Preparation method of N-substituted 3-aminomethyl pyrrolidine

A technology of aminomethylpyrrolidine and sulfonyl group is applied in the field of preparation of pharmaceutical intermediates and can solve the problems of limited industrial application, danger and high production cost

Inactive Publication Date: 2010-12-08
江苏国华生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This route uses highly toxic cyanide, which is not only dangerous

Method used

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  • Preparation method of N-substituted 3-aminomethyl pyrrolidine
  • Preparation method of N-substituted 3-aminomethyl pyrrolidine
  • Preparation method of N-substituted 3-aminomethyl pyrrolidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of methyl-1-benzyl-5-carbonylpyrrolidine-3-carboxylate (8)

[0022]

[0023] Add dimethyl itaconate (158.15 g, 1 mol) and benzylamine (107.15 g, 1 mol) into a 1 L three-neck round bottom flask, heat the oil bath to 90° and stir the reaction. The reaction was stopped after the completion of the reaction monitored by TLC. Cool to room temperature, spin dry, add 500mL of dichloromethane, 100mL of dilute hydrochloric acid, shake and separate the layers, separate the organic layer, add saturated sodium bicarbonate solution, shake and separate the layers, separate the organic layer, wash with saturated sodium chloride solution once, Dry over anhydrous sodium sulfate, spin dry, and recrystallize with ethyl acetate and petroleum ether to obtain 200 g of product with a yield of 86%.

Embodiment 2

[0025] Preparation of (1-benzylpyrrolidin-3-yl)methanol (9)

[0026]

[0027] In a 1L three-neck round-bottomed flask, add lithium aluminum tetrahydride (40g, 1.07mol), add 1.2L tetrahydrofuran under ice bath, add human compound (8) (100g, 0.43mol), remove the ice bath, and heat up in the oil bath To 66 ° of reaction, TLC monitors the end of the reaction. Cool to room temperature, add 10% NaOH solution, filter with suction, spin dry the filtrate, add 200 mL of water, adjust the pH to 9-10 with solid sodium carbonate, extract the product with dichloromethane, wash the organic layer with saturated sodium chloride, and dry with anhydrous sodium sulfate , spin-dried to obtain 80g product, yield 97%.

Embodiment 3

[0029] Preparation of (1-benzylpyrrolidin-3-yl)methyl methanesulfonate (10)

[0030]

[0031] In a 1L single-necked flask, add compound (9) (75g, 0.39mol), triethylamine (47mL, 59mol), methanesulfonyl chloride (36mL, 0.47mol), 375mL tetrahydrofuran, react at room temperature, and monitor the completion of the reaction by TLC. Add saturated sodium bicarbonate solution to make the pH of the aqueous phase 7-8, extract the product with ethyl acetate, wash the organic layer with water, wash the organic layer with saturated sodium chloride, dry with anhydrous sodium sulfate, and spin dry to obtain 90g of product with a yield of 86 %.

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Abstract

The invention discloses a preparation method of N-substituted 3-aminomethyl pyrrolidine. 1-benzyl-3-aminomethyl pyrrolidine and 3-tertiary-butoxy carbonyl-aminomethyl pyrrolidine are prepared by using polydiallyl itaconate and benzylamine as the raw materials through the reaction in seven steps of cyclization, reduction, substitution, hydrolyzation, protection, hydrogenation, and the like. The invention has the advantages of low-cost and easily-obtained raw materials, temperate reaction condition, simple operation process, low cost and the high yield.

Description

(1) Technical field [0001] The invention relates to a method for preparing a pharmaceutical intermediate, in particular to a method for 1-benzyl-3-aminomethylpyrrolidine and 3-tert-butoxycarbonylaminomethylpyrrolidine. (2) Background technology [0002] Pyrrolidine amine compounds are a class of important pharmaceutical intermediates, especially 3-aminomethylpyrrolidine (compound 1) is widely used in many drug molecules. For example, the structure of antihistamine mepyrazine (compound 2), quinolone bactericidal drug (compound 3) and drugs with anti-HIV activity (compound 4, 5) all contain this intermediate. [0003] [0004] 1-Benzyl-3-aminomethylpyrrolidine and 3-tert-butoxycarbonylaminomethylpyrrolidine as intermediates with different monoprotection on the two N atoms of 3-aminomethylpyrrolidine (compounds 6, 7,) , the demand in the international pharmaceutical and chemical market has been strong. [0005] But there are not many reports about the preparation of these ...

Claims

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Application Information

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IPC IPC(8): C07D207/09
Inventor 葛敏王学涛胡春晨
Owner 江苏国华生物科技有限公司
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