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Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd

A technology of nicotinic acid and chlorinating agent, applied in the direction of organic chemistry, etc., can solve problems such as the need for chromatographic purification, and achieve the effect of reasonable selection of reaction process

Inactive Publication Date: 2007-12-19
CHANGZHOU HEQUAN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved in the present invention is: solve the problem of chromatographic purification in the existing 2-chloro-5-fluoro-nicotinic acid preparation process; shorten the route of the existing synthesis process, improve the overall yield, reduce costs, and be suitable It is suitable for large-scale production; avoiding the use of odorous methyl mercaptan; providing an industrial preparation method of 2-chloro-5-fluoro-nicotinic acid

Method used

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  • Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd
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  • Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Synthesis of 2-chloro-5-fluoro-nicotinic acid (POCl 3 , 50℃, 12h)

[0024] The first step: the synthesis of 5-fluoro-nicotinic acid

[0025] Add triethylamine (101.0g, 1.0mol) and 5% palladium carbon catalyst (4g) in 2,6-dichloro-5-fluoro-nicotinic acid (100g, 0.476mol) in absolute ethanol solution (2.4L) , hydrogenated at 3 atmospheres and room temperature for 12 hours. The catalyst was removed by filtration and concentrated to obtain the product (66.2 g, 0.468 mol), yield: 98%. 1 H NMR (400MHz, DMSO-d 6 ): 68.91(s, 1H), 8.81(d, J=2.8Hz, 1H), 8.09(dd, J=8.8&2.8Hz, 1H); Ms(M + +1, 142).

[0026] The second step: the synthesis of nitroxide-5-fluoro-nicotinic acid

[0027] 5-Fluoro-nicotinic acid (50g, 0.36mol) was dissolved in glacial acetic acid (500mL), and 30% H 2 o 2 (74mL, 0.72mol), heated to 100°C, reacted overnight, distilled off glacial acetic acid under reduced pressure, washed with water to obtain the product (53g, 0.34mol), yield: 95%. 1 H NMR (40...

Embodiment 2

[0031] Synthesis of 2-chloro-5-fluoro-nicotinic acid

[0032] In 2,6-dichloro-5-fluoro-nicotinic acid (50g, 0.238mol) in absolute ethanol solution (1.2L), add triethylamine (50.5g, 0.5mol) and Raney nickel catalyst (5g), Hydrogenation was carried out at 5 atmospheres and room temperature for 12 hours. The catalyst was removed by filtration and concentrated to obtain the product (32.8 g, 0.232 mol), yield: 97%.

[0033] In the process of preparing 2-chloro-5-fluoro-nicotinic acid, the corresponding products were prepared according to the nitrogen oxidation and chlorination process conditions and operating steps described in the second and third steps in the above example 1, and the test data were as above Example 1 shows.

Embodiment 3

[0035] Synthesis of 2-chloro-5-fluoro-nicotinic acid (POCl 3 +PCl 5 , 70℃, 12h)

[0036] According to the reaction conditions and operation methods described in the first step and the second step in the above example 1, the nitrogen oxide-5-fluoro-nicotinic acid intermediate was prepared. Then, nitroxide-5-fluoro-nicotinic acid (10 g, 63.7 mmol) was dissolved in POCl 3 (50mL), under ice bath, add PCl 5 , (20g) was heated to 50°C, stirred for 12h, and POCl was evaporated under reduced pressure 3 , adding 50 g of crushed ice, stirring, precipitated a beige solid, filtered to obtain 11 g of crude product, recrystallized from water to obtain pure product (6.7 g, 38.2 mmol), yield: 60%.

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Abstract

An industrial process for preparing 2-chloro-5-fluoro-nicotinic acid from 2,6-dichloro-5-fluoro-nicotinic acid includes catalytic hydrogenating, nitroxidizing and chlorinating. Its advantages are high outpt rate, and short process.

Description

Technical field: [0001] The invention relates to a preparation method of a nicotinic acid drug intermediate with chlorine and fluorine groups, in particular to an industrial preparation method of 2-chloro-5-fluoro-niacin. Background technique: [0002] 2-Chloro-5-fluoro-nicotinic acid is a relatively important drug intermediate, but so far there is no effective synthetic method to prepare this product. Two preparation methods have been reported in the literature. One method is to use 2, 6-dichloro-5-fluoro-nicotinic acid ethyl ester is first reacted with methyl mercaptan, and then hydrogenated with Raney nickel as a catalyst to remove the methyl mercapto group to obtain 2-chloro-5-fluoro-nicotinic acid ethyl ester, which is then hydrolyzed to obtain 2-Chloro-5-fluoro-nicotinic acid (J.Med.Chem.1993, 2678-2688); Another method is to start from 2-hydroxy-nicotinic acid, first nitrate and then chlorinate to get 2-chloro-5- Nitro-nicotinic acid, which is reduced by iron powder ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/80
Inventor 施峰施一峰马汝建唐苏翰李革
Owner CHANGZHOU HEQUAN PHARMA CO LTD
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