Preparation of duloxetine hydrochloride

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

Active Publication Date: 2017-07-21
SHANGHAI WANXIANG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] 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, which restricts industrial production, and the yield is only 70%. Although we have prepared compound II through three-step reactions, our three-step reactions can be used directly without treatment. The next step reaction, and finally prepared a qualified product that meets the quality standards, and the total yield of the three-step reaction is 80%, the operation is simple, and it is convenient for industrial production

Method used

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  • Preparation of duloxetine hydrochloride
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  • Preparation of duloxetine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] A: Preparation of 2-thiophene-2-dimethylaminomethyl ethyl ketone hydrochloride

[0055] Dissolve 55g (0.44mol) 2-acetylthiophene, 44.7g (0.55mol) dimethylamine hydrochloride, 19.4g (0.61mol) paraformaldehyde in 190ml isopropanol, add 4.3ml concentrated hydrochloric acid and reflux for reaction 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%.

[0056] B: Preparation of N,N-dimethyl-3hydroxy-3-(2-thiophene)-propylamine

[0057] 85g (0.38mol) 2-thiophene-2-dimethylaminomethyl ethyl ketone hydrochloride, 260ml ethanol and 130ml water are mixed and stirred to dissolve, slowly add 13.9g NaOH at room temperature, adjust the PH value to 11-12, then add 14.5 g (0.37 mol) of sodium borohydride was reacted at room temperature overnight. After the reaction was completed, 160 ml of acetone was added to quench the reaction, and the ethanol was ev...

Embodiment 2

[0067] A: Preparation of (S)-N,N-dimethyl-3-p-nitrobenzoate-3-(2-thienyl)propylamine

[0068] 29g (0.16mol) (R)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine (prepared by resolution in Example 1), 31g (0.19mol) p-nitrobenzene Formic acid, 49.4g (0.19mol) triphenylphosphorus, mixed and dissolved in 240ml tetrahydrofuran, cooled to 0~5℃ in an ice bath, slowly dripped 32.9g (0.19mol) diethyl azodicarboxylate, the temperature did not exceed At 10°C, after dropping the ice bath, warming to room temperature, and reacting overnight. After the reaction is completed by TLC, 150ml of dichloromethane is added to the reaction solution, washed with saturated sodium carbonate solution, the aqueous phase is extracted with 80ml of dichloromethane, and the organic phases are combined , Dried with anhydrous magnesium sulfate, filtered, evaporated to dryness under reduced pressure to obtain a reddish brown oil, which was directly used in the next step without treatment.

[0069] B: Preparation of ...

Embodiment 1，2

[0079] Comparison of main reaction conditions and yields of Examples 1, 2 and Comparative Examples

[0080]

[0081] It can be seen from the comparison of the above embodiments:

[0082] 1. After the R-configuration compound obtained by the resolution is converted into the S-configuration, the total yield of duloxetine hydrochloride prepared by the S-configuration alone is increased by nearly 47% (increased yield=[ Total yield of R-configuration preparation / (total yield of R-configuration preparation+total yield of S-configuration preparation)]×100%).

[0083] 2. Using 1-chloroethyl chloroformate instead of phenyl chloroformate during demethylation not only greatly shortens the reaction time, but also directly generates duloxetine hydrochloride, which reduces the reaction steps and shortens the production cycle ( It is shortened by about 44h), and the yield is also increased by nearly 7%, which reduces the production cost.

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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

[0001] Technical field: [0002] The invention belongs to the field of organic chemistry and medicinal chemistry, and specifically relates to a synthesis process of duloxetine hydrochloride. [0003] Background technique: [0004] Duloxetine hydrochloride (Duloxetine.HCl) is 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: [0005] [0006] The synthetic route is as follows: [0007] [0008] After the above route is split with S-mandelic acid, the R configuration compound is discarded, which causes a waste of raw materials; a strong alkaline environment is required for demethylation, and the reaction time is more than 24h, and the reaction period is long. [0009] The Chinese patent application number is CN200510027737.3, the publication number is CN100364986C, and the invention name is S-(...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/20
CPCC07D333/20
Inventor 袁相富赵铭张崇东
Owner SHANGHAI WANXIANG PHARMA
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