TWI761299B - 製備曲前列環素(treprostinil)之方法 - Google Patents
製備曲前列環素(treprostinil)之方法 Download PDFInfo
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- TWI761299B TWI761299B TW104132764A TW104132764A TWI761299B TW I761299 B TWI761299 B TW I761299B TW 104132764 A TW104132764 A TW 104132764A TW 104132764 A TW104132764 A TW 104132764A TW I761299 B TWI761299 B TW I761299B
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- 238000000034 method Methods 0.000 title claims abstract description 61
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 title claims abstract description 41
- 229960005032 treprostinil Drugs 0.000 title claims abstract description 34
- 230000008569 process Effects 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 140
- 150000001875 compounds Chemical class 0.000 claims description 116
- -1 salt monohydrate Chemical class 0.000 claims description 95
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 125000006239 protecting group Chemical group 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- 239000003054 catalyst Substances 0.000 claims description 33
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000012298 atmosphere Substances 0.000 claims description 20
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 18
- 229910052710 silicon Inorganic materials 0.000 claims description 18
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 15
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 15
- 238000007254 oxidation reaction Methods 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 15
- MQIKJSYMMJWAMP-UHFFFAOYSA-N dicobalt octacarbonyl Chemical group [Co+2].[Co+2].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] MQIKJSYMMJWAMP-UHFFFAOYSA-N 0.000 claims description 13
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 12
- 125000005104 aryl silyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 11
- 150000002825 nitriles Chemical class 0.000 claims description 10
- 230000003647 oxidation Effects 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 229910000085 borane Inorganic materials 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 7
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 150000003751 zinc Chemical class 0.000 claims description 6
- HLQZCRVEEQKNMS-UHFFFAOYSA-N 1-(chloromethyl)-4-phenylbenzene Chemical compound C1=CC(CCl)=CC=C1C1=CC=CC=C1 HLQZCRVEEQKNMS-UHFFFAOYSA-N 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 150000004795 grignard reagents Chemical class 0.000 claims description 5
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 5
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 claims description 4
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002524 organometallic group Chemical group 0.000 claims description 4
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- 238000005835 Pfitzner-Moffat oxidation reaction Methods 0.000 claims description 3
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006140 methanolysis reaction Methods 0.000 claims description 3
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 3
- 229910003445 palladium oxide Inorganic materials 0.000 claims description 3
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 claims description 3
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 claims description 3
- DOKGVQFKRMEKJX-ZFORQUDYSA-N (1r,2r,3as,9as)-1-[(3s)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[b]naphthalen-2-ol Chemical compound C1=CC=C(OC)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 DOKGVQFKRMEKJX-ZFORQUDYSA-N 0.000 claims description 2
- 238000007239 Wittig reaction Methods 0.000 claims description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- GFTXWCQFWLOXAT-UHFFFAOYSA-M magnesium;cyclohexane;bromide Chemical compound [Mg+2].[Br-].C1CC[CH-]CC1 GFTXWCQFWLOXAT-UHFFFAOYSA-M 0.000 claims description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 1
- 238000006859 Swern oxidation reaction Methods 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 103
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 90
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 86
- 239000000203 mixture Substances 0.000 description 81
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 54
- 239000011541 reaction mixture Substances 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 34
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical class [Na+].C1=CC=C(OCC([O-])=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 IQKAWAUTOKVMLE-ZSESPEEFSA-M 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- 239000013078 crystal Substances 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 23
- 239000012043 crude product Substances 0.000 description 22
- 239000003921 oil Substances 0.000 description 22
- 239000002585 base Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 238000004587 chromatography analysis Methods 0.000 description 16
- 239000008346 aqueous phase Substances 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 12
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 12
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- KXYGKDBONOVZOM-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene Chemical group C1=CC=CC2=C3CC=CC3=CC=C21 KXYGKDBONOVZOM-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 5
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- XWCQLLDGXBLGMD-UHFFFAOYSA-M magnesium;pentane;bromide Chemical compound [Mg+2].[Br-].CCCC[CH2-] XWCQLLDGXBLGMD-UHFFFAOYSA-M 0.000 description 4
- 150000004682 monohydrates Chemical class 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 229940076133 sodium carbonate monohydrate Drugs 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- XMDFGRGFVRKBKS-UHFFFAOYSA-N zinc;pentane Chemical compound [Zn+2].CCCC[CH2-].CCCC[CH2-] XMDFGRGFVRKBKS-UHFFFAOYSA-N 0.000 description 4
- FMCGSUUBYTWNDP-MWLCHTKSSA-N (1s,2r)-2-(dimethylamino)-1-phenylpropan-1-ol Chemical compound CN(C)[C@H](C)[C@@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-MWLCHTKSSA-N 0.000 description 3
- QRIZNMGCIBXULQ-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene-1-carbonitrile Chemical compound C1=CC=CC2=C3C(C#N)C=CC3=CC=C21 QRIZNMGCIBXULQ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OQOUDZFBMYRNCD-UHFFFAOYSA-N 3-methoxy-2-prop-2-enylbenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1CC=C OQOUDZFBMYRNCD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 101100402341 Caenorhabditis elegans mpk-1 gene Proteins 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 101001059431 Mus musculus MAP/microtubule affinity-regulating kinase 3 Proteins 0.000 description 3
- JWIPGAFCGUDKEY-UHFFFAOYSA-L O[Cr](Cl)(=O)=O.C1=CC=NC=C1 Chemical compound O[Cr](Cl)(=O)=O.C1=CC=NC=C1 JWIPGAFCGUDKEY-UHFFFAOYSA-L 0.000 description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 238000006317 isomerization reaction Methods 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000011916 stereoselective reduction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- YZTJUPHUOUPJGX-DOZCWEBVSA-N (1R,2R,9aS)-5-methoxy-1-[3-(oxan-2-yloxy)propyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol Chemical compound COC1=C2CC3[C@H](CC2=CC=C1)[C@H]([C@@H](C3)O)CCCOC1OCCCC1 YZTJUPHUOUPJGX-DOZCWEBVSA-N 0.000 description 2
- SLUZNPPRHLJMRM-KZMDNLFVSA-N (9aS)-5-methoxy-1-[3-(oxan-2-yloxy)propyl]-1,3,3a,4,9,9a-hexahydrocyclopenta[b]naphthalen-2-one Chemical compound COC1=CC=CC2=C1CC1CC(=O)C(CCCOC3CCCCO3)[C@H]1C2 SLUZNPPRHLJMRM-KZMDNLFVSA-N 0.000 description 2
- TZRUKFFDSQQSCK-UHFFFAOYSA-N 2-pent-4-ynoxyoxane Chemical compound C#CCCCOC1CCCCO1 TZRUKFFDSQQSCK-UHFFFAOYSA-N 0.000 description 2
- HWLHJDIDFDIRDN-UHFFFAOYSA-N 3-(methoxymethoxy)prop-1-yne Chemical compound COCOCC#C HWLHJDIDFDIRDN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- LCYGZGSKHQWBGH-UHFFFAOYSA-N P(=O)(OC)(OC)O.CC1=CC=CC=C1 Chemical compound P(=O)(OC)(OC)O.CC1=CC=CC=C1 LCYGZGSKHQWBGH-UHFFFAOYSA-N 0.000 description 1
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- MGHQBQYRVDMFNH-NWGOQBBVSA-N [(1R,2R,3aS,9aS)-5-methoxy-1-[(E)-3-oxooct-1-enyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)O[C@@H]2C[C@H]3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2\C=C\C(CCCCC)=O)C=C1 MGHQBQYRVDMFNH-NWGOQBBVSA-N 0.000 description 1
- JJAMRZCKWFTTOP-NNTYPUFZSA-N [(1S,2R,9aS)-1-(hydroxymethyl)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)O[C@@H]2CC3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2CO)C=C1 JJAMRZCKWFTTOP-NNTYPUFZSA-N 0.000 description 1
- NZWHMJXLGDCEGV-FFURYCECSA-N [(1S,2R,9aS)-5-methoxy-1-(methoxymethoxymethyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)O[C@@H]2CC3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2COCOC)C=C1 NZWHMJXLGDCEGV-FFURYCECSA-N 0.000 description 1
- WHILQLIHIYLBPC-OYHNWAKOSA-N [Si](C)(C)(C(C)(C)C)O[C@H]1C=2[C@@H](CC3=C(C=CC=C13)OC)CC(C=2COCOC)=O Chemical compound [Si](C)(C)(C(C)(C)C)O[C@H]1C=2[C@@H](CC3=C(C=CC=C13)OC)CC(C=2COCOC)=O WHILQLIHIYLBPC-OYHNWAKOSA-N 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
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- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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- 230000008878 coupling Effects 0.000 description 1
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- 238000000113 differential scanning calorimetry Methods 0.000 description 1
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- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
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- BDUPRNVPXOHWIL-UHFFFAOYSA-N dimethyl sulfite Chemical compound COS(=O)OC BDUPRNVPXOHWIL-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
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- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 125000000468 ketone group Chemical group 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
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- 150000002736 metal compounds Chemical class 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
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- 230000003287 optical effect Effects 0.000 description 1
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- PUPAWTXNPAJCHR-UHFFFAOYSA-N oxazaborole Chemical compound O1C=CB=N1 PUPAWTXNPAJCHR-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
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- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
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- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
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Images
Classifications
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Abstract
本發明提供製備式(I)之曲前列環素(treprostinil)及其鹽之新穎方法,其在建構環系統期間使用許多新的中間物。
Description
本發明關於式I之曲前列環素(treprostinil)及以鹼得到的其鹽非晶形物、無水物、單水合物和多水合物之製備,通式III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV和XV之曲前列環素中間物,及彼等之製備。
曲前列環素為具有血小板凝集抑制及血管舒張活性之合成的前列環素衍生物,其可以皮下、靜脈內、吸入或經口形式投予。
其治療領域為肺動脈高壓(肺動脈高壓,PAH)的治療(Drugs,2012,72(18)2351-2363)。
已知許多建構曲前列環素的苯并茚結構部分之方法。已在Drugs of the Future,2001,26(4)364-374公告迄今所述之合成途徑的摘要。
比較合成途徑,以專利說明書WO99/21830 A1中所述之葆森-侃德(Pauson-Khand)環化法似乎是建構環系統的最有效方法。
根據專利說明書WO 99/21830 A1(US 6441245 B1)中所述之實施例,關鍵的苯并茚中間物係藉由圖1中所概述之反應途徑合成。
接著將關鍵中間物以圖2中所展示之已知的化學反應轉變成曲前列環素。
氘化曲前列環素衍生物之製備揭示於專利說明書WO
2009/158010 A1中。
閉環係以葆森-侃德環化法進行。亦在該例子中,具有三鍵之鏈係由至少7個碳原子所組成。自葆森-侃德環化法所生成之分子已含有曲前列環素側鏈(圖3)。
在專利說明書WO 2011/153363 A1及WO 99/21830 A1中所述之方法之間的差別如下:含有三鍵的側鏈與醛之偶合係在掌性觸媒((+)-N-甲基麻黃素)的存在下進行,在此方式中以一個步驟獲得掌性醇而不形成消旋性醇。在此方式中消除一個氧化步驟及立體選擇性還原反應。
使八羰基二鈷的量降低(而不是等莫耳比,僅使用2-15莫耳%)且閉環係在一氧化碳壓力下進行。完整的合成流程呈示於圖4中。
在專利說明書WO 2012/009816 A1中所述之合成亦利用形成苯并茚環的葆森-侃德環化法。合成的新穎性在於酚系羥基係以對-甲氧基苯甲基(PMB)保護基保護。
亦在此例子中,具有三鍵的側鏈含有至少7個碳原子。
自葆森-侃德環化法所生成之分子已含有曲前列環素側鏈。
完整的合成流程呈示於圖5中。
曲前列環素鹽之合成係在專利說明書WO 2009/078965(PCT/US2008/013686)(United Therapeutics)中詳細地提出。其說明結晶狀二乙醇胺鹽之製備作用。
根據該方法,苯并茚腈係經由苯并茚結構的芳族烴基之烷基化而獲得(圖6)。
苯并茚腈水解成曲前列環素且不分離而轉變成結晶狀二乙醇胺鹽(圖7)。
曲前列環素係藉由以酸處理而自曲前列環素二乙醇胺鹽產生(圖8)。
在相分離之後,將乙酸乙酯相蒸發,將殘餘物以水性乙醇結晶,以過濾收集且乾燥。
經由二乙醇胺鹽純化有效至沒必要以層析術純化苯并茚腈衍生物。
高純度的曲前列環素可以各種鹼轉變成所欲高純度的鹽。
形成鈉鹽的詳細說明係說明於專利說明書WO 2012/088607中。
根據該說明,將苯并茚衍生物以溴乙酸甲酯烷基化且將未純化的所得曲前列環素甲酯藉由使用在甲醇-水溶劑混合物中的氫氧化鉀水解成曲前列環素。
接著將反應混合物以氫氯酸酸化,濾出沉澱之白色固體,以甲醇-水混合物清洗,在真空中乾燥且轉變成鈉鹽(圖9)。
吾等的目標為制訂其中僅在合成結束時建造在低碳鏈中的掌性中心之方法,且其為穩健且完全可擴展之方法。
本發明的目的為製備式I之曲前列環素及以鹼得到的其鹽非晶形物、無水物、以及其單水合物和多水合物之方法。
較佳地可使用甲氧基甲基、甲氧基乙氧基甲基或四氫哌喃基作為R1保護基,可使用甲基作為R2,可使用含有矽原子之保護基作為R3保護基,較佳為第三丁基二甲基矽基,可使用對-苯基苯甲醯基作為R4保護基。
本發明另外關於光學活性通式II化合物之製備
在此式中,R2 代表-(CH2)nY,其中Y 代表氫原子、鹵素原子、苯基、腈、-OR5或-COOR5基團,其中R5意指C1-4烷基、四氫哌喃基、三(C1-4)烷基矽基或(C1-4)烷基-二(C6-10)芳基矽基,且n代表1、2、3、4。
根據本發明,可製備通式II化合物,所以將通式III化合物氫化
在此式中,R2的意義係如上文所定義,或移除通式IVb.化合物之R4保護基,
在此式中,R2的意義係如上文所定義,且R4 代表含有矽原子之保護基、三苯甲基、甲氧基三苯甲基、對-甲氧基苯甲基、甲氧基甲基、乙氧基甲基、甲氧基乙氧基甲基、甲硫基甲基、苯甲氧基甲基或C1-13醯基,其先決條件為R4保護基必須選擇性地可自R2移除。
通式III化合物之氫化係在觸媒的存在下進行。
可使用氧化鉑、Pd/C觸媒作為觸媒,較佳為Pd/C觸媒。
通式III化合物為新穎化合物,
在此式中,R2 代表-(CH2)nY,其中Y 代表氫原子、鹵素原子、苯基、-OR5或-COOR5基團,其中R5意指C1-4烷基、四氫哌喃基、三(C1-4)烷基矽基或(C1-4)烷基-二(C6-10)芳基矽基,且n代表1、2、3、4-,其先決條件為-COOR5中的R5不可以代表C1-4烷基。
-在此式中R2 具有如上文所定義之意義,且R4 代表含有矽原子之保護基、三苯甲基、甲氧基三苯甲基、對-甲氧基苯甲基、甲氧基甲基、乙氧基甲基、甲氧基乙氧基甲基、甲硫基甲基、苯甲氧基甲基或C1-13醯基,其先決條件為R4保護基必須選擇性地可自R2移除。
含有矽原子之R4保護基較佳為苯基二甲基矽基、三乙基矽基、三異丙基矽基、第三丁基二甲基矽基或第三丁基二苯基矽基。
R4保護基的移除係在鹼的存在下以甲醇解進行。
通式IV化合物為新穎的化合物
在此式中,R2 代表-(CH2)nY,其中Y 代表氫原子、鹵素原子、苯基、腈、-OR5或-COOR5基團,其中R5 意指C1-4烷基、四氫哌喃基、三(C1-4)烷基矽基或(C1-4)烷基-二(C6-10)芳基矽基,n 代表1、2、3、4,R4 代表含有矽原子之保護基、三苯甲基、甲氧基三苯甲基、對-甲氧基苯甲基、甲氧基甲基、乙氧基甲基、甲氧基乙氧基甲基、甲硫基甲基、苯甲氧基甲基或C1-13醯基,其先決條件為R4保護基必須選擇性地可自R2移除,且虛線代表單鍵或雙鍵。
-在此式中R2 代表-(CH2)nY,其中Y 代表氫原子、鹵素原子、苯基、腈、-OR5或-COOR5基團,其中R5 意指C1-4烷基、四氫哌喃基、三(C1-4)烷基矽基或(C1-4)烷基-二(C6-10)芳基矽基,n 代表1、2、3、4,且R4 代表含有矽原子之保護基、三苯甲基、甲氧基三苯甲基、對-甲氧
基苯甲基、甲氧基甲基、乙氧基甲基、甲氧基乙氧基甲基、甲硫基甲基、苯甲氧基甲基或C1-13醯基,其先決條件為R4保護基必須選擇性地可自R2移除。
式V化合物之還原反應係在氧氮硼雜環戊烷(oxazaboroline)觸媒的存在下以硼烷化合物進行。
使用兒茶酚硼烷、硼烷-二乙基苯胺複合物、硼烷-二甲硫醚複合物作為硼烷化合物,較佳為硼烷-二甲硫醚複合物。
通式V化合物為新穎的化合物。
可製備新穎的通式V化合物,所以將通式VIa.化合物
在此式中,R2和R4的意義係如上文所定義,
在威提反應中與以下通式化合物反應
CH3-(CH2)4-CO-CH2-PO(OR6)2在此式中,R6代表C1-4烷基或苯基。
可製備新穎的通式IVb.化合物,
-在此式中R2 代表-(CH2)nY,其中Y 代表氫原子、鹵素原子、苯基、腈、-OR5或-COOR5基團,其中R5 意指C1-4烷基、四氫哌喃基、三(C1-4)烷基矽基或(C1-4)烷基-二(C6-10)芳基矽基,n 代表1、2、3、4,且R4 代表含有矽原子之保護基、三苯甲基、甲氧基三苯甲基、對甲氧基苯甲基、甲氧基甲基、乙氧基甲基、甲氧基乙氧基甲基、甲硫基甲基、苯甲氧基甲基或C1-13醯基,其先決條件為R4保護基必須選擇性地可自R2移除,故而將通式VIb.化合物與有機金屬試劑在掌性觸媒的存在下反應
-在此式中R2和R4具有如上文所定義之意義。
可使用二戊基鋅或戊基溴化鎂作為有機金屬試劑,可使用(2S)-3-外-(嗎啉基)異莰醇作為掌性觸媒。
通式VIa.及VIb.化合物為新穎的化合物。
可製備通式VI化合物,
-在此式中R2 代表-(CH2)nY,其中Y 代表氫原子、鹵素原子、苯基、腈、-OR5或-COOR5基團,其中R5 意指C1-4烷基、四氫哌喃基、三(C1-4)烷基矽基或(C1-4)烷基-二(C6-10)芳基矽基,n 代表1、2、3、4,R4 代表含有矽原子之保護基、三苯甲基、甲氧基三苯甲基、對甲氧基苯甲基、甲氧基甲基、乙氧基甲基、甲氧基乙氧基甲基、甲硫基甲基、苯甲氧基甲基或C1-13醯基,其先決條件為R4保護基必須選擇性地可自R2移除,且x代表0或2,所以將通式VII化合物氧化
-在此式中x、R2和R4 具有如上文所定義之意義。
式VII化合物之氧化反應係以PCC(氯鉻酸吡啶)或在史旺(Swern)條件下(草醯氯/DMSO/有機鹼)或以TEMPO(2,2,6,6-四甲基-1-哌啶氧基自由基)或在普菲茨納-莫法特(Pfitzner-Moffat)條件下(DCC(二環己基碳二醯亞胺)/DMSO/酸)進行。
通式VII化合物為新穎的化合物。
可製備新穎的通式VII化合物,故而在酸性介質中移除通式VIII化合物之R1保護基
在此式中,R1 代表含有矽原子之保護基、四氫哌喃基、三苯甲基、甲氧基甲基、乙氧基甲基、甲氧基乙氧基甲基、甲硫基甲基、苯甲氧基甲基,其先決條件為R1保護基必須選擇性地可自R2和R4移除,x、R2和R4 具有如上文所定義之意義。
含有矽原子之保護基R1較佳為苯基二甲基矽基、三乙基矽基、三異丙基矽基、第三丁基二甲基矽基或第三丁基二苯基矽基。
通式VIII化合物為新穎的化合物。
較佳地使用以對-苯基苯甲醯氯作為適合於引入基團R4之化合物。
通式IX化合物為新穎的化合物。
通式X化合物之還原反應可以二異丁基氫化鋁、鋁氫化鋰、異丙醇鋁或硼氫化鈉進行,較佳為硼氫化鈉。
可製備新穎的通式X化合物,故而將通式XI化合物催化氫化
在此式中,x、R1和R2 具有如上文所定義之意義,R3 代表含有矽原子之保護基、四氫哌喃基、三苯甲基、甲氧基甲基、乙氧基甲基、甲氧基乙氧基甲基、甲硫基甲基、苯甲氧基甲基或C1-13醯基,且在x=0的情況下異構化。
可使用Pd/C觸媒或氧化鈀作為氫化式XI化合物之觸媒,較佳為Pd/C觸媒。通式XI化合物為新穎的化合物。可製備新穎的通式XI化合物,故而將通式XII化合物進行分子內環化作用
在此式中x、R1、R2和R3 具有如上文所定義之意義。
有利地使用葆森-侃德環化法進行分子內環化作用。使用八羰基二鈷進行葆森-侃德環化法。
八羰基二鈷可以等莫耳比或少於等莫耳比或大於等莫耳比使用。
反應較佳地在一氧化碳氛圍中使用乙酸乙酯作為溶劑進行。
可製備新穎的通式XII化合物,故而將通式XIII化合物與適合於引入基團R3的化合物反應
在此式中,x、R1和R2具有如上文所定義之意義。
可製備新穎的通式XIII化合物,故而a.)將通式XIV化合物選擇性地還原,
在此式中,x、R1和R2具有如上文所定義之意義,或b.)將通式XVI化合物
在此式中,R2 具有如上文所定義之意義,
與通式XVII化合物在掌性鹼及鋅鹽的存在下反應
在此式中,R1及x 具有如上文所定義之意義。
通式XIV化合物之還原反應係在掌性氧氮硼雜環戊烷觸媒的存在下以硼烷化合物進行。
可使用硼烷-二甲硫醚複合物、兒茶酚硼烷或硼烷-二乙基苯胺複合物作為硼烷化合物,較佳為硼烷-二甲硫醚複合物,可使用掌性胺醇或二胺作為掌性鹼,較佳為(+)-N-甲基麻黃素。
在通式XVI與XVII化合物之反應中,較佳地可使用三氟甲磺酸鋅作為鋅鹽。
式XV化合物之氧化反應係以PCC(氯鉻酸吡啶)或在史旺反應條件下(草醯氯/DMSO/有機鹼)進行。
在此式中,R1 具有如上文所定義之意義,且x為0或2。
可使用甲基、乙基、丙基、丁基、環己基溴化鎂作為格任亞試劑,較佳為甲基溴化鎂。
本發明的另一目的為製備以鹼得到的式I之曲前列環素的鹽非晶形物、無水物、單水合物和多水合物之新穎方法。
呈一般形式的曲前列環素鹽(在該等之中的曲前列環素鈉鹽)於WO99/25357(United Therapeutics)中說明,未以化學-物理數據特徵化。在Exhibit 1-Applicant's submission to EP1628654(United Therapeutics)中首次以所述之曲前列環素鈉鹽的熔點為56℃。
WO 2012/088607(Alphora)說明用於製備曲前列環素鈉鹽之新方法,其中將曲前列環素溶解在與水混溶的有機溶劑中以形成曲前列環素溶液,接著將溶液與含有鹼金屬陽離子的水溶液反應,以形成含有曲前列環素鹽的反應混合物,容許鹽結晶且收集所形成之鹽。
根據本發明,以鹼得到的式I之曲前列環素的鹽非晶形物、無水物、單水合物和多水合物係由以下方式製得:將曲前列環素溶解在極性溶劑中的方式製得,將固體鹼添加至溶液中,將反應混合物攪動,且在完全形成鹽時,將溶液過濾,濃縮,將濃縮物溶劑以結晶用有機溶劑交換且結晶出曲前列環素鹽。
為了以鹼得到的式I之曲前列環素的鹽,可使用C1-5開鏈或支鏈有機醇作為極性溶劑,較佳為乙醇,可使用含有所欲鹼之陽離子的無溶劑有機或無機鹼作為鹼,例如含有鹼金屬陽離子或鹼土金屬陽離子
的有機或無機鹼,例如碳酸鈉單水合物、碳酸氫鈉或甲醇鈉,較佳為碳酸鈉水合物。
將反應混合物在惰性氛圍中攪動,直到完成鹽的形成為止。
根據本發明的一個實施態樣,可使用水性醚-、酯-或酮-型溶劑作為結晶用有機溶劑,亦即可使用開鏈或支鏈之單或混合醚作為醚-型溶劑,較佳為甲基第三丁基醚。
結晶較佳地在介於50℃-(-40℃)之間的溫度下進行。
使用含有鈉陽離子的有機或無機鹼之上述方法的結果,獲得結晶狀曲前列環素鈉鹽單水合物(形式A),其為新化合物。
根據本發明的另一實施態樣,若結晶用有機溶劑為無水的醚-、酯-或酮-型溶劑,則獲得非晶形曲前列環素鈉鹽,其為新化合物。
根據本發明,曲前列環素鈉鹽無水物(形式B)可藉由進行上述方法直到結晶步驟且在60-100℃或真空中進行結晶而獲得。另一可能的方法是將鈉鹽單水合物在不或僅微溶解鹽之溶劑中處理且在60-90℃下攪拌1-6小時。較佳地可使用己烷、庚烷、甲苯、乙酸乙酯作為溶劑。
若將曲前列環素鈉鹽單水合物或無水物保持在60%水分含量的氛圍中48小時或繼續於空氣中5-8天,則獲得新穎的曲前列環素鈉鹽多水合物(形式C)。
不同形式的DSC及X-射線粉末繞射(XRPD)光譜顯示於圖14-22中。
該等上述鹽形式顯示用於製備醫藥調配物的穩定性及適用性。
在本發明較佳的實施態樣中:將炔丙醇以甲氧基甲基保護。
將經保護之炔丙醇(XVII)與2-烯丙基-3-甲氧基苯甲醛(XVI)在甲基溴化鎂格任亞試劑的存在下反應。將因此獲得的消旋性醇(XV)氧化。
氧化反應例如係以史旺氧化方法或以鉻(VI)氧化來進行。
酮XIV之立體選擇性還原反應得到掌性醇XIII。
立體選擇性還原反應可例如以硼烷-二甲硫醚複合物在Corey觸
媒的存在下進行。
掌性醇XIII可藉由將經保護之炔丙醇(XVII)與2-烯丙基-3-甲氧基苯甲醛(XVI)在掌性鹼(例如(+)-N-甲基麻黃素)及三氟甲磺酸鋅的存在下反應而直接製得。
將羥基以第三丁基二甲基矽基保護,將矽基醚(XII)在八羰基二鈷的存在下以葆森-侃德反應環化。反應的結果為三環(XI)係藉由併入CO分子而形成。
環化作用可使用等莫耳量的八羰基二鈷,或更佳地以催化量的八羰基二鈷在一氧化碳氛圍下進行。
將矽氧基以催化氫化作用移除且將5員環的雙鍵飽和。三環酮(X)之立體結構係以鹼(二氮雜雙環壬烷/乙醇)異構化而形成。
將酮基還原(IX),將所得二級羥基以對-苯基苯醯基(PPB)保護(VIII)。
將甲氧基甲基保護基以酸(VII)處理而裂解。
將一級羥基氧化(VI)。
將所得醛VI不分離而與2-酮基-庚基膦酸酯反應。
將因此獲得烯酮V以選擇性還原方法還原,例如以硼烷-二甲硫醚複合物在Corey觸媒的存在下。
將所得式IV化合物的對-苯基苯醯基保護基在鹼的存在下以甲醇解而移除。
以催化氫化作用飽和式III之烯醇的雙鍵得到式II之苯并茚衍生物。
根據本發明的另一較佳的實施態樣,使用2-戊-4-炔氧基四氫哌喃作為起始料,而不是經保護之炔丙醇。側鏈係在掌性觸媒的存在下藉由與二戊基鋅或戊基溴化鎂反應而以立體選擇性建造。
式II之苯并茚為曲前列環素之關鍵中間物,將其以已知的化學步驟轉變成曲前列環素。
第一化學步驟為甲醚的裂解。甲基的移除係在鹵化鋁的存在下以硫醇進行。
選擇三氯化鋁作為鹵化鋁,選擇不臭的十二烷基硫醇而不是常
使用的乙硫醇作為硫醇來製備三羥基衍生物(圖10)。
下一步驟為芳族羥基與鹵乙酸酯(例如,溴或氯乙酸乙酯或甲酯)的烷基化反應。在吾等的方法中,將三羥基衍生物以溴乙酸乙酯烷基化(圖11)。
乙酯衍生物的水解得到結晶狀曲前列環素。
在吾等的方法中,水解係在四氫呋喃中以氫氧化鈉水溶液進行。
將曲前列環素溶解在乙醇中且將固體碳酸鈉單水合物添加至其中,以形成鹽(圖13)。
將溶液經由微過濾器過濾,將乙醇以經水飽和之甲基第三丁基醚交換且在室溫下結晶出曲前列環素鈉鹽。
根據本發明的方法之優點:
˙苯并茚三環的形成不需要昂貴的掌性起始材料。
˙側鏈的建構係以完全可擴展且穩健的化學步驟(維提反應或經修飾之維提反應)實現,該等步驟係用於前列腺素化學中或在掌性觸媒的存在下使用有機金屬化合物以立體選擇性進行。
˙可將威提反應中所獲得的烯酮以立體選擇性反應轉變成具有良好產率的所需鏡像異構物。
˙所使用之對-苯基苯甲醯基(PPB-基團)可完全以UV偵測。
˙PPB-基團提高中間物的結晶能力且因此有助於彼等純化。
參圖1、2、4和5所示。
根據本發明的方法之更多細節係以實施例展示,而非限制本發明於此等實施例。
將2.27毫升炔丙醇及8毫升二甲氧基甲烷溶解在8毫升甲苯中。將0.66克對-甲苯磺酸及0.33克溴化鋰添加至溶液中。將反應混合物在室溫下攪拌20小時,以碳酸氫鈉溶液和水清洗。將有機相乾燥且以未蒸發的溶液前進至下一步驟。
產量:約2克(50%)產物於溶液中。
NMR數據:(DMSO-d6),1H NMR(500MHz):4.62ppm(H-4,2),s;4.16ppm(H-3,2),d,J=2.3Hz;3.41ppm(H-1,1),t,J=2.3Hz;3.26ppm(H-5,3),s;13C NMR(125.8MHz):94.15ppm(C-4),79.90ppm(C-2),76.97ppm(C-1),54.97ppm(C-5),53.60ppm(C-3)。
將64克(0.64莫耳)3-(甲氧基甲氧基)-1-丙炔(TREPO-1)在氮氛圍中溶解在600毫升無水四氫呋喃中且將溶液加熱至60-65℃。將220毫升乙基溴化鎂溶液(在二乙醚中的3M溶液)(0.66莫耳)緩慢地添加至反應混合物中。在添加完成時,將反應混合物在回流溫度下加熱45分鐘,接著在冷卻至0-5℃之後,逐滴添加在100毫升無水四氫呋喃中的100克2-烯丙基-3-甲氧基苯甲醛(VPK-5)(0.57莫耳)之溶液。將混合物在室溫下攪拌。當反應完成時,將混合物冷卻至0℃且將NaHSO4(硫酸氫鈉)溶液添加至其中。在攪動之後,將相分離,將水層以乙酸乙酯萃取。將合併的有機相以NaHCO3(碳酸氫鈉)溶液清洗且經硫酸鈉乾燥。濾出乾燥材料,將過濾物溶液在真空中蒸發。以未
純化的粗製產物前進至下一步驟。
產量:156.8克(100%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.32ppm(H-6,1),dd,J=7.8Hz和0.8Hz;7.24ppm(H-5,1),m(t),J=7.9Hz,6.87ppm(H-4,1),d(dd),J=7.8Hz和~1.0Hz;5.98ppm(H-14,1),ddt,J=17.1Hz,10.2Hz和5.8Hz;5.67ppm(H-7,1),m(dt),J=5.4Hz和1.6Hz;4.985ppm(H-15a,1),dq,J=10.1Hz和1.6Hz;4.93ppm(H-15b,1),dq,J=17.1Hz和1.8Hz;4.69ppm(H-11,2),s;4.28ppm(H-10,2),d,J=1.7Hz;3.82ppm(H-16,3),s;3.61ppm(H-13a,1),ddt,J=15.7Hz,5.8Hz和1.6Hz;3.55ppm(H-13b,1),ddt,J=15.7Hz,5.8Hz和1.6Hz;3.36ppm(H-12,3),s;2.55ppm(OH-7,1),d,J=5.5Hz;13C NMR(125.8MHz):157.75ppm(C-3),139.93ppm(C-1),136.99ppm(C-14),127.59ppm(C-5),125.97pm(C-2),119.31ppm(C-6),114.89ppm(C-15),110.93ppm(C-4),94.93ppm(C-11);86.25ppm(C-8),82.01ppm(C-9),61.98ppm(C-7),55.88ppm(C-16);55.63ppm(C-12),54.59ppm(C-10),29.53ppm(C-13)。
1c.)製備1-(2-烯丙基-3-甲氧基苯基)-4-甲氧基甲氧基-丁-2-炔-1-酮(TREP-2)
將200克矽膠懸浮在1.5公升乙酸乙酯中且將470克(2.18莫耳)氯鉻酸吡啶(PCC)添加至其中。將0.5公升乙酸乙酯中的150克(0.54莫耳)TREP-1之溶液在25±5℃下以攪拌添加至橘色懸浮液中。將反應混合物在35±5℃下攪拌。在反應結束時,將二異丙醚及矽膠添加至混合物中。將懸浮液過濾,將固體材料以乙酸乙酯清洗。將液體
過濾物在真空中蒸發。將粗製產物在矽膠上以使用己烷:乙酸乙酯溶析劑的層析術純化。
產量:88.1克(59.2%)淺棕色油
將93毫升草醯氯溶解在1.7公升二氯甲烷中且在-75/-85℃下與148毫升二甲基亞碸(DMSO)反應。將179克TREP-1在-75/-85℃下添加至混合物中。在攪拌1小時之後,將反應混合物以621毫升三乙胺及NaHSO4溶液淬滅。將有機相以二氯甲烷萃取,將合併的有機相以1M NaHCO3溶液清洗。將粗製產物在矽膠上以層析術純化。
產量:140克(79%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.75ppm(H-6,1),dd,J=7.8Hz和0.9Hz;7.305ppm(H-5,1),t,J=8.0Hz;7.08ppm,(H-4,1),d(dd),J=8.1Hz和~1.0Hz;5.96ppm(H-14,1),ddt,J=17.1Hz,10.1Hz和6.2Hz;5.01-4.92ppm(H-15,2),m(in:4.98ppm(H-15b,1),dq,J=17.2Hz和1.7Hz和4.94ppm(H-15a,1),dq,J=10.1Hz和1.6Hz);4.745ppm(H-11,2),s;4.45ppm(H-10,2),s;3.85ppm(H-16,3),s;3.78ppm(H-13,2),dt,J=6.2Hz和1.5Hz;3.40ppm(H-12,3),s;13C NMR(125.8MHz):179.21ppm(C-7),158.21ppm(C-3),136.66ppm(C-14);133.60ppm(C-1);130.29ppm(C-2),126.98ppm(C-5),124.98ppm(C-6),115.42ppm(C-4),114.93ppm(C-15),95.38ppm(C-11),88.69ppm(C-9),85.73ppm(C-8),56.16ppm(C-16),55.87ppm(C-12),54.32ppm(C-10),29.78ppm(C-13)。
1d.)製備(1S)-1-(2-烯丙基-3-甲氧基苯基)-4-(甲氧基甲氧基)丁-2-炔-1-醇(TREP-3)
將85克TREP-2(0.31莫耳)在氮氛圍下溶解在600毫升無水四氫呋喃(THF)中。將溶液冷卻至0-5℃且將370毫升(0.37莫耳)氧氮硼雜環戊烷溶液(在甲苯中的1M溶液)添加至其中。將混合物冷卻至(-30)℃且將50毫升(0.52莫耳)硼烷-二甲硫醚複合物在(-30)℃逐滴添加至其中。將反應混合物在該溫度下攪拌。在反應結束時,容許混合物溫熱至(-15)℃,小心地添加200毫升甲醇(形成劇烈發泡及熱)。在添加甲醇之後,將反應混合物攪拌30分鐘,接著在0-5℃下添加NH4Cl溶液且將淬滅的反應混合物以3 x 2.5公升乙酸乙酯萃取。將合併的有機相以水清洗且經硫酸鈉乾燥。濾出乾燥材料,將過濾物蒸發。
產量:85.6克(100%)淺棕色油。
將216毫克(0.59毫莫耳)三氟甲磺酸鋅及82毫克(0.45毫莫耳)(+)-N-甲基麻黃素裝入反應容器中,以氮氣湧入10分鐘,接著添加1毫升蒸餾甲苯及63微升(0.45毫莫耳)三乙胺。將反應混合物在室溫下攪拌1小時,接著添加250微升(0.45毫莫耳)TREPO-1溶液,且在攪拌15分鐘之後添加24微升VPK-5(2-烯丙基-3-甲氧基苯甲醛)(0.14毫莫耳)。在室溫下攪拌24小時之後,將反應混合物以1毫升NH4Cl飽和溶液淬滅。將水相以甲苯萃取,將合併的有機相連續以
NaHCO3溶液及NaCl飽和溶液清洗,接著蒸發。
產量:30毫克(78%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.32ppm(H-6,1),dd,J=7.8Hz和0.9Hz;7.25ppm(H-5,1),m(t),J=8.0Hz,6.875ppm(H-4,1),d(dd),J=7.8Hz和~1.0Hz;5.98ppm(H-14,1),ddt,J=17.1Hz,10.2Hz和5.8Hz;5.68ppm(H-7,1),寬峰;4.99ppm(H-15a,1),dq,J=10.1Hz和1.6Hz;4.93ppm(H-15b,1),dq,J=17.1Hz和1.8Hz;4.70ppm(H-11,2),s;4.285ppm(H-10,2),d,J=1.8Hz;3.82ppm(H-16,3),s;3.62ppm(H-13a,1),ddt,J=15.7Hz,5.8Hz和1.6Hz;3.545ppm(H-13b,1),ddt,J=15.7Hz,5.8Hz和1.6Hz;3.36ppm(H-12,3),s;2.34ppm(OH-7,1),寬峰;13C NMR(125.8MHz):157.79ppm(C-3),139.90ppm(C-1),137.06ppm(C-14),127.67ppm(C-5),125.99pm(C-2),119.35ppm(C-6),114.96ppm(C-15),110.98ppm(C-4),94.99ppm(C-11);86.18ppm(C-8),82.13ppm(C-9),62.10ppm(C-7),55.93ppm(C-16);55.70ppm(C-12),54.62ppm(C-10),29.57ppm(C-13)。
將85克(0.31莫耳)TREP-3及26.6克(0.39莫耳)咪唑溶解在850毫升甲苯中。將溶液冷卻至5-10℃且添加56.8克(0.38莫耳)第三丁基二甲基矽基氯(TBDMSCl)。將反應混合物在室溫下攪拌4小時,接著在攪動下添加500毫升水。將相分離,將水層以甲苯萃取,將合併的有機相在真空中蒸發。將粗製產物在矽膠上使用己烷:乙酸乙酯溶析劑層析分離。
產量:104.2克(86.7%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.27ppm(H-6,1),m(dd),J=7.9Hz和1.1Hz,7.225ppm(H-5,1),t,J=7.9Hz;6.83ppm(H-4,1),dd,J=7.9Hz和1.0Hz;5.95ppm(H-14,1),dddd,J=17.0Hz,10.3Hz,6.5Hz和5.3Hz;5.64ppm(H-7,1),t,J=1.5Hz;5.00-4.91ppm(H-15,2),m(4.98ppm(H-15a,1),dq,J=10.1Hz和1.6Hz;4.94ppm(H-15b,1),dq,J=17.1Hz和1.8Hz);4.67ppm(H-11,2),s;4.22ppm(H-10,2),m;3.82ppm(H-16,3);s;3.62ppm(H-13a,1),ddt,J=15.7Hz,5.1Hz和1.9Hz;3.49ppm(H-13b,1),ddt,J=15.7Hz,6.5Hz和1.5Hz;3.34ppm(H-12,3),s;0.91ppm(H-20,H-21和H-22,9),s;0.13ppm,(H-17/H-18,3),s;0.085(H-18/H-17,3),s;13C NMR(125.8MHz):157.50ppm(C-3),141.44ppm(C-1),136.55(C-14),127.32(C-5),124.78ppm(C-2),118.73ppm(C-6),114.71ppm(C-15),110.10ppm(C-4),94.80ppm(C-11),87.16(C-8),80.71ppm(C-9),62.27ppm(C-7),55.82ppm(C-16),55.63(C-12),54.60ppm(C-10),29.59ppm(C-13),25.93ppm(C-20,C-21和C-22),18.40ppm(C-19),-4.45ppm(C-17/C-18),-4.74ppm(C-18/C-17)。
1f1.方法(以100莫耳%之八羰基二鈷)
將93克(0.24莫耳)TREP-4在氮氛圍中溶解在930毫升乙酸乙酯中且將85.5克(0.25莫耳)八羰基二鈷添加至溶液中。將反應混合物在室溫下攪拌2.5小時且接著溫熱至60-70℃。引出在密閉容器中釋放的一氧化碳。在反應結束時,將混合物冷卻至室溫且以起泡的空氣流過2小時。將反應混合物過濾,將沉澱物以乙酸乙酯清洗。將合併
的過濾物溶液在真空中蒸發。將粗製產物在矽膠上使用己烷:乙酸乙酯溶析劑層析分離。
產量:64.6克(64.8%)淺棕色油。
1f2.方法(以10莫耳%之八羰基二鈷+一氧化碳氣體)
將93克(0.24莫耳)TREP-4在氮氛圍中溶解在930毫升乙酸乙酯中且將8.55克(0.025莫耳)八羰基二鈷添加至其中。以一氧化碳湧入容器,將反應混合物在室溫下攪拌2.5小時且接著加熱至60-70℃。在反應結束時,將混合物冷卻至室溫。過濾,將沉澱物以乙酸乙酯清洗。將合併的過濾物溶液在真空中蒸發。將粗製產物在矽膠上使用己烷:乙酸乙酯溶析劑層析分離。
產量:85克(85%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.24ppm(H-22,1),m(t),J=8.0-7.4Hz,6.92ppm(H-23,1),d,J=7.3Hz;6.79ppm(H-21,1),d,J=7.8Hz;5.775ppm(H-7,1),s;4.68-.453ppm(H-15,2),m,(in:4.62ppm(H-15a,1),d,J=5.6Hz和4.59ppm(H-15b,1),d,J=5.6Hz);4.30ppm(H-13,2),m;3.815ppm(H-2,3),s;3.55ppm(H-4a,1),dd,J=16.9Hz和7.3Hz;3.45ppm(H-9,1),m(ddd),J~7.8-7.0Hz;3.33ppm(H-17,3),s;2.75ppm(H-10a,1),dd,J=18.7Hz和5.8Hz;2.33-2.15ppm(H-10b和H-4b,2),m,(in:2.27ppm(H-10b,1),d,J~19.5Hz和2.22ppm(H-4b,1),dd,J=16.8Hz和10.2Hz);0.82ppm(H-27,H-28和H-29,9),s;0.15ppm(H-24/H-25,3),s;0.10ppm(H-24/H-25,3),s;13C NMR(125.8MHz):208.44ppm(C-11),176.76ppm(C-8),156.93ppm(C-3),138.31ppm(C-6),132.99ppm(C-12),127.61ppm(C-22),124.88ppm(C-5),122.07ppm(C-23),109.41ppm(C-21),96.42ppm(C-15),65.25ppm(C-7),59.07ppm(C-13),55.55ppm(C-17),55.47ppm(C-2),42.32ppm(C-10),33.49ppm(C-4),32.61ppm(C-9),25.75ppm(C-27,C-28和C-29),18.20ppm(C-26),-4.19ppm(C-24/C-25),-4.32ppm(C-25/C-24)。
將63克(0.15莫耳)TREP-5溶解在630毫升乙酸乙酯中且將19毫升吡啶添加至溶液中。將反應混合物在6巴壓力下經25克10%之鈀/木炭觸媒氫化。在反應結束時,濾出觸媒且以乙酸乙酯清洗。將過濾物在真空中蒸發。將粗製產物在矽膠上使用己烷:乙酸乙酯之混合物作為溶析劑層析分離。在0℃下自己烷-乙酸乙酯之混合物結晶出蒸發之主要流份且以過濾收集。為了異構化,將蒸發之母液溶解在100毫升甲苯與60毫升乙醇之混合物中。將12毫升DBN試劑(2,3,4,6,7,8-六氫吡咯并1,2-a]嘧啶)在0℃下添加至其中且將混合物攪動15分鐘。接著將反應混合物以NaHSO4溶液淬滅,以甲基第三丁基醚萃取且蒸發。將殘餘物在矽膠上使用己烷:乙酸乙酯之混合物作為溶析劑層析分離。在0℃下自己烷-乙酸乙酯混合物結晶出蒸發之主要流份。以過濾收集晶體且與先前收穫之晶體合併。
產量:30.2克(69.1%)白色晶體。Mp:65-67℃。
NMR數據:(CDCl3),1H NMR(500MHz):7.13ppm(H-22,1),m(t),J=7.9Hz,6.78ppm(H-23,1),d,J=7.6Hz;6.71ppm(H-21,1),d,J=8.2Hz;4.62-4.56ppm(H-15,2),m,(in:4.60ppm(H-15a,1),d,J=6.5Hz和4.58ppm(H-15b,1),d,J=6.5Hz);3.86ppm(H-13a,1),dd,J=9.8Hz和4.2Hz;3.81ppm(H-2,3),s;3.67ppm(H-13b,1),m(dd),J=9.8Hz和3.6Hz,3.35ppm(H-17,3),s;3.09ppm(H-7a,1),dd,J=16.6Hz和6.5Hz;3.03ppm(H-4a,1),dd,J=17.3Hz和7.1Hz,2.82ppm(H-7b,1),m(dd),J=16.6Hz和3.6Hz,2.715ppm(H-8,1),m(dtd),J=10.3Hz,6.8Hz和3.7Hz,2.605ppm(H-9,1),m(dqd),J~8.7Hz,~7.3Hz和3.1Hz;2.47ppm(H-10a,1),m(dd),J=18.1Hz和7.6Hz,2.29-2.205ppm(H-4b和H-10b,2),m;2.07ppm(H-12,1),m(ddd),J=10.5Hz和~3.6Hz;13C NMR(125.8MHz):218.28ppm(C-11),156.96ppm(C-3),136.27ppm
(C-6),126.58ppm(C-22),124.50ppm(C-5),121.34ppm(C-23),107.60ppm(C-21),96.65ppm(C-15),64.64ppm(C-13),55.40ppm(C-2),55.31ppm(C-17),51.68ppm(C-12),46.46ppm(C-10),35.99ppm(C-8),31.06ppm(C-7),30.61ppm(C-9),25.59ppm(C-4)。
將22克(75.8毫莫耳)TREP-6溶解在100毫升甲苯中,將100毫升乙醇添加至其中且將溶液冷卻至(-)15-(-)25℃。將3克(79.3毫莫耳)硼氫化鈉(NaBH4)添加至溶液中且將反應混合物攪拌,同時保持上述溫度。在反應結束時,將pH以NaHSO4溶液設定至pH=4-6。繼續攪拌30分鐘,接著將相分離。將水相以甲苯萃取。將合併的有機相連續以NaHCO3溶液及水清洗,接著在硫酸鈉上乾燥。濾出乾燥材料,將過濾物溶液在真空中蒸發。
產量:22.15克(100%)無色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.10ppm(H-22,1),t,J=7.8Hz;6.79-6.73ppm(H-21和H-22,2),m(in:6.765ppm(H-23,1),d,J=7.3Hz和6.76ppm(H-21,1),d,J=8.2Hz);4.64ppm(H-15,2),s;3.91ppm(H-11,1),td,J=9.8Hz和6.4Hz;3.83-3.74ppm(H-2和H-13a,4),m(in:3.81ppm(H-2,3),s和3.80ppm(H-13a,1),dd,J=9.2Hz和4.7Hz);3.59ppm(H-13b,1),t(dd),J=9.0Hz;3.38ppm(H-17,3),s;2.79-2.69ppm(H-4a和H-7a,2),m(in:2.76ppm(H-4a,1),dd,J=14.7Hz和6.2Hz和2.72ppm(H-7a,1),dd,J=14.2Hz和6.2Hz);2.61-2.53ppm(H-4b和OH-11,2),m(in:2.58ppm(OH-11,1),寬峰和2.56ppm(H-4b,1),dd,J=14.7Hz和6.2Hz);2.45ppm(H-7b,1),dd,J=14.3Hz和
6.2Hz;2.31ppm(H-9,1),m(tdt),J=10.6Hz,7.4Hz和6.3Hz;2.20ppm(H-10a,1),ddd,J=12.0Hz,7.3Hz和6.4Hz;1.96ppm(H-8,1),tt,J=10.4Hz和6.1Hz;1.60ppm(H-12,1),qd/dddd,J=9.2Hz和4.8Hz;1.20ppm(H-10b,1),dt,J=11.9Hz和10.5Hz;13C NMR(125.8MHz):156.72ppm(C-3),140.18ppm(C-6),126.89(C-5),126.34ppm(C-22),120.60ppm(C-23),108.64ppm(21),96.73ppm(C-15),76.30ppm(C-11),70.75ppm(C-13),55.69ppm(C-2),55.43ppm(C-17),51.91ppm(C-12),40.45ppm(C-10),37.82ppm(C-8),33.37ppm(C-7),33.20ppm(C-9),25.62ppm(C-4)。
將22克(75毫莫耳)TREP-7溶解在氮氛圍下50毫升吡啶中且將17.9克(82毫莫耳)對-苯基苯甲醯氯(PPB-Cl)在最高50℃之溫度下添加至其中。將反應混合物在50-60℃下攪拌。在反應結束時,添加乙醇及水且將混合物冷卻至0/5℃-ra。在攪拌3小時之後,濾出晶體且以乙醇-水混合物清洗。
產量:34.1克(96%)白色晶體。Mp:106-107℃。
NMR數據:(CDCl3),1H NMR(500MHz):8.06ppm(H-26和H-26’,2),m(d),J=8.5Hz;7.65-7.59ppm(H-27,H-27’,H-30和H-30’,4),m,(in:7.63ppm(H-27和H-27’,2),m(d),J=8.5Hz和7.61ppm(H-30和H-30’,2),m(d),J~7.5Hz);7.47ppm(H-31和H-31’,2),m(t),J~7.5Hz;7.39ppm(H-32,1),m(t/tt),J=7.4Hz;7.15ppm(H-22,1),t,J=7.8Hz;6.83ppm(H-23,1),d,J=7.5Hz;6.79ppm(H-21,1),d,J=8.1Hz;5.23ppm(H-11,1),td,J=8.7Hz和6.2Hz;4.64ppm(H-15,2),m(s);
3.83ppm(H-2,3),s;3.72-3.63ppm(H-13,2),m(in:3.69ppm(H-13a,1),dd,J=9.9Hz和4.8Hz和3.66ppm(H-13b,1),dd,J=9.9Hz和5.3Hz);3.35ppm(H-17,3),s;2.87ppm(H-4a和H-7a,2),m(dd),J=14.7Hz和6.1Hz;2.68-2.58ppm(H-4b和H-7b,2),m(in:2.65ppm(H-7b,1),dd,J=15.1Hz和6.3Hz和2.62ppm(H-4b,1),dd,J=15.5Hz和6.2Hz);2.53-2.40ppm(H-9和H-10a,2),m(in:2.475ppm(H-10a,1),m和2.465ppm(H-9,1),m);2.305ppm(H-8,1),m(tt),J=9.4Hz和6.3Hz;2.01ppm(H-12,1),m(tt),J=8.9Hz和4.9Hz;1.41ppm(H-10b,1),m;13C NMR(125.8MHz):166.40ppm(C-24),156.74ppm(C-3),145.65ppm(C-28),140.18ppm(C-29),140.03ppm(C-6),130.20ppm(C-26和C-26’,2),129.35ppm(C-25),129.03ppm(C-31和C-31’,2),128.22ppm(C-32),127.39ppm(C-30和C-30’,2),127.10ppm(C-27和C-27’,2),126.69(C-5),126.38ppm(C-22),120.71ppm(C-23),108.46ppm(21),96.72ppm(C-15),76.16ppm(C-11),67.41ppm(C-13),55.65ppm(C-2),55.32ppm(C-17),50.16ppm(C-12),37.93ppm(C-10),37.55ppm(C-8),33.70ppm(C-9),33.28ppm(C-7),25.72ppm(C-4)。
將28克(59.2毫莫耳)TREP-8溶解在140毫升四氫呋喃中且將280毫升甲醇添加至溶液中。
在方法1i1中,將140毫升5M氫氯酸添加至混合物中且在45-50℃下攪拌。
在方法1i2中,將14克對-甲苯磺酸單水合物添加至混合物中且在45-50℃下攪拌。
在反應結束時,將混合物以NaHCO3溶液中和,蒸餾出有機溶劑。將殘餘物以乙酸乙酯萃取,將合併的有機相以水清洗,在硫酸鈉上乾燥。將粗製產物在矽膠上使用己烷:乙酸乙酯之混合物作為溶析劑層析分離。
產量:23.4克(92%)無色油。
NMR數據:(CDCl3),1H NMR(500MHz):8.05ppm(H-26和H-26’,2),m(d),J=8.5Hz;7.65-7.58ppm(H-27,H-27’,H-30和H-30’,4),m,(in:7.63ppm(H-27和H-27’,2),m(d),J=8.5Hz和7.60ppm(H-30和H-30’,2),m(d),J~7.4Hz);7.46ppm(H-31和H-31’,2),m(t),J~7.5Hz;7.39ppm(H-32,1),m(t/tt),J=7.3Hz;7.14ppm(H-22,1),t,J=7.8Hz;6.82-6.76ppm(H-21和H-23,2),m(in:6.792ppm(H-23,1),d,J~7.3Hz和6.788ppm(H-21,1),d,J~8.4Hz);5.21ppm(H-11,1),td,J=9.3Hz和6.5Hz;3.84ppm(H-2,3),s;3.71ppm(H-13,2),m;2.86-2.76ppm(H-4a和H-7a,2),m(in:2.82ppm(H-7a,1),dd,J=14.6Hz和6.3Hz和2.80ppm(H-4a,1),dd,J=15.0Hz和6.2Hz);2.73-2.64ppm(H-4b和OH-13,2),m(in:2.70ppm(H-4b,1),dd,J=15.1Hz和5.8Hz和2.67ppm(OH-13,1),寬峰);2.56ppm(H-7b,1),dd,J=14.6Hz和5.6Hz;2.45ppm(H-9,1),m;2.40-2.31ppm(H-8和H-10a,2),m(in:2.365ppm(H-10a,1),m,J~11.9和7.0和2.35ppm(H-8,1),m,J=10.4Hz和7.1Hz);1.71ppm(H-12,1),m tt,J=9.2Hz和4.1Hz;1.53ppm(H-10b,1),dt,J=12.1Hz和9.5Hz;13C NMR(125.8MHz):167.40ppm(C-24),156.86ppm(C-3),146.01ppm(C-28),140.08ppm(C-29),139.79ppm(C-6),130.34ppm(C-26和C-26’,2),129.06ppm(C-31和C-31’,2),128.83ppm(C-25),128.32ppm(C-32),127.41ppm(C-30和C-30’,2),127.16ppm(C-27和C-27’,2),126.51(C-5),126.42ppm(C-22),120.88ppm(C-23),108.52ppm(C-21),75.40ppm(C-11),61.16ppm(C-13),55.69ppm(C-2),52.83ppm(C-12),37.56ppm(C-10),36.32ppm(C-8),33.01ppm(C-9),32.71ppm(C-7),25.48ppm(C-4)。
將20克(46.7毫莫耳)TREP-9在惰性氛圍中溶解在200毫升無水甲苯中。添加30克二環己基碳二醯亞胺(DCC)及10毫升在磷酸中的二甲基亞碸。將反應混合物加熱至50℃且分批添加另外5毫升在磷酸中的二甲基亞碸。當氧化完成時,將反應混合物冷卻至-10℃且在此溫度下添加4克(71毫莫耳)氫氧化鉀及接著添加在甲苯中的10.9克(49毫莫耳)2-酮庚基磷酸二甲酯之溶液。在反應結束時,將混合物在攪動下倒在酸溶液上。濾出沉澱之晶體且清洗。將過濾物相分離,將有機相以1M碳酸氫鈉溶液清洗及接著以稀釋的氫氯酸溶液清洗。將有機相蒸發且在矽膠管柱上使用甲苯:己烷溶析劑的層析術純化。
產量:23克(94,3%)淺棕色油。
將20克(46.7毫莫耳)TREP-9溶解在200毫升甲苯中且將0.9克溴化鉀及0,2克TEMPO/(2,2,6,6-四甲基-哌啶-1-基)氧基/觸媒添加至溶液中。將反應混合物冷卻至0℃-(+10℃)之範圍,添加150毫升次氯酸鈉溶液(活性氯含量為6-14%)且將混合物在此溫度下攪拌。當氧化完成時,將反應混合物的相分離,將有機相以Na2S2O3水溶液、以KBr水溶液及最後以水清洗。
將10.9克(49毫莫耳)2-酮庚基磷酸二甲酯及100毫升3M氫氧化鉀溶液添加至有機相中。將反應混合物在室溫下攪動。在反應完成之後,將相分離且將有機相以1M硫酸氫鈉溶液及15%之NaCl溶液清洗。
將有機相蒸發且在矽膠管柱上使用甲苯:己烷溶析劑的層析術純化。
產量:23克(94.35%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):8.00ppm(H-26和H-26’,2),m(d),J=8.3Hz;7.64-7.56ppm(H-27,H-27’,H-30和H-30’,4),m,(in:7.61ppm(H-27和H-27’,2),m(d),J=8.4Hz和7.59ppm(H-30和H-30’,2),m(d),J~7.7Hz);7.45ppm(H-31和H-31’,2),m(t),J~7.5Hz;7.38ppm(H-32,1),m(t/tt),J=7.3Hz;7.165ppm(H-22,1),t,J=7.9Hz;6.83-6.76ppm(H-13,H-21和H-23,3),m(in:6.80ppm(H-21和H-23,2),d,J=7.9Hz和6.80ppm(H-13,1),dd,J=15.8Hz和8.3Hz);6.12ppm(H-14,1),d,J=15.8Hz;5.18ppm(H-11,1),td,J=9.6Hz和6.2Hz;3.83ppm(H-2,3),m(s);2.79-2.70ppm(H-4和H-7a,3),m(in:2.75ppm(H-7a,1),dd,J=14.7Hz和5.9Hz和2.73ppm(H-4,2),d,J=5.5Hz);2.62-2.48ppm(H-7b,H-9,H-10a和H-16,5),m(in:2.565ppm(H-9,1),m;2.55ppm(H-16,1),t,J=7.4Hz;2.53ppm(H-10a,1),m;2.515ppm(H-7b,1),m);2.40-2.27ppm(H-8和H-12,2),m(in:2.36ppm(H-12,1),m和2.31ppm(H-8,1),m);1.67-1.53ppm(H-17,2),m(tt),J=7.4Hz,1.38-1.22ppm(H-10b,H-18和H-19,5),m(in:1.34ppm(H-10b,1),m(dt),J~11.8Hz和9.6Hz;1.29ppm(H-19,2)m和1.28ppm(H-18,2)m);0.87ppm(H-20,3),m(t),J=6.9Hz;13C NMR(125.8MHz):200.85ppm(C-15),166.23ppm(C-24),156.99ppm(C-3),146.53ppm(C-13),145.89ppm(C-28),140.14ppm(C-29),139.28ppm(C-6),131.85ppm(C-14),130.22ppm(C-26和C-26’,2),129.05ppm(C-31和C-31’,2),128.93ppm(C-25),128.28ppm(C-32),127.41ppm(C-30和C-31’,2),127.14ppm(C-27和C-27’,2),126.70(C-22),126.23ppm(C-5),120.93ppm(C-23),108.76ppm(C-21),77.31ppm(C-11),55.69ppm(C-2),53.49ppm(C-12),40.24ppm(C-8),40.16ppm(C-16),37.89ppm(C-10),33.16ppm(C-9),31.88ppm(C-7),31.58ppm(C-18),25.32ppm(C-4),24.08ppm(C-17),22.60ppm(C-19),14.05ppm(C-20)。
將3.017克二異丙胺在氮氛圍中以攪拌溶解在13.6毫升四氫呋喃(THF)中且將17.9毫升丁基鋰(BuLi)之己烷溶液(在己烷中的1.6M溶液)在0±5℃下添加至其中。將混合物在室溫下攪拌1小時。
將1.85克甲基膦酸二甲酯及1.77毫升己酸甲酯在氮氛圍中以攪拌溶解在10.2毫升四氫呋喃(THF)中。將溶液冷卻至0/-5℃且在此溫度下以約30分鐘期間逐滴添加二異丙基醯化鋰(LDA)溶液。將反應混合物在0/-5℃下攪拌1小時且添加37毫升2M NaHCO3溶液。在室溫下繼續攪拌1小時,將相分離,將水相以甲基第三丁基醚(TBME)萃取。將合併的有機相以氯化鈉飽和溶液清洗,在真空中蒸發且在45±5℃之水浴上以旋轉器蒸發甲苯而乾燥。
產量:2.718克(90%)黃色油。
NMR數據:(DMSO),1H NMR(500MHz):3.65ppm(H-9和H-10,6),d,J=11.2Hz;3.26ppm(H-1,2),m(d),J=22.1Hz,2.555ppm(H-3,2),t,J=7.2Hz;1.45ppm(H-4,2),qui(tt),J=7.3Hz;1.32-1.15ppm(H-5和H-6,4),m,(in:1.26ppm(H-6,2),m和1.20ppm(H-5,2),m);0.85ppm(H-7,3),t,J=7.2Hz;13C NMR(125.8MHz):202.23ppm(C-2),d,J=5.9Hz;52.47ppm(C-9和C-10,2),d,J=6.3Hz;43.04ppm(C-3),d,J=1.4Hz;40.21ppm(C-1),d,J=125.5Hz,30.50ppm(C-5);22.40ppm(C-4);21.82ppm(C-6),13.72ppm(C-7);31P NMR(202.46MHz):23.52ppm(P-8),m.
將19克(36.3毫莫耳)TREP-11在氮氛圍下溶解在190毫升無水四氫呋喃中。將溶液冷卻至0-5℃且添加36.3毫升(36.3毫莫耳)氧氮硼雜環戊烷溶液(1M甲苯溶液)。將混合物冷卻至(-30)℃且同時保持此溫度,將9.5毫升(99毫莫耳)硼烷-二甲硫醚複合物逐滴添加至其中。將反應混合物在此溫度下攪拌。在反應結束時,容許混合物溫熱至(-15)℃且將甲醇小心添加至其中(形成劇烈發泡及熱)。將混合物攪拌30分鐘且接著將NaHSO4溶液在0-5℃下添加至其中。濾出沉澱之晶體且以甲苯清洗。將液體過濾物以3 x 50毫升甲苯萃取。將合併的有機相以水清洗且經硫酸鈉乾燥。濾出乾燥材料且將過濾物蒸發。
產量:18.2克(95.4%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):8.02ppm(H-26和H-26’,2),m(d),J=8.4Hz;7.63-7.56ppm(H-27,H-27’,H-30和H-30’,4),m,(in:7.60ppm(H-27和H-27’,2),m(d),J=8.3Hz和7.59ppm(H-30和H-30’,2),m(d),J~7.1Hz);7.45ppm(H-31和H-31’,2),m(t),J~7.4Hz;7.38ppm(H-32,1),m(t/tt),J=7.3Hz;7.15ppm(H-22,1),m(t),J=7.8Hz;6.83-6.76ppm(H-21和H-23,2),m(in:6.79ppm(H-21和H-23,2),m);5.635ppm(H-13,1),dd,J=15.4Hz和7.6Hz;5.54ppm(H-14,1),m(dd),J=15.4Hz和6.4Hz,5.09ppm(H-11,1),td,J=9.5Hz和6.1Hz,4.085ppm(H-15,1),m(q),J=6.4Hz,3.82ppm(H-2,3),m(s),2.79-2.70ppm(H-4a和H-7a,2),m(in:2.74ppm(H-4a和H-7a,2),m(dd),J~13.8Hz和~5.5Hz);2.665ppm(H-4b,1),m(dd),J=14.9Hz和5.2Hz,2.57-2.41ppm(H-7b,H-9和H-10a,3),m(in:2.51ppm(H-7,1),m(dd),J=14.6Hz和4.6Hz;2.48ppm(H-9,1),m;2.47ppm(H-10a,1),m);2.25-2.11ppm(H-8和H-12,2),m,(in:2.20ppm(H-12,1),m和2.18
ppm(H-8,1),m);1.68ppm(OH-15,1),寬峰;1.60-1.39ppm(H-16,2),m,(in:1.51ppm(H-16a,1),m和1.45ppm(H-16b,1),m);1.38-1.18ppm(H-10b,H-17,H-18和H-19,7),m,(in:1.31ppm(H-10b和H-17a,2),m;1.25ppm(H-17b,H-18和H-19,5)m);0.85ppm(H-20,3),m(t),J=6.8Hz 13C NMR(125.8MHz):166.50ppm(C-24),156.90ppm(C-3),145.71ppm(C-28),140.18ppm(C-29),139.89ppm(C-6),135.69ppm(C-13),131.52ppm(C-14),130.18ppm(C-26和C-26’,2),129.26ppm(C-25),129.03ppm(C-31和C-31’,2),128.22ppm(C-32),127.38ppm(C-30和C-30’,2),127.10ppm(C-27和C-27’,2),126.55ppm(C-5),126.49(C-22),120.87ppm(C-23),108.58ppm(C-21),77.84ppm(C-11),72.76ppm(C-15),55.68ppm(C-2),53.53ppm(C-12),40.14ppm(C-8),37.66ppm(C-10),37.26ppm(C-16),33.00ppm(C-9),32.02ppm(C-7),31.86ppm(C-18),25.53ppm(C-4),25.12ppm(C-17),22.71ppm(C-19),14.14ppm(C-20)。
將17克(32.4毫莫耳)TREP-12溶解在70毫升甲醇中,添加4.2克(30.3毫莫耳)K2CO3且將混合物在40℃下攪拌,直到反應結束。當達成所欲轉化時,將反應混合物冷卻至0℃且將磷酸溶液分批添加至其中。濾出沉澱之對-苯基苯醯基甲酯(PPB-甲酯)且清洗。將過濾物濃縮,將水及甲苯添加至其中且將相分離。將水相以甲苯萃取,將有機相經Na2SO4乾燥,濾出乾燥材料,將過濾物蒸發且在矽膠管柱上以層析術純化(使用己烷:甲基第三丁基醚之混合物溶析劑)。自己烷與甲基第三丁基醚之混合物結晶出主要流份。濾出沉澱之晶體,清
洗且乾燥。
產量:8克(72%)白色晶體。Mp:75-77℃。
NMR數據:(CDCl3),1H NMR(500MHz):7.10ppm(H-22,1),t,J=7.8Hz;6.78-6.70ppm(H-21和H-23,2),m(in:6.75ppm(H-21,1),m(d),J=8.3Hz和6.73ppm(H-23,1),m(d),J=7.4Hz);5.52-5.42ppm(H-13和H-14,2),m(in:5.47ppm(H-13和H-14,2),m);4.04ppm(H-15,1),m,J=6.5Hz和3.2Hz;3.80ppm(H-2,3),s;3.70ppm(H-11,1),td,J=10.1Hz和6.1Hz;2.70-2.46ppm(H-4a,H-7a,H-7b,OH-11和OH-15,5),m(in:2.66ppm(H-4a,1),m(dd),J=14.9Hz和6.2Hz;2.63ppm(H-7a,1),m(dd),J~14.9Hz和~6.1Hz;2.59ppm(H-4b,1),m(dd),J=14.7Hz和5.6Hz;2.57ppm(OH-11和OH-15,2),m(寬峰));2.40-2.27ppm(H-7b和H-9,2),m(in:2.37ppm(H-7b,1),m(dd),J=14.3Hz和5.4Hz;2.32ppm(H-9,1),m);2.23-2.13ppm(H-10a,1),m,(in:2.19ppm(H-10a,1),m(ddd),J=12.1Hz,7.4Hz和6.4Hz);2.02ppm(H-8,1),m(tt),J=10.9Hz和5.5Hz;1.71ppm(H-12,1),m;1.57ppm(H-16a,1),m;1.48ppm(H-16b,1),m;1.43-1.23ppm(H-17,H-18和H-19,6),m,(in:1.37ppm(H-17a,1),m;1.33ppm(H-19,2),m;1.325ppm(H-17b,1),m;1.32ppm(H-18,2),m);1.08ppm(H-10b,1)m(dt/q),J=11.7Hz和10.5Hz;0.91ppm(H-20,3),m(t),J=6.9Hz;13C NMR(125.8MHz):156.81ppm(C-3),140.33ppm(C-6),136.20ppm(C-14),133.38ppm(C-13),126.87ppm(C-5),126.38(C-22),120.77ppm(C-23),108.58ppm(C-21),75.87ppm(C-11),73.32ppm(C-15),56.94ppm(C-12),55.71ppm(C-2),40.61ppm(C-8),40.49ppm(C-10),37.29ppm(C-16),32.73ppm(C-9),32.21ppm(C-7),31.85ppm(C-18),25.54ppm(C-4),25.37ppm(C-17),22.78ppm(C-19),14.18ppm(C-20)。
將7.7克(22.3毫莫耳)TREP-13溶解在77毫升甲基乙酮與154毫升乙醇之混合物中。將反應混合物在6巴壓力下經以亞硝酸鈉去活化之0.77克10%之鈀/木炭觸媒氫化。在反應結束時,濾出觸媒,以乙酸乙酯清洗,將過濾物在真空中蒸發且自己烷:乙酸乙酯之混合物結晶出殘餘物。
產量:6.4克(83%)白色晶體。Mp:71-72℃。
NMR數據:(CDCl3),1H NMR(500MHz):7.09ppm(H-22,1),t,J=7.8Hz;6.78-6.71ppm(H-21和H-23,2),m(in:6.75ppm(H-23,1),m(d),J~7.4Hz和6.74ppm(H-21,1),m(d),J=8.1Hz);3.80ppm(H-2,3),s;3.71ppm(H-11,1),td,J=9.6Hz和6.1Hz;3.59ppm(H-15,1),m;2.83-2.69ppm(H-4a和H-7a,2),m(in:2.79ppm(H-4a,1),m(dd),J=14.7Hz和6.1Hz;2.74ppm(H-7a,1),m(dd),J=14.3Hz和6.2Hz);2.51-2.40ppm(H-4b és H-7b,2),m(in:2.47ppm(H-4b,1),m(dd),J=14.8Hz和6.5Hz;2.44ppm(H-7b,1),m(dd)),J=14.4Hz和6.6Hz);2.40-2.19ppm(H-9和OH-11/OH-15,2),m(in:2.31ppm(OH-11/OH-15,1),寬峰和2.22ppm(H-9,1),m,J=10.2Hz和~7.0Hz);2.19-1.97ppm(H-10a和OH-11/OH-15,2),m,(in:2.155ppm(H-10a,1),m(ddd),J=11.7Hz,7.4Hz和6.1Hz和2.08ppm(OH-11/OH-15,1),寬峰);1.92-1.74ppm(H-8和H-11/H-15/water,2),m,(in:1.87ppm(H-8,1),m(tt),J=10.0Hz和6.4Hz和1.81ppm(OH-11/OH-15,1),寬峰);1.69-1.50ppm(H-13和H-14,4),m(in:1.62ppm(H-13a和H-14a,2)m;1.57ppm(H-13b,1),m和1.55ppm(H-14b,1),m);1.50-1.38ppm(H-16和H-17a,3),m(in:1.47ppm(H-16a,1),m和1.435ppm(H-16b,1),m和1.43ppm(H-17a,1),m);1.38-1.22ppm(H-12,H-17b,H-18和H-19,
6),m(in:1.32ppm(H-19,2),m;1.31ppm(H-17b,1),m;1.30ppm(H-12和H-18,3),m);1.14ppm(H-10b,1),m(dt),J=11.5Hz和10.1Hz;0.90ppm(H-20,3),m(t),J=6.9Hz;13C NMR(125.8MHz):156.64ppm(C-3),140.65ppm(C-6),127.09ppm(C-5),126.26(C-22),120.60ppm(C-23),108.51ppm(C-21),77.51ppm(C-11),72.70ppm(C-15),55.72ppm(C-2),52.40ppm(C-12),41.54ppm(C-10),41.44ppm(C-8),37.58ppm(C-16),35.14ppm(C-14),33.82ppm(C-7),32.96ppm(C-9),32.05ppm(C-18),28.77ppm(C-13),25.88ppm(C-4),25.52ppm(C-17),22.78ppm(C-19),14.18ppm(C-20)。
將400克無水氯化鋁添加至氮氛圍下的2.4公升1-十二烷基硫醇中。將混合物冷卻至0-5℃且將560毫升二氯甲烷中的200克TREP-14之溶液添加至其中。將反應混合物在室溫下攪拌。在反應結束時,將混合物倒在4公升水上且添加664毫升2M硫酸氫鈉。將相分離,將水相以乙酸乙酯萃取。將有機相以氯化鈉飽和溶液清洗,經硫酸鈉乾燥且蒸發。自己烷結晶出殘餘物。濾出晶體,清洗且自己烷:乙酸乙酯之混合物再結晶。
產量:182克(95%)白色晶體。Mp:113-115℃。
NMR數據:(CDCl3),1H NMR(500MHz):6.99ppm(H-22,1),t,J=7.7Hz;6.73ppm(H-23,1),d,J=7.4Hz;6.65ppm(H-21,1),d,J=8.0Hz;4.95ppm(OH-3,1),s;3.75ppm(H-11,1),td,J=9.4Hz和6.2Hz;3.62ppm(H-15,1),m;2.78-2.675ppm(H-4a和H-7a,2),m(in:2.735ppm(H-7a,1),m(dd),J=14.0Hz和7.0Hz;2.72ppm(H-4a,1),m(dd),J=14.6Hz和6.5Hz);2.51-2.42ppm(H-4b和H-7b,2),m(in:2.47ppm
(H-4b,1),m(dd),J=14.6Hz和6.3Hz;2.46ppm(H-7b,1),m(dd)),J=14.2Hz和6.2Hz);2.28ppm(H-9,1),m,J=10.3Hz,~7.3Hz和~6.5Hz;2.175ppm(H-10a,1),m(ddd/dt),J=12.0Hz,7.3Hz和6.4Hz;1.95-1.85ppm(H-8,1),m(in:1.90ppm(H-8,1),m(tt),J=10.0Hz和6.2Hz);1.72-1.61ppm(H-13a和H-14a,2),m(in:1.655ppm(H-14a,1),m和1.65ppm(H-14a,1),m);1.61-1.51ppm(H-13b和H-14b,2),m(in:1.56ppm(H-14b,1),m和1.55ppm(H-13b,1),m);1.51-1.385ppm(H-16和H-17a,3),m(in:1.48ppm(H-16a,1),m和1.44ppm(H-16b和H-17a,2),m);1.385-1.22ppm(H-12,H-17b,H-18和H-19,6),m(in:1.32ppm(H-19,2),m;1.31ppm(H-17b,1),m;1.305ppm(H-18,2),m;1.285ppm(H-12,1),m);1.16ppm(H-10b,1),dt,J=11.8Hz和10.2Hz;0.90ppm(H-20,3),m(t),J=6.9Hz;13C NMR(125.8MHz):152.65ppm(C-3),141.00ppm(C-6),126.39(C-22),124.60ppm(C-5),120.67ppm(C-23),113.15ppm(C-21),77.56ppm(C-11),72.79ppm(C-15),52.30ppm(C-12),41.50ppm(C-10),41.41ppm(C-8),37.58ppm(C-16),35.09ppm(C-14),33.74ppm(C-7),33.00ppm(C-9),32.05ppm(C-18),28.78ppm(C-13),26.12ppm(C-4),25.52ppm(C-17),22.79ppm(C-19),14.20ppm(C-20)。
將170克(0.51莫耳)TREP-15溶解在3.4公升丙酮中。將340克(2.46莫耳)無水碳酸鉀及89.6克(0.536莫耳)溴乙酸乙酯添加至溶液中且將混合物在30-35℃下攪。在反應結束時,將反應混合物過濾,將
過濾物蒸發。以TBME(甲基第三丁基醚):己烷之混合物自殘餘物結晶出產物,濾出,清洗且乾燥。
產量:203克(95%)白色晶體。Mp:53-55℃。
NMR數據:(CDCl3,1H NMR(500MHz):7.03ppm(H-22,1),t,J=7.8Hz;6.78ppm(H-23,1),d,J=7.4Hz;6.605ppm(H-21,1),d,J=8.2Hz;4.58ppm(H-2,2),s;4.23ppm(H-24,2),q,J=7.1Hz;3.66ppm(H-11,1),td,J=9.6Hz和6.2Hz;3.55ppm(H-15,1),m;2.87ppm(H-4a,1),dd,J=14.7Hz和6.1Hz;2.80-2.455ppm(H-4b,H-7a,OH-11和OH-15,4),m(in:2.72ppm(H-7a,1),dd,J=14.2Hz和6.2Hz;2.67ppm(OH-11和OH-15,2),2.50ppm(H-4b,1),dd,J=14.7Hz和6.7Hz);2.42ppm(H-7b,1),dd,J=14.2Hz和6.8Hz;2.25-2.07ppm(H-9和H-10a,2),m,(in:2.20ppm(H-9,1),m,J=10.2Hz,~6.5-7.1Hz;2.125ppm(H-10a,1),m(ddd/dt),J~12.0Hz,~7.2Hz和~6.2Hz),1.83ppm(H-8,1),m(tt),J=9.9Hz和6.6Hz;1.70-1.57ppm(H-13a和H-14a,2),m(in:1.635ppm(H-14a,1),m和1.625ppm(H-14a,1),m);1.57-1.36ppm(H-13b,H-14b,H-16和H-17a,5),m(in:1.50ppm(H-14b,1),m;1.48ppm(H-13b,1),m;1.435ppm(H-16a,1),m;1.415ppm(H-17a,1),m,1.40ppm(H-16b,1),m);1.36-1.19ppm(H-12,H-17b,H-18,H-19和H-25,9),m(in:1.295ppm(H-19,2),m;1.28ppm(H-17b,1),m;1.275ppm(H-18,2),m;1.27ppm(H-25,3),t,J=7.1Hz;1.24ppm(H-12,1),m);1.14ppm(H-10b,1),dt,J=11.6Hz和10.2Hz;0.88ppm(H-20,3),t,J=6.9Hz;
13C NMR(125.8MHz):169.32ppm(C-1),154.94ppm(C-3),141.15ppm(C-6),127.92(C-5),126.11ppm(C-22),121.55ppm(C-23),109.76ppm(C-21),77.16ppm(C-11),72.47ppm(C-15),66.12ppm(C-2),61.26ppm(C-24),52.31ppm(C-12),41.27ppm(C-8),41.25ppm(C-10),37.49ppm(C-16),35.06ppm(C-14),33.88ppm(C-7),32.80ppm(C-9),31.99ppm(C-18),28.63ppm(C-13),26.08ppm(C-4),25.47ppm(C-17),22.71ppm(C-19),14.22(C-25),14.13ppm(C-20)。
將180克(0.43莫耳)TREP-16(乙酯)溶解在650毫升四氫呋喃中。在氮氛圍下及室溫下添加2.7公升0.5M氫氧化鈉溶液且將反應混合物在室溫下攪拌。在反應結束時,將混合物以蒸餾之甲基第三丁基醚清洗。將甲基第三丁基醚添加至鹼性水相中且將混合物的pH以1M硫酸氫鈉溶液設定至pH3。接著將酸性水相以甲基第三丁基醚萃取,將合併的有機相以水清洗且蒸發。
產量:165克(98%)結晶油。
NMR數據(d6-DMSO),1H NMR(400MHz):12.915(COOH-1,1),寬峰;7.03ppm(H-22,1),t,J=7.8Hz;6.76ppm(H-23,1),d,J=7.4Hz;6.68ppm(H-21,1),d,J=8.2Hz;4.62ppm(H-2,2),s;4.47ppm(OH-11,1),寬峰;4.21ppm(OH-15,1),寬峰;3.47ppm(H-11,1),m(q),J~8.0Hz;3.35ppm(H-15,1),m,2.80-2.60ppm(H-4a和H-7a,2),m(in:2.725ppm(H-4a,1),dd,J=14.7Hz和6.2Hz;2.67ppm(H-7a,1),dd,J=14.2Hz和6.2Hz);2.48-2.34ppm(H-4b和H-7b,2),m(in:2.49ppm(H-4b,1),dd,J=14.6Hz和6.6Hz;2.39ppm(H-7b,1),dd,J=14.2Hz和6.5Hz);2.11ppm(H-9,1),m(tq),J~10.1Hz和~6.7Hz;1.955ppm(H-10a,1),m(ddd/dt),J=12.1Hz和6.7Hz;1.76ppm(H-8,1),m(tt),J=10.0Hz和6.2Hz;1.61ppm(H-13a,1)m;1.53-1.33ppm(H-14,H-16a和H-17a,4),m(in:1.46ppm(H-14a,1),m;1.43ppm(H-14b,1),m;1.38ppm(H-17a,1),m;1.35ppm(H-16a,1),m);1.33-1.15ppm(H-13b,H-16b,H-17b,H-18和H-19,7),m(in:1.32ppm(H-13b,1),m;1.30ppm(H-16b,1),m;1.275ppm(H-19,2),m;1.26ppm(H-17b,1),m;1.25ppm(H-18,2),m);1.15-0.93ppm(H-10b和H-13,2),m(in:H-1.09ppm(H-12,1),m(tt),J=9.0Hz和6.1Hz;1.00ppm(H-10b,1),m(ddd/dt),J=11.7Hz和10.2Hz);0.87ppm(H-20,3),m(t),J=6.9Hz;13C NMR(100MHz):170.36ppm(C-1),154.63ppm(C-3),
140.56ppm(C-6),126.75ppm(C-5),125.85(C-22),120.65ppm(C-23),109.37ppm(C-21),75.44ppm(C-11),70.13ppm(C-15),64,96ppm(C-2),51.49ppm(C-12),41.15ppm(C-10),40.48ppm(C-8),37.06ppm(C-16),35.03ppm(C-14),33.37ppm(C-7),32.42ppm(C-9),31.53ppm(C-18),28.36ppm(C-13),25.62ppm(C-4),24.96ppm(C-17),22.18ppm(C-19),13.96ppm(C-20)。
1s1.)將150克(0.384莫耳)曲前列環素溶解在2公升乙醇中。將碳酸鈉單水合物26.2克(0.211莫耳)添加其其中且將混合物在惰性氛圍下及室溫下攪拌。當過濾之樣品的pH達到7-9之值時,將混合物經由5微米孔徑過濾器過濾。將過濾物溶液在旋轉器上濃縮至約225克。將濃縮物溶解在經水飽和之甲基第三丁基醚中且容許在室溫下結晶。濾出晶體,在室溫下清洗且在真空中以20-50℃乾燥。
產量:158克(100%)曲前列環素鈉鹽單水合物(〝A〞形式),白色晶體。Mp:95-99℃。
1s2.)將150克(0.384莫耳)曲前列環素溶解在2公升乙醇中。將35.5克(0.422莫耳)碳酸氫鈉添加至其中且將混合物在惰性氛圍下及室溫下攪拌。當過濾之樣品的pH達到7-8之值,將混合物經由5微米孔徑過濾器過濾且將過濾物溶液在旋轉器上濃縮至約225克。將濃縮物溶解在經水飽和之甲基第三丁基醚中且容許在室溫下結晶。濾出晶體,在室溫下清洗且在真空中以20-50℃乾燥。
產量:158克(100%)曲前列環素鈉鹽單水合物(〝A〞形式),白色晶體。Mp:95-99℃。
1s3.)將150克(0.384莫耳)曲前列環素溶解在2公升乙醇中。將21克(0.39莫耳)甲醇鈉添加至其中且將混合物在惰性氛圍下及室溫下攪拌,直到溶解。將溶液經由5微米孔徑過濾器過濾。將過濾物溶液在旋轉器上濃縮至約225克。將濃縮物溶解在經水飽和之甲基第三丁基醚中且容許在室溫下結晶。濾出晶體,在室溫下清洗且在真空中以20-50℃乾燥。
產量:158克(100%)曲前列環素鈉鹽單水合物(〝A〞形式),白色晶體。Mp:95-99℃。
1s4.)將24克(61.45毫莫耳)曲前列環素溶解在360毫升乙醇中且將7.62克(61.45毫莫耳)碳酸鈉單水合物添加至其中。將混合物在惰性氛圍下及室溫下攪拌,直到完全溶解。接著將溶液經由5微米孔徑過濾器過濾且將過濾物溶液在旋轉器上濃縮至約225克。將乙醇添加至濃縮物中且將溶液再濃縮。將濃縮物溶解在甲基第三丁基醚中且容許在室溫下結晶。以過濾收集晶體,清洗且在真空中以20-50℃乾燥。
產量:22.8克(90%)曲前列環素鈉鹽,白色固體(非晶形物形式)。Mp:65-90℃。
曲前列環素鈉鹽單水合物(〝A〞形式)之分析特徵:Mp:95-99℃
DSC峰:94-99℃
純度:以HPLC的99.9面積%
15-表-曲前列環素:以HPLC的0.0面積%
水合量:4.3%
比光旋度(c=1%,甲醇,25℃):+41℃
硫酸化灰分:16.8%
NMR數據:(d6-DMSO),1H NMR(500MHz):6.95ppm(H-22,1),t,J=7.8Hz;6.65ppm(H-23,1),d,J=7.4Hz;6.61ppm(H-21,1),d,J=8.2Hz;4.97-3.93ppm(H-2,OH-11和OH-15,4),m(in:4.54ppm(OH-11,1),寬峰;4.32ppm(OH-15,1),寬峰;4.13ppm(H-2,2),s);3.47ppm(H-11,1),td,J=9.4Hz和6.2Hz;3.35ppm(H-15,1),m(tt),J~7.0Hz和4.3Hz;2.75ppm(H-4a,1),dd,J=14.5Hz和6.1Hz;2.65
ppm(H-7a,1),dd,J=14.1Hz和6.1Hz;2.42-2.32ppm(H-4b和H-7b,2),m(in:2.38ppm(H-4b,1),dd,J=14.5Hz和6.8Hz;2.355ppm(H-7b,1),dd,J=14.1Hz和6.9Hz);2.08ppm(H-9,1),m(tq),J~10.1Hz和~7.0Hz;1.96ppm(H-10a,1),m(ddd/dt),J=12.1Hz和6.6Hz;1.73ppm(H-8,1),m(tt),J=9.8Hz和6.7Hz;1.61ppm(H-13a,1)m;1.52-1.32ppm(H-14,H-16a和H-17a,4),m(in:1.455ppm(H-14a,1),m;1.42ppm(H-14b,1),m;1.38ppm(H-17a,1),m;1.34ppm(H-16a,1),m);1.32-1.16ppm(H-13b,H-16b,H-17b,H-18和H-19,7),m(in:1.31ppm(H-13b,1),m;1.285ppm(H-16b,1),m;1.275ppm(H-19,2),m;1.26ppm(H-17b,1),m;1.25ppm(H-18,2),m);1.11ppm(H-12,1),m(tt),J=9.0Hz和6.3Hz,1.02ppm(H-10b,1),m(ddd/dt),J=11.3Hz和10.3Hz);0.865ppm(H-20,3),m(t),J=6.9Hz;
13C NMR(125.8MHz):171.55ppm(C-1),155.89ppm(C-3),139.91ppm(C-6),126.38ppm(C-5),125.52(C-22),119.30ppm(C-23),109.74ppm(C-21),75.53ppm(C-11),70.14ppm(C-15),68,29ppm(C-2),51.58ppm(C-12),41.26ppm(C-10),40.63ppm(C-8),37.06ppm(C-16),35.07ppm(C-14),33.59ppm(C-7),32.55ppm(C-9),31.54ppm(C-18),28.40ppm(C-13),25.82ppm(C-4),24.97ppm(C-17),22.19ppm(C-19),13.98ppm(C-20)。
將曲前列環素鈉鹽單水合物(〝A〞形式)之DSC圖形顯示於圖15和16上。
將曲前列環素鈉鹽單水合物(〝A〞形式)之XRPD圖形顯示於圖20上。
1t.)製備曲前列環素鈉鹽無水物(〝B〞形式)Mp.:125-129℃):
1t1.)可依照實施例1s1-1s2-1s3中之任一程序,除了下列以外:濾出所獲得的晶體,清洗且在真空中以60-100℃乾燥。
1t2.)可依照實施例1s1-1s2-1s3中之任一程序,除了下列以外:所獲得的晶體在真空中以60-100℃乾燥。
1t3.)將曲前列環素鈉鹽單水合物懸浮液在不或僅微溶解其之溶劑中以60-90℃攪動1-6小時。溶劑可為例如己烷、庚烷、甲苯或乙
酸乙酯。曲前列環素鈉鹽無水物(〝B〞形式)之DSC圖形顯示於圖17和18上。曲前列環素鈉鹽無水物(〝B〞形式)之XRPD圖形顯示於圖21上。
1v.)製備曲前列環素鈉鹽多水合物(〝C〞形式):
1v1.)將曲前列環素鈉鹽單水合物(〝A〞形式)保持在60%水分含量之氛圍下的操作器中48小時,或將曲前列環素鈉鹽單水合物保持在空氣下5-8天。
1v2.)曲前列環素鈉鹽無水物(〝B〞形式)保持在60%水分含量之氛圍下的操作器中48小時,或保持在空氣下5-8天。曲前列環素鈉鹽多水合物(〝C〞形式)之DSC圖形顯示於圖19上。曲前列環素鈉鹽多水合物(〝C〞形式)之XRPD圖形顯示於圖22上。曲前列環素鈉鹽(非晶形物形式)之DSC圖形顯示於圖14上。
以TGA/SDTA851e,Mettler Toledo儀器進行熱重量分析(TGA)。
以DSC 1 Stare System,Mettler Toledo進行差示掃描熱量分析。
以XPERT-PRO-PANalytical儀器進行XRPD分析。
使用以下的實驗條件:X-射線管名稱:PW3373/10 Cu,陽極材料:Cu
所使用的波長:意欲之波長類型:Kα,Kα1(Å):1,540598
掃描範圍(°):2,0000-40,0014
將552克4-戊炔-1-醇溶解在5.5公升蒸餾之甲苯中。將677毫升二氫哌喃及在120毫升四氫呋喃中的19.5克對-甲苯磺酸(PTSA)之溶液添加至溶液中。將反應混合物在室溫下攪拌。在反應結束時,將混合物以三乙胺淬滅,以碳酸氫鈉溶液和水清洗。將有機相蒸發。以未純化的粗製產物前進至下一步驟。
產量:1062克(96%)無色油。
NMR數據:(CDCl3),1H NMR(500MHz):4.59ppm(H-6,1),dd,J=4.0Hz和3.1Hz;3.90-3.79ppm(H-1a和H-10a,2),m,(in:3.86ppm(H-10a,1),ddd,J=11.3Hz,8.2Hz和3.2Hz;3.82ppm(H-1a,1),dt,J=9.8Hz和6.2Hz);3.54-3.44ppm(H-1b和10Hb,2),m,(in:3.50ppm(H-10b,1),m;3.48ppm(H-1b,1),dt,J=9.8Hz和6.2Hz);2.31ppm(H-3,2),m(tdd),J=7.1Hz,2.5Hz和1.5Hz;1.94ppm(H-5,1),t,J=2.6Hz;1.87-1.765ppm(H-2和H-8a,3),m(tt/qui),(in:1.81ppm(H-2,2),qui/tt,J=6.6Hz;1.82ppm(H-8a,1),m);1.70ppm(H-7a,1),m;1.615-1.47ppm(H-7a,H-8a,H-9,4),m,(in:1.58ppm(H-7b,1),m;1.57ppm(H-9a,1),m,1.525ppm(H-9b,1),m;1.52ppm(H-8b,1),m);13C NMR(125.8MHz):98.95ppm(C-6),84.13ppm(C-4),68.56ppm(C-5),65.93ppm(C-1),62.35ppm(C-10),30.81ppm(C-7),28.84ppm(C-2),25.61ppm(C-9),19.65ppm(C-8),15.48ppm(C-3)。
將1062克MPKO-1在惰性氛圍中溶解在8.5公升無水四氫呋喃中且接著在60-65℃下緩慢地添加1920毫升乙基溴化鎂溶液(在醚中的3M溶液)。將反應混合物攪拌45分鐘,冷卻且接著將930毫升四氫呋喃中的927克VPK-5(2-烯丙基-3-甲氧基苯甲醛)之溶液添加至其中。在反應結束時,將混合物以1M NaHSO4溶液淬滅,將水相以乙酸乙酯萃取,將合併的有機相以0.5M NaHCO3溶液和15%之NaCl溶液清洗,乾燥且濃縮至2.4公斤。以未純化的濃縮之粗製產物前進至下一步驟。
產量:成為淺棕色油的100%(1812克)MPK-1。
NMR數據:(CDCl3),1H NMR(500MHz):7.34ppm(H-6,1),dd,J=7.8Hz和0.7Hz;7.24ppm(H-5,1),m(t),J=8.0Hz,與殘餘的CDCl3溶劑之峰重疊;6.86ppm(H-4,1),d(d寬峰),J=8.0Hz;5.985ppm(H-14,1),ddt,J=17.1Hz,10.2Hz和5.9Hz;5.62ppm(H-7,1),寬峰;4.98ppm(H-15a,1),dq(ddt),J=10.1Hz,1.8Hz和1.6Hz;4.93ppm(H-15b,1),dq(ddt),J=17.1Hz,1.8Hz和1.7Hz;4.57ppm(H-17,1),m,J=2.5Hz;3.88-3.77ppm(H-12a,H-16 és H-21a,5),m,(in:3.85ppm(H-21a,1),m;3.82ppm(H-16,3),s;3.81ppm(H-12a,1),dd,15.9Hz和6.2Hz);3.625ppm(H-13a,1),ddt,J=15.7Hz,5.8Hz和1.6Hz;3.55ppm(H-13b,1),ddt,J=15.7Hz,5.9Hz和1.6Hz;3.505-3.43ppm(H-12b和H-21b,2),m,(in:3.47ppm(H-21b,1),m;3.46ppm(H-12b,1),m);2.37ppm(H-10,2),td,J=7.1Hz和1.8Hz;2.30ppm(OH-7,1),寬峰;1.87-1.75ppm(H-11和H-19a,3),m,(in:1.815ppm(H-11,2),tt(qui),J=6.7Hz;1.81ppm(H-19a,1),m);1.69ppm(H-18a,1),m;1.62-1.45ppm(H-18b,H-19b和H-20,4),m,(in:1.565ppm(H-18b,1),m;1.56
ppm(H-20a,1),m;1.51ppm(H-20b,1),m;1.505ppm(H-19b,1)m);13C NMR(125.8MHz):157.74ppm(C-3),140.75ppm(C-1),137.20ppm(C-14),127.52ppm(C-5),125.94pm(C-2),119.32ppm(C-6),114.86ppm(C-15),110.74ppm(C-4),98.90ppm(C-17);86.66ppm(C-9),80.55ppm(C-8),66.03ppm(C-12),62.32ppm(C-21),62.23ppm(C-7),55.91ppm(C-16);30.77ppm(C-18),29.56ppm(C-13),28.82ppm(C-11),25.57ppm(C-20),19.63ppm(C-19),15.93ppm(C-10)。
將4公斤氯鉻酸吡啶(PCC)添加至惰性氛圍中的12公升乙酸乙酯中且接著添加1.7公斤無水乙酸鈉。將懸浮液在室溫下攪拌15分鐘,接著添加在先前步驟中所獲得的2.4公斤MPK-1溶液。在反應結束時,將二異丙醚及矽膠添加至混合物中。在攪拌15-20分鐘之後,將混合物過濾,將矽膠以乙酸乙酯清洗且將過濾物溶液蒸發。將粗製產物在矽膠管柱上使用己烷:乙酸乙酯之梯度混合物作為溶析劑的層析術純化。收集含有產物的流份,濃縮,以水清洗,經硫酸鈉乾燥,濾出乾燥且將過濾物溶液蒸發。
產量:1246克(69%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.73ppm(H-6,1),dd,J=7.8Hz和0.7Hz;7.29ppm(H-5,1),t,J=8.0Hz;7.04ppm(H-4,1),d(d寬峰),J=8.0Hz;5.97ppm(H-14,1),ddt,J=17.1Hz,10.1Hz和6.2Hz;4.985ppm(H-15b,1),dq(ddt),J=17.1Hz和1.7Hz;4.94ppm(H-15a,1),dq(ddt),J=10.1Hz和1.6Hz;4.60ppm(H-11,1),m(dd),
J=4.0Hz和2.9Hz;3.91-3.81ppm(H-12a,H-16和H-21a,5),m,(in:3.86ppm(H-12a,1),m,3.855ppm(H-21a,1),m;3.85ppm(H-16,3),s);3.78ppm(H-13,2),dt,J=6.2Hz和1.5Hz;3.55-3.46ppm(H-12b和H-21b,2),m,(in:3.51ppm(H-12b,1),m(dt),J=9.9Hz和6.0Hz;3.50ppm(H-21b,1),m);2.585ppm(H-10,2),td,J=7.1Hz和1.4Hz;1.925ppm(H-11,2),tt(qui),J=6.6Hz;1.82ppm(H-19a,1),m;1.71ppm(H-18a,1),m;1.64-1.46ppm(H-18b,H-19b和H-20,4),m,(in:1.575ppm(H-18b,1),m;1.57ppm(H-20a,1),m;1.53ppm(H-20b,1),m;1.52ppm(H-19b,1)m);13C NMR(125.8MHz):180.21ppm(C-7),158.20ppm(C-3),137.53ppm(C-1),136.90ppm(C-14),130.04pm(C-2),126.85ppm(C-5),124.75ppm(C-6),115.01ppm(C-4),114.89ppm(C-15),99.05ppm(C-17);95.03ppm(C-9),81.97ppm(C-8),65.84ppm(C-12),62.46ppm(C-21),56.20ppm(C-16);30.78ppm(C-18),29.89ppm(C-13),28.23ppm(C-11),25.58ppm(C-20),19.68ppm(C-19),16.38ppm(C-10)。
將1246克MPK-2在惰性氛圍下溶解在6.3公升無水四氫呋喃中。將溶液冷卻至0-5℃且添加在1M甲苯溶液中的5.73公升R-(+)-2-甲基-CBS-氧氮硼雜環戊烷。接著將混合物冷卻至(-40)-(-35)℃且添加925毫升硼烷-二甲硫醚複合物。在反應結束時,將混合物以甲醇及5%之NH4Cl溶液淬滅,將水相以乙酸乙酯萃取,將有機相以水清洗,乾燥,過濾且蒸發。將粗製產物在矽膠管柱上使用己烷:乙酸乙酯之混合物溶析劑的層析術純化。
產量:1178克(94%)淺棕色油
NMR數據:(CDCl3),1H NMR(500MHz):7.35ppm(H-6,1),d,J=7.8Hz,7.24ppm(H-5,1),m(t),J=8.0Hz,6.86ppm(H-4,1),d,J=8.1Hz;5.99ppm(H-14,1),ddt,J=17.1Hz,10.3Hz和5.7Hz;5.62ppm(H-7,1),t,J=1.8Hz;4.98ppm(H-15a,1),dq,J=10.1Hz és 1.8Hz;4.94ppm(H-15b,1),dq,J=17.2Hz和1.7Hz;4.57ppm(H-17,1),m,J=2.4Hz;3.91-3.74ppm(H-12a,H-16和H-21a,5),m,(in:3.84ppm(H-21a,1),m;3.82ppm(H-16,3),s;3.82ppm(H-12a,1),m);3.63ppm(H-13a,1),ddt,J=15.6Hz,5.8Hz和1.7Hz;3.55ppm(H-13b,1),ddt,J=15.6Hz,5.8Hz和1.7Hz;3.51-3.41ppm(H-12b和H-21b,2),m,(in:3.475ppm(H-21b,1),m;3.47ppm(H-12b,1),m(dt),J=9.7Hz和6.1Hz);2.44-2.20ppm(OH-7和H-10,3),m,(in:2.37ppm(H-10,2),td,J=7.1Hz和1.6Hz;2.30ppm(OH-7,1),寬峰);1.90-1.75ppm(H-11和H-19a,3),m,(in:1.815ppm(H-11,2),tt(qui),J=6.7Hz;1.81ppm(H-19a,1),m);1.69ppm(H-18a,1),m;1.62-1.44ppm(H-18b,H-19b和H-20,4),m,(in:1.57ppm(H-18b,1),m;1.56ppm(H-20a,1),m;1.515ppm(H-20b,1),m;1.51ppm(H-19b,1)m);
13C NMR(125.8MHz):157.76ppm(C-3),140.77ppm(C-1),137.20ppm(C-14),127.51ppm(C-5),125.96pm(C-2),119.33ppm(C-6),114.85ppm(C-15),110.75ppm(C-4),98.91ppm(C-17);86.66ppm(C-9),80.57ppm(C-8),66.03ppm(C-12),62.32ppm(C-21),62.24ppm(C-7),55.91ppm(C-16);30.77ppm(C-18),29.56ppm(C-13),28.83ppm(C-11),25.58ppm(C-20),19.63ppm(C-19),15.93ppm(C-10)。
將先前步驟所獲得的粗製MPK-3(理論量1253克)溶解在10公升甲苯中且將409克咪唑添加至溶液中。將反應混合物冷卻至5-10℃且添加在50%甲苯溶液中的2.02公升第三丁基二甲基氯矽烷(TBDMS-Cl)。將混合物在室溫下攪拌。在反應結束時,將水添加至混合物中且濾出不可溶雜質。將過濾殘餘物以甲苯清洗,將過濾物相分離,將有機相蒸發。將粗製產物在矽膠管柱上使用己烷:乙酸乙酯之混合物作為溶析劑的層析術純化。
產量:1515克(91%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.27ppm(H-6,1),m(d/dd),J=8.0Hz和1.0Hz,7.21ppm(H-5,1),t,J=8.0Hz;6.81ppm(H-4,1),d(dd),J=8.1Hz和0.7Hz;5.95ppm(H-14,1),dddd,J=16.9Hz,10.3Hz,6.4Hz和5.4Hz;5.575ppm(H-7,1),t,J=1.7Hz;5.00-4.90ppm(H-15,2),m,(in:4.97ppm(H-15a,1),dq,J~10.2Hz和1.6Hz;4.94ppm(H-15b,1),dq,J~16.9Hz和1.8Hz);4.55ppm(H-17,1),m;3.87-3.73ppm(H-12兩個立體異構物,H-16和H-21a,5),m,(in:3.83ppm(H-21a,1),m;3.81ppm(H-16,3),s;3.780ppm和3.778ppm(H-12a,1),dt,J=9.8Hz和6.3Hz);3.61ppm(H-13a,1),ddt,J=15.6Hz,5.2Hz和1.8Hz;3.55-3.38ppm(H-12b,H-13b和H-21b,3),m,(in:3.505ppm(H-13b,1),m(dd),J=15.6Hz和6.4Hz;3.46ppm(H-21b,1),m;3.42ppm(H-12b,1),dt,J=9.8Hz和6.3Hz);2.295ppm(H-10,2),m(td),J=7.2Hz和1.9Hz;1.86-1.73ppm(H-11和H-19a,3),m,(in:1.805ppm(H-19a,1),m;1.77ppm(H-11,2),tt(qui),J=6.7Hz);1.68ppm(H-18a,1),m;1.64-1.45ppm(H-18b,H-19b és H-20,4),m,(in:1.56ppm(H-20a,
1),m;1.55ppm(H-18b,1),m;1.51ppm(H-20b,1),m;1.50ppm(H-19b,1)m);0.91ppm(H-24,H-25和H-26,9),m(s),0.12ppm(H-22/H-23,3),s,0.09ppm(H-23/H-22,3),s。
13C NMR(125.8MHz):157.47ppm(C-3),142.27ppm(C-1),136.71ppm(C-14),127.20ppm(C-5),124.75pm(C-2),118.64ppm(C-6),114.61ppm(C-15),109.88ppm(C-4),98.95ppm(C-17);85.12ppm(C-9),81.51ppm和81.50ppm(C-8),66.15ppm和66.13ppm(C-12),62.45ppm(C-21),62.30ppm(C-7),55.81ppm(C-16);30.79ppm(C-18),29.58ppm(C-13),28.86ppm和28.84(C-11),25.99ppm(C-25,C-26和C-27,3),25.60ppm(C-20),19.67ppm(C-19),18.45ppm(C-24),15.93ppm(C-10),-4.36ppm(C-22/C-23),-4.69ppm(C-23/C-22)。
將1427克MPK-4在惰性氛圍中溶解在11.5公升二甲氧基乙烷中且接著添加1070克八羰基二鈷。將反應混合物在室溫下攪拌2.5小時,接著將其加熱至60-70℃且攪拌3小時。在反應結束時,以起泡的空氣流過混合物。持續起泡隔夜。接著將反應混合物過濾,以乙酸乙酯清洗且蒸發。將粗製產物在矽膠管柱上使用己烷:二異丙醚之混合物作為溶析劑的層析術純化。
產量:1363克(90%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.22ppm(H-22,1),t,J=7.9Hz;6.96-6.87ppm(H-23,1),m(in:6.93ppm(H-23,0.5)d,J=7.7Hz;6.90ppm(H-23,0.5),d,J=7.7Hz);6.78ppm(H-21,1),d,J=8.1Hz;
5.55ppm(H-7,0.5),s;5.21ppm(H-7,0.5),s;4.50ppm(H-24,0.5),m(dd),J=4.1Hz和2.9Hz;4.26ppm(H-24,0.5),m(dd),J=4.1Hz和2.9Hz;3.84-3.74ppm(H-2,H-28,3.5),m(in:3.81ppm(H-2,3),s;3.78ppm(H-28,0.5),m(ddd),J=11.3Hz,8.2Hz和3.2Hz);3.70ppmn(H-28,0.5),ddd,J=11.3Hz,8.0Hz和3.2Hz;3.66-3.55ppm(H-15a,1),m(in:3.63ppm(H-15a,0.5),dt,J=9.9Hz和5.3Hz;3.58ppm(H-15a,0.5),ddd,J=9.9Hz,7.4Hz和5.6Hz);3.55-3.47ppm(H-4a,1),m(in:3.52ppm(H-4a,0.5),dd,J=17.1Hz和7.4Hz;3.51ppm(H-4a,0.5),dd,J=17.0和7.4Hz);3.43-3.27ppm(H-9,H-15b,H-28b,2.5),m(in:3.38ppm(H-28b,1),m;3.35ppm(H-9,1),m;3.315ppm(H-15b,0.5),m(dt),J=9.9Hz和5.9Hz);3.06ppm(H-15b,0.5),ddd,J=9.5Hz,8.6Hz和4.8Hz;2.745-2.65ppm(H-10a,1),m(in:2.702ppm(H-10a,0.5),dd,J=18.8Hz和6.4Hz;2.700ppm(H-10a,0.5),dd,J=18.8Hz和6.4Hz);2.46-2.30ppm(H-13,2),m(in:2.42ppm(H-13a,0.5),m;2.40ppm(H-13a,0.5),m;2.385ppm(H-13b,0.5),m;2.34ppm(H-13b,0.5),m);2.25-2.18ppm(H-10b,1),m(in:2.212ppm(H-10b,0.5),dd,J=18.8Hz和1.3Hz;2.210ppm(H-10b,0.5),dd,J=18.8Hz和1.3Hz);2.175-2.07ppm(H-4b,1),m(in:2.13ppm(H-4b,0.5),dd,J=17.1Hz和8.9Hz;2.115ppm(H-4b,0.5),dd,J=17.1和8.9Hz);1.875-1.72ppm(H-14a和H-26,2),m(in:1.80ppm(H-26,1),m;1.78ppm(H-14a,0.5),m;1.75ppm(H-14a,0.5),m);1.72-1.58ppm(H-14b和H-25a,2),m(in:1.64ppm(H-25a,1),m;1.63ppm(H-14b,1),m);1.58-1.38ppm(H-25b,H-26b和H-27,4),m(in:1.53ppm(H-25b,1),m;1.51ppm(H-27b,1)m;1.48ppm(H-26b,1),m;1.41ppm(H-27b,1),m);0.82ppm(H-32,H-33和H-34,9),s;0.16-0.12ppm(H-29/H-30,3),m(s)(in:0.143ppm(H-29/H-30,1.5),s;0.135ppm(H-29/H-30,1.5),s);0.10-0.055ppm(H-30/H-29,3),m(in:0.082ppm(H-30/H-29,1.5),s,0.077ppm(H-30/H-29,1.5),s,13C NMR(125.8MHz):209.78ppm(C-11),173.52ppm和173.25ppm(C-8),156.95ppm和156.92ppm(C-3),138.43ppm和138.36ppm(C-6),136.94ppm和136.64ppm(C-12),127.45ppm和127.39ppm(C-22),125.11pm和
125.10ppm(C-5),122.25ppm和122.12ppm(C-23),109.32ppm和109.31ppm(C-21),98.82ppm和98.73ppm(C-24),66.64ppm和65.97ppm(C-15),65.34ppm和65.23ppm(C-7),62.36ppm和62.26ppm(C-28),55.45ppm(C-2);42.32ppm和42.29ppm(C-10),33.76ppm和33.50ppm(C-4),32.33ppm和32.31ppm(C-9),30.87ppm和30.84ppm(C-25),28.56ppm和28.21ppm(C-14),25.77ppm(C-32,C-33和C-34,3),25.58ppm(C-27),19.80ppm和19.68ppm(C-26),18.21ppm和18.20ppm(C-31),-4.01ppm和-4.03ppm(C-29/C-30),-4.15ppm(C-30/C-29)。
將1363克MPK-5溶解在5.5公升乙醇中,添加60克碳酸鉀及480克10%之Pd(C)觸媒,且在適當的惰性化之後,將反應混合物在6巴氫壓力下及室溫下攪拌。在反應結束時,濾出觸媒,以乙醇清洗且將過濾物溶液蒸發。將粗製產物在矽膠管柱上使用己烷:乙酸乙酯之混合物作為溶析劑的層析術純化。
產量:703克(70%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.10ppm(H-22,1),t,J=7.9Hz,6.74-6.64ppm(H-21和H-23,2),m(in:6.69ppm(H-21,1)d,J~8.4Hz;6.71ppm(H-23,1),d,J~8.3Hz),4.60ppm(H-24,1),m(dd),J=4.1Hz和3.0Hz;3.93-3.76ppm(H-2,H-15a和H-28a,5),m(in:3.87ppm(H-28a,1),m;3.82ppm(H-2,3),s;3.805ppm(H-15a,1),m),3.575-3.335ppm(H-15b和H-28b,2),m(in:3.51ppm(H-28b,1),m;3.44ppm(H-15b,1),m),2.95ppm(H-4a,1),m(dd),J=18.3Hz和7.4Hz,
2.80ppm(H-4b,1),d,J=18.2Hz;2.77-2.625ppm(H-7a和H-9,2),m(in:2.74ppm(H-7a,0.5),m(dd),J=16.7Hz和5.9Hz;2.73ppm(H-7a,0.5),m(dd),J=16.7Hz和5.9Hz;2.68ppm(H-9,1),m),2.56ppm(H-8,1),m(tt/qui),J=5.9Hz和5.5Hz,2.50-2.37ppm(H-10a和H-12,2),m(in:2.44ppm(H-10a,1),dd,J=18.8Hz和8.2Hz;2.41ppm(H-12,1),m(ddd),J=5.5Hz),2.23ppm(H-7b,1),dd,J=16.5Hz和11.7Hz,2.00-1.79ppm(H-10b,H-13a和H-26a,3),m(in:1.93ppm(H-10b,1),dd,J=18.9Hz和12.1Hz;1.905ppm(H-13a,1),m;1.84ppm(H-26a,1),m),1.79-1.64ppm(H-14和H-25a,3),m(in:1.79ppm(H-25a,1),m;1.76ppm(H-14a,1),m;1.71ppm(H-14b,1),m),1.64-1.39ppm(H-13b,H-25b,H-26b和H-27,5),m(in:1.59ppm(H-25b,1),m;1.57ppm(H-27a,1),m;1.53ppm(H-26b,1),m;1.52ppm(H-27b,1),m;1.45ppm(H-13b,1),m),13C NMR(125.8MHz):219.34ppm(C-11),157.72ppm(C-3),136.06和136.04ppm(C-6)126.29ppm(C-22),123.37ppm(C-5),121.19ppm(C-23),107.46ppm(C-21),99.09ppm和98.96ppm(C-24),67.57ppm和67.45ppm(C-15),62.48ppm(C-28),56.82ppm(C-12),55.34ppm(C-2),41.86ppm(C-10),35.51ppm(C-8),31.69ppm(C-9),30.90ppm和30.87ppm(C-25),28.32ppm和28.28ppm(C-14),26.65ppm(C-7),25.60ppm(C-27),24.55ppm(C-4),21.48ppm和21.43ppm(C-13),19.77ppm(C-26)。
將703克MPK-6溶解在14公升乙醇中,將溶液冷卻且在
(-)15-(-)10℃下添加42克硼氫化鈉。將反應混合物攪動。在反應結束時,將混合物以乙酸淬滅且蒸餾出乙醇。在添加水及乙酸乙酯之後,將相分離,將水相以乙酸乙酯萃取。將合併的有機相以1M NaHCO3溶液和水清洗,乾燥,過濾且蒸發。以未純化的粗製產物前進至下一步驟。
產量:636克(90%)淺棕色油。
NMR數據:(CDCl3),1H NMR(500MHz):7.125-7.04ppm(H-22,1),m(in:7.09ppm(H-22,0.5),t,J=7.8Hz;7.08ppm(H-22,0.5),t,J=7.8Hz);6.79-6.71ppm(H-21和H-23,2),m(in:6.760ppm(H-21,0.5),m(d),J=7.6Hz;6.754ppm(H-21,0.5),m(d),J=7.6Hz;6.738ppm(H-23,0.5),m(d),J~8.3Hz;6.735ppm(H-23,0.5),m(d),J=7.8Hz);4.63-4.52ppm(H-24,1),m(in:4.585ppm(H-24,0.5),m(dd),J=4.1Hz和3.1Hz;4.56ppm(H-24,0.5),m(dd),J=4.3Hz和2.9Hz);3.87ppm(H-28a,0.5),m(ddd);3.84-3.67ppm(H-2,H-11,H-15a和H-28a,5.5),m(in:3.805ppm(H-28a,0.5),m;3.80ppm(H-2,3),s;3.795ppm(H-15a,0.5),m;3.75ppm(H-15a,0.5),m;3.715ppm(H-11,1),td,J=9.8Hz和6.2Hz);3.54-3.46ppm(H-28b,1),m(in:3.50ppm(H-28b,0.5),m;3.48ppm(H-28b,0.5),m);3.46-3.36ppm(H-15b,1),m(in:3.43ppm(H-15b,0.5),dt,J=9.6Hz和6.2Hz;3.40ppm(H-15b,0.5),dt,J=9.6Hz和6.5Hz);2.82-2.70ppm(H-4a和H-7a,2),m(in:2.775ppm(H-4a,1),dd,J=14.6Hz和6.1Hz;2.746ppm(H-7a,0.5),m(dd),J=14.1Hz和6.2;2.741ppm(H-7a,0.5),m(dd),J=14.3Hz和6.2);2.54-2.41ppm(H-4b和H-7b,2),m(in:2.497ppm(H-4b,0.5),m(dd),J=14.7Hz和6.5Hz;2.492ppm(H-4b,0.5),m(dd),J=14.7Hz和6.4Hz;2.455ppm(H-7b,1),dd,J=14.3Hz和6.4Hz);2.30-2.04ppm(H-9,H-10和OH-11,2.5),m(in:2.249ppm(H-9,0.5),m(tt),J=10.3Hz和6.9Hz;2.214ppm(H-9,0.5),m(tt),J=10.0Hz和6.8Hz;2.16ppm(H-10a,1),m(dt/ddd),J=12.0Hz,7.1Hz和6.3Hz;2.15ppm(OH-11,0.5),寬峰);2.00ppm(OH-11,0.5),1.93-1.64ppm(H-8,H-14,H-25a和H-26a,5),m(in:1.88ppm(H-8,1),m(tt),J=10.0Hz和6.3Hz;1.82ppm(H-26a,0.5),m;1.795ppm(H-14a,
1),m;1.79ppm(H-26a,0.5),m;1.755ppm(H-14b,1),m;1.695ppm(H-25a,1),m);1.64-1.44ppm(H-13,H25b,H-26b和H-27,6),m(in:1.58ppm(H-13a,1),m;1.565ppm(H-25b,1),m;1.56ppm(H-13b,1),m;1.555ppm(H-27a,1),m;1.53ppm(H-26b,0.5),m;1.505ppm(H-27b,1),m;1.50ppm(H-26b,0.5),m);1.38-1.20ppm(H-12,1),m(in:1.32ppm(H-12,0.5),m,J~9.2Hz和6.6Hz;1.29ppm(H-12,0.5),m;J~9.2Hz和6.6Hz),1.19-1.08ppm(H-10,1),m(in:1.16ppm(H-10b,0.5),m(ddd),J~10.0Hz;1.12ppm(H-10b,0.5),m(ddd),J~10.0Hz);
13C NMR(125.8MHz):156.23ppm(C-3),140.64ppm和140.55ppm(C-6),127.04ppm和127.02ppm(C-5)126.20ppm(C-22),120.58ppm(C-23),108.43ppm和108.41ppm(C-21),99.09ppm和99.07ppm(C-24),77.37ppm(C-11),68.39ppm和68.36ppm(C-15),62.52ppm和62.42ppm(C-28),55.67ppm(C-2),51.96ppm(C-12),41.61ppm和41.41ppm(C-8),41.56ppm和41.53ppm(C-10),33.81ppm和33.76ppm(C-7),32.94ppm(C-9),30.81ppm和30.76ppm(C-25),29.90ppm和29.74ppm(C-13),27.73ppm和27.66ppm(C-14),25.83ppm(C-4),25.55ppm和25.52ppm(C-27),19.79ppm和19.69ppm(C-26)。
將636克MPK-7在惰性氛圍中溶解在1.4公升吡啶中且將508克對-苯基苯甲醯氯添加至溶液中。將反應混合物在50-60℃下攪拌。在反應結束時,添加水及甲基第三丁基醚,將相分離,將水相以甲基第三丁基醚萃取。將合併的有機相連續以NaHSO4溶液、K2CO3溶液
和水清洗,乾燥,過濾且蒸發。將粗製產物在矽膠上以使用己烷:乙酸乙酯之混合物作為溶析劑的層析術純化。
產量:763克(80%)白色晶體。Mp:140-143℃。
NMR數據:(CDCl3),1H NMR(500MHz):8.06ppm(H-31和H-31’,2),d,J=8.4Hz;7.66-7.58ppm(H-32,H-32’,H-35和H-35’,4),m(in:7.63ppm(H-32和H-32’,2),m(d),J=8.5Hz;7.61ppm(H-35和H-35’,2),m(d),J=7.3Hz);7.46ppm(H-36和H-36’,2),m(t),J=7.5Hz;7.39ppm(H-37,1),m(t),J=7.4Hz;7.14ppm(H-22,1),t,J=7.8Hz;6.82ppm(H-23,1),m(d/d寬峰),J=7.4Hz;6.77ppm(H-21,1),d,J=8.2Hz;5.03ppm(H-11,1),td,J=8.4Hz和6.3Hz;4.565ppm(H-24,1),m;3.895-3.79ppm(H-2和H-28a,4),m(in:3.85ppm(H-28a,1),m;3.82ppm(H-2,3),s);3.79-3.72ppm(H-15a,1),m(in:3.758ppm(H-15a,0.5),dt,J=9.7Hz和6.6Hz;3.752ppm(H-15a,0.5),dt,J=9.7Hz和6.5Hz);3.48ppm(H-28b,1),m;3.45-3.375ppm(H-15b,1),m(in:3.416ppm(H-15b,0.5),dt,J=9.6Hz和6.6Hz;3.410ppm(H-15b,0.5),dt,J=9.6Hz和6.4Hz);2.95-2.81ppm(H-4a和H-7a,2),m(in:2.91ppm(H-4a,1),dd,J=14.9Hz和6.2Hz;2.85ppm(H-7a,1),dd,J=14.5Hz和6.3);2.635-2.34ppm(H-4b,H-7b,H-9和H-10a,4),m(in:2.589ppm(H-7b,0.5),m(dd),J=14.4Hz和6.9Hz;2.587ppm(H-7b,0.5),m(dd),J=14.6Hz和7.0Hz;2.535ppm(H-4b,1),dd,J=14.9Hz和7.2Hz;2.48ppm(H-10a,1),m(ddd),J=6.4Hz;2.40ppm(H-9,1),m,J~7.7Hz);2.03ppm(H-8,1),m(tt),J=9.1Hz和6.8Hz;1.88-1.45ppm(H-12,H-13,H-14,H-25,H-26和H-27,11),m(in:1.83ppm(H-12,1),m;1.81ppm(H-26a,1),m;1.77ppm(H-14a,1),m;1.74ppm(H-14b,1),m;1.69ppm(H-25a,1),m;1.63ppm(H-13a,1),m;1.60ppm(H-13b,1),m;1.57ppm(H-25b,1),m;1.55ppm(H-27a,1),m;1.51ppm(H-27b,1),m;1.50ppm(H-26b,1),m);1.385ppm(H-10b,1),dt,J=12.3Hz和8.7Hz;13C NMR(125.8MHz):166.44ppm(C-29),156.64ppm(C-3),145.64ppm(C-33),140.26ppm(C-6);140.21ppm(C-34),130.20ppm(C-31 és C-31’,2),129.44ppm(C-30),129.03ppm(C-36和C-36’,2),128.21
ppm(C-37),127.39ppm(C-35和C-35’,2),127.12ppm(C-32和C-32’,2),126.83ppm(C-5),126.33ppm(C-22),120.58ppm和120.57ppm(C-23),108.42ppm(C-21),99.02ppm(C-24),80.04ppm和80.00ppm(C-11),67.88ppm和67.84ppm(C-15),62.51ppm和62.49ppm(C-28),55.65ppm(C-2),49.58ppm(C-12),41.00ppm和40.99ppm(C-8),38.00ppm(C-10),33.85ppm(C-9),33.80ppm(C-7),30.89ppm和30.88ppm(C-25),29.61ppm和29.58ppm(C-13),27.91ppm和27.89ppm(C-14),25.92ppm(C-4),25.61ppm(C-27),19.81ppm和19.80ppm(C-26)。
將574克MPK-8溶解在1.2公升四氫呋喃中。添加4.6公升甲醇且接著小心地添加145毫升濃縮氫氯酸與145毫升水之混合物。在反應結束時,將混合物以1M NaHCO3溶液淬滅且蒸餾出溶劑。將殘餘水相以乙酸乙酯萃取,將合併的有機相以水清洗,乾燥,過濾且蒸發。將蒸發之粗製產物在矽膠上以層析術純化。
產量:376克(78%)無色油。
NMR數據:(CDCl3),1H NMR(500MHz):8.05ppm(H-31和H-31’,2),d,J=8.4Hz;7.67-7.57ppm(H-32,H-32’,H-35和H-35’,4),m(in:7.63ppm(H-32和H-32’,2),m(d),J=8.4Hz;7.605ppm(H-35和H-35’,2),m(d),J=7.2Hz);7.46ppm(H-36和H-36’,2),m(t),J=7.5Hz;7.39ppm(H-37,1),m(t),J=7.3Hz;7.14ppm(H-22,1),t,J=7.8Hz;6.81ppm(H-23,1),d,J=7.4Hz;6.78ppm(H-21,1),d,J=8.2Hz;5.05ppm(H-11,1),td,J=8.3Hz和6.3Hz;3.82ppm(H-2,3),s,3.66ppm(H-15,
2),m;2.94-2.80ppm(H-4a和H-7a,2),m(in:2.90ppm(H-4a,1),dd,J=14.9Hz和6.1Hz;2.845ppm(H-7a,1),dd,J=14.5Hz和6.3);2.63-2.50ppm(H-4b和H-7b,2),m(in:2.58ppm(H-7b,1),dd,J=14.6Hz和6.8Hz;2.55ppm(H-4b,1),dd,J=15.0Hz和7.0Hz);2.50-2.35ppm(H-9和H-10a,2),m(in:2.465ppm(H-10a,1),m(ddd),J=12.3Hz,7.6Hz和6.3Hz;2.40ppm(H-9,1),m,J~7.6Hz);2.03ppm(H-8,1),m(tt),J=8.9Hz和6.9Hz,1.81ppm(H-12,1),m(tt),J=8.2Hz和6.7Hz;1.77-1.45ppm(H-13和H-14,4),m(in:1.73ppm(H-14a,1),m;1.70ppm(H-14b,1),m;1.625ppm(H-13a,1),m;1.60ppm(H-13b,1),m),1.39ppm(H-10b,1),dt,J=12.2Hz和8.6Hz,
13C NMR(125.8MHz):166.50ppm(C-29),156.66ppm(C-3),145.72ppm(C-33),140.16ppm(C-6和C-34,2);130.20ppm(C-31和C-31’,2),129.33ppm(C-30),129.04ppm(C-36和C-36’,2),128.24ppm(C-37),127.39ppm(C-35和C-35’,2),127.16ppm(C-32和C-32’,2),126.78ppm(C-5),126.37ppm(C-22),120.58ppm(C-23),108.45ppm(C-21),79.86ppm(C-11),63.29ppm(C-15),55.65ppm(C-2),49.36ppm(C-12),40.96ppm(C-8),37.98ppm(C-10),33.76ppm(C-9),33.69ppm(C-7),30.77ppm(C-14),28.98ppm(C-13),25.88ppm(C-4)。
將140毫升草醯氯在惰性氛圍中溶解在4.2公升二氯甲烷中。將溶液冷卻至(-)-60℃且添加在1130毫升二氯甲烷中的227毫升二甲基亞碸之溶液,且接著在攪拌之後添加在690毫升二氯甲烷中的376克MPK-9之溶液。持續在(-)-60℃下攪拌。在反應結束時,將混合物以添加830毫升三乙胺淬滅。將混合物攪動1小時而不冷卻,接著將溫
度上升至10℃且添加1M NaHSO4溶液。將水相以二氯甲烷萃取,將合併的有機相以水清洗,乾燥且蒸發。將粗製產物先在矽膠管柱上以使用己烷:乙酸乙酯之混合物作為溶析劑的層析術及接著自甲苯:己烷之混合物結晶而純化。
產量:374克(100%)白色晶體。Mp:94-96℃。
NMR數據:(CDCl3),1H NMR(500MHz):9.78ppm(H-15,1),t,J=1.3Hz;8.05ppm(H-31和H-31’,2),m(d),J=8.5Hz;7.68-7.57ppm(H-32,H-32’,H-35和H-35’,4),m(in:7.64ppm(H-32和H-32’,2),m(d),J=8.5Hz;7.61ppm(H-35和H-35’,2),m(d),J=7.0Hz);7.46ppm(H-36和H-36’,2),m(t),J=7.6Hz;7.39ppm(H-37,1),m(t),J=7.4Hz;7.15ppm(H-22,1),t,J=7.8Hz,6.82ppm(H-23,1),d,J=7.4Hz;6.78ppm(H-21,1),d,J=8.2Hz,5.02ppm(H-11,1),td,J=8.3Hz和6.3Hz;3.82ppm(H-2,3),s;2.935-2.79ppm(H-4a和H-7a,2),m(in:2.865ppm(H-4a,1),dd,J=14.9Hz和6.1Hz;2.835ppm(H-7a,1),dd,J=14.4Hz和6.3);2.65-2.53ppm(H-4b,H-7b和H-14,4),m(in:2.61ppm(H-14,2),ddd,J=7.6Hz,6.5Hz和1.1Hz;2.576ppm(H-7b,1),dd,J=14.5Hz和6.3Hz;2.568ppm(H-4b,1),dd,J=14.9Hz和6.5Hz);2.53-2.36ppm(H-9和H-10β,2),m(in:2.485ppm(H-10β,1),ddd,J=12.1Hz,7.6Hz和6.4Hz;2.42ppm(H-9,1),m);2.075-1.89ppm(H-8和H-13a,2),m(in:2.02ppm(H-8,1),m,1.94ppm(H-13a,1),m);1.85-1.73ppm(H-12和H-13b,2),m(in:1.80ppm(H-14b,1),m;1.79ppm(H-12,1),m);1.345ppm(H-10α,1),dt,J=12.2Hz和8.8Hz,13C NMR(125.8MHz):202.22ppm(C-15),166.33ppm(C-29),156.71ppm(C-3),145.85ppm(C-33),140.11ppm(C-34);139.82ppm(C-6),130.20ppm(C-31和C-31’,2),129.11ppm(C-30),129.06ppm(C-36和C-36’,2),128.28ppm(C-37),127.40ppm(C-35和C-35’,2),127.21ppm(C-32和C-32’,2),126.60ppm(C-5),126.46ppm(C-22),120.66ppm(C-23),108.54ppm(C-21),79.48ppm(C-11),55.65ppm(C-2),48.70ppm(C-12),41.95ppm(C-14),40.79ppm(C-8),37.91ppm(C-10),33.53ppm(C-9),33.29ppm(C-7),25.73ppm(C-4),24.69ppm(C-13)。
將7.5克MIB*觸媒添加至惰性氛圍中的4.5公升蒸餾之甲苯中且接著添加1800毫升二戊基鋅。將混合物在室溫下攪動。在攪動1小時之後,在室溫下添加在1.5公升蒸餾之甲苯中的300克MPK-10之溶液且將混合物攪拌,直到進行偶合反應。接著將反應混合物在劇烈攪動下倒在氫氯酸溶液上。持續攪拌,直到鋅鹽完全分解,接著產物以乙酸乙酯萃取。將有機相以水和氯化鈉飽和溶液清洗且接著蒸發。將粗製產物在矽膠管柱上以使用甲苯:甲基第三丁基醚之混合物作為溶析劑的梯度層析術純化。
產量:300克(86%)黃色油。
NMR數據:(CDCl3),1H NMR(500MHz):8.05ppm(H-31和H-31’,2),m(d),J=8.3Hz;7.68-7.53ppm(H-32,H-32’,H-35和H-35’,4),m(in:7.63ppm(H-32和H-32’,2),m(d),J=8.3Hz;7.605ppm(H-35和H-35’,2),m(d),J=7.5Hz),7.46ppm(H-36和H-36’,2),m(t),J=7.6Hz,7.39ppm(H-37,1),m(t),J=7.3Hz,7.14ppm(H-22,1),t,J=7.8Hz,6.82ppm(H-23,1),d,J=7.4Hz;6.78ppm(H-21,1),d,J=8.2Hz,5.05
ppm(H-11,1),td,J=8.2Hz和6.4Hz,3.82ppm(H-2,3),s,3.61ppm(H-15,1),m;2.955-2.80ppm(H-4a和H-7a,2),m(in:2.905ppm(H-4a,1),dd,J=14.9Hz和6.1Hz;2.85ppm(H-7a,1),dd,J=14.5Hz和6.3),2.66-2.51ppm(H-4b和H-7b,2),m(in:2.585ppm(H-7b,1),dd,J=14.5Hz和6.8Hz;2.54ppm(H-4b,1),dd,J=15.1Hz和7.0Hz),2.51-2.35ppm(H-9和H-10a,2),m(in:2.47ppm(H-10a,1),ddd,J=12.3Hz,7.6Hz和6.4Hz;2.41ppm(H-9,1),m),2.03ppm(H-8,1),m(tt),J=9.0Hz和6.8Hz,1.81ppm(H-12,1),m,1.75-1.48ppm(H-13和H-14,4),m(in:1.675ppm(H-13a,1),m;1.62ppm(H-14a,1),m;1.59ppm(H-13b,1),m;1.545ppm(H-14b,1),m);1.48-1.33ppm(H-10b,H-16,H-17a和OH-15,5),m(in:1.43ppm(H-16a,1),m;1.41ppm(H-17a,1),m;1.40ppm(H-16b,1),m;1.39ppm(H-10b,1),m),1.33-1.17ppm(H-17b,H-18和H-19,5),m(in:1.28ppm(H-19,2),m;1.27ppm(H-17b,1),m;1.26ppm(H-18,2),m),0.86ppm(H-20,3),m(t),J=6.8Hz,
13C NMR(125.8MHz):166.46ppm(C-29),156.67ppm(C-3),145.70ppm(C-33),140.21ppm/140.14ppm(C-6/C-34),130.20ppm(C-31和C-31’,2),129.39ppm(C-30),129.04ppm(C-36和C-36’,2),128.24ppm(C-37),127.40ppm(C-35和C-35’,2),127.13ppm(C-32和C-32’,2),126.82ppm(C-5),126.36ppm(C-22),120.60ppm(C-23),108.45ppm(C-21),79.83ppm(C-11),73.13ppm(C-15),55.66ppm(C-2),49.41ppm(C-12),40.94ppm(C-8),38.03ppm(C-10),37.55ppm(C-16),35.11ppm(C-14),33.78ppm(C-9),33.67ppm(C-7),32.02ppm(C-18),28.53ppm(C-13),25.92ppm(C-4),25.43ppm(C-17),22.76ppm(C-19),14.16ppm(C-20)。
將267克鋅-銅合金(10%之銅,90%之鋅)添加至550克凡士林中。將混合物在惰性氛圍中加熱至約60℃,接著開始攪動且將混合物加熱至160℃。在連續回流及強力冷卻下添加188毫升1-戊基碘與186毫升1-戊基溴之混合物。在添加之後持續攪動1小時,同時保持溫度。接著將混合物冷卻至約60℃。在110-150℃之內溫及0.5-1.5毫巴真空下蒸餾出產物。
2l.2)製備4-苯基苯甲酸[(1R,2R,9aS)-1-[(3S)-3-羥基辛基]-5-甲氧基-2,3,3a,4,9,9a-六氫-1H-環戊[b]萘-2-基]酯(PPB-TREP-14)
將1.3毫升Ti(OiPr)4溶解在16毫升二氯甲烷中,且在冷卻至(-)70℃之後,將1.1毫升(2.2毫莫耳)戊基溴化鎂(在二乙醚中的2M溶液)添加至混合物中。將100毫克(0.22毫莫耳)MPK-10、10毫克(R)-(+)-1,1'-聯(2-萘酚)及0.4毫升Ti(OiPr)4溶解在4毫升二氯甲烷中,將溶液冷卻至0/+5℃且將戊基溴化鎂試劑溶液添加至其中。在0/+5℃下持續攪拌。在反應結束時,小心地添加2毫升1:1之氫氯酸-水混合物。將相分離,將有機相以5毫升水清洗,乾燥且蒸發。粗製產物含有0-20%之15-表-PPB-TREP-14異構物。將產物在矽膠以使用己烷:乙酸乙酯之混合物作為溶析劑的層析術純化。
產量:90毫克(77%)黃色油。
將250克PPB-TREP-14溶解在1公升四氫呋喃中,將2.5公升甲醇及150克碳酸鉀添加至溶液中且將將混合物在45℃下攪拌。在反應結束時,將混合物pH以稀釋的磷酸設定至2-4。濾出沉澱之晶體且以甲醇清洗。將過濾物溶液濃縮,將乙酸乙酯添加至濃縮產物中,
將相分離,將水相以乙酸乙酯萃取,將合併的有機相以氯化鈉溶液清洗且蒸發。將粗製產物在矽膠管柱上以使用己烷:乙酸乙酯之混合物作為溶析劑的層析術純化。在二異丙醚:己烷之混合物中結晶出蒸發之主要流份。
產量:125克(76%)白色晶體。Mp:71-72℃。
Claims (23)
- 一種製備式I之曲前列環素(treprostinil)及以鹼得到的其非晶形鹽形式、鹽類無水物、及鹽類單水合物和多水合物之方法
- 根據申請專利範圍第1項之方法,其特徵在於使用甲氧基甲基、甲氧基乙氧基甲基或四氫哌喃基作為R1保護基,使用甲基作為R2保護基,使用含有矽原子之保護基作為R3保護基,使用對-苯基苯甲醯基作為R4保護基。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟a1)中,使用甲基-、乙基-、丙基-、丁基-、環己基-溴化鎂作為格任亞試劑。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟a1)中,該式XV化合物之氧化反應係以史旺(Swern)氧化反應進行。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟a1)中,該還原反應係在掌性氧氮硼雜環戊烷觸媒的存在下以硼烷化合物進行。
- 根據申請專利範圍第5項之方法,其特徵在於使用硼烷-二甲硫醚複合物、兒茶酚硼烷或硼烷-二乙基苯胺複合物作為硼烷化合物。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟a2)中,使用掌性胺醇或二胺作為掌性鹼。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟a2)中,使用三氟甲磺酸鋅作為鋅鹽。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟b)中,該分子內環化作用係以葆森-侃德(Pauson-Khand)環化法進行。
- 根據申請專利範圍第9項之方法,其特徵在於該葆森-侃德環化法係使用八羰基二鈷進行。
- 根據申請專利範圍第10項之方法,其特徵在於八羰基二鈷係以等莫耳量或少於等莫耳量或大於等莫耳量使用。
- 根據申請專利範圍第9-11項中任一項之方法,其特徵在於該反應係在一氧化碳氛圍下進行。
- 根據申請專利範圍第9-11項中任一項之方法,其特徵在於該反應係在乙酸乙酯中進行。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟c)中,使用Pd/C或氧化鈀觸媒作為該式XI化合物氫化作用之觸媒。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟d)中,該式X化合物之還原反應係以二異丁基氫化鋁、鋁氫化鋰、異丙醇鋁或硼氫化鈉 進行。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟e)中,使用對-苯基苯甲醯氯作為適合於引入基團R4之化合物。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟g)中,該式VII化合物之氧化反應係在史旺條件下、或以TEMPO、或在普菲茨納-莫法特(Pfitzner-Moffat)條件下進行。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟h1)中,該式V化合物之還原反應係在氧氮硼雜環戊烷觸媒的存在下以硼烷化合物進行。
- 根據申請專利範圍第18項之方法,其特徵在於使用兒茶酚硼烷、硼烷-二乙基苯胺複合物、硼烷-二甲硫醚複合物作為硼烷化合物。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟i)中,該所使用之觸媒為氧化鈀觸媒或Pd/C觸媒。
- 根據申請專利範圍第1項之方法,其特徵在於在步驟h1)或h2)中,該R4保護基之裂解係在鹼的存在下以甲醇解(methanolysis)進行。
- 一種曲前列環素中間物,其選自具有通式III、IV或V之化合物在式III中,
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HU231296B1 (hu) * | 2018-03-09 | 2022-09-28 | Chinoin Zrt | Eljárás treprostinil-dietanol-amin só B polimorf formájának előállítására |
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