CN101239920A - Method for preparing sarpogrelate hydrochloride - Google Patents
Method for preparing sarpogrelate hydrochloride Download PDFInfo
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- CN101239920A CN101239920A CNA200710019934XA CN200710019934A CN101239920A CN 101239920 A CN101239920 A CN 101239920A CN A200710019934X A CNA200710019934X A CN A200710019934XA CN 200710019934 A CN200710019934 A CN 200710019934A CN 101239920 A CN101239920 A CN 101239920A
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Abstract
Provided is a preparing method of sarpogrelate hydrochloride, characterized in that 2-((3-methoxyl)styrylcoumarin)phenol mixture containing triphenylphosphine oxide is catalyzed and hydrogenated, and then reacted with epichlorohydrin and dimethylamine to obtain 2-(dimethylamino)-1-(o-(m-methoxyphenylethyl)phenoxymethyl)ethanol, at the same time, triphenylphosphine oxide is separated or not, reacted with succinic anhydride, salt-formed with chlorine hydride, and re-crystallization by a proper solvent, so as to obtain sarpogrelate hydrochloride.
Description
Technical field
The present invention relates to a kind of preparation method of Sarpogrelatehydrochloride, more specifically, relate to a kind of method of using 2-((3-methoxyl group) styryl) phenol that contains triphenylphosphine oxide as the feedstock production Sarpogrelatehydrochloride.
Background technology
Sarpogrelatehydrochloride (Sarpogrelate Hydrochloride) chemical name Succinic Acid (2-dimethylin-1-neighbour (anisylethyl) Phenoxymethyl) carbethoxy hydrochloride (Butanedioic Acid, mono 2-(Dimethylamino)-1-[[o-(m-methoxyphenethyl) phenoxy] methyl] ethyl ester hydrochloride, CAS RegistryNumber:135159-51-2, structural formula is as follows:
This product can selectivity antagonism thrombocyte and serotonin (5-HT) acceptor of blood vessel, suppresses platelet aggregation, clinically is used to improve the ischemia symptoms such as ulcer, pain and creeping chill that chronic arteria occlusion disease causes.
Pharmaceutical chemistry magazine (J.Med.Chem.) 1990,33:1818-1823 has reported the synthetic route of this product:
4485258 of United States Patent (USP)s directly adopt pure intermediate 2-((3-methoxyl group) styroyl) phenol (III) to carry out subsequent preparation, the preparation of not mentioned this intermediate and issues of purification.
2-((3-methoxyl group) styroyl) phenol (III) prepares by catalytic hydrogenation intermediate 2-((3-methoxyl group) styryl) phenol (II), yet 2-((3-methoxyl group) styryl) phenol (II) normally passes through the Wittg prepared in reaction, can produce a large amount of triphenylphosphine oxides, be difficult to remove, present existing method is all by crossing the chromatographic column purifying:
Pharmaceutical chemistry magazine (J.Med.Chem.) 1990 is removed triphenylphosphine oxide by silicagel column among the 33:1818-1823;
Pharmaceutical chemistry magazine (J.Med.Chem.) 2006,49 (22): 6607-6613 is then with containing behind the mixture hydrogenation of triphen phosphine oxide after the silicagel column purifying.
Existing method all is to adopt chromatographic process to separate before hydrogenation or after the hydrogenation, yet crossing silicagel column is inappropriate in big production economically, adopt this method to produce Sarpogrelatehydrochloride and will be difficult to the expansion scale, and cost is higher, therefore needs the method for the new economy of research to produce Sarpogrelatehydrochloride.
And the husky Gray of the hydrochloric acid of bibliographical information uses acetone recrystallization.Through inventor's evidence, Sarpogrelatehydrochloride does not dissolve in acetone substantially, and the acetone of 200 times of volumes still fails to make the product dissolving under reflux state, is not a good recrystallization solvent for this product acetone obviously.
Chinese patent CN1824647A mentions and uses acetone-water as recrystallization solvent, and the inventor tests and finds to adopt this system to be difficult to obtain highly purified product.
Therefore, need to seek new suitable product purification method.
Summary of the invention
Through scrutinizing 2-((3-methoxyl group) styroyl) phenol, the structure and the physicochemical property of triphenylphosphine oxide and Sarpogrelate key intermediate 2-(dimethylamino)-1-(adjacent-(anisylethyl)) Phenoxymethyl ethanol (V), through a large amount of tests, the invention provides a kind of with dimethylamine reaction before need not all or part of method for preparing Sarpogrelate from triphenylphosphine oxide, promptly the intermediate 2-that obtains through the Wittg prepared in reaction ((3-methoxyl group) styryl) phenol mixture need not to remove triphenylphosphine, directly carry out hydrogenation, then with epichlorohydrin reaction, again and dimethylamine reaction amination obtain the mixture of intermediate 2-(dimethylamino)-1-(adjacent-(anisylethyl)) Phenoxymethyl ethanol (V) and triphen phosphine oxide, can utilize this moment the greatest differences of the salt of this intermediate and triphenylphosphine oxide solubleness in solution to remove the triphen phosphine oxide easily and obtain Sarpogrelate with succinic anhydride esterification again, or intermediate V mixture and succinic anhydride esterification generate Sarpogrelate and add and remove the triphen phosphine oxide again after acid or alkali make the Sarpogrelate salify, the salt of Sarpogrelate adopts methyl alcohol, ethanol, acetonitrile equal solvent or its mixture recrystallization, can obtain purity greater than 98% even greater than 99.5% highly purified product, the residual quantity that does not contain triphen phosphine oxide or triphen phosphine oxide in the finished product is within the scope of medicine permission.
The present invention can realize by following steps;
1, (presses document J.Med.Chem.1990 through the intermediate II of Wittg prepared in reaction, the 33:1818-1823 preparation, without removing or all do not remove triphenylphosphine oxide, contain triphen phosphine oxide 10%-90%) be dissolved in the appropriate solvent, under the catalysis of catalyzer, obtain the mixture of intermediate III and triphenylphosphine oxide with the hydrogen hydro-reduction.
The solvent that this reaction is used is to be not easy under this reaction conditions and moisture or water-free one or more solvents of reactant react with, and the alcohol of or unsaturated alkyl saturated as C1-C10 is as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, phenylcarbinol; Ether is as ether, isopropyl ether, propyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl-phenoxide; Amine, diethylamine, triethylamine, thanomin in this way; Carboxylic acid and acid amides are as formic acid, acetate, butyric acid, dimethyl formamide; Halogenated alkane is as methylene dichloride, chloroform, ethylene dichloride; Aromatic hydrocarbons or halogenated aryl hydrocarbon are as benzene,toluene,xylene, chlorobenzene.
The catalyzer that this reaction is used can be all load or unsupported containing metal or catalyzer of metallic compound of can be used for the ethylene linkage catalytic hydrogenation, as palladium metal, nickel, ruthenium, platinum, rhodium etc., particularly palladium carbon, Raney's nickel, platinum oxide etc., the amount of catalyzer is the 0.01-200% of substrate weight, preferably 0.1-50%;
The pressure of this reaction is 0.1-10Mpa, preferably 0.1-1Mpa;
The temperature of this reaction is-10-150 ℃, and preferably 0-100 ℃;
The time of this reaction is 0.1-200 hour, preferably 0.5-96 hour.
2, contain the intermediate III of triphenylphosphine oxide and epoxy chloropropane at suitable solvent, as dimethyl formamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, suitable inorganic or organic bases, as sodium hydride, hydrolith, pyridine, triethylamine, catalysis generates the mixture that contains intermediate compound IV down, and then generates the mixture that contains intermediate V with the dimethylamine reaction.
3, the mixture that contains intermediate V be dissolved in not with the miscible organic solution of water in, with acidic aqueous solution intermediate V is extracted into aqueous phase, separatory, water is further removed remaining triphenylphosphine oxide and other non-water soluble impurities with organic solvent washing again, with aqueous solution furnishing alkalescence, with organic solvent intermediate V is extracted drying more then, concentrate, can obtain pure intermediate V free alkali; Or add suitable acid this intermediate salify is separated out from organic solvent solution, can obtain the salt of the higher intermediate V of purity, this free alkali or salt can obtain Sarpogrelate with the Succinic anhydried prepared in reaction.
The used organic solvent of this step can be all inactive not miscible with water organic solvents difficult and the reactant react with, as C1-C10 halogenated alkane such as chloroform, methylene dichloride, ethylene dichloride, C1-C10 alkyl oxide such as ether, isopropyl ether, propyl ether, methyl tertiary butyl ether, carboxylicesters such as methyl acetate, ethyl acetate, propyl acetate, aromatic hydrocarbons or chlorinated aromatic hydrocarbons such as benzene,toluene,xylene, chlorobenzene, bromobenzene.
The used acid of this step comprise can and 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) salifiable inorganic or organic acid of ethanol, can be that to be selected from but to be not limited to be in mineral acids such as hydrochloric acid, sulfuric acid, Hydrogen bromide or C1-C8 organic carboxyl acid or organic sulfonic acid such as methylsulfonic acid, trifluoracetic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, formic acid, tartrate, camphorsulfonic acid, butene dioic acid etc. one or two or more kinds.
The used alkali of this step comprises inorganic or organic bases, as the salt of alkaline-earth metal, and one or more in ammoniacal liquor, organic amine, particularly lithium hydroxide, sodium hydroxide, potassium hydroxide, ammoniacal liquor, salt of wormwood, the yellow soda ash.
4, the intermediate V that contains triphenylphosphine oxide also can make 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethanol salify and separates out from solution by add acid in the solution of organic solvent, and the triphen phosphine oxide is retained in the solution and reach the separation purpose.
The solvent that this reaction is used is to be not easy under this reaction conditions and moisture or water-free one or more solvents of reactant react with, and the alcohol of or unsaturated alkyl saturated as C1-C10 is as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, phenylcarbinol; Ether is as ether, isopropyl ether, propyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl-phenoxide; Amine, diethylamine, triethylamine, thanomin in this way; Carboxylic acid and acid amides are as formic acid, acetate, butyric acid, dimethyl formamide; Halogenated alkane is as methylene dichloride, chloroform, ethylene dichloride; Aromatic hydrocarbons or halogenated aryl hydrocarbon are as benzene,toluene,xylene, chlorobenzene.
The used acid of this step is as 3 indications.
5, the intermediate V that contains triphenylphosphine oxide also can continue to react in appropriate organic solvent with Succinic anhydried, obtain Sarpogrelate, with acid or alkali salify, triphen phosphine oxide etc. is difficult for salifiable impurity to be stayed in the solution then, and Sarpogrelate is separated out from solution with the form of salt.
The suitable solvent of this step is included in one or more organism that are not easy under the reaction conditions with the reactant react with, the alkane such as the pentane that comprise C2-C10, hexane, hexanaphthene, heptane, sherwood oil, C2-C10 ether such as ether, propyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, C3-C10 ketone such as acetone, butanone, pentanone, cyclopentanone, pimelinketone, the carboxylicesters of C2-C10 is formic acid particularly, acetate, the ester that propionic acid and C1-C5 alcohol form, the halogenated alkane of C1-C10 such as chloroform, methylene dichloride, ethylene dichloride, aromatic hydrocarbons or arene derivatives such as toluene, dimethylbenzene, chlorobenzene.
What this step was used can comprise inorganic or organic acid with the salifiable acid of Sarpogrelate, can be that to be selected from but to be not limited to be organic carboxyl acid or the organic sulfonic acid of mineral acids such as hydrochloric acid, sulfuric acid, Hydrogen bromide or C1-C8, as in methylsulfonic acid, trifluoracetic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, formic acid, tartrate, the camphorsulfonic acid etc. one or two or more kinds, particularly preferably be hydrochloric acid (or hydrogenchloride).
What this step was used can comprise mineral alkali with the salifiable alkali of Sarpogrelate, as the salt of basic metal and alkaline-earth metal, or ammonia, or organic bases, as the organic amine of C1-C10, pyridine etc.
The salt of the Sarpogrelate that 6, prepares particularly hydrochloride can be with the refining purity product of higher (as more than 98%) that obtains of appropriate solvent.Ideal medicine recrystallization solvent should be that solubleness is moderate, nontoxic or low toxicity, and boiling point is low to be easy to drying and to remove.Test through the inventor, the alkane of C2-C10 such as pentane, hexane, hexanaphthene, heptane, sherwood oil, C2-C10 ether such as ether, propyl ether, isopropyl ether, C3-C10 ketone such as acetone, butanone, pentanone, cyclopentanone, pimelinketone, the carboxylicesters of C2-C10 such as formic acid, acetate, the ester that propionic acid and C1-C5 alcohol form, the halogenated alkane of C1-C10 such as chloroform, methylene dichloride, ethylene dichloride, aromatic hydrocarbons or arene derivatives such as toluene, dimethylbenzene, chlorobenzene is all very little unsuitable separately as the recrystallization solvent of Sarpogrelatehydrochloride to the solubleness of Sarpogrelatehydrochloride to the reflux temperature in room temperature, use water as and moisturely in recrystallization solvent or the organic solvent also can not get highly purified product more than 5%, and methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile, propionitrile, acetate, ethylene glycol monomethyl ether, 1, the 4-dioxane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetramethylene sulfone, two or more mixture of dimethyl sulfoxide (DMSO) or its, or itself and acetone, ethyl acetate, the mixture of ether etc. is the recrystallization solvent that relatively is fit to.
The present invention makes the suitability for industrialized production of Sarpogrelatehydrochloride easier, has advantage easy and simple to handle, that production cost is low.
Embodiment
Specifically, the present invention can be illustrated by following examples, but scope of the present invention is not limited only to these embodiment.
Embodiment 1 2-((3-methoxyl group) styroyl) phenol (mixture)
Will be through Wittg prepared in reaction (J.Med.Chem.1990, ((3-methoxyl group) styryl) phenol mixture of 2-33:1818-1823) 100 kilograms (containing triphenylphosphine oxide 55%) is added in the 1000L autoclave, add 450 liters of ethanol, 5% Pd-C15 kilogram adds hydrogen to 0.5Mpa, temperature control stirs hydrogenation 3 hours for 50 ℃, filter, concentrate, get light yellow oil, yield 96%, HPLC detect and show that hydrogenation is complete.
Embodiment 2 2-((3-methoxyl group) styroyl) phenol (mixture)
To be added in the reaction flask through the 2-of Wittg prepared in reaction ((3-methoxyl group) styryl) phenol mixture 190 grams (containing triphenylphosphine oxide 52%), add methyl alcohol 1000ml, Raney's nickel 20 grams, feed hydrogen, 40 ℃ are stirred hydrogenation 10 hours, filter, and concentrate, get light yellow oil, HPLC detects and shows that hydrogenation is complete.
Embodiment 3 2-((3-methoxyl group) styroyl) phenol (mixture)
With embodiment 1, use 10% palladium carbon instead, pressure is 1MPa, room temperature reaction, yield 95%.
Embodiment 4 2-((3-methoxyl group) styroyl) phenol (mixture)
Will be through the 2-of Wittg prepared in reaction ((3-methoxyl group) styryl) phenol mixture 10 grams (through the preliminary triphen phosphine oxide of removing, contain triphenylphosphine oxide 15%) be added in the 100ml flask, add acetic acid 50ml, platinum oxide 1 gram, stir hydrogenation 10 hours at 30 ℃, filter, concentrate, get light yellow oil, yield 98%.
Embodiment 5 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethylate hydrochlorate
Embodiment 1 resulting oily matter 10kg is added in 60 liters of dimethyl formamides, add 2.5 kilograms of 60% sodium hydrides (being dissolved in mineral oil) in batches, stir, slowly add 15 kilograms of epoxy chloropropane, stirring at room reaction 10 hours, removal of solvent under reduced pressure and unnecessary epoxy chloropropane, add 100 liters of toluene, 50 liters of frozen water wash 2 times, anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and residual thing adds 100 liters of tetrahydrofuran (THF)s, 55 kilograms of 30% dimethylamine agueous solutions, 40 ℃ of stirring reactions of temperature control 5 hours, concentrating under reduced pressure removes and desolvates, and adds 100 liters of ethyl acetate, 100 liters of 10% hydrochloric acid, fully stirred 1 hour, tell organic layer, water layer is again with 50 liters of ethyl acetate washings 2 times, water layer is regulated pH=9 with 20% sodium hydroxide, with 100 liters of ethyl acetate, 50 liters, 50 liters are extracted three times, merge organic layer, 50 liters of washings of saturated aqueous common salt, anhydrous magnesium sulfate drying, the elimination siccative, filtrate feeds dry hydrogen chloride, and the white solid of separating out filters, dry, get 6.2 kilograms of 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethylate hydrochlorates, yield 82%, HPLC purity 98.8%.
Embodiment 6 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethanol
With embodiment 5, the pressurization of the ethyl acetate solution of elimination siccative concentrates to remove and desolvates, and obtains lurid 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethanol oily matter, yield 92%, HPLC purity 98.6%.
Embodiment 7 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethylate hydrochlorate
Embodiment 1 resulting oily matter 1kg is added in 6 liters of dimethyl formamides, add 0.3 kilogram of 60% sodium hydride (being dissolved in mineral oil) in batches, stir, slowly add 1.2 kilograms of epoxy chloropropane, stirring at room reaction 7 hours, removal of solvent under reduced pressure and unnecessary epoxy chloropropane, add 10 liters of toluene, 3 liters of frozen water wash anhydrous magnesium sulfate drying 2 times, filter, filtrate decompression concentrates, and residual thing adds 1,10 liters of 4-dioxane, 5 kilograms of 30% dimethylamine agueous solutions, 35 ℃ of stirring reactions of temperature control 5 hours, concentrating under reduced pressure removes and desolvates, and adds 10 liters of methylene dichloride, feed hydrogenchloride, the white solid of separating out filters, and drying gets 0.55 kilogram of 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethylate hydrochlorate, yield 77%, HPLC purity 98.7%.
Embodiment 8 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethanol vitriol
With embodiment 5, the ethyl acetate solution of elimination siccative adds vitriolic ethyl acetate dilute solution, the solid filtering of separating out, and drying gets the light yellow solid powder, yield 86%, HPLC purity is greater than 98%.
Embodiment 9 Sarpogrelatehydrochlorides
2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethylate hydrochlorate that embodiment 5 is obtained adds in 10 premium on currency for 1 kilogram, regulates pH=8 with 20% sodium hydroxide, with 30 liters of extractions of ethyl acetate, anhydrous magnesium sulfate drying, add Succinic anhydried 350g, reflux 3 hours is cooled to room temperature, feeding hydrogen chloride gas separates out product, filter, filter cake adds in 10 liters of methyl alcohol, adds gac 100g, reflux 30 minutes, take off charcoal, be cooled to room temperature, the Sarpogrelatehydrochloride of separating out filters, dry, get 1.1 kilograms of white powders, yield 87%, fusing point 145-147 ℃, HPLC purity 99% does not detect the triphen phosphine oxide.
1H-NMR(Brucker?AV-500，DMSO-D6，δ，ppm)：1.08(m，4H)，2.8(t，10H)，3.5(t，2H)，
3.7(s，3H)，4.2(t，2H)，5.6(s，1H)，6.7(m，1H)，6.8(t，1H)，6.83(d，1H)，6.88(m，1H)，6.97(m，1H)，7.1-7.2(m，2H)，11.2(brs，1H)，12.2(brs，1H)
13C-NMR(Brucker?AV-500，DMSO-D6，δ，ppm)：28.6，29.1，31.7，35.6，42.0，47.0，54.8，66.9，67.4，111.2，111.7，113.9，120.6，120.9，127.2，129.2，129.7，129.9，143.4，155.7，159.2，171.8，173.2。
Embodiment 10 Sarpogrelatehydrochlorides
2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethylate hydrochlorate that embodiment 5 is obtained adds in 10 premium on currency for 1 kilogram, regulates pH=8 with 20% sodium hydroxide, with 30 liters of extractions of ethyl acetate, anhydrous magnesium sulfate drying, add Succinic anhydried 350g, reflux 3 hours is cooled to room temperature, the ethyl acetate solution that adds hydrogenchloride is separated out product, filter, filter cake adds in 100 liters of ethanol, adds gac 100g, reflux 30 minutes, take off charcoal, be cooled to room temperature, the Sarpogrelatehydrochloride of separating out filters, dry, get 1.1 kilograms of white powders, yield 87%, fusing point 146-148 ℃, HPLC purity 99.1% does not detect the triphen phosphine oxide.
Embodiment 11 Sarpogrelatehydrochlorides
2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethanol oily matter 100g that embodiment 6 is obtained joins in 0.6 liter of tetrahydrofuran (THF), add Succinic anhydried 40g, reflux 5 hours, be cooled to room temperature, feed hydrogen chloride gas product is separated out, filter, filter cake adds in 2 liters of acetonitriles, add gac 10g, reflux 10 minutes is taken off charcoal, be cooled to room temperature, the Sarpogrelatehydrochloride of separating out filters, and drying gets white powder 130g, yield 92%, fusing point 145-148 ℃, HPLC purity 99.3% does not detect the triphen phosphine oxide.
Embodiment 12 Sarpogrelatehydrochlorides
Embodiment 3 resulting oily matter 5kg are added in 30 liters of dimethyl formamides, add 1.2 kilograms of 60% sodium hydrides (being dissolved in mineral oil) in batches, stir, slowly add 7 kilograms of epoxy chloropropane, stirring at room reaction 10 hours, removal of solvent under reduced pressure and unnecessary epoxy chloropropane, add 50 liters of toluene, 20 liters of frozen water wash anhydrous magnesium sulfate drying 2 times, filter, filtrate decompression concentrates, and residual thing adds 50 liters of tetrahydrofuran (THF)s, 25 kilograms of 30% dimethylamine agueous solutions, stirring at room reaction 8 hours, concentrating under reduced pressure removes and desolvates, add 50 liters of ethyl acetate, Succinic anhydried 1.5kg, reflux 2 hours, be cooled to room temperature, feed hydrogen chloride gas product is separated out, filter, filter cake adds in 50 liters of methyl alcohol, add gac 500g, reflux 30 minutes is taken off charcoal, adds 20 liters in acetone, stirring is cooled to room temperature, the Sarpogrelatehydrochloride of separating out filters, and drying gets 4 kilograms of white powders, yield 87%, fusing point 146-149 ℃, HPLC purity 98.7% does not detect the triphen phosphine oxide.
Embodiment 13 Sarpogrelatehydrochlorides
Get Sarpogrelatehydrochloride crude product 10g, add dimethyl formamide 30ml heating and make dissolving, add gac 1g, be incubated 10 minutes, take off charcoal while hot, add acetone 100ml, the room temperature standing over night, filter, washing with acetone gets product 8.6g, yield 86%, fusing point 144-147 ℃, HPLC purity 99.6% does not detect the triphen phosphine oxide.
Embodiment 14 Sarpogrelatehydrochlorides
Get Sarpogrelatehydrochloride crude product 10kg, add methyl alcohol 100kg heating and make dissolving, add gac 1kg, refluxed 20 minutes, and took off charcoal while hot, add ethyl acetate 100kg, the room temperature standing over night, filter, the ethyl acetate washing gets product 8.2kg, yield 82%, fusing point 145-147 ℃, HPLC purity 98.9% does not detect the triphen phosphine oxide.
Embodiment 15 Sarpogrelatehydrochlorides
Get Sarpogrelatehydrochloride crude product 10g, add 1,4-dioxane 80ml heating makes dissolving, adds gac 1g, is incubated 10 minutes, take off charcoal while hot, the cooling standing over night is filtered, and washing with alcohol gets product 8.9g, yield 89%, fusing point 144-148 ℃, HPLC purity 99.0% does not detect the triphen phosphine oxide.
It is recrystallization solvent that Comparative Examples adopts acetone-water
Get Sarpogrelatehydrochloride 10g (HPLC 98.6%), added acetone 2000ml reflux 30 minutes, major part is not dissolved, add 100ml water, heating for dissolving adds gac 1g, be incubated 10 minutes, take off charcoal while hot, the cooling standing over night is filtered, washing with acetone, get product 8.5g, yield 85%, HPLC purity 95.0%.
Claims (8)
1. the preparation method of a Sarpogrelatehydrochloride, 2-((3-methoxyl group) styryl) phenol mixture that it is characterized in that containing the triphen phosphine oxide is through catalytic hydrogenation, again and the reaction of epoxy chloropropane, dimethylamine obtain 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethanol, separate or do not separate the triphen phosphine oxide this moment, obtain Sarpogrelate with the Succinic anhydried reaction, with the hydrogenchloride salify, obtain Sarpogrelatehydrochloride then.
2. according to the method for claim 1, contain triphenylphosphine oxide 10-90% in 2-((3-methoxyl group) styryl) phenol mixture, have more the representational 20-60% of being.
3. according to the method for claim 1, the used catalyzer of catalytic hydrogenation is load or the unsupported containing metal or the catalyzer of metallic compound, as simple substance and compounds thereof such as palladium, nickel, ruthenium, platinum, rhodiums, particularly palladium carbon, Raney's nickel, platinum oxide etc., the amount of catalyzer is the 0.01-100% of substrate weight, preferably 0.1-50%.
4. according to the method for claim 1, the removal of triphen phosphine oxide is by 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethanol and sour salify being increased the solubility properties difference of itself and triphen phosphine oxide, make 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethylate is separated out from solvent and the triphen phosphine oxide is dissolved in the organic solvent, or make 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) ethylate be dissolved in aqueous phase and carry out.
5. according to the method for claim 1, the removal of triphen phosphine oxide is after reaction generates Sarpogrelate, adds acid and the Sarpogrelate salify is separated out carry out from solution.
6. according to claim 4,5 method, adding and 2-(dimethylamino)-1-(neighbour-(anisylethyl) Phenoxymethyl) salifiable acid of ethanol be to be selected from the organic carboxyl acid of mineral acids such as hydrogenchloride, hydrogen bromide, sulfuric acid or C1-C8, in the organic sulfonic acid one or more.
7. according to the method for claim 1, the Sarpogrelatehydrochloride that obtains can adopt alcohol, ether, nitrile, carboxylic acid, acid amides, ester or its mixture recrystallization of recrystallization solvent such as C1-C8 to obtain highly purified product.
8. according to the method for claim 7, recrystallization solvent is acetonitrile, propionitrile, 1,4-dioxane, tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetramethylene sulfone, dimethyl sulfoxide (DMSO) or the mixture more than two kinds, or the mixture of itself and methyl alcohol, ethanol, acetone, ethyl acetate, ether, isopropyl ether etc.
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| JP2013213032A (en) * | 2012-04-01 | 2013-10-17 | Eshyasi Pharma Ltd | Method for industrially producing (2rs)-1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]fhenoxy]propane-2-il succinic hydrogen hydrochloride |
| CN108205034A (en) * | 2017-12-29 | 2018-06-26 | 天津红日药业股份有限公司 | One kind contains the related substance detecting method of sarpogrelate hydrochloride intermediate |
| CN109824527A (en) * | 2019-03-18 | 2019-05-31 | 安徽峆一药业股份有限公司 | A kind of synthetic method of sarpogrelate hydrochloride |
| CN111514150A (en) * | 2020-05-22 | 2020-08-11 | 清华大学 | Application of TPPO in inhibiting FPP-induced cell death and corresponding reperfusion injury |
| CN111807976A (en) * | 2020-07-29 | 2020-10-23 | 深圳市道科思医药有限公司 | Novel method for preparing sarpogrelate hydrochloride |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5832847A (en) * | 1981-08-20 | 1983-02-25 | Mitsubishi Chem Ind Ltd | (3-aminopropoxy)bibenzyl compound |
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| CN101967104A (en) * | 2008-11-10 | 2011-02-09 | 上海密江国际贸易有限公司 | IV type crystal, method for preparing the same and pharmaceutical composition comprising the same |
| CN102372643A (en) * | 2010-08-13 | 2012-03-14 | 天津市科林化工有限公司 | Preparation method for sarpogrelate hydrochloride |
| CN102516043A (en) * | 2011-12-13 | 2012-06-27 | 北大国际医院集团西南合成制药股份有限公司 | Preparation method of Sarpogrelate intermediate 2-((3-methoxy) phenethyl) phenol |
| JP2013213032A (en) * | 2012-04-01 | 2013-10-17 | Eshyasi Pharma Ltd | Method for industrially producing (2rs)-1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]fhenoxy]propane-2-il succinic hydrogen hydrochloride |
| CN103242179A (en) * | 2013-05-08 | 2013-08-14 | 深圳万乐药业有限公司 | Preparation method of high-purity sarpogrelate hydrochloride |
| CN103242179B (en) * | 2013-05-08 | 2014-12-17 | 深圳万乐药业有限公司 | Preparation method of high-purity sarpogrelate hydrochloride |
| CN108205034A (en) * | 2017-12-29 | 2018-06-26 | 天津红日药业股份有限公司 | One kind contains the related substance detecting method of sarpogrelate hydrochloride intermediate |
| CN108205034B (en) * | 2017-12-29 | 2020-10-27 | 天津红日药业股份有限公司 | Method for detecting related substances containing sarpogrelate hydrochloride intermediate |
| CN109824527A (en) * | 2019-03-18 | 2019-05-31 | 安徽峆一药业股份有限公司 | A kind of synthetic method of sarpogrelate hydrochloride |
| CN111514150A (en) * | 2020-05-22 | 2020-08-11 | 清华大学 | Application of TPPO in inhibiting FPP-induced cell death and corresponding reperfusion injury |
| CN111807976A (en) * | 2020-07-29 | 2020-10-23 | 深圳市道科思医药有限公司 | Novel method for preparing sarpogrelate hydrochloride |
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