Preparation method of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride

Abstract

The invention provides a preparation method of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride. The preparation method is characterized in that maltol is used as a raw material, and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride is generated by methylation, ammonification, chlorination, oxidation, methoxy substitution, hydroxymethylation and secondary chlorination reaction in turn. According to the preparation method provided by the invention, synthesis route is simple and clear, and maltol is used as the raw material, thus cost is reduced, and the yield reaches above 75%.

Description

Technical field

[0001] The invention relates to a preparation method of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, which belongs to the field of medicine manufacturing. Background technique

[0002] 2-Chloromethyl-3,4-dimethoxypyridine hydrochloride is an important intermediate for the synthesis of a new drug pantoprazole. The existing preparation of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride The salt method is generally synthesized with 2-methyl-3-hydroxypyridine as a raw material through a 7-step reaction such as methylation, nitration, and methoxylation. However, such raw materials do not have domestic products and need to be imported and purchased, and the cost will increase. If furan is used as raw material to synthesize by oneself, the yield will be very low, less than 60%, and the purity will be very low. Summary of the invention

[0003] In order to overcome the shortcomings of the prior art, the present invention provides a method for preparing 2-chlorom...

Examples

Embodiment 1

[0015] (1) Add 31.5g of maltol to 20g of sodium hydroxide aqueous solution, stir, cool to 0°C in an ice water bath, slowly add 63 dimethyl phosphate dropwise, control the temperature at 2°C, continue in the ice water bath after dropping After stirring for 3h, pour the mixed solution into 5% 100ml sodium hydroxide solution, stir, extract three times with dichloromethane, wash the extract with water until it is neutral, add anhydrous sodium sulfate to dry, heat in a water bath to evaporate the solvent, Distill under reduced pressure to obtain 19.8 g of colorless liquid 3-methoxy-2-methyl-4H-pyran-4-one with a yield of 77%;

[0016] (2). Add 13.2g of 3-methoxy-2-methyl-4H-pyran-4-one to 360mld of concentrated ammonia water, stir at 40°C for 3h, evaporate the water under reduced pressure, the residue Cool, precipitate crystals, filter, wash the filter cake with water to neutrality, and recrystallize it with acetone to obtain 10.1 g of white crystals of 3-methoxy-2-methyl-4(1H)-pyrido...

Embodiment 2

[0023] (1) Add 50g of maltol to 25g of sodium hydroxide aqueous solution, stir, cool to 2°C in an ice water bath, slowly add 80g of dimethyl phosphate dropwise, control the temperature at 4°C, continue to stir in the ice water bath after dropping 6h, pour the mixed solution into 5% 100ml sodium hydroxide solution, stir, extract with dichloromethane three times, wash the extract with water until it is neutral, add anhydrous sodium sulfate to dry, heat in a water bath to evaporate the solvent, and then reduce 38.6g of colorless liquid 3-methoxy-2-methyl-4H-pyran-4-one was obtained by pressure distillation; the yield was 78%;

[0024] (2). Add 13.2g of 3-methoxy-2-methyl-4H-pyran-4-one to 360ml of concentrated ammonia water, stir at 45℃ for 6h, evaporate the water under reduced pressure, and cool the residue to separate out After the crystals were filtered, the filter cake was washed with water to neutrality, and then recrystallized with acetone to obtain 11.1 g of white crystals of...

Technical field

[0001] The invention relates to a preparation method of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, which belongs to the field of medicine manufacturing. Background technique

[0002] 2-Chloromethyl-3,4-dimethoxypyridine hydrochloride is an important intermediate for the synthesis of a new drug pantoprazole. The existing preparation of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride The salt method is generally synthesized with 2-methyl-3-hydroxypyridine as a raw material through a 7-step reaction such as methylation, nitration, and methoxylation. However, such raw materials do not have domestic products and need to be imported and purchased, and the cost will increase. If furan is used as raw material to synthesize by oneself, the yield will be very low, less than 60%, and the purity will be very low. Summary of the invention

[0003] In order to overcome the shortcomings of the prior art, the present invention provides a method for preparing 2-chlorom...

Examples

Embodiment 1

[0015] (1) Add 31.5g of maltol to 20g of sodium hydroxide aqueous solution, stir, cool to 0°C in an ice water bath, slowly add 63 dimethyl phosphate dropwise, control the temperature at 2°C, continue in the ice water bath after dropping After stirring for 3h, pour the mixed solution into 5% 100ml sodium hydroxide solution, stir, extract three times with dichloromethane, wash the extract with water until it is neutral, add anhydrous sodium sulfate to dry, heat in a water bath to evaporate the solvent, Distill under reduced pressure to obtain 19.8 g of colorless liquid 3-methoxy-2-methyl-4H-pyran-4-one with a yield of 77%;

[0016] (2). Add 13.2g of 3-methoxy-2-methyl-4H-pyran-4-one to 360mld of concentrated ammonia water, stir at 40°C for 3h, evaporate the water under reduced pressure, the residue Cool, precipitate crystals, filter, wash the filter cake with water to neutrality, and recrystallize it with acetone to obtain 10.1 g of white crystals of 3-methoxy-2-methyl-4(1H)-pyrido...

Embodiment 2

[0023] (1) Add 50g of maltol to 25g of sodium hydroxide aqueous solution, stir, cool to 2°C in an ice water bath, slowly add 80g of dimethyl phosphate dropwise, control the temperature at 4°C, continue to stir in the ice water bath after dropping 6h, pour the mixed solution into 5% 100ml sodium hydroxide solution, stir, extract with dichloromethane three times, wash the extract with water until it is neutral, add anhydrous sodium sulfate to dry, heat in a water bath to evaporate the solvent, and then reduce 38.6g of colorless liquid 3-methoxy-2-methyl-4H-pyran-4-one was obtained by pressure distillation; the yield was 78%;

[0024] (2). Add 13.2g of 3-methoxy-2-methyl-4H-pyran-4-one to 360ml of concentrated ammonia water, stir at 45℃ for 6h, evaporate the water under reduced pressure, and cool the residue to separate out After the crystals were filtered, the filter cake was washed with water to neutrality, and then recrystallized with acetone to obtain 11.1 g of white crystals of...