CN102659673A - Preparation method of amlodipine free alkali - Google Patents
Preparation method of amlodipine free alkali Download PDFInfo
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- CN102659673A CN102659673A CN2012101377646A CN201210137764A CN102659673A CN 102659673 A CN102659673 A CN 102659673A CN 2012101377646 A CN2012101377646 A CN 2012101377646A CN 201210137764 A CN201210137764 A CN 201210137764A CN 102659673 A CN102659673 A CN 102659673A
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- CN
- China
- Prior art keywords
- amlodipine
- free alkali
- preparation
- toluene
- phthaloyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960000528 amlodipine Drugs 0.000 title claims abstract description 42
- 239000003513 alkali Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title claims abstract 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 70
- AHHPZGUFLGCZCF-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 4-(2-chlorophenyl)-2-[2-(1,3-dioxoisoindol-2-yl)ethoxymethyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(COCCN2C(C3=CC=CC=C3C2=O)=O)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl AHHPZGUFLGCZCF-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 5
- 238000001953 recrystallisation Methods 0.000 claims abstract description 5
- 239000012043 crude product Substances 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 34
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 abstract 1
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 241000628997 Flos Species 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RTLPJNYVZDKMIY-UHFFFAOYSA-N 2-n-methylbenzene-1,2-dicarboxamide Chemical compound CNC(=O)C1=CC=CC=C1C(N)=O RTLPJNYVZDKMIY-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960004005 amlodipine besylate Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of amlodipine free alkali, and the method is characterized by comprising the following steps of: (1) by virtue of taking methylbenzene as a reaction solvent and a 40wt% of monomethylamine water solution as deprotection agent, carrying out deprotection on phthaloyl amlodipine, thus obtaining a crude product of amlodipine free alkali; and (2) dissolving the crude product of amlodipine free alkali by use of methylbenzene, and dripping normal hexane into the solution for recrystallization, thus obtaining the high-purity amlodipine free alkali. The preparation method has the characteristics of being convenient to operate, short in reaction time, stable in reaction state and suitable for industrial production.
Description
Technical field
The invention belongs to the chemical pharmaceutical field, the preparation method of the free alkali of particularly a kind of amlodipine.
Background technology
Amlodipine besylate is a third generation bihydropyridine type calcium antagonist.Compare with similar antihypertensive drugs, have advantages such as oral absorption is good, bioavailability is high, long half time, and untoward reaction is few.At present, this kind is the hypertensive choice drug of treatment, and its sales volume occupies the first place of world's painstaking effort tubing medicine, has extraordinary market outlook.
The phthaloyl amlodipine is this medicine commonplace midbody at present.Desire to make the free alkali of amlodipine, need this midbody is carried out deprotection.Deprotecting regent commonly used has: Hydrazine Hydrate 80, monomethylamine aqueous solution and methylamine alcohol solution.As follows:
Hydrazine Hydrate 80 is during as deprotecting regent, and the reaction times is short, can accomplish in 2 hours, and the phthalhydrazide that generates is removed (being insoluble to ethanol) easily.But Hydrazine Hydrate 80 is poisonous and the danger of blast is arranged, and the phthalhydrazide that generates deposition, wraps up the free alkali of amlodipine easily.Repeatedly after the washing, the free alkali of still residual a lot of amlodipines in the phthalhydrazide deposition causes yield on the low side.
The document utilization methylamine alcohol solution that has, like WO2006003672A1, but methylamine alcohol solution is difficult to buy on market.
The document utilization Monomethylamine gas that has, like WO2007096724A1, but not easy to operate.
The document utilization monomethylamine aqueous solution that has carries out deprotection, not with an organic solvent, and like US2007260065A1.Because the phthaloyl amlodipine is water insoluble, thereby causes the reaction times to reach 25 hours, and aftertreatment is loaded down with trivial details.
WO2005023769A1 also is to use monomethylamine aqueous solution, carries out deprotection, and reaction solvent is a methylene dichloride.The inventor attempts the technology of repetition WO2005023769A1, then the free alkali bullion of amlodipine is made with extra care.When making with extra care, find to have the floss of a large amount of indissolubles with toluene.The inventor attempts it is filtered out, but is difficult to filter, and must use the pressurization suction filtration.Find that after deliberation the floss of indissoluble is the deprotection reaction process, the compound---N-methyl phthalic diamide (structure is shown in the following figure) that group of taking off and Monomethylamine generate, and wrap up the free alkali of certain amlodipine.So utilize the yield and the quality of the free alkali of amlodipine that this technology makes all on the low side, and be not easy to operation.
Proof thus: the deprotection reaction process, the generation of the group of taking off and Monomethylamine compound---N-methyl phthalic diamide, the solubleness in toluene is very little.This conclusion is reminded personnel of the present invention: use toluene as the deprotection reaction solvent, when reaction finished washing, N-methyl phthalic diamide should just be retained in water layer, thereby should be able to solve difficult filtering problem when making with extra care.
Summary of the invention
The preparation method who the purpose of this invention is to provide the free alkali of a kind of amlodipine, have be convenient to operate, the reaction times is short, suitability for industrialized production is stablized, is suitable for to response behaviour characteristics.
The preparation method of the free alkali of a kind of amlodipine of the present invention generates the free alkali of amlodipine with phthaloyl amlodipine deprotection, may further comprise the steps:
(1) with toluene be reaction solvent, the monomethylamine aqueous solution of 40wt% obtains the free alkali bullion of amlodipine as deprotection agent with phthaloyl amlodipine deprotection;
(2) with toluene to the free alkali dissolving crude product of amlodipine, drip normal hexane again and carry out recrystallization, the free alkali of highly purified amlodipine.
Wherein, the quantity relative ratio relationship between each material is preferably toluene in the step (1): the monomethylamine aqueous solution of 40wt%: phthaloyl amlodipine=4 ~ 10ml:5 ~ 7ml:1g, temperature of reaction are preferably 20～40 ℃.
Quantity relative ratio relationship in the step (2) between each material is preferably toluene: normal hexane: phthaloyl amlodipine=1 ~ 2ml:1 ~ 3ml:1g, recrystallization temperature are preferably 30～60 ℃.
The invention has the advantages that: (1) has solved phthaloyl amlodipine insoluble problem in the Monomethylamine aqueous systems, has shortened the reaction times; (2) initial reaction stage; The phthaloyl amlodipine can not be dissolved in the toluene of dosage (solubleness of phthaloyl amlodipine in methylene dichloride is very big, initial reaction stage, the phthaloyl amlodipine can be dissolved in the methylene dichloride of dosage fully) fully; Carrying out along with reaction; Dissolve, react, be converted into the free alkali of amlodipine gradually, and then the hydrolysis of ester group in the phthaloyl amlodipine molecule of having drawn up, also helped improving the yield of the free alkali of amlodipine; (3) will react the free alkali of amlodipine that produces and be retained in toluene layer, the hydrolysis of ester group in the molecule of having drawn up has improved the yield of the free alkali of amlodipine; (4) solubleness of the free alkali of amlodipine in toluene of reaction generation is also less than the solubleness in methylene dichloride; Carrying out along with reaction; Having the free alkali of amlodipine constantly is precipitated out; And then the hydrolysis of the ester group in the free base molecule of amlodipine of having drawn up, also helped improving the yield of the free alkali of amlodipine; (5) solved the difficult filtering problem of previous patent.
Embodiment
Below in conjunction with embodiment the present invention is further specified.
Embodiment 1:
In retort, drop into the monomethylamine aqueous solution 806Kg of phthaloyl amlodipine 130Kg, toluene 563Kg and 40wt%, 40 ℃ were reacted 6 hours.Reaction finishes, and stops to stir, and leaves standstill 30 minutes, tells organic phase; Water is used twice of methylbenzene extraction again; Merge organic phase, wash twice.Organic phase is used anhydrous sodium sulfate drying.Press filtration then, filtrate decompression is distilled to dried, gets the free alkali bullion of amlodipine.
In the free alkali bullion of gained amlodipine, add toluene 130Kg, be heated to 60 ℃, bullion is dissolved fully.Then, under this temperature, drip normal hexane 120Kg, 6 hours after-filtration of crystallization get the free sodafining article of amlodipine 80Kg, and deprotection reaction is 81.1% with refining two step total recoverys.
Embodiment 2:
In retort, drop into the monomethylamine aqueous solution 806Kg of phthaloyl amlodipine 130Kg, toluene 563Kg and 40wt%, 20 ℃ were reacted 11 hours.Reaction finishes, and stops to stir, and leaves standstill 30 minutes, tells organic phase; Water is used twice of methylbenzene extraction again; Merge organic phase, wash twice.Organic phase is used anhydrous sodium sulfate drying.Press filtration then, filtrate decompression is distilled to dried, gets the free alkali bullion of amlodipine.
In the free alkali bullion of gained amlodipine, add toluene 125Kg, be heated to 30 ℃, bullion is dissolved fully.Then, under this temperature, drip normal hexane 125Kg, 6 hours after-filtration of crystallization get the free sodafining article of amlodipine 81Kg, and deprotection reaction is 82.2% with refining two step total recoverys.
Embodiment 3:
In retort, drop into the monomethylamine aqueous solution 806Kg of phthaloyl amlodipine 130Kg, toluene 563Kg and 40wt%, 30 ℃ were reacted 6 hours.Reaction finishes, and stops to stir, and leaves standstill 30 minutes, tells organic phase; Water is used twice of methylbenzene extraction again; Merge organic phase, wash twice.Organic phase is used anhydrous sodium sulfate drying.Press filtration then, filtrate decompression is distilled to dried, gets the free alkali bullion of amlodipine.
In the free alkali bullion of gained amlodipine, add toluene 130Kg, be heated to 50 ℃, bullion is dissolved fully.Then, under this temperature, drip normal hexane 120Kg, 6 hours after-filtration of crystallization get the free sodafining article of amlodipine 80Kg, and deprotection reaction is 81.1% with refining two step total recoverys.
Claims (3)
1. the preparation method of the free alkali of amlodipine generates the free alkali of amlodipine with phthaloyl amlodipine deprotection, it is characterized in that may further comprise the steps:
(1) with toluene be reaction solvent, the monomethylamine aqueous solution of 40wt% obtains the free alkali bullion of amlodipine as deprotection agent with phthaloyl amlodipine deprotection;
(2) with toluene to the free alkali dissolving crude product of amlodipine, drip normal hexane again and carry out recrystallization, the free alkali of highly purified amlodipine.
2. the preparation method of the free alkali of amlodipine according to claim 1; It is characterized in that the quantity relative ratio relationship between each material is the monomethylamine aqueous solution of toluene: 40wt% in the step (1): phthaloyl amlodipine=4 ~ 10ml:5 ~ 7ml:1g, temperature of reaction are 20～40 ℃.
3. the preparation method of the free alkali of amlodipine according to claim 1; It is characterized in that the quantity relative ratio relationship between each material is a toluene in the step (2): normal hexane: phthaloyl amlodipine=1 ~ 2ml:1 ~ 3ml:1g, recrystallization temperature are 30～60 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101377646A CN102659673A (en) | 2012-05-07 | 2012-05-07 | Preparation method of amlodipine free alkali |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101377646A CN102659673A (en) | 2012-05-07 | 2012-05-07 | Preparation method of amlodipine free alkali |
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| Publication Number | Publication Date |
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| CN102659673A true CN102659673A (en) | 2012-09-12 |
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| CN2012101377646A Pending CN102659673A (en) | 2012-05-07 | 2012-05-07 | Preparation method of amlodipine free alkali |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838656A (en) * | 2012-09-29 | 2012-12-26 | 德州诚瑞达生物科技有限公司 | Preparation method of L-alanyl-L-glutamine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1496353A (en) * | 2001-03-13 | 2004-05-12 | ����ҩƷ��ҵ��ʽ���� | The preparation method of amlodipine |
| WO2005023769A1 (en) * | 2003-09-04 | 2005-03-17 | Cipla Limited | Process for the preparation of amlodipine salts |
| WO2007096724A1 (en) * | 2006-02-21 | 2007-08-30 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of amlodipine besylate |
-
2012
- 2012-05-07 CN CN2012101377646A patent/CN102659673A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1496353A (en) * | 2001-03-13 | 2004-05-12 | ����ҩƷ��ҵ��ʽ���� | The preparation method of amlodipine |
| WO2005023769A1 (en) * | 2003-09-04 | 2005-03-17 | Cipla Limited | Process for the preparation of amlodipine salts |
| WO2007096724A1 (en) * | 2006-02-21 | 2007-08-30 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of amlodipine besylate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838656A (en) * | 2012-09-29 | 2012-12-26 | 德州诚瑞达生物科技有限公司 | Preparation method of L-alanyl-L-glutamine |
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Application publication date: 20120912 |