Synthetic process of acipimox

Abstract

The invention provides a synthesis process of acipimox, which comprises: 1) in an aqueous solution, under the action of a catalyst, reacting 5-methylpyrazine-2-carboxylic acid with hydrogen peroxide; Step 1) Add an auxiliary agent to the solution obtained, wherein the auxiliary agent is selected from one of sulfite, bisulfite, oxalic acid and oxalate; 3) Add to the solution obtained in step 2) Activated carbon, filter; and 4) The solution obtained in step 3) is cooled to crystallize and dried to obtain the finished product of acipimox. The synthesis process of the invention can effectively reduce the number of crystallization times, avoid recrystallization operation, improve yield and reduce production cost.

Description

technical field

[0001] The invention belongs to the field of pharmacy, and in particular relates to a synthesis process of acipimox. Background technique

[0002] Acipimox (Acipimox) is a kind of hypolipidemic drug developed and listed by Italian Farmitalia Carol Erba Company in 1985, which can inhibit the release of free fatty acids from adipose tissue, reduce blood very low density lipoprotein and low density lipoprotein, thereby It can reduce the concentration of triglyceride and cholesterol in the blood, and can also promote the increase of high-density lipoprotein, so it is mainly used to treat type II A, II R, III, IV and V hyperlipoproteinemia. It has the characteristics of strong lipid-lowering effect, less adverse reactions, good tolerance, suitable for long-term medication and the like. In addition, acilimus can also promote glucose metabolism in patients with non-insulin-dependent diabetes mellitus, which is related to lowering blood sugar; and can effectively re...

Examples

preparation example Construction

[0027] In the process of studying the preparation process of acipimox, the present inventors discovered unexpectedly through a large number of screening tests: after the reaction mother liquor obtained in the existing acipimox synthesis process is processed by some specific auxiliary agents, Then add activated carbon for decolorization treatment, and a qualified finished product can be obtained through one cooling crystallization. The above process can effectively reduce the number of crystallization times and avoid recrystallization operations, thus greatly simplifying the production process, improving the synthesis yield, and reducing the overall cost.

[0028] Specifically, the present invention provides:

[0029] A synthesis process of acipimox, which comprises:

[0030] 1) In an aqueous solution, under the action of a catalyst, 5-methylpyrazine-2-carboxylic acid and hydrogen peroxide react as shown in the following formula II,

[0031]

[0032] 2) adding an auxiliary...

Embodiment 1

[0056] Add 6.2g (19mmol) of sodium tungstate dihydrate into a 1L reaction flask, add 400ml of water, stir to dissolve, add 1.9g (19mmol) of concentrated sulfuric acid while stirring, and continue to add 204g (1.8mol) of hydrogen peroxide (30%), Stir evenly, add 207.2g (1.5mol) of 5-methylpyrazine-2-carboxylic acid, heat in a water bath to 60°C, keep stirring for 8 hours, add 31.2g (0.3mol) of sodium bisulfite, and continue stirring for 1 hour. Add 12 g of activated carbon, continue to stir for 1 hour, filter while it is hot, cool the filtrate to 4 ° C, keep for 3 hours, filter, and dry the filter cake at 100 ° C for 3 hours to obtain 196.2 g of off-white crystalline powder with a HPLC purity of 99.35%. The rate is 84.9%.

Embodiment 2

[0058] Add 6.2g (19mmol) of sodium tungstate dihydrate into a 1L reaction flask, add 400ml of water, stir to dissolve, add 1.9g (19mmol) of concentrated sulfuric acid while stirring, and continue to add 306g (2.7mol) of hydrogen peroxide (30%), Stir evenly, add 207.2g (1.5mol) of 5-methylpyrazine-2-carboxylic acid, heat in a water bath to 80°C, keep stirring for 4 hours, add 151.2g (1.2mol) of sodium sulfite, continue stirring for 0.5 hours, and add 20g of activated carbon , continue to stir for 1 hour, filter while hot, cool the filtrate to -4 ° C, keep for 3 hours, filter, and dry the filter cake at 80 ° C for 3 hours to obtain 192.2 g of off-white crystalline powder, HPLC purity 99.1%, yield 83.1 %.

technical field

[0001] The invention belongs to the field of pharmacy, and in particular relates to a synthesis process of acipimox. Background technique

[0002] Acipimox (Acipimox) is a kind of hypolipidemic drug developed and listed by Italian Farmitalia Carol Erba Company in 1985, which can inhibit the release of free fatty acids from adipose tissue, reduce blood very low density lipoprotein and low density lipoprotein, thereby It can reduce the concentration of triglyceride and cholesterol in the blood, and can also promote the increase of high-density lipoprotein, so it is mainly used to treat type II A, II R, III, IV and V hyperlipoproteinemia. It has the characteristics of strong lipid-lowering effect, less adverse reactions, good tolerance, suitable for long-term medication and the like. In addition, acilimus can also promote glucose metabolism in patients with non-insulin-dependent diabetes mellitus, which is related to lowering blood sugar; and can effectively re...

Examples

preparation example Construction

[0027] In the process of studying the preparation process of acipimox, the present inventors discovered unexpectedly through a large number of screening tests: after the reaction mother liquor obtained in the existing acipimox synthesis process is processed by some specific auxiliary agents, Then add activated carbon for decolorization treatment, and a qualified finished product can be obtained through one cooling crystallization. The above process can effectively reduce the number of crystallization times and avoid recrystallization operations, thus greatly simplifying the production process, improving the synthesis yield, and reducing the overall cost.

[0028] Specifically, the present invention provides:

[0029] A synthesis process of acipimox, which comprises:

[0030] 1) In an aqueous solution, under the action of a catalyst, 5-methylpyrazine-2-carboxylic acid and hydrogen peroxide react as shown in the following formula II,

[0031]

[0032] 2) adding an auxiliary...

Embodiment 1

[0056] Add 6.2g (19mmol) of sodium tungstate dihydrate into a 1L reaction flask, add 400ml of water, stir to dissolve, add 1.9g (19mmol) of concentrated sulfuric acid while stirring, and continue to add 204g (1.8mol) of hydrogen peroxide (30%), Stir evenly, add 207.2g (1.5mol) of 5-methylpyrazine-2-carboxylic acid, heat in a water bath to 60°C, keep stirring for 8 hours, add 31.2g (0.3mol) of sodium bisulfite, and continue stirring for 1 hour. Add 12 g of activated carbon, continue to stir for 1 hour, filter while it is hot, cool the filtrate to 4 ° C, keep for 3 hours, filter, and dry the filter cake at 100 ° C for 3 hours to obtain 196.2 g of off-white crystalline powder with a HPLC purity of 99.35%. The rate is 84.9%.

Embodiment 2

[0058] Add 6.2g (19mmol) of sodium tungstate dihydrate into a 1L reaction flask, add 400ml of water, stir to dissolve, add 1.9g (19mmol) of concentrated sulfuric acid while stirring, and continue to add 306g (2.7mol) of hydrogen peroxide (30%), Stir evenly, add 207.2g (1.5mol) of 5-methylpyrazine-2-carboxylic acid, heat in a water bath to 80°C, keep stirring for 4 hours, add 151.2g (1.2mol) of sodium sulfite, continue stirring for 0.5 hours, and add 20g of activated carbon , continue to stir for 1 hour, filter while hot, cool the filtrate to -4 ° C, keep for 3 hours, filter, and dry the filter cake at 80 ° C for 3 hours to obtain 192.2 g of off-white crystalline powder, HPLC purity 99.1%, yield 83.1 %.

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