Method for preparing D-biotin bromide intermediate

Abstract

The invention discloses a method for preparing a D-biotin bromide intermediate. The method comprises: S1) carrying out a reaction on a compound 3 and a 1-bromo-3-methoxypropane magnesium bromide Grignard reagent to obtain a compound 4; S2) carrying out a reflux dewatering reaction on the compound 4 under the action of p-toluenesulfonic acid to obtain a compound 5; S3) carrying out a hydrogenationreaction on the compound 5 to obtain a compound 6; and S4) carrying out a cyclization reaction on the compound 6 to obtain a bromide intermediate. According to the present invention, the 1-bromo-3-methoxypropane magnesium bromide Grignard reagent is prepared through self-initiation; the method has advantages of mild reaction conditions, simple and safe operation, easy large-scale production and the like; and with the method, the total molar yield of the four steps can achieve more than 75%, the product purity is up to more than 98%, and the inexpensive and easily-available palladium carbon catalyst can be used in the hydrogenation reaction and can be recycled.

Description

technical field [0001] The invention relates to a method for preparing a D-biotin bromide intermediate, belonging to the technical field of medicinal chemistry. Background technique [0002] D-Biotin, also known as vitamin H, is one of the water-soluble B vitamins. It is widely distributed in animal and plant tissues, such as mainly in liver, kidney, egg yolk, yeast and milk, and also in Plant seeds, pollen, molasses, fungi, fresh vegetables and fruits. D-biotin is an important vitamin, the prosthetic group of carboxylase, and one of the important coenzymes in the intermediate metabolism of sugar, protein and fat. The lack of biotin in humans can cause symptoms such as dermatitis, loss of appetite, nausea, vomiting, depigmentation, and hair loss. D-biotin is also necessary for the normal growth of poultry and livestock, so it is widely used in medical treatment and feed additives. [0003] The chemical name of D-biotin is: (3aS-(3aα,4β,6aα)-hexahydro-2-oxo-1H-thieno[3,4-d...

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Problems solved by technology

[0007] Because the total yield of the above-mentioned route has only 51% (in thiolactone intermediate 3), in order to meet the requirements of suitability for industrialized production, in 2001, the Chemical Journal of Universities, 2001, 27 (7), reported the above-mentioned route in 1141-1146 The following process improvement was carried out: compound 3 and 3-methoxypropylmagnesium bromide were refluxed in an inexpensive methyl tert-butyl ether (MTBE) solvent for Grignard alkylation reaction, and the compound was completely converted into the compound within 5 hours 4; then dehydrated by TsOH-silica gel to generate compound 5; under the induction of two chiral centers of 3aS and 6aR, the palladium / ammonium formate reduced body was dispersed in D296 resin for catalytic hydrogen transfer reaction to obtain stereospecific compound 6, and then Under the phase-transfer catalysis of bromogeramine (DBMAB), react 3 hours at 75 ℃ with 35% hydrobromic acid, promptly obtain bromine salt intermediate; Although this improved technique can make four-step yield reach 73%, but this technique is industrial Can run into following two problems in the production: the one, in the Grignard reaction step of the first step, use iodine as initiator, cause triggering reaction very violently, the worker's control is inconvenient, and safety accident easily takes place; The catalyst used in the three-step hydrogenation reaction is an ion exchange resin D296 supported palladium catalyst, which is not easy to obtain, consumes a large amount and is not easy to recycle and reuse, so that the production cost is high and it is not suitable for large-scale production.

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