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Synthesis method of fipronil intermediate

A cyano and dichloride technology is applied in the synthesis of pharmaceutical intermediates and in the field of synthesizing 5-amino-3-cyano-1-pyrazole disulfide, which can solve the problem that the finished product of fipronil does not meet the registration standard and increase the The process steps and the refining effect are unknown, and the effects of avoiding the discharge of bromine-containing wastewater, high purity and content, and reducing production costs are achieved.

Active Publication Date: 2021-10-08
HISUN PHARMACEUTICAL NANTONG CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] CN201910856787.4 discloses 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole (I) and sulfur monochloride to prepare 5-amino-3- The method of cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (formula III), but the preparation of pyrazole disulfide from sulfur monochloride will produce mono Sulfur, trisulfide, tetrasulfur and even pentasulfur impurities, and using sulfur chloride as a raw material system will produce a small amount of elemental sulfur, which will affect the subsequent reaction. Even if the product is purified to obtain a higher purity product, the following problems still exist: One is that the refining effect is unknown, and the other is that the process steps are increased and the operation is complicated
Will be degraded into unknown impurity in oxidation reaction process, cause the finished product of fiprenil not to meet domestic veterinary drug registration standard (sulfonyl ≤0.5%, sulfide ≤0.5%, other single impurity ≤0.2%, total impurity ≤2.0 %)

Method used

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  • Synthesis method of fipronil intermediate
  • Synthesis method of fipronil intermediate
  • Synthesis method of fipronil intermediate

Examples

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Embodiment 1

[0035] Add 200mL acetonitrile, 100g 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) (0.31mol) and 59.3g Ammonium thiocyanate (0.78mol) was stirred, and 253g (3.72mol) of 50% hydrogen peroxide was added dropwise. The temperature of the reaction solution was controlled at -20°C to -15°C during the dropwise addition. Compound intermediate (II). Add 200 mL of water and adjust the pH to 9.0 with ammonia water. Raise the temperature to 80°C and stir for 1 hour. After the reaction is over, cool down to 0°C and keep it for 1 hour. Filter and dry to obtain 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-benzene Base) pyrazole disulfide (III) 102.1g, yield 93.1%, HPLC purity 99.80%, external standard content 98.9%.

Embodiment 2

[0037] Add 1500mL acetonitrile and 100g 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) (0.31mol) and 94.5g Ammonium thiocyanate (1.24mol) was stirred, and 106g (1.55mol) of 50% hydrogen peroxide was added dropwise. The temperature of the reaction solution was controlled at 0°C to 10°C during the dropwise addition. Add 1500 mL of water and adjust the pH to 11.0 with ammonia gas. The temperature was raised to 50° C. for 3 hours, and the reaction was completed. Cool down to 5°C for 1 hour, filter and dry to obtain 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) 98.7 g, yield 90.0%, HPLC purity 99.90%, external standard content 98.5%.

Embodiment 3

[0039] Add 500mL DMF and 100g 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) (0.31mol) and 71.0g sulfur Ammonium cyanate (0.93mol) was stirred, and 169g (2.48mol) of 50% hydrogen peroxide was added dropwise. The temperature of the reaction solution was -10°C to 0°C during the dropwise addition. Add 500 mL of water and adjust the pH to 10.0 with ammonia gas. The temperature was raised to 70° C. for 1 hour, and the reaction was completed. Cool down to 5°C for 1 hour, filter and dry to obtain 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) 105.0 g, yield 95.8%, HPLC purity 99.35%, external standard content 99.1%.

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Abstract

The invention provides a synthesis method of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl) pyrazole disulfide (III), and belongs to the field of medicine synthesis. The method comprises the following steps: (1) reacting 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethylphenyl) pyrazole (I) with ammonium thiocyanate and hydrogen peroxide to obtain a thiocyanide intermediate (II); and (2) carrying out a condensation reaction on the thiocyanide intermediate (II) prepared in the step (1) to obtain the 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl) pyrazole disulfide (III). The method avoids the use of bromine, and is environment-friendly, low in production cost, relatively high in purity and yield of the obtained product, and easy for industrial production.

Description

Technical field [0001] The invention relates to the field of drug synthesis, specifically to a method for synthesizing drug intermediates, and in particular to a method for synthesizing 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-benzene). base) pyrazole disulfide method. Background technique [0002] 5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole disulfide (hereinafter referred to as pyrazole disulfide, compound of formula III) is an in vitro veterinary killer. A key intermediate for the insecticide Fipreronil. Fiprenil is a highly efficient and broad-spectrum insecticide, so pyrazole disulfide has broad application prospects as an intermediate for Fiprenil. [0003] [0004] CN201910856787.4 discloses the preparation of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) and sulfur monochloride The method of cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (formula III), but when preparing pyrazole disulfide c...

Claims

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Application Information

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IPC IPC(8): C07D231/18
CPCC07D231/18
Inventor 徐伟伟姜栋明陆颖逊陈圣宇王敬彬
Owner HISUN PHARMACEUTICAL NANTONG CO LTD
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