CN103880748B - A kind of hydrochloric acid Ivabradine analog and its preparation method and application - Google Patents
A kind of hydrochloric acid Ivabradine analog and its preparation method and application Download PDFInfo
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- CN103880748B CN103880748B CN201410134746.1A CN201410134746A CN103880748B CN 103880748 B CN103880748 B CN 103880748B CN 201410134746 A CN201410134746 A CN 201410134746A CN 103880748 B CN103880748 B CN 103880748B
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- 0 C*c1cc(CC(N(CCCN(*)C[C@@](Cc2c3)c2cc(**)c3O)CC2)=O)c2cc1* Chemical compound C*c1cc(CC(N(CCCN(*)C[C@@](Cc2c3)c2cc(**)c3O)CC2)=O)c2cc1* 0.000 description 1
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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 a kind of hydrochloric acid Ivabradine analog (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-base)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-dione hydrochlorides (I) and preparation method thereof, and the application of compound in the quality controling research of hydrochloric acid Ivabradine.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specially a kind of hydrochloric acid Ivabradine analog and synthetic method thereof 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 forbidding or the treatment not tolerating beta-blockers, the normal patients with stable angina of sinus rhythm, be also in the pre-market approval stage in China at present.Its chemical name is 3-{3-[{ [(7S)-3,4-dimethoxy dicyclo [4.2.0] pungent-1,3,5-triolefin-7-base]-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, in operational path Selecting research experimentation, applicant finds, no matter be according to four kinds of preparation methods disclosed in above patent text, or according to certainly grinding technique, in final finished dosage form, all have the unknown and impurity that content is larger of a kind of structure, its generation cannot be avoided by the optimized choice of preparation technology.
Moreover, this impurity also has photosensitivity, finds in preparation stability experiment subsequently, along with experiment process, this foreign matter content obviously increases, and be the impurity that content in finished dosage form is maximum, it has vital impact to the safety and effectiveness of the medicine that finally dispatches from the factory.
Therefore, determine chemical structure and the preparation method of this impurity, to setting up detection method, analysing impurity content, and determine rational limit of impurities thus carry out the quality control of hydrochloric acid Ivabradine and clinical drug safety to detect and all serve vital effect.
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-base)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-dione hydrochloride (I) and its preparation method and application.
Synthetic method of the present invention comprises following process:
Specifically, comprise the steps:
(a) 2,3-dimethoxy-phenylethylamine II under the condition of weak base catalysis, in polar aprotic solvent, react generation 7,8-dimethoxy-4 ' with oxalic acid, 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III;
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), preferred 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-base)-methyl)-N-methyl-propyl]-1-amine IV reaction generation (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-base)-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) polar aprotic 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-base)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone V react with hydrogenchloride saturated solution and generate (S)-3-{3-[(4 in non-protonic solvent, 5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-base)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-dione hydrochloride 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, ethanolic hydrogen chloride saturated solution.
Wherein, non-protonic solvent is selected from ether, ethyl acetate, acetonitrile, acetone etc.
Standard reference material can be provided for the quality control of hydrochloric acid Ivabradine and clinical drug safety detect by the present invention to the chemical structure of hydrochloric acid Ivabradine analog and preparation method, ensure clinical drug safety reliability.And this preparation method is simple to operate, reaction conditions is gentle, can 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 5
1h NMR schemes;
Accompanying drawing 3: compound (I) embodiment 5
13c NMR schemes;
Accompanying drawing 4: the ESI figure of 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 done content of the present invention.
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 terminates, 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 terminates, poured into by reaction solution in 2L purified water, stir 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), after stirring 0.5h, add the chloro-N-of (S)-3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-base)-methyl)-N-methyl-propyl]-1-amine IV 63.1g(0.222mol), insulated and stirred reaction 24h.After reaction terminates, poured into by reaction solution in the purified water of precooling, after stirring 5min, add dichloromethane extraction (200mL × 2), organic phase, with after purified water washing, adds the dry 1h of anhydrous sodium sulphate 100g.Filter, be evaporated to dry, obtain (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-base)-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-base)-methyl)-N-methyl-propyl]-1-amine IV 63.1g(0.222mol), triethylamine 27.2g(0.269mol) and, insulated and stirred reaction 32h.After reaction terminates, poured into by reaction solution in the purified water of precooling, after stirring 5min, add dichloromethane extraction (200mL × 2), organic phase, with after purified water washing, adds the dry 1h of anhydrous sodium sulphate 100g.Filter, be evaporated to dry, obtain (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-base)-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-base)-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-base)-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 (6)
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, it is characterized in that, reaction process is as follows:
Comprise the steps:
(a) 2,3-dimethoxy-phenylethylamine II under the condition of weak base catalysis, in polar aprotic solvent, react generation 7,8-dimethoxy-4 ' with oxalic acid, 5-dihydro-1H-benzazepine-1,2 (3H)-diketone III;
(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-base)-methyl)-N-methyl-propyl]-1-amine IV reaction generation (S)-3-{3-[(4,5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-base)-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-base)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-diketone V react with hydrogenchloride saturated solution and generate (S)-3-{3-[(4 in non-protonic solvent, 5-dimethoxy-1,2-dihydro cyclobutadiene benzene-1-base)-methyl] methylamino } propyl group-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-1,2 (3H)-dione hydrochloride I;
Wherein, the described weak base of step (a) is selected from dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid or N, N-carbonyl dimidazoles, described polar aprotic solvent is selected from acetonitrile, methylene dichloride, acetone, DMF;
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, described organic solvent is selected from N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), 1,2-glycol dimethyl ether;
The described non-protonic solvent of step (c) is selected from ether, ethyl acetate, acetonitrile or acetone.
3. preparation method according to claim 2, is characterized in that, the described weak base of step (a) is dicyclohexylcarbodiimide.
4. preparation method according to claim 2, is characterized in that, the weightmeasurement ratio 1:10-15 of the described compound ii of step (a) and polar aprotic solvent.
5. preparation method according to claim 2, is characterized in that, the weightmeasurement ratio of the described compound III of step (b) and organic solvent is 1:10-15.
6. the application of hydrochloric acid Ivabradine analog (I) according to claim 1 in the quality control of hydrochloric acid Ivabradine.
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| 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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| FR2681862B1 (en) * | 1991-09-27 | 1993-11-12 | Adir Cie | NOVELS (BENZOCYCLOALKYL) ALKYLAMINES, THEIR PREPARATION PROCESS, AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2868777B1 (en) * | 2004-04-13 | 2006-05-26 | Servier Lab | NOVEL PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
| FR2891827B1 (en) * | 2005-10-11 | 2007-12-28 | Servier Lab | CRYSTALLINE DELTAD FORM OF IVABRADINE HYDROCHLORIDE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| CN101284813B (en) * | 2007-04-12 | 2012-08-15 | 上海优拓医药科技有限公司 | Preparation method of ivabradine |
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