WO2013093528A1 - Process for the preparation of travoprost - Google Patents
Process for the preparation of travoprost Download PDFInfo
- Publication number
- WO2013093528A1 WO2013093528A1 PCT/HU2012/000132 HU2012000132W WO2013093528A1 WO 2013093528 A1 WO2013093528 A1 WO 2013093528A1 HU 2012000132 W HU2012000132 W HU 2012000132W WO 2013093528 A1 WO2013093528 A1 WO 2013093528A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- crystallization
- carried out
- travoprost
- Prior art date
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- 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 title claims abstract description 49
- 229960002368 travoprost Drugs 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 47
- 230000008569 process Effects 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 238000002425 crystallisation Methods 0.000 claims abstract description 24
- 230000008025 crystallization Effects 0.000 claims abstract description 24
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 7
- -1 p-phenyl-benzoyl protecting group Chemical group 0.000 claims abstract description 6
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 5
- 125000000686 lactone group Chemical group 0.000 claims abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 230000009467 reduction Effects 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 238000005886 esterification reaction Methods 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 8
- 230000032050 esterification Effects 0.000 claims description 8
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 238000002844 melting Methods 0.000 claims description 6
- 230000008018 melting Effects 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 230000003247 decreasing effect Effects 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 claims description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 238000011097 chromatography purification Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000006140 methanolysis reaction Methods 0.000 claims description 2
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims 2
- 229930195733 hydrocarbon Natural products 0.000 claims 2
- 150000002430 hydrocarbons Chemical class 0.000 claims 2
- 150000002576 ketones Chemical class 0.000 claims 2
- 238000010898 silica gel chromatography Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000543 intermediate Substances 0.000 description 32
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 229940093499 ethyl acetate Drugs 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000006722 reduction reaction Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- 238000004293 19F NMR spectroscopy Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 150000002085 enols Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 230000005595 deprotonation Effects 0.000 description 3
- 238000010537 deprotonation reaction Methods 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 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 description 2
- VSEVUQXKWHTETG-UHFFFAOYSA-N 2h-cyclopenta[b]furan-2,5-diol Chemical compound OC1=CC2=CC(O)OC2=C1 VSEVUQXKWHTETG-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 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 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000011916 stereoselective reduction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 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 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
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- RTLMATDNIKWIIO-UHFFFAOYSA-N 2-n,2-n,6-n,6-n-tetrakis(2-chloroethyl)-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diamine Chemical compound C=12N=C(N(CCCl)CCCl)N=C(N3CCCCC3)C2=NC(N(CCCl)CCCl)=NC=1N1CCCCC1 RTLMATDNIKWIIO-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- HJRHGQQOWINKNO-UHFFFAOYSA-N 4-carboxybutylphosphanium;bromide Chemical compound [Br-].OC(=O)CCCC[PH3+] HJRHGQQOWINKNO-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FLEHAOYBYPJWKG-SHQPEEILSA-N O=C(COc1cccc(C(F)(F)F)c1)/C=C/[C@H]([C@@H](C1)[C@H](C2)OC1=O)[C@@H]2OC(c(cc1)ccc1-c1ccccc1)=O Chemical compound O=C(COc1cccc(C(F)(F)F)c1)/C=C/[C@H]([C@@H](C1)[C@H](C2)OC1=O)[C@@H]2OC(c(cc1)ccc1-c1ccccc1)=O FLEHAOYBYPJWKG-SHQPEEILSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- PSEHHVRCDVOTID-VMAIWCPRSA-N chloro-bis[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@H]([C@@H]1C)B(Cl)[C@H]2[C@H](C)[C@]3(C[C@@](C2)(C3(C)C)[H])[H])[C@@]2([H])C(C)(C)[C@]1([H])C2 PSEHHVRCDVOTID-VMAIWCPRSA-N 0.000 description 1
- 239000012004 corey–bakshi–shibata catalyst Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 1
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- 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
- C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the subject of our invention is a novel process for the preparation of travoprost.
- Stereoselectivity of the enone ⁇ enol reduction is 88.7 % (Example 10.).
- the 15-epi impurity is removed by protection of the OH-groups of the diol with tert-butyl-dimethylsilyl group (TBDMS) and crystallization of the thus obtained protected diol.
- TDMS tert-butyl-dimethylsilyl group
- the overall yield is 7%.
- the starting compound of formula (II) can be prepared for example by oxidation of the PPB- Corey-lactone of formula (XII)
- the PPB-Corey-lactone is oxidized under Pfitzner-Moffatt reaction conditions into the aldehyde (Pfitzner, K.E., Moffatt J.G.; J.Am.Chem.Soc. 1963, 85, 3027), then the lower chain is built up with the help of Horner- Wadsworth-Emmons (HWE) reaction (Wadsworth, W.; Org. React., 1977, 25, 73) - by use of the appropriate phosphonate - under water-free conditions, in the presence of solid potassium hydroxide.
- HWE Horner- Wadsworth-Emmons
- potassium tert-butylate lithium carbonate
- DBU lithium- or magnesium halogenides
- triethylamine potassium hexamethyl disilazide (KHMDS) or crown ether bases - we applied solid potassium hydroxide which is economical and can be safely used in industrial scale.
- KHMDS potassium hexamethyl disilazide
- the HWE reaction is carried out in an aprotic organic solvent in a temperature range of 40-(- 50)°C, preferably at (- 10)°C, by using as solvent an aromatic hydrocarbon, such as toluene or an ether, like tetrahydrofuran, methyl tetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, diethyl ether or their mixtures.
- the selective reduction of the compound of formula (II) is accomplished with a borane-type reducing agent.
- (-)-B- chlorodiisopinocampheylborane (DIP -CI) catecholborane, especially catecholborane may be applied.
- the reduction of the compound of formula (II) is carried out in the presence of a chiral catalyst.
- chiral catalyst CBS- oxazaborolidine can be used.
- the reaction is carried out in the presence of an organic solvent, at a temperature between (10°C) and (-80°C), preferably between (-10°C) and (-20°C).
- solvent toluene hexane, heptane, pentane, tetrahydrofuran, methyltetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, diethyl ether or their mixtures may be applied, among others toluene - tetrahydrofuran mixtures are used.
- the resulting compound of formula (III) is purified by crystallization, while the amount of the undesired isomer is lowered in a significant manner.
- the crystalline form of the compound of formula (III) has not been known before, it is a novel form. Crystallization is carried out in polar or apolar solvents or in the mixture of them.
- the crystallization is performed between (-20)-70°C, in such a way that the material is dissolved in alcohol at reflux temperature and crystallized by cooling gradually. The crystals are then filtered off, washed and dried.
- Reduction of the compound of formula (III) may be carried out with diisobutyl-aluminum hydride (DIBAL-H).
- DIBAL-H diisobutyl-aluminum hydride
- solvent inert aprotic solvents such as THF, toluene, hexane, and heptane may be applied.
- the reaction is performed at a temperature between (-80°C) and (- 50°C), especially between (-80°C) and (-70°C).
- the PPB-protecting group may be removed in a known way by methanolysis, under basic conditions, especially in the presence of potassium carbonate.
- the resulting intermediate of formula (V) is purified by crystallization, while the amount of the undesired isomer is decreased under a strickt limit value.
- the crystalline form of the compound of formula (V) has not been described before, it is a novel form. Crystallization is carried out in the mixture of polar and apolar solvents. As for the mixture of polar and apolar solvents, an ethyl acetate - hexane mixture may be used. Transformation of the compound of formula (V) into the compound of formula (VI) is accomplished by Wittig reaction, while esterification of the compound of formula (VI) is carried out with isopropyl iodide.
- cyclic tertiary amides such as N-methylpyrrolidone and/or 1,3- dimethylimidazolidinone are used as solvents.
- the esterification is performed at a temperature between 20-90°C, especially between 40-50°C.
- a further subject of the invention is the novel compound of formula (IV)
- Travoprost In one embodiment of the invention, which starts from the PPB-Corey-lactone, the lower chain is constructed with the help of the appropriate phosphonate, by Horner- Wadsworth- Emmons reaction. For the deprotonation of the phosphonate the inexpensive and in industrial scale safely applicable solid potassium hydroxide is used. Reduction of the resulting Travoprost 1. intermediate (enone -compound of Formula (II)) is carried out in the presence of a 2-methyl-CBS-oxazaborolidine catalyst, with a borane-type reducing agent, like catecholborane, resulting in a stereoselectivity of 90%. The thus obtained Travoprost 2.
- intermediate enone -compound of Formula (II)
- a borane-type reducing agent like catecholborane
- intermediate (enol - compound of Formula (III)) is purified by crystallization and reduced with diisobutylaluminum hydride (DIBAL-H). From the resulting Travoprost 3. intermediate (PPB-triol - compound of Formula (IV)) the PPB-protecting group is removed and the thus obtained Travoprost 4. intermediate (triol - compound of Formula (V)) is purified by crystallization. Travoprost 5.
- intermediate (acid - compound of Formula VI) is prepared by Wittig reaction. Finally, the esterification is carried out with isopropyl iodide in DMI (1,3- dimethylimidazolidin-2-one) solvent to obtain the ester (Travoprost - Formula (I)).
- DMI 1,3-dimethylimidazolidinone
- EP 2 143 712 Al, WO 2011/046569 Al dimethylformamide
- DMI is a solvent used in the beauty industry.
- the formyl-impurities which generate from the widely used dimethylformamide solvent are not formed from DMI.
- the esterification reaction can be carried out with very high conversion, without forming new impurities (-100%). ⁇ The overall yield of the new process is very high, 16%, which is more than double of the yield described in WO 2011/055377 Al (7%).
- the reaction mixture is poured onto 1 M hydrochloric acid solution and the mixture is stirred.
- the precipitated crystals are filtered off and washed.
- the phases of the filtrate are separated, the organic phase is washed with 1M sodium hydrogen carbonate solution and then with diluted hydrochloric acid solution.
- the organic phase is evaporated and purified by chromatography on a silica gel column (eluent: toluene - ethyl acetate mixture).
- the main fraction is evaporated and crystallized from ethyl acetate - hexane mixture.
- a multi-neck flask is charged under nitrogen atmosphere with 701 g of enol which is then dissolved in 6.8 L of room temperature THF.
- the clear solution is cooled to -75°C and in approximately 30 minutes the pre-cooled (-75°C) 1 M hexane solution of 2921 ml diisobutylaluminum hydride (DIBAL-H) is added to it.
- DIBAL-H diisobutylaluminum hydride
- the reaction mixture is stirred at - 75 °C until the reaction is completed. After reaching the suitable conversion, the reaction mixture is poured onto the mixture of NaHS0 4 solution and ethyl acetate.
- the phases are separated, the aqueous phase is extracted with ethyl acetate, the united organic phase is washed with NaHC0 3 solution and with diluted hydrochloric acid solution, and then evaporated while adding triethylamine (TEA) to it. 639.5 g oil is obtained.
- TAA triethylamine
- the precipitated crystals are solved in 10 folds ethyl-acetate, thereafter 10 folds n-hexane is added and the solution is mixed at room temperature. To the crystal-suspension obtained 20 folds n-hexane is added and mixed at room temperature. The precipitated crystals are filtered, washed with a mixture of hexane: ethyl-acetate and dried.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2014548213A JP6174040B2 (en) | 2011-12-21 | 2012-12-10 | Preparation method of travoprost |
US14/367,317 US9212125B2 (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost |
BR112014014060A BR112014014060A2 (en) | 2011-12-21 | 2012-12-10 | process for the preparation of travoprost |
CN201280063528.2A CN103998423B (en) | 2011-12-21 | 2012-12-10 | The preparation method of travoprost |
KR1020147020311A KR102027889B1 (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost |
EP12816098.3A EP2802562B1 (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost |
CA2859923A CA2859923C (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost |
ES12816098T ES2721662T3 (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost |
RU2014129492A RU2631316C2 (en) | 2011-12-21 | 2012-12-10 | Method of obtaining travoprost |
MX2014007684A MX2014007684A (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost. |
IN3482CHN2014 IN2014CN03482A (en) | 2011-12-21 | 2012-12-10 | |
PL12816098T PL2802562T3 (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost |
IL232625A IL232625B (en) | 2011-12-21 | 2014-05-14 | Process for the preparation of travoprost |
ZA2014/04440A ZA201404440B (en) | 2011-12-21 | 2014-06-17 | Process for the preparation of travoprost |
HK14112063.1A HK1198584A1 (en) | 2011-12-21 | 2014-12-01 | Process for the preparation of travoprost |
US14/928,629 US20160137621A1 (en) | 2011-12-21 | 2015-10-30 | Process for the preparation of travoprost |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU1100701A HU231203B1 (en) | 2011-12-21 | 2011-12-21 | Novel process for the preparation of travoprost |
HUP1100701 | 2011-12-21 |
Related Child Applications (2)
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US14/367,317 A-371-Of-International US9212125B2 (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost |
US14/928,629 Division US20160137621A1 (en) | 2011-12-21 | 2015-10-30 | Process for the preparation of travoprost |
Publications (1)
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WO2013093528A1 true WO2013093528A1 (en) | 2013-06-27 |
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PCT/HU2012/000132 WO2013093528A1 (en) | 2011-12-21 | 2012-12-10 | Process for the preparation of travoprost |
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US (2) | US9212125B2 (en) |
EP (1) | EP2802562B1 (en) |
JP (1) | JP6174040B2 (en) |
KR (1) | KR102027889B1 (en) |
CN (1) | CN103998423B (en) |
BR (1) | BR112014014060A2 (en) |
CA (1) | CA2859923C (en) |
ES (1) | ES2721662T3 (en) |
HK (1) | HK1198584A1 (en) |
HU (1) | HU231203B1 (en) |
IL (1) | IL232625B (en) |
IN (1) | IN2014CN03482A (en) |
MX (1) | MX2014007684A (en) |
PL (1) | PL2802562T3 (en) |
RU (1) | RU2631316C2 (en) |
TR (1) | TR201905687T4 (en) |
TW (1) | TWI640500B (en) |
WO (1) | WO2013093528A1 (en) |
ZA (1) | ZA201404440B (en) |
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EP2837621A1 (en) * | 2013-08-15 | 2015-02-18 | Chirogate International Inc. | Processes for the preparation of isomer free prostaglandins |
KR20160134741A (en) * | 2014-03-13 | 2016-11-23 | 키노인 기요기스제르 에스 베기에스제티 테르메크에크 기야라 제트알티. | New process for the preparation of high purity prostaglandins |
EP3950672A4 (en) * | 2019-03-27 | 2023-01-11 | Kyowa Pharma Chemical Co., Ltd. | Method for producing pkrostaglandin |
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PT2723714T (en) * | 2011-06-02 | 2017-08-18 | Chinoin Zrt | Novel processes for the preparation of prostaglandin amides |
WO2017062770A1 (en) | 2015-10-08 | 2017-04-13 | Silverberg Noah | Punctal plug and bioadhesives |
EP4252776A3 (en) | 2020-02-06 | 2023-11-22 | Ocular Therapeutix, Inc. | Compositions and methods for treating ocular diseases |
EP4261206A1 (en) * | 2020-12-23 | 2023-10-18 | Kyowa Pharma Chemical Co., Ltd. | Method for separating geometrical isomer |
CN114671906B (en) * | 2020-12-24 | 2024-03-15 | 武汉武药制药有限公司 | Process for preparing travoprost intermediates |
CN115806517A (en) * | 2022-12-21 | 2023-03-17 | 上海彩迩文生化科技有限公司 | Preparation method of high-purity dinoprost |
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- 2012-12-10 MX MX2014007684A patent/MX2014007684A/en unknown
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- 2012-12-10 RU RU2014129492A patent/RU2631316C2/en active
- 2012-12-10 TR TR2019/05687T patent/TR201905687T4/en unknown
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- 2012-12-10 CA CA2859923A patent/CA2859923C/en active Active
- 2012-12-10 US US14/367,317 patent/US9212125B2/en active Active
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ZA201404440B (en) | 2015-12-23 |
CN103998423A (en) | 2014-08-20 |
RU2014129492A (en) | 2016-02-10 |
RU2631316C2 (en) | 2017-09-21 |
TWI640500B (en) | 2018-11-11 |
HK1198584A1 (en) | 2015-04-30 |
KR102027889B1 (en) | 2019-10-04 |
JP6174040B2 (en) | 2017-08-02 |
KR20140107541A (en) | 2014-09-04 |
TR201905687T4 (en) | 2019-05-21 |
US20140343299A1 (en) | 2014-11-20 |
HUP1100701A2 (en) | 2013-07-29 |
EP2802562B1 (en) | 2019-01-23 |
IN2014CN03482A (en) | 2015-07-03 |
CA2859923C (en) | 2020-11-24 |
HU231203B1 (en) | 2021-10-28 |
EP2802562A1 (en) | 2014-11-19 |
US9212125B2 (en) | 2015-12-15 |
TW201336816A (en) | 2013-09-16 |
CN103998423B (en) | 2018-04-27 |
PL2802562T3 (en) | 2019-08-30 |
IL232625A0 (en) | 2014-06-30 |
ES2721662T3 (en) | 2019-08-02 |
JP2015506343A (en) | 2015-03-02 |
BR112014014060A2 (en) | 2017-06-13 |
MX2014007684A (en) | 2014-07-28 |
US20160137621A1 (en) | 2016-05-19 |
CA2859923A1 (en) | 2013-06-27 |
IL232625B (en) | 2019-03-31 |
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