WO2016202232A1 - Procédé de synthèse dun sel d'amine de (4s)-n-boc-4-méthoxy méthyl-l-proline - Google Patents

Procédé de synthèse dun sel d'amine de (4s)-n-boc-4-méthoxy méthyl-l-proline Download PDF

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Publication number
WO2016202232A1
WO2016202232A1 PCT/CN2016/085661 CN2016085661W WO2016202232A1 WO 2016202232 A1 WO2016202232 A1 WO 2016202232A1 CN 2016085661 W CN2016085661 W CN 2016085661W WO 2016202232 A1 WO2016202232 A1 WO 2016202232A1
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WO
WIPO (PCT)
Prior art keywords
boc
amine salt
methoxymethyl
carboxylic acid
proline
Prior art date
Application number
PCT/CN2016/085661
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English (en)
Chinese (zh)
Inventor
林文清
朱剑平
刘小波
郑宏杰
Original Assignee
重庆博腾制药科技股份有限公司
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
Priority claimed from CN201610383150.4A external-priority patent/CN106256819B/zh
Application filed by 重庆博腾制药科技股份有限公司 filed Critical 重庆博腾制药科技股份有限公司
Publication of WO2016202232A1 publication Critical patent/WO2016202232A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to the technical field of medicine, in particular to a method for synthesizing a (4S)-N-Boc-4-methoxymethyl-L-proline amine salt.
  • Hepatitis C virus referred to as hepatitis C and hepatitis C
  • HCV Hepatitis C Virus
  • hepatitis C is still antiviral.
  • the anti-hepatitis drugs on the market are treated with polydiethanol interferon (PEN-IFN) and ribavirin; HCV NS3-4A protease inhibitors (Telaprevir, Boceprevir, Simeprevir HCV NS5A protease inhibitor (Daclatasvir); nucleoside polymerase inhibitor (sofosbuvir), non-nucleoside polymerase inhibitor, gene therapy, and the like.
  • PEN-IFN polydiethanol interferon
  • ribavirin HCV NS3-4A protease inhibitors
  • HCV NS3-4A protease inhibitors Telaprevir, Boceprevir, Simeprevir HCV NS5A protease inhibitor (Daclatasvir
  • nucleoside polymerase inhibitor sofosbuvir
  • non-nucleoside polymerase inhibitor gene therapy, and the like.
  • Newly marketed antiviral drugs are generally more expensive, such as Sofosbuvir for a 12-week course at $84,000 (in the US, 28-piece/bottle Sovaldi wholesaler (WAC) costs are $28,000, per At $1,000, most patients require 12 weeks of treatment and the total cost will be $84,000. This price is unaffordable for most low-income patients. Therefore, the development of drugs with high efficiency, low toxicity, long-lasting efficacy and low price has far-reaching social significance.
  • WAC 28-piece/bottle Sovaldi wholesaler
  • GS-5816 (4S)-N-Boc-4-methoxymethyl-L-proline or salt is an important intermediate of anti-hepatitis C drug GS-5816 developed by Gilead Company of the United States.
  • GS-5816 is a class of NS5A protease inhibitors and is currently in Phase 2 clinical trials. The drug has been used in Phase III clinical trials in combination with PSI-7977 (Sofosbuvir) to treat gene type 1-6 and is expected to be available in 2016.
  • PSI-7977 Sofosbuvir
  • the synthesis method of (4S)-N-Boc-4-methoxymethyl-L-proline mainly uses L-hydroxyproline as a raw material or a multi-step reaction to obtain a product, such as WO2012068234 As shown in the above, the N atom and the carboxyl group of L-hydroxyproline are protected. After the hydroxybenzene is sulfonated, the upper cyano group increases the carbon atom, is oxidized to a carboxyl group and then reduced to a hydroxyl group, and finally the methyl group is obtained to obtain a methoxy group. base.
  • the method has a long reaction route, high raw material cost and production cost, is difficult to purify, and has low yield. And so on.
  • an object of the present invention is to provide a novel synthesis method of (4S)-N-Boc-4-methoxymethyl-L-proline amine salt, which makes the oxidation system more efficient by the salt formation system.
  • the product is easier to purify and separate, the obtained product has high quality, good stability, relatively low raw material cost and production cost, and no safety hazard problem, that is, economical and environmentally friendly.
  • the method for synthesizing the (4S)-N-Boc-4-methoxymethyl-L-proline amine salt (TM) of the present invention comprises the following steps:
  • R 1 , R 2 , R 3 are independently selected from the group consisting of hydrogen and a hydrocarbyl compound
  • R 1 , R 2 , and R 3 in the amination are independently selected from a C 1 -C 6 hydrocarbyl compound; or, R 1 is hydrogen, and R 2 and R 3 are independently selected from C 1 a hydrocarbyl compound of -C 8 ; or R 1 and R 2 are both hydrogen, and R 3 is selected from a C 1 -C 10 hydrocarbyl compound;
  • the amine compound is one of tert-butylamine, dicyclohexylamine, benzylamine, (S)-phenethylamine, amantadine;
  • step a the (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid (IM3) is obtained by the following method: (2S)-N-Boc-4- Oxopyrrolidine-2-carboxylic acid (IM2) is prepared by Wittig reaction,
  • the reagent for the Wittig reaction is methoxymethyltriphenylphosphonium chloride, or methoxymethyltriphenylphosphonium chloride with potassium t-butoxide, n-butyllithium, sodium hydride, diiso a mixture of one or more of propylamino lithium;
  • the ratio of the molar amount of each of the reagent reagents to (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid (IM2) is from 1 to 3:1;
  • L-hydroxyproline (RM1) is subjected to Boc protection to obtain N-Boc-L-hydroxyproline (IM1) and then subjected to oxidation reaction;
  • reaction reagent for the oxidation reaction is one of sodium dichloroisocyanurate, sodium hypochlorite, tetramethylpiperidine oxynitride or a mixture thereof;
  • the solvent of the palladium hydrocarbon reduction reaction is water.
  • a novel synthesis method of a (4S)-N-Boc-4-methoxymethyl-L-proline amine salt of the present invention which makes the oxidation system more efficient by a salt formation system
  • the product is easier to purify and separate, and the obtained product has high purity and good stability, and the product is directly hydrogenated by the intermediate IM4 (salt of IM3) to reduce the reaction step, the raw material cost and the production cost are relatively low, and there is no safety.
  • the hidden danger problem is economic and environmental protection.
  • the organic phase was combined and washed with 300 mL of brine. , liquid separation, the organic phase was dried over anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated to give an oil.
  • the organic phase was combined and washed with 300 mL of brine. , the liquid was separated, and the organic phase was dried over anhydrous sodium sulfate for 2h, filtered, and the filtrate was concentrated to give an oily solid, which was white solid, weight 230 g, yield 99.0%;
  • the organic phase was combined and washed with 300 mL of brine. , the liquid was separated, and the organic phase was dried over anhydrous sodium sulfate for 2h, filtered, and the filtrate was concentrated to give an oily solid, which was white solid, weight 230 g, yield 99.0%;
  • the reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3 ⁇ 50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and (S)-phenylethyl was added dropwise at 20-30 °C. The amine (262 mmol) was salted and filtered to obtain IM4, the yield was 62.1%, and the purity was 96%;
  • the organic phase was combined and washed with 300 mL of brine. , the liquid was separated, and the organic phase was dried over anhydrous sodium sulfate for 2h, filtered, and the filtrate was concentrated to give an oily solid, which was white solid, weight 230 g, yield 99.0%;
  • the reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3 ⁇ 50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and benzylamine (262 mmol) was added dropwise at 20-30 °C. Salt, filtered to obtain IM4, yield 41.1%, purity 99%;
  • the reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3 ⁇ 50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and amantadine (262 mmol) was added dropwise at 20-30 °C. Salt formation, filtration to obtain IM4, yield 65%, purity 97%;
  • the reaction was quenched by dropwise addition of a saturated sodium hydrogen carbonate solution. Stir for 30 min, filter, and filter cake washed with 3 ⁇ 50 mL water. The aqueous phase was combined, 40% citric acid was added to the aqueous phase, the pH was adjusted to 3-4, and then extracted three times with 800 mL of ethyl acetate. The organic phase of IM3 was combined, and triethylenediamine DABCO was added dropwise at 20-30 °C. (262 mmol) salt formation, filtration to obtain IM4, yield 60%, purity 97%;

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

Abstract

L'invention concerne un procédé de synthèse d'un sel d'amine de (4S)-N-Boc-4-méthoxy méthyl-L-proline (TM), comprenant les étapes suivantes consistant à : a. faire réagir l'acide (2S)-N-Boc-4-méthoxy méthylène pyrrolidine-2-carboxylique avec le composé amine NR1R2R3 pour obtenir un sel d'amine de l'acide (2S)-N-Boc-4-méthoxy méthylène pyrrolidine-2-carboxylique; et b. obtenir un sel d'amine de (4S)-N-Boc-4-méthoxy méthyl-L-proline à partir d'un sel d'amine de l'acide (2S)-N-Boc-4-méthoxy méthylène pyrrolidine-2-carboxylique par l'intermédiaire d'une réaction de réduction par l'hydrogène à l'aide de palladium sur charbon, R1, R2 et R3 étant indépendamment choisis parmi l'hydrogène et des composés hydroxyle. En utilisant un système de formation de sel, le système d'oxydation est plus efficace et le produit est plus facile à séparer et à purifier. De ce fait, le produit obtenu a une pureté élevée et une bonne stabilité. Le coût des matières premières et le coût de production sont relativement faibles, et il n'y a aucun risque potentiel d'accident, ce qui est économique et respectueux de l'environnement.
PCT/CN2016/085661 2015-06-19 2016-06-14 Procédé de synthèse dun sel d'amine de (4s)-n-boc-4-méthoxy méthyl-l-proline WO2016202232A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510343644.5 2015-06-19
CN201510343644 2015-06-19
CN201610383150.4A CN106256819B (zh) 2015-06-19 2016-06-02 一种(4S)-N-Boc-4-甲氧基甲基-L-脯氨酸胺盐的合成方法
CN201610383150.4 2016-06-02

Publications (1)

Publication Number Publication Date
WO2016202232A1 true WO2016202232A1 (fr) 2016-12-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111620802A (zh) * 2020-06-18 2020-09-04 山西千岫制药有限公司 一种头孢托罗中间体(r)-1-苄基-3-氨基吡咯烷的制备方法
CN115028553A (zh) * 2022-06-16 2022-09-09 上海瀚鸿科技股份有限公司 一种手性N-Boc/Cbz-顺式-(1R,2S)-环己二胺的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012068234A2 (fr) * 2010-11-17 2012-05-24 Gilead Sciences, Inc. Composés antiviraux
CN103946220A (zh) * 2011-11-03 2014-07-23 施万制药 含有片段{2-[4-(联苯-4-基)-1h-咪唑-2-基]吡咯烷-1-羰基甲基}胺的杆状丙型肝炎病毒抑制剂
CN104418784A (zh) * 2013-09-04 2015-03-18 浙江九洲药业股份有限公司 一种抗病毒药物中间体的拆分方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012068234A2 (fr) * 2010-11-17 2012-05-24 Gilead Sciences, Inc. Composés antiviraux
CN103946220A (zh) * 2011-11-03 2014-07-23 施万制药 含有片段{2-[4-(联苯-4-基)-1h-咪唑-2-基]吡咯烷-1-羰基甲基}胺的杆状丙型肝炎病毒抑制剂
CN104418784A (zh) * 2013-09-04 2015-03-18 浙江九洲药业股份有限公司 一种抗病毒药物中间体的拆分方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111620802A (zh) * 2020-06-18 2020-09-04 山西千岫制药有限公司 一种头孢托罗中间体(r)-1-苄基-3-氨基吡咯烷的制备方法
CN115028553A (zh) * 2022-06-16 2022-09-09 上海瀚鸿科技股份有限公司 一种手性N-Boc/Cbz-顺式-(1R,2S)-环己二胺的制备方法
CN115028553B (zh) * 2022-06-16 2024-03-26 上海瀚鸿科技股份有限公司 一种手性N-Boc/Cbz-顺式-(1R,2S)-环己二胺的制备方法

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