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Preparation method of amorolfine hydrochloride

The technology of amorolfine hydrochloride and amorolfine hydrochloride is applied in the field of preparation of amorolfine hydrochloride, which can solve the problems of high waste water treatment cost, high palladium catalysis cost, large safety risk, etc. The effect of high yield and high safety

Inactive Publication Date: 2020-09-25
JIANGSU FUBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although WO2007113218A1 is improved compared with the original research, there are still deficiencies: (1) the first step of Heck reaction, the reaction solvent DMF is moderately toxic, the cost of wastewater treatment is high, and it is easy to decompose at high temperature; (2) the second step of reductive amination reaction, palladium The cost of catalysis is high, metal borohydride produces a large amount of hydrogen, and the safety risk is relatively large

Method used

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  • Preparation method of amorolfine hydrochloride
  • Preparation method of amorolfine hydrochloride
  • Preparation method of amorolfine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach 1

[0034] 1. The preparation of the first intermediate shown in formula III:

[0035]

[0036] 10Kg of 3-(4-tert-amylphenyl)-2-methylpropanol shown in formula II, 9Kg of triethylamine, 80Kg of toluene, at 0°C, slowly add 6Kg of methanesulfonyl chloride dropwise, after the dropwise addition is completed, the temperature is raised to Stir at 25°C for 6 hours. After the reaction is complete, add water, separate and collect the organic phase, extract the water phase with 20Kg toluene once more, combine the organic phases, dry over anhydrous sodium sulfate, filter, and condense the dry solvent to obtain 12Kg of the first compound shown in formula III. Intermediate product, yield 88.6%.

[0037] 2. The preparation of the second intermediate shown in formula IV:

[0038]

[0039] Take 6.5Kg of the first intermediate represented by formula III, 4.4Kg of triethylamine, 3Kg of cis-2,6-dimethylmorpholine, 52Kg of toluene, stir at 25°C for 8h, after the reaction is complete, adjust th...

Embodiment approach 2

[0044] 1. The preparation of the first intermediate shown in formula III:

[0045]

[0046] 10Kg of 3-(4-tert-amylphenyl)-2-methylpropanol represented by formula II, 12Kg of N,N-diisopropylethylamine, 80Kg of toluene, slowly drop 7.8Kg of methanesulfonate at 0°C Acyl chloride, after the dropwise addition, raise the temperature to 25°C, stir for 6 hours, after the reaction is complete, add water, separate and collect the organic phase, extract the water phase with 20Kg toluene once more, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the dry solvent 11Kg of the first intermediate product represented by formula III was obtained, with a yield of 84.2%.

[0047] 2. The preparation of the second intermediate shown in formula IV:

[0048]

[0049]Take 6.5Kg of the first intermediate shown in formula III, 5.6Kg of triethylamine, 2.8Kg of cis-2,6-dimethylmorpholine, 52Kg of dichloromethane, stir at 25°C for 8h, after the reaction is compl...

Embodiment approach 3

[0054] 1. The preparation of the first intermediate shown in formula III:

[0055]

[0056] 10Kg of 3-(4-tert-amylphenyl)-2-methylpropanol shown in formula II, 14Kg of triethylamine, 80Kg of dichloromethane, at 0°C, slowly add 10Kg of methanesulfonyl chloride dropwise, the dropwise addition is completed, Raise the temperature to 25°C, stir for 6 hours, after the reaction is complete, add water, separate and collect the organic phase, extract the water phase with 20Kg toluene once more, combine the organic phases, dry over anhydrous sodium sulfate, filter, and condense the dry solvent to obtain 10.8Kg of formula III The first intermediate product is shown, and the yield is 80.0%.

[0057] 2. The preparation of the second intermediate shown in formula IV:

[0058]

[0059] Take 6.5Kg of the first intermediate represented by formula III, 8.4Kg of N,N-diisopropylethylamine, 3.8Kg of cis-2,6-dimethylmorpholine, 52Kg of tetrahydrofuran, stir at 25°C for 8h, and the reaction i...

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Abstract

The invention relates to the technical field of pharmaceutical preparations. The invention discloses a preparation method of amorolfine hydrochloride. The method comprises the following steps: with 3-(4-tert-amylphenyl)-2-methyl propanol as a raw material, under alkaline condition, performing a reaction on the raw material with methylsulfonyl chloride and performing nucleophilic substitution reaction with cis-2,6-dimethylmorpholine; and finally performing a reaction with hydrogen chloride gas to form the amorolfine hydrochloride, that is, the final product. According to the present invention,the method has advantages of cheap raw material source, easily-controlled process operation, high yield, stable quality, less impurity, significantly-reduced cost compared to other methods, suitability for industrial production, and the like.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of amorolfine hydrochloride. Background technique [0002] Amorolfine hydrochloride (amorolfine hydrochloride), the chemical name is 4-(3-p-tert-pentylphenyl-2-methylpropyl)-cis-2,6-dimethylmorpholine hydrochloride, CAS The registration number is 78613-38-4, and the chemical structure is as follows: [0003] [0004] Amorolfine hydrochloride is an antifungal drug developed by Roche and registered in Europe by French Galderma in March 2002. Its trade name is Loceryl. Squalene monooxygenase (SQLE) is the target, which is suitable for skin infection and fungal infection. About amorolfine hydrochloride synthetic technique, prior art has described: [0005] The synthetic route of the original research patent EP1749826 amorolfine hydrochloride is as follows: [0006] [0007] The original research patent EP1749826 synthetic route: (1) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/30
CPCC07D265/30
Inventor 陈亮黄金友何林受
Owner JIANGSU FUBANG PHARMA