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Synthetic method of ethyl 5-bromo-2-methylnicotinate

A technology of methyl nicotinic acid ethyl ester and synthesis method, which is applied in the direction of organic chemistry, can solve the problems of high safety risk, few synthesis reports, and unsuitability for large-scale industrial production, so as to improve stability and avoid column chromatography process Effect

Inactive Publication Date: 2019-02-01
上海睿腾医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] There are few reports about its synthesis in the literature: the 2002 patent EP1180514 started from nitromalonic dialdehyde and ethyl aminocrotonate, and synthesized 5-bromo-2-methylnicotinic acid ethyl ester through a three-step reaction, but the first step The yield of the ring-closing reaction is only 30%, and nitromalondialdehyde is an explosive product, which has a high safety risk during storage and use. Therefore, this synthetic route is not suitable for large-scale industrial production. Its synthetic reaction is as follows:

Method used

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  • Synthetic method of ethyl 5-bromo-2-methylnicotinate

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Experimental program
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Effect test

Embodiment 1

[0037] Add ethyl acetoacetate (7.0 g) and dioxane (140 g) to a 250 mL three-necked flask, lower the temperature of the system to -10° C. in an ice-salt bath, add potassium tert-butoxide (6.4 g), intermediate III (23.8 g) and DABCO (6.1 g) were stirred for 5 hours, ammonium acetate (10.0 g) was added, and the temperature was raised to 60° C. for 16 hours, monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, poured into ice water (200 g), added MTBE (50 g), stirred for 1 hour and separated into layers, the aqueous phase MTBE (50 g) was extracted once, and the organic phase was added anhydrous sodium sulfate (20 g). Let dry for 1 hour. Filter, concentrate with a rotary evaporator, dissolve the residue with hot n-heptane (30.0 g), cool down to -20°C, stir for 1 hour, filter, and dry under reduced pressure to obtain ethyl 5-bromo-2-methylnicotinate , 7.8 grams of white solid, yield 60.0%, purity 99.4% (see Table 1).

[0038] Its ...

Embodiment 2

[0041] Add ethyl acetoacetate (7.0 g) and 2-methyltetrahydrofuran (70 g) into a 250 mL three-necked flask, lower the temperature of the system to -8° C. in an ice-salt bath, add potassium tert-butoxide (3.5 g), intermediate Compound III (21.0 g) and DABCO (3.5 g) were stirred for 4 hours, ammonium acetate (7.0 g) was added, and the temperature was raised to 55° C. for 15 hours, monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, poured into ice water (180 grams), added MTBE (46 grams), stirred for 1 hour and separated into layers, the aqueous phase MTBE (46 grams) was extracted once, and the organic phase was added anhydrous sodium sulfate (20 grams). Let dry for 1 hour. Filtrate, concentrate with a rotary evaporator, dissolve the residue with hot n-heptane (20.0 g), cool to 0°C, stir for 1 hour, filter, and dry under reduced pressure to obtain ethyl 5-bromo-2-methylnicotinate. 6.4 g of white solid, yield 49.0%.

Embodiment 3

[0043] Add ethyl acetoacetate (7.0 g) and tetrahydrofuran (210 g) into a 250 mL three-necked flask, lower the temperature of the system to -6°C under an ice-salt bath, add potassium tert-butoxide (7.0 g), intermediate III (22.5 gram) and DABCO (4.5 grams), stirred for 4 hours, added ammonium acetate (9.0 grams), heated to 57 ° C for 16 hours, TLC monitoring until the end of the reaction. The reaction solution was cooled to room temperature, poured into ice water (180 grams), added MTBE (48 grams), stirred for 1 hour and separated into layers, the aqueous phase MTBE (46 grams) was extracted once, and the organic phase was added anhydrous sodium sulfate (20 grams). Let dry for 1 hour. Filtrate, concentrate with a rotary evaporator, dissolve the residue with hot n-heptane (25.0 g), raise it to 20°C, stir for 1 hour, filter, and dry under reduced pressure to obtain ethyl 5-bromo-2-methylnicotinate. 6.4 g of white solid, yield 49.0%.

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Abstract

The invention discloses a synthetic method of ethyl 5-bromo-2-methylnicotinate, comprising the steps of adding ethyl acetyl acetate and base A into solvent B to carry out enolization; adding intermediate III and DABCO (1,4-diazabicyclo[2.2.2]octane) to allow reacting; adding ammonium acetate to carry out cyclization; adding water for quenching, and extracting with organic solvent C; removing the organic solvent C to obtain a crude product to be crystallized; recrystallizing the crude product to be crystallized to obtain ethyl 5-bromo-2-methylnicotinate. On the basis of 5-chloro-2-methylnicotinate synthetic process developed by Meck, stability of the intermediate III is evidently improved by changing the reaction solvents and reducing the reaction temperature; therefore, a production can besmoothly acquired by reacting; crystallization purification is applied in post-treatment, so that time-consuming manpower-consuming column chromatography step is avoided; the average yield is up to 70%; the purity is up to 99.0% and above; the synthetic method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing ethyl 5-bromo-2-methylnicotinate. Background technique [0002] As an important pharmaceutical and chemical raw material, ethyl 5-bromo-2-methylnicotinate is widely used in the synthesis of pharmaceutical intermediates, and its structural formula is as follows: [0003] [0004] There are few reports about its synthesis in the literature: the 2002 patent EP1180514 started from nitromalonic dialdehyde and ethyl aminocrotonate, and synthesized 5-bromo-2-methylnicotinic acid ethyl ester through a three-step reaction, but the first step The yield of the ring-closing reaction is only 30%, and nitromalondialdehyde is an explosive product, which has a high safety risk during storage and use. Therefore, this synthetic route is not suitable for large-scale industrial production. Its synthetic reaction is as follows: [0005] [0006] In 2017, the...

Claims

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Application Information

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IPC IPC(8): C07D213/803
CPCC07D213/803
Inventor 周涛王西施克茂张一平
Owner 上海睿腾医药科技有限公司
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