CN101768116B - Preparation method for Ivabradine - Google Patents
Preparation method for Ivabradine Download PDFInfo
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- CN101768116B CN101768116B CN200810246546.XA CN200810246546A CN101768116B CN 101768116 B CN101768116 B CN 101768116B CN 200810246546 A CN200810246546 A CN 200810246546A CN 101768116 B CN101768116 B CN 101768116B
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- AQSRHFYHXNSUAO-OAQYLSRUSA-N CN(CCCN(C=Cc(cc1OC)c(C2)cc1OC)C2=O)C[C@@H](Cc1c2)c1cc(OC)c2OC Chemical compound CN(CCCN(C=Cc(cc1OC)c(C2)cc1OC)C2=O)C[C@@H](Cc1c2)c1cc(OC)c2OC AQSRHFYHXNSUAO-OAQYLSRUSA-N 0.000 description 1
- ACRHBAYQBXXRTO-OAQYLSRUSA-N CN(CCCN(CCc(c(C1)c2)cc(OC)c2OC)C1=O)C[C@@H](C1)c(cc2OC)c1cc2OC Chemical compound CN(CCCN(CCc(c(C1)c2)cc(OC)c2OC)C1=O)C[C@@H](C1)c(cc2OC)c1cc2OC ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 description 1
- VWPSZWNLEFZFQB-UHFFFAOYSA-N COc(cc(CC(N(CCCI)C=C1)=O)c1c1)c1OC Chemical compound COc(cc(CC(N(CCCI)C=C1)=O)c1c1)c1OC VWPSZWNLEFZFQB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method for Ivabradine. Catalytic hydrogenation is carried out on a formula (II) compound to obtain a formula (III) compound, reaction is carried out between the formula (III) compound and a formula (IV) compound under the action of base catalysis, and a catalyst is removed through filtration and separated to obtain the target compound.
Description
Technical field
The present invention relates to the S 16257-2 of synthesis type (I), be 3-{3-[{[(7S)-3,4-dimethoxy dicyclo [4.2.0] pungent-1,3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group }-7,8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone, and the preparation method of the additive salt of pharmaceutically acceptable acid.
Background technology
S 16257-2 and the additive salt forming with pharmaceutically acceptable acid thereof, more specifically for its hydrochloride has very valuable pharmacology and treat characteristic, especially decreasing heart rate (bradycardic) characteristic, thereby these compounds be used for the treatment of or prevent the various clinical settings of myocardial ischemia as stenocardia, myocardial infarction and relevant arhythmicity, and relating to the various pathologic conditions of arhythmicity, especially supraventricular arhythmicity and heart failure.
The preparation method who has described S 16257-2 and hydrochloride thereof in European patent specification EP 0534859, its route is as follows:
Aforesaid method shortcoming is that the acquisition of S 16257-2 need to pass through column chromatography, and reaction yield is very low, has all limited its industrialization above.
Chinese patent CN200510051779.0 has reported the novel method of synthesis of ivabradine in addition, and its route is as follows:
Above-mentioned route two-step reaction all uses noble metal palladium charcoal to make catalyzer, and all working pressure still reactions, although total recovery is higher, from the viewpoint of cost with can have drawback by this route of industrialization.
In view of the pharmacy value of S 16257-2 and salt, particularly its hydrochloride, be necessary to obtain S 16257-2 by more effective synthetic method, the method must comprehensive cost, yield, can industrialization etc. all respects factor, obtain S 16257-2 and salt thereof, particularly hydrochloride with minimum step and satisfied yield.
Summary of the invention
The invention provides the method for preparing S 16257-2, be different from the method that EP 0534859 and CN200510051779.0 report, it can be by the synthetic method of the S 16257-2 obtaining of the initial yield with one step, excellence of the salt of formula (IV) compound.
More specifically, the present invention relates to the synthetic method of the additive salt of S 16257-2, itself and the pharmaceutically acceptable acid of formula (I), it is characterized in that formula (II) compound
Wherein Y represents halogen, hydroxyl and the hydroxyl to the protection of toluene benzenesulfonyl, obtains formula (III) compound through catalytic hydrogenation:
Wherein Y as above defines, and this compound, under base catalysis, reacts with formula (IV) compound,
Wherein HX represents pharmaceutically acceptable acid,
Remove by filter after catalyzer separation, directly obtain the additive salt of S 16257-2 and sour HX, when obtaining the S 16257-2 of free alkali, optionally make the effect of this compound experience alkali.
The method makes to be started with the yield of one step, excellence and the additive salt of the S 16257-2 that purity directly obtains by the salt of formula (IV) compound, and spy is standby is that its hydrochloride becomes possibility.
In the catalyzer of formula (II) hydrogenation of compounds reaction, can be palladium, platinum, nickel, rhodium and their compound, special for being form or the oxide form of load, be preferably palladium charcoal.
The pressure of formula (II) hydrogenation of compounds reaction is 1-10atm, preferably normal pressure.
The temperature of formula (II) hydrogenation of compounds reaction is 20-60 ℃, preferably 30-40 ℃.
Preferably in alcoholic solvent, carry out in the reaction of formula (II) hydrogenation of compounds, this alcoholic solvent comprises methyl alcohol, ethanol and Virahol etc., more preferably methyl alcohol.
More advantageously not separation and purification formula (III) compound, is directly used in crude product and formula (IV) compound.
Basic catalyst for formula (III) compound and the reaction of formula (IV) compound is inorganic weak bases, preferably Anhydrous potassium carbonate and anhydrous sodium carbonate, more preferably Anhydrous potassium carbonate.
Being needs to add iodination reagent priming reaction, the preferred potassiumiodide of this iodination reagent in formula (III) compound and the reaction of formula (IV) compound.
The solvent that can be used for formula (III) compound and the reaction of formula (IV) compound is nonacid solvent, can be alcoholic solvent, ketones solvent, is preferably acetone.
In the method according to the invention, preferably use the special case of formula (II) compound and formula (III) compound, Y wherein represents halogen, hydroxyl and the hydroxyl to the protection of toluene benzenesulfonyl.
The special case of formula (II) compound and formula (III) compound, Y wherein represents halogen, hydroxyl and the hydroxyl to the protection of toluene benzenesulfonyl.Be new compound, they in chemistry or pharmaceutical industry, particularly S 16257-2 and with the additive salt of pharmaceutically acceptable acid synthetic in, can be used as intermediate, they have formed integral part of the present invention thus.
Use formula (IV) compound according to the preferred method of the present invention, HX wherein represents the special case of formula (IV) compound of hydrochloride, thereby the hydrochloride of production (I) S 16257-2, this salt is recrystallization in the mixed solvent of methyl alcohol and methylene dichloride, can be used as the activeconstituents of pharmaceutical preparation, as the purposes in the medicine of bradycardic.
Figure of description
Fig. 1: 3-(3-hydroxypropyl)-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-2 (3H)-one, nuclear-magnetism figure,
Fig. 2: the hydrochloride of S 16257-2, nuclear-magnetism figure.
Embodiment
Embodiment 1:3-(3-hydroxypropyl)-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-2 (3H)-one 2.3g3-(3-hydroxypropyl)-7,8-dimethoxy-1H-benzazepine-2 (3H)-one and 1.8g 10%Pd/C join in 20mL methyl alcohol, then in system, slowly pass into H
2, make the interior bubbling of system even.Heating systems makes it at 40 ℃, react 24h.Suction filtration reclaims Pd/C, and filtrate revolving steamed to obtain white solid 1.97g, yield: 85%, and 102.5 ℃ of fusing points.1H-NMR(CDCl
3，400MHz)，δ1.72-1.75(t，2H)，3.05-3.08(t，2H)，3.48-3.51(t，2H)，3.58-3.61(t，2H)，3.71-3.74(q，2H)，3.84-3.85(d，8H)，6.57-6.60(d，2H)。Nuclear-magnetism figure is shown in accompanying drawing 1
Embodiment 2: the hydrochloride preparation of S 16257-2
0.4g 3-(3-hydroxypropyl)-7,8-dimethoxy-4 ', 5-dihydro-1H-benzazepine-2 (3H)-one and 0.3g (S)-(4,5-dimethoxy-1,2-dihydrobenzo cyclobutyl-1-yl)-N-methyl methylamine joins in 10mL in acetone, and then adds 0.2g KI and 0.5g K
2cO
3, start to stir and be heated to and reflux.Stopped reaction after reaction 24h.Suction filtration, filtrate is spin-dried for to obtain sticky solid, and solid is dispersed in water, and suction filtration obtains filter cake, and filtrate discards.Then with dissolving in ethyl acetate, the HCl solution washing of 3N, is then in harmonious proportion to pH to 7-8 with sodium hydroxide solution, anhydrous magnesium sulfate drying, and vacuum rotary steam obtains oily matter.Oily matter is dispersed in and in ethyl acetate, becomes mono-hydrochloric salts, obtain 0.5g white crystalline powder, yield 75%, 196.3 ℃ of fusing points with methyl alcohol and acetone recrystallization.
1h-NMR (D
2o, 500MHz), δ 2.15 (s, 2H), 2.66-2.70 (d, 2H), 2.91 (s, 3H), 3.00-3.03 (t, 2H), 3.12-3.14 (t, 2H), 3.16-3.18 (t, 1H), 3.23-3.29 (t, 1H), 3.41-3.44 (t, 1H), 3.56-3.60 (t, 1H), 3.62-3.66 (d, 6H), 3.68-3.75 (m, 3H), 3.81-3.84 (d, 6H), 3.86-3.90 (q, 2H), 3.93-3.96 (t, 1H), 6.64-6.80 (q, 4H), nuclear-magnetism figure is shown in accompanying drawing 2.
Claims (2)
1. the preparation method of a S 16257-2 pharmaceutically acceptable acid additive salt, it is characterized in that formula (II) compound obtains formula (III) compound through catalytic hydrogenation, under base catalysis, react with formula (IV) compound, remove by filter after catalyzer separation, obtain the additive salt of S 16257-2 and sour HX
Wherein Y representation hydroxy, HX represents pharmaceutically acceptable acid; The pressure of described hydrogenation is normal pressure, and temperature is 30-40 ℃, and not separation and purification formula (III) compound; In formula (III) compound and the reaction of formula (IV) compound, take acetone as solvent, adding potassiumiodide is iodination reagent, and adding Anhydrous potassium carbonate is basic catalyst; HX in formula (IV) compound represents hydrochloride.
2. according to the preparation method of claim 1, wherein obtain hydrochloride recrystallization in the mixed solvent of acetone and methyl alcohol of S 16257-2.
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| CN200810246546.XA CN101768116B (en) | 2008-12-29 | 2008-12-29 | Preparation method for Ivabradine |
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| CN200810246546.XA CN101768116B (en) | 2008-12-29 | 2008-12-29 | Preparation method for Ivabradine |
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| CN102827080B (en) * | 2012-09-12 | 2014-03-19 | 江苏宇田生物医药科技有限公司 | Novel synthetic method of ivabradine and novel intermediate product of ivabradine |
| CN104447554B (en) * | 2013-09-22 | 2017-02-15 | 广东众生药业股份有限公司 | Preparation method for ivabradine and hydrochloride thereof |
Citations (3)
| 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 |
| CN101284813A (en) * | 2007-04-12 | 2008-10-15 | 上海优拓医药科技有限公司 | Preparation method of ivabradine |
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- 2008-12-29 CN CN200810246546.XA patent/CN101768116B/en not_active Expired - Fee Related
Patent Citations (3)
| 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 |
| CN101284813A (en) * | 2007-04-12 | 2008-10-15 | 上海优拓医药科技有限公司 | Preparation method of ivabradine |
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