Method for synthesizing N-Boc-3-pyrrolidine formaldehyde

A technology of pyrrolidine carboxaldehyde and synthesis method, which is applied in the field of synthesis of N-Boc-3-pyrrolidine carboxaldehyde, can solve the problems of high price of Pd/C, unsuitable for scale-up production, cumbersome post-processing, etc., and achieves great practical value and Social and economic benefits, low production cost, simple and reliable method

Active Publication Date: 2017-04-26
武汉恒和达生物医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The raw materials used in route 1 cannot be purchased in the market and need to be synthesized by yourself. In addition, it also needs to use Pd / C catalytic hydrogenation. Pd / C is expensive and requires high equipment, which leads to high reaction costs and is not suitable for scale-up production.
The yield of the first step of route 2 is low, and the final reduction reaction uses relatively expensive DIBAL-H (which reacts violently with water to produce hydrogen). The reaction solvent needs to be dry and anhydrous, and the post-treatment is cumbersome and unnecessary Adapt to scale-up production

Method used

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  • Method for synthesizing N-Boc-3-pyrrolidine formaldehyde

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Embodiment 1

[0033] (1) Put 4Kg of dimethyl itaconate, 580g of camphorsulfonic acid, 50g of 4A molecular sieve and 20L of methanol into the reaction kettle, add 3.8Kg of ammonium acetate, and then raise the temperature to 50°C for 5 hours. Add water to quench the reaction, extract with ethyl acetate, wash the organic phase successively with saturated aqueous sodium bicarbonate solution and saturated brine, concentrate the organic phase to obtain a light yellow oily liquid, and obtain 3.3 Kg of methyl 5-oxo-3-pyrrolidinecarboxylate, Yield 92%.

[0034] (2) Dissolve 2 kg of methyl 5-oxo-3-pyrrolidinecarboxylate in 20 liters of tetrahydrofuran, add 1.9 kg of sodium borohydride in batches at room temperature, and slowly add 3.9 kg of boron trifluoride ether solution dropwise after the addition, After the dropwise addition, stir at room temperature for 10 minutes, heat to reflux, react for about 4 hours, add water to quench the reaction, extract with ethyl acetate, concentrate to obtain a light...

Embodiment 2

[0038] (1) Put 4Kg of dimethyl itaconate, 2.27kg of oxalic acid, 50g of 4A molecular sieve and 20L of ethanol into the reaction kettle, add 3.8Kg of ammonium acetate, and then reflux for 8 hours. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and the organic phase was concentrated to obtain 2.8 Kg of methyl 5-oxo-3-pyrrolidinecarboxylate, with a yield of 78%.

[0039] (2) Dissolve 2 kg of methyl 5-oxo-3-pyrrolidinecarboxylate in 20 liters of tetrahydrofuran, add 1.9 kg of sodium borohydride in batches at room temperature, and slowly add 3.2 kg of trifluoroacetic acid dropwise after the addition is complete. Then stir at room temperature for 10 minutes, heat to reflux, react for about 4 hours, add water to quench the reaction, extract with EA, concentrate to obtain a light yellow oily liquid, dissolve this light yellow oily liquid in 20 etha...

Embodiment 3

[0043] (1) Put 4Kg of dimethyl itaconate, 2.27kg of oxalic acid, 50g of 4A molecular sieve and 20L of ethanol into the reaction kettle, add 3.8Kg of ammonium acetate, and then reflux for 8 hours. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and the organic phase was concentrated to obtain 2.8 Kg of methyl 5-oxo-3-pyrrolidinecarboxylate, with a yield of 78%.

[0044] (2) Dissolve 2 kg of methyl 5-oxo-3-pyrrolidinecarboxylate in 20 liters of tetrahydrofuran, add 1.9 kg of sodium borohydride in batches at room temperature, and slowly add 3.9 kg of boron trifluoride ether solution dropwise after the addition, After the dropwise addition, stir at room temperature for 10 minutes, heat to reflux, react for about 4 hours, add water to quench the reaction, extract with ethyl acetate, concentrate to obtain a light yellow oily liquid, dissolve the l...

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Abstract

The invention discloses a method for synthesizing N-Boc-3-pyrrolidine formaldehyde. The method comprises that dimethyl itaconate as a raw material undergoes an intramolecular cyclization reaction to produce methyl 5-oxo-3-pyrrolidine carboxylate, then the methyl 5-oxo-3-pyrrolidine carboxylate undergoes a reduction reaction to produce pyrrolidine-3-methanol, then the pyrrolidine-3-methanol is subjected to Boc protection so that N-Boc-pyrrolidine-3-methanol is obtained, and finally, the N-Boc-pyrrolidine-3-methanol is oxidized to form a final product compound. The method is simple and convenient, has a low cost, content greater than 99%, produces small environmental pollution and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of synthesis of organic intermediates, in particular to a synthesis method of N-Boc-3-pyrrolidine formaldehyde. Background technique [0002] N-Boc-3-pyrrolidinecarbaldehyde is an important organic chemical intermediate and a key synthetic raw material for many medicines, pesticides and newly developed active molecules. [0003] At present, there are few companies that can stably supply this product in the market, and the output is very low, and the price is very expensive, which cannot meet the needs of industrialized production. [0004] There are two routes for the synthesis of the compound reported in the literature at present; [0005] Synthetic Route 1 (WO2005049605A1) [0006] [0007] Synthetic Route 2 (CN101993404A) [0008] [0009] The raw materials used in route 1 cannot be purchased in the market and need to be synthesized by yourself. In addition, it also needs to use Pd / C catalytic hy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08
CPCC07D207/08
Inventor 周叶兵鲁东安刘杰张圣波
Owner 武汉恒和达生物医药有限公司
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