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Preparation method of L-hydroxyproline

A hydroxyproline and hydroxyl oxidation technology, applied in the field of preparation of L-hydroxyproline, can solve problems such as drug safety risks, endangering human health, pollution, etc., and achieve uniform and stable reactions, convenient operation, and expanded applications range effect

Active Publication Date: 2016-02-03
SICHUAN TONGSHENG AMINO ACID CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the source of L-hydroxyproline is mainly to hydrolyze proteins such as gelatin, bone glue, casein, soybean skin, etc. All are obtained through animal extraction, so there is potential TSE / BSE pollution. The so-called TSE refers to transmissible spongiosa encephalopathy, and BSE refers to mad cow disease, that is, bovine cerebral spongiform disease. There is also a certain risk in the safety of the product, and it may even endanger human health, and even cause death in severe cases.

Method used

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  • Preparation method of L-hydroxyproline
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  • Preparation method of L-hydroxyproline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation method of L-hydroxyproline is as follows:

[0043] (1) Add 100g of pyroglutaminol, 16.5g of p-toluenesulfonic acid monohydrate, 130g of benzaldehyde, and 350g of toluene into a 2L reaction flask in sequence, heat at 70-120°C and reflux for 4-6h, evaporate the solvent by distillation under reduced pressure Toluene was used to obtain an oil, which was purified by column chromatography to obtain 40.5g TSSA0200-A, HPLC: 95%, yield: 23%;

[0044] (2) Take 30g of TSSA0200-A, add 900mL of tetrahydrofuran, add 90g of MoOPH into a 2L reaction flask, lower the temperature to -40~-50°C under the protection of nitrogen, add 240g of LiHMDS dropwise, react for 6-10h, extract the reaction, and obtain 9.7 by column chromatography gTSSA0200-B, HPLC: 94.2%, yield: 30%;

[0045] (3) Add TSSA0200-B5g into a 100mL three-necked flask, add 50mL tetrahydrofuran under nitrogen protection, cool down to -15~-20°C, add 0.8g lithium tetrahydrogen aluminum, heat up to room temperatu...

Embodiment 2

[0049] The preparation method of L-hydroxyproline is as follows:

[0050] (1) Add 100 g of pyroglutaminol, 20 g of boron trifluoride diethyl ether, 15 g of benzaldehyde, and 450 g of toluene into a 2L reaction flask in sequence, heat at 120°C and reflux for 4-6 hours, distill and concentrate under reduced pressure to evaporate the solvent toluene to obtain an oily substance, Purified by column chromatography to obtain 37.6 g of TSSA0200-A, HPLC: 95%; yield: 21.3%.

[0051] (2) Take 30g of TSSA0200-A, add 900mL of tetrahydrofuran, add 120g of MoOPH into a 2L reaction flask, lower the temperature to -50°C under the protection of nitrogen, add 300g of potassium hydride dropwise, react for 6-10h, extract the reaction, and obtain 9.7 by column chromatography gTSSA0200-B, HPLC: 94.2%; Yield: 30%.

[0052] (3) Add TSSA0200-B5g into a 100mL three-neck flask, add 50mL tetrahydrofuran under nitrogen protection, cool down to -15°C, add 1.2g lithium tetrahydrogen aluminum, heat up to roo...

Embodiment 3

[0056] The preparation method of L-hydroxyproline is as follows:

[0057] (1) Add 100g of pyroglutaminol, 18g of p-toluenesulfonic acid monohydrate, 80g of benzaldehyde, and 400g of toluene into a 2L reaction flask in turn, heat at 70°C and reflux for 4-6h, distill and concentrate under reduced pressure to evaporate the solvent toluene to obtain an oil The product was purified by column chromatography to obtain 39.5g TSSA0200-A, HPLC: 95%; 22.4%.

[0058] (2) Take 30g of TSSA0200-A, add 900mL of tetrahydrofuran, add 100g of MoOPH into a 2L reaction flask, lower the temperature to -40°C under the protection of nitrogen, add LiHMDS260g dropwise, react for 6-10h, extract the reaction, and obtain 9.7g of TSSA0200-B by column chromatography , HPLC: 94.2%; 30%.

[0059] (3) Add 5g of TSSA0200-B into a 100mL three-neck flask, add 50mL of tetrahydrofuran under nitrogen protection, cool down to -15°C, add 1g of sodium borohydride, heat up to room temperature and react for 6-8h, extrac...

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Abstract

The invention provides a preparation method of L-hydroxyproline, which comprises the following steps: (A) by taking pyroglutaminol and benzaldehyde as raw materials, carrying out condensation dehydration under the catalysis condition of an acidic catalyst to generate an intermediate product (3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2]oxazol-5(3H)-one; and (B) sequentially carrying out beta-carbonyl oxidation reaction, carbonyl reduction reaction, catalytic hydrogenation reaction and hydroxyl oxidation reaction on the intermediate product to obtain L-hydroxyproline. The preparation method of L-hydroxyproline, provided by the embodiment of the invention, abandons the traditional way of animal extraction, is carried out by adopting a synthetic method, and has the effects of short reaction route, capability of avoiding potential TSE / BSE pollution, high product yield and relatively high purity.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of L-hydroxyproline. Background technique [0002] As the main raw material of the antiviral drug atazanavir, L-hydroxyproline has high application value. [0003] At present, the source of L-hydroxyproline is mainly to hydrolyze proteins such as gelatin, bone glue, casein, soybean skin, etc. All are obtained through animal extraction, so there is potential TSE / BSE pollution. The so-called TSE refers to transmissible spongiosa encephalopathy, and BSE refers to mad cow disease, that is, bovine cerebral spongiform disease. There are also certain risks in the safety of the system, and it may even endanger human health, and even cause death in severe cases. [0004] In view of this, the present invention is proposed. Contents of the invention [0005] The object of the present invention is to provide a preparation method of L-hydroxyproline, which abandons the previo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07B2200/07C07D207/16
Inventor 李德勇黄青春伍万兵陈纹锐张丽白顺强
Owner SICHUAN TONGSHENG AMINO ACID CO LTD
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