2-methyl nicotinate as well as preparation method and application thereof

Abstract

The invention relates to 2-methyl nicotinate as well as a preparation method and application thereof. The preparation method comprises the following steps: (1) reacting 1, 1, 3, 3-tetramethoxypropane or 1, 1, 3, 3-tetraethoxypropane under the action of acid to obtain a compound B; (2) reacting the compound B and beta-aminocrotonate in a first organic solvent to obtain 2-methyl nicotinate, wherein no foul acrolein is used in the process, the safety coefficient of production is effectively improved, the reaction raw materials are easy to obtain, the conditions are mild, the operation is simple, the yield is greater than 65%, the product purity reaches 98% or above, and the method is suitable for industrial production and has a wide application prospect. The obtained product can be used as an intermediate for synthesizing 2-methyl nicotinic acid, and can be used for synthesizing medicines.

Description

technical field

[0001] The invention relates to the technical field of organic synthesis, in particular to a 2-methylnicotinate and its preparation method and application. Background technique

[0002] 2-Methylnicotinate is a colorless or pale yellow liquid with a pungent odor, easily soluble in organic solvents such as alcohol, ethyl acetate, and methylene chloride, and is a key intermediate for the synthesis of 2-methylnicotinic acid. 2-Methylnicotinic acid is an intermediate of a specific ATP-competitive IKKβ inhibitor drug ML-120B, and also an intermediate of an oncolytic drug BAY-1082439; The intermediate of nicotinic acid is very important.

[0003] In the prior art, there are literatures ("Hirai, Sho; Horikawa, Yurie; Asahara, Haruyasu; Nishiwaki, Nagatoshi., Chemical Communications, 2007, 53(15), 2390-2393") reporting 2-methylnicotinate The synthesis method is to use methyl β-aminocrotonate and acrolein as raw materials, react with toluene in a sealed tube at 120 °...

Examples

Embodiment 1

[0071] The present embodiment provides a kind of preparation method of methyl 2-methylnicotinate, specifically as follows:

[0072] (1) Add 2.0 mol of 1,1,3,3-tetramethoxypropane into the reactor at room temperature, add 2.5 mol of 20% hydrochloric acid under stirring, control the temperature at 40°C, and react for 4 hours; 2.5 mol means The molar weight of HCl in hydrochloric acid is the same as follows;

[0073] (2) Add 1mol of methyl β-aminocrotonate and 6mol of methyl alcohol into the reactor, control the reaction temperature at 50° C., and react for 6 hours;

[0074] Wherein, the molar ratio of methyl β-aminocrotonate, 1,1,3,3-tetramethoxypropane, hydrochloric acid and methanol is 1.0:2.0:2.5:6.0;

[0075] (3) Concentrate the above reaction solution under reduced pressure, neutralize the concentrated solution with 10% aqueous sodium hydroxide solution to system pH=5.0, add ethyl acetate with 5 times the quality of methyl β-aminocrotonate to the system, and extract the p...

Embodiment 2

[0082] The present embodiment provides a kind of preparation method of methyl 2-methylnicotinate, specifically as follows:

[0083](1) Add 2.5 mol of 1,1,3,3-tetramethoxypropane into the reactor at room temperature, add 3.0 mol of hydrochloric acid with a mass concentration of 20% under stirring, control the temperature at 40°C, and react for 3 hours;

[0084] (2) Add 1mol of methyl beta-aminocrotonate and 6mol of methyl alcohol into the reactor, control the reaction temperature at 60° C., and react for 5 hours;

[0085] Wherein, the molar ratio of methyl β-aminocrotonate, 1,1,3,3-tetramethoxypropane, hydrochloric acid and methanol is 1.0:2.5:3.0:7.0;

[0086] (3) Concentrate the above reaction solution under reduced pressure, neutralize the concentrated solution with 10% aqueous sodium hydroxide solution until the system pH=6.0, add ethyl acetate with 6 times the mass of methyl β-aminocrotonate to the system, and extract the phase, add 4 times the quality of methyl β-aminocr...

Embodiment 3

[0093] The present embodiment provides a kind of preparation method of methyl 2-methylnicotinate, specifically as follows:

[0094] (1) Add 2.0 mol of 1,1,3,3-tetramethoxypropane into the reactor at room temperature, add 2.0 mol of hydrochloric acid with a mass concentration of 25% under stirring, control the temperature at 45°C, and react for 3 hours;

[0095] (2) Add 1mol of methyl β-aminocrotonate and 7mol of methyl alcohol into the reactor, control the reaction temperature at 60° C., and react for 7 hours;

[0096] Wherein, the molar ratio of methyl β-aminocrotonate, 1,1,3,3-tetramethoxypropane, hydrochloric acid and methanol is 1.0:2.0:2.0:7.0;

[0097] (3) Concentrate the above reaction solution under reduced pressure, neutralize the concentrated solution with 10% aqueous sodium hydroxide solution until the system pH=7.0, add ethyl acetate with 7 times the quality of methyl β-aminocrotonate to the system, and extract the phase, add 5 times the quality of methyl β-aminoc...

technical field

[0001] The invention relates to the technical field of organic synthesis, in particular to a 2-methylnicotinate and its preparation method and application. Background technique

[0002] 2-Methylnicotinate is a colorless or pale yellow liquid with a pungent odor, easily soluble in organic solvents such as alcohol, ethyl acetate, and methylene chloride, and is a key intermediate for the synthesis of 2-methylnicotinic acid. 2-Methylnicotinic acid is an intermediate of a specific ATP-competitive IKKβ inhibitor drug ML-120B, and also an intermediate of an oncolytic drug BAY-1082439; The intermediate of nicotinic acid is very important.

[0003] In the prior art, there are literatures ("Hirai, Sho; Horikawa, Yurie; Asahara, Haruyasu; Nishiwaki, Nagatoshi., Chemical Communications, 2007, 53(15), 2390-2393") reporting 2-methylnicotinate The synthesis method is to use methyl β-aminocrotonate and acrolein as raw materials, react with toluene in a sealed tube at 120 °...

Examples

Embodiment 1

[0071] The present embodiment provides a kind of preparation method of methyl 2-methylnicotinate, specifically as follows:

[0072] (1) Add 2.0 mol of 1,1,3,3-tetramethoxypropane into the reactor at room temperature, add 2.5 mol of 20% hydrochloric acid under stirring, control the temperature at 40°C, and react for 4 hours; 2.5 mol means The molar weight of HCl in hydrochloric acid is the same as follows;

[0073] (2) Add 1mol of methyl β-aminocrotonate and 6mol of methyl alcohol into the reactor, control the reaction temperature at 50° C., and react for 6 hours;

[0074] Wherein, the molar ratio of methyl β-aminocrotonate, 1,1,3,3-tetramethoxypropane, hydrochloric acid and methanol is 1.0:2.0:2.5:6.0;

[0075] (3) Concentrate the above reaction solution under reduced pressure, neutralize the concentrated solution with 10% aqueous sodium hydroxide solution to system pH=5.0, add ethyl acetate with 5 times the quality of methyl β-aminocrotonate to the system, and extract the p...

Embodiment 2

[0082] The present embodiment provides a kind of preparation method of methyl 2-methylnicotinate, specifically as follows:

[0083](1) Add 2.5 mol of 1,1,3,3-tetramethoxypropane into the reactor at room temperature, add 3.0 mol of hydrochloric acid with a mass concentration of 20% under stirring, control the temperature at 40°C, and react for 3 hours;

[0084] (2) Add 1mol of methyl beta-aminocrotonate and 6mol of methyl alcohol into the reactor, control the reaction temperature at 60° C., and react for 5 hours;

[0085] Wherein, the molar ratio of methyl β-aminocrotonate, 1,1,3,3-tetramethoxypropane, hydrochloric acid and methanol is 1.0:2.5:3.0:7.0;

[0086] (3) Concentrate the above reaction solution under reduced pressure, neutralize the concentrated solution with 10% aqueous sodium hydroxide solution until the system pH=6.0, add ethyl acetate with 6 times the mass of methyl β-aminocrotonate to the system, and extract the phase, add 4 times the quality of methyl β-aminocr...

Embodiment 3

[0093] The present embodiment provides a kind of preparation method of methyl 2-methylnicotinate, specifically as follows:

[0094] (1) Add 2.0 mol of 1,1,3,3-tetramethoxypropane into the reactor at room temperature, add 2.0 mol of hydrochloric acid with a mass concentration of 25% under stirring, control the temperature at 45°C, and react for 3 hours;

[0095] (2) Add 1mol of methyl β-aminocrotonate and 7mol of methyl alcohol into the reactor, control the reaction temperature at 60° C., and react for 7 hours;

[0096] Wherein, the molar ratio of methyl β-aminocrotonate, 1,1,3,3-tetramethoxypropane, hydrochloric acid and methanol is 1.0:2.0:2.0:7.0;

[0097] (3) Concentrate the above reaction solution under reduced pressure, neutralize the concentrated solution with 10% aqueous sodium hydroxide solution until the system pH=7.0, add ethyl acetate with 7 times the quality of methyl β-aminocrotonate to the system, and extract the phase, add 5 times the quality of methyl β-aminoc...

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