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Novel synthetic method of (S)-3-morpholinyl carboxylic acid

A technology of morpholino carboxylic acid and a new method, which is applied in the synthesis of organic intermediates and pharmaceutical intermediates, can solve the problems of harsh reaction conditions, many by-products, and low yield, and achieve mild reaction conditions and few by-products , Response-specific effect

Active Publication Date: 2012-08-01
上海常丰生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] (S)-3-Morpholinyl carboxylic acid is an organic pharmaceutical intermediate with a wide range of uses. The existing synthetic technology usually has expensive raw materials, high cost, harsh reaction conditions, low yield, and is not suitable for industrialization. Production and other shortcomings
[0003] In terms of raw material selection, the prior art usually uses hydroxyl raw materials and ketones containing unsaturated double bonds to react under catalyst conditions, so that the subsequent acylation reaction The conditions of the ring-closing process are improved, a certain temperature is required, the catalyst is not easy to choose, there are more by-products, and the yield is also low

Method used

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  • Novel synthetic method of (S)-3-morpholinyl carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The first step reaction operation process

[0031] Dissolve 10.5g of L-serine in 20ml of tert-butyl acetate, slowly add 2g of perchloric acid in 5ml of aqueous solution at 0°C, the reaction solution is slowly warmed to room temperature, stirred at room temperature for 8 hours, then washed with 10ml of water, 10ml Wash with ammonium chloride, combine the water phases, adjust the pH to 9-10 with potassium carbonate, extract with 100ml*3 dichloromethane, dry the dichloromethane with anhydrous sodium sulfate, and spin dry to obtain 10.0g (65.0%) of light yellow Oil intermediate 2 (L-serine tert-butyl ester).

[0032] The second step reaction operation process

[0033] Dissolve 10g of intermediate 2 in 100ml of dichloromethane, slowly add 8.4g of chloroacetic acid chlorine in 30ml of dichloromethane solution dropwise at 0°C, and slowly warm the reaction solution to room temperature, stir at room temperature for 1 hour, add 50ml (50 %) of sodium bicarbonate aqueous solution...

Embodiment 2

[0041] The first step reaction operation process

[0042] Dissolve 10.5g of L-serine in 30ml of tert-butyl acetate, slowly add 4g of perchloric acid in 5ml of aqueous solution at 0°C, and slowly heat up the reaction solution to 20-40°C, and stir at 20-40°C 10 hours, then washed with 15ml of water and 15ml of ammonium chloride, combined the water phases, adjusted the pH to 9-10 with potassium carbonate, extracted with 100ml*3 dichloromethane, dried the dichloromethane with anhydrous sodium sulfate, and spin-dried to obtain 10.0 g (65.0%) of intermediate 2 (tert-butyl L-serine) as a pale yellow oil.

[0043] The second step reaction operation process

[0044] Dissolve 10g of intermediate 2 in 100ml of dichloromethane, slowly add 13.5g of chloroacetic acid chlorine in 50ml of dichloromethane solution dropwise at 10°C, and slowly heat up the reaction solution to 20-30°C, and at 20-30°C Stir for 1 hour, add 50ml (50%) of aqueous sodium bicarbonate solution, separate layers, wash ...

Embodiment 3

[0052] The first step reaction operation process

[0053] Dissolve 10.5g of L-serine in 20ml of tert-butyl acetate, slowly add 3g of perchloric acid in 5ml of aqueous solution at 5°C, and slowly heat up the reaction solution to 50-60°C, and stir at 50-60°C for 8 hours , then washed with 10ml of water, washed with 10ml of ammonium chloride, combined the water phases, adjusted the pH to 9-10 with potassium carbonate, extracted with 100ml*3 dichloromethane, dried the dichloromethane with anhydrous sodium sulfate, and spin-dried to obtain 10.0g (65.0%) Intermediate 2 (tert-butyl L-serine) as pale yellow oil.

[0054] The second step reaction operation process

[0055] Dissolve 10g of intermediate 2 in 100ml of dichloromethane, slowly add dropwise 10g of chloroacetic acid chlorine in 30ml of dichloromethane solution at 0°C, the reaction solution is slowly heated to 30-40°C, and stirred at 30-40°C for 1 hour , add 50ml (50%) of aqueous sodium bicarbonate solution, separate layers, w...

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Abstract

The invention discloses a synthetic method of (S)-3-morpholinyl carboxylic acid, which comprises the following steps: (1) taking L-serine as a raw material to synthesize L-serine tert-butyl ester; (2) dissolving L-serine tert-butyl ester in dichloromethane, adding a dichloromethane solution of chloroacetyl chloride drop by drop to obtain N-chloroacetyl-L-serine tert-butyl ester; (3) dissolving N-chloroacetyl-L-serine tert-butyl ester in a toluene solution, adding the toluene solution of sodium ethoxide drop by drop to obtain (S)-5-oxo 3-morpholinyl carboxylic acid tert-butyl ester; (4) dissolving (S)-5-oxo 3-morpholinyl carboxylic acid tert-butyl ester in methanol, successively adding aluminum trichloride and sodium borohydride to carry out a reaction to obtain the (S)-3-morpholinyl carboxylic acid tert-butyl ester; (5) dissolving (S)-3-morpholinyl carboxylic acid tert-butyl ester in methanol, adding a methanol solution of hydrogen chloride for reacting to obtain the (S)-3-morpholinyl carboxylic acid. The method of the invention has the advantages of mild reaction condition, easily available raw material and less three waste, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a new method for synthesizing a pharmaceutical intermediate (S)-3-morpholino carboxylic acid, belonging to the fields of organic intermediate synthesis and pharmaceutical intermediate synthesis. Background technique [0002] (S)-3-Morpholinyl carboxylic acid is an organic pharmaceutical intermediate with a wide range of uses. The existing synthetic technology usually has expensive raw materials, high cost, harsh reaction conditions, low yield, and is not suitable for industrialization. Production and other shortcomings. [0003] In terms of raw material selection, the prior art usually uses hydroxyl raw materials and ketones containing unsaturated double bonds to react under the conditions of a catalyst, which improves the conditions of the subsequent acylation reaction and ring-closing process, requires a certain temperature, and the catalyst is not easy. selection, more by-products and lower yields. [0004] L-serine is a w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/30
Inventor 张博
Owner 上海常丰生物医药科技有限公司
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