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A kind of synthetic method of (s)-3-pyrrolidinol hydrochloride

A technology of pyrrolidinol and synthetic method, applied in the direction of organic chemistry, etc., can solve the problems of long steps, high reaction temperature, consumption of iodine simple substance, etc., achieve cleanliness and high efficiency of functional group conversion, reduce reaction temperature, and increase yield Effect

Active Publication Date: 2022-04-26
ANHUI DEXINJIA BIOPHARM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The downside is that the steps are longer
The yield is medium, the method is simple and easy, the disadvantage is that the steps are long
[0012] Literature (Liao Yunfeng. Preparation of 3-(S)-(-)-(1-carbamoyl-1,1-benzhydryl)pyrrolidine tartrate[J]. Chinese Journal of Pharmaceutical Industry. 2011,42(5 )) reported a high temperature dehydration with L-malic acid and benzylamine, NaBH 4 / I 2 Reduction of amide, debenzylation of palladium carbon to obtain (S)-3-pyrrolidinol, xylene dehydration at 190°C is used in this route, the reaction temperature is high, and there are certain safety hazards, NaBH 4 / I 2 Reduction of amide, the yield is 81%, but consumes a large amount of iodine simple substance, increases the cost, is difficult to recycle, and produces a large amount of waste water, which is difficult to handle

Method used

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  • A kind of synthetic method of (s)-3-pyrrolidinol hydrochloride
  • A kind of synthetic method of (s)-3-pyrrolidinol hydrochloride
  • A kind of synthetic method of (s)-3-pyrrolidinol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Synthesis of (3S)-N-benzyl-3-hydroxypyrrolidine-2,5-dione

[0025] L-malic acid (100g, 1eq) was added to a 1L bottle with mechanical stirring, added to methanol (230mL), stirred and dissolved, and benzylamine (80g, 1eq) was added dropwise at a low temperature of 0-5°C. The temperature does not exceed 10°C, add dropwise for about half an hour, after the dropwise addition is complete, stir at room temperature for 3 hours, concentrate methanol until no fraction flows out, add 500mL of N-methylpyrrolidone, add 3A molecular sieves (130g), heat up to 100°C, and react 6 Hours, hot filtration, recovery of molecular sieves. The filtrate was concentrated to obtain a crude solid product, which was recrystallized from ethanol to obtain 125 g of (3S)-N-benzyl-3-hydroxypyrrolidine-2,5-dione with a yield of 82% and a purity of 98.3%.

[0026] Synthesis of (S)-3-pyrrolidinol hydrochloride

[0027] (3S)-N-Benzyl-3-hydroxypyrrolidine-2,5-dione (100g) was added to a 1L autoclave, 500mL ...

Embodiment 2

[0029] Synthesis of (3S)-N-benzyl-3-hydroxypyrrolidine-2,5-dione

[0030] L-malic acid (300g, 1eq) was added to a 3L bottle with mechanical stirring, added to methanol (700mL), stirred and dissolved, and benzylamine (240g, 1eq) was added dropwise at a low temperature of 0-5°C. The temperature does not exceed 10°C, add dropwise for about half an hour, after the dropwise addition is complete, stir at room temperature for 3 hours, concentrate methanol until no fraction flows out, add 1.5L of toluene, add 4A molecular sieve (390g), heat up to 105°C, and react for 5-6 hours , hot filtration, and recovery of molecular sieves. The filtrate was concentrated to obtain a crude solid, which was recrystallized from ethanol to obtain 390 g of (3S)-N-benzyl-3-hydroxypyrrolidine-2,5-dione with a yield of 85% and a purity of 98.5%.

[0031] Synthesis of (S)-3-pyrrolidinol hydrochloride

[0032] (3S)-N-Benzyl-3-hydroxypyrrolidine-2,5-dione (100g) was added to a 1L autoclave, 500mL of ethanol...

Embodiment 3

[0034] Synthesis of (3S)-N-benzyl-3-hydroxypyrrolidine-2,5-dione

[0035]L-malic acid (100g, 1eq) was added to a 1L bottle with mechanical stirring, added to methanol (230mL), stirred and dissolved, and benzylamine (80g, 1eq) was added dropwise at a low temperature of 0-5°C. The temperature does not exceed 10°C, add dropwise for about half an hour, after the dropwise addition is complete, stir at room temperature for 3 hours, concentrate methanol until no fraction flows out, add 500mL of toluene, add 3A molecular sieves (100g), heat up to 80°C, react for 6 hours, and filter hot , to recover molecular sieves. The filtrate was concentrated to obtain a crude solid, which was recrystallized from ethanol to obtain 114 g of (3S)-N-benzyl-3-hydroxypyrrolidine-2,5-dione, with a yield of 82% and a purity of 88.4%.

[0036] Synthesis of (S)-3-pyrrolidinol hydrochloride

[0037] (3S)-N-Benzyl-3-hydroxypyrrolidine-2,5-dione (10g) was added to the autoclave, 50mL of ethanol was added, an...

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Abstract

The invention discloses a method for synthesizing (S)-3-pyrrolidinol hydrochloride, which belongs to the field of pharmaceutical synthesis. The method uses L-malic acid and benzylamine as raw materials to obtain (3S)-N-N through dehydration amidation Benzyl-3-hydroxypyrrolidine-2,5-dione, followed by one-pot reduction, debenzylation, and salt formation to synthesize (S)-3-pyrrolidinol hydrochloride. The invention has the advantages of short synthetic route, simple operation, high yield, good product purity and favorable industrial production.

Description

technical field [0001] The invention belongs to the field of medicine synthesis and relates to a synthesis method of (S)-3-pyrrolidinol hydrochloride. Background technique [0002] Larotrectinib (LOXO-101) trade name is Vitrakvi, and its Chinese name is: Larotrectinib or Larotrectinib. It is an ATP-competitive, oral selective inhibitor for the tropomyosin-related kinase (TRK) family Three subtypes of the receptor (TRKA, B and C) have 50% inhibitory concentrations in the nanomolar range. On November 27, 2018, the FDA accelerated the approval of the pan-cancer targeted drug Vitrakvi (larotrectinib) jointly developed by Bayer and Loxo Oncology for the treatment of adults and children with locally advanced or metastatic solid tumors carrying NTRK gene fusions. [0003] Molecular formula of larotrectinib: C 21 h 22 f 2 N 6 o 2 , molecular weight: 428.4, CAS: 1223403-58-4, chemical name: (3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrrolidinyl] Azolo[1,5-A]pyrimid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/12
CPCC07D207/12
Inventor 张启龙许坤王红磊高令峰郑庚修李学坤
Owner ANHUI DEXINJIA BIOPHARM
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