CN103880748A - Ivabradine hydrochloride structure analogue and preparation method and application thereof - Google Patents
Ivabradine hydrochloride structure analogue and preparation method and application thereof Download PDFInfo
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- CN103880748A CN103880748A CN201410134746.1A CN201410134746A CN103880748A CN 103880748 A CN103880748 A CN 103880748A CN 201410134746 A CN201410134746 A CN 201410134746A CN 103880748 A CN103880748 A CN 103880748A
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- dimethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
Abstract
The invention provides an ivabradine hydrochloride structure analogue (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro-benzene cyclobutadiene-1-yl)-methyl] methylamino}propyl-7,8-dimethoxy-4,5-dihydro-1H- benzazepine-1,2(3H)-dione hydrochloride (I) and a preparation method thereof, and application of the compound in quality control research of ivabradine hydrochloride.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specially a kind of hydrochloric acid Ivabradine analog and synthetic method and application.
Background technology
Hydrochloric acid Ivabradine (Ivabradine hydrochloride), developed by French Shi Weiya company (Servier), within 2006, go on the market in the first batch in Ireland, clinically for to forbidding or do not tolerate the treatment of beta-blockers, the normal patients with stable angina of sinus rhythm, at present in China also in the pre-market approval stage.Its chemical name is 3-{3-[{[(7S)-3,4-dimethoxy dicyclo [4.2.0] pungent-1,3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group }-1,3,4,5-tetrahydrochysene-7,8-dimethoxy-2H-3-benzazepine-2-keto hydrochloride, structural formula is as follows:
The preparation method of four kinds of S 16257-2s is disclosed in existing patent documentation US5296482, CN1683341, CN101723897, CN102498102, select in research experiment process at operational path, applicant finds, no matter be according to disclosed four kinds of preparation methods in above patent text, or according to certainly grinding technique, in final preparation finished product, all have a kind of structure the unknown and the larger impurity of content, its generation cannot be avoided by preparation technology's optimized choice.
Moreover, this impurity also has photosensitivity, in preparation stability experiment subsequently, finds, along with experiment process, this foreign matter content obviously increases, and is the impurity of content maximum in preparation finished product, and its safety and effectiveness on the medicine that finally dispatches from the factory has vital impact.
Therefore, determine chemical structure and the preparation method of this impurity, to setting up detection method, analysing impurity content, thus and determine that rational limit of impurities is carried out the quality control of hydrochloric acid Ivabradine and clinical drug safety detects the vital effect of all having played.
Summary of the invention
The invention provides a kind of hydrochloric acid Ivabradine analog (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-dione hydrochlorides (I) and its preparation method and application.
Synthetic method of the present invention comprises following process:
Particularly, comprise the steps:
(a) 2,3-dimethoxy-phenylethylamine II is reacted in polar aprotic solvent with oxalic acid and is generated 7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III under the condition of weak base catalysis;
Wherein, weak base is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid (TBTU), N ' N-carbonyl dimidazoles (CDI), preferably DCC.
Wherein, polar aprotic solvent is selected from: acetonitrile, methylene dichloride, acetone or DMF.The weightmeasurement ratio 1:10-15 of compound ii and polar aprotic solvent.
(b) 7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III under the condition of base catalysis in organic solvent with the chloro-N-[(4 of (S)-3-, 5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl)-N-methyl-propyl]-1-amine IV reaction generation (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone V;
Wherein, alkali is selected from the one in salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydrogen, potassium tert.-butoxide, triethylamine.
Wherein, organic solvent is selected from DMF (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) (DMSO), 1,2-glycol dimethyl ether (DME) isopolarity non-protonic solvent.The weightmeasurement ratio of compound III and organic solvent is 1:10-15.
(c) (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone V are reacted generation (S)-3-{3-[(4 with hydrogenchloride saturated solution in non-protonic solvent, 5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone I;
Wherein, hydrogenchloride saturated solution is selected from hydrogenchloride acetonitrile saturated solution, hydrogenchloride acetone saturated solution, hydrogenchloride ethyl acetate saturated solution, hydrogenchloride ether saturated solution, hydrogenchloride Virahol saturated solution, hydrogenchloride alcohol saturated solution.
Wherein, non-protonic solvent is selected from ether, ethyl acetate, acetonitrile, acetone etc.
Chemical structure by the present invention to hydrochloric acid Ivabradine analog and preparation method can provide standard reference material for the quality control of hydrochloric acid Ivabradine and clinical drug safety detect, and ensure clinical drug safety reliability.And this preparation method is simple to operate, reaction conditions gentleness, can be with the highly purified hydrochloric acid Ivabradine analog of the acquisition of higher yields.
Figure of description
Accompanying drawing 1: the HPLC collection of illustrative plates of compound (I) embodiment 5;
Accompanying drawing 2: compound (I) embodiment's 5
1h NMR figure;
Accompanying drawing 3: compound (I) embodiment's 5
13c NMR figure;
The ESI figure of accompanying drawing 4: compound (I) embodiment 5.
Specific embodiment
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment, but concrete embodiment is not the restriction that content of the present invention is done.
Embodiment 1: the preparation of compound III
In 500mL methylene dichloride, add 3,4-dimethoxy-phenylethylamine (II) 50g(0.3mol), oxalic acid 30g(0.33mol), DCC138g(0.67mol) and, stirring reaction 3h.After reaction finishes, filter, evaporated under reduced pressure filtrate, residue isopropyl acetate recrystallization, obtains off-white color solid 7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III 49g, yield 73%.
Embodiment 2: the preparation of compound III
In 500mL DMF, add 3,4-dimethoxy-phenylethylamine (II) 50g(0.3mol), oxalic acid 30g(0.33mol), TBTU215g(0.67mol) and, stirring reaction 3h.After reaction finishes, reaction solution is poured in 2L purified water, stirred 0.5h, filter, filter cake isopropyl acetate recrystallization, obtains off-white color solid 7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III 40g, yield 60%.
Embodiment 3: the preparation of compound V
In 500mL DMF, add 7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III 49g(0.208mol), potassium tert.-butoxide 30.4g(0.269mol), stir after 0.5h, add the chloro-N-[(4 of (S)-3-, 5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl)-N-methyl-propyl]-1-amine IV 63.1g(0.222mol), insulated and stirred reaction 24h.After reaction finishes, reaction solution is poured in the purified water of precooling, stirred after 5min, add dichloromethane extraction (200mL × 2), organic phase, with after purified water washing, adds anhydrous sodium sulphate 100g to be dried 1h.Filter, be evaporated to dryly, obtain (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone V 104g, yield 85%.
Embodiment 4: the preparation of compound V
In 500mL DME, add 7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III 49g(0.208mol), the chloro-N-[(4 of (S)-3-, 5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl)-N-methyl-propyl]-1-amine IV 63.1g(0.222mol), triethylamine 27.2g(0.269mol) and, insulated and stirred reaction 32h.After reaction finishes, reaction solution is poured in the purified water of precooling, stirred after 5min, add dichloromethane extraction (200mL × 2), organic phase, with after purified water washing, adds anhydrous sodium sulphate 100g to be dried 1h.Filter, be evaporated to dryly, obtain (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone V 97g, yield 79%.
Embodiment 5: the preparation of chemical compounds I
In 500mL acetonitrile, add (S)-3-{3-[(4, 5-dimethoxy-1, 2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7, 8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1, 2 (3H)-diketone V 104g(0.216mol), drip isopropanol solution of hydrogen chloride, insulated and stirred crystallization 3h, centrifugal, drying under reduced pressure, obtain off-white color solid (S)-3-{3-[(4, 5-dimethoxy-1, 2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7, 8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1, 2 (3H)-diketone I 71g, yield 63%, HPLC purity detecting value is that 98.87%(refers to accompanying drawing 1),
1h NMR (500MHz, CDCl
3) δ: 2.041～2.054(m, 2H), 2.885(s, 3H), 3.169～3.188(m, 4H), 3.305～3.411(m, 3H), 3.527～3.555(m, 3H), 3.683～3.841(m, 15H), 6.811(s, 1H), 6.884～6.888(m, 1H), 6.943(s, 1H), 7.099(s, 1H), 10.250(s, 1H) (referring to accompanying drawing 2),
13c NMR (500MHz, d6-DMSO) δ: 22.43,33.19,34.98,37.07,39.61,42.54,45.47,52.98,55.51,55.78,55.85,55.85,58.36,107.67,108.05,110.97,112.97,125.80,134.14,135.11,136.40,147.54,149.44,150.39,153.02,166.73,192.78(refers to accompanying drawing 3), ESI m/z483.1[M-HCl+H]
+, 484.1[M-HCl+H+1]
+, 505.1[M-HCl+Na]
+(referring to accompanying drawing 4).
Claims (9)
1. a hydrochloric acid Ivabradine analog, is characterized in that, structure is as shown in I:
2. the preparation method of hydrochloric acid Ivabradine analog as claimed in claim 1, is characterized in that, reaction process is as follows:
Comprise the steps:
(a) 2,3-dimethoxy-phenylethylamine II is reacted in polar aprotic solvent with oxalic acid and is generated 7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III under the condition of weak base catalysis;
(b) 7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III under the condition of base catalysis in organic solvent with the chloro-N-[(4 of (S)-3-, 5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl)-N-methyl-propyl]-1-amine IV reaction generation (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone V;
(c) (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone V are reacted generation (S)-3-{3-[(4 with hydrogenchloride saturated solution in non-protonic solvent, 5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-yl)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone I.
3. preparation method according to claim 2, it is characterized in that, the described weak base of step (a) is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid (TBTU) or N, N-carbonyl dimidazoles (CDI).
4. preparation method according to claim 3, is characterized in that, the described weak base of step (a) is dicyclohexylcarbodiimide (DCC).
5. preparation method according to claim 2, is characterized in that, the described polar aprotic solvent of step (a) is selected from acetonitrile, methylene dichloride, acetone, DMF, the weightmeasurement ratio 1:10-15 of compound ii and polar aprotic solvent.
6. preparation method according to claim 2, is characterized in that, the described alkali of step (b) is selected from salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydrogen, potassium tert.-butoxide or triethylamine.
7. preparation method according to claim 2, is characterized in that, the described organic solvent of step (b) is selected from N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), 1,2-glycol dimethyl ether, the weightmeasurement ratio of compound III and organic solvent is 1:10-15.
8. preparation method according to claim 2, is characterized in that, the described non-protonic solvent of step (c) is selected from ether, ethyl acetate, acetonitrile or acetone.
9. the application of hydrochloric acid Ivabradine analog claimed in claim 1 (I) in the quality control of hydrochloric acid Ivabradine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669554A (en) * | 2016-02-22 | 2016-06-15 | 徐建立 | Ivabradine hydrochloride impurity and preparation method and application thereof |
| CN108727266A (en) * | 2017-04-18 | 2018-11-02 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of Ivabradine impurity |
| CN109970647A (en) * | 2019-04-03 | 2019-07-05 | 重庆德诚永道医药有限公司 | The preparation method and purposes of a kind of Ivabradine analogue or its hydrochlorate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN1683341A (en) * | 2004-04-13 | 2005-10-19 | 瑟维尔实验室 | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
| CN1948293A (en) * | 2005-10-11 | 2007-04-18 | 瑟维尔实验室 | Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it |
| CN101284813A (en) * | 2007-04-12 | 2008-10-15 | 上海优拓医药科技有限公司 | Preparation method of ivabradine |
-
2014
- 2014-04-03 CN CN201410134746.1A patent/CN103880748B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN1683341A (en) * | 2004-04-13 | 2005-10-19 | 瑟维尔实验室 | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
| CN1948293A (en) * | 2005-10-11 | 2007-04-18 | 瑟维尔实验室 | Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it |
| CN101284813A (en) * | 2007-04-12 | 2008-10-15 | 上海优拓医药科技有限公司 | Preparation method of ivabradine |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669554A (en) * | 2016-02-22 | 2016-06-15 | 徐建立 | Ivabradine hydrochloride impurity and preparation method and application thereof |
| CN108727266A (en) * | 2017-04-18 | 2018-11-02 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of Ivabradine impurity |
| CN109970647A (en) * | 2019-04-03 | 2019-07-05 | 重庆德诚永道医药有限公司 | The preparation method and purposes of a kind of Ivabradine analogue or its hydrochlorate |
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