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Synthesis method of doxepin hydrochloride

A technology of doxepin hydrochloride and a synthesis method, applied in the field of drug synthesis, can solve the problems of complex process, harsh synthesis conditions and the like, and achieve the effects of simple process, high repetition rate and low cost

Pending Publication Date: 2021-11-02
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is exactly in order to provide a kind of synthetic method of doxepin hydrochloride, to overcome the problems such as relatively harsh synthetic conditions and complex process in the prior art

Method used

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  • Synthesis method of doxepin hydrochloride
  • Synthesis method of doxepin hydrochloride
  • Synthesis method of doxepin hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Slowly added triethyl phosphite (90.18g, 542.73mmol) into 3-chloro-1-(N,N-dimethyl)propylamine (60g, 493.38mmol), heated to 140°C, and stirred for 8h. After the reaction solution was cooled, it was quenched by adding water, extracted three times with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure. Distilled under reduced pressure to obtain 97.5 g of 3-(N,N-dimethyl)propyl diethyl phosphate (compound 3) with a yield of 88.5%.

[0046] 1 H NMR (400MHz,D 2 O)δ3.77–3.69(m,4H),3.01(q,J=7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J=12.0,6.4Hz,2H),1.66( dq,J=12.0,6.4Hz,2H),0.99(t,J=7.1Hz,6H). 13 CNMR (125MHz,D 2 O) δ61.30, 61.25, 57.74, 57.66, 44.73, 26.05, 25.29, 24.13, 24.07, 16.23, 16.18.

Embodiment 2

[0048] Slowly added triethyl phosphite (90.18g, 542.73mmol) into 3-chloro-1-(N,N-dimethyl)propylamine (60g, 493.38mmol), heated to 140°C, and stirred for 8h. After the reaction solution was cooled, it was quenched by adding water, extracted three times with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure to obtain a crude product.

[0049] Dissolve the above crude product in ethyl acetate, pass through hydrogen chloride, stir and crystallize at room temperature for 5 hours, suction filter and dry to obtain 3-(N,N-dimethyl)propyl phosphate diethyl ester hydrochloride ( The amount of compound 4) was 110.8 g, and the yield was 86.47%.

[0050] 1 H NMR (400MHz,D 2 O)δ3.88(tt, J=15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J=7.0,6.2Hz,2H),2.60(s,6H),1.93( dq,J=12.0,6.4Hz,2H),1.66(dq,J=12.0,6.4Hz,2H),0.99(t,J=7.1Hz,6H). 13 C NMR (125MHz, D 2 O) δ61.30, 61.25, 57.74, 57.66, 44.73, 26.05, 25.29, 24.13, 24.07, 16.23, 16.18.

Embodiment 3

[0052] Slowly added triethyl phosphite (90.18g, 542.73mmol) into 3-chloro-1-(N,N-dimethyl)propylamine (60g, 493.38mmol), heated to 140°C, and stirred for 8h. After the reaction solution was cooled, it was quenched by adding water, extracted three times with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure to obtain a crude product.

[0053] Dissolve the above crude product in ethyl acetate, add concentrated hydrochloric acid (12N) dropwise to adjust the pH to 1-2, stir and crystallize at room temperature for 5 hours, filter with suction, and dry to obtain 3-(N,N-dimethyl) The amount of diethyl propyl phosphate hydrochloride (compound 4) was 109.8 g, and the yield was 85.69%.

[0054] 1 H NMR (400MHz,D 2 O)δ3.88(tt, J=15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J=7.0,6.2Hz,2H),2.60(s,6H),1.93( dq,J=12.0,6.4Hz,2H),1.66(dq,J=12.0,6.4Hz,2H),0.99(t,J=7.1Hz,6H). 13 C NMR (125MHz, D 2 O) δ61.30, 61.25, 57.74, 57.66, 44.73, 26.05, 25.29, 24.13, 24...

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Abstract

The invention relates to a synthesis method of doxepin hydrochloride. The method comprises the following synthesis steps: (1) subjecting phosphite ester and 3-chloro-1-(N, N-dimethyl) propylamine to Arbuzov reaction, obtaining 3-(N, N-dimethyl) propyl phosphate through distillation and purification, or obtaining 3-(N, N-dimethyl) propyl phosphate hydrochloride through salifying crystallization of 3-(N, N-dimethyl) propyl phosphate and hydrochloric acid; (2) carrying out Wittig reaction on the 3-(N, N-dimethyl) propyl phosphate or the hydrochloride thereof and 6, 11-dihydrodibenzo [b, e] oxepin-11-one under the condition of strong alkali to obtain doxepin; and (3) carrying out salt forming reaction on the doxepin and hydrochloric acid to prepare the doxepin hydrochloride. In the first reaction step, the yield of the alkyl phosphate product prepared by the Arbuzov reaction is high, so that the yield and the purity of the final product doxepin hydrochloride are ensured. Compared with the prior art, the method has the advantages of simple process, low production cost, few process steps and the like.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis and relates to a synthesis method of doxepin hydrochloride. Background technique [0002] Doxepin Hydrochloride (Doxepin Hydrochloride), is a cis Mixture of trans isomers. Its CAS number is 1229-29-4, and its chemical structure is as follows: [0003] [0004] Doxepin hydrochloride is a commonly used tricyclic antidepressant for the treatment of depression and anxiety neurosis. Doxepin hydrochloride is a non-selective monoamine uptake inhibitor, and its mechanism of action is to increase the concentration of the synaptic cleft by inhibiting the reuptake of norepinephrine (NE) and 5-hydroxytryptamine (5-HT), thereby exerting antidepressant effects. It also has anxiolytic and sedative effects. Doxepin hydrochloride is well absorbed orally, with a bioavailability of 13-45%, a half-life (t1 / 2) of 8-12 hours, and an apparent volume of distribution (Vd) of 9-33L / kg. It is mainly metaboliz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/12
CPCC07D313/12
Inventor 黄金文刘福力吴范宏倪壮薛康燕唐慧朱冉冉许超张兰玲
Owner SHANGHAI INST OF TECH
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