CN104803976A - Industrial production method of Alogliptin benzoate raw material medicine - Google Patents
Industrial production method of Alogliptin benzoate raw material medicine Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses an industrial production method of Alogliptin benzoate raw material medicine. According to the method, ethanol/water mixed solvents are used as crystallization solvents; the ethanol/water mixed solvents and Alogliptin benzoate crude products are heated and flow back to a state that the solution is clear; the temperature is lowered, and crystal seeds are added; the gradient temperature reduction crystal separation is carried out; centrifugation and drying are carried out, and the Alogliptin benzoate raw material medicine is obtained. The adopted mixed solvents have low toxicity, and a better environment-friendly effect can be achieved. Compared with the method in the prior art, the industrial production method provided by the invention has the advantages that the solvent use type is reduced, the process is simple, the yield is high, and the production cost is reduced; through the method, the purity of the obtained Alogliptin benzoate finished product is at least 99.8 percent, the single impurity content is lower than or equal to 0.05 percent, the ethanol residue is low (lower than or equal to 0.1 percent) and is much lower than the limit of 0.5 percent of medical raw material medicine; impurities X generated by the reaction between phthalic acid and Alogliptin can be removed.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of industrial process of SYR-322 bulk drug.
Background technology
SYR-322 (Alogliptin Benzoate), chemical name is 2-[[6-[(3R)-3-amino-1-piperidyl]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] benzonitrile benzoic acid salt, structure is as shown in formula I
It is a kind of DPP-IV inhibitor of Japanese military field pharmaceutical development.It promotes the concentration dependent insulin secretion with sugar by the plasma concentration improving GLP-1 in body, maintains the level of glucagon-1 peptide and glucose-dependent-insulinotropic peptide in body, increases the secretion of Regular Insulin, thus plays hypoglycemic curative effect.
Chinese patent 201310106584.6 discloses a kind of Benzoic acid alogliptin crystal form compound, and adopt methyl alcohol and ethyl acetate to refine in its synthesis technique, yield only has 65%; Chinese patent 201410236391.7 discloses a kind of process for purification of SYR-322, and the method is by SYR-322 crude product under benzoic existence, and in methyl alcohol, crystallization obtains SYR-322 fine work; Chinese patent 201410388488.X discloses a kind of preparation method of SYR-322 polymorph crystals, uses methyl alcohol and methyl tertiary butyl ether as recrystallization solvent; In above patent, methyl alcohol used is two kind solvents, and toxicity is comparatively large, and be not suitable for the refining production of final step of bulk drug, methyl tertiary butyl ether is expensive, and production cost is high.
Chinese patent 201310195299.6 discloses a kind of mass production processes of polymorphic high-content benzoic acid alogliptin, first refine with water para Toluic Acid, then carry out at one or more mixture of tetrahydrofuran (THF), ethyl acetate, acetonitrile, methyl alcohol and salting out, described solvent is preferably dehydrated alcohol; This method needs first para Toluic Acid to carry out refinement treatment, increases operation, simultaneously also very high to the purity requirement of Egelieting, requires >=99.5%, needs the purification step increasing Egelieting in actual production, is unfavorable for producing.
We study discovery, usually there is a small amount of phthalic acid impurity in phenylformic acid, can react and generate following impurity (code name: impurity X), and the existing process for purification of this impurity cannot refine removing in salification process with Egelieting:
Also find simultaneously, no matter be adopt refining methanol, or adopt dehydrated alcohol to refine, all can inclusion solvent molecule in SYR-322 molecule, cause SYR-322 dissolvent residual high, the demand of Medicinal crude drug cannot be met.
Summary of the invention
The object of the present invention is to provide a kind of industrial process of highly purified SYR-322 bulk drug;
The object of the invention is to be achieved through the following technical solutions:
An industrial process for SYR-322 bulk drug, described method comprises the steps:
Add in reactor by mixed solvent, SYR-322 crude product respectively, reflux is clarified to solution, and cooling adds crystal seed, gradient cooling crystallization, centrifugal, dry, to obtain final product.
Described mixed solvent is dehydrated alcohol and purified water, ratio from 80/20 to 98/2, preferably 95/5;
In the add-on of described mixed solvent and mixed solvent, the ratio of water has much relations, as long as can dissolve SYR-322 crude product under solvent adding amount heated reflux condition under normal circumstances.When the ratio of dehydrated alcohol and purified water is 95/5, the add-on of required mixed solvent is 10-15 times of volume of SYR-322 crude product quantity, preferably 12 times of volumes.
Described Seed charge is the 0-0.5% of SYR-322 crude product quantity, and Seed charge preferably 0.2%, also can not add crystal seed, but adding crystal seed can shorten the production time in actual production, reduces production energy consumption, enhances productivity.
In described gradient cooling crystallization, temperature range is followed successively by 35-55 DEG C of crystallization (preferred 40-50 DEG C), 15-35 DEG C crystallization (preferred 20-30 DEG C), 0-15 DEG C crystallization (preferred 5-10 DEG C);
The industrial process of SYR-322 bulk drug of the present invention, adopt ethanol/water mixed solvent as recrystallisation solvent, toxicity is low, more environmental protection; Compared with method disclosed in prior art, reduce solvent and use kind, technique is simple, and yield is high, and production cost reduces; By above method, the SYR-322 finished product purity obtained is at least 99.8%, single impurity≤0.05%, and alcohol residue low (≤0.1%), far below 0.5% limit of Medicinal crude drug; Can remove and react by phthalic acid and Egelieting the impurity X produced.
Embodiment
following embodiment is used for proving further but being not limited to the present invention.
embodiment 1: the preparation of SYR-322 crude product
1, the preparation of intermediate A G1
Chloro-to N-Methyl pyrrolidone 41.2kg, 6-3-6-Methyl Uracil 10.0kg and diisopropylethylamine 12.07kg is added in 100L enamel reaction still, then 2-cyano-benzyl bromide 13.43kg is joined in reaction solution, be warmed up to 60 ~ 70 DEG C, stirring reaction 4h.TLC monitoring display 6-chloro-3-6-Methyl Uracil raw material point disappears (developping agent PE:EA=2:1, GF254) substantially.Cooled to by reaction solution between 20 ~ 30 DEG C, more slowly joined in reaction solution by purified water 50.0kg, period keeps temperature lower than 35 DEG C, finishes rear continuation stirring 30 minutes.Be cooled to 5 ~ 10 DEG C, insulated and stirred 1.5h.Centrifugal, 50.0kg purified water is washed in batches, then adds in reactor by gained solid, adds Virahol 39.3kg, stir 1.5h, centrifugal, 12.6.3kg Virahol washs in batches, 60 DEG C of forced air drying 5h, obtain incarnadine powder solid (AG1) 16.5kg, yield 96.3%.
2, the preparation of intermediate A G2
Virahol 129.3kg and water 16.45kg is joined in 300L enamel reaction still, open and stir, then add 16.45kg intermediate A G1, R-3-amino piperidine dihydrochloride 11.36kg, 19.8kg Anhydrous potassium carbonate successively, stir, be warmed up to 60 ~ 65 DEG C, temperature control reacts about 24h.TLC monitors AG1 raw material only surplus a little (developping agent PE:EA=2:1, GF254).After reaction terminates, be cooled to 40 ~ 50 DEG C, suction filtration, Virahol 33.6kg drip washing filter cake, concentrate filtrate to substantially more dry, add tetrahydrofuran (THF) 29.3kg, be evaporated to dry, then add tetrahydrofuran (THF) 175.7kg, stirring and dissolving, add anhydrous sodium sulphate 33kg, at reactor standing and drying 8h, stir 3.5h.Filter, filter cake 30kg tetrahydrofuran (THF) gradation washing, merging filtrate, filtrate reduced in volume is to dry.Add dehydrated alcohol 32.5kg again, heating for dissolving, be warming up to 60-65 DEG C of insulation 15min, spontaneous combustion cooling is spent the night.Logical icy salt solution cooling, is cooled to 18 DEG C of crystallizatioies, continues to be cooled to 5 ~ 10 DEG C of insulation crystallization 2.5h, and centrifugal, 13kg absolute ethanol washing, dry, 60 DEG C of forced air drying 4h, obtain 13.92kg off-white color solid AG2, yield 68.7%.
3, intermediate A G3(SYR-322 crude product) preparation
Open and stir, tetrahydrofuran (THF) 52.0kg is added in reactor together with 7.73kg intermediate A G2, is heated to 50 DEG C of dissolvings.Benzoic tetrahydrofuran solution is added dropwise under insulation, after adding, continue insulation 35min, logical cooling circulating water is cooled to 20-25 DEG C, continues insulation crystallization 2.0h, centrifugal, products obtained therefrom tetrahydrofuran (THF) 10.0kg washs, 60 DEG C of forced air drying 3h, obtain the intermediate A G3 of 9.91kg white, yield 94.2%.Purity is 99.35%, and impurity X is 0.13%.
embodiment 2
In invention implementation process, compare research with published correlation technique, and carried out screening investigating to key process parameter of the present invention, the results are shown in Table 1:
As can be seen from the above results, the technology of the present invention is compared with public technology, and environmental protection more, yield is high, and product purity is higher, and dissolvent residual is low, is also conducive to the removal of impurity X.
embodiment 3
Add SYR-322 crude product 5.0kg, dehydrated alcohol 57 liters and 3 liters, water (ethanol/water=95/5) in a kettle., reflux is clarified to solution, press filtration, to clean area, is cooled to 50 DEG C and adds crystal seed 10.0g, 40-50 DEG C of insulation crystallization 2h, logical refrigeration cycle water for cooling 20-30 DEG C continues insulation 1h, be cooled to 5-10 DEG C again and continue insulation crystallization 1h, centrifugal, 60 DEG C of forced air drying 5h, obtain the SYR-322 finished product 4.52kg of white, yield 90.4%.Purity is 99.96%, and single impurity is 0.036%, and alcohol residue 0.07% does not detect impurity X.
embodiment 4
Add SYR-322 crude product 5.0kg, dehydrated alcohol 47.5 liters and 2.5 liters, water (ethanol/water=95/5) in a kettle., reflux is clarified to solution, press filtration, to clean area, is cooled to 50 DEG C and adds crystal seed 25.0g, 45-55 DEG C of insulation crystallization 2h, logical refrigeration cycle water for cooling 25-35 DEG C continues insulation 1h, be cooled to 0-5 DEG C again and continue insulation crystallization 1h, centrifugal, 60 DEG C of forced air drying 5h, obtain the SYR-322 finished product 4.58kg of white, yield 91.6%.Purity is 99.90%, and single impurity is 0.038%, and alcohol residue 0.11% does not detect impurity X.
embodiment 5
Add SYR-322 crude product 5.0kg, dehydrated alcohol 31.5 liters and 3.5 liters, water (ethanol/water=90/10) in a kettle., reflux is clarified to solution, press filtration, to clean area, is cooled to 50 DEG C and adds crystal seed 15.0g, 40-50 DEG C of insulation crystallization 2h, logical refrigeration cycle water for cooling 20-30 DEG C continues insulation 1h, be cooled to 5-10 DEG C again and continue insulation crystallization 1h, centrifugal, 60 DEG C of forced air drying 5h, obtain the SYR-322 finished product 4.29kg of white, yield 85.8%.Purity is 99.94%, and single impurity is 0.035%, and alcohol residue 0.07% does not detect impurity X.
embodiment 6
Add SYR-322 crude product 5.0kg, dehydrated alcohol 58.8 liters and 1.2 liters, water (ethanol/water=98/2) in a kettle., reflux is clarified to solution, press filtration is to clean area, be cooled to 40-50 DEG C of crystallization, do not add crystal seed, observe after 2 hours and obviously have product to separate out, continue 40-50 DEG C of insulation crystallization 2h, logical refrigeration cycle water for cooling 20-30 DEG C continues insulation 1h, be cooled to 5-10 DEG C again and continue insulation crystallization 1h, centrifugal, 60 DEG C of forced air drying 5h, obtain the SYR-322 finished product 4.45kg of white, yield 89.0%.Purity is 99.91%, and single impurity is 0.043%, and alcohol residue 0.05% does not detect impurity X.
embodiment 7
Add SYR-322 crude product 5.0kg, dehydrated alcohol 71.25 liters and 3.75 liters, water (ethanol/water=95/5) in a kettle., reflux is clarified to solution, press filtration, to clean area, is cooled to 50 DEG C and adds crystal seed 10.0g, 35-45 DEG C of insulation crystallization 2h, logical refrigeration cycle water for cooling 15-20 DEG C continues insulation 1h, be cooled to 0-5 DEG C again and continue insulation crystallization 1h, centrifugal, 60 DEG C of forced air drying 5h, obtain the SYR-322 finished product 4.36kg of white, yield 87.2%.Purity is 99.93%, and single impurity is 0.036%, and alcohol residue 0.12% does not detect impurity X.
embodiment 8
Add SYR-322 crude product 5.0kg, dehydrated alcohol 24.0 liters and 6.0 liters, water (ethanol/water=80/20) in a kettle., reflux is clarified to solution, press filtration, to clean area, is cooled to 50 DEG C and adds crystal seed 10.0g, 40-50 DEG C of insulation crystallization 2h, logical refrigeration cycle water for cooling 20-30 DEG C continues insulation 1h, be cooled to 5-10 DEG C again and continue insulation crystallization 1h, centrifugal, 60 DEG C of forced air drying 5h, obtain the SYR-322 finished product 4.08kg of white, yield 81.6%.Purity is 99.89%, and single impurity is 0.042%, and alcohol residue 0.13% does not detect impurity X.
Claims (9)
1. an industrial process for SYR-322 bulk drug, is characterized in that the method comprises the steps:
Add in reactor by mixed solvent, SYR-322 crude product respectively, reflux is clarified to solution, and cooling adds crystal seed, gradient cooling crystallization, centrifugal, dry, to obtain final product.
2. the method for claim 1, it is characterized in that mixed solvent described in the method is dehydrated alcohol and purified water, ratio is from 80/20 to 98/2.
3. method as claimed in claim 2, is characterized in that the ratio of dehydrated alcohol and purified water in the method is 95/5.
4. method as claimed in claim 1 or 2, is characterized in that the add-on of mixed solvent described in the method is can dissolve SYR-322 crude product under heated reflux condition.
5. method as claimed in claim 3, is characterized in that the add-on of mixed solvent described in the method is 10-15 times of volume of SYR-322 crude product quantity, preferably 12 times of volumes.
6. the method as described in as arbitrary in claim 1-5, is characterized in that Seed charge described in the method is the 0-0.5% of SYR-322 crude product quantity, preferably 0.2%.
7. the method as described in as arbitrary in claim 1-5, is characterized in that can not adding crystal seed in the method.
8. the method as described in as arbitrary in claim 1-7, is characterized in that in the crystallization of gradient cooling described in the method, temperature range is followed successively by 35-55 DEG C of crystallization, 15-35 DEG C crystallization, 0-15 DEG C crystallization.
9. method as claimed in claim 8, is characterized in that in the crystallization of gradient cooling described in the method, temperature range is followed successively by 40-50 DEG C of crystallization, 20-30 DEG C crystallization, 5-10 DEG C crystallization.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105968091A (en) * | 2016-05-05 | 2016-09-28 | 青岛辰达生物科技有限公司 | Method for preparing drug Alogliptin for treating diabetes type II |
| CN106749177A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of SYR-322 |
| CN106831706A (en) * | 2017-02-04 | 2017-06-13 | 辰欣药业股份有限公司 | A kind of process for purification of SYR-322 |
| CN107954978A (en) * | 2017-10-27 | 2018-04-24 | 常州市阳光药业有限公司 | The preparation method of alogliptin benzoate |
| CN109232532A (en) * | 2018-11-08 | 2019-01-18 | 重庆科瑞南海制药有限责任公司 | A kind of industrialized preparing process of alogliptin benzoate |
| CN111253324A (en) * | 2020-03-17 | 2020-06-09 | 湖北扬信医药科技有限公司 | Preparation method of alogliptin impurity |
| CN112028754A (en) * | 2020-06-17 | 2020-12-04 | 浙江美诺华药物化学有限公司 | Preparation method of safinamide mesylate intermediate |
| CN113307777A (en) * | 2020-02-27 | 2021-08-27 | 石药集团欧意药业有限公司 | Alogliptin benzoate intermediate and preparation method of Alogliptin benzoate |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105968091A (en) * | 2016-05-05 | 2016-09-28 | 青岛辰达生物科技有限公司 | Method for preparing drug Alogliptin for treating diabetes type II |
| CN106749177A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of SYR-322 |
| CN106831706A (en) * | 2017-02-04 | 2017-06-13 | 辰欣药业股份有限公司 | A kind of process for purification of SYR-322 |
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| CN109232532A (en) * | 2018-11-08 | 2019-01-18 | 重庆科瑞南海制药有限责任公司 | A kind of industrialized preparing process of alogliptin benzoate |
| CN113307777A (en) * | 2020-02-27 | 2021-08-27 | 石药集团欧意药业有限公司 | Alogliptin benzoate intermediate and preparation method of Alogliptin benzoate |
| CN113307777B (en) * | 2020-02-27 | 2023-01-17 | 石药集团欧意药业有限公司 | Alogliptin benzoate intermediate and preparation method of Alogliptin benzoate |
| CN111253324A (en) * | 2020-03-17 | 2020-06-09 | 湖北扬信医药科技有限公司 | Preparation method of alogliptin impurity |
| CN112028754A (en) * | 2020-06-17 | 2020-12-04 | 浙江美诺华药物化学有限公司 | Preparation method of safinamide mesylate intermediate |
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Application publication date: 20150729 |