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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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[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-chloro-5-amino-nicotinic acid, 2-chloro-5-amino-nicotinic acid was diazotized in fluoboric acid The obtained diazonium fluoroborate is heated to obtain 2-chloro-5-fluoro-nicotinic acid (EP0634413A1)
[0007] In the literature synthesis route 1, one must replace 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester with the smelly methyl mercaptan, and at the same time use Raney nickel as the catalyst to selectively remove the methyl mercapto group, Yield is only about 30%, and this reaction has higher requirements on the type of Raney nickel, and the product cannot be obtained with general Raney nickel; and the synthesis process of document synthesis route 2 is too long, and the final diazonium fluoroborate is heated The yield of fluorination reaction is too low and difficult to operate
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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-niacinmedicine 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...
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