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Preparation method for (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione

A benzhydryl and 4-d technology, which is applied in the field of biotin intermediate preparation, can solve problems such as hidden dangers, complicated operation, and high product cost, and achieve the effects of high safety, easy storage, and easy operation

Active Publication Date: 2014-01-22
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is currently the main route adopted by domestic manufacturers. Although the chiral resolving agent is cheap and easy to obtain, this method has the disadvantages of low product yield, poor quality, cumbersome operation and long working hours, resulting in high cost of the final product.
[0004] Chinese patent CN1768063A discloses a method for stereoselectively synthesizing d-lactone. In the disclosed method, the alkali metal hydroxide needs to be added in the form of an aqueous solution, and the operation is relatively complicated. Potential safety hazards, not conducive to industrial production

Method used

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  • Preparation method for (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione
  • Preparation method for (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione
  • Preparation method for (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Adopting the impact of different alkali metal hydroxide hydrates on the reaction yield:

[0026] (1) Add 20g (35.4mmol) of dicarboxylic acid monoester into the three-necked flask, add 300ml of anhydrous tetrahydrofuran, stir to dissolve, then add 40.5mmol of alkali metal hydroxide hydrate, the alkali metal hydroxide hydrate The selection is shown in Table 1. Stir at 20°C until a large amount of dicarboxylic acid monoester alkali metal salt solids are precipitated.

[0027] (2) Raise the temperature to 50-60°C, slowly add 40ml of reducing agent lithium borohydride tetrahydrofuran solution (containing 55.1mmol of lithium borohydride) dropwise. After the dropwise addition, the reaction was continued for 4 h, and tetrahydrofuran was evaporated under atmospheric pressure. Cool down to room temperature, add 300ml of water, and extract the aqueous layer twice with 120ml of toluene. The aqueous phase, which contains the alkali metal hydroxycarboxylate, remains.

[0028](3) P...

Embodiment 2

[0032] The influence of the aqueous solution prepared by different alkali metal hydroxides on the reaction yield:

[0033] (1) Add 20g (35.4mmol) of dicarboxylic acid monoester into the three-necked flask, add 300ml of anhydrous tetrahydrofuran, stir to dissolve, and then add an aqueous solution of alkali metal hydroxide prepared from alkali metal hydroxide and water. See Table 2 for the selection of alkali metal hydroxide and water, and stir at 20°C until a large amount of dicarboxylic acid monoester alkali metal salt solids are precipitated.

[0034] (2) Raise the temperature to 50-60°C, slowly add 40ml of reducing agent lithium borohydride tetrahydrofuran solution (containing 55.1mmol of lithium borohydride) dropwise. After the dropwise addition, the reaction was continued for 4 h, and tetrahydrofuran was evaporated under atmospheric pressure. Cool down to room temperature, add 300ml of water, and extract the aqueous layer twice with 120ml of toluene. The aqueous phase, w...

Embodiment 3

[0039] The impact of different additions of alkali metal hydroxide hydrate on the reaction yield:

[0040] (1) Add 20g (35.4mmol) of dicarboxylic acid monoester into the three-necked flask, add 300ml of anhydrous tetrahydrofuran, stir to dissolve, then add alkali metal hydroxide hydrate, the amount of alkali metal hydroxide hydrate is different See Table 3 for the selection conditions, and stir at 20°C until a large amount of dicarboxylic acid monoester alkali metal salt solids are precipitated.

[0041] (2) Raise the temperature to 50-60°C, slowly add 40ml of reducing agent lithium borohydride tetrahydrofuran solution (containing 55.1mmol of lithium borohydride) dropwise. After the dropwise addition, the reaction was continued for 4 h, and tetrahydrofuran was evaporated under atmospheric pressure. Cool down to room temperature, add 300ml of water, and extract the aqueous layer twice with 120ml of toluene. The aqueous phase, which contains the alkali metal hydroxycarboxylate...

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Abstract

The invention provides a preparation method for (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione, which is applied to the field of preparation of biotin intermediates. The method comprises the following steps: in the presence of an organic solvent, reacting (4S,5R)-1,3-dibenzyl-2-oxo-4,5-imidazolidinedicarboxylic acid-5-[(s)-2-hydroxy-1-toluene-2,2-diphenethyl]ester with alkali metal hydroxide hydrate to produce dicarboxylic acid monoester alkali metal salt; subjecting the dicarboxylic acid monoester alkali metal salt and complex borohydride to a reduction reaction so as to produce hydroxycarboxylic acid alkali metal salt; and subjecting the hydroxycarboxylic acid alkali metal salt to a cyclization reaction in an acidic environment so as to produce (3aS,6aR)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione; wherein the alkali metal hydroxide hydrate comprises alkali metal hydroxide monohydrate and alkali metal hydroxide dihydrate. The invention has the following advantages: raw materials are easily available and convenient to store, operation in the reaction process is easy and convenient, has high security and is low in cost, the yield of the produced product is high, and the method is applicable to industrial production.

Description

technical field [0001] The invention relates to a (3aS,6aR)-1,3-benzhydryl-tetrahydro-1H-furo[3,4-d]imidazole-2,4-dione in the field of biotin intermediate preparation method of preparation. Background technique [0002] (3aS,6aR)-1,3-Benzhydryl-tetrahydro-1H-furo[3,4-d]imidazole-2,4-dione, English name (3aS,6aR)-1,3- dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-dione, referred to as d-lactone, see the attached structure figure 1 , formula C 19 h 18 N 2 o 3 , molecular weight 332.37, CAS No. 28092-62-8, is the key intermediate required for the industrial production of d-biotin (vitamin H, coenzyme R). [0003] The asymmetric synthesis of d-lactones from cyclic meso carboxylic anhydrides with the aid of chiral alcohols is well known in the art. Han Weihua and others mentioned in "Progress in the Synthesis of Biotin Intermediate Lactone" ("Chemical Bulletin" 2004 Issue 08) that the cyclic imide was asymmetrically synthesized using the chloramphenicol intermediate D-am...

Claims

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Application Information

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IPC IPC(8): C07D491/048
CPCC07D491/048
Inventor 刘永明郎福山俎云龙刘艳
Owner NORTHEAST PHARMA GRP
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