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Preparation method for L-hydroxyproline

A technology of hydroxyproline and glutamic acid, which is applied in the field of preparation of L-hydroxyproline, can solve the problems of high production cost and slow production efficiency, and achieve low production cost, extended application range, yield and purity high effect

Inactive Publication Date: 2016-08-10
南通普悦生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has indeed avoided the risk of carrying viruses from proposing L-hydroxyproline from animal source raw materials, but because it will construct new biological strains and need to screen the strains, the production cost is higher and the production efficiency is lower. slow

Method used

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  • Preparation method for L-hydroxyproline
  • Preparation method for L-hydroxyproline
  • Preparation method for L-hydroxyproline

Examples

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Embodiment 1

[0037] This embodiment relates to a preparation method of L-hydroxyproline, specifically comprising the following steps:

[0038] Add 60kg of glutamic acid into a 200L electric heating stainless steel reaction tank, carry out oil bath dehydration reaction at 220-290°C, keep it at 140°C for 55min, and put it into 10L of water;

[0039] Stir and cool, centrifuge to obtain crude pyroglutamic acid, add water to the crude pyroglutamic acid at 65°C to saturation, centrifugally filter, cool to 35°C for crystallization, centrifuge the crystals, wash and dry to obtain pyroglutamic acid Fine product 28kg, yield 54% (based on glutamic acid feeding theoretical yield), melting point is 159~161 ℃, [a] 20 =-11.6 (C=2, H 2 O);

[0040] According to the feed ratio of pyroglutamic acid, absolute ethanol, and thionyl chloride as 1mol: 100ml: (0.06~1.2) mol, add 10L of absolute ethanol to a dry three-necked flask, cool to - Below 5°C, add 300ml of thionyl chloride dropwise, add 1000g of pyrogl...

Embodiment 2

[0048] This embodiment relates to a preparation method of L-hydroxyproline, specifically comprising the following steps:

[0049] Add 80kg of glutamic acid into a 200L electric heating stainless steel reaction tank, carry out dehydration reaction in oil bath at 250-270°C, keep it at 160°C for 50min, then put it into 10L of water;

[0050] Stir and cool, centrifuge to obtain the crude pyroglutamic acid, add water to the crude pyroglutamic acid at 50°C to saturation, centrifugally filter, cool to 30°C for crystallization, centrifuge the crystal, wash and dry to obtain pyroglutamic acid Fine product 37kg, yield 53.8% (based on glutamic acid feeding theoretical yield), melting point is 158.5 ~ 161 ° C, [a] 20 =-11.5 (C=2, H 2 O);

[0051] According to the feed ratio of pyroglutamic acid, absolute ethanol and concentrated sulfuric acid is 1mol: 100ml: (0.06 ~ 1.2) mol, add 10L of absolute ethanol to a dry three-necked flask, and cool down to -5°C with ice salt water Next, add 25...

Embodiment 3

[0059] This embodiment relates to a preparation method of L-hydroxyproline, specifically comprising the following steps:

[0060] Add 60kg of glutamic acid to a 200L electric heating stainless steel reaction tank, carry out oil bath dehydration reaction at 220-250°C, keep it at 140°C for 55min, and then put it into 10L of water;

[0061] Stir and cool, centrifuge to obtain crude pyroglutamic acid, add water to the crude pyroglutamic acid at 65°C to saturation, centrifugally filter, cool to 35°C for crystallization, centrifuge the crystals, wash and dry to obtain pyroglutamic acid Fine product 28kg, yield 54% (based on glutamic acid feeding theoretical yield), melting point is 158.5~161 ℃, [a] 20 =-11.5 (C=2, H 2 O);

[0062] According to the feed ratio of pyroglutamic acid, absolute ethanol, and hydrochloric acid is 1mol: 100ml: (0.06 ~ 1.2) mol, add 1L of absolute ethanol to a dry three-necked flask, and cool down to below -5°C with ice salt water , add 150g of hydrochlori...

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Abstract

The invention provides a preparation method for L-hydroxyproline. The preparation method comprises the following steps: preparing pyroglutamic acid; preparing pyroglutamate; preparing pyroglutamic acid alcohol; preparing (3R,7aS)-3-phenyltetrahydropyrrolo[1,2]oxazole-5(3H)-one; and preparing L-hydroxyproline. Compared with the prior art, the invention has the following beneficial effects: the method overcomes the problems that a traditional manner of extraction of L-hydroxyproline from an animal donor has potential safety hazards and that production of L-hydroxyproline is limited as biological raw materials are utilized, and can synthesize L-hydroxyproline under the condition of shortage of biological raw materials; synthetic methods for L-hydroxyproline are enriched; the added value of L-hydroxyproline is increased; the application scope of L-hydroxyproline can be further broadened; prepared L-hydroxyproline is high in yield and purity, so the synthesis purity of atazanavir is indirectly improved; and common raw materials can be selected in preparation of L-hydroxyproline, so production cost is low.

Description

technical field [0001] The invention relates to a preparation method of L-hydroxyproline, which belongs to the technical field of amino acid synthesis. Background technique [0002] As an important intermediate in the synthesis of antiviral drug atazanavir, L-hydroxyproline has high application value. At present, the main source of L-hydroxyproline is hydrolyzing gelatin, bone glue, casein, soybean hulls and other proteins with hydrochloric acid, extracting imidic acid by nitrosation method, and then refining and crystallizing after separation by resin chromatography. Because they are all obtained through animal extraction, there is potential TSE / BSE contamination, that is, transmissible spongiform encephalopathy and bovine cerebral spongiform disease. In this way, the safety of the drug also has certain risks when the drug is subsequently synthesized and prepared, and even It will endanger human health and even cause death in severe cases. [0003] In view of this, there ...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 王林
Owner 南通普悦生物医药有限公司
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