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Synthetic method of 7-MAC intermediate

A synthesis method, the technology of metoxycephalosporin, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of 7-TMCA synthesis method not mentioned, low reactivity, insufficient reaction, etc., to reduce production costs, reduce costs, The effect of easy operation

Active Publication Date: 2010-04-21
CANGZHOU SENARY CHEM SCI TEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This patent does not mention the synthesis method of 7-TMCA, and the raw material methyl sulfide chloride used when obtaining imidization is not highly reactive, which will cause insufficient reaction
In the synthesis of raw material diphenyldiazomethane, there are unfavorable factors such as high cost and cumbersome operation by reacting benzophenone hydrazone with chloramine T.

Method used

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  • Synthetic method of 7-MAC intermediate
  • Synthetic method of 7-MAC intermediate
  • Synthetic method of 7-MAC intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (1), Synthesis of 7-TMCA: In a 1000ml four-necked reaction flask, add 21.74 grams of 7-ACA, 13 grams of methylmercaptotetrazolium, and 200 grams of acetonitrile, stir evenly, cool to 0°C to 5°C, add concentrated Sulfuric acid 180g, react at 30°C for 3 hours, after the reaction, cool the reaction liquid to 0°C-5°C, add 750g of purified water dropwise, control the temperature during the dropwise addition to less than 20°C, add concentrated ammonia water dropwise to adjust the pH value to 4.0, and control the temperature When the temperature is lower than 20°C, stir for 30 minutes and grow crystals for 1 hour. Then filter, rinse twice with water and acetone respectively to obtain a wet product, vacuum-dry at below 40°C until the weight content of water is less than 1%, and the powder is collected to obtain about 22 grams of the product.

[0024] (2), the synthesis of formula III intermediate:

[0025] A. Preparation of methyl sulfide bromide: Add 16.4 grams of dimethyl di...

Embodiment 2

[0032] (1), the synthesis of 7-TMCA is the same as in Example 1.

[0033] (2), the synthesis of formula III intermediate:

[0034] The preparation of A, methyl thio bromide is the same as in Example 1.

[0035] B, the preparation of diphenyldiazomethane is the same as in Example 1.

[0036] C. Synthesis of the intermediate of formula III: 1000ml four-neck bottle with reflux condenser, put 22 grams of 7-TMCA, stir for 10 minutes with an appropriate amount of dichloromethane, add 40 grams of hexamethyldisilamine (HMDS) dropwise, and react for 4 hours , the rest of the operations were the same as in Example 1, and about 29.5 grams of the intermediate of formula III were obtained, the HPLC purity was ≥99%, and the moisture content was ≤0.8% (weight).

[0037] (3), the synthesis of 7-MAC is the same as in Example 1.

Embodiment 3

[0039] (1), the synthesis of 7-TMCA is the same as in Example 1.

[0040] (2), the synthesis of formula III intermediate:

[0041] The preparation of A, methyl thio bromide is the same as in Example 1.

[0042] B, the preparation of diphenyldiazomethane is the same as in Example 1.

[0043] C, the synthesis of formula III intermediate: in this step, use the mixed solution of trimethyl monochlorosilane (TMCS), diazabicyclo (DBU) and trimethyl iodosilane (TMIS) as carboxyl protecting agent, the mixing The volume ratio of each composition of liquid is 1: 1: 1, and all the other are identical with embodiment 1 this step.

[0044] (3), the synthesis of 7-MAC is the same as in Example 1.

[0045] The HPLC purity of the 7-MAC obtained in this embodiment is ≥98%, the light transmittance is ≥80%, and the moisture content is ≤0.5% (weight).

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Abstract

The invention discloses a synthetic method of a 7-MAC intermediate, which comprises the following steps: reacting 7-ACA as raw material with MMTZ to obtain 7-TMAC; enabling the 7-TMAC and methyl sulfur bromide to undergo imidization, and then, reacting the imidization product with diphenyl diazomethane to obtain the intermediate; and enabling the intermediate and a methoxylation reagent to undergo methoxylation reaction to obtain a finished product. In the synthetic method, the 7-ACA which can be obtained easily is used as original material to synthesize the 7-TMAC, thereby reducing the production cost. In the imidization reagent of the synthetic method, methyl sulfur chloride is replaced by the methyl sulfur bromide, thereby increasing the reaction activity, improving the yield, simplifying the operation and reducing the cost.

Description

technical field [0001] The present invention relates to a synthetic method of a pharmaceutical intermediate, especially a key mother nucleus of methoxycephalosporin 7-αmethoxy-7-amino-3-methyltetrazolium thiomethyl cephalosporanic acid benzidine The synthetic method of base ester (referred to as 7-MAC). Background technique [0002] Metoxycephalosporin refers to a cephalosporin with a trans-methoxyl group on the 7th carbon of the β-lactam ring of the cephalosporin nucleus. The destructive power to the β-lactam ring is weakened, so that this class of antibiotics has strong resistance to β-lactamase, and has strong antibacterial ability against some bacteria that produce β-lactamase. Such cephalosporins mainly include cefmetazole, cefotetan, cefbuperazone, cefminox, etc., and 7-αmethoxy-7-amino-3-methyltetrazolium thiomethyl cephalosporanic acid benzidine 7-MAC (abbreviated as 7-MAC) is the key core of these cephalosporin products, which has the following chemical structure:...

Claims

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Application Information

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IPC IPC(8): C07D501/18C07D501/04
Inventor 牛志刚白松明李志刚于树岭
Owner CANGZHOU SENARY CHEM SCI TEC
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