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Method for synthesizing N-Boc-L-propargyl glycine

A technology of propargyl glycine and a synthesis method, which is applied in the synthesis field of N-Boc-L-propargyl glycine, can solve the problems of strict control of process parameters, large loss of raw materials, inconvenient operation, etc., and achieves reduction of purification and treatment process, improve ee value, reduce the effect of production cost

Inactive Publication Date: 2017-08-25
济南同路医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] EP1705252 introduced a method for splitting racemic propargylglycine by biological enzymatic method. The yield of this method is low, the loss of raw materials is large, the process parameters need to be strictly controlled, and the operation is inconvenient

Method used

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  • Method for synthesizing N-Boc-L-propargyl glycine
  • Method for synthesizing N-Boc-L-propargyl glycine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation of compound 3

[0042] Add 26.7g (0.1mol) of compound 2 to 300ml of 1mol / L sodium hydroxide aqueous solution (0.3mol), stir at 25°C until it is completely dissolved, that is, the reaction is over, adjust the pH to 7 with 1mol / L hydrochloric acid, a large amount of white The solid precipitated out and was suction-filtered. The filter cake was washed with 50 ml of water and dried to obtain 22.7 g of compound 3 with a yield of 95% and a purity of 98.0%.

[0043] Preparation of compound 5

[0044] Add 30g (0.125mol) of compound 3, 29g (-)-1R, 2S, 5R-8-phenylmenthol (0.125mol), and 300ml of dichloromethane into a 500ml reaction flask in turn, start stirring, and wait for the solid to dissolve After that, add 1.5g (0.0125mol) of 4-dimethylaminopyridine, and react at 25°C for 16h. After the reaction is completed, the reaction solution is washed three times with saturated brine, concentrated to dry light yellow solid, and washed with 100ml of ethanol / water (3:1 ) ...

Embodiment 2

[0048] Preparation of compound 3

[0049] Add 26.7g (0.1mol) of compound 2 to 500ml of 1mol / L potassium hydroxide aqueous solution (0.5mol), stir at 25°C until it is completely dissolved, and the reaction is completed, adjust the pH to 7 with 1mol / L hydrochloric acid, a large amount of white solid Precipitate, filter with suction, wash the filter cake with 100ml of water, and dry to obtain 21.5g of compound 3, with a yield of 90% and a purity of 98.1%.

[0050] Preparation of compound 5

[0051] Add 30g (0.125mol) of compound 3, 32.2g (-)-1R, 2S, 5R-8-naphthyl menthol (0.139mol), and 300ml of dichloromethane into a 500ml reaction flask in turn, start stirring, and wait until the solid After dissolving, add 1.5g (0.0125mol) of 4-dimethylaminopyridine, and react at 25°C for 16h. After the reaction is completed, the reaction solution is washed three times with saturated brine, concentrated to dryness as a light yellow solid, and washed with 100ml of ethanol / water (3: 1) Heat to...

Embodiment 3

[0055] Preparation of compound 3

[0056] Add 26.7g (0.1mol) of compound 2 to 200ml of 1mol / L sodium hydroxide aqueous solution (0.2mol), stir at 25°C until it is completely dissolved, that is, the reaction is over, adjust the pH to 7 with 1mol / L hydrochloric acid, and a large amount of white The solid was precipitated, filtered with suction, the filter cake was washed with 50 ml of water, and dried to obtain 22.6 g of compound 3 with a yield of 94.6% and a purity of 98.0%.

[0057] Preparation of compound 5

[0058] Add 30g (0.125mol) of compound 3, (-)-1R, 2S, 5R-8-(4-methoxymethylbenzene) menthol (0.125mol), and 300ml of dichloromethane into a 500ml reaction flask in sequence , start stirring, after the solid dissolves, add 1.5g (0.0125mol) 4-dimethylaminopyridine, react at 25°C for 16h, the reaction is completed, the reaction solution is washed three times with saturated saline, concentrated to dry light yellow solid, and used 100ml Ethanol / water (5:1) was heated to diss...

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Abstract

The invention provides a method for synthesizing N-Boc-L-propargyl glycine. According to the synthetic method, N-glycine ethyl ester serves as an initial raw material, and a target compound is synthesized through a three-step reaction. In the product preparation process, chiral synthesis is performed in the second step by adopting a chiral reagent, and the ee value of the product is increased. In the final step, a 'one-pot' process is adopted, the purification and treatment process of the intermediate link is reduced, the process operation is simplified, the solvent usage amount and the sewage discharge amount are reduced, the production cost is reduced, energy conservation and consumption reduction are realized, and the influence on the environment is alleviated. According to the product prepared by the process, the total yield is more than 70%, the purity detected by HPLC (High Performance Liquid Chromatography) is more than 99%, and the ee value is more than 98%. The method disclosed by the invention is easy to operate, high in yield and high in purity and is favorable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of chemistry, in particular to a method for synthesizing N-Boc-L-propargylglycine. Background technique [0002] N-Boc-L-propargylglycine is the key starting material for the synthesis of the ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin, and there are few literatures on its preparation. [0003] Tetrahedron: Asymmetry, 7 (1996), 1771 introduced a chiral method for synthesizing L-propargylglycine, which uses a biphenyl chiral reagent, but the obtained L-propargylglycine ee value is only 66%. [0004] Tetrahedron: Asymmetry, 9 (1998) 2121 introduces a nickel ligand chiral catalyst, the ee value is only 94%, which cannot meet the product quality requirements. [0005] EP1705252 introduced a method for splitting racemic propargylglycine by biological enzymatic method. The method has low yield, large loss of raw materials, strict control of process parameters and inconvenient operation. Contents ...

Claims

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Application Information

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IPC IPC(8): C07C269/04C07C271/22C07C249/02C07C251/24C07B53/00
CPCC07B53/00C07B2200/07C07C249/02C07C269/04C07C271/22C07C251/24
Inventor 俞仑张庆刘卫聪李家园苏广礼刘伟
Owner 济南同路医药科技发展有限公司
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