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Preparation method of 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine

A technology of isothiocyanate and trifluoromethyl, which is applied in the field of preparation of 5-isothiocyanate-3-trifluoromethyl-2-cyanopyridine, can solve complex operation process, thiophosgene production, Difficulty in purchasing, harsh response conditions, etc.

Inactive Publication Date: 2019-11-15
ZHEJIANG LANGHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The synthetic method of reported 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine is to be raw material with 5-amino-3-trifluoromethyl-2-cyanopyridine, and sulfur light Gas reaction to obtain the target compound. Because thiophosgene is difficult to produce and purchase, and it is a low-boiling liquid that needs to be stored below 4°C, it is more complicated to use, and the excess thiophosgene is also more troublesome to deal with, which is likely to cause environmental pollution. , so the raw material thiophosgene required for this preparation method is not easy to get, the reaction conditions are harsh, and the operation process is complicated

Method used

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  • Preparation method of 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine

Examples

Experimental program
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preparation example Construction

[0032] The preparation method of the present embodiment specifically comprises the following steps:

[0033] Step 1: 5-amino-3-trifluoromethyl-2-cyanopyridine (formula Ⅰ), triethylenediamine dissolved in the first solvent, adding carbon disulfide (CS 2 ), carry out the first-stage reaction at 30-110° C., and precipitate a solid, which is filtered and washed with suction to obtain dithioformate (Formula II).

[0034] In this example, the molar ratio of raw material 5-amino-3-trifluoromethyl-2-cyanopyridine to triethylenediamine and carbon disulfide is 1:1~5:1~5, such as 1:1:1 , 1:1:2, 1:2:1, 1:3:4, 1:4:3 or 1:5:5, wherein the molar ratio of triethylenediamine and carbon disulfide is greater than that of 5-amino-3-tri The amount molar ratio of fluoromethyl-2-cyanopyridine, the molar ratio of the amount of triethylenediamine and carbon disulfide can be equal, 5-amino-3-trifluoromethyl-2-cyanopyridine and triethylenediamine, carbon disulfide The molar ratio of the amount used ...

Embodiment 1

[0052] This embodiment provides a kind of 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine, which is prepared according to the following preparation method:

[0053] (1) Add 18.7g (0.1mol) of 5-amino-3-trifluoromethyl-2-cyanopyridine, 33.6g (0.3mol) of triethylenediamine and 561g of toluene into the reaction flask, and heat to 50-60 ℃, then add 22.8g (0.3mol) of carbon disulfide dropwise within 2 hours, continue to stir and react at 50-60℃ for 20 hours after the dropwise addition, cool to room temperature, a large amount of solid precipitates, filter with suction, wash with a small amount of toluene, and dry , to obtain 35 g of dithioformate solid, with a yield of 93.3%.

[0054] (2) Add 35 g of the above dithioformate solids and 350 g of dichloromethane into the reaction flask, cool to 5-10°C, and dropwise add BTC / dichloromethane prepared by 9.1 g (0.031 mol) of BTC and 45 g of dichloromethane. The methane solution was incubated for 20 hours after the dropwise addition to ...

Embodiment 2

[0059] This embodiment provides a kind of 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine, which is prepared according to the following preparation method:

[0060] Add 18.7g (0.1mol) of 5-amino-3-trifluoromethyl-2-cyanopyridine, 34g (0.33mol) of triethylenediamine and 374g of dichloromethane in the reaction flask, heat to reflux, and then Add 25.1g (0.33mol) of carbon disulfide dropwise within 1 hour. After the dropwise addition, continue to reflux and stir for 12 hours, cool to room temperature, a large amount of solid precipitates, filter with suction, wash with a small amount of dichloromethane, and dry to obtain dithioformic acid Salt solid 31.2g, yield 83.2%.

[0061] Add 30 g of the above-mentioned dithioformate solids and 600 g of toluene into the reaction flask, heat to 50-60 ° C, dropwise add the BTC / toluene solution prepared by 9.5 g of BTC and 47 g of toluene, and keep it warm for 20 hours after the addition is completed to obtain The reaction solution.

[006...

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Abstract

The embodiment of the invention provides a preparation method of 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine, and relates to the field of chemical synthesis. The preparation method of the 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine mainly comprises the steps that 5-amino-3-trifluoromethyl-2-cyanopyridine and triethylene diamine are dissolved in a first solvent, carbon disulfide is added, a first-stage reaction is conducted at 30-100 DEG C, solids are separated out, and through suction filtration and washing, dithio-formate is obtained; the dithio-formate is dissolved in a secondsolvent, the temperature is controlled to 0-60 DEG C, stage addition of bis(trichloromethyl)carbonic ester is conducted, and a second-stage reaction is conducted. According to the preparation method,the raw materials are easy to obtain, the process is simple, the operation is convenient, and the preparation method is suitable for industrial production.

Description

technical field [0001] This application relates to the field of chemical synthesis, in particular to a preparation method of 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine. Background technique [0002] 5-isothiocyanoyl-3-trifluoromethyl-2-cyanopyridine, that is, 5-isothiocyanoyl-3-(trifluoromethyl)pyridine-2-cyano is a new drug for the treatment of prostate cancer—A The key intermediate of apalutamide has a good market prospect. The synthetic method of reported 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine is to be raw material with 5-amino-3-trifluoromethyl-2-cyanopyridine, and sulfur light Gas reaction to obtain the target compound. Because thiophosgene is difficult to produce and purchase, and it is a low-boiling liquid that needs to be stored below 4°C, it is more complicated to use, and the excess thiophosgene is also more troublesome to deal with, which is likely to cause environmental pollution. , so the raw material thiophosgene required by the preparatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/84
CPCC07D213/84
Inventor 林邦平王远聪陈忠平
Owner ZHEJIANG LANGHUA PHARMA
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