WO2023279671A1

WO2023279671A1 - Method for synthesizing fipronil intermediate

Info

Publication number: WO2023279671A1
Application number: PCT/CN2021/139846
Authority: WO
Inventors: 徐伟伟; 姜栋明; 陆颖逊; 陈圣宇; 王敬彬
Original assignee: 浙江海正药业股份有限公司; 海正药业南通有限公司
Priority date: 2021-07-05
Filing date: 2021-12-21
Publication date: 2023-01-12
Also published as: CN113480482A; CN113480482B

Abstract

Provided in the present invention is a method for synthesizing 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III), which belongs to the field of pharmaceutical synthesis. The method comprises: (1) allowing 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) to react with ammonium thiocyanate and hydrogen peroxide to obtain a thiocyanate intermediate (II); and (2) carrying out a condensation reaction on the thiocyanide intermediate (II) prepared in step (1) to obtain the 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III). In the present invention, the method avoids the use of bromine, is environmentally friendly, and has low production costs, the obtained product has a high purity and yield, and industrial production thereof is easy.

Description

A kind of synthetic method of fipronil intermediate

technical field

The invention relates to the field of drug synthesis, in particular to a method for synthesizing a drug intermediate, in particular to a method for synthesizing 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-benzene base) pyrazole disulfide method.

Background technique

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 The key intermediate of insecticide fipronil. Fiprenil is a kind of efficient broad-spectrum insecticide, so pyrazole disulfide has wide application prospect as the intermediate of fepronil.

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. Moreover, the reaction system for preparing pyrazole disulfide compounds with sulfur monochloride in this patent requires water removal treatment. If water is contained, the hydrogen chloride produced by the reaction will be dissolved and affect the reaction process. During the reaction, water needs to be controlled and nitrogen purging is used to remove hydrogen chloride. gas, the reaction conditions are harsh.

CN200910219776.1 patent describes a synthetic method of pyrazole disulfide, which is divided into two steps. First, in acetic acid and 1,2-dichloroethane, 5-amino-3-cyano-1-(2,6 -Dichloro-4-trifluoromethylphenyl)pyrazole (I) reacts with ammonium thiocyanate and bromine to generate a thiocyanide intermediate, which is condensed in ethanol to obtain 5-amino-3 -cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide. However, this method uses bromine, which is a volatile liquid with strong toxicity and corrosiveness. After use, bromine-containing wastewater will be generated, polluting the environment, and the cost of sewage treatment is relatively high. Moreover, the present invention does not disclose a complete technical solution. For example, in the second step, the thiocyanide intermediate cannot condense itself into pyrazole disulfide in ethanol.

In addition, the document Journal of Fluorine Chemistry 127 (2006) 948-953 discloses the preparation method of Fiprenil, which is also a conventional method for those skilled in the art to prepare Fiprenil, i.e. 5-amino-3-cyano- Synthesis of 5-amino-3-cyano-1-(2,6- Dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (Ⅳ), and then obtain fiprenyl (Ⅴ) through oxidation reaction. The reaction formula is as follows:

In this preparation process, the synthesis of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (IV) is a free base reaction, due to the mixing of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) and hydrosulfite in DMF and water Solubility in solvents is poor, this reaction involves a three-phase reaction, the reaction conditions are harsh, for 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl) The quality requirements of pyrazole disulfide (III) are very high. The inventor found after a large number of experiments: when the external standard content of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) is low At 95%, it will cause the next reaction to be unable to react completely, and the residual 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl) pyrazole disulfide (III) It is difficult to remove in the subsequent refining process, and it is brought to 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthio In pyrazole (IV). 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 %).

Therefore, looking for a 5-amino-3-cyano-1-(2,6 -Dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) is necessary for an external standard content of not less than 95%.

Contents of the invention

The invention provides a kind of synthetic method of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III), which avoids The use of bromine is improved, the environment is friendly, the production cost is low, the reaction yield and purity are high, and it has the significance of industrialized production. The method includes:

(1) 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole (I) reacts with ammonium thiocyanate and hydrogen peroxide to obtain a thiocyanide intermediate (II);

(2) The thiocyanide intermediate (II) prepared in step (1) is condensed under alkaline conditions to obtain 5-amino-3-cyano-1-(2,6-dichloro-4- Trifluoromethyl-phenyl) pyrazole disulfide (III), the alkaline condition is pH 9.0-11.0,

In a preferred embodiment, the solvent used in the step (1) is acetonitrile, N,N-dimethylformamide

(DMF) or N,N-dimethylacetamide (DMAC), the preferred solvent is acetonitrile.

In a preferred embodiment, the reaction temperature of the step (1) is -20°C to 10°C.

In a preferred embodiment, the reaction time after adding hydrogen peroxide in the step (1) is 5 minutes to 2 hours.

In a preferred embodiment, the alkaline substance used in the step (2) is ammonia water or ammonia gas or aqueous sodium hydroxide solution (preferably 5%-30%).

In a preferred embodiment, the reaction temperature in step (2) is 50-80°C.

In a preferred embodiment, the reaction time of the step (2) is 1-3 hours.

In a preferred embodiment, the solvent in the step (2) is water, and preferably, the volume of the water is the same as that of the solvent in the step (1).

In a preferred embodiment, the step (2) further includes: after stopping the reaction, lower the temperature to 0-20°C and keep it warm for 0.5-1.5 hours, filter and dry to obtain 5-amino-3-cyano-1-(2,6 -Dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III).

In a preferred embodiment, the volume of solvent used in the step (1) is the same as that of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I ) has a volume-to-mass ratio of 2-15:1, and the unit is mL/g.

In a preferred embodiment, in the step (1), ammonium thiocyanate and 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole ( I) The molar ratio is 2.5-4:1.

In a preferred embodiment, hydrogen peroxide and 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) mole The ratio is 5-12:1, preferably, the concentration of the hydrogen peroxide is: 30%-50% (mass ratio).

5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide prepared when the pH in the step (2) condensation reaction of the present invention is 9.0 to 11.0 The yield, purity and content of compound (III) are higher, wherein, the yield is all above 90%, the HPLC purity is all above 99.35%, and the external standard content is all above 98.5%. When pH<9, the reaction will be incomplete (reactant thiocyanide intermediate II remains too much), and when pH>11, 5-amino-3-cyano-1-(2,6-di Chloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) will be degraded, resulting in reduced yield, purity and content, and the prepared 5-amino-3-cyano-1-(2, The external standard content of 6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) is lower than 95%.

Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

① The present invention avoids the use of bromine, avoids the discharge of bromine-containing wastewater, is environmentally friendly, does not require bromine-containing wastewater treatment, and has a lower price of hydrogen peroxide, which reduces production costs.

2. The raw materials used in the present invention are cheap and easy to get, and the product yield, purity and content are high (5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyridine The azole disulfide (III) external standard content is more than 98.5%), the impurity content is low, the production process is simple, and it is a synthetic process that can realize industrialization.

detailed description

The following examples further illustrate the present invention, but it is necessary to point out that the following examples are only used to describe the content of the invention, and do not constitute a limitation to the protection scope of the present invention, and the protection scope of the present invention is as the criterion with claims.

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated; unless otherwise indicated, various starting materials and reagents were commercially available and used without further purification; unless otherwise indicated, various solvents were As an industrial grade solvent, it was used directly without further treatment.

The intermediate control involved in the present invention and the detection of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) is Detected by high performance liquid chromatography (HPLC).

The instrument and chromatographic conditions are as follows: the model of the liquid chromatograph is Shimadzu 20A series high performance liquid chromatograph, the chromatographic column is Dalian Yilite Hypersil C18 ODS2, 4.6×250mm, 5μm or equivalent; the mobile phase is methanol: acetonitrile: water = 50 /20/30 (volume ratio); flow rate: 1.0mL/min; UV detection wavelength: 220nm; injection volume: 5μL; column temperature: 25°C; running time: 50 minutes. Sample solution preparation: Weigh 50 mg of the sample to be tested, place it in a 100 mL volumetric flask, dissolve it with methanol and dilute to the mark.

Wherein, the HPLC purity (purity for short) of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl) pyrazole disulfide (formula III) refers to the highly efficient The purity of the main peak measured by the liquid chromatography area normalization method, the content of the thiocyanide intermediate (II) in the second step reaction solution refer to the component content measured by the high performance liquid chromatography area normalization method. The external standard content of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (formula III) is based on the standard HPLC external standard method The standard substance of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (formula III) was obtained from Hisun Pharmaceutical Nantong Co., Ltd. self-made, the content is 99.5%.

Example 1

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%.

Example 2

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%.

Example 3

Add 500mLDMF and 100g 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) (0.31mol) and 71.0g sulfur to the four-neck flask 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%.

Example 4

Add 1000mL acetonitrile and 100g 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) (0.31mol) and 71.0g Ammonium thiocyanate (0.93mol) was stirred, and 282g (2.5mol) of 30% hydrogen peroxide was added dropwise. The temperature of the reaction solution was -20°C to -10°C during the dropwise addition. Add 1000mL of water and adjust the pH to 9.5 with ammonia water. 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) 102.9 g, yield 93.8%, HPLC purity 99.62%, external standard content 99.0%.

Example 5

Add 1000mLN in the four-neck flask, N-dimethylacetamide and 100g 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) (0.31mol) and 71.0g ammonium thiocyanate (0.93mol) were stirred, and 282g (2.5mol) of 50% hydrogen peroxide was added dropwise. minutes to stop the reaction. 1000 mL of water was added, and the pH was adjusted to 11.0 with 5% aqueous sodium hydroxide solution. The temperature was raised to 70° C. for 1 hour, and the reaction was completed. Cool down to 5°C and keep warm for 1 hour, filter and dry to obtain 100g of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III) , yield 91.2%, HPLC purity 99.70%, external standard content 99.5%.

Embodiment 6 comparative examples (the pH of the second step condensation reaction is 8.0)

Add 1000mL acetonitrile and 100g 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) (0.31mol) and 71.0g Ammonium thiocyanate (0.93mol) was stirred, and 282g (2.5mol) of 30% hydrogen peroxide was added dropwise. The temperature of the reaction solution was -20°C to -10°C during the dropwise addition. Add 1000mL of water and adjust the pH to 8.0 with ammonia water. The temperature was raised to 70° C. for 1 hour, and the content of the thiocyanide intermediate (II) was detected by HPLC to be 19.87% (required that the thiocyanide intermediate (II) ≤ 1.0%), and the reaction failed.

Embodiment 7 comparative examples (the pH of the second step condensation reaction is 12.0)

Add 1000mL acetonitrile and 100g 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (I) (0.31mol) and 71.0g Ammonium thiocyanate (0.93mol) was stirred, and 282g (2.5mol) of 30% hydrogen peroxide was added dropwise. The temperature of the reaction solution was -20°C to -10°C during the dropwise addition. Add 1000mL of water and adjust the pH to 8.0 with ammonia water. Raise the temperature to 70°C for 1 hour, cool to 5°C for 1 hour, filter and dry to obtain 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyridine Azole disulfide (III) 98g, yield 89.3%, HPLC purity 95.80%, external standard content 93.2%.

Claims

A synthetic method of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole disulfide (III), characterized in that the method include:

(1) 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole (I) reacts with ammonium thiocyanate and hydrogen peroxide to obtain a thiocyanide intermediate (II);

(2) The thiocyanide intermediate (II) obtained in step (1) is condensed under alkaline conditions to obtain 5-amino-3-cyano-1-(2,6-dichloro-4-tri Fluoromethyl-phenyl) pyrazole disulfide (III), the alkaline condition is pH 9.0-11.0
The method according to claim 1, characterized in that, the solvent used in the step (1) is acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide, preferably acetonitrile.
The method according to claim 1 or 2, characterized in that the reaction temperature of the step (1) is -20°C to 10°C.
The method according to any one of claims 1-3, characterized in that the reaction time of the step (1) is 5 minutes to 2 hours.
The method according to any one of claims 1-4, characterized in that the alkaline substance used in the step (2) is ammonia water or ammonia gas or aqueous sodium hydroxide solution.
The method according to any one of claims 1-5, characterized in that the reaction temperature of the step (2) is 50-80°C.
The method according to any one of claims 1-6, characterized in that the reaction time of the step (2) is 1-3 hours.
The method according to any one of claims 1-7, wherein the solvent used in the step (1) is mixed with 5-amino-3-cyano-1-(2,6-dichloro-4-tri The volume-mass ratio of fluoromethylphenyl)pyrazole (I) is 2-15:1, and the unit is mL/g.
The method according to any one of claims 1-8, wherein in the step (1), hydrogen peroxide and 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoro The molar ratio of methylphenyl)pyrazole (I) is 5-12:1.
The method according to any one of claims 1-9, characterized in that, in the step (1), ammonium thiocyanate and 5-amino-3-cyano-1-(2,6-dichloro-4 The molar ratio of -trifluoromethylphenyl)pyrazole (I) is 2.5-4:1.