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Synthetic method for 4-bromo-6-chloronicotinaldehyde

A synthetic method, the technology of chloronicotinic aldehyde, applied in the direction of organic chemistry, etc., can solve the problems of poor economic benefits and environmental impact, long process steps, complicated operation, etc., and achieve environmental friendliness, simplification of reaction process and post-treatment Process, the effect of optimizing the reaction conditions

Active Publication Date: 2019-04-19
上海毕得医药科技股份有限公司
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  • Claims
  • Application Information

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Problems solved by technology

4-Bromo-6-chloronicotinaldehyde is an important intermediate of FGFR4 enzyme selective inhibitors. The yield of the original production synthesis process is only 35%. The operation is complicated, the process steps are long, the reaction is difficult, and the yield is low. Economic benefits and Environmental impact is not good

Method used

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  • Synthetic method for 4-bromo-6-chloronicotinaldehyde
  • Synthetic method for 4-bromo-6-chloronicotinaldehyde
  • Synthetic method for 4-bromo-6-chloronicotinaldehyde

Examples

Experimental program
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Effect test

Embodiment 1

[0042] The first step is the synthesis of compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate:

[0043] Add 150g of ethyl 4,6-dichloronicotinic acid (0.68mol) and 93.5g of 4-methoxybenzylamine (0.68mol) into a 3000ml dry three-necked flask, mechanically stir, heat to 40°C, stir and react overnight After the completion of the reaction detected by thin layer chromatography (TLC), it was added to ice water, extracted with ethyl acetate 3 times, backwashed with saturated brine, dried by adding anhydrous sodium sulfate, and the column was eluted [eluent : (Petroleum ether: ethyl acetate=40:1)] 196 g of compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate was obtained, and the yield was 90%.

[0044] The second step is the synthesis of compound (2) ethyl 4-amino-6-chloronicotinate:

[0045] Add 196g of compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinic acid (0.61mol) to 1500ml of trifluoroacetic acid (20mol), and heat at 50℃~60℃ After reacting overni...

Embodiment 2

[0053] The first step is the synthesis of compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate:

[0054] 150g of ethyl 4,6-dichloronicotinate (0.68mol) and 93.5g of 4-methoxybenzylamine (0.68mol) were added to a 3000ml dry three-necked flask, stirred mechanically, and reacted overnight at room temperature. According to TLC detection, the raw material did not react completely. It was added to ice water, extracted 3 times with ethyl acetate, backwashed with saturated brine, dried by adding anhydrous sodium sulfate, and the column layer was eluted [eluent: (petroleum ether: Ethyl acetate=40:1)] 120 g of compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinic acid was obtained, and the yield was 55%.

[0055] The second step is the synthesis of compound (2) ethyl 4-amino-6-chloronicotinate:

[0056] 120g compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinic acid (0.37mol) was added to 600ml trifluoroacetic acid (8.07mol) and heated at 50℃~60 React overnigh...

Embodiment 3

[0064] The first step is the synthesis of compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate:

[0065] Add 150g of ethyl 4,6-dichloronicotinate (0.68mol) and 187g of 4-methoxybenzylamine (1.36mol) into a 3000ml dry three-necked flask, mechanically stir, heat to a reaction temperature of 60℃, and stir to react Overnight, TLC detection showed that the reaction was complete, added to ice water, extracted with ethyl acetate 3 times, backwashed with saturated brine, dried with anhydrous sodium sulfate, and the column layer was eluted [eluent: (petroleum ether: Ethyl acetate=40:1)] to obtain 109 g of compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate with a yield of 50%.

[0066] The second step is the synthesis of compound (2) ethyl 4-amino-6-chloronicotinate:

[0067] Add 109g of compound (1) 6-chloro-4-((4-methoxybenzyl)amino)nicotinic acid ethyl ester (0.34mol) to 1010ml of trifluoroacetic acid (13.59mol), and heat at 50℃~60 React overnight at ℃, check by ...

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Abstract

The invention provides a synthetic method for 4-bromo-6-chloronicotinaldehyde, and relates to the field of pharmaceutical chemistry. A synthetic route includes as follows: ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate can be obtained through the reaction of ethyl 4,6-dichloronicotinate and 4-methoxybenzylamine; ethyl 4-amino-6-chloronicotinate can be obtained through the reaction of the ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate and trifluoroacetic acid; ethyl 4-bromo-6-chloronicotinate can be obtained through the reaction of the ethyl 4-amino-6-chloronicotinate and tert-butyl nitrite and benzyltriethylammonium bromide; (4-bromo-6-chloropyridin-3-yl)methanol can be obtained through the reaction of the ethyl 4-bromo-6-chloronicotinate and diisobutylaluminium hydride under a certain condition; and the (4-bromo-6-chloropyridin-3-yl)methanol can be further reacted under the synthetic action of manganese dioxide, so that a target product 4-bromo-6-chloronicotinaldehyde can beobtained. The disclosed synthetic method is mild in reaction condition, low in production cost and suitable for large-scale industrial production.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of 4-bromo-6-chloronicotinaldehyde. Background technique [0002] FGFR4 enzyme (tyrosine kinase) selective inhibitor for the treatment of diseases caused by FGFR4 or FGF19. FGFR4 has a significant selective inhibitory effect and has broad application prospects in the treatment of tumors such as liver cancer, gastric cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer and breast cancer. 4-Bromo-6-chloronicotinaldehyde is an important intermediate of FGFR4 enzyme selective inhibitor. The original production synthesis process yield is only 35%, the operation is complicated, the process steps are long, the reaction is difficult, and the yield is low. The environmental impact is not good. Summary of the invention [0003] The object of the present invention is to provide a method for synthesizing 4-bromo-6-chloron...

Claims

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Application Information

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IPC IPC(8): C07D213/61
CPCC07D213/61
Inventor 余国春郦荣浩涂强
Owner 上海毕得医药科技股份有限公司
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