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Method for preparing amorolfine hydrochloride

A technology of amorolfine hydrochloride and glacial acetic acid, which is applied in the direction of organic chemistry, can solve the problems of not meeting the requirements of high-temperature reaction, unsafe high-pressure reaction equipment, and little application value, and achieves easy control, less side reactions, and overall The effect of high yield

Active Publication Date: 2013-01-23
ZHEJIANG HISOAR PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] There are still defects in WO2007113218A1 process: (1) the first step Heck reaction, the reaction solvent DMF has moderate toxicity, and the International Agency for Research on Cancer (IARC) believes that it may be a carcinogen
Polar protic solvents, such as the lower alcohols described in this patent, cannot meet the high-temperature reaction requirements, and polar protic solvents with high boiling points have poor solubility to palladium catalysts, making it difficult to react
Non-polar solvents basically do not dissolve palladium catalysts, so the application value is not great
(2) In the second step of reductive amination reaction, the cost of using precious metal palladium to catalyze hydrogenation is higher, and the high-pressure reaction equipment is unsafe; adopting metal borohydride reduction is easy to generate a large amount of hydrogen, causing potential safety hazards, and 3-tert The reduction of pentylphenyl-2-methylpropanal to the corresponding alcohol increases the impurity; the reduction by-product of metal cyanoborohydride is highly toxic
(3) product yield is on the low side, and the total yield of embodiment product is about 50%

Method used

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  • Method for preparing amorolfine hydrochloride
  • Method for preparing amorolfine hydrochloride
  • Method for preparing amorolfine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Add 2600mL of acetic anhydride, 5200mL of glacial acetic acid, 350g of sodium periodate, and 1236g of iodine into a 10L clean reaction kettle, cool to 5°C, add 810mL of sulfuric acid dropwise, control the dropwise addition within 1 hour, and then add 1130g of tert-amylbenzene , stirred at room temperature for more than 16 hours, and the reaction of raw materials was detected by thin-layer chromatography. Pour the reaction solution into 8L of water and 4L of dichloromethane mixture, extract and separate layers, wash the organic layer once with 4L of 25% aqueous sodium sulfite solution, dry the organic layer with anhydrous sodium sulfate, distill off the solvent dichloromethane to obtain a residue It is 2013 g of 4-iodo-tert-amylbenzene, yield: 96%, GC purity 94.2%. 1H-NMR spectrum data: (400MHz, CDCl 3 ): 0.73 (3H, t, J = 7.4Hz), 1.31 (6H, s), 1.67 (2H, q, J = 7.4Hz), 7.13 (2H, d, J = 8.56Hz), 7.66 (2H, d , J=8.56Hz).

Embodiment 2

[0060] In a 10L clean reactor, add 2kg of 4-iodo-tert-amylbenzene prepared according to the method of Example 1, 6L of N-methylpyrrolidone, nitrogen protection, start stirring, add palladium acetate 300g, sodium bicarbonate 1.7kg, Finally, 2.5 kg of 2-methallyl alcohol was added, and the temperature was raised to 105° C. to react, and the GC content of 4-iodo-tert-amylbenzene was detected to monitor the reaction progress, and the reaction was completed in 2 hours. Cool to room temperature, filter, concentrate the filtrate, add 12L of ethyl acetate to dissolve the residue, wash with 20L of water, rectify the organic phase, collect fractions at 125-128°C (vacuum degree ≤ -0.099Mpa), and obtain 3-tert-amylbenzene 1.41 kg of 2-methylpropanal, yield: 88.6%, GC purity: 93.5%. 1H-NMR spectrum data: (400MHz, CDCl 3 ): 0.69 (3H, t, J = 7.45Hz), 1.11 (3H, d, J = 6.87Hz), 1.29 (6H, s), 1.65 (2H, q, J = 7.43Hz), 2.60 (1H, dd , J = 13.52Hz), 2.69 (1H, J = 7.06Hz), 3.08 (1H, dd, J = 13.54...

Embodiment 3

[0063] In a 10L clean reactor, add 2kg of 4-iodo-tert-amylbenzene prepared according to the method in Example 1, 6L of N-methylpyrrolidone, protect with nitrogen, start stirring, add 150g of palladium acetate, 2.5kg of dipotassium hydrogen phosphate , and finally add 1.8kg of 2-methallyl alcohol, heat up to 130°C for reaction, detect the GC content of 4-iodo-tert-amylbenzene to control the reaction process, and the reaction ends in 10 hours. Cool to room temperature, filter, concentrate the filtrate, add 12L ethyl acetate to dissolve the residue, wash with 20L water, concentrate the organic phase, recover ethyl acetate, add the residue dropwise to 10L saturated sodium bisulfite solution at room temperature, and precipitate a solid. Stir for 6 hours, filter, wash the filter cake with 5L of ethyl acetate, disperse the solid in 10L of 1 mol / L hydrochloric acid, stir at room temperature for 5 hours, extract the reaction solution with 10L of ethyl acetate, dry over anhydrous magnesi...

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Abstract

The invention relates to a method for preparing amorolfine hydrochloride. The method comprises the following steps of: reacting 4-iodo-tert-amylbenzene with 2-methylallyl alcohol by taking N-methylpyrrolidone as a solvent in the presence of a palladium catalyst and alkali to obtain 3-tert-pentylphenyl-2-methyl propanal; performing reductive amination reaction of the obtained 3-tert-pentylphenyl-2-methyl propanal and cis-2,6-dimethylmorpholine by taking sodium triacetoxyborohydride as a reducing agent in the presence of glacial acetic acid to obtain amorolfine; and transforming the amorolfine into the amorolfine hydrochloride. The invention has the advantages that the process is reasonable, is beneficial to the environment, health, and safety (EHS), and is suitable for industrialized production, wastewater is easy to biodegrade, the reaction selectivity is high, the high-yield high-purity product is obtained, and the like.

Description

technical field [0001] The invention relates to a preparation method of amorolfine hydrochloride. Background technique [0002] Amorolfine hydrochloride (amorolfine hydrochloride), the chemical name is cis-4-[3-[4-(1,1-dimethyl-propyl)phenyl]-2-methylpropyl]-2,6 -Dimethyl-morpholine hydrochloride, the CAS registration number is 78613-38-4, and its chemical structure is as follows: [0003] [0004] Amorolfine hydrochloride is an antifungal drug developed by Roche and launched in 1991 under the trade name Leceryl. About the synthetic technique of amorolfine hydrochloride, prior art has described: [0005] U.S. Patent US7795425B2 discloses the synthetic route of amorolfine hydrochloride as follows: [0006] [0007] Synthetic route of US7795425B2: (1) condensation reaction of 2-methylcinnamaldehyde and cis-2,6-dimethylmorpholine to obtain cis-4-(3-phenyl-2-methylpropyl)-2,6- Dimethyl-morpholine hydrochloride, (2) cis-4-(3-phenyl-2-methylpropyl)-2,6-dimethyl-morpholin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/30
CPCC07D265/30
Inventor 唐方辉张群辉叶彬彬王晓艳
Owner ZHEJIANG HISOAR PHARMA
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