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Preparation method of 5-(2-oxytetrahydrothiophene imidazole-4(2H)-alkenyl pentanoic acid compounds

A technology of benzimidazole and phenyltetrahydroimidazole is applied in the field of preparation of d-biotin intermediate 5-alkenyl)valeric acid compounds, which can solve serious side reactions, difficult separation and purification, and many reaction impurities. problems, to achieve the effect of easy separation, good safety and high yield

Active Publication Date: 2019-03-22
ZHEJIANG NHU CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The methods reported by Subhash P.Chavan and Chen Kexi all use zinc powder reduction and cyclization under acidic conditions. The reaction has many impurities, serious side reactions, and difficult separation and purification.

Method used

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  • Preparation method of 5-(2-oxytetrahydrothiophene imidazole-4(2H)-alkenyl pentanoic acid compounds
  • Preparation method of 5-(2-oxytetrahydrothiophene imidazole-4(2H)-alkenyl pentanoic acid compounds
  • Preparation method of 5-(2-oxytetrahydrothiophene imidazole-4(2H)-alkenyl pentanoic acid compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: (3S,7aR)-6-benzyl-7-(2-oxocyclohexyl)-3-phenyltetrahydroimidazo[1,5-c]thiazol-5(3H)-one preparation

[0064] In a 500mL three-necked flask equipped with mechanical stirring and a thermometer, add 200mL of dichloromethane, and drop 32.6g (0.1mol) of compound (1a) (R 1 = phenyl, R 2 = benzyl, R 3 =H), add 18.7g (0.11mol) of 1-cyclohexenyloxytrimethylsilane, protect with nitrogen, stir and cool to -45°C, add 14.2g (0.1mol) of boron trifluoride diethyl ether dropwise in half an hour, Control the temperature at -45~-10℃, stir and react for 2~3 hours; after the reaction is completed, raise the temperature to -5~0℃, add water 50mL dropwise, separate layers, add dichloromethane 100mL×2 to extract twice, combine dichloromethane The methane organic phase was washed twice with saturated aqueous sodium bicarbonate solution 50mL×2, the above dichloromethane layer was evaporated, and the product was dried to obtain the target product (2a)(3S,7aR)-6-benzyl-7-(2 -Oxocycl...

Embodiment 14

[0066] Example 14: 6-((3S,7aR)-6-benzyl-5-oxo-3-phenylhexahydroimidazo[1,5-c]thiazol-7-yl-6-oxohexanoic acid Sodium preparation

[0067] In a 500mL autoclave with mechanical stirring and a thermometer, add 300mL of ethanol, and put the compound (2a)(3S,7aR)-6-benzyl-7-(2-oxocyclohexyl)- 3-Phenyltetrahydroimidazo[1,5-c]thiazol-5(3H)-one 40.6g(0.1mol)(R 1 = phenyl, R 2 = benzyl), add 4.0g (0.1mol) of sodium hydroxide, 26.2g (0.1mol) of cocatalyst triphenylphosphine, feed air to 0.3MPa (gauge pressure), stir and heat up to 40°C for reaction, with the reaction If the pressure drops, continue to add air. When the pressure does not drop, release the pressure to 0MPa (gauge pressure), and refill the air to 0.3MPa (gauge pressure). If the pressure does not drop, the previous reaction is completed (oxygen It is not necessary to release the pressure until the early reaction is completed). Remove the pressure, add 0.4g (0.005mol) of manganese dioxide, feed air until the reaction is c...

Embodiment 27

[0069] Example 27: Preparation of 6-((5R)-1,3-dibenzyl-5-(mercaptomethyl)-2-oxoimidazol-4-yl)-6-oxohexanoic acid

[0070] In a 500mL three-neck flask with mechanical stirring and a thermometer, put the compound (3a) 6-((3S,7aR)-6-benzyl-5-oxo-3-phenylhexahydro Imidazo[1,5-c]thiazol-7-yl-6-oxohexanoic acid sodium aqueous solution 320mL, containing compound (3a) 46.0g (0.1mol) (R 1 = phenyl, R 2 = benzyl), add 32.7g (0.5mol) of 500 mesh zinc powder at room temperature, protect with nitrogen, stir and heat up to 40°C, add dropwise 30% NaOH (26.6g, 0.2mol), control the pH value at 11.0~13.0, control The temperature is 40-45°C, stirring and reacting for 5-6 hours; after the reaction is completed, remove it by hot filtration, wash the filter cake with 100mL water, adjust the pH value of the filtrate to 3.5-4.0 with 30% HCl solution, add 200mL×2 toluene to extract twice , the toluene extract was washed twice with 50mL×2 water to obtain the target product (4a) 6-((5R)-1,3-dibenzyl-5...

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Abstract

The invention discloses a preparation method of 5-(2-oxytetrahydrothiophene imidazole-4(2H)-alkenyl pentanoic acid compounds. The preparation method comprises the following steps: performing reactionon (3S,7aR)-6-substituted benzyl-7-alkoxy-3-substituted phenyl tetrahydroimidazole[1,5-c]thiazole-5(3H)-ketone and 1-cyclohexene oxytrimethylsilane to generate (3S,7aR)-6-substituted benzyl-7-(2-oxycyclohexyl)-3-substituted tetrahydroimidazole[1,5-c]thiazole-5(3H)-ketone, and sequentially performing ring-opening reaction, reduction ring-opening reaction, cyclization and elimination reaction to obtain the 5-(2-oxytetrahydrothiophene imidazole-4(2H)-alkenyl pentanoic acid compounds. The preparation method has the advantages of little side reaction, high yield, environmental friendliness, mild and easily controlled reaction condition and simplicity in aftertreatment, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical raw materials, in particular to a preparation method of a d-biotin intermediate 5-(2-oxotetrahydrothienoimidazole-4(2H)-enyl)pentanoic acid compound. Background technique [0002] d-biotin is also called vitamin H and coenzyme R, and its chemical name is (3aS,4S,6aR)-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentane Acids, belonging to the water-soluble B vitamins, are used as medicines and feed additives. D-biotin is distributed in animal and plant tissues and can be isolated from liver extract and egg yolk. It is a component of various carboxylase prosthetic groups and is an essential substance for the growth and development of animals and plants. d-biotin is now generally obtained by chemical synthesis. [0003] The structure of d-biotin is as follows: [0004] [0005] The specific synthetic method of d-biotin is as follows: [0006] Chen Fen'er and others reported a synth...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 钱洪胜车来滨吴可军张凯超张甲春胡建权李其川于凯姜恒菊韦念想
Owner ZHEJIANG NHU CO LTD
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