TWI653222B - 用於製備前列腺素醯胺之新穎方法(一) - Google Patents
用於製備前列腺素醯胺之新穎方法(一) Download PDFInfo
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- TWI653222B TWI653222B TW105137755A TW105137755A TWI653222B TW I653222 B TWI653222 B TW I653222B TW 105137755 A TW105137755 A TW 105137755A TW 105137755 A TW105137755 A TW 105137755A TW I653222 B TWI653222 B TW I653222B
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- general formula
- bimatoprost
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 150000003180 prostaglandins Chemical class 0.000 title description 5
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 title 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 150000002148 esters Chemical class 0.000 claims abstract description 26
- 239000013078 crystal Substances 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 13
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 11
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 239000004210 ether based solvent Substances 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003759 ester based solvent Substances 0.000 claims description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims 2
- 229960002470 bimatoprost Drugs 0.000 abstract description 43
- 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 abstract description 42
- 238000002844 melting Methods 0.000 abstract description 28
- 238000006243 chemical reaction Methods 0.000 abstract description 23
- 230000008018 melting Effects 0.000 abstract description 22
- 150000001408 amides Chemical class 0.000 abstract description 12
- 150000001412 amines Chemical class 0.000 abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 10
- -1 prostaglandin amide Chemical class 0.000 abstract description 10
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 239000002253 acid Substances 0.000 abstract description 6
- 125000002877 alkyl aryl group Chemical group 0.000 abstract description 6
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
- 125000005843 halogen group Chemical group 0.000 abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 6
- 125000004430 oxygen atom Chemical group O* 0.000 abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 6
- 229920006395 saturated elastomer Polymers 0.000 abstract description 6
- 125000004434 sulfur atom Chemical group 0.000 abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- RLRHXLXCAWJBGX-UHFFFAOYSA-N 2-chloro-1,3-dimethyl-1,2-dihydroimidazol-1-ium;chloride Chemical compound [Cl-].CN1C=C[NH+](C)C1Cl RLRHXLXCAWJBGX-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 2
- 125000005842 heteroatom Chemical group 0.000 abstract description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 238000002360 preparation method Methods 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 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
- 239000010410 layer Substances 0.000 description 16
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002329 infrared spectrum Methods 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-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
- 239000012535 impurity Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical group CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 239000002178 crystalline material Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 150000002596 lactones Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 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
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group 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
- 230000015572 biosynthetic process Effects 0.000 description 3
- 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 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 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
- BNGPVKSKKYIJCR-UHFFFAOYSA-N 2-chloro-1,3-dimethylimidazolidine;hydrochloride Chemical compound [Cl-].CN1CC[NH+](C)C1Cl BNGPVKSKKYIJCR-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
- 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 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 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
- SXADHRIREHPQTN-MWBCMDMXSA-N [(3ar,4r,5r,6as)-2-hydroxy-4-[(e,3s)-3-hydroxy-5-phenylpent-1-enyl]-3,3a,4,5,6,6a-hexahydro-2h-cyclopenta[b]furan-5-yl] 4-phenylbenzoate Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC(=O)C=1C=CC(=CC=1)C=1C=CC=CC=1)CC1=CC=CC=C1 SXADHRIREHPQTN-MWBCMDMXSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 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
- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-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
- 241000208340 Araliaceae Species 0.000 description 1
- CTWFIQXAAISNBW-UHFFFAOYSA-N CN1CN(C=C1)C.[Cl] Chemical compound CN1CN(C=C1)C.[Cl] CTWFIQXAAISNBW-UHFFFAOYSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000010779 crude oil Substances 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
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- FNKQFBWKNIGIOS-UHFFFAOYSA-N furan-2,5-diol Chemical compound OC1=CC=C(O)O1 FNKQFBWKNIGIOS-UHFFFAOYSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 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
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 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
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- DYVOLUUJJDFBFC-UHFFFAOYSA-N tripotassium butan-1-olate Chemical compound [K+].[K+].[K+].CCCC[O-].CCCC[O-].CCCC[O-] DYVOLUUJJDFBFC-UHFFFAOYSA-N 0.000 description 1
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
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
-
- 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
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
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Abstract
本發明係關於用於製備通式I的前列腺素醯胺之方法
-其中在式中用虛線標示的鍵可以是單鍵或雙鍵,在位置5,6及13,14在雙鍵之情形下,其可以是順式或反式位向,Q代表羥基且Z代表羥基或側氧基,R1及R2獨立地代表氫原子或直鏈或支鏈的C1-10烷基或芳烷基,隨意地經-ONO2、或芳烷基或芳基取代,其含有雜原子,
R3代表直鏈或支鏈、飽和或不飽和的C4-6烴基,或C4-10烷基環烷基或環烷基,或隨意地經烷基或鹵素原子取代之苯基、C7-10烷基芳基或雜芳基,Y代表(CH2)n或O原子或S原子,且其中n=0-3,其特徵在於:通式(II)的酸
其中在式中用虛線標示的鍵可以是單鍵或雙鍵,在位置5,6及13,14在雙鍵之情形下,其可以是順式或反式位向,Q代表羥基且Z代表羥基或側氧基,R3代表直鏈或支鏈、飽和或不飽和的C4-6烴基,或C4-10烷基環烷基或環烷基,或隨意地經烷基或鹵素原子取代之苯基、C7-10烷基芳基或雜芳基,Y代表(CH2)n或O原子或S原子,且其中n=0-3,i)與合適引入基團R4的化合物反應,其中R4代表式a.)之基團,
且所得的通式(III)之醯胺
其中R3、R4、Y及n之意義是如上述定義,係與通式(IV)之胺反應NHR 1 R 2 IV.-其中R1及R2之意義是如上述定義,或ii)與合適引入基團R5的化合物反應,其中R5代表式b.)、c.)、d.)或e.)之基團,
其中(X)代表鹵素原子或氫原子,且所得的通式(V)之經活化的酯
其中R3、R5、Y及n之意義是如上述定義,係與通式(IV)之胺反應,或iii.)在氯化2-氯-1,3-二甲基咪唑及鹼存在下,與通式(IV)之胺反應,其中R1及R2之意義是如上述定義。
本發明之其他具體實施例是用於製備式(IB)的比馬前列腺素(bimatoprost)的高熔點結晶形式II之方法。
本發明之其他具體實施例是用於製備結晶形式的式(IIB)化合物之方法。
Description
本發明之主題是用於製備通式(I)的前列腺素醯胺之方法。
在通式(I)的化合物中
取代基之意義如下:用虛線標示的鍵可以是單鍵或雙鍵,在位置5,6及13,14在雙鍵之情形下,其可以是順式或反式位向,Q代表羥基且Z代表羥基或側氧基,R1及R2獨立地代表氫原子或直鏈或支鏈的C1-10烷基或芳烷基,隨意地經-ONO2、或芳烷基或芳基取代,其含有雜原子,
R3代表直鏈或支鏈、飽和或不飽和的C4-6烴基,或C4-10烷基環烷基或環烷基,或隨意地經烷基或鹵素原子取代之苯基、C7-10烷基芳基或雜芳基,Y代表(CH2)n或O原子或S原子,且n=0-3。
為了經濟地製備前列腺素醯胺衍生物,適當經取代的前列腺酸(prostan acid)須經活化。
根據目前的技藝狀態,羧酸可以經由轉化成其混合的酐、活化的酯或活化的醯胺類而經活化,而且這些化合物可以隨後經由與適當的胺類反應而進一步轉化成所要的前列腺素醯胺衍生物。
對於上述的可能性,化學性非常敏感的前列腺素酸經由酯形成之活化作用是揭示例如在EP 0 660 716。
根據此方法,藉助於烷基鹵化物而形成起始的酯且該酯隨後與適當的胺反應而得到醯胺官能基。此方法的缺點是要避免在合成結束時-最後步驟-使用烷基鹵化物,因為烷基鹵化物經證明是基因毒性藥物。此外,所得的酯必須在高溫下與適當的胺長時間反應且轉化很少超過50%(EP0660716,42頁,實例12)。考量前列腺素之已知的溫度敏感性,其在高溫的處理不利地影響在此方法所得的前列腺素衍生物之雜質情形及產量。
混合的酐之製備及其與經適當取代的胺之反應是陳述在WO9153206。
此方法的缺點是用於製備混合的酐之活性鹵化劑-鹵化的甲酸酯、特戊醯氯及其他-經證明是基因毒性化合物。
在WO2005058812(23頁)陳述的方法中,起始的羧酸是藉由使用活化劑1-(3-二甲胺基丙基)-3-碳化二醯亞胺鹽酸鹽(EDC HCl)及乙胺而直接轉化成乙基醯胺。在醯胺化反應期間,在位置11及15的羥基是用四氫吡喃(THP)保護基保護,其隨後被移除。
根據本發明,我們發現經由新穎經活化的酯類及新穎經活化的醯胺類,可以在溫和的反應條件下,以高產量及高純度製備通式(I)的化合物。
根據本發明,製備通式(I)的化合物可以經由使通式(II)的酸
其中在式中用虛線標示的鍵可以是單鍵或雙鍵,在位置5,6及13,14在雙鍵之情形下,其可以是順式或反式位向,Q代表羥基且Z代表羥基或側氧基,
R3代表直鏈或支鏈、飽和或不飽和的C4-6烴基,或C4-10烷基環烷基或環烷基,或隨意地經烷基或鹵素原子取代之苯基、C7-10烷基芳基或雜芳基,Y代表(CH2)n或O原子或S原子,且n=0-3,i)與合適引入R4的化合物反應,其中R4代表式a.)之基團,
且如此所得的通式(III)之醯胺
其中Q、Z、R3、R4、Y及n之意義是如上述定義,與通式(IV)之胺反應NHR 1 R 2 IV.其中R1及R2之意義是如上述定義,或ii)與合適引入R5的化合物反應,其中R5代表式b.)、c.)、d.)或e.)之基團,
其中(X)代表鹵素原子或氫原子,且如此所得的通式(V)之經活化的酯
其中Q、Z、R3、R5、Y及n之意義是如上述定義,與通式(IV)之胺反應,其中R1及R2之意義是如上述定義。
我們還發現根據本發明通式(I)的化合物也可以經由在氯化2-氯-1,3-二甲基咪唑(2-chloro-1,3-dimethylimidazolinium chloride)及鹼存在下,使通式(II)的化合物與通式(IV)的化合物反應而製備,其中在式中的取代基之意義是如上述定義(方法iii)。
通式(III)及(V)的中間物是新穎的化合物。
至於合適引入R4的化合物,較宜是1,1’-羰基二咪唑(DCI)或1,1’-硫羰基二咪唑,在特定情況下在活化劑存在下引入R5的化合物,是N-羥基琥珀醯亞胺、N-羥基鄰苯二甲醯亞胺、N-羥基-5-原冰片烯-內-2,3-二甲醯胺、1-羥基苯并三唑、(苯并三唑-1-氧基)參(二甲胺基)鏻六氟磷酸鹽、N,N’-二琥珀醯亞胺基碳酸酯(DSC)或N,N’-二琥珀醯亞胺基草酸酯,尤其是可以施加N,N’-二琥珀醯亞胺基碳酸酯。
至於活化劑,是N,N’-二異丙基碳化二醯亞胺、N,N’-二環己基碳化二醯亞胺或2-氯-1,3-二甲基氯化咪唑(2-chloro-1,3-dimethylimidazolinium chloride),較宜施加N,N’-二異丙基碳化二醯亞胺。
根據本發明在方法i)的過程中,可以在醚類溶劑或芳族溶劑或極性非質子溶劑或在其混合物中引入R4,使用例如二異丙醚、第三丁基甲基醚、2-甲基四氫呋喃、甲苯、茴香醚、二甲基甲醯胺、二甲亞碸、N-甲基吡咯酮,尤其是四氫呋喃。所得的通式(III)經活化的醯胺在有或無分離後與通式(IV)之胺反應。引入R4期間的反應溫度是在20-80℃之間,較宜是70℃,而式(III)與(IV)化合物之反應是在20-80℃之間進行,較宜在室溫。
根據本發明在方法ii)的過程中,引入R5是在醚類溶劑或芳族溶劑或極性非質子溶劑或在其混合物中進行,使用例如二異丙醚、第三丁基甲基醚、2-甲基四氫呋喃、甲苯、茴香醚、二甲基甲醯胺、二甲亞碸、N-甲基吡咯酮,尤其是四氫呋喃。所
得的通式(V)經活化的酯在有或無分離後與通式(IV)之胺反應。引入R5期間的反應溫度是在0-80℃之間,較宜在室溫,而式(V)與(IV)化合物之反應是在20-80℃之間進行,較宜在室溫。
根據本發明在方法iii)的過程中,反應是在醚類溶劑或芳族溶劑或極性非質子溶劑或在其混合物中進行,使用例如二異丙醚、第三丁基甲基醚、2-甲基四氫呋喃、甲苯、茴香醚、二甲基甲醯胺、二甲亞碸、N-甲基吡咯酮或四氫呋喃。至於鹼,可以使用經常施加的鹼,例如吡啶、N-甲基嗎福啉、二異丙基乙基胺、1,5-二氮雜二環[4,3,0]壬-5-烯、1,8-二氮雜二環[5,4,0]十一碳-7-烯或三乙胺。
反應是在0-70℃之間的溫度進行,通式(II)化合物在有機溶劑中的溶液是在0-70℃,較宜在30℃,加入通式(IV)化合物、氯化2-氯-1,3-二甲基咪唑及2莫耳當量的鹼。混合物先在此溫度攪拌且隨後逐漸加熱直到起始物質消失。藉由TLC追蹤反應。
方法i、ii或iii也可以在「單鍋」條件下進行。
至於通式(IV)之胺,合適於最終化合物的胺,在比馬前列腺素之情形可以使用乙胺。
對於通式(IA)化合物之製備
其中R1、R2、R3、Y及n之意義是如上述定義,使用根據本發明通式(IIA)之化合物作為起始物質。
通式(IIA)之化合物
其中在式中R3代表直鏈或支鏈、飽和或不飽和的C4-6烴基,或C4-10烷基環烷基或環烷基,或隨意地經烷基或鹵素原子取代之苯基、C7-10烷基芳基或雜芳基,Y代表(CH2)n或O原子或S原子,且n=0-3,可以根據本發明製備,藉由還原通式(XII)之內酯二醇
其中R3、Y及n之意義是如上述定義,成為通式(XIII)之內酯三醇
其中R3、Y及n之意義是如上述定義,隨後移除通式(XIII)化合物之保護基,如此得到通式(XIV)之化合物,
其中R3、Y及n之意義是如上述定義,藉由Wittig反應而轉化成通式(IIA)之化合物。
通式(XII)化合物之反應可以藉由已知方法進行,例如用二異丁基氫化鋁在四氫呋喃介質中。保護基可以經由已知方法在酸性或鹼性介質中移除,較宜在鹼性介質。
通式(XIII)之內酯三醇衍生物
其中R3代表直鏈或支鏈、飽和或不飽和的C4-6烴基,或C4-10烷基環烷基或環烷基,或隨意地經烷基或鹵素原子取代之苯基、C7-10烷基芳基或雜芳基,Y代表(CH2)n或O原子或S原子,且n=0-3,是新穎的化合物。
根據本發明之另一個具體實施例,特殊的通式IIA化合物,其中R3代表苯基且Y代表-(CH2)-,式(IIB)化合物也可以製備成結晶形式。
式(IIB)化合物之結晶形式是新穎的化合物。
式(IIB)化合物可以在結晶形式製備,其方法是在含有式(IIB)化合物之混合物中加入酯類及醚類溶劑之混合物。
根據此方法,二甲醚、二乙醚、二異丙醚,較宜是二乙醚
及二異丙醚是作為醚型溶劑使用,及醋酸乙酯、醋酸甲酯、醋酸異丙酯,較宜是醋酸異丙酯作為酯型溶劑使用。結晶作用是在-30℃及30℃之間進行,較宜在0-25℃之間。如此所得的結晶之懸浮液攪拌1-24小時,較宜是8小時,隨後過濾並用醚類溶劑清洗,較宜用二異丙醚。過濾後的結晶在25-50℃之間的真空下乾燥,較宜在35-40℃。
通式(II)及(XII)之化合物可以藉由已知的方法製備,例如揭示在US 5359095、WO 93/00329。
根據本發明方法之優點是所要的比馬前列腺素最終產物-如果需要時-可以經由結晶的比馬前列腺素酸合成。根據本發明方法之另一個優點是所要的最終產物是經由新穎的中間物之結晶、活化的酯或醯胺合成,其-如果需要時-可以分離且-如果需要時-可以藉由結晶或層析法純化。由於施加羧酸活化劑(例如DSC、DCI),不需要保護位置9、11及15的二級羥基,沒有觀察到平行的反應例如二聚物形成,不論是在活化的酯或活化的醯胺之情形,或在最終醯胺形成之條件下,且根據本發明經活化的羧酸衍生物容易在高產量及純度下分離。
訝異地發現本發明結晶經活化的羧酸衍生物可以藉由結晶法容易地純化以消除雜質且也可以在溫和的反應條件及在高產量下,簡易地轉化成所要的醯胺最終產物。
熟知在活性醫藥成份(API)之情形中,雜質的量是一個關鍵的議題,在比馬前列腺素之情形中,每種未知雜質的量必須低於0.1%。根據本發明之方法-為了保持此非常嚴格的限制-使用比馬前列腺素酸之結晶作用及活性羧酸衍生物之結晶作用
代替在WO09153206中揭示的昂貴製備級HPLC解離。
本發明之另一個具體實施例是製備式(IB)的比馬前列腺素之高熔點結晶形式II之方法。
藉由根據本發明之方法,可以製備化學與熱動力學安定且無其他結晶形式的比馬前列腺素之高熔點結晶形式II。
下面的專利申請案是關於比馬前列腺素產物之結晶作用:US 2005/0209337 A1、WO 2009/153206 A2、US 2009/0163596 A1。在US 2009/0163596 A1的實例30中,比馬前列腺素之高熔點結晶形式(DSC峰讀值79℃)(進一步:結晶形式II)是藉由其X-光繞射、其在KBr片中的IR光譜及藉由其DSC及TGA曲線而鑑定。WO 2009/153206揭示藉由製備級HPLC,隨後藉由結晶法而純化比馬前列腺素產物。結晶作用是從乙腈溶劑或從乙腈作為溶解溶劑且TBME(第三丁基甲基醚)作為沈澱溶劑而進行。根據該描述,藉由此方法可以製備比馬前列腺素之高熔點結晶形式(DSC峰讀值79℃)。藉由重複該方法,我們沒有成功得到比馬前列腺素之高熔點結晶形式。US 2009/0163596揭示比馬前列腺素之結晶形式I及其製備。比馬前列腺素之結晶形式I是藉由其熔點(62-64℃)、藉由DSC、X-光
繞射及IR研究而鑑定。其詳細描述結晶方法,例如溶解方法(在接近沸點溫度之有機溶劑中或有機溶解-與沈澱-溶劑的混合物中)、冷卻方法、從母液分離沈澱的結晶形式及乾燥方法(在低溫的真空下)。比馬前列腺素之高熔點結晶形式(DSC峰讀值79℃)無法藉由在US 2009/0163596揭示的方法製備。
藉由本發明之方法,可以製備比馬前列腺素之化學與熱動力學安定、高熔點之結晶形式II(=高熔點之結晶形式(DSC峰讀值79℃))其不含結晶形式I。形式II是藉由其熔點(72-78℃)、藉由DSC研究及藉由IR與X-光粉末繞射研究而鑑定。
本發明方法之本質是,從處理且蒸發後含有比馬前列腺素之反應混合物,或從比馬前列腺素之任何結晶或非結晶的形式或從其任何比例之混合物,經由從質子或醚類溶劑之結晶作用,可以製備熱動力學安定之純的形式II。結晶方法如下:將計算量的溶劑添加至油性或結晶的粗比馬前列腺素中,然後乾燥並定期暴露至機械效應。
根據上述,本發明係關於用於製備式(IB)的比馬前列腺素之結晶形式II的方法,其特徵是將算量的醚類或質子溶劑添加至處理且蒸發後含有比馬前列腺素之反應混合物、或比馬前列腺素之任何結晶或非結晶的形式或其任何比例之混合物中,如果需要時將所得的混合物暴露至機械效應,然後乾燥並均勻化。
在上述方法中所得的結晶形式II之熔點是在72-78℃之間,根據DSC研究之吸熱峰是在73-79℃之間且熔化熱高於75焦耳/克。
圖6、8及4分別呈現在根據本發明方法所得的結晶形式II之DSC曲線、X-光粉末繞射曲線及IR光譜。
圖5、7及3分別呈現結晶形式I之DSC曲線、X-光粉末繞射曲線及IR光譜。
在根據本發明之方法中,我們使用計算的量,適宜是20-60重量%,較宜是35重量%的質子溶劑,尤其是醇類例如甲醇、乙醇及/或水。較宜使用水作為質子溶劑。
至於機械效應,我們施加攪拌或刮擦,或兩者。添加的溶劑是經由乾燥而移除。乾燥是在-60℃及70℃之間的溫度,尤其在35℃,在真空進行。
至於醚類溶劑,我們施加計算的量,較宜是2000-8000重量%的二甲醚、二乙醚、二異丙醚,較宜是二乙醚。添加的溶劑是經由乾燥而移除。乾燥是在低溫,較宜在0-(-)50℃之間,藉由通過氮氣而進行。
產物的鑑定是藉助於下面的分析儀器而進行:NMR光譜是藉由Bruker-Avance III-500MHz儀器而記錄,DSC曲線藉由Mettler-Toledo DSC 1/700儀器,IR光譜藉由Perkin-Elmer Spektrum 400 FT-IR光譜儀,MS光譜藉由Shimadzu LC-MS-IT-TOF儀器。熔點是藉由Büchi Melting Point B-545裝置測定。
本發明之其他細節是在實例中描述,但本發明不受限於這些實例。
圖1實例1a的內酯三醇之IR光譜。
圖2實例1/c1的比馬前列腺素酸之IR光譜。
圖3實例14/a的形式I之IR光譜。
圖4實例10.)的形式II之IR光譜。
圖5實例14/a的形式I之DSC曲線。
圖6實例10的形式II之DSC曲線。
圖7實例14/a的形式I之X-光繞射曲線。
圖8實例10的形式II之X-光繞射曲線。
圖9實例1/c2.)的比馬前列腺素酸之X-光繞射曲線。
圖10實例1/c2.)的比馬前列腺素酸之DSC曲線。
將55克的[1,1’-聯苯]-4-羧酸((3aR,4R,5R,6aS)-六氫-4-[(1E,3S)-3-羥基-5-苯基-1-戊烯-1-基]-2-側氧基-2H-環戊[b]呋喃-5-基)酯(PPB-內酯二醇)之內酯基
所得的PPB-內酯三醇之結構式:
在第三丁基甲基醚(TBME):己烷混合物結晶後,從粗油得到41.6克白色結晶。
熔點:91.1-91.7℃
實例1a之內酯三醇的IR光譜如圖1所示。
13C及1H NMR數據:
*重疊的1H NMR訊號(在括弧中的數字係指訊號基團在PMR光譜中的位置編號,方向:朝向減少轉移)
**13C NMR訊號與DMSO溶劑的多重譜線重疊。
將46.2克的[1,1’-聯苯]-4-羧酸((3aR,4R,5R,6aS)-六氫-4-[(1E,3S)-3-羥基-5-苯基-1-戊烯-1-基]-2-羥基-2H-環戊[b]呋
喃-5-基)酯(PPB-內酯三醇)油溶解在230毫升甲醇中且在加入6.6克K2CO3後在35-45℃去醯基化。在(-)5-0℃用0.5M磷酸溶液將反應混合物的pH調整至7-8。將沈澱的結晶過濾並用甲醇:水混合物清洗。將母液蒸發,用醋酸乙酯萃取,將有機層經由Na2SO4乾燥,將乾燥的物質過濾並將產物經由加入己烷而結晶化。得到26克白色結晶的物質。
產物之結構式:
熔點:98-103℃
13C及1H NMR數據:
*重疊的1H NMR訊號(在括弧中的數字係指訊號基團在PMR光譜中的位置編號,方向:朝向減少轉移)。
c1.)將108克4-羧基丁基溴化鏻(KBFBr)溶解在800毫升THF中並將溶液冷卻至0-(-)5℃。在此溶液中先加入91克第三丁醇鉀(KOtBu),且攪拌並冷卻至(-10)-(-15)℃後,加入25克內酯三醇在THF中的溶液。當達到預期的轉化後,用水將反應混合物破壞,隨後加入EtOAc。將水層用EtOAc清洗。將水層用NaHSO4溶液酸化至pH=2並用EtOAc萃取。將合併的有機層用15% NaCl溶液清洗,經由Na2SO4乾燥,過濾並蒸發。將殘留物從醋酸乙酯與二異丙醚之混合物結晶化。將結晶過濾並清洗,將過濾液蒸發。將所得的黃色油經由層析法在矽膠上用二異丙醚-丙酮洗提液純化。得到25.5克油。
所得的比馬前列腺素酸之IR光譜如圖2所示。
c2.)將實例1/c1.)所得的產物溶解在60毫升醋酸異丙酯中並在攪拌下在其中加入40毫升二乙醚。將少量的比馬前列腺素酸之種子結晶添加至反應混合物中。在攪拌下逐漸冷卻至0℃並在其中加入約60毫升二異丙醚。將懸浮液在此溫度攪拌一夜後過濾並用二異丙醚清洗且在真空下乾燥,得到20.4克結晶狀比馬前列腺素酸。
所得的比馬前列腺素酸之DSC曲線是列在圖10且X-光粉末繞射曲線是在圖9。
產物之結構式:
熔點:63.0-65.5℃
13C及1H NMR數據:
*部份或完全重疊的1H NMR訊號(在括弧中的數字係指訊號基團在PMR光譜中的位置編號,方向:朝向減少轉移)。
將27.5克實例1/c2.)的比馬前列腺素酸溶解在270毫升THF
中並在室溫下在其中加入13.7克N,N’-二異丙基碳化二醯亞胺,隨後加入13.7克N-羥基琥珀醯亞胺。將混合物在此溫度攪拌後倒在1N NaHSO4溶液及第三丁基甲基醚(TBME)之混合物上。將液層分離。將有機層用1N NaHCO3溶液清洗,將水性-鹼性層用TBME萃取。將合併的有機層經由Na2SO4乾燥,過濾並蒸發。將殘留物從己烷:丙酮之混合物結晶化,得到30.04克白色結晶狀物質。
產物:
熔點:93.5-103.4℃
3.)將27.5克實例1/c1.)的比馬前列腺素酸溶解在270毫升THF中並在室溫下在其中加入11.5克碳酸鉀及19.6克N,N’-二珀醯亞胺基碳酸酯。將反應混合物在攪拌下逐漸加熱至60℃且隨後倒在1N NaHSO4溶液及第三丁基甲基醚(TBME)之混合物上。將液層分離。將有機層用1N NaHCO3溶液清洗,將水性-鹼性層用TBME萃取。將合併的有機層經由Na2SO4乾燥,過濾並蒸發。將殘留物從己烷:丙酮之混合物結晶化,得到30.9克白色結晶狀物質。
產物:
熔點:93.5-103.4℃
13C及1H NMR數據:
將2克的比馬前列腺素酸溶解在20毫升THF中並在室溫下在此溶液中加入1克N-羥基-酞醯亞胺。將反應混合物攪拌2小時後倒在1N NaHSO4溶液及第三丁基甲基醚(TBME)之混合物上。將液層分離。將有機層用1N NaHCO3溶液清洗,將水性-鹼性層用TBME萃取。將合併的有機層經由Na2SO4乾燥,過濾並蒸發。將殘留物從己烷:丙酮之混合物結晶化,得到1.5克白色結晶狀物質。
產物:
熔點:83.2-84.5℃
13C及1H NMR數據:
將27.5克的比馬前列腺素酸溶解在270毫升THF中並在室溫下在此溶液中加入13.7克N,N’-二異丙基碳化二醯亞胺,隨後
加入13.7克N-羥基琥珀醯亞胺。將混合物在室溫攪拌。所得的活化酯不分離。
完成酯形成後,將70毫升在THF中的2M乙胺溶液添加至反應混合物中。將混合物攪拌直到達成預期的轉化,然後將其倒在1N NaHSO4溶液及第三丁基甲基醚(TBME)之混合物上。將液層分離。將有機層用1N NaHCO3溶液清洗,將水性-鹼性層用TBME萃取。將合併的有機層經由Na2SO4乾燥,過濾並蒸發後得到25.4克油。
產物:
13C及1H NMR數據:
MS數據
MS光譜:
正游離化:
預期的化學式:
C25H37NO4
測量的實際質量:438.2648[M+Na]+
預期的實際質量:438.2615[M+Na]+ △M=3.3mDa及7.53ppm
C25H35NO3(M-H2O)
測量的實際質量:398.2655[M-H2O+H]+
預期的實際質量:398.2690[M-H2O+H]+ △M=-3.5mDa及8.79ppm
MSMS(前驅物離子:438.26)
預期的化學式:
C25H35NO3(M-H2O)
測量的實際質量:420.2520[M-H2O+Na]+
預期的實際質量:420.2509[M-H2O+Na]+ △M=1.1mDa及2.62
ppm
C25H32NO3(M-H2O-5H)
測量的實際質量:394.2366[M-H2O-5H]+
預期的實際質量:394.2377[M-H2O-5H]+ △M=-1.1mDa及2.79ppm
C25H30NO2(M-2xH2O-5H)
測量的實際質量:376.2258[M-2xH2O-5H]+
預期的實際質量:376.2271[M-2xH2O-5H]+ △M=-1.3mDa及3.46ppm
將27.5克的比馬前列腺素酸溶解在270毫升THF中並在室溫下在此溶液中加入11.5克碳酸鉀及19.6克N,N’-二珀醯亞胺基碳酸酯。將反應混合物在攪拌下逐漸加熱至60℃。所得的活化酯不分離。
活化的酯形成後,將70毫升在THF中的2M乙胺溶液添加至反應混合物中。當反應完成後將混合物倒在1N NaHSO4溶液及EtOAc之混合物上。將有機層用1N NaHCO3溶液清洗,將水性-
鹼性層用EtOAc萃取。將合併的有機層用NaCl溶液清洗並經由Na2SO4乾燥。將乾燥的物質過濾,將過濾液蒸發後得到25.7克油。
產物:
將27.5克的比馬前列腺素酸溶解在270毫升吡啶中並在其中加入13.7克1,1’-羰基二咪唑。將混合物在20-25℃攪拌直到發生活化的醯胺形成。所得的活化醯胺不分離。
將70毫升在THF中的2M乙胺溶液添加至在室溫的反應混合物中並將混合物攪拌直到達成預期的轉化。然後將混合物倒
在1N NaHSO4溶液及第三丁基甲基醚(TBME)之混合物上。將液層分離,將有機層用1N NaHCO3溶液清洗並將水性-鹼性層用TBME萃取。將合併的有機層經由Na2SO4乾燥,過濾並將過濾液蒸發後得到23.82克油。
產物:
將30.9克根據實例3經活化的酯溶解在270毫升THF中並在此溶液中加入70毫升溶解在THF中的2M乙胺溶液。反應完成後,將混合物倒在1N NaHSO4溶液及EtOAc之混合物上。將有機層用1N NaHCO3溶液清洗。將水性-鹼性層用EtOAc萃取。將合併的有機層用NaCl溶液清洗並經由Na2SO4乾燥。將乾燥的物質過濾並將過濾液蒸發。在所得的油中加入35重量%的水且產物結晶化。得到24.8克高於99.5%純度之白色比馬前列腺素結晶。
產物:
熔點:71.9-72.5℃
HPLC:99.6%比馬前列腺素,低於0.3%反-比馬前列腺素,0.1%其他雜質
將2.00克比馬前列腺素酸溶解在20毫升四氫呋喃(THF)中並在30℃先加入1.29克氯化2-氯-1,3-二甲基咪唑及1.44毫升三乙胺,經10分鐘攪拌後,加入2.57毫升在THF中的2M乙胺溶液。將反應混合物在1小時內逐漸加熱至70℃並將混合物在此溫度攪拌直到起始物質消失(約1小時)。藉由TLC追蹤反應。
反應完成後,將混合物倒在1N NaHSO4溶液及醋酸異丙酯(iPrOAc)之混合物上。將有機層用1N NaHCO3溶液清洗,將水性-鹼性層用iPrOAc萃取。將合併的有機層用NaCl溶液清洗並經由Na2SO4乾燥。將乾燥的物質過濾並將過濾液蒸發後得到1.41克油。
產物:
在根據實例6製備的比馬前列腺素油中,加入35重量%的純水。將混合物充分攪拌後在最高35℃的溫度之真空下乾燥,且每2小時攪拌並刮擦。完成乾燥後,將混合物均勻化。此產物之IR光譜列在圖4且此產物之DSC曲線列在圖6。生產的形式II之X-光繞射曲線列在圖8。
產量:96.9%
熔點:78℃
DSC起點:73.56℃
將根據實例5製備的粗比馬前列腺素在加熱下溶解在3000倍量的二乙醚中。然後在(-)20-(-)30℃藉由緩慢通過氮氣將溶劑移除。將所得的結晶均勻化,或先暴露至機械效應且隨後均勻化。
產量:94.4%
熔點:75.9℃
DSC起點:72.92℃
在根據實例6製備的粗比馬前列腺素中加入35重量%的甲醇。將混合物充分攪拌後在最高35℃的溫度之真空下乾燥,且每2小時攪拌並刮擦。完成乾燥後,將混合物均勻化。
產量:95.8%
熔點:77.2℃
DSC起點:73.07℃
在根據實例6製備的粗比馬前列腺素中加入17.5重量%的純水及17.5重量%的乙醇。將混合物充分攪拌後在最高35℃的溫度之真空下乾燥,且每2小時攪拌並刮擦。完成乾燥後,將混合物均勻化。
產量:92.3%
熔點:72.9℃
DSC起點:72.96℃
5.2克的粗比馬前列腺素從106克乙腈結晶化:將混合物加熱至接近沸點之溫度,使熱溶液冷卻至室溫並將混合物在此溫度攪拌1小時,然後在0-5℃攪拌2小時。將沈澱的結晶過濾,用20克冷(0-5℃)乙腈清洗並在0-5℃的真空下乾燥1小時,在室溫經半小時且在30-40℃經2小時。
得到4.3克的比馬前列腺素之結晶形式I。其IR光譜是列在圖3,其DSC曲線是列在圖5且其形式I之X-光繞射曲線是列在圖7。
產量:83%
熔點:62.1℃
DSC起點:63.61℃
在根據實例14a製備的比馬前列腺素之結晶形式I中加入35重量%的純水。將混合物充分攪拌後在最高35℃的溫度之真空下乾燥,且每2小時攪拌並刮擦。完成乾燥後,將混合物均勻化。
產量:97.3%
熔點:77.7℃
DSC起點:73.14℃
在結晶形式II及I的的50%-50%混合物中,加入35重量%的純水。將混合物充分攪拌後在最高35℃的溫度之真空下乾燥,且每2小時攪拌並刮擦。完成乾燥後,將混合物均勻化。
產量:97.6%
熔點:78.2℃
DSC起點:73.77℃
Claims (5)
- 根據申請專利範圍第1項之方法,其特徵為使用二乙醚及二異丙醚作為醚型溶劑。
- 根據申請專利範圍第1項之方法,其特徵為使用醋酸異丙酯作為酯型溶劑。
- 根據申請專利範圍第1項之方法,其特徵為結晶懸浮液係經過濾並用醚型溶劑清洗。
- 根據申請專利範圍第1項之方法,其特徵為該過濾的結晶是在25至50℃之間的真空下乾燥。
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