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Improved method for preparing N-methyl-3-phenyl-3-hydroxy-propylamine

A technology of phenyl and hydroxyl, which is applied in the field of preparation of N-methyl-3-phenyl-3-hydroxy-propylamine, which can solve the problems of high cost, low yield and difficult industrialization

Inactive Publication Date: 2008-11-05
EAST CHINA UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In summary, the existing methods for preparing N-methyl-3-phenyl-3-hydroxyl-propylamine have their own advantages and disadvantages, but their common defects are that the cost is high and the yield is low and it is difficult to industrialize

Method used

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  • Improved method for preparing N-methyl-3-phenyl-3-hydroxy-propylamine

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preparation example Construction

[0016] The method for preparing N-methyl-3-phenyl-3-hydroxyl-propylamine of the present invention is characterized in that said preparation method comprises the steps:

[0017] (1) Compound (II), paraformaldehyde and compound (III) are placed in C 1 ~C 4 In the monohydric alcohol, the molar ratio of compound (II), paraformaldehyde and compound (III) is 1: (1.0~4.0): (1.0~3.0), carry out Mannich reaction under the condition that has acid catalyst presence to obtain compound (IV );

[0018] Among them, the recommended acid catalysts are HCl, H 2 SO 4 , PCl 3 , PCl 5 or POCl 3 , the preferred monohydric alcohol is methanol, ethanol, propanol or butanol.

[0019] (2) Place compound (IV) and compound (V) in an aprotic solvent, and in the presence of a base, reflux for 1 to 3 hours to obtain compound (VI);

[0020] Among them, the recommended aprotic solvent is benzene, toluene or xylene, and the recommended base is KOH, NaOH, Ba(OH) 2 , Ca(OH) 2 , Na 2 CO 3 , K 2 CO 3...

Embodiment 1

[0028] (1) N-methyl-N-benzyl-3-phenyl-3-carbonyl-propylamine hydrochloride:

[0029] Add 84.7g (0.72mol) of N-methylbenzylamine and 250mL of absolute ethanol into a 500mL three-necked flask, and feed HCl gas into the ice-water bath until the solution pH<3, then add 26.2g (0.87mol) of paraformaldehyde and 70g (0.58mol) of acetophenone was heated, stirred and refluxed for 7h, cooled naturally, stirred at room temperature for 3h, filtered with suction, the filter cake was washed with ethanol, and dried to obtain 154.4g of white solid, yield: 91.5%. mp 192~194°C, HPLC content 99.9%.

[0030] 1 H-NMR(DMSO)δ: 2.70(s, 3H, N-CH 3 ), 3.20~3.50 (m, 2H, N-CH 2 ), 3.68(t, 2H, CO-CH 2 , J=7.5Hz), 4.35 (AB, 2H, Ar-CH 2 , J=13.0Hz), 7.40~8.00 (m, 10H, Ar-H).

[0031] (2) N-methyl-N-ethoxycarbonyl-3-phenyl-3-carbonyl-propylamine:

[0032] With 116g (0.40mol) N-methyl-N-benzyl-3-phenyl-3-carbonyl-propylamine hydrochloride, 42.4g (0.40mol) Na 2 CO 3 and 52.1g (0.48mol) ClCO 2 Add Et i...

Embodiment 2

[0041] (1) N-methyl-N-benzyl-3-phenyl-3-carbonyl-propylamine hydrochloride:

[0042] Add 84.7g (0.72mol) of N-methylbenzylamine and 250mL of absolute ethanol into a 500mL three-necked flask, add 75mL of concentrated hydrochloric acid dropwise in an ice-water bath, and add 26.2g (0.87mol) of paraformaldehyde and 70g (0.58mol) of acetophenone was heated, stirred and refluxed for 7h, cooled naturally, stirred at room temperature for 3h, filtered with suction, the filter cake was washed with ethanol, and dried to obtain 154.4g of white solid, yield: 91.5%. mp 192-194°C.

[0043] (2) N-methyl-N-phenoxycarbonyl-3-phenyl-3-carbonyl-propylamine:

[0044] 116g (0.40mol) N-methyl-N-benzyl-3-phenyl-3-carbonyl-propylamine hydrochloride, 42.4g (0.40mol) Na 2 CO 3 and 74.8g (0.48mol) ClCO 2 Ph was added to a 1000mL three-necked flask, and 300mL toluene was added as a solvent, heated to reflux for 3.5h, cooled, suction filtered, the filter cake was washed with a small amount of toluene, ...

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Abstract

The present invention relates to a preparation method of N-methyl-3-phenyl-3-hydroxy-propylamine. Said method uses acetophenone as initial raw material, and includes the following steps: firstly, making acetophenone and compound (C) produce Mannich reaction to obtain the compound (D), then making compound (D), and compound (E) produce reaction to obtain compound (F), reducing compound (F) to obtain compound (G), finally hydrolyzing compound (G) so as to obtain the invented target compound. Besides, said invention also provides the chemical structure formula of the above-mentioned every compound.

Description

technical field [0001] The invention relates to a preparation method of N-methyl-3-phenyl-3-hydroxyl-propylamine. Background technique [0002] Fluoxetine hydrochloride (Fluooxetine hydrochloride), the chemical name is N-methyl-3-phenyl-3-(4-trifluoromethylphenoxy) propylamine hydrochloride, is a drug used to treat various depressive disorders. Medicines for mental disorders. [0003] N-methyl-3-phenyl-3-hydroxyl-propylamine is one of the important intermediates for the preparation of fluoxetine hydrochloride. So far, the method for preparing N-methyl-3-phenyl-3-hydroxyl-propylamine is mainly divided into three kinds, the first kind (US.Pat.No.4,902,710, US.Pat.No.5,936,124, US.Pat.No. .No.5,166,437, US.Pat.No.5,225,585, EP 529842, EP 380924, WO 0037425, TL.1989.30(39):5207-5210, TL.1991.32(16):1901-1904, J.Org.Chem. 1988.53 (13): 2916-2920, etc.) is: using 3-substituted (halogen, dialkylamine, amino or ethoxycarbonyl) propiophenone as the starting material, first after r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C269/04C07C271/16
Inventor 吴范宏陈国美杨雪艳奚倬勋
Owner EAST CHINA UNIV OF SCI & TECH
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