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Preparation method of 2, 4-diamino-6-chloropyrimidine

A chloropyrimidine and diamine-based technology, applied in the field of pharmaceutical raw material preparation, can solve the problems of high cost, low equipment utilization rate, complicated procedures and the like, and achieve the effects of high temperature stability, safe and gentle quenching, and obvious cost advantage.

Pending Publication Date: 2021-12-07
江苏睿实生物科技有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Organic compound 2,4-diamino-6-chloropyrimidine (English name: 2,4-Diamino-6-chloropyrimidine, abbreviated DACP) is the main raw material for the synthesis of Minoxidil (Minoxidil). Auxiliary materials in the electrolysis industry, according to existing literature reports, the DACP obtained by chlorination of 2,4-diamino-6-hydroxypyrimidine under phosphorus oxychloride in the production process generally has low yield, cumbersome procedures, and produces a large amount of Phosphorus wastewater and high cost
[0003] Existing production technology roughly divides two kinds, and the one, ("Shandong Pharmaceutical Industry" 1996 the 15th volume the 4th period " the synthetic research of minoxidine "), through water quenching and neutralization after completion of reaction, then use It is obtained by extraction with ethyl acetate. This method uses a large amount of phosphorus oxychloride, and after quenching, it uses several times the alkali for neutralization treatment, which is easy to produce a huge amount of waste water, and experiments have proved that the extraction efficiency is extremely low, requiring 30-40 times the ethyl acetate to complete the extraction, resulting in low equipment utilization and unable to increase production
[0004] The second is the existing patented methods that have been disclosed. Although some methods have simple and convenient process and are easy to industrialize, the yields described are quite different from the actual ones, and the product content is relatively low, so there are still high costs and poor market competitiveness. The problem

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  • Preparation method of 2, 4-diamino-6-chloropyrimidine

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Experimental program
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Effect test

Embodiment 1

[0027] Weigh 2,4-diamino-6-hydroxypyrimidine (12.6g) into the three-necked flask, add POCl 3 (53.5g) was added into the reaction flask, the temperature was raised to 105°C, and stirred for 6h. After the reaction, the excess POCl was evaporated 3 , lowered the temperature to 30-40°C, slowly added ethanol (37ml) dropwise, raised the temperature to reflux reaction for 2h after dropping, lowered the temperature, and added ethyl acetate (96ml). Cool and stir for 2h, filter. 17.8 g of DACP hydrochloride was obtained.

[0028] Add DACP hydrochloride into water (40ml), heat up to 70°C to dissolve, neutralize with ammonia water to pH 6-7, extract with ethyl acetate, dry and concentrate to obtain DACP pure product 11.8g, yield 82.0%, HPLC: 99.2% . [M+H+]=145.1, H-NMR (DMSO-d6): δ6.64 (S, NH2), δ6.42 (S, NH2), δ5.73 (S, Ar-H).

Embodiment 2

[0030] Weigh 2,4-diamino-6-hydroxypyrimidine (12.6g) into the three-necked flask, add POCl 3 (76.5g) was added into the reaction flask, the temperature was raised to 105°C, and stirred for 6h. After the reaction, the excess POCl was evaporated 3 , lower the temperature to 30-40°C, slowly add ethanol (60ml) dropwise, after the dropping, raise the temperature to reflux for 2h, cool down, and add acetone (60ml). Cool and stir for 2h, filter. 15.4 g of DACP hydrochloride was obtained.

[0031] DACP hydrochloride was added to water (40ml), heated to 70°C to dissolve, neutralized with ammonia water to pH 6-7, extracted with ethyl acetate, dried and concentrated to obtain 10.5g of pure DACP with a yield of 73.0%.

Embodiment 3

[0033] Weigh 2,4-diamino-6-hydroxypyrimidine (12.6g) into the three-necked flask, add POCl 3 (76.5g) was added into the reaction flask, the temperature was raised to 105°C, and stirred for 6h. After the reaction, the excess POCl was evaporated 3 , the temperature was lowered to 30-40°C, methanol (40ml) was slowly added dropwise, after the dropwise temperature was raised to reflux for 2h, the temperature was lowered, and acetonitrile (60ml) was added. Cool and stir for 2h, filter. 16.2 g of DACP hydrochloride was obtained.

[0034] DACP hydrochloride was added to water (40ml), dissolved at 70°C, neutralized with ammonia water to pH 6-7, extracted with ethyl acetate, dried and concentrated to obtain 11.1g of DACP with a yield of 77.1%.

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Abstract

The invention provides a preparation method of 2, 4-diamino-6-chloropyrimidine, which comprises the steps of chlorinating by taking 2, 4-diamino-6-hydroxypyrimidine as a raw material under the action of phosphorus oxychloride, quenching by using alcohol, dispersing by using an organic solvent to obtain 2, 4-diamino-6-hydroxypyrimidine hydrochloride, and neutralizing the hydrochloride by using ammonia water to obtain the 2, 4-diamino-6-hydroxypyrimidine. According to the method, phosphorus oxychloride is quenched by using alcohol, so that the quenching is safer. In addition, a dispersing agent with relatively low polarity is added to separate out a product, the recovery rate is greater than 70%, the highest recovery rate can reach 82%, and the generated phosphate ester is lower in boiling point than phosphoric acid, easy to recover and obvious in cost advantage.

Description

technical field [0001] The invention belongs to the technical field of preparation of medical raw materials, and in particular relates to a preparation method of 2,4-diamino-6-chloropyrimidine. Background technique [0002] Organic compound 2,4-diamino-6-chloropyrimidine (English name: 2,4-Diamino-6-chloropyrimidine, abbreviated DACP) is the main raw material for the synthesis of Minoxidil (Minoxidil). Auxiliary materials in the electrolysis industry, according to existing literature reports, the DACP obtained by chlorination of 2,4-diamino-6-hydroxypyrimidine under phosphorus oxychloride in the production process generally has low yield, cumbersome procedures, and produces a large amount of Phosphorus waste water and high cost. [0003] Existing production technology roughly divides two kinds, and the one, ("Shandong Pharmaceutical Industry" 1996 the 15th volume the 4th period " the synthetic research of minoxidine "), through water quenching neutralization after reaction ...

Claims

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Application Information

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IPC IPC(8): C07D239/48
CPCC07D239/48
Inventor 周海亮梁志寿高慧丽
Owner 江苏睿实生物科技有限公司
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