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Method for synthesizing 4-oxo-L-proline derivative

A technology for proline and derivatives, which is applied in the field of chemical drug intermediate preparation, can solve the problems of high cost, high price and high cost, and achieves the effects of improving yield, low cost and easy operation.

Active Publication Date: 2015-07-22
SICHUAN TONGSHENG AMINO ACID CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This method uses expensive precious metal Ru catalyst, which is expensive and costly, and is not suitable for industrial production
[0013] 4. Existing patents use clean oxidant sodium hypochlorite aqueous solution, but the raw material of this process is amino-protected L-hydroxyproline derivatives
[0016] In the existing technique of synthesizing 4-oxo-L-proline derivative derivatives with L-hydroxyproline as raw material, there are mainly the following problems: the use of heavy metal oxidants and precious metal catalysts does not have advantages in process cost, Not suitable for industrial production

Method used

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  • Method for synthesizing 4-oxo-L-proline derivative
  • Method for synthesizing 4-oxo-L-proline derivative
  • Method for synthesizing 4-oxo-L-proline derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Synthesis of N-Boc-L-4-oxoproline

[0064] The structural formula of N-Boc-L-4-oxoproline is as follows:

[0065]

[0066] Get 1kg of L-hydroxyproline and dissolve it in 50kg of water to obtain a reaction solution;

[0067] Lower the temperature of the reaction solution to -5°C, add 1.9kg of trichloroisocyanuric acid to the reaction solution, control the reaction temperature to less than 0°C, take 238g of tetramethylpiperidine nitrogen oxide (TEMPO), and slowly add it to the reaction solution ;

[0068] After the addition is complete, keep the temperature of the reaction solution lower than 0°C, and carry out the reaction. After TLC monitors that the reaction is complete, control the temperature of the reaction solution to be lower than 0°C, and adjust the pH of the reaction solution to 8-9 with triethylamine;

[0069] Dissolve 2 kg of di-tert-butyl dicarbonate in 2 L of tetrahydrofuran to obtain a THF solution of amino-protecting agent, and slowly add this solutio...

Embodiment 2

[0076] Synthesis of N-Boc-L-4-oxoproline

[0077] The structural formula of N-Boc-L-4-oxoproline is as follows:

[0078]

[0079] Get 1kg of L-hydroxyproline and dissolve it in 45kg of water to obtain a reaction solution;

[0080] Lower the temperature of the reaction solution to -10°C, add 5.2kg of 12% sodium hypochlorite solution to the reaction solution, control the reaction temperature to less than 0°C, take 119g of TEMPO, and slowly add it to the reaction solution;

[0081] After the addition is complete, keep the temperature of the reaction solution lower than 0°C, and carry out the reaction. After TLC monitors that the reaction is complete, control the temperature of the reaction solution to be lower than 0°C, and adjust the pH of the reaction solution to 8-9 with N,N-diisopropylethylamine;

[0082] Dissolve 1.5kg of di-tert-butyl dicarbonate in 2L of tetrahydrofuran to obtain a THF solution of amino-protecting agent, and slowly add this solution into the reaction s...

Embodiment 3

[0089] Synthesis of N-Cbz-L-4-oxoproline

[0090] The structural formula of N-Cbz-L-4-oxoproline is as follows:

[0091]

[0092] Get 1kg of L-hydroxyproline and dissolve it in 50kg of water to obtain a reaction solution;

[0093] Lower the temperature of the reaction solution to -5°C, take 1.9kg of trichloroisocyanuric acid and add it to the reaction solution, control the reaction temperature below 0°C, take 238g of TEMPO, and slowly add it to the reaction solution;

[0094] After the addition is complete, keep the temperature of the reaction solution lower than 0°C, and carry out the reaction. After TLC monitors that the reaction is complete, control the temperature of the reaction solution to be lower than 0°C, and adjust the pH of the reaction solution to 8-9 with triethylamine;

[0095] Dissolve 2.1 kg of benzyloxycarbonyl succinimide in 1.75 L of tetrahydrofuran to obtain a THF solution of an amino-protecting agent, and slowly add this solution to the reaction soluti...

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Abstract

The invention relates to the field of preparation methods of chemical drug intermediates, in particular to a method for synthesizing a 4-oxo-L-proline derivative. The method comprises steps as follows: L-hydroxyproline and an oxidant are mixed, and a mixture is obtained and reacts to produce an intermediate product; after an amino-group protective agent is added to a solution containing the intermediate product, the mixture reacts continuously; then, the mixture has a quenching reaction and is subjected to acidification, extraction, separation, drying and purification, and the 4-oxo-L-proline derivative is obtained. According to the method for synthesizing the 4-oxo-L-proline derivative, the primary raw material L-hydroxyproline is low in cost and easy to obtain; the whole synthesizing steps are convenient, simple and easy to operate; poisonous reagents such as heavy metals and the like are not used in the production process, and the 4-oxo-L-proline derivative is environment-friendly, low in cost and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of preparation methods of chemical drug intermediates, in particular to a method for synthesizing 4-oxo-L-proline derivatives. Background technique [0002] N-B°C-4-oxo-L-proline derivatives, as an important drug intermediate, are widely used in the synthesis of drugs. In particular, N-B°C-4-oxoproline is used in the synthesis of the hypoglycemic drug teneligliptin and the drug Ledipasvir for treating hepatitis C. N-B°C-4-oxo-L-proline is usually obtained from L-hydroxyproline through two-step reaction of protection of amino group and oxidation of hydroxyl group. [0003] For the existing synthesis of N-B°C-4-oxo-L-proline, see the reports in the following literature: [0004] 1. Using L-hydroxyproline as a raw material, first protect the amino group at B°C (tert-butoxycarbonyl), and then oxidize with Jones oxidant (WO2002102799) or Collins reagent (Bioorganic & Medicinal Chemistry, 14(7), 2253-2265; 2006 ) [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/24
CPCC07D207/24
Inventor 燕青陈纹锐伍万兵黄青春李德勇张丽
Owner SICHUAN TONGSHENG AMINO ACID CO LTD
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