Preparation of duloxetine hydrochloride

A technology of duloxetine hydrochloride and mandelic acid, which is applied in the fields of organic chemistry and pharmaceutical chemistry, can solve the problems of increasing costs, restricting industrial production, increasing production cycles, etc., and achieves cost saving, shortening production cycles, and reducing salt-forming steps Effect

Active Publication Date: 2015-08-12
SHANGHAI WANXIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although the above-mentioned patent also utilizes the MITSUNOBU reaction to prepare the R-configuration compound to obtain the compound II, and it is prepared by a one-step reaction, but it needs to be purified by column chromatography to obtain the compound II for the next step reaction, which is in industrial production. The last one is to increase the cost, and the second is to increase the production cycle...

Method used

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  • Preparation of duloxetine hydrochloride
  • Preparation of duloxetine hydrochloride
  • Preparation of duloxetine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] A: Preparation of 2-thiophene-2-dimethylaminomethyl ethyl ketone hydrochloride

[0052] Dissolve 55g (0.44mol) of 2-acetylthiophene, 44.7g (0.55mol) of dimethylamine hydrochloride, and 19.4g (0.61mol) of paraformaldehyde in 190ml of isopropanol, add 4.3ml of concentrated hydrochloric acid, and reflux After 8 hours, it was cooled to room temperature and filtered with suction. The filter cake was washed with 50 ml of cold ethanol, and dried to obtain 88.7 g of white solid, with a yield of 92.4%.

[0053] B: Preparation of N,N-dimethyl-3-hydroxy-3-(2-thiophene)-propylamine

[0054] 85g (0.38mol) 2-thiophene-2-dimethylaminomethyl ethyl ketone hydrochloride, 260ml ethanol and 130ml water were mixed and stirred to dissolve, and 13.9g NaOH was slowly added at room temperature to adjust the pH value to 11-12, and then added 14.5 g (0.37 mol) of sodium borohydride was reacted overnight at room temperature. After the reaction was completed, 160 ml of acetone was added to quench ...

Embodiment 2

[0064] A: Preparation of (S)-N,N-dimethyl-3-p-nitrobenzoate-3-(2-thienyl)propylamine

[0065] 29g (0.16mol) (R)-N, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (resolved in Example 1), 31g (0.19mol) p-nitrobenzene Formic acid, 49.4g (0.19mol) of triphenylphosphine, mixed and dissolved in 240ml of tetrahydrofuran, cooled in an ice bath to 0-5°C, slowly added 32.9g (0.19mol) of diethyl azodicarboxylate, the temperature did not exceed 10°C, remove the ice bath after dripping, warm up to room temperature, react overnight, after TLC detects that the reaction is complete, add 150ml of dichloromethane to the reaction solution, wash with saturated sodium carbonate solution, extract the aqueous phase with 80ml of dichloromethane, and combine the organic phases , dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a reddish-brown oil, which was directly used in the next reaction without treatment.

[0066] B: Preparation of (S...

Embodiment 1，2

[0076] Embodiment 1, the comparison of 2 and comparative example main reaction conditions and yield

[0077]

[0078] Can find out by above-mentioned embodiment comparison:

[0079] 1. After the R-configuration compound obtained by resolution is converted into S-configuration, the total yield of duloxetine hydrochloride prepared by using S-configuration alone has increased by nearly 47% (the yield=[ Total yield of R-configuration preparation / (total yield of R-configuration preparation+total yield of S-configuration preparation)]×100%).

[0080] 2, during demethylation, replace phenyl chloroformate with 1-chloroethyl chloroformate, not only the reaction time is greatly shortened, and it directly generates duloxetine hydrochloride, which reduces the reaction steps and shortens the production cycle ( shortened about 44h), and the yield has also increased by nearly 7%, reducing production costs.

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Abstract

The invention belongs to the fields of organic chemistry and pharmaceutical chemistry, and particularly relates to a synthesis technique of duloxetine hydrochloride. By converting the R configuration compound into S configuration, compared with the duloxetine hydrochloride prepared from the single S-configuration compound, the total yield is enhanced by nearly 47%, and the production cost is lowered. 1-chloroethylchloroformate is used instead of phenyl chloro-formate to directly generate the duloxetine hydrochloride during demethylation, thereby reducing the salification step, shortening the production cycle and saving the cost.

Description

Technical field: [0001] The invention belongs to the fields of organic chemistry and medicinal chemistry, and in particular relates to a synthesis process of duloxetine hydrochloride. Background technique: [0002] Duloxetine hydrochloride (Duloxetine.HCl) was developed and synthesized by Eli Lilly and Company, the chemical name is (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2- Thienyl) propylamine hydrochloride is a preferred antidepressant in modern clinical research. Its structural formula I is as follows: [0003] [0004] The synthetic route is as follows: [0005] [0006] After the above route is resolved with S-mandelic acid, the R-configuration compound is discarded, resulting in a waste of raw materials; demethylation requires a strong alkaline environment, and the reaction time is more than 24 hours, and the reaction cycle is long. [0007] The Chinese patent application number is CN200510027737.3, the publication number is CN100364986C, and the invention name ...

Claims

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Application Information

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IPC IPC(8): C07D333/20
CPCC07D333/20
Inventor 袁相富赵铭张崇东
Owner SHANGHAI WANXIANG PHARMA
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