A kind of preparation method of duloxetine

A technology of duloxetine and compounds, which is applied in the field of duloxetine preparation, can solve the problems of difficulty in obtaining duloxetine with high optical purity, which is not conducive to the cost reduction of duloxetine, and the high price of 1-fluoronaphthalene. Achieve the effects of being conducive to green industrial production, classic reaction types, and high reaction selectivity

Active Publication Date: 2022-07-01
XINFA PHARMA
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Problems solved by technology

[0007] This route needs to use (S)-mandelic acid to resolve the reduction product 3-N,N-dimethylamino-l-(thiophen-2-yl)-1-propanol to obtain S-3-N,N- Dimethylamino-l-(thiophen-2-yl)-1-propanol and racemization of R-3-N,N-dimethylamino-l-(thiophen-2-yl)-1-propanol, After resolution, multiple resolution-racemization-resolution cycles, the comprehensive recovery of the optically active intermediate S-3-N, N-dimethylamino-l-(thiophen-2-yl)-1-propanol The yield is only 66%, the operation is cumbersome, the atom economy is low, and the yield is low
The etherification step utilizes 1-fluoronaphthalene and S-3-N,N-dimethylamino-l-(thiophen-2-yl)-1-propanol for etherification, S-3-N,N-dimethylamino -l-(thiophen-2-yl)-1-propanol has low activity, and the etherification reaction requires strong base sodium hydride and higher reaction temperature, while strong base sodium hydride and higher reaction temperature will lead to thiophene ortho-carbon atoms The configuration is reversed, and partial racemization occurs, so that the optical purity of the obtained target product is low, it is difficult to purify, and it is difficult to obtain duloxetine with high optical purity
At the same time, the high price of 1-fluoronaphthalene is not conducive to the cost reduction of duloxetine

Method used

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  • A kind of preparation method of duloxetine
  • A kind of preparation method of duloxetine
  • A kind of preparation method of duloxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1: Preparation of (S)-3-(1-naphthyloxy)-3-(2-thienyl)propanal (IV)

[0078] To a 2L four-necked flask equipped with a spherical condenser, stirring, thermometer and constant pressure dropping funnel, add 400 g of 1,2-dichloroethane, 138.2 g (1.0 mol) of 3-(2-thienyl)- 2-Acrolein (II), 26.0 g (0.08 mol) (S)-2-(1-trimethylsiloxy-1,1-diphenyl)methyltetrahydropyrrole (III1), 5-10 After stirring for half an hour, a mixed solution of 201.9 g (1.4 moles) of 1-naphthol and 400 g of 1,2-dichloroethane was added dropwise from a constant pressure dropping funnel, and the dropwise addition was completed in 3 hours. The reaction was stirred for 5 hours. Add 300 g of 20% aqueous sodium carbonate solution, stir at 20-25°C for half an hour, and separate layers. The obtained organic layer is washed once with 100 g of 5% hydrochloric acid and once with 100 g of saturated aqueous sodium chloride solution. The organic phase was dried with 25 grams of anhydrous sodium sulfate for ...

Embodiment 2

[0082] Example 2: Preparation of (S)-3-(1-naphthyloxy)-3-(2-thienyl)propanal (IV)

[0083] To a 2L four-necked flask equipped with a spherical condenser, stirring, thermometer and constant pressure dropping funnel, add 400 g of toluene, 138.2 g (1.0 mol) of 3-(2-thienyl)-2-propenal (II) , 32.5 g (0.1 mol) (S)-2-(1-trimethylsiloxy-1,1-diphenyl)methyltetrahydropyrrole (III1), after stirring at 10-15 °C for half an hour, the A mixed solution of 230.7 g (1.6 moles) of 1-naphthol and 600 g of toluene was added dropwise to a constant pressure dropping funnel, the dropwise addition was completed in 3 hours, and the reaction was stirred at 15-20° C. for 5 hours thereafter. Add 400 grams of 20% sodium carbonate aqueous solution, stir at 20-25°C for half an hour, and separate the layers. The obtained organic layer is washed once with 100 grams of 5% hydrochloric acid and once with 100 grams of saturated sodium chloride aqueous solution. The organic phase was dried with 25 grams of anhy...

Embodiment 3

[0084] Example 3: Preparation of (S)-3-(1-naphthyloxy)-3-(2-thienyl)propanal (IV)

[0085]To a 2L four-necked flask equipped with a spherical condenser, stirring, thermometer and constant pressure dropping funnel, add 400 g of 1,2-dichloroethane, 138.2 g (1.0 mol) of 3-(2-thienyl)- 2-Acrolein (II), 39.5 g (0.1 mol) (S)-2-(1-triethylsiloxy-1,1-di-p-methylphenyl)methyltetrahydropyrrole (III2), After stirring for half an hour at 5-10 °C, a mixed solution of 201.9 g (1.4 moles) of 1-naphthol and 400 g of 1,2-dichloroethane was added dropwise from a constant pressure dropping funnel, and the dropwise addition was completed for 3 hours, and thereafter 10 The reaction was stirred at -15°C for 5 hours. Add 300 g of 20% aqueous sodium carbonate solution, stir at 20-25°C for half an hour, and separate layers. The obtained organic layer is washed once with 100 g of 5% hydrochloric acid and once with 100 g of saturated aqueous sodium chloride solution. The organic phase was dried with 2...

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Abstract

The invention provides a preparation method of duloxetine. The method uses 1-naphthol and 3-(2-thienyl)-2-acrolein as starting materials, and obtains (S) through an addition reaction under the action of a catalyst. )-3-(1-naphthyloxy)-3-(2-thienyl) propionaldehyde, then carry out imidization reaction with methylamine, and obtain duloxetine through reduction reaction. The raw materials of the invention are cheap and easy to obtain, do not need expensive 1-fluoronaphthalene, sodium hydride and a cumbersome splitting process, the cost is low, the technological process is safe and easy to operate, the amount of three wastes produced is small, and it is green and environmentally friendly, and the reaction atom economy is high. , the reaction selectivity of each step is high, the side reactions are few, and the optical purity and yield of the target product are high, which is beneficial to the green industrial production.

Description

technical field [0001] The invention relates to a preparation method of duloxetine, belonging to the fields of organic chemistry and medicinal chemistry. Background technique [0002] Duloxetine (Duloxetine, I), chemical name (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-l-propanamine, is produced by Lilly of the United States A dual serotonin and norepinephrine reuptake inhibitor developed by (Lilly) company was launched in the United States and Europe in 2004 and in China in 2007 for antidepressants. [0003] [0004] At present, the more economical and feasible synthetic route of duloxetine is obtained by using 2-acetylthiophene as raw material, and with paraformaldehyde and dimethylamine hydrochloride through Mannich reaction, reduction, resolution, etherification and demethylation. The target product, see Scheme 1. This route is described in detail in the paper "Synthetic Chemistry, 2004, 12(6), 551-553", Chinese Patent CN101391991A, US Patent US5023269 and World Pa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/20
CPCC07D333/20C07B2200/07
Inventor 戚聿新屈虎吕强三腾玉奇
Owner XINFA PHARMA
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