CN103848789B - A kind of preparation method of Ivabradine - Google Patents
A kind of preparation method of Ivabradine Download PDFInfo
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- CN103848789B CN103848789B CN201210499744.3A CN201210499744A CN103848789B CN 103848789 B CN103848789 B CN 103848789B CN 201210499744 A CN201210499744 A CN 201210499744A CN 103848789 B CN103848789 B CN 103848789B
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- ivabradine
- resolving agent
- aqueous solution
- salify
- resolving
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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
Abstract
The present invention relates to a kind of preparation method of Ivabradine,, by split the DL body (II) of Ivabradine with resolving agent, obtain the Ivabradine (I) of required object S configuration. The method utilize chirality tartaric acid through the two acidylates of benzoyl or substituted benzoyl as resolving agent and described DL body the salify crystallization splitting step in alcohols solvent or the alcohols solvent aqueous solution; obtain Ivabradine (I) with higher yields, resolved product optical purity reaches more than 99%. This method for splitting can perform well in the preparation of chiral drug Ivabradine and the control of optical purity thereof.
Description
Technical field
The present invention relates to obtain by fractionation the Ivabradine (I) of single optical configuration S configurationMethod. The method according to this invention preparation and the Ivabradine (I) that obtains, can with pharmaceuticallyOfficinal salt is synthesized in acceptable sour addition.
Background technology
Ivabradine (Ivabradine), structural formula as shown in the formula (I), chemical name3-[3-[[[(7S)-3,4-dimethoxy two encircles [4.2.0] pungent-1,3,5-triolefin-7-yl] methyl] methylamino] thirdBase]-1,3,4,5-tetrahydrochysene-7,8-dimethoxy-2H-3-benzo-aza-2-ketone and with pharmaceutically canSour addition salts, the especially hydrochloride accepted, have and be worth high pharmacological properties and treatmentEffect, the especially performance to heart rate decrease, makes these compounds can be used for treatment or preventionThe various clinical symptoms of myocardial ischaemia, as angina pectoris, miocardial infarction and the rhythm and pace of moving things that occurs together disorderlyDisorderly, and can be used for the treatment of or prevent variously to relate to RD particularly the supraventricular rhythm and pace of moving things is disorderlyRandom symptom.
The hydrochloride of Ivabradine, the earliest by Shi Weiya company (Servier) research and development, its ShenHydrochloric acid Ivabradine please obtains European medical evaluation office (EMEA) on November 3rd, 200527 in Europe country's listings of approval, ProductName Procoralan, formulation is Film coated tablets, agentGauge lattice: 5mg/ sheet and 7.5mg/ sheet, for there is taboo maybe can not tolerate to BextraThe symptomatic treatment of chronic stable angina pectoris of regular sinus rhythm, it suppresses by selectiveBe responsible for controlling sinoatrial node spontaneous depolarization and regulate the If passage of heart rate to play a role, ProcoralanSelectively acting, in sinoatrial node, does not affect intracardiac conduction, myocardial contraction or ventricular bipolarization.Different from anginal common medicine beta-blocker, Procoralan do not cause sex dysfunction, because of gasRoad shrinks and spasm causes respiratory system bad reaction and bradycardia or rebound phenomenon. OrderFront people generally believe, reducing heart rate is the anginal important channel of control, as firstThe hydrochloric acid Ivabradine of pure reducing heart rate, Procoralan is cardiovascular disease in 20 years in the pastIn medicine treatment, one of make progress the most significantly, opened up a prospect for treating at present angina pectorisBright new way. The angina pectoris treatment guide of ESC (ESC) has been recommended to stablizeProperty patient with angina pectoris use this product.
The patent that report is prepared about this compound the earliest has EP05348059, and its Patents isUS5296482, this patent has been described the synthetic route of detailed Ivabradine, wherein several belowWalk important reaction as follows:
Can find out the depending on of optical purity of end-product Ivabradine (I) from this synthetic routeThe optical purity of compound (IV), so as the important intermediate of synthesis of ivabradine (I),Compound (IV) becomes many companies, school or scientific research institutions and competitively studies synthetic object, sideFado relates to the fractionation research of mutual-through type raceme compound (VII):
Wherein R is-CH2NHCH3,-CN ,-COOH or-CH2NH2Deng.
Directly or again carry out subsequent reactions by splitting general formula raceme compound (VII), changedCompound (IV), because its optical purity directly has influence on the light of end-product Ivabradine (I)Learn purity, therefore its fractionation effect is most important.
Find by studying multinomial fractionation patent, fractionation general formula raceme compound (VII) obtainsCompound (IV), for the synthesis of Ivabradine (I), can ensure to obtain high light substantiallyThe target product of purity, but some of them patented method, or only for laboratory operation, after amplificationExtremely sad filter, has influence on actual fractionation effect, is unfavorable for industrialization; Or resolved product opticsPurity is not high, causes final synthetic Ivabradine (I) optical purity not high; Or fractionation is producedThing optical purity is very high, but yield is very low.
If the fractionation of raceme compound (VII) is failed enantiomter to be controlled at requirementWithin critical field, this enantiomerism cognition is taken in end-product so, affects the light of end-productLearn purity, according to prior art, not yet find that effective means can be by different in Ivabradine (I)Structure body impurity is removed, and certainly will cause like this waste of material.
Given this, research by resolving racemic (II) thus method obtain height with high yieldThe Ivabradine (I) of optical purity and effectively to control its optical purity be very necessary.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the invention provides a kind of passing through raceme(II) splits, and obtains the preparation method of chiral drug Ivabradine (I).
The inventor finds after research extensively and profoundly, and conventional acid resolving agent, for racemizationThe fractionation of body (II) is invalid substantially: have can not and raceme (II) various moltenIn agent, effectively generate precipitation and separate, as N-acetyl-Pidolidone, N-acetyl-D-Glu etc.;Although the energy and the raceme (II) that have generate precipitation in specific solvent, not selective,Precipitation is still raceme, as L-(-)-tartaric acid, D-(-)-tartaric acid etc.
The inventor is surprised to find that after research extensively and profoundly, in tested multiple common acidProperty resolving agent in, only have through the chirality tartaric acid of the two acidylates of benzoyl or substituted benzoyl asDibenzoyl-L-tartaric acid (L-DBTA), dibenzoyl-D-tartaric acid (D-DBTA), twoTo toluyl-L-TARTARIC ACID (L-DTTA) or two pairs of toluyl-D-tartaric acid (D-DTTA),Raceme (II) effectively can be split.
Specifically, preparation method of the present invention comprises that use resolving agent becomes with raceme (II)Salt crystallization, splits and obtains the salt that Ivabradine becomes with resolving agent, then the free formula (I) that obtainsShown in the step of Ivabradine, described resolving agent is the two acyls of benzoyl or substituted benzoylThe chirality tartaric acid of changing, as dibenzoyl-L-tartaric acid (L-DBTA), dibenzoyl-D-winestoneAcid (D-DBTA), two pairs of toluyl-L-TARTARIC ACIDs (L-DTTA) or two couples of toluyl-D-Tartaric acid (D-DTTA); Preferably dibenzoyl-L-tartaric acid (L-DBTA) or two pairs of tolueneFormyl-L-TARTARIC ACID (L-DTTA).
Salify crystallization of the present invention, split process are carried out in conventional solvent, preferably organicIn solvent, carry out, described organic solvent is alcohols solvent or its aqueous solution more preferably, furtherSay, described solvent comprises that single alcohol kind solvent or its aqueous solution and two kinds or above alcohols mix moltenAgent or its aqueous solution, preferred alcohols kind solvent refers to that carbon number is no more than 3 lower aliphatic alcohols, choosingFrom methyl alcohol, ethanol, propyl alcohol or isopropyl alcohol. Described solvent is preferably ethanol or its aqueous solution, secondAlcohol ratio preferably 50 ~ 100%, more preferably absolute ethyl alcohol.
About solvent load, need be from the viewpoint of the optical purity of resolved product and yield two, thisThe fractionation salify that invention is described and the volume of re-crystallization step solvent for use be raceme (II) orThe 10-60 that gained splits salt throwing amount doubly measures (g/mL), and preferably 10-20 doubly measures (g/mL).
About the consumption of resolving agent, theoretically, by the correspondence of soda acid base salt-forming reaction, racemizationThe mol ratio of body (II) and resolving agent should be 2:1; If only consider to obtain corresponding target structureType, can get mol ratio is 4:1; If mole salify such as consideration obtains acid salt, also can getMol ratio is 1:1; Generally speaking, higher resolving agent ratio is conducive to obtain with comparatively ideal yieldTo the resolved product of high-optical-purity, the mol ratio of raceme and resolving agent, suitable scope is passableBe 4:1 to 1:2, preferred ratio is at 2:1 to 1:1, and excessive resolving agent does not have splitting effectLarger help.
In free the present invention, split the process of salt (being the salt that Ivabradine becomes with resolving agent)Be conventional, can dissociate with alkali, it is water-soluble that alkali used is preferably alkali-metal hydroxideLiquid, preferably sodium hydrate aqueous solution; Extract solvent used, generally select routine to be used as extractionHydrophobic organic solvent, as ethyl acetate, carrene and chloroform etc., ethyl acetate andCarrene, more preferably carrene.
In order to improve the optical purity of the Ivabradine (I) that fractionation obtains, to splitting gainedTo the step that is recrystallized of fractionation salt (being the salt that Ivabradine becomes with resolving agent) haveTime be necessary. The process that splits salify in the present invention generally can be carried out at normal temperatures, necessityIn time, also can carry out under the condition of heating, and can be at the bar of heating as the step 1 of recrystallizationUnder part, carry out, first heating makes to split salt and dissolves in described solvent, then slow at ambient temperatureSlowly complete the process of recrystallization. Indication Crystallization Process herein all carries out under lasting stirring.In general, through the product of secondary recrystallization, optical purity is gratifying often, itsEe value is generally more than 99%.
Medicinal for being applicable to, the present invention also provides a kind of preparation side of Ivabradine officinal saltMethod, it comprises the step that obtains Ivabradine after above-mentioned resolving racemic (II), also comprisesThe step of Ivabradine and pharmaceutically acceptable sour salify, the step of described salify adoptsMethod is conventional, for the insider who was subject to professional training, accomplishes that this point comparativelyEasily.
In a preferred embodiment of the present invention, Ivabradine of the present inventionPreparation method comprises the following steps:
(1) make raw material with the raceme (II) of Ivabradine, with described resolving agent describedSalify crystallization in alcohols solvent or its aqueous solution, filters the crude product that obtains splitting salt;
(2) by (1) step gained crude product with (1) same solvent in the one or many that is recrystallized,Obtain the fractionation salt of different optical purity, dry;
(3) after (2) step gained solid is free with described alkali, obtain Ivabradine (I),Optional by described Ivabradine and pharmaceutically acceptable sour salify.
The method according to this invention, can obtain optical purity with the yield up to 80% left and right and be not less than99% Ivabradine (I), thus provide one to prepare the method for Ivabradine (I)Effective means with one raising and control Ivabradine (I) optical purity, has solved existingThe difficult problem that technology cannot be removed for isomer impurities in Ivabradine, thus can effectively reduceLoss, application prospect is very wide.
Detailed description of the invention
Explain in further detail the present invention below with reference to embodiment, embodiments of the invention are only usedIn explanation technical scheme of the present invention, and non-limiting essence of the present invention.
Embodiment 1
In reactor, add raceme (II) 2.6g(5.6mmol of Ivabradine) and nothingWater-ethanol 26.0ml(10 doubly measures), heating adds L-DTTA1.1g after oil is all dissolved(2.8mmol), dissolve, stirring at room temperature crystallization, suction filtration, is dried to obtain white solid 0.8g, HPLC:S is configured as 94.0%, total recovery: 33.7%(calculates with the initial middle S configuration amount that feeds intake).
Embodiment 2
In reactor, add raceme (II) 4.0g(8.5mmol), and absolute ethyl alcohol 40.0ml(10 times of amounts), heating adds L-DTTA3.3g(8.5mmol after oil is all dissolved), moltenSeparate, stirring at room temperature crystallization, suction filtration, is dried to obtain white solid 3.7g, and HPLC:S is configured as 75.5%.
Above-mentioned solid 3.5g and absolute ethyl alcohol 45.5ml(13 are doubly measured) put in reactor,Be heated to reflux molten clear, let cool stirring and crystallizing, suction filtration, is dried to obtain white solid 2.8g, HPLC:S is configured as 96.2%.
Above-mentioned solid 2.7g and absolute ethyl alcohol 32.4ml(12 are doubly measured) put in reactor,Be heated to reflux molten clear, let cool stirring and crystallizing, suction filtration, is dried to obtain white solid 2.4g, HPLC:S is configured as 99.2%, three step yield: 72.1%(and calculates with the initial middle S configuration amount that feeds intake).
By the mother liquid obtained merging of salify and purification step in above-mentioned split process, be concentrated into volumeHour, letting cool stirring and crystallizing, suction filtration, is dried to obtain white solid 1.1g, and HPLC:S is configured as89.7%, with after refining 2 times of 10 times of amount absolute ethyl alcohols, obtain white solid 0.4g, HPLC:S is configured as 99.4%, splits total recovery: 81.3%(and calculates with the initial middle S configuration amount that feeds intake).
Embodiment 3
In reactor, add raceme (II) 4.0g(8.5mmol) and absolute ethyl alcohol 80.0ml,(20 times of amounts), heating adds L-DTTA3.3g(8.5mmol after oil is all dissolved), moltenSeparate, stirring at room temperature crystallization, suction filtration, is dried to obtain white solid 3.6g, and HPLC:S is configured as 82.0%.
Above-mentioned solid 3.5g and absolute ethyl alcohol 140.0ml(40 are doubly measured) put in reactor,Be heated to reflux molten clear, let cool stirring and crystallizing, suction filtration, is dried to obtain white solid 2.4g, HPLC:S is configured as 97.3%.
Above-mentioned solid 2.3g and absolute ethyl alcohol 30.0ml(13 are doubly measured) put in reactor,Be heated to reflux molten clear, let cool stirring and crystallizing, suction filtration, is dried to obtain white solid 2.2g, HPLC:S is configured as 99.7%, three step yield: 64.7%(and calculates with the initial middle S configuration amount that feeds intake).
By the mother liquid obtained merging of salify and purification step in above-mentioned split process, be concentrated into volumeHour, letting cool stirring and crystallizing, suction filtration, is dried to obtain white solid 1.3g, and HPLC:S is configured as88.6%, with after refining 2 times of 15 times of amount absolute ethyl alcohols, obtain white solid 0.5g, HPLC:S is configured as 99.5%, splits total recovery: 78.4%(and calculates with the initial middle S configuration amount that feeds intake).
Embodiment 4
In reactor, add raceme (II) 3.8g(8.1mmol) and absolute ethyl alcohol 95.0ml(25 times of amounts), heating adds L-DTTA3.2g(8.3mmol after oil is all dissolved), moltenSeparate, stirring at room temperature crystallization, suction filtration, is dried to obtain white solid 2.9g, and HPLC:S is configured as 88.1%.
Above-mentioned solid 2.9g and absolute ethyl alcohol 38.0ml(13 are doubly measured) put in reactor,Be heated to reflux molten clear, let cool stirring and crystallizing, suction filtration, is dried to obtain white solid 2.5g, HPLC:S is configured as 97.4%.
Above-mentioned solid 2.5g and absolute ethyl alcohol 42.5ml(17 are doubly measured) put in reactor,Be heated to reflux molten clear, let cool stirring and crystallizing, suction filtration, is dried to obtain white solid 2.4g, HPLC:S is configured as 99.8%, three step yield: 69.2%(and calculates with the initial middle S configuration amount that feeds intake).
By the mother liquid obtained merging of salify and purification step in above-mentioned split process, be concentrated into volumeHour, letting cool stirring and crystallizing, suction filtration, is dried to obtain white solid 1.0g, and HPLC:S is configured as90.3%, with after refining 2 times of 13 times of amount absolute ethyl alcohols, obtain white solid 0.4g, HPLC:S is configured as 99.4%, splits total recovery: 80.8%(and calculates with the initial middle S configuration amount that feeds intake).
Embodiment 5
In reactor, add Ivabradine 1.84kg(3.9mol, HPLC:S is configured as99.5%) and absolute ethyl alcohol 36.0L(20 doubly measure) solution, then add L-DTTA1.6kg(4.1mol), stirring and dissolving, stirring at room temperature crystallization, rejection filter, with absolute ethyl alcohol 10.0L washing,Dry to obtain the about 5.0kg of wet product, directly refining.
Above-mentioned wet product and absolute ethyl alcohol (50.0L) are put in reactor, be heated to reflux moltenClearly, 10 DEG C of left and right stirring and crystallizing, rejection filter, with absolute ethyl alcohol 5.0L washing, dry wet product approximately4.4kg, directly re-refines.
Above-mentioned wet product and absolute ethyl alcohol (50.0L) are put in reactor, be heated to reflux moltenClearly, 10 DEG C of left and right stirring and crystallizing, rejection filter, with absolute ethyl alcohol 3.0L washing, white admittedly dryBody 2.95kg.
By after free with NaOH above-mentioned solid, dichloromethane extraction faint yellow grease1.71kg, HPLC:S is configured as 99.98%, total recovery: 92.9%.
Embodiment 6
In reactor, add raceme (II) 3.5g(7.5mmol) and absolute methanol 70.0ml(20 times of amounts), heating adds L-DTTA2.9g(7.5mmol after oil is all dissolved), moltenSeparate, stirring at room temperature crystallization, suction filtration, is dried to obtain white solid 2.5g, and HPLC:S is configured as 85.4%.
Above-mentioned solid 2.5g and absolute methanol 37.5ml(15 are doubly measured) put in reactor,Be heated to reflux molten clear, let cool stirring and crystallizing, suction filtration, is dried to obtain white solid 2.2g, HPLC:S is configured as 98.6%.
Above-mentioned solid 2.2g and absolute methanol 33.0ml(15 are doubly measured) put in reactor,Be heated to reflux molten clear, let cool stirring and crystallizing, suction filtration, is dried to obtain white solid 2.0g, HPLC:S is configured as 99.9%, three step yield: 62.6%(and calculates with the initial middle S configuration amount that feeds intake).
By the mother liquid obtained merging of salify and re-crystallization step in above-mentioned split process, be concentrated into volumeHour, let cool stirring and crystallizing, suction filtration, dry white solid 0.8g, the HPLC:S configuration of obtainingBe 87.5%, with after 15 times of amount absolute methanol recrystallizations 2 times, obtain white solid 0.4g, HPLC:S is configured as 99.5%, splits total recovery: 75.2%(and calculates with the initial middle S configuration amount that feeds intake).
Claims (12)
1. suc as formula the preparation method of the chiral drug Ivabradine shown in (I),
Described method comprises use resolving agent and DL body (II) salify crystallization, splits and obtains herCut down the fixed salt becoming with resolving agent of mine-laying, then dissociate and obtain Ivabradine shown in formula (I)Step,
Described resolving agent is two pairs of toluyl-L-TARTARIC ACIDs.
2. method according to claim 1, the mol ratio of DL body (II) and resolving agentFor 4:1 to 1:2.
3. method according to claim 2, the mol ratio of DL body (II) and resolving agentFor be 2:1 to 1:1.
4. the method for claim 1, is characterized in that the step of described salify crystallization existsIn the aqueous solution of alcohols solvent or alcohols solvent, carry out.
5. method as claimed in claim 4, is characterized in that described alcohols solvent is carbon atomNumber is no more than 3 lower aliphatic alcohols, is selected from methyl alcohol, ethanol, propyl alcohol or isopropyl alcohol.
6. method as claimed in claim 4, is characterized in that the step of described salify crystallization existsIn the aqueous solution of ethanol or ethanol, carry out.
7. method as claimed in claim 5, is characterized in that the step of described salify crystallization existsIn absolute ethyl alcohol, carry out.
8. the method for claim 1, is characterized in that described free step enters in alkaliOK, described alkali is alkali-metal hydroxide aqueous solution.
9. method according to claim 8, is characterized in that described alkali is NaOHThe aqueous solution.
10. the method for claim 1, characterized by further comprising described IvabradineBe recrystallized the again step of one or many of the salt becoming with resolving agent.
The preparation method of 11. 1 kinds of Ivabradine officinal salts, is characterized in that comprising rightPreparation method described in requirement 1 and the step of Ivabradine and pharmaceutically acceptable sour salify.
12. methods according to claim 11, is characterized in that pharmaceutically acceptable acidFor hydrochloric acid.
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