US20110288179A1 - Bimatoprost crystalline form i - Google Patents
Bimatoprost crystalline form i Download PDFInfo
- Publication number
- US20110288179A1 US20110288179A1 US13/113,136 US201113113136A US2011288179A1 US 20110288179 A1 US20110288179 A1 US 20110288179A1 US 201113113136 A US201113113136 A US 201113113136A US 2011288179 A1 US2011288179 A1 US 2011288179A1
- Authority
- US
- United States
- Prior art keywords
- bimatoprost
- mixture
- crystalline form
- mmol
- vacuo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 title claims abstract description 171
- 229960002470 bimatoprost Drugs 0.000 title claims abstract description 167
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims description 106
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 38
- 239000012535 impurity Substances 0.000 claims description 8
- 239000002537 cosmetic Substances 0.000 claims 2
- 238000000746 purification Methods 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000003860 storage Methods 0.000 abstract description 4
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 59
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 58
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 44
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 150000002596 lactones Chemical class 0.000 description 29
- 239000012453 solvate Substances 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 239000002244 precipitate Substances 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 238000000634 powder X-ray diffraction Methods 0.000 description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- 238000011084 recovery Methods 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- 239000007832 Na2SO4 Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 150000002576 ketones Chemical class 0.000 description 19
- YFHHIZGZVLHBQZ-KDACTHKWSA-N 17-phenyl-trinor-prostaglandin F2alpha Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)CC1=CC=CC=C1 YFHHIZGZVLHBQZ-KDACTHKWSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000009835 boiling Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 238000000113 differential scanning calorimetry Methods 0.000 description 15
- 239000003960 organic solvent Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 14
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 11
- OZCBJWOYRKMMPF-QWPROEHNSA-N 15-ketobimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(=O)CCC1=CC=CC=C1 OZCBJWOYRKMMPF-QWPROEHNSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 229940125898 compound 5 Drugs 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 150000004702 methyl esters Chemical class 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 7
- AQOKCDNYWBIDND-ABRBVVEGSA-N 5-trans-17-phenyl trinor Prostaglandin F2alpha ethyl amide Chemical compound CCNC(=O)CCC\C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-ABRBVVEGSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000004611 spectroscopical analysis Methods 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012296 anti-solvent Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical group [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- UQBYFURYGYNQLQ-FDBOBMRISA-N methyl (z)-7-[(1r,2r,3r,5s)-3,5-dihydroxy-2-[(e,3s)-3-hydroxy-5-phenylpent-1-enyl]cyclopentyl]hept-5-enoate Chemical compound COC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 UQBYFURYGYNQLQ-FDBOBMRISA-N 0.000 description 5
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 5
- 239000012258 stirred mixture Substances 0.000 description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 238000007239 Wittig reaction Methods 0.000 description 4
- JKHADYMACPRLAF-XLFIOJMBSA-N [(3aR,4R,5R,6aS)-4-[(E,3R)-3-[tert-butyl(dimethyl)silyl]oxy-5-phenylpent-1-enyl]-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl] 4-phenylbenzoate Chemical compound O([C@@H]1C[C@@H]2OC(=O)C[C@@H]2[C@H]1/C=C/[C@H](O[Si](C)(C)C(C)(C)C)CCc1ccccc1)C(=O)c(cc1)ccc1-c1ccccc1 JKHADYMACPRLAF-XLFIOJMBSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000002738 chelating agent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- SZJVIFMPKWMGSX-AKHDSKFASA-N corey lactone 4-phenylbenzoate Chemical compound O([C@H]1[C@@H]([C@H]2CC(=O)O[C@H]2C1)CO)C(=O)C(C=C1)=CC=C1C1=CC=CC=C1 SZJVIFMPKWMGSX-AKHDSKFASA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QNROIJKWXNUYHE-ZQQQANHYSA-N CC(C)(C)[C@@H](/C=C/[C@H]1[C@H](PPB=O)C[C@@H]2OC(=O)C[C@@H]21)CCC1=CC=CC=C1.C[Si](C)=O Chemical compound CC(C)(C)[C@@H](/C=C/[C@H]1[C@H](PPB=O)C[C@@H]2OC(=O)C[C@@H]21)CCC1=CC=CC=C1.C[Si](C)=O QNROIJKWXNUYHE-ZQQQANHYSA-N 0.000 description 3
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- AQOKCDNYWBIDND-ZPFRTTICSA-N (z)-7-[(1r,2r,3r,5s)-3,5-dihydroxy-2-[(e,3r)-3-hydroxy-5-phenylpent-1-enyl]cyclopentyl]-n-ethylhept-5-enamide Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-ZPFRTTICSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
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- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical group O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
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- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 2
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- PSEHHVRCDVOTID-VMAIWCPRSA-N chloro-bis[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@H]([C@@H]1C)B(Cl)[C@H]2[C@H](C)[C@]3(C[C@@](C2)(C3(C)C)[H])[H])[C@@]2([H])C(C)(C)[C@]1([H])C2 PSEHHVRCDVOTID-VMAIWCPRSA-N 0.000 description 2
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- OSVXSBDYLRYLIG-UHFFFAOYSA-N dioxidochlorine(.) Chemical compound O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 2
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 239000003039 volatile agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Definitions
- the invention relates to novel polymorphic form I of crystalline bimatoprost, method for preparation thereof and new crystalline intermediates in the preparation.
- This form I of crystalline bimatoprost is used in purification of crude bimatoprost, and in storage of bimatoprost as active pharmaceutical intermediate.
- Use of the physical form of bimatoprost in the manufacture of a medicament is also disclosed.
- Elevated intraocular pressure is the major risk factor associated with the etiology of glaucoma, a progressive optic neuropathy that can ultimately cause blindness.
- Prostamide analogs represent potent therapeutic agents in clinical management of glaucoma and other conditions associated with elevated intraocular pressure.
- the synthetic prostamide analog used to reduce IOP includes (9S,11R,15S)-9,11,15-trihydroxy-17-phenyl-18,19,20-trinor-5Z,13E-prostadienoic acid ethylamide
- bimatoprost known under international nonproprietary name bimatoprost, currently marketed by Allergan as LumiganTM—0.03% bimatoprost ophthalmic solution for the treatment of open-angle glaucoma and ocular hypertension ( Drugs Aging, 2002, 19, 231).
- US2005/209337 discloses crystalline physical form of bimatoprost, which we designate as form A.
- the form is characterized by powder x-ray diffractometry, IR DRIFTS (KBr) spectroscopy, DSC and TGA.
- the present invention includes new polymorphic form of bimatoprost which is the most thermodynamically stable polymorph of bimatoprost and method for preparation thereof.
- the present invention provides crystalline form I of bimatoprost and method for preparation thereof.
- the new crystalline form of bimatoprost is the most stable solid form of bimatoprost.
- the new form of bimatoprost may be prepared so as to be substantially free of other physical forms.
- the present invention also provides a method for purifying crude bimatoprost from related impurities, which comprises the steps of:
- the present invention also provides the use of bimatoprost crystalline form I in the manufacture of a medicament.
- the medicament is prepared by combining a therapeutically effective amount of bimatoprost crystalline form I, as an active ingredient, with conventional pharmaceutically-acceptable excipients, e.g. an ophthalmically-acceptable vehicle, and by preparation of unit dosage forms suitable for pharmaceutical use, e.g. topical ocular use.
- the present invention also provides new crystalline intermediate in the synthesis of bimatoprost-crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5a.
- the crystalline intermediate is useful for complete isolation of desired crystalline (3aR,4R,5R,6aS)-4-[3S-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5 as MTBE solvate
- FIG. 1 shows a characteristic x-ray powder diffraction pattern of bimatoprost crystalline form I, according to embodiments of the present invention.
- Vertical axis intensity (counts per second);
- Horizontal axis 20 (degrees).
- FIG. 2 shows the differential scanning calorimetry (DSC) curve of bimatoprost crystalline form I, according to embodiments of the invention.
- FIG. 3 shows the infrared spectrum (diffuse reflectance, DRIFTS) of bimatoprost crystalline form I in potassium bromide, according to embodiments of the invention.
- FIG. 4 shows the infrared spectrum of bimatoprost crystalline form I in potassium bromide, according to embodiments of the invention.
- FIG. 5 shows the infrared spectrum of bimatoprost crystalline form I in Nujol, according to embodiments of the invention.
- FIG. 6 shows the 1 H nuclear magnetic resonance (NMR) spectrum of compound 5 MTBE solvate in CDCl 3 , according to embodiments of the invention.
- FIG. 7 shows a characteristic x-ray powder diffraction pattern of compound 5 MTBE solvate, according to embodiments of the present invention.
- Vertical axis intensity (counts per second);
- Horizontal axis 2 ⁇ (degrees).
- FIG. 8 shows the infrared spectrum (diffuse reflectance, DRIFTS) of compound 5 MTBE solvate in potassium bromide, according to embodiments of the invention.
- FIG. 9 shows the differential scanning calorimetry (DSC) curve of compound 5 MTBE solvate, according to embodiments of the invention.
- FIG. 10 shows the thermograviometric (TGA) curve of compound 5 MTBE solvate, according to embodiments of the invention.
- FIG. 11 shows the 1 H nuclear magnetic resonance (NMR) spectrum of compound 5a in CDCl 3 , according to embodiments of the invention.
- FIG. 12 shows a characteristic x-ray powder diffraction pattern of compound 5a, according to embodiments of the present invention.
- Vertical axis intensity (counts per second);
- Horizontal axis 2 ⁇ (degrees).
- FIG. 13 shows the infrared spectrum (KBr) of compound 5a in potassium bromide, according to embodiments of the invention.
- FIG. 14 shows the differential scanning calorimetry (DSC) curve of compound 5a, according to embodiments of the invention.
- US2005/209337 discloses crystalline physical form of bimatoprost, which we designate as form A.
- the present invention discloses, according to its first aspect, a new crystalline form of bimatoprost, which we designate as form I.
- the bimatoprost crystalline form I may be prepared so as to be substantially free of other physical forms.
- the present invention provides a process for producing crystalline form I substantially free from other physical forms of bimatoprost by crystallization of bimatoprost in any physical form from an organic solvent or from a mixture of organic solvent and anti-solvent.
- the crystallization comprises the steps of:
- the said organic solvent is selected from the group consisting of alcohols, esters, ketones, chloroorganic solvents, or mixture thereof.
- said alcohols are selected from the group consisting of methanol, ethanol, isopropanol, butanol, isobutanol, t-butanol or mixture thereof.
- said esters are selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate or mixture thereof.
- said ketones are selected from the group consisting of acetone, methyl ethyl ketone, isopropylacetone or mixture thereof.
- said chloroorganic solvents are selected from the group consisting of dichloromethane, chloroform, chlorobenzene or mixture thereof.
- the said anti-solvent is selected from the group consisting of hydrocarbons, ethers or mixture thereof.
- the anti-solvent is saturated hydrocarbon.
- said saturated hydrocarbon is selected from the group consisting of pentane, heptane, hexane, cyclohexane or mixture thereof.
- said ethers are selected from the group consisting of diethyl ether, diisopropyl ether, MTBE or mixture thereof.
- a pure crystalline organic compound has, in general, a definite melting point range.
- the melting point is defined as the point at which the sample is entirely in the liquid phase.
- Bimatoprost crystalline form I has a characteristic melting point range determined by the capillary method from 62 to 64° C.
- DSC Differential scanning calorimetry
- XRPD x-ray powder diffraction
- IR infrared
- the DSC curve of form I ( FIG. 2 ) exhibits a melting endotherm at approximately 60-66° C.
- Bimatoprost crystalline form I also exhibits distinctive x-ray powder diffraction pattern, as depicted in FIG. 1 .
- the pattern has characteristic peaks expressed in degrees 20 at approximately 5.4 ⁇ 0.2, 10.9 ⁇ 0.2, 11.3 ⁇ 0.2, 13.7 ⁇ 0.2, 16.6 ⁇ 0.2, 17.5 ⁇ 0.2, 19.9 ⁇ 0.2, 20.7 ⁇ 0.2 and 22.7 ⁇ 0.2.
- the crystalline form I was characterized by an infrared diffuse reflectance spectrum in potassium bromide as depicted in FIG. 3 .
- the crystalline form I was further characterized by an infrared absorption spectrum carried out in potassium bromide and in Nujol as depicted in FIGS. 4 and 5 .
- Bimatoprost crystalline form I is the most stable crystalline modification of bimatoprost in a temperature range between ⁇ 70 and +30° C. Stability data supports the retest period of not less than 6 months if bimatoprost crystalline form I is stored in an appropriate container at 2 to 8° C. and at 25° C.
- bimatoprost crystalline form I rests primarily (but not exclusively) in its thermodynamic stability. Besides its greater stability, form I shows advantages with respect to form A because of the possibility of its preparation by crystallization employing different solvents in a wide temperature range. For example, the crystalline form I may be easily prepared by recrystallizing, triturating, or reslurring of crystalline form A.
- carbodiimides are selected from the group of N,N-dicyclohexylcarbodiimide (DCC) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC).
- DCC N,N-dicyclohexylcarbodiimide
- EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide
- crude bimatoprost is prepared by reaction of bimatoprost acid methyl ester with ethylamine as described in US2004/171873, US2005/209337, US2005/154220 and U.S. Pat. No. 5,352,708.
- Y is a leaving group
- the methylation agent is methyl iodide, bromide, methanesulfonate, p-toluenesulfonate, 2,4-dinitrophenylsulfonate or triflate.
- the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
- DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
- the base is K 2 CO 3 .
- the base is cesium carbonate, hydrogencarbonate, hydroxide or fluoride or mixture thereof. If cesium alkali is used as base in the methylation reaction cesium salt of bimatoprost acid
- the methylation reaction of bimatoprost acid 3 is provided in the presence of solvent.
- the solvent is aprotic organic solvent. More preferably, the solvent is polar organic solvent.
- the polar organic solvent is N,N-dimethylformamide (DMF), N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone (NMP), dimethyl sulfoxide (DMSO), sulfolane or HMPA.
- the solvent is DMF.
- the bimatoprost acid methyl ester 2 prepared by the reaction may be used in following amination reaction without purification; however ester 2 may be purified by flash chromatography.
- ester 2 may be purified by flash chromatography.
- the purification is provided by preparative LC on silica gel or PhenomenexTM Luna CN silica gel.
- the bimatoprost acid 2 is prepared by Wittig reacting of lactol
- the Wittig reaction is provided in the presence of aprotic organic solvent. More preferably, the solvent is ether-type solvent. Most preferably the solvent is THF. Analytical HPLC showed that crude bimatoprost acid 3 prepared by the Wittig reaction contains up to 5% of 5-trans isomer 3b.
- the lactol 4 may be prepared by reducing compound of formula
- the reaction temperature range is ⁇ 50 to +20° C., more preferably ⁇ 30 to 0° C.
- i-Bu 2 AlH to lactone 5 at ⁇ 50 to +20° C. (preferably at ⁇ 30 to 0° C.) to attain about 95-99% conversion of lactone group.
- the reaction is provided in the presence of aprotic organic solvent. More preferably, the solvent is toluene, CH 2 Cl 2 , THF, ether or mixture thereof.
- the lactone 5 is prepared by process comprising:
- the reduction of the compound 6 may be carried out with any reagent capable to reduce ketone function to alcohol.
- An example of the reagent is NaBH 4 or (i-PrO) 3 Al.
- the reduction of the compound 6 is carried out with ( ⁇ )-B-chlorodiisopinocampheylborane or with borane in the presence of 2-alkyl-CBS-oxazaborolydines. More preferably the reduction is carried out with ( ⁇ )-B-chlorodiisopinocamphenylborane in organic solvent.
- the organic solvent is THF, ether, 1,2-dimethoxyethane, toluene, hexane, CH 2 Cl 2 or mixtures of these solvents.
- the invention provides crystalline MTBE solvate of (3aR,4R,5R,6aS)-4-[3S-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5
- Crystalline MTBE solvate of lactone 5 has a characteristic melting point range determined by the capillary method from 60 to 64° C.
- DSC Differential scanning calorimetry
- XRPD x-ray powder diffraction
- IR infrared
- Crystalline lactone 5 MTBE solvate exhibits a melting endotherm at approximately 60-66° C.
- Crystalline lactone 5 MTBE solvate also exhibits distinctive x-ray powder diffraction pattern, as depicted in FIG. 7 .
- the pattern has characteristic peaks expressed in degrees 20 at approximately 6.5 ⁇ 0.2, 7.1 ⁇ 0.2, 12.2 ⁇ 0.2, 12.5 ⁇ 0.2, 13.1 ⁇ 0.2, 13.6 ⁇ 0.2, 14.6 ⁇ 0.2, 15.0 ⁇ 0.2, 15.8 ⁇ 0.2, 16.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.0 ⁇ 0.2, 17.3 ⁇ 0.2, 18.0 ⁇ 0.2, 18.2 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19.7 ⁇ 0.2, 20.5 ⁇ 0.2, 20.8 ⁇ 0.2, 21.0 ⁇ 0.2, 21.8 ⁇ 0.2, 22.2 ⁇ 0.2, 23.0 ⁇ 0.2, 23.3 ⁇ 0.2, 24.2 ⁇ 0.2, 25.5 ⁇ 0.2, 26.5 ⁇ 0.2 and 26.7 ⁇ 0.2.
- the crystalline lactone 5 MTBE solvate was characterized by an infrared diffuse reflectance spectrum in potassium bromide as depicted in FIG. 8 .
- the invention further provides crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5a.
- Crystalline lactone 5a has a characteristic melting point range determined by the capillary method from 93 to 94° C.
- Crystalline lactone 5a ( FIG. 14 ) exhibits a melting endotherm at approximately 83-97° C.
- Crystalline lactone 5a also exhibits distinctive x-ray powder diffraction pattern, as depicted in FIG. 12 .
- the pattern has characteristic peaks expressed in degrees 20 at approximately 5.7 ⁇ 0.2, 6.3 ⁇ 0.2, 14.0 ⁇ 0.2, 14.5 ⁇ 0.2, 14.8 ⁇ 0.2, 15.5 ⁇ 0.2, 16.3 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 17.8 ⁇ 0.2, 18.1 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 19.3 ⁇ 0.2, 21.5 ⁇ 0.2, 22.0 ⁇ 0.2, 22.4 ⁇ 0.2 and 23.8 ⁇ 0.2.
- Lactone 5a was characterized by 1 H NMR (CDCl 3 ), powder x-ray diffractometry, DSC, and IR (KBr) spectroscopy as set forth above and illustrated in FIGS. 11-14 .
- Crystallinity of compounds 5 (as MTBE solvate) and 5a give very rare option to isolate the compounds in highly pure form with high yield from 5/5a 1:1 mixture by simple crystallization procedure.
- the compound of the formula 7 may be prepared by Horner-Emmons-Wadsworth reaction of Corey aldehyde of formula 8
- the base is BuLi, NaH or Et 3 N/LiCl. More preferably, the base is alkali.
- the alkali is LiOH, NaOH, KOH, CsOH, Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 .
- the base is an aqueous alkali.
- the Horner-Emmons-Wadsworth reaction is provided in the presence of organic solvents.
- the solvent is CH 2 Cl 2 , CHCl 3 , toluene, THF, MTBE, ether or mixture thereof.
- Corey aldehyde 8 may be prepared by oxidation of ( ⁇ )-Corey lactone 5-(4-phenylbenzoate) of formula 9
- the oxidation of ( ⁇ )-Corey lactone 5-(4-phenylbenzoate) 9 may be carried out with any oxidizing system capable to oxidize primary alcohol to aldehyde.
- An example of the oxidizing system is CrO 3 /C 5 H 5 N, Cl 2 /PhSMe, DMSO/DCC/ft, or Dess-Martin reagent.
- the oxidizing system is aq NaClO/TEMPO, more preferably aq NaClO/TEMPO/NaBr, most preferably NaClO/TEMPO/NaBr/1-PrOH.
- bimatoprost The major related impurities in bimatoprost that can be formed during synthesis or storage of bimatoprost, included the following:
- the key step of the synthesis is isomerisation of methyl ester 10 to its 5-trans isomer 11 by irradiation in the presence of Ph 2 S.
- the present invention provides a method for purifying crude bimatoprost from related impurities, which comprises the steps of:
- bimatoprost that is substantially free of 15R- and 5-trans isomers of bimatoprost.
- bimatoprost containing less than 0.2% each of 15R- and 5-trans isomers can be produced.
- bimatoprost containing less than 0.1% each of 15R- and 5-trans isomers can be produced.
- bimatoprost containing less than 0.05% each of 15R- and 5-trans isomers can be produced.
- the present invention also provides the use of bimatoprost crystalline form I in the manufacture of a medicament.
- the medicament is prepared in two steps, preparation of a composition containing bimatoprost and manufacture of unit dosage forms suitable for pharmaceutical use, e.g. topical ocular use.
- the composition is prepared by combining a therapeutically effective amount of bimatoprost crystalline form I, as an active ingredient, with conventional pharmaceutically-acceptable excipients, e.g. an ophthalmically-acceptable vehicle.
- the therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
- compositions of the present invention may further comprise various formulatory ingredients, such as ophthalmically acceptable diluents, buffers, hydrochloric acid, sodium hydroxide, antimicrobial preservatives, stabilizers, tonicity adjustors, viscosity-enhancing agents, chelating agents, antioxidants, surfactants and/or solubilizers and combinations thereof.
- formulatory ingredients such as ophthalmically acceptable diluents, buffers, hydrochloric acid, sodium hydroxide, antimicrobial preservatives, stabilizers, tonicity adjustors, viscosity-enhancing agents, chelating agents, antioxidants, surfactants and/or solubilizers and combinations thereof.
- the diluent is purified water.
- Preservatives are used in multi-use ophthalmic formulations to prevent microbial contamination of the composition after the packaging has been opened.
- a number of preservatives have been used including quaternary ammonium salts, mercury compounds, alcohols and stabilized chlorine dioxide.
- Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, phenylmercuric nitrate, PolyquadTM.
- Viscosity-enhancing agents may be added as needed or convenient. They include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, polyethylene glycol, or combinations thereof.
- Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, dextrose, propylene glycol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
- buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Hydrochloric acid or sodium hydroxide may be used to adjust the pH of these formulations as needed.
- Preferred surfactants are, for example, polyethoxylated castor oil, Tween 80, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose and hydroxyethyl cellulose cyclodextrin.
- excipient components which may be included in the ophthalmic preparations, are chelating agents.
- the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
- DMAP 4-N,N-dimethylaminopyridine
- DMSO dimethyl sulfoxide
- DRIFTS diffuse reflectance infrared Fourier-transform spectrum (spectroscopy);
- DSC differential scanning calorimetry;
- FT-IR Fluorier-transform infrared;
- GC gas chromatography;
- HPLC high performance liquid chromatography;
- HMPA hexamethylphosphoramide;
- INN International Nonproprietary Name
- USAN United States Adopted Name
- XRPD x-ray powder diffraction.
- the LC purity was determined by separating a sample by High performance liquid chromatography (HPLC) and calculating the area percentage thereof of each peak.
- HPLC High performance liquid chromatography
- the chromatographic analysis of bimatoprost is based on a chiral reversed-phase HPLC method with an optically active tris(3,5-dimethylphenylcarbamate) of cellulose immobilized on silica support stationary phase and a mobile phase buffered at pH 4.5.
- HPLC method was carried out using a 10 ⁇ m ChiralpakTM OD-R 250 ⁇ 4.6 mm column (Diacel).
- Diluent mixture A/B 25:75, sample concentration—about 0.5 mg per 1 mL, injection volume—20 ⁇ L; a mobile phase—gradient A/B 25:75 for 0 min, 25:75 for 25 min, 35:65 for 35 min, 35:65 for 60 min, 25:75 for 65 min, 25:75 for 80 min wherein A is MeCN and B is Et 3 N (1.0 mL) solution in water (1 L), pH adjusted with 85% H 3 PO 4 up to 4.5. Column temperature 35° C.; a flow rate of 0.7 mL/min; and a UV detector at 200 nm.
- Infrared (IR) absorption spectra were obtained by Nicolet Impact 410 FT-IR spectrophotometer using a dispersion of solid sample material in KBr or Nujol.
- Infrared DRIFTS spectra were obtained by Nicolet Impact 410 FT-IR spectrophotometer equipped with Pike Technologies EasiDiff Diffuse Reflectance Accessory using a dispersion of solid sample material in KBr.
- Powder x-ray diffraction patterns were obtained by methods known in the art using PANALYTICAL (Philips) X'Pert Pro MPD x-ray powder diffraction system (CuK ⁇ radiation, PW3050/60 goniometer, PW3015/20 X'Celerator detector). The Bragg-Brentano scheme was used for beam focusing.
- Melting points were determined in open capillary tubes with Buchi B-545 capillary melting point apparatus or Mettler-Toledo FP-900 Thermosystem with FP-81 HT Melting Point Cell and FP-90 central processor, or Electrothermal IA 9300 digital melting point apparatus, and are uncorrected.
- the melting points generally depend on the purity level of the samples.
- bimatoprost crystalline form I has been found to have a melting point between 62 and 64° C.
- the aqueous layer was separated and extracted with CH 2 Cl 2 (50 mL).
- the combined organic layers was added dropwise over 1 h to a stirred mixture of a solution of BnCH 2 COCH 2 PO(OMe) 2 (15.4 g, 60.0 mmol) in CH 2 Cl 2 (20 mL) and 30% NaOH (8.0 g, 60.0 mmol) at 0-5° C.
- the mixture was stirred 0.5 h at the same temperature and treated with 10% aq. citric acid (100 mL).
- the aqueous layer was separated and extracted with CH 2 Cl 2 (50 mL).
- the combined organic layers were dried over Na 2 SO 4 , filtered through short silica gel column and concentrated in vacuo.
- the x-ray powder diffraction pattern of crystalline MTBE solvate of compound 5 has characteristic peaks expressed in degrees 20 at approximately 6.5, 7.1, 12.2, 12.5, 13.1, 13.6, 14.6, 15.0, 15.8, 16.2, 16.3, 17.0, 17.3, 18.0, 18.2, 18.8, 19.5, 19.7, 20.5, 20.8, 21.0, 21.8, 22.2, 23.0, 23.3, 24.2, 25.5, 26.5 and 26.7.
- IR DRIFTS (KBr): 2949, 2931, 2854, 1765, 1715, 1607, 1361, 1266, 1203, 1170, 1118, 1095, 1080, 972, 912, 852, 839, 775, 745, and 699 cm ⁇ 1 .
- Compound 5 MTBE solvate was characterized by 1 H NMR (CDCl 3 ), powder x-ray diffractometry, IR DRIFTS (KBr) spectroscopy, DSC and TGA as set forth above and in FIGS. 6 , 7 , 8 , 9 and 10 .
- the x-ray powder diffraction pattern of crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5a has characteristic peaks expressed in degrees 20 at approximately 5.7, 6.3, 14.0, 14.5, 14.8, 15.5, 16.3, 17.0, 17.5, 17.8, 18.1, 18.6, 18.9, 19.3, 21.5, 22.0, 22.4 and 23.8.
- Lactone 5a was characterized by 1 H NMR (CDCl 3 ), powder x-ray diffractometry, DSC, and IR (KBr) spectroscopy as set forth above and illustrated in FIGS. 11-14 .
- Method B A mixture of compound 5 MTBE solvate (1.0 g, 1.7 mmol), 32% HCl (0.1 mL, 0.3 mmol) and MeOH (6 mL) was stirred for 2 h at 40° C. and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold MeOH and dried in vacuo to give alcohol 6 as white crystals.
- Method A A solution of C 5 H 5 N.SO 3 (0.32 g) in DMSO (3.5 mL) was added dropwise to a stirred solution of alcohol 6a (0.30 g) and Et 3 N (0.40 g) in CH 2 Cl 2 (4 mL) at ⁇ 5 to 0° C. The mixture was stirred at the same temperature for 1 h (TLC monitoring) and poured into cold water (15 mL). The mixture was stirred for 10 min at 0-5° C. The organic layer was separated, the water layer was extracted with CH 2 Cl 2 (3 ⁇ 5 mL). The combined organic layers were washed with brine (3 ⁇ 10 mL), dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Method B 5% aq. NaOCl (40 mL, TLC monitoring) was added dropwise to a stirred mixture of alcohol 6a (0.53 g, 1.1 mmol), TEMPO (4 mg, 0.025 mmol), NaBr (12 mg, 0.12 mmol), NaHCO 3 (0.3 g, 3.6 mmol), CH 2 Cl 2 (3 mL) and water (3 mL) at rt and the mixture was stirred for 1 h. The aqueous layer was separated and extracted with CH 2 Cl 2 (3 mL). The combined organic layer was dried over Na 2 SO 4 and filtered trough short silica gel column. The residue was concentrated in vacuo and crystallized from MeOH (5 mL) to give 0.37 g (70%) of ketone 7.
- i-Bu 2 AlH (20% w/w solution in toluene, 59.5 mL, 72 mmol) was added dropwise to a stirred solution of lactone 5 MTBE solvate (15.0 g, 21.8 mmol) in toluene (100 mL) at ⁇ 25 to ⁇ 20° C.
- the mixture was stirred for 1 h at the same temperature, heated to ⁇ 10° C. and quenched by slow addition of 10% aq citric acid (210 g, 109 mmol) keeping reaction temperature below 20° C.
- the resulted suspension was stirred for 1 h at rt until most of solids disappeared.
- the aqueous phase was separated and extracted with toluene (50 mL).
- i-Bu 2 AlH (20% w/w in toluene, 50 mL, 60.0 mmol) was added dropwise to a stirred solution of lactone 5a (10.74 g, 18.0 mmol) in toluene (70 mL), at ⁇ 25 to ⁇ 15° C.
- lactone 5a (10.74 g, 18.0 mmol) in toluene (70 mL)
- the mixture was stirred at the same temperature for 2 h, then heated to ⁇ 10° C. and quenched by slow addition of 10% aq citric acid (173 mL, 90.0 mmol).
- the resulted mixture was stirred for 1 h at rt until the most of solids were disappeared.
- the aqueous phase was separated and extracted with toluene (50 mL).
- the pH of the mixture was adjusted to 7.5-8.0 with 20% aq citric acid, most of THF was evaporated in vacuo and extracted with MTBE (3 ⁇ 150 mL). The combined organics were washed with 5% NaHCO 3 (adjusted to pH 8 with 20% aq citric acid, 2 ⁇ 100 mL) and brine, and concentrated in vacuo. The residue was dissolved in MeOH (80 mL), the solution was cooled to 0° C., and 3 N HCl (21.5 mL, 64.5 mmol) was slowly added keeping reaction temperature below 10° C. The resulted mixture was stirred for 5 h at 0 to 5° C. and quenched by addition of 10% NaOH (44 g, 110 mmol).
- the mixture was stirred for 1 h at 40° C., most of MeOH was evaporated in vacuo and the aqueous phase was extracted with MTBE (4 ⁇ 70 mL).
- the combined organics were washed with 10% NaOH (40 mL), the aqueous layers were combined and acidified to pH 3.5-4.5 with 20% aq citric acid.
- the resulted mixture was extracted with MTBE (3 ⁇ 100 mL), the combined organics were washed with brine, dried over Na 2 SO 4 , filtered and passed through silica gel column (45 g).
- the pH of the mixture was adjusted to 7.5-8.0 with 20% aq citric acid, the most of THF was evaporated and the aqueous mixture was extracted with MTBE (3 ⁇ 120 mL). The combined organics were washed with 5% NaHCO 3 (adjusted to pH 7.7-8.0 with 20% aq citric acid, 2 ⁇ 30 mL) and brine and concentrated in vacuo.
- a solution of the residue in MeOH (50 mL) was treated with 3 N HCl (15 mL) at 0° C. The resulted mixture was stirred for 4 h at 0-4° C. and quenched by addition of 10% NaOH (44 mL).
- the mixture was stirred for 1 h at 40° C., the most of MeOH was evaporated in vacuo and the aqueous phase was extracted with MTBE (4 ⁇ 70 mL).
- the combined organics were washed with 10% NaOH (30 mL), the aqueous layers were combined and acidified to pH 3.5-4.5 with 20% aq citric acid.
- the resulted mixture was extracted with MTBE (3 ⁇ 100 mL), the combined organics were washed with brine, dried over Na 2 SO 4 , filtered and passed through silica gel column (60 g).
- ester 2a A mixture of ester 2a (3.30 g, 8.2 mmol), imidazole (5.58 g, 82.0 mmol) and t-BuMe 2 SiCl (6.18 g, 41.0 mmol) in DMF (20 mL) was stirred overnight at rt and the reaction was quenched by addition of 10% aq citric acid (100 mL). The mixture was extracted with MTBE (3 ⁇ 30 mL), the combined organics were washed with a 10% NaHCO 3 (30 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified on a silica gel (70 g, eluted with heptane, then heptane/EtOAc 10:1) to give 6.01 g (98%) of ester 10 as light oil.
- ester 2b (3.73 g, 5.0 mmol) and Bu 4 NF (1 M solution in THF, 25 mL, 25.0 mmol) was stirred 14 h at rt and concentrated in vacuo.
- a solution of the residue in CH 2 Cl 2 was washed with 10% aq citric acid, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
- the residue was purified by chromatography on a silica gel (30 g, eluent CH 2 Cl 2 , then CH 2 Cl 2 /EtOAc 1:1) to give 1.65 g (82%) of ester 2b.
- ester 2 [9.0 g, 22.4 mmol, contain (by HPLC) 3.5% of 5-trans isomer], 70% aq EtNH 2 (40 mL, 503 mmol) and MeOH (45 mL) was stirred in a well closed flask at 24 to 27° C. for 72 h and concentrated in vacuo. The residue was portioned between EtOAc (100 mL) and water (60 mL).
- the bimatoprost (7.5 g) was crystallized from EtOAc (75 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C.
- bimatoprost crystalline form I as white powder with 99% purity by HPLC, 0.6% 5-trans isomer 1b, NMT 0.1% of 15R-isomer 1a, and NMT 0.1% of 15-keto bimatoprost 1c; mp 64-66° C.; [ ⁇ ] D 20 +36° (c 1, MeOH).
- the x-ray powder diffraction pattern of bimatoprost crystalline form I has characteristic peaks expressed in degrees 20 at approximately 5.4, 6.2, 10.9, 11.3, 13.7, 16.6, 17.5, 18.3, 18.6, 18.9, 19.4, 19.7, 19.9, 20.7, 20.9, 21.6, 22.7 and 28.2.
- IR DRIFTS (KBr): 3426.6, 3390.7, 3320.8, 3083.3, 3059.3, 3010.8, 2911.8, 2863.8, 1618.1, 1544.8, 1495.6, 1453.5, 1370.0, 1344.6, 1316.0, 1289.1, 1259.9, 1247.9, 1150.6, 1096.4, 1053.4, 1026.3, 975.0, 919.7, 767.4, 746.0, 728.1, 697.7, 607.2 and 597.6 cm ⁇ 1 .
- IR (KBr): 3414.9, 3326.6, 3085.5, 3025.1, 3011.5, 2929.6, 2914.2, 2864.9, 1644.8, 1619.2, 1546.2, 1496.2, 1454.6, 1372.9, 1346.0, 1317.3, 1290.4, 1260.9, 1249.3, 1229.4, 1203.6, 1151.9, 1097.2, 1054.5, 1028.6, 975.4, 920.5, 767.6, 747.5, 721.7, 698.9, 596.2, 545.9, 491.2 and 463.0 cm ⁇ 1 .
- IR (Nujol): 3418.5, 3328.2, 3085.2, 3062.4, 2953.1, 2925.4, 2854.7, 1619.6, 1545.3, 1496.3, 1456.5, 1376.5, 1346.2, 1316.5, 1290.0, 1261.0, 1248.7, 1229.1, 1203.3, 1151.1, 1122.6, 1097.5, 1054.6, 1027.1, 975.9, 961.0, 920.3, 768.1, 721.8, 697.8, 595.7 and 545.4 cm ⁇ 1 .
- Crystalline form I of bimatoprost was characterized by powder x-ray diffractometry, DSC, IR DRIFTS (KBr), IR (KBr) and IR (Nujol) spectroscopy as set forth above and illustrated in FIGS. 1-5 .
- Bimatoprost with 98% purity contain 1% of 5-trans isomer (0.5 g) was crystallized from isopropylacetone (10 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.4 g (80% recovery) of bimatoprost crystalline form I as white powder with 99% purity (by HPLC), containing 0.6% of 5-trans isomer.
- Bimatoprost with 98.5% purity (by HPLC), contain 0.8% of 5-trans isomer (0.5 g) was crystallized from EtOAc (5 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C.
- bimatoprost crystalline form I as white powder with 99.3% purity (by HPLC), containing 0.5% of 5-trans isomer, 0.05% of 15R-isomer and 0.01% of 15-keto bimatoprost.
- Bimatoprost form A (prepared according to US2005/209337, 0.3 g) was crystallized from mixture of EtOAc (1.5 mL) and MTBE (3 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.25 g (83% recovery) of bimatoprost crystalline form I as white powder.
- Bimatoprost (0.4 g) was crystallized from mixture of MeOH (0.5 mL) and MTBE (10 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.3 g (75% recovery) of bimatoprost crystalline form I as white powder.
- Bimatoprost (0.5 g) was crystallized from mixture of t-BuOH (3 mL) and heptane (5 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.35 g (70% recovery) of bimatoprost crystalline form I as white powder.
- Bimatoprost (0.4 g) was crystallized from toluene (6 mL) as follows: dissolving the bimatoprost at 70° C., allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.38 g (95% recovery) of bimatoprost crystalline form I as white powder.
- Bimatoprost form A containing 2.5% (by HPLC) of 5-trans isomer (0.3 g) was crystallized from EtOAc (1.5 mL) and MTBE (3 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.25 g (83% recovery) of bimatoprost crystalline form I as white powder with 99.0% purity by HPLC, 0.8% trans-isomer.
- Bimatoprost (0.53 g) was crystallized from CH 2 Cl 2 (3.0 g) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) CH 2 Cl 2 (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.31 g (59% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.53 g) was crystallized from isobutyl methyl ketone (15.06 g) as follows: dissolving the bimatoprost at 60° C., allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) isobutyl methyl ketone (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.52 g (98% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.50 g) was crystallized from t-BuOMe (71.7 g) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) t-BuOMe (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.52 g (98% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.46 g) was crystallized from toluene (70.92 g) as follows: dissolving the bimatoprost at 70° C., allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) toluene (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.30 g (65% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.52 g) was crystallized from MeCN (10.6 g) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) MeCN (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.43 g (83% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.51 g) was crystallized from EtOAc (8.1 g) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) EtOAc (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.42 g (82% recovery) of bimatoprost crystalline form I.
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Abstract
The invention provides a novel polymorphic form I of crystalline bimatoprost, method for preparation thereof and new crystalline intermediates in the preparation. This form I of crystalline bimatoprost is used in purification of crude bimatoprost and in storage of bimatoprost as active pharmaceutical intermediate. Use of the physical form of bimatoprost in the manufacture of a medicament is also disclosed.
Description
- This application is a Continuation of U.S. patent application Ser. No. 11/896,002, filed Aug. 29, 2007 which claims priority of Israeli Application Number 177762, filed Aug. 29, 2006, which is hereby incorporated by reference in its entirety.
- The invention relates to novel polymorphic form I of crystalline bimatoprost, method for preparation thereof and new crystalline intermediates in the preparation. This form I of crystalline bimatoprost is used in purification of crude bimatoprost, and in storage of bimatoprost as active pharmaceutical intermediate. Use of the physical form of bimatoprost in the manufacture of a medicament is also disclosed.
- Elevated intraocular pressure (TOP) is the major risk factor associated with the etiology of glaucoma, a progressive optic neuropathy that can ultimately cause blindness. Prostamide analogs represent potent therapeutic agents in clinical management of glaucoma and other conditions associated with elevated intraocular pressure. The synthetic prostamide analog used to reduce IOP includes (9S,11R,15S)-9,11,15-trihydroxy-17-phenyl-18,19,20-trinor-5Z,13E-prostadienoic acid ethylamide
- known under international nonproprietary name bimatoprost, currently marketed by Allergan as Lumigan™—0.03% bimatoprost ophthalmic solution for the treatment of open-angle glaucoma and ocular hypertension (Drugs Aging, 2002, 19, 231).
- US2005/209337 discloses crystalline physical form of bimatoprost, which we designate as form A. The form is characterized by powder x-ray diffractometry, IR DRIFTS (KBr) spectroscopy, DSC and TGA. The present invention includes new polymorphic form of bimatoprost which is the most thermodynamically stable polymorph of bimatoprost and method for preparation thereof.
- The present invention provides crystalline form I of bimatoprost and method for preparation thereof. The new crystalline form of bimatoprost is the most stable solid form of bimatoprost. Moreover, the new form of bimatoprost may be prepared so as to be substantially free of other physical forms.
- The present invention also provides a method for purifying crude bimatoprost from related impurities, which comprises the steps of:
- a) dissolving crude bimatoprost in an organic solvent or a mixture of organic solvent and anti-solvent at or near the boiling point;
b) allowing the hot solution to cool;
c) separating the precipitate from the supernatant solution;
d) drying the resulting solid in vacuo at low temperature and then at 30 to 40° C. to give purified bimatoprost in crystalline form I. - The present invention also provides the use of bimatoprost crystalline form I in the manufacture of a medicament. The medicament is prepared by combining a therapeutically effective amount of bimatoprost crystalline form I, as an active ingredient, with conventional pharmaceutically-acceptable excipients, e.g. an ophthalmically-acceptable vehicle, and by preparation of unit dosage forms suitable for pharmaceutical use, e.g. topical ocular use.
- The present invention also provides new crystalline intermediate in the synthesis of bimatoprost-crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5a.
- The crystalline intermediate is useful for complete isolation of desired crystalline (3aR,4R,5R,6aS)-4-[3S-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5 as MTBE solvate
- from reaction mixture and for recovery of by-product.
-
FIG. 1 shows a characteristic x-ray powder diffraction pattern of bimatoprost crystalline form I, according to embodiments of the present invention. Vertical axis: intensity (counts per second); Horizontal axis: 20 (degrees). -
FIG. 2 shows the differential scanning calorimetry (DSC) curve of bimatoprost crystalline form I, according to embodiments of the invention. -
FIG. 3 shows the infrared spectrum (diffuse reflectance, DRIFTS) of bimatoprost crystalline form I in potassium bromide, according to embodiments of the invention. -
FIG. 4 shows the infrared spectrum of bimatoprost crystalline form I in potassium bromide, according to embodiments of the invention. -
FIG. 5 shows the infrared spectrum of bimatoprost crystalline form I in Nujol, according to embodiments of the invention. -
FIG. 6 shows the 1H nuclear magnetic resonance (NMR) spectrum of compound 5 MTBE solvate in CDCl3, according to embodiments of the invention. -
FIG. 7 shows a characteristic x-ray powder diffraction pattern of compound 5 MTBE solvate, according to embodiments of the present invention. Vertical axis: intensity (counts per second); Horizontal axis: 2θ (degrees). -
FIG. 8 shows the infrared spectrum (diffuse reflectance, DRIFTS) of compound 5 MTBE solvate in potassium bromide, according to embodiments of the invention. -
FIG. 9 shows the differential scanning calorimetry (DSC) curve of compound 5 MTBE solvate, according to embodiments of the invention. -
FIG. 10 shows the thermograviometric (TGA) curve of compound 5 MTBE solvate, according to embodiments of the invention. -
FIG. 11 shows the 1H nuclear magnetic resonance (NMR) spectrum of compound 5a in CDCl3, according to embodiments of the invention. -
FIG. 12 shows a characteristic x-ray powder diffraction pattern of compound 5a, according to embodiments of the present invention. Vertical axis: intensity (counts per second); Horizontal axis: 2θ (degrees). -
FIG. 13 shows the infrared spectrum (KBr) of compound 5a in potassium bromide, according to embodiments of the invention. -
FIG. 14 shows the differential scanning calorimetry (DSC) curve of compound 5a, according to embodiments of the invention. - US2005/209337 discloses crystalline physical form of bimatoprost, which we designate as form A. The present invention discloses, according to its first aspect, a new crystalline form of bimatoprost, which we designate as form I. Moreover, the bimatoprost crystalline form I may be prepared so as to be substantially free of other physical forms.
- The present invention provides a process for producing crystalline form I substantially free from other physical forms of bimatoprost by crystallization of bimatoprost in any physical form from an organic solvent or from a mixture of organic solvent and anti-solvent. Preferably, the crystallization comprises the steps of:
- a) dissolving crude bimatoprost in an organic solvent or a mixture of organic solvent and anti-solvent at or near the boiling point;
b) allowing the hot solution to cool;
c) separating the precipitate from the supernatant solution;
d) drying the resulting solid in vacuo at low temperature and then at 30 to 40° C. to yield bimatoprost crystalline form I substantially free from other physical forms. - The said organic solvent is selected from the group consisting of alcohols, esters, ketones, chloroorganic solvents, or mixture thereof. Preferably, said alcohols are selected from the group consisting of methanol, ethanol, isopropanol, butanol, isobutanol, t-butanol or mixture thereof. Preferably, said esters are selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate or mixture thereof. Preferably, said ketones are selected from the group consisting of acetone, methyl ethyl ketone, isopropylacetone or mixture thereof. Preferably, said chloroorganic solvents are selected from the group consisting of dichloromethane, chloroform, chlorobenzene or mixture thereof.
- The said anti-solvent is selected from the group consisting of hydrocarbons, ethers or mixture thereof. Preferably, the anti-solvent is saturated hydrocarbon. Preferably, said saturated hydrocarbon is selected from the group consisting of pentane, heptane, hexane, cyclohexane or mixture thereof. Preferably, said ethers are selected from the group consisting of diethyl ether, diisopropyl ether, MTBE or mixture thereof.
- A pure crystalline organic compound has, in general, a definite melting point range. The melting point is defined as the point at which the sample is entirely in the liquid phase. Bimatoprost crystalline form I has a characteristic melting point range determined by the capillary method from 62 to 64° C.
- Differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD) and infrared (IR) spectroscopy were used to characterize the new form.
- The DSC curve of form I (
FIG. 2 ) exhibits a melting endotherm at approximately 60-66° C. - Bimatoprost crystalline form I also exhibits distinctive x-ray powder diffraction pattern, as depicted in
FIG. 1 . The pattern has characteristic peaks expressed indegrees 20 at approximately 5.4±0.2, 10.9±0.2, 11.3±0.2, 13.7±0.2, 16.6±0.2, 17.5±0.2, 19.9±0.2, 20.7±0.2 and 22.7±0.2. - The crystalline form I was characterized by an infrared diffuse reflectance spectrum in potassium bromide as depicted in
FIG. 3 . The crystalline form I was further characterized by an infrared absorption spectrum carried out in potassium bromide and in Nujol as depicted inFIGS. 4 and 5 . - Bimatoprost crystalline form I is the most stable crystalline modification of bimatoprost in a temperature range between −70 and +30° C. Stability data supports the retest period of not less than 6 months if bimatoprost crystalline form I is stored in an appropriate container at 2 to 8° C. and at 25° C.
- The importance of bimatoprost crystalline form I rests primarily (but not exclusively) in its thermodynamic stability. Besides its greater stability, form I shows advantages with respect to form A because of the possibility of its preparation by crystallization employing different solvents in a wide temperature range. For example, the crystalline form I may be easily prepared by recrystallizing, triturating, or reslurring of crystalline form A.
- Crude non-crystalline bimatoprost may be prepared by amidation of bimatoprost acid 3
- with ethylamine optionally in the presence of carbodiimides. Preferably, the carbodiimides are selected from the group of N,N-dicyclohexylcarbodiimide (DCC) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC). Preferably, crude bimatoprost is prepared by reaction of bimatoprost acid methyl ester with ethylamine as described in US2004/171873, US2005/209337, US2005/154220 and U.S. Pat. No. 5,352,708.
- Methyl ester of
bimatoprost acid 2 - may be prepared by reacting of bimatoprost acid 3 with methylation agent MeY
wherein Y is a leaving group, in the presence of base. - Preferably, the methylation agent is methyl iodide, bromide, methanesulfonate, p-toluenesulfonate, 2,4-dinitrophenylsulfonate or triflate.
- Optionally, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preferably, the base is K2CO3. Most preferably, the base is cesium carbonate, hydrogencarbonate, hydroxide or fluoride or mixture thereof. If cesium alkali is used as base in the methylation reaction cesium salt of bimatoprost acid
- is obtained as intermediate in the reaction.
- Preferably, the methylation reaction of bimatoprost acid 3 is provided in the presence of solvent. Preferably, the solvent is aprotic organic solvent. More preferably, the solvent is polar organic solvent. For example, the polar organic solvent is N,N-dimethylformamide (DMF), N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone (NMP), dimethyl sulfoxide (DMSO), sulfolane or HMPA. Preferably the solvent is DMF.
- The bimatoprost
acid methyl ester 2 prepared by the reaction may be used in following amination reaction without purification; howeverester 2 may be purified by flash chromatography. Preferably the purification is provided by preparative LC on silica gel or Phenomenex™ Luna CN silica gel. - According to embodiment of the invention, the
bimatoprost acid 2 is prepared by Wittig reacting of lactol - with a metal salt of 5-(triphenylphosphoranylidene)pentanoic acid following by desilylation of intermediate protected bimatoprost acid.
- Preferably, the Wittig reaction is provided in the presence of aprotic organic solvent. More preferably, the solvent is ether-type solvent. Most preferably the solvent is THF. Analytical HPLC showed that crude bimatoprost acid 3 prepared by the Wittig reaction contains up to 5% of 5-trans isomer 3b.
- The lactol 4 may be prepared by reducing compound of formula
- wherein with i-Bu2AlH at temperature range from −80 to −50° C. Preferably, the reaction temperature range is −50 to +20° C., more preferably −30 to 0° C. To increase the yield of lactol 4 it is desirable to add i-Bu2AlH to lactone 5 at −50 to +20° C. (preferably at −30 to 0° C.) to attain about 95-99% conversion of lactone group. Preferably, the reaction is provided in the presence of aprotic organic solvent. More preferably, the solvent is toluene, CH2Cl2, THF, ether or mixture thereof.
- The process of the present invention for the synthesis of bimatoprost may be summarized by the
Scheme 1. Analytical HPLC showed thatcrude bimatoprost 1 prepared according toScheme 1 contains up to 5% of 5-trans isomer 1b (from the Wittig reaction). - In one embodiment of the invention, the lactone 5 is prepared by process comprising:
- reduction of the carbonyl group of ketone 7
- to yield a mixture of compounds of formulae 6 and 6a
- which are subsequently converted into a mixture of compounds 5 and
- followed by isolation of the compounds 5 and 5a from the mixture.
- The process for the synthesis of compound 5 from enone 7 may be summarized by the following Scheme 2:
- Basis of the synthesis is easy separation of lactone 5 as crystalline MTBE solvate from mixture of 5 and 5a isomers. The potential of the separation method may be illustrated by isolation of highly pure lactone 5 as MTBE solvate with 40% recovery and lactone 5a as solvent free crystalline compound with 33% recovery by serial of simple crystallizations of 1:1 mixture of 5 and 5a isomers from MTBE and hydrocarbon solvent.
- The reduction of the compound 6 may be carried out with any reagent capable to reduce ketone function to alcohol. An example of the reagent is NaBH4 or (i-PrO)3Al. Preferably the reduction of the compound 6 is carried out with (−)-B-chlorodiisopinocampheylborane or with borane in the presence of 2-alkyl-CBS-oxazaborolydines. More preferably the reduction is carried out with (−)-B-chlorodiisopinocamphenylborane in organic solvent. Preferably the organic solvent is THF, ether, 1,2-dimethoxyethane, toluene, hexane, CH2Cl2 or mixtures of these solvents.
- In another embodiment of the invention, the invention provides crystalline MTBE solvate of (3aR,4R,5R,6aS)-4-[3S-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5
- Crystalline MTBE solvate of lactone 5 has a characteristic melting point range determined by the capillary method from 60 to 64° C.
- Differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD) and infrared (IR) spectroscopy were used to characterize the new form.
- Crystalline lactone 5 MTBE solvate (
FIG. 9 ) exhibits a melting endotherm at approximately 60-66° C. - Crystalline lactone 5 MTBE solvate also exhibits distinctive x-ray powder diffraction pattern, as depicted in
FIG. 7 . The pattern has characteristic peaks expressed indegrees 20 at approximately 6.5±0.2, 7.1±0.2, 12.2±0.2, 12.5±0.2, 13.1±0.2, 13.6±0.2, 14.6±0.2, 15.0±0.2, 15.8±0.2, 16.2±0.2, 16.3±0.2, 17.0±0.2, 17.3±0.2, 18.0±0.2, 18.2±0.2, 18.8±0.2, 19.5±0.2, 19.7±0.2, 20.5±0.2, 20.8±0.2, 21.0±0.2, 21.8±0.2, 22.2±0.2, 23.0±0.2, 23.3±0.2, 24.2±0.2, 25.5±0.2, 26.5±0.2 and 26.7±0.2. - The crystalline lactone 5 MTBE solvate was characterized by an infrared diffuse reflectance spectrum in potassium bromide as depicted in
FIG. 8 . The crystalline lactone 5 - MTBE solvate was further characterized by 1H NMR spectrum carried out in CDCl3 as depicted in
FIG. 11 . - In another embodiment of the invention, the invention further provides crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5a.
- Crystalline lactone 5a has a characteristic melting point range determined by the capillary method from 93 to 94° C.
- Crystalline lactone 5a (
FIG. 14 ) exhibits a melting endotherm at approximately 83-97° C. - Crystalline lactone 5a also exhibits distinctive x-ray powder diffraction pattern, as depicted in
FIG. 12 . The pattern has characteristic peaks expressed indegrees 20 at approximately 5.7±0.2, 6.3±0.2, 14.0±0.2, 14.5±0.2, 14.8±0.2, 15.5±0.2, 16.3±0.2, 17.0±0.2, 17.5±0.2, 17.8±0.2, 18.1±0.2, 18.6±0.2, 18.9±0.2, 19.3±0.2, 21.5±0.2, 22.0±0.2, 22.4±0.2 and 23.8±0.2. - Lactone 5a was characterized by 1H NMR (CDCl3), powder x-ray diffractometry, DSC, and IR (KBr) spectroscopy as set forth above and illustrated in
FIGS. 11-14 . - Crystallinity of compounds 5 (as MTBE solvate) and 5a give very rare option to isolate the compounds in highly pure form with high yield from 5/5a 1:1 mixture by simple crystallization procedure.
- In another embodiment of the invention, it is proposed process for utilization of undesired compound 5a to compound 7 which process comprises the steps of converting compound 5a into compound 6a and oxidizing the hydroxyl group of the compound 6a.
- According to embodiment of the invention, the compound of the formula 7 may be prepared by Horner-Emmons-Wadsworth reaction of Corey aldehyde of
formula 8 - with a β-ketophosphonate BnCH2COCH2PO(OMe)2 in the presence of base. Preferably, the base is BuLi, NaH or Et3N/LiCl. More preferably, the base is alkali. For example the alkali is LiOH, NaOH, KOH, CsOH, Na2CO3, K2CO3 or Cs2CO3. Most preferably, the base is an aqueous alkali. Preferably, the Horner-Emmons-Wadsworth reaction is provided in the presence of organic solvents. For example, the solvent is CH2Cl2, CHCl3, toluene, THF, MTBE, ether or mixture thereof.
- According to embodiment of the invention,
Corey aldehyde 8 may be prepared by oxidation of (−)-Corey lactone 5-(4-phenylbenzoate) of formula 9 - The oxidation of (−)-Corey lactone 5-(4-phenylbenzoate) 9 may be carried out with any oxidizing system capable to oxidize primary alcohol to aldehyde. An example of the oxidizing system is CrO3/C5H5N, Cl2/PhSMe, DMSO/DCC/ft, or Dess-Martin reagent. Preferably, the oxidizing system is aq NaClO/TEMPO, more preferably aq NaClO/TEMPO/NaBr, most preferably NaClO/TEMPO/NaBr/1-PrOH.
- The process for the synthesis of enone 7 from (−)-Corey lactone 5-(4-phenylbenzoate) 9 may be summarized by the following Scheme 3:
- The major related impurities in bimatoprost that can be formed during synthesis or storage of bimatoprost, included the following:
- methyl ester of bimatoprost acid 2:
- bimatoprost acid 3:
- 5-trans bimatoprost 1b:
- 15(R) bimatoprost 1a:
- 15-keto bimatoprost 1c:
- As mentioned above, impurities 5-trans bimatoprost 1b, 15R-bimatoprost 1a, 15-keto bimatoprost 1c could be formed during synthesis or storage of bimatoprost. These compounds were synthesized as analytical markers for HPLC analysis and characterized. We prepared 15R-bimatoprost 1a from lactone 5a according to Scheme 4.
- 5-trans Bimatoprost 1b was prepared from
methyl ester 2 according to Scheme 5. - The key step of the synthesis is isomerisation of
methyl ester 10 to its 5-trans isomer 11 by irradiation in the presence of Ph2S. - 15-keto Bimatoprost 1c was prepared by selective oxidation of 15-hydroxy group of bimatoprost.
- It has been found that the 5-trans and 15R-isomers of bimatoprost are particularly difficult to remove because they have similar physical and chemical properties to bimatoprost. We found that it is possible to separate of bimatoprost from the impurities using an HPLC purification system. However the HPLC purification is expensive and is not practical for large scale separations.
- These problems have been solved by the use of crystalline form I in purification of bimatoprost. The present invention provides a method for purifying crude bimatoprost from related impurities, which comprises the steps of:
- a) dissolving crude bimatoprost in an organic solvent or a mixture of organic solvent and anti-solvent under reflux conditions;
b) allowing the hot solution to cool;
c) separating the precipitate from the supernatant solution;
d) drying the resulting solid in vacuo at low temperature and then at 30 to 40° C. to give bimatoprost crystalline form I with desired LC purity. - By using the process of the present invention, it has been found possible to produce bimatoprost that is substantially free of 15R- and 5-trans isomers of bimatoprost. Using the process of the present invention, bimatoprost containing less than 0.2% each of 15R- and 5-trans isomers can be produced. In particular, bimatoprost containing less than 0.1% each of 15R- and 5-trans isomers can be produced. Preferably, bimatoprost containing less than 0.05% each of 15R- and 5-trans isomers can be produced.
- The above processes thus enable bimatoprost having an extremely high degree of purity can be obtained, e.g. greater than 98% pure, greater than 99% pure, greater than 99.5% pure. Indeed, it has been found possible to achieve bimatoprost purities of greater than 99.8%.
- The present invention also provides the use of bimatoprost crystalline form I in the manufacture of a medicament. The medicament is prepared in two steps, preparation of a composition containing bimatoprost and manufacture of unit dosage forms suitable for pharmaceutical use, e.g. topical ocular use. Preferably, the composition is prepared by combining a therapeutically effective amount of bimatoprost crystalline form I, as an active ingredient, with conventional pharmaceutically-acceptable excipients, e.g. an ophthalmically-acceptable vehicle. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations.
- In addition to the above-described principal active ingredients, the compositions of the present invention may further comprise various formulatory ingredients, such as ophthalmically acceptable diluents, buffers, hydrochloric acid, sodium hydroxide, antimicrobial preservatives, stabilizers, tonicity adjustors, viscosity-enhancing agents, chelating agents, antioxidants, surfactants and/or solubilizers and combinations thereof.
- Preferably, the diluent is purified water.
- Preservatives are used in multi-use ophthalmic formulations to prevent microbial contamination of the composition after the packaging has been opened. A number of preservatives have been used including quaternary ammonium salts, mercury compounds, alcohols and stabilized chlorine dioxide. Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, phenylmercuric nitrate, Polyquad™.
- Viscosity-enhancing agents may be added as needed or convenient. They include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, polyethylene glycol, or combinations thereof.
- Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, dextrose, propylene glycol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
- Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Hydrochloric acid or sodium hydroxide may be used to adjust the pH of these formulations as needed.
- Preferred surfactants are, for example, polyethoxylated castor oil,
Tween 80, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose and hydroxyethyl cellulose cyclodextrin. - Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
- The following abbreviations are used:
- Bn=benzyl;
br.=broad;
Bu=n-butyl;
i-Bu=i-butyl;
d=doublet;
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene;
i-Bu2AlH=diisobutylaluminium hydride; - DMSO=dimethyl sulfoxide;
DRIFTS=diffuse reflectance infrared Fourier-transform spectrum (spectroscopy);
DSC=differential scanning calorimetry;
FT-IR=Fourier-transform infrared;
GC=gas chromatography;
HPLC=high performance liquid chromatography;
HMPA=hexamethylphosphoramide; - IOP=intraocular pressure;
i-PrOH=isopropanol;
IR=infrared;
LC=liquid chromatography;
m=multiplet;
MTBE=tert-butyl methyl ether;
NMT=not more than;
NMP=1-methyl-2-pyrrolidinone;
NMR=nuclear magnetic resonance;
PPB=4-phenylbenzoyl;
PPTS=pyridinium p-toluenesulfonate;
rt=room temperature;
s=singlet;
t=triplet;
THF=tetrahydrofuran;
TGA=thermogravimetric analysis; - XRPD=x-ray powder diffraction.
- The following example is illustrative, but not limiting, of the methods of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in chemical synthesis and which are obvious to those skilled in the art are within the spirit and scope of the invention.
- All reagents and solvents were purchased from Aldrich Chemical Company unless specified otherwise and used without further purification. All reactions were provided under argon or nitrogen atmosphere.
- The LC purity was determined by separating a sample by High performance liquid chromatography (HPLC) and calculating the area percentage thereof of each peak. The chromatographic analysis of bimatoprost is based on a chiral reversed-phase HPLC method with an optically active tris(3,5-dimethylphenylcarbamate) of cellulose immobilized on silica support stationary phase and a mobile phase buffered at pH 4.5. HPLC method was carried out using a 10 μm Chiralpak™ OD-R 250×4.6 mm column (Diacel). Diluent—mixture A/B 25:75, sample concentration—about 0.5 mg per 1 mL, injection volume—20 μL; a mobile phase—gradient A/B 25:75 for 0 min, 25:75 for 25 min, 35:65 for 35 min, 35:65 for 60 min, 25:75 for 65 min, 25:75 for 80 min wherein A is MeCN and B is Et3N (1.0 mL) solution in water (1 L), pH adjusted with 85% H3PO4 up to 4.5. Column temperature 35° C.; a flow rate of 0.7 mL/min; and a UV detector at 200 nm.
- NMR spectra were recorded on a Bruker AM-200 (1H at 200 MHz, 13C at 50 MHz) and Bruker AM-400 (1H at 400 MHz) instruments using CDCl3 (unless otherwise stated) as a solvent, and chemical shifts are in 6 (ppm) relative to internal TMS.
- Infrared (IR) absorption spectra were obtained by Nicolet Impact 410 FT-IR spectrophotometer using a dispersion of solid sample material in KBr or Nujol. Infrared DRIFTS spectra were obtained by Nicolet Impact 410 FT-IR spectrophotometer equipped with Pike Technologies EasiDiff Diffuse Reflectance Accessory using a dispersion of solid sample material in KBr.
- Powder x-ray diffraction patterns were obtained by methods known in the art using PANALYTICAL (Philips) X'Pert Pro MPD x-ray powder diffraction system (CuKα radiation, PW3050/60 goniometer, PW3015/20 X'Celerator detector). The Bragg-Brentano scheme was used for beam focusing.
- Melting points were determined in open capillary tubes with Buchi B-545 capillary melting point apparatus or Mettler-Toledo FP-900 Thermosystem with FP-81 HT Melting Point Cell and FP-90 central processor, or Electrothermal IA 9300 digital melting point apparatus, and are uncorrected. The melting points generally depend on the purity level of the samples. Typically, bimatoprost crystalline form I has been found to have a melting point between 62 and 64° C.
- Measurements of difference between the temperature of a sample and a reference pan that are subject to the same temperature program (differential scanning calorimetry, DSC) were obtained on a Mettler-Toledo DSC 822e Differential Scanning calorimeter.
-
- A solution of (−)-Corey lactone 5-(4-phenylbenzoate) 9 (17.6 g, 50.0 mmol) and TEMPO (0.16 g, 1.0 mmol) in CH2Cl2 (100 mL) was added to a solution of NaBr (0.5 g, 5.0 mmol), NaHCO3 (12.6 g, 150.0 mmol) and IPA (6.0 g, 100.0 mmol) in water (100 mL). 5% aq. NaOCl (about 150 mL) was added dropwise to the stirred mixture at −5 to 0° C. until disappearance of Corey lactone (TLC monitoring). The obtained mixture was stirred for 0.5 h at the same temperature. The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic layers was added dropwise over 1 h to a stirred mixture of a solution of BnCH2COCH2PO(OMe)2 (15.4 g, 60.0 mmol) in CH2Cl2 (20 mL) and 30% NaOH (8.0 g, 60.0 mmol) at 0-5° C. The mixture was stirred 0.5 h at the same temperature and treated with 10% aq. citric acid (100 mL). The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered through short silica gel column and concentrated in vacuo. The oily residue (24.2 g) was dissolved in refluxed EtOH (150 mL) and cooled in ice bath. The precipitate was filtered off, washed with cold EtOH and dried in vacuo to give 20.1 g (84%) of ketone 7 with 99.4% purity by HPLC: mp 129-130° C., [α]20 D −142° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 2.32-2.63 (m, 3H); 2.84-2.97 (m, 7H); 5.00-5.10 (m, 1H); 5.20-5.35 (m, 1H); 6.20 (d, J=16 Hz, 1H); 6.65 (dd, J=16 and 8 Hz, 1H); 7.15-7.67 (m, 12H); 8.03 (d, J=8 Hz, 2H).
-
- A solution of (−)-DIP-Chloride™ (77.0 g, 0.24 mol) in CH2Cl2 (150 mL) was added dropwise during 2 h to a stirred solution of ketone 7 (57.7 g, 0.12 mol) in CH2Cl2 (300 mL) at −25 to −30° C. The mixture was stirred overnight at the same temperature and treated with MeOH (100 mL) at rt. The obtained mixture was stirred for 0.5 h and washed with 20% aq. NH4Cl (250 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from MeOH to give 49.8 g (86%) of mixture alcohols 6 and 6a with 6/6a ratio about 97:3 by HPLC.
-
- A mixture of alcohols 6 and 6a with 6/6a ratio about 97:3 by HPLC (15.4 g, 32.0 mmol), CH2Cl2 (75 mL), t-BuMe2SiCl (7.2 g, 48.0 mmol) and imidazole (6.5 g, 96.0 mmol) was refluxed for 1 h and mixed with 10% aq. citric acid (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered through the column with silica gel (30 g) and concentrated in vacuo. The residue was crystallized from MTBE to give 16.2 g (76%) of (3aR,4R,5R,6aS)-4-[3S-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5 as MTBE solvate with 99.8% purity by HPLC: mp 60-64° C.; [α]20 D −84° (
c 1, MeCN); 1H NMR (CDCl3) δ 8.04 (d, J=8 Hz, 2H), 7.60 (m, 4H), 7.42 (m, 3H), 7.15 (m, 5H), 5.58 (m, 2H), 5.22 (q, J=5.5 Hz, 1H), 5.01 (t, J=5.5 Hz, 1H), 4.12 (q, J=5.5 Hz, 1H), 3.18 (s, 3H), 2.69 (m, 7H), 2.20 (m, 1H), 1.79 (m, 2H), 1.17 (s, 9H), 0.85 (s, 9H), −0.02 (d, J=12 Hz, 6H). - The x-ray powder diffraction pattern of crystalline MTBE solvate of compound 5 has characteristic peaks expressed in
degrees 20 at approximately 6.5, 7.1, 12.2, 12.5, 13.1, 13.6, 14.6, 15.0, 15.8, 16.2, 16.3, 17.0, 17.3, 18.0, 18.2, 18.8, 19.5, 19.7, 20.5, 20.8, 21.0, 21.8, 22.2, 23.0, 23.3, 24.2, 25.5, 26.5 and 26.7. - IR DRIFTS (KBr): 2949, 2931, 2854, 1765, 1715, 1607, 1361, 1266, 1203, 1170, 1118, 1095, 1080, 972, 912, 852, 839, 775, 745, and 699 cm−1.
- Compound 5 MTBE solvate was characterized by 1H NMR (CDCl3), powder x-ray diffractometry, IR DRIFTS (KBr) spectroscopy, DSC and TGA as set forth above and in
FIGS. 6 , 7, 8, 9 and 10. -
- NaBH4 (1.7 g, 44 mmol) was added in three portions to a stirred mixture of ketone 7 (21.0 g, 43.7 mmol), CH2Cl2 (125 mL) and MeOH (125 mL) at 0-4° C. during 1 h. The obtained mixture was stirred for 1 h at 0-4° C. and concentrated in vacuo. A mixture of the residue, CH2Cl2 (200 mL) and 5% NaHCO3 (100 mL) was stirred for 1 h at 25° C. The aqueous phase was separated and extracted with CH2Cl2 (50 mL). The combined organics were washed with 5% NaHCO3 (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 20.0 g (95%) of mixture 6 and 6a with ratio 6/6a ˜1:1.
- A solution of the residue (20.0 g, 41.4 mmol) and imidazole (4.3 g, 62.2 mmol) in CH2Cl2 (200 mL) was treated with a solution of t-BuMe2SiCl (7.5 g, 49.7 mmol) in CH2Cl2 (30 mL). The resulted suspension was refluxed for 2 h, cooled to 10° C. and quenched by addition of 10% aq citric acid (60 mL). The phases were separated, the organic one was washed with water (100 mL) and 10% NaHCO3 (30 mL), dried over Na2SO4, filtered and passed through silica gel (30 g). The column was washed with CH2Cl2 (300 mL) and the combined filtrates were evaporated under reduced pressure to give 25.0 g of mixture 5 and 5a with ratio 5/5a ˜1:1. The residue (25 g) was crystallized from MTBE (100 mL) to give 9.3 g of crude lactone 5 MTBE solvate (0.6% of 5a) as white solid. The crude product was re-crystallized from MTBE (80 mL) affording 8.5 g (30% from ketone 7) of lactone 5 MTBE solvate (0.02% of 5a) as white crystalline powder. mp 60-64° C.; [α]20 D −84° (
c 1, MeCN). - All filtrates were combined and concentrated in vacuo. A mixture of the residue (18.0 g), heptane (165 mL) and toluene (15 mL) was stirred for 0.5 h at 70° C. and for 12 h at rt. The precipitate was filtered off, washed with heptane on the filter and dried in vacuo to give 8.0 g of crude lactone 5a preferably (4% of 5). Two additional crystallizations of the crude product afforded 6.0 g (24% from ketone 7) of lactone 5a as white crystalline powder with 99.7% purity (0.2% of 5) by HPLC, mp 93-94° C. and [α]D 20 −92° (
c 1, CHCl3). - All filtrates were combined again, evaporated and treated as described above to give additionally 2.8 g (10% from ketone 7) of lactone 5 MTBE solvate and 2.2 g (9% from ketone 7) of lactone 5a. Total 11.3 g (40% from ketone 7) of lactone 5 MTBE solvate and 8.2 g (33% from ketone 7) of lactone 5a was prepared.
- (3aR,4R,5R,6aS)-4-[3S-(t-Butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one MTBE solvate was characterized by 1H NMR (CDCl3), powder x-ray diffractometry, IR DRIFTS (KBr) spectroscopy, DSC and TGA as set forth above and in
FIGS. 6-10 . - (3a R,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5a: H1 NMR (200 MHz) δ 8.00 (d, 2H, J 8.3 Hz), 7.58 (m, 4H), 7.35 (m, 3H), 7.15 (m, 3H), 7.06 (t, 2H, J 7.1 Hz), 5.60 (m, 2H), 5.22 (dd, 1H, J1 6.1 Hz, J2 12.0 Hz), 5.04 (dd, J1 4.3 Hz, J2 12.0 Hz), 4.11 (q, 1H, J 5.8 Hz), 2.85-2.44 (m, 7H), 2.20 (m, 1H), 1.73 (m, 2H), 0.85 (m, 9H), −0.02 (d, 6H, J 7.3 Hz).
- The x-ray powder diffraction pattern of crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5a has characteristic peaks expressed in
degrees 20 at approximately 5.7, 6.3, 14.0, 14.5, 14.8, 15.5, 16.3, 17.0, 17.5, 17.8, 18.1, 18.6, 18.9, 19.3, 21.5, 22.0, 22.4 and 23.8. IR (KBr): 3428.8, 3061.1 3027.7, 2952.1, 2928.7, 2884.0, 2855.8, 1761.7, 1714.4, 1608.2, 1487.6, 1471.1, 1454.3, 1404.6, 1360.1, 1313.0, 1276.0, 1181.3, 1114.1, 1082.5, 1061.0, 1006.6, 974.3, 901.8, 869.0, 836.1, 776.6, 748.2, 698.6, and 670.0 cm−1. - Lactone 5a was characterized by 1H NMR (CDCl3), powder x-ray diffractometry, DSC, and IR (KBr) spectroscopy as set forth above and illustrated in
FIGS. 11-14 . -
- A solution of (−)-DIP-Chloride™ (282.3 g, 0.88 mol) in CH2Cl2 (500 mL) was added dropwise during 2 h to a stirred solution of ketone 7 (210.0 g, 0.44 mol) in CH2Cl2 (1.6 L) at −25 to −30° C. The mixture was stirred 12 h at the same temperature, heated to −3° C. and treated with 10% aq. NH4Cl (400 mL). The obtained mixture was stirred for 1 h at rt. The aqueous layer was separated and extracted with CH2Cl2 (2×150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to a half of volume. A mixture of the residue and imidazole (179.8 g, 2.64 mol) was treated with a solution of t-BuMe2SiCl (265.3 g, 1.76 mol) in CH2Cl2 (500 mL). The resulted suspension was refluxed for 2 h, cooled to 10° C. and quenched by addition of 10% aq citric acid (1.5 L). The phases were separated, the organic one was washed with water (300 mL) and 10% NaHCO3 (300 mL), dried over Na2SO4, filtered and passed through silica gel (250 g). The column was washed with CH2Cl2 (2 L) and the combined filtrates were evaporated under reduced pressure. The residue (350 g) was crystallized from MTBE (2.4 L) to give 232.0 g of crude lactone 5 MTBE solvate (0.6% of 5a) as white solid. The crude product was re-crystallized from MTBE (2 L) affording 217 g (72% from ketone 7) of lactone 5 MTBE solvate (0.02% of 5a) as white crystalline powder.
-
- Method A. A mixture of compound 5 MTBE solvate (0.69 g, 1.2 mmol), 1 M solution of Bu4NF in THF (1.4 mL, 1.4 mmol) and THF (4 mL) was stirred for 3 h at rt and treated with water (20 mL). The obtained mixture was extracted with MTBE. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from MeOH to give alcohol 6 as white crystals with mp 126-128° C.: 1H NMR (CDCl3) is in agreement with the structure.
- Method B. A mixture of compound 5 MTBE solvate (1.0 g, 1.7 mmol), 32% HCl (0.1 mL, 0.3 mmol) and MeOH (6 mL) was stirred for 2 h at 40° C. and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold MeOH and dried in vacuo to give alcohol 6 as white crystals.
-
- Cleavage of silyl-protective group of compound 5a following by column chromatography purification on silica gel gives alcohol 6a as white crystals with mp 81-83° C. (Et2O/hexane): [α]D 20 −124.5° (
c 1, MeCN); 1H NMR (CDCl3) δ: 7.08-8.05 (m, 14H); 5.51-5.74 (m, 2H); 5.21-5.30 (m, 1H); 5.02-5.07 (m, 1H); 4.09-4.13 (m, 1H); 2.46-2.92 (m, 7H); 2.18-2.28 (m, 1H); 1.66-1.86 (m, 3H). 13C(CDCl3) δ: 31.6; 34.8; 37.6; 38.7; 42.7; 54.1; 71.6; 79.0; 83.1; 125.9; 127.1; 127.2; 128.2; 128.3; 128.8; 128.9; 130.1; 136.2; 139.9; 141.5; 146.1; 165.9; 176.2. -
- Method A. A solution of C5H5N.SO3 (0.32 g) in DMSO (3.5 mL) was added dropwise to a stirred solution of alcohol 6a (0.30 g) and Et3N (0.40 g) in CH2Cl2 (4 mL) at −5 to 0° C. The mixture was stirred at the same temperature for 1 h (TLC monitoring) and poured into cold water (15 mL). The mixture was stirred for 10 min at 0-5° C. The organic layer was separated, the water layer was extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with brine (3×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. A solution of the residue in MeOH (1 mL) was cold to −10° C. and kept at the same temperature for 3 h. The precipitated crystals were filtered, washed on filter with cold MeOH (2×1 mL) and dried under reduced pressure to a constant weight to give 0.26 g (87% yield) of crude ketone 7 with 94% purity by HPLC. The crude ketone 7 was recrystallizated from MeOH gave crystalline ketone 7 with mp 134-135° C. and [α]D 20 −141.7° (c 1.26, MeCN).
- Method B. 5% aq. NaOCl (40 mL, TLC monitoring) was added dropwise to a stirred mixture of alcohol 6a (0.53 g, 1.1 mmol), TEMPO (4 mg, 0.025 mmol), NaBr (12 mg, 0.12 mmol), NaHCO3 (0.3 g, 3.6 mmol), CH2Cl2 (3 mL) and water (3 mL) at rt and the mixture was stirred for 1 h. The aqueous layer was separated and extracted with CH2Cl2 (3 mL). The combined organic layer was dried over Na2SO4 and filtered trough short silica gel column. The residue was concentrated in vacuo and crystallized from MeOH (5 mL) to give 0.37 g (70%) of ketone 7.
-
- i-Bu2AlH (20% w/w solution in toluene, 59.5 mL, 72 mmol) was added dropwise to a stirred solution of lactone 5 MTBE solvate (15.0 g, 21.8 mmol) in toluene (100 mL) at −25 to −20° C. The mixture was stirred for 1 h at the same temperature, heated to −10° C. and quenched by slow addition of 10% aq citric acid (210 g, 109 mmol) keeping reaction temperature below 20° C. The resulted suspension was stirred for 1 h at rt until most of solids disappeared. The aqueous phase was separated and extracted with toluene (50 mL). The combined organics were washed with 5% NaHCO3 (50 mL), dried over Na2SO4, filtered and passed through silica gel column (80 g). The column was eluted with CH2Cl2 (1 L) and then with the mixture CH2Cl2/EtOAc 1:1 (1 L), the fractions containing lactol 4 were combined and concentrated in vacuo to give 9.0 g (99%) of lactol 4 with 98.5% purity by HPLC.
-
- i-Bu2AlH (20% w/w in toluene, 50 mL, 60.0 mmol) was added dropwise to a stirred solution of lactone 5a (10.74 g, 18.0 mmol) in toluene (70 mL), at −25 to −15° C. The mixture was stirred at the same temperature for 2 h, then heated to −10° C. and quenched by slow addition of 10% aq citric acid (173 mL, 90.0 mmol). The resulted mixture was stirred for 1 h at rt until the most of solids were disappeared. The aqueous phase was separated and extracted with toluene (50 mL). The combined organics were washed with 5% NaHCO3 (50 mL), dried over Na2SO4, filtered and passed through silica gel column (60 g). The column was eluted with CH2Cl2 (1 L) and then with the mixture CH2Cl2/EtOAc 1:1 (1 L), the fractions containing the lactol 4a were combined and concentrated in vacuo to give 7.5 g (%) of lactol 4a as viscous oil with 98.5% purity by HPLC.
-
- t-BuOK (19.4 g, 172.0 mmol) was added in three portions to a mixture of HOOC(CH2)4PPh3 + Br− (38.3 g, 86.0 mmol) and THF (mL) at −5 to 0° C. The obtained mixture was stirred for 0.5 h at the same temperature and a solution of lactol 4 (9.0 g, 21.5 mmol) in dry THF (50 mL) was slowly added. The mixture was stirred for 10 h at 0 to 5° C. and quenched by addition of water (200 mL). The pH of the mixture was adjusted to 7.5-8.0 with 20% aq citric acid, most of THF was evaporated in vacuo and extracted with MTBE (3×150 mL). The combined organics were washed with 5% NaHCO3 (adjusted to
pH 8 with 20% aq citric acid, 2×100 mL) and brine, and concentrated in vacuo. The residue was dissolved in MeOH (80 mL), the solution was cooled to 0° C., and 3 N HCl (21.5 mL, 64.5 mmol) was slowly added keeping reaction temperature below 10° C. The resulted mixture was stirred for 5 h at 0 to 5° C. and quenched by addition of 10% NaOH (44 g, 110 mmol). The mixture was stirred for 1 h at 40° C., most of MeOH was evaporated in vacuo and the aqueous phase was extracted with MTBE (4×70 mL). The combined organics were washed with 10% NaOH (40 mL), the aqueous layers were combined and acidified to pH 3.5-4.5 with 20% aq citric acid. The resulted mixture was extracted with MTBE (3×100 mL), the combined organics were washed with brine, dried over Na2SO4, filtered and passed through silica gel column (45 g). The column was eluted with MTBE (500 mL) and EtOAc (800 mL), the fractions containing bimatoprost acid were combined and concentrated in vacuo to give 7.5 g (90%) of bimatoprost acid 3 as slight yellow semisolid mass. Analytical HPLC showed that the product contained about 3.5% of the 5-trans isomer (from the Wittig reaction). -
- t-BuOK (16.2 g, 144.0 mmol) was added in three portions to a stirred mixture of HOOC(CH2)4PPh3 + Br− (31.9 g, 72.0 mmol) and THF (mL) at −5° C. The mixture was stirred for 0.5 h at −3° C. and a solution of lactol 4a (7.5 g, 18.0 mmol) in dry THF (50 mL) was slowly added. The mixture was stirred for 10 h at 0° C. and quenched by addition of water (200 mL). The pH of the mixture was adjusted to 7.5-8.0 with 20% aq citric acid, the most of THF was evaporated and the aqueous mixture was extracted with MTBE (3×120 mL). The combined organics were washed with 5% NaHCO3 (adjusted to pH 7.7-8.0 with 20% aq citric acid, 2×30 mL) and brine and concentrated in vacuo. A solution of the residue in MeOH (50 mL) was treated with 3 N HCl (15 mL) at 0° C. The resulted mixture was stirred for 4 h at 0-4° C. and quenched by addition of 10% NaOH (44 mL). The mixture was stirred for 1 h at 40° C., the most of MeOH was evaporated in vacuo and the aqueous phase was extracted with MTBE (4×70 mL). The combined organics were washed with 10% NaOH (30 mL), the aqueous layers were combined and acidified to pH 3.5-4.5 with 20% aq citric acid. The resulted mixture was extracted with MTBE (3×100 mL), the combined organics were washed with brine, dried over Na2SO4, filtered and passed through silica gel column (60 g). The column was eluted with CH2Cl2 (300 mL), CH2Cl2/EtOAc 1:1 (300 mL) and EtOAc (600 mL), the fractions containing 3a were combined and concentrated in vacuo to give 4.6 g (65%) of 15R-bimatoprost acid 3a as yellow oil.
-
- A mixture of bimatoprost acid 3 (7.5 g, 19.3 mmol), MeI (1.8 mL, 29.0 mmol), Cs2CO3 (7.6 g, 23.2 mmol) and DMF (50 mL) was stirred for 4 h at 0 to 4° C., acidified to pH 4 with 3% aq citric acid, heated to rt and extracted with MTBE (3×70 mL). The combined organics were washed with 5% NaHCO3 (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 7.6 g (98%) of
ester 2 as oil. -
- A mixture of acid 3a (4.3 g, 11.0 mmol), MeI (2.3 g, 16.0 mmol), Cs2CO3 (5.2 g, 16.0 mmol) and DMF (30 mL) was stirred for 4 h at 0-4° C., acidified to pH 4 with 3% aq citric acid (120 mL), heated to rt and extracted with MTBE (3×40 mL). The combined organics were washed with 5% NaHCO3 (50 mL), dried over Na2SO4, filtered and concentrated in vacuo The residue was purified by chromatography on silica gel (30 g, eluted with CH2Cl2, CH2Cl2/EtOAc 1:1, 300 mL and then EtOAc 600 mL) to give 4.0 g (91%) of ester 2a as oil.
-
- A mixture of ester 2a (3.0 g, 7.5 mmol), 70% aq EtNH2 (15 mL, 189 mmol) and MeOH (15 mL) was stirred for 72 h at rt in well-closed flask and concentrated in vacuo. The oil residue was portioned between EtOAc (100 mL) and water (60 mL). The aqueous phase was separated and extracted with EtOAc (30 mL). The combined organics were washed with 10% NaHCO3 (2×30 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on a silica gel column (30 g, eluted with EtOAc then EtOAc/MeOH 10:1) to give 2.4 g (79%) of 15R-bimatoprost 1a as light yellow viscous oil.
-
- A mixture of ester 2a (3.30 g, 8.2 mmol), imidazole (5.58 g, 82.0 mmol) and t-BuMe2SiCl (6.18 g, 41.0 mmol) in DMF (20 mL) was stirred overnight at rt and the reaction was quenched by addition of 10% aq citric acid (100 mL). The mixture was extracted with MTBE (3×30 mL), the combined organics were washed with a 10% NaHCO3 (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on a silica gel (70 g, eluted with heptane, then heptane/EtOAc 10:1) to give 6.01 g (98%) of
ester 10 as light oil. -
- A mixture of ester 10 (6.00 g, 8.0 mmol) and Ph2S2 (0.35 g, 0.16 mmol) in toluene (60 mL) was irradiated with 400W halogen lamp under reflux conditions for 8 h and concentrated in vacuo. The residue was purified on a silica gel (70 g, eluted with heptane, then heptane/EtOAc 10:1) to give 5.51 g of mixture trans- and cis-isomers with ratio about 4 to 1. This mixture was separated on a silica gel modified with AgNO3 (24.0 g of AgNO3 on 200.0 g of silica gel, eluted with heptane then heptane/toluene 50:1) to give 3.85 g (70%) of ester 11 as transparent viscous oil.
-
- A mixture of ester 2b (3.73 g, 5.0 mmol) and Bu4NF (1 M solution in THF, 25 mL, 25.0 mmol) was stirred 14 h at rt and concentrated in vacuo. A solution of the residue in CH2Cl2 was washed with 10% aq citric acid, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on a silica gel (30 g, eluent CH2Cl2, then CH2Cl2/EtOAc 1:1) to give 1.65 g (82%) of ester 2b.
-
- A solution of ester 2b (1.21 g, 3.0 mmol) in the mixture of MeOH (8 mL) and 70% aq EtNH2 (8 mL, 101 mmol) was stirred in the well-closed flask for 72 h at rt. The volatiles were removed under reduced pressure and the oil residue was dissolved in CH2Cl2 and purified on a silica gel (30 g, eluent EtOAc then EtOAc/MeOH 10:1) to give 1.03 g (83%) of 5-trans bimatoprost 1b as light yellow viscous oil.
-
- A mixture of bimatoprost 1 (0.33 g, 0.8 mmol), DDQ (0.68 g, 3.0 mmol), CH2Cl2 (5 mL) and 1,4-dioxane (5 mL) was stirred for 24 h at 40° C. and evaporated in vacuo. The residue was purified by chromatography on a silica gel (20 g, eluent EtOAc then EtOAc/MeOH 20:1) to give 0.21 g (63%) of 15-keto bimatoprost 1c as yellow oil.
-
- A mixture of ester 2 [9.0 g, 22.4 mmol, contain (by HPLC) 3.5% of 5-trans isomer], 70% aq EtNH2 (40 mL, 503 mmol) and MeOH (45 mL) was stirred in a well closed flask at 24 to 27° C. for 72 h and concentrated in vacuo. The residue was portioned between EtOAc (100 mL) and water (60 mL). The phases were separated, the aqueous one was extracted with EtOAc (30 mL) and the combined organics were washed with 10% NaHCO3 (2×30 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo to give 8.0 g (86%) of crude bimatoprost containing 3.5% (by HPLC) of 5-trans isomer 1b. The crude bimatoprost was crystallized from a mixture of EtOAc (27 mL) and MTBE (54 mL) as follows: dissolving the crude bimatoprost at or near the boiling point and allowing the hot solution to cool to rt. Additional MTBE (40 mL) was added and the mixture was stirred for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold MTBE (2×20 mL) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 7.5 g (80%) of bimatoprost crystalline form I as white solid with 98% purity by HPLC, less than 1% of 5-trans isomer 1b. The bimatoprost (7.5 g) was crystallized from EtOAc (75 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 6.7 g (90% recovery) of bimatoprost crystalline form I as white powder with 99% purity by HPLC, 0.6% 5-trans isomer 1b, NMT 0.1% of 15R-isomer 1a, and NMT 0.1% of 15-keto bimatoprost 1c; mp 64-66° C.; [α]D 20+36° (
c 1, MeOH). - The x-ray powder diffraction pattern of bimatoprost crystalline form I has characteristic peaks expressed in
degrees 20 at approximately 5.4, 6.2, 10.9, 11.3, 13.7, 16.6, 17.5, 18.3, 18.6, 18.9, 19.4, 19.7, 19.9, 20.7, 20.9, 21.6, 22.7 and 28.2. - IR DRIFTS (KBr): 3426.6, 3390.7, 3320.8, 3083.3, 3059.3, 3010.8, 2911.8, 2863.8, 1618.1, 1544.8, 1495.6, 1453.5, 1370.0, 1344.6, 1316.0, 1289.1, 1259.9, 1247.9, 1150.6, 1096.4, 1053.4, 1026.3, 975.0, 919.7, 767.4, 746.0, 728.1, 697.7, 607.2 and 597.6 cm−1.
- IR (KBr): 3414.9, 3326.6, 3085.5, 3025.1, 3011.5, 2929.6, 2914.2, 2864.9, 1644.8, 1619.2, 1546.2, 1496.2, 1454.6, 1372.9, 1346.0, 1317.3, 1290.4, 1260.9, 1249.3, 1229.4, 1203.6, 1151.9, 1097.2, 1054.5, 1028.6, 975.4, 920.5, 767.6, 747.5, 721.7, 698.9, 596.2, 545.9, 491.2 and 463.0 cm−1.
- IR (Nujol): 3418.5, 3328.2, 3085.2, 3062.4, 2953.1, 2925.4, 2854.7, 1619.6, 1545.3, 1496.3, 1456.5, 1376.5, 1346.2, 1316.5, 1290.0, 1261.0, 1248.7, 1229.1, 1203.3, 1151.1, 1122.6, 1097.5, 1054.6, 1027.1, 975.9, 961.0, 920.3, 768.1, 721.8, 697.8, 595.7 and 545.4 cm−1.
- Crystalline form I of bimatoprost was characterized by powder x-ray diffractometry, DSC, IR DRIFTS (KBr), IR (KBr) and IR (Nujol) spectroscopy as set forth above and illustrated in
FIGS. 1-5 . - Crude bimatoprost containing (by HPLC) 2% to 5% 5-trans isomer was dissolved in mixture of EtOAc and MTBE at or near the boiling point. The solution was slowly cooled to 0-5° C. The precipitate was filtered and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give crystalline bimatoprost form I, containing (by HPLC) not more than 1% of 5-trans isomer. Repeated crystallization procedures give crystalline bimatoprost form I as white powder with not less than 99% purity (by HPLC), containing not more than 0.5% of 5-trans isomer, not more than 0.1% of 15R-isomer 1a, and not more than 0.1% of 15-keto bimatoprost 1c.
- Bimatoprost with 98% purity (by HPLC), contain 1% of 5-trans isomer (0.5 g) was crystallized from isopropylacetone (10 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.4 g (80% recovery) of bimatoprost crystalline form I as white powder with 99% purity (by HPLC), containing 0.6% of 5-trans isomer.
- Bimatoprost with 98% purity (by HPLC), contain 1% of 5-trans isomer (0.5 g) was crystallized from t-BuOAc (9 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.45 g (90% recovery) of bimatoprost crystalline form I as white powder with 99.2% purity (by HPLC), containing 0.6% of 5-trans isomer.
- Bimatoprost with 98% purity (by HPLC), contain 1% of 5-trans isomer (0.7 g) was crystallized from BuOAc (5 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.6 g (86% recovery) of bimatoprost crystalline form I as white powder with 99.4% purity (by HPLC), containing 0.5% of 5-trans isomer.
- Bimatoprost with 98.5% purity (by HPLC), contain 0.8% of 5-trans isomer (0.5 g) was crystallized from EtOAc (5 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.45 g (90% recovery) of bimatoprost crystalline form I as white powder with 99.3% purity (by HPLC), containing 0.5% of 5-trans isomer, 0.05% of 15R-isomer and 0.01% of 15-keto bimatoprost.
- Bimatoprost form A (prepared according to US2005/209337, 0.3 g) was crystallized from mixture of EtOAc (1.5 mL) and MTBE (3 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.25 g (83% recovery) of bimatoprost crystalline form I as white powder.
- Bimatoprost (0.4 g) was crystallized from mixture of MeOH (0.5 mL) and MTBE (10 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.3 g (75% recovery) of bimatoprost crystalline form I as white powder.
- Bimatoprost (0.5 g) was crystallized from mixture of t-BuOH (3 mL) and heptane (5 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.35 g (70% recovery) of bimatoprost crystalline form I as white powder.
- A mixture of oily bimatoprost (prepared according to U.S. Pat. No. 5,352,708, 1.0 g) and ether (20 mL) was stirred for 0.5 h at or near the boiling point, slowly cooled to 0-5° C. The precipitate was filtered and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.94 g (94% recovery) of bimatoprost crystalline form I as white powder.
- A mixture of bimatoprost (0.4 g) and heptane (10 mL) was stirred at 70° C. for 2 h, slowly cooled to 0-5° C., filtered and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. affording 0.38 g (95% recovery) of bimatoprost crystalline form I as white solid.
- Bimatoprost (0.4 g) was crystallized from toluene (6 mL) as follows: dissolving the bimatoprost at 70° C., allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.38 g (95% recovery) of bimatoprost crystalline form I as white powder.
- Bimatoprost form A containing 2.5% (by HPLC) of 5-trans isomer (0.3 g) was crystallized from EtOAc (1.5 mL) and MTBE (3 mL) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.25 g (83% recovery) of bimatoprost crystalline form I as white powder with 99.0% purity by HPLC, 0.8% trans-isomer.
- Bimatoprost (0.53 g) was crystallized from CH2Cl2 (3.0 g) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) CH2Cl2 (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.31 g (59% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.53 g) was crystallized from isobutyl methyl ketone (15.06 g) as follows: dissolving the bimatoprost at 60° C., allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) isobutyl methyl ketone (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.52 g (98% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.50 g) was crystallized from t-BuOMe (71.7 g) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) t-BuOMe (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.52 g (98% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.46 g) was crystallized from toluene (70.92 g) as follows: dissolving the bimatoprost at 70° C., allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) toluene (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.30 g (65% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.52 g) was crystallized from MeCN (10.6 g) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) MeCN (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.43 g (83% recovery) of bimatoprost crystalline form I.
- Bimatoprost (0.51 g) was crystallized from EtOAc (8.1 g) as follows: dissolving the bimatoprost at or near the boiling point, allowing the hot solution to cool to rt, keeping the mixture for 1 h at rt and for 2 h at 0 to 5° C. The precipitate was filtered off, washed on the filter with cold (0 to 5° C.) EtOAc (2.0 g) and dried in vacuo for 1 h at 0 to 5° C., for 0.5 h at rt and for 2 h at 30 to 40° C. to give 0.42 g (82% recovery) of bimatoprost crystalline form I.
- Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.
Claims (9)
1. A pure bimatoprost, wherein said bimatoprost contains (by HPLC) not more than (NMT) 2% of sum of all related impurities and 1% of 5-trans isomer.
2. The pure bimatoprost according to claim 1 , wherein said bimatoprost contains (by HPLC) not more than (NMT) 1.5% of sum of all related impurities and 0.7% of 5-trans isomer.
3. The pure bimatoprost according to claim 1 , wherein said bimatoprost contains (by HPLC) not more than (NMT) 1% of sum of all related impurities and 0.5% of 5-trans isomer.
4. The pure bimatoprost according to claim 1 , wherein said bimatoprost is free of 5-trans and 15(R)-isomers of bimatoprost.
5. The pure bimatoprost according to claim 1 , wherein said bimatoprost contains by LC not more than (NMT) 0.2% each of 5-trans isomer and 15(R) isomer.
6. The pure bimatoprost according to claim 1 , wherein said bimatoprost contains by LC not more than (NMT) 0.1% each of 5-trans isomer and 15(R) isomer.
7. The pure bimatoprost according to claim 1 , wherein said bimatoprost contains by LC not more than (NMT) 0.05% each of 5-trans isomer and 15(R) isomer.
8. A method for preparing a pharmaceutical or cosmetic composition by combining effective amount of said bimatoprost according to claim 1 with a pharmaceutical or cosmetic acceptable vehicle.
9. Use of crystalline form I of bimatoprost for the preparation of pure bimatoprost.
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CN103288698A (en) * | 2013-05-07 | 2013-09-11 | 北京洛斯顿精细化工有限公司 | Novel method for synthetizing prostaglandin analogue |
US10456293B2 (en) | 2012-10-26 | 2019-10-29 | Forsight Vision5, Inc. | Ophthalmic system for sustained release of drug to eye |
US11224602B2 (en) | 2015-04-13 | 2022-01-18 | Forsight Vision5, Inc. | Ocular insert composition of a semi-crystalline or crystalline pharmaceutically active agent |
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CN102596097B (en) | 2009-06-03 | 2015-05-20 | 弗赛特实验室有限责任公司 | Anterior segment drug delivery |
NZ599316A (en) * | 2009-10-16 | 2013-02-22 | Cayman Chemical Co Inc | Process for the preparation of f-series prostaglandins |
CN102050772B (en) * | 2009-11-02 | 2013-08-21 | 上海天伟生物制药有限公司 | Bimatoprost crystal as well as preparation method and purposes thereof |
CN102712584B (en) * | 2009-11-23 | 2014-10-29 | 阿勒根公司 | 7-[3,5-dihydroxy-2- (3-hydroxy-5-phenyl-pent-1-enyl)- cyclopentyl]-n-ethyl-hept-5-enamide (bimatoprost) in crystalline form ii, methods for preparation, and methods for use thereof |
US9238621B2 (en) * | 2011-06-02 | 2016-01-19 | Chinoin Zrt | Processes for the preparation of prostaglandin amides |
WO2013003827A2 (en) * | 2011-06-29 | 2013-01-03 | Allergan, Inc. | Macrogol 15 hydroxystearate formulations |
US20150157642A1 (en) * | 2011-08-05 | 2015-06-11 | Gordon C. Tang | Cosmetic method for changing the appearance of eyes |
GB201210235D0 (en) | 2012-06-11 | 2012-07-25 | Univ Bristol | Compound and method |
US9447014B2 (en) | 2012-12-28 | 2016-09-20 | Allergan, Inc. | Tromethamine salt of bimatoprost acid in crystalline form, methods for preparation, and methods for use thereof |
JP2017502089A (en) | 2014-01-10 | 2017-01-19 | マニスティー パートナーズ エルエルシーManistee Partners Llc | Migraine treatment |
US10273206B2 (en) | 2014-06-27 | 2019-04-30 | Allergan, Inc. | Tromethamine salt of bimatoprost acid in crystalline form 1, methods for preparation, and methods for use thereof |
CN108084073B (en) * | 2017-12-05 | 2019-10-29 | 重庆药友制药有限责任公司 | A method of purifying Bimatoprost |
WO2020055760A1 (en) | 2018-09-10 | 2020-03-19 | Mirati Therapeutics, Inc. | Combination therapies |
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US8846073B2 (en) * | 2006-12-19 | 2014-09-30 | Allergan, Inc. | Low temperature processes for making cyclic lipid implants for intraocular use |
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Cited By (3)
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US10456293B2 (en) | 2012-10-26 | 2019-10-29 | Forsight Vision5, Inc. | Ophthalmic system for sustained release of drug to eye |
CN103288698A (en) * | 2013-05-07 | 2013-09-11 | 北京洛斯顿精细化工有限公司 | Novel method for synthetizing prostaglandin analogue |
US11224602B2 (en) | 2015-04-13 | 2022-01-18 | Forsight Vision5, Inc. | Ocular insert composition of a semi-crystalline or crystalline pharmaceutically active agent |
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