阅读说明：本技术 一种头孢吡普侧链中间体的合成制备方法 (Synthesis and preparation method of cefepime side chain intermediate ) 是由 王作弟 于 2020-06-18 设计创作，主要内容包括：本发明公开了一种头孢吡普侧链中间体的合成制备方法,包括以下步骤：以化合物7-[2-(5-氨基-[1,2,4]噻二唑-3-基)-2-三苯甲氧基亚氨基-乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂-二环并[4.2.0]辛-2-烯-2-羧酸二苯甲基酯为原料,将反应物原料、草酰氯及二甲基亚砜分别用二氯甲烷溶液稀释,稀释完后进行混合,低温反应1-2h,低温下滴加有机碱搅拌0.5h,然后升温至0℃,滴加水,溶液由悬浮液变成澄清液,分层,有机层用盐水洗,干燥,旋干得目标产物7-[2-(5-氨基-[1,2,4]噻二唑-3-基)-2-三苯甲氧基亚氨基-乙酰氨基]-3-甲酰基-8-氧代-5-硫杂-1-氮杂-二环并[4.2.0]辛-2-烯-2-羧酸二苯甲基酯。本发明摩尔收率及高效液相检测纯度都较高。(The invention discloses a synthesis preparation method of a cefepime side chain intermediate, which comprises the following steps: using a compound 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-triphenylmethoxy imino-acetamido ] -3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate as a raw material, respectively diluting reactant raw materials, oxalyl chloride and dimethyl sulfoxide with a dichloromethane solution, mixing after dilution, reacting at a low temperature for 1-2h, dropwise adding an organic base at a low temperature, stirring for 0.5h, heating to 0 ℃, dropwise adding water, enabling the solution to become a clear solution from a suspension, layering, washing an organic layer with brine, drying, spin-drying to obtain a target product 7- [2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-trityloxyimino-acetamido ] -3-formyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester. The invention has high molar yield and high performance liquid detection purity.)

1. A synthetic preparation method of a cefepime side chain intermediate is characterized by comprising the following steps:

(1) taking a compound 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-triphenylmethoxy imino-acetamido ] -3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate as a raw material, and respectively diluting the reactant raw material, oxalyl chloride and dimethyl sulfoxide with a dichloromethane solution for later use;

(2) dropwise adding the diluted dimethyl sulfoxide solution into the diluted oxalyl chloride solution, activating at low temperature for 0.5-1h, and then dropwise adding the diluted raw material solution, wherein the oxidation reaction time is 1-5h at the temperature of-50-70 ℃;

(3) dropping organic base at the temperature of-50-70 ℃, stirring for 0.5h, then heating to 0 ℃, dropping 100g of water, changing the solution into clear solution from the suspension, layering, washing the organic layer with brine, drying, and spin-drying to obtain a white foam target product 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-trityloxyimino-acetamido ] -3-formyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate, wherein the reaction formula is as follows:

2. the method for synthesizing and preparing the cefepime side chain intermediate as claimed in claim 1, wherein the organic base is triethylamine.

3. The synthetic preparation method of cefepime side chain intermediate as claimed in claim 1, characterized in that the temperature is-65 ℃.

4. The synthetic preparation method of the cefepime side chain intermediate as claimed in claim 1, characterized in that the oxidation reaction time is 2 h.

5. The method for synthesizing and preparing cefepime side chain intermediate as claimed in any one of claims 1 to 2, wherein the molar ratio of the raw materials oxalyl chloride, dimethyl sulfoxide and organic base is 1.0: 1.0-1.5: 2.0-3.0: 3.0-6.0.

6. The method for synthesizing and preparing cefepime side chain intermediate as claimed in claim 4, wherein the molar ratio of the raw material oxalyl chloride to dimethyl sulfoxide to the organic base is 1.0: 1.1: 2.2: 4.0.

Technical Field

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a synthetic preparation method of a cefepime side chain intermediate.

Background

The cephalosporin is a fifth generation cephalosporin antibiotic drug, developed by basilea pharmaceutical, and approved to be marketed in canada 6.30.2008, and can inhibit synthesis and metabolism of bacterial cell walls, so that the cephalosporin plays a bactericidal role, has antibacterial activity on gram-positive bacteria, gram-negative bacteria and anaerobic bacteria, is the first cephalosporin drug effective on MRSA and VRSA, and has a wide application prospect, and the cephalosporin is an important intermediate in the synthesis process of the cephalosporin.

The chemical name of the compound is as follows: 7- [2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-trityloxyimino-acetamido ] -3-formyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester, the present synthetic method has been reported more (Hebei chemical volume 35, 4 th and Chinese antibiotic journal about new progress in the development of broad spectrum cephalosporin antibiotics [ J ], etc.), excessive oxidation to carboxylic acid, and due to being two-phase, stirring is not uniform, causing problems of yield, impurities, cost, and scale.

Chinese invention patent (publication No. CN1915997A) discloses oxidation by sodium hypochlorite: dissolving 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-trityloxyimino-acetamido ] -3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate in dichloromethane, treating with an aqueous solution of potassium bromide and sodium bicarbonate, treating the mixture at 0 ℃ with a dichloromethane solution of 2,2, 6, 6-tetramethylpiperidine oxide, reacting the mixture with an aqueous solution of sodium hypochlorite under vigorous stirring, filtering, washing an organic layer with brine, drying, filtering, stirring with silica, filtering, and evaporating to dryness to obtain the product. The method is complicated to operate, and the reaction product is unstable and easily reoxidized, so that it is not suitable for large-scale production.

Chinese invention patent (publication No. CN1915997A) also discloses oxidation by manganese dioxide: dissolving 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-trityloxyimino-acetamido ] -3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate in a mixed solvent of tetrahydrofuran and dichloromethane, adding manganese dioxide in portions under stirring to react, and adding activated carbon and ethyl acetate to the obtained suspension. The mixture was concentrated, n-hexane was added to the resulting suspension, and the mixture was purified by silica gel chromatography using a 1:2 mixture of n-hexane and ethyl acetate as an eluent. The product fractions were collected, evaporated to dryness under suction vacuum and the resulting foam triturated with tert-butyl methyl ether to give the title compound as a yellow powder. The method has high requirement on the activity of manganese dioxide, low conversion rate of reaction products, difficult separation of products by post-treatment, need of column chromatography purification and separation, higher cost and unsuitability for large-scale production.

Therefore, a preparation method of 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-trityloxyimino-acetamido ] -3-formyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester which is a cephalosporin important intermediate and has high yield and is suitable for large-scale production is needed in the field.

Disclosure of Invention

In order to overcome the defects of low reaction conversion rate and difficult separation of post-treatment in the prior art, the invention provides the synthesis and preparation method of the cefepime side chain intermediate, which has high molar yield and high-performance liquid detection purity, can provide guarantee for the quality and cost of subsequent products and meets the requirement of large-scale production.

A synthetic preparation method of a cefepime side chain intermediate is characterized by comprising the following steps:

(1) taking a compound 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-triphenylmethoxy imino-acetamido ] -3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate as a raw material, and respectively diluting the reactant raw material, oxalyl chloride and dimethyl sulfoxide with a dichloromethane solution for later use;

(2) dropwise adding the diluted dimethyl sulfoxide solution into the diluted oxalyl chloride solution, activating at low temperature for 0.5-1h, and then dropwise adding the diluted raw material solution, wherein the oxidation reaction time is 1-5h at the temperature of-50-70 ℃;

(3) dropwise adding organic base at the temperature of-50-70 ℃, stirring for 0.5h, heating to 0 ℃, dropwise adding water, changing the solution into clear solution from the suspension, layering, washing an organic layer with brine, drying, and spin-drying to obtain a white foam target product 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-trityloxyimino-acetamido ] -3-formyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate, wherein the reaction formula is as follows:

preferably, the organic base is triethylamine.

Preferably, the temperature is-65 ℃.

Preferably, the reaction time is 2 h.

Further, the molar ratio of the raw materials to the oxalyl chloride to the dimethyl sulfoxide to the organic base is 1.0: 1.0-1.5: 2.0-3.0: 3.0-6.0.

Preferably, the molar ratio of the raw material to the oxalyl chloride to the dimethyl sulfoxide to the organic base is 1.0: 1.1: 2.2: 4.0.

The invention takes a compound 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-triphenylmethoxy imino-acetamido ] -3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate as a raw material, and uses dimethyl sulfoxide as an oxidant and organic alkali to oxidize hydroxyl in the structure of the raw material compound into carbonyl under the synergistic action of oxalyl chloride in a low-temperature environment to obtain a target compound.

Compared with other synthesis methods, the synthesis method of 7- [2- (5-amino- [1, 2, 4] thiadiazole-3-yl) -2-triphenylmethoxyimino-acetamido ] -3-formyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-diphenylmethyl carboxylate has good tolerance to functional groups of substrates and high conversion rate of reaction products, and the purity (LC) of the product provided by the method can reach 98%, so that the product provided by the method has great advantages in purity and meets the amplification requirement.

Detailed Description

The present invention will be described in detail with reference to examples, but the scope of the invention to be claimed is not limited to the scope expressed by the examples.