CN107955002A - The preparation method of Eliquis and its intermediate - Google Patents

The preparation method of Eliquis and its intermediate Download PDF

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Publication number
CN107955002A
CN107955002A CN201711444031.6A CN201711444031A CN107955002A CN 107955002 A CN107955002 A CN 107955002A CN 201711444031 A CN201711444031 A CN 201711444031A CN 107955002 A CN107955002 A CN 107955002A
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preparation
eliquis
eliquis intermediate
intermediate compound
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CN107955002B (en
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陈健
刘振峰
应述欢
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Shanghai Yunshengyan Neoplasm Technology Co ltd
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Shanghai Bocimed Pharmaceutical 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

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The invention discloses the preparation method of Eliquis and its intermediate.The present invention provides a kind of preparation method of Eliquis intermediate compound I, comprise the following steps：In organic solvent, under the conditions of alkali is existing, Eliquis intermediate II and p-fluoronitrobenzene is subjected to nucleophilic substitution and obtain Eliquis intermediate compound I.The preparation method step of the present invention is short, safety easy to operate, post-processing step is simple, environmental-friendly, total recovery is high, obtained product purity is high, production cost is low, atom utilization is high, is suitable for industrialized production.

Description

The preparation method of Eliquis and its intermediate
Technical field
The present invention relates to the preparation method of Eliquis and its intermediate.
Background technology
Novel antibacterial medicine Eliquis (Apixaban, III) is Shi Guibao combines out with Pfizer global strategy cooperation Send out and sell anticoagulant product.2011, approval was taken the lead in for hip joint or the knee pass of selecting a time in 27 state of European Union and Iceland, Norway Save the prevention of replacement operation adult patient Venous Thrombosis；In January, 2013, obtains state food and drug administration and issues The import drug permit of hair, the adult patients for displacement technique of selecting a time for hip joint or knee joint, prevent venous thromboembolism thing Part, in April, 2013 is formally in Discussion on Chinese Listed.
Eliquis is new oral anticoagulant, and recommended dose 2.5mg is daily to take orally twice, effectively prevents vein Thromboembolism does not increase bleeding risk at the same time, without routine monitoring coagulation function, is also adjusted without dosage.
Eliquis intermediate compound I is to synthesize the important intermediate of Eliquis III.Disclosing under the conditions of the prior art The Eliquis intermediate synthetic method of report have patent document CN102675314A, CN103159670A and CN103694237A etc. is reported.
The method of the reports such as patent document CN102675314A is paranitroanilinum condensation, cyclisation, chloro, dechlorination, condensation Obtain.Step is longer, and uses sodium hydride, and operational danger is big；Using phosphorus pentachloride environmental pollution problem than more serious, dechlorination Need high temperature etc.；This route steps is long, yield is relatively low (four step total recoverys are 43.7%), cost is higher.So there is an urgent need to more Change prior art condition, it is necessary to find one it is easy to operate, convenient method carries out the preparation of Eliquis intermediate, step Shorter, safe operation, and adapt to the needs of industrialized production.
The content of the invention
The technical problems to be solved by the invention be in order to overcome the preparation method step of Eliquis in the prior art it is long, Operational danger is big, environmental pollution is serious, production equipment requires height, last handling process is cumbersome, yield is low, production cost is high, no The defects of being suitable for industrialized production and provide a kind of preparation method of Eliquis and its intermediate.The preparation side of the present invention Method step is short, safety easy to operate, post-processing step is simple, environmental-friendly, total recovery is high, obtained product purity is high, production Cost is low, atom utilization is high, is suitable for industrialized production.
The present invention provides a kind of preparation method of Eliquis intermediate compound I, it comprises the following steps：In organic solvent In, under the conditions of alkali is existing, Eliquis intermediate II and p-fluoronitrobenzene are subjected to nucleophilic substitution and obtain Eliquis Intermediate compound I；
The preparation method of the Eliquis intermediate compound I preferably carries out under protective gas protection, the protection gas The preferred nitrogen of body and/or argon gas.
In the preparation method of the Eliquis intermediate compound I, the preferred ether solvent of the organic solvent, amide-type One or more in solvent, acetals solvent and sulfoxide type solvents.The preferred tetrahydrofuran of the ether solvent, dimethyl four One or more in hydrogen furans, isopropyl ether and 1,4- dioxane.The amide solvent preferred N, N- dimethyl formyl Amine and/or DMAC N,N' dimethyl acetamide.The preferred N,N-dimethylformamide diethyl acetal of the acetals solvent.Described The preferred dimethyl sulfoxide (DMSO) of sulfoxide type solvents.
In the preparation method of the Eliquis intermediate compound I, the organic solvent and Eliquis intermediate II Volume mass ratio preferred 4mL/g~20mL/g, further preferred 5mL/g~10mL/g, such as 4mL/g, 5mL/g, 10mL/ G, 15mL/g or 20mL/g.
In the preparation method of the Eliquis intermediate compound I, the preferred inorganic base of the alkali；The inorganic base is excellent Select potassium tert-butoxide, sodium tert-butoxide, trimethyl silicane potassium alcoholate, trimethyl silicane sodium alkoxide, tert-pentyl alcohol potassium and one kind or more in sodium tert-amyl alcohol Kind.
In the preparation method of the Eliquis intermediate compound I, the alkali and the Eliquis intermediate II Molar ratio preferably 1~10, further preferred 2~10, such as 2,3,5,6 or 10.
In the preparation method of the Eliquis intermediate compound I, the p-fluoronitrobenzene and Eliquis intermediate The ratio of II preferably 1~10, further preferred 1.5~10, such as 1.5,2,2.5,5 or 10.
In the preparation method of the Eliquis intermediate compound I, preferably 20 DEG C of the temperature of the nucleophilic substitution ~80 DEG C, further preferred 40 DEG C~60 DEG C, such as 40 DEG C~50 DEG C or 50 DEG C~60 DEG C.
In the preparation method of the Eliquis intermediate compound I, the process of the nucleophilic substitution can use Routine monitoring method (such as TLC, HPLC or NMR) in this area is detected, and is generally disappeared with Eliquis intermediate II When for reaction terminal, when the time preferably 1 of the nucleophilic substitution is small~24 it is small when, it is further preferred 2 it is small when~24 Hour, for example, 2 it is small when, 3 it is small when, 4 it is small when, 12 it is small when or 24 it is small when.
The preparation method of the Eliquis intermediate compound I preferably uses following steps：To Eliquis intermediate II with In the mixture that organic solvent is formed, alkali is added, p-fluoronitrobenzene is then added and carries out nucleophilic substitution, is obtained described Eliquis intermediate compound I.
The preparation method of the Eliquis intermediate compound I preferably uses following post-processing step：After reaction, it is quenched React, extract, wash, dry, filter, being concentrated to give the Eliquis intermediate compound I crude product.Described is quenched reaction preferably Using saturated ammonium chloride solution.The preferred esters solvent of solvent that the extraction uses, the preferred acetic acid second of the esters solvent Ester.The number of the extraction preferably 1 time~3 times, such as 1 time.The washing preferably successively using inorganic base aqueous solution and Saline solution is washed.The mass concentration of the inorganic base aqueous solution preferably 1%~20%, such as 10%, the quality Concentration refers to that the quality of inorganic base accounts for the percentage of inorganic base aqueous solution gross mass.The preferred sodium acid carbonate of the inorganic base.Institute The mass concentration for the saline solution stated preferably 1%~20%, such as 15%, the mass concentration refers to that the quality of sodium chloride accounts for food The percentage of brine gross mass.The drying is preferably dried using drier, the preferred anhydrous slufuric acid of the drier Sodium.The filtering and concentration can use the conventional method of the generic operation in this area.The concentration is preferably concentrated in vacuo, The vacuum of the vacuum concentration preferably -0.01MPa~-0.1MPa, such as -0.085MPa~-0.1MPa, the vacuum Preferably 45 DEG C~55 DEG C of the temperature of concentration.
The Eliquis intermediate compound I crude product is preferably through being recrystallized to give the Eliquis intermediate compound I.It is described Recrystallization preferably using the mixed solvent of esters solvent and ether solvent.The esters solvent ethyl acetate；It is described The preferred cyclohexyl methyl ether of ether solvent；The volume ratio preferably 1~5 of the esters solvent and the ether solvent, Such as 1.
The recrystallization preferably uses following steps：The solution that Eliquis intermediate compound I crude product and solvent are formed, it is cold But crystallization, be dried to obtain Eliquis intermediate compound I, the solvent is esters solvent and the mixed solvent of ether solvent.It is described " solution that Eliquis intermediate compound I crude product and solvent are formed " preferably 75 DEG C~85 DEG C of temperature, the cooling crystallization Preferably 0~5 DEG C of temperature, when the time preferably 1 of the cooling crystallization is small~5 it is small when, such as 2 it is small when.The drying is preferred Vacuum drying；The vacuum drying pressure preferably -0.01MPa~-0.1MPa.The vacuum drying temperature preferably 45 DEG C~55 DEG C, when the vacuum drying time preferably 8 is small~12 it is small when.
The preparation method of Eliquis intermediate compound I of the present invention preferably further includes Eliquis intermediate II Preparation method, it comprises the following steps：In organic solvent, in the presence of alkali, by -2 (1H)-pyrroles of 5,6- dihydros -3- (4- morpholinyls) Pyridine ketone and [(4- methoxyphenyls) diazanyl] ethyl chloroacetate are condensed to yield the Eliquis intermediate II；
The preparation method of the Eliquis intermediate II preferably carries out under protective gas protection, the protection gas The preferred nitrogen of body and/or argon gas.
In the preparation method of the Eliquis intermediate II, the preferred esters solvent of the organic solvent, fragrance One or more in varsol and ether solvent.The esters solvent ethyl acetate, isopropyl acetate, acetic acid are just One or more in butyl ester, isobutyl acetate and tert-butyl acetate.The preferred toluene of the aromatic hydrocarbon solvent, dimethylbenzene and One or more in ethylbenzene.The preferred tetrahydrofuran of the ether solvent, dimethyl-tetrahydrofuran, isopropyl ether and 1,4- dioxies One or more in six rings.
In the preparation method of the Eliquis intermediate II, the organic solvent and 5, the 6- dihydros- Preferred 10mL/g~the 50mL/g of volume ratio of -2 (1H)-pyridones of 3- (4- morpholinyls), such as 10.1mL/g, 19.8mL/g, 29.7mL/g, 39.6mL/g or 49.5mL/g.
In the preparation method of the Eliquis intermediate II, the preferred organic base of the alkali or inorganic base；It is described The preferred triethylamine of organic base, diisopropyl ethyl amine, the one or more in Tri-n-Propylamine and tri-n-butylamine；Described is inorganic One or more in the preferred potassium carbonate of alkali, sodium carbonate, potassium hydroxide and sodium hydroxide, further preferred potassium carbonate.Work as use During inorganic base, preferably reacted in the presence of a phase transfer catalyst, the preferred tetran-butylphosphonium bromide of the phase transfer catalyst The molar ratio preferably 0.001~0.1, further preferred 0.01 of ammonium, the phase transfer catalyst and the inorganic base~ 0.05, such as 0.03.
In the preparation method of the Eliquis intermediate II, the alkali and 5,6- dihydro -3- (4- morpholinyls) - The molar ratio preferably 1~10 of 2 (1H)-pyridones.When using organic base, the alkali and 5,6- dihydro -3- (4- morpholines Base) -2 (1H)-pyridones molar ratio further preferred 1~5, such as 1.5,2 or 5；When using inorganic base, the alkali With the molar ratio further preferred 3~10 of -2 (1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls), such as 4 or 10.
In the preparation method of the Eliquis intermediate II, described [(4- methoxyphenyls) diazanyl] monoxone The molar ratio preferably 1~5 of ethyl ester and -2 (the 1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls), further preferably 1.2~5, such as 1.2,1.5,2,2.5 or 5.
In the preparation method of the Eliquis intermediate II, preferably 65 DEG C of the temperature of the condensation reaction~ 115 DEG C, further preferred 75 DEG C~105 DEG C, such as 75 DEG C~85 DEG C, 85 DEG C~95 DEG C or 95 DEG C~105 DEG C.
In the preparation method of the Eliquis intermediate II, when the time preferably 1 of the condensation reaction is small~ 30 it is small when, it is further preferred 12 it is small when~24 it is small when, such as 12 it is small when, 16 it is small when, 20 it is small when or 24 it is small when.
The preparation method of the Eliquis intermediate II preferably uses following steps：Alkali is added to, organic solvent, The mixing that -2 (1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls) and [(4- methoxyphenyls) diazanyl] ethyl chloroacetate are formed In thing, carry out condensation reaction and obtain the Eliquis intermediate II.
The preparation method of the Eliquis intermediate II preferably uses following post-processing step：After reaction, it is cold But, acid is added, stirs, reaction, extraction is quenched, concentration, drying, obtains Eliquis intermediate II crude product.The acid is preferably Organic acid, the preferred trifluoroacetic acid of the organic acid.When the time of the stirring preferably 1 is small~5 it is small when, such as 2 it is small when.Institute The reaction that is quenched stated preferably uses inorganic base aqueous solution, the mass concentration preferably 1%~30% of the inorganic base aqueous solution, example Such as 10%, the mass concentration refers to that the quality of inorganic base accounts for the percentage of inorganic base aqueous solution gross mass.Described is inorganic The preferred sodium acid carbonate of alkali.The extraction, concentration, recrystallization, vacuum drying can use the routine of the generic operation in this area Method.The preferred esters solvent of solvent that the extraction uses；The esters solvent ethyl acetate.The extraction Number preferably 1 time~3 times, such as 1 time.The washing preferably uses inorganic base and brine It successively.Described is inorganic The mass percentage of alkali preferably 1%~50%, further preferred 5%~20%, such as 10%, the mass percentage Refer to that the quality of inorganic base accounts for the percentage of inorganic base aqueous solution gross mass.The preferred sodium acid carbonate of the inorganic base.Described The mass percentage of saline solution preferably 1%~50%, further preferred 5%~20%, such as 15%, the quality percentage Content refers to that the quality of sodium chloride accounts for the percentage of saline solution gross mass.The number of the washing preferably 1~6 time, such as 2 times Or 4 times.The drying is preferably dried using drier, the preferred anhydrous sodium sulfate of the drier.
Eliquis intermediate II crude product preferably obtains the Eliquis intermediate by recrystallization, vacuum drying again II。
The recrystallization preferably uses following steps：Eliquis intermediate II crude product is formed with organic solvent molten Liquid, cooling crystallization obtain the Eliquis intermediate II.It is described " Eliquis intermediate II crude product with it is organic molten Dosage form into solution " preferably 60 DEG C~90 DEG C of temperature, such as 75 DEG C~85 DEG C.Preferably 0 DEG C of the temperature of the cooling crystallization ~5 DEG C, when the time preferably 1 of described cooling crystallization is small~5 it is small when, such as 2 it is small when.It is described to recrystallize the organic solvent used It is preferred that esters solvent；The esters solvent ethyl acetate.The concentration is preferably concentrated in vacuo；The vacuum concentration Preferably 45 DEG C~55 DEG C of temperature, the vacuum concentration pressure preferably -0.01MPa~-0.1MPa (such as -0.085MPa~- 0.1MPa).Preferably 45 DEG C~55 DEG C of the vacuum drying temperature, when the vacuum drying time preferably 8 is small~12 Hour, the vacuum drying pressure preferably -0.01MPa~-0.1MPa.
In the present invention, the preparation method of the Eliquis intermediate compound I preferably uses following syntheti c route：
Present invention also offers the preparation method of Eliquis intermediate compound IV, it comprises the following steps：As described above Preparation method the Eliquis intermediate compound I and then in organic solvent is made, under palladium carbon catalysis, by described Ah Piperazine sand class's intermediate compound I carries out reduction reaction with hydrogen, obtains the Eliquis intermediate compound IV；
The preparation method of the Eliquis intermediate compound IV can use the routine side of such reduction reaction in this area Method, following reaction method specifically preferred according to the invention and condition：
In the preparation method of the Eliquis intermediate compound IV, the preferred alcohols solvent of the organic solvent；It is described Alcohols solvent preferred alcohol.
In the preparation method of the Eliquis intermediate compound IV, in the organic solvent and the Eliquis Volume mass ratio preferred 1mL/g~50mL/g, further preferred 15mL/g~30mL/g, such as the 10mL/g of mesosome I.
In the preparation method of the Eliquis intermediate compound IV, the temperature preferably 40 DEG C~65 of the reduction reaction DEG C, further preferred 50 DEG C~55 DEG C.
In the preparation method of the Eliquis intermediate compound IV, the preferred 0.1MPa of pressure of the reduction reaction~ 0.5MPa, further preferred 0.3MPa~0.4MPa.
In the preparation method of the Eliquis intermediate compound IV, the process of the reduction reaction can use ability Common detection methods (such as TLC, HPLC or NMR) are detected in domain, when generally being disappeared with the Eliquis intermediate compound I For the terminal of reaction, when the time preferably 1 of the reduction reaction is small~10 it is small when, it is further preferred 2 it is small when~6 it is small when, example As 4 it is small when.
The preparation method of the Eliquis intermediate compound IV preferably uses following post-processing step：After reaction, it is cold But, filter, wash, vacuum concentration obtains Eliquis intermediate compound IV.Preferably 45 DEG C~55 DEG C of the temperature of the vacuum concentration, The vacuum concentration pressure preferably -0.01MPa~-0.1MPa, such as -0.085MPa~-0.1MPa.
Present invention also offers the preparation method of Eliquis intermediate V, it comprises the following steps：As described above The Eliquis intermediate compound IV and then in organic solvent is made in preparation method, will be described under the conditions of alkali is existing Eliquis intermediate compound IV carries out condensation reaction with 5- bromines valeric chloride, obtains the Eliquis intermediate V；
The preparation method of the Eliquis intermediate V can use the routine side of such condensation reaction in this area Method, following reaction method specifically preferred according to the invention and condition：
In the preparation method of the Eliquis intermediate V, the preferred halogenated hydrocarbon solvent of the organic solvent；Institute The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent stated；The preferred dichloromethane of the chlorinated hydrocarbon solvent.
In the preparation method of the Eliquis intermediate V, in the organic solvent and the Eliquis Volume mass ratio preferred 1mL/g~50mL/g, further preferred 5mL/g~15mL/g, such as the 10mL/g of mesosome IV.
In the preparation method of the Eliquis intermediate V, the preferred inorganic base of the alkali；The inorganic base is excellent Select sodium hydroxide and/or potassium hydroxide.
In the preparation method of the Eliquis intermediate V, the alkali and the Eliquis intermediate compound IV Molar ratio preferably 1~10, further preferred 2~8, such as 5.2.
In the preparation method of the Eliquis intermediate V, the 5- bromines valeric chloride and the Eliquis The molar ratio of intermediate compound IV preferably 1~3, further preferred 1.1~1.5, such as 1.1.
In the preparation method of the Eliquis intermediate V, the temperature preferably 10 DEG C~50 of the condensation reaction DEG C, further preferred 20 DEG C~40 DEG C, such as 30 DEG C~35 DEG C.
In the preparation method of the Eliquis intermediate V, the process of the condensation reaction can use ability Common detection methods (such as TLC, HPLC or NMR) are detected in domain, are generally disappeared with the Eliquis intermediate compound IV When for reaction terminal, when the time preferably 1 of the condensation reaction is small~10 it is small when, it is further preferred 4 it is small when~8 it is small when, Such as 6 it is small when.
The preparation method of the Eliquis intermediate V preferably uses following post-processing step：After reaction, it is quenched Reaction, extraction, concentrate, be dry, obtaining Eliquis intermediate V crude products.The reaction that is quenched preferably uses water.The extraction Take, concentrate, recrystallizing, being dried in vacuo the conventional method that can use the generic operation in this area.The extraction uses molten The preferred halogenated hydrocarbon solvent of agent；The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent；The chlorinated hydrocarbon solvent is preferred Dichloromethane.The number of the extraction preferably 1 time~3 times, such as 1 time.The washing preferably successively using inorganic base and Brine It.The mass percentage of the inorganic base preferably 1%~50%, further preferred 5%~20%, such as 10%, the mass percentage refers to that the quality of inorganic base accounts for the percentage of inorganic base aqueous solution gross mass.The nothing The preferred sodium acid carbonate of machine alkali.The mass percentage of the saline solution preferably 1%~50%, further preferred 5%~20%, Such as 15%, the mass percentage refers to that the quality of sodium chloride accounts for the percentage of saline solution gross mass.The washing Number preferably 1~6 time, such as 4 times.The drying is preferably dried using drier, the drier preferably without Aqueous sodium persulfate.
Eliquis intermediate V crude products preferably obtain the Eliquis intermediate by recrystallization, vacuum drying again V。
The recrystallization preferably uses following steps：Eliquis intermediate V crude products are formed with organic solvent molten Liquid, cooling crystallization obtain the Eliquis intermediate V." Eliquis intermediate V crude products and the organic solvent Preferably 60~80 DEG C of the temperature of the solution of formation ", such as 75 DEG C.Preferably 15~20 DEG C of the temperature of the cooling crystallization, it is described Cooling crystallization time preferably 1 it is small when~2 it is small when, such as 1 it is small when.
It is described to recrystallize the preferred esters solvent of organic solvent used；The esters solvent ethyl acetate.It is described Concentration be preferably concentrated in vacuo；Preferably 45 DEG C~55 DEG C of the temperature of the vacuum concentration, the vacuum concentration pressure preferably- 0.01MPa~-0.1MPa, such as -0.075MPa~-0.09MPa.Preferably 45 DEG C~55 DEG C of the vacuum drying temperature, When the vacuum drying time preferably 8 is small~12 it is small when, the vacuum drying pressure preferably -0.01MPa~- 0.1MPa。
Present invention also offers the preparation method of Eliquis III, it comprises the following steps：Preparation as described above The Eliquis intermediate V and then in organic solvent is made in method, under the conditions of alkali is existing, by the Ah piperazine Husky class's intermediate V carries out condensation reaction with formamide, obtains the Eliquis III；
The preparation method of the Eliquis III can use the conventional method of such condensation reaction in this area, this Invention particularly preferably following reaction method and condition：
In the preparation method of the Eliquis III, the organic solvent preferred amide class solvent；The acyl The preferred N,N-dimethylformamide of amine solvent.
In the preparation method of the Eliquis III, the organic solvent and the Eliquis intermediate V Volume mass ratio preferred 1mL/g~50mL/g, further preferred 5mL/g~15mL/g, such as 10mL/g.
In the preparation method of the Eliquis III, the preferred inorganic base of the alkali；The preferred first of the inorganic base One or more in sodium alkoxide, sodium ethoxide and potassium tert-butoxide.
In the preparation method of the Eliquis III, mole of the alkali and the Eliquis intermediate V Ratio preferably 1~30, further preferred 4~15, such as 8.5.
In the preparation method of the Eliquis III, the formamide is with the Eliquis intermediate V's Molar ratio preferably 1~3, further preferred 1.1~1.5, such as 1.2.
In the preparation method of the Eliquis III, preferably 0 DEG C~40 DEG C of the temperature of the condensation reaction, into Preferably 10 DEG C~30 DEG C of one step, such as 15 DEG C~20 DEG C.
In the preparation method of the Eliquis intermediate V, the process of the condensation reaction can use ability Common detection methods (such as TLC, HPLC or NMR) are detected in domain, when generally being disappeared with the Eliquis intermediate V For the terminal of reaction, when the time preferably 1 of the condensation reaction is small~10 it is small when, it is further preferred 2 it is small when~6 it is small when, example As 4 it is small when.
The preparation method of the Eliquis III preferably uses following post-processing step：After reaction, add water, Filtering, washing obtain Eliquis III crude products.The filtering and washing can use the routine side of the generic operation in this area Method.The washing preferably uses ether solvent；The preferred methyl tertiary butyl ether(MTBE) of the ether solvent.
Eliquis III crude products preferably obtain the Eliquis III by recrystallization, vacuum drying again.Described Recrystallization preferably uses following steps：The solution that Eliquis III crude products are formed with organic solvent, cooling crystallization obtain described Eliquis III.The temperature preferably 60 DEG C~80 of " solution that Eliquis III crude products are formed with organic solvent " DEG C, such as 75 DEG C.Preferably 5 DEG C~10 DEG C of the temperature of the cooling crystallization, when the time preferably 1 of the cooling crystallization is small~ 2 it is small when, such as 1 it is small when.The mixed solvent for recrystallizing the organic solvent preferred amide class solvent used and ether solvent.Institute The preferred N,N-dimethylformamide of amide solvent stated；The preferred methyl tertiary butyl ether(MTBE) of the ether solvent.The ethers The volume ratio preferably 1~5 of solvent and the amide solvent, such as 4.Preferably 45 DEG C of the vacuum drying temperature~ 55 DEG C, when the vacuum drying time preferably 8 is small~12 it is small when, the vacuum drying pressure preferably -0.01MPa ~-0.1MPa.
The preparation method of heretofore described Eliquis III, it is preferred to use following synthetic route：
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, each preferably up to the present invention Example.
The reagents and materials used in the present invention are commercially available.
In the present invention, the room temperature refers to environment temperature, is 10 DEG C~35 DEG C.
The positive effect of the present invention is：Preparation method reaction condition of the invention is gentle, post-processing step is simple, Synthetic route is short, total recovery is high (up to 67.3%), obtained Eliquis intermediate compound I product purity is high, purity can be with Reach more than 98%, production cost is low, atom utilization is high, is suitable for industrialized production；And thus intermediate can be prepared Obtaining meeting the Eliquis III of bulk pharmaceutical chemicals standard, (purity is more than 99.5%, 0.1%) single contaminant is less than.
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality Apply among a scope.The experimental method of actual conditions is not specified in the following example, according to conventional methods and conditions, or according to business Product specification selects.
Embodiment
Embodiment 1：The preparation of Eliquis intermediate II
Under nitrogen protection, -2 (1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls) are added into ethyl acetate 540mL 18.2g and [(4- methoxyphenyls) diazanyl] ethyl chloroacetate 38.5g, stirs lower addition triethylamine 20.3g, heating reaction to 75 ~85 DEG C and stir 16 it is small when.15~25 DEG C are cooled to, trifluoroacetic acid 32mL is added dropwise after filtering, when 15~25 DEG C of stirrings 2 are small. Add mass percentage and be quenched that (mass percentage refers to the quality of sodium acid carbonate for 10% sodium bicarbonate aqueous solution Account for the percentage of sodium bicarbonate aqueous solution gross mass), then it is extracted with ethyl acetate 1 time.Organic phase is with mass percentage (mass percentage refers to sodium chloride for 15% brine It for 10% sodium bicarbonate aqueous solution and mass percentage Quality account for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Filter and concentrate in vacuo (45 DEG C~55 DEG C ,- 0.085MPa~-0.1MPa) obtain yellow solid.This yellow solid adds 150mL ethyl acetate, is heated to 75~85 DEG C and stirs Mix 1 it is small when dissolve, be cooled to 0~5 DEG C and stir 2 it is small when, filtering, washed with 0~5 DEG C of ethyl acetate, after draining- 0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain light yellow solid 24.7g, yield 78.3%, HPLC purity 98.44%.
Embodiment 2：The preparation of Eliquis intermediate II
Under nitrogen protection, -2 (1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls) are added into ethyl acetate 360mL 18.2g and [(4- methoxyphenyls) diazanyl] ethyl chloroacetate 30.8g, stirs lower addition diisopropyl ethyl amine 19.4g, heating Reaction to 85~95 DEG C and stir 20 it is small when.15~25 DEG C are cooled to, trifluoroacetic acid 35mL is added dropwise after filtering, is stirred at 15~25 DEG C Mix 2 it is small when.Add mass percentage and be quenched that (mass percentage refers to bicarbonate for 10% sodium bicarbonate aqueous solution The quality of sodium accounts for the percentage of sodium bicarbonate aqueous solution gross mass, similarly hereinafter), then it is extracted with ethyl acetate 1 time.Organic phase matter Amount percentage composition is 10% sodium bicarbonate aqueous solution and mass percentage is that (the quality percentage contains 15% brine It Amount refers to that the quality of sodium chloride accounts for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Filter and concentrate in vacuo (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) obtains yellow solid.Yellow solid adds 150mL ethyl acetate, is heated to 75~85 DEG C and stir 1 it is small when dissolve, be cooled to 0~5 DEG C and stir 2 it is small when, filtering, washed with 0~5 DEG C of ethyl acetate, After draining
- 0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain light yellow solid 25.6g yield 81.2%, HPLC purity 98.30%.
Embodiment 3：The preparation of Eliquis intermediate II
Nitrogen protection under, added into toluene 720mL -2 (1H)-pyridone 18.2g of 5,6- dihydros -3- (4- morpholinyls) and [(4- methoxyphenyls) diazanyl] ethyl chloroacetate 64.1g, stirs lower addition tri-n-butylamine 92.6g, heating reaction to 95~105 DEG C and stir 12 it is small when.15~25 DEG C are cooled to, trifluoroacetic acid 50mL is added dropwise after filtering, when 15~25 DEG C of stirrings 2 are small.Add Mass percentage is quenched that (mass percentage refers to that the quality of sodium acid carbonate accounts for carbon for 10% sodium bicarbonate aqueous solution The percentage of sour hydrogen sodium water solution gross mass, similarly hereinafter), then it is extracted with ethyl acetate 1 time.Organic phase is with mass percentage (mass percentage refers to sodium chloride for 15% brine It for 10% sodium bicarbonate aqueous solution and mass percentage Quality account for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Filter and concentrate in vacuo (45 DEG C~55 DEG C ,- 0.085MPa~-0.1MPa) obtain yellow solid.Yellow solid adds 150mL ethyl acetate, is heated to 75~85 DEG C and stirs 1 dissolves when small, be cooled to 0~5 DEG C and stir 2 it is small when, filtering, washed with 0~5 DEG C of ethyl acetate, after draining- 0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain light yellow solid 23.2g, yield 73.6%, HPLC purity 98.87%.
Embodiment 4：The preparation of Eliquis intermediate II
Under nitrogen protection, -2 (1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls) are added into tetrahydrofuran 450mL 9.1g and [(4- methoxyphenyls) diazanyl] ethyl chloroacetate 64.2g, stirs lower addition potassium carbonate 69g, tetra-n-butyl ammonium bromide 0.49g.When heating is reacted to 75~85 DEG C and stirring 24 is small.15~25 DEG C are cooled to, trifluoroacetic acid 68mL is added dropwise after filtering, When 15~25 DEG C of stirrings 2 are small.Add mass percentage and the (mass percentage is quenched for 10% sodium bicarbonate aqueous solution Refer to that the quality of sodium acid carbonate accounts for the percentage of sodium bicarbonate aqueous solution gross mass, similarly hereinafter), then it is extracted with ethyl acetate 1 time. Organic phase is 10% sodium bicarbonate aqueous solution with mass percentage and mass percentage is that 15% brine It is (described Mass percentage refers to that the quality of sodium chloride accounts for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Filtering is simultaneously It is concentrated in vacuo (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) and obtains yellow solid.Yellow solid adds 75mL ethyl acetate, It is heated to dissolving when 75~85 DEG C and small stirring 1, when being cooled to 0~5 DEG C and small stirring 2, filtering, with 0~5 DEG C of ethyl acetate Washing, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain light yellow solid 11.5g, yield 72.9%, HPLC purity 97.85%.
Embodiment 5：The preparation of Eliquis intermediate II
Under nitrogen protection, -2 (1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls) are added into Isosorbide-5-Nitrae-dioxane 92mL 9.1g and [(4- methoxyphenyls) diazanyl] ethyl chloroacetate 25.6g, stirs lower addition potassium hydroxide 11.3g, tetra-n-butyl bromine Change ammonium 0.49g.When heating is reacted to 95~105 DEG C and stirring 20 is small.15~25 DEG C are cooled to, trifluoroacetic acid is added dropwise after filtering 32mL, when 15~25 DEG C of stirrings 2 are small.Add mass percentage and the (quality is quenched for 10% sodium bicarbonate aqueous solution Percentage composition refers to that the quality of sodium acid carbonate accounts for the percentage of sodium bicarbonate aqueous solution gross mass), then carried out with ethyl acetate Extraction.For 10% sodium bicarbonate aqueous solution, (mass percentage refers to sodium acid carbonate to organic phase mass percentage Quality account for the percentage of sodium bicarbonate aqueous solution gross mass) and mass percentage be the 15% brine It (matter Amount percentage composition refers to that the quality of sodium chloride accounts for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Filter and true Sky concentration (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) obtains yellow solid.Yellow solid adds 75mL ethyl acetate, adds Heat to 75~85 DEG C and stir 1 it is small when dissolve, be cooled to 0~5 DEG C and stir 2 it is small when, filtering, washed with 0~5 DEG C of ethyl acetate Wash, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain light yellow solid 11.8g, yield 74.8%, HPLC purity 97.83%.
Embodiment 6：The preparation of Eliquis intermediate compound I
Under nitrogen protection, into n,N-Dimethylformamide 158mL, (HPLC is pure by addition Eliquis intermediate II 15.8g 98.44%) degree, stirs at 0~10 DEG C and adds potassium tert-butoxide 28.0g, when stirring 1~2 is small at 0~10 DEG C；0~10 Stirred at DEG C and add p-fluoronitrobenzene 17.6g, when stirring 2 is small at 50~60 DEG C.The ammonium chloride that saturation is added after cooling is molten Liquid is quenched, and is then extracted with ethyl acetate once.Organic phase mass concentration is the 10% sodium bicarbonate aqueous solution (quality Concentration refers to that the quality of sodium acid carbonate accounts for the percentage of sodium bicarbonate aqueous solution gross mass) and mass concentration be 15% salt washing Wash (mass concentration refers to that the quality of sodium chloride accounts for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying. Filter and concentrate in vacuo (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) and obtain light yellow solid.Add 50mL ethyl acetate With 50mL cyclohexyl methyl ethers, it is heated to dissolving when 75~85 DEG C and small stirring 1, when being cooled to 0~5 DEG C and small stirring 2, mistake Filter, wash with 0~5 DEG C of ethyl acetate, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C be dried in vacuo 8 it is small when~ 12 it is small when, obtain light yellow solid 17.7g, yield 81.1% (two-step reaction total recovery 63.5%), HPLC purity 98.79%.
Embodiment 7：The preparation of Eliquis intermediate compound I
Under nitrogen protection, into n,N-Dimethylformamide 79mL, (HPLC is pure by addition Eliquis intermediate II 15.8g 98.30%) degree, stirs at 10~20 DEG C and adds potassium tert-butoxide 16.8g, when stirring 1~2 is small at 10~20 DEG C；10 Stirred at~20 DEG C and add p-fluoronitrobenzene 14.1g, when stirring 4 is small at 40~50 DEG C.Add the ammonium chloride solution of saturation It is quenched, is then extracted with ethyl acetate 1 time.(quality is dense for 10% sodium bicarbonate aqueous solution for organic phase mass concentration Degree refer to that the quality of sodium acid carbonate accounts for the percentage of sodium bicarbonate aqueous solution gross mass) and mass concentration be 15% brine It (mass concentration refers to that the quality of sodium chloride accounts for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Cross Filter and be concentrated in vacuo (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) and obtain light yellow solid.Add 50mL ethyl acetate and 50mL cyclohexyl methyl ethers, are heated to dissolving when 75~85 DEG C and small stirring 1, when being cooled to 0~5 DEG C and small stirring 2, filtering, Washed with 0~5 DEG C of ethyl acetate, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 Hour, obtain light yellow solid 18.1g, yield 82.9% (two-step reaction total recovery 67.3%), HPLC purity 98.89%.
Embodiment 8：The preparation of Eliquis intermediate compound I
Under nitrogen protection, Eliquis intermediate II 15.8g (HPLC purity is added into dimethyl sulfoxide (DMSO) 63mL 98.87%), stirred at 5~15 DEG C and add sodium tert-butoxide 9.6g, when stirring 1~2 is small at 5~15 DEG C；At 5~15 DEG C It is lower to stir and add p-fluoronitrobenzene 10.6g, when stirring 3 is small at 50~60 DEG C.The ammonium chloride solution for adding saturation is quenched, so After be extracted with ethyl acetate 1 time.For 10% sodium bicarbonate aqueous solution, (mass concentration refers to carbon to organic phase mass concentration The quality of sour hydrogen sodium accounts for the percentage of sodium bicarbonate aqueous solution gross mass) and mass concentration for 15% brine It it is (described Mass concentration refers to that the quality of sodium chloride accounts for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Filter simultaneously vacuum Concentration (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) obtains light yellow solid.Add 50mL ethyl acetate and 50mL hexamethylenes Ylmethyl ether, is heated to dissolving when 75~85 DEG C and small stirring 1, when being cooled to 0~5 DEG C and small stirring 2, filtering, with 0~5 DEG C Ethyl acetate washing, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain Light yellow solid 17.5g, yield 80.2% (two-step reaction total recovery 59.0%), HPLC purity 98.73%.
Embodiment 9：The preparation of Eliquis intermediate compound I
Under nitrogen protection, Eliquis intermediate II 7.9g (HPLC purity is added into tetrahydrofuran 158mL 97.85%), stirred at 5~15 DEG C and add sodium tert-amyl alcohol 27.5g, when stirring 1~2 is small at 5~15 DEG C；At 5~15 DEG C It is lower to stir and add p-fluoronitrobenzene 35.2g, when stirring 24 is small at 40~50 DEG C.The ammonium chloride solution for adding saturation is quenched (mass percentage refers to that the quality of ammonium chloride accounts for the percentage of aqueous ammonium chloride solution gross mass), then with acetic acid second Ester extracts 1 time.For 10% sodium bicarbonate aqueous solution, (mass concentration refers to the matter of sodium acid carbonate to organic phase mass concentration Amount accounts for the percentage of sodium bicarbonate aqueous solution gross mass) and mass concentration be that (mass concentration is 15% brine It The quality for referring to sodium chloride accounts for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Filter and concentrate in vacuo (45 DEG C ~55 DEG C, -0.085MPa~-0.1MPa) obtain light yellow solid.25mL ethyl acetate and 25mL cyclohexyl methyl ethers are added, It is heated to dissolving when 75~85 DEG C and small stirring 1, when being cooled to 0~5 DEG C and small stirring 2, filtering, with 0~5 DEG C of ethyl acetate Washing, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain light yellow solid 8.4g, yield 77.0% (two-step reaction total recovery 56.1%), HPLC purity 98.75%.
Embodiment 10：The preparation of Eliquis intermediate compound I
Under nitrogen protection, Eliquis intermediate II 7.9g (HPLC purity is added into Isosorbide-5-Nitrae-dioxane 118mL 97.83%), stirred at 5~15 DEG C and add tert-pentyl alcohol potassium 18.9g, when stirring 1~2 is small at 5~15 DEG C；At 5~15 DEG C It is lower to stir and add p-fluoronitrobenzene 17.6g, when stirring 12 is small at 50~60 DEG C.The ammonium chloride solution for adding saturation is quenched (mass percentage refers to that the quality of ammonium chloride accounts for the percentage of aqueous ammonium chloride solution gross mass), then with acetic acid second Ester is extracted.For 10% sodium bicarbonate aqueous solution, (mass concentration refers to sodium acid carbonate to organic phase mass concentration Quality accounts for the percentage of sodium bicarbonate aqueous solution gross mass) and mass concentration be the 15% brine It (mass concentration Refer to that the quality of sodium chloride accounts for the percentage of common salt aqueous solution gross mass), anhydrous sodium sulfate drying.Filter and concentrate in vacuo (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) obtain light yellow solid.Add 25mL ethyl acetate and 25mL cyclohexyl methyls Ether, is heated to dissolving when 75~85 DEG C and small stirring 1, when being cooled to 0~5 DEG C and small stirring 2, filtering, with 0~5 DEG C of acetic acid Ethyl ester wash, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain light yellow Solid 7.7g, yield 76.3% (total recovery 57.1%), HPLC purity 98.39%.
Embodiment 11：The preparation of Eliquis III (according to the method for document CN102675314A)
16.9g Eliquis intermediate compound Is are added into hydriding reactor, mass percentage is (described for 5% palladium-carbon catalyst Mass percentage refers to that the quality of palladium accounts for the percentage of palladium carbon gross mass) 1.7g, ethanol 170mL, in 0.3~0.4MPa hydrogen When stirring 4 is small at pressure and 50~55 DEG C.Cooling, filtering, washing and be concentrated in vacuo (45 DEG C~55 DEG C, -0.085MPa~- 0.1MPa) obtain Eliquis intermediate compound IV 15.7g, yield 100%.
15.7g Eliquis intermediate compound IVs are dissolved in 160mL anhydrous methylene chlorides, add finely ground sodium hydroxide 4.0g, 5- bromine valeric chloride 8.4g are added dropwise to, finely ground sodium hydroxide 4.0g is added after adding, when stirring 6 is small at 30~35 DEG C.Add Enter water quenching to go out, then extracted with dichloromethane.Organic phase mass percentage is (described for 10% sodium bicarbonate aqueous solution Mass percentage refer to that the quality of sodium acid carbonate accounts for the percentage of sodium bicarbonate aqueous solution gross mass) and mass percentage For 15% brine It, (mass percentage refers to that the quality of sodium chloride accounts for the percentage of common salt aqueous solution gross mass Than), anhydrous sodium sulfate drying.(25 DEG C~45 DEG C, -0.075MPa~-0.09MPa) is filtered and concentrated in vacuo, into residue Add ethyl acetate 96mL, be heated to 75 DEG C dissolving after slow cooling to 15 DEG C~20 DEG C and stir 1 it is small when.Filtering, uses acetic acid Ethyl ester wash, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain 9.52g Eliquis intermediate V, yield 50.4%.
9.52g Eliquis intermediates V is dissolved in n,N-Dimethylformamide 95mL, formamide 9.5mL is added, 0 DEG C~5 DEG C at mass percentage is added dropwise (mass percentage refers to methanol for 30% methanol solution of sodium methylate 27.0g The quality of sodium accounts for the percentage of methanol solution of sodium methylate gross mass), when 15 DEG C~20 DEG C stirrings 4 are small.Water 190mL is added, 15 DEG C~20 DEG C stirrings 1 are filtered when small, are washed with methyl tertiary butyl ether(MTBE), and n,N-Dimethylformamide 24mL is added after draining, is added Methyl tertiary butyl ether(MTBE) 96mL is slowly added to after heat to 75 DEG C of dissolvings, when being cooled to 5 DEG C~10 DEG C and small stirring 1.Filtering, uses methyl Tertbutyl ether wash, after draining -0.01MPa~-0.1MPa, 45 DEG C~55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain 6.29g Eliquis III, yield 70.3%, HPLC purity 99.91%, maximum single miscellaneous 0.056%.
Comparative example 1：The preparation method of Eliquis intermediate compound I
Method according to patent document CN102675314A prepares Eliquis intermediate compound I, the total recovery of four-step reaction 43.7%, product HPLC purity 97.54%.
Potassium carbonate 40g, water 30mL, paranitroanilinum 57.2g, tetrahydrofuran 272mL, tetra-n-butyl are added into reaction bulb Ammonium bromide 2.0g, stirs and 5- bromine valeric chlorides 89.5g is added dropwise at room temperature.When stirring 1 is small after dripping off, potassium hydroxide 26.4g is added, When stirring 4 is small at room temperature, water 40mL and ethyl acetate 60mL, stratification after stirring are added, organic phase is washed with saturated common salt Wash, anhydrous sodium sulfate drying, filter and concentrate in vacuo (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) obtain it is light yellow solid Body.Add ethyl acetate 100mL, be stirred at room temperature 2 it is small when, filtering, after draining -0.01MPa~-0.1MPa, 45 DEG C~ 55 DEG C vacuum drying 8 it is small when~12 it is small when, obtain 1- (4- nitrobenzophenones) -2- piperidones 76g, yield 90%.
19.2g1- (4- nitrobenzophenones) -2- piperidones is taken, chlorobenzene 100mL, phosphorus pentachloride 63.4g is added, is heated to 53 DEG C React 2 it is small when.It is cooled to room temperature, water 30mL is added dropwise, is extracted with dichloromethane, merges organic phase and anhydrous sodium sulfate drying, mistake Filter and be concentrated in vacuo (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) and obtain 3,3- bis- chloro- 1- (4- nitrobenzophenones) -2- piperidines Ketone 39.7g, yield 75%.
19.55g3 is taken, 3- bis- chloro- 1- (4- nitrobenzophenones) -2- piperidones, adds n,N-Dimethylformamide 200mL, chlorine Change lithium 2.94g, be heated to 105 DEG C, lithium carbonate 54g is added portionwise.When 105 DEG C of stirrings 4 are small.Cooling, adds water quenching to go out, and filters, Filtrate, filtrate are extracted with dichloromethane, are merged organic phase and anhydrous sodium sulfate drying, are filtered and concentrated in vacuo (45 DEG C~55 DEG C, -0.085MPa~-0.1MPa) obtain the chloro- 1- of 3- (4- nitrobenzophenones) -2- piperidines -3- ketenes 17.5g, yield 90%.
The chloro- 1- of 4.0g 3- (4- nitrobenzophenones) -2- piperidines -3- ketenes is taken, adds toluene 80mL, [(4- methoxyphenyls) Diazanyl] ethyl chloroacetate 4.87g, 96 DEG C are heated to, is slowly added to triethylamine 4.6mL, then when 96 DEG C of stirrings 2 are small.Cooling, Add water quenching to go out, extracted with toluene, merge organic phase and anhydrous sodium sulfate drying, filter and concentrate in vacuo (45 DEG C~65 DEG C ,- 0.085MPa~-0.1MPa) obtain Eliquis intermediate compound I 5.0g, yield 72%.Four-step reaction total recovery 43.7%.

Claims (10)

1. a kind of preparation method of Eliquis intermediate compound I, it is characterised in that it comprises the following steps：In organic solvent, alkali Under the conditions of existing, Eliquis intermediate II and p-fluoronitrobenzene are subjected to nucleophilic substitution and obtain Eliquis intermediate I；
2. the preparation method of Eliquis intermediate compound I as claimed in claim 1, it is characterised in that：
The preparation method of the Eliquis intermediate compound I carries out under protective gas protection；
And/or
In the preparation method of the Eliquis intermediate compound I, the organic solvent for ether solvent, amide solvent, One or more in acetals solvent and sulfoxide type solvents；
And/or
In the preparation method of the Eliquis intermediate compound I, the organic solvent and the body of Eliquis intermediate II Product mass values are 4mL/g~20mL/g；
And/or
In the preparation method of the Eliquis intermediate compound I, the alkali is inorganic base；
And/or
In the preparation method of the Eliquis intermediate compound I, the alkali rubs with the Eliquis intermediate II Your ratio is 1~10；
And/or
In the preparation method of the Eliquis intermediate compound I, the p-fluoronitrobenzene and Eliquis intermediate II Ratio is 1~10；
And/or
In the preparation method of the Eliquis intermediate compound I, the temperature of the nucleophilic substitution is 20 DEG C~80 DEG C；
And/or
In the preparation method of the Eliquis intermediate compound I, time of the nucleophilic substitution for 1 it is small when~it is 24 small When.
3. the preparation method of Eliquis intermediate compound I as claimed in claim 2, it is characterised in that：
When the preparation method of the Eliquis intermediate compound I carries out under protective gas protection；The protective gas is Nitrogen and/or argon gas；
And/or
In the preparation method of the Eliquis intermediate compound I, the ether solvent is tetrahydrofuran, dimethyl tetrahydro furan Mutter, the one or more in isopropyl ether and 1,4- dioxane；
And/or
In the preparation method of the Eliquis intermediate compound I, the amide solvent for n,N-Dimethylformamide and/ Or DMAC N,N' dimethyl acetamide；
And/or
In the preparation method of the Eliquis intermediate compound I, the acetals solvent is n,N-Dimethylformamide two Ethyl acetals；
And/or
In the preparation method of the Eliquis intermediate compound I, the sulfoxide type solvents are dimethyl sulfoxide (DMSO)；
And/or
In the preparation method of the Eliquis intermediate compound I, the organic solvent and the body of Eliquis intermediate II Product mass values are 5mL/g~10mL/g；
And/or
In the preparation method of the Eliquis intermediate compound I, the inorganic base is potassium tert-butoxide, sodium tert-butoxide, front three One or more in base silanol potassium, trimethyl silicane sodium alkoxide, tert-pentyl alcohol potassium and sodium tert-amyl alcohol；
And/or
In the preparation method of the Eliquis intermediate compound I, the alkali rubs with the Eliquis intermediate II Your ratio is 2~10；
And/or
In the preparation method of the Eliquis intermediate compound I, the p-fluoronitrobenzene and Eliquis intermediate II Ratio is 1.5~10；
And/or
In the preparation method of the Eliquis intermediate compound I, the temperature of the nucleophilic substitution is 40 DEG C~60 DEG C；
And/or
In the preparation method of the Eliquis intermediate compound I, time of the nucleophilic substitution for 2 it is small when~it is 24 small When；
And/or
The preparation method of the Eliquis intermediate compound I uses following steps：To Eliquis intermediate II and organic solvent In the mixture of formation, alkali is added, p-fluoronitrobenzene is then added and carries out nucleophilic substitution, obtain the Eliquis Intermediate compound I.
4. the preparation method of Eliquis intermediate compound I as claimed in claim 1, it is characterised in that：
The preparation method of the Eliquis intermediate compound I further comprises the preparation method of Eliquis intermediate II, it is wrapped Include following steps：In organic solvent, in the presence of alkali, by -2 (1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls) and [(4- methoxies Base phenyl) diazanyl] ethyl chloroacetate is condensed to yield the Eliquis intermediate II；
5. the preparation method of Eliquis intermediate compound I as claimed in claim 4, it is characterised in that：
The preparation method of the Eliquis intermediate II carries out under protective gas protection；
And/or
In the preparation method of the Eliquis intermediate II, the organic solvent is esters solvent, arene is molten One or more in agent and ether solvent；
And/or
In the preparation method of the Eliquis intermediate II, the organic solvent and 5, the 6- dihydro -3- (4- Morpholinyl) volume ratios of -2 (1H)-pyridones is 10mL/g~50mL/g；
And/or
In the preparation method of the Eliquis intermediate II, the alkali is organic base or inorganic base；
And/or
In the preparation method of the Eliquis intermediate II, the alkali and 5,6- dihydro -3- (4- morpholinyls) -2 The molar ratio of (1H)-pyridone is 1~10；
And/or
In the preparation method of the Eliquis intermediate II, described [(4- methoxyphenyls) diazanyl] ethyl chloroacetate Molar ratio with -2 (the 1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls) is 1~5；
And/or
In the preparation method of the Eliquis intermediate II, the temperature of the condensation reaction is 65 DEG C~115 DEG C；
And/or
In the preparation method of the Eliquis intermediate II, time of the condensation reaction for 1 it is small when~30 it is small when.
6. the preparation method of Eliquis intermediate compound I as claimed in claim 5, it is characterised in that：
When the preparation method of the Eliquis intermediate II carries out under protective gas protection, the protective gas is Nitrogen and/or argon gas；
And/or
In the preparation method of the Eliquis intermediate II, the esters solvent for ethyl acetate, isopropyl acetate, One or more in n-butyl acetate, isobutyl acetate and tert-butyl acetate；
And/or
In the preparation method of the Eliquis intermediate II, the aromatic hydrocarbon solvent is toluene, dimethylbenzene and second One or more in benzene；
And/or
In the preparation method of the Eliquis intermediate II, the ether solvent is tetrahydrofuran, dimethyl tetrahydro One or more in furans, isopropyl ether and 1,4- dioxane；
And/or
In the preparation method of the Eliquis intermediate II, the organic base for triethylamine, diisopropyl ethyl amine, One or more in Tri-n-Propylamine and tri-n-butylamine；
And/or
In the preparation method of the Eliquis intermediate II, the inorganic base is potassium carbonate, sodium carbonate, potassium hydroxide With the one or more in sodium hydroxide；When using inorganic base, reacted in the presence of a phase transfer catalyst,
And/or
In the preparation method of the Eliquis intermediate II, when using organic base, the alkali and 5,6- dihydro -3- The molar ratio of (4- morpholinyls) -2 (1H)-pyridone is 1~5；When using inorganic base, the alkali and 5,6- dihydro -3- The molar ratio of (4- morpholinyls) -2 (1H)-pyridone is 3~10；
And/or
In the preparation method of the Eliquis intermediate II, described [(4- methoxyphenyls) diazanyl] ethyl chloroacetate Molar ratio with -2 (the 1H)-pyridones of 5,6- dihydros -3- (4- morpholinyls) is 1.2~5；
And/or
In the preparation method of the Eliquis intermediate II, the temperature of the condensation reaction is 75 DEG C~105 DEG C；
And/or
In the preparation method of the Eliquis intermediate II, time of the condensation reaction for 12 it is small when~it is 24 small When.
7. the preparation method of Eliquis intermediate compound I as claimed in claim 6, it is characterised in that：
In the preparation method of the Eliquis intermediate II, when using inorganic base, in the presence of a phase transfer catalyst into During row reaction, the phase transfer catalyst is tetra-n-butyl ammonium bromide；
And/or
In the preparation method of the Eliquis intermediate II, when using inorganic base, in the presence of a phase transfer catalyst into During row reaction, the molar ratio of the phase transfer catalyst and the inorganic base is 0.001~0.1.
8. a kind of preparation method of Eliquis intermediate compound IV, it is characterised in that it comprises the following steps：By claim 1~7 The Eliquis intermediate compound I and then in organic solvent is made in any one of them preparation method, under palladium carbon catalysis, The Eliquis intermediate compound I and hydrogen are subjected to reduction reaction, obtain the Eliquis intermediate compound IV；
9. a kind of preparation method of Eliquis intermediate V, it is characterised in that it comprises the following steps：According to claim 8 institute The Eliquis intermediate compound IV and then in organic solvent is made in the preparation method stated, under the conditions of alkali is existing, by institute The Eliquis intermediate compound IV stated carries out condensation reaction with 5- bromines valeric chloride, obtains the Eliquis intermediate V；
10. a kind of preparation method of Eliquis III, it is characterised in that it comprises the following steps：According to described in claim 9 The Eliquis intermediate V and then in organic solvent is made in preparation method, will be described under the conditions of alkali is existing Eliquis intermediate V carries out condensation reaction with formamide, obtains the Eliquis III；
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CN111253392A (en) * 2019-12-17 2020-06-09 哈尔滨珍宝制药有限公司 Method for preparing apixaban
CN113666924A (en) * 2021-08-30 2021-11-19 上海金不换兰考制药有限公司 Preparation method of apixaban intermediate
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