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A kind of synthetic method of 4-bromo-6-chloronicotinaldehyde

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

Active Publication Date: 2021-02-09
上海毕得医药科技股份有限公司
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  • Claims
  • Application Information

AI Technical Summary

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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  • A kind of synthetic method of 4-bromo-6-chloronicotinaldehyde
  • A kind of synthetic method of 4-bromo-6-chloronicotinaldehyde
  • A kind of synthetic method of 4-bromo-6-chloronicotinaldehyde

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of the first step compound (1) 6-chloro-4-((4-methoxybenzyl) amino) nicotinic acid ethyl ester:

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

[0044] Synthesis of the second step compound (2) 4-amino-6-chloronicotinic acid ethyl ester:

[0045] Add 196g of compound (1) 6-chloro-4-((4-methoxybenzyl)amino)nicotinic acid ethyl ester (0.61mol) into 1500ml of trifluoroacetic acid (20mol) and heat at 50°C to 60°C ...

Embodiment 2

[0053] Synthesis of the first step compound (1) 6-chloro-4-((4-methoxybenzyl) amino) nicotinic acid ethyl ester:

[0054] Add 150g of ethyl 4,6-dichloronicotinate (0.68mol) and 93.5g of 4-methoxybenzylamine (0.68mol) into a 3000ml dry three-necked flask, stir mechanically, and react with stirring overnight at room temperature. As detected by TLC, the raw materials were not completely reacted, added to ice water, extracted three times with ethyl acetate, backwashed once with saturated brine, dried by adding anhydrous sodium sulfate, and eluted by column [eluent: (petroleum ether: Ethyl acetate=40:1)] to obtain 120 g of compound (1) ethyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate, with a yield of 55%.

[0055] Synthesis of the second step compound (2) 4-amino-6-chloronicotinic acid ethyl ester:

[0056] Add 120 g of compound (1) 6-chloro-4-((4-methoxybenzyl) amino) nicotinic acid ethyl ester (0.37 mol) into 600 ml of trifluoroacetic acid (8.07 mol), heat at 50 ° C to 60 Re...

Embodiment 3

[0064] Synthesis of the first step compound (1) 6-chloro-4-((4-methoxybenzyl) amino) nicotinic acid ethyl ester:

[0065] Add 150g of ethyl 4,6-dichloronicotinate (0.68mol) and 187g of 4-methoxybenzylamine (1.36mol) into a 3000ml dry three-necked flask, stir mechanically, heat to the reaction temperature of 60°C, and stir the reaction Overnight, TLC detection, the reaction was complete, added to ice water, extracted 3 times with ethyl acetate, backwashed once with saturated saline, added anhydrous sodium sulfate to dry, column 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] Synthesis of the second step compound (2) 4-amino-6-chloronicotinic acid ethyl ester:

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

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Abstract

The invention provides a method for synthesizing 4-bromo-6-chloronicotinic aldehyde, which relates to the field of medicinal chemistry. The synthetic route is to react 4,6-dichloronicotinic acid ethyl ester and 4-methoxybenzylamine to obtain 6-chloro-nicotinic acid 4‑((4‑methoxybenzyl) amino) nicotinic acid ethyl ester, 6‑chloro‑4‑((4‑methoxybenzyl) amino) nicotinic acid ethyl ester and trifluoroacetic acid react to give 4‑amino ‑6‑chloronicotinic acid ethyl ester, 4‑amino‑6‑chloronicotinic acid ethyl ester and tert-butyl nitrite react with benzyltriethylammonium bromide to give 4‑bromo‑6‑chloronicotinic acid ethyl ester, 4 ‑Bromo‑6‑chloronicotinic acid ethyl ester reacts with diisobutylaluminum hydride under certain conditions to obtain 4‑bromo‑6‑chloronicotinol, and 4‑bromo‑6‑chloronicotinol is further catalyzed by manganese dioxide The following reaction is carried out to obtain the target product 4-bromo-6-chloronicotinic aldehyde; the synthetic method disclosed by the invention has mild reaction conditions, reduces production costs, and is 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 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 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. Contents of the invention [0003] The purpose of the present invention is to provide a synthesis method of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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