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Preparation method of lanoconazole

A technology of lanoconazole and suranoconazole, which is applied in the field of preparation of lanoconazole, can solve the problems of unstable reaction and low yield, improve yield and purity quality, avoid excessive impurities, Guarantee the effect of stable reaction

Pending Publication Date: 2022-06-17
浙江东亚药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention aims at the defects existing in the above prior art, and provides a preparation method of lanoconazole, which solves the problems of unstable reaction and low yield in the prior art

Method used

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  • Preparation method of lanoconazole
  • Preparation method of lanoconazole
  • Preparation method of lanoconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] 150±5kg of anhydrous methanol was pumped into the reactor, stirring was started, 20kg (107.2mol) of 2-chloromandelic acid and 0.5kg of concentrated sulfuric acid were added, the hot water valve was opened, the temperature was raised to 65° C. for reflux reaction for 3h, and the reaction ended. After cooling down to room temperature, add 10% sodium hydroxide aqueous solution dropwise to the reaction solution to adjust the pH value to near neutrality, after stabilization, then heat up to 50 ℃~60 ℃ to carry out vacuum distillation to recover methanol solvent When it is dry, add 20±2kg of dichloromethane to the residue, stir and mix without uniformity, obtain a light yellow liquid viscous substance containing compound VI of dichloromethane, and directly proceed to the next step.

Embodiment 2

[0044]

[0045] The dichloromethane solvent of 200 ± 5kg was pumped into the reactor, stirring was started, the compound VI obtained in the above-mentioned embodiment 1 was completely dissolved, the basic catalyst DMF of 0.4kg was added, and the temperature was raised to 40~45 ℃ under stirring. Add the mixed solution of 16.3kg (128.6mol) of oxalyl chloride and 20±2kg of dichloromethane in a clean and dry high-level tank, and the temperature of the dropwise addition process is controlled within this range. After the dropwise addition, the reflux reaction is continued for 1h. , the reaction solution is slowly cooled down to room temperature, and then slowly add cold water 50 ± 5kg to the reaction kettle, and then use a mass percentage of 20% Na 2 CO 3 Aqueous solution 70 ± 5kg, adjust the pH value of the reaction solution to 6 ~ 7, stir for 30 minutes, stand for stratification, collect the organic phase, the upper layer aqueous phase can be extracted once with 50 ± 5kg of dic...

Embodiment 3

[0047]

[0048] In the yellow liquid compound II that above-mentioned embodiment 2 obtains, add 200 ± 5kg methanol solvent, carry out cooling and cooling, the reaction liquid system is cooled to 0~5 ℃, add potassium borohydride again in batches and the total amount is 14.4kg ( 268mol), control the feeding in 2~3h, and then control the temperature at 0~5℃ under ice bath cooling to continue the reaction for 2h. After the reaction, let the system temperature reach room temperature and continue to stir the reaction for 2h. After the end, use the mass percentage as 10% dilute hydrochloric acid was used to adjust the pH of the system to neutrality, then the temperature was raised to 50-60°C, and the methanol solvent was evaporated under reduced pressure to recover the methanol solvent, and about 100 ± 5kg was evaporated. Analyze the crystal, centrifuge, remove the white solid salt, wash with 20 ± 2kg methanol, the filtrate continues to concentrate under reduced pressure, steam abo...

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Abstract

The invention relates to a preparation method of lanoconazole, and belongs to the technical field of medicine synthesis. The invention aims to solve the problems of unstable reaction and low yield in the prior art. The invention provides a preparation method of lanoconazole, which comprises the following steps: by taking 2-chloromandelic acid as a raw material, firstly carrying out esterification reaction and chlorination reaction to synthesize an intermediate compound as shown in a formula II, and further carrying out reduction reaction on the compound as shown in the formula II in the presence of hydroboron to obtain a compound as shown in a formula III; in the presence of an acid applying agent, reacting the compound shown in the formula III with methylsulfonyl chloride to obtain a compound shown in a formula IV; the preparation method comprises the following steps: adding 1-imidazolyl acetonitrile, carbon dioxide and a phase transfer catalyst into a mixed solution of an organic solvent and water, adding a strongly alkaline potassium salt for reaction to obtain a reaction solution, adding a weakly alkaline buffer system into the reaction solution, then adding an intermediate compound shown as a formula IV for cyclization reaction, and after the cyclization reaction is finished, concentrating to remove the solvent and recrystallizing to obtain the compound shown as the formula IV. The corresponding product lanoconazole is obtained. The method has the effects of mild and stable reaction and high yield.

Description

technical field [0001] The invention relates to a preparation method of lanoconazole, and belongs to the technical field of drug synthesis. Background technique [0002] Lanoconazole (lanoconazole, 1) is a new and potent imidazole antifungal drug developed by Japan Tsumura Co., Ltd. and first listed in Japan in 1994. Its trade name is [0003] [0004] As a new generation of antifungal drugs, lanoconazole has the same mechanism of action as other imidazoles, mainly by inhibiting the de-14-methylation stage of 14-methyllanosterol to inhibit the synthesis of ergosterol in fungal cells. Antifungal effect. Clinically, it has strong antibacterial activity against a wide range of pathogenic fungi: including yeast, dermatophytes, fungi, dimorphic fungi, Aspergillus, Penicillium and Candida, especially against Trichophyton efficient. It is used for the treatment of fungal infections including tinea pedis, tinea corporis, tinea cruris, candidiasis, tinea versicolor and other ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/06C07C303/28C07C309/66
CPCC07D409/06C07C303/28C07C309/66
Inventor 张道明王佃龙陈玲娣李达刘亚清池骋刚丽霞
Owner 浙江东亚药业股份有限公司
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