CN103923080B - A kind of method preparing antithrombotic reagent Eliquis - Google Patents
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Abstract
The invention discloses a kind of method preparing antithrombotic reagent Eliquis, it is characterized in that: in polar organic solvent, with compounds Ⅳ for raw material, in the basic conditions, temperature 10 DEG C-100 DEG C, response time is obtain compound antithrombotic reagent Eliquis through hydrolysis in 5-60 minute, antithrombotic reagent Eliquis is obtained by recrystallization, making beating, column chromatography purification, the invention have the advantage that yield is high and extract, dry, making beating, filter, the operational approach such as crystallization and recrystallization, post processing is simple and convenient, is easier to realize large-scale production。
Description
Technical field
The present invention relates to the synthetic method of antithrombotic reagent Eliquis, belong to field of medicament synthesis technical field。
Background technology
Eliquis (Apixaban, BMS-562247), chemistry 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxo-piperidino) phenyl)-4 by name, 5,6,7-tetrahydrochysene-1H-pyrazolo (3,4-c) pyridine-3-carboxamides, U.S. chemical abstract registration number CAS:503612-47-3, this medicine is the direct Xa factor inhibitor of a kind of new oral by Bristol-Myers Squibb Co. and Pfizer's joint research and development。This medicine in March, 2011 at European Union's approval listing, trade name Eliquis, the venous thromboembolism (VTE) that the adult patients of hip joint or knee replacements that is clinically used for preventing carrying out selecting a time occurs。Clinical study results shows, injects compared with a 40mg Enoxaparin (enoxaparin) with every day, and every day, oral twice this medicine was to the VTE better effects if of appearance after prevention knee joint and replacement of total hip, and will not increase bleeding risk。This product shows the selectivity of height, good bioavailability and efficient therapeutic effect, and its performance is significantly better than razaxaban (Razaxaban), is used for treating deep venous thrombosis (DVT) and pulmonary infarction in interior phlebothrombosis。This medical instrument has that safety is high, need not accept to monitor with adjusts dosage, orally available, lack etc. advantage without cross resistance and untoward reaction, be expected to become oral antithrombotic first-line drug。
At present, prior art includes in the patent documentation that the synthetic method of Eliquis is relevant, PintoD.J.P.etal.J.Med.Chem.2007,50 (22), 5339-5356；WO2010/030983, WO2003/049681 and CN101967145 etc., disclose multiple synthetic method。The discovery procedure of Eliquis has been carried out detailed discussion and has given a pharmaceutical chemistry synthetic route (Scheme1) by document (PintoD.J.P.etal.J.Med.Chem.2007,50 (22), 5339-5356)。
The route of Scheme1, with paraiodoaniline for initiation material, obtains compound 1,1 with 5-bromine valeric chloride after phosphorus pentachloride chlorination by amidatioon ring-closure reaction, and under excessive morpholine exists, backflow condensation eliminates to obtain intermediate 2。It is prepared that another intermediate 3 is occurred Japp-Klingmann hydrazone to close reaction with 2-chloroacetyl acetacetic ester by initiation material P-nethoxyaniline after diazotising, intermediate 3 and intermediate 2 are obtained by reacting compound 4 through cyclization-elimination, there is Ullmann reacting generating compound 5 with δ-valerolactam in compound 4, compound 5 aminolysis in the ethylene glycol solution of ammonia obtains target compound Eliquis under the catalysis of Hydro-Giene (Water Science).。AuspexPharmaceuticals, Inc. in world patent WO2010/030983 disclosed in 2010, it is prepared for this medicine with same route, 4 and-valerolactam condensation reaction yield are brought up to 29%, but total recovery only has 1.3%, additionally, costliness containing iodine organic reagent also limit this route use。
Bristol-MyersSquibb company gives an other synthetic route in world patent WO2003/049681 disclosed in 2003, this route employ costliness containing iodine organic reagent, total recovery only has 5.2%；Bristol-MyersSquibb company disclosed again technique patent (US2006/0069258) Scheme2 of this medicine in 2006:
The route of Scheme2, with paranitroanilinum for raw material, obtains compound 7,7 with 5-bromine valeric chloride after phosphorus pentachloride dichloride by amidatioon ring-closure reaction, and under lithium carbonate and lithium chloride exist, heat condensation eliminates to obtain intermediate 9。Another intermediate 3 is occurred Japp-Klingmann hydrazone synthetic reaction to prepare with 2-chloroacetyl acetacetic ester by initiation material P-nethoxyaniline after diazotising, intermediate 3 and intermediate 9 are obtained by reacting compound 10 through cyclization-elimination, 10 obtain amino-compound 11 through palladium carbon hydro-reduction, 11 obtain compound 5 with 5-bromine valeric chloride by amidatioon ring-closure reaction, finally in DMF and Methanamide, obtain target compound Eliquis through aminolysis。Although this route total recovery obtains certain raising, but adopts linear synthetic route, route is longer, not easily realizes large-scale production；Also using the raw material of the unstable and difficult post processings such as substantial amounts of 5-bromine valeric chloride and phosphorus pentachloride, expensive palladium carbon hydrogenation conditions, these deficiencies all limit industrialized production simultaneously；Final step aminolysis employs DMF and makes solvent, and solvent easily remains and not easily removes, and makes product be extremely difficult to API standard。
Summary of the invention
The present invention provides a kind of method preparing antithrombotic reagent Eliquis。
A kind of method preparing antithrombotic reagent Eliquis, comprises the steps:
The preparation of compound A: the first step: with P-nethoxyaniline for raw material, at-10 DEG C of-0 DEG C of temperature, P-nethoxyaniline diazonium tetrafluoroborate is generated under the effect of sodium nitrite, water and Tetrafluoroboric acid, response time is 20-50 minute, and wherein the mol ratio of aminoanisole, Tetrafluoroboric acid, sodium nitrite and water is 1.0:1.0:1.0:10-1.0:5.0:5.0:50；Second step: with methyl formate and 2-halogen acetonitrile for raw material, at-5 DEG C-0 DEG C, the product obtained and P-nethoxyaniline diazonium Tetrafluoroboric acid reactant salt is acted under oxolane and sodium methoxide solution, response time is 0.25-8 hour, obtain compound A, compound A passes through recrystallization, mixed solvent making beating or column chromatography method purification obtain, wherein 2-halogen acetonitrile, methyl formate, Feldalat NM, P-nethoxyaniline diazonium tetrafluoroborate, the mol ratio of oxolane 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 chemical formula of compound A is:Wherein, Z can be Cl, Br, I；
The preparation of compound B: with 5,6-dihydro-pyran-2-ketone is raw material, at 0 DEG C-30 DEG C, in non-proton organic solvent, carry out bromination by bromine, response time is 0.5-6 hour, obtain compound B, compound B by extracting, dry or obtaining after concentration, wherein, the mol ratio of 5,6-dihydro-pyran-2-ketone, bromine and non-proton organic solvent is 1.0:1.0:5.0-1.0:3.0:50；The chemical formula of compound B is:
Wherein, X is Br；
The preparation of compounds I: in non-polar organic solvent, under alkali condition, compounds I is obtained for raw material by ring-closure reaction with compound A and compound B, compounds I is obtained by making beating, mixed solvent making beating or column chromatography purification, reaction temperature is 20 DEG C-100 DEG C, response time is 1-10 hour, and the mol ratio of compound A, compound B and alkali is 0.5:0.5:0.5-3:4.5:9；The chemical formula of compounds I is:
The preparation of compound ii: in non-polar solven, under the catalysis of Lewis acid, reaction temperature is 0 DEG C-80 DEG C, compounds I and compound C carry out urethane exchange and obtain compound ii, wherein compounds I: the mol ratio of compound C:Lewis acid is 1.0:1.0:1.0-1.0:5.0:10, response time is 3-5 hour, and compound ii is obtained by recrystallization, mixed solvent making beating or column chromatography purification, and the chemical formula of compound ii and compound C is:
The preparation of compound III: under non-protonic solvent, in the basic conditions, the mol ratio of compound ii and alkali is 1.0:1.0-1.0:10, reaction temperature is between 0 DEG C-50 DEG C, compound ii drips halide reagent or mesyl chloride, p-methyl benzene sulfonic chloride and trifluoromethylbenzene chloride solution is obtained by reacting compound III, response time is 30-60 minute, and compound III is obtained by recrystallization, mixed solvent making beating, column chromatography purification, and the chemical formula of compound III is:
Wherein, R can be Cl, Br, I, OSO2Me、OSO2CF3、OSO2Ph-p-Me；
The preparation of compounds Ⅳ: in non-protonic solvent, compound III is in the basic conditions, the mol ratio of compound III and alkali is 1.0:1.0-1.0:10, temperature is between 0 DEG C-100 DEG C, response time is obtain compounds Ⅳ after molecule cyclization in 1-8 hour, compounds Ⅳ is obtained by recrystallization, mixed solvent making beating or column chromatography purification, and the chemical formula of compounds Ⅳ is:
The preparation of Eliquis: in polar organic solvent, with compounds Ⅳ for raw material, under alkaline conditions, the mol ratio of compounds Ⅳ and alkali is 1.0:1.0-1.0:20, temperature 10 DEG C-100 DEG C, response time is obtain compound antithrombotic reagent Eliquis through hydrolysis in 5-60 minute, and antithrombotic reagent Ah paisa class is obtained by recrystallization, making beating or column chromatography purification, the chemical formula of Eliquis:
Due to the utilization of technique scheme, the present invention compared with prior art, has the advantage, that
1, the present invention adopts initiation material aminoanisole and 5,6-dihydro-pyran-2-ketone are the commonly used raw material in organic drug synthesis field, low price and also be readily obtained；
2, in the present invention, each step reaction temperature is all between-10 DEG C-100 DEG C, and reaction condition is gentleer, simple and safe operation, environmentally friendly, it is easy to carry out industrialized production；
3, the present invention in each intermediate link only with such as: extract, dry, making beating, filter, the operational approach such as crystallization and recrystallization, post processing is simple and convenient, is easier to realize large-scale production；
4, route of the present invention is novel, obtains multiple brand-new intermediate and the stable in properties of intermediate in building-up process, easy and simple to handle, it is easy to accomplish industrialized great production。
5, the yield of the present invention is high。
Detailed description of the invention
By specific embodiment, the present invention will be further described below。
Embodiment one:
Preparation process about compound A:
The first step: P-nethoxyaniline is dissolved in Tetrafluoroboric acid and water, it is cooled to-10 DEG C with cryosel bath--5 DEG C, slowly dropping sodium nitrite is dissolved in the solution of water, temperature keeps 0 DEG C--and 5 DEG C, after dripping, reaction continues stirring 20-50 minute, preferred mixing time is 30-40 minute, it is filtered afterwards, the filter cake washed with diethylether cooled down, filter cake normal-temperature vacuum dries and obtains gray solid product P-nethoxyaniline diazonium tetrafluoroborate, wherein aminoanisole, 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 includes the numerical range in any subinterval therein, non-exclusively can enumerate: 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: Feldalat NM is dissolved in anhydrous tetrahydro furan, stir to obtain colorless suspension, it is cooled to-5 DEG C-0 DEG C with cryosel bath, dropping methyl formate, stir 0.25-0.5 hour after dripping, start to drip the 2-halogen acetonitrile being dissolved in anhydrous tetrahydro furan, wherein, halogen acetonitrile is 2-fluoride acetonitrile, 2-chloroacetonitrile, 2-bromoacetonitrile, 2-iodoacetonitrile, one or more in 2-astatine acetonitrile, preferably 2-chloroacetonitrile solution, reactant liquor is become clarification from muddiness, slowly become muddy again, continue stirring reaction in 0.25-8 hour to terminate, the preferred time is 6-8 hour, temperature keeps-5 DEG C-0 DEG C, dropping in reaction system is dissolved in the solution of the P-nethoxyaniline diazonium tetrafluoroborate of water, stirring 1-5 hour is continued after dripping, preferably 2-3 hour, after reaction terminates, reaction system is layered, aqueous phase is extracted with ethyl acetate, dry, concentrating under reduced pressure obtains residue, residue is pulled an oar in petroleum ether, filter, filtration cakes torrefaction obtains faint yellow solid product A, wherein, 2-halogen acetonitrile, methyl formate, Feldalat NM, P-nethoxyaniline diazonium tetrafluoroborate, the mol ratio of oxolane 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 includes the numerical range in any subinterval therein, non-exclusively can enumerate: 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%。1HNMR(400MHz,CDCl3, ppm) and δ 8.46 (s, 1H), 7.12 (d, J=8.8Hz, 2H), 6.90 (d, J=8.8Hz, 2H), 3.80 (s, 3H) .MS:210 (M+1)。
Embodiment two:
Preparation process about compound B
By 5,6-dihydro] pyran-2-one is dissolved in non-proton organic solvent, wherein, non-proton organic solvent includes one or more in toluene, dichloromethane, dichloroethanes, chloroform, preferably dichloromethane, keeps 25 DEG C-30 DEG C by temperature, is slowly added dropwise bromine and is dissolved in the solution of dichloromethane, reaction stirring 2-5 hour, it is preferred that for 4-5 hour。After reaction terminates, reaction system is cooled to 0 DEG C-5 DEG C, stir 0.5-1 hour, system dilute with water, separate organic facies, aqueous phase dichloromethane extraction, the organic facies saturated common salt water washing merged, dried over sodium sulfate, concentrate drying obtains colorless liquid product B, wherein, 5, 6-dihydro-pyran-2-ketone, the mol ratio of bromine and dichloromethane is 1.0:1.0:5.0-1.0:3.0:50, this scope includes the numerical range in any subinterval therein, non-exclusively can enumerate: 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%。1HNMR(400MHz,CDCl3,ppm)δ7.29(t,1H),4.49(t,2H),2.59-2.56(m,2H)。
Embodiment three:
The preparation process of compounds I
Being dissolved in non-polar organic solvent by compound A and compound B, wherein non-polar organic solvent can be toluene, dioxane, oxolane, dichloromethane, dichloroethanes, one or more in chloroform, it is preferred that for toluene, addition alkali, alkali can be triethylamine, in the organic bases such as pyridine one or more, it is possible to for sodium carbonate, sodium bicarbonate, potassium carbonate, in the inorganic bases such as potassium bicarbonate one or more, it is preferred that for triethylamine, be warming up to 20 DEG C-100 DEG C, preferred temperature is 80 DEG C-100 DEG C, stirring reaction 1-10 hour, it is preferred that mixing time is 8-10 hour, afterwards reaction system being down to 20 DEG C-30 DEG C, filtrate water dilutes, layering, organic facies saturated common salt water washing, dried over sodium sulfate, concentrate to obtain residue, residue is stirring to pulp in ethyl acetate, filters, and vacuum drying obtains product as light yellow solid I, wherein, compound A, compound B, the mol ratio of triethylamine is 0.5:0.5:0.5-3:4.5:9, and this scope includes the numerical range in any subinterval therein, non-exclusively can enumerate: 1.0:1.0:1.5-2.5:4.0:9, 1.5:1.5:2.5-2:3.5:9, it is preferred that mol ratio is 1:1.2:3, yield: 80%-85%。1HNMR(400MHz,CDCl3, ppm) and δ 7.47 (d, J=9.2Hz, 2H), 6.98 (d, J=9.2Hz, 2H), 4.64 (t, J=6.0Hz, 2H), 3.86 (s, 3H), 3.13 (t, J=6.4Hz, 2H) .MS:270 (M+1)。
Embodiment four:
The preparation process of compound ii
Method one:
Compound C is dissolved in non-polar solven, non-polar solven can be toluene, dimethylbenzene, dichloromethane, dichloroethanes, the wherein solution of preferably dichloroethanes, it is cooled to 0 DEG C-10 DEG C, Lewis acid is dripped under nitrogen protection, Lewis acid can be trimethyl aluminium, chloro dimethyl chloride, in aluminum chloride one or more, wherein, preferably trimethyl aluminium, after dripping, rise to and reaction 1-3 hour is stirred at room temperature, preferably after 1-2 hour, the dichloroethane solution of dropping compounds I, then heat to 60 DEG C-80 DEG C, preferably 60 DEG C-70 DEG C, react 1-2 hour, reaction system is down to 20 DEG C-30 DEG C, with saturated aqueous ammonium chloride solution cancellation, layering, aqueous phase dichloroethanes extracts, the organic facies saturated common salt water washing merged, dried over sodium sulfate, concentrate drying obtains product as light yellow solid II, wherein compounds I: compound C: the mol ratio of trimethyl aluminium is 1.0:1.0:1.0-1.0:5.0:10, this scope includes the numerical range in any subinterval therein, non-exclusively can enumerate: 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:
Being suspended in non-polar solven by compounds I and compound C, non-polar solven can be toluene, dimethylbenzene, dichloromethane, dichloroethanes, wherein preferably xylene solvent, in dimethylbenzene, is warming up to 100 DEG C-105 DEG C, and stirring reaction is overnight；Being cooled to room temperature, vacuum rotary steam removes solvent, crosses column purification and obtains product as light yellow solid II, wherein compounds I: compound C: the mol ratio of dimethylbenzene is 1:1.3:50:, yield: 70%-75%。1HNMR(400MHz,CDCl3, ppm) and δ 11.00 (s, 1H), 7.64 (d, J=8.8Hz, 2H), 7.32 (d, J=8.8Hz, 2H), 7.11 (d, J=8.4Hz, 2H), 6.87 (d, J=8.8Hz, 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 base, organic base 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, dichloromethane, dichloroethanes, one or more in chloroform, preferably dichloromethane, under nitrogen protection, it is cooled to 0 DEG C-5 DEG C, it is slowly added to halide reagent, mesyl chloride, p-methyl benzene sulfonic chloride or to trifluoromethylbenzene chloride solution, wherein halide reagent can be phosphorus pentachloride, phosphorus oxychloride, hydrogen chloride, carbon tetrachloride, 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, when halide reagent, hydroxyl in compound ii is transformed into halogen, preferably mesyl chloride；System rises to 20 DEG C of-30 DEG C of stirring reactions 1-3 hour。Reactant liquor pours cancellation in frozen water into, separate organic facies, aqueous phase dichloromethane extraction, organic facies saturated common salt water washing, dried over sodium sulfate, concentrate drying obtains product as light yellow solid III, wherein compound ii is 1.0:1.0-1.0:10 with the mol ratio of triethylamine, this scope includes the numerical range in any subinterval therein, non-exclusively can enumerate: 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%。
1HNMR(400MHz,CDCl3, ppm) and δ 8.84 (s, 1H), 7.45 (d, J=8.4Hz, 2H), 7.29 (d, J=8.4Hz, 2H), 7.01 (d, J=8.8Hz, 2H), 6.97 (d, J=8.8Hz, 2H), 4.52 (t, J=6.0Hz, 2H), 3.81 (s, 3H), 3.54-3.53 (m, 2H), 3.20 (t, J=6.0Hz, 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, oxolane, dichloromethane, dichloroethanes or chloroform, preferably anhydrous tetrahydro furan, at 0 DEG C-100 DEG C, preferably 0 DEG C-10 DEG C, adding alkali, alkali can be one or more in the organic base such as triethylamine, DMAP, DIPEA；Can be one or more in the inorganic bases such as sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate, it is preferred that for tert-butyl group potassium alcoholate, stirring reaction 1-5 hour。Reactant liquor pours cancellation in frozen water into, layering, aqueous phase is extracted with ethyl acetate, the organic facies saturated common salt water washing merged, dried over sodium sulfate, concentrate drying obtains product as light yellow solid IV, wherein, the mol ratio of compound III and tert-butyl group potassium alcoholate is 1.0:1.0-1.0:10, this scope includes the numerical range in any subinterval therein, non-exclusively can enumerate: 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, it is preferred that mol ratio is 1:2, yield: 90%-95%。
1HNMR(400MHz,CDCl3, ppm) and δ 7.47 (d, J=9.2Hz, 2H), 7.32 (d, J=8.8Hz, 2H), 7.27 (d, J=8.8Hz, 2H), 6.93 (d, J=8.8Hz, 2H), 4.14 (t, J=7.2Hz, 2H), 3.81 (s, 3H), 3.59-3.58 (m, 2H), 3.15 (t, J=6.4Hz, 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 base such as triethylamine, DMAP, DIPEA；Can be sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, one or more in the inorganic base such as sodium bicarbonate and potassium bicarbonate, preferably DMAP is suspended in non-protonic solvent, non-protonic solvent can be: toluene, oxolane, dichloromethane, one or more in dichloroethanes or chloroform, preferably in toluene, it is heated to reflux, the temperature being heated to is 60 DEG C-100 DEG C, preferably 60 DEG C-80 DEG C, stirring reaction 1-8 hour, preferably 6-8 hour, reaction is down to 20-30 DEG C, layering, organic facies saturated common salt water washing, dried over sodium sulfate, concentrate to obtain residue, silica column purification, wherein the eluant for silica column purification is made up of dichloromethane and methanol, dichloromethane: the volume ratio of methanol is 95:5, obtain product as light yellow solid IV, wherein compound III is 1.0:1.0-1.0:10 with the mol ratio of DMAP, this scope includes the numerical range in any subinterval therein, non-exclusively can enumerate: 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 room temperature, being added in alkali by compound V, alkali can be one or more in the inorganic bases such as sodium hydroxide, Lithium hydrate or potassium hydroxide, it is preferred that for sodium hydrate aqueous solution, is warming up to 10 DEG C-100 DEG C, stirring reaction 5-60 minute, it is preferred that for 30-40 minute；After reaction terminates, system is down to 20 DEG C-30 DEG C, with dichloromethane extraction, layering, dry, concentrating under reduced pressure, residue silica column purification, wherein the eluant for silica column purification is made up of dichloromethane and methanol, dichloromethane: the volume ratio of methanol is 30:1, obtain white powder product Eliquis, the mol ratio of compounds Ⅳ and sodium hydrate aqueous solution is 1.0:1.0-1.0:20, this scope includes the numerical range in any subinterval therein, non-exclusively can enumerate: 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%。
1HNMR(400MHz,CDCl3, ppm) and δ 7.47 (d, J=9.2Hz, 2H), 7.34 (d, J=8.8Hz, 2H), 7.26 (d, J=8.8Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 6.85 (drs, 1H), 5.51 (drs, 1H), 4.11 (t, J=7.2Hz, 2H), 3.82 (s, 3H), 3.59-3.57 (m, 2H), 3.37 (t, J=6.4Hz, 2H), 2.56-2.55 (m, 2H), 1.94-1.92 (m, 4H) .MS:460 (M+1)。
1, the present invention adopts initiation material aminoanisole and 5,6-dihydro-pyran-2-ketone are the commonly used raw material in organic drug synthesis field, low price and also be readily obtained。
2, in the present invention, each step reaction temperature is all between-10 DEG C-100 DEG C, and reaction condition is gentleer, simple and safe operation, environmentally friendly, it is easy to carry out industrialized production
3, the present invention in each intermediate link only with such as: extract, dry, making beating, filter, the operational approach such as crystallization and recrystallization, post processing is simple and convenient, is easier to realize large-scale production。
4, route of the present invention is novel, obtains multiple brand-new intermediate and the stable in properties of intermediate in building-up process, easy and simple to handle, it is easy to accomplish industrialized great production。
5, the yield of the present invention is high。
Claims (1)
1. the method preparing antithrombotic reagent Eliquis, it is characterised in that:
The preparation of compound A: the first step: with P-nethoxyaniline for raw material, at-10 DEG C of-0 DEG C of temperature, P-nethoxyaniline diazonium tetrafluoroborate is generated under the effect of sodium nitrite, water and Tetrafluoroboric acid, response time is 20-50 minute, and wherein the mol ratio of aminoanisole, Tetrafluoroboric acid, sodium nitrite and water is 1.0:1.0:1.0:10-1.0:5.0:5.0:50；Second step: with methyl formate and 2-halogen acetonitrile for raw material, at-5 DEG C-0 DEG C, the product obtained and P-nethoxyaniline diazonium Tetrafluoroboric acid reactant salt is acted under oxolane and sodium methoxide solution, response time is 0.25-8 hour, obtain compound A, compound A passes through recrystallization, mixed solvent making beating or column chromatography method purification obtain, wherein 2-halogen acetonitrile, methyl formate, Feldalat NM, P-nethoxyaniline diazonium tetrafluoroborate, the mol ratio of oxolane 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 chemical formula of compound A is:Wherein, Z can be Cl, Br, I；
The preparation of compound B: with 5,6-dihydro-pyran-2-ketone is raw material, at 0 DEG C-30 DEG C, in non-proton organic solvent, carry out bromination by bromine, response time is 0.5-6 hour, obtain compound B, compound B by extracting, dry or obtaining after concentration, wherein, the mol ratio of 5,6-dihydro-pyran-2-ketone, bromine and non-proton organic solvent is 1.0:1.0:5.0-1.0:3.0:50；The chemical formula of compound B is:
Wherein, X is Br；
The preparation of compounds I: in non-polar organic solvent, under alkali condition, compounds I is obtained for raw material by ring-closure reaction with compound A and compound B, compounds I is obtained by making beating, mixed solvent making beating or column chromatography purification, reaction temperature is 20 DEG C-100 DEG C, response time is 1-10 hour, and the mol ratio of compound A, compound B and alkali is 0.5:0.5:0.5-3:4.5:9；The chemical formula of compounds I is:
The preparation of compound ii: in non-polar solven, under the catalysis of Lewis acid, reaction temperature is 0 DEG C-80 DEG C, compounds I and compound C carry out urethane exchange and obtain compound ii, wherein compounds I: the mol ratio of compound C:Lewis acid is 1.0:1.0:1.0-1.0:5.0:10, response time is 3-5 hour, and compound ii is obtained by recrystallization, mixed solvent making beating or column chromatography purification, and the chemical formula of compound ii and compound C is:
The preparation of compound III: under non-protonic solvent, in the basic conditions, the mol ratio of compound ii and alkali is 1.0:1.0-1.0:10, reaction temperature is between 0 DEG C-50 DEG C, compound ii drips halide reagent or mesyl chloride, p-methyl benzene sulfonic chloride and trifluoromethylbenzene chloride solution is obtained by reacting compound III, response time is 30-60 minute, and compound III is obtained by recrystallization, mixed solvent making beating, column chromatography purification, and the chemical formula of compound III is:
Wherein, R can be Cl, Br, I, OSO2Me、OSO2CF3、OSO2Ph-p-Me；
The preparation of compounds Ⅳ: in non-protonic solvent, compound III is in the basic conditions, the mol ratio of compound III and alkali is 1.0:1.0-1.0:10, temperature is between 0 DEG C-100 DEG C, response time is obtain compounds Ⅳ after molecule cyclization in 1-8 hour, compounds Ⅳ is obtained by recrystallization, mixed solvent making beating or column chromatography purification, and the chemical formula of compounds Ⅳ is:
The preparation of Eliquis: in polar organic solvent, with compounds Ⅳ for raw material, under alkaline conditions, the mol ratio of compounds Ⅳ and alkali is 1.0:1.0-1.0:20, temperature 10 DEG C-100 DEG C, response time is obtain compound antithrombotic reagent Eliquis through hydrolysis in 5-60 minute, and antithrombotic reagent Eliquis is obtained by recrystallization, making beating or column chromatography purification, the chemical formula of Eliquis:
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| CN104262338B (en) * | 2014-09-28 | 2016-11-30 | 浙江天宇药业股份有限公司 | A kind of Eliquis and the synthetic method of intermediate thereof |
| CN104447738A (en) * | 2014-11-04 | 2015-03-25 | 南京正大天晴制药有限公司 | Apixaban structural analogue and preparation method thereof |
| CN106045931B (en) * | 2016-05-26 | 2018-10-23 | 东华大学 | A kind of 5- phenyl -1-（4- methoxyphenyls）The preparation method of -1H- tetrazoles |
| CN109400606B (en) * | 2018-12-26 | 2020-01-17 | 山东鲁抗医药股份有限公司 | Method for refining apixaban from apixaban crude product |
| CN110041245A (en) * | 2019-04-29 | 2019-07-23 | 常州恒邦药业有限公司 | A kind of preparation of Eliquis and its intermediate |
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