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Propylamine derivative and its application in preparing tomocetin

A technology of atomoxetine and its derivatives, which is applied in the field of propylamine derivatives and its application, can solve the problems of difficult preparation of raw materials, harsh reaction conditions, troublesome operation, etc., and achieve the effect of reasonable preparation route

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

AI Technical Summary

Problems solved by technology

[0010] The biggest advantage of method A is that the synthetic route is simple, but its disadvantages are: (a) when compound 3 and o-cresol form ether, it is easy to eliminate side reactions, which affects the purity of the product; (b) compound 7 needs to be prepared in a high vacuum (0.03 torr) distillation, troublesome operation and high equipment requirements, not easy to industrialized production; (c) amination reaction needs to be carried out in an autoclave, the reaction temperature is 140 ℃, and the reaction pressure is 10kg / cm 2 , the reaction time is 12 hours
[0025] The main defect of method D is: raw material (compound 11) preparation difficulty and harsh reaction condition
[0026] In summary, the existing methods for preparing atomoxetine have their own advantages and disadvantages, but their common disadvantage is that it is difficult to industrialize

Method used

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  • Propylamine derivative and its application in preparing tomocetin
  • Propylamine derivative and its application in preparing tomocetin
  • Propylamine derivative and its application in preparing tomocetin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Preparation of N-methyl-N-benzyl-3-phenyl-3-(2-methylphenoxy)propylamine

[0062] (1) Preparation of N-methyl-N-benzyl-3-phenyl-3-carbonyl-propylamine hydrochloride:

[0063] Add 30 mL of concentrated hydrochloric acid dropwise to 36.2 g (0.30 moL) of N-methylbenzylamine until pH=2, and remove the solvent by rotary evaporation to obtain benzylamine hydrochloride. Dilute the obtained benzylamine hydrochloride, 11.2 g (0.37 moL) of paraformaldehyde and 30.0g (0.25moL) of acetophenone were added to a 250mL three-necked flask in turn, and 100mL of absolute ethanol was added as a solvent, and 5mL of concentrated hydrochloric acid was added, heated and stirred under reflux for 7h, cooled naturally, stirred at room temperature for 3h, and pumped After filtering, the filter cake was washed with ethanol, and dried to obtain 66.0 g of white solid, mp 192-194°C, HPLC content 99.9%, yield 92%.

[0064] 1 H-NMR(DMSO)δ: 2.70(s, 3H, N-CH 3 ), 3.40 (m, 2H, N-CH 2 ), 3.65 (m, 2H, CO...

Embodiment 2～5

[0070] The following compounds can be prepared in a manner similar to Example 1, specifically in Table 1

[0071] Table 1

[0072]

[0073] Application of N-methyl-N-benzyl-3-phenyl-3-(2-methylphenoxy)propylamine in the preparation of atomoxetine

Embodiment 7

[0075] (1) Preparation of N-methyl-N-ethoxycarbonyl-3-phenyl-3-(2-methylphenoxy)propylamine:

[0076] 34.5g (0.10moL) N-methyl-N-benzyl-3-phenyl-3-(2-methylphenoxy) propylamine, 4.1g (0.03moL) K 2 CO 3 , 16.2g (0.15mol) ClCO 2 Et was dissolved in 100mL toluene and heated to reflux for 3h. Heating was stopped and cooled naturally, the solvent was concentrated, and recrystallized from n-hexane to obtain 31.0 g of a yellow solid, mp: 79-81° C., HPLC content 99.6%. Yield 95%.

[0077] 1 H-NMR (CDCl 3 )δ: 1.15 (m, 3H, C-CH 3 ), 2.15 (m, 2H, CO-CH 2 ), 2.32(s, 3H, Ar-CH 3 ), 2.83 (s, 3H, N-CH 3 ), 3.45 (m, 2H, N-CH 2 ), 4.00 (m, 2H, CO 2 -CH 2 ), 5.15 (s, 1H, O-CH), 6.55-7.32 (m, 9H, Ar-H).

[0078] (2) Preparation of N-methyl-3-phenyl-3-(2-methylphenoxy)propylamine (tomoxetine):

[0079] Add 32.7g (0.10mol) of N-methyl-N-ethoxycarbonyl-3-phenyl-3-(2-methylphenoxy)propylamine, 22.4g (0.4mol) of KOH, and 200mL of n-butanol to In a 500mL three-neck flask, heat to reflux...

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Abstract

The present invention relates to a propylamine derivative and its application in preparation of tomoxetine (atomoxetine raceme). Said invention also provides its chemical structure formula, and the invented preparation method is simple, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a kind of propylamine derivative and application thereof, specifically relate to a kind of N-methyl, N-benzyl or substituted benzyl, 3-phenyl, 3-o-tolyloxypropylamine and its preparation of tomoxicillin Ting (atomoxetine racemate) in the application. Background technique [0002] Atomoxetine hydrochloride (Atomoxetine HCl,), the chemical name is (+)-(R)-N-methyl-3-(2-methylphenoxy)-3-amphetamine hydrochloride, is Selective serotonin (5-HT) reuptake inhibitor antidepressants are also good drugs for treating attention deficit disorder and hyperactivity disorder. [0003] At present, the methods for preparing atomoxetine are mainly divided into two categories: one is to directly prepare atomoxetine by asymmetric synthesis; the other is to first synthesize atomoxetine racemate (atomoxetine , whose structure is shown in Formula 1), and then obtain the target object by splitting atomoxetine. The second method is currently ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/62C07C213/08
Inventor 吴范宏陈国美杨雪艳
Owner EAST CHINA UNIV OF SCI & TECH
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