TWI640500B - 製備曲伏***素之新穎方法 - Google Patents
製備曲伏***素之新穎方法 Download PDFInfo
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- TWI640500B TWI640500B TW101148584A TW101148584A TWI640500B TW I640500 B TWI640500 B TW I640500B TW 101148584 A TW101148584 A TW 101148584A TW 101148584 A TW101148584 A TW 101148584A TW I640500 B TWI640500 B TW I640500B
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- travoprost
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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 39
- 229960002368 travoprost Drugs 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- -1 p -phenyl-benzyl group Chemical group 0.000 claims abstract description 8
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 5
- 125000006239 protecting group Chemical group 0.000 claims abstract description 4
- 238000011916 stereoselective reduction Methods 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims abstract description 3
- 125000000686 lactone group Chemical group 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 29
- 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 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 238000006722 reduction reaction Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000005886 esterification reaction Methods 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 7
- 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000000354 decomposition reaction Methods 0.000 claims 1
- 230000005484 gravity Effects 0.000 claims 1
- 238000010898 silica gel chromatography Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 238000002329 infrared spectrum Methods 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 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
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 235000021317 phosphate Nutrition 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 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
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 230000005595 deprotonation Effects 0.000 description 3
- 238000010537 deprotonation reaction Methods 0.000 description 3
- 150000002085 enols Chemical class 0.000 description 3
- 239000012454 non-polar solvent Substances 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 2
- 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
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 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
- 150000002009 diols Chemical class 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 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
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 150000002940 palladium Chemical class 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel 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
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 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
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- DBUJFULDVAZULB-UHFFFAOYSA-N 1-methoxypentane Chemical compound CCCCCOC DBUJFULDVAZULB-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
- VHEYCTCATJSAAI-UHFFFAOYSA-N 4-phenylbenzenecarboximidamide Chemical group C1=CC(C(=N)N)=CC=C1C1=CC=CC=C1 VHEYCTCATJSAAI-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-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
- FYJKEHKQUPSJDH-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;potassium Chemical compound [K].C[Si](C)(C)N[Si](C)(C)C FYJKEHKQUPSJDH-UHFFFAOYSA-N 0.000 description 1
- 150000001409 amidines Chemical group 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- YPWBYWNNJVSNPQ-UHFFFAOYSA-N borane;n,n-diethylaniline Chemical class B.CCN(CC)C1=CC=CC=C1 YPWBYWNNJVSNPQ-UHFFFAOYSA-N 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
- 239000001273 butane Substances 0.000 description 1
- UOALEFQKAOQICC-UHFFFAOYSA-N chloroborane Chemical compound ClB UOALEFQKAOQICC-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 239000012004 corey–bakshi–shibata catalyst Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- HBNBMOGARBJBHS-UHFFFAOYSA-N dimethylarsane Chemical compound C[AsH]C HBNBMOGARBJBHS-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
- 239000011261 inert gas Substances 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 235000010448 lactitol Nutrition 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
- 238000006140 methanolysis reaction Methods 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical group CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N o-dihydroxy-benzene Natural products OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 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 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 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
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
Landscapes
- 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)
- Furan Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本發明係關於一種用於製備式(I)的曲伏***素之方法
其包括將式(II)化合物
立體選擇性地還原,所得的式(III)化合物
(III)
如果需要時結晶化,將式(III)化合物的內酯基還原,移除如此所得的式(IV)化合物之p-苯基-苯甲醯基保護基,
所得的式(V)三醇,
如果需要時在結晶化後,藉由Wittig反應而轉化成式(VI)之酸
其隨後酯化。
Description
本發明係關於一種用於製備曲伏***素之新穎方法。
式(I)之曲伏***素
是一種已知的***素衍生物用於治療青光眼及高眼壓(US 5510383)。
曲伏***素之製備方法是揭示例如在EP 2143712、WO 2011/046569、WO 2011/055377。
根據EP 2143712之方法是顯示在圖1。
烯酮→烯醇還原之立體選擇性是88.7%(實例10)。
根據揭示在WP 2011/046569之方法,15-epi雜質是藉由用第三丁基-二甲基矽烷基(TBDMS)保護二醇之OH-基,並將如此所得經保護的二醇結晶化而移除。
在根據WO 2011/055377之方法中,烯酮→烯醇轉化是用N,N-二乙基苯胺-硼烷複合物作為還原劑,在Corey觸媒(CBS- 唑硼烷(oxazaborolidine))存在下進行。產物藉由製備級HPLC純化。整體產量是7%。
我們旨在尋找一種具有更高立體選擇性及更佳產量之方法。
本發明之目的是製備式(I)之曲伏***素
其係經由立體選擇性還原式(II)化合物,
還原所得的式(III)化合物之內酯基,
移除如此所得的式(IV)化合物之p-苯基苯甲醯基保護基,
藉由Wittig反應將所得的式(V)三醇
轉化成式(VI)之酸
其隨後酯化。
式(II)之起始化合物之製備可例如藉由將式(XII)之PPB-Corey-內酯
氧化成醛,其隨後在HWE反應中用式(XIII)之磷酸酯
在無水介質中,在固體氫氧化鉀存在下,轉化成式(II)化合物。
根據本發明方法的一個具體實施例,該PPB-Corey-內酯是在Pfitzner-Moffatt反應條件下氧化成醛(Pfitzner,K.E.,Moffatt J.G.;J.Am.Chem.Soc. 1963,85,3027),隨後藉助Horner-Wadsworth-Emmons(HWE)反應(Wadsworth,W.;Org.React.,1977,25,73)-經由使用適當的磷酸酯-在無水條件下,在固體氫氧化鉀存在下,建立下層鏈。對於磷酸酯之去質子化-替代使用普遍陳述的氫化鈉、第三丁醇鉀、碳酸鋰、DBU、鋰-或鎂鹵化物、三乙胺、六甲基二矽氮烷鉀(KHMDS)或冠醚基質-我們使用經濟且可以在工業規模下安全使用的氫氧化鉀。
該HWE反應是在非質子有機溶劑中,在40-(-50)℃的溫度範圍,在(-10)℃較佳,藉由使用芳族烴例如甲苯或醚例如四氫呋喃、甲基四氫呋喃、環戊基甲基醚、二甲氧基乙烷、第三丁基甲基醚、二異丙基醚、***或其混合物作為溶劑而進行。根據本發明方法的另一個具體實施例,式(II)化合物之選擇性還原是使用硼烷型還原劑達成。
關於硼烷型還原劑,可以使用硼烷-二甲基硫、(-)-B-二異松蒎基氯硼烷(DIP-Cl)、兒茶酚硼烷,尤其是兒茶酚硼烷。根據本發明方法的一個具體實施例,式(II)化合物之還原是在對掌性觸媒存在下進行。關於對掌性觸媒,可以使用CBS- 唑硼烷。該反應是在有機溶劑存在下,在(10℃)及(-80℃)之間的溫度範圍進行,在(-10℃)及(-20℃)之間較佳。關於溶劑,可以使用甲苯、己烷、庚烷、戊烷、四氫呋喃、甲基四氫呋喃、環戊基甲基醚、二
甲氧基乙烷、第三丁基甲基醚、二異丙基醚、***或其混合物,其中包括使用甲苯-四氫呋喃混合物。
所得的式(III)化合物是藉由結晶法純化,其中不要的異構物的量是在顯著的方式中降低。式(III)化合物之結晶形式先前尚未得知,其是一種新穎的形式。結晶是在極性或非極性溶劑或在其混合物中進行。
在根據本發明方法的一個具體實施例中,結晶是在(-20)-70℃之間進行,此方法是將物質溶解在迴流溫度的醇中,並藉由逐漸冷卻而結晶。然後將晶體過濾,清洗並乾燥。
式(III)化合物之還原可以用二異丁基-氫化鋁(DIBAL-H)進行。關於溶劑,可以使用惰性非質子溶劑例如THF、甲苯、己烷、及庚烷。該反應是在(-80℃)及(-50℃)之間的溫度進行,尤其是(-80℃)及(-70℃)之間。
DIBAL-H還原之產物,式(IV)中間物,是一新穎的化合物。
經PPB-保護的基團可以在鹼性條件下,尤其是在碳酸鉀存在下,在已知的方式中藉由甲醇分解而移除。
在本發明方法的另一個具體實施例中,所得的式(V)中間物是藉由結晶而純化,其中不要的異構物的量是在嚴格的限制值下降低。式(V)化合物之結晶形式先前未經陳述,其是一新穎的形式。結晶是在極性及非極性溶劑之混合物中進行。關於極性及非極性溶劑之混合物,可以使用醋酸乙酯-己烷混合物。式(V)化合物轉化成式(VI)化合物是藉由Wittig反應達成,而式(VI)化合物之酯化是用異丙基碘進行。
在酯化反應中,是使用環狀三級醯胺例如N-甲基吡咯酮及/或1,3-二甲基咪唑啶酮作為溶劑。酯化是在20-90℃之間的溫度進行,尤其是40-50℃之間。
本發明之另一個方面是新穎的式(IV)化合物
及其用於製備曲伏***素之用途。
另外,本發明之主題是式(III)之結晶化合物
其熔點是129.5-134.5℃,及其用於製備曲伏***素之用途。
另外,本發明之主題是式(V)之結晶化合物
其熔點是85.4-86.6℃,及其用於製備曲伏***素之用途。
根據本發明完整合成曲伏***素之一個具體實施例是列在下面圖示1:
在本發明之一個具體實施例中,其自PPB-Corey-內酯起始,下層鏈是藉助合適的磷酸酯經由Horner-Wadsworth-Emmons反應而建造。對於磷酸酯之去質子化,是使用便宜且在工業規模下安全可行的固體氫氧化鉀。所得的曲伏***素1.中間物(烯酮-式(II)化合物)之還原是在2-甲基-CBS- 唑硼烷觸媒存在下,用硼烷型還原劑例如兒茶酚硼烷進行,導致立體選擇性是
90%。如此所得的曲伏***素2.中間物(烯醇-式(III)化合物)是藉由結晶而純化並用二異丁基氫化鋁(DIBAL-H)還原。從所得的曲伏***素3.中間物(PPB-三醇-式(IV)化合物)移除PPB-保護基且如此所得的曲伏***素4.中間物(三醇-式(V)化合物)是藉由結晶而純化。曲伏***素5.中間物(酸-式(VI)化合物)是藉由Wittig反應而製備。最後,酯化是在DMI(1,3-二甲基咪唑啶-2-酮)溶劑中用異丙基碘進行而得到酯(曲伏***素-式(I))。
本發明陳述的方法之優點:
‧在HWE反應中,製備式(II)之起始化合物時,磷酸酯之去質子化是用便宜且在工業規模下安全可行的固體氫氧化鉀進行-代替目前普遍且廣泛使用的昂貴且可燃性的氫化鈉。
‧在曲伏***素的合成中,使用CBS- 唑硼烷及兒茶酚硼烷進行15-酮基之還原是一新的解決方法,先前未曾實施,藉此可達到甚至高於90-92%的非對掌異構性過量。在EP 2 143712陳述的方法中,使用DIP-Cl之選擇性是de(S)=88.7%。在WO 2011/055377 A1陳述的方法中,除了CBS觸媒之外,使用N,N-二乙基苯胺-硼烷複合物,但是沒有提供立體選擇性的程度。
‧純化策略是完全新穎,因為移除15-epi-雜質是不使用層析法,而是藉由結晶在高產量下完成,不同於文獻中已知的MPLC(中度壓力層析純化法)(WO 2011/046569 A1)或製備級HPLC(WO 2011/055377 A1)方法。
‧式(III)化合物及式(V)化合物之結晶形式先前未經陳述於文獻中。在本方法中,該結晶形式也用於純化中間物及移除不要的雜質。
‧在酯化步驟中,是使用1,3-二甲基咪唑啶酮(DMI)作為新穎的溶劑,其不具有強烈的毒性,不同於一般使用的二甲基甲醯胺(EP 2 143 712 A1、WO 2011/046569 A1)。DMI是一種在美容行業中使用的溶劑。另一個優點是從廣泛使用的二甲基甲醯胺溶劑衍生的甲醯基-雜質不會從DMI形成。酯化反應可以在非常高的轉化下進行,沒有形成新的雜質(~100%)。
‧該新的方法之整體產量非常高,16%,其超過兩倍在WO 2011/055377 A1陳述的產量(7%)。
‧本發明的其他細節是包括但不限於下面的實例。
第1圖係完全合成根據本發明曲伏***素之一個具體實施例。
第2圖係曲伏***素1.中間物IR光譜。
第3圖係曲伏***素2.中間物IR光譜。
第4圖係曲伏***素3.中間物IR光譜。
第5圖係曲伏***素4.中間物IR光譜。
第6圖係曲伏***素5.中間物IR光譜。
第7圖係曲伏***素IR光譜。
1.建造下層鏈(氧化及HWE反應)
製備[1,1’-聯苯基]-4-羧酸,(3aR,4R,5R,6aS)-六氫-2-酮基-4-[(1E)-3-酮基-4-[3-(三氟甲基)苯氧基]-1-丁烯-1-基]-2H-環戊[b]呋喃-5酯/
式(II)化合物/
將1069克PPB-Corey-內酯懸浮在惰性氣壓下的11.1升無水甲苯中。在此懸浮液中加入1.4升二異丙基碳二醯亞胺且隨後加入0.855升在磷酸中的二甲亞碸。將反應混合物加熱至50℃且隨後逐份加入另0.34升在磷酸中的二甲亞碸。氧化反應完成後,將混合物冷卻至-10℃並保持此溫度,依序加入316克氫氧化鉀及1.45公斤在甲苯溶液中的曲伏***素磷酸鹽。當HWE反應完成後,將反應混合物倒在1M氫氯酸溶液上並攪拌混合物。將沈澱的晶體過濾並清洗。將過濾液的液層分離,將有機層用1M碳酸氫鈉溶液清洗後用稀釋的氫氯酸溶液清洗。將有機層蒸發並在矽膠管柱上經由層析法純化(洗提液:甲苯-醋酸乙酯混合物)。將主要部份蒸發並從醋酸乙酯-己烷混合物結晶化。
產量:915克,55%。
熔點:112.5-114.5℃
曲伏***素1.中間物之IR光譜列在圖2。
曲伏***素1.中間物1H、13C及19F NMR數據:
曲伏***素1.中間物(烯酮-式(II)):
2. 15-酮基-還原(立體選擇性還原)
製備[1,1’-聯苯基]-4-羧酸,(3aR,4R,5R,6aS)-六氫-4-[(1E,3R)-3-羥基-4-[3-(三氟甲基)苯氧基]-1-丁烯-1-基]-2-酮基-2H-環戊[b]呋喃-5酯/式(III)化合物/
將279毫升兒茶酚硼烷溶解在4.6升四氫呋喃(THF)中並在其中加入1M甲苯溶液之549毫升R-(+)-2-甲基-CBS- 唑硼烷。將混合物冷卻至-10℃並保持此溫度,加入915克在6.9升THF中的曲伏***素1.中間物(烯酮-式(II))。當反應完成時,藉由與13升1M NaHSO4溶液攪拌而將混合物分解。然後加入醋酸乙酯並將液層分離。將有機層用NaOH溶液清洗後用氫氯酸溶液清洗。將有機層經由硫酸鈉乾燥,過濾,蒸發並先從己烷:丙酮混合物結晶,然後從甲醇結晶而移除不要的異構物de(S)92%→de(S)98%。(de係指:非對掌異構性過量)。
產量:701克,55% de(S):98%。
熔點:129.5-134.5℃
曲伏***素2.中間物之IR光譜列在圖3。
曲伏***素2.中間物1H、13C及19F NMR數據:
3.內酯還原(製備乳醇)
製備[1,1’-聯苯基]-4-羧酸,(3aR,4R,5R,6aS)-六氫-4-[(1E,3R)-3-羥基-4-[3-(三氟甲基)苯氧基]-1-丁烯-1-基]-2-羥基-環戊[b]呋喃-5酯/式(IV)化合物/
在氮氣壓下在一多頸燒瓶內加入701克烯醇其隨後溶解在室溫的THF中。將透明溶液冷卻至-75℃且在約30分鐘後在其中加入預先冷卻(-75℃)的2921毫升二異丁基氫化鋁(DIBAL-H)之1M己烷溶液。將反應混合物在-75℃攪拌直到反應完成。達到合適的轉化後,將反應混合物倒在NaHSO4溶液與醋酸乙酯之混合物上。將液層分離,將水層用醋酸乙酯萃取,將合併的有機層用NaHCO3溶液及用稀釋的氫氯酸溶液清洗,且隨後加入三乙胺(TEA)並蒸發。得到639.5克油。
產量:639.5克,91%。
曲伏***素3.中間物之IR光譜列在圖4。
曲伏***素3.中間物1H、13C及19F NMR數據:
曲伏***素3.中間物,非對掌異構物A
曲伏***素3.中間物,非對掌異構物B
4.移除保護基(製備三醇)
4a.製備2H-環戊[b]呋喃-2,5-二醇,六氫-4-[(1E,3R)-3-羥基-4-[3-(三氟甲基)苯氧基]-1-丁烯-1-基]-,(3aR,4R,5R,6aS)-/式(V)化
合物/
將639.5克PPB-三醇溶解在6.4升甲醇中並將溶液加熱至40℃。加入95克K2CO3並將混合物在40℃攪拌至反應完成。到達合適的轉化後,將反應混合物冷卻至2℃並逐份加入磷酸。將沈澱的PPB-甲酯晶體過濾並清洗。將過濾液濃縮,加入水及醋酸乙酯並將液層分離。將水層用醋酸乙酯萃取,經由Na2SO4乾燥並將溶液蒸發。將粗油從醋酸乙酯:己烷混合物結晶化。將沈澱的晶體過濾,用己烷:醋酸乙酯混合物清洗並乾燥。
產量:367克,85%
熔點:85.4-86.6℃
4b.結晶化2H-環戊[b]呋喃-2,5-二醇,六氫-4-[(1E,3R)-3-羥基-4-[3-(三氟甲基)苯氧基]-1-丁烯-1-基]-,(3aR,4R,5R,6aS)-/式(V)化合物-三醇/
將沈澱的晶體溶解在10倍醋酸乙酯中,隨後加入10倍正己烷並將溶液在室溫混合。在所得的晶體-懸浮液中加入20倍正己烷並在室溫混合。將沈澱的晶體過濾,用己烷:醋酸乙酯混合物清洗並乾燥。在任何時間重複上述步驟,不要的異構物的
量可以降低至任何量,也可能降低不要的異構物的量至低於可忽略的極限(<0.05%)。
產量:52-85%(取決於再結晶的次數)。
曲伏***素4.中間物之IR光譜列在圖5。
曲伏***素4.中間物1H、13C及19FNMR數據:
曲伏***素4.中間物,非對掌異構物A 1H、13C及19F NMR數據:
曲伏***素4.中間物,非對掌異構物B 1H、13C及19F NMR數據:
5.建造上層鏈(製備曲伏***素酸)
製備5-庚酸,7-[(1R,2R,3R,5S)-3,5-二羥基-2-[(1E,3R)-3-羥基-4-[3-(三氟甲基)苯氧基]-1-丁烯-1-基]環戊基]-,(5Z)-/式(VI)化合物/
在氮氣壓下,將1509克4-羧基丁基-溴化磷(KBFBr)溶解在12.8升THF中,將溶液冷卻至0℃,並藉由維持該溫度,逐份加入1.12公斤的第三丁醇鉀。攪拌15分鐘後,將反應混合物冷卻至(-)10℃,然後加入溶解在2.24升THF中的367克三醇並將
混合物在(-10)℃攪拌。當反應完成時,加入水及甲苯將反應混合物分解。將水層用二氯甲烷(DKM)萃取並用NaHSO4的溶液酸化。然後加入醋酸乙酯,將液層分離並將水層用醋酸乙酯萃取。將合併的有機層用稀釋的氯化鈉溶液清洗,經由Na2SO4乾燥,將乾燥的物質過濾,將過濾液清洗並將過濾液溶液蒸發。將殘留物從丙酮:二異丙基醚混合物結晶。將觸媒過濾,用二異丙基醚:丙酮混合物清洗。將母液蒸發。
產量:463克,103%。
曲伏***素5.中間物之IR光譜列在圖6。
曲伏***素5.中間物1H、13C及19F NMR數據:
6.製備曲伏***素/式(I)化合物/
將463克曲伏***素酸溶解在2.3升1,3-二甲基咪唑啶酮(DMI)中,並加入420克K2CO3及300毫升異丙基碘。將反應混合物在45℃攪拌。反應完成後,加入NaHSO4溶液、水、己烷及醋酸乙酯。搖動混合物,然後將液層分離且下面水層是用己烷:醋酸乙酯混合物萃取。將合併的有機層用水清洗,經由Na2SO4乾燥,將乾燥的物質過濾並將溶液蒸發。將產物在矽膠上藉由層析法純化,使用二異丙醚、丙酮、二氯甲烷、異丙醇混合物作為洗提液。
產量:338.7克,67%。
曲伏***素之IR光譜列在圖7。
曲伏***素1H、13C及19F NMR數據:
Claims (13)
- 一種用於製備式(I)之曲伏***素之方法,其包括使用兒茶酚硼烷作為還原劑及使用CBS-唑硼烷作為觸媒,將式(II)化合物立體選擇性還原,且該還原於四氫呋喃或四氫呋喃與甲苯之混合物中進行,將所得的式(III)化合物藉由在己烷:丙酮混合物及在甲醇中結晶而純化,以便將不要的羥基表異構物(epimer)的量降低至1.0%,並還原式(III)化合物之內酯基,移除如此所得的式(IV)化合物之p-苯基-苯甲醯基保護基,將所得的式(V)三醇在醋酸乙酯:己烷之混合物中結晶而純化,其中以適當重複的結晶步驟將不要的異構物的量降低至0.05%,然後將式(V)化合物藉由Wittig反應而轉化成式(VI)之酸,其隨後酯化,其中該式(VI)化合物之酯化是用異丙基碘在環狀三級-醯胺型溶劑中進行。
- 根據請求項1定義之方法,其包括該還原是在(-)10及(-)20℃之間的溫度進行。
- 根據請求項1或2定義之結晶,其包括該結晶是在(-20)-70℃之間的溫度進行,方式是將物質溶解在迴流溫度的醇中,藉由逐漸冷卻而結晶,且隨後過濾,清洗並乾燥。
- 根據請求項1定義之方法,其包括式(III)化合物之還原是用二異丁基氫化鋁進行。
- 根據請求項1定義之方法,其包括式(IV)化合物之p-苯基苯甲醯基保護基是在鹼性條件下藉由甲醇分解而移除。
- 根據請求項5定義之方法,其包括該保護基是在碳酸鉀存在下移除。
- 根據請求項1定義之方法,其包括使用N-甲基吡咯酮或1,3-二甲基咪唑啶酮作為環狀三級-醯胺型溶劑。
- 根據請求項7定義之方法,其包括該酯化是在20-90℃的溫度範圍內進行。
- 根據請求項8定義之方法,其包括該酯化是在40-50℃的溫度範圍內進行。
- 根據請求項1定義之方法,其包括該式(I)產物是藉由層析法而純化。
- 根據請求項10定義之方法,其包括該產物是藉由重力矽膠層析法而純化,其使用二異丙醚及丙酮,然後是二氯甲烷、異丙醇混合物作為洗提液。
- 一種用於請求項1定義之方法中的式(IV)化合物,
- 一種根據請求項12定義之式(IV)化合物於製備請求項1定義之式(I)的曲伏***素之用途。
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Publication number | Priority date | Publication date | Assignee | Title |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2143712A1 (en) * | 2008-07-10 | 2010-01-13 | Sandoz AG | Improved Process for the Production of Prostaglandins and Prostaglandin Analogs |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2328131C3 (de) * | 1973-05-30 | 1986-11-13 | Schering AG, 1000 Berlin und 4709 Bergkamen | Neues Verfahren zur Herstellung von Prostaglandin-F↓2↓↓α↓ und seinen Analogen |
HU184948B (en) * | 1981-04-14 | 1984-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing 5-substituted 4-oxo-pgi down 1 derivatives |
HU190007B (en) | 1982-05-06 | 1986-08-28 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu | Process for producing new aromatic prostacylin analogues |
CS239696B1 (cs) * | 1984-05-03 | 1986-01-16 | Jiri Hajek | Způsob dělení 15S-a 15R-isomerů 4-/4-/substituovaných X-fenoxy/-3-hydroxy-1butenyí/hexahydro-5-hydroxy- -2H-cyklopenta[b]furan-2-onů |
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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 |
US7166730B2 (en) * | 2000-01-27 | 2007-01-23 | Fine Tech Laboratories, Ltd | Process for the preparation of prostaglandin derivatives |
GB0112699D0 (en) * | 2001-05-24 | 2001-07-18 | Resolution Chemicals Ltd | Process for the preparation of prostglandins and analogues thereof |
GB0329379D0 (en) * | 2003-12-19 | 2004-01-21 | Johnson Matthey Plc | Prostaglandin synthesis |
ME02433B (me) * | 2004-01-05 | 2016-09-20 | Nicox Sa | Nitrooksiderivati prostaglandina |
IT1393112B1 (it) * | 2009-02-27 | 2012-04-11 | Sifavitor S R L | Procedimento per la preparazione di derivati di prostaglandine |
CA2777290C (en) * | 2009-10-16 | 2016-06-28 | 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 |
EP2495235B1 (en) | 2011-03-04 | 2015-08-05 | Newchem S.p.A. | Process for the synthesis of prostaglandins and intermediates thereof |
PT2723714T (pt) | 2011-06-02 | 2017-08-18 | Chinoin Zrt | Novos processos para a preparação de amidas de prostaglandina |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2143712A1 (en) * | 2008-07-10 | 2010-01-13 | Sandoz AG | Improved Process for the Production of Prostaglandins and Prostaglandin Analogs |
Non-Patent Citations (4)
Title |
---|
Aswathanarayanappa, C. et al., Org. Process Res. Dev., 2011, 15: 1085-1087 * |
Cho, B. C., Tetrahedron, 2006, 62: 7621-7643 * |
SYLVIANE GIORGI-RENAULT et. al., "Heterocyclic Quinones. XIII. Dimerization in the Series of 5,8-Quinazolinediones: Synthesis and Antitumor Effect of Bis(4-amino-5,8-quinazolinediones)", Chem. Pharm. Bull., 1988, Vol. 36, No. 10, page 3933-3947 * |
SYLVIANE GIORGI-RENAULT et. al., "Heterocyclic Quinones. XIII. Dimerization in the Series of 5,8-Quinazolinediones: Synthesis and Antitumor Effect of Bis(4-amino-5,8-quinazolinediones)", Chem. Pharm. Bull., 1988, Vol. 36, No. 10, page 3933-3947。 |
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