CN105218464A - The synthesis technique of acipimox - Google Patents
The synthesis technique of acipimox Download PDFInfo
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Abstract
The invention provides a kind of synthesis technique of acipimox, it comprises: 1) in aqueous, under catalyst action, 5-Methylpyrazine-2-carboxylic acid and hydrogen peroxide is reacted; 2) to step 1) add auxiliary agent in the solution that obtains, wherein, described auxiliary agent is selected from the one in sulphite, hydrosulphite, oxalic acid and oxalate; 3) to step 2) add gac in the solution that obtains, filter; And 4) by step 3) solution that obtains carries out decrease temperature crystalline, dry, thus obtain acipimox finished product.Synthesis technique of the present invention can reduce crystallisation times effectively, avoids recrystallization operation, improves yield, reduces production cost.
Description
Technical field
The invention belongs to pharmacy field, in particular to a kind of synthesis technique of acipimox.
Background technology
Acipimox (Acipimox) is by a kind of hypolipidemic of Italian FarmitaliaCarolErba company in exploitation listing in 1985, it can suppress fatty tissue to discharge free fatty acids, reduce vldl and low-density lipoprotein in blood, thus triglyceride and cholesterol concentration in blood are declined, also can promote that high-density lipoprotein (HDL) increases, therefore be mainly used in treatment IIA, IIR, III, IV and V-type hyperlipoproteinemia.It is strong that it has effect for reducing fat, and untoward reaction is few, better tolerance, is suitable for the features such as long-term prescription.In addition acipimox can also promote the glucose metabolism of non-insulin-dependent diabetes mellitus (NIDDM) patient, relevant with reduction blood sugar; And effectively can reduce the danger of coronary heart disease.It is not combined with plasma proteins in vivo, not by metabolism, excretes in prototype, so can not increase the danger of blood uric acid and cholelith.Therefore, acipimox is treatment hyperlipidaemia, especially with the medicine that diabetes, gout, coronary heart disease are comparatively satisfied with.
In the prior art, the synthesis technique of acipimox can see (such as) following scientific and technical literature: Chinese Journal of Pharmaceuticals ChineseJournalofPharmaceuticals2009,40 (10), what wherein adopt is the first synthesizing methyl quinoxaline of pyruvic aldehyde and O-Phenylene Diamine, then potassium permanganate oxidation, sulfuric acid catalysis decarboxylation, obtain 5-methyl-2-pyrazine carboxylic acid, acipimox crude product is obtained with hydrogen peroxide oxidation again under the catalysis of sodium wolframate, obtained acipimox crude product, then form acipimox finished product through activated carbon decolorizing, recrystallization.But above-mentioned technique of the prior art not only exists the shortcoming of technique extremely unstable, and the crude product foreign matter content generated is high, after needing to carry out recrystallization purifying, can obtain the acipimox finished product meeting States Pharmacopoeia specifications purity.But at present in actual production process, the operational condition due to recrystallization requires strict, and technique is loaded down with trivial details, and length consuming time, greatly reduce production efficiency, therefore there is obvious defect in above-mentioned technique in actual industrial production, and its application is limited by very large.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of synthesis technique of acipimox.
Specifically, the invention provides:
(1) synthesis technique for acipimox, it comprises:
1) in aqueous, under catalyst action, 5-Methylpyrazine-2-carboxylic acid and hydrogen peroxide is made to occur as shown in the formula the reaction shown in II,
2) to step 1) add auxiliary agent in the solution that obtains, wherein, described auxiliary agent is selected from the one in sulphite, hydrosulphite, oxalic acid and oxalate;
3) to step 2) add gac in the solution that obtains, filter; And
4) by step 3) solution that obtains carries out decrease temperature crystalline, dry, thus obtain acipimox finished product.
(2) synthesis technique Gen Ju (1), wherein, in step 1) in, the mol ratio of described hydrogen peroxide and described 5-Methylpyrazine-2-carboxylic acid is (1.0-1.8): 1, is preferably (1.1-1.6): 1.
(3) synthesis technique Gen Ju (1), wherein, step 1) described in catalyzer be sodium wolframate; The mol ratio of described sodium wolframate and described 5-Methylpyrazine-2-carboxylic acid is preferably (0.01-0.1): 1.
(4) synthesis technique Gen Ju (3), wherein, step 1) temperature of reaction of described reaction is 40-90 DEG C, is preferably 50-80 DEG C.
(5) synthesis technique Gen Ju (1), wherein, step 1) reaction times of described reaction is 1-12 hour, is preferably 2-8 hour.
(6) synthesis technique Gen Ju (1), wherein, step 2) described in sulphite be inorganic sulfite, be preferably S-WAT or potassium sulfite.
(7) synthesis technique Gen Ju (1), wherein, step 2) described in hydrosulphite be inorganic bisulfites, be preferably sodium bisulfite or Potassium hydrogen sulfite.
(8) synthesis technique Gen Ju (1), wherein, step 2) described in oxalate be inorganic oxalate, be preferably sodium oxalate or potassium oxalate.
(9) synthesis technique Gen Ju (1), wherein, step 2) described in auxiliary agent and the mol ratio of described 5-Methylpyrazine-2-carboxylic acid not higher than 0.8: 1.
(10) synthesis technique Gen Ju (1), wherein, in step 2) in, step 1) reaction times of the solution that obtains and described auxiliary agent is 0.5-3 hour.
(11) synthesis technique Gen Ju (1), wherein, in step 4) in, by step 3) solution that obtains cools to-5 ~ 20 DEG C, crystallization, dry, thus obtain acipimox finished product.
The present invention compared with prior art has the following advantages and positively effect:
The invention provides a kind of new synthesis process of Acipimox, wherein particularly by reaction mother liquor after specific auxiliary agent of the present invention processes, then add gac and carry out desolventing technology, just obtain qualified finished product by decrease temperature crystalline.Above-mentioned steps can reduce crystallisation times effectively, avoid recrystallization operation, the acipimox finished product meeting States Pharmacopoeia specifications purity just can be obtained from reaction mother liquor by primary crystallization, therefore enormously simplify production technique, shorten the time of post-processing step, and improve yield, reduce production cost.In addition, above-mentioned technique can also once stop process and complete in reactor, therefore simple and easy to do, is particularly suitable in industrialized production.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
Unless otherwise indicated, the chemical name of " acipimox " as herein described is that 5-methyl-4-is oxidized-2-pyrazine carboxylic acid, and its structural formula is as follows:
The present inventor is in the preparation technology of research acipimox, by a large amount of shaker tests, have been surprisingly found that: the reaction mother liquor that existing synthesis process of Acipimox is obtained, after some specific auxiliary agent processes, add gac again and carry out desolventing technology, just obtain qualified finished product by a decrease temperature crystalline.Said process can reduce crystallisation times effectively, avoids recrystallization operation, therefore enormously simplify production technique, improves synthesis yield, and comprehensive cost is minimized.
Specifically, the invention provides:
A synthesis technique for acipimox, it comprises:
1) in aqueous, under catalyst action, 5-Methylpyrazine-2-carboxylic acid and hydrogen peroxide is made to occur as shown in the formula the reaction shown in II,
2) to step 1) add auxiliary agent in the solution that obtains, wherein, described auxiliary agent is selected from the one in sulphite, hydrosulphite, oxalic acid and oxalate;
3) to step 2) add gac in the solution that obtains, filter; And
4) by step 3) solution that obtains carries out decrease temperature crystalline, dry, thus obtain acipimox finished product.
Preferably, in step 1) in, the mol ratio of described hydrogen peroxide and described 5-Methylpyrazine-2-carboxylic acid is (1.0-1.8): 1.If mol ratio is lower than 1.0: 1, then the transformation efficiency of 5-Methylpyrazine-2-carboxylic acid is not enough, and yield reduces; Add-on, higher than 1.8: 1, can not significantly improve acipimox yield, causes the waste of raw material on the contrary, and side reaction may be caused to increase.More preferably, the mol ratio of described hydrogen peroxide and described 5-Methylpyrazine-2-carboxylic acid is (1.1-1.6): 1.
Preferably, step 1) described in catalyzer be sodium wolframate.More preferably, the mol ratio of described sodium wolframate and described 5-Methylpyrazine-2-carboxylic acid is (0.01-0.1): 1.If mol ratio is lower than 0.01, then weaken catalytic effect, thus cause reaction times significant prolongation; If mol ratio is more than 0.1, can not speed of response be significantly improved, cause the waste of raw material on the contrary.
Preferably, step 1) described reaction carries out in the presence of acid.More preferably, described acid is sulfuric acid.More preferably, the mol ratio of described sodium wolframate and described sulfuric acid is 1: 1.
Preferably, step 1) temperature of reaction of described reaction is 40-90 DEG C.If temperature of reaction is lower than 40 DEG C, speed of response is slow, and the reaction times extends; If reaction, higher than 90 DEG C, can cause peroxide decomposition, result in the waste of raw material, and may introduce unnecessary side reaction.Temperature of reaction is more preferably 50-80 DEG C.
Preferably, step 1) reaction times of described reaction is 1-12 hour.The selection of time of reaction is relevant with temperature of reaction, is generally 1-12 hour, is preferably 2-8 hour.
Preferably, step 2) described in sulphite be inorganic sulfite, be preferably S-WAT or potassium sulfite.
Preferably, step 2) described in hydrosulphite be inorganic bisulfites, be preferably sodium bisulfite or Potassium hydrogen sulfite.
Preferably, step 2) described in oxalate be inorganic oxalate, be preferably sodium oxalate or potassium oxalate.
Preferably, step 2) described in auxiliary agent be selected from one in S-WAT, sodium bisulfite, potassium sulfite, Potassium hydrogen sulfite, oxalic acid, sodium oxalate, potassium oxalate.
Preferably, step 2) described in auxiliary agent and the mol ratio of described 5-Methylpyrazine-2-carboxylic acid not higher than 0.8: 1.The present inventor found through experiments, if mol ratio is more than 0.8: 1, can not significantly improves purity and the yield of acipimox finished product, cause the waste of raw material on the contrary.
Preferably, in step 2) in, step 1) reaction times of the solution that obtains and described auxiliary agent is 0.5-3 hour.
Preferably, in step 3) in, the weight of the gac added is for according to step 1) described in the 0.01-0.2 of acipimox theoretical weight that calculates of 5-Methylpyrazine-2-carboxylic acid doubly.
Preferably, in step 4) in, by step 3) solution that obtains cools to-5 ~ 20 DEG C, crystallization, dry, thus obtain acipimox finished product.More preferably, described drying temperature is 80-110 DEG C.
In a preferred embodiment of the invention, described synthesis technique comprises the steps:
A) add Disodium tungstate (Na2WO4) dihydrate in a kettle., add water dissolution, then add the equimolar dilute sulphuric acid with Disodium tungstate (Na2WO4) dihydrate, add aqueous hydrogen peroxide solution, then add 5-Methylpyrazine-2-carboxylic acid, be warmed up to 40-80 DEG C of reaction 1-12 hour;
B) after reaction terminates, add auxiliary agent S-WAT, continue reaction 0.5-3 hour;
C) add and calculate theoretical output acipimox 0.01-0.2 times of gac according to 5-Methylpyrazine-2-carboxylic acid, continue to stir 0.5-3 hour, filtered while hot.
D) filtrate is cooled to-5 ~ 20 DEG C, continues to stir 0.5-3 hour, filters, and filter cake is dry between 80-110 DEG C, can obtain acipimox finished product.
Mode by the following examples further explains and describes content of the present invention, but these embodiments are not to be construed as limiting the scope of the invention.
In the examples below, other if no special instructions, each reagent all commercially, such as, Nanning chemical pharmacy company limited.
Embodiment 1
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction flask, add 400ml water, stirring and dissolving, 1.9g (19mmol) vitriol oil is added under stirring, continue to add 204g (1.8mol) hydrogen peroxide (30%), stir, add 5-Methylpyrazine-2-carboxylic acid 207.2g (1.5mol), heating in water bath is to 60 DEG C, insulated and stirred 8 hours, add sodium bisulfite 31.2g (0.3mol), continue stirring 1 hour, add gac 12g, continue stirring 1 hour, filtered while hot, filtrate is cooled to 4 DEG C, keep 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtain off-white color crystalline powder 196.2g, HPLC purity 99.35%, yield 84.9%.
Embodiment 2
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction flask, add 400ml water, stirring and dissolving, 1.9g (19mmol) vitriol oil is added under stirring, continue to add 306g (2.7mol) hydrogen peroxide (30%), stir, add 5-Methylpyrazine-2-carboxylic acid 207.2g (1.5mol), heating in water bath is to 80 DEG C, insulated and stirred 4 hours, add S-WAT 151.2g (1.2mol), continue stirring 0.5 hour, add gac 20g, continue stirring 1 hour, filtered while hot, filtrate is cooled to-4 DEG C, keep 3 hours, filter, filter cake is dried 3 hours at 80 DEG C, obtain off-white color crystalline powder 192.2g, HPLC purity 99.1%, yield 83.1%.
Embodiment 3
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction flask, add 400ml water, stirring and dissolving, 1.9g (19mmol) vitriol oil is added under stirring, continue to add 204g (1.8mol) hydrogen peroxide (30%), stir, add 5-Methylpyrazine-2-carboxylic acid 207.2g (1.5mol), heating in water bath is to 60 DEG C, insulated and stirred 8 hours, add potassium sulfite 47.4g (0.3mol), continue stirring 1 hour, add gac 12g, continue stirring 1 hour, filtered while hot, filtrate is cooled to 4 DEG C, keep 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtain off-white color crystalline powder 195.7g, HPLC purity 99.37%, yield 84.6%.
Embodiment 4
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction flask, add 400ml water, stirring and dissolving, 1.9g (19mmol) vitriol oil is added under stirring, continue to add 272g (2.4mol) hydrogen peroxide (30%), stir, add 5-Methylpyrazine-2-carboxylic acid 207.2g (1.5mol), heating in water bath is to 70 DEG C, insulated and stirred 6 hours, add Potassium hydrogen sulfite 108g (0.9mo1), continue stirring 1 hour, add gac 15g, continue stirring 1 hour, filtered while hot, filtrate is cooled to 4 DEG C, keep 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtain off-white color crystalline powder 189.5g, HPLC purity 98.9%, yield 82.0%.
Embodiment 5
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction flask, add 400ml water, stirring and dissolving, 1.9g (19mmol) vitriol oil is added under stirring, continue to add 204g (1.8mol) hydrogen peroxide (30%), stir, add 5-Methylpyrazine-2-carboxylic acid 207.2g (1.5mol), heating in water bath is to 60 DEG C, insulated and stirred 8 hours, add oxalic acid 27g (0.3mol), continue stirring 1 hour, add gac 12g, continue stirring 1 hour, filtered while hot, filtrate is cooled to 4 DEG C, keep 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtain off-white color crystalline powder 196.0g, HPLC purity 99.3%, yield 84.7%.
Embodiment 6
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction flask, add 400ml water, stirring and dissolving, 1.9g (19mmol) vitriol oil is added under stirring, continue to add 204g (1.8mol) hydrogen peroxide (30%), stir, add 5-Methylpyrazine-2-carboxylic acid 207.2g (1.5mol), heating in water bath is to 60 DEG C, insulated and stirred 8 hours, add sodium oxalate 40.2g (0.3mol), continue stirring 1 hour, add gac 12g, continue stirring 1 hour, filtered while hot, filtrate is cooled to 4 DEG C, keep 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtain off-white color crystalline powder 195.3g, HPLC purity 99.21%, yield 84.5%.
Embodiment 7
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction flask, add 400ml water, stirring and dissolving, 1.9g (19mmol) vitriol oil is added under stirring, continue to add 204g (1.8mol) hydrogen peroxide (30%), stir, add 5-Methylpyrazine-2-carboxylic acid 207.2g (1.5mol), heating in water bath is to 60 DEG C, insulated and stirred 8 hours, add potassium oxalate 55.2g (0.3mol), continue stirring 1 hour, add gac 12g, continue stirring 1 hour, filtered while hot, filtrate is cooled to 4 DEG C, keep 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtain off-white color crystalline powder 195.1g, HPLC purity 99.24%, yield 84.4%.
Comparative example 1
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction flask, add 400ml water, stirring and dissolving, 1.9g (19mmol) vitriol oil is added under stirring, continue to add 204g (1.8mol) hydrogen peroxide (30%), stir, add 5-Methylpyrazine-2-carboxylic acid 207.2g (1.5mol), heating in water bath is to 60 DEG C, insulated and stirred 8 hours, be cooled to 4 DEG C, keep 3 hours, filter, dry 3 hours at 100 DEG C, obtain Light yellow crystals powder 202.44g, HPLC purity 93.21%, crude yield 87.6%.
Products obtained therefrom is added 600g deionized water, add 12g gac, be heated to 90 DEG C, insulated and stirred 1 hour, filtered while hot, filtrate is cooled to 4 DEG C, keeps 3 hours, filters, filter cake is dried 3 hours at 100 DEG C, obtain off-white color crystalline powder 164.4g, HPLC purity 99.68%, total recovery 71.1%.
Claims (11)
1. a synthesis technique for acipimox, it comprises:
1) in aqueous, under catalyst action, 5-Methylpyrazine-2-carboxylic acid and hydrogen peroxide is made to occur as shown in the formula the reaction shown in II,
2) to step 1) add auxiliary agent in the solution that obtains, wherein, described auxiliary agent is selected from the one in sulphite, hydrosulphite, oxalic acid and oxalate;
3) to step 2) add gac in the solution that obtains, filter; And
4) by step 3) solution that obtains carries out decrease temperature crystalline, dry, thus obtain acipimox finished product.
2. synthesis technique according to claim 1, wherein, in step 1) in, the mol ratio of described hydrogen peroxide and described 5-Methylpyrazine-2-carboxylic acid is (1.0-1.8): 1, is preferably (1.1-1.6): 1.
3. synthesis technique according to claim 1, wherein, step 1) described in catalyzer be sodium wolframate; The mol ratio of described sodium wolframate and described 5-Methylpyrazine-2-carboxylic acid is preferably (0.01-0.1): 1.
4. synthesis technique according to claim 3, wherein, step 1) temperature of reaction of described reaction is 40-90 DEG C, is preferably 50-80 DEG C.
5. synthesis technique according to claim 1, wherein, step 1) reaction times of described reaction is 1-12 hour, is preferably 2-8 hour.
6. synthesis technique according to claim 1, wherein, step 2) described in sulphite be inorganic sulfite, be preferably S-WAT or potassium sulfite.
7. synthesis technique according to claim 1, wherein, step 2) described in hydrosulphite be inorganic bisulfites, be preferably sodium bisulfite or Potassium hydrogen sulfite.
8. synthesis technique according to claim 1, wherein, step 2) described in oxalate be inorganic oxalate, be preferably sodium oxalate or potassium oxalate.
9. synthesis technique according to claim 1, wherein, step 2) described in auxiliary agent and the mol ratio of described 5-Methylpyrazine-2-carboxylic acid not higher than 0.8: 1.
10. synthesis technique according to claim 1, wherein, in step 2) in, step 1) reaction times of the solution that obtains and described auxiliary agent is 0.5-3 hour.
11. synthesis techniques according to claim 1, wherein, in step 4) in, by step 3) solution that obtains cools to-5 ~ 20 DEG C, crystallization, dry, thus obtain acipimox finished product.
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| CN110156682A (en) * | 2019-06-05 | 2019-08-23 | 南京焕然生物科技有限公司 | A kind of preparation method of azacyclo- N- oxide |
| CN112125857A (en) * | 2019-06-25 | 2020-12-25 | 鲁南制药集团股份有限公司 | Preparation method of acipimox |
| CN113929631A (en) * | 2020-07-13 | 2022-01-14 | 鲁南制药集团股份有限公司 | Purification method of acipimox |
| CN113929631B (en) * | 2020-07-13 | 2024-04-12 | 鲁南制药集团股份有限公司 | Purification method of acipimox |
| CN115073384A (en) * | 2021-12-29 | 2022-09-20 | 山东新时代药业有限公司 | Acipimox crystal form and preparation method thereof |
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