CN102558216A - Preparation method of prasugrel - Google Patents
Preparation method of prasugrel Download PDFInfo
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- CN102558216A CN102558216A CN2010106079127A CN201010607912A CN102558216A CN 102558216 A CN102558216 A CN 102558216A CN 2010106079127 A CN2010106079127 A CN 2010106079127A CN 201010607912 A CN201010607912 A CN 201010607912A CN 102558216 A CN102558216 A CN 102558216A
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Abstract
The invention provides a compound represented by a general formula II. In the general formula II, R1, R2 and R3 can be identical or different and respectively represent one of the following atoms or groups: a hydrogen atom, a substituted or unsubstituted alkyl group and a substituted or unsubstituted aryl group. According to the invention, an intermediate is utilized to prepare prasugrel, thus operation is simplified, reaction condition is mild, reaction is stable and yield is high; and particularly, in the process of preparing prasugrel utilizing the intermediate, a 'one-pot porridge' operation process is adopted, so as to greatly simplify the reaction operation.
Description
Technical field
The present invention relates to the new preparation method of a kind of prasugrel.
Background technology
The formula I compound (hydrochloric acid prasugrel) that shows below is a kind of novel platelet suppressant drug, is the oral antiplatelet drug of being released altogether by Lilly and three, at present in the U.S. and European Union's listing.The hydrochloric acid prasugrel is a kind of hemostasis new drug of Thienopyridines, is a kind of prodrug, forms bioactive molecule through after the metabolism in vivo, brings into play the activity of platelet aggregation-against with thrombocyte P2Y12 receptors bind.
Prasugrel is a kind of hemostasis new drug of Thienopyridines, is a kind of prodrug, forms bioactive molecule through after the metabolism in vivo, brings into play the activity of platelet aggregation-against with thrombocyte P2Y12 receptors bind.TRITON-TIMI 38 clinical trials show; Prasugrel has than the better anticoagulant effect of clopidogrel, can make heart of patient onste, apoplexy, because of the integrated risk of deaths from heart disease reduces by 20%, and instant effect; Good effect; Good resistance and bioavailability are arranged, the bigger protection effect to anti-stroke and mortality risk can be provided, but cause patient's bleeding more.
The clinical efficacy aspect; TRITON-TIMI 38 clinical trials show; Relatively prasugrel and clopidogrel are applied to the curative effect and the security of acute coronary syndrome, and prasugrel group validity terminal point incident (cardiac death, non-lethality myocardial infarction, palsy etc.) incidence all is lower than the clopidogrel group.
Ternberg etc. are respectively with prasugrel, clopidogrel and Frosst) combined utilization treatment atherosclerosis; The result shows; Compare with clopidogrel (300mg loading dose and 75mg maintenance dose), prasugrel (60mg loading dose and 10mg maintenance dose) demonstrates the effect of better anticoagulant.In addition, the prasugrel difference between individuals is less, and non-response rate is lower on the pharmacodynamics.
The BMO capital market analyst of company represent; Also there is a bright spot in prasugrel; Be that the diabetic subject uses this medicine can't meet with danger of bleeding property, concerning the diabetic subject who accepts the support operation, prasugrel can successfully be used as a kind of special-purpose medicaments and be used.
In Chinese patent 92111584, a kind of compound method of prasugrel is disclosed, its synthetic route is following:
This route uses compound 2 (2-oxygen-2,4,5,6,7; 7 α-six hydrogen thieno-[3,2-c] pyridine) and compound 3 (alpha-brominated adjacent luorobenzyl cyclopropyl ketone) under alkaline condition, react and obtain compound 4 (5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5,6; 7,7 α-six hydrogen thieno-[3,2-c] pyridine), acidylate obtains prasugrel (2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2,4 then; 5,6, the 7-THTP is [3,2-c] pyridine also).
But aforesaid method exists long reaction time, aftertreatment to need column chromatography, is not suitable for defectives such as suitability for industrialized production in the process of synthetic compound 3.
At document " Chinese Journal of Pharmaceuticals " 2009,40 (4), 244-246, author report that a synthetic route is following:
4,5,6, the 7-THTP also [3,2-c] pyridine hydrochlorides (5) through the protection after; Get 2-oxo-N-trityl-2,4,5,6,7 with n-Butyl Lithium, tributyl borate reaction and oxidation; 7 α-six hydrogen thieno-[3,2-C] pyridines (7), deprotection obtains 2-oxo-2,4,5 again; 6,7,7 α-six hydrogen thieno-[3,2-C] pyridine hydrochlorides (8); Be raw material with adjacent fluorine bromobenzyl again, in diethyl ether solution, make cyclopropyl-2-luorobenzyl ketone (9), obtain α-cyclopropyl carbonyl-2-fluorobenzyl bromide (10) with NBS bromination 7, in the presence of acid binding agent through grignard reaction; In acetonitrile,, generate 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4 with compound 8; 5,6,7; 7 α-six hydrogen thieno-[3,2-C] pyridine gets prasugrel (1) through the diacetyl oxide acetylize again.
But this route need use low temperature, and need use butyllithium, tributyl borate, severe reaction conditions; Compound 10 is a liquid, and unstable, is difficult to obtain the higher product of purity, causes when synthetic compound 11, needs column chromatography to carry out purifying, is difficult to carry out suitability for industrialized production.
Provide at present a kind of more easy and simple to handle, cost is lower, is suitable for the synthetic route of suitability for industrialized production.
Summary of the invention
One of the object of the invention just provides a kind of novel process for preparing prasugrel, so that this route can overcome the above-mentioned defective of prior art, make it to be suitable for industrialized production, and yield increases than existing methods.
Another object of the present invention provides extremely preparation method of a kind of new midbody that is used to prepare prasugrel.
The inventor has found one type of suitable prasugrel intermediate through research, utilizes this midbody to prepare prasugrel, can simplify the operation, mild reaction conditions, stable reaction, yield be higher.Especially advantageously, utilize this midbody to carry out the 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, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
In a preferred embodiment of the present invention, R1, R2, R3 can be identical or different, representes the C1-C10 alkyl separately, is preferably the C1-C8 alkyl, is the C1-C6 alkyl better, is preferably the C1-C4 alkyl.
The present invention provides a kind of method for preparing above-mentioned general formula I I compound on the other hand, said method comprising the steps of: make 4,5; 6, the 7-THTP is the compound reaction of [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl also; R1 wherein; R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, 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-tert silicon chlorides and trimethylammonium silicon chlorides.
In a preferred embodiment of the present invention, under the condition that alkaline catalysts exists, make 4,5,6, the 7-THTP also compound of [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl reacts; Preferably, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst.
The present invention provides a kind of method for preparing prasugrel on the other hand, and said method comprises the steps:
(1) makes general formula I I compound and alpha-brominated adjacent luorobenzyl cyclopropyl reactive ketone
Wherein, R1, R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, 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 that alkaline catalysts exists, carry out above-mentioned steps (1); Preferably, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst.
In a preferred embodiment of the present invention, under the condition that phase-transfer catalyst exists, carry out above-mentioned steps (1); Preferably, said phase-transfer catalyst be selected from Tetrabutyl amonium bromide, benzyltriethylammoinium chloride (TEBA),, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, DTAC and tetradecyl trimethyl ammonium chloride.
In a preferred embodiment of the present invention, under the condition that alkaline catalysts exists, carry out above-mentioned steps (2); Preferably, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst; And/or, under the condition that the acylations catalyzer exists, carry out above-mentioned steps (2); Preferably, said acylations catalyzer is selected from 4-dimethylamino pyridine (DMAP), N-Methylimidazole.
A further aspect of the present invention provides the general formula I I compound purposes in the preparation prasugrel,
Wherein, R1, R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
Embodiment
In the present invention, if there is not special explanation, percentage ratio (%) or part all refer to weight percentage or the weight part with respect to compsn.
In the present invention, if there is not special explanation, each related component or its preferred ingredient can be combined to form new technical scheme each other.
In the present invention, if there is not special explanation, all embodiments that this paper mentioned and preferred implementation can be combined to form new technical scheme each other.
In the present invention, if there is not special explanation, all technical characterictics that this paper mentioned and preferred feature can be combined to form new technical scheme each other.
In the present invention, if there is not opposite explanation, each components contents sum is 100% in the compsn.
In the present invention, if there is not opposite explanation, the umber sum of each component can be 100 weight parts in the compsn.
In the present invention, only if other explanations are arranged, numerical range " a-b " expression a representes that to the breviary of any real number combination between the b wherein a and b are real numbers.For example all listed the whole real numbers between " 0-5 " among numerical range " 0-5 " expression this paper, " 0-5 " just the breviary of these combinations of values representes.
In the present invention, only if other explanations are arranged, integer numerical range " a-b " expression a representes that to the breviary of the combination of the arbitrary integer between the b wherein a and b are integers.For example integer numerical range " 1-N " expression 1,2 ... N, wherein N is an integer.
In the present invention, only if other explanations are arranged, the multicomponent mixture of said each element of " its combination " expression, for example two kinds, three kinds, four kinds and up to the multicomponent mixture of maximum possible.
If do not particularly point out, the used term " a kind of " of this specification sheets refers to " at least a ".
If do not particularly point out, the benchmark of percentage ratio of the present invention (comprising weight percentage) all is the gross weight of said compsn.
" scope " disclosed herein is with the form of the lower limit and the upper limit.Can be respectively one or more lower limits and one or more upper limit.Given range limits through a selected lower limit and a upper limit.The border that the selected lower limit and the upper limit define special scope.All can carry out restricted portion by this way and comprise with capable of being combined, and promptly any lower limit can be combined to form a scope with any upper limit.For example, listed the scope of 60-120 and 80-110, be interpreted as that the scope of 60-110 and 80-120 also reckons with to special parameter.In addition, if if the minimum extent value of listing 1 and 2 and listed maximum range value 3,4 and 5, the scope below then could all reckon with: 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; Straight or branched, replacement or the unsubstituted alkyl of " alkyl " expression C1-C10; Better straight or branched, replacement or the unsubstituted alkyl of expression C1-C8 are better represented C1-C6 straight or branched, replacement or unsubstituted alkyl, preferably represent C1-C4 straight or branched, replacement or unsubstituted alkyl.
In this article; Except as otherwise noted, replacement or the unsubstituting aromatic yl of C6-C20 such as " aryl " or " aromatic base " expression represent that better C6-C16 replaces or unsubstituted aryl; Better expression C6-C14 replaces or unsubstituted aryl, representes that preferably C6-C10 replaces or unsubstituted aryl.
In this article, except as otherwise noted, " substituting group " expression C1-C10 alkyl, C1-C10 alkoxyl group, halogen and hydroxyl.
In this article, except as otherwise noted, " halogen ", " halogen " or " halo " expression fluorine, chlorine, bromine and 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, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
In a preferred embodiment of the present invention, R1, R2, R3 can be identical or different, representes the C1-C10 alkyl separately, is preferably the C1-C8 alkyl, is the C1-C6 alkyl better, is preferably the C1-C4 alkyl.
The present invention provides a kind of method for preparing above-mentioned general formula I I compound on the other hand, said method comprising the steps of: make 4,5; 6, the 7-THTP is the compound reaction of [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl also; R1 wherein; R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
In a preferred embodiment of the present invention, R1, R2, R3 can be identical or different, representes the C1-C10 alkyl separately, is preferably the C1-C8 alkyl, is the C1-C6 alkyl better, is preferably the C1-C4 alkyl.
In another preferred embodiment of the present invention, the compound of general formula R 1R2R3SiCl is selected from tri-tert silicon chlorides and trimethylammonium silicon chlorides.
In a preferred embodiment of the present invention, make 4,5,6, the 7-THTP also step of the compound reaction of [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl preferably carries out in organic solvent.Said organic solvent can be conventional, and those of ordinary skill in the art combines prior art can direct derivation to go out which organic solvent again according to description of the invention and can be used for the present invention.In a preferred embodiment of the present invention, said organic solvent is selected from (1) arene: like benzene,toluene,xylene etc.; (2) fat hydrocarbon: like pentane, hexane, octane etc.; (3) alicyclic hydrocarbon type: like hexanaphthene, pimelinketone, toluene pimelinketone etc.; (4) halogenated hydrocarbons: like chlorobenzene, dichlorobenzene, methylene dichloride etc.; (5) alcohols: like methyl alcohol, ethanol, Virahol etc.; (6) ethers: like ether, propylene oxide etc.; (7) ester class: like ritalin, vinyl acetic monomer, propyl acetate etc.; (8) ketone: like acetone, espeleton, mibk etc.; (9) diol, derivatives: like ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether etc.; 10. other: like acetonitrile, pyridine, phenol etc.In another preferred embodiment of the present invention, said organic solvent is selected from halohydrocarbon for example methylene dichloride, chloroform, trichloromethane and ethylene dichloride and THF etc.
In the present invention; Make 4; 5,6,7-THTP also [3; 2-C] temperature of step of compound reaction of pyridine hydrochloric acid and general formula R 1R2R3SiCl is conventional, those of ordinary skill in the art combines prior art can direct derivation to go out which temperature again according to description of the invention and can be used for the present invention.In a preferred embodiment of the present invention, said temperature is 0-100 ℃, is preferably 10-50 ℃, is 15-30 ℃ better, is preferably room temperature (promptly 25 ℃).
In the present invention, preferably under the condition that alkaline catalysts exists, make 4,5,6, the 7-THTP also compound of [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl reacts.In a preferred embodiment of the present invention, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst.
The present invention provides a kind of method for preparing prasugrel on the other hand, and said method comprises the steps:
(1) makes general formula I I compound and alpha-brominated adjacent luorobenzyl cyclopropyl reactive ketone
Wherein, R1, R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, 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, representes the C1-C10 alkyl separately, is preferably the C1-C8 alkyl, is the C1-C6 alkyl better, is preferably the C1-C4 alkyl.
In a preferred embodiment of the present invention, said step (1) is preferably carried out in organic solvent.Said organic solvent can be conventional, and those of ordinary skill in the art combines prior art can direct derivation to go out which organic solvent again according to description of the invention and can be used for the present invention.In a preferred embodiment of the present invention, said organic solvent is selected from (1) arene: like benzene,toluene,xylene etc.; (2) fat hydrocarbon: like pentane, hexane, octane etc.; (3) alicyclic hydrocarbon type: like hexanaphthene, pimelinketone, toluene pimelinketone etc.; (4) halogenated hydrocarbons: like chlorobenzene, dichlorobenzene, methylene dichloride etc.; (5) alcohols: like methyl alcohol, ethanol, Virahol etc.; (6) ethers: like ether, propylene oxide etc.; (7) ester class: like ritalin, vinyl acetic monomer, propyl acetate etc.; (8) ketone: like acetone, espeleton, mibk etc.; (9) diol, derivatives: like ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether etc.; 10. other: like acetonitrile, pyridine, phenol etc.In another preferred embodiment of the present invention, said organic solvent is selected from halohydrocarbon for example methylene dichloride, chloroform, trichloromethane and ethylene dichloride and THF etc.
In the present invention, the temperature of above-mentioned steps (1) is conventional, and those of ordinary skill in the art combines prior art can direct derivation to go out which temperature again according to description of the invention and can be used for the present invention.In a preferred embodiment of the present invention, said temperature is 0-100 ℃, is preferably 10-50 ℃, is 15-30 ℃ better, is preferably room temperature (promptly 25 ℃).
In the present invention, preferably under the condition that alkaline catalysts exists, carry out above-mentioned steps (1).In a preferred embodiment of the present invention, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst.
In the present invention, preferably under the condition that phase-transfer catalyst exists, carry out above-mentioned steps (1).In a preferred embodiment of the present invention, said phase-transfer catalyst be selected from Tetrabutyl amonium bromide, benzyltriethylammoinium chloride (TEBA),, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, DTAC and tetradecyl trimethyl ammonium chloride.
In a preferred embodiment of the present invention, said step (2) is preferably carried out in organic solvent.Said organic solvent can be conventional, and those of ordinary skill in the art combines prior art can direct derivation to go out which organic solvent again according to description of the invention and can be used for the present invention.In a preferred embodiment of the present invention, said organic solvent is selected from (1) arene: like benzene,toluene,xylene etc.; (2) fat hydrocarbon: like pentane, hexane, octane etc.; (3) alicyclic hydrocarbon type: like hexanaphthene, pimelinketone, toluene pimelinketone etc.; (4) halogenated hydrocarbons: like chlorobenzene, dichlorobenzene, methylene dichloride etc.; (5) alcohols: like methyl alcohol, ethanol, Virahol etc.; (6) ethers: like ether, propylene oxide etc.; (7) ester class: like ritalin, vinyl acetic monomer, propyl acetate etc.; (8) ketone: like acetone, espeleton, mibk etc.; (9) diol, derivatives: like ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether etc.; 10. other: like acetonitrile, pyridine, phenol etc.In another preferred embodiment of the present invention, said organic solvent is selected from halohydrocarbon for example methylene dichloride, chloroform, trichloromethane and ethylene dichloride and THF etc.
In the present invention, the temperature of above-mentioned steps (2) is conventional, and those of ordinary skill in the art combines prior art can direct derivation to go out which temperature again according to description of the invention and can be used for the present invention.In a preferred embodiment of the present invention, said temperature is 0-100 ℃, is preferably 10-50 ℃, is 15-30 ℃ better, is preferably room temperature (promptly 25 ℃).
In the present invention, preferably under the condition that alkaline catalysts exists, carry out above-mentioned steps (2).In a preferred embodiment of the present invention, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst.
In the present invention, preferably under the condition that the acylations catalyzer exists, carry out above-mentioned steps (2).In a preferred embodiment of the present invention, said acylations catalyzer is selected from 4-dimethylamino pyridine (DMAP), N-Methylimidazole.
The present invention also provides the purposes of general formula I I compound in the preparation prasugrel,
Wherein, R1, R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
Below describe the present invention in detail through embodiment, but following examples only are exemplary, scope of the present invention is not limited thereto.
Embodiment
Embodiment 1:2-three uncle's fourth siloxies-4,5,6, the 7-THTP is the preparation of [3,2-C] pyridine also
700g 4,5, and 6; 7-THTP also [3,2-C] pyridine hydrochloric acid (Shanghai root of Dahurian angelica waffle subject skill ltd) joins in the 5L methylene dichloride (Chemical Reagent Co., Ltd., Sinopharm Group), adds 857g tri-tert silicon chlorides (ACROS), slowly adds 700ml triethylamine (Chemical Reagent Co., Ltd., Sinopharm Group); Stirring at room 2-3 hour; TLC (Chemical Reagent Co., Ltd., Sinopharm Group) detection reaction is complete, adds the 1000ml washing, separatory; Underpressure distillation obtains product (825g, yield 99%) behind the anhydrous magnesium sulfate drying
1HNMR (600MHz, CDCl
3): 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, the 7-THTP is the preparation of [3,2-c] pyridine also
The product that embodiment 1 is obtained adds 5000ml methylene dichloride, 1400ml TEA and 80g four butyl bromation amine (Chemical Reagent Co., Ltd., Sinopharm Group), drips alpha-brominated adjacent luorobenzyl cyclopropyl ketone (1100-1200g) (Shanghai root of Dahurian angelica waffle subject skill ltd).After being added dropwise to complete, reflux, and continue to stir 3 hours, the TLC detection reaction is complete; Add 4-dimethylamino pyridine (DMAP) (Chemical Reagent Co., Ltd., Sinopharm Group) 25g, drip triethylamine (1000ml), add diacetyl oxide (Chemical Reagent Co., Ltd., Sinopharm Group) (750ml), room temperature reaction; The TLC detection reaction is complete, adds water stratification, dichloromethane extraction; Saturated sodium bicarbonate is washed, concentrate oily matter, crystallization promptly gets the prasugrel white solid.
1HNMR(600MHz，CDCl
3)：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-three silyloxies-4,5,6,7-THTP are the preparation of [3,2-C] pyridine also
700g 4,5, and 6; 7-THTP also [3,2-C] pyridine hydrochloric acid joins in the 5L methylene dichloride, adds 400g tri-tert silicon chlorides, slowly adds the 700ml triethylamine; Stirring at room 2-3 hour, the TLC detection reaction was complete, added the 1000ml washing; Separatory, underpressure distillation obtains product (821g, yield 99%) behind the anhydrous magnesium sulfate drying.
1HNMR(600MHz，CDCl
3)：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, the 7-THTP is the preparation of [3,2-c] pyridine also
The product that embodiment 3 is obtained adds 5000ml methylene dichloride, 1400ml TEA and 80g four butyl bromation amine, drips alpha-brominated adjacent luorobenzyl cyclopropyl ketone (1100-1200g).After being added dropwise to complete, reflux, and continue to stir 3 hours, the TLC detection reaction is complete; Add 4-dimethylamino pyridine (DMAP) 25g, drip triethylamine (1000ml), add diacetyl oxide (750ml), room temperature reaction; The TLC detection reaction is complete, adds water stratification, dichloromethane extraction; Saturated sodium bicarbonate is washed, concentrate oily matter, crystallization promptly gets the prasugrel white solid.
1HNMR(600MHz，CDCl
3)：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, the 7-THTP is the preparation of [3,2-c] pyridine also
700g thiophene salt joins in the 5L methylene dichloride (DCM), adds 600g TBS, slowly adds 700ml triethylamine (TEA), stirring at room 2-3h; The TLC detection reaction is complete; Add 1400mlTEA then, add the 80g four butyl bromation amine again, dropping 1100-1200g bromide.After being added dropwise to complete, reflux, and continue to stir 3 hours, the TLC detection reaction is complete; Add 4-dimethylamino pyridine (DMAP) 25g, drip 1000ml TEA, add the 750ml aceticanhydride; Room temperature reaction, the TLC detection reaction is complete, adds water stratification; DCM extraction, saturated sodium bicarbonate is washed, concentrate oily matter.Crystallization promptly gets the prasugrel white solid.
1HNMR(600MHz，CDCl
3)：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 (10)
1. the compound represented of following general formula I I:
Wherein, R1, R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
2. compound as claimed in claim 1 is characterized in that, R1, and R2, R3 can be identical or different, representes the C1-C10 alkyl separately, is preferably the C1-C8 alkyl, is the C1-C6 alkyl better, is preferably the C1-C4 alkyl.
3. a method for preparing above-mentioned general formula I I compound said method comprising the steps of: make 4,5; 6, the 7-THTP is the compound reaction of [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl also; R1 wherein; R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
4. method as claimed in claim 3 is characterized in that, the compound of general formula R 1R2R3SiCl is selected from tri-tert silicon chlorides and trimethylammonium silicon chlorides.
5. method as claimed in claim 3 is characterized in that, under the condition that alkaline catalysts exists, makes 4,5,6, and the 7-THTP also compound of [3,2-C] pyridine hydrochloric acid and general formula R 1R2R3SiCl reacts; Preferably, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst.
6. method for preparing prasugrel, said method comprises the steps:
(1) makes general formula I I compound and alpha-brominated adjacent luorobenzyl cyclopropyl reactive ketone
Wherein, R1, R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl;
(2) product and the acetic anhydride that step (1) are obtained obtain prasugrel.
7. method as claimed in claim 6 is characterized in that, under the condition that alkaline catalysts exists, carries out above-mentioned steps (1); Preferably, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst.
8. method as claimed in claim 6 is characterized in that, under the condition that phase-transfer catalyst exists, carries out above-mentioned steps (1); Preferably, said phase-transfer catalyst be selected from Tetrabutyl amonium bromide, benzyltriethylammoinium chloride (TEBA),, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, DTAC and tetradecyl trimethyl ammonium chloride.
9. method as claimed in claim 6 is characterized in that, under the condition that alkaline catalysts exists, carries out above-mentioned steps (2); Preferably, said alkaline catalysts comprises for example for example salt of wormwood and yellow soda ash of triethylamine, methylamine and TERTIARY BUTYL AMINE and inorganic base catalyst of organic alkali catalyst; And/or, under the condition that the acylations catalyzer exists, carry out above-mentioned steps (2); Preferably, said acylations catalyzer is selected from 4-dimethylamino pyridine (DMAP), N-Methylimidazole.
10. general formula I I compound is in the purposes of preparation in the prasugrel,
Wherein, R1, R2, R3 can be identical or different, representes a kind of in following atom or the group separately: Wasserstoffatoms, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
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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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| 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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