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A kind of synthetic method of dopexamine hydrochloride intermediate

A technology of dopexamine hydrochloride and a synthetic method, which is applied in the field of synthesis of dopexamine hydrochloride intermediates, can solve the problems of long production cycle, increased environmental and equipment pressure, complicated operation, etc., and achieve high product yield, The preparation process is quick and convenient, and the effect of high product purity

Active Publication Date: 2017-11-03
JIANGSU TOHOPE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] This method has long steps and complicated operations, resulting in a long production cycle. At the same time, a large amount of acyl chloride reagents are used in the synthesis process, which increases the pressure on the environment and equipment.

Method used

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  • A kind of synthetic method of dopexamine hydrochloride intermediate
  • A kind of synthetic method of dopexamine hydrochloride intermediate
  • A kind of synthetic method of dopexamine hydrochloride intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1 (condensation reaction 1 / scheme one):

[0042] Add 60 mL of anhydrous methanol, 6-chloro-1-hexanol (V) (13.66 g, 100 mmol), 2-phenylethylamine (IV) (14.54 g, 120 mmol) and 60 mL of anhydrous methanol into the reaction flask, and heat to 60 ° C to react 8 After 1 hour, TLC detected that the raw material basically disappeared, concentrated to dryness, added 80mL cyclohexane, heated to reflux and all solids were dissolved, cooled to -0.5-0°C, kept stirring and crystallized for 6 hours, filtered, and collected filter cake, 50-55°C After vacuum drying, 21.05 g of off-white solid 6-(2-phenethylamino)-1-hexanol (III) was obtained, with a yield of 95.1%.

Embodiment 2

[0043] Embodiment 2 (condensation reaction 2 / scheme one):

[0044] Add 6-(2-phenethylamino)-1-hexanol (III) (22.13g, 100mmol), 2-(3,4-dimethoxyphenyl) ethylamine (II) ( 23.56g, 130mmol), Raney nickel 0.5g, sodium hydroxide 5.0g, heated to 135°C until the system was in a molten state, kept the reaction for 5 hours, TLC detected that the raw materials basically disappeared, dropped to 10-15°C, added dichloromethane 100mL, stirred for 30 minutes and then filtered, the filtrate was washed with water, dried, and concentrated under reduced pressure to obtain N-(2-(3,4-dimethoxyphenyl)ethyl)-N'-(2-phenylethyl )-1,6-hexanediamine (I) 36.92g, yield 96.0%.

Embodiment 3

[0045] Embodiment 3 (condensation reaction 3 / scheme two):

[0046] Add 60 mL of anhydrous methanol, 6-chloro-1-hexanol (V) (13.66 g, 100 mmol), 2-(3,4-dimethoxyphenyl) ethylamine (II) (23.56 g) into the reaction flask , 130mmol) and heated to 60°C for 8 hours, TLC detected that the raw materials basically disappeared, concentrated to dryness, added 80mL cyclohexane, heated to reflux and all solids were dissolved, cooled to -0.5~0°C, kept stirring and crystallized for 6 hours , filtered, and the filter cake was collected, dried in vacuo at 50-55° C. to obtain 26.35 g of off-white solid 6-(2-(3,4-dimethoxyphenyl)ethylamino)-1-hexanol (VI), Yield 93.6%.

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Abstract

The invention discloses a dopexamine hydrochloride intermediate, that is, N-(2-(3,4-dimethoxyphenyl)ethyl)-N'-(2 -Phenylethyl)-1, the synthetic method of 6-hexanediamine, described N-(2-(3,4-dimethoxyphenyl) ethyl)-N'-(2-phenylethyl )-1,6-hexanediamine (I) is made from 6-chloro-1-hexanol (V) having a structure such as formula (V) as a starting material through a unit reaction formed by two-step condensation reactions . Compared with the prior art, the present invention has higher yield, simple process, safe and reliable operation, green and environmental protection, is suitable for industrialized production, and promotes the economic and technological development of the crude drug.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a synthesis method of dopexamine hydrochloride intermediates. Background technique [0002] Dopexamine hydrochloride (Dopexamino, Dopacard) is a newly synthesized catecholamine drug, its chemical name is 4-(2-((6-((2-phenylethyl)amino)hexyl)amino)ethyl Base)-1,2-benzenediol, which can increase the blood flow of kidney, myocardium and skeletal muscle, is clinically used for patients with acute heart failure and low cardiac output after cardiac surgery. [0003] At present, the published synthetic route and preparation method have been reported for dopexamine hydrochloride. After analysis, it is found that although the routes are different, most of them involve an important intermediate, namely N-3,4-dimethoxyphenethyl -N'-phenethyl-1,6-hexanediamine (I). [0004] [0005] The preparation of ...

Claims

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Application Information

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IPC IPC(8): C07C217/60C07C213/02
Inventor 龚利锋陆惠刚袁跃华顾晔殷屹峰钱振青周小军
Owner JIANGSU TOHOPE PHARMA