CN104418848A - Preparation method of rivaroxaban - Google Patents
Preparation method of rivaroxaban Download PDFInfo
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- CN104418848A CN104418848A CN201310395570.0A CN201310395570A CN104418848A CN 104418848 A CN104418848 A CN 104418848A CN 201310395570 A CN201310395570 A CN 201310395570A CN 104418848 A CN104418848 A CN 104418848A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 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 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003960 organic solvent Substances 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 230000007062 hydrolysis Effects 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- 239000000376 reactant Substances 0.000 claims abstract description 6
- 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
- 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 31
- 229950010535 razaxaban Drugs 0.000 claims description 31
- 239000008346 aqueous phase Substances 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 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
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 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 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 235000010755 mineral Nutrition 0.000 claims description 8
- 238000000605 extraction Methods 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
- 239000002585 base Substances 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- -1 chloro-benzylidene Chemical group 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 239000012071 phase Substances 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 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
- 238000003756 stirring Methods 0.000 description 12
- 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
- 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
- 150000001263 acyl chlorides Chemical class 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- KQNFOQLHSVJXPR-UHFFFAOYSA-N 2-chlorothiophene formyl chloride Chemical compound ClC1=CC=CS1.C(=O)Cl KQNFOQLHSVJXPR-UHFFFAOYSA-N 0.000 description 2
- 206010014522 Embolism venous Diseases 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 238000012805 post-processing 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
- 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229960004676 antithrombotic agent 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000006353 environmental stress Effects 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000009861 stroke prevention Effects 0.000 description 1
- 239000000126 substance Substances 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
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, be specifically related to a kind of preparation method of small molecules antithrombotics razaxaban.
Background technology
Razaxaban (Rivaroxaban), the chloro-N-{ of chemical name 5-[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-base) phenyl]-1,3-oxazolidone-5-base] methyl } thiophene-2-carboxylic acid amides, No. CAS is 366789-02-8, shown in following structural:
Razaxaban is the first oral direct Xa factor inhibitor in the whole world of Beyer Co., Ltd's exploitation, Xa factor is had to the selectivity of height, both the Xa factor in unbound state can have been suppressed, also can suppress the Xa factor of bonding state, its reactive site in conjunction with the Ⅹ a factor comparatively closely but have reversibility, does not have direct effect to platelet aggregation simultaneously.Razaxaban to go through listing in Canada, for the prevention of the venous thromboembolism (VTE) of the full hip of selectivity or Total knee arthroplasty postoperative patient person in September, 2008.Within 2009, razaxaban is in Discussion on Chinese Listed, and U.S. FDA in 2011 is ratified it and is applied to atrial fibrillation stroke prevention.
The preparation of relevant razaxaban has been reported, and as US7157456, US7351823 and other documents, but it is long that these methods exist synthetic route, and total recovery is on the low side, is unfavorable for environment protection, is unsuitable for and realizes industrialized defect.
It is shorter that the patent WO2012159992 of Ying Tekuimu (INTERQUIM S.A.) company discloses a kind of route, the razaxaban preparation method that yield is higher:
But, there are some problems in the method, as: due to the facile hydrolysis of compound IV, cause the aftertreatment when Compound II per Chengs azolactone ring with compound III Suo He can not with the trimethyl carbinol lithium in sour neutralization reaction process, otherwise compound IV will be caused to be hydrolyzed into amine, enter water layer, yield is declined greatly; And if acid adding does not directly extract, due to a large amount of existence of highly basic, cause extraction process very easily emulsification, bring great difficulty to post-processing operation.This preparation method uses the multiple organic solvents such as methylene dichloride, ethyl acetate, Virahol in whole process, and mixed organic solvents is difficult to recovery, not only adds cost, is also unfavorable for environment protection, and industrialization is difficult to realize.
Hunan China normal university is in patent application CN102786516, also method similar to the above is disclosed, in the embodiment that it is announced, aftertreatment and the follow-up hydrolysis of preparation compound IV are done and walk process, in order to avoid the described problem being hydrolyzed into amine and causing yield to decline, have employed Phenylsulfonic acid, tosic acid neutralization, like this, but unnecessary organic acid is caused to remain, substantially prolongs hydrolysis time simultaneously, cause intermediate to darken, and in follow-up reaction and post-processing operation, be difficult to color to remove; In addition, the method is prepared in the aftertreatment of compound IV and follow-up hydrolysis and is not added water, adopt the method directly adding ethanol and concentrated hydrochloric acid, and in this two-step reaction, several organic solvents such as ethyl acetate, methylene dichloride, methyl alcohol, ethanol are used, and the hydrochloride of compound V is the easy moisture absorption in filtration procedure, causes filtration difficulty, also can not implement industrialization.Therefore, need to find the effective ways preparing razaxaban.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research and design is with an organic solvent less, and aftertreatment is simple, reduces technological operation step, effectively reduces the preparation method of the razaxaban of environmental pollution, to be suitable for suitability for industrialized production.
The invention provides a kind of preparation method of razaxaban.
The inventive method comprises the following steps:
(1) formula II compound (4-(morpholine-3-ketone phenyl)-benzyl carbamate) with the chloro-3-of formula III compound (S)-1-[(4-chlorine benzylidene)-amino]-propyl-2-alcohol under organic solvent, trimethyl carbinol lithium exist, ring production IV compound ((S)-5-{ [(4-chlorine benzylidene)-amino]-methyl }-3-(4-morpholine-3-ketone group-phenyl)-oxazolidine-2-ketone) is closed in coupling;
(2) reactant of upper step reaction is without aftertreatment, directly adds hydrochloric acid hydrolysis, production V compound (4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-ketone); Hydrolysis is finished, reactant organic solvent extraction, and removing organic phase, retains aqueous phase for subsequent use;
(3) add mineral alkali and formula VI compound 5-chlorothiophene formyl chloride in aqueous phase, after reaction, obtain formula I razaxaban.
In the inventive method, the alkali described in step (1) is trimethyl carbinol lithium; The mol ratio of trimethyl carbinol lithium and Compound II per is 5:1-1:1, be preferably 4:1-2:1, the mol ratio of Compound II per and compound III is 1:1-1:5, be preferably 1:1-1:2, organic solvent is selected from methylene dichloride, chloroform, toluene, methyl tertbutyl ketone, be preferably methylene dichloride, the mass/volume of formula II compound and organic solvent used, than being 1:5-1:20, is preferably 1:5-1:10; Temperature of reaction is 60 DEG C-150 DEG C, is preferably solvent reflux temperature; Reaction times is 5-20 hour, is preferably 10-20 hour.
Concentration of hydrochloric acid described in step (2) is 3.7%-37%, and the mol ratio of hydrochloric acid and formula IV compound is 5:1-1:1, and the time of hydrolysis is 10 minutes-5 hours, and be preferably 10 minutes-1 hour, hydrolysising reacting temperature is 0-50 DEG C, is preferably 5-30 DEG C; Described is selected from methylene dichloride, chloroform, toluene, methyl tertbutyl ketone for the organic solvent extracted; Extraction times is 1-3 time, and each quantity of solvent of extraction and the volume ratio of step (1) organic solvent amount are 1:5-1:1;
Mineral alkali described in step (3) is selected from salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassium hydroxide or sodium hydroxide, is preferably salt of wormwood and sodium carbonate; The consumption of mineral alkali and the mol ratio of formula VI compound are 3:1-1:1, are preferably 3:1-2:1; The mol ratio of compound V and compound VI is 1:1-1:5, is preferably 1:1-1:2; Temperature of reaction is 0-50 DEG C, is preferably 0-30 DEG C; Reaction times is 1-5 hour, is preferably 2-5 hour.
Effect of the present invention:
(1) a kind of organic solvent is only used in the three-step reaction of the inventive method and aftertreatment thereof, owing to being single organic solvent, therefore can being easy to recovery, thus greatly reducing environmental stress, reduce production cost.
(2) reaction of step (3) 5-chlorothiophene formyl chloride and compound V is carried out in aqueous phase, usually, the reaction of acyl chlorides and amine, fat-soluble due to acyl chlorides, being difficult to disperse and acyl chlorides meets the reason of sour facile hydrolysis at aqueous phase, is generally the reaction being difficult to realize at single aqueous phase system acyl chlorides and amine.But, the present inventor is surprised to find, in single aqueous phase system, 5-chlorothiophene formyl chloride has enough dispersity, and the speed of its hydrolysis is far smaller than the speed becoming acid amides with compound V, and the acid amides of generation is separated out in water, can easily by simple filter operation, obtain razaxaban with higher yields, this has very outstanding feature and be significant progress in the synthesis technology field of razaxaban.
(3), in step (1), for ensureing reacting completely of Compound II per, excessive compound III is used; Generally, after condensation ring closure reaction is finished, excessive compound III in follow-up acid hydrolysis step (2), can be hydrolyzed into amine (formula VII compound), in next step reaction, produce impurity compound VIII further:
But, the present inventor is surprised to find when implementing this scheme, the hydrolysate compound VI I of residual compounds III, may be due to the simultaneous hydroxyl of its close position and the amino Highly solvated effect at aqueous phase and water, the reactive behavior of its amino is caused to be far smaller than compound V, therefore, in the process that subsequent step (3) reacts, the existence of compound VI II just do not detected.
(4) step (1) of the present invention program, owing to not carrying out the aftertreatments such as extraction and directly acid hydrolysis, thus avoid in prior art the problem that the emulsification (alkaline condition) that occurs when being difficult to the extraction evaded or acidic conditions cause intermediate yield to decline;
(5) the present invention program's operation steps is simple, and step (1) and (2) realize the operate continuously for the treatment of different things alike, and eliminate the process of intermediate.
Therefore, the inventive method greatly reduces technological operation step, and aftertreatment is simple, only uses an organic solvent, decrease environmental pollution, reduce production cost, be suitable for scale suitability for industrialized production, have larger using value in reaction and aftertreatment thereof.
Embodiment
One, (S)-5-{ [(the chloro-benzylidene of 4-)-amino]-methyl } preparation of-3-(4-morpholine-3-ketone group-phenyl)-oxazolidine-2-ketone (IV)
Two, embodiment 1
Compound II per (4-(morpholine-3-ketone phenyl)-benzyl carbamate is added in 100 milliliters of there-necked flasks) (3.0 grams, 9.2 mmoles), methylene dichloride (30 milliliters), adds trimethyl carbinol lithium (1.63 grams, 20.4 mmoles), compound III (the chloro-3-of (S)-1-[(4-chlorine benzylidene)-amino]-propyl-2-alcohol) (2.2 grams, 9.2 mmoles), reflux 20 hours, is chilled to 10 DEG C, not treated, be directly used in next step reaction.
Embodiment 2
Add Compound II per (3.0 grams, 9.2 mmoles) in 100 milliliters of there-necked flasks, chloroform (42 milliliters), adds trimethyl carbinol lithium (2.45 grams, 30.4 mmoles), compound III (3.2 grams, 13.8 mmoles), reflux 15 hours, be chilled to 20 DEG C, not treated, be directly used in next step reaction.
Embodiment 3
Compound II per (3.0 grams is added in 100 milliliters of there-necked flasks, 9.2 mmoles), methyl tertbutyl ketone (42 milliliters), adds trimethyl carbinol lithium (3.7 grams, 46.3 mmoles), compound III (4.3 grams, 18.4 mmoles), reflux 20 hours, is chilled to 0 DEG C, not treated, be directly used in next step reaction.
Embodiment 4
Add Compound II per (3.0 grams, 9.2 mmoles) in 100 milliliters of there-necked flasks, toluene (21 milliliters), adds trimethyl carbinol lithium (0.76 gram, 9.2 mmoles), compound III (2.2 grams, 9.2 mmoles), reflux 16 hours, be chilled to 10 DEG C, not treated, be directly used in next step reaction.
Three, 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } preparation of morpholine-3-ketone (V)
Embodiment 5
In the system of embodiment 1, add the hydrochloric acid 20 milliliters that concentration is 3.7%, stir 20 minutes, divide phase of deoiling, aqueous phase methylene dichloride washes twice, each 10 milliliters.Removing organic phase, merges aqueous phase for subsequent use.
Embodiment 6
In the system of embodiment 2, add the hydrochloric acid 14 milliliters that concentration is 7.4%, stir 15 minutes, divide phase of deoiling, aqueous phase chloroform washes twice, each 10 milliliters.Removing organic phase, merges aqueous phase for subsequent use.
Embodiment 7
In the system of embodiment 3, add the hydrochloric acid 8.4 milliliters that concentration is 18.5%, stir 30 minutes, divide phase of deoiling, aqueous phase methyl tertbutyl ketone washes twice, each 10 milliliters.Removing organic phase, merges aqueous phase for subsequent use.
Embodiment 8
In the system of embodiment 4, add the hydrochloric acid 12 milliliters that concentration is 3.7%, stir 40 minutes, divide phase of deoiling, aqueous phase toluene washes twice, each 10 milliliters.Removing organic phase, merges aqueous phase for subsequent use.
Four, the preparation of razaxaban (Rivaroxaban) (I)
Embodiment 9
In the aqueous phase that embodiment 5 obtains, add 2.16 grams, sodium carbonate (20.4 mmole), stirring and dissolving, drip compound VI 1.665 grams (9.2 mmole), maintain the temperature at 5 DEG C to stir 3 hours, filter, filter cake is washed, 60 DEG C of forced air dryings, obtain razaxaban 2.8 grams, three step total recoverys 70%.
Confirm as razaxaban 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：δ166.437，161.283，154.569，138.929，137.548，136.964，133.747，128.915，128.603，126.403，118.816，71.803，68.206，63.948，49.485，47.915，42.688
MS（ESI）：m/z=436.17（M+H
+）
Embodiment 10
In the aqueous phase that embodiment 6 obtains, add 2.54 grams, salt of wormwood (18.4 mmole), stirring and dissolving, drip compound VI 1.665 grams (9.2 mmole), maintain the temperature at 10 DEG C to stir 3 hours, filter, filter cake is washed, 80 DEG C of forced air dryings, obtain razaxaban 3.0 grams, three step total recoverys 75%.
Confirm as razaxaban after testing.
Embodiment 11
In the aqueous phase that embodiment 7 obtains, add 1.1 grams, sodium hydroxide (27.6 mmole), stirring and dissolving, drip compound VI 1.665 grams (9.2 mmole), maintain the temperature at 20 DEG C and stir 2 hours, filter, filter cake is washed, 60 DEG C of forced air dryings, obtain razaxaban crude product 2.9 grams, three step total recoverys 72%.
Confirm as razaxaban after testing.
Embodiment 12
In the aqueous phase that embodiment 8 obtains, add 1.23 grams, potassium hydroxide (22 mmole), stirring and dissolving, drip compound VI 1.665 grams (9.2 mmole), maintain the temperature at 30 DEG C and stir 1.5 hours, filter, filter cake is washed, 80 DEG C of forced air dryings, obtain razaxaban crude product 2.5 grams, three step total recoverys 62%.
Confirm as razaxaban after testing.
Claims (7)
1. a preparation method for razaxaban, is characterized in that, the method comprises the following steps:
(1) formula II compound (4-(morpholine-3-ketone phenyl)-benzyl carbamate) and the chloro-3-of formula III compound (S)-1-[(4-chlorine benzylidene)-amino]-propyl-2-alcohol, under organic solvent, trimethyl carbinol lithium exist, coupling pass ring production IV compound ((S)-5-{ [(the chloro-benzylidene of 4-)-amino]-methyl-3-(4-morpholine-3-ketone group-phenyl)-oxazolidine-2-ketone);
(2) reactant of upper step reaction is without aftertreatment, directly adds hydrochloric acid hydrolysis, production V compound (4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl } morpholine-3-ketone); Hydrolysis is finished, reactant organic solvent extraction, and removing organic phase, retains aqueous phase for subsequent use;
(3) add mineral alkali and formula VI compound 5-chlorothiophene formyl chloride in aqueous phase, after reaction, obtain formula I razaxaban.
2. the preparation method of a kind of razaxaban according to claim 1, is characterized in that, the alkali described in step (1) is trimethyl carbinol lithium; The mol ratio of trimethyl carbinol lithium and Compound II per is 5:1-1:1, and the mol ratio of Compound II per and compound III is 1:1-1:5, and organic solvent is selected from methylene dichloride, chloroform, toluene, methyl tertbutyl ketone; The mass/volume of formula II compound and described organic solvent is than being 1:5-1:20, and temperature of reaction is 60 DEG C-150 DEG C, and the reaction times is 5-20 hour.
3. the preparation method of a kind of razaxaban according to claim 2, it is characterized in that, the mol ratio of step (1) trimethyl carbinol lithium and Compound II per is 4:1-2:1, the mol ratio of Compound II per and compound III is 1:1-1:2, organic solvent is methylene dichloride, the mass/volume of formula II compound and organic solvent used is than being 1:5-1:10, and temperature of reaction is solvent reflux temperature, and the reaction times is 10-20 hour.
4. the preparation method of a kind of razaxaban according to claim 1, it is characterized in that, concentration of hydrochloric acid described in step (2) is 3.7%-37%, the mol ratio of hydrochloric acid and formula IV compound is 5:1-1:1, the time of hydrolysis is 10 minutes-5 hours, hydrolysising reacting temperature is 0 DEG C-50 DEG C, described is selected from methylene dichloride, chloroform, toluene or methyl tertbutyl ketone for the organic solvent extracted, extraction times is 1-3 time, and each quantity of solvent of extraction and the volume ratio of step (1) organic solvent amount are 1:5-1:1.
5. the preparation method of a kind of razaxaban according to claim 4, is characterized in that, the hydrochloric acid described in step (2) and the mol ratio of formula IV compound are 4:1-2:1, and hydrolysis time is 10 minutes-1 hour, and hydrolysising reacting temperature is 5 DEG C-30 DEG C.
6. the preparation method of a kind of razaxaban according to claim 1, it is characterized in that, mineral alkali described in step (3) is selected from salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassium hydroxide or sodium hydroxide, the consumption of mineral alkali and the mol ratio of formula VI compound are 3:1-1:1, the mol ratio of compound V and compound VI is 1:1-1:5, temperature of reaction is 0 DEG C-50 DEG C, and the reaction times is 1-5 hour.
7. the preparation method of a kind of razaxaban according to claim 6, is characterized in that, the mineral alkali described in step (3) is selected from salt of wormwood or sodium carbonate; The consumption of mineral alkali and the mol ratio of formula VI compound are 3:1-2:1, and the mol ratio of compound V and compound VI is 1:1-1:2; Temperature of reaction is 0 DEG C-30 DEG C; Reaction times is 2-5 hour.
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| CN109232551A (en) * | 2018-10-11 | 2019-01-18 | 东南大学 | Razaxaban isopropylidene impurity reference substance and preparation method thereof |
| CN110551111A (en) * | 2019-08-29 | 2019-12-10 | 上海海翔医药科技发展有限公司 | Preparation method of rivaroxaban intermediate |
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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 |
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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 |
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| CN109232551A (en) * | 2018-10-11 | 2019-01-18 | 东南大学 | Razaxaban isopropylidene impurity reference substance and preparation method thereof |
| CN109232551B (en) * | 2018-10-11 | 2020-06-02 | 东南大学 | Rivaroxaban isopropylidene impurity reference substance and preparation method thereof |
| CN110551111A (en) * | 2019-08-29 | 2019-12-10 | 上海海翔医药科技发展有限公司 | Preparation method of rivaroxaban intermediate |
| CN110551111B (en) * | 2019-08-29 | 2022-04-26 | 上海海翔医药科技发展有限公司 | Preparation method of rivaroxaban intermediate |
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