JP6693859B2 - プロスタグランジンアミドの新規製造方法 - Google Patents
プロスタグランジンアミドの新規製造方法 Download PDFInfo
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- JP6693859B2 JP6693859B2 JP2016234694A JP2016234694A JP6693859B2 JP 6693859 B2 JP6693859 B2 JP 6693859B2 JP 2016234694 A JP2016234694 A JP 2016234694A JP 2016234694 A JP2016234694 A JP 2016234694A JP 6693859 B2 JP6693859 B2 JP 6693859B2
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- bimatoprost
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- added
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- 238000004519 manufacturing process Methods 0.000 title description 9
- -1 prostaglandin amide Chemical class 0.000 title description 8
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 claims description 47
- 229960002470 bimatoprost Drugs 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- 238000002844 melting Methods 0.000 claims description 20
- 230000008018 melting Effects 0.000 claims description 19
- 239000011541 reaction mixture Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 5
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 3
- 230000004927 fusion Effects 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
- 239000000243 solution Substances 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 23
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 22
- 150000002148 esters Chemical class 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 17
- YFHHIZGZVLHBQZ-KDACTHKWSA-N 17-phenyl-trinor-prostaglandin F2alpha Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)CC1=CC=CC=C1 YFHHIZGZVLHBQZ-KDACTHKWSA-N 0.000 description 16
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 238000002329 infrared spectrum Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 10
- 239000011259 mixed solution Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 238000002441 X-ray diffraction Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 5
- BNGPVKSKKYIJCR-UHFFFAOYSA-N 2-chloro-1,3-dimethylimidazolidine;hydrochloride Chemical compound [Cl-].CN1CC[NH+](C)C1Cl BNGPVKSKKYIJCR-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 125000002877 alkyl aryl group Chemical group 0.000 description 4
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 239000003849 aromatic solvent Substances 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000003880 polar aprotic solvent Substances 0.000 description 3
- 239000003586 protic polar solvent Substances 0.000 description 3
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 2
- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- XJRIDJAGAYGJCK-UHFFFAOYSA-N (1-acetyl-5-bromoindol-3-yl) acetate Chemical compound C1=C(Br)C=C2C(OC(=O)C)=CN(C(C)=O)C2=C1 XJRIDJAGAYGJCK-UHFFFAOYSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-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
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 description 1
- YFHHIZGZVLHBQZ-XFJSVXGXSA-N 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenylpent-1-enyl]cyclopentyl]hept-5-enoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)CC=CCCCC(O)=O)CC1=CC=CC=C1 YFHHIZGZVLHBQZ-XFJSVXGXSA-N 0.000 description 1
- YFHHIZGZVLHBQZ-UHFFFAOYSA-N 7-[3,5-dihydroxy-2-(3-hydroxy-5-phenylpent-1-enyl)cyclopentyl]hept-5-enoic acid Chemical compound OC1CC(O)C(CC=CCCCC(O)=O)C1C=CC(O)CCC1=CC=CC=C1 YFHHIZGZVLHBQZ-UHFFFAOYSA-N 0.000 description 1
- OXQYFEHYIDANAW-ZUVFATPXSA-N CCCCC(CCC/C=C\C[C@H]([C@H](CC1)/C=C/[C@H](CCC2C=CC=CC2)O)[C@H]1O)=O Chemical compound CCCCC(CCC/C=C\C[C@H]([C@H](CC1)/C=C/[C@H](CCC2C=CC=CC2)O)[C@H]1O)=O OXQYFEHYIDANAW-ZUVFATPXSA-N 0.000 description 1
- ULFWPYVQMYCYLO-QWUUOUIZSA-N CCNC(CCC/C=C\C[C@H](C(CC1)/C=C/[C@H](CCc2ccccc2)O)[C@H]1O)=O Chemical compound CCNC(CCC/C=C\C[C@H](C(CC1)/C=C/[C@H](CCc2ccccc2)O)[C@H]1O)=O ULFWPYVQMYCYLO-QWUUOUIZSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- IOSHTSDVYQBEHR-VMTDXPCOSA-N O[C@@H](CCC1CC=C=CC1)/C=C/C(C(C/C=C\CCCC(ON(C(CC1)=O)C1=O)=O)[C@H](C1)O)[C@@H]1O Chemical compound O[C@@H](CCC1CC=C=CC1)/C=C/C(C(C/C=C\CCCC(ON(C(CC1)=O)C1=O)=O)[C@H](C1)O)[C@@H]1O IOSHTSDVYQBEHR-VMTDXPCOSA-N 0.000 description 1
- 0 O[C@@](CCc1ccccc1)C=C[C@@]([C@]1[C@](C2)O*C1)[C@@]2O Chemical compound O[C@@](CCc1ccccc1)C=C[C@@]([C@]1[C@](C2)O*C1)[C@@]2O 0.000 description 1
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
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- 229940100198 alkylating agent Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- OMAHFYGHUQSIEF-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) oxalate Chemical compound O=C1CCC(=O)N1OC(=O)C(=O)ON1C(=O)CCC1=O OMAHFYGHUQSIEF-UHFFFAOYSA-N 0.000 description 1
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- 239000012043 crude product 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
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000686 lactone group Chemical group 0.000 description 1
- KORSLKJRGVYMOA-UHFFFAOYSA-N n-ethylhept-5-enamide Chemical compound CCNC(=O)CCCC=CC KORSLKJRGVYMOA-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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Description
破線で示す結合は単結合でも二重結合でもよく、5,6位及び13,14位が二重結合の場合には、シス型配座でもトランス型配座でもよく、
Qはヒドロキシル基を表し、Zはヒドロキシル基又はオキソ基を表し、
R1及びR2は独立して水素原子、又は場合により−ONO2基で置換された直鎖状もしくは分岐鎖状C1−10アルキル基もしくはアラルキル基、又はヘテロ原子を含むアラルキル基もしくはアリール基を表し、
R3は直鎖状もしくは分岐鎖状飽和もしくは不飽和C4−6炭化水素基、又はC4−10アルキルシクロアルキル基もしくはシクロアルキル基、又は場合によりアルキル基もしくはハロゲン原子で置換されたフェニル基、C7−10アルキルアリール基もしくはヘテロアリール基を表し、
Yは(CH2)n基又はO原子又はS原子を表し、
n=0〜3である。
率が50%を越えることは稀である(EP0660716、第42頁、実施例12)。周知の通り、プロスタグランジンは感温性であるため、高温処理はこうして得られるプロスタグランジン誘導体の不純物プロファイルと収率に悪影響を与える。
破線で示す結合は単結合でも二重結合でもよく、5,6位及び13,14位が二重結合の場合には、シス型配座でもトランス型配座でもよく、
Qはヒドロキシル基を表し、Zはヒドロキシル基又はオキソ基を表し、
R3は直鎖状もしくは分岐鎖状飽和もしくは不飽和C4−6炭化水素基、又はC4−10アルキルシクロアルキル基もしくはシクロアルキル基、又は場合によりアルキル基もしくはハロゲン原子で置換されたフェニル基、C7−10アルキルアリール基もしくはヘテロアリール基を表し、
Yは(CH2)n基又はO原子又はS原子を表し、
n=0〜3である。]の酸を、
i)R4基[なお、R4は式a):
NHR1R2 IV
(式中、R1及びR2の意味は上記に定義した通りである。)のアミンと反応させるか、あるいは、
ii)R5基[なお、R5は式b)、c)、d)又はe):
チルホルムアミド、ジメチルスルホキシド、N−メチルピロリドン、特にテトラヒドロフランを使用する。得られた一般式(V)の活性化エステルを単離後、又は単離せずに一般式(IV)のアミンと反応させる。
R3は直鎖状もしくは分岐鎖状飽和もしくは不飽和C4−6炭化水素基、又はC4−10アルキルシクロアルキル基もしくはシクロアルキル基、又は場合によりアルキル基もしくはハロゲン原子で置換されたフェニル基、C7−10アルキルアリール基もしくはヘテロアリール基を表し、
Yは(CH2)n基又はO原子又はS原子を表し、
n=0〜3である。]の化合物は、本発明に従い、一般式(XII):
Yは(CH2)n基又はO原子又はS原子を表し、n=0〜3である。]のラクトールトリオール誘導体は新規化合物である。
法を追試した処、高融点結晶形態のビマトプロストを得ることはできなかった。
a)[1,1’−ビフェニル]−4−カルボン酸((3aR,4R,5R,6aS)−ヘキサヒドロ−4−[(1E,3S)−3−ヒドロキシ−5−フェニル−1−ペンテン−1−イル]−2−ヒドロキシ−2H−シクロペンタ[b]フラン−5−イル)エステル(PPB−ラクトールトリオール)の製造
−65〜−85℃のテトラヒドロフラン(THF)溶媒1000ml中で下式:
融点:91.1〜91.7℃。
[1,1’−ビフェニル]−4−カルボン酸((3aR,4R,5R,6aS)−ヘキサヒドロ−4−[(1E,3S)−3−ヒドロキシ−5−フェニル−1−ペンテン−1−イル]−2−ヒドロキシ−2H−シクロペンタ[b]フラン−5−イル)エステル(PPB−ラクトールトリオール)の油状物46.2gをメタノール230mlに溶解し、K2CO36.6gの添加後、35〜45℃にて脱アシル化した。−5〜0℃にて0.5Mリン酸溶液を加えて反応混合物のpHを7〜8に調整した。析出した結晶を濾別し、メタノールと水の混液で洗浄した。母液を蒸発させ、酢酸エチルで抽出し、有機相をNa2SO4で乾燥し、乾燥剤を濾別し、ヘキサンを加えて生成物を結晶化させた。白色結晶生成物26gを得た。
)−3−ヒドロキシ−5−フェニル−1−ペンテン−1−イル]シクロペンチル]−5−ヘプテン酸((5Z)−ビマトプロスト酸)の製造:
c1)4−カルボキシブチルホスホニウムブロミド(KBFBr)108gをTHF800mlに溶解し、この溶液を0〜−5℃まで冷却した。この溶液に先ずカリウムtert−ブチレート(KOtBu)91gを加えた後、撹拌し、−10〜−15℃まで冷却後、ラクトールトリオール25gのTHF溶液を加えた。予想転化率に達したら、反応混合物を水でクエンチした後、EtOAcを加えた。水相をEtOAcで洗浄した。水層をNaHSO4溶液でpH=2まで酸性化し、EtOAcで抽出した。有機相を合わせて15%NaCl溶液で洗浄し、Na2SO4で乾燥し、濾過し、蒸発させた。残渣を酢酸エチルとジイソプロピルエーテルの混液から結晶化させた。結晶を濾別し、洗浄し、濾液を蒸発させた。ジイソプロピルエーテル−アセトンを溶離液とし、得られた黄色い油状物をシリカゲルクロマトグラフィーにより精製し、油状物25.5gを得た。
実施例1/c2のビマトプロスト酸27.5gをTHF270mlに溶解し、これに室温にてN,N’−ジイソプロピルカルボジイミド13.7gを加えた後、N−ヒドロキシスクシンイミド13.7gを加えた。混合物をこの温度にて撹拌後、1N NaHSO4溶液とtert−ブチルメチルエーテル(TBME)の混液に注いだ。相分離した。有機相を1N NaHCO3溶液で洗浄し、アルカリ水相をTBMEで抽出した。有機相を合わせてNa2SO4で乾燥し、濾過し、蒸発させた。残渣をヘキサンとアセトンの混液から結晶化させ、白色結晶生成物30.04gを得た。
ビマトプロスト酸2gをTHF20mlに溶解し、この溶液に室温にてN−ヒドロキシフタルイミド1gとN,N’−ジイソプロピルカルボジイミド1mlを加えた。反応混合物を2時間撹拌後、1N NaHSO4溶液とtert−ブチルメチルエーテル(TBME)の混液に注いだ。相分離し、有機相を1N NaHCO3溶液で洗浄し、アルカリ水相をTBMEで抽出した。有機相を合わせてNa2SO4で乾燥し、濾過し、蒸発させた。残渣をヘキサンとアセトンの混液から結晶化させ、白色結晶生成物1.5gを得た。
ビマトプロスト酸27.5gをTHF270mlに溶解し、この溶液に室温にてN,N’−ジイソプロピルカルボジイミド13.7gを加えた後、N−ヒドロキシスクシンイミド13.7gを加えた。混合物を室温で撹拌した。得られた活性化エステルを単離しなかった。
MSスペクトル:
正イオン化:
C25H37NO4
厳密な質量測定値:438.2648[M+Na]+
厳密な質量予想値:438.2615[M+Na]+
ΔM=3.3mDa及び7.53ppm。
C25H35NO3(M−H2O)
厳密な質量測定値:398.2655[M−H2O+H]+
厳密な質量予想値:398.2690[M−H2O+H]+
ΔM=−3.5mDa及び8.79ppm。
C25H35NO3(M−H2O)
厳密な質量測定値:420.2520[M−H2O+Na]+
厳密な質量予想値:420.2509[M−H2O+Na]+
ΔM=1.1mDa及び2.62ppm。
C25H32NO3(M−H2O−5H)
厳密な質量測定値:394.2366[M−H2O−5H]+
厳密な質量予想値:394.2377[M−H2O−5H]+
ΔM=−1.1mDa及び2.79ppm。
C25H30NO2(M−2xH2O−5H)
厳密な質量測定値:376.2258[M−2xH2O−5H]+
厳密な質量予想値:376.2271[M−2xH2O−5H]+
ΔM=−1.3mDa及び3.46ppm。
ビマトプロスト酸27.5gをTHF270mlに溶解し、この溶液に室温にて炭酸カリウム11.5gと炭酸N,N’−ジスクシンイミジル19.6gを加えた。反応混合物を撹拌下に60℃まで徐々に加熱した。得られた活性化エステルを単離しなかった。
ビマトプロスト酸27.5gをピリジン270mlに溶解し、これに1,1’−カルボニルジイミダゾール13.7gを加えた。活性化アミド形成が生じるまで混合物を20〜25℃にて撹拌した。得られた活性化アミドを単離しなかった。
実施例3の活性化エステル30.9gをTHF270mlに溶解し、この溶液にエチルアミンの2M THF溶液70mlを加えた。反応の完了後、混合物を1N NaHSO4溶液とEtOAcの混液に注いだ。有機相を1N NaHCO3溶液で洗浄した。アルカリ水相をEtOAcで抽出した。有機相を合わせてNaCl溶液で洗浄し、Na2SO4で乾燥した。乾燥剤を濾別し、濾液を蒸発させた。得られた油状物に35質量%の水を加え、生成物を結晶化させた。99.5%を上回る純度の白色ビマトプロスト結晶24.8gを得た。
ビマトプロスト酸2.00gをテトラヒドロフラン(THF)20mlに溶解し、30℃にて先ず2−クロロ−1,3−ジメチルイミダゾリニウムクロリド(DMC)1.29gとトリエチルアミン1.44mlを加えた後、10分間撹拌後にエチルアミンの2M THF溶液2.57mlを加えた。反応混合物を1時間かけて70℃まで徐々に加熱し、出発材料がなくなるまで(約1時間)混合物をこの温度で撹拌した。反応をTLCによりモニターした。
実施例6に従って製造したビマトプロスト油状物に35質量%の量の精製水を加えた。混合物を強く撹拌後、2時間おきに撹拌及び擦りながら最高温度35℃にて減圧乾燥した。完全に乾燥後、混合物をホモジナイズした。この生成物のIRスペクトルを図IVに示し、この生成物のDSC曲線を図VIに示す。生成された形態IIのX線回折曲線を図VIIIに示す。
収率:96.9%
Mp.:78℃
DSC開始温度:73.56℃。
実施例5に従って製造した粗製ビマトプロストを加熱下に3000倍量のジエチルエーテルに溶解した。次に窒素ガスを緩やかに通じることにより、−20〜−30℃にて溶媒を除去した。得られた結晶をホモジナイズするか、又は先ず機械的作用を加えた後にホモジナイズした。
収率:94.4%
Mp.:75.9℃
DSC開始温度:72.92℃。
実施例6に従って製造した粗製ビマトプロストに35質量%の量のメタノールを加えた。混合物を強く撹拌後、2時間おきに撹拌及び擦りながら最高温度35℃にて減圧乾燥した。完全に乾燥後、混合物をホモジナイズした。
収率:95.8%
Mp.:77.2℃
DSC開始温度:73.07℃。
実施例6に従って製造した粗製ビマトプロストに17.5質量%の量の精製水と17.5質量%の量のエタノールを加えた。混合物を強く撹拌後、2時間おきに撹拌及び擦りながら最高温度35℃にて減圧乾燥した。完全に乾燥後、混合物をホモジナイズした。
収率:92.3%
Mp.:72.9℃
DSC開始温度:72.96℃。
a)(特許出願US20090163596の実施例38による)ビマトプロスト結晶形態Iの製造
粗製ビマトプロスト5.2gをアセトニトリル106gから結晶化させた。混合物を沸点付近の温度まで加熱し、高温の溶液を室温まで冷却し、混合物をこの温度で1時間撹拌後、0〜5℃で2時間撹拌した。析出した結晶を濾別し、冷温(0〜5℃)のアセトニトリル20gで洗浄し、0〜5℃にて1時間、室温にて30分間、更に30〜40℃にて2時間減圧乾燥した。
収率:83%
Mp.:62.1℃
DSC開始温度:63.61℃。
実施例14aに従って製造した結晶形態Iのビマトプロストに35質量%の量の精製水を加えた。混合物を強く撹拌後、2時間おきに撹拌及び擦りながら最高温度35℃にて減圧乾燥した。完全に乾燥後、混合物をホモジナイズした。
収率:97.3%
Mp.:77.7℃
DSC開始温度:73.14℃。
結晶形態II及びIのビマトプロストの50%−50%混合物に35質量%の量の精製水を加えた。混合物を強く撹拌後、2時間おきに撹拌及び擦りながら最高温度35℃にて減圧乾燥した。完全に乾燥後、混合物をホモジナイズした。
収率:97.6%
Mp.:78.2℃
DSC開始温度:73.77℃。
Claims (5)
- 35質量%の量のメタノール、エタノール及び/又は水を利用することを特徴とする請求項1に記載の方法。
- メタノール又はエタノールを使用することを特徴とする請求項1に記載の方法。
- 水を使用することを特徴とする請求項1に記載の方法。
- 機械的作用として撹拌又は擦る又はその両方を利用することを特徴とする請求項1に記載の方法。
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