CN102558216B - The preparation method of prasugrel - Google Patents
The preparation method of prasugrel Download PDFInfo
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Abstract
The compound that provides following general formula I I to represent, wherein, R1, R2, R3 can be identical or different, represents separately the one in following atom or group: hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl. Utilize above-mentioned intermediate to be prepared prasugrel, can simplify the operation, mild reaction conditions, stable reaction, yield be higher. Especially advantageously, utilize this intermediate to carry out prasugrel preparation, can adopt the operating procedure of " a pot of porridge ", the operation of simplifying greatly.
Description
Technical field
The present invention relates to the preparation method that a kind of prasugrel is new.
Background technology
The formula I compound (hydrochloric acid prasugrel) showing is below a kind of novel platelet suppressant drug, be byLilly and the three oral antiplatelet drugs of releasing altogether, at present in the U.S. and European Union's listing. Hydrochloric acid pulaGray is the one hemostasis new drug of Thienopyridines, is a kind of pro-drug, shape after metabolism in vivoBecome bioactive molecule, bring into play the activity of platelet aggregation-against with blood platelet P2Y12 receptors bind.
Prasugrel is the one hemostasis new drug of Thienopyridines, is a kind of pro-drug, passes through in vivoAfter metabolism, form bioactive molecule, bring into play the activity of platelet aggregation-against with blood platelet P2Y12 receptors bind.TRITON-TIMI38 clinical testing demonstration, prasugrel has than the better anticoagulant effect of clopidogrel,Can make heart of patient onste, apoplexy, because the integrated risk of deaths from heart disease reduces by 20%, and instant effect,Good effect, has good drug resistance and bioavilability, and the larger guarantor to anti-stroke and mortality risk can be providedProtect effect, but cause patient's bleeding more.
Clinical efficacy aspect, TRITON-TIMI38 clinical testing shows, relatively prasugrel and chlorine pyrrole latticeThunder is applied to the efficacy and saferry of acute coronary syndrome, prasugrel group validity terminal event(cardiac death, non-lethality myocardial infarction, palsy etc.) incidence is all lower than clopidogrel group.
Ternberg philosophy is by prasugrel, clopidogrel and aspirin use in conjunction treatment artery congee sampleSclerosis, result shows, compares pula lattice with clopidogrel (300mg loading dose and 75mg maintenance dose)Thunder (60mg loading dose and 10mg maintenance dose) demonstrates the effect of better inhibition platelet aggregation. SeparatelyOutward, prasugrel individual difference is less, and in pharmacodynamics, non-response rate is lower.
BMO capital market the analyst of company represent, prasugrel also exists bright spot, i.e. a diabeticUse this medicine can't meet with hemorrhage danger, concerning accepting the diabetic of support operation, pulaGray can be successfully used as a kind of special-purpose medicaments and be used.
In Chinese patent 92111584, a kind of synthetic method of prasugrel is disclosed, its synthetic routeAs follows:
This route use compound 2 (2-oxygen-2,4,5,6,7,7 α-six hydrogen thieno [3,2-c] pyridines) andCompound 3 (alpha-brominated adjacent luorobenzyl cyclopropyl ketone) reacts and obtains compound 4 (5-(α under alkali condition-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5,6,7,7 α-six hydrogen thieno [3,2-c] pyridines),Then acidylate obtains prasugrel (2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2,4,5,6,7-thiophane is [3,2-c] pyridine also).
But said method, in the process of synthetic compound 3, exists reaction time length, post processing to need postChromatography, be not suitable for the defects such as suitability for industrialized production.
At document " Chinese Journal of Pharmaceuticals " 2009,40 (4), 244-246, author reports that one is closedBecome route as follows:
4,5,6,7-thiophane also [3,2-c] pyridine hydrochloride (5) through protection after, with n-BuLi, boronAcid tributyl reacts and is oxidized to obtain 2-oxo-N-trityl-2,4,5,6,7,7 α-six hydrogen thienos[3,2-C] pyridine (7), then deprotection obtains 2-oxo-2,4,5,6,7,7 α-six hydrogen thienos [3,2-C]Pyridine hydrochloride (8); Taking adjacent fluorine bromobenzyl as raw material, in diethyl ether solution, make ring third through grignard reaction againBase-2-luorobenzyl ketone (9), obtains α-cyclopropyl carbonyl-2-fluorobenzyl bromide (10) by NBS bromination 7,Under acid binding agent exists, in acetonitrile, with compound 8, generate 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5,6,7,7 α-six hydrogen thieno [3,2-C] pyridines, then obtain prasugrel (1) through acetic anhydride acetylation.
But this route need to use low temperature, and need to use butyl lithium, butyl borate, reaction barPart harshness; Compound 10 is a liquid, and unstable, is difficult to obtain the product that purity is higher, causesIn the time of synthetic compound 11, need column chromatography to carry out purifying, be difficult to carry out suitability for industrialized production.
Now provide that one is more easy and simple to handle, cost is lower, be suitable for the synthetic route of suitability for industrialized production.
Summary of the invention
One of object of the present invention is just to provide a kind of new technology of preparing prasugrel, to make this route energyThe above-mentioned defect that enough overcomes prior art, make it to be suitable for industrialized production, and yield has than existing methodsInstitute improves.
Another object of the present invention is to provide a kind of new intermediate for the preparation of prasugrel extremelyPreparation method.
The inventor, through research, has found the suitable prasugrel intermediate of a class, utilizes this intermediate to enterRow is prepared prasugrel, can simplify the operation, mild reaction conditions, stable reaction, yield be higher. EspeciallyAdvantageously, utilize this intermediate to carry out prasugrel preparation, can adopt the operating procedure of " a pot of porridge ",The operation of simplifying greatly.
The compound that one aspect of the present invention provides following general formula I I to represent:
Wherein, R1, R2, R3 can be identical or different, represents separately the one in following atom or group:Hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
In a preferred embodiment of the present invention, R1, R2, R3 can be identical or different, represents separately C1-C10Alkyl, preferably C1-C8 alkyl, more preferably C1-C6 alkyl, is preferably C1-C4 alkyl.
The present invention provides a kind of method of preparing above-mentioned general formula I I compound, described method bag on the other handDraw together following steps: make also [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl of 4,5,6,7-thiophaneCompound reaction, wherein R1, R2, R3 can be identical or different, represents separately following atom or baseOne in group: hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
In a preferred embodiment of the present invention, the compound of general formula R 1R2R3SiCl is selected from tri-tertSilicon chloride and trimethyl silicon chloride.
In a preferred embodiment of the present invention, under the condition existing at base catalyst, make 4,5,6,7-tetrahydrochyseneThieno [3,2-C] pyridine hydrochloric acid reacts with the compound of general formula R 1R2R3SiCl; Preferably, described inBase catalyst comprises organic alkali catalyst for example triethylamine, methylamine and tert-butylamine and inorganic base catalystFor example potash and sodium carbonate.
The present invention provides a kind of method of preparing prasugrel on the other hand, and described method comprises following stepRapid:
(1) make general formula I I compound and alpha-brominated adjacent luorobenzyl cyclopropyl reactive ketone
Wherein, R1, R2, R3 can be identical or different, represents separately the one in following atom or group:Hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl;
(2) product and the acetic anhydride that step (1) are obtained, obtain prasugrel.
In a preferred embodiment of the present invention, under the condition existing at base catalyst, carry out above-mentioned steps (1);Preferably, described base catalyst comprise organic alkali catalyst for example triethylamine, methylamine and tert-butylamine andFor example potash of inorganic base catalyst and sodium carbonate.
In a preferred embodiment of the present invention, under the condition existing at phase transfer catalyst, carry out above-mentioned stepSuddenly (1); Preferably, described phase transfer catalyst is selected from TBAB, benzyl triethyl ammonium chlorineChange ammonium (TEBA),, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), trioctylphosphine methylAmmonium chloride, DTAC and tetradecyl trimethyl ammonium chloride.
In a preferred embodiment of the present invention, under the condition existing at base catalyst, carry out above-mentioned steps (2);Preferably, described base catalyst comprise organic alkali catalyst for example triethylamine, methylamine and tert-butylamine andFor example potash of inorganic base catalyst and sodium carbonate; And/or, the condition existing at acyl group catalystUnder carry out above-mentioned steps (2); Preferably, described acyl group catalyst is selected from 4-dimethylamino pyridine(DMAP), N-methylimidazole.
A further aspect of the present invention provides general formula I I compound in the purposes of preparing in prasugrel,
Wherein, R1, R2, R3 can be identical or different, represents separately the one in following atom or group:Hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
Detailed description of the invention
In the present invention, if not special explanation, percentage (%) or part all refer to respect to combinationThe percetage by weight of thing or weight portion.
In the present invention, if not special explanation, related each component or its preferred ingredient can phasesBe combined to form mutually new technical scheme.
In the present invention, if not special explanation, all embodiment mentioned in this article and preferredEmbodiment can be combined to form new technical scheme mutually.
In the present invention, if not special explanation, all technical characterictic mentioned in this article and preferredFeature can be combined to form new technical scheme mutually.
In the present invention, if there is no contrary explanation, in composition, the content sum of each component is 100%.
In the present invention, if there is no contrary explanation, in composition, the umber sum of each component can be 100Weight portion.
In the present invention, unless there are other explanations, number range " a-b " represents that a is to the arbitrary real between bThe breviary that array is closed represents, wherein a and b are real numbers. For example number range " 0-5 " has represented hereinThrough all having listed the whole real numbers between " 0-5 ", " 0-5 " just the breviary of these combinations of values represents.
In the present invention, unless there are other explanations, integer number range " a-b " represents that a is to appointing between bMeaning integer combinations breviary represent, wherein a and b are integers. For example integer number range " 1-N " tableShow 1,2 ... N, wherein N is integer.
In the present invention, unless there are other explanations, " its combination " represents that the multicomponent of described each element mixesThing, for example two kinds, three kinds, four kinds and until the multicomponent mixture of maximum possible.
If do not particularly not pointed out, this description term " one " used refers to " at least one ".
If do not particularly not pointed out, the benchmark of percentage of the present invention (comprising percetage by weight) is allThe gross weight of described composition.
" scope " disclosed herein is with the form of lower limit and the upper limit. Can be respectively one or more lower limits,With one or more upper limits. Given range limits by a selected lower limit and a upper limit. ChoosingFixed lower limit and the upper limit define the border of special scope. All scopes that can limit are by this wayComprise with capable of being combined, any lower limit can be combined to form a scope with any upper limit. For example, forSpecial parameter has been listed the scope of 60-120 and 80-110, is interpreted as the model of 60-110 and 80-120Enclose also and expect. In addition, if the minimum zone value of listing 1 and 2, and if would list maximum modelEnclose value 3,4 and 5, scope below can all expect: 1-3,1-4,1-5,2-3,2-4,And 2-5.
In this article, except as otherwise noted, the ratio of each component or weight all refer to dry weight.
In this article, except as otherwise noted, " alkyl " represent C1-C10 straight or branched, replacement orUnsubstituted alkyl, better represents straight or branched, replacement or the unsubstituted alkyl of C1-C8, better tableShow C1-C6 straight or branched, replacement or unsubstituted alkyl, preferably represent C1-C4 straight or branched, getGeneration or unsubstituted alkyl.
In this article, except as otherwise noted, the replacement of expression C6-C20 such as " aryl " or " aromatic radical "Or unsubstituting aromatic yl, better represent that C6-C16 replaces or unsubstituted aryl, better represent that C6-C14 replacesOr unsubstituted aryl, preferably represent that C6-C10 replaces or unsubstituted aryl.
In this article, except as otherwise noted, " substituting group " represent C1-C10 alkyl, C1-C10 alkoxyl,Halogen and hydroxyl.
In this article, except as otherwise noted, " halogen ", " halogen " or " halo " represent fluorine, chlorine, bromineAnd iodine.
The compound that one aspect of the present invention provides following general formula I I to represent:
Wherein, R1, R2, R3 can be identical or different, represents separately the one in following atom or group:Hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
In a preferred embodiment of the present invention, R1, R2, R3 can be identical or different, represents separately C1-C10Alkyl, preferably C1-C8 alkyl, more preferably C1-C6 alkyl, is preferably C1-C4 alkyl.
The present invention provides a kind of method of preparing above-mentioned general formula I I compound, described method bag on the other handDraw together following steps: make also [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl of 4,5,6,7-thiophaneCompound reaction, wherein R1, R2, R3 can be identical or different, represents separately following atom or baseOne in group: hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
In a preferred embodiment of the present invention, R1, R2, R3 can be identical or different, represents separately C1-C10Alkyl, preferably C1-C8 alkyl, more preferably C1-C6 alkyl, is preferably C1-C4 alkyl.
In another preferred embodiment of the present invention, the compound of general formula R 1R2R3SiCl is selected from three tertiary fourthsBase silicon chloride and trimethyl silicon chloride.
In a preferred embodiment of the present invention, make also [3,2-C] pyridine hydrochloric acid of 4,5,6,7-thiophaneThe step of reacting with the compound of general formula R 1R2R3SiCl is preferably carried out in organic solvent. Described haveMachine solvent can be conventional, those of ordinary skill in the art according to description of the invention again in conjunction with existing skillWhich organic solvent is art can direct derivation go out and can be used for the present invention. In a preferred embodiment of the present invention,Described organic solvent is selected from (1) arene: as benzene,toluene,xylene etc.; (2) fat hydrocarbon: as pentaAlkane, hexane, octane etc.; (3) alicyclic hydrocarbon type: as cyclohexane, cyclohexanone, toluene cyclohexanone etc.; (4) halogenationHydro carbons: as chlorobenzene, dichloro-benzenes, carrene etc.; (5) alcohols: as methyl alcohol, ethanol, isopropyl alcohol etc.; (6)Ethers: as ether, expoxy propane etc.; (7) ester class: as methyl acetate, ethyl acetate, propyl acetate etc.;(8) ketone: as acetone, espeleton, methylisobutylketone etc.; (9) diol, derivatives: as glycol monoethyl ether,Ethylene glycol monoethyl ether, ethylene glycol monobutyl ether etc.; 10. other: as acetonitrile, pyridine, phenol etc. In the present inventionAnother preferred embodiment in, described organic solvent is selected from halogenated hydrocarbons for example carrene, chloroform, three chloromethanesAlkane and dichloroethanes and oxolane etc.
In the present invention, make also [3,2-C] pyridine hydrochloric acid and general formula of 4,5,6,7-thiophaneThe temperature of the step of the compound reaction of R1R2R3SiCl is conventional, those of ordinary skill in the art's rootCan direct derivation go out which temperature in conjunction with prior art again according to description of the invention and can be used for the present invention. At thisIn a preferred embodiment of invention, described temperature is 0-100 DEG C, preferably 10-50 DEG C, more preferably 15-30DEG C, be preferably room temperature (25 DEG C).
In the present invention, under the condition preferably existing at base catalyst, make 4,5,6,7-thiophane also[3,2-C] pyridine hydrochloric acid reacts with the compound of general formula R 1R2R3SiCl. Of the present invention one preferablyIn example, described base catalyst comprise organic alkali catalyst for example triethylamine, methylamine and tert-butylamine andFor example potash of inorganic base catalyst and sodium carbonate.
The present invention provides a kind of method of preparing prasugrel on the other hand, and described method comprises following stepRapid:
(1) make general formula I I compound and alpha-brominated adjacent luorobenzyl cyclopropyl reactive ketone
Wherein, R1, R2, R3 can be identical or different, represents separately the one in following atom or group:Hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl;
(2) product and the acetic anhydride that step (1) are obtained, obtain prasugrel.
In a preferred embodiment of the present invention, above-mentioned R1, R2, R3 can be identical or different, represents separatelyC1-C10 alkyl, preferably C1-C8 alkyl, more preferably C1-C6 alkyl, is preferably C1-C4 alkyl.
In a preferred embodiment of the present invention, described step (1) is preferably carried out in organic solvent.Described organic solvent can be conventional, and those of ordinary skill in the art is according to description of the invention combination againWhich organic solvent is prior art can direct derivation go out and can be used for the present invention. In a preferred reality of the present inventionIn example, described organic solvent is selected from (1) arene: as benzene,toluene,xylene etc.; (2) fat hydrocarbon:As pentane, hexane, octane etc.; (3) alicyclic hydrocarbon type: as cyclohexane, cyclohexanone, toluene cyclohexanone etc.; (4)Halogenated hydrocarbons: as chlorobenzene, dichloro-benzenes, carrene etc.; (5) alcohols: as methyl alcohol, ethanol, isopropyl alcohol etc.;(6) ethers: as ether, expoxy propane etc.; (7) ester class: as methyl acetate, ethyl acetate, propyl acetate etc.;(8) ketone: as acetone, espeleton, methylisobutylketone etc.; (9) diol, derivatives: as glycol monoethyl ether,Ethylene glycol monoethyl ether, ethylene glycol monobutyl ether etc.; 10. other: as acetonitrile, pyridine, phenol etc. In the present inventionAnother preferred embodiment in, described organic solvent is selected from halogenated hydrocarbons for example carrene, chloroform, three chloromethanesAlkane and dichloroethanes and oxolane etc.
In the present invention, the temperature of above-mentioned steps (1) is conventional, those of ordinary skill in the art's rootCan direct derivation go out which temperature in conjunction with prior art again according to description of the invention and can be used for the present invention. At thisIn a preferred embodiment of invention, described temperature is 0-100 DEG C, preferably 10-50 DEG C, more preferably 15-30DEG C, be preferably room temperature (25 DEG C).
In the present invention, under the condition preferably existing at base catalyst, carry out above-mentioned steps (1). At thisIn a bright preferred embodiment, described base catalyst comprises organic alkali catalyst for example triethylamine, methylamineWith tert-butylamine and for example potash of inorganic base catalyst and sodium carbonate.
In the present invention, under the condition preferably existing at phase transfer catalyst, carry out above-mentioned steps (1).In a preferred embodiment of the present invention, described phase transfer catalyst is selected from TBAB, benzylTriethyl ammonium chloride (TEBA),, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), threeOctyl group ammonio methacrylate, DTAC and tetradecyl trimethyl ammonium chloride.
In a preferred embodiment of the present invention, described step (2) is preferably carried out in organic solvent.Described organic solvent can be conventional, and those of ordinary skill in the art is according to description of the invention combination againWhich organic solvent is prior art can direct derivation go out and can be used for the present invention. In a preferred reality of the present inventionIn example, described organic solvent is selected from (1) arene: as benzene,toluene,xylene etc.; (2) fat hydrocarbon:As pentane, hexane, octane etc.; (3) alicyclic hydrocarbon type: as cyclohexane, cyclohexanone, toluene cyclohexanone etc.; (4)Halogenated hydrocarbons: as chlorobenzene, dichloro-benzenes, carrene etc.; (5) alcohols: as methyl alcohol, ethanol, isopropyl alcohol etc.;(6) ethers: as ether, expoxy propane etc.; (7) ester class: as methyl acetate, ethyl acetate, propyl acetate etc.;(8) ketone: as acetone, espeleton, methylisobutylketone etc.; (9) diol, derivatives: as glycol monoethyl ether,Ethylene glycol monoethyl ether, ethylene glycol monobutyl ether etc.; 10. other: as acetonitrile, pyridine, phenol etc. In the present inventionAnother preferred embodiment in, described organic solvent is selected from halogenated hydrocarbons for example carrene, chloroform, three chloromethanesAlkane and dichloroethanes and oxolane etc.
In the present invention, the temperature of above-mentioned steps (2) is conventional, those of ordinary skill in the art's rootCan direct derivation go out which temperature in conjunction with prior art again according to description of the invention and can be used for the present invention. At thisIn a preferred embodiment of invention, described temperature is 0-100 DEG C, preferably 10-50 DEG C, more preferably 15-30DEG C, be preferably room temperature (25 DEG C).
In the present invention, under the condition preferably existing at base catalyst, carry out above-mentioned steps (2). At thisIn a bright preferred embodiment, described base catalyst comprises organic alkali catalyst for example triethylamine, methylamineWith tert-butylamine and for example potash of inorganic base catalyst and sodium carbonate.
In the present invention, under the condition preferably existing at acyl group catalyst, carry out above-mentioned steps (2).In a preferred embodiment of the present invention, described acyl group catalyst is selected from 4-dimethylamino pyridine(DMAP), N-methylimidazole.
The present invention also provides general formula I I compound in the purposes of preparing in prasugrel,
Wherein, R1, R2, R3 can be identical or different, represents separately the one in following atom or group:Hydrogen atom, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
Describe by the following examples the present invention in detail, but following examples are only exemplary, thisBright scope is not limited to this.
Embodiment
The tertiary fourth of embodiment 1:2-tri-siloxy-4,5,6,7-thiophane is the preparation of [3,2-C] pyridine also
700g4,5,6,7-thiophane is [3,2-C] pyridine hydrochloric acid (limited public affairs of Shanghai root of Dahurian angelica waffle subject skill alsoDepartment) join in 5L carrene (Chemical Reagent Co., Ltd., Sinopharm Group), add 857g tri-unclesButyl chloride SiClx (ACROS), slowly add 700ml triethylamine (Chemical Reagent Co., Ltd., Sinopharm Group),Stirring at room temperature 2-3 hour, TLC (Chemical Reagent Co., Ltd., Sinopharm Group) detection reaction is complete, adds1000ml washing, separatory, after anhydrous magnesium sulfate drying, decompression distillation obtains product (825g, yield 99%)1HNMR(600MHz，CDCl3)：δ＝6.35(s，1H)，4.47(s，2H)，3.99(m，2H)，3.30(m，2H)，1.03(S，27H)。MS-ESI(m/z)：156[M+H]。
Embodiment 2:2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2,4,5,6,7-Thiophane is the preparation of [3,2-c] pyridine also
The product that embodiment 1 is obtained adds 5000ml carrene, 1400mlTEA and 80g tetra-fourthsBase amine bromide (Chemical Reagent Co., Ltd., Sinopharm Group), drips alpha-brominated adjacent luorobenzyl cyclopropyl ketone(1100-1200g) (Shanghai root of Dahurian angelica waffle is learned Science and Technology Ltd.). After being added dropwise to complete, add hot reflux,And continue to stir 3 hours, TLC detection reaction is complete, adds 4-dimethylamino pyridine (DMAP) (stateChemical reagent Co., Ltd of medicine group) 25g, drip triethylamine (1000ml), add acetic anhydride (traditional Chinese medicinesChemical reagent Co., Ltd of group) (750ml), room temperature reaction, TLC detection reaction is complete, adds moistureLayer, dichloromethane extraction, saturated sodium bicarbonate is washed, and concentrates to obtain grease, and it is white that crystallization obtains prasugrelLook solid.1HNMR(600MHz，CDCl3)：δ＝7.08～7.49(m，4H)，6.25(s，1H)，4.81(s，1H)， 3.46～3.57(m，2H)，2.75～2.90(m，2H)，2.28～2.29(m，1H)，2.27(s，3H)，1.00～1.05(m，4H)。MS-ESI(m/z)：374[M+H]。
Embodiment 3:2-tri-silyloxy-4,5,6,7-thiophane is the preparation of [3,2-C] pyridine also
700g4,5,6,7-thiophane also [3,2-C] pyridine hydrochloric acid joins in 5L carrene, addsEnter 400g tri-tert silicon chloride, slowly add 700ml triethylamine, stirring at room temperature 2-3 hour, TLCDetection reaction is complete, adds 1000ml washing, separatory, and after anhydrous magnesium sulfate drying, decompression distillation is producedThing (821g, yield 99%).1HNMR(600MHz，CDCl3)：δ＝6.35(s，1H)，4.47(s，2H)，3.99(m，2H)，3.30(m，2H)，0.73(S，9H)。MS-ESI(m/z)：374[M+H]。
Embodiment 4:2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2,4,5,6,7-Thiophane is the preparation of [3,2-c] pyridine also
The product that embodiment 3 is obtained adds 5000ml carrene, 1400mlTEA and 80g tetra-fourthsBase amine bromide, drips alpha-brominated adjacent luorobenzyl cyclopropyl ketone (1100-1200g). After being added dropwise to complete, addHot reflux, and continue to stir 3 hours, TLC detection reaction is complete, adds 4-dimethylamino pyridine (DMAP)25g, drips triethylamine (1000ml), adds acetic anhydride (750ml), room temperature reaction, and TLC detectsReact completely, add water stratification, dichloromethane extraction, saturated sodium bicarbonate is washed, and concentrates to obtain grease, analysesCrystalline substance obtains prasugrel white solid.1HNMR(600MHz，CDCl3)：δ＝7.08～7.49(m，4H)，6.25(s，1H)，4.81(s，1H)，3.46～3.57(m，2H)，2.75～2.90(m，2H)，2.28～2.29(m，1H)，2.27(s，3H)，1.00～1.05(m，4H)。MS-ESI(m/z)：374[M+H]
Embodiment 5:2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2,4,5,6,7-Thiophane is the preparation of [3,2-c] pyridine also
700g thiophene salt joins in 5L carrene (DCM), adds 600gTBS, slowly adds700ml triethylamine (TEA), stirring at room temperature 2-3h, TLC detection reaction is complete, then adds 1400mlTEA, then add 80g four butyl bromation amine, dropping 1100-1200g bromide. After being added dropwise to complete,Add hot reflux, and continue to stir 3 hours, TLC detection reaction is complete, adds 4-dimethylamino pyridine(DMAP) 25g, drips 1000mlTEA, adds 750ml aceticanhydride, room temperature reaction, TLC detection reactionCompletely, add water stratification, DCM extraction, saturated sodium bicarbonate is washed, and concentrates to obtain grease. Crystallization obtains generalGlug thunder white solid.1HNMR(600MHz，CDCl3)：δ＝7.08～7.49(m，4H)，6.25(s，1H)，4.81(s，1H)，3.46～3.57(m，2H)，2.75～2.90(m，2H)，2.28～2.29(m，1H)，2.27(s，3H)，1.00～1.05(m，4H)。MS-ESI(m/z)：374[M+H]。
Claims (13)
1. prepare a method for prasugrel, described method comprises the steps:
(1) make general formula I I compound and alpha-brominated adjacent luorobenzyl cyclopropyl reactive ketone
Wherein, R1, R2, R3 can be identical or different, represents separately the one in following atom or group:C1-C6 alkyl and phenyl;
(2) product and the acetic anhydride that step (1) are obtained, obtain prasugrel.
2. the method for claim 1, is characterized in that, under the condition existing, enters at base catalystRow above-mentioned steps (1).
3. method as claimed in claim 2, is characterized in that, described base catalyst comprises that organic base urgesAgent and inorganic base catalyst.
4. method as claimed in claim 3, is characterized in that, described organic alkali catalyst is selected from three secondAmine, methylamine and tert-butylamine.
5. method as claimed in claim 3, is characterized in that, described inorganic base catalyst is selected from carbonic acidPotassium and sodium carbonate.
6. the method for claim 1, is characterized in that, the condition existing at phase transfer catalystUnder carry out above-mentioned steps (1).
7. method as claimed in claim 6, is characterized in that, described phase transfer catalyst is selected from four fourthsBase ammonium bromide, benzyltriethylammoinium chloride, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, trioctylphosphine methylAmmonium chloride, DTAC and tetradecyl trimethyl ammonium chloride.
8. the method for claim 1, is characterized in that, under the condition existing, enters at base catalystRow above-mentioned steps (2).
9. method as claimed in claim 8, is characterized in that, described base catalyst comprises that organic base urgesAgent and inorganic base catalyst.
10. method as claimed in claim 8, is characterized in that, described organic alkali catalyst is selected from three secondAmine, methylamine and tert-butylamine.
11. methods as claimed in claim 8, is characterized in that, described inorganic base catalyst is selected from carbonic acidPotassium and sodium carbonate.
12. the method for claim 1, is characterized in that, the condition existing at acyl group catalystUnder carry out above-mentioned steps (2).
13. methods as claimed in claim 12, is characterized in that, described acyl group catalyst is selected from 4-Dimethylamino pyridine and N-methylimidazole.
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| CN101735241A (en) * | 2009-12-24 | 2010-06-16 | 浙江普洛家园药业有限公司 | Prasugrel intermediate and preparation method thereof |
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