US20040249172A1 - Process for the preparationof prostaglandins and analogues thereof - Google Patents
Process for the preparationof prostaglandins and analogues thereof Download PDFInfo
- Publication number
- US20040249172A1 US20040249172A1 US10/478,513 US47851304A US2004249172A1 US 20040249172 A1 US20040249172 A1 US 20040249172A1 US 47851304 A US47851304 A US 47851304A US 2004249172 A1 US2004249172 A1 US 2004249172A1
- Authority
- US
- United States
- Prior art keywords
- formula
- compound
- group
- alkyl
- mixture
- 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
- 238000000034 method Methods 0.000 title claims abstract description 154
- 230000008569 process Effects 0.000 title claims abstract description 115
- 150000003180 prostaglandins Chemical class 0.000 title abstract description 11
- 229940094443 oxytocics prostaglandins Drugs 0.000 title abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 30
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 25
- 238000000746 purification Methods 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 229
- 239000000203 mixture Substances 0.000 claims description 122
- 238000006243 chemical reaction Methods 0.000 claims description 95
- 125000003118 aryl group Chemical group 0.000 claims description 82
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 79
- 125000001424 substituent group Chemical group 0.000 claims description 79
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- 229960001160 latanoprost Drugs 0.000 claims description 58
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 claims description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 50
- 125000005843 halogen group Chemical group 0.000 claims description 43
- 239000003480 eluent Substances 0.000 claims description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 35
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 28
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 229930195733 hydrocarbon Natural products 0.000 claims description 24
- 150000002430 hydrocarbons Chemical class 0.000 claims description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 21
- -1 piperidin-1-oxy radical Chemical class 0.000 claims description 21
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 20
- 239000004215 Carbon black (E152) Substances 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 230000009467 reduction Effects 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 14
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 14
- 238000005984 hydrogenation reaction Methods 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- 238000007239 Wittig reaction Methods 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
- 150000001298 alcohols Chemical class 0.000 claims description 9
- YLFIGGHWWPSIEG-UHFFFAOYSA-N aminoxyl Chemical compound [O]N YLFIGGHWWPSIEG-UHFFFAOYSA-N 0.000 claims description 9
- VMKAFJQFKBASMU-KRWDZBQOSA-N (3as)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole Chemical compound C([C@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-KRWDZBQOSA-N 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002346 iodo group Chemical group I* 0.000 claims description 7
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 235000010288 sodium nitrite Nutrition 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- XNJGWTIQYUPOAF-UHFFFAOYSA-N 1,3,2-oxazaborole Chemical compound O1B=NC=C1 XNJGWTIQYUPOAF-UHFFFAOYSA-N 0.000 claims description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 4
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- 239000010948 rhodium Substances 0.000 claims description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 4
- 238000005809 transesterification reaction Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 238000006056 electrooxidation reaction Methods 0.000 claims description 2
- 150000002497 iodine compounds Chemical class 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- NYCVSSWORUBFET-UHFFFAOYSA-M sodium;bromite Chemical compound [Na+].[O-]Br=O NYCVSSWORUBFET-UHFFFAOYSA-M 0.000 claims description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- 150000003169 prostaglandin F2α derivatives Chemical class 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 110
- 0 BC(O)cc[C@H]1[C@H](O)C[C@H](O)[C@@H]1C/C=C\CCCC.BC(O)cc[C@H]1[C@H](O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O Chemical compound BC(O)cc[C@H]1[C@H](O)C[C@H](O)[C@@H]1C/C=C\CCCC.BC(O)cc[C@H]1[C@H](O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O 0.000 description 102
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 229940093499 ethyl acetate Drugs 0.000 description 34
- 239000000047 product Substances 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 25
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 24
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- 238000004809 thin layer chromatography Methods 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 150000001299 aldehydes Chemical class 0.000 description 17
- 238000000926 separation method Methods 0.000 description 17
- 238000006722 reduction reaction Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- WDIWAJVQNKHNGJ-UHFFFAOYSA-N CC(C)[Si](C)(C)C Chemical compound CC(C)[Si](C)(C)C WDIWAJVQNKHNGJ-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- 230000008020 evaporation Effects 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 11
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- CZDYPVPMEAXLPK-UHFFFAOYSA-N C[Si](C)(C)C Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000002044 hexane fraction Substances 0.000 description 7
- 150000002596 lactones Chemical class 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- ONYIBVIIOCEBIV-UHFFFAOYSA-N 1-dimethoxyphosphoryl-4-phenylbutan-2-one Chemical compound COP(=O)(OC)CC(=O)CCC1=CC=CC=C1 ONYIBVIIOCEBIV-UHFFFAOYSA-N 0.000 description 6
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- 238000006884 silylation reaction Methods 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000005708 Sodium hypochlorite Substances 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 5
- FSEGVXNIAJCDNZ-UHFFFAOYSA-N BC(=O)CP(C)(C)=O Chemical compound BC(=O)CP(C)(C)=O FSEGVXNIAJCDNZ-UHFFFAOYSA-N 0.000 description 4
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 4
- NDHMOBCVFGMXRK-FVCCEPFGSA-N [(3ar,4r,5r,6as)-4-formyl-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl] benzoate Chemical compound O([C@H]1[C@@H]([C@H]2CC(=O)O[C@H]2C1)C=O)C(=O)C1=CC=CC=C1 NDHMOBCVFGMXRK-FVCCEPFGSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 4
- WWSWYXNVCBLWNZ-QIZQQNKQSA-N fluprostenol 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)OC1=CC=CC(C(F)(F)F)=C1 WWSWYXNVCBLWNZ-QIZQQNKQSA-N 0.000 description 4
- 229950009951 fluprostenol Drugs 0.000 description 4
- NMRPBPVERJPACX-UHFFFAOYSA-N octan-3-ol Chemical compound CCCCCC(O)CC NMRPBPVERJPACX-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- VXIKDBJPBRMXBP-UHFFFAOYSA-N 3H-pyrrole Chemical compound C1C=CN=C1 VXIKDBJPBRMXBP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WAZOGZDOWPTXIB-BKLVVQOLSA-N CC(O)CC[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 Chemical compound CC(O)CC[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 WAZOGZDOWPTXIB-BKLVVQOLSA-N 0.000 description 3
- KWTUBBMVEVQJTA-QYUQZIQASA-N CCCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 Chemical compound CCCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 KWTUBBMVEVQJTA-QYUQZIQASA-N 0.000 description 3
- VJGGHXVGBSZVMZ-QIZQQNKQSA-N Cloprostenol 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)OC1=CC=CC(Cl)=C1 VJGGHXVGBSZVMZ-QIZQQNKQSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- XMDHRDDKCRNISB-ZTWUSJMCSA-N [(3ar,4r,5r,6as)-2-oxo-4-[(e)-3-oxo-5-phenylpent-1-enyl]-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl] benzoate Chemical compound C(\[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)C=1C=CC=CC=1)=C/C(=O)CCC1=CC=CC=C1 XMDHRDDKCRNISB-ZTWUSJMCSA-N 0.000 description 3
- 150000003973 alkyl amines Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- 229960004409 cloprostenol Drugs 0.000 description 3
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- RPUSRLKKXPQSGP-UHFFFAOYSA-N methyl 3-phenylpropanoate Chemical compound COC(=O)CCC1=CC=CC=C1 RPUSRLKKXPQSGP-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 3
- 229960002368 travoprost Drugs 0.000 description 3
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- UOWIYNWMROWVDG-UHFFFAOYSA-N 1-dimethoxyphosphorylpropan-2-one Chemical compound COP(=O)(OC)CC(C)=O UOWIYNWMROWVDG-UHFFFAOYSA-N 0.000 description 2
- VUZNLSBZRVZGIK-UHFFFAOYSA-N 2,2,6,6-Tetramethyl-1-piperidinol Chemical compound CC1(C)CCCC(C)(C)N1O VUZNLSBZRVZGIK-UHFFFAOYSA-N 0.000 description 2
- WPBVSCPWVCXYEM-KTDZLYPOSA-N C.CC[Si](CC)(CC)O[C@@H](CCC1=CC=CC=C1)CC[C@H]1[C@H](O[Si](CC)(CC)CC)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O.CC[Si](CC)(CC)O[C@H]1C[C@@H](O)[C@H](CC[C@H](CCC2=CC=CC=C2)O[Si](CC)(CC)CC)[C@H]1C/C=C\CCCC(=O)O.[H][C@]12C[C@@H](O[Si](CC)(CC)CC)[C@H](CC[C@H](CCC3=CC=CC=C3)O[Si](CC)(CC)CC)[C@@]1([H])CC(O)O2 Chemical compound C.CC[Si](CC)(CC)O[C@@H](CCC1=CC=CC=C1)CC[C@H]1[C@H](O[Si](CC)(CC)CC)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O.CC[Si](CC)(CC)O[C@H]1C[C@@H](O)[C@H](CC[C@H](CCC2=CC=CC=C2)O[Si](CC)(CC)CC)[C@H]1C/C=C\CCCC(=O)O.[H][C@]12C[C@@H](O[Si](CC)(CC)CC)[C@H](CC[C@H](CCC3=CC=CC=C3)O[Si](CC)(CC)CC)[C@@]1([H])CC(O)O2 WPBVSCPWVCXYEM-KTDZLYPOSA-N 0.000 description 2
- UMHMGUBWVNNZCK-XTROKMFRSA-N C1CCOC1.[H][C@]12CCCN1B(C)OCC2(C1=CC=CC=C1)C1=CC=CC=C1.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](/C=C/C(=O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](/C=C/[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2 Chemical compound C1CCOC1.[H][C@]12CCCN1B(C)OCC2(C1=CC=CC=C1)C1=CC=CC=C1.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](/C=C/C(=O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](/C=C/[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2 UMHMGUBWVNNZCK-XTROKMFRSA-N 0.000 description 2
- OKLMAUPVQWPSOL-AVKAUUGGSA-N CB1OB(C)OB(C)O1.[H][C@]1(C(O)(C2=CC=CC=C2)C2=CC=CC=C2)CCCN1.[H][C@]12CCCN1B(C)OCC2(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CB1OB(C)OB(C)O1.[H][C@]1(C(O)(C2=CC=CC=C2)C2=CC=CC=C2)CCCN1.[H][C@]12CCCN1B(C)OCC2(C1=CC=CC=C1)C1=CC=CC=C1 OKLMAUPVQWPSOL-AVKAUUGGSA-N 0.000 description 2
- ZTUTWQLMHJRYGX-JKSPWAQMSA-N CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1.CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O[Si](CC)(CC)CC)C[C@@H](O[Si](CC)(CC)CC)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC Chemical compound CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1.CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O[Si](CC)(CC)CC)C[C@@H](O[Si](CC)(CC)CC)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC ZTUTWQLMHJRYGX-JKSPWAQMSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- GMNVDJCWHYPPQY-LGXSMSCMSA-N [H][C@]12C[C@@H](O)[C@H](/C=C/[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](O)[C@H](CC[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2 Chemical compound [H][C@]12C[C@@H](O)[C@H](/C=C/[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](O)[C@H](CC[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2 GMNVDJCWHYPPQY-LGXSMSCMSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- KPSZWAJWFMFMFF-UHFFFAOYSA-N delta-Hexylen-alpha-carbonsaeure Natural products CC=CCCCC(O)=O KPSZWAJWFMFMFF-UHFFFAOYSA-N 0.000 description 2
- KPSZWAJWFMFMFF-NSCUHMNNSA-N delta-heptenoic acid Chemical compound C\C=C\CCCC(O)=O KPSZWAJWFMFMFF-NSCUHMNNSA-N 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 description 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 1
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 description 1
- RLUPXYAZLVEDEQ-PGTMKDAZSA-N BC(O)/C=C/[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 Chemical compound BC(O)/C=C/[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 RLUPXYAZLVEDEQ-PGTMKDAZSA-N 0.000 description 1
- JQVRVMVUWAKEEC-UHFFFAOYSA-N BC.BC(=O)CP(=O)(OC)OC.COP(C)(=O)OC.[Li]CP(=O)(OC)OC Chemical compound BC.BC(=O)CP(=O)(OC)OC.COP(C)(=O)OC.[Li]CP(=O)(OC)OC JQVRVMVUWAKEEC-UHFFFAOYSA-N 0.000 description 1
- RLUPXYAZLVEDEQ-JLGZTPMPSA-N B[C@H](O)/C=C/[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 Chemical compound B[C@H](O)/C=C/[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 RLUPXYAZLVEDEQ-JLGZTPMPSA-N 0.000 description 1
- GAAAAOHPTUALLU-GOFVFXDOSA-N B[C@H](O)CC[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 Chemical compound B[C@H](O)CC[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 GAAAAOHPTUALLU-GOFVFXDOSA-N 0.000 description 1
- DVIKDQUTIODXAB-OXHMTHTHSA-N C1CCOC1.[H][C@]12C[C@@H](O[Si](CC)(CC)CC)[C@H](CC[C@H](CCC3=CC=CC=C3)O[Si](CC)(CC)CC)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](O[Si](CC)(CC)CC)[C@H](CC[C@H](CCC3=CC=CC=C3)O[Si](CC)(CC)CC)[C@@]1([H])CC(O)O2 Chemical compound C1CCOC1.[H][C@]12C[C@@H](O[Si](CC)(CC)CC)[C@H](CC[C@H](CCC3=CC=CC=C3)O[Si](CC)(CC)CC)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](O[Si](CC)(CC)CC)[C@H](CC[C@H](CCC3=CC=CC=C3)O[Si](CC)(CC)CC)[C@@]1([H])CC(O)O2 DVIKDQUTIODXAB-OXHMTHTHSA-N 0.000 description 1
- LHZMHPDASXOJPL-GOSISDBHSA-N CB(N1[C@@H]2CCC1)OCC2(c1ccccc1)c1ccccc1 Chemical compound CB(N1[C@@H]2CCC1)OCC2(c1ccccc1)c1ccccc1 LHZMHPDASXOJPL-GOSISDBHSA-N 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N CC(C)C Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- JSSLNEAEZRGSKN-UHFFFAOYSA-N CC(C)C.CC(C)C Chemical compound CC(C)C.CC(C)C JSSLNEAEZRGSKN-UHFFFAOYSA-N 0.000 description 1
- PJKCDUBZXAXHLS-RTMPHQGJSA-N CC(C)C1=C(C(C)C)C(=O)CC1.CC(C)C1=CCC(=O)[C@@H]1C(C)C.CC(C)[C@H]1C(=O)C[C@@H](O)[C@@H]1C(C)C.CC(C)[C@H]1C(=O)C[C@H](O)[C@@H]1C(C)C.CC(C)[C@H]1C=CC(=O)[C@@H]1C(C)C Chemical compound CC(C)C1=C(C(C)C)C(=O)CC1.CC(C)C1=CCC(=O)[C@@H]1C(C)C.CC(C)[C@H]1C(=O)C[C@@H](O)[C@@H]1C(C)C.CC(C)[C@H]1C(=O)C[C@H](O)[C@@H]1C(C)C.CC(C)[C@H]1C=CC(=O)[C@@H]1C(C)C PJKCDUBZXAXHLS-RTMPHQGJSA-N 0.000 description 1
- XMQZPICAQDNOBD-GKFIRBOCSA-N CC(O)/C=C/[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 Chemical compound CC(O)/C=C/[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 XMQZPICAQDNOBD-GKFIRBOCSA-N 0.000 description 1
- POWZNZQMXGXZSN-MTAIEDJOSA-N CCCC(O)CC[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 Chemical compound CCCC(O)CC[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 POWZNZQMXGXZSN-MTAIEDJOSA-N 0.000 description 1
- KWTUBBMVEVQJTA-YOTQDZALSA-N CCCC/C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 Chemical compound CCCC/C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 KWTUBBMVEVQJTA-YOTQDZALSA-N 0.000 description 1
- DEEJZOATISFYAK-UJOBHVPUSA-N CCCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)CCCCC Chemical compound CCCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)CCCCC DEEJZOATISFYAK-UJOBHVPUSA-N 0.000 description 1
- PXGPLTODNUVGFL-YNNPMVKQSA-N CCCCC[C@@H](/C=C/[C@H]([C@@H](C/C=C\CCCC(O)=O)[C@H](C1)O)[C@@H]1O)O Chemical compound CCCCC[C@@H](/C=C/[C@H]([C@@H](C/C=C\CCCC(O)=O)[C@H](C1)O)[C@@H]1O)O PXGPLTODNUVGFL-YNNPMVKQSA-N 0.000 description 1
- SZYSLDNDQCUMDJ-QKMKSKRWSA-N CCCOC(=O)CCC/C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@H](O)CCC1=CC=CC=C1 Chemical compound CCCOC(=O)CCC/C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@H](O)CCC1=CC=CC=C1 SZYSLDNDQCUMDJ-QKMKSKRWSA-N 0.000 description 1
- NWFVGFGIHJLMSD-MLNPEAOSSA-N CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)COC1=CC=CC(C)=C1.O=C(O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/C(O)COC1=CC=CC(C(F)(F)F)=C1.O=C(O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)COC1=CC=CC(Cl)=C1 Chemical compound CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)COC1=CC=CC(C)=C1.O=C(O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/C(O)COC1=CC=CC(C(F)(F)F)=C1.O=C(O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)COC1=CC=CC(Cl)=C1 NWFVGFGIHJLMSD-MLNPEAOSSA-N 0.000 description 1
- SZYSLDNDQCUMDJ-SCTZCWPJSA-N CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@H](O)CCC1=CC=CC=C1 Chemical compound CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@H](O)CCC1=CC=CC=C1 SZYSLDNDQCUMDJ-SCTZCWPJSA-N 0.000 description 1
- BZEASDVKFKVJPS-JZNKRPDYSA-N CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O[Si](CC)(CC)CC)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC.CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O[Si](CC)(CC)CC)C[C@@H](O)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC.CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O[Si](CC)(CC)CC)C[C@@H](O[Si](CC)(CC)CC)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC Chemical compound CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O[Si](CC)(CC)CC)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC.CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O[Si](CC)(CC)CC)C[C@@H](O)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC.CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O[Si](CC)(CC)CC)C[C@@H](O[Si](CC)(CC)CC)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC BZEASDVKFKVJPS-JZNKRPDYSA-N 0.000 description 1
- XTTYTHOAVUWTPQ-NGIZHZPSSA-N CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O[Si](CC)(CC)CC)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC.CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O[Si](CC)(CC)CC)C[C@@H](O)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC.CC[Si](CC)(CC)O[C@@H](CCC1=CC=CC=C1)CC[C@H]1[C@H](O[Si](CC)(CC)CC)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O.CC[Si](CC)(CC)O[C@H]1C[C@@H](O)[C@H](CC[C@H](CCC2=CC=CC=C2)O[Si](CC)(CC)CC)[C@H]1C/C=C\CCCC(=O)O Chemical compound CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O[Si](CC)(CC)CC)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC.CCCOC(=O)CCC/C=C\C[C@H]1[C@@H](O[Si](CC)(CC)CC)C[C@@H](O)[C@@H]1CC[C@H](CCC1=CC=CC=C1)O[Si](CC)(CC)CC.CC[Si](CC)(CC)O[C@@H](CCC1=CC=CC=C1)CC[C@H]1[C@H](O[Si](CC)(CC)CC)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O.CC[Si](CC)(CC)O[C@H]1C[C@@H](O)[C@H](CC[C@H](CCC2=CC=CC=C2)O[Si](CC)(CC)CC)[C@H]1C/C=C\CCCC(=O)O XTTYTHOAVUWTPQ-NGIZHZPSSA-N 0.000 description 1
- LCZDWPKGWXFANX-UHFFFAOYSA-N CCOc1cccc(C(F)(F)F)c1 Chemical compound CCOc1cccc(C(F)(F)F)c1 LCZDWPKGWXFANX-UHFFFAOYSA-N 0.000 description 1
- FJWRGPWPIXAPBJ-UHFFFAOYSA-N CC[Si](C)(C)CC Chemical compound CC[Si](C)(C)CC FJWRGPWPIXAPBJ-UHFFFAOYSA-N 0.000 description 1
- SWXWAMYQSFDGCX-UHFFFAOYSA-N COC(=O)CCC1=CC=CC=C1.COP(=O)(CC(=O)CCC1=CC=CC=C1)OC.COP(C)(=O)OC Chemical compound COC(=O)CCC1=CC=CC=C1.COP(=O)(CC(=O)CCC1=CC=CC=C1)OC.COP(C)(=O)OC SWXWAMYQSFDGCX-UHFFFAOYSA-N 0.000 description 1
- HJJICINPGBLBSX-UHFFFAOYSA-N COP(=O)(CC(=O)CCC1=CC=CC=C1)OC.COP(=O)(CC(C)=O)OC Chemical compound COP(=O)(CC(=O)CCC1=CC=CC=C1)OC.COP(=O)(CC(C)=O)OC HJJICINPGBLBSX-UHFFFAOYSA-N 0.000 description 1
- KROQWTHDZYKYPG-UHFFFAOYSA-N COP(=O)(CC(=O)CCC1=CC=CC=C1)OC.COP(C)(=O)OC Chemical compound COP(=O)(CC(=O)CCC1=CC=CC=C1)OC.COP(C)(=O)OC KROQWTHDZYKYPG-UHFFFAOYSA-N 0.000 description 1
- UJOODZQQMHOYCD-OMDASQEMSA-N COP(=O)(CC(=O)CCC1=CC=CC=C1)OC.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](/C=C/C(=C)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2 Chemical compound COP(=O)(CC(=O)CCC1=CC=CC=C1)OC.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](/C=C/C(=C)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2 UJOODZQQMHOYCD-OMDASQEMSA-N 0.000 description 1
- GPZWPXAUTHOPKA-UHFFFAOYSA-N CP(C)(=O)CC(=O)CCC1=CC=CC=C1 Chemical compound CP(C)(=O)CC(=O)CCC1=CC=CC=C1 GPZWPXAUTHOPKA-UHFFFAOYSA-N 0.000 description 1
- LRMLWYXJORUTBG-UHFFFAOYSA-N CP(C)(C)=O Chemical compound CP(C)(C)=O LRMLWYXJORUTBG-UHFFFAOYSA-N 0.000 description 1
- WAZOGZDOWPTXIB-CHHOWFRJSA-N C[C@H](O)CC[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 Chemical compound C[C@H](O)CC[C@H]1[C@H](O)C[C@@H]2OC(=O)C[C@@H]21 WAZOGZDOWPTXIB-CHHOWFRJSA-N 0.000 description 1
- KJPBTURKWHQVOU-MINWWSKLSA-N ClCCl.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](C=O)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](CO)[C@@]1([H])CC(=O)O2.[Na]OCl Chemical compound ClCCl.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](C=O)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](CO)[C@@]1([H])CC(=O)O2.[Na]OCl KJPBTURKWHQVOU-MINWWSKLSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- NKXZELRUQFNWBC-VHJJIYPMSA-N O=C(/C=C/[C@H]1[C@H](OB(P)P)C[C@@H]2OC(=O)C[C@@H]21)CCC1=CC=CC=C1 Chemical compound O=C(/C=C/[C@H]1[C@H](OB(P)P)C[C@@H]2OC(=O)C[C@@H]21)CCC1=CC=CC=C1 NKXZELRUQFNWBC-VHJJIYPMSA-N 0.000 description 1
- PFIFPUGALHSEKD-RKCGEVCRSA-N O=C1C[C@H]2[C@H](C[C@@H](O)[C@@H]2/C=C/[C@@H](O)CCC2=CC=CC=C2)O1 Chemical compound O=C1C[C@H]2[C@H](C[C@@H](O)[C@@H]2/C=C/[C@@H](O)CCC2=CC=CC=C2)O1 PFIFPUGALHSEKD-RKCGEVCRSA-N 0.000 description 1
- CQVHXVLSHMRWEC-UTSKFRMZSA-N O=C1C[C@H]2[C@H](C[C@@H](O)[C@@H]2CC[C@@H](O)CCC2=CC=CC=C2)O1 Chemical compound O=C1C[C@H]2[C@H](C[C@@H](O)[C@@H]2CC[C@@H](O)CCC2=CC=CC=C2)O1 CQVHXVLSHMRWEC-UTSKFRMZSA-N 0.000 description 1
- NKPHTOANMCHHMR-JZAWBGDQSA-N O=C1C[C@H]2[C@H](C[C@@H](OB(P)P)[C@@H]2CC[C@@H](O)CCC2=CC=CC=C2)O1 Chemical compound O=C1C[C@H]2[C@H](C[C@@H](OB(P)P)[C@@H]2CC[C@@H](O)CCC2=CC=CC=C2)O1 NKPHTOANMCHHMR-JZAWBGDQSA-N 0.000 description 1
- WNOZTGFBZJCTFH-MVIOUDGNSA-N O=C1C[C@H]2[C@H](C[C@@H](OB(P)P)[C@@H]2CO)O1 Chemical compound O=C1C[C@H]2[C@H](C[C@@H](OB(P)P)[C@@H]2CO)O1 WNOZTGFBZJCTFH-MVIOUDGNSA-N 0.000 description 1
- OBRRYUZUDKVCOO-FVCCEPFGSA-N O=C1C[C@H]2[C@H](C[C@@H](OC(=O)C3=CC=CC=C3)[C@@H]2CO)O1 Chemical compound O=C1C[C@H]2[C@H](C[C@@H](OC(=O)C3=CC=CC=C3)[C@@H]2CO)O1 OBRRYUZUDKVCOO-FVCCEPFGSA-N 0.000 description 1
- RDWZBWVDSHTXLT-ODHFDHEPSA-N OC1C[C@H]2[C@H](C[C@@H](O)[C@@H]2CC[C@@H](O)CCC2=CC=CC=C2)O1 Chemical compound OC1C[C@H]2[C@H](C[C@@H](O)[C@@H]2CC[C@@H](O)CCC2=CC=CC=C2)O1 RDWZBWVDSHTXLT-ODHFDHEPSA-N 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 1
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- GARJBSALNOSCIO-FJRKSDITSA-N [H][C@]12C[C@@H](O)[C@H](/C=C/[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](/C=C/[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2 Chemical compound [H][C@]12C[C@@H](O)[C@H](/C=C/[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](OOCC3=CC=CC=C3)[C@H](/C=C/[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2 GARJBSALNOSCIO-FJRKSDITSA-N 0.000 description 1
- CIVIRUOWGMFQHB-RRMNVCNASA-N [H][C@]12C[C@@H](O)[C@H](CC[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](O[Si](CC)(CC)CC)[C@H](CC[C@H](CCC3=CC=CC=C3)O[Si](CC)(CC)CC)[C@@]1([H])CC(=O)O2 Chemical compound [H][C@]12C[C@@H](O)[C@H](CC[C@@H](O)CCC3=CC=CC=C3)[C@@]1([H])CC(=O)O2.[H][C@]12C[C@@H](O[Si](CC)(CC)CC)[C@H](CC[C@H](CCC3=CC=CC=C3)O[Si](CC)(CC)CC)[C@@]1([H])CC(=O)O2 CIVIRUOWGMFQHB-RRMNVCNASA-N 0.000 description 1
- 239000004015 abortifacient agent Substances 0.000 description 1
- 231100000641 abortifacient agent Toxicity 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005267 amalgamation Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- BRTALTYTFFNPAC-UHFFFAOYSA-N boroxin Chemical compound B1OBOBO1 BRTALTYTFFNPAC-UHFFFAOYSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- OGCGXUGBDJGFFY-INIZCTEOSA-N diphenyl-[(2s)-pyrrolidin-2-yl]methanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)[C@@H]1CCCN1 OGCGXUGBDJGFFY-INIZCTEOSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- SYJRVVFAAIUVDH-UHFFFAOYSA-N ipa isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- QPNOPWWAMGQISP-UHFFFAOYSA-N n,n'-dicyclohexylmethanediimine;methylsulfinylmethane Chemical compound CS(C)=O.C1CCCCC1N=C=NC1CCCCC1 QPNOPWWAMGQISP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical group PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012857 repacking Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F295/00—Macromolecular compounds obtained by polymerisation using successively different catalyst types without deactivating the intermediate polymer
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- 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
-
- 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
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Definitions
- the present invention relates to a novel process for the synthesis of prostaglandins and prostaglandin analogues.
- this invention relates to the synthesis of PGF 2 ⁇ and analogues thereof.
- Prostaglandin F 2 ⁇ ⁇ PGF 2 ⁇ -7-[3,5-dihydroxy-2-(3-hydroxy-1-octenyl)-cyclopentyl]-5-heptenoic acid ⁇ has the structure:
- This compound causes uterine contraction and is used clinically to induce and accelerate labour, and as an abortifacient.
- Prostaglandins are generally characterised by the substituents on the cyclopentyl ring.
- the PGF 2 ⁇ prostaglandins and prostaglandin analogues generally have two hydroxyl groups in a cis configuration relative to the cyclopentane ring, and two side chains in a trans configuration relative to each other, each side chain having one double bond.
- Analogues of PGF 2 ⁇ can have a different number of double bonds in the side chains, and the substituents along the side chains may vary. Additionally, in some PGF 2 ⁇ analogues, the side chain carboxylic acid group may be esterified.
- PGF 2 ⁇ analogues having therapeutic use are cloprostenol, which contains a chlorophenyl ether side chain substituent, fluprostenol, which contains a trifluoromethylphenyl ether side chain substituent, and travoprost:
- Latanoprost [13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF 2 ⁇ -isopropyl] is an example of a PGF 2 ⁇ analogue having one saturated side chain and wherein the carboxylic acid group is esterified:
- This compound is used in the clinic for the reduction of elevated intra-ocular pressure in patients with open angle glaucoma and ocular hypertension.
- Prostaglandin analogues based on PGF 2 ⁇ for use in the treatment of glaucoma and ocular hypertension are described in, for example, European patent number 0 364 417 B1.
- the procedures for the synthesis of PGF 2 ⁇ analogues described therein start from an advanced-stage intermediate, 16-phenyl-17,18,19,20-trinor PGF 2 ⁇ , or the tetranor homologue thereof.
- European patent number EP 0 544 899 B1 describes a process for the synthesis of 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF 2 ⁇ esters of the formula:
- [0013] is prepared by transforming the hydroxymethyl group of the protected Corey lactone, with an oxidising agent (dicyclohexylcarbodiimide) to form the corresponding aldehyde. Reaction of the aldehyde with a phenylphosphonium salt forms the above intermediate.
- the present invention provides a process for the preparation of prostaglandin derivatives having the Formulae (I-A) and (I-B):
- B represents a substituent selected from the group consisting of:
- R′′ represents C 1 -C 20 alkyl (preferably a C 1 to C 6 alkyl group, e.g. methyl, ethyl, propyl and iso-propyl), C 3 to C 8 cycloalkyl (e.g. cyclohexyl, cyclopropyl, cyclobutyl) or C 6 to C 10 aryl (preferably phenyl).
- a preferred R′′ group is iso propyl.
- R′′ is other than an alkyl, cycloalkyl or aryl group.
- R′′ groups include, but are not limited to, unsaturated C 1 to C 20 alkyl, unsaturated C 3 to C 8 cycloalkyl, wherein the saturated or unsaturated alkyl or cycloalkyl groups, or aryl groups can be substituted with one or more (typically 1 to 3) substituents such as CF 3 , C 1 to C 6 alkoxy, CN.
- R′′ groups include C 6 to C 10 heterocycloalkyl (e.g. piperidinyl), C 6 to C 10 heteroaryl (such as pyridyl) and substituted C 6 to C 10 aryl (including substituents such as CF 3 , C 1 to C 6 alkoxy, CN).
- Scheme 1 illustrates one route to the synthesis of compounds of Formula (I-A) and (I-B), starting from a protected-Corey lactone compound of Formula (X):
- the intermediate (VI-A) in Scheme 1 can be made by carrying out steps (a) and (b) as shown in Scheme 1, and substituting steps (c), (d), and (e) in Scheme 1 with the steps (e′), (c′) and (d′) as shown in the following Scheme 2:
- Scheme 3 illustrates an alternative procedure for the synthesis of compounds of Formula (I-A) and (I-B), starting from intermediates of structure (IIIa) and (IIIb):
- Scheme 4 shows an alternative procedure for the synthesis of compounds of Formula (I-B) starting from the intermediates of Formula (IIa) and (IIb):
- A represents C 6 to C 10 aryl which may be substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl;
- the above reaction may be carried out by electrooxidation in the presence of the organic nitroxyl radical.
- the oxidation reaction may be carried out in the presence of a nitroxyl radical and at least one molar equivalent of a co-oxidant selected from the group consisting of m-chloroperbenzoic acid, high-valent metal salts, sodium bromite, sodium or calcium hypochlorite, N-chlorosuccinimide or hypervalent iodine compounds such as [bis(acetoxy)iodo]benzene.
- the co-oxidant is sodium hypochlorite.
- the stable organic radical preferably comprises a completely ⁇ -substituted piperidin-1-oxy radical, such as 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO, free radical).
- TEMPO free radical
- Prior art oxidation procedures for oxidising the compound of Formula (X) to form the compound of Formula (IX) include the use of dimethylsulfoxide-dicyclohexylcarbodiimide.
- such a method requires isolation of the aldehyde (IX). Since the aldehyde (IX) is not particularly stable in solution, an amount of decomposition product is usually observed during work-up.
- the aldehyde (IX) solution obtained in this step can be employed in the subsequent step without isolation of the aldehyde, thus minimising any decomposition.
- A represents C 6 to C 10 aryl which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl;
- B represents a substituent selected from the group consisting of: (i) C 1 to C 6 alkyl, (ii) C 7 to C 1-6 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 ,
- a and B are as defined as above, and each R′′′ is the same or different (preferably the same) and each represents a C 1 to C 6 alkyl group (preferably methyl), the process being carried out in the presence of lithium chloride and an organic base (such as tertiary alkylamines, e.g. di-iso-propylethylamine).
- an organic base such as tertiary alkylamines, e.g. di-iso-propylethylamine.
- the compounds of Formula (IX) are commercially available or can be made from commercially available starting materials.
- the compound of Formula (IX) may be prepared by the process described in U.S. Pat. No. 3,778,450.
- dimethyl-(2-oxo-4-phenylbutyl)phosphonate may be produced from dimethyl-(2-oxo-propyl)phosphonate via the following reaction:
- a strong base e.g. n BuLi
- R y can represent any group that can form a leaving group —OR y .
- Typical R y groups include C 1 to C 6 alkyl, such as methyl, or ethyl (methyl is preferred).
- the product from this reaction can be typically purified by distillation.
- this reaction is usually free of side reactions compared with the prior art process using dimethyl(2-oxopropyl)phosphonate.
- the reaction is preferably carried out at temperatures in the range of ⁇ 20° C. to 40° C., and preferably ⁇ 10° C. to 30° C.
- Suitable solvents for this reaction include those selected from the group consisting of benzene, toluene, acetonitrile, dichloromethane, diethylether, and mixtures thereof.
- the group A preferably represents an unsubstituted C 6 to C 10 aryl group (e.g. phenyl).
- substituents for the group A include those selected from C 6 to C 10 aryl group being substituted with one substituent selected from halo or phenyl. Further preferred substituents for the group A include unsubstituted or substituted phenyl wherein the substituent is selected from halo or phenyl. In a preferred process, the group A represents phenyl.
- A represents unsubstituted C 6 to C 10 aryl
- B represents a substituent selected from the group consisting of:
- Suitable reducing agents for the reduction of the side chain oxo group include borane-dimethylsulfide complex, lithium tri-sec-butylborohydride, ⁇ LiB[CH(CH 3 )CH(C 2 H 5 ] 3 H ⁇ (L-Selectride RTM ) and sodium borohydride.
- a non-stereoselective reducing agent may be used (e.g. LiAlH 4 , NaBH 4 and other metallic hydrides).
- the reducing agent suitably comprises borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine catalyst (“Corey catalyst”) because of the greater selectivity towards the production of a major amount of the desired isomer.
- Corey catalyst a chiral oxazaborolidine catalyst
- a preferred reagent for the reduction reaction is borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine catalyst (Corey catalyst).
- the group A in the compound of Formula (VII) in addition to being unsubstituted C 6 to C 10 aryl, can also represent C 6 to C 10 aryl substituted with one to three substituents independently selected from the group consisting of (i) halo, i.e. fluoro, chloro, bromo or iodo, (ii) C 1 to C 6 alkyl and (iii) Ce to C 10 aryl, such as phenyl.
- borane-dimethylsulfide complex in combination with a Corey catalyst is especially preferred because the reaction takes place with excellent selectivity. In fact, a marked improvement in stereoselectivity is seen compared with the reaction using L-Selectride RTM .
- a further advantage is that the reduction reaction using borane-dimethylsulfide complex can be carried out at a higher temperature (typically ⁇ 15° C. to ⁇ 18° C.) compared with L-Selectride RTM , which requires a reaction temperature of less than ⁇ 70° C.
- the Corey catalyst comprises a chiral oxazaborolidine compound [see J. Am. Chem. Soc., 109, 5551, (1987) and J. Am. Chem. Soc. 109, 7925, (1987) and references cited in Lancaster Catalogue 2000-2001, page 819] such as (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrole[1,2-c][1,3,2]oxazaborole, may be prepared by reaction of the appropriate chiral prolinol [such as the commercially available (R)-(+)- ⁇ , ⁇ -diphenylprolinol] with a trialkyl boroxine, e.g.:
- reaction is carried out in inert conditions in a solvent such as toluene, diethylether or tetrahydrofuran.
- a solvent such as toluene, diethylether or tetrahydrofuran.
- the oxazaborolidine catalyst is employed as a solution in the reduction step.
- the dashed line forms an optional double bond
- B represents a substituent selected from the group consisting of:
- R′ represents the substituent:
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- A represents C 6 to C 10 aryl which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl;
- R x , R y and R z are as defined above and X represents F, Cl, Br or I.
- the deprotection step (a) wherein the protecting group A on the hydroxyl group of the cyclopentane ring is removed, is preferably carried out in the presence of a base.
- Preferred bases for use in the deprotection reaction includes those selected from the group consisting of K 2 CO 3 , Na 2 CO 3 and Li 2 CO 3 , with K 2 CO 3 being particularly preferred.
- Suitable solvents for the deprotection reaction include alcohols, such as methanol, ethanol and isopropanol.
- step (a) The isolation of the deprotected product from step (a) may be carried out by standard chromatography procedures. However, it has been found that the deprotected product can advantageously be isolated by extraction with hexane fractions, thus avoiding the use of time consuming and expensive chromatographic procedures.
- the hydrogenation step can be carried out using any suitable hydrogenation catalyst such as palladium, platinum or rhodium, which may be supported on an inert support, such as carbon.
- a suitable hydrogenation catalyst is 5% palladium on carbon.
- the hydrogenation reaction is carried out in the presence of sodium nitrite, preferably in aqueous solution.
- This procedure avoids the formation of elimination products and thus results in improved yields (typically greater than 95%) of the compounds of Formula (VI-A).
- Suitable solvents for the hydrogenation reaction include alcohols such as methanol and ethanol.
- the mixture is preferably stirred with dilute hydrochloric acid to remove the nitrite (by conversion to nitrous acid, which decomposes at ambient temperature). This procedure ensures that nitrite is not carried through to the subsequent synthetic procedures.
- the role of the sodium nitrite in the hydrogenation reaction is to avoid the formation of elimination products, that is, the elimination of a water molecule from the side chain of the starting material and, as a consequence, formation of the fully saturated deoxygenated analogue of the desired product.
- the compound produced in step (a) having the Formula (VI) or the compound produced in step (b) having the Formula (VI-A) is reacted with a silylating agent (X)Si(R x )(R y )(R z ).
- the groups R x , R y , and R z can be the same or different each represents a C 1 to C 6 alkyl group or a C 6 to C 10 aryl group.
- each of the groups R x , R y , and R z are independently selected from methyl, ethyl, butyl, isopropyl.
- silylating agents for use in step (c) are selected from the group consisting of trimethylsilyl chloride, triethylsilyl chloride and tert-butyldimethylsilyl chloride. Triethylsilyl chloride is particularly preferred.
- the silylation step is preferably carried out in the presence of a base, for example an organic base, such as imidazole or trialkylamines, such as triethylamine.
- a base for example an organic base, such as imidazole or trialkylamines, such as triethylamine.
- Suitable solvents for use in the silylation reaction include polar aprotic solvents such as tetrahydrofuran or dimethylsulfoxide, or chlorinated solvents such as dichloromethane.
- polar aprotic solvents such as tetrahydrofuran or dimethylsulfoxide
- chlorinated solvents such as dichloromethane.
- the reaction is carried out in a solvent comprising dimethylformamide.
- silyl protecting groups in accordance with the present invention is advantageous because it generally results in cleaner reactions, with higher yields compared with reactions wherein the hydroxyl group is not protected.
- silyl protecting groups in the present process has particular advantages compared with the prior art process employing, e.g. benzoyl- and para-phenylbenzoyl (PPB)-protecting groups because silyl groups are stable to the subsequent reduction reaction with e.g. DIBAL-H (di-iso-butylaluminium).
- PPB para-phenylbenzoyl
- a second advantage of using silyl protecting groups in the subsequent Wittig reaction [step (i) in Scheme 1], is that the formation of the desired cis isomer is favoured.
- Silyl protecting groups have the further advantage in that they generally increase the lipophilic character of the molecules, so that their derivatives are readily soluble in organic solvents.
- removal of the phosphine oxide by-product is facilitated because the silyl-protected Wittig reaction product [(IIIa)/(IIIb)] is soluble in hexane, whereas the triphenylphosphine oxide is insoluble, thus allowing separation by filtration.
- Subsequent purification of the product can be carried out by silica gel filtration, rather than a full chromatographic purification.
- a further advantage of employing silyl protecting groups is that these protecting groups can be removed under mild conditions, as discussed below.
- [0104] can be made from compounds of Formula (VIII) by a process comprising the steps of:
- R x , R y and R z are as defined above and X represents F, Cl, Br or I.
- Steps (a) to (c) of this process are depicted as steps (e′), (c′) and (d′) in Scheme 2.
- Step (d) corresponds to step (f) of Scheme 1, the product of which is a compound of Formula (V) wherein the dashed and solid line represents a single bond.
- the hydrogenation, reduction, deprotection and silylation steps in this alternative procedure are carried out as for the immediately preceding process to form the compounds of Formula (V).
- B represents a substituent selected from the group consisting of:
- R′ represents the substituent:
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- a suitable reducing agent for this process is di-iso-butylaluminium hydride DIBAL-H), and the reaction may be carried out in e.g. tetrahydrofuran.
- B represents a substituent selected from the group consisting of:
- R′ represents the substituent:
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- R w represents C 1 to C 6 alkyl or C 6 to C 10 aryl
- X represents fluoro, chloro, bromo or iodo.
- the group R w represents phenyl.
- the group X preferably represents bromo.
- [0135] are commercially available, or can be prepared by reaction of a phosphine, P(R w ) 3 , with HO 2 C(CH 2 ) 4 —X′ (wherein X′ represents halide, e.g. F, Cl, Br or I).
- Suitable bases for the forming the ylide include those selected from the group consisting of butyllithium, sodium amide, sodium hydride, and alkali metal alkoxides, including sodium methoxide, sodium ethoxide, potassium ethoxide and potassium tert-butoxide. Potassium tert-butoxide is a particularly preferred base.
- a suitable solvent for this reaction is tetrahydrofuran.
- the ylide may be formed by the reaction of (4-carboxybutyl)-triphenylphosphonium bromide with potassium tert-butoxide:
- the ylide can be generated using 3 equivalents of the phosphonium halide and 6 equivalents of base, i.e. a ratio of phosphonium halide and base of 1:2, but is preferably generated using 2.15 equivalents of the phosphonium halide and 4 equivalents of base.
- the silyl protecting groups of the hydroxyl substituent on the cyclopentyl ring may migrate to the hydroxyl group formed by the opening of the lactol ring, to result in a mixture of 9- and 11-silylated isomers of Formula (IIIa) and (IIIb).
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- R x , R y and R z are as defined above and X represents F, Cl, Br or I.
- This procedure is advantageously carried out where a mixture of the compounds of Formula (IIIa) and Formula (IIIb) are formed as the products of the Wittig reaction.
- the reaction of such a mixture with at least one molar equivalent of a silylating agent, preferably the same silylating agent as is used to protect the hydroxyl groups of the compounds of Formula (V), enables the mixture of compounds of Formula (IIIa) and (IIIb) to be “amalgamated” into a single product of Formula (XI) for subsequent reaction steps.
- a molar equivalent of silylating agent to starting material is employed. Typically, 1.1 to 2 molar equivalents are employed. The formation of a single product allows for better control of subsequent reaction steps and purification.
- the dashed line represents an optional double bond
- B represents a substituent selected from the group consisting of: (i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 ;
- R′ represents the substituent:
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- R′′ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
- the mixture may be alkylated by the process indicated above, to form a mixture of 9- and 11-silylated esters of Formula (IIa) and (IIb).
- the silylation it is also possible to carry out the silylation after the alkylation step, i.e. on the mixture of compounds of Formula (IIa) and (IIb).
- a further aspect of the present invention provides a process for the production of a compound of Formula (XII):
- R′ represents the substituent:
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- R′′ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
- R x , R y and R z are as defined above and X represents F, Cl, Br or I.
- this process is preferably carried out in the presence of at least a molar equivalent of silylating agent, and even more preferably 1.1 to 2 molar equivalents of silylating agent is employed. Again, this step leads to the “amalgamation” of the mixture of compounds of Formula (IIa) and (IIb) to form a single product [i.e. compounds of Formula (XII)] which facilitates control of subsequent reaction steps and purification of subsequent intermediates.
- R′ is the same and each represents the substituent:
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- R′′ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- R′′ represents a C 1 to C 6 alkyl group (e.g. isopropanol) or C 3 to C 8 cycloalkyl (e.g. cyclohexanol).
- the above process may be carried out optionally in the presence of a weak acid catalyst, such as pyridinium p-toluenesulfonate.
- a weak acid catalyst such as pyridinium p-toluenesulfonate.
- the reaction should be carried out in the absence of water, to avoid deprotection of the silyl groups.
- B represents a substituent selected from the group consisting of:
- B represents a substituent selected from the group consisting of:
- R′′ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
- Suitable reagents for removal of the silyl groups from the compounds of Formula (IIIa), (IIIb), (XI), (IIa), (IIb) and (XII) include weak acids such as acetic acid and citric acid.
- An especially preferred weak acid is pyridinium p-toluenesulfonate.
- the reaction may be carried out in any suitable solvent or solvent mixtures.
- An especially preferred solvent for the deprotection reaction comprises acetone and water.
- the compounds of Formulae (VI), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A), (I-B), (XI), (XII) and (XIV) are single enantiomers (i.e. the wavy line in the side chain represents or ).
- a stereoselective reducing agent e.g. borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine (Corey) catalyst] in step (c) of Scheme 1, or step (c′) in Scheme 2.
- the group B in the compounds of Formula (XII), (XI), (VII), (VII), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) or (I-B) is selected from the group consisting of (I) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl wherein the aryl group is unsubstituted and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which is substituted with a substituent selected from halo or CF 3 .
- solid and dashed lines in each of Formulae (XII), (XI) (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) and (I-B) forms a double bond.
- B preferably represents —CH 2 CH 2 Ph.
- B preferably represents a substituent selected from the group consisting of:
- the process of the present invention is generally applicable for the synthesis of prostaglandins and prostaglandin analogues, particularly PGF 2 ⁇ and analogues thereof.
- the process is particularly useful for the production of a compound selected from the group consisting of:
- the present invention provides a process for the synthesis of latanoprost comprising the steps of:
- A represents a C 6 to C 10 aryl group, preferably phenyl, which may be substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl,
- each R′′′ the same or different and each represents a C 1 to C 6 alkyl group (preferably methyl), in the presence of lithium chloride and an organic base, to form the compound of Formula (VIII) wherein B is
- R x , R y and R z are as defined as above (a particularly preferred silylating agent being triethylsilyl chloride) as defined above to form a compound of Formula (V) wherein B is —CH 2 CH 2 Ph:
- R′ represents:
- X represents F, Cl, Br or I, with a strong base (such as potassium t-butoxide), to form a compound of Formula (IIIa) or (IIIb) wherein B is —CH 2 CH 2 Ph:
- steps (1) to (10) correspond to steps (a)-(b)-(c)-(d)-(e)-(f)-(h)-(i)-(j)-(k) in Scheme 1 above.
- latanoprost can be formed by a procedure involving carrying out steps (1) and (2) of the preceding process, replacing steps (3), (4) and (5) with the following steps (3′), (4′) and (5′), and thereafter carrying out steps (6-(10) as described in the preceding process.
- Steps (3′), (4′) and (5′) are as follows:
- each R′ is as defined as above;
- novel intermediates for the synthesis of a compound of Formula (I-A) or (I-B) as defined above include the following:
- A represents unsubstituted C 6 to C 10 aryl
- B represents a substituent selected from the group consisting of: (i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 ; and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 .
- R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
- A represents unsubstituted C 6 to C 10 aryl, and B is as defined herein;
- the group A represents phenyl
- the compounds of Formulae (VII), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (XI), (XII), (XIII) and (XIV) are single enantiomers (i.e. the wavy line in the side chain represents or ).
- the solid and dashed lines represent a single bond and B represents —CH 2 CH 2 Ph.
- the group R′ is preferably:
- the group R′′ preferably represents iso-propyl.
- the present invention further provides the use of any novel intermediate as defined as above in the manufacture of latanoprost and the use of any novel intermediate as defined as above in the manufacture of cloprostenol, fluprostenol, PGF 2 ⁇ , travoprost, or a PGF (preferably PGF 2 ⁇ ) analogue.
- the present invention also provides the use of a silylating reagent of formula
- the group X represents F, Cl, Br or I and R x , R y and R z are as previously defined, for protecting a hydroxyl group of an intermediate in the synthesis of a prostaglandin or prostaglandin analogue, such as prostaglandin or prostaglandin analogues based on PG-A, PG-B, PG-C PG-D or PGF.
- a prostaglandin or prostaglandin analogue such as prostaglandin or prostaglandin analogues based on PG-A, PG-B, PG-C PG-D or PGF.
- the use of these silylating agents is particularly suitable in the synthesis of prostaglandin PGF 2 ⁇ or prostaglandin analogues based on PGF 2 ⁇ , including latanoprost, cloprostenol, fluprostenol and travoprost. Of these, latanoprost is particularly preferred.
- R x , R y and R z are methyl, ethyl and tert-butyl.
- a particularly preferred silylating reagent is triethylsilylchloride.
- hatched lines attached to the cyclopentane ring indicate bonds that are below the plane of the ring (i.e. bonds in an alpha configuration).
- Solid wedges attached to the cyclopentane ring indicate bonds that are above the plane of the ring (rings in the beta configuration). It is to be understood that a wavy line, i.e.
- [0286] represents bonds in either the alpha or beta configuration, and includes single enantiomers, i.e.:
- the present invention further provides a process for the purification of latanoprost by HPLC comprising the use as an eluent, of a mixture comprising a hydrocarbon, an alcohol and, optionally, acetonitrile.
- the eluent comprises a hydrocarbon, an alcohol and acetonitrile.
- acetonitrile as a component of the eluent in the HPLC purification of latanoprost results in an improved separation of the impurities.
- the use of acetonitrile as a component of the above eluent mixture results in a significantly improved separation of the hitherto difficult to separate 15(S)-trans isomer of latanoprost.
- the 15(S)-trans isomer does not co-elute with the latanoprost, i.e.
- the eluent systems in the present purification process comprises a hydrocarbon in an amount range of 80-99 volume percent and an alcohol in an amount range of 1-20 volume percent.
- the eluent comprises a hydrocarbon in an amount range of 85-99 volume percent and an alcohol in an amount range of 1-15 volume percent.
- an eluent comprising a hydrocarbon in an amount range of 88-98 volume percent and an alcohol in an amount range of 2-12 volume percent.
- the eluent comprises a hydrocarbon in an amount range of 85-99 volume percent, an alcohol in an amount of 0.5-10 volume percent and acetonitrile in an amount of 0.5-5 volume percent.
- an eluent comprises a hydrocarbon in an amount range of 86-98 volume percent, an alcohol in an amount of 1-8 volume percent and acetonitrile in an amount of 1-6 volume percent.
- an eluent comprising a hydrocarbon in an amount range of 90-96 volume percent, an alcohol in an amount of 2-6 volume percent and acetonitrile in an amount of 2-4 volume percent.
- the hydrocarbon is a C 5 to C 8 straight chain, branched or cyclic hydrocarbon, wherein the hydrocarbon is preferably an n-alkane. Hexane and heptane are especially preferred.
- the hydrocarbon employed in the eluent may comprise a mixture of e.g. alkanes, such as hexane fraction. It has been found that good results have been obtained with n-heptane.
- Preferred alcohols in the above eluent systems are C 1 to C 8 straight chain, branched or cyclic alkanols, with C 1 to C 5 straight chain or branched alkanols being particularly preferred.
- methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol or butan-2-ol are especially useful. Good results have been obtained with propan-2-ol (isopropanol) as the alcohol component.
- the use of ethanol as the alcohol component has also produced good separations.
- the alcohol component of the eluent can include mixtures of one or more alkanols, e.g. combinations of two or more of isopropanol, ethanol and methanol may be used, e.g mixtures in ratios of 1:1 to 3:1 have been successfully employed.
- a preferred eluent system comprises n-heptane:isopropanol:acetonitrile.
- Preferred volume percent ranges of n-heptane: isopropanol:acetonitrile are 90-96%:2-7%:2-5%.
- the ratios of n-heptane:isopropanol: acetonitrile are in the ranges 92-94%:3-5%:2-4%. Good results have been obtained with ratios of 93%: 4%:3%.
- HPLC procedures are preferably carried out on a silica gel column.
- suitable columns include Waters RTM Spherisorb, Phenomenex RTM Luna Cyano and Phenomenex RTM Luna Silica.
- latanoprost that is substantially free of the 15(S)-cis isomer, the 15(S)-trans isomer and the 15(R)-trans isomer.
- latanoprost containing less than 0.3% in total of any combination of: 15(S)-cis isomer, 15(S)-trans isomer and 15(R)-trans isomer may be produced.
- latanoprost containing less than 0.1% each of 15(S)-cis-, 15(S)-trans- and 15(R)-trans isomers can be produced.
- DIBAL-H di-iso-butylaluminiumhydride
- DBU [1,8-diazabicyclo(5.4.0)undec-7-ene]
- alkyl refers to C 1 to C 6 straight or branched carbon chains. Particularly preferred alkyl groups for the compounds and processes of the invention include methyl, ethyl, propyl, isopropyl, butyl, and tertiary butyl.
- aryl represents a carbocyclic group containing from six to fifteen carbon atoms and having at least one aromatic ring. Particularly preferred aryl groups for any of the compounds and methods of the present invention include phenyl and naphthyl.
- aralkyl refers to an alkyl group as defined above wherein one or more hydrogen atoms (preferably one) have been replaced by unsubstituted C 6 to C 10 aryl groups as defined above.
- a preferred aralkyl group for the compounds and methods of the invention is benzyl.
- halo refers to fluoro, chloro, bromo or iodo.
- substantially free of a particular impurity refers to less than 1%, preferably less than 0.5%, more preferably, less than 0.3% and even more preferably, less than 0.1% of the impurity.
- a 0.5M solution of potassium bromide was prepared by dissolving KBr (11.9 g) in purified water and then diluting with additional water to 200 ml.
- PGX-6 (225.1 g, 0.556M) was dissolved in dry tetrahydrofuran (3.5 L) in an inert atmosphere and ‘Corey catalyst’ prepared according to Example 4 (0.25M in toluene, 223 ml, 0.1 eq.) added. The mixture was cooled to approximately ⁇ 15° C. and a solution of borane-methyl sulfide complex (10M BH 3 concentration, 41.7 ml, 417 mMol, 0.75 eq.) in dry tetrahydrofuran (450 ml) was added whilst maintaining the temperature at ca. 15° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC.
- borane-methyl sulfide complex (10M BH 3 concentration, 41.7 ml, 417 mMol, 0.75 eq.
- PGX 6 315.2 g, 0.779M was dissolved in dry tetrahydrofuran (5.7 L) in an inert atmosphere and ‘Corey catalyst’ (0.25M in toluene, 312 ml, 0.1 eq.) added. The mixture was cooled to approximately ⁇ 15° C. and a solution of borane-methyl sulfide complex (10M BH 3 concentration, 58.5 ml, 0.585M, 0.75 eq.) in dry tetrahydrofuran (630 ml) added whilst maintaining the temperature at ca. 15° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC.
- borane-methyl sulfide complex 10M BH 3 concentration, 58.5 ml, 0.585M, 0.75 eq.
- the crude mixture of epimers PGX-7/PGX-8 (686.5 g) made according to the synthetic procedure described in Example 5a was crystallised from heptane fraction/ethyl acetate (7:3) to give a crystalline mixture of epimers PGX-7 and PGX-8 (480.4 g) that is free of other impurities.
- the filtrates from the crystallisation were evaporated to give an oil (150.3 g) comprising mainly impure PGX-7/PGX-8.
- Injection 1 Injection of an aliquot of crystalline PGX-7/PGX-8 stock solution (A) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7. The column was then flushed with eluent to elute any remaining PGX-8.
- Injection 2 Injection of an aliquot of crystalline PGX-7/PGX-8 stock solution (A) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7. Column flushed with methanol then equilibration of column with eluent.
- Injection 3 Injection of an aliquot of impure PGX-7/PGX-8 stock solution (B) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7 and impure PGX-7. Discarded silica gel and re-packed column with fresh silica gel and repeat cycle.
- PGX-7 (152.0 g, 0.374M, 1.0 eq.) was dissolved in dry methanol (2.28 L) under an inert atmosphere and potassium carbonate (31.0 g, 0.224M, 0.6 eq.) added in one portion. The mixture was stirred at ambient temperature for 3 h until TLC showed the reaction was complete. 5M Hydrochloric acid (65.5 ml) was added to adjust the apparent pH of the solution to about 6.8-7.0 and the mixture then evaporated to dryness in vacuo. The sticky residue was treated with water (1.5 L) and the pH adjusted to 6.8-7.0 by the addition of 1M hydrochloric acid (7 ml).
- Heptane (0.45 L) was added, the mixture agitated vigorously and the precipitated solid filtered off and washed with heptane (2 ⁇ 150 ml) on the filter. The solid was then triturated with a further quantity of heptane (2 ⁇ 150 ml). All the heptane washes were combined and added to the original filtrates. The aqueous phase was separated off, washed with heptane (2 ⁇ 150 ml) and then extracted with ethyl acetate (1 ⁇ 450 ml, 3 ⁇ 150 ml). The previously isolated solid was added to the combined ethyl acetate extracts and the mixture shaken until a solution formed.
- PGX-9 (111.5 g 0.369M, 1.0 eq.) was dissolved in ethanol (1.67 L) and 5% palladium on carbon (5.58 g) added followed by a solution of sodium nitrite (8.90 g, 0.129M, 0.35 eq.) in water (100 ml). The mixture was then hydrogenated for 5 h until shown to be complete by TLC. 1M Hydrochloric acid (260 ml) was added and the mixture stirred for 1 h. The solids were removed by filtration through celite, the filtrates then evaporated to give an oily-solid residue which was partitioned between ethyl acetate (0.45 L) and water (0.45 L).
- Example 7 On completion of the reaction described in Example 7, 1M hydrochloric acid was added and the reaction mixture stirred for 60 minutes as described in Example 7. The pH of the mixture was adjusted to between 5 and 6 by addition of solid sodium hydrogen carbonate prior to the filtration of the used catalyst, and evaporation of the filtrate to dryness. The work-up is then completed as described in Example 7 by extraction of the product into ethyl acetate.
- Example 7a illustrates the improved procedure:
- PGX 9 326.5 g, 1.08M, 1.0 eq. was dissolved in ethanol (6.5 L) and 5% palladium on carbon (16.3 g) added followed by a solution of sodium nitrite (26 g, 0.377M, 0.35 eq.) in water (200 ml). The mixture was then hydrogenated for 1.5 h until shown to be complete by TLC. 1M Hydrochloric acid (750 ml) was added and the mixture stirred for 1 h. The pH was adjusted to 5-6 by the addition of solid sodium hydrogen carbonate (55 g).
- PGX-10 (109.7 g, 0.360M, 1.0 eq.) was dissolved in dry dimethyl formamide (720 ml) under an inert atmosphere.
- Imidazole 29.4 g, 0.432M, 1.2 eq.
- triethylamine (102.9 ml, 74.69 g, 0.738M, 2.05 eq.) were added and the mixture then cooled to approximately 0° C.
- Triethylchlorosilane (111.2 g, 0.738M, 2.05 eq.) was added over 15 minutes at less than 10° C. The mixture was allowed to warm to room temperature and stirred for 2 h until TLC showed the reaction was complete.
- PGX-11 (186.8 g, 0.3505M, 1.0 eq.) was dissolved in dry tetrahydrofuran (1.86 L) under an inert atmosphere and the solution cooled to less than ⁇ 70° C.
- Diisobutylaluminium hydride (1.1M in toluene solution, 701 ml, 0.7711M, 2.2 eq.) was added to the reaction whilst maintaining the temperature below ⁇ 70° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC. Methanol (132 ml) was added and the mixture allowed to warm to ⁇ 5° C.
- the amount of (4-carboxybutyl)triphenylphosphonium bromide used in the above reaction is 3.0 equivalents with respect to the amount of starting material PGX-12 used.
- it is treated with 5.6 equivalents of potassium tert-butoxide.
- the slight deficit in the amount of potassium tert-butoxide used with respect to (4-carboxybutyl)triphenylphosphonium bromide is deliberate to ensure that all of the potassium tert-butoxide is consumed and is not present during the reaction with the lactol.
- the organic layer was separated off and the aqueous layer acidified to pH 6 with an additional quantity of 3% aqueous citric acid solution (0.72 L) and then re-extracted with ethyl acetate (2 ⁇ 0.33 L).
- the combined organic phases were washed with 3% aqueous citric acid solution (2 ⁇ 0.8 L), 5% sodium hydrogen carbonate solution (2 ⁇ 0.8 L) and saturated brine (2 ⁇ 1.6 L).
- the solvent was evaporated off and heptane (1.0 L) and ethyl acetate (80 ml) added to the residue. The mixture was cooled to ⁇ 20° C. and agitated vigorously. After 30 minutes at ⁇ 20° C.
- PGX-17 (0.504 g, 0.65 mmol) was weighed into a 50 ml round bottom flask equipped with a magnetic follower. Acetone (6.5 ml) was added and the resulting colourless solution stored at room temperature under a gentle stream of argon.
- the crude product was purified by flash column chromatography.
- a flash column was prepared using silica gel 60 (6 g) and hexane fraction/EtOAc (1:1) as the eluent.
- the crude product (7 mg was removed as retention sample) was dissolved in the eluent (2 ml) and loaded onto the column.
- the column was then eluted with hexane fraction/EtOAc mixtures as follows: Hexane fraction/EtOAc 1:1 50 ml 1:2 150 ml 1:3 80 ml
- PGX-17 (170.0 g, 0.219M) was dissolved in acetone (1.9 L) under an inert atmosphere and a solution of pyridinium-p-toluenesulphonate (4.52 g, 18.0 mMol, 0.08 eq.) in water (0.3 L) added. The resulting mixture was stirred at ambient temperature for 3 h until TLC showed the reaction to be complete. After evaporation of the organic volatiles the residue was added to a mixture of ethyl acetate (2.1 L) and brine (2 L). The layers were separated and the aqueous phase further extracted with ethyl acetate (1 L). The organics were combined and washed with brine (0.5 L).
- HPLC purification of latanoprost was carried out using a Waters RTM Spherisorb silica gel column.
- the isocratic eluent system comprised a hydrocarbon and an alcohol in volume percent ranges of 88-98% and 2-12% respectively.
- the hydrocarbons used were n-hexane, hexane fraction, n-heptane or heptane fraction.
- the alcohols used were isopropanol, ethanol or methanol, either singly or in combination in ratios of 1:1 to 3:1.
- HPLC separations of latanoprost were carried out using a Waters RTM Spherisorb silica gel column.
- the isocratic eluent system comprised hydrocarbon: alcohol:acetonitrile in volume percent ratios of 90-96%: 2-6%: 2-4%.
- the hydrocarbons used were n-hexane, hexane fraction, n-heptane or heptane fraction.
- the alcohols used were either isopropanol or ethanol.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)
- Furan Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
- The present invention relates to a novel process for the synthesis of prostaglandins and prostaglandin analogues. In particular, this invention relates to the synthesis of PGF2α and analogues thereof.
-
- This compound causes uterine contraction and is used clinically to induce and accelerate labour, and as an abortifacient.
- Prostaglandins are generally characterised by the substituents on the cyclopentyl ring. The PGF2α prostaglandins and prostaglandin analogues generally have two hydroxyl groups in a cis configuration relative to the cyclopentane ring, and two side chains in a trans configuration relative to each other, each side chain having one double bond. Analogues of PGF2α can have a different number of double bonds in the side chains, and the substituents along the side chains may vary. Additionally, in some PGF2α analogues, the side chain carboxylic acid group may be esterified.
-
- These compounds have prostaglandin F agonist activity and are used in the clinic for treating glaucoma and ocular hypertension.
-
- This compound is used in the clinic for the reduction of elevated intra-ocular pressure in patients with open angle glaucoma and ocular hypertension.
- Prostaglandin analogues based on PGF2α for use in the treatment of glaucoma and ocular hypertension are described in, for example, European patent number 0 364 417 B1. The procedures for the synthesis of PGF2α analogues described therein start from an advanced-stage intermediate, 16-phenyl-17,18,19,20-trinor PGF2α, or the tetranor homologue thereof.
-
-
-
- is prepared by transforming the hydroxymethyl group of the protected Corey lactone, with an oxidising agent (dicyclohexylcarbodiimide) to form the corresponding aldehyde. Reaction of the aldehyde with a phenylphosphonium salt forms the above intermediate.
-
-
- A subsequent Wittig reaction followed by esterification forms the desired PGF2α product.
- The process disclosed in EP 0 544 899 B1 suffers from a major drawback in that only moderate or low yields are achieved in certain steps. In particular, according to the examples, the yield for the first step (reaction of the PPB-protected Corey lactone with triphenyl-(4-phenyl-3-oxobutylphosphonium iodide on a small scale was only around 49%. Even on a large scale, the reported yield was only around 53%.
- These low yields at the outset result in, at best, difficulties in purifying the intermediates, and at worse, a loss of valuable and expensive starting material. Additionally, the reported yield of 38% in the second step (reduction of the side chain oxo group), is also less than satisfactory.
- Furthermore, only moderate yields are achieved in subsequent reaction steps, resulting in a dramatic reduction of the overall yield.
- In an alternative synthesis described in B. Resul et al., J. Med. Chem. (1993), 36, pp. 243-248, a similar route was employed, with the exception that the deprotection step was carried out before the reduction of the oxo group of the lactone. This process also suffers from low yields (about 58%) in the first step, and only moderate or low yields were reported for subsequent steps.
- In view of the prior art procedures and the problems associated therewith, it is an object of the present invention to provide an alternative process for the synthesis of PGF2α and analogues and salts thereof. Further objects of at least specific embodiments of the invention include the provision of a synthetic route with good yields and intermediates that can be readily purified.
-
- wherein:
- B represents a substituent selected from the group consisting of:
- (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo and CF3; and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3; and
- R″ represents C1-C20 alkyl (preferably a C1 to C6 alkyl group, e.g. methyl, ethyl, propyl and iso-propyl), C3 to C8 cycloalkyl (e.g. cyclohexyl, cyclopropyl, cyclobutyl) or C6 to C10 aryl (preferably phenyl). A preferred R″ group is iso propyl.
- It will be appreciated by a person of skill in the art that the present invention can be applied to the synthesis of compounds of Formula (I-A) and (I-B) wherein R″ is other than an alkyl, cycloalkyl or aryl group. In fact, the group R″ can represent any group that can be introduced by reaction of an acid intermediate of the compound of Formula (I-A) or (I-B) with a compound R″—X (X=halo, and preferably iodo) in the presence of a base, such as DBU. Examples of other suitable R″ groups include, but are not limited to, unsaturated C1 to C20 alkyl, unsaturated C3 to C8 cycloalkyl, wherein the saturated or unsaturated alkyl or cycloalkyl groups, or aryl groups can be substituted with one or more (typically 1 to 3) substituents such as CF3, C1 to C6 alkoxy, CN. Other examples of suitable R″ groups include C6 to C10 heterocycloalkyl (e.g. piperidinyl), C6 to C10 heteroaryl (such as pyridyl) and substituted C6 to C10 aryl (including substituents such as CF3, C1 to C6 alkoxy, CN).
- The embodiments of the process of the present invention is shown in Schemes 1-4:
-
-
-
-
-
- wherein
- A represents C6 to C10 aryl which may be substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C1 to C6 alkyl and (iii) unsubstituted C6 to C10 aryl;
-
- to an oxidation reaction in the presence of a catalytic amount of a stable organic nitroxyl radical.
- The above reaction may be carried out by electrooxidation in the presence of the organic nitroxyl radical.
- Alternatively, the oxidation reaction may be carried out in the presence of a nitroxyl radical and at least one molar equivalent of a co-oxidant selected from the group consisting of m-chloroperbenzoic acid, high-valent metal salts, sodium bromite, sodium or calcium hypochlorite, N-chlorosuccinimide or hypervalent iodine compounds such as [bis(acetoxy)iodo]benzene. Preferably, the co-oxidant is sodium hypochlorite.
- The stable organic radical preferably comprises a completely α-substituted piperidin-1-oxy radical, such as 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO, free radical).
- Prior art oxidation procedures for oxidising the compound of Formula (X) to form the compound of Formula (IX) include the use of dimethylsulfoxide-dicyclohexylcarbodiimide. However, such a method requires isolation of the aldehyde (IX). Since the aldehyde (IX) is not particularly stable in solution, an amount of decomposition product is usually observed during work-up.
- Advantageously, in the present method of oxidation of the compound of Formula (IX) using a stable organic radical such as TEMPO free radical, the aldehyde (IX) solution obtained in this step can be employed in the subsequent step without isolation of the aldehyde, thus minimising any decomposition.
-
- wherein
- A represents C6 to C10 aryl which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C1 to C6 alkyl and (iii) unsubstituted C6 to C10 aryl;
- B represents a substituent selected from the group consisting of: (i) C1 to C6 alkyl, (ii) C7 to C1-6 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo and CF3 and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3,
-
-
- wherein A and B are as defined as above, and each R′″ is the same or different (preferably the same) and each represents a C1 to C6 alkyl group (preferably methyl), the process being carried out in the presence of lithium chloride and an organic base (such as tertiary alkylamines, e.g. di-iso-propylethylamine).
- The compounds of Formula (IX) are commercially available or can be made from commercially available starting materials. For example, the compound of Formula (IX) may be prepared by the process described in U.S. Pat. No. 3,778,450.
-
-
-
-
-
-
- The product from this reaction can be typically purified by distillation. Advantageously, this reaction is usually free of side reactions compared with the prior art process using dimethyl(2-oxopropyl)phosphonate.
- The process described above for producing the compound of formula Vil is a modified Horner-Wadsworth-Emmons reaction carried out in milder conditions, in which the usual base used to generate the anion of the phosphonate, sodium hydride in THF or potassium carbonate in toluene, is replaced by a base selected from the group consisting of tertiary alkylamines, such as triethylamine and diisopropylethylamine and DBU [1,8-diazabicyclo(5.4.0)undec-7-ene]. Advantageously, unlike the prior art methods which can lead to poor to moderate yields of the product (VIII), the use of milder reagents, i.e. lithium cations from lithium chloride, in combination with these tertiary alkylamines leads to cleaner reactions with high yield of product.
- The reaction is preferably carried out at temperatures in the range of −20° C. to 40° C., and preferably −10° C. to 30° C. Suitable solvents for this reaction include those selected from the group consisting of benzene, toluene, acetonitrile, dichloromethane, diethylether, and mixtures thereof.
- In the compound of Formula (VIII), the group A preferably represents an unsubstituted C6 to C10 aryl group (e.g. phenyl).
- Other preferred substituents for the group A include those selected from C6 to C10 aryl group being substituted with one substituent selected from halo or phenyl. Further preferred substituents for the group A include unsubstituted or substituted phenyl wherein the substituent is selected from halo or phenyl. In a preferred process, the group A represents phenyl.
-
- wherein
- A represents unsubstituted C6 to C10 aryl;
- B represents a substituent selected from the group consisting of:
- (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo and CF3 and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3;
-
- Suitable reducing agents for the reduction of the side chain oxo group include borane-dimethylsulfide complex, lithium tri-sec-butylborohydride, {LiB[CH(CH3)CH(C2H5]3H} (L-SelectrideRTM) and sodium borohydride. Where the final product is desired as a racemate (such as fluprostenol), a non-stereoselective reducing agent may be used (e.g. LiAlH4, NaBH4 and other metallic hydrides).
- Where the final product is desired as a single isomer (e.g. as in latanoprost), the reducing agent suitably comprises borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine catalyst (“Corey catalyst”) because of the greater selectivity towards the production of a major amount of the desired isomer. Although this reaction strongly favours the production of the desired isomer, any undesired isomer which may be formed, may be separated by chromatographic techniques, such as flash column chromatography.
- Thus, a preferred reagent for the reduction reaction is borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine catalyst (Corey catalyst). In this embodiment of the present invention, the group A in the compound of Formula (VII), in addition to being unsubstituted C6 to C10 aryl, can also represent C6 to C10 aryl substituted with one to three substituents independently selected from the group consisting of (i) halo, i.e. fluoro, chloro, bromo or iodo, (ii) C1 to C6 alkyl and (iii) Ce to C10 aryl, such as phenyl.
- The use of borane-dimethylsulfide complex in combination with a Corey catalyst is especially preferred because the reaction takes place with excellent selectivity. In fact, a marked improvement in stereoselectivity is seen compared with the reaction using L-SelectrideRTM. A further advantage is that the reduction reaction using borane-dimethylsulfide complex can be carried out at a higher temperature (typically −15° C. to −18° C.) compared with L-SelectrideRTM, which requires a reaction temperature of less than −70° C.
- The Corey catalyst comprises a chiral oxazaborolidine compound [see J. Am. Chem. Soc., 109, 5551, (1987) and J. Am. Chem. Soc. 109, 7925, (1987) and references cited in Lancaster Catalogue 2000-2001, page 819] such as (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrole[1,2-c][1,3,2]oxazaborole, may be prepared by reaction of the appropriate chiral prolinol [such as the commercially available (R)-(+)-α,α-diphenylprolinol] with a trialkyl boroxine, e.g.:
- The reaction is carried out in inert conditions in a solvent such as toluene, diethylether or tetrahydrofuran. The oxazaborolidine catalyst is employed as a solution in the reduction step.
-
- wherein
- the dashed line forms an optional double bond;
- B represents a substituent selected from the group consisting of:
- (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6alkyl, halo and CF3 and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3; and
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl;
- the process comprising the steps of:
-
- wherein A represents C6 to C10 aryl which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C1 to C6 alkyl and (iii) unsubstituted C6 to C10 aryl;
-
-
-
- wherein Rx, Ry and Rz are as defined above and X represents F, Cl, Br or I.
- The deprotection step (a) wherein the protecting group A on the hydroxyl group of the cyclopentane ring is removed, is preferably carried out in the presence of a base. Preferred bases for use in the deprotection reaction includes those selected from the group consisting of K2CO3, Na2CO3 and Li2CO3, with K2CO3 being particularly preferred.
- Suitable solvents for the deprotection reaction include alcohols, such as methanol, ethanol and isopropanol.
- The isolation of the deprotected product from step (a) may be carried out by standard chromatography procedures. However, it has been found that the deprotected product can advantageously be isolated by extraction with hexane fractions, thus avoiding the use of time consuming and expensive chromatographic procedures.
- For the production of prostaglandin derivatives having one saturated side chain, such as latanoprost described above, it is convenient at this stage, i.e. after the deprotection step (a), to hydrogenate the double bond in the side chain to form the intermediate of Formula (VI-A).
- The hydrogenation step can be carried out using any suitable hydrogenation catalyst such as palladium, platinum or rhodium, which may be supported on an inert support, such as carbon. An example of a suitable hydrogenation catalyst is 5% palladium on carbon.
- In a preferred procedure, the hydrogenation reaction is carried out in the presence of sodium nitrite, preferably in aqueous solution. This procedure avoids the formation of elimination products and thus results in improved yields (typically greater than 95%) of the compounds of Formula (VI-A). Suitable solvents for the hydrogenation reaction include alcohols such as methanol and ethanol. On completion of the hydrogenation reaction, the mixture is preferably stirred with dilute hydrochloric acid to remove the nitrite (by conversion to nitrous acid, which decomposes at ambient temperature). This procedure ensures that nitrite is not carried through to the subsequent synthetic procedures.
- Without wishing to be bound by theory, the role of the sodium nitrite in the hydrogenation reaction is to avoid the formation of elimination products, that is, the elimination of a water molecule from the side chain of the starting material and, as a consequence, formation of the fully saturated deoxygenated analogue of the desired product.
- In order to produce the compound of Formula (V), the compound produced in step (a) having the Formula (VI) or the compound produced in step (b) having the Formula (VI-A) is reacted with a silylating agent (X)Si(Rx)(Ry)(Rz). The groups Rx, Ry, and Rz can be the same or different each represents a C1 to C6 alkyl group or a C6 to C10 aryl group. Preferably, each of the groups Rx, Ry, and Rz are independently selected from methyl, ethyl, butyl, isopropyl. Particularly preferred silylating agents for use in step (c) are selected from the group consisting of trimethylsilyl chloride, triethylsilyl chloride and tert-butyldimethylsilyl chloride. Triethylsilyl chloride is particularly preferred.
- The silylation step is preferably carried out in the presence of a base, for example an organic base, such as imidazole or trialkylamines, such as triethylamine.
- Suitable solvents for use in the silylation reaction include polar aprotic solvents such as tetrahydrofuran or dimethylsulfoxide, or chlorinated solvents such as dichloromethane. Preferably, however, the reaction is carried out in a solvent comprising dimethylformamide.
- The use of silyl protecting groups in accordance with the present invention is advantageous because it generally results in cleaner reactions, with higher yields compared with reactions wherein the hydroxyl group is not protected.
- The use of silyl protecting groups in the present process has particular advantages compared with the prior art process employing, e.g. benzoyl- and para-phenylbenzoyl (PPB)-protecting groups because silyl groups are stable to the subsequent reduction reaction with e.g. DIBAL-H (di-iso-butylaluminium).
- In fact, the presence of benzoyl- and PPB-protecting groups prevents the use of many reducing agents, including DIBAL-H, in the subsequent reduction of the lactone ring to form the lactol, because such a reaction can result in the reduction of the oxo moieties in the protecting groups. Thus, in prior art procedures wherein DIBAL is employed as a reducing agent and wherein the starting material comprises benzoyl- or PPB-protecting groups, starting materials must be deprotected prior to the reduction step. However, the presence of unprotected hydroxyl groups in the DIBAL-H reduction step is undesirable because each free hydroxyl group or the starting material coordinates with DIBAL-H. As a result, the use of additional equivalents of DIBAL-H becomes necessary.
- A second advantage of using silyl protecting groups in the subsequent Wittig reaction [step (i) in Scheme 1], is that the formation of the desired cis isomer is favoured. Silyl protecting groups have the further advantage in that they generally increase the lipophilic character of the molecules, so that their derivatives are readily soluble in organic solvents. Thus, in the Wittig reaction, removal of the phosphine oxide by-product is facilitated because the silyl-protected Wittig reaction product [(IIIa)/(IIIb)] is soluble in hexane, whereas the triphenylphosphine oxide is insoluble, thus allowing separation by filtration. Subsequent purification of the product can be carried out by silica gel filtration, rather than a full chromatographic purification.
- A further advantage of employing silyl protecting groups is that these protecting groups can be removed under mild conditions, as discussed below.
-
- can be made from compounds of Formula (VIII) by a process comprising the steps of:
-
-
-
-
-
- wherein Rx, Ry and Rz are as defined above and X represents F, Cl, Br or I.
- Steps (a) to (c) of this process are depicted as steps (e′), (c′) and (d′) in Scheme 2. Step (d) corresponds to step (f) of Scheme 1, the product of which is a compound of Formula (V) wherein the dashed and solid line represents a single bond. The hydrogenation, reduction, deprotection and silylation steps in this alternative procedure are carried out as for the immediately preceding process to form the compounds of Formula (V).
-
- wherein:
- the dashed line forms an optional double bond;
- B represents a substituent selected from the group consisting of:
- (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6alkyl, halo and CF3 and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3; and
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl;
-
- A suitable reducing agent for this process is di-iso-butylaluminium hydride DIBAL-H), and the reaction may be carried out in e.g. tetrahydrofuran.
-
- wherein
- the dashed line forms an optional double bond;
- B represents a substituent selected from the group consisting of:
- (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo and CF3 and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3; and
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl;
-
-
- O2C(CH2)4P(Rw)3X
- with a strong base, wherein
- Rw represents C1 to C6 alkyl or C6 to C10 aryl; and
- X represents fluoro, chloro, bromo or iodo.
- Preferably, the group Rw represents phenyl. The group X preferably represents bromo.
- Reagents of formula:
- HO2C(CH2)4P(Rw)3X
- are commercially available, or can be prepared by reaction of a phosphine, P(Rw)3, with HO2C(CH2)4—X′ (wherein X′ represents halide, e.g. F, Cl, Br or I). Suitable bases for the forming the ylide include those selected from the group consisting of butyllithium, sodium amide, sodium hydride, and alkali metal alkoxides, including sodium methoxide, sodium ethoxide, potassium ethoxide and potassium tert-butoxide. Potassium tert-butoxide is a particularly preferred base. A suitable solvent for this reaction is tetrahydrofuran.
-
- The ylide can be generated using 3 equivalents of the phosphonium halide and 6 equivalents of base, i.e. a ratio of phosphonium halide and base of 1:2, but is preferably generated using 2.15 equivalents of the phosphonium halide and 4 equivalents of base.
- During the Wittig reaction, the silyl protecting groups of the hydroxyl substituent on the cyclopentyl ring may migrate to the hydroxyl group formed by the opening of the lactol ring, to result in a mixture of 9- and 11-silylated isomers of Formula (IIIa) and (IIIb).
- Although the mixture of compounds (IIIa) and (IIIb) can be separated e.g. by chromatographic procedures, separation is not necessary at this stage because the protecting groups are removed in subsequent reaction steps. Thus, in the process according to the invention, it is preferred that such a mixture of the 9- and 11-silylated isomers (IIIa) and (IIIb) is used in the subsequent reaction step without separation.
-
- wherein
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl;
-
- wherein Rx, Ry and Rz are as defined above and X represents F, Cl, Br or I.
- This procedure is advantageously carried out where a mixture of the compounds of Formula (IIIa) and Formula (IIIb) are formed as the products of the Wittig reaction. The reaction of such a mixture with at least one molar equivalent of a silylating agent, preferably the same silylating agent as is used to protect the hydroxyl groups of the compounds of Formula (V), enables the mixture of compounds of Formula (IIIa) and (IIIb) to be “amalgamated” into a single product of Formula (XI) for subsequent reaction steps. Preferably, in this step, at least a molar equivalent of silylating agent to starting material is employed. Typically, 1.1 to 2 molar equivalents are employed. The formation of a single product allows for better control of subsequent reaction steps and purification.
-
- wherein
- the dashed line represents an optional double bond;
- B represents a substituent selected from the group consisting of: (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo and CF3 and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3;
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl; and
- R″ represents C1 to C6 alkyl or C3 to C8 cycloalkyl;
- the process comprising subjecting a compound of Formula (IIIa) or Formula (IIIb) or a mixture thereof, to reaction with an alkyl halide of formula R″-Hal, wherein R″ represents a C1 to C6 alkyl group (such as isopropyl) or a C3 to C8 cycloalkyl group, and “Hal” represents chloro, bromo, or iodo (preferably iodo), in the presence of DBU.
- As indicated above, when the Wittig reaction results in migration of the silyl protecting group to form a mixture of 9- and 11-silylated isomers of Formula (IIIa) and (IIIb), the mixture may be alkylated by the process indicated above, to form a mixture of 9- and 11-silylated esters of Formula (IIa) and (IIb). Instead of carrying out a silylation of a mixture of compounds of Formula (IIIa) and (IIIb), it is also possible to carry out the silylation after the alkylation step, i.e. on the mixture of compounds of Formula (IIa) and (IIb).
-
- wherein
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl; and
- R″ represents C1 to C6 alkyl or C3 to C8 cycloalkyl,
-
- wherein Rx, Ry and Rz are as defined above and X represents F, Cl, Br or I.
- As indicated above for the silylation of the mixture of compounds of Formula (IIIa) and (IIIb), this process is preferably carried out in the presence of at least a molar equivalent of silylating agent, and even more preferably 1.1 to 2 molar equivalents of silylating agent is employed. Again, this step leads to the “amalgamation” of the mixture of compounds of Formula (IIa) and (IIb) to form a single product [i.e. compounds of Formula (XII)] which facilitates control of subsequent reaction steps and purification of subsequent intermediates.
- It has been found that in the steps wherein the mixtures of compound of Formula (IIa) and (IIb) or mixtures of compounds of Formula (lla) and (IIIb) are reacted with silylating agents to form single products of Formula (XII) and Formula (XI) respectively (i.e. precursors to the target compounds of Formula IA and IB), purification is facilitated. Advantageously, it has been found that the compounds of Formula (XII) and (XI) can be purified by simply by filtration through silica gel, thus obviating the need to perform a full chromatographic separation, which is particularly undesirable at the late stage of the synthetic process. One reason for this is that the presence of three silyl groups in the compounds of Formula (XII) and (XI) leads to highly lipophilic molecules, which are highly soluble in heptane and thus can be easily separated from the more polar impurities.
-
- wherein:
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl; and
- R″ represents C1 to C6 alkyl or C3 to C8 cycloalkyl;
-
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl;
- to a reaction with an alcohol, having the formula R″—OH, wherein R″ represents a C1 to C6 alkyl group (e.g. isopropanol) or C3 to C8 cycloalkyl (e.g. cyclohexanol).
- The above process may be carried out optionally in the presence of a weak acid catalyst, such as pyridinium p-toluenesulfonate. The reaction should be carried out in the absence of water, to avoid deprotection of the silyl groups.
-
- wherein
- B represents a substituent selected from the group consisting of:
- (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo and CF3 and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3;
- the process comprising removing the silyl protecting groups, R′, from a compound selected from the group consisting of
-
-
- wherein B and R′ are as defined above.
-
- wherein
- B represents a substituent selected from the group consisting of:
- (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo and CF3 and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3; and
- R″ represents C1 to C6 alkyl or C3 to C8 cycloalkyl;
- the process comprising removing the silyl protecting groups R′ from a compound selected from the group consisting of:
-
- and
-
- wherein B and R″ are as defined as above.
- The deprotection of the silyl protecting groups R′ is advantageously carried out in mild reaction conditions. Suitable reagents for removal of the silyl groups from the compounds of Formula (IIIa), (IIIb), (XI), (IIa), (IIb) and (XII) include weak acids such as acetic acid and citric acid. An especially preferred weak acid is pyridinium p-toluenesulfonate.
- The reaction may be carried out in any suitable solvent or solvent mixtures. An especially preferred solvent for the deprotection reaction comprises acetone and water.
- In accordance with preferred embodiments of the present invention, the compounds of Formulae (VI), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A), (I-B), (XI), (XII) and (XIV) are single enantiomers (i.e. the wavy line in the side chain represents or ). As discussed above, such compounds can be made by using a stereoselective reducing agent [e.g. borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine (Corey) catalyst] in step (c) of Scheme 1, or step (c′) in Scheme 2.
- In accordance with preferred embodiments of the present invention, the group B in the compounds of Formula (XII), (XI), (VII), (VII), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) or (I-B) is selected from the group consisting of (I) C1 to C6 alkyl, (ii) C7 to C16 aralkyl wherein the aryl group is unsubstituted and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which is substituted with a substituent selected from halo or CF3.
- Even more preferred are compounds of Formula (XII), (XI), (VIII), (VII), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) or (I-B) wherein B is selected from the group consisting of (i) C1 to C6 straight chain alkyl, (ii) —(CH2)2Ph and (iii) —CH2ORa, wherein Ra represents a phenyl group substituted with a chloro or CF3 group.
-
- In a further preferred embodiment of the present invention, the solid and dashed lines in each of Formulae (XII), (XI) (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) and (I-B) forms a single bond.
- In yet another preferred embodiment, the solid and dashed lines in each of Formulae (XII), (XI) (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) and (I-B) forms a double bond.
- For the compounds of Formulae (XII), (XI) (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) and (I-B) wherein the solid and dashed line represents a single bond, B preferably represents —CH2CH2Ph.
-
-
- In a preferred embodiment, the present invention provides a process for the synthesis of latanoprost comprising the steps of:
-
- wherein A represents a C6 to C10 aryl group, preferably phenyl, which may be substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C1 to C6 alkyl and (iii) unsubstituted C6 to C10 aryl,
-
-
-
- (3) reducing the side chain oxo group of the compound of Formula (VIII) using borane-dimethylsulfide complex, the reduction being carried out in the presence of a chiral oxazaborolidine catalyst, such as (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrole[1,2c][1,3,2]oxazaborole, to form a compound of Formula (VIII) wherein B is —CH2CH2Ph:
-
-
-
-
-
-
-
- O2C(C H2)4PP h3X
-
- or a mixture thereof;
-
- or a mixture thereof; and
-
- The above steps (1) to (10) correspond to steps (a)-(b)-(c)-(d)-(e)-(f)-(h)-(i)-(j)-(k) in Scheme 1 above.
- In an alternative process, latanoprost can be formed by a procedure involving carrying out steps (1) and (2) of the preceding process, replacing steps (3), (4) and (5) with the following steps (3′), (4′) and (5′), and thereafter carrying out steps (6-(10) as described in the preceding process. Steps (3′), (4′) and (5′) are as follows:
- (3′) subjecting the double bond of the compound of Formula (VIII) to a hydrogenation reaction in the presence of a hydrogenation catalyst (e.g. palladium, platinum or rhodium), the reaction being carried out optionally in the presence of sodium nitrite, to form a compound of Formula (XIII) wherein B is —CH2CH2Ph:
- (4′) reducing the side chain oxo group of the above compound of Formula (XIII) using borane-dimethylsulfide complex, the reduction being carried out in the presence of a chiral oxazaborolidine catalyst, such as (R)tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrole[1,2c]-[1,3,2]oxazaborole, to form a compound of Formula (XIV) wherein B is —CH2CH2Ph:
- and
-
- This procedure corresponds to steps (a)-(b)-(e′)-(c′)-(d′)-(f-(h)-(i)-(j)-(k) depicted in Scheme 1 and Scheme 2.
-
- and further carrying out the steps of:
-
- wherein each R′ is as defined as above;
-
- and
- (11a) removing the protecting groups R′ to form latanoprost.
- These steps (9a) to (11a) correspond to steps (m)-(O)-(p) in Scheme 2 above.
-
- and carrying out the further steps of:
-
- and
- (11b) removing the protecting groups R′ to form latanoprost.
- The above steps (10b) and (11b) correspond to steps (q)-(r) shown in Scheme 3 above.
- According to a further aspect of the present invention, there are provided novel intermediates for the synthesis of a compound of Formula (I-A) or (I-B) as defined above. The novel intermediates include the following:
-
- wherein
- A represents unsubstituted C6 to C10 aryl; and
- B represents a substituent selected from the group consisting of: (i) C1 to C6 alkyl, (ii) C7 to C16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo and CF3; and (iii) —(CH2)nORa, wherein n represents 1, 2 or 3 and Ra represents a C6 to C10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1 to C6 alkyl, halo or CF3.
-
- and single enantiomers thereof, wherein A and B are as defined herein;
-
- and single enantiomers thereof wherein B is as defined herein;
-
- and single enantiomers thereof wherein B is as defined herein;
-
-
- wherein Rx, Ry and Rz are the same or different and each independently represents C1 to C6 alkyl, C6 to C10 aryl or C7 to C16 aralkyl;
-
- and single enantiomers thereof wherein B and R′ are as defined herein;
-
- and single enantiomers, and mixtures thereof wherein B and R′ are as defined herein;
-
- and single enantiomers and mixtures thereof wherein B. R′ and R″ are as defined herein;
-
- and single enantiomers thereof wherein B and R′ are as defined herein;
-
- and single enantiomers thereof wherein B and R′ are as defined herein;
-
- wherein A represents unsubstituted C6 to C10 aryl, and B is as defined herein; and
-
- and single enantiomers thereof wherein A represents unsubstituted C6 to C10 aryl and B is as defined herein.
- Preferably, in any of the structures herein, the group A represents phenyl.
-
-
- Preferably, for the intermediates of Formula (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (XI) and (XII), the solid and dashed lines represent a single bond and B represents —CH2CH2Ph.
-
-
- In the compounds of Formula (XII), (IIa), (IIb) and (I-B), the group R″ preferably represents iso-propyl.
- The present invention further provides the use of any novel intermediate as defined as above in the manufacture of latanoprost and the use of any novel intermediate as defined as above in the manufacture of cloprostenol, fluprostenol, PGF2α, travoprost, or a PGF (preferably PGF2α) analogue.
-
- wherein the group X represents F, Cl, Br or I and Rx, Ry and Rz are as previously defined, for protecting a hydroxyl group of an intermediate in the synthesis of a prostaglandin or prostaglandin analogue, such as prostaglandin or prostaglandin analogues based on PG-A, PG-B, PG-C PG-D or PGF. The use of these silylating agents is particularly suitable in the synthesis of prostaglandin PGF2α or prostaglandin analogues based on PGF2α, including latanoprost, cloprostenol, fluprostenol and travoprost. Of these, latanoprost is particularly preferred.
- Preferred Rx, Ry and Rz are methyl, ethyl and tert-butyl. A particularly preferred silylating reagent is triethylsilylchloride.
-
- by the provision of one or more additional reaction steps in order to modify the functional groups on the cyclopentyl ring—for example, oxidation of the cyclopentyl ring oxo groups in the PGF derivatives would result in either the PGD or PGE analogues.
- As used herein hatched lines attached to the cyclopentane ring indicate bonds that are below the plane of the ring (i.e. bonds in an alpha configuration). Solid wedges attached to the cyclopentane ring indicate bonds that are above the plane of the ring (rings in the beta configuration). It is to be understood that a wavy line, i.e.
-
-
-
- It has been found that the major impurities in latanoprost, particular when produced by the methods of the present invention, include the following:
-
-
-
- In particular, it has been found that the isomers of latanoprost are particularly difficult to remove because they have similar physical and chemical properties to latanoprost.
- The present applicant has found that it is possible to obtain a separation of latanoprost from the 15(S)-cis-, 15(S)-trans- and 15(R)trans isomers of latanoprost using an HPLC purification system with a chiral column. However chiral columns are expensive and are not practical for large scale separations.
- These problems have been solved by the use of a non-chiral column and a particular eluent mixture in the HPLC purification of latanoprost. Accordingly, the present invention further provides a process for the purification of latanoprost by HPLC comprising the use as an eluent, of a mixture comprising a hydrocarbon, an alcohol and, optionally, acetonitrile.
- The use of such an eluent combination is a particularly preferred method of purification of latanoprost when made by the processes of the present invention. It has been found that the above eluent mixtures can achieve an extremely high purity of the latanoprost.
- Preferably, the eluent comprises a hydrocarbon, an alcohol and acetonitrile. Advantageously, it has been found that the use of acetonitrile as a component of the eluent in the HPLC purification of latanoprost results in an improved separation of the impurities. In particular, the use of acetonitrile as a component of the above eluent mixture results in a significantly improved separation of the hitherto difficult to separate 15(S)-trans isomer of latanoprost. In particular, it has been found that the 15(S)-trans isomer does not co-elute with the latanoprost, i.e. a baseline separation of latanoprost of the 15(S)-trans isomer can be achieved. As a result, a higher yield of pure latanoprost may be obtained using the above eluent system compared with prior art procedures.
- In particular the eluent systems in the present purification process comprises a hydrocarbon in an amount range of 80-99 volume percent and an alcohol in an amount range of 1-20 volume percent. Preferably, the eluent comprises a hydrocarbon in an amount range of 85-99 volume percent and an alcohol in an amount range of 1-15 volume percent. Even more preferred is an eluent comprising a hydrocarbon in an amount range of 88-98 volume percent and an alcohol in an amount range of 2-12 volume percent.
- In the preferred acetonitrile-containing eluent systems of the present purification process, the eluent comprises a hydrocarbon in an amount range of 85-99 volume percent, an alcohol in an amount of 0.5-10 volume percent and acetonitrile in an amount of 0.5-5 volume percent. Preferred is an eluent comprises a hydrocarbon in an amount range of 86-98 volume percent, an alcohol in an amount of 1-8 volume percent and acetonitrile in an amount of 1-6 volume percent. Especially preferred is an eluent comprising a hydrocarbon in an amount range of 90-96 volume percent, an alcohol in an amount of 2-6 volume percent and acetonitrile in an amount of 2-4 volume percent.
- In the above eluent systems it is preferred that the hydrocarbon is a C5 to C8 straight chain, branched or cyclic hydrocarbon, wherein the hydrocarbon is preferably an n-alkane. Hexane and heptane are especially preferred. The hydrocarbon employed in the eluent may comprise a mixture of e.g. alkanes, such as hexane fraction. It has been found that good results have been obtained with n-heptane.
- Preferred alcohols in the above eluent systems are C1 to C8 straight chain, branched or cyclic alkanols, with C1 to C5 straight chain or branched alkanols being particularly preferred. Of these, methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol or butan-2-ol are especially useful. Good results have been obtained with propan-2-ol (isopropanol) as the alcohol component. The use of ethanol as the alcohol component has also produced good separations. The alcohol component of the eluent can include mixtures of one or more alkanols, e.g. combinations of two or more of isopropanol, ethanol and methanol may be used, e.g mixtures in ratios of 1:1 to 3:1 have been successfully employed.
- A preferred eluent system comprises n-heptane:isopropanol:acetonitrile. Preferred volume percent ranges of n-heptane: isopropanol:acetonitrile are 90-96%:2-7%:2-5%. Preferably, the ratios of n-heptane:isopropanol: acetonitrile are in the ranges 92-94%:3-5%:2-4%. Good results have been obtained with ratios of 93%: 4%:3%.
- The above HPLC procedures are preferably carried out on a silica gel column. Examples of suitable columns include WatersRTM Spherisorb, PhenomenexRTM Luna Cyano and PhenomenexRTM Luna Silica.
- By using the above separation procedures, it has been found possible to produce latanoprost that is substantially free of the 15(S)-cis isomer, the 15(S)-trans isomer and the 15(R)-trans isomer. In particular, latanoprost containing less than 0.3% in total of any combination of: 15(S)-cis isomer, 15(S)-trans isomer and 15(R)-trans isomer may be produced. Using the process of the present invention, latanoprost containing less than 0.1% each of 15(S)-cis-, 15(S)-trans- and 15(R)-trans isomers can be produced.
- The above processes thus enable latanoprost 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 latanoprost purities of greater than 99.8%.
- The following abbreviations have been used:
- HPLC=high pressure liquid chromatography
- MPLC=medium pressure liquid chromatography
- L-Selectride=lithium tri-sec-butylborohydride
- DMS=dimethylsulfide
- DIBAL-H=di-iso-butylaluminiumhydride
- PPB=para-phenylbenzoyl
- DBU=[1,8-diazabicyclo(5.4.0)undec-7-ene]
-
- TEMPO, free radical=2,2,6,6-tetramethyl-1-piperidinyloxy, free radical
- EtOAc=ethylacetate
- DMF=dimethylformamide
- TsOH=para-toluenesulphonic acid
-
- As used herein the term “alkyl” refers to C1 to C6 straight or branched carbon chains. Particularly preferred alkyl groups for the compounds and processes of the invention include methyl, ethyl, propyl, isopropyl, butyl, and tertiary butyl.
- The term “aryl” represents a carbocyclic group containing from six to fifteen carbon atoms and having at least one aromatic ring. Particularly preferred aryl groups for any of the compounds and methods of the present invention include phenyl and naphthyl.
- The term “aralkyl” refers to an alkyl group as defined above wherein one or more hydrogen atoms (preferably one) have been replaced by unsubstituted C6 to C10 aryl groups as defined above. A preferred aralkyl group for the compounds and methods of the invention is benzyl.
- The term “halo” refers to fluoro, chloro, bromo or iodo.
- The term “substantially free” of a particular impurity refers to less than 1%, preferably less than 0.5%, more preferably, less than 0.3% and even more preferably, less than 0.1% of the impurity.
- The following examples illustrates the preparation of latanoprost in accordance with the present invention:
- Solvents (chromatography grade) were dried over 3 Å molecular sieves prior to use. Purified water was obtained from Loveridge.
- The products obtained in the reactions were sealed under argon and stored in a cold room at 4° C. until required.
- Column chromatography was carried out on Merck silica gel 60.
- As a precaution, where indicated, reactions were carried out under argon. Reaction progress was monitored by thin layer chromatography.
- Unless indicated otherwise, final products were dried under high vacuum at a pressure of about 0.01 kPa.
-
- A 0.5M solution of potassium bromide was prepared by dissolving KBr (11.9 g) in purified water and then diluting with additional water to 200 ml.
- 2.1M Sodium hypochlorite solution (476 ml, 1M) was diluted to 1 L by the addition of purified water to give a 1M solution. The pH was then adjusted to 8.83 by the addition, with stirring, of solid sodium bicarbonate.
- (−)-Benzyl Corey Lactone (PGX-4) (200 g, 0.724M, 1 eq.) was dissolved in dichloromethane (2 L) under an inert atmosphere and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) free radical (1.13 g, 7.24 mmol, 0.01 eq.) and the aqueous potassium bromide solution prepared above added. The mixture was cooled to approximately 0° C. with stirring and a portion of the aqueous sodium hypochlorite solution prepared above (100 ml) added at this temperature. The reaction was allowed to warm to 10° C. and an additional quantity of the aqueous sodium hypochlorite solution (896 ml) added at 10-15° C. over 40 minutes. After stirring for 20 minutes the reaction was shown to be complete by TLC. The layers were separated, the aqueous phase extracted with dichloromethane (200 ml) and the combined organic phases then washed with water (200 ml) before drying over magnesium sulfate. Filtration and washing of the filtercake with dichloromethane (2×200 ml) gave (1S,5R,6R,7R)-7-benzoyloxy-6-formyl-2-oxabicyclo[3.3.0]octan-3-one (PGX-5) as a solution in dichloromethane.
-
- Dimethyl methyl phosphonate (PGX-1) (346.2 g, 2.79M, 1.95 eq.) was dissolved in tetrahydrofuran (2.4 L) and the resulting solution cooled to −70° C. under an inert atmosphere. n-Butyllithium (2.5M in tetrahydrofuran, 1.0 L, 2.5M, 1.75 eq.) was added over 105 minutes whilst maintaining the temperature below −65° C. The resulting white suspension was stirred at approximately −70° C. for 20 minutes. A solution of methyl 3-phenyl propionate (PGX-2) (234.8 g, 1.43M, 1.0 eq.) in tetrahydrofuran (400 ml) was then added over 30 minutes whilst maintaining the temperature below −65° C. The mixture was left to stir at approximately −70° C. for 2.5 h until the reaction was complete by TLC. After allowing to warm to approximately 0° C. the reaction was quenched by addition of water (800 ml). tert-Butylmethyl ether (1.0 L) was added and the mixture allowed to separate. The organic phase was extracted with water (5×500 ml), and the combined aqueous phases acidified to pH 2 by the addition of 10% hydrochloric acid (ca. 110 ml). The product was extracted into tert-butylmethyl ether (2×800 ml, then 5×500 ml) and the combined organics dried over magnesium sulfate. Filtration, washing the filtercake with tert-butylmethyl ether (400 ml) and evaporation gave the crude product as an oil (240.4 g). Distillation under reduced pressure (bp 152-156° C. at 8×10−5-1×10−4 torr) gave dimethyl (2-oxo-4-phenylbutyl)phosphonate as an almost colourless oil (214.1 g 58%).
-
- The phosphonate ester (PGX-3) (176.2 g, 0.69M, 0.95 eq.) was dissolved in dry acetonitrile (1.8 L) in an inert atmosphere and lithium chloride (153.4 g, 3.62M, 5.0 eq.) added. The mixture was cooled to approximately −15° C. and dry diisopropyl ethylamine (178.1 g, 1.38M, 1.9 eq.) added over 10 minutes whilst maintaining this temperature. After stirring for about 100 minutes a solution of the aldehyde (PGX-5) in dry dichloromethane (from Step 2) (assumed 0.72M, 1.0 eq.) was added over 20 minutes whilst maintaining the temperature at ca. −15° C. The reaction was then allowed to warm to ambient temperature with stirring until TLC showed it was complete. Water (200 ml) was added and the mixture evaporated in vacuo to remove the majority of the acetonitrile. The residual slurry was partitioned between water (2.0 L) and ethyl acetate (2.0 L). The organic phase was separated off and the aqueous extracted with ethyl acetate (2×500 ml). The combined organics were washed with saturated brine (2×1 L) and dried over magnesium sulfate. After filtration, the solvent was evaporated off to a residual weight of ca. 540 g and hexane (1 L) then added to the residue. After cooling to 4° C. with stirring for 90 minutes the solid was filtered off, washed with hexane:ethyl acetate 4:1 (2×200 ml) and dried in vacuo at ambient temperature to give (1S,5R,6R,7R)-7-benzoyloxy-6-[3-oxo-5-phenyl-(E)-1-pentenyl]-2-oxabicyclo[3.3.0]octan-3-one as a white solid (225.8 g, 77%).
-
- (R)-(+), 1,1-Diphenylprolinol (15.20 g, 60.0 mMol) was dissolved in toluene (600 ml) under an inert atmosphere and trimethylboroxine (7.57 g, 60.3 mMol, 1.0 eq.) added. The mixture was heated to reflux and approximately half of the toluene was distilled off via a Dean-Stark trap. Further toluene (350 ml) was added and this was also distilled off via the Dean-Stark trap until a total of 710 ml of distillate had been collected. The reaction mixture was then allowed to cool to ambient temperature to give (R)tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole as a 0.25M solution in toluene.
-
- PGX-6 (225.1 g, 0.556M) was dissolved in dry tetrahydrofuran (3.5 L) in an inert atmosphere and ‘Corey catalyst’ prepared according to Example 4 (0.25M in toluene, 223 ml, 0.1 eq.) added. The mixture was cooled to approximately −15° C. and a solution of borane-methyl sulfide complex (10M BH3 concentration, 41.7 ml, 417 mMol, 0.75 eq.) in dry tetrahydrofuran (450 ml) was added whilst maintaining the temperature at ca. 15° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC. Methanol (200 ml) was added over 30 minutes and the mixture allowed to warm to approximately 0° C. before acidification with 10% aqueous hydrochloric acid (1.2 L). Ethyl acetate (2.4 L) was added and the layers allowed to separate. The aqueous phase was extracted with ethyl acetate (1×0.8 L, 1×0.4 L) and the combined organic phases washed with water (1×1.6 L, 3×0.8 L) and then brine (1 L). Drying over magnesium sulfate, filtration and evaporation in vacuo gave the crude product (containing a mixture of the desired 3(S)-isomer, PGX-7, and the undesired 3(R)-isomer PGX-8) as an oil (242.7 g). This was dissolved in dichloromethane:ethyl acetate 2:1 (720 ml) and chromatographed on silica gel 60 (12.8 Kg) eluting with dichloromethane:ethyl acetate 2:1. Impure fractions containing a mixture of PGX-7 and PGX-8 were evaporated and re-chromatographed under the same conditions. Fractions free from PGX-8 (by TLC) were combined and evaporated. Drying in vacuo at ambient temperature gave the desired product (1S,5R,6R,7R)-7-benzoyloxy-6-[3(S)-3-hydroxy-5-phenyl-l(E pentenyl]-2-oxa-bicyclo[3.3.0]octan-3-one as a white solid (167.9 g, 74.2%).
-
- PGX 6 (315.2 g, 0.779M) was dissolved in dry tetrahydrofuran (5.7 L) in an inert atmosphere and ‘Corey catalyst’ (0.25M in toluene, 312 ml, 0.1 eq.) added. The mixture was cooled to approximately −15° C. and a solution of borane-methyl sulfide complex (10M BH3 concentration, 58.5 ml, 0.585M, 0.75 eq.) in dry tetrahydrofuran (630 ml) added whilst maintaining the temperature at ca. 15° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC. Methanol (290 ml) was added over 30 minutes and the mixture allowed to warm to approximately 0° C. before acidification with 10% aqueous hydrochloric acid (1.7 L). Ethyl acetate (3 L) was added and the layers allowed to separate. The aqueous phase was extracted with ethyl acetate (1×1.1 L, 1×0.55 L) and the combined organic phases washed with water (1×2 L, 3×1 L) and then brine (1.5 L). Drying over magnesium sulfate, filtration and evaporation in vacuo gave the crude product (containing a mixture of PGX 7 and the undesired isomer PGX 8) as an oil (349.3 g). The oil was purified by the procedure given in Example 5b.
- Note:
- The chromatographic procedure described in Example 5 in which a 2:1 mixture of dichloromethane:ethylacetate is employed as an eluent for medium pressure chromatography (MPLC) on a silica gel column, suffers from the disadvantage that the column must be re-packed after each separation before subsequent aliquots of the epimeric product mixture can be processed. Thus, such a procedure employs large quantities of both stationary phase and eluent, as well as being time consuming. An improved procedure is given below (Example 5b):
- According to an improved procedure, the crude mixture of epimers PGX-7/PGX-8 (686.5 g) made according to the synthetic procedure described in Example 5a was crystallised from heptane fraction/ethyl acetate (7:3) to give a crystalline mixture of epimers PGX-7 and PGX-8 (480.4 g) that is free of other impurities. The filtrates from the crystallisation were evaporated to give an oil (150.3 g) comprising mainly impure PGX-7/PGX-8.
- The crystalline mixture was dissolved in dichloromethane:ethyl acetate (2:1) mixture to give a stock solution (A). The evaporated impure PGX-7/PGX-8 mixture was dissolved in dichloromethane:ethyl acetate (2:1) mixture to give a second stock solution (B). The isomer PGX-7 was then separated from PGX-8 by medium pressure chromatography (MPLC) on a silica gel column by sequential injection of aliquots of the stock solutions according to the following protocol:
- Injection 1: Injection of an aliquot of crystalline PGX-7/PGX-8 stock solution (A) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7. The column was then flushed with eluent to elute any remaining PGX-8.
- Injection 2: Injection of an aliquot of crystalline PGX-7/PGX-8 stock solution (A) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7. Column flushed with methanol then equilibration of column with eluent.
- Injection 3: Injection of an aliquot of impure PGX-7/PGX-8 stock solution (B) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7 and impure PGX-7. Discarded silica gel and re-packed column with fresh silica gel and repeat cycle.
- The above strategy increases the throughput of PGX-7 considerably and avoids the need to re-pack the column after every injection.
- The column fractions containing the impure PGX-7 are recycled to give more pure PGX-7 utilising the above protocol, except that more than three injections per column can be performed before re-packing the column.
- Fractions free from PGX-8 (by TLC) were combined and evaporated. Drying in vacuo at ambient temperature gave (1S,5R,6R,7R)-7-benzoyloxy-6-[3(S)-3-hydroxy-5-phenyl-l(E)-pentenyl]-2-oxabicyclo[3.3.0]octan-3-one (PGX-7) as a white solid (445.2 g).
-
- PGX-7 (152.0 g, 0.374M, 1.0 eq.) was dissolved in dry methanol (2.28 L) under an inert atmosphere and potassium carbonate (31.0 g, 0.224M, 0.6 eq.) added in one portion. The mixture was stirred at ambient temperature for 3 h until TLC showed the reaction was complete. 5M Hydrochloric acid (65.5 ml) was added to adjust the apparent pH of the solution to about 6.8-7.0 and the mixture then evaporated to dryness in vacuo. The sticky residue was treated with water (1.5 L) and the pH adjusted to 6.8-7.0 by the addition of 1M hydrochloric acid (7 ml). Heptane (0.45 L) was added, the mixture agitated vigorously and the precipitated solid filtered off and washed with heptane (2×150 ml) on the filter. The solid was then triturated with a further quantity of heptane (2×150 ml). All the heptane washes were combined and added to the original filtrates. The aqueous phase was separated off, washed with heptane (2×150 ml) and then extracted with ethyl acetate (1×450 ml, 3×150 ml). The previously isolated solid was added to the combined ethyl acetate extracts and the mixture shaken until a solution formed. This was washed with saturated brine (2×250 ml) and dried over magnesium sulfate. Filtration and evaporation in vacuo gave (1S,5R,6R,7R)-7-hydroxy-6-[3(S)-3-hydroxy-5-phenyl-l(E)-pentenyl]-2-oxabicyclo[3.3.0]octan-3-one as a pale yellow oil (112.1 g, 99.1%).
-
- PGX-9 (111.5 g 0.369M, 1.0 eq.) was dissolved in ethanol (1.67 L) and 5% palladium on carbon (5.58 g) added followed by a solution of sodium nitrite (8.90 g, 0.129M, 0.35 eq.) in water (100 ml). The mixture was then hydrogenated for 5 h until shown to be complete by TLC. 1M Hydrochloric acid (260 ml) was added and the mixture stirred for 1 h. The solids were removed by filtration through celite, the filtrates then evaporated to give an oily-solid residue which was partitioned between ethyl acetate (0.45 L) and water (0.45 L). The layers were separated and the aqueous extracted with ethyl acetate (2×0.33 L). The combined organics were washed with brine (2×0.22 L) and then dried over sodium sulfate containing 5% sodium hydrogen carbonate. Filtration and evaporation gave (1S,5R,6R,7R)-7-Hydroxy-6-[3(R)-(3-hydroxy-5-phenyl)pentyl]-2-oxabicyclo[3.3.0]octan-3-one as a yellow oil (110.4 g, 98.4%)
- Note:
- It has been found to be possible to reduce the time period during which the product PGX-10 is in the acid medium during the HCl work-up, and thus minimise the potential of an acid-catalysed epimerisation of the side-chain hydroxyl group of (1S,5R,6R,7R)-7-Hydroxy-6-[3(R)-(3-hydroxy-5-phenyl)-pentyl]-2-oxabicyclo[3.3.0]octan-3-one
- Thus, in the modified procedure, on completion of the reaction described in Example 7, 1M hydrochloric acid was added and the reaction mixture stirred for 60 minutes as described in Example 7. The pH of the mixture was adjusted to between 5 and 6 by addition of solid sodium hydrogen carbonate prior to the filtration of the used catalyst, and evaporation of the filtrate to dryness. The work-up is then completed as described in Example 7 by extraction of the product into ethyl acetate. The following Example 7a illustrates the improved procedure:
-
- PGX 9 (326.5 g, 1.08M, 1.0 eq.) was dissolved in ethanol (6.5 L) and 5% palladium on carbon (16.3 g) added followed by a solution of sodium nitrite (26 g, 0.377M, 0.35 eq.) in water (200 ml). The mixture was then hydrogenated for 1.5 h until shown to be complete by TLC. 1M Hydrochloric acid (750 ml) was added and the mixture stirred for 1 h. The pH was adjusted to 5-6 by the addition of solid sodium hydrogen carbonate (55 g). The solids were removed by filtration through celite, the filtrates then evaporated to give an oily-solid residue which was partitioned between ethyl acetate (1.3 L) and water (1.3 L). The layers were separated and the aqueous extracted with ethyl acetate (2×0.975 L). The combined organics were washed with brine (2×0.65 L) and then dried over sodium sulfate. Filtration and evaporation gave (1S,5R,6R,7R)-7-Hydroxy-6-[3(R)-(3-hydroxy-5-phenyl)pentyl]-2-oxabicyclo[3.3.0]octan-3-one as a yellow oil (311.5 g, 94.8%).
-
- PGX-10 (109.7 g, 0.360M, 1.0 eq.) was dissolved in dry dimethyl formamide (720 ml) under an inert atmosphere. Imidazole (29.4 g, 0.432M, 1.2 eq.) and triethylamine (102.9 ml, 74.69 g, 0.738M, 2.05 eq.) were added and the mixture then cooled to approximately 0° C. Triethylchlorosilane (111.2 g, 0.738M, 2.05 eq.) was added over 15 minutes at less than 10° C. The mixture was allowed to warm to room temperature and stirred for 2 h until TLC showed the reaction was complete. After re-cooling to 10° C., hexane (0.55 L) and water (1 L) were added and the layers separated. The aqueous phase was extracted with hexane (1×0.2 L, 1×0.1 L) and the combined organics then washed with water (2×0.5 L) and brine (2×0.5 L). Drying over magnesium sulfate, filtration and evaporation in vacuo gave (1S,5R,6R,7R)-6-[3(R)-(5-phenyl-3-triethylsilyloxy)pentyl]-7-triethylsilyloxy-2-oxabicyclo[3.3.0] octan-3-one as a yellow oil (187.4 g, 97.6%).
-
- PGX-11 (186.8 g, 0.3505M, 1.0 eq.) was dissolved in dry tetrahydrofuran (1.86 L) under an inert atmosphere and the solution cooled to less than −70° C. Diisobutylaluminium hydride (1.1M in toluene solution, 701 ml, 0.7711M, 2.2 eq.) was added to the reaction whilst maintaining the temperature below −70° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC. Methanol (132 ml) was added and the mixture allowed to warm to −5° C. before addition of water (2 L) followed by acidification to pH 3 with 2M aqueous sodium hydrogen sulphate solution (1.54 L, 8.8 eq.). Ethyl acetate (0.66 L) was added and the layers allowed to separate. The aqueous phase was extracted with ethyl acetate (1×0.26 L, 1×0.13 L) and the combined organics then washed with water (2×1.3 L) and brine (2×1.3 L). Drying over magnesium sulfate and evaporation in vacuo gave (1S,3RS,5R,6R,7R)-6-[3(R)-(5-phenyl-3-triethylsilyloxy)pentyl]-7-triethylsilyloxy-2-oxabicyclo[3.3.0]octan-3-ol as an almost colourless oil (182.5 g).
-
- (4-Carboxybutyl)-triphenylphosphonium bromide (459.0 g, 1.0353M, 3.0 eq.) was suspended in dry tetrahydrofuran (1.84 L) under an inert atmosphere and the mixture cooled to 0° C. 1.07M Potassium tert-butoxide in tetrahydrofuran solution (1.806 L, 1.93M, 5.6 eq.) was then added over 60 minutes at 0° C. After the addition was complete the reaction was allowed to warm to approximately 20° C. and stirred for 1 hour before re-cooling to 0° C. A solution of PGX-12 (184.6 g, 0.3451M, 1.0 eq.) in tetrahydrofuran (0.27 L) was then added at this temperature. The mixture was allowed to warm to room temperature and stirred for 75 minutes until TLC showed the reaction was complete. After re-cooling to 0° C. the mixture was quenched by the addition of water (3 L) and then acidified to pH 5 with 5% aqueous citric acid solution (1.6 L). The product was extracted into ethyl acetate (1×1.0 L, 2×0.4 L) and the combined organics then washed with brine (2×0.7 L). Drying over magnesium sulfate, filtration and evaporation in vacuo gave a mixture of (Z)-7-{(1R, 2R, 3R, 5S)-5-hydroxy-2-[3(R)-(5-phenyl-3-triethylsilyloxy)pentyl]-3-(triethylsilyloxy) cyclo-pentyl}-5-heptenoic acid and (Z)-7-{(1R,2R,3R,5S)-3-hydroxy-2-[3(R)-(5-phenyl-3-triethyl-silyloxy) pentyl]-5-(triethylsilyloxy)cyclopentyl)5-heptenoic acid as a yellow oil (461.7 g). This crude product containing triphenylphosphine oxide by-product was used without purification in the next step of the synthesis.
- Note:
- The amount of (4-carboxybutyl)triphenylphosphonium bromide used in the above reaction is 3.0 equivalents with respect to the amount of starting material PGX-12 used. In order to generate the ylide and the carboxylate salt, it is treated with 5.6 equivalents of potassium tert-butoxide. The slight deficit in the amount of potassium tert-butoxide used with respect to (4-carboxybutyl)triphenylphosphonium bromide (2.0 equivalents required; 1.87 equivalents used) is deliberate to ensure that all of the potassium tert-butoxide is consumed and is not present during the reaction with the lactol.
- However, the present applicant has found that 2.15 equivalents of (4-carboxybutyl)triphenylphosphonium bromide and 4.0 equivalents of potassium tert-butoxide with respect to the amount of the lactol starting material PGX-12 can be used. Advantageously, this leads to a better conversion of PGX-12 to PGX-13/PGX-14. This is illustrated in Example 10a:
-
- (4-Carboxybutyl)-triphenylphosphonium bromide (965.5 g, 2.18M, 2.15 eq.) was suspended in dry tetrahydrofuran (4.4 L) under an inert atmosphere and the mixture cooled to 0° C. 0.98M Potassium tert-butoxide in tetrahydrofuran solution (4.135 L, 4.05M, 4.0 eq.) was then added over 60 minutes at 0° C. After the addition was complete the reaction was allowed to warm to approximately 20° C. and stirred for 1 hour before re-cooling to 0° C. A solution of PGX-12 (542.3 g, 1.013M, 1.0 eq.) in tetrahydrofuran (1 L) was then added at this temperature. The mixture was allowed to warm to room temperature and stirred for 60 minutes until TLC showed the reaction was complete. After re-cooling to 0° C. the mixture was quenched by the addition of water (8.6 L) and then acidified to pH 5 with 5% aqueous citric acid solution (4.5 L). The product was extracted into ethyl acetate (1×3 L, 2×1.2 L) and the combined organics then washed with brine (2×2 L). Drying over magnesium sulfate, filtration and evaporation in vacuo gave a mixture of (Z)-7-{(1R,2R,3R,5S)-5-hydroxy-2-[3(R)-(5-phenyl-3-triethylsilyloxy)pentyl]-3-(triethylsilyloxy) cyclopentyl}-5-heptenoic acid and (Z)-7-{(1R,2R,3R,5S)-3-hydroxy-2-[3(R)-(5-phenyl-3-triethyl-silyloxy) pentyl]-5-(triethylsilyloxy)cyclo-pentyl)5-heptenoic acid as a yellow oil (1095.6 g). This crude product containing triphenylphosphine oxide by-product was used without purification in the next step of the synthesis.
-
- The PGX-13/14 mixture (461.1 g, assumed to contain 0.3446M, 1.0 eq.) was dissolved in acetone (2.13 L) under an inert atmosphere and dry 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (290.1 ml, 1.94M, 5.63 eq.) added at ambient temperature. After stirring for approximately 15 minutes, 2-iodopropane (329.7 g, 1.94M, 5.63 eq.) was added and the mixture then stirred for 16 h at ambient temperature. TLC showed that the reaction was incomplete. An additional quantity of DBU (19.1 ml, 0.1275M, 0.37 eq.) was added followed, after 20 minutes, by 2-iodopropane (21.7 g, 0.1275M, 0.37 eq.). After stirring for 4.5 h at ambient temperature the reaction was shown to be complete by TLC. The bulk of the acetone (ca. 1.72 L) was evaporated in vacuo and the residue partitioned between ethyl acetate (0.67 L) and 3% aqueous citric acid solution (1.6 L). The organic layer was separated off and the aqueous layer acidified to pH 6 with an additional quantity of 3% aqueous citric acid solution (0.72 L) and then re-extracted with ethyl acetate (2×0.33 L). The combined organic phases were washed with 3% aqueous citric acid solution (2×0.8 L), 5% sodium hydrogen carbonate solution (2×0.8 L) and saturated brine (2×1.6 L). After drying over magnesium sulfate followed by filtration the solvent was evaporated off and heptane (1.0 L) and ethyl acetate (80 ml) added to the residue. The mixture was cooled to −20° C. and agitated vigorously. After 30 minutes at −20° C. the precipitated solid was filtered off and washed on the filter with heptane:ethyl acetate 9:1 (6×200 ml). Evaporation of the filtrates in vacuo gave a yellow oil. Heptane (600 ml) was added and the solution cooled to −20° C. After 30 minutes the precipitate was filtered off and washed on the filter with heptane (3×100 ml). The filtrate was evaporated in vacuo to give a mixture of isopropyl (Z)-7-{(1R,2R,3R,5S)-5-hydroxy-2-[3(R)-(5-phenyl-3-triethylsilyloxy) pentyl]-3-(tri-ethylsilyloxy)cyclopentyl}-5-heptenoate and isopropyl (Z)-7-{(1R,2R,3R,5S)-3-hydroxy-2-[3(R)-(5-phenyl-3-triethylsilyloxy)pentyl]-5-(triethylsilyloxy)cyclo-pentyl}-5-heptenoate as a yellow oil (238.4 g).
-
- The PGX-15/16 mixture (237.79 g, assumed to contain 0.344M) was dissolved in dry dimethylformamide (700 ml) under an inert atmosphere. Imidazole (14.04 g, 0.206M, 0.6 eq.) and triethylamine (50.3 ml, 0.361M, 1.05 eq.) were added and the mixture cooled to approximately 0° C. Triethylchlorosilane (60.6 ml, 54.4 g, 0.361M, 1.05 eq.) was then added and the mixture allowed to warm to ambient temperature. Stirring was continued for 2 h until the reaction was shown to be complete by TLC. The reaction mixture was then partitioned between heptane (1.07 L) and water (2.67 L). After separation, the aqueous phase was further extracted with heptane (2×0.27 L). The combined organics were washed with water (2×1.3 L) and then saturated brine (2×1.3 L). After drying over magnesium sulfate followed by filtration the solvent was evaporated in vacuo to give the crude product (235.0 g) as a thick yellow oil. This was dissolved in heptane (90 ml) and purified by column chromatography on silica gel (352.5 g) eluting with heptane and then heptane:ethyl acetate 95:5. The relevant fractions were combined and the solvent evaporated in vacuo to give isopropyl (Z)-7-{(1R,2R,3R,5S)-3,5-bis(triethylsilyloxy)-2-[3(R)-(5-phenyl-3-triethylsilyloxy) pentyl]cyclopentyl}-5-heptenoate as a pale yellow oil (210.5 g).
-
- PGX-17 (0.504 g, 0.65 mmol) was weighed into a 50 ml round bottom flask equipped with a magnetic follower. Acetone (6.5 ml) was added and the resulting colourless solution stored at room temperature under a gentle stream of argon.
- A solution of pyridinium-p-toluenesulfonate (Aldrich, 13 mg) in water (0.9 ml) was prepared and added to the reaction solution. The resulting white cloudy suspension was stored at room temperature under a stream of argon. The mixture cleared after about 20 min to give a colourless solution. TLC after 3 hr indicated complete conversion to the required product. The stirring was then stopped and the reaction mixture concentrated under reduced pressure to remove the acetone. The residue was partitioned between ethylacetate (10 ml) and saturated NaCl (15 ml). The organic phase was separated and the aqueous layer extracted with more ethylacetate (2×7.5 ml). The combined organic extracts were washed with saturated NaCl (2×10 ml), dried over MgSO4 (0.5 g) and evaporated to dryness under reduced pressure. The crude product was obtained as a colourless oil.
- The crude product was purified by flash column chromatography. A flash column was prepared using silica gel 60 (6 g) and hexane fraction/EtOAc (1:1) as the eluent. The crude product (7 mg was removed as retention sample) was dissolved in the eluent (2 ml) and loaded onto the column. The column was then eluted with hexane fraction/EtOAc mixtures as follows:
Hexane fraction/EtOAc 1:1 50 ml 1:2 150 ml 1:3 80 ml - The fractions containing the pure product were combined and evaporated to dryness under reduced pressure. The pure product was obtained as a colourless viscous oil which was dried under high vacuum (0.01 kPa) to constant weight (0.251 g, yield 89.3%).
-
- PGX-17 (170.0 g, 0.219M) was dissolved in acetone (1.9 L) under an inert atmosphere and a solution of pyridinium-p-toluenesulphonate (4.52 g, 18.0 mMol, 0.08 eq.) in water (0.3 L) added. The resulting mixture was stirred at ambient temperature for 3 h until TLC showed the reaction to be complete. After evaporation of the organic volatiles the residue was added to a mixture of ethyl acetate (2.1 L) and brine (2 L). The layers were separated and the aqueous phase further extracted with ethyl acetate (1 L). The organics were combined and washed with brine (0.5 L). Evaporation in vacuo gave a pale yellow oil (166.4 g). This was dissolved in hexane:ethyl acetate 1:1 (0.25 L) and purified by chromatography on silica gel (1.87 Kg) eluting with hexane ethyl acetate (1:1 then 1:2 then 1:3). The relevant fractions were combined and evaporated to give an almost colourless oil (78.0 g). This was further purified by isocratic preparative HPLC on a silica column eluting with heptane (88-95%): methanol/isopropanol (1/2) (5-12%). Evaporation of the relevant combined cuts gave isopropyl (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[3(R)-(3-hydroxy-5-phenyl)pentyl]cyclopentyl)}-5-heptenoate (latanoprost) as an almost colourless oil (50.2 g, 53.0%).
- HPLC purification of latanoprost was carried out using a WatersRTM Spherisorb silica gel column. The isocratic eluent system comprised a hydrocarbon and an alcohol in volume percent ranges of 88-98% and 2-12% respectively. The hydrocarbons used were n-hexane, hexane fraction, n-heptane or heptane fraction. The alcohols used were isopropanol, ethanol or methanol, either singly or in combination in ratios of 1:1 to 3:1.
- The results of typical HPLC runs using the above eluent system are shown below:
Amount Product Run 1 Run 2 Latanoprost 99.89% 99.83% 15(S)-cis isomer 0.08% 0.09% 15(S)-trans isomer 0.03% 0.07% 15(R)-trans isomer not detected not detected - Thus, it can be seen that the above solvent system achieves a latanoprost purity of greater than 99.8% and the amounts of the undesired isomers are all less than 0.1%.
- HPLC separations of latanoprost were carried out using a WatersRTM Spherisorb silica gel column. The isocratic eluent system comprised hydrocarbon: alcohol:acetonitrile in volume percent ratios of 90-96%: 2-6%: 2-4%. The hydrocarbons used were n-hexane, hexane fraction, n-heptane or heptane fraction. The alcohols used were either isopropanol or ethanol.
- The following results are shown for a HPLC separation of latanoprost using as eluent, a mixture of heptane:isopropanol:acetonitrile in the volume percent ratios of 93%:4%:3%. The relative retention times of latanoprost, and the 15(S)-cis, 15(S)-trans and 15(R)-trans isomers are shown below:
Product Relative Retention Time Latanoprost 1.00 15(S)-cis isomer 0.95 15(S)-trans isomer 1.13 15(R)-trans isomer 1.23 - The above results indicate that an excellent degree of separation of latanoprost from the undesired isomers thereof can be achieved using an eluent system comprising acetonitrile. Similar results were achieved with PhenomenexRTM Luna Cyano and PhenomenexRTM Luna Silica columns. Using this procedure, it is possible to achieve latanoprost that is substantially pure, or is completely free, of the hitherto difficult to remove isomers.
Claims (48)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/189,986 US7268239B2 (en) | 2001-05-24 | 2005-07-27 | Process for the preparation of prostaglandins and analogues thereof |
US11/189,985 US7498458B2 (en) | 2001-05-24 | 2005-07-27 | Process for the preparation of prostaglandins and analogues thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0112699.4 | 2001-05-24 | ||
GBGB0112699.4A GB0112699D0 (en) | 2001-05-24 | 2001-05-24 | Process for the preparation of prostglandins and analogues thereof |
PCT/GB2002/002462 WO2002096898A2 (en) | 2001-05-24 | 2002-05-24 | Process for the preparation of prostaglandins and analogues thereof |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/189,985 Division US7498458B2 (en) | 2001-05-24 | 2005-07-27 | Process for the preparation of prostaglandins and analogues thereof |
US11/189,986 Division US7268239B2 (en) | 2001-05-24 | 2005-07-27 | Process for the preparation of prostaglandins and analogues thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040249172A1 true US20040249172A1 (en) | 2004-12-09 |
Family
ID=9915243
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/478,513 Abandoned US20040249172A1 (en) | 2001-05-24 | 2002-05-24 | Process for the preparationof prostaglandins and analogues thereof |
US11/189,986 Expired - Fee Related US7268239B2 (en) | 2001-05-24 | 2005-07-27 | Process for the preparation of prostaglandins and analogues thereof |
US11/189,985 Expired - Fee Related US7498458B2 (en) | 2001-05-24 | 2005-07-27 | Process for the preparation of prostaglandins and analogues thereof |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/189,986 Expired - Fee Related US7268239B2 (en) | 2001-05-24 | 2005-07-27 | Process for the preparation of prostaglandins and analogues thereof |
US11/189,985 Expired - Fee Related US7498458B2 (en) | 2001-05-24 | 2005-07-27 | Process for the preparation of prostaglandins and analogues thereof |
Country Status (15)
Country | Link |
---|---|
US (3) | US20040249172A1 (en) |
EP (2) | EP2311820A1 (en) |
JP (2) | JP4475943B2 (en) |
CN (2) | CN101003503A (en) |
AU (1) | AU2002321396B2 (en) |
BR (1) | BR0209984A (en) |
CA (1) | CA2448088A1 (en) |
GB (1) | GB0112699D0 (en) |
HU (1) | HUP0400047A3 (en) |
IL (1) | IL159030A0 (en) |
NO (1) | NO329883B1 (en) |
NZ (1) | NZ529634A (en) |
SK (1) | SK14362003A3 (en) |
WO (1) | WO2002096898A2 (en) |
ZA (1) | ZA200308916B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050261374A1 (en) * | 2001-05-24 | 2005-11-24 | Resolution Chemicals Limited | Process for the preparation of prostaglandins and analogues thereof |
WO2007041273A2 (en) * | 2005-09-29 | 2007-04-12 | Eastar Chemical Corp. | Process for the production of intermediates for making prostaglandin derivatives such as latanoprost, travaprost, and bimatoprost |
US20080033176A1 (en) * | 2006-08-07 | 2008-02-07 | Daiichi Fine Chemical Co., Ltd. | Method for preparing prostaglandin derivative |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7321057B2 (en) * | 2004-08-02 | 2008-01-22 | R-Tech Ueno, Ltd. | Method for manufacturing prostaglandin analogue |
PL212658B1 (en) * | 2005-04-18 | 2012-11-30 | Inst Farmaceutyczny | Method for obtaining the derivatives of 13,14-dihydro-PGF₂α |
US7511168B2 (en) | 2006-01-18 | 2009-03-31 | Shih-Yi Wei | Processes and intermediates for the preparations of prostaglandins |
US8546114B2 (en) | 2006-01-18 | 2013-10-01 | Chirogate International Inc. | Processes for the preparation of optically active cyclopentenones and cyclopentenones prepared therefrom |
KR101353187B1 (en) * | 2006-02-07 | 2014-01-17 | 수캄포 아게 | Method for preparing prostaglandin derivative |
JP2008037782A (en) * | 2006-08-04 | 2008-02-21 | Daiichi Fine Chemical Co Ltd | Method for producing prostaglandine derivative |
US20090233830A1 (en) * | 2008-03-14 | 2009-09-17 | Penny Sue Dirr | Automatic detergent dishwashing composition |
EP2135860A1 (en) | 2008-06-20 | 2009-12-23 | Sandoz AG | Improved process for the production of bimatoprost |
EP2143712A1 (en) | 2008-07-10 | 2010-01-13 | Sandoz AG | Improved Process for the Production of Prostaglandins and Prostaglandin Analogs |
IT1392492B1 (en) | 2008-12-24 | 2012-03-09 | Ind Chimica Srl | PROCESS FOR THE PURIFICATION OF LATANOPROST, SYNTHETIC ANALOGUE OF PROSTAGLANDINA PGF2ALFA. |
KR101045935B1 (en) * | 2009-03-11 | 2011-07-01 | 연성정밀화학(주) | Method for preparing prostaglandin derivative |
WO2011005505A2 (en) | 2009-06-22 | 2011-01-13 | Johnson Matthey Public Limited Company | Method for the purification of prostaglandins |
US8901319B2 (en) * | 2009-10-16 | 2014-12-02 | Cayman Chemical Company, Incorporated | Process for the preparation of F-series prostaglandins |
CA2777352A1 (en) * | 2009-11-05 | 2011-05-12 | Biocon Limited | A novel process for the preparation of prostaglandins and intermediates thereof |
WO2011095990A2 (en) | 2010-02-03 | 2011-08-11 | Fdc Limited | Process for the purification of prostaglandins and analogues thereof |
EP2495235B1 (en) | 2011-03-04 | 2015-08-05 | Newchem S.p.A. | Process for the synthesis of prostaglandins and intermediates thereof |
HU231203B1 (en) * | 2011-12-21 | 2021-10-28 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Novel process for the preparation of travoprost |
TWI435752B (en) * | 2012-08-15 | 2014-05-01 | Everlight Chem Ind Corp | Method of purification of prostaglandins including fluorine atoms by preparative hplc |
US9115109B2 (en) | 2013-08-15 | 2015-08-25 | Chirogate International Inc. | Processes and intermediates for the preparations of isomer free prostaglandins |
HU231214B1 (en) | 2014-03-13 | 2021-11-29 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | New process for preparing high purity prostaglandins |
CN104513186B (en) * | 2015-01-13 | 2016-10-05 | 宁波第二激素厂 | A kind of preparation method of optically pure dextrorotation Cloprostenol Sodium |
HU231175B1 (en) * | 2015-12-04 | 2021-06-28 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Production of latanoprostene bunod by gravity column chromatography, in optional, previously definied quality |
EP3950672A4 (en) * | 2019-03-27 | 2023-01-11 | Kyowa Pharma Chemical Co., Ltd. | Method for producing pkrostaglandin |
CN112608294B (en) * | 2020-12-16 | 2021-10-26 | 西安国康瑞金制药有限公司 | Preparation method of latanoprost |
EP4261206A1 (en) * | 2020-12-23 | 2023-10-18 | Kyowa Pharma Chemical Co., Ltd. | Method for separating geometrical isomer |
CN115991691B (en) * | 2023-03-23 | 2023-05-16 | 西南交通大学 | Preparation method and application of latanoprost intermediate |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3549688A (en) * | 1967-02-16 | 1970-12-22 | Gen Electric | Process for the preparation of carboxylic acid esters |
US3931279A (en) * | 1973-05-21 | 1976-01-06 | The Upjohn Company | 5-Oxa prostaglandin F2.sub.α analogs |
US3978229A (en) * | 1974-04-11 | 1976-08-31 | Ono Pharmaceutical Co., Ltd. | Synergistic composition comprising PGF2.sub.α and PGE2 |
US4158667A (en) * | 1976-02-04 | 1979-06-19 | The Upjohn Company | 6-Keto PGF analogs |
US4346228A (en) * | 1975-04-18 | 1982-08-24 | Schering Aktiengesellschaft | Novel 11-oxoprostaglandin derivatives |
US4680415A (en) * | 1985-06-24 | 1987-07-14 | Hoffmann-La Roche Inc. | Intermediates for 7-fluoro dihydro PGI compounds |
US5223537A (en) * | 1991-07-23 | 1993-06-29 | Kabi Pharmacia Ab | Method and composition for treatment of gastric and duodenal disorders |
US5321128A (en) * | 1988-09-06 | 1994-06-14 | Kabi Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US6184250B1 (en) * | 1993-08-03 | 2001-02-06 | Alcon Laboratories, Inc. | Use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension |
Family Cites Families (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3778450A (en) | 1971-03-23 | 1973-12-11 | Upjohn Co | Certain bicyclic lactones |
CA971957A (en) | 1971-12-13 | 1975-07-29 | Upjohn Company (The) | PROCESS FOR PREPARING PROSTAGLANDIN E'S FROM PROSTAGLANDIN F.alpha.'S |
US4100355A (en) | 1972-09-15 | 1978-07-11 | The Upjohn Company | 8β,12α-PGE2 -type compounds |
US3864387A (en) | 1973-05-21 | 1975-02-04 | Upjohn Co | 5-Oxa phenyl-and phenoxy-substituted prostaglandin F{HD 1{301 {0 {B analogs |
US4036832A (en) * | 1974-07-03 | 1977-07-19 | Pfizer Inc. | 15-Substituted-ω-pentanorprostaglandins |
DE2434133C2 (en) * | 1974-07-12 | 1987-03-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | 15,15-Ethylenedioxy-prostanoic acid derivatives, processes for their preparation and medicaments containing these compounds |
EP0059307A1 (en) * | 1981-02-26 | 1982-09-08 | Grünenthal GmbH | Preparation of 2-oxa-bicyclo(3.3.0)octane compounds and their derivatives |
US4599353A (en) | 1982-05-03 | 1986-07-08 | The Trustees Of Columbia University In The City Of New York | Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma |
JPS6137752A (en) * | 1984-07-30 | 1986-02-22 | Kuraray Co Ltd | Separation and purification of highly unsaturated long-chain fatty acid or its ester |
US4943635A (en) | 1987-08-27 | 1990-07-24 | President & Fellows Of Harvard College | Enantioselective reduction of ketones |
EP0394263B1 (en) | 1987-09-04 | 1994-03-16 | The Upjohn Company | Process for production of prostaglandin intermediates |
WO1990002553A1 (en) * | 1988-09-06 | 1990-03-22 | Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
JP2855450B2 (en) | 1989-09-11 | 1999-02-10 | 小野薬品工業株式会社 | Method for producing intermediate of prostaglandin derivative |
SE9002596D0 (en) | 1990-08-08 | 1990-08-08 | Pharmacia Ab | A METHOD OF SYNTHESIS OF PROSTAGLANDIN DERIVATIVES |
JPH085873B2 (en) | 1990-08-21 | 1996-01-24 | 株式会社上野製薬応用研究所 | Manufacturing method of prostaglandin intermediate |
EP0472338A3 (en) * | 1990-08-21 | 1993-05-19 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Method of manufacturing prostaglandin intermediate |
HU212570B (en) | 1991-06-24 | 1996-08-29 | Chinoin Gyogyszer Es Vegyeszet | Process for producing 13,14-dihydro-15(r)-17-phenyl-18,19,20-trinor-pgf2alfa-isopropylester |
US5688819A (en) | 1992-09-21 | 1997-11-18 | Allergan | Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
DE69327717T2 (en) | 1992-09-30 | 2000-06-21 | R-Tech Ueno, Ltd. | METHOD FOR PRODUCING ALPHA, BETA-UNSATURATED KETONES |
DE4323331A1 (en) | 1993-07-08 | 1995-01-12 | Schering Ag | Novel bicyclic lactones |
US5510383A (en) | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
NL194919C (en) * | 1993-09-07 | 2003-07-04 | Tno | Process for oxidizing carbohydrates. |
US5545665A (en) | 1993-12-28 | 1996-08-13 | Allergan | Cyclopentane(ene) heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents |
US5698733A (en) | 1994-09-30 | 1997-12-16 | Alcon Laboratories, Inc. | Use of 9-deoxy prostaglandin derivatives to treat glaucoma |
HU223345B1 (en) | 1995-12-20 | 2004-08-30 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Process for stereoselective reducing alpha, beta-unsaturated ketones |
US6649653B1 (en) * | 1996-11-12 | 2003-11-18 | Alcon Manufacturing, Ltd. | 15-fluoro prostaglandins as ocular hypotensives |
SE9702681D0 (en) | 1997-07-10 | 1997-07-10 | Pharmacia & Upjohn Ab | Method and composition for treatment of impotence |
SE9702706D0 (en) | 1997-07-11 | 1997-07-11 | Pharmacia & Upjohn Ab | Prostaglandin derivatives devoid of side effects for the treatment of glaucoma |
WO1999012899A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | A process for making prostaglandin f analogs |
WO2000020386A1 (en) | 1998-10-05 | 2000-04-13 | Alcon Laboratories, Inc. | Stannane synthesis of prostanoids |
SE9900025D0 (en) | 1999-01-08 | 1999-01-08 | Synphora Ab | Method and composition for treatment of female sexual dysfunction |
AU2960000A (en) | 1999-01-08 | 2000-07-24 | University Of Massachusetts | Detection of human immunodeficiency virus |
JP3501025B2 (en) | 1999-07-15 | 2004-02-23 | 松下電器産業株式会社 | Electric cooker |
IL134241A (en) * | 2000-01-27 | 2006-06-11 | Finetech Pharmaceutical Ltd | Process for the preparation of latanoprost |
AU3328601A (en) | 2000-02-01 | 2001-08-14 | Cayman Chemical Co Inc | Internal 1,15-lactones of fluprostenol and related prostaglandin F<sub>2alpha</sub> analogs and their use in the treatment of glaucoma and intraocular hypertension |
AU2000237291A1 (en) | 2000-03-07 | 2001-09-17 | Daimlerchrysler Ag | Skin effect heating system for a structural member |
AU2001261019A1 (en) * | 2000-05-15 | 2001-11-26 | Pharmacia And Upjohn Company | Process and intermediates to prepare latanoprost |
GB0112699D0 (en) * | 2001-05-24 | 2001-07-18 | Resolution Chemicals Ltd | Process for the preparation of prostglandins and analogues thereof |
IL159632A0 (en) * | 2001-07-17 | 2004-06-01 | Upjohn Co | Process and intermediates to prepare latanoprost |
-
2001
- 2001-05-24 GB GBGB0112699.4A patent/GB0112699D0/en not_active Ceased
-
2002
- 2002-05-24 EP EP10186205A patent/EP2311820A1/en not_active Withdrawn
- 2002-05-24 EP EP02755096A patent/EP1389198A2/en not_active Withdrawn
- 2002-05-24 CN CNA2006100636760A patent/CN101003503A/en active Pending
- 2002-05-24 CA CA002448088A patent/CA2448088A1/en not_active Abandoned
- 2002-05-24 AU AU2002321396A patent/AU2002321396B2/en not_active Ceased
- 2002-05-24 SK SK1436-2003A patent/SK14362003A3/en not_active Application Discontinuation
- 2002-05-24 CN CNB028146344A patent/CN1301986C/en not_active Expired - Fee Related
- 2002-05-24 IL IL15903002A patent/IL159030A0/en unknown
- 2002-05-24 HU HU0400047A patent/HUP0400047A3/en unknown
- 2002-05-24 WO PCT/GB2002/002462 patent/WO2002096898A2/en active IP Right Grant
- 2002-05-24 US US10/478,513 patent/US20040249172A1/en not_active Abandoned
- 2002-05-24 BR BR0209984-5A patent/BR0209984A/en not_active IP Right Cessation
- 2002-05-24 JP JP2003500077A patent/JP4475943B2/en not_active Expired - Fee Related
- 2002-05-24 NZ NZ529634A patent/NZ529634A/en not_active IP Right Cessation
-
2003
- 2003-11-14 ZA ZA200308916A patent/ZA200308916B/en unknown
- 2003-11-20 NO NO20035162A patent/NO329883B1/en not_active IP Right Cessation
-
2005
- 2005-07-27 US US11/189,986 patent/US7268239B2/en not_active Expired - Fee Related
- 2005-07-27 US US11/189,985 patent/US7498458B2/en not_active Expired - Fee Related
-
2009
- 2009-12-08 JP JP2009278234A patent/JP2010053149A/en active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3549688A (en) * | 1967-02-16 | 1970-12-22 | Gen Electric | Process for the preparation of carboxylic acid esters |
US3931279A (en) * | 1973-05-21 | 1976-01-06 | The Upjohn Company | 5-Oxa prostaglandin F2.sub.α analogs |
US3978229A (en) * | 1974-04-11 | 1976-08-31 | Ono Pharmaceutical Co., Ltd. | Synergistic composition comprising PGF2.sub.α and PGE2 |
US4346228A (en) * | 1975-04-18 | 1982-08-24 | Schering Aktiengesellschaft | Novel 11-oxoprostaglandin derivatives |
US4158667A (en) * | 1976-02-04 | 1979-06-19 | The Upjohn Company | 6-Keto PGF analogs |
US4680415A (en) * | 1985-06-24 | 1987-07-14 | Hoffmann-La Roche Inc. | Intermediates for 7-fluoro dihydro PGI compounds |
US5321128A (en) * | 1988-09-06 | 1994-06-14 | Kabi Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5223537A (en) * | 1991-07-23 | 1993-06-29 | Kabi Pharmacia Ab | Method and composition for treatment of gastric and duodenal disorders |
US6184250B1 (en) * | 1993-08-03 | 2001-02-06 | Alcon Laboratories, Inc. | Use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050261374A1 (en) * | 2001-05-24 | 2005-11-24 | Resolution Chemicals Limited | Process for the preparation of prostaglandins and analogues thereof |
US7498458B2 (en) | 2001-05-24 | 2009-03-03 | Resolution Chemicals Limited | Process for the preparation of prostaglandins and analogues thereof |
WO2007041273A2 (en) * | 2005-09-29 | 2007-04-12 | Eastar Chemical Corp. | Process for the production of intermediates for making prostaglandin derivatives such as latanoprost, travaprost, and bimatoprost |
WO2007041273A3 (en) * | 2005-09-29 | 2007-10-25 | Eastar Chemical Corp | Process for the production of intermediates for making prostaglandin derivatives such as latanoprost, travaprost, and bimatoprost |
US20090287003A1 (en) * | 2005-09-29 | 2009-11-19 | Jiang Xing Chen | Process for the production of intermediates for making prostaglandin derivatives such as latanaprost, travaprost, and bimatoprost |
US20080033176A1 (en) * | 2006-08-07 | 2008-02-07 | Daiichi Fine Chemical Co., Ltd. | Method for preparing prostaglandin derivative |
US7642370B2 (en) | 2006-08-07 | 2010-01-05 | Daiichi Fine Chemical Co., Ltd. | Method for preparing prostaglandin derivative |
Also Published As
Publication number | Publication date |
---|---|
US7498458B2 (en) | 2009-03-03 |
NZ529634A (en) | 2004-11-26 |
WO2002096898A3 (en) | 2003-03-20 |
NO329883B1 (en) | 2011-01-17 |
JP2010053149A (en) | 2010-03-11 |
US20050261374A1 (en) | 2005-11-24 |
IL159030A0 (en) | 2004-05-12 |
JP4475943B2 (en) | 2010-06-09 |
CA2448088A1 (en) | 2002-12-05 |
ZA200308916B (en) | 2007-11-28 |
CN101003503A (en) | 2007-07-25 |
AU2002321396B2 (en) | 2007-10-18 |
BR0209984A (en) | 2004-04-06 |
EP1389198A2 (en) | 2004-02-18 |
CN1533385A (en) | 2004-09-29 |
EP2311820A1 (en) | 2011-04-20 |
GB0112699D0 (en) | 2001-07-18 |
CN1301986C (en) | 2007-02-28 |
HUP0400047A2 (en) | 2004-04-28 |
NO20035162D0 (en) | 2003-11-20 |
SK14362003A3 (en) | 2004-05-04 |
JP2005503354A (en) | 2005-02-03 |
WO2002096898A2 (en) | 2002-12-05 |
US20050272877A1 (en) | 2005-12-08 |
US7268239B2 (en) | 2007-09-11 |
HUP0400047A3 (en) | 2007-05-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7268239B2 (en) | Process for the preparation of prostaglandins and analogues thereof | |
AU2002321396A1 (en) | Process for the preparation of prostaglandins and analogues thereof | |
EP1385819B1 (en) | Process for preparing prostaglandin derivatives and stereospecific starting material thereof | |
JP5653827B2 (en) | Prostaglandin synthesis | |
US4238414A (en) | 2-Decarboxy-2-aminomethyl-6a-carba-PGI2 compounds | |
US4705806A (en) | Prostacyclin analogs | |
WO2010109476A2 (en) | Improved process for the preparation of prostaglandins and analogues thereof | |
JP2018528940A (en) | Method for making beraprost | |
US4732914A (en) | Prostacyclin analogs | |
US4060540A (en) | Novel 3-triphenylmethoxy-1-alkynes, 3-triphenyl-methoxy-1-trans-alkenyl-dialkyl-alanes, and lithium 3-triphenylmethoxy-1-trans-alkenyl-dialkyl alanates | |
KR101522218B1 (en) | Processes and intermediates for the preparations of prostaglandins | |
US4123456A (en) | Novel 11-hydroxy-9-keto-5,6-cis-13,14-cis-prostadienoic acid derivatives | |
US4343949A (en) | Novel 2-substituted-3,4-epoxycyclopentan-1-ones, 2-substituted-3,4-epoxycyclopentan-1-ols, and various 2-substituted-cyclopentenones | |
RU2774634C2 (en) | Method for production and purification of misoprostol | |
US4179574A (en) | Novel 2-substituted-3,4-epoxycyclopentan-1-ones, 2-substituted-3,4-epoxycyclopentan-1-ols, and various 2-substituted-cyclo-pentenones | |
US4632997A (en) | Method for preparing cis-bicyclo[3.3.0]octylidene derivative | |
JP2839841B2 (en) | Process for producing prostaglandin E1s, and synthetic intermediate thereof | |
EP0553352B1 (en) | Novel prostaglandin i2 derivatives | |
EP1085012B1 (en) | Process for producing a purified prostaglandin derivative | |
US4110368A (en) | Hydro substituted prostanoic acids and esters | |
US4439365A (en) | Novel hydroxy substituted prostanoic acids, esters, congeners, intermediates and process | |
JPH034558B2 (en) | ||
JPS6341376B2 (en) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: RESOLUTION CHEMICALS LIMITED, UNITED KINGDOM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CASCADE BIOCHEM LIMITED;REEL/FRAME:014796/0927 Effective date: 20031120 Owner name: RESOLUTION CHEMICALS LIMITED, UNITED KINGDOM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GREENWOOD, ALAN KENNETH;MCHATTIE, DEREK;THOMPSON, DAVID GEORGE;REEL/FRAME:014796/0918;SIGNING DATES FROM 20040211 TO 20040213 Owner name: CASCADE BIOCHEM LIMITED, UNITED KINGDOM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CLISSOLD, DEREK WYNDHAM;REEL/FRAME:014796/0980 Effective date: 20040216 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |