methylènecyclopentyl)Purines et Pyrimidines
WO2010074534A2 (fr) 2008-12-26 2010-07-01 Hanmi Pharm. Co., Ltd. Nouvel intermédiaire et procédé de préparation d'entécavir l'utilisant
WO2012006964A1 (fr) 2010-07-15 2012-01-19 台州市奥翔医药科技有限公司 Procédé de synthèse de l'entécavir et composé intermédiaire associé
CN102417506A (zh) * 2010-09-27 2012-04-18 杭州赛利药物研究所有限公司 一种抗病毒药物恩替卡韦的制备方法
EP2474548A1 (fr) * 2010-12-23 2012-07-11 Esteve Química, S.A. Procédé de préparation d'un médicament antiviral et ses intermédiaires

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0481754A2 (fr) 1990-10-18 1992-04-22 E.R. Squibb & Sons, Inc. Hydroxymethyl(methylènecyclopentyl)Purines et Pyrimidines
WO2010074534A2 (fr) 2008-12-26 2010-07-01 Hanmi Pharm. Co., Ltd. Nouvel intermédiaire et procédé de préparation d'entécavir l'utilisant
WO2012006964A1 (fr) 2010-07-15 2012-01-19 台州市奥翔医药科技有限公司 Procédé de synthèse de l'entécavir et composé intermédiaire associé
EP2594569A1 (fr) * 2010-07-15 2013-05-22 Zhejiang Ausun Pharmaceutical Co., Ltd. Procédé de synthèse de l'entécavir et composé intermédiaire associé
CN102417506A (zh) * 2010-09-27 2012-04-18 杭州赛利药物研究所有限公司 一种抗病毒药物恩替卡韦的制备方法
EP2474548A1 (fr) * 2010-12-23 2012-07-11 Esteve Química, S.A. Procédé de préparation d'un médicament antiviral et ses intermédiaires

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CHEM. SOC. REV., vol. 31, 2003, pages 195
CHEMICAL REVIEWS, vol. 109, 2009, pages 2551
JOSE L. CHIARA ET AL.: "1-Silyl-2,6 diketones: Versatile intermediates for the divergent synthesis of five- and six-membered carbocycles under radical and anionic conditions", ORGANIC LETTERS, vol. 8, no. 18, 8 August 2006 (2006-08-08), USAMERICAN CHEMICAL SOCIETY, pages 3935 - 3938, XP002734623, ISSN: 1523-7060 *
ORG. REACTIONS, vol. 38, 1990, pages 1
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037363A (zh) * 2015-07-13 2015-11-11 山东罗欣药业集团股份有限公司 一种恩替卡韦化合物的新合成方法
CN109293508A (zh) * 2018-10-30 2019-02-01 常州博海威医药科技股份有限公司 一种恩替卡韦中间体的制备方法
CN109293508B (zh) * 2018-10-30 2021-01-22 常州博海威医药科技股份有限公司 一种恩替卡韦中间体的制备方法

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