CN104418848B - Preparation method of rivaroxaban - Google Patents
Preparation method of rivaroxaban Download PDFInfo
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- CN104418848B CN104418848B CN201310395570.0A CN201310395570A CN104418848B CN 104418848 B CN104418848 B CN 104418848B CN 201310395570 A CN201310395570 A CN 201310395570A CN 104418848 B CN104418848 B CN 104418848B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 title abstract description 7
- 229960001148 rivaroxaban Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- 239000012071 phase Substances 0.000 claims abstract description 17
- 230000007062 hydrolysis Effects 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 12
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- 239000000376 reactant Substances 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 230000008878 coupling Effects 0.000 claims abstract description 3
- 238000010168 coupling process Methods 0.000 claims abstract description 3
- 238000005859 coupling reaction Methods 0.000 claims abstract description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 claims description 24
- 229950010535 razaxaban Drugs 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 11
- 229910052744 lithium Inorganic materials 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- -1 chloro- benzals Chemical class 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 claims 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims 1
- 229910001948 sodium oxide Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000011084 recovery Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- 238000007605 air drying Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BDRTVPCFKSUHCJ-UHFFFAOYSA-N molecular hydrogen;potassium Chemical compound [K].[H][H] BDRTVPCFKSUHCJ-UHFFFAOYSA-N 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000009861 stroke prevention Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011883 total knee arthroplasty Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides a preparation method of rivaroxaban. The preparation method comprises the following steps: coupling and performing ring-closing on a compound as shown in formula II described in the specification and a compound as shown in formula III described in the specification in the presence of an organic solvent and lithium tert-butoxide to generate a compound as shown in formula IV; (2) directly adding the reactants which are not subjected to after-treatment and obtained in the last-step reaction into hydrochloric acid to hydrolyze to generate a compound as shown in formula V; after the hydrolysis is completed, extracting the reactants by an organic solvent, removing an organic phase and keeping a water phase for later use; and (3) adding inorganic alkali and the compound as shown in formula VI into the water phase, and reacting to obtain the compound rivaroxaban as shown in formula I. The preparation method of the rivaroxaban disclosed by the invention can be used for greatly reducing the technological operation steps, and is simple in after-treatment; only one organic solvent is used in the reaction and the after-treatment thereof, so that the environmental pollution is reduced and the production cost is lowered, and therefore, the preparation method is suitable for large-scale industrial production and has a great application value.
Description
Technical field
The present invention relates to the preparation of medicine, and in particular to a kind of preparation method of small molecule anti-coagulants razaxaban.
Background technology
Razaxaban（Rivaroxaban）, the chloro- N- of chemical name 5- { [(5S) -2- oxos -3- [4- (3- oxomorpholin -4-
Base) phenyl] -1,3- oxazolidone -5- bases] methyl } thiophene -2- carboxylic acid amides, No. CAS is 366789-02-8, with following structural
It is shown：
Razaxaban is the global first oral directly Xa factor inhibitor of Beyer Co., Ltd's exploitation, has height to Xa factor
Selectivity, can both suppress the Xa factor in free state, may also suppress the Xa factor of bonding state, it combines the Ⅹ a factors
Active site more closely but with invertibity, while there is no direct effect to platelet aggregation.The profit of in September, 2008 cuts down sand
Class goes through to list in Canada, for selective full hip or the venous thromboembolism of Total knee arthroplasty postoperative patient person（VTE）'s
Prevention.Razaxaban in 2009 in Discussion on Chinese Listed, ratify it and be applied to atrial fibrillation stroke prevention by U.S. FDA in 2011.
The preparation of related razaxaban it has been reported that such as US7157456, US7351823 and other documents, but, this
A little methods have that synthetic route is long, and total recovery is low, is unfavorable for environmental protection, is unsuitable for realizing industrialized defect.
Ying Tekuimu（INTERQUIM S.A.）It is shorter that patent WO2012159992 of company discloses a kind of route, yield
Higher razaxaban preparation method：
But, the method be present, such as：Due to the facile hydrolysis of compound IV, cause in compound II and chemical combination
Post processing during thing III Suo He Cheng azolactone rings can not be with the tert-butyl alcohol lithium during sour neutralization reaction, otherwise will causing
Compound IV is hydrolyzed into amine, into water layer, is greatly reduced yield；And if acid adding is not directly extracted, due to depositing in a large number for highly basic
, cause extraction process easily to emulsify, bring great difficulty to post-processing operation.The preparation method is used in whole process
Various organic solvents such as dichloromethane, ethyl acetate, isopropanol, mixed organic solvents are difficult to recovery, not only increased into
This, is also unfavorable for environmental protection, and industrialization is difficult to.
Hunan China normal university also discloses that method similar to the above in patent application CN102786516, public at it
In the embodiment of cloth, process is made and is walked in the post processing of prepare compound IV and follow-up hydrolysis, in order to avoid described hydrolysis
Cause the problem of yield decline into amine, employ benzene sulfonic acid, p-methyl benzenesulfonic acid neutralization, so, but cause unnecessary organic acid
Residual, while substantially prolongs hydrolysis time, causes intermediate to darken, and in follow-up reaction and post processing behaviour
In work, it is difficult to remove color；In addition, not adding water in the post processing of the method prepare compound IV and follow-up hydrolysis, adopt
With directly plus ethanol and concentrated hydrochloric acid method, and in this two-step reaction, used ethyl acetate, dichloromethane, methyl alcohol, ethanol
Etc. several organic solvents, and the hydrochloride of compound V easy moisture absorption in filter process, cause filtration difficulty, also can not possibly be real
Construction Industry.It is, thus, sought for preparing the effective ways of razaxaban.
The content of the invention
The technical problem to be solved is to overcome above-mentioned weak point, and research and design is less using organic molten
Agent, post processing is simple, reduces technological operation step, effectively reduces the preparation method of the razaxaban of environmental pollution, is suitable for work
Industry metaplasia is produced.
The invention provides a kind of preparation method of razaxaban.
The inventive method is comprised the following steps：
（1）Formula II compound（4-（Morpholine -3- ketone phenyl）- benzyq carbamate）With formula III compound（S）The chloro- 3- of -1-
[（4- chlorine benzals）- amino] in the presence of organic solvent, tert-butyl alcohol lithium, coupling cyclization generates formula IV compound to -propyl- 2- alcohol
（（S）- 5- { [(4- chlorine benzals）- amino]-methyl } -3- (4- morpholines -3- ketone groups-phenyl)-oxazolidine -2- ketone）；
（2）The reactant of upper step reaction is not post-treated, is directly added into hydrochloric acid hydrolysis, generates Formula V compound（4-{4-
[(5S) -5- (amino methyl) -2- oxos -1,3- oxazolidine -3- bases] phenyl } morpholine -3- ketone）；Hydrolysis is finished, and reactant is with organic
Solvent extraction, removes organic phase, retains water mutually standby；
（3）Inorganic base and Formula IV compound 5- chlorothiophene formyl chlorides are added in water phase, compound of formula I profit is obtained after reaction and is cut down
Sha Ban.
In the inventive method, the alkali described in step (1) is tert-butyl alcohol lithium；The mol ratio of tert-butyl alcohol lithium and compound II is 5:
1-1:1, preferably 4:1-2:The mol ratio of 1, compound II and compound III is 1:1-1:5, preferably 1:1-1:2, You Jirong
Agent is selected from dichloromethane, chloroform, toluene, preferably methyl tertbutyl ketone, dichloromethane, Formula II compound and organic solvent used
Mass/volume ratio be 1:5-1:20, preferably 1:5-1:10；Reaction temperature is 60 DEG C -150 DEG C, preferably solvent refluxing temperature
Degree；Reaction time is 5-20 hours, preferably 10-20 hours.
Step（2）Described concentration of hydrochloric acid is 3.7%-37%, and hydrochloric acid is 5 with the mol ratio of formula IV compound：1-1：1, water
The time of solution is -5 hours 10 minutes, and preferably -1 hour 10 minutes, hydrolysising reacting temperature was 0-50 DEG C, preferably 5-30 DEG C；
The described organic solvent for extraction is selected from dichloromethane, chloroform, toluene, methyl tertbutyl ketone；Extraction times are 1-3 time,
The quantity of solvent for extracting every time and step（1）The volume ratio of organic solvent amount is 1:5-1:1；
Step（3）Described inorganic base is selected from potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, potassium hydroxide or hydrogen-oxygen
Change sodium, preferably potassium carbonate and sodium carbonate；The consumption of inorganic base is 3 with the mol ratio of Formula IV compound:1-1:1, preferably 3:
1-2:1；The mol ratio of compound V and compound VI is 1:1-1:5, preferably 1:1-1:2；Reaction temperature is 0-50 DEG C, preferably
For 0-30 DEG C；Reaction time is 1-5 hours, preferably 2-5 hours.
The effect of the present invention：
（1）A kind of organic solvent is only used in the three-step reaction of the inventive method and its post processing, due to being single organic molten
Agent, therefore recovery can be easy to, so as to greatly reduce environmental pressure, reduce production cost.
（2）Step（3）The reaction of 5- chlorothiophenes formyl chloride and compound V is carried out in water phase, generally, acyl chlorides and amine
Reaction, it is fat-soluble due to acyl chlorides, the reason for water is mutually difficult to disperse and acyl chlorides meets sour facile hydrolysis, be usually difficult in list
Aqueous phase system realizes the reaction of acyl chlorides and amine.However, surprisingly, it was found that in single aqueous phase system, 5- chlorothiophene first
Acyl chlorides has enough decentralization, and the speed of its hydrolysis is far smaller than the speed with compound V into acid amides, and the acid amides of generation exists
Separate out in water, easily by simple filter operation can obtain razaxaban with higher yields, this has significant
Feature and be significant progress in the synthesis technology field of razaxaban.
（3）Step（1）In, it is to ensure that the reaction of compound II is complete, using excessive compound III；Generally,
After condensation ring closure reaction is finished, excessive compound III can be in follow-up acid hydrolysis step（2）In, it is hydrolyzed into amine（Formula VII
Compound）, impurity compound VIII is further produced in next step reaction：
But, it has surprisingly been found that the hydrolysate compound VII of residual compounds III when the present inventor implements this scheme,
The Highly solvated that the simultaneous hydroxyl of its close position and amino are likely due in water phase and water is acted on, and causes its amino
Reactivity is far smaller than compound V, therefore, in subsequent step（3）During reaction, just it is not detected by compound VIII's
Exist.
（4）The step of the present invention program（1）, due to not carrying out the post processing such as extracting and direct acid hydrolysis, so as to avoid
The emulsification occurred when being difficult to the extraction evaded in prior art（Alkalescence condition）Or acid condition causes under intermediate yield
The problem of drop；
（5）The present invention program operating procedure is simple, step（1）With（2）The continuous operation that realization is treated different things alike, eliminates centre
The process of body.
Therefore, the inventive method greatly reduces technological operation step, and post processing is simple, only uses in reaction and its post processing
Organic solvent, reduces environmental pollution, reduces production cost, is suitable for scale industrialized production, there is larger application
Value.
Specific embodiment
First,（S）- 5- { [(the chloro- benzals of 4-）- amino]-methyl } -3- (4- morpholines -3- ketone groups-phenyl)-oxazolidine -2-
Ketone（IV）Preparation
2nd, embodiment 1
Compound II is added in 100 milliliters of there-necked flasks（4-（Morpholine -3- ketone phenyl）- benzyq carbamate）（3.0 grams, 9.2
MM）, dichloromethane（30 milliliters）, add tert-butyl alcohol lithium（1.63 grams, 20.4 mMs）, compound III（（S）- 1- is chloro-
3-[（4- chlorine benzals）- amino] -propyl- 2- alcohol）（2.2 grams, 9.2 mMs）, it is heated to reflux 20 hours, it is cooled to 10 DEG C, without
Process, be directly used in next step reaction.
Embodiment 2
Compound II is added in 100 milliliters of there-necked flasks（3.0 gram, 9.2 mMs）, chloroform（42 milliliters）, add the tert-butyl alcohol
Lithium（2.45 grams, 30.4 mMs）, compound III（3.2 grams, 13.8 mMs）, it is heated to reflux 15 hours, it is cooled to 20 DEG C, no
Jing process, is directly used in next step reaction.
Embodiment 3
Compound II is added in 100 milliliters of there-necked flasks（3.0 grams, 9.2 mMs）, methyl tertbutyl ketone（42 milliliters）, plus
Enter tert-butyl alcohol lithium（3.7 grams, 46.3 mMs）, compound III（4.3 grams, 18.4 mMs）, it is heated to reflux 20 hours, it is cooled to 0
DEG C, without process, it is directly used in next step reaction.
Embodiment 4
Compound II is added in 100 milliliters of there-necked flasks（3.0 grams, 9.2 mMs）, toluene（21 milliliters）, add the tert-butyl alcohol
Lithium（0.76 gram, 9.2 mMs）, compound III（2.2 grams, 9.2 mMs）, it is heated to reflux 16 hours, it is cooled to 10 DEG C, without
Process, be directly used in next step reaction.
3rd, 4- { 4- [(5S) -5- (amino methyl) -2- oxos -1,3- oxazolidine -3- bases] phenyl } morpholine -3- ketone（V）'s
Prepare
Embodiment 5
In the system of embodiment 1,20 milliliters of the hydrochloric acid that concentration is 3.7% is added, stirred 20 minutes, divided and go oil phase, water phase
Washed twice with dichloromethane, 10 milliliters every time.Organic phase is removed, merges water mutually standby.
Embodiment 6
In the system of embodiment 2,14 milliliters of the hydrochloric acid that concentration is 7.4% is added, stirred 15 minutes, divided and go oil phase, water phase
Washed twice with chloroform, 10 milliliters every time.Organic phase is removed, merges water mutually standby.
Embodiment 7
In the system of embodiment 3,8.4 milliliters of the hydrochloric acid that concentration is 18.5% is added, stirred 30 minutes, divided and remove oil phase, water
Washed twice with methyl tertbutyl ketone, 10 milliliters every time.Organic phase is removed, merges water mutually standby.
Embodiment 8
In the system of embodiment 4,12 milliliters of the hydrochloric acid that concentration is 3.7% is added, stirred 40 minutes, divided and go oil phase, water phase
Washed twice with toluene, 10 milliliters every time.Organic phase is removed, merges water mutually standby.
4th, razaxaban（Rivaroxaban）（I）Preparation
Embodiment 9
In the water phase that embodiment 5 is obtained, 2.16 grams of sodium carbonate is added（20.4 mMs）, stirring and dissolving, dropwise addition chemical combination
VI1.665 gram of thing（9.2 mM）, maintain the temperature at 5 DEG C and stir 3 hours, to filter, filter cake washing, 60 DEG C of forced air dryings are got profit
Cut down 2.8 grams of husky class, three step total recoverys 70%.
Razaxaban is confirmed as after testing：
1H-NMR：（Brucker AVANCE400K, solvent D-DMSO）：δ 8.994 (t, 1H), 7.702 (d, 1H), 7.577
(d, 2H), 7.422 (d, 2H), 7.198 (d, 1H), 4.867～4832 (q, 1H), 4.216～4.172 (m, 3H), 3.987～
3.962 (m, 2H), 3.978～3.841 (m, 1H), 3.728～3.7032 (m, 2H), 3.631～3.604 (m, 2H)
13C-NMR：δ 166.437,161.283,154.569,138.929,137.548,136.964,133.747,
128.915,128.603,126.403,118.816,71.803,68.206,63.948,49.485,47.915,42.688
MS（ESI）：m/z=436.17（M+H+）
Embodiment 10
In the water phase that embodiment 6 is obtained, 2.54 grams of potassium carbonate is added（18.4 mMs）, stirring and dissolving, dropwise addition chemical combination
VI1.665 gram of thing（9.2 mM）, maintain the temperature at 10 DEG C and stir 3 hours, to filter, filter cake washing, 80 DEG C of forced air dryings are obtained
3.0 grams of razaxaban, three step total recoverys 75%.
Razaxaban is confirmed as after testing.
Embodiment 11
In the water phase that embodiment 7 is obtained, 1.1 grams of NaOH is added（27.6 mMs）, stirring and dissolving, dropwise addition chemical combination
VI1.665 gram of thing（9.2 mM）, maintain the temperature at 20 DEG C and stir 2 hours, to filter, filter cake washing, 60 DEG C of forced air dryings are obtained
2.9 grams of razaxaban crude product, three step total recoverys 72%.
Razaxaban is confirmed as after testing.
Embodiment 12
In the water phase that embodiment 8 is obtained, 1.23 grams of potassium hydroxide is added（22 mMs）, stirring and dissolving, dropwise addition chemical combination
VI1.665 gram of thing（9.2 mM）, maintain the temperature at 30 DEG C and stir 1.5 hours, filter, filter cake washing, 80 DEG C of forced air dryings,
Obtain 2.5 grams of razaxaban crude product, three step total recoverys 62%.
Razaxaban is confirmed as after testing.
Claims (4)
1. a kind of preparation method of razaxaban, it is characterised in that the method is comprised the following steps：
(1) Formula II compound (4- (morpholine -3- ketone phenyl)-benzyq carbamate) and chloro- the 3- [(4- of formula III compound (S) -1-
Chlorine benzal)-amino] -propyl- 2- alcohol, in the presence of organic solvent, tert-butyl alcohol lithium, coupling cyclization generation formula IV compound ((S)-
5- { [(the chloro- benzals of 4-)-amino]-methyl } -3- (4- morpholines -3- ketone groups-phenyl)-oxazolidine -2- ketone)；
(2) reactant that reaction is walked on is not post-treated, is directly added into hydrochloric acid and hydrolyzes, generation Formula V compound (4- 4- [(5S)-
5- (amino methyl) -2- oxo -1,3- oxazolidine -3- bases] phenyl } morpholine -3- ketone)；Hydrolysis is finished, and reactant is extracted with organic solvent
Take, remove organic phase, retain water mutually standby；
(3) inorganic base and Formula IV compound 5- chlorothiophene formyl chlorides are added in water phase, compound of formula I profit is obtained after reaction and is cut down sand
Class；
The mol ratio of step (1) tert-butyl alcohol lithium and compound II is 5:1-1:1, compound II and compound III mole
Than for 1:1-1:5, organic solvent is selected from dichloromethane, chloroform, toluene, methyl tertbutyl ketone；Formula II compound and described organic
The mass/volume ratio of solvent is 1:5-1:20, reaction temperature is 60 DEG C -150 DEG C, and the reaction time is 5-20 hours；Step (2) institute
The concentration of hydrochloric acid stated is 3.7%-37%, and hydrochloric acid is 5 with the mol ratio of formula IV compound：1-1：1, the time of hydrolysis is 10 points
Clock -5 hours, hydrolysising reacting temperature is 0 DEG C -50 DEG C, and the described organic solvent for extraction is selected from dichloromethane, chloroform, first
Benzene or methyl tertbutyl ketone, extraction times are 1-3 time, every time the volume ratio of the quantity of solvent of extraction and step (1) organic solvent amount
For 1:5-1:1；Inorganic base described in step (3) is selected from potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, potassium hydroxide or hydrogen
Sodium oxide molybdena, the consumption of inorganic base is 3 with the mol ratio of Formula IV compound:1-1:The mol ratio of 1, compound V and compound VI is
1:1-1:5, reaction temperature is 0 DEG C -50 DEG C, and the reaction time is 1-5 hours.
2. the preparation method of a kind of razaxaban according to claim 1, it is characterised in that step (1) tert-butyl alcohol lithium and
The mol ratio of compound II is 4:1-2:The mol ratio of 1, compound II and compound III is 1:1-1:2, organic solvent is dichloro
The mass/volume ratio of methane, Formula II compound and organic solvent used is 1:5-1:10, reaction temperature is solvent reflux temperature,
Reaction time is 10-20 hours.
3. a kind of preparation method of razaxaban according to claim 1, it is characterised in that the hydrochloric acid described in step (2)
It is 4 with the mol ratio of formula IV compound：1-2：1, hydrolysis time is -1 hour 10 minutes, and hydrolysising reacting temperature is 5 DEG C -30 DEG C.
4. the preparation method of a kind of razaxaban according to claim 1, it is characterised in that inorganic described in step (3)
Alkali is selected from potassium carbonate or sodium carbonate；The consumption of inorganic base is 3 with the mol ratio of Formula IV compound:1-2:1, compound V and chemical combination
The mol ratio of thing VI is 1:1-1:2；Reaction temperature is 0 DEG C -30 DEG C；Reaction time is 2-5 hours.
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| CN102786516A (en) * | 2012-08-21 | 2012-11-21 | 湖南师范大学 | Method for synthesizing rivaroxaban |
| WO2012159992A1 (en) * | 2011-05-20 | 2012-11-29 | Interquim, S.A. | Process for obtaining rivaroxaban and intermediate thereof |
| CN102827154A (en) * | 2011-06-14 | 2012-12-19 | 上海科胜药物研发有限公司 | New method for synthesizing rivaroxaban intermediate 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-ketone |
| WO2013120465A1 (en) * | 2012-02-16 | 2013-08-22 | Zentiva, K.S. | A process for the preparation of rivaroxaban based on the use of (s)-epichlorohydrin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012159992A1 (en) * | 2011-05-20 | 2012-11-29 | Interquim, S.A. | Process for obtaining rivaroxaban and intermediate thereof |
| CN102827154A (en) * | 2011-06-14 | 2012-12-19 | 上海科胜药物研发有限公司 | New method for synthesizing rivaroxaban intermediate 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-ketone |
| WO2013120465A1 (en) * | 2012-02-16 | 2013-08-22 | Zentiva, K.S. | A process for the preparation of rivaroxaban based on the use of (s)-epichlorohydrin |
| CN102786516A (en) * | 2012-08-21 | 2012-11-21 | 湖南师范大学 | Method for synthesizing rivaroxaban |
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