CN103923080A - Method for preparing antithrombotic drug apixaban - Google Patents

Method for preparing antithrombotic drug apixaban Download PDF

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CN103923080A
CN103923080A CN201410135239.XA CN201410135239A CN103923080A CN 103923080 A CN103923080 A CN 103923080A CN 201410135239 A CN201410135239 A CN 201410135239A CN 103923080 A CN103923080 A CN 103923080A
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compd
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CN103923080B (en
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吴嗣林
彭少平
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Shanghai Hongbo Zhiyuan pharmaceutical Limited by Share Ltd
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SUZHOU JINGHONG BIOTECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention discloses a method for preparing an antithrombotic drug apixaban. The method is characterized in that a compound IV is used as a raw material to perform a hydrolysis reaction for 5-60 minutes at 10-100 DEG C in a polar organic solvent under an alkaline condition, and is transformed into a compound antithrombotic drug apixaban; the antithrombotic drug apixaban is prepared by re-crystallizing, sizing and column chromatography purification. The method has the advantage of high yield, is simple and convenient in the subsequent treatment due to extraction, drying, sizing, filtering, crystallizing, recrystallizing and other operation methods, and large-scale production is easily realized.

Description

A kind of method of preparing antithrombotic reagent Eliquis
Technical field
The present invention relates to the synthetic method of antithrombotic reagent Eliquis, belong to field technical field of medicine synthesis.
Background technology
Eliquis (Apixaban, BMS-562247), chemistry 1-(4-p-methoxy-phenyl)-7-oxo-6-(4-(2-oxo-piperidino) phenyl by name)-4,5,6,7-tetrahydrochysene-1H-pyrazolo (3,4-c) pyridine-3-carboxamide, U.S. chemical abstract registration number CAS:503612-47-3, the direct Xa factor inhibitor of a kind of new oral of Gai Yaoshiyou Bristol-Myers Squibb Co. and Pfizer's joint research and development.This medicine in March, 2011 in European Union's approval listing, trade(brand)name Eliquis, the clinical venous thromboembolism (VTE) occurring for the adult patients of prevent to select a time hip joint or knee replacements.Clinical study result shows, compares with injecting 40 mg enoxaparins (enoxaparin) every day, and the VTE better effects if that every day, oral twice this medicine occurred after to prevention knee joint and replacement of total hip, and can not increase bleeding risk.This product shows the selectivity of height, good bioavailability and efficient result for the treatment of, and its performance is better than razaxaban (Razaxaban) greatly, is used for the treatment of deep venous thrombosis (DVT) and pulmonary infarction in interior phlebothrombosis.That this medical instrument has is safe, needn't accept monitoring with adjust dosage, can be oral, without cross resistance and the advantage such as untoward reaction is few, be expected to become oral antithrombotic first-line drug.
At present, in prior art, in the relevant patent documentation of the synthetic method of Eliquis, comprise Pinto D. J.P. et al. J. Med. Chem. 2007,50 (22), 5339-5356; WO2010/030983, WO2003/049681 and CN101967145 etc., disclose a plurality of synthetic methods.Document (Pinto D. J.P. et al. J. Med. Chem. 2007,50 (22), 5339-5356) discovery procedure of Eliquis has been carried out to detailed discussion and provided a pharmaceutical chemistry synthetic route ( scheme 1).
Scheme 1
scheme 1route take paraiodoaniline as starting raw material, by amidation ring-closure reaction, obtain compound with 5-bromine valeryl chloride 1, 1after phosphorus pentachloride chlorination, intermediate is eliminated to obtain in the condensation that refluxes under excessive morpholine exists 2.Another intermediate 3by starting raw material P-nethoxyaniline, after diazotization, with 2-chloroacetyl acetacetic ester, Japp-Klingmann hydrazone occurring closes to react and makes, intermediate 3with intermediate 2through cyclization-elimination reaction, obtain compound 4, compound 4under the catalysis of cuprous iodide, there is Ullmann reacting generating compound with δ-Valerolactim 5, compound 5in the ethylene glycol solution of ammonia, ammonia solution obtains target compound Eliquis.Auspex Pharmaceuticals, Inc. in 2010, in disclosed world patent WO 2010/030983, with same route, prepared this medicine, by 4, bring up to 29% with-Valerolactim condensation reaction yield, but total recovery only has 1.3%, in addition, the expensive iodine organic reagent that contains also limits this route utilization.
Bristol-Myers Squibb company provided an other synthetic route in disclosed world patent WO2003/049681 in 2003, this route has been used expensive containing iodine organic reagent, and total recovery only has 5.2%; Bristol-Myers Squibb company discloses again the technique patent (US2006/0069258) of this medicine in 2006 scheme 2:
Scheme 2
scheme 2route take p-Nitroaniline as raw material, by amidation ring-closure reaction, obtain compound with 5-bromine valeryl chloride 7, 7after phosphorus pentachloride dichloride, under Quilonum Retard and lithium chloride existence, add thermal condensation and eliminate to obtain intermediate 9.There is Japp-Klingmann hydrazone building-up reactions with 2-chloroacetyl acetacetic ester by starting raw material P-nethoxyaniline and make in another intermediate 3, intermediate after diazotization 3with intermediate 9through cyclization-elimination reaction, obtain compound 10, 10through the reduction of palladium hydrocarbonize, obtain aminocompound 11, 11by amidation ring-closure reaction, obtain compound with 5-bromine valeryl chloride 5, finally in DMF and methane amide, through ammonia, solve target compound Eliquis.Although this route total recovery obtains certain raising, but adopts linear synthetic route, route is longer, is difficult for realizing large-scale production; Also use the raw material of the unstable and difficult aftertreatment such as a large amount of 5-bromine valeryl chlorides and phosphorus pentachloride simultaneously, expensive palladium hydrocarbonize condition, these deficiencies have all limited suitability for industrialized production; Final step ammonia solution has been used DMF to make solvent, solvent easily residual being difficult for remove, make product be difficult to reach API standard.
Summary of the invention
The invention provides a kind of method of preparing antithrombotic reagent Eliquis.
For achieving the above object, the technical solution used in the present invention is: a kind of method of preparing antithrombotic reagent Eliquis, it is characterized in that: in polar organic solvent, take compounds Ⅳ as raw material, under alkaline condition, the mol ratio of compounds Ⅳ and alkali is 1.0:1.0-1.0:20,10 °-100 ° of temperature, reaction times is through hydrolysis, to obtain compound antithrombotic reagent Eliquis in 5-60 minute, antithrombotic reagent Eliquis obtains by recrystallization, making beating, column chromatography purification, and the chemical formula of compounds Ⅳ is:
，
（Ⅳ）。(Eliquis)
Wherein polar organic solvent can be one or more in small molecules fatty alcohol, tetrahydrofuran (THF), DMF; Alkali can be mineral alkali, such as: one or more in sodium hydroxide, lithium hydroxide or potassium hydroxide.
The preparation process of compounds Ⅳ: in non-protonic solvent, compound III is under alkaline condition, the mol ratio of compound III and alkali is 1.0:1.0-1.0:10, temperature is between 0 °-100 °, reaction times is after molecule cyclization, to obtain compounds Ⅳ in 1-8 hour, compounds Ⅳ can obtain by recrystallization, mixed solvent making beating, column chromatography purification, and the chemical formula of compound III is:
（Ⅲ）
Wherein, R can be Cl, Br, I, OSO 2me, OSO 2cF 3, OSO 2ph, OSO 2ph-p-Me.
Wherein, non-protonic solvent can be one or more in toluene, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride or chloroform; Alkali can be organic bases or mineral alkali, and organic bases can be one or more in triethylamine, DMAP, DIPEA; Mineral alkali can be one or more in sodium hydrogen, sodium tert-butoxide, potassium tert.-butoxide, salt of wormwood, sodium carbonate, sodium bicarbonate and saleratus.
The preparation process of compound III: under non-protonic solvent, under alkaline condition, the mol ratio of compound ii and alkali is 1.0:1.0-1.0:10, temperature of reaction is between 0 °-50 °, in compound ii, drip halide reagent or methylsulfonyl chloride, p-methyl benzene sulfonic chloride and trifluoromethylbenzene chloride solution is reacted and obtains compound III, reaction times is 30-60 minute, and compound III obtains by recrystallization, mixed solvent making beating, column chromatography purification, and the chemical formula of compound ii is:
（Ⅱ）
Wherein, non-protonic solvent can be one or more in toluene, methylene dichloride, ethylene dichloride, chloroform; Organic bases can be one or more of the tertiary amine organic basess such as triethylamine, DMAP, DIPEA; Halide reagent can be in phosphorus pentachloride, phosphorus oxychloride, hydrogenchloride, tetracol phenixin, triphenylphosphine, chlorine, NCS, cyanuric chloride, NBS, phosphorus tribromide, hydrogen bromide, carbon tetrabromide, triphenylphosphine, bromine, NIS, hydrogen iodide and iodine the mixing of one or more.
The preparation process of compound ii: in non-polar solvent, under the catalysis of Lewis acid, temperature of reaction is 0 °-80 °, chemical compounds I and Compound C are carried out ammonia transesterify and are obtained compound ii, chemical compounds I wherein: Compound C: the mol ratio of Lewis acid is 1.0:1.0:1.0-1.0:5.0:10, reaction times is 3-5 hour, and compound ii obtains by recrystallization, mixed solvent making beating, column chromatography purification, and the chemical formula of chemical compounds I is:
（Ⅰ）
Non-polar solvent can be one or more in toluene, dimethylbenzene, methylene dichloride, ethylene dichloride; Lewis acid can be one or more in trimethyl aluminium, chloro dimethyl chloride, aluminum chloride.
The preparation process of chemical compounds I: in non-polar organic solvent, under alkaline condition, take compd A and compd B obtains chemical compounds I by ring-closure reaction as raw material, chemical compounds I obtains by making beating, mixed solvent making beating, column chromatography purification, temperature of reaction is 20 °-100 °, reaction times is 1-8 hour, compd A: compd B: the mol ratio of alkali is 0.5:0.5:0.5-3:4.5:9, and the chemical formula of compd A is: , the chemical formula of compd B is: ,
Wherein, wherein, Z can be Cl, Br, I, OSO 2me, OSO 2ph, OSO 2ph-p-Me;
X can be Cl, Br, I or NR 1r 2;
R 1and R 2can be C 1-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
Or NR 1r 2it is by following former molecular 3-8 ring: carbon atom, a N and 0-1 Sauerstoffatom.
Wherein, non-polar organic solvent can be one or more in toluene, dioxane, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform; Alkali can be one or more in the organic basess such as triethylamine, pyridine, also can be one or more in the mineral alkalis such as sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus.
The preparation process of compd A: the first step: take P-nethoxyaniline as raw material, at-10 ° of-0 ° of temperature, under the effect of Sodium Nitrite, water and Tetrafluoroboric acid, generate P-nethoxyaniline diazonium a tetrafluoro borate, temperature of reaction is 20-50 minute, and wherein the mol ratio of anisidine, Tetrafluoroboric acid, Sodium Nitrite and water is 1.0:1.0:1.0:10-1.0:5.0:5.0:50;
Second step: take methyl-formiate and 2-halogen acetonitrile is raw material, at-5 °-0 °, product and P-nethoxyaniline diazonium Tetrafluoroboric acid reactant salt that under tetrahydrofuran (THF) and sodium methoxide solution, effect obtains, the reaction times is 0.25-8 hour, obtains compound a, compound acan obtain by method purifying such as recrystallization, mixed solvent making beating, column chromatographies, wherein the mol ratio of 2-halogen acetonitrile, methyl-formiate, sodium methylate, P-nethoxyaniline diazonium a tetrafluoro borate, tetrahydrofuran (THF) and water is 1.0:1.0:1.0:1.0:20:5.0-1.0:5.0:5.0:5.0:50:30.
The preparation process of compd B: for raw material, under 0 °-30 °, in non-proton organic solvent, carry out bromination by bromine with 5,6-dihydro-pyran-2-one, the reaction times is 0.5-6 hour, obtains compound b, compound bcan be dried by extraction, after concentrating, obtain, wherein, the mol ratio of 5,6-dihydro-pyran-2-one, bromine and non-proton organic solvent is 1.0:1.0:5.0-1.0:3.0:50;
Wherein, one or more in the preferred toluene of non-proton organic solvent, methylene dichloride, ethylene dichloride, chloroform.
Due to the utilization of technique scheme, compared with prior art, the advantage having is in the present invention:
1, the starting raw material anisidine that the present invention adopts and 5,6-dihydro-pyran-2-one are the raw material that the synthetic field of organic drug generally adopts, low price and easily obtaining.
2, in the present invention, each step reaction temperature is all between-10 °-100 °, and reaction conditions is gentleer, and simple and safe operation is environmentally friendly, easily carries out suitability for industrialized production
2, the present invention only adopts such as working method such as: extraction, dry, making beating, filtration, crystallization and recrystallizations in each middle-chain, and aftertreatment is simple and convenient, than being easier to realize scale operation.
3, route of the present invention is novel, obtains a plurality of brand-new intermediates in building-up process, and the stable in properties of intermediate, easy and simple to handle, is easy to realize industrialized production.
4, yield of the present invention is high.
Embodiment
By specific embodiment, the present invention will be further described below.
Embodiment mono-:
Preparation process about compd A:
The first step: P-nethoxyaniline is dissolved in Tetrafluoroboric acid and water, with cryosel, bathe and be cooled to-10 °--5 °, slowly drip the water-soluble solution of Sodium Nitrite, temperature keeps 0 °--5 °, drip rear reaction and continue to stir 20-50 minute, preferably churning time is 30-40 minute, filter afterwards, filter cake washs with cooling good ether, the dry gray solid product P-nethoxyaniline diazonium a tetrafluoro borate that obtains of filter cake normal-temperature vacuum, anisidine wherein, Tetrafluoroboric acid, the mol ratio of Sodium Nitrite and water is 1.0:1.0:1.0:10-1.0:5.0:5.0:50, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:1.5:1.5:15-1.0:4.5:4.5:45, 1.0:2.0:2.0:20-1.0:4.0:4.0:40, 1.0:3.0:3.0:30-1.0:3.5:3.5:35, preferred mol ratio is 1.0:1.5:1.5:30, yield: 90-95 %.
Second step: sodium methylate is dissolved in anhydrous tetrahydro furan, stir to obtain colourless suspension, with cryosel, bathe and be cooled to-5 ℃-0 °, drip methyl-formiate, drip rear stirring 0.25-0.5 hour, start to drip the 2-halogen acetonitrile that is dissolved in anhydrous tetrahydro furan, wherein, halogen acetonitrile is 2-fluoride acetonitrile, 2-chloromethyl cyanide, 2-bromoacetonitrile, 2-iodomethyl cyanide, one or more in 2-astatine acetonitrile, 2-chloromethyl cyanide solution preferably, reaction solution becomes clarification from muddiness, slowly become again muddy, continuing to stir reaction in 0.25-8 hour finishes, the preferred time is 6-8 hour, temperature keeps-5 °-0 °, the solution of water-soluble P-nethoxyaniline diazonium a tetrafluoro borate will be dripped in reaction system, drip rear continuation and stir 1-5 hour, 2-3 hour preferably, after reaction finishes, reaction system layering, water is extracted with ethyl acetate, dry, concentrating under reduced pressure obtains residue, residue is pulled an oar in sherwood oil, filter, filtration cakes torrefaction obtains faint yellow solid product a, wherein, 2-halogen acetonitrile, methyl-formiate, sodium methylate, P-nethoxyaniline diazonium a tetrafluoro borate, the mol ratio of tetrahydrofuran (THF) and water is 1.0:1.0:1.0:1.0:20:5.0-1.0:5.0:5.0:5.0:50:30, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:1.5:1.5:1.5:25:10-1.0:4.5:4.5:4.5:45:25, 1.0:2.0:2.0:2.0:30:15-1.0:4.0:4.0:4.0:35:20, preferred mol ratio is 1.0:1.0:1.2:25:10, yield: 80%-86 %. 1H NMR (400 MHz, CDCl 3, ppm) δ 8.46(s, 1H), 7.12(d, J =8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.80(s, 3H). MS: 210(M+1)。
Embodiment bis-:
Preparation process about compd B
By 5,6-dihydro] pyran-2-one is dissolved in non-proton organic solvent, wherein, non-proton organic solvent comprises one or more in toluene, methylene dichloride, ethylene dichloride, chloroform, preferably methylene dichloride, keeps 25 °-30 ° by temperature, slowly drips the solution that bromine is dissolved in methylene dichloride, 2-5 hour, preferably 4-5 hour are stirred in reaction.After reaction finishes, reaction system is cooled to 0 °-5 °, stirs 0.5-1 hour, and system dilute with water, separates organic phase, water dichloromethane extraction, and the saturated common salt water washing of the organic phase of merging, dried over sodium sulfate, concentrate drying obtains colorless liquid product b,wherein, 5, the mol ratio of 6-dihydro-pyran-2-one, bromine and methylene dichloride is 1.0:1.0:5.0-1.0:3.0:50, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:1.3:10-1.0:2.7:45,1.0:1.7:5.0-1.0:2.4:35,1.0:2.0:20-1.0:2.2:30, preferred mol ratio is 1:1.3:20, yield: 80%-86 %. 1H NMR (400 MHz, CDCl 3, ppm) δ 7.29(t, 1H), 4.49(t, 2H), 2.59-2.56 (m, 2H)。
Embodiment tri-:
The preparation process of chemical compounds I
Compd A and compd B are dissolved in non-polar organic solvent, wherein non-polar organic solvent can be toluene, dioxane, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, one or more in chloroform, toluene preferably, add alkali, alkali can be triethylamine, in the organic basess such as pyridine one or more, also can be sodium carbonate, sodium bicarbonate, salt of wormwood, in the mineral alkalis such as saleratus one or more, triethylamine preferably, be warming up to 20 °-100 °, preferred temperature is 80 °-100 °, stirring reaction 1-10 hour, preferred churning time is 8-10 hour, afterwards reaction system is down to 20 °-30 °, filtrate water dilution, layering, organic phase saturated common salt water washing, dried over sodium sulfate, concentrate to obtain resistates, resistates is stirring to pulp in ethyl acetate, filter, vacuum-drying obtains light yellow solid product I, wherein, compd A, compd B, the mol ratio of triethylamine is 0.5:0.5:0.5-3:4.5:9, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:1.0:1.5-2.5:4.0:9, 1.5:1.5:2.5-2:3.5:9, preferred mol ratio is 1:1.2:3, yield: 80 %-85%. 1H NMR (400 MHz, CDCl 3, ppm) δ7.47 (d, J =9.2 Hz, 2H), 6.98 (d, J = 9.2 Hz, 2H), 4.64 (t, J = 6.0 Hz, 2H), 3.86(s, 3H), 3.13 (t, J = 6.4 Hz, 2H). MS: 270(M+1)。
Embodiment tetra-:
The preparation process of compound ii
method one:
By compound cbe dissolved in non-polar solvent, non-polar solvent can be toluene, dimethylbenzene, methylene dichloride, ethylene dichloride, the solution of ethylene dichloride preferably wherein, be cooled to 0 °-10 °, under nitrogen protection, drip Lewis acid, Lewis acid can be trimethyl aluminium, chloro dimethyl chloride, in aluminum chloride one or more, wherein, trimethyl aluminium preferably, after dripping, rise to stirring at room reaction 1-3 hour, preferably after 1-2 hour, drip the dichloroethane solution of chemical compounds I, then be warming up to 60 °-80 °, preferably 60 °-70 °, reaction 1-2 hour, reaction system is down to 20 °-30 °, with saturated aqueous ammonium chloride solution cancellation, layering, water extracts with ethylene dichloride, the organic phase saturated common salt water washing merging, dried over sodium sulfate, concentrate drying obtains light yellow solid product II, chemical compounds I wherein: compound c: the mol ratio of trimethyl aluminium is 1.0:1.0:1.0-1.0:5.0:10, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:1.5:2.0-1.0:4.5:8,1.0:2.5:4.0-1.0:3.5:6, preferred mol ratio is 1:1.5:3, yield: 85 %-90%.
method two:
By chemical compounds I and compound cbe suspended in non-polar solvent, non-polar solvent can be toluene, dimethylbenzene, methylene dichloride, ethylene dichloride, and wherein xylene solvent preferably, in dimethylbenzene, is warming up to 100 °-105 °, and stirring reaction spends the night; Be cooled to room temperature, vacuum rotary steam, except desolventizing, is crossed column purification and is obtained light yellow solid product II, wherein chemical compounds I: compound c:the mol ratio of dimethylbenzene is 1:1.3:50:, yield: 70%-75 %. 1H NMR (400 MHz, CDCl 3, ppm) δ 11.00 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.26(s, 1H), 3.85 (t, 2H), 3.71(s, 3H), 3.57 (m, 2H), 2.88 (t, 2H), 2.51 (m, 2H),1.93 (m, 4H). MS: 460(M+1)。
Embodiment five:
The preparation process of compound III
By compound ii and organic bases, organic bases can be triethylamine, DMAP, one or more in the tertiary amines such as DIPEA, preferably triethylamine is dissolved in non-protonic solvent, aprotic solvent can be toluene, methylene dichloride, ethylene dichloride, one or more in chloroform, methylene dichloride preferably, under nitrogen protection, be cooled to 0 °-5 °, slowly add halide reagent, methylsulfonyl chloride, p-methyl benzene sulfonic chloride or to trifluoromethylbenzene chloride solution, wherein halide reagent can be phosphorus pentachloride, phosphorus oxychloride, hydrogenchloride, tetracol phenixin, triphenylphosphine, chlorine, NCS, cyanuric chloride, NBS, phosphorus tribromide, hydrogen bromide, carbon tetrabromide, triphenylphosphine, bromine, NIS, the mixing of one or more in hydrogen iodide and iodine, under halide reagent condition, hydroxyl in compound ii is transformed into halogen, methylsulfonyl chloride preferably, system rises to 20 ° of-30 ° of stirring reaction 1-3 hour.Reaction solution is poured cancellation in frozen water into, separate organic phase, water dichloromethane extraction, organic phase saturated common salt water washing, dried over sodium sulfate, concentrate drying obtains light yellow solid product III, wherein the mol ratio of compound ii and triethylamine is 1.0:1.0-1.0:10, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:2.0-1.0:9,1.0:3.0-1.0:8,1.0:4.0-1.0:7,1.0:5.0-1.0:6, preferred mol ratio is 1:2, yield: 90 %-95%.
1H NMR (400 MHz, CDCl 3, ppm) δ 8.84 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.81(s, 3H), 3.54-3.53 (m, 2H), 3.20 (t, J = 6.0 Hz, 2H), 3.02 (s, 3H) 2.42-2.39 (m, 2H), 1.92-1.90 (m, 4H). MS: 538(M+1)。
Embodiment six:
The preparation process of compounds Ⅳ
method one:
Compound III is dissolved in non-protonic solvent, non-protonic solvent can be one or more in toluene, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride or chloroform, anhydrous tetrahydro furan preferably, under 0 °-100 °, preferably 0 °-10 °, add alkali, alkali can be one or more in the organic basess such as triethylamine, DMAP, DIPEA; Can be one or more in the mineral alkalis such as sodium hydrogen, sodium tert-butoxide, potassium tert.-butoxide, salt of wormwood, sodium carbonate, sodium bicarbonate and saleratus, tertiary butyl potassium alcoholate preferably, stirring reaction 1-5 hour.Reaction solution is poured cancellation in frozen water into, layering, water is extracted with ethyl acetate, the organic phase saturated common salt water washing merging, dried over sodium sulfate, concentrate drying obtains light yellow solid product IV, wherein, the mol ratio of compound III and tertiary butyl potassium alcoholate is 1.0:1.0-1.0:10, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:2.0-1.0:9,1.0:3.0-1.0:8,1.0:4.0-1.0:7,1.0:5.0-1.0:6, preferred mol ratio is 1:2, yield: 90 %-95%.
1H NMR (400 MHz, CDCl 3, ppm) δ 7.47 (d, J = 9.2 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 7.2 Hz, 2H), 3.81(s, 3H), 3.59-3.58 (m, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.56-2.54 (m, 2H),1.96-1.93 (m, 4H). MS: 442(M+1)。
method two:
By compound III and alkali, alkali can be one or more in the organic basess such as triethylamine, DMAP, DIPEA, can be sodium hydrogen, sodium tert-butoxide, potassium tert.-butoxide, salt of wormwood, sodium carbonate, one or more in the mineral alkali such as sodium bicarbonate and saleratus, preferably DMAP is suspended in non-protonic solvent, non-protonic solvent can be: toluene, tetrahydrofuran (THF), methylene dichloride, one or more in ethylene dichloride or chloroform, preferably in toluene, reflux, the temperature being heated to is 60 °-100 °, preferably 60 °-80 °, stirring reaction 1-8 hour, 6-8 hour preferably, 20-30 ° is down in reaction, layering, organic phase saturated common salt water washing, dried over sodium sulfate, concentrate to obtain residue, silicagel column purifying, wherein the eluent for silicagel column purifying consists of methylene dichloride and methyl alcohol, methylene dichloride: the volume ratio of methyl alcohol is 95:5, obtain light yellow solid product IV, wherein the mol ratio of compound III and DMAP is 1.0:1.0-1.0:10, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:2.0-1.0:9, 1.0:3.0-1.0:8, 1.0:4.0-1.0:7, 1.0:5.0-1.0:6, preferred mol ratio is 1:3, yield: 85%-90 %.
Embodiment seven:
The preparation process of Eliquis
Under normal temperature, compound V is added in alkali, alkali can be one or more in the mineral alkalis such as sodium hydroxide, lithium hydroxide or potassium hydroxide, aqueous sodium hydroxide solution preferably, be warming up to 10 °-100 °, stirring reaction 5-60 minute, preferably 30-40 minute, after reaction finishes, system is down to 20 °-30 °, with dichloromethane extraction, layering, dry, concentrating under reduced pressure, residue silicagel column purifying, wherein the eluent for silicagel column purifying consists of methylene dichloride and methyl alcohol, methylene dichloride: the volume ratio of methyl alcohol is 30:1, obtain white powder product Eliquis, the mol ratio of compounds Ⅳ and aqueous sodium hydroxide solution is 1.0:1.0-1.0:20, this scope has comprised the numerical range in any sub-range wherein, non-exclusively can exemplify: 1.0:4-1.0:18, 1.0:6-1.0:16, 1.0:8-1.0:14, 1.0:10-1.0:12, preferred mol ratio is 1:10, yield: 80-85 %.
1H NMR (400 MHz, CDCl 3, ppm) δ 7.47 (d, J = 9.2 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.85 (drs, 1H), 5.51(drs, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.82(s, 3H), 3.59-3.57 (m, 2H), 3.37 (t, J = 6.4 Hz, 2H), 2.56-2.55 (m, 2H),1.94-1.92 (m, 4H). MS: 460(M+1)。
1, the starting raw material anisidine that the present invention adopts and 5,6-dihydro-pyran-2-one are the raw material that the synthetic field of organic drug generally adopts, low price and easily obtaining.
2, in the present invention, each step reaction temperature is all between-10 °-100 °, and reaction conditions is gentleer, and simple and safe operation is environmentally friendly, easily carries out suitability for industrialized production
2, the present invention only adopts such as working method such as: extraction, dry, making beating, filtration, crystallization and recrystallizations in each middle-chain, and aftertreatment is simple and convenient, than being easier to realize scale operation.
3, route of the present invention is novel, obtains a plurality of brand-new intermediates in building-up process, and the stable in properties of intermediate, easy and simple to handle, is easy to realize industrialized production.
4, yield of the present invention is high.

Claims (7)

1. a method of preparing antithrombotic reagent Eliquis, it is characterized in that: in polar organic solvent, take compounds Ⅳ as raw material, under alkali condition, the mol ratio of compounds Ⅳ and alkali is 1.0:1.0-1.0:20,10 °-100 ° of temperature, and the reaction times is through hydrolysis, to obtain compound antithrombotic reagent Eliquis in 5-60 minute, antithrombotic reagent Eliquis obtains by recrystallization, making beating, column chromatography purification, and the chemical formula of compounds Ⅳ is:
，
(IV) (Eliquis).
2. a kind of method of preparing antithrombotic reagent Eliquis according to claim 1, it is characterized in that: the preparation process of compounds Ⅳ: in non-protonic solvent, compound III is under alkaline condition, the mol ratio of compound III and alkali is 1.0:1.0-1.0:10, temperature is between 0 °-100 °, reaction times is after molecule cyclization, to obtain compounds Ⅳ in 1-8 hour, compounds Ⅳ can obtain by recrystallization, mixed solvent making beating, column chromatography purification, and the chemical formula of compound III is:
（Ⅲ）
Wherein, R can be Cl, Br, I, OSO 2me, OSO 2cF 3, OSO 2ph, OSO 2ph-p-Me.
3. a kind of method of preparing antithrombotic reagent Eliquis according to claim 2, it is characterized in that: the preparation process of compound III: under non-protonic solvent, under alkaline condition, the mol ratio of compound ii and alkali is 1.0:1.0-1.0:10, temperature of reaction is between 0 °-50 °, in compound ii, drip halide reagent or methylsulfonyl chloride, p-methyl benzene sulfonic chloride and trifluoromethylbenzene chloride solution reaction is obtained to compound III, reaction times is 30-60 minute, compound III is passed through recrystallization, mixed solvent making beating, column chromatography purification obtains, the chemical formula of compound II is:
（Ⅱ）。
4. a kind of method of preparing antithrombotic reagent Eliquis according to claim 3, it is characterized in that: the preparation process of compound ii: in non-polar solvent, under the catalysis of Lewis acid, temperature of reaction is 0 °-80 °, chemical compounds I and Compound C are carried out ammonia transesterify and are obtained compound ii, wherein chemical compounds I: compound c: the mol ratio of Lewis acid is 1.0:1.0:1.0-1.0:5.0:10, and the reaction times is 3-5 hour, and compound ii obtains by recrystallization, mixed solvent making beating, column chromatography purification, and the chemical formula of chemical compounds I is:
（Ⅰ） （C） 。
5. a kind of method of preparing antithrombotic reagent Eliquis according to claim 4, it is characterized in that: the preparation process of chemical compounds I: in non-polar organic solvent, under alkaline condition, take compd A and compd B obtains chemical compounds I by ring-closure reaction as raw material, chemical compounds I obtains by making beating, mixed solvent making beating, column chromatography purification, temperature of reaction is 20 °-100 °, reaction times is 1-10 hour, the mol ratio of compd A, compd B, alkali is 0.5:0.5:0.5-3:4.5:9, and the chemical formula of compd A is: , the chemical formula of compd B is: ,
Wherein, wherein, Z can be Cl, Br, I, OSO 2me, OSO 2ph, OSO 2ph-p-Me;
X can be Cl, Br, I or NR 1r 2;
R 1and R 2can be C 1-6alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
Or NR 1r 2it is by following former molecular 3-8 ring: carbon atom, a N and 0-1 Sauerstoffatom.
6. a kind of method of preparing antithrombotic reagent Eliquis according to claim 5, it is characterized in that: the preparation process of compd A: the first step: take P-nethoxyaniline as raw material, at-10 ° of-0 ° of temperature, under the effect of Sodium Nitrite, water and Tetrafluoroboric acid, generate P-nethoxyaniline diazonium a tetrafluoro borate, temperature of reaction is 20-50 minute, and wherein the mol ratio of anisidine, Tetrafluoroboric acid, Sodium Nitrite and water is 1.0:1.0:1.0:10-1.0:5.0:5.0:50;
Second step: take methyl-formiate and 2-halogen acetonitrile is raw material, at-5 °-0 °, product and P-nethoxyaniline diazonium Tetrafluoroboric acid reactant salt that under tetrahydrofuran (THF) and sodium methoxide solution, effect obtains, the reaction times is 0.25-8 hour, obtains compound a, compound acan obtain by method purifying such as recrystallization, mixed solvent making beating, column chromatographies, wherein the mol ratio of 2-halogen acetonitrile, methyl-formiate, sodium methylate, P-nethoxyaniline diazonium a tetrafluoro borate, tetrahydrofuran (THF) and water is 1.0:1.0:1.0:1.0:20:5.0-1.0:5.0:5.0:5.0:50:30.
7. a kind of method of preparing antithrombotic reagent Eliquis according to claim 5, it is characterized in that: the preparation process of compd B: with 5,6-dihydro-pyran-2-one is raw material, under 0 °-30 °, in non-proton organic solvent, by bromine, carry out bromination, the reaction times is 0.5-6 hour, obtains compound b, compound bcan be dried by extraction, after concentrating, obtain, wherein, the mol ratio of 5,6-dihydro-pyran-2-one, bromine and non-proton organic solvent is 1.0:1.0:5.0-1.0:3.0:50.
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