WO2011004402A2 - Improved process for the preparation of ambrisentan and novel intermediates thereof - Google Patents
Improved process for the preparation of ambrisentan and novel intermediates thereof Download PDFInfo
- Publication number
- WO2011004402A2 WO2011004402A2 PCT/IN2010/000464 IN2010000464W WO2011004402A2 WO 2011004402 A2 WO2011004402 A2 WO 2011004402A2 IN 2010000464 W IN2010000464 W IN 2010000464W WO 2011004402 A2 WO2011004402 A2 WO 2011004402A2
- Authority
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- WIPO (PCT)
- Prior art keywords
- formula
- ambrisentan
- solvents
- solution
- ray diffraction
- Prior art date
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- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 title claims abstract description 102
- 229960002414 ambrisentan Drugs 0.000 title claims abstract description 101
- 238000000034 method Methods 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 239000000543 intermediate Substances 0.000 title description 13
- 239000002904 solvent Substances 0.000 claims description 55
- 239000000243 solution Substances 0.000 claims description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 29
- 239000004305 biphenyl Substances 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- 239000002585 base Substances 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 20
- 235000014655 lactic acid Nutrition 0.000 claims description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- ZHPSNGCLCHWTRG-UHFFFAOYSA-N 4,6-dimethyl-2-methylsulfonylpyrimidine Chemical compound CC1=CC(C)=NC(S(C)(=O)=O)=N1 ZHPSNGCLCHWTRG-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- -1 diphenyl propionate Chemical compound 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000012296 anti-solvent Substances 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 8
- 235000010290 biphenyl Nutrition 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 5
- 108010037444 diisopropylglutathione ester Proteins 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 4
- 238000010908 decantation Methods 0.000 claims description 4
- 229940113088 dimethylacetamide Drugs 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 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
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-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
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- RQJWOLFMWKZKCJ-UHFFFAOYSA-N 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(C(O)C(O)=O)(OC)C1=CC=CC=C1 RQJWOLFMWKZKCJ-UHFFFAOYSA-N 0.000 description 19
- 239000007787 solid Substances 0.000 description 16
- 238000010992 reflux Methods 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000011343 solid material Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 150000002431 hydrogen Chemical group 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 0 COC(C(*)[O+])(c1ccccc1)c1ccccc1 Chemical compound COC(C(*)[O+])(c1ccccc1)c1ccccc1 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- OUJTZYPIHDYQMC-IBGZPJMESA-N (2r)-2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoic acid Chemical compound O([C@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-IBGZPJMESA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000001144 powder X-ray diffraction data Methods 0.000 description 3
- 235000020071 rectified spirit Nutrition 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- PINPOEWMCLFRRB-LURJTMIESA-N (1s)-1-(4-chlorophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(Cl)C=C1 PINPOEWMCLFRRB-LURJTMIESA-N 0.000 description 2
- RAEVOBPXEHVUFY-LURJTMIESA-N 4187-53-5 Chemical compound C[C@H](N)C1=CC=C([N+]([O-])=O)C=C1 RAEVOBPXEHVUFY-LURJTMIESA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MJTYPPBFTMKLGA-UHFFFAOYSA-N CCc(c(Cl)c1)ccc1Cl Chemical compound CCc(c(Cl)c1)ccc1Cl MJTYPPBFTMKLGA-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013618 particulate matter Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- RQJWOLFMWKZKCJ-CQSZACIVSA-N (2s)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C([C@H](O)C(O)=O)(OC)C1=CC=CC=C1 RQJWOLFMWKZKCJ-CQSZACIVSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- XPCHQESFRULWBG-UHFFFAOYSA-N 2,4-dichloro-n-ethylaniline Chemical compound CCNC1=CC=C(Cl)C=C1Cl XPCHQESFRULWBG-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- VHJKDOLGYMULOP-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)ethanamine Chemical class NCCC1=CC=C(Cl)C=C1Cl VHJKDOLGYMULOP-UHFFFAOYSA-N 0.000 description 1
- WJBMRZAHTUFBGE-UHFFFAOYSA-N 2-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC(CCN)=C1 WJBMRZAHTUFBGE-UHFFFAOYSA-N 0.000 description 1
- FNSCAEVESYEXFD-UHFFFAOYSA-N 3-methoxy-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(CC(O)=O)(OC)C1=CC=CC=C1 FNSCAEVESYEXFD-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- BWJHJLINOYAPEG-HOTGVXAUSA-N 8-chloro-6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclopentyl]-7-methyl-2H-1,3-benzoxazin-4-one Chemical compound ClC1=C(C(=CC=2C(N(COC=21)[C@@H]1[C@H](CCC1)O)=O)CC=1C=NC(=CC=1)Cl)C BWJHJLINOYAPEG-HOTGVXAUSA-N 0.000 description 1
- HWINBBUYLKWIBO-UHFFFAOYSA-N CC(C)c1cc(OC)ccc1 Chemical compound CC(C)c1cc(OC)ccc1 HWINBBUYLKWIBO-UHFFFAOYSA-N 0.000 description 1
- CJWGCBRQAHCVHW-ZETCQYMHSA-N C[C@@H](c1cc(OC)ccc1)N Chemical compound C[C@@H](c1cc(OC)ccc1)N CJWGCBRQAHCVHW-ZETCQYMHSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis 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
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
- 241001558496 Talpa caeca Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000002788 crimping Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229940090243 letairis Drugs 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- AYOOGWWGECJQPI-NSHDSACASA-N n-[(1s)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(3-propan-2-yloxy-1h-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine Chemical compound N1C(OC(C)C)=CC(N2C3=NC(N[C@@H](C)C=4N=CC(F)=CN=4)=CC=C3N=C2)=N1 AYOOGWWGECJQPI-NSHDSACASA-N 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention provides an improved process for the preparation of
- the present invention also provides a novel intermediate for the preparation of Ambrisentan and a process for the preparaion of the intermediate.
- the invention also describes a new crystalline form of Ambrisentan.
- Ambrisentan a potent selective endothelin receptor antagonist, is utilized for the treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis. It blocks the endothelin receptor on vascular smooth muscle cells and cardiac myocytes, preventing vasoconstriction and smooth muscle proliferation.
- Ambrisentan is marketed under the trade name Letairis (TM) or Volibris(R). Ambrisentan is chemically known as (S)-2-((4, 6-dimethylpyrimidin-2-yl) oxy)-3- methoxy-3, 3- diphenyl propanoic acid and has the structural formula as shown in formula (I).
- US 7109205 discloses and claims Ambrisentan.
- the patent also discloses the process for the preparation of Ambrisentan as per a similar scheme as in the above patent.
- This specification also discloses the preparation of Ambrisentan according to the above process.
- the present invention provides a process for resolution of racemic 2- hydroxy-3-methoxy-3, 3-diphenylpropanoic acid (VIII) that does not have the above- mentioned disadvantages but can readily be carried out on an industrial scale.
- the inventors of the present invention surpri singly found the improved resolution of the racemate compound (VIII) by reacting the racemic acid with a suitable optically active amine and subsequently separating off the diastereomeric salt with high chiral purity. Additionally the same diastereomeric salt can further be utilized for the preparation of Ambrisentan.
- the present invention discloses an improved process for preparing Ambrisentan.
- the present invention discloses an improved process for preparing Ambrisentan wherein the chiral amine base used as resolving agent, provides a novel intermediate that is used in preparation of Ambrisentan of high enantiomeric purity.
- FIG. 1 is a powder X-ray diffraction (XRPD) pattern of the crystalline Ambrisentan according to the present invention.
- FIG. 2 is a Differential scanning calorimetry of crystalline Ambrisentan according to the present invention.
- FIG. 3 is a powder X-ray diffraction (XRPD) pattern of the crystalline (S)-3- methoxyphenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate according to the present invention.
- XRPD powder X-ray diffraction
- FIG. 4 is a powder X-ray diffraction (XRPD) pattern of the crystalline (R)-2, 4- dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3 diphenyl propionate according to the present invention.
- XRPD powder X-ray diffraction
- Ambrisentan The process includes:
- Xj is selected from hydrogen, halogen, nitro, (Ci -C 4 ) alkyl or (Ci-C 4 ) alkoxy group
- X 2 at each occurrence is independently selected from hydrogen, halogen, nitro a (Ci-C 4 ) alkyl or (Ci-C 4 ) alkoxy group, in suitable solvent to obtain a diastereomeric salt of 2- hydroxypropanoic acids of formula (II)
- Embodiments of the process may include one or more of the following features.
- the resolution of racemic 2-hydroxypropanoic acid of Formula (VIII) may be carried out in the presence of one or more suitable solvents.
- the reaction of the diastereomeric salt of 2-hydroxypropanoic acid of Formula (II) with 4,6-dimethyl-2- (methylsulfonyl)pyrimidine of Formula (VII) may be carried out in the presence of one or more suitable bases in one or more suitable solvents.
- the diastereomeric salt of 2- hydroxypropanoic acid of Formula (II) may be recrystallized from solvents prior to condensation with 4,6-dimethyl-2-(methylsulfonyl)pyrirnidine of Formula (VII).
- Xi is selected from hydrogen, halogen, nitro, (Ci-C 4 ) alkyl or (Ci-C 4 ) alkoxy group
- X 2 at each occurrence is independently selected from hydrogen, halogen, nitro a (Ci-C 4 ) alkyl or (Ci-C 4 ) alkoxy group.
- a process for the purification of ambrisentan includes obtaining a solution of ambrisentan in one or more suitable solvents and recovering the pure ambrisentan by removal of the solvents.
- Removing the solvent may include, for example, one or more of distillation, distillation under vacuum, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
- Embodiments of the process may include one or more of the following features.
- the solution of ambrisentan may be obtained by heating or stirring, or a combination of both.
- the solution may be obtained by adding a suitable base and acidifying the solution so obtained with a suitable acid until pH about 2-3.
- the product so obtained may be further or additionally purified to obtain desired purity levels.
- the process may include further forming the product so obtained into a finished dosage form.
- the process may produce the pure ambrisentan having a purity of more than 99% and a chiral purity of more than 99.8% by HPLC.
- the polymorphic form of ambrisentan may have the X-ray diffraction pattern of Figure 1 and Differential Scanning Calorimetry graph of Figure 2.
- a process for preparing the polymorphic Form I of ambrisentan includes obtaining a solution of ambrisentan in one or more suitable solvent(s); optionally, adding a suitable anti- solvents) to the solution; and isolating the Form I of ambrisentan by removing the solvents.
- Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, evaporation, decantation, and centrifugation and other suitable techniques as known to a person skilled in the art.
- Embodiments of the process may include one or more of the following features.
- the solution may be concentrated before adding the anti-solvent.
- the solution may be cooled before removing the solvents.
- the product obtained may be further or additionally dried to achieve the desired moisture values.
- the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
- composition comprising a therapeutically effective amount of polymorphic Form I of ambrisentan, and one or more pharmaceutically acceptable carriers, excipients or diluents.
- THF tetrahydrofuran
- DCM dichloromethane
- DMF dimethyl formamide
- DIPE diisopropyl ether
- DMSO dimethyl sulfoxide
- LHMDS Lithium hexamethyl disilazide
- KHMDS Potassium hexamethyl disilazide
- MTBE Methyl tertiary butyl ether
- (S)-3- Methoxy PEA refers.
- the inventors have developed a process for the preparation of Ambrisentan using novel intermediate of formula (II) by resolving 2-hydroxypropanoic acid of Formula (VIII),
- Suitable solvents which can be used for above resolution may include one or more of water, DMSO, DMF, acetonitrile, diethyl ether, 1,4-dioxane, MTBE, 2-methyl THF, dimethyl acetamide, DCM, DIPE, THF, (Ci-C 6 ) alcohols such as ethanol, methanol, isopropanol, tert-butanol and the like.
- reaction of diastereomeric salt of 2-hydroxypropanoic acids (II) with 4, 6- dimethyl-2-(methylsulfonyl) pyrimidine (VII) may be carried out in the presence of suitable base in one or more suitable solvent.
- Suitable bases which can be used for above coupling may include one or more of lithium diisopropyl amide, sodium amide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, LHMDS, KHMDS, potassium tert butoxide, sodium tert butoxide and the like.
- Suitable solvents which can be used may include one or more of DMSO, DMF, acetonitrile, acetone, diethyl ether, 1,4-dioxane, 2-methyl THF, dimethyl acetamide, DCM, DIPE, THF and the like or mixture thereof.
- Xi is selected from hydrogen, halogen, nitro, (Ci-C 4 ) alkyl or (Ci-C 4 ) alkoxy group
- X 2 at each occurrence is independently selected from hydrogen, halogen, nitro a (Ci-C 4 ) alkyl or (Ci-C 4 ) alkoxy group.
- a process for the preparation of the novel intermediate of Formula (II), as a diastereomeric salt is provided, by resolving racemic 2- hydroxypropanoic acid of Formula (VIII) with an optically active chiral amine of Formula (IX), with either in (S) or (R) configuration, Xi & X 2 are as defined earlier, in suitable solvent.
- Suitable solvents which can be used for above resolution may include one or more of water, DMSO, DMF, acetonitrile, diethyl ether, 1,4-dioxane, MTBE, 2-methyl THF, dimethyl acetamide, DCM, DIPE, THF, (Ci -C 6 ) alcohols such as ethanol, methanol, isopropanol, tert-butanol and the like or suitable mixtures thereof
- the other enantiomer i.e. R-isomer of 2-hydroxypropanoic acid can also be prepared by resolution with suitable optically active base.
- the inventors also have developed a process for the purification of ambrisentan by obtaining a solution of ambrisentan in one or more suitable solvents and recovering the pure ambrisentan by removal of the solvents.
- ambrisentan may be prepared according to the present invention or may be prepared by any of the methods known in the art.
- solvent includes one or more of alcohols, esters, chlorinated solvents, nitriles, ketones, ethers, aprotic polar solvents or mixtures thereof.
- the solution of ambrisentan in a solvent can be obtained by dissolving, slurrying, stirring, or a combination thereof.
- the solution of ambrisentan may be obtained by heating the solvent. It may be heated from about 25 0 C to reflux temperature.
- the solution of ambrisentan can also be obtained by suspending ambrisentan in water and adding a solution of one or more suitable bases.
- the resultant solution can be clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities.
- the solution may be cooled before removing the solvents.
- the solution may be acidified with suitable aqueous solution of acids to precipitate ambrisentan.
- Suitable bases which can be used may include one or more of carbonates, bicarbonates or alkali bases.
- the acids used may be organic acids, for example, acetic acid, formic acid, and the like, or inorganic acids, for example, dilute hydrochloric acid or dilute sulfuric acid.
- the solvent may be removed by a technique which includes, for example, distillation, distillation under vacuum, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
- the product obtained may be further or additionally dried to achieve the desired moisture values.
- the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
- the pure ambrisentan has a purity of more than 99% and a chiral purity more than 99.8% by HPLC.
- the inventors also have developed a process for the preparation of a novel polymorphic form of ambrisentan, designated as Form I, by obtaining a solution of ambrisentan in one or more solvents; optionally, adding one or more suitable anti- solvents; and isolating the Form I of ambrisentan by removing the solvents.
- the term "obtaining” includes mixing, adding, slurrying, stirring, heating, or a combination thereof.
- the solution of ambrisentan may be obtained by heating the solvent. It may be heated from about 25 0 C to reflux temperature.
- the resultant solution can be clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities.
- the solution so obtained may be concentrated to reduce the amount of solvent.
- the solution may be concentrated by removing the solvent completely to get a residue.
- the solvent may be removed under reduced pressure, to obtain crystalline ambrisentan.
- a suitable anti-solvent may be added to the solution to precipitate the ambrisentan.
- the solution may be heated after adding the anti-solvent.
- the solution may be cooled before removing the solvents.
- ambrisentan to be used as the starting material for preparation of the novel polymorph can be prepared by any process known in the literature or may be obtained by the process of the present invention.
- the solution of ambrisentan may be prepared in one or more solvents, including, for example, alcohols, esters, chlorinated solvents, nitriles, ketones, ethers, aprotic polar solvents, and suitable mixtures of one or more of these solvents.
- solvents including, for example, alcohols, esters, chlorinated solvents, nitriles, ketones, ethers, aprotic polar solvents, and suitable mixtures of one or more of these solvents.
- any solvent can be used as an anti-solvent in which ambrisentan is insoluble, practically insoluble or very slightly soluble.
- the terms insoluble, practically insoluble and very slightly soluble have their ordinary meanings as defined in United
- suitable anti-solvents which may be used include non polar solvent such as hydrocarbons and water or a mixture thereof.
- the novel polymorphic Form I of ambrisentan may exhibit characteristic 2-theta values at about 7.462, 8.239, 11.781, 12.703, 13.587, 14,842, 16.703, 17.660, 18.120, 18.740, 20.518, 21.741, 22.722, 24.139, 25.221, 26.641, 27.521, 30.860 ⁇ 0.2 degrees 2 ⁇ .
- the PXRD pattern of Form I of ambrisentan may further exhibit characteristic 2- theta values at about 7.980, 8.781, 12.08,12.999,14.499, 15.100, 17.441, 17.939, 18.499, 20.120, 21.499, 22.261, 22.959, 24.701, 25.461, 27.241, 37.440 ⁇ 0.2 degrees 2 ⁇ .
- Form I of ambrisentan may exhibit a Differential Scanning Calorimetry graph having endothermic peaks at about 156.1 ° C ⁇ 2 ° C and about 166.6 ° C ⁇ 2 ° C.
- the polymorphic Form I of ambrisentan may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
- the intermediate of Formula (II) may be purified by obtaining a solution of the novel intermediate of Formula (II) in one or more suitable solvents, adding a suitable anti-solvent to the solution; and isolating the pure novel intermediate of Formula (II).
- any solvent can be used as an anti-solvent in which the novel intermediate of Formula (II) is insoluble, practically insoluble or very slightly soluble.
- the terms insoluble, practically insoluble and very slightly soluble have their ordinary meanings as defined in United States Pharmacopoeia 2002.
- suitable anti- solvents which may be used include hexane, pentane, hexane, heptane, petroleum ether, methyl /-butyl ether, cyclohexane, toluene, diethyl ether and octane, water or mixture thereof.
- the preferable compound from the compound of formula (II) are (S)-3-mthoxypehenylethylammonium (S)-2-hydroxy-3- methoxy 3, 3-diphenyl propionate of formula (Ha) and (R)-2, 4- dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3 diphenyl propionate of formula (lib).
- the invention is provided a novel polymorphic form of (S)-3- methoxyphenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate of formula (Ha).
- the polymorphic form of formula (Ha) may have the X-ray diffraction pattern of Fig. 3
- the invention is provided a novel polymorphic form of (R)-2, 4-dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate of formula (lib).
- the polymorphic form of formula (lib) may have the X-ray diffraction pattern of Fig. 4.
- the novel polymorphic form of the (R)-2, 4-dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3 diphenyl propionate of formula (lib) exhibits characteristic 2.theta. values at about 8.49, 11.51, 11.88, 17.00, 18.74, 21.13 and 23.03 ⁇ 0.2 degrees 2 ⁇ .
- the PXRD pattern of (R)-2, 4-dichlorophenylethylammonium (S)-2- hydroxy-3 -methoxy 3, 3 diphenyl propionate of formula (lib) further exhibits characteristic 2.theta. values at 10.22, 12.22, 13.89, 14.30, 19.25, 20.49, 24.14, 25.48 and 34.13 ⁇ 0.2 degrees 2 ⁇ .
- the complete x-ray powder spectrum was recorded with a Rigaku D/Max 2200 VPC X-ray powder diffractometer model using copper radiation.
- the X-ray diffraction pattern was recorded by keeping the instrument parameters as below:
- Scan mode Continuous, Scan speed: 3.000°/min., Sampling width: 0.020°, Scan axes:
- Sample Size Approx. l-2mg
- Sample Pans Hermetic/Crimping Pans
- reaction mixture (3.244 mmol) was added to the reaction mixture in one lot.
- the reaction mixture was stirred at room temperature for 6 hours and subsequently dumped into cold water and washed the aqueous layer with toluene. Aqueous layer was collected and acidified with
- Example-8 Process for the preparation of crystalline form of ambrisentan
- the crystalline form of Ambrisentan was characterized by PXRD peaks at about 7.462, 7.980, 8.239, 8.781, 11.781, 12.080, 12.703, 12.999, 13.587, 14.499, 14.842, 15.100, 16.703, 17.441, 17.660, 17.939, 18.120, 18.499, 18.740, 20.120, 20.518, 21.499, 21.741, 22.261, 22.722, 22.959, 24.139, 24.701, 25.221, 25.461, 26.641, 27.241, 27.521, 30.860, 31.901, 32.659, 35.803, 36.360, 37.003, 37.440 ⁇ 0.2-theta (Fig.l)
- solvent such as ethanol, THF, MIBK and isopropyl alcohol following similar procedure as above.
- Example-9 Preparation of amorphous ambrisentan
- Example- 1 Purification of (S)-3-mthoxypehenylethylammonium (S)-2-hydroxy-3- methoxy 3, 3-diphenyl propionate
- reaction mixture was stirred under reflux for 0.5 hr and cooled to room temperature and again stirred at room temperature for 1.5 hour. Solid material was filtered, washed with rectified spirit and dried.
- Example-13 Preparation of (R)-2. 4-dichlorophenylethylammonium (S)-2-hvdroxy-3- methoxy 3. 3-diphenyl propionate
- *Input refers to diastereomeric salt of 3, 3-diphenyl-2-hydroxy-3-methoxy propionic acid
- racemic Ambrisentan methyl ester was taken in a 100 mL 3 necked flask. Subsequently, 22.4 mL of 1, 4 dioxane was added & stirred the reaction mixture. Aqueous solution of (2.35g) of sodium hydroxide dissolved in 15 mL water was added in to the reaction mixture and was gently refluxed for 3 hrs. The reaction mixture was cooled and dumped into water. After suitable work up racemic Ambrisentan was obtained.
- racemic Ambrisentan was prepared in different batches and the results are summarized in Table 4 given below.
- reaction mixture was cooled to 20 0 C then 48.5 g 4, 6-dimethyl-2-methylsulfonyl pyrimidine was added. The reaction mixture was stirred at 30 0 C for 3 hrs and subsequently dumped in water and again stirred for 10 min. The reaction mixture was extracted with cyclohexane, charcoalised and acidified to get crude Ambrisentan.
- Example 58 Process for the purification of ambrisentan
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Abstract
The invention relates to improved processes for the preparation of ambrisentan. The invention also relates to a novel intermediate useful in the preparation of ambrisentan and a process for the preparation of the intermediate. The invention also relates to new polymorphic form of ambrisentan. In particular, it relates to a polymorphic form, designated as Form I of ambrisentan and a process for the preparation of the Form I.
Description
IMPROVED PROCESS FOR THE PREPARATION OF AMBRISENTAN AND NOVEL INTERMEDIATES THEREOF
FIELD OF INVENTION
The present invention provides an improved process for the preparation of
Ambrisentan. The present invention also provides a novel intermediate for the preparation of Ambrisentan and a process for the preparaion of the intermediate. The invention also describes a new crystalline form of Ambrisentan.
BACKGROUND OF THE INVENTION
Ambrisentan, a potent selective endothelin receptor antagonist, is utilized for the treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis. It blocks the endothelin receptor on vascular smooth muscle cells and cardiac myocytes, preventing vasoconstriction and smooth muscle proliferation.
Ambrisentan is marketed under the trade name Letairis (TM) or Volibris(R). Ambrisentan is chemically known as (S)-2-((4, 6-dimethylpyrimidin-2-yl) oxy)-3- methoxy-3, 3- diphenyl propanoic acid and has the structural formula as shown in formula (I).
(I) US 5703017 broadly discloses several molecules generally, which are 3-(Het) aryl carboxylic acid derivatives. The compounds disclosed also include Ambrisentan. In the specification, synthetic schemes for preparation of the molecules and for their intermediates are disclosed. The general methods of preparation involve coupling the epoxide of formula III (for example, with R=COOR) with alcohols or thiols of formula IV according to the following scheme:
Scheme 1
US 7109205 discloses and claims Ambrisentan. The patent also discloses the process for the preparation of Ambrisentan as per a similar scheme as in the above patent. This specification also discloses the preparation of Ambrisentan according to the above process.
This patent also describes the preparation in laboratory scale of (S)-2-hydroxy-
3-methoxy-3, 3-diphenylpropanoic acid (compound V) by resolution of the corresponding racemate using L-proline methyl ester and (S)-l-(4-nitrophenyl) ethylamine. By this resolution, yield of 35 % based on the racemate and an optical purity of 99.8% were achieved.
US 6559338 describe a process of resolution of 2-hydroxypropanoic acid by using an optically active base (S)-l-(4-chlorophenyl) ethylamine and then one of the diastereomeric salts formed is separated off. However the optically active base used here is very expensive and would not be preferable for large-scale production.
Additionally, the objective of this resolution has not been clearly defined.
However, the US 6559338 also state that, it has been found that when this described reaction step was scaled up (several kg to 100 kg), additional working steps became necessary in order to ensure a high optical purity. The diastereomeric salt of (S)-2-hydroxypropanoic acid and (S)-l-(4-nitrophenyl) ethylamine crystallizes with difficulty and therefore cannot be filtered off readily either, so that some of the mother liquor remains in the crystals together with the enantiomer to be separated off. Only when the crystals were additionally stirred in the tank together with fresh solvent, and when the crystals that had been filtered off are copiously rewashed, the required optical purity was obtained.
Therefore, the present invention provides a process for resolution of racemic 2-
hydroxy-3-methoxy-3, 3-diphenylpropanoic acid (VIII) that does not have the above- mentioned disadvantages but can readily be carried out on an industrial scale.
In addition, the inventors of the present invention surpri singly found the improved resolution of the racemate compound (VIII) by reacting the racemic acid with a suitable optically active amine and subsequently separating off the diastereomeric salt with high chiral purity. Additionally the same diastereomeric salt can further be utilized for the preparation of Ambrisentan.
Thus, the present invention discloses an improved process for preparing Ambrisentan. The present invention discloses an improved process for preparing Ambrisentan wherein the chiral amine base used as resolving agent, provides a novel intermediate that is used in preparation of Ambrisentan of high enantiomeric purity.
WO2010017918 disclosed the amorphous form of Ambrisentan and process for the preparation of thereof. It is well known that amorphous forms have several limitations in terms of stability, processability etc. thereby making the crystalline form of any compound more preferable. The present inventors have surprisingly found a new crystalline form of Ambrisentan which is stable, easily processable & can be used to obtain the commercial form of Ambrisentan in chirally and chemically pure form. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a powder X-ray diffraction (XRPD) pattern of the crystalline Ambrisentan according to the present invention.
FIG. 2 is a Differential scanning calorimetry of crystalline Ambrisentan according to the present invention.
FIG. 3 is a powder X-ray diffraction (XRPD) pattern of the crystalline (S)-3- methoxyphenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate according to the present invention.
FIG. 4 is a powder X-ray diffraction (XRPD) pattern of the crystalline (R)-2, 4- dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3 diphenyl propionate according to the present invention.
SUMMARY OF THE INVENTION
In one general aspect there is provided a novel process for the preparation of
Ambrisentan. The process includes:
Formula VHI
with optically active chiral amine base of formula (IX),
Formula IX
where the resolving agent amine is with either in (S) or (R) configuration, Xj is selected from hydrogen, halogen, nitro, (Ci -C4) alkyl or (Ci-C4) alkoxy group, and X2 at each occurrence is independently selected from hydrogen, halogen, nitro a (Ci-C4) alkyl or (Ci-C4) alkoxy group, in suitable solvent to obtain a diastereomeric salt of 2- hydroxypropanoic acids of formula (II)
Formula II
b) reacting diastereomeric salt of 2-hydroxypropanoic acids of formula (II) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (VII),
Formula VII
to obtain ambrisentan.
Embodiments of the process may include one or more of the following features. For example, the resolution of racemic 2-hydroxypropanoic acid of Formula (VIII) may be carried out in the presence of one or more suitable solvents. The reaction of the diastereomeric salt of 2-hydroxypropanoic acid of Formula (II) with 4,6-dimethyl-2-
(methylsulfonyl)pyrimidine of Formula (VII) may be carried out in the presence of one or more suitable bases in one or more suitable solvents. The diastereomeric salt of 2- hydroxypropanoic acid of Formula (II) may be recrystallized from solvents prior to condensation with 4,6-dimethyl-2-(methylsulfonyl)pyrirnidine of Formula (VII).
In another general aspect, there is provided a compound of formula (II),
where the resolving agent amine is with either in (S) or (R) configuration, Xi is selected from hydrogen, halogen, nitro, (Ci-C4) alkyl or (Ci-C4) alkoxy group, and X2 at each occurrence is independently selected from hydrogen, halogen, nitro a (Ci-C4) alkyl or (Ci-C4) alkoxy group.
In another aspect there is provided a process for the purification of ambrisentan. The process includes obtaining a solution of ambrisentan in one or more suitable solvents and recovering the pure ambrisentan by removal of the solvents.
Removing the solvent may include, for example, one or more of distillation, distillation under vacuum, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
Embodiments of the process may include one or more of the following features. For example, the solution of ambrisentan may be obtained by heating or stirring, or a combination of both. Alternatively, the solution may be obtained by adding a suitable base and acidifying the solution so obtained with a suitable acid until pH about 2-3.
The product so obtained may be further or additionally purified to obtain desired purity levels.
The process may include further forming the product so obtained into a finished dosage form.
The process may produce the pure ambrisentan having a purity of more than 99% and a chiral purity of more than 99.8% by HPLC.
In another general aspect there is provided a novel polymorphic form of ambrisentan, hereinafter designated as Form I.
The polymorphic form of ambrisentan may have the X-ray diffraction pattern of Figure 1 and Differential Scanning Calorimetry graph of Figure 2.
In another general aspect there is provided a process for preparing the polymorphic Form I of ambrisentan. The process includes obtaining a solution of ambrisentan in one or more suitable solvent(s); optionally, adding a suitable anti- solvents) to the solution; and isolating the Form I of ambrisentan by removing the solvents.
Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, evaporation, decantation, and centrifugation and other suitable techniques as known to a person skilled in the art.
Embodiments of the process may include one or more of the following features. For example, the solution may be concentrated before adding the anti-solvent. The solution may be cooled before removing the solvents.
The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
In another aspect there is provided a pharmaceutical composition comprising a therapeutically effective amount of polymorphic Form I of ambrisentan, and one or more pharmaceutically acceptable carriers, excipients or diluents.
In another general aspect there is provided a novel polymorphic form of (S)-3- methoxyphenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate of formula (Ha). The polymorphic form of formula (Ha) may have the X-ray diffraction pattern of Fig. 3
Formula(IIa)
In another general aspect there is provided a novel polymorphic form of (R)-2, 4-dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate of formula (lib). The polymorphic form of formula (lib) may have the X-ray diffraction pattern of Fig. 4.
Formula (lib)
The details of all the embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.
DETAILED DESCRIPTION
As used herein, the term "THF" refers to tetrahydrofuran, the term "DCM" refers to dichloromethane, the term "DMF" refers to dimethyl formamide, the term "DIPE" refers to diisopropyl ether, the term "DMSO" refers to dimethyl sulfoxide, the term "LHMDS" refers to Lithium hexamethyl disilazide, the term "KHMDS" refers to Potassium hexamethyl disilazide and the term "MTBE" refers to Methyl tertiary butyl ether, the term "(S)-3- Methoxy PEA" refers. to (S)-l(3-methoxyphenyl) ethylamine and the term "(R)/(S) -2,4-dichloro PEA" refers to (R)/(S)-l(2,4-dichlorophenyl) ethylamine, the term "(S)-4 chloro PEA" refers to (S)-l-(4-chlorophenyl) ethylamine Purity of diastereomeric salt (R) / (S) -2, 4-dichlorophenylethylammonium (S)-2- hydroxy-3-methoxy-3, 3-diphenyI propionate or (S)-3-mthoxypehenylethyl ammonium (S)-2-hydroxy-3-methoxy-3,3-diphenyl propionate refers to the purity of related propionic acid.
The inventors have developed a process for the preparation of Ambrisentan using novel intermediate of formula (II) by resolving 2-hydroxypropanoic acid of Formula (VIII),
a) resolving 2-hydroxypropanoic acids of formula (VIII),
Formula VIII
Formula IX
where the resolving agent amine is with either in (S) or (R) configuration, Xi & X2 are as defined earlier, in suitable solvent to give diastereomeric salt of 2-hydroxypropanoic acids of formula (II), and
Formula II
b) reacting the diastereomeric salt of 2-hydroxypropanoic acids of Formula (II) with either in (S) or (R) configuration, Xi & X2 are as defined earlier, with 4,6- dimethyl-2-(methylsulfonyl)pyrimidine (VII) in presence of a suitable base, to obtain the ambrisentan.
Formula VII
In general, the reaction of 2-hydroxypropanoic acids (VIII) with optically active chiral amine base of formula (IX), with either in (S) or (R) configuration, Xi & X2 are as defined earlier may be carried out in the presence of one or more suitable solvent. Suitable solvents which can be used for above resolution may include one or more of water, DMSO, DMF, acetonitrile, diethyl ether, 1,4-dioxane, MTBE, 2-methyl THF, dimethyl acetamide, DCM, DIPE, THF, (Ci-C6) alcohols such as ethanol, methanol, isopropanol, tert-butanol and the like. Mixtures of all of these solvents are also contemplated.
The reaction of diastereomeric salt of 2-hydroxypropanoic acids (II) with 4, 6- dimethyl-2-(methylsulfonyl) pyrimidine (VII) may be carried out in the presence of suitable base in one or more suitable solvent.
Suitable bases which can be used for above coupling may include one or more of lithium diisopropyl amide, sodium amide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, LHMDS, KHMDS, potassium tert butoxide, sodium tert butoxide and the like.
Suitable solvents which can be used may include one or more of DMSO, DMF, acetonitrile, acetone, diethyl ether, 1,4-dioxane, 2-methyl THF, dimethyl acetamide, DCM, DIPE, THF and the like or mixture thereof.
In another aspect, a novel intermediate of Formula (II) used in the preparation of ambrisentan is provided,
with either in (S) or (R) configuration, Xi is selected from hydrogen, halogen, nitro, (Ci-C4) alkyl or (Ci-C4) alkoxy group, and X2 at each occurrence is independently selected from hydrogen, halogen, nitro a (Ci-C4) alkyl or (Ci-C4) alkoxy group.
In another aspect, a process for the preparation of the novel intermediate of Formula (II), as a diastereomeric salt is provided, by resolving racemic 2- hydroxypropanoic acid of Formula (VIII) with an optically active chiral amine of Formula (IX), with either in (S) or (R) configuration, Xi & X2 are as defined earlier, in suitable solvent.
In general, the reaction of 2-hydroxypropanoic acids (VIII) with optically active chiral amine base of formula (IX) with either in (S) or (R) configuration, Xi & X2 are defined earlier may be carried out in the presence of suitable solvent.
Suitable solvents which can be used for above resolution may include one or more of water, DMSO, DMF, acetonitrile, diethyl ether, 1,4-dioxane, MTBE, 2-methyl THF, dimethyl acetamide, DCM, DIPE, THF, (Ci -C6) alcohols such as ethanol, methanol, isopropanol, tert-butanol and the like or suitable mixtures thereof
Alternatively, the other enantiomer i.e. R-isomer of 2-hydroxypropanoic acid can also be prepared by resolution with suitable optically active base.
The inventors also have developed a process for the purification of ambrisentan by obtaining a solution of ambrisentan in one or more suitable solvents and recovering the pure ambrisentan by removal of the solvents.
The ambrisentan may be prepared according to the present invention or may be prepared by any of the methods known in the art.
The term "solvent" includes one or more of alcohols, esters, chlorinated solvents, nitriles, ketones, ethers, aprotic polar solvents or mixtures thereof.
The solution of ambrisentan in a solvent can be obtained by dissolving, slurrying, stirring, or a combination thereof. The solution of ambrisentan may be obtained by heating the solvent. It may be heated from about 250C to reflux temperature. The solution of ambrisentan can also be obtained by suspending ambrisentan in water and adding a solution of one or more suitable bases.
The resultant solution can be clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities.
The solution may be cooled before removing the solvents. The solution may be acidified with suitable aqueous solution of acids to precipitate ambrisentan.
Suitable bases which can be used may include one or more of carbonates, bicarbonates or alkali bases. The acids used may be organic acids, for example, acetic acid, formic acid, and the like, or inorganic acids, for example, dilute hydrochloric acid or dilute sulfuric acid.
The solvent may be removed by a technique which includes, for example, distillation, distillation under vacuum, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
The pure ambrisentan has a purity of more than 99% and a chiral purity more than 99.8% by HPLC.
The inventors also have developed a process for the preparation of a novel polymorphic form of ambrisentan, designated as Form I, by obtaining a solution of ambrisentan in one or more solvents; optionally, adding one or more suitable anti- solvents; and isolating the Form I of ambrisentan by removing the solvents.
The term "obtaining" includes mixing, adding, slurrying, stirring, heating, or a combination thereof. The solution of ambrisentan may be obtained by heating the solvent. It may be heated from about 250C to reflux temperature. The resultant solution can be clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities. The solution so obtained may be concentrated to reduce the amount of solvent. The solution may be concentrated by removing the solvent completely to get a residue. The solvent may be removed under reduced pressure, to obtain crystalline ambrisentan.
A suitable anti-solvent may be added to the solution to precipitate the ambrisentan. The solution may be heated after adding the anti-solvent.
In one aspect, the solution may be cooled before removing the solvents.
The ambrisentan to be used as the starting material for preparation of the novel polymorph can be prepared by any process known in the literature or may be obtained by the process of the present invention.
The solution of ambrisentan may be prepared in one or more solvents, including, for example, alcohols, esters, chlorinated solvents, nitriles, ketones, ethers, aprotic polar solvents, and suitable mixtures of one or more of these solvents.
In general, any solvent can be used as an anti-solvent in which ambrisentan is insoluble, practically insoluble or very slightly soluble. The terms insoluble, practically insoluble and very slightly soluble have their ordinary meanings as defined in United
States Pharmacopoeia 2002. For example, suitable anti-solvents which may be used include non polar solvent such as hydrocarbons and water or a mixture thereof.
The novel polymorphic Form I of ambrisentan may exhibit characteristic 2-theta values at about 7.462, 8.239, 11.781, 12.703, 13.587, 14,842, 16.703, 17.660, 18.120, 18.740, 20.518, 21.741, 22.722, 24.139, 25.221, 26.641, 27.521, 30.860 ± 0.2 degrees 2Θ. The PXRD pattern of Form I of ambrisentan may further exhibit characteristic 2- theta values at about 7.980, 8.781, 12.08,12.999,14.499, 15.100, 17.441, 17.939, 18.499, 20.120, 21.499, 22.261, 22.959, 24.701, 25.461, 27.241, 37.440 ± 0.2 degrees 2Θ.
Further, Form I of ambrisentan may exhibit a Differential Scanning Calorimetry graph having endothermic peaks at about 156.1 ° C ± 2 ° C and about 166.6 ° C ± 2 ° C.
The polymorphic Form I of ambrisentan may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
Alternatively, the intermediate of Formula (II) may be purified by obtaining a solution of the novel intermediate of Formula (II) in one or more suitable solvents, adding a suitable anti-solvent to the solution; and isolating the pure novel intermediate of Formula (II).
In general, any solvent can be used as an anti-solvent in which the novel intermediate of Formula (II) is insoluble, practically insoluble or very slightly soluble. The terms insoluble, practically insoluble and very slightly soluble have their ordinary meanings as defined in United States Pharmacopoeia 2002. For example, suitable anti- solvents which may be used include hexane, pentane, hexane, heptane, petroleum ether, methyl /-butyl ether, cyclohexane, toluene, diethyl ether and octane, water or mixture thereof.
In one of the preferred embodiments the preferable compound from the compound of formula (II) are (S)-3-mthoxypehenylethylammonium (S)-2-hydroxy-3- methoxy 3, 3-diphenyl propionate of formula (Ha) and (R)-2, 4- dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3 diphenyl propionate of formula (lib).
In an embodiment, the invention is provided a novel polymorphic form of (S)-3- methoxyphenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate of formula (Ha). The polymorphic form of formula (Ha) may have the X-ray diffraction pattern of Fig. 3
Formula(IIa)
The novel polymorphic form of the (S)-3-methoxyphenylethylammonium (S)-2- hydroxy-3-methoxy 3, 3-diphenyl propionate of formula (Ha) exhibits characteristic
2.theta. values at about 7.05, 10.15, 12.15, 13.87, 17.86, 23.01 and 24.80 ± 0.2 degrees 2Θ. The PXRD pattern of (S)-3-methoxyphenylethylammonium (S)-2-hydroxy-3-
methoxy 3,3-diphenyl propionate of formula (Ha) further exhibits characteristic 2.theta. values at about 8.39, 11.39, 13.87, 18.87, 21.90 and 24.18 ± 0.2 degrees 2Θ.
In an another embodiment, the invention is provided a novel polymorphic form of (R)-2, 4-dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate of formula (lib). The polymorphic form of formula (lib) may have the X-ray diffraction pattern of Fig. 4.
Formula (lib)
The novel polymorphic form of the (R)-2, 4-dichlorophenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3 diphenyl propionate of formula (lib) exhibits characteristic 2.theta. values at about 8.49, 11.51, 11.88, 17.00, 18.74, 21.13 and 23.03 ± 0.2 degrees 2Θ. The PXRD pattern of (R)-2, 4-dichlorophenylethylammonium (S)-2- hydroxy-3 -methoxy 3, 3 diphenyl propionate of formula (lib) further exhibits characteristic 2.theta. values at 10.22, 12.22, 13.89, 14.30, 19.25, 20.49, 24.14, 25.48 and 34.13 ± 0.2 degrees 2Θ.
Analytical processes;
The complete x-ray powder spectrum was recorded with a Rigaku D/Max 2200 VPC X-ray powder diffractometer model using copper radiation. The X-ray diffraction pattern was recorded by keeping the instrument parameters as below:
X-ray: Cu/40kv/30mA, Diverging slit: 1°, Scattering slit: 1°, Receiving slit: 0.15 mm, Monochromator RS: 0.8 mm, Counter: Scintillation counter,
Scan mode: Continuous, Scan speed: 3.000°/min., Sampling width: 0.020°, Scan axes:
2 theta vs. CPS, Scan range: 2° to 40.0°' τheta offset: 0.000
Differential scanning calorimetric analysis was carried out in a DSC-60 model from Shimadzu (S/W: TA-60 WS Aquisition version 2.1.0.0) by keeping following parameters,
Sample Size: Approx. l-2mg, Sample Pans: Hermetic/Crimping Pans,
Start Temperature: 500C, End Temperature: 3000C, Rate of Heating: 10 °C/min., Purge Gas: Nitrogen, Flow rate: 20 ml/min
The invention is further illustrated by the following examples, which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Example 1: Preparation of (R)-2, 4-dichlorophenylethylammonium (S)-2- hydroxy-3-methoxy 3, 3 diphenyl propionate
In a 25 mL three neck flask, attached with stirrer, thermometer, condenser with guard tube, over water bath, (Ig) racemic 2-hydroxy-3-methoxy 3, 3 diphenyl propanoic acid and 10 mL methyl t-butyl ether was added at room temperature and stirred for 5 min. To the clear yellow solution, 10 mL methanol was added and then heated. Solution was refluxed gently. To this reaction mixture of (0.349 gm) (R)-2, 4- dichloro PEA and 6 mL methyl t-butyl ether was added. The solution was refluxed for 1 hour to obtain clear solution and clear solution was allowed to cool naturally. The solution was stirred at room temperature for 3 hrs. Solid material was filtered, washed with 5 mL methyl t-butyl ether and dried.
Yield 212 mg. (24.96 %), HPLC purity: 99.9 %, Chiral purity: 99.4 %.
Example 2 : Preparation of (S)-2, 4-dichlorophenylethylammonium (R)-2-hydroxy-3- methoxy 3. 3 diphenyl propionate
In a 50 mL three neck flask, attached with stirrer, thermometer, condenser with guard tube, over water bath (1 g) racemic 2-hydroxy-3-methoxy 3, 3 diphenyl propanoic acid and 10 mL methyl t-butyl ether at room temperature was added and stirred for 5 min. To the clear yellow solution, 10 mL methanol was added and then heated. Solution was refluxed gently.
To this reaction, mixture of (0.454 g) (S)-2, 4-dichloro PEA and 6 mL methyl t- butyl ether was added. The solution was refluxed for 1 hour and hazy solution was allowed to cool naturally. The hazy solution was stirred at room temperature for 3 hrs. Solid material was filtered, washed with 5 mL methyl t-butyl ether and dried. Yield: 298 mg. (35 %). HPLC purity: 99.9 %. Chiral purity: 99.3 %.
Similarly, (S)-2, 4-dichlorophenylethylammonium (R)-2-hydroxy-3-methoxy 3, 3 diphenyl propionate was prepared in different batches and the results are summarized in table 1 given below.
Table-1
* Input refers to propionic acid deriv.
Example-4: Preparation of ambrisentan
In a 25 mL three neck flask with stirring arrangement, (lgm) (R)-2, 4- dichlorophenylethyl ammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate and (0.622 gm) sodium tertiary butoxide (6.488 mmol) in 10 ml DMF at 25 0C were taken and stirred for 5 min. (0.604gm) 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (3.244 mmol) was added to the reaction mixture in one lot. The reaction mixture was stirred at room temperature for 4 hours and subsequently dumped into cold water and aqueous layer was washed with toluene. Aqueous layer was collected and acidified with HCl to adjust pH to 2. Solid white material was precipitated. Solid white material was precipitated. The solid so obtained was filtered, washed with water and dried.
Yield: 0.62 gm (75.7 %), HPLC Purity: 98.73 %, Chiral Purity: 100 %
Example-5: Preparation of ambrisentan
In a 25 mL three neck flask with stirring arrangement, (1 gm) (R)-2, 4- dichlorophenylethyl ammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate and (0.726 gm) potassium tertiary butoxide (6.488 mmol) in 10 ml DMF at 25 0C were taken and stirred for 5 min. (0.604 gm) 4,6-dimethyl-2-(methylsulfonyl)pyrimidine
(3.244 mmol) was added to the reaction mixture in one lot. The reaction mixture was
stirred at room temperature for 6 hours and subsequently dumped into cold water and washed the aqueous layer with toluene. Aqueous layer was collected and acidified with
HCl to pH 2. The solid was extracted with ethyl acetate, and wash the ethyl acetate layer with' water followed by brine. Dry over sodium sulphate and concentrated on
Buchi Rotavapor.
Yield: 0.4 gm, HPLC Purity: 63.05 %
Example-6: Preparation of (S)-3-methoxyphenylethyl ammonium (S)-2-hvdroxy-3- methoxy-3, 3-diphenyl propionate
In a 50 mL three necked flask, equipped with a magnetic stirrer, water condenser, thermometer and addition funnel, (0.5 g) (1.84 m.mole) 2-hydroxy-3- methoxy-3, 3-diphenyl propanoic acid and 5 ml acetonitrile at 25-30 0C was charged.
The clear reaction mixture was heated at reflux. Subsequently, (0.166 g) (1.10 mmol)
(S)-3- methoxy PEA diluted in acetonitrile was added drop wise to the reaction mixture at reflux temperature. Solid was precipitated within 5 - 10 minutes and then after the precipitated solid was stirred at reflux temperature for 0.5 hours. Further the reaction mixture was cooled gradually at 25 - 30 0C and stirred for 1.5 hrs. The solid was filtered and washed with acetonitrile, and dried.
Yield: 0.295 g (75.9 %), HPLC Purity: 99.46 %, Chiral Purity: 98.39
Example-7: Preparation of ambrisentan
In a 25 mL three necked flask with stirring arrangement, (0.2 gm) (S)-3- methoxyphenylethyl ammonium (S)-2-hydroxy-3-methoxy-3, 3-diphenylpropionate (0.47 mmol) and (0.136 gm) sodium tertiary butoxide (1.417 mmol) in 2 mL DMF (10 volumes) at 25 0C was taken and stirred for 5 min. Subsequently, 0.132 gm 4, 6- dimethyl-2-(methylsulfonyl) pyrimidine (0.708 mmol) was added to the reaction
mixture in one lot. The reaction mixture was stirred at room temperature for 1.5 hours and subsequently dumped into cold water and which on suitable work-up give the solid
Ambrisentan.
Yield: 0.09 gm (50.33 %), HPLC Purity: 97.98 %, Chiral Purity: 98.33 %
Example-8: Process for the preparation of crystalline form of ambrisentan
In a 500 mL three necked flask with stirring and refluxing arrangement, (17.5 gm) crude Ambrisentan was taken in 122.5 ml absolute ethanol and refluxed to obtain clear solution. Subsequently, 87.5 ml DM water was added and further refluxed for 20 minutes to obtain clear solution. The reaction mixture was kept at room temperature for 24 hours. Crystalline solid was obtained. The solid was filtered, washed with 50 % ethanol and dried.
Yield: 14.7 g (84 %), HPLC purity: 99.84 %, chiral purity: 100.0 %
The crystalline form of Ambrisentan was characterized by PXRD peaks at about 7.462, 7.980, 8.239, 8.781, 11.781, 12.080, 12.703, 12.999, 13.587, 14.499, 14.842, 15.100, 16.703, 17.441, 17.660, 17.939, 18.120, 18.499, 18.740, 20.120, 20.518, 21.499, 21.741, 22.261, 22.722, 22.959, 24.139, 24.701, 25.221, 25.461, 26.641, 27.241, 27.521, 30.860, 31.901, 32.659, 35.803, 36.360, 37.003, 37.440 ± 0.2-theta (Fig.l) Similarly the crystalline form of Ambrisentan is prepared by using solvent such as ethanol, THF, MIBK and isopropyl alcohol following similar procedure as above. Example-9: Preparation of amorphous ambrisentan
In 25 mL three necked flask, (0.2 gm) Ambrisentan and 1 ml 10 % sodium hydroxide solution was taken. The reaction mixture was stirred to get clear solution, charcoalised and then acidified with HCl to pH 2. Solid white material was precipitated. The solid mass was filtered and washed with water till neutral. It was dried.
Yield: 0.14 gm (70 %), HPLC Purity: 99.82 %, Chiral Purity: 98.34 %
Example- 10: Preparation of (S)-3-methoxyphenylethylammonium (S)-2-hydroxy-3- methoxy 3, 3-diphenyl propionate
In 2 liter three necked flask, (90.0 g) (0.33 mole) 3, 3-diphenyl-2-hydroxy-3- methoxy propionic acid and 0.9 liter acetonitrile was taken. Subsequently, the reaction mixture was stirred and heated at reflux temperature. (30 g) (0.198 mole) (S)-3- methoxy PEA, in 90 mL acetonitrile was added drop wise in 10 minute time interval. Further, the reaction mixture was stirred under reflux for 0.5 hr. The reaction mixture was cooled at room temperature and was stirred for 1.5 hour. Solid material was filtered, washed with acetonitrile and dried.
Yield: 65.0 g, (92.9 %), HPLC purity: 99.82 %, Chiral purity: 96.57 %.
Example- 1 1: Purification of (S)-3-mthoxypehenylethylammonium (S)-2-hydroxy-3- methoxy 3, 3-diphenyl propionate
In 3 liter three necked flask, (6Og) chiralamine salt and mixture of (1.350 L) ethanol and (15OmL) water was taken. Subsequently, the reaction mixture was stirred and heated at reflux temperature for 30 min. Solid material was precipitated at 60-65 0C and was cooled to room temperature. The reaction mixture was further stirred at 0-5 0C for 35-40 min. Solid material was filtered, washed with cold aqueous ethanol and dried. Yield: 53.6 g, (89.3 %). HPLC purity: 99.91 %. Chiral purity: 100 %.
IR (KBr): (3435 cm"1, 2933 cm"1, 2831 cm"1, 2526 cm"1, 2173 cm"1, 1905 cm"1, 1575 cm"1, 1531 cm 1, 1450 cm"1, 1352 cm"1, 1234 cm"1, 1143cm"1, 1099 cm"1, 1041 cm"1, 964 cm 1, 833 cm"1, 773 cm"1, 698 cm"1, 632 cm"1, 555cm"1.
1H NMR (400 MHz, DMSO D6): δ = 8.00-6.87 (m, 17H), 4.72 (s, IH), 4.18 (s, IH), 3.74 (s, 3H), 3.17 (s, 3H), 1.39 (s, 3H).
13C NMR (400 MHz, DMSO D6) δ = 21.422, 49.836, 51.625, 55.082, 73.083, 84.395, 112.251, 113.386, 1 18.688, 126.010, 126.560, 126.905, 128.332, 128.754, 129.612, 142.450, 143.666, 144.625, 159.367, 173.598.
MS: m/z = 148.7 and 270.8 [M"]
PXRD peaks at about 7.05, 8.39, 10.15, 11.39, 12.15, 13.32, 13.87, 14.21, 14.51, 15.21, 17.07, 17.86, 18.87, 20.47, 21.25, 21.90, 23.01, 24.18, 24.80, 25.53, 26.69, 27.43, 28.09, 29.22, 30.43, 30.90, 31.43, 31.62, 32.12, 32.63, 33.64, 34.12, 34.84, 37.24, 38.34 and 39.04° ± 0.2° (2Θ) (Fig-3).
Example-12: Preparation of (S)-3-methoxyphenylethylammonium (S)-2-hvdroxy-3- methoxy 3, 3-diphenyl propionate
In 100 mL three necked flask, (5g) (0.018 mole) 3, 3-diphenyl-2-hydroxy-3- methoxy propionic acid and 50 mL rectified spirit was taken. Subsequently, the reaction mixture was stirred and heated at reflux temperature. (1.8g) (0.01 1 mole) (S)-
3- methoxy PEA, in 5 mL rectified spirit was added drop wise in 10 min. time interval
The reaction mixture was stirred under reflux for 0.5 hr and cooled to room temperature and again stirred at room temperature for 1.5 hour. Solid material was filtered, washed with rectified spirit and dried.
Yield: 3.3 g, (85.0 %), HPLC purity: 99.91 %, Chiral purity: 99.38 %.
Example-13: Preparation of (R)-2. 4-dichlorophenylethylammonium (S)-2-hvdroxy-3- methoxy 3. 3-diphenyl propionate
In a 5 liter three necked flask, (302 g )(1.10 mole) 3, 3-diphenyl-2-hydroxy-3- methoxy propanoic acid and 3.02 liter acetonitrile was taken. Subsequently, the reaction mixture was stirred and heated at reflux temperature. (105.4 g) (0.55 mole) (R)-2, 4-dichloro PEA, in 50 mL acetonitrile was added drop wise in 45 min. time interval Solid material was precipitated during this addition. The reaction mixture was stirred under reflux for 1 hr and cooled to room temperature. The reaction mixture was further stirred at room temperature for 1 hour. Solid material was filtered, washed with acetonitrile and dried.
Yield: 219 g, (85.41 %), HPLC purity: 99.94 %, Chiral purity: 95.01 %.
Similarly, different diastereomeric salt of (S)-2-hydroxy-3 -methoxy 3, 3-diphenyl propionate was prepared using different chiral amine in different batches and the results are summarized in Table 2 given below.
Table 2;
* Input refers to 3, 3-diphenyl-2-hydroxy-3-methoxy propionic acid
Example-24: Purification of (R)-2. 4-dichlorophenylethylammonium (S)-2-hydroxy-3- methoxy 3, 3-diphenyl propionate
In a 3 liter three necked flask, (10Og) chiral amine salt in mixture of 1.7601iter acetonitrile and 440 mL water was taken. The reaction mixture was stirred and heated under reflux to obtain a clear solution. This clear solution was transferred in 5 liter beaker and stored at -20 0C for 15 hours. Solid was filtered, washed with acetonitrile and dried.
Yield: 91 g (91 %), HPLC purity: 99.84 %. Chiral purity: 99.98 %.
IR (KBr): (3466 cm"1, 3055 cm"1, 2974 cm"1, 2935 cm"1, 2875 cm"1, 2831 cm"1, 2540 cm"1, 1637 cm"1, 1591 cm"1, 1539 cm"1, 1479 cm"1, 1442 cm 1, 1404 cm"1, 1352 cm"1, 1097 cm"1, 1045 cm"1, 725 cm"1, 696 cm"1, 634 cm"1, 1 1 15 cm"1, 677 cm"1, 634 cm"1, 546 cm"1.
1H NMR (400 MHz, DMSO D6): δ = 7.67 (d IH), 7.60 (d, IH), 7.47 (dd, IH), 7.34 (dd, 4H), 7.23 - 7.12 (m, 6H), 4.84 (s, IH), 4.47 (quartet, IH) , 1.31 (d, 3H)
13C NMR (400 MHz, DMSO D6) δ = 21.719, 46.557, 51.976, 62.253, 73.250, 84.247, 99.599, 126.272, 126.334, 126.791, 127.160, 127.835, 128.254, 128.662, 128.757, 128.809, 132.464, 132.631, 136.947, 139.990, 143.139, 144.132, 173.405. .
MS: m/z = 270.8 [M-I]
PXRD peaks at about 8.49, 10.22, 1 1.51, 1 1.88, 12.22, 13.89, 14.30, 17.00, 17.86, 18.74, 19.25, 20.49, 21.13, 21.90, 23.03, 24.14, 24.69, 25.48, 26.27, 27.35, 28.09, 28.76, 29.26, 30.35, 31.65, 32.09, 33.51, 34.13, 34.68, 35.11, 36.13, 37.09, 38.14 and 39.02 ° ± 0.2° (2θ).(Fig.4)
Similarly, purification of different diastereomeric salt of (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionic acid using different solvent in different batches were done and the results are summarized in Table 3 given below.
Table: 3
*Input refers to diastereomeric salt of 3, 3-diphenyl-2-hydroxy-3-methoxy propionic acid
Example-38: Preparation racemic ambrisentan
In a 100 mL 3 necked flask, (2.24 g) (0.0057 mol) racemic Ambrisentan methyl ester was taken. Subsequently, 22.4 mL of 1, 4 dioxane was added & stirred the reaction mixture. Aqueous solution of (2.35g) of sodium hydroxide dissolved in 15 mL water was added in to the reaction mixture and was gently refluxed for 3 hrs. The reaction mixture was cooled and dumped into water. After suitable work up racemic Ambrisentan was obtained.
Yield: 1.6 g (74.07 %), HPLC purity: 99.06 %.
Similarly, racemic Ambrisentan was prepared in different batches and the results are summarized in Table 4 given below.
Example-40: Preparation (R)-ambrisentan
In a 25 mL three necked flask, (0.150 g) (S) 2, 4-dichlorophenethyl ammonium salt of (S) 2-hydroxy-3-methoxy 3, 3-diphenyl propionate, 22.68 mg lithium hydride and 3 mL DMF were taken. Subsequently, (76 mg) 4, 6-dimethyl-2-methylsulfonyl pyrimidine was added in to the reaction mixture. Reaction mixture was stirred at 30-32 0C for 48 hours and diluted with water. After suitable work up and acidification gives 94.7 mg (R)-Ambrisentan.
Similarly, (R)-Ambrisentan was prepared in different batch and the results are summarized in Table 5 given below.
Table 5:
Example 42: Preparation of ambrisentan
In a 1 liter four necked flask, (73.5 g) (0.17 mole) (S)-3- methoxyphenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate,
(50 g) sodium f-butoxide and 367.5 mL DMF were taken at room temperature.
Reaction mixture was cooled to 20 0C then 48.5 g 4, 6-dimethyl-2-methylsulfonyl pyrimidine was added. The reaction mixture was stirred at 30 0C for 3 hrs and subsequently dumped in water and again stirred for 10 min. The reaction mixture was extracted with cyclohexane, charcoalised and acidified to get crude Ambrisentan.
Yield: 59.7 g (90.9%), HPLC Purity: 98.79 %, Chiral purity: 99.92 %.
Similarly crude Ambrisentan was prepared in different batches using (R)-2, 4- dichloro PEA salt or (S)-3-methoxy PEA salt and the results are summarized in Table 6 given below.
Table: 6
* Input refers to diastereomeric salt of 3, 3-diphenyl-2-hydroxy-3-methoxy propionic acid
Example 53: Process for the purification of ambrisentan
In 500 mL three necked flask, (29.5 g) (0.077 moles) crude Ambrisentan and 206.5 mL DM water was taken at room temperature. Subsequently, 45 mL 10 % sodium hydroxide solution was added to obtained clear solution. (1.475 g) activated charcoal was added and stirred the reaction mixture at room temperature. The reaction mixture was filtered through hyflow and washed with water. Clear filtrate was acidified with dilute hydrochloric acid to precipitate the solid mass, which was filtered and dried. Yield: 27.5 g (93 %), HPLC purity: 99.52 %, Chiral purity: 99.91 %.
Similarly crude Ambrisentan was purified in different batches and the results are summarized in Table 7 given below.
Example 58: Process for the purification of ambrisentan
In a 500 mL three necked flask, (26.2 g) (0.069 mole) Ambrisentan (obtained after first purification) and 183.4 mL ethanol was taken. The reaction mixture was heated with stirring to obtain a clear solution. Subsequently, 131 mL DM water was added and stirred under reflux for 30-45 minute. The reaction mixture was allowed to cool to precipitate solid mass after some time. The reaction mixture was again stirred at
25-30 0C for 45 min. Solid was filtered and dried.
Yield: 22.0 g (84 %), HPLC purity: 99.63 %, Chiral purity: 99.87 %.
IR (KBr): (3057 cm"1, 2966 cm"1, 2835 cm"1, 1753 cm"1, 1597 cm"1, 1558 cm"1, 1444 cm"1, 1406 cm"1, 1379 cm"1, 1301 cm"1, 1 192 cm"1, 1114cm"1, 1053 cm"1, 972 cm"1, 748 cm"1 , 700 cm"1 , 609 cm"1 , 549 cm"1.
1H NMR (400 MHz, DMSO D6): δ = 12.54 (s IH), 7.35-7.18 (m, 10H), 6.92 (s IH),
6.16 (s, IH), 3.38 (s, 3H), 2.33 (s, 6H).
13C NMR (400 MHz, DMSO D6) δ = 23.328, 53.025, 77.587, 83.168, 114.751,
126.978, 126.991, 127.234, 127.667, 127.714, 127.846, 141.461, 142.635, 163.201,
169.050, 169.061.
MS: m/z = 378.9 [M+]
PXRD peaks at about 7.48, 8.86, 12.25, 12.96, 13.99, 15.04, 15.45, 16.61, 17.73, 18.14, 18.14, 18.66, 19.37, 20.46, 21.89, 22.93, 23.20, 24.17, 25.12, 25.43, 26.29,
26.73, 27.41, 28.22, 28.76, 29.25, 29.88, 30.33, 31.85, 32.10, 32.73, 33.92, 34.74,
35.90, 36.55, and 38.35° ± 0.2° (2Θ).
Similarly crude Ambrisentan was purified in different batches and the results are summarized in Table 8 given below.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims
1. A process for preparing Ambrisentan of formula (I),
(I)
the process comprising:
Formula VIII
Formula IX
with either in (S) or (R) configuration, Xi & X2 are as defined earlier in the specification, to obtain a diastereomeric salt of 2-hydoxypropanoic acid of Formula (II); and
b) reacting the diastereomeric salt of 2-hydoxypropanoic acid of Formula (II) with either in (S) or (R) configuration, Xi & X2 are as defined earlier in the specification, with 4, 6-dimethyl-2-(methylsulfonyl) pyrimidine of Formula (VII),
Formula (VII)
to obtain the ambrisentan of Formula (I).
2. The process of claim 1, wherein the resolution of racemic 2-hydroxypropanoic acid of Formula (VIII) is carried out in the presence of one or more suitable solvent(s).
3. The process of claim 2, wherein the suitable solvent comprises one or more of water, DMSO, DMF, acetonitrile, diethyl ether, 1,4-dioxane, MTBE, 2-methyl THF, dimethyl acetamide, DCM, DIPE, THF, and (Ci -C6) alcohols.
4. The process of claim 1, wherein the reaction of the diastereomeric salt of 2- hydoxypropanoic acid of Formula (II) with 4, 6-dimethyl-2-(methylsulfonyl) pyrimidine of Formula (VII) is carried out in the presence of one or more suitable bases.
5. The process of claim 4, wherein the suitable base comprises one or more of lithium diisopropyl amide, sodium amide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, LHMDS, KHMDS, potassium tert-butoxide, and sodium tert-butoxide.
6. The process of claim 1, wherein the step (b) is carried out at a temperature of from about -10 0C to room temperature.
7. The process of claim 1, wherein the compound of Formula (II) is recrystallized prior to condensation with 4, 6-dimethyl-2-(methylsulfonyl) pyrimidine of Formula
(VII).
8. A compound of formula-(II):
with either in (S) or (R) configuration, Xi & X2 are as defined in claim 1.
9. A process for preparing compound of formula (II), with either in (S) or (R) configuration, Xj & X2 are as defined in claim 1.
the process comprising:
a) resolving racemic 2-hydroxy propanoic acid of formula (VIII),
Formula VIII
Formula IX
with either in (S) or (R) configuration, Xi & X2 are as defined in claim 1.
b) separating the compound of Formula (II).
10. Polymorphic Form I of ambrisentan having at least one of the following characteristics:
i) a powder X-ray diffraction pattern substantially in accordance with
Figure 1 ;
ii) a powder X-ray diffraction pattern having peaks at about 7.462, 8.239,
1 1.781, 12.703, 13.587, 14.842, 16.703, 17.660, 18.120, 18.740, 20.518, 21.741, 22.722, 24.139, 25.221, 26.641, 27.521, 30.860 ± 0.2 degrees 2- theta;
iii) a powder X-ray diffraction pattern having additional peaks at about 7.980, 8.781, 12.08,12.999,14.499, 15.100, 17.441, 17.939, 18.499, 20.120, 21.499, 22.261, 22.959, 24.701, 25.461, 27.241, 37.440 ± 0.2 degrees 2-thetas
11. Polymorphic Form I of ambrisentan having a Differential Scanning Calorimetry graph, wherein one characteristic endothermic peak is obtained between about 156.1° C and about 166.6° C.
12. A process for the preparation of polymorphic Form I of ambrisentan, the process comprising obtaining a solution of ambrisentan in one or more solvents; optionally, adding one or more anti-solvents to the solution; and isolating the Form I of ambrisentan by removing the solvents.
13. The process of claim 12, wherein the solvent comprises one or more of alcohols, esters, chlorinated solvents, nitriles, ketones, ethers, aprotic polar solvents or mixtures thereof.
14. The process of claim 12, wherein the anti-solvent comprises one or more of non polar solvent such as hydrocarbons and water or a mixture thereof.
15. A pharmaceutical composition comprising a therapeutically effective amount of polymorphic Form I of ambrisentan, and one or more pharmaceutically acceptable carriers, excipients or diluents.
16.A process for the purification of ambrisentan, the process comprising obtaining a solution of ambrisentan in one or more solvents and recovering pure ambrisentan by removal of the solvents.
17. The process of claim 16, wherein the solvent comprises one or more of alcohols, esters, chlorinated solvents, nitriles, ketones, ethers, aprotic polar solvents, water, or mixtures thereof.
18. The process of claim 16, wherein removing the solvent comprises one or more of distillation, distillation under vacuum, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
19. The process of claim 16, wherein obtaining the solution of ambrisentan further comprising treating with a dilute aqueous solution of a suitable base; and acidifying the solution with a suitable acid until pH about 7-8.
20. The process of claim 19, wherein the suitable base comprises one or more of carbonates, bicarbonates, or alkali metal hydroxide bases.
21. The process of claim 19, wherein the suitable acid comprises one or both of organic acids and inorganic acids.
22. The process of claim 16, further comprising additional purification of the product obtained.
23. The process of claim 16, wherein the pure ambrisentan has a purity of more than 99% and a chiral purity of more than 99.8% when measured by HPLC.
24. A compound of formula-(IIa):
Formula (Ha)
25. The crystalline form of (S)-3-methoxyphenylethylammonium (S)-2-hydroxy-3- methoxy 3, 3-diphenyl propionate of formula (Ha) having at least one of the following characteristics:
i) a powder X-ray diffraction pattern substantially in accordance with Figure 4;
ii) a powder X-ray diffraction pattern having peaks at about 7.05, 10.15, 12.15,
13.87, 17.86, 23.01 and 24.80 ± 0.2 degrees 2-theta;
iii) a powder X-ray diffraction pattern having additional peaks at about 8.39,
1 1.39, 13.87, 18.87, 21.90 and 24.18 ± 0.2 degrees 2-thetas.
26. A compound of formula-(IIb):
Formula (lib)
27. The crystalline form of (R)-2, 4-dichlorophenylethylammonium (S)-2-hydroxy-3- methoxy 3, 3 diphenyl propionate of formula (lib) having at least one of the following characteristics:
i) a powder X-ray diffraction pattern substantially in accordance with Figure 5;
ii) a powder X-ray diffraction pattern having peaks at about 8.49, 1 1.51, 11.88, 17.00, 18.74, 21.13 and 23.03 ± 0.2 degrees 2- theta;
iii) a powder X-ray diffraction pattern having additional peaks at about 10.22, 12.22, 13.89, 14.30, 19.25, 20.49, 24.14, 25.48 and 34.13 ± 0.2 degrees 2-thetas.
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US13/382,988 US8962832B2 (en) | 2009-07-10 | 2010-07-12 | Process for the preparation of ambrisentan and novel intermediates thereof |
JP2012519124A JP5531097B2 (en) | 2009-07-10 | 2010-07-12 | Improved process for preparing ambrisentan and novel intermediates thereof |
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WO2014139087A1 (en) * | 2013-03-12 | 2014-09-18 | 江苏康缘药业股份有限公司 | Racemization method of chiral 2-[(4,6-dimethylpyrimidine-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid |
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JP2015502916A (en) * | 2011-10-19 | 2015-01-29 | シプラ・リミテッド | Method for preparing endothelin receptor antagonist |
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EP2712865A1 (en) | 2014-04-02 |
EP2451786B1 (en) | 2014-01-22 |
EP2712865B1 (en) | 2016-03-16 |
EP2451786A2 (en) | 2012-05-16 |
US20120184573A1 (en) | 2012-07-19 |
HK1192880A1 (en) | 2014-09-05 |
WO2011004402A3 (en) | 2011-03-10 |
JP2012532863A (en) | 2012-12-20 |
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