Preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol

A two-substituted, thienyl-based technology is applied in the field of preparation of duloxetine intermediates, which can solve the problems of high environmental pressure, large amount of paraformaldehyde and dimethylamine hydrochloride, and inability to recycle and reuse, and achieves less three wastes. , the effect of low cost and high total yield

Inactive Publication Date: 2017-12-19
天台宜生生化科技有限公司
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0007] Although the synthesis method of this intermediate is very mature, and the industrial production is also very stable, the amount of paraformaldehyde and di

Method used

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  • Preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol
  • Preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol
  • Preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol

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Experimental program
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Embodiment 1

[0042] Example 1: N,N -Synthesis of dimethylamino-1-(2-thienyl)-1-propenone

[0043] 2-acetylthiophene:bis(trichloromethyl)carbonate according to the molar ratio of substances: N,N -Disubstituted formamide: 1.0:0.32:1.15:1.5 feed of organic base; 12.6g of 2-acetylthiophene, 9.5g of bis(trichloromethyl)carbonate, N,N - Disubstituted carboxamides are N, N -Dimethylformamide, the feeding quality is 8.4g, the organic base is barium hydroxide, and the feeding quality is 17.1g; Organic solvent A is methanol 125mL, and its volume consumption is 10mL / g of 2-acetylthiophene quality; Solvent B is For 10 mL of dichloromethane, the volume used is 1 mL / g of the mass of bis(trichloromethyl)carbonate.

[0044] First put N,N - Dimethylformamide was added to the reaction flask, mechanical stirring was started, the temperature was cooled to 0°C in an ice bath, and a dichloromethane solution in which bis(trichloromethyl)carbonate was dissolved was added dropwise. After the dropwise additio...

Embodiment 2

[0046] 2-acetylthiophene:bis(trichloromethyl)carbonate according to the molar ratio of substances: N,N -Disubstituted formamide: 1.0:0.7:2.5:2 feed of organic base; 12.6g of 2-acetylthiophene, 20.7g of bis(trichloromethyl)carbonate, N,N - Disubstituted carboxamides are N,N -Dimethylformamide, the feeding quality is 18.3g, the organic base is sodium methylate, and the feeding quality is 10.8g; Organic solvent A is methanol 250mL, and its volumetric dosage is 20mL / g of 2-acetylthiophene quality; Solvent B is 1 , 60mL of 4-dioxane, the volume dosage is 3mL / g of the mass of bis(trichloromethyl)carbonate.

[0047] 80 ℃ of temperature of reaction, other operations are with embodiment 1, obtain N,N - 16.7 g of dimethylamino-1-(2-thienyl)-1-propenone, yield 92.2%.

Embodiment 3

[0049] 2-acetylthiophene:bis(trichloromethyl)carbonate according to the molar ratio of substances: N,N -Disubstituted formamide: 1.0:1.0:3.6:3 feed of organic base; 12.6g of 2-acetylthiophene, 29.7g of bis(trichloromethyl)carbonate, N,N - Disubstituted carboxamides are N,N -Dimethylformamide, the feeding quality is 26.3g, the organic base is sodium acetate, and the feeding quality is 41g; Organic solvent A is methanol 380mL, and its volumetric dosage is 30mL / g of 2-acetylthiophene quality; Solvent B is ethyl acetate Esters 150mL, the volume dosage is 5mL / g of bis(trichloromethyl)carbonate mass.

[0050] 60 DEG C of temperature of reaction, other operation is with embodiment 1, obtains N,N - 15.7 g of dimethylamino-1-(2-thienyl)-1-propenone, yield 86.7%.

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Abstract

The invention discloses a preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol shown as the formula (I). The method comprises: taking 2-acetyl thiophene shown in the formula (II) as a raw material, and allowing 2-acetyl thiophene to completely react with di(trichloromethyl)carbonic ester (III) and N,N-disubstituted methanamide (IV) in an organic solvent under the catalysis of an organic base to obtain N,N-disubstituted amino-1-(2-thienyl)-1-acrylketone shown as the formula (V); and performing hydrogenation reduction with lithium aluminium hydride to obtain N,N-disubstituted amino-1-(2-thienyl)-1-propanol shown as the formula (VI); and performing splitting with S-mandelic acid and recrystallization with ethyl acetate to obtain the target product shown as the formula (I). The preparation method is low in cost, mild in reaction condition, less in waste water, waste gas and industrial residue, small in energy consumption, and high in yield. The preparation method is safe and is suitable for industrial production.

Description

technical field [0001] The invention discloses a preparation method of a duloxetine intermediate, in particular to a ( S )-3- N,N - Process for the preparation of disubstituted amino-1-(2-thienyl)-1-propanols. Background technique [0002] Duloxetine Hydrochloride (Duloxetine Hydrochloride) is a dual inhibitor of serotonin and norepinephrine reuptake, trade name Cymbalta, clinically used for the treatment of depression, stress urinary incontinence, depression associated with Chronic pain, diabetic peripheral neuropathic pain. [0003] ( S )-3- N,N -Dimethylamino-1-(2-thienyl)-1-propanol is the key intermediate of duloxetine, and its structure is as follows: [0004] [0005] The main preparation method of this intermediate reported in the literature is: [0006] Using 2-acetylthiophene as raw material, react with paraformaldehyde and dimethylamine hydrochloride to generate 3- N,N -Dimethylamino-1-(2-thienyl)-1-propanone, then through sodium borohydride reduction, c...

Claims

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Application Information

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IPC IPC(8): C07D333/20C07D333/22C07B57/00
CPCC07D333/20C07B57/00C07B2200/07C07D333/22
Inventor 夏建胜李坚军何亚文
Owner 天台宜生生化科技有限公司
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