Preparation method of clotrimazole

A technology of clotrimazole and chlorophenyl, which is applied in the field of medicinal chemistry, can solve the problems of inconsistency, unfavorable industrial production, high equipment and operation requirements, etc., to reduce the risk of impact, shorten the process cycle, and reduce the cost of equipment and operation required effect

Active Publication Date: 2020-07-17
无锡富泽药业有限公司
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  • Abstract
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Problems solved by technology

[0005] There are two traditional chemical synthesis methods for clotrimazole, one is to use o-chlorotoluene as raw material, and obtain or o-chlorobenzotrichlorotoluene through chlorination reaction, Friedel-Crafts reaction and condensation reaction, and then through Friedel-Crafts reaction, hydrolysis reaction and Condensation reaction; this method either uses the highly toxic substance "benzene" or a phosphate compound with a genotoxic warning structure, which does not meet the requirements of contemporary drug research
The other one takes o-chlorobenzoic acid as a raw material and obtains it through reactions such as esterification reaction, Grignard reaction, hydrolysis reaction, chlorination reaction and condensation reaction; although this method can separate (2-chlorophenyl ) diphenylchloromethane, but it has high requirements for equipment and operation, which is not conducive to industrial production

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  • Preparation method of clotrimazole
  • Preparation method of clotrimazole
  • Preparation method of clotrimazole

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Embodiment 1

[0028] This embodiment discloses a preparation method of clotrimazole, including step 1 and step 2, the overall reaction flow formula is:

[0029]

[0030] Step 1: (2-chlorophenyl) diphenylmethanol is chlorinated into (2-chlorophenyl) diphenylchloromethane, and the specific operations are as follows:

[0031] Add 1L of toluene and 100g of (2-chlorophenyl) benzylmethanol to a 2L three-necked flask, stir to dissolve, add 5ml of N,N-dimethylformamide and 10g of thionyl chloride, and raise the temperature to 60-65°C to initiate , start to add 91g of thionyl chloride dropwise after triggering, and control the temperature during the process not to exceed 65°C.

[0032] After the reaction was completed, the temperature was raised to 90-95°C, and atmospheric distillation was started, and the distillation was continued for 2 hours after no obvious fractions flowed out. The temperature was lowered to 30-35°C, and distillation under reduced pressure was carried out at this temperatur...

Embodiment 2

[0037] This embodiment discloses a preparation method of clotrimazole, including step 1 and step 2, the overall reaction flow formula is:

[0038]

[0039] Step 1: (2-chlorophenyl) diphenylmethanol is chlorinated into (2-chlorophenyl) diphenylchloromethane, and the specific operations are as follows:

[0040] Add 500L of toluene and 100g of (2-chlorophenyl) benzylmethanol to a 1L three-necked flask, stir to dissolve, add 5ml of N,N-dimethylformamide and 10g of thionyl chloride, and raise the temperature to 60-65°C to trigger. After initiation, 91 g of thionyl chloride was added dropwise (the temperature was controlled not to exceed 65° C. during the process). After the dropwise addition, keep warm and stir at 60-65°C for 2h.

[0041] After the reaction is completed, cool the reaction solution to 30-40°C, concentrate under reduced pressure at 30-40°C, add 500mL of toluene after solid precipitation, continue to concentrate under reduced pressure at 30-40°C, and collect about...

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Abstract

The invention provides a preparation method of clotrimazole. The preparation method comprises the following steps: step 1, chlorinating (2-chlorphenyl) diphenyl methanol into (2-chlorphenyl) diphenylchloromethane; 2, subjecting (2-chlorphenyl) diphenyl chloromethane and imidazole to condensation to form clotrimazole; the total reaction flow formula is shown in the specification. The invention provides a preparation method of clotrimazole. The initial raw materials (2-chlorphenyl) diphenyl methanol and imidazole are easy to obtain and stable in performance; reaction condition mildness, a product which is unstable when meeting water and synthesized in step 1 does not need to be separated and purified, and can be applied directly in step 2, not only are the requirements on equipment and operation reduced, but also the risk of influencing the quality of the raw material medicine is reduced; the preparation method is simple in operation, short in process period, high in product purity andsuitable for industrial production, , in addition, the reaction solvent in the step 1 is also the reaction solvent in the step 2, emission of three wastes is reduced, and environmental protection is better facilitated.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of clotrimazole. Background technique [0002] Clotrimazole, the chemical name is 1-[(2-chlorophenyl) benzhydryl]-1H-imidazole, CAS: 23593-75-1, has the chemical structure shown in the following formula: [0003] [0004] Clotrimazole is a broad-spectrum antifungal drug, which has good antibacterial effect on various fungi, especially Candida albicans. Its mechanism of action is to inhibit the synthesis of fungal cell membrane and affect its metabolic process. It has antibacterial effect on superficial fungi and some deep fungi. [0005] There are two traditional chemical synthesis methods for clotrimazole, one is to use o-chlorotoluene as a raw material, and obtain or o-chlorobenzotrichlorotoluene through chlorination reaction, Friedel-Crafts reaction and condensation reaction, and then through Friedel-Crafts reaction, hydrolysis reaction and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/62
CPCC07D233/62
Inventor 吴鹏程胡新祥谢卫锋
Owner 无锡富泽药业有限公司
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