CN105732484A - Preparation method of Nimodipine - Google Patents
Preparation method of Nimodipine Download PDFInfo
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- CN105732484A CN105732484A CN201410765194.4A CN201410765194A CN105732484A CN 105732484 A CN105732484 A CN 105732484A CN 201410765194 A CN201410765194 A CN 201410765194A CN 105732484 A CN105732484 A CN 105732484A
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- nimodipine
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- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 title claims abstract description 22
- 229960000715 nimodipine Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 18
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 17
- 150000002191 fatty alcohols Chemical class 0.000 claims abstract description 9
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 7
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- -1 ammonia ester Chemical class 0.000 abstract 3
- YCKAGGHNUHZKCL-UHFFFAOYSA-N propan-2-yl 3-aminobut-2-enoate Chemical compound CC(C)OC(=O)C=C(C)N YCKAGGHNUHZKCL-UHFFFAOYSA-N 0.000 abstract 2
- UVZJPCAZMGLNTB-UHFFFAOYSA-N 2-methoxyethyl 2-[(3-nitrophenyl)methylidene]-3-oxobutanoate Chemical compound COCCOC(=O)C(C(C)=O)=CC1=CC=CC([N+]([O-])=O)=C1 UVZJPCAZMGLNTB-UHFFFAOYSA-N 0.000 abstract 1
- 239000007810 chemical reaction solvent Substances 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- 238000009413 insulation Methods 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 230000006837 decompression Effects 0.000 description 7
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the pharmaceutical technical field, and more specifically to a preparation method of Nimodipine. The preparation method includes an ammonia ester reaction and a cyclization reaction. In the ammonia ester reaction, after an ammonia-filling reaction ends, firstly an inorganic salt is added to remove water from the ammonia ester reaction, and then isopropyl 3-aminocrotonate is obtained through rectification. The cyclization reaction is carried out on the isopropyl 3-aminocrotonate and 2-(3-nitrobenzylidene)-acetoacetate-2-methoxyethyl ester, and a fatty alcohol is used as a reaction solvent. The preparation method of the Nimodipine has the advantages that the finished product yield is high, the primary yield reaches 85-89%, the quality is good, the solvent can be recycled and reused, and the raw material cost can be greatly reduced. Total impurities detected by HPLC can decrease to 0.1-0.3% from 0.4-1.0% in the original technology.
Description
Technical field
The invention belongs to pharmaceutical technology field, the preparation method being specifically related to a kind of nimodipine.
Background technology
Nimodipine (Nimodipine) chemical name is for 2,6-dimethyl-4-(3-nitrobenzophenone)-1,4-dihydro-3,5-pyridinedicarboxylic acid-2-methoxyethyl-(1-the first and second base) ester, belong to the calcium-channel antagonists of dihydropyridines, it is adaptable to cerebral vasospasm and the convalescent blood circulation of acute cerebrovascular disease after the Subarachnoid Hemorrhage of a variety of causes improve.The synthesis technique of current nimodipine adopts the following step:
A, reactive urethane:
B, ring-closure reaction
Owing to reactive urethane generates water in logical ammonia course of reaction, the reactant liquor that the logical ammonia of former technique terminates is made directly rectification, due to the existence of water in reactant liquor, cause that in high temperature distillation process, back reaction carries out, make the 3-amino .beta.-methylacrylic acid isopropyl ester generated in logical ammonia course of reaction, can decompose in the water generation back reaction of distillation process with generation, in any case cause existing technique to increase logical ammonia amount, 3-amino .beta.-methylacrylic acid isopropyl ester gas Chromatographic Determination content can only achieve 89～91%, it is impossible to continues to improve.Former technique ring-closure reaction uses the mixed solvent of isopropanol and hexamethylene, wherein isopropanol is 1:4 with the volume ratio of hexamethylene, 3-amino .beta.-methylacrylic acid isopropyl ester dropping temperature is 65～70 DEG C, and reaction end needs crude product centrifugation, then refines to obtain nimodipine finished product with refining solvent.Former process recovery ratio is relatively low, and finished product HPLC checked for impurities content is 0.4～1.0%.
Summary of the invention
The preparation method that it is an object of the invention to provide the nimodipine that a kind of process recovery ratio is high and impurity level is few.
The preparation method of nimodipine of the present invention, including reactive urethane and ring-closure reaction, it is characterised in that the reactions steps of reactive urethane and ring-closure reaction is:
A, in reactive urethane, logical ammonia reaction is initially charged inorganic salt and reactive urethane liquid is dewatered after terminating, and then rectification obtains 3-amino .beta.-methylacrylic acid isopropyl ester again；
B, the 3-amino .beta.-methylacrylic acid isopropyl ester of gained and 2-(3-Nitrobenzol methylene)-acetoacetic acid-2-methoxy acrylate are carried out ring-closure reaction using fatty alcohol as reaction dissolvent；
Wherein, in reactive urethane, inorganic salt is the one in anhydrous calcium chloride, sodium chloride, anhydrous magnesium sulfate or sodium sulfate, and inorganic salt and reactive urethane liquid weight ratio are 1:30～40.
In ring-closure reaction, the temperature of ring-closure reaction is 30～70 DEG C, and the mol ratio of each group material is:
2-(3-Nitrobenzol methylene)-acetoacetic acid-2-methoxy acrylate: 3-amino .beta.-methylacrylic acid isopropyl ester: fatty alcohol=1:1.0～1.2:5～10.Wherein said fatty alcohol is the fatty alcohol of C1～C3.
Moisture is separated, it is possible to reduce 3-amino .beta.-methylacrylic acid isopropyl ester catches up with hydrolysis when ammonia and rectification, finally can improve the content of 3-amino .beta.-methylacrylic acid isopropyl ester, and gas Chromatographic Determination content is up to more than 98% before it is an advantage of the current invention that improved rear rectification；The raising of 3-amino .beta.-methylacrylic acid isopropyl ester content, ring-closure reaction side reaction is few, and this technique product yield is high, yield up to 85～89%, quality good, solvent can be greatly lowered the cost of raw material by recovery.Nimodipine end product quality is greatly improved, and HPLC detects total impurities can be reduced to 0.1～0.3% by the 0.4～1.0% of former technique.
Simultaneously as 3-amino .beta.-methylacrylic acid isopropyl ester content improves and the reduction of ring-closure reaction temperature so that cyclization side reaction reduces, refinement mother liquor colloid amount greatly reduces, refinement mother liquor can be recycled product smoothly, and the response rate is up to about 6～8%, and ring essence total recovery is up to 92～95%.Refining solvent remains unchanged, and still uses isopropanol and hexamethylene, will not change the crystal formation of existing finished product, isopropanol and hexamethylene and can realize recycled.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1:
64kg isopropanol and 0.4kg triethylamine are put into retort, is warming up to 75 DEG C, drip ketene dimer 90kg, time for adding 1 hour, control temperature 80 ± 2 DEG C, then insulation reaction 3 hours between 90 DEG C.It is cooled to 0 DEG C, logical ammonia 5 hours, logical ammonia amount 18kg, stand insulation reaction 3 hours.Add anhydrous calcium chloride 5.7kg, stirring and dissolving 30 minutes, static 3 little time-division water.Colorless oil 3-amino .beta.-methylacrylic acid isopropyl ester 125kg, yield 81.5%, content 98.8% are distilled to obtain in decompression.
52kg3-amino .beta.-methylacrylic acid isopropyl ester, 100kg2-(3-Nitrobenzol methylene)-acetoacetic acid-2-methoxy acrylate and 105kg methanol are put into retort, it is warming up to 30 DEG C, insulation reaction 1 hour, back flow reaction 1 hour, decompression distillating carbinol is to no longer distillating.Reaction terminates, and adds isopropanol 74kg and thiacyclohexane 220kg.It is cooled to 25 DEG C, insulation crystallization 1 hour, continue to be cooled to 20 DEG C, centrifuge washing dries, and obtains faint yellow nimodipine 124kg, yield 86.9%, and HPLC measures total impurities 0.22%.
Embodiment 2:
65kg isopropanol and 0.5kg triethylamine are put into retort, is warming up to 75 DEG C, drip ketene dimer 90kg, time for adding 2 hours, control temperature 80 ± 2 DEG C, then insulation reaction 3 hours between 95 DEG C.It is cooled to 10 DEG C, logical ammonia 5 hours, logical ammonia amount 18kg, stand insulation reaction 3 hours.Add anhydrous magnesium sulfate 4.3kg, stirring and dissolving 30 minutes, static 3 little time-division water.Colorless oil 3-amino .beta.-methylacrylic acid isopropyl ester 126kg, yield 82.2%, content 98.4% are distilled to obtain in decompression.
56kg3-amino .beta.-methylacrylic acid isopropyl ester, 100kg2-(3-Nitrobenzol methylene)-acetoacetic acid-2-methoxy acrylate and 122kg ethanol are put into retort, it is warming up to 70 DEG C, insulation reaction 1 hour, back flow reaction 1 hour, decompression distillation ethanol is to no longer distillating.Reaction terminates, and adds isopropanol 74kg and thiacyclohexane 220kg.It is cooled to 60 DEG C, insulation crystallization 1 hour, continue to be cooled to 25 DEG C, centrifuge washing dries, and obtains faint yellow nimodipine 125kg, yield 87.6%, and HPLC measures total impurities 0.18%.
Embodiment 3:
65kg isopropanol and 0.6kg triethylamine are put into retort, is warming up to 75 DEG C, drip ketene dimer 90kg, time for adding 1.5 hours, control temperature 80 ± 2 DEG C, then insulation reaction 3 hours between 90 DEG C.It is cooled to 5 DEG C, logical ammonia 5 hours, logical ammonia amount 20kg, stand insulation reaction 3 hours.Add sodium chloride 5.0kg, stirring and dissolving 30 minutes, static 3 little time-division water.Colorless oil 3-amino .beta.-methylacrylic acid isopropyl ester 126kg, yield 82.2%, content 98.1% are distilled to obtain in decompression.
58kg3-amino .beta.-methylacrylic acid isopropyl ester, 100kg2-(3-Nitrobenzol methylene)-acetoacetic acid-2-methoxy acrylate and 102kg isopropanol are put into retort, it is warming up to 50 DEG C of insulation reaction 1 hour, back flow reaction 1 hour, decompression distillation isopropanol is to no longer distillating.Reaction terminates, and adds isopropanol 74kg and thiacyclohexane 220kg.It is cooled to 30 DEG C, insulation crystallization 1 hour, continue to be cooled to 25 DEG C, centrifuge washing dries, and obtains faint yellow nimodipine 126kg, yield 88.3%, and HPLC measures total impurities 0.25%.
Comparative example 1:
64kg isopropanol and 0.4kg triethylamine are put into retort, is warming up to 75 DEG C, drip ketene dimer 90kg, time for adding 1.5 hours, control temperature 80 ± 2 DEG C, then insulation reaction 3 hours between 95 DEG C.It is cooled to 10 DEG C, logical ammonia 5 hours, logical ammonia 18kg, stand insulation reaction 3 hours.Colorless oil 3-amino .beta.-methylacrylic acid isopropyl ester 124kg, yield 80.9%, content 89.4% are distilled to obtain in decompression.
72L isopropanol, 228L thiacyclohexane and 80kg2-(3-Nitrobenzol methylene)-acetoacetic acid-2-methoxy acrylate are put into retort, temperature 65 DEG C, drips 3-amino .beta.-methylacrylic acid isopropyl ester 45kg.Intensification azeotropic band water, is to slowly warm up to 90 DEG C.After reaction terminates, add isopropanol, each 100L of thiacyclohexane.Being cooled to 10 DEG C, stand 2 hours, centrifuge washing obtains crude product.Putting into isopropanol and each 100L of thiacyclohexane in tank again, added by above-mentioned crude product, be warming up to 75 DEG C of dissolvings, binder, be cooled to less than 25 DEG C, centrifuge washing dries, and obtains faint yellow nimodipine 90kg, yield 78.8%, and HPLC measures total impurities 0.74%.
Claims (6)
1. a preparation method for nimodipine, including reactive urethane and ring-closure reaction, it is characterised in that the reactions steps of reactive urethane and ring-closure reaction is:
A, in reactive urethane, logical ammonia reaction is initially charged inorganic salt and reactive urethane liquid is dewatered after terminating, and then rectification obtains 3-amino .beta.-methylacrylic acid isopropyl ester again；
B, the 3-amino .beta.-methylacrylic acid isopropyl ester of gained and 2-(3-Nitrobenzol methylene)-acetoacetic acid-2-methoxy acrylate are carried out ring-closure reaction using fatty alcohol as reaction dissolvent.
2. the preparation method of nimodipine according to claim 1, it is characterised in that inorganic salt and reactive urethane liquid weight ratio are 1:30～40.
3. the preparation method of nimodipine according to claim 1, it is characterised in that in ring-closure reaction, the mol ratio of each group material is:
2-(3-Nitrobenzol methylene)-acetoacetic acid-2-methoxy acrylate: 3-amino .beta.-methylacrylic acid isopropyl ester: fatty alcohol=1:1.0～1.2:5～10.
4. the preparation method of nimodipine according to claim 1, it is characterised in that the temperature of ring-closure reaction is 30～70 DEG C.
5. the preparation method of nimodipine according to claim 2, it is characterised in that inorganic salt is the one in anhydrous calcium chloride, sodium chloride, anhydrous magnesium sulfate or sodium sulfate.
6. the preparation method of nimodipine according to claim 3, it is characterised in that fatty alcohol is the fatty alcohol of C1～C3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410765194.4A CN105732484A (en) | 2014-12-11 | 2014-12-11 | Preparation method of Nimodipine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410765194.4A CN105732484A (en) | 2014-12-11 | 2014-12-11 | Preparation method of Nimodipine |
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| CN105732484A true CN105732484A (en) | 2016-07-06 |
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| CN201410765194.4A Pending CN105732484A (en) | 2014-12-11 | 2014-12-11 | Preparation method of Nimodipine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107840802A (en) * | 2017-10-31 | 2018-03-27 | 南通醋酸化工股份有限公司 | A kind of preparation technology of isopropyl acetoacetate |
| CN108152411A (en) * | 2017-12-19 | 2018-06-12 | 嘉实（湖南）医药科技有限公司 | The detection method of impurity in 3- amino -2- M Crs |
| CN110294674A (en) * | 2018-03-21 | 2019-10-01 | 南通醋酸化工股份有限公司 | A kind of tubular type continuous flow reaction unit and the method for preparing isopropyl acetoacetate |
| CN110294676A (en) * | 2018-03-21 | 2019-10-01 | 南通醋酸化工股份有限公司 | A kind of method and system preparing ethyl acetoacetate using tubular type continuous flow reactor |
| CN111875535A (en) * | 2020-07-03 | 2020-11-03 | 湖南省药品检验研究院(湖南药用辅料检验检测中心) | Nimodipine impurity IV reference substance and preparation method and application thereof |
| CN116003311A (en) * | 2022-11-30 | 2023-04-25 | 山东新华制药股份有限公司 | Method for synthesizing nitrendipine by utilizing ionic liquid catalysis |
-
2014
- 2014-12-11 CN CN201410765194.4A patent/CN105732484A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107840802A (en) * | 2017-10-31 | 2018-03-27 | 南通醋酸化工股份有限公司 | A kind of preparation technology of isopropyl acetoacetate |
| CN108152411A (en) * | 2017-12-19 | 2018-06-12 | 嘉实（湖南）医药科技有限公司 | The detection method of impurity in 3- amino -2- M Crs |
| CN108152411B (en) * | 2017-12-19 | 2020-07-07 | 湖南新领航检测技术有限公司 | Method for detecting impurities in 3-amino-2-methyl crotonate |
| CN110294674A (en) * | 2018-03-21 | 2019-10-01 | 南通醋酸化工股份有限公司 | A kind of tubular type continuous flow reaction unit and the method for preparing isopropyl acetoacetate |
| CN110294676A (en) * | 2018-03-21 | 2019-10-01 | 南通醋酸化工股份有限公司 | A kind of method and system preparing ethyl acetoacetate using tubular type continuous flow reactor |
| CN111875535A (en) * | 2020-07-03 | 2020-11-03 | 湖南省药品检验研究院(湖南药用辅料检验检测中心) | Nimodipine impurity IV reference substance and preparation method and application thereof |
| CN116003311A (en) * | 2022-11-30 | 2023-04-25 | 山东新华制药股份有限公司 | Method for synthesizing nitrendipine by utilizing ionic liquid catalysis |
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