A kind of preparation method of clotrimazole

A clotrimazole and chlorophenyl technology, applied in the field of medicinal chemistry, can solve the problems of poor compliance, high equipment and operation requirements, unfavorable industrial production, etc., to reduce the risk of impact, shorten the process cycle, and reduce the discharge of three wastes Effect

Active Publication Date: 2022-03-11
无锡富泽药业有限公司
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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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  • A kind of preparation method of clotrimazole
  • A kind of preparation method of clotrimazole
  • A kind of 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 complete, cool the reaction solution to 30-40°C, concentrate under reduced pressure at 30-40°C, add 500 mL 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 kind of preparation method of clotrimazole, comprises the following steps: Step 1: (2-chlorophenyl) diphenyl carbinol is chlorinated into (2-chlorophenyl) diphenylchloromethane; Step 2: (2-chlorophenyl) diphenylchloromethane and imidazole are condensed into clotrimazole; the overall reaction flow formula is: a kind of preparation method of clotrimazole provided by the invention, starting material (2-chlorophenyl) Diphenylmethanol and imidazole are easy to obtain and have stable performance, and the reaction conditions are mild. The water-unstable product synthesized in step 1 can be directly used in step 2 without separation and purification, which not only reduces the requirements for equipment and operation, but also reduces the The risk of affecting the quality of raw materials, simple operation, short process cycle, and high product purity are suitable for industrial production. In addition, the reaction solvent in step 1 is also the reaction solvent in step 2, which reduces the discharge of three wastes and is more conducive to environmental protection.

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 Patents(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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