Preparation of 2-Cl-5-F-nicotinate and nicotonic acid

Inactive Publication Date: 2005-05-11
上海药明康德新药开发有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] 2-Chloro-5-fluoro-nicotinic acid ester and 2-chloro-5-fluoro-nicotinic acid are relatively important drug intermediates, but so far there is no effective synthetic method to prepare this product, and it has been reported in the literature Two preparation methods, one method is to use 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester to react with methyl mercaptan first, and then use Raney nickel as a catalyst to hydrogenate and remove methyl mercapto to obtain 2-chloro- 5-Fluoro-nicotinic acid ethyl ester, and 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 and first nitrate Then chlorinated to give 2-chloro-5-nitro-nicotinic acid, which was reduced by iron powder to give 2-c

Method used

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  • Preparation of 2-Cl-5-F-nicotinate and nicotonic acid
  • Preparation of 2-Cl-5-F-nicotinate and nicotonic acid
  • Preparation of 2-Cl-5-F-nicotinate and nicotonic acid

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Effect test

Embodiment 1

[0018] The first step: the synthesis of 2-chloro-5-fluoro-nicotinic acid ethyl ester

[0019] Add triethylamine (32 g, 0.32 mol) and Lindlar catalyst (2.5 g) to ethyl acetate solution (1.2 L) of 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester (50 g, 0.21 mol), Hydrogenation was carried out at 3 atmospheres at room temperature for 12 hours. The catalyst was removed by filtration, the reaction solution was concentrated and then column chromatographed to obtain 2-chloro-5-fluoro-nicotinic acid ethyl ester (24.1 g, 0.12 mol, yield: 55%) as a colorless oil. 1 H NMR (400MHz, CDCl 3 ): δ8.36(d, J=2.8Hz, 1H), 7.88(dd, J=8.0 & 2.8Hz, 1H), 4.40(q, J=7.2Hz, 2H), 1.39(t, J=7.2Hz ,2H); 13 C NMR (400MHz, CDCl 3 ): δ164.5(C), 160.5(C), 158.0(C), 146.0(d, J=10.8Hz, C), 141.3(d, J=99.6Hz, CH), 146.0(d, J=10.8 Hz, C), 129.2(d, J=13.6Hz, C), 128.5(d, J=85.4Hz, CH), 63.9(d, J=48.0Hz, CH 2 ), 15.4 (CH 3 ); Ms(M + +1204206).

[0020] The second step: the synthesis of 2-chloro-5-fluoro...

Embodiment 2

[0023] Synthesis of 2-amino-5-fluoro-nicotinic acid ethyl ester

[0024] Add triethylamine (32 g, 0.32 mol) and 5% Pd-C catalyst ( 1.0 g), hydrogenated at normal pressure and room temperature for 12 hours. The catalyst was removed by filtration, the reaction liquid was concentrated and then column chromatographed to obtain oily 2-chloro-5-fluoro-nicotinic acid ethyl ester (18.4 g, 0.09 mol, yield: 43%).

Embodiment 3

[0026] Synthesis of 2-chloro-5-fluoro-nicotinic acid ethyl ester

[0027] Add triethylamine (32g, 0.32mol) and 5% Raney nickel (1.0 g) Hydrogenation at normal pressure at 40°C for 12 hours. The catalyst was removed by filtration, the reaction solution was concentrated and then column chromatographed to obtain oily ethyl 2-chloro-5-fluoro-nicotinate (18.4 g, 0.09 mol, yield: 25%).

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Abstract

Production of 2-chlorine-5-fluorine-nicotinate and acid is carried out by 2-chlorine-5-fluorine-nicotinate and related carboxylic acid selective dechlorinating, and 2-chlorine-5-fluorine-nicotinate hydrolyzing 2-chlorine-5-fluorine-niacin under the exist of alkaline substances. It can be used for 2-chlorine-5-fluorine-nicotinate and 2-chlorine-5-fluorine-niacin medicine intermediate.

Description

Technical field: [0001] The invention relates to a preparation method of nicotinic acid ester with chlorine and fluorine groups and nicotinic acid drug intermediates, in particular to a preparation method of 2-chloro-5-fluoro-nicotinic acid ester and acid. Background technique: [0002] 2-Chloro-5-fluoro-nicotinic acid ester and 2-chloro-5-fluoro-nicotinic acid are relatively important drug intermediates, but so far there is no effective synthetic method to prepare this product, and it has been reported in the literature Two preparation methods, one method is to use 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester to react with methyl mercaptan first, and then use Raney nickel as a catalyst to hydrogenate and remove methyl mercapto to obtain 2-chloro- 5-Fluoro-nicotinic acid ethyl ester, and 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 and first nitrate Then chlorinated to gi...

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/803
Inventor 施峰施一峰马汝建李革
Owner 上海药明康德新药开发有限公司
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