A kind of synthetic method of d-biotin

A synthesis method and biotin technology, applied in the direction of organic chemistry, etc., can solve problems such as potential safety hazards, and achieve the effects of increasing yield, improving reaction efficiency and being environmentally friendly.

Active Publication Date: 2016-08-31
ZHEJIANG NHU CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Convert (2S,3S,4S)-5-(3,4-diamino-tetrahydrothiophen-2-yl)pentanoic acid into d-biotin, the ring-closing reagent used is generally phosgene, the publication number is CN Chinese patent application 1374312A discloses a preparation method of d-biotin, which includes (2S,3S,4S)-5-(3,4-diamino-tetrahydrothiophen-2-yl)pentyl The step of acid ring-closing to generate d-biotin, the ring-closing reagent used is trichloromethyl chloroformate (diphosgene) or bis(trichloromethyl) carbonate (triphosgene), the product obtained by the preparation method The yield is high. However, when diphosgene and triphosgene are used as reaction raw materials, the intermediate phosgene is inevitably produced, which has great potential safety hazards. During the production process, it is necessary to strictly seal the equipment and absorb the tail gas. process

Method used

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  • A kind of synthetic method of d-biotin
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  • A kind of synthetic method of d-biotin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] In a 500ml polytetrafluoroethylene-lined autoclave, put in (2S,3S,4S)-5-(3,4-diamino-tetrahydrothiophen-2-yl)valeric acid 30.0g (98.5%, 0.1354mol) , put 200 g of dimethyl carbonate (99.2%, 2.2044 mol), and 3.5 g of boron trifluoride-diethyl ether complex. After feeding, the autoclave is filled with high-purity nitrogen to 0.3MPa, and then exhausted to 0.05MPa, and then replaced twice, for a total of three replacements. After the last replacement, ensure that the residual nitrogen pressure in the autoclave is about 0.05MPa. After the replacement is completed, the electric heating of the autoclave is turned on, and the heating temperature is set to 150°C. When the internal temperature reaches 150°C, the time is started, and the holding reaction is carried out. The pressure at this time is about 0.3-0.6MPa (related to the residual pressure after the last replacement).

[0036]During the reaction, the content of the reaction solution was detected by sampling high-performan...

Embodiment 2

[0048] In a 500ml polytetrafluoroethylene-lined autoclave, put in (2S,3S,4S)-5-(3,4-diamino-tetrahydrothiophen-2-yl)valeric acid 30.0g (98.5%, 0.1354mol) , put into diethyl carbonate 300g (99.0%, 2.5169mol), trisulfomethane (CAS: 54322-33-7) 2.2g. After feeding, the autoclave is filled with high-purity nitrogen to 0.3MPa, and then exhausted to 0.05MPa, and then replaced twice, for a total of three replacements. After the last replacement, ensure that the residual nitrogen pressure in the autoclave is about 0.05MPa. After the replacement, the electric heating of the autoclave was turned on, and the heating temperature was set to 170°C. When the internal temperature reaches 120°C, the time is started, and the heat preservation reaction is carried out. The pressure at this time is about 0.4-0.6MPa (related to the residual pressure after the last replacement).

[0049] During the reaction, the content of the reaction solution was detected by sampling high-performance liquid chrom...

Embodiment 3～14

[0054] In Examples 3 to 14, the reaction was carried out according to the input amounts of the raw materials in Table 1 and the reaction conditions in Table 2, and the other conditions were the same as those in Example 1.

[0055] Table 1 Raw material input amount of Examples 3-14

[0056]

[0057] The reaction conditions and reaction results of Table 2 Examples 3-14

[0058]

[0059] From the results in Table 2, it can be seen that the efficiency of the reaction catalyzed by the Lewis acid is generally higher than that of the protic acid, and the reaction time is shorter.

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Abstract

The invention discloses a method for synthesizing d-biotin. The method comprises the following steps: carrying out cyclization on (2S, 3S, 4S)-5-(3,4-diamido-thiophane-2-yl) valeric acid and carbonic ester under the effect of an acid catalyst; carrying out post-treatment to obtain the d-biotin after the reaction is ended, wherein the structure of the carbonic ester is shown in the specification; R<1> and R<2> are independently selected from C1-C5 alkyls; the acid catalyst is one or combination of more of a protonic acid and a lewis acid. By adopting the synthetic method, the carbonic ester is adopted as a reagent to replace triphosgene or diphosgene to react, and generation of a virulent phosgene intermediate is avoided, so that the method is friendlier to the environment; meanwhile, the reaction efficiency is improved by selecting a specific catalyst, and the yield of the d-biotin is increased.

Description

technical field [0001] The present invention relates to organic synthesis reactions in the field of chemistry, in particular to a method for forming d-biotin through cyclization reaction. Background technique [0002] d-biotin, also known as vitamin H and coenzyme R, has the structure shown in formula (I), is a water-soluble vitamin, and also belongs to the vitamin B family. It is a necessary substance for the synthesis of vitamin C and an indispensable substance for the normal metabolism of fat and protein. [0003] [0004] At present, d-biotin can be prepared by biosynthesis or chemical synthesis. Due to the large demand of d-biotin, chemical synthesis has more important application significance. [0005] The Chinese patent application with publication number CN 1145072A discloses an improved method for preparing d-biotin intermediate products. The chemical name for benzylbiotin is 5-[(3aS,4S,6aR)-1,3-dibenzyl-hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl ] valeric ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 张谦吴英李松松石春晓
Owner ZHEJIANG NHU CO LTD
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