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Preparation method of thiophenyl guanidine impurity B

A thioguanidine and impurity technology, which is applied in the field of preparation of thioguanidine impurity B, can solve the problem that it is difficult to purify and meet the purity requirements of reference grades, and achieves the effects of simple operation, easy availability of starting materials, and short synthetic route.

Pending Publication Date: 2021-11-19
CHANGZHOU YABANG QH PHARMACHEM +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Because thioguanidine is degraded in acid, not only impurity B but also impurity C are obtained, so it is a mixture, and it is difficult to purify to meet the purity requirements of the reference grade.

Method used

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  • Preparation method of thiophenyl guanidine impurity B
  • Preparation method of thiophenyl guanidine impurity B
  • Preparation method of thiophenyl guanidine impurity B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Condensation: Add 28.8g (0.1mol) of N-(2-amino-5-phenylthio-phenyl)-2-methoxy-acetamide, 173g of ethanol, and 50% hydration in a 250mL four-neck flask Hydrazine 200g, start stirring, raise the temperature to 80-85°C, and keep it warm for 10 hours.

[0032] (2) Crystallization: the above reaction solution was cooled to 20°C, suction filtered, the filter cake was washed with water until the pH was 7, and the wet product was dried at 50°C for 16 hours to obtain 24.2 g of a dry product of off-white phenylthioguanidine impurity B, which was collected. The rate is 89.5%. The purity by HPLC was 99.9%.

[0033] [M+1]=271.20 (see figure 1 )

[0034] 1 HNMR (CDCl 3 )δ: 3.46(s,3H),4.75(s,2H),7.12-7.16(t,1H),7.20-7.25(d,4H),7.32-7.34(d,1H),7.53,7.54(d, 1H), 7.68(s,1H), 9.39(s,1H). (See figure 2 )

[0035] 13 CNMR (CDCl 3 ):59.13, 68.20, 76.74-77.25, 116.00, 119.68, 126.20, 127.7-128.01, 128.98-129.22, 137.87-138.26, 138.72, 152.54. (See image 3 )

Embodiment 2

[0037] (1) Condensation: Add 28.8g (0.1mol) of N-(2-amino-5-phenylthio-phenyl)-2-methoxy-acetamide, 230g of acetonitrile, 80% hydrated in a 250mL four-neck flask 180g of hydrazine, start stirring, raise the temperature to 85-90°C, and keep it warm for 6 hours.

[0038] (2) Crystallization: the above reaction solution was cooled to 25°C, suction filtered, the filter cake was washed with water until the pH was 8, and the wet product was dried at 60°C for 12 hours to obtain 23.7 g of a dry product of off-white thioguanidine impurity B, which was collected The rate is 87.7%. The purity by HPLC was 99.8%.

Embodiment 3

[0040] (1) Condensation: Add 28.8g (0.1mol) of N-(2-amino-5-phenylthio-phenyl)-2-methoxy-acetamide, 115g of methanol, and 40% hydration in a 250mL four-neck flask 125g of hydrazine, start stirring, raise the temperature to 78-80°C, and keep the temperature for 15 hours.

[0041] (2) Crystallization: the above reaction solution was cooled to 30°C, suction filtered, the filter cake was washed with water until the pH was 8, and the wet product was dried at 90°C for 10 hours to obtain 23.1 g of off-white dry product of thioguanidine impurity B, which was collected The rate is 85.5%. The purity by HPLC was 99.9%.

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Abstract

The invention discloses a preparation method of a thiophenyl guanidine impurity B. In a polar solvent, hydrazine hydrate is used as a base catalyst, N-(2-amino-5-thiophenyl-phenyl)-2-methoxyl-acetamide is used as an initial raw material, and the thiophenyl guanidine impurity B is obtained through the procedures of cyclization reaction, crystallization and drying. The synthesis route is short, the initial raw materials are easy to obtain, the reaction condition is mild, the operation is simple and convenient, the impurity can be obtained without column chromatography, the purity of the prepared impurity can reach 99.5% or above, and the impurity can be used as a reference substance for quality research.

Description

technical field [0001] The invention belongs to the field of chemistry or medicinal chemistry, and in particular relates to a preparation method of benzoguanidine impurity B. Background technique [0002] The broad-spectrum anthelmintic drug benzoguanidine (Febante1), also known as Febante1, is mainly used to treat and control gastrointestinal roundworms, lungworms, tapeworms, etc. in cattle, sheep, pigs, horses and other animals. It has high efficiency and low toxicity. , The residence time in the body is short, and the safety range is large. The chemical name of non-bantyr (1) is [[2-[(methoxyacetyl)amino]-4-(phenylthio)phenyl]carbimino]biscarbamate dimethyl ester, the first It was successfully developed by Bayer Pharmaceutical Company of Germany, and its synthetic route is rarely reported in China. [0003] [0004] There are three known impurities of benzoguanidine, namely: [0005] 1) Impurity A [0006] [0007] 2) Impurity B [0008] [0009] 3) Impurity...

Claims

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Application Information

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IPC IPC(8): C07D235/12
CPCC07D235/12
Inventor 苏文杰符岩宋暄王学成张建峰朱建民
Owner CHANGZHOU YABANG QH PHARMACHEM