WO2015104605A1 - A process for preparing rivaroxaban or a pharmaceutically acceptable salt thereof - Google Patents
A process for preparing rivaroxaban or a pharmaceutically acceptable salt thereof Download PDFInfo
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- WO2015104605A1 WO2015104605A1 PCT/IB2014/067072 IB2014067072W WO2015104605A1 WO 2015104605 A1 WO2015104605 A1 WO 2015104605A1 IB 2014067072 W IB2014067072 W IB 2014067072W WO 2015104605 A1 WO2015104605 A1 WO 2015104605A1
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- Prior art keywords
- formula
- pharmaceutically acceptable
- rivaroxaban
- acceptable salt
- reaction
- Prior art date
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- 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 claims abstract description 58
- 229960001148 rivaroxaban Drugs 0.000 title claims abstract description 57
- 150000003839 salts Chemical class 0.000 title claims abstract description 54
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 63
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 150000007970 thio esters Chemical class 0.000 claims abstract description 20
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 23
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 229940086542 triethylamine Drugs 0.000 claims description 12
- -1 2-benzothiazolyl Chemical group 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- FJZRGCRGZHFBST-UHFFFAOYSA-N S-(1,3-benzothiazol-2-yl) 5-chlorothiophene-2-carbothioate Chemical compound ClC1=CC=C(S1)C(SC=1SC2=C(N1)C=CC=C2)=O FJZRGCRGZHFBST-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 235000011181 potassium carbonates Nutrition 0.000 claims description 7
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 claims description 6
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 14
- 239000000203 mixture Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000002955 isolation Methods 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- KKDHWGOHWGLLPR-UHFFFAOYSA-N 1,1-bis(sulfanylidene)-3h-1,3-benzothiazole-2-thione Chemical compound C1=CC=C2S(=S)(=S)C(S)=NC2=C1 KKDHWGOHWGLLPR-UHFFFAOYSA-N 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- 0 *SC(c([s]1)ccc1Cl)=O Chemical compound *SC(c([s]1)ccc1Cl)=O 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BXEAAHIHFFIMIE-UHFFFAOYSA-N 3-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC=CC=1Cl BXEAAHIHFFIMIE-UHFFFAOYSA-N 0.000 description 1
- MHCRLDZZHOVFEE-UHFFFAOYSA-N 4-(4-aminophenyl)morpholin-3-one Chemical compound C1=CC(N)=CC=C1N1C(=O)COCC1 MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 description 1
- DEXXSYVEWAYIGZ-LBPRGKRZSA-N 4-[4-[(5s)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholin-3-one Chemical compound O=C1O[C@@H](CN)CN1C1=CC=C(N2C(COCC2)=O)C=C1 DEXXSYVEWAYIGZ-LBPRGKRZSA-N 0.000 description 1
- BMPDCQVRKDNUAP-UHFFFAOYSA-N 5-chlorothiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)S1 BMPDCQVRKDNUAP-UHFFFAOYSA-N 0.000 description 1
- KSZRKQZHNWPBAK-UHFFFAOYSA-N 5-chlorothiophene-2-carbothioic S-acid Chemical compound SC(=O)C1=CC=C(Cl)S1 KSZRKQZHNWPBAK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- AYMQOSNTEFNUTQ-UHFFFAOYSA-N S-(1,2-benzoxazol-3-yl) 5-chlorothiophene-2-carbothioate Chemical compound ClC1=CC=C(S1)C(SC1=NOC2=C1C=CC=C2)=O AYMQOSNTEFNUTQ-UHFFFAOYSA-N 0.000 description 1
- PZEREMKWHMZGBQ-UHFFFAOYSA-N S-methyl 5-chlorothiophene-2-carbothioate Chemical compound ClC1=CC=C(S1)C(SC)=O PZEREMKWHMZGBQ-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution 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
- 238000005406 washing Methods 0.000 description 1
- 229940055725 xarelto Drugs 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
Definitions
- the present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof.
- the present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof.
- the process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale.
- the product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC.
- the drug compound having the adopted name "Rivaroxaban” has chemical name, 5- chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5- yljmethyl)- 2-thiophenecarboxamide; and has the structural formula I,
- Rivaroxaban is a factor Xa inhibitor useful as oral anticoagulant. Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
- DVT deep vein thrombosis
- PE pulmonary embolism
- myocardial infract myocardial infract
- angina pectoris and restenoses after angioplasty or aortocoronary bypass
- cerebral stroke CAD
- transitory ischemic attacks and peripheral arterial occlusive diseases.
- U.S. Patent No. 7, 157,456 describes Rivaroxaban and process for the preparation thereof.
- the process of US '456 for rivaroxaban involves reaction of 2-[(2S)-2-oxiranylmethyl]- lH-isoindole-l,3(2H)-dione with 4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)- 2-hydroxy-3- ⁇ [4-(3-oxo-4-morpholiny)phenyl]amino Jpropyl)- lH-isoindole- 1 ,3(2H)- dione, which on cyclization using ⁇ , ⁇ -carbonyl diimidazole to afford 2-( ⁇ 5S)-2-Oxo-3- [4-(3-oxo-4-morpholiny)phenyl]-l,3-oxazolidin-5-yl ⁇ methyl)-lH-isoindole-l,3(2H)
- the present invention provides a process for the preparation of Rivaroxaban intermediates, or pharmaceutically acceptable salt thereof.
- the present invention is to provide thioester of Formula II,
- R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole.
- the present invention is to provide thioester of Formula IIA,
- the present invention is to provide a process for the preparation of Rivaroxaban o
- R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, , benzimidazole, benzisoxazole, with the 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3- oxazolidin-3-yl]phenyl ⁇ morpholine-3-one of formula III,
- Rivaroxaban or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof.
- the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
- the process includes the step of, reacting thioester of formula IIA or pharmaceutically acceptable salt thereof
- Rivaroxaban pharmaceutically acceptable salt thereof isolating the Rivaroxaban pharmaceutically acceptable salt thereof.
- alkyl refers to methyl, ethyl, n- propyl, isopropyl and butyl.
- aryl refers to phenyl, naphthyl or substituted phenyl and naphthyl.
- the substitution can be with alkyl, halo, nitro, amine and the like.
- the intermediates and starting materials of the present invention may be used as free bases or its salts.
- Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.
- the present invention is to provide thioesters of Formula II,
- R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole and benzisoxazole.
- the compound of formula II of the present invention is selected from the compounds of,
- the process for the preparation of compound of Formula II which includes the step of reacting 5-chlorothiophene-2-carboxylic acid with the sulfide compound (R'-S-R or R'- S-S-R), wherein R' is benzothiazolyl, acetyl, substituted or unsubstituted benzoyl or benzopyridyl.
- the reaction may be performed in presence of a tri-(lower alkyl)- or tri(aryl) phosphine or phosphite, such as triphenylphosphine.
- a base includes but are not limited to organic base such as dimethylamine, diethylamine or triethylamine and inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide.
- the reaction may be performed at the temperature range of between -30°C to 100°C, such as the temperature range of between -30°C to 60°C, or -5 °C to 5°C.
- the reaction may be performed in an inert, non-hydroxy-containing, organic solvent, for example a chlorinated hydrocarbon, such as methylene chloride; an ester solvent, such as ethyl acetate and optionally in the presence of water.
- a chlorinated hydrocarbon such as methylene chloride
- an ester solvent such as ethyl acetate
- the present invention is to provides, thioester of Formula IIA,
- the process includes the step of, esterifyin chlorothiophene-2-carboxylic acid of formula IV,
- the esterification reaction is performed in presence of solvent and base.
- the solvent includes but are not limited to a chlorinated solvent such as dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; an ester such as ethyl acetate, and the like; a nitrile such as acetonitrile, propionitrile, and the like.
- the reaction is performed in presence of base includes but are not limited to organic base such as dimethylamine, diethylamine or triethylamine and inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide preferably triethylamine.
- organic base such as dimethylamine, diethylamine or triethylamine
- inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide preferably triethylamine.
- the temperature for performing the esterification is in between -30°C to 40°C more preferably at -5°C to 5°C.
- the reaction may be maintained for a period of 30 minutes to 2 hours to complete at -5°C to 5°C for the completion.
- Isolation of compound of formula IIA carried out by means of filtration and washed with methylene chloride.
- the compound dried under vacuum at temperature range between 50°C to 60°C.
- the present invention is to provide a process for the preparation of Rivaroxaban o
- the process includes the step of , reacting thioester of formula II or pharmaceutically acceptable salt thereof
- R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole, or a pharmaceutically acceptable salt thereof with the 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl ⁇ morpholine- -one of formula III,
- Rivaroxaban or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof
- the reaction may be carried out in the presence of an organic solvent and a base and optionally in the presence of water.
- the reaction may be carried out at a temperature ranging from -5°C to about ambient temperature.
- the organic solvent used is selected from tetrahydrofuran, N,N- dimethylacetamide, N,N-dimethylformamide (DMF), chlorinated hydrocarbons, ketones, esters or a mixture thereof.
- the reaction is carried out in the presence of bases such as inorganic base or organic base.
- the organic base is selected from group of triethylamine, methyl amine, diisopropyl amine, N-methylpiperidine, pyridine, 1,8-diazabicycloundecene, 4-dimethylamino pyridine, or a mixture thereof; inorganic base is selected from group of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.
- the compound of formula III may be prepared from the known processes, for example, US 7,157,456.
- the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
- the process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof
- Rivaroxaban or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof.
- reaction may be carried out in the presence of an organic solvent and a base as herein described and optionally in the presence of water.
- the reaction may be carried out at a temperature ranging from -5°C to about ambient temperature for about 2 to 12 hours.
- the organic solvent used is selected from tetrahydrofuran, N,N-dimethylacetamide, N,N- dimethylformamide, chlorinated hydrocarbons, ketones, esters or a mixture thereof.
- the reaction is carried out in the presence of bases such as inorganic base or organic base.
- the organic base is selected from group of triethylamine, methyl amine, diisopropyl amine, N-methylpiperidine, pyridine, 1,8-diazabicycloundecene, 4-dimethylamino pyridine, or a mixture thereof;
- inorganic base is selected from group of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.
- the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
- the process includes the steps of , a) esterification of 5-chlorothiophene-2-carboxylic acid with l,2-bis(2- benzothiazolyl) disulfide in the presence of triphenylphosphine to obtain the S- benzo[d]thiazol-2-yl 5-chlorothiophene-2-carbothioate in the solvent
- Rivaroxaban carried out by means of quenching of reaction after completion with water, followed by repeated extraction in methylene chloride.
- the pH of methylene chloride layer is adjusted in the range of 6 to 7 with 2N hydrochloric acid. Finally distillation of solvent yields Rivaroxaban.
- the present invention provides a Rivaroxaban, has purity more than 99.9 %.
- the solvent is selected from the group of one or more chlorinated solvent, ester solvent, and nitrile solvent.
- the chlorinated solvent is selected from the group of one or more dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; an ester is selected from the group of one or more ethyl acetate, and the like; a nitrile is selected from the group of one or more acetonitrile, propionitrile.
- Rivaroxaban or a pharmaceutically acceptable salt thereof obtained from the present invention is useful for pharmaceutical composition.
- the present invention relates to pharmaceutical composition
- pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt obtained from the present invention and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the use as anticoagulant in a mammal in need thereof.
- EXAMPLE 2 A process for the preparation of rivaroxaban Exemplified procedure in example 1 with the replacement thioester of compound IIA with S-methyl 5-chlorothiophene-2-carbothioate in N,N-dimethylacetamide and water with potassium carbonate were used in place of triethylamine, during workup methylene chloride was used in mixture of N,N dimethyl acetamide and water to extract the Rivaroxaban.
- triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) were taken in methylene chloride and reaction mixture was stirred at 28°C -30°C for 1 hr.
- the 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added to the above reaction mixture.
- the reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1 hr 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholine-3-one (lOg) and triethylamine (3.8g) were added.
Abstract
The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The present invention especially relates to a process for the preparation of Rivaroxaban from thioester of formula II, or a pharmaceutically acceptable salt thereof, wherein R is leaving group.
Description
A PROCESS FOR PREPARING RIVAROXABAN OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
Field of Invention
The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The novel thioester intermediate represented by formula II
Formula II
or a pharmaceutically acceptable salt thereof, wherein R is leaving group.
Background of the invention
The drug compound having the adopted name "Rivaroxaban" has chemical name, 5- chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5- yljmethyl)- 2-thiophenecarboxamide; and has the structural formula I,
Formula I
The commercial pharmaceutical product XARELTO® tablets, contains rivaroxaban as active ingredient. Rivaroxaban is a factor Xa inhibitor useful as oral anticoagulant. Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
U.S. Patent No. 7, 157,456 describes Rivaroxaban and process for the preparation thereof. The process of US '456 for rivaroxaban involves reaction of 2-[(2S)-2-oxiranylmethyl]- lH-isoindole-l,3(2H)-dione with 4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)- 2-hydroxy-3- { [4-(3-oxo-4-morpholiny)phenyl]amino Jpropyl)- lH-isoindole- 1 ,3(2H)- dione, which on cyclization using Ν,Ν-carbonyl diimidazole to afford 2-({5S)-2-Oxo-3- [4-(3-oxo-4-morpholiny)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)- dione, which on reacted with methylamine followed by reaction with 5-chlorothiophene- 2-carbonyl chloride to provide Rivaroxaban.
Various processes for the preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.S. Patent Nos. 7,585,860; 7,351,823, 7,816,355, and 8,101,609; patent application Nos. WO 2011/012321, WO 2012/156983, WO 2012/153155, WO 2013/053739, WO 2013/098833, WO 2013/156936, WO 2013/152168, WO 2013/120464, WO 2013/164833, US 2012/0283434 and US 2013/184457; and J. Med. Chem. 2005, 48, 5900-5908.
The reported processes suffers one or the other problems like lower yield, use of carcinogenic reagents like hydrobromic acid at elevated temperature, longer reaction time, and the like.
Therefore, there is a need to develop a simple and industrially feasible process for Rivaroxaban and its intermediates or a pharmaceutically acceptable salt thereof.
Summary of the Invention
The present invention provides a process for the preparation of Rivaroxaban intermediates, or pharmaceutically acceptable salt thereof.
In an aspect, the present invention is to provide thioester of Formula II,
or a pharmaceutically acceptable salt thereof, wherein R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole.
In another aspect, the present invention is to provide thioester of Formula IIA,
Formula IIA
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention is to provide a process for the preparation of Rivaroxaban o
Formula I
or a pharmaceutically acceptable salt thereof, the process involves the reacting thioester of formula II,
Formula II
or a pharmaceutically acceptable salt thereof, wherein R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, , benzimidazole, benzisoxazole, with the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3- oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,
Formula III
or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof.
In another aspect, the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
Formula I or a pharmaceutically acceptable salt thereof, the process includes the step of, reacting thioester of formula IIA or pharmaceutically acceptable salt thereof
Formula IIA
with the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3- one of formula III,
Formula III
or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban pharmaceutically acceptable salt thereof.
Description of the Invention
The term "alkyl" as used herein, unless otherwise defined, refers to methyl, ethyl, n- propyl, isopropyl and butyl.
The term "aryl" as used herein, unless otherwise defined, refers to phenyl, naphthyl or substituted phenyl and naphthyl. The substitution can be with alkyl, halo, nitro, amine and the like.
The intermediates and starting materials of the present invention may be used as free bases or its salts.
The salt or pharmaceutically acceptable salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.
In an aspect, the present invention is to provide thioesters of Formula II,
or a pharmaceutically acceptable salt thereof, wherein R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole and benzisoxazole.
In an embodiment, the compound of formula II of the present invention is selected from the compounds of,
or a pharmaceutically acceptable salt thereof.
The process for the preparation of compound of Formula II, which includes the step of reacting 5-chlorothiophene-2-carboxylic acid with the sulfide compound (R'-S-R or R'- S-S-R), wherein R' is benzothiazolyl, acetyl, substituted or unsubstituted benzoyl or benzopyridyl.
The reaction may be performed in presence of a tri-(lower alkyl)- or tri(aryl) phosphine or phosphite, such as triphenylphosphine.
The reaction may be performed in presence of a base includes but are not limited to organic base such as dimethylamine, diethylamine or triethylamine and inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide.
The reaction may be performed at the temperature range of between -30°C to 100°C, such as the temperature range of between -30°C to 60°C, or -5 °C to 5°C.
The reaction may be performed in an inert, non-hydroxy-containing, organic solvent, for example a chlorinated hydrocarbon, such as methylene chloride; an ester solvent, such as ethyl acetate and optionally in the presence of water.
Isolation of compound of formula-II carried out by means of filtration and followed by washing with methylene chloride solvent. The compound dried under vacuum at temperature range between 50°C to 60°C.
In another aspect, the present invention is to provides, thioester of Formula IIA,
Formula IIA
or a pharmaceutically acceptable salt thereof.
In another aspect of the present invention provides a process for the preparat compound of Formula
or pharmaceutically acceptable salt thereof, the process includes the step of, esterifyin chlorothiophene-2-carboxylic acid of formula IV,
Formula IV
with l,2-bis(2-benzothiazol l) disulfide of Formula V,
Formula V
in the presence of triphenylphosphine and base to obtain the compound of Formula IIA.
The esterification reaction is performed in presence of solvent and base. The solvent includes but are not limited to a chlorinated solvent such as dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; an ester such as ethyl acetate, and the like; a nitrile such as acetonitrile, propionitrile, and the like.
The reaction is performed in presence of base includes but are not limited to organic base such as dimethylamine, diethylamine or triethylamine and inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide preferably triethylamine.
The temperature for performing the esterification is in between -30°C to 40°C more preferably at -5°C to 5°C. The reaction may be maintained for a period of 30 minutes to 2 hours to complete at -5°C to 5°C for the completion.
Isolation of compound of formula IIA carried out by means of filtration and washed with methylene chloride. The compound dried under vacuum at temperature range between 50°C to 60°C.
In another aspect, the present invention is to provide a process for the preparation of Rivaroxaban o
Formula I
or a pharmaceutically acceptable salt thereof, the process includes the step of , reacting thioester of formula II or pharmaceutically acceptable salt thereof
Formula II
wherein R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole, or a pharmaceutically acceptable salt thereof with the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholine- -one of formula III,
Formula III
or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof
The reaction may be carried out in the presence of an organic solvent and a base and optionally in the presence of water.
The reaction may be carried out at a temperature ranging from -5°C to about ambient temperature. The organic solvent used is selected from tetrahydrofuran, N,N- dimethylacetamide, N,N-dimethylformamide (DMF), chlorinated hydrocarbons, ketones, esters or a mixture thereof.
The reaction is carried out in the presence of bases such as inorganic base or organic base.
The organic base is selected from group of triethylamine, methyl amine, diisopropyl amine, N-methylpiperidine, pyridine, 1,8-diazabicycloundecene, 4-dimethylamino pyridine, or a mixture thereof; inorganic base is selected from group of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.
The compound of formula III may be prepared from the known processes, for example, US 7,157,456.
In another aspect, the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
Formula I
or a pharmaceutically acceptable salt thereof, the process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof
with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,
Formula III
or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof.
The reaction may be carried out in the presence of an organic solvent and a base as herein described and optionally in the presence of water.
The reaction may be carried out at a temperature ranging from -5°C to about ambient temperature for about 2 to 12 hours.
The organic solvent used is selected from tetrahydrofuran, N,N-dimethylacetamide, N,N- dimethylformamide, chlorinated hydrocarbons, ketones, esters or a mixture thereof.
The reaction is carried out in the presence of bases such as inorganic base or organic base. The organic base is selected from group of triethylamine, methyl amine, diisopropyl amine, N-methylpiperidine, pyridine, 1,8-diazabicycloundecene, 4-dimethylamino pyridine, or a mixture thereof; inorganic base is selected from group of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.
In another aspect, the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
Formula I
or a pharmaceutically acceptable salt thereof, the process includes the steps of , a) esterification of 5-chlorothiophene-2-carboxylic acid with l,2-bis(2- benzothiazolyl) disulfide in the presence of triphenylphosphine to obtain the S- benzo[d]thiazol-2-yl 5-chlorothiophene-2-carbothioate in the solvent
(b) reacting S-benzo[d]thiazol-2-yl 5-chlorothiophene-2-carbothioate with 4-{4- [(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one or a pharmaceutically acceptable salt thereof. c) isolating from reaction mixture Rivaroxaban its salts thereof.
Isolation of Rivaroxaban carried out by means of quenching of reaction after completion with water, followed by repeated extraction in methylene chloride. The pH of methylene chloride layer is adjusted in the range of 6 to 7 with 2N hydrochloric acid. Finally distillation of solvent yields Rivaroxaban.
In another aspect, the present invention provides a Rivaroxaban, has purity more than 99.9 %.
The solvent is selected from the group of one or more chlorinated solvent, ester solvent, and nitrile solvent. The chlorinated solvent is selected from the group of one or more dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; an ester is selected from the group of one or more ethyl acetate, and the like; a nitrile is selected from the group of one or more acetonitrile, propionitrile.
The resultant Rivaroxaban or a pharmaceutically acceptable salt thereof obtained from the present invention is useful for pharmaceutical composition.
In another aspect, the present invention relates to pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt obtained from the present invention and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the use as anticoagulant in a mammal in need thereof.
The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.
EXAMPLES
EXAMPLE 1 : A process for the preparation of Rivaroxaban
To the mixture of thioester (as referred as compound IIA, 10.7g), 4-{4-[(5S)-5- (aminomethyl)-2-oxo- 1 ,3-oxazolidin-3-yl]phenyl}morpholine-3-one( lOg) in tetrahydrofuran (30 ml),water (30 ml) under stirring triethylamine (3.8g) was added The reaction mixture was further stirred at 5-10°C for 4-6 hours. After completion of the reaction, it was quenched with water & extracted in methylene chloride (250 ml x 2). The aqueous layer was back extracted using methylene chloride and methylene chloride layers were combined and its pH was adjusted to 6-7 with 2 N hydrochloric acid. Finally, the organic layer was concentrated to get desired product. The product obtained was dried to yield Rivaroxaban.
Yield: 11.5
Purity: 99.3 %
EXAMPLE 2: A process for the preparation of rivaroxaban
Exemplified procedure in example 1 with the replacement thioester of compound IIA with S-methyl 5-chlorothiophene-2-carbothioate in N,N-dimethylacetamide and water with potassium carbonate were used in place of triethylamine, during workup methylene chloride was used in mixture of N,N dimethyl acetamide and water to extract the Rivaroxaban.
EXAMPLE 3: A process for the preparation of Rivaroxaban
Exemplified procedure in example 1 with the replacement thioester of compound IIA with S-benzo[d]thiazol-2-yl 5-chlorothiophene-2-carbothioate in N,N- dimethylformamide with sodium carbonate were used and followed similar process of example 2 to isolate the Rivaroxaban.
EXAMPLE 4: A process for the preparation of rivaroxaban
Exemplified procedure in example 1 with the replacement thioester of compound IIA with S-3H-l,2,3-triazol-4-yl 5-chlorothiophene-2-carbothioate in dichloromethane with N-methylpiperidine were used to get the Rivaroxaban.
EXAMPLE 5: A process for the preparation of Rivaroxaban
Exemplified procedure in example 1 with the replacement thioester of compound IIA with S-benzo[d]isoxazol-3-yl 5-chlorothiophene-2-carbothioate in acetone with potassium hydroxide were used and similar workup process of example 2was followed to get the Rivaroxaban.
EXAMPLE 6: A process for intermediate of Formula IIA:
The mixture of triphenylphosphine (161.32 gm) and mercaptobenzothiazole disulphide (214.72 gm) in methylene chloride was stirred at 25-30°C for 1 hr. 5-chlorothiophene-2-
carboxylic acid (lOOg) and triethyl amine (52.8g) were added at 10°C in the above mixture and reaction mixture was stirred at 10-20 °C for 2 hrs. After completion of the reaction, reaction mixture was filtered washed with methylene chloride (200 ml), followed by removed of methylene chloride and drying yields title compound.
Yield: 150 gm
Purity: < 98.40 %
EXAMPLE 7: One pot process for Rivaroxaban
The triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) were taken in methylene chloride and reaction mixture was stirred at 28°C -30°C for 1 hr. The 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added to the above reaction mixture. The reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1 hr 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one (lOg) and triethylamine (3.8g) were added. The resulting reaction mixture further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. aqueous layer was separated and washed with methylene chloride. The organic layer was acidified to pH 6-7 with 2N hydrochloric acid and finally the organic layer was concentrated to get desired product. The product was purified and dried to yield Rivaroxaban.
Yield: 10.0 gm
Purity: 99.3 %
EXAMPLE 8: One pot process for Rivaroxaban
Exemplified procedure in example 7 with the replacement of solvent ethyl acetate and base potassium hydroxide were used to get the rivaroxaban.
EXAMPLE 9: One pot process for Rivaroxaban
Exemplified procedure in example 7 with the replacement of solvent acetonitile and base potassium carbonate were used, methylene chloride was added in the reaction mixture to extract the Rivaroxaban.
Claims
1. A process for the preparation of Rivaroxaban of formula I,
Formula I
or a pharmaceutically acceptable salt thereof, the process comprises the step of reacting of thioester of formula II or pharmaceutically acceptable salts thereof,
Formula II
wherein R is leaving group with 4-{4-[(5S)-5-(aminomethyl)-2-oxo- l,3- oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,
Formula III
or a pharmaceutically acceptable salt thereof.
2. The process of claim 1 , wherein leaving group is selected from alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole and benzisoxazole.
3. The process of claim 1, wherein Rivaroxaban has a purity of more than 99 %, when measured by HPLC
4. The process of claim 1 , wherein the compound of Formula II is thioester of formula IIA,
Formula IIA
5. The process of claim 1 , wherein the reaction is performed in presence of base and solvent.
6. A thioester of compound of Formula II or a pharmaceutically acceptable salt thereof.
Formula II
wherein R is leaving group.
7. The compound of claim 6, wherein leaving group is selected from alkyl, aryl, 2- pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, or benzisoxazole;
8. The compound of claim 6, wherein alkyl group is methyl, ethyl, n-propyl, isopropyl, butyl and aryl group is phenyl, naphthyl or substituted phenyl and naphthyl.
9. The compound of claim 6, is selected from the compounds of
10. A thioester of compound
Formula IIA
or a pharmaceutically acceptable salt thereof.
11. A process for the preparation of compound of Formula IIA,
Formula IIA
or pharmaceutically acceptable salt thereof, the process comprises the step of esterification of 5-chlorothiophene-2-carboxylic acid of formula IV
Formula IV
with l,2-bis(2-benzothiazol l) disulfide of Formula V
Formula V
in the presence of triphenylphosphine and base.
12. The process of claim 11 , wherein the reaction is performed in presence of
chlorinated solvent selected from the group of one or more dichloromethane, dichloroethane, chloroform, chlorobenzene; an ester selected from the group of one or more ethyl acetate; a nitrile solvents selected from the group of one or more acetonitrile and propionitrile.
13. The process of claim 11 , wherein the reaction is performed in dichloromethane solvent.
14. A process for the preparation of Rivaroxaban of Formula I,
Formula I
or a pharmaceutically acceptable salt thereof, which comprises reaction of thioester of formula IIA or pharmaceutically acceptable salt thereof
Formula IIA
with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine- 3 -one of formu
Formula III
or a pharmaceutically acceptable salt thereof.
15. The process of claim 14, wherein Rivaroxaban obtained has a purity of more than 99 %, when measured by HPLC.
16. The process of claim 14, wherein the reaction is preformed in the presence of solvent selected from the group of one or moretetrahydrofuran, N,N- dimethylacetamide, N,N-dimethylformamide, chlorinated hydrocarbons selected from the group of one or more dichloromethane, dichloroethane, chloroform, chlorobenzene, ketones such as acetone.
17. The process of claim 14, wherein the reaction is preformed in tetrahydrofuran solvent.
18. The process of claim 11 and 14, wherein the reaction is performed in the presence of organic or inorganic base.
19. The process of claim 11 and 14, wherein organic base is selected from one or
more dimethylamine, diethylamine or triethylamine.
20. The process of claim 11 and 14, wherein inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide.
The process of claim 11 and 14, wherein the reaction is performed in the presence of triethyl amine.
22. A process for the preparation of rivaroxaban of Formula I,
Formula I
or a pharmaceutically acceptable salt thereof, the process comprises the steps of , a) esterification of 5-chlorothiophene-2-carboxylic acid with l,2-bis(2- benzothiazolyl) disulfide in the presence of triphenylphosphine to obtain the S- benzo[d]thiazol-2-yl 5-chlorothiophene-2-carbothioate in the solvent
(b) reacting S-benzo[d]thiazol-2-yl 5-chlorothiophene-2-carbothioate with 4-{4- [(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one or a pharmaceutically acceptable salt thereof. c) isolating from reaction mixture Rivaroxaban its salts thereof.
The process of claim 22, wherein the solvents are chlorinated solvent such as dichloromethane, dichloroethane, chloroform and chlorobenzene.
The process of claim 22, wherein the solvents are an ester such as ethyl acetate.
The process of claim 22, wherein the solvents are nitrile solvent selected from acetonitrile and propionitrile.
The process of claim 22, wherein Rivaroxaban has purity of more than 99 %, when measured by HPLC
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