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Preparation method of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile

A technology of propyl and amino groups, applied in the field of organic synthesis, can solve the problems of unfavorable industrial production, risk of production enlargement, long reaction steps, etc., and achieve the effects of short steps, reduction of three wastes, and short route steps

Pending Publication Date: 2022-02-25
苏州楚凯药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The disadvantages of this route are: hydrogen peroxide is an explosive product, and the production scale-up is more dangerous; the reaction steps are longer and the labor cost is higher, which is not conducive to industrial production
[0010] The method reported in the above literature requires the use of control products, dangerous operation, and long steps, so it is necessary to find a simple and low-cost route suitable for industrialization

Method used

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  • Preparation method of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile
  • Preparation method of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile
  • Preparation method of 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile

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Experimental program
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Effect test

Embodiment 1

[0046]

[0047] Add malononitrile (11.67g, 0.177mol), acetone (13mL, 0.177mol) and chloroform (100mL) into the reaction flask, and slowly add aluminum oxide (35g). After the dropwise addition, react at 20-25°C for 1h. After the reaction was completed, it was filtered, extracted with chloroform (2*50 mL), and concentrated to obtain 17 g of the compound of formula (I) (yield 100%).

Embodiment 2

[0049]

[0050] Add intermediate formula (I) compound (30g, 0.28mol), NBS (65g, 0.37mol), benzoyl peroxide (0.6g, 2.48mmol) and chloroform (90mL) into the reaction flask, heat up to 60-70°C Reflux reaction for 15h. After the reaction was completed, it was cooled, filtered, washed with chloroform, and the filtrate was concentrated and then rectified to obtain 36.6 g of the compound of formula (II) (yield 70%).

Embodiment 3

[0052]

[0053] Add the compound of formula (II) (13.1g, 62mmol), n-propylamine (5.5g, 93mmol), ethanol (100mL) into the reaction flask, and react at 20-30°C for 6h. After the reaction is completed in LC, dry it under reduced pressure Ethanol, 200mL of water and 200mL of ethyl acetate were added, the organic phase was separated and dried to obtain a crude product, the crude product was salted with HCl / EA, the precipitated product was filtered, and 10.4g of product formula (Ⅲ) compound was obtained after freeing (90% yield). 1 H NMR(400MHz,DMSO)δ0.801-0.838(m,3H),1.534-1.589(m,2H),1.916-1.919(s,3H),3.553-3.589(m,2H),5.626(s,2H ), 5.955-5.958(s,1H).

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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an intermediate 4-methyl-1-propyl-2-amino-1H-pyrrole-3-nitrile of uconafil. The method comprises the following steps: carrying out condensation on malononitrile and acetone under the action of alkali to obtain a compound shown in a formula (I), and brominating the compound shown in the formula (I) to obtain a compound shown in a formula (II); then performing condensation and ring closing on the compound in the formula (II) and propylamine to obtain a target product compound in a formula (III). The invention provides a simple and cost-reducing industrial production route for the uconafil intermediate, and has the advantages of short reaction steps, simple and convenient reaction, avoidance of use of pipe products, and realization of stable industrial production and preparation.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of eucnafil intermediate 4-methyl-1-propyl-2-amino-1H-pyrrole-3-carbonitrile. Background technique [0002] Yonkenafil is a five- and six-membered heterocyclic ketone analogue of Cyclic Guanosine monophosphate (cGMP), which is independently developed by Chinese researchers and has independent intellectual property rights. A novel phosphodiesterase (Phosphodiesterase, PDE) V inhibitor. Preliminary pharmacodynamic studies have shown that the compound has a very good selective inhibitory effect on PDE V, which is significantly better than the existing PDE V inhibitor drugs sildenafil and vardenafil on the market. Pharmacological experiments show that eukenafil has a high tolerance dose in animals, good safety, good safety, and side effects are significantly lower than existing drugs on the market, and it is expected to become a new drug fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34
CPCC07D207/34
Inventor 余飞飞刘现军郑行行张中剑黄文飞
Owner 苏州楚凯药业有限公司
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