CN107001221A - 用于制备曲前列尼尔的方法 - Google Patents
用于制备曲前列尼尔的方法 Download PDFInfo
- Publication number
- CN107001221A CN107001221A CN201580066416.6A CN201580066416A CN107001221A CN 107001221 A CN107001221 A CN 107001221A CN 201580066416 A CN201580066416 A CN 201580066416A CN 107001221 A CN107001221 A CN 107001221A
- Authority
- CN
- China
- Prior art keywords
- group
- formula
- represent
- compound
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960005032 treprostinil Drugs 0.000 title claims abstract description 90
- 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 89
- 238000000034 method Methods 0.000 title claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- -1 salt anhydride Chemical class 0.000 claims description 222
- 150000001875 compounds Chemical class 0.000 claims description 136
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 129
- 239000000203 mixture Substances 0.000 claims description 122
- 239000002585 base Substances 0.000 claims description 55
- 238000006243 chemical reaction Methods 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- 239000000376 reactant Substances 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 38
- 229910052710 silicon Inorganic materials 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 239000003513 alkali Substances 0.000 claims description 33
- 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 33
- 239000003054 catalyst Substances 0.000 claims description 31
- 239000013078 crystal Substances 0.000 claims description 29
- 239000012298 atmosphere Substances 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 159000000000 sodium salts Chemical class 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 229910017052 cobalt Inorganic materials 0.000 claims description 13
- 239000010941 cobalt Substances 0.000 claims description 13
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 13
- 230000009467 reduction Effects 0.000 claims description 13
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 12
- 230000003647 oxidation Effects 0.000 claims description 12
- 238000007254 oxidation reaction Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000006647 Pauson-Khand annulation reaction Methods 0.000 claims description 10
- 229910052796 boron Inorganic materials 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 150000002118 epoxides Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 229910000085 borane Inorganic materials 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 7
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 7
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- RGBMRUSMRXNIDE-UHFFFAOYSA-N carbonic acid;sodium;hydrate Chemical compound O.[Na].OC(O)=O RGBMRUSMRXNIDE-UHFFFAOYSA-N 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 5
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 5
- 150000004682 monohydrates Chemical class 0.000 claims description 5
- 125000002524 organometallic group Chemical group 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 150000003751 zinc Chemical class 0.000 claims description 5
- 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 claims description 4
- MPJOJCZVGBOVOV-UHFFFAOYSA-N 2-phenylbenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1C1=CC=CC=C1 MPJOJCZVGBOVOV-UHFFFAOYSA-N 0.000 claims description 4
- CRIGZHQSHKIPFT-UHFFFAOYSA-N CCCCC[Zn]CCCCC Chemical compound CCCCC[Zn]CCCCC CRIGZHQSHKIPFT-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 238000007239 Wittig reaction Methods 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
- 238000006317 isomerization reaction Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- NGOCMUBXJDDBLB-UHFFFAOYSA-N trifluoromethanesulfonic acid;zinc Chemical compound [Zn].OS(=O)(=O)C(F)(F)F NGOCMUBXJDDBLB-UHFFFAOYSA-N 0.000 claims description 4
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- DTGKSKDOIYIVQL-MRTMQBJTSA-N Isoborneol Natural products C1C[C@@]2(C)[C@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-MRTMQBJTSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 claims description 3
- 238000005336 cracking Methods 0.000 claims description 3
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 claims description 3
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 3
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 3
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 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
- 150000001414 amino alcohols Chemical class 0.000 claims description 2
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 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
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 6
- 229910052738 indium Inorganic materials 0.000 claims 2
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 claims 1
- 238000005835 Pfitzner-Moffat oxidation reaction Methods 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 238000000151 deposition Methods 0.000 claims 1
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 238000010276 construction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 109
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 87
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 82
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 54
- 229940093499 ethyl acetate Drugs 0.000 description 40
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-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 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- 239000003921 oil Substances 0.000 description 22
- 239000012043 crude product Substances 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 239000012071 phase Substances 0.000 description 17
- 239000003480 eluent Substances 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- 150000002148 esters Chemical class 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- 229960001866 silicon dioxide Drugs 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000013019 agitation Methods 0.000 description 11
- 0 CC1C(C)*CC1 Chemical compound CC1C(C)*CC1 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical class C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- KXYGKDBONOVZOM-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene Chemical group C1=CC=CC2=C3CC=CC3=CC=C21 KXYGKDBONOVZOM-UHFFFAOYSA-N 0.000 description 6
- 150000008064 anhydrides Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 4
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- VMKAFJQFKBASMU-KRWDZBQOSA-N (3as)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole Chemical compound C([C@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-KRWDZBQOSA-N 0.000 description 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
- 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 101001059431 Mus musculus MAP/microtubule affinity-regulating kinase 3 Proteins 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000002045 lasting effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- JTHLRRZARWSHBE-UHFFFAOYSA-N pent-4-yn-2-ol Chemical compound CC(O)CC#C JTHLRRZARWSHBE-UHFFFAOYSA-N 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- PMJHHCWVYXUKFD-SNAWJCMRSA-N (E)-1,3-pentadiene Chemical compound C\C=C\C=C PMJHHCWVYXUKFD-SNAWJCMRSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 101100495328 Mus musculus Cdk7 gene Proteins 0.000 description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 238000006859 Swern oxidation reaction Methods 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 150000002561 ketenes Chemical class 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 238000011916 stereoselective reduction Methods 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229920001187 thermosetting polymer Polymers 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical class COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- PPNCOQHHSGMKGI-UHFFFAOYSA-N 1-cyclononyldiazonane Chemical compound C1CCCCCCCC1N1NCCCCCCC1 PPNCOQHHSGMKGI-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical class CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- VGWCMMMUQPLVGN-UHFFFAOYSA-N 9h-cyclopenta[b]naphthalene Chemical compound C1=CC=C2CC3=CC=CC3=CC2=C1 VGWCMMMUQPLVGN-UHFFFAOYSA-N 0.000 description 1
- 229910000906 Bronze Inorganic materials 0.000 description 1
- DRTRPRQZTUZROQ-OHUBXFBSSA-N CCCCCC(CCC(C1)C(C[C@H](C)O)Cc2c1cccc2[O]=C)O Chemical compound CCCCCC(CCC(C1)C(C[C@H](C)O)Cc2c1cccc2[O]=C)O DRTRPRQZTUZROQ-OHUBXFBSSA-N 0.000 description 1
- HHLMLPXOMTXZRL-INCJBFHASA-N CCCCCC(CCC([C@@H](C1)O)C(CC2=CCC3)C1CC2=C3C=O)O Chemical compound CCCCCC(CCC([C@@H](C1)O)C(CC2=CCC3)C1CC2=C3C=O)O HHLMLPXOMTXZRL-INCJBFHASA-N 0.000 description 1
- ZKGOHOFYAXICSP-UHFFFAOYSA-N COCOCCC(c1c(CC=C)c(OC)ccc1)=O Chemical compound COCOCCC(c1c(CC=C)c(OC)ccc1)=O ZKGOHOFYAXICSP-UHFFFAOYSA-N 0.000 description 1
- AHOJIADBHYSOEX-SBXXRYSUSA-N C[C@](C1)(C=C(C2)C1Cc1c2cccc1O)O Chemical compound C[C@](C1)(C=C(C2)C1Cc1c2cccc1O)O AHOJIADBHYSOEX-SBXXRYSUSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910000881 Cu alloy Inorganic materials 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- KKUKTXOBAWVSHC-UHFFFAOYSA-N Dimethylphosphate Chemical compound COP(O)(=O)OC KKUKTXOBAWVSHC-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- FEMUGDLJTLOACG-UHFFFAOYSA-N O1NBCC1.CCCCC Chemical compound O1NBCC1.CCCCC FEMUGDLJTLOACG-UHFFFAOYSA-N 0.000 description 1
- 208000020193 Pulmonary artery hypoplasia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- AGOHFSTXLQFGLL-UHFFFAOYSA-N [Mg].[Br-].C(C)[PH3+] Chemical compound [Mg].[Br-].C(C)[PH3+] AGOHFSTXLQFGLL-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical class Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000010405 anode material Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical class OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 1
- MKJQIOMCOYQKNP-UHFFFAOYSA-N bromomethane;magnesium Chemical compound [Mg].BrC MKJQIOMCOYQKNP-UHFFFAOYSA-N 0.000 description 1
- 239000010974 bronze Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- NGPGYVQZGRJHFJ-UHFFFAOYSA-N chembl1604790 Chemical compound OC1=CC(O)=CC=C1N=NC1=CC=C([N+]([O-])=O)C=C1 NGPGYVQZGRJHFJ-UHFFFAOYSA-N 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical compound [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 description 1
- KUNSUQLRTQLHQQ-UHFFFAOYSA-N copper tin Chemical compound [Cu].[Sn] KUNSUQLRTQLHQQ-UHFFFAOYSA-N 0.000 description 1
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- ZNKWHSAIKLCIFO-UHFFFAOYSA-N dimethyl 2-oxoheptyl phosphate Chemical class CCCCCC(=O)COP(=O)(OC)OC ZNKWHSAIKLCIFO-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N dimethylsulfide Substances CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- NCCOOTMRZHTROF-UHFFFAOYSA-N ethylphosphanium;bromide Chemical class [Br-].CC[PH3+] NCCOOTMRZHTROF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical class [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical class O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000006207 phenyl benzoyl methyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(=O)C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/243—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/54—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings
- C07C13/547—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings at least one ring not being six-membered, the other rings being at the most six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/37—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with a hydroxy group on a condensed system having three rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/05—Preparation of ethers by addition of compounds to unsaturated compounds
- C07C41/06—Preparation of ethers by addition of compounds to unsaturated compounds by addition of organic compounds only
- C07C41/08—Preparation of ethers by addition of compounds to unsaturated compounds by addition of organic compounds only to carbon-to-carbon triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/48—Preparation of compounds having groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/30—Compounds having groups
- C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
- C07C45/305—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation with halogenochromate reagents, e.g. pyridinium chlorochromate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/50—Use of additives, e.g. for stabilisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrane Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明提供了一种用于制备式(I)的曲前列尼尔及其盐的新方法,其在环系统的建造的过程中使用若干种新的中间体。
Description
本发明涉及式I的曲前列尼尔(treprostinil)及其与碱的无定形形式 (amorph)、无水物(anhydrate)、一水合物(monohydrate)和多水合物(polyhydrate) 盐的制备,涉及通式III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、 XIV和XV的曲前列尼尔中间体并涉及其制备。
曲前列尼尔是一种具有血小板聚集抑制和舒血管活性的合成的前列环素衍生物,其可以皮下、静脉内、吸入或口服形式施用。
其治疗领域为肺动脉高压(Pulmonary Arterial Hypertension,PAH)的治疗(Drugs,2012,72(18)2351-2363)。
对于曲前列尼尔的苯并茚结构部分的构建而言,若干方法是已知的。迄今为止描述的合成路线的概述已经公开在Drugs of the Future,2001,26(4) 364-374中。
比较这些合成路线,描述在专利说明书WO99/21830 A1中的 Pauson-Khand环化似乎是用于构建环系统最有效的方法。
根据专利说明书WO 99/21830 A1(US 6441245 B1)中描述的实施例,通过图1中概述的反应路线合成苯并茚关键中间体。
图1在描述部分的末端,实施例之前进行了展示。
然后通过如在描述部分的末端,实施例之前展示的图2中所示的已知化学反应将关键中间体转化成曲前列尼尔。
在专利说明书WO 2009/158010 A1中,公开了氘化的曲前列尼尔衍生物的制备。
闭环通过Pauson-Khand环化进行。在该案例中,具有三键的链也由至少7个碳原子构成。由Pauson-Khand环化生成的分子已经含有曲前列尼尔侧链(图3)。
图3
-其中Z(1,3,4)’和Y(1,2,3)’表示氢或氘
-其中R1’是任选含有1个或多个氘的苯基。
专利说明书WO 2011/153363 A1和WO 99/21830 A1中所述的方法之间的区别如下:
含有三键的侧链与醛的偶联是在手性催化剂((+)-N-甲基麻黄碱)的存在下进行,以在一个步骤中获得手性醇而不形成外消旋醇的方式进行。以该方式,去除了一个氧化步骤和立体选择性还原。
已经降低了八羰基二钴的量(仅使用了2-15mol%而不是等摩尔比)并且闭环是在一氧化碳压力下进行。
全合成方案呈现在描述部分的末端,实施例之前的图4中。
专利说明书WO 2012/009816 A1中描述的合成也使用了Pauson-Khand 环化来形成苯并茚环。该合成中的新颖性在于酚羟基被对甲氧基苄基(PMB) 保护基保护。
在该案例中,具有三键的侧链也含有至少7个碳原子。
由Pauson-Khand环化形成的分子将已经含有曲前列尼尔侧链。
全合成方案呈现在描述部分的末端,实施例之前的图5中。
曲前列尼尔盐的合成在专利说明书WO 2009/078965 (PCT/US2008/013686)(United Therapeutics)中详细地给出。其描述了结晶性二乙醇胺盐的制备。
根据该方法,经由苯并茚结构的芳族羟基的烷基化获得苯并茚腈。(图 6)
图6
所述苯并茚腈被水解成曲前列尼尔,并且在未经分离的情况下转化成结晶性二乙醇胺盐。(图7)
图7
通过用酸处理从曲前列尼尔二乙醇胺盐释放曲前列尼尔。(图8)
图8
在分离各相之后,蒸发乙酸乙酯相,将残余物用含水乙醇结晶,经过滤收集并干燥。
通过二乙醇胺盐纯化是如此有效的,以至于无需通过色谱法纯化苯并茚腈衍生物。
可以用各种碱将高纯度曲前列尼尔转化成期望的高纯度盐。
钠盐形成的详细描述描述于专利说明书WO 2012/088607中。
根据该说明书,将苯并茚衍生物用溴乙酸甲酯烷基化,并通过使用氢氧化钾在甲醇-水溶剂混合物中的溶液将所得曲前列尼尔甲酯未经纯化地水解成曲前列尼尔。
然后将反应混合物用盐酸酸化,滤出析出的白色固体,用甲醇-水混合物洗涤,真空干燥并转化成钠盐。(图9)
图9
我们的目的是详述一种方法,其中下部链中的手性中心仅在合成的末尾才构造出来,并且该方法是稳健的(robust)并且具有良好的可扩展性(well scalable)。
本发明的主题是一种用于制备式I的曲前列尼尔及其与碱的无定形形式、无水物盐以及其一水合物和多水合物的方法
其特征在于,
a.)通式XVII的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团-,
前提条件是R1保护基必须可选择性地从R2和R4移除,且
x表示0或2-,
和通式XVI的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基- 二(C6-10)芳基甲硅烷基-基团并且n表示1、2、3、4-,
a1.)在格氏试剂的存在下反应,并且将所得到的通式XV的化合物
-其中在该式中x、R1和R2的含义如上面所定义-
氧化,和
将所得到的通式XIV的化合物
-其中在该式中x、R1和R2的含义如上面所定义-
选择性地还原,或
a2.)在手性碱和锌盐的存在下反应,和
将步骤a1.)或a2.)中获得的通式XIII的化合物
-其中在该式中x、R1和R2的含义如上面所定义-
与适合于引入基团R3的化合物反应
-其中R3表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-或 C1-13酰基-基团-,
b.)使所得到的通式XII的化合物
-其中在该式中x、R1、R2和R3的含义如上面所定义-
经历分子内环化,
c.)将所得到的通式XI的化合物
-其中在该式中x、R1、R2和R3的含义如上面所定义-
催化氢化,并且在其中x=0的情况下,将其异构化,
d.)将所得到的通式X的化合物
-其中在该式中x、R1、R2的含义如上面所定义-,
还原,
e.)将所得到的通式IX的化合物
-其中在该式中x、R1和R2的含义如上面所定义-
与适合于引入基团R4的化合物反应
-其中R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,并且R1必须可选择性地从R4移除,
f.)在酸性介质中从所得到的通式VIII的化合物
-其中在该式中x、R1、R2和R4的含义如上面所定义-
裂解R1保护基,
g)将所得到的通式VII的化合物
-其中在该式中x、R2和R4的含义如上面所定义-
氧化,
h.)将所得到的通式VI的化合物
-其中在该式中x、R2和R4的含义如上面所定义-
h1.)在其中x表示0的情况下,与以下通式化合物在Wittig反应中反应
CH3-(CH2)4-CO-CH2-PO(OR6)2
-其中在该式中R6表示C1-4烷基-或苯基-基团-,和
将所得到的通式V的化合物
-其中在该式中R2和R4的含义如上面所定义-
选择性地还原,
将所得到的通式IVa.的化合物的保护基
-其中在该式中R2和R4的含义如上面所定义-
R4移除,
将所得到的通式III.的化合物
-其中在该式中R2的含义如上面所定义-
氢化,或
h2.)在其中x表示2的情况下,在手性催化剂的存在下与有机金属试剂反应,和
将所得到的通式IVb.的化合物的保护基R4
-其中在该式中R2和R4的含义如上面所定义-
R4移除,
i)将步骤h1.)或h2.)中获得的通式II.的化合物
-其中在该式中R2的含义如上面所定义-
通过已知方法转化为式I的曲前列尼尔,并且如果需要的话,转化为其与碱的无定形形式、无水物、一水合物和多水合物盐。
作为R1保护基,可优选应用甲氧基甲基-、甲氧基乙氧基甲基-或四氢吡喃基-基团;作为R2保护基,可应用甲基基团;作为R3保护基,可应用含有硅原子的保护基,优选叔丁基二甲基甲硅烷基基团;作为R4保护基,可应用对苯基苯甲酰基基团。
本发明还涉及通式II的光学活性化合物的制备
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基- 二(C6-10)芳基甲硅烷基-基团,和
n表示1、2、3、4。
根据本发明,可如此制备通式II.的化合物,使得通式III的化合物
-其中在该式中R2的含义如上面所定义-
被氢化,或
通式IVb.的化合物的R4保护基
-其中在该式中R2的含义如上面所定义,和
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除-
被移除。
通式III的化合物的氢化在催化剂的存在下进行。
作为催化剂,可应用氧化铂、Pd/C催化剂,优选Pd/C催化剂。
通式III的化合物
是新颖的
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基- 二(C6-10)芳基甲硅烷基-基团,和
n表示1、2、3、4-,
前提条件是-COOR5中的R5不能表示C1-4烷基。
可如此制备通式III的化合物,使得通式IVa.的化合物的R4保护基
-其中在该式中
R2具有上面所定义的含义,和
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除-
R4被移除。
含有硅原子的R4保护基优选苯基二甲基甲硅烷基-、三乙基甲硅烷基-、三异丙基甲硅烷基-、叔丁基二甲基甲硅烷基-或叔丁基二苯基甲硅烷基-基团。
R4保护基的移除通过在碱的存在下的甲醇解进行。
通式IV的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基- 二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,和
虚线表示单键或双键-
是新颖的化合物。
可如此制备通式IVa.的新颖的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基- 二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,和
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,
使得通式V的化合物
-其中在该式中R2和R4的含义如上面所定义-
被选择性地还原。
式V的化合物的还原在氧氮硼杂环戊烷(oxazaborolidine)催化剂的存在下用硼烷化合物进行。
作为硼烷化合物,应用儿茶酚硼烷、硼烷-二乙基苯胺络合物、硼烷-二甲基硫醚络合物,优选硼烷-二甲基硫醚络合物。
通式V的化合物是新颖的。
可如此制备通式V的新颖的化合物,使得通式VIa.的化合物
-其中在该式中R2和R4的含义如上面所定义-
与如下通式化合物在Wittig反应中反应
CH3-(CH2)4-CO-CH2-PO(OR6)2
-其中在该式中R6表示C1-4烷基-或苯基-基团。
可如此制备通式IVb.的新颖的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基- 二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,和
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,
使得通式VIb.的化合物
-其中在该式中
R2和R4具有如上面所定义的含义-,
在手性催化剂的存在下与有机金属试剂反应。
作为有机金属试剂,可应用二戊基锌或戊基溴化镁;作为手性催化剂,可应用(2S)-3-外-(吗啉代)异冰片。
通式VIa.和VIb.的化合物是新颖的。
可如此制备通式VI的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基- 二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,和
x表示0或2-,
使得通式VII的化合物
-其中在该式中
x、R2和R4具有如上面所定义的含义-
被氧化。
式VII的化合物的氧化用PCC(氯铬酸吡啶鎓)进行,或在Swern条件(草酰氯/DMSO/有机碱)下进行,或用TEMPO(2,2,6,6-四甲基-1-哌啶基氧基自由基)进行,或在Pfitzner-Moffat条件(DCC(二环己基碳二亚胺)/DMSO/酸)下进行。
通式VII的化合物是新颖的。
可如此制备通式VII的新颖的化合物,使得通式VIII的化合物的R1保护基
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
x、R2和R4具有如上面所定义的含义-
被在酸性介质中移除。
含有硅原子的保护基R1优选苯基二甲基甲硅烷基-、三乙基甲硅烷基-、三异丙基甲硅烷基-、叔丁基二甲基甲硅烷基-或叔丁基二苯基甲硅烷基-基团。
通式VII的化合物I是新颖的。
可如此制备通式VIII的新颖的化合物,使得通式IX.的化合物
-其中在该式中
x、R1和R2具有如上面所定义的含义-
与适合于引入基团R4的化合物反应。
作为适合于引入基团R4的化合物,优选应用对苯基苯甲酰氯。
通式IX的化合物是新颖的。
可如此制备通式IX的新颖的化合物,使得通式X的化合物
-其中在该式中
x、R1和R2具有如上面所定义的含义-
被还原。
通式X的化合物的还原可用二异丁基氢化铝、氢化铝锂、异丙醇铝或硼氢化钠,优选硼氢化钠进行。
可如此制备通式X的新颖的化合物,使得通式XI的化合物
-其中在该式中
x、R1和R2具有如上面所定义的含义,
R3表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-或C1-13酰基-基团-被催化氢化,和
在其中x=0的情况下,其被异构化。
对于式XI的化合物的氢化,作为催化剂,可使用Pd/C催化剂或氧化铂,优选Pd/C催化剂。
通式XI的化合物是新颖的。
可如此制备通式XI的新颖的化合物,使得通式XII的化合物
-其中在该式中
x、R1、R2和R3具有如上面所定义的含义-
经历分子内环化。
对于分子内环化,有利地应用Pauson-Khand环化方法。Pauson-Khand 环化使用八羰基二钴进行。
八羰基二钴可以等摩尔比或小于等摩尔比或大于等摩尔比应用。
反应优选在一氧化碳气氛中使用乙酸乙酯作为溶剂进行。
可如此制备通式XII的新颖的化合物,使得通式XIII的化合物
-其中在该式中
x、R1和R2具有如上面所定义的含义-
与适合于引入基团R3的化合物反应。
可如此制备通式XIII的新颖的化合物,使得
a.)通式XIV的化合物
-其中在该式中
x、R1和R2具有如上面所定义的含义-
被选择性地还原,或
b.)通式XVI的化合物
-其中在该式中
R2具有如上面所定义的含义-,
在手性碱和锌盐的存在下与通式XVII的化合物反应
-其中在该式中
R1和x具有如上面所定义的含义。
通式XIV的化合物的还原在手性氧氮硼杂环戊烷催化剂的存在下用硼烷化合物进行。
作为硼烷化合物,可应用硼烷-二甲基硫醚络合物、儿茶酚硼烷或硼烷- 二乙基苯胺络合物,优选硼烷-二甲基硫醚络合物;作为手性碱,可应用手性氨基醇或二胺,优选(+)-N-甲基麻黄碱。
在通式XVI和XVII的化合物的反应中,作为锌盐,可优选应用三氟甲磺酸锌。
可如此制备通式XIV的新颖的化合物,使得通式XV的化合物
-其中在该式中
x、R1和R2具有如上面所定义的含义-,
被氧化。
式XV的化合物的氧化用PCC(氯铬酸吡啶鎓)进行或在Swern反应条件 (草酰氯/DMSO/有机碱)下进行。
可如此制备通式XV的新颖的化合物,使得通式XVI的化合物
-其中在该式中
R2具有如上面所定义的含义-,
在格氏试剂的存在下与通式XVII的化合物反应
-其中在该式中
R1具有上面所定义的含义并且x是0或2-。
作为格氏试剂,可应用甲基-、乙基-、丙基-、丁基-、环己基-溴化镁,优选甲基溴化镁。
本发明的另一个主题是用于制备式I的曲前列尼尔与碱的无定形形式、无水物、一水合物和多水合物盐的新颖的方法
在曲前列尼尔盐中,其中通用形式的曲前列尼尔钠盐描述于 WO99/25357(UnitedTherapeutics)中,而没有用化学-物理数据来表征它们。申请人提交至EP1628654(UnitedTherapeutics)的证据1中第一次提及曲前列尼尔钠盐的熔点为56℃。
WO 2012/088607(Alphora)描述了一种用于制备曲前列尼尔钠盐的新方法,其中将曲前列尼尔溶解于与水可混溶的有机溶剂中以形成曲前列尼尔溶液,然后将该溶液与含有碱金属阳离子的水溶液反应以形成含有曲前列尼尔盐的反应混合物,使该盐结晶并收集形成的盐。
根据本发明,式I的曲前列尼尔与碱的无定形形式、无水物、一水合物和多水合物盐以如下方式制备:将曲前列尼尔溶解于极性溶剂中,将固体碱加入该溶液中,搅动反应混合物并且当盐形成完成时,将溶液过滤、浓缩,将浓缩物的溶剂交换为结晶的有机溶剂,并结晶曲前列尼尔盐。
为了制备式I的曲前列尼尔与碱的盐,作为极性溶剂,可应用C1-5开链或支链有机醇,优选乙醇;作为碱,可应用无溶剂的含有期望的盐的阳离子的有机或无机碱,例如含有碱金属阳离子或碱土金属阳离子的有机或无机碱,例如碳酸钠一水合物、碳酸氢钠或甲醇钠,优选碳酸钠的水合物。
反应混合物在惰性气氛中搅动,直到盐形成完成。
根据本发明的一个实施方案,作为结晶含水醚-、酯-或酮-型溶剂的有机溶剂,即作为醚-型溶剂,可应用开链或支链简单或混合醚,优选叔丁基甲基醚。
结晶优选在50℃-(-40℃)之间的温度进行。
作为使用含有钠阳离子的有机或无机碱的上述方法的结果,获得了白色结晶性曲前列尼尔钠盐一水合物(形式A),其为一种新化合物。
根据本发明的另一个实施方案,如果结晶的有机溶剂是不含水的醚-、酯-或酮-型溶剂,则获得无定形曲前列尼尔钠盐,其为一种新化合物。
根据本发明,曲前列尼尔钠盐无水物(形式B)可通过进行上述方法直至结晶步骤并在60-100℃或在真空中进行结晶来制备。另一种可能的方法是,将钠盐一水合物吸收在不溶解或仅微溶盐的溶剂中并在60-90℃搅拌1-6小时。作为溶剂,优选可应用己烷、庚烷、甲苯、乙酸乙酯。
如果将曲前列尼尔钠盐一水合物或无水物保持在60%水含量的气氛中达48小时或保持在空气中达5-8天,则获得新颖的曲前列尼尔钠盐多水合物(形式C)。
不同形式的DSC和X-射线粉末衍射(XRPD)谱显示于图14-22中。
这些上述盐形式显示了用于制备药物制剂的合适的稳定性和适用性。
在本发明的优选实施方案中:
炔丙基醇用甲氧基甲基基团保护。
被保护的炔丙基醇(XVII)在甲基溴化镁格氏试剂的存在下与2-烯丙基 -3-甲氧基苯甲醛(XVI)反应。将由此获得的外消旋醇(XV)氧化。
例如通过Swern氧化方法或通过用铬(VI)氧化进行氧化。
酮XIV的立体选择性还原产生手性醇XIII。
立体选性还原可例如在Corey催化剂的存在下用硼烷-二甲基硫醚络合物进行。
可通过在手性碱,例如(+)-N-甲基麻黄碱和三氟甲磺酸锌的存在下使被保护的炔丙基醇(XVII)与2-烯丙基-3-甲氧基苯甲醛(XVI)反应直接制备手性醇XIII。
羟基基团用叔丁基二甲基甲硅烷基基团保护,甲硅烷基醚(XII)在八羰基二钴的存在下在Pauson-Khand反应中被环化。作为反应的结果,通过掺入 CO分子形成三环(XI)。
环化可在一氧化碳气氛下使用等摩尔量的八羰基二钴或更优选使用催化量的八羰基二钴进行。
通过催化氢化移除甲硅烷基氧基基团,并且五元环的双键是饱和的。三环酮(X)的立体结构通过用碱(二氮杂二环壬烷/乙醇)异构化形成。
还原氧代基团(IX),用对苯基苯甲酰基(PPB)基团(VIII)保护所得到的仲羟基基团。
通过用酸(VII)处理裂解甲氧基甲基保护基。
将伯羟基基团氧化(VI)。
将所得到的醛VI未经分离地与膦酸2-氧代-庚酯反应。
将由此得到的烯酮V通过选择性还原方法还原,例如在Corey催化剂的存在下用硼烷-二甲基硫醚络合物。
将所得到的式IV的化合物的对苯基苯甲酰基保护基通过在碱的存在下的甲醇解移除。
通过催化氢化进行的式III的烯醇的双键的饱和产生了式II的苯并茚衍生物。
根据本发明的另一个优选的实施方案,将2-戊-4-炔氧基四氢吡喃而不是被保护的炔丙基醇用作起始原料。通过在手性催化剂的存在下与二戊基锌或戊基溴化镁反应立体选择性地构建侧链。
式II的苯并茚是曲前列尼尔的关键中间体,通过已知化学步骤将其转化为曲前列尼尔。
第一个化学步骤是甲基醚的裂解。甲基基团的移除用硫醇在卤化铝的存在下进行。
对于卤化铝,选择三氯化铝,对于硫醇,选择没有气味的十二烷基硫醇而不是常用的乙硫醇来制备三羟基衍生物。(图10)
图10
下一步是用卤代乙酸酯,例如溴-或氯乙酸乙基-或甲基酯烷基化芳族羟基基团。在我们的方法中,用溴乙酸乙酯烷基化三羟基衍生物。(图11)
图11
乙酯衍生物的水解产生结晶性曲前列尼尔。
在我们的方法中,水解用氢氧化钠水溶液在四氢呋喃中进行。
当反应完成时,将反应混合物用叔丁基甲基醚洗涤。通过加入酸水溶液将水相的pH设定为pH≤3。用叔丁基甲基醚萃取曲前列尼尔,洗涤产物溶液并蒸发。(图12)
图12
对于盐形成,将曲前列尼尔溶解于乙醇中并将固体碳酸钠一水合物加入其中。(图13)。
图13
将溶液经微孔过滤器过滤,将乙醇交换为已经用水饱和的叔丁基甲基醚并在室温结晶曲前列尼尔钠盐。
根据本发明的方法的优点在于:
·苯并茚三环的形成不需要昂贵的手性起始原料。
·侧链的构建是通过用于前列腺素化学中的具有良好的可扩展性的和稳健的化学步骤(Wittig-或改良的Wittig反应)来实现的,或通过在手性催化剂的存在下使用有机金属化合物而立体选择性地进行。
·在Wittig反应中获得的烯酮可在立体选择性反应中以良好的收率转化为期望的对映异构体。
·所应用的对苯基苯甲酰基基团(PPB-基团)是在UV中可被良好地检测的。
·所述PPB-基团提高了中间体的结晶能力并有助于它们的纯化。
图1、2、4和5如下所示:
图1、2、4、5:
图1
TBDMS=叔丁基二甲基甲硅烷基
PCC=氯铬酸吡啶鎓
Corey催化剂:
图2
图4
其中,P1和P2=醇-保护基,R=(CH2)mCO2R1,m=1、2、3和
R1=烷基或THP或TBDMS或取代的-或未取代的苄基基团
图5
其中PMB=对甲氧基苄基,Bn=苄基,
Z=羧基基团或羧酸衍生物,X=卤素原子
本发明的方法的更多细节由实施例说明,而非使本发明限于实施例。
实施例
实施例1.
1a.)
制备3-(甲氧基甲氧基)-1-丙炔(MOM-丙炔醇,TREPO-1)
将2.27ml炔丙醇和8ml二甲氧基甲烷溶解于8ml甲苯中。向溶液中加入0.66g对甲苯磺酸和0.33g溴化锂。将反应混合物在室温搅拌20小时,用碳酸氢钠溶液和用水洗涤。将有机相干燥并将溶液未经蒸发地转移至下一步骤中。
收率:约2g(50%)产物,在溶液中。
NMR数据:(DMSO-d6),1H NMR(500MHz):4.62ppm(H-4,2),s;4.16 ppm(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)。
1b.)制备1-(2-烯丙基-3-甲氧基苯基)-4-甲氧基甲氧基-丁-2-炔-1-醇 (TREP-1)(非选择性炔基化)
将64g(0.64mol)3-(甲氧基甲氧基)-1-丙炔(TREPO-1)在氮气气氛下溶解于600ml无水四氢呋喃中并将溶液加热至60-65℃。向反应混合物中缓慢加入220ml乙基溴化镁溶液(3M在乙醚中的溶液)(0.66mol)。在加入结束时,将反应混合物在回流温度加热45分钟,然后在冷却至0-5℃后,逐滴加入 100g 2-烯丙基-3-甲氧基苯甲醛(VPK-5)(0.57mol)在100ml无水四氢呋喃中的溶液。将混合物在室温搅拌。当反应完成时,将混合物冷却至0℃并将 NaHSO4(硫酸氢钠)溶液加入其中。搅动后,分离各相,将水层用乙酸乙酯萃取。将合并的有机相用NaHCO3(碳酸氢钠)溶液洗涤并经硫酸钠干燥。将干燥的物质滤出,并将滤液溶液在真空中蒸发。将粗产物未经纯化地转移至下一步骤中。
收率:156.8g(100%)淡棕色油。
NMR数据:(CDCl3),1H NMR(500MHz):7.32ppm(H-6,1),dd,J=7.8 Hz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;5.67 ppm(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(125.8 MHz):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.)制备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)
1c1.方法(用PCC氧化)
将200g硅胶悬浮于1.5l乙酸乙酯中并将470g(2.18mol)氯铬酸吡啶鎓 (PCC)加入其中。在搅拌下在25±5℃向该橙色的混悬液中加入150g(0.54mol) TREP-1在0.5l乙酸乙酯中的溶液。将反应混合物在35±5℃搅拌。在反应结束时,将二异丙基醚和硅胶加入混合物中。将混悬液过滤,将固体物质用乙酸乙酯洗涤。在真空中蒸发液体滤液。将粗产物通过使用己烷:乙酸乙酯洗脱剂的硅胶色谱纯化。
收率:88.1g(59.2%)淡棕色油。
1c2.方法(Swern氧化)
将93ml草酰氯溶解于1.7l二氯甲烷中并在-75/-85℃与148ml二甲基亚砜(DMSO)反应。在-75/-85℃向混合物中加入179g TREP-1。在搅拌1小时后,将反应混合物用621ml三乙胺和NaHSO4溶液淬灭。将有机相用二氯甲烷萃取,将合并的有机相用1M NaHCO3溶液洗涤。将粗产物通过硅胶色谱纯化。
收率:140g(79%)淡棕色油。
NMR数据:(CDCl3),1H NMR(500MHz):7.75ppm(H-6,1),dd,J=7.8 Hz和0.9Hz;7.305ppm(H-5,1),t,J=8.0Hz;7.08ppm,(H-4,1),d(dd),J=8.1 Hz和~1.0Hz;5.96ppm(H-14,1),ddt,J=17.1Hz,10.1Hz和6.2Hz;5.01-4.92 ppm(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),54.32 ppm(C-10),29.78ppm(C-13)。
1d.)制备(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)
1d1.方法(选择性还原)
在氮气气氛下将85g TREP-2(0.31mol)溶解在600ml无水四氢呋喃 (THF)中。将溶液冷却至0-5℃并将370ml(0.37mol)氧氮硼杂环戊烷溶液(1M 在甲苯中的溶液)加入其中。将混合物冷却至(-30)℃并将50ml(0.52mol)硼烷-二甲基硫醚络合物在(-30)℃逐滴加入其中。将反应混合物在该温度搅拌。在反应结束时将混合物温热至(-15)℃,小心加入200ml甲醇(强烈发泡和热形成)。在甲醇加入后,将反应混合物搅拌30分钟,然后在0-5℃加入NH4Cl 溶液并将淬灭的反应混合物用3x 2.5l乙酸乙酯萃取。将合并的有机相用水洗涤并经硫酸钠干燥。将干燥的物质滤出,蒸发滤液。
收率:85.6g(100%)淡棕色油。
1d2.方法(选择性炔基化)
向反应容器中加入216mg(0.59mmol)三氟甲磺酸锌和82mg(0.45 mmol)(+)-N-甲基麻黄碱,用氮气吹扫10分钟,然后加入1ml蒸馏甲苯和 63μl(0.45mmol)三乙胺。将反应混合物在室温搅拌1小时,然后加入250μl (0.45mmol)TREPO-1溶液并在15分钟搅拌后加入24μl VPK-5(2-烯丙基-3- 甲氧基苯甲醛)(0.14mmol)。在室温搅拌24小时后,将反应混合物用1ml 饱和NH4Cl溶液淬灭。将水相用甲苯萃取,将合并的有机相接连用NaHCO3溶液和饱和NaCl溶液洗涤,然后蒸发。
收率:30mg(78%)淡棕色油。
NMR数据:(CDCl3),1H NMR(500MHz):7.32ppm(H-6,1),dd,J=7.8 Hz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;5.68 ppm(H-7,1),宽峰;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),宽峰;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)。
1e.)制备[(1S)-1-(2-烯丙基-3-甲氧基苯基)-4-(甲氧基甲氧基)丁-2-炔氧基]-叔丁基二甲基甲硅烷(TREP-4)
在850ml甲苯中溶解85g(0.31mol)TREP-3和26.6g(0.39mol)咪唑。将溶液冷却至5-10℃并加入56.8g(0.38mol)叔丁基二甲基氯硅烷 (TBDMSCl)。将反应混合物在室温搅拌4小时,然后在搅动下加入500ml 水。分离各相,将水层用甲苯萃取,将合并的有机相在真空中蒸发。将粗产物在硅胶上使用己烷:乙酸乙酯洗脱剂进行色谱纯化。
收率:104.2g(86.7%)淡棕色油。
NMR数据:(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=7.9 Hz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);4.67 ppm(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),118.73 ppm(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),54.60 ppm(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)。
1f.)制备(3aS,9R)-9-[叔丁基(二甲基)甲硅烷基]氧基-5-甲氧基-1-(甲氧基甲氧基甲基)-3,3a,4,9-四氢环戊二烯并[b]萘-2-酮(TREP-5)
1f1.方法(采用100mol%八羰基二钴)
将93g(0.24mol)TREP-4在氮气气氛下溶解于930ml乙酸乙酯中并向溶液中加入85.5g(0.25mol)八羰基二钴。将反应混合物在室温搅拌2.5小时,然后温热至60-70℃。将释放出的一氧化碳气体在密闭系统中引出。在反应结束时将混合物冷却至室温并向其中通入空气鼓泡12小时。将反应混合物过滤,将析出物用乙酸乙酯洗涤。将合并的滤液溶液在真空中蒸发。将粗产物在硅胶上使用己烷:乙酸乙酯洗脱剂进行色谱纯化。
收率:64.6g(64.8%)淡棕色油。
1f2.方法(采用10mol%八羰基二钴+一氧化碳气体)
在氮气气氛下将93g(0.24mol)TREP-4溶解于930ml乙酸乙酯中并将 8.55g(0.025mol)八羰基二钴加入其中。将容器用一氧化碳吹扫,将反应混合物在室温搅拌2.5小时,然后加热至60-70℃。在反应结束时将混合物冷却至室温,过滤,将析出物用乙酸乙酯洗涤。将合并的滤液溶液在真空中蒸发。将粗产物在硅胶上使用己烷:乙酸乙酯洗脱剂进行色谱纯化。
收率:85g(85%)淡棕色油。
NMR数据:(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;3.815 ppm(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=18.7 Hz和5.8Hz;2.33-2.15ppm(H-10b和H-4b,2),m,(在: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),33.49 ppm(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)。
1g.)制备(1S,9aS)-5-甲氧基-1-(甲氧基甲氧基甲基)-1,3,3a,4,9,9a-六氢环戊二烯并[b]萘-2-酮(TREP-6)
将63g(0.15mol)TREP-5溶解于630ml乙酸乙酯中并将19ml吡啶加入至溶液中。将反应混合物在6巴压力下经25g 10%炭载钯催化剂氢化。在反应结束时,将催化剂滤出并用乙酸乙酯洗涤。将滤液在真空中蒸发。将粗产物在硅胶上使用己烷:乙酸乙酯混合物作为洗脱剂进行色谱纯化。将蒸发的主要级分在0℃从己烷-乙酸乙酯混合物中结晶并通过过滤收集。为了异构化,将蒸发的母液溶解于100ml甲苯和60ml乙醇的混合物中。在0℃将12 mlDBN试剂(2,3,4,6,7,8-六氢吡咯并[1,2-a]嘧啶)加入其中并将混合物搅动15 分钟。然后将反应混合物用NaHSO4溶液淬灭,用叔丁基甲基醚萃取并蒸发。将残余物在硅胶上使用己烷:乙酸乙酯混合物作为洗脱剂进行色谱纯化。将蒸发的主要级分在0℃从己烷-乙酸乙酯混合物中结晶。通过过滤收集晶体并与先前得到的晶体合并。
收率:30.2g(69.1%)白色晶体。Mp:65-67℃。
NMR数据:(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,(在: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=17.3 Hz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,2.29-2.205 ppm(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)。
1h.)制备(1S,2R,9aS)-5-甲氧基-1-(甲氧基甲氧基甲基)-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-醇(TREP-7)
将22g(75.8mmol)TREP-6溶解于100ml甲苯中,将100ml乙醇加入其中并将溶液冷却至(-)15-(-)25℃。向溶液中加入3g(79.3mmol)硼氢化钠 (NaBH4)并将反应混合物搅拌,同时保持上述温度。在反应结束时,用NaHSO4溶液将pH设定为pH=4-6。将搅拌持续进行30分钟,然后分离各相。将水相用甲苯萃取。将合并的有机相接连用NaHCO3溶液和水洗涤,然后经硫酸钠干燥。将干燥的物质滤出,并将滤液溶液在真空中蒸发。
收率:22.15g(100%)无色油。
NMR数据:(CDCl3),1H NMR(500MHz):7.10ppm(H-22,1),t,J=7.8Hz; 6.79-6.73ppm(H-21和H-22,2),m(在: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(在: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(在:2.76 ppm(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(在:2.58ppm(OH-11,1),宽峰和2.56ppm(H-4b,1),dd,J=14.7Hz和6.2Hz);2.45ppm(H-7b,1),dd,J=14.3 Hz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),55.43 ppm(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)。
1i.)制备4-苯基苯甲酸[(1S,2R,9aS)-5-甲氧基-1-(甲氧基甲氧基甲基)-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(TREP-8)
在氮气气氛下将22g(75mmol)TREP-7溶解于50ml吡啶中,并在最高50℃的温度将17.9g(82mmol)对苯基苯甲酰氯(PPB-Cl)加入其中。将反应混合物在50-60℃搅拌。在反应结束时,加入乙醇和水并将混合物冷却至 0/5℃-ra。在3小时搅拌后,将晶体滤出并用乙醇-水混合物洗涤。
收率:34.1g(96%)白色晶体。Mp:106-107℃。
NMR数据:(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,(在: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~7.5 Hz);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;6.79 ppm(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(在:3.69ppm (H-13a,1),dd,J=9.9Hz和4.8Hz和3.66ppm(H-13b,1),dd,J=9.9Hz和5.3 Hz);3.35ppm(H-17,3),s;2.87ppm(H-4a和H-7a,2),m(dd),J=14.7Hz和6.1 Hz;2.68-2.58ppm(H-4b和H-7b,2),m(在: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(在:2.475ppm(H-10a,1),m和2.465ppm(H-9,1),m);2.305 ppm(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),33.70 ppm(C-9),33.28ppm(C-7),25.72ppm(C-4)。
1j.)制备4-苯基苯甲酸[(1S,2R,9aS)-1-(羟基甲基)-5-甲氧基 -2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(TREP-9)
将28g(59.2mmol)TREP-8溶解于140ml四氢呋喃中并向溶液中加入 280ml甲醇。
在方法1i1.中,将140ml 5M盐酸加入至混合物中并在45-50℃搅拌。
在方法1i2.中,将14g对甲苯磺酸一水合物加入至混合物中并在 45-50℃搅拌。
在反应结束时,将混合物用NaHCO3溶液中和,蒸馏除去有机溶剂。将残余物用乙酸乙酯萃取,将合并的有机相用水洗涤,经硫酸钠干燥。将粗产物在硅胶上使用己烷:乙酸乙酯混合物作为洗脱剂进行色谱纯化。
收率:23.4g(92%)无色油。
NMR数据:(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,(在: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~7.4 Hz);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 (在:6.792ppm(H-23,1),d,J~7.3Hz和6.788ppm(H-21,1),d,J~8.4Hz);5.21 ppm(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(在: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(在:2.70ppm(H-4b,1),dd,J=15.1Hz和5.8Hz和2.67ppm (OH-13,1),宽峰);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(在: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),140.08 ppm(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),33.01 ppm(C-9),32.71ppm(C-7),25.48ppm(C-4)。
1k.)制备4-苯基苯甲酸[(1R,2R,3aS,9aS)-5-甲氧基-1-[(E)-3-氧代辛-1-烯基]-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(TREP-11)
在惰性气氛中将20g(46.7mmol)TREP-9溶解于200ml无水甲苯中。加入30g二环己基碳二亚胺(DCC)和10ml二甲基亚砜在磷酸中的溶液。将反应混合物加热至50℃并分批加入另一部分的5ml二甲基亚砜在磷酸中的溶液。当氧化完成时,将反应混合物冷却至-10℃并在该温度加入4g(71 mmol)氢氧化钾,然后加入10.9g(49mmol)2-氧代-庚基磷酸二甲酯在甲苯中的溶液。在反应结束时,在搅动下,将混合物倒在酸溶液上。将析出的晶体滤出并洗涤。分离滤液的各相,将有机相用1M碳酸氢钠溶液洗涤,然后用稀盐酸溶液稀释。将有机相蒸发并通过使用甲苯:己烷洗脱剂的硅胶柱色谱纯化。
收率:23g(94,3%)淡棕色油。
1k/2的替代方法
将20g(46,7mmol)TREP-9溶解于200ml甲苯中并将0.9g溴化钾和0.2g TEMPO/(2,2,6,6-四甲基-哌啶-1-基)氧基/催化剂加入至溶液中。将反应混合物冷却至0℃-(+10℃)的范围并加入150ml次氯酸钠溶液(活性氯含量为6-14%) 并将混合物在该温度搅拌。当氧化完成时,分离反应混合物的各相,将有机相用Na2S2O3水溶液、KBr水溶液洗涤,最后用水洗涤。
将10,9g(49mmol)2-氧代-庚基磷酸二甲酯和100ml 3M氢氧化钾溶液加入至有机相中。将反应混合物在室温搅动。在反应完成后,分离各相并将有机相用1M硫酸氢钠溶液和15%NaCl溶液洗涤。
将有机相蒸发并通过使用甲苯:己烷洗脱剂的硅胶柱色谱纯化。
收率:23g(94,35%)淡棕色油。
NMR数据:(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,(在: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~7.7 Hz);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(在: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 (在:2.75ppm(H-7a,1),dd,J=14.7Hz和5.9Hz和2.73ppm(H-4,2),d,J=5.5 Hz);2.62-2.48ppm(H-7b,H-9,H-10a和H-16,5),m(在: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(在: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(在:1.34ppm(H-10b,1),m(dt),J~11.8Hz和9.6Hz;1.29 ppm(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),22.60 ppm(C-19),14.05ppm(C-20)。
制备2-氧代-庚基膦酸二甲酯
制备二异丙基氨基锂(LDA)
在氮气气氛中,在搅拌下将3.017g二异丙基胺溶解于13.6ml四氢呋喃 (THF)中,并在0±5℃向其中加入17.9ml丁基锂(BuLi)的己烷溶液(1.6M在己烷中的溶液)。将混合物在室温搅拌1小时。
膦酸酯形成
在氮气气氛下,在搅拌下,将1.85g甲基膦酸二甲酯和1.77ml己酸甲酯溶解于10.2ml四氢呋喃(THF)中。将溶液冷却至0/-5℃并在该温度在约30 分钟的时间段内逐滴加入二异丙基氨基锂(LDA)溶液。将反应混合物在 0/-5℃搅拌1小时,然后加入37ml 2MNaHCO3溶液。将搅拌在室温继续进行1小时,分离各相,将水相用叔丁基甲基醚(TBME)萃取。将合并的有机相用饱和氯化钠溶液洗涤,在真空中蒸发并通过在45±5℃的水浴上在旋转蒸发仪(rotadest)中在其上蒸馏甲苯进行干燥。
收率:2.718g(90%)黄色油。
NMR数据:(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,(在:1.26 ppm(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。
1l.)制备4-苯基苯甲酸[(1R,2R,3aS,9aS)-1-[(E,3S)-3-羟基辛-1-烯基]-5-甲氧基-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(TREP-12)
在氮气气氛下将19g(36.3mmol)TREP-11溶解于190ml无水四氢呋喃中。将溶液冷却至0-5℃并加入36.3ml(36.3mmol)氧氮硼杂环戊烷溶液(1M 甲苯溶液)。将混合物冷却至(-30)℃,同时保持在该温度,将9.5ml(99mmol) 硼烷-二甲基硫醚络合物逐滴加入其中。将反应混合物在该温度搅拌。在反应结束时,使混合物温热至(-15)℃并小心地将甲醇加入其中(强烈起泡和热形成)。将混合物搅拌30分钟,然后在0-5℃将NaHSO4溶液加入其中。将析出的晶体滤出并用甲苯洗涤。将液体滤液用3x 50ml甲苯萃取。将合并的有机相用水洗涤并经硫酸钠干燥。将干燥的物质滤出并将滤液蒸发。
收率:18.2g(95.4%)淡棕色油。
NMR数据:(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,(在: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~7.1 Hz);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(在: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(在: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(在:2.51ppm(H-7,1),m(dd),J=14.6 Hz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,(在:2.20ppm(H-12,1),m和2.18ppm(H-8,1),m);1.68 ppm(OH-15,1),宽峰;1.60-1.39ppm(H-16,2),m,(在: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, (在: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),129.26 ppm(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),25.53 ppm(C-4),25.12ppm(C-17),22.71ppm(C-19),14.14ppm(C-20)。
1m.)制备(1R,3aS,9aS)-1-[(E)-3-羟基辛-1-烯基]-5-甲氧基-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-醇(TREP-13)
将17g(32.4mmol)TREP-12溶解于70ml甲醇中,加入4.2g(30.3mmol) K2CO3并将混合物在40℃搅拌,直到反应结束。当到达期望的转化时,将反应混合物冷却至0℃并将磷酸溶液分批加入其中。将析出的对苯基苯甲酰基甲酯(PPB-甲酯)滤出并洗涤。将滤液浓缩,将水和甲苯加入其中并分离各相。将水相用甲苯萃取,将有机相经Na2SO4干燥,将干燥的物质滤出,将滤液蒸发并通过硅胶柱色谱纯化(使用己烷:叔丁基甲基醚混合物洗脱剂)。主要级分从己烷和叔丁基甲基醚的混合物中结晶。将析出的晶体滤出,洗涤和干燥。
收率:8g(72%)白色晶体。Mp:75-77℃。
NMR数据:(CDCl3),1H NMR(500MHz):7.10ppm(H-22,1),t,J=7.8Hz; 6.78-6.70ppm(H-21和H-23,2),m(在: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(在: 5.47ppm(H-13和H-14,2),m);4.04ppm(H-15,1),m,J=6.5Hz和3.2Hz;3.80 ppm(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(在: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(宽峰));2.40-2.27ppm(H-7b和H-9,2),m(在:2.37ppm(H-7b,1),m(dd),J=14.3 Hz和5.4Hz;2.32ppm(H-9,1),m);2.23-2.13ppm(H-10a,1),m,(在: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,(在: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),136.20 ppm(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),25.37 ppm(C-17),22.78ppm(C-19),14.18ppm(C-20)。
1n.)制备(1R,3aS,9aS)-1-(3-羟基辛基)-5-甲氧基-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-醇(TREP-14)
将7.7g(22.3mmol)TREP-13溶解在77ml甲基乙基酮和154ml乙醇的混合物中。将反应混合物在6巴压力下经0.77g 10%用亚硝酸钠钝化的炭载钯催化剂氢化。在反应结束时将催化剂滤出,用乙酸乙酯洗涤,将滤液在真空中蒸发并将残余物从己烷:乙酸乙酯混合物中结晶。
收率:6.4g(83%)白色晶体。Mp:71-72℃。
NMR数据:(CDCl3),1H NMR(500MHz):7.09ppm(H-22,1),t,J=7.8Hz; 6.78-6.71ppm(H-21和H-23,2),m(在: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(在: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-4bés H-7b,2),m(在: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(在:2.31ppm (OH-11/OH-15,1),宽峰和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,(在:2.155ppm(H-10a,1),m (ddd),J=11.7Hz,7.4Hz和6.1Hz和2.08ppm(OH-11/OH-15,1),宽峰); 1.92-1.74ppm(H-8和H-11/H-15/水,2),m,(在:1.87ppm(H-8,1),m(tt), J=10.0Hz和6.4Hz和1.81ppm(OH-11/OH-15,1),宽峰);1.69-1.50ppm (H-13和H-14,4),m(在: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(在:1.47 ppm(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(在: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),32.05 ppm(C-18),28.77ppm(C-13),25.88ppm(C-4),25.52ppm(C-17),22.78ppm (C-19),14.18ppm(C-20)。
1o.)制备(1R,2R,3aS,9aS)-1-[(3S)-3-羟基辛基]-2,3,3a,4,9,9a-六氢-1H-苯并[f]茚-2,5-二醇(TREP-15)
在氮气气氛下向2.4l 1-十二烷基硫醇中加入400g无水氯化铝。将混合物冷却至0-5℃并将200g TREP-14在560ml二氯甲烷中的溶液加入其中。将反应混合物在室温搅拌。在反应结束时将混合物倒在4l水上,然后加入 664ml 2M硫酸氢钠。分离各相,将水相用乙酸乙酯萃取。将有机相用饱和氯化钠溶液洗涤,经硫酸钠干燥并蒸发。残余物从己烷中结晶。将晶体滤出,洗涤并从己烷:乙酸乙酯混合物中重结晶。
收率:182g(95%)白色晶体。Mp:113-115℃。
NMR数据:(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(在:2.735ppm(H-7a,1),m(dd),J=14.0 Hz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(在:2.47ppm(H-4b,1),m(dd),J=14.6Hz和6.3Hz;2.46 ppm(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6.4 Hz;1.95-1.85ppm(H-8,1),m(在:1.90ppm(H-8,1),m(tt),J=10.0Hz和6.2 Hz);1.72-1.61ppm(H-13a和H-14a,2),m(在:1.655ppm(H-14a,1),m和1.65 ppm(H-14a,1),m);1.61-1.51ppm(H-13b和H-14b,2),m(在:1.56ppm(H-14b, 1),m和1.55ppm(H-13b,1),m);1.51-1.385ppm(H-16和H-17a,3),m(在: 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(在: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(125.8 MHz):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),35.09 ppm(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)。
1p.)制备2-[[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氢-2-羟基-1-[(3S)-3-羟基辛基]-1H-苯并[f]茚-5-基]氧基]乙酸乙酯(TREP-16)
将170g(0.51mol)TREP-15溶解于3.4l丙酮中。向溶液中加入340g (2.46mol)无水碳酸钠和89.6g(0.536mol)溴乙酸乙酯并将混合物在30-35℃搅拌。在反应结束时将反应混合物过滤,蒸发滤液。将产物用TBME(叔丁基甲基醚):己烷混合物从残余物中结晶,滤出,洗涤和干燥。
收率:203g(95%)白色晶体。Mp:53-55℃。
NMR数据:
(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;3.55 ppm(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(在: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6.7 Hz);2.42ppm(H-7b,1),dd,J=14.2Hz和6.8Hz;2.25-2.07ppm(H-9和H-10a,2),m,(在: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(在: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(在: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(在: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),141.15 ppm(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)。
1q.)制备2-[[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氢-2-羟基-1-[(3S)-3-羟基辛基]-1H-苯并[f]茚-5-基]氧基]乙酸(曲前列尼尔)
将180g(0.43mol)TREP-16(乙酯)溶解于650ml四氢呋喃中。在氮气气氛下,在室温加入2.7l 0.5M氢氧化钠溶液并将反应混合物在室温搅拌。在反应结束时,将混合物用蒸馏过的叔丁基甲基醚洗涤。向含水碱性相中加入叔丁基甲基醚并用1M硫酸氢钠溶液将混合物的pH设定为pH≤3。然后将含水酸性相用叔丁基甲基醚萃取,将合并的有机相用水洗涤并蒸发。
收率:165g(98%)结晶油。
NMR数据(d6-DMSO),1H NMR(400MHz):12.915(COOH-1,1),宽峰; 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),宽峰;4.21 ppm(OH-15,1),宽峰;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(在: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(在: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(在:1.32ppm(H-13b,1),m;1.30ppm(H-16b,1),m;1.275 ppm(H-19,2),m;1.26ppm(H-17b,1),m;1.25ppm(H-18,2),m);1.15-0.93 ppm(H-10b和H-13,2),m(在: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),109.37 ppm(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)。
1s.)制备(1R,2R,3aS,9aS)-2-[2-羟基-1-[3(S)-羟基辛基]-2,3,3a,4,9,9a-六氢 -1H-苯并[f]茚-5-基氧基]乙酸钠盐(曲前列尼尔钠盐)
1s1.)将150g(0.384mol)曲前列尼尔溶解于2l乙醇中。将碳酸钠一水合物26.2g(0.211mol)加入其中,并将混合物在惰性气氛下在室温搅拌。当过滤后的样品的pH值达到7-9时,将混合物经5μm孔径过滤器过滤。将滤液溶液在旋转蒸发仪上浓缩至约225g。将浓缩物溶解于已经用水饱和的叔丁基甲基醚中并使其在室温结晶。将晶体滤出,在室温洗涤并在真空中在 20-50℃干燥。
收率:158g(100%)曲前列尼尔钠盐一水合物(形式“A”),白色晶体。 Mp:95-99℃。
1s2.)将150g(0.384mol)曲前列尼尔溶解于2l乙醇中。将35.5g(0.422 mol)碳酸氢钠加入其中,并将混合物在惰性气氛下在室温搅拌。当过滤后的样品的pH值达到7-8时,将混合物经5μm孔径过滤器过滤,并将滤液溶液在旋转蒸发仪上浓缩至约225g。将浓缩物溶解于已经用水饱和的叔丁基甲基醚中并使其在室温结晶。将晶体滤出,在室温洗涤并在真空中在20-50℃干燥。
收率:158g(100%)曲前列尼尔钠盐一水合物(形式“A”),白色晶体。 Mp:95-99℃。
1s3.)将150g(0.384mol)曲前列尼尔溶解于2l乙醇中。将21g(0.39mol) 甲醇钠加入其中,并将混合物在惰性气氛下在室温搅拌直到溶解。将溶液经 5μm孔径过滤器过滤。将滤液溶液在旋转蒸发仪上浓缩至约225g。将浓缩物溶解于已经用水饱和的叔丁基甲基醚中并使其在室温结晶。将晶体滤出,在室温洗涤并在真空中在20-50℃干燥。
收率:158g(100%)曲前列尼尔钠盐一水合物(形式“A”),白色晶体。 Mp:95-99℃。
1s4.)将24g(61.45mmol)曲前列尼尔溶解于360ml乙醇中并将7.62g (61.45mmol)碳酸钠一水合物加入其中。将混合物在惰性气氛下在室温搅拌直到完全溶解。然后将溶液经5μm孔径过滤器过滤,并将滤液溶液在旋转蒸发仪上浓缩。向浓缩物中加入乙醇并将溶液再次浓缩。将浓缩物溶解于叔丁基甲基醚中并使其在室温结晶。通过过滤收集晶体,洗涤并在真空中在 20-50℃干燥。
收率:22.8g(90%)曲前列尼尔钠盐,白色固体(无定形形式)。Mp: 65-90℃
曲前列尼尔钠盐一水合物(形式“A”)的分析表征:
Mp:81-109℃
DSC峰:94-99℃
纯度:99.9(HPLC面积%)
15-表-曲前列尼尔:0.0(HPLC面积%)
水含量:4.3%
比旋光度(c=1%,甲醇25℃):+41°
硫酸处理灰:16.8%
NMR数据:(d6-DMSO),1H NMR(500MHz):6.95ppm(H-22,1),t,J=7.8 Hz;6.65ppm(H-23,1),d,J=7.4Hz;6.61ppm(H-21,1),d,J=8.2Hz;4.97-3.93 ppm(H-2,OH-11和OH-15,4),m(在:4.54ppm(OH-11,1),宽峰;4.32ppm (OH-15,1),宽峰;4.13ppm(H-2,2),s);3.47ppm(H-11,1),td,J=9.4Hz和6.2 Hz;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;2.65ppm(H-7a,1),dd,J=14.1Hz和6.1Hz;2.42-2.32ppm (H-4b和H-7b,2),m(在: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(在: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(在: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(125.8 MHz):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),40.63 ppm(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)。
曲前列尼尔钠盐一水合物(形式“A”)的DSC图展示于图15和16上。
曲前列尼尔钠盐一水合物(形式“A”)的XRPD图展示于图20上。
1t.)制备曲前列尼尔钠盐无水物(形式“B”)Mp.:125-129℃):
1t1.)可遵循实施例1s1-1s2-1s3中的任一程序,除了以下之外:
将得到的晶体滤出,洗涤并在真空中干燥在60-100℃。
1t2.)可遵循实施例1s1-1s2-1s3中的任一程序,将得到的晶体在60-100℃在真空中干燥。
1t3.)在60-90℃将曲前列尼尔钠盐一水合物在混悬液中在不溶解或仅微溶它的溶剂中搅动1-6小时。溶剂可为例如己烷、庚烷、甲苯或乙酸乙酯。
曲前列尼尔钠盐无水物(形式“B”)的DSC图展示于图17和18上。
曲前列尼尔钠盐无水物(形式“B”)的XRPD图展示于图21上。
1v.)制备曲前列尼尔钠盐多水合物(形式“C”):
1v1.)将曲前列尼尔钠盐一水合物(形式“A”)在60%水含量的气氛下保持在控制器(manipulator)中48小时,或将曲前列尼尔钠盐一水合物保持在空气中5-8天。
1v2.)将曲前列尼尔钠盐无水物(形式“B”)在60%水含量的气氛下保持在控制器中48小时,或保持在空气中5-8天。
曲前列尼尔钠盐多水合物(形式“C”)的DSC图展示于图19上。
曲前列尼尔钠盐多水合物(形式“C”)的XRPD图展示于图22上。
曲前列尼尔钠盐(无定形形式)的DSC图展示于图14上。
曲前列尼尔钠盐的表征:
热重分析(TGA)已通过TGA/SDTA851e,Mettler Toledo instrument进行。
差示扫描量热分析已通过DSC 1 Stare System,Mettler Toledo进行。
XRPD分析已通过XPERT-PRO-PANalytical instrument进行。
已经使用下述实验条件:
X-射线管名称:PW3373/10 Cu,阳极材料:Cu
使用的波长:预期的波长类型:Kα,Kα1 1,540598
扫描范围(°):2,0000-40,0014
实施例2.)
2a.)制备2-戊-4-炔氧基-四氢吡喃(MPKO-1)
在5.5 l蒸馏过的甲苯中溶解552 g 4-戊炔-1-醇。向溶液中加入677 ml 二氢吡喃和19.5 g对甲苯磺酸(PTSA)在120 ml四氢呋喃中的溶液。将反应混合物在室温搅拌。在反应结束时将混合物用三乙胺淬灭,用碳酸氢钠溶液和水洗涤。将有机相蒸发。将粗产物未经纯化地转移至下一步骤中。
收率:1062 g(96%)无色油。
NMR数据:
(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,(在: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,(在:3.50ppm(H-10b,1),m;3.48ppm(H-1b,1),dt,J=9.8 Hz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),(在: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,(在: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(125.8 MHz):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),19.65 ppm(C-8),15.48ppm(C-3)。
2b.)制备1-(2-烯丙基-3-甲氧基苯基)-6-四氢吡喃-2-基氧基-己-2-炔-1-醇(MPK-1)
在惰性气氛中将1062g MPKO-1溶解于8.5l无水四氢呋喃中,然后在 60-65℃缓慢加入1920ml乙基溴化镁溶液(3M在乙醚中的溶液)。将反应混合物搅拌45分钟,冷却并然后将927g VPK-5(2-烯丙基-3-甲氧基苯甲醛) 在930ml四氢呋喃中的溶液加入其中。在反应结束时将混合物用1M NaHSO4溶液淬灭,将水相用乙酸乙酯萃取,将合并的有机相用0.5MNaHCO3溶液和15%NaCl溶液洗涤,干燥并浓缩至2.4kg。将浓缩的粗产物未经纯化地转移至下一步骤中。
收率:100%(1812g)MPK-1,为淡棕色油。
NMR数据:
(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,与残余的CDCl3溶剂的峰部分重叠;6.86 ppm(H-4,1),d(d宽峰),J=8.0Hz;5.985ppm(H-14,1),ddt,J=17.1Hz,10.2 Hz和5.9Hz;5.62ppm(H-7,1),宽峰;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-16és H-21a,5),m, (在: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;3.55 ppm(H-13b,1),ddt,J=15.7Hz,5.9Hz和1.6Hz;3.505-3.43ppm(H-12b和 H-21b,2),m,(在: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),宽峰;1.87-1.75ppm (H-11和H-19a,3),m,(在: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,(在:1.565ppm(H-18b,1),m;1.56ppm(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),62.23 ppm(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)。
2c.)制备1-(2-烯丙基-3-甲氧基苯基)-6-四氢吡喃-2-基氧基-己-2-炔-1- 酮(MPK-2)
在惰性气氛中向12l乙酸乙酯中加入4kg氯铬酸吡啶鎓(PCC),然后加入1.7kg无水乙酸钠。将混悬液在室温搅拌15分钟,然后加入2.4kg在先前步骤中获得的MPK-1溶液。在反应结束时,将二异丙基醚和硅胶加入混合物中。在搅拌15-20分钟后,将混合物过滤,将硅胶用乙酸乙酯洗涤并将滤液溶液蒸发。将粗产物通过在硅胶柱上的色谱法纯化,使用己烷:乙酸乙酯的梯度混合物作为洗脱剂。收集含有产物的级分,浓缩,用水洗涤,经硫酸钠干燥,将干燥的物质滤出并将滤液溶液蒸发。
收率:1246g(69%)淡棕色油。
NMR数据:
(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宽峰),J=8.0Hz;5.97 ppm(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,(在: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,(在: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;1.64-1.46 ppm(H-18b,H-19b和H-20,4),m,(在: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)。
2d.)制备(1S)-1-(2-烯丙基-3-甲氧基苯基)-6-四氢吡喃-2-基氧基-己-2-炔 -1-醇(MPK-3)
在惰性气氛下将1246g MPK-2溶解于6.3l无水四氢呋喃中。将溶液冷却至0-5℃并加入5.73l R-(+)-2-甲基-CBS-氧氮硼杂环戊烷在1M甲苯中的溶液。然后将混合物冷却至(-40)-(-35)℃并加入925ml硼烷-二甲基硫醚络合物。在反应结束时将混合物用甲醇和5%NH4Cl溶液淬灭,将水相用乙酸乙酯萃取,将有机相用水洗涤,干燥,过滤并蒸发。将粗产物通过使用己烷:乙酸乙酯混合物洗脱剂的硅胶柱色谱纯化。
收率:1178g(94%)淡棕色油。
NMR数据:
(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=10.1Hzés 1.8Hz;4.94ppm(H-15b,1),dq,J=17.2Hz和1.7 Hz;4.57ppm(H-17,1),m,J=2.4Hz;3.91-3.74ppm(H-12a,H-16和H-21a,5), m,(在: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,(在:3.475 ppm(H-21b,1),m;3.47ppm(H-12b,1),m(dt),J=9.7Hz和6.1Hz);2.44-2.20 ppm(OH-7和H-10,3),m,(在:2.37ppm(H-10,2),td,J=7.1Hz和1.6Hz;2.30 ppm(OH-7,1),宽峰);1.90-1.75ppm(H-11和H-19a,3),m,(在: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,(在: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),66.03 ppm(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)。
2e.)制备[(1S)-1-(2-烯丙基-3-甲氧基苯基)-6-四氢吡喃-2-基氧基-己-2-炔 -1-氧基]叔丁基二甲基甲硅烷(MPK-4)
将在先前的步骤中获得的粗制的MPK-3(理论量1253g)溶解于10l甲苯中并向溶液中加入409g咪唑。将反应混合物冷却至5-10℃并加入2.02l 叔丁基二甲基氯硅烷(TBDMS-Cl)在50%甲苯中的溶液。将混合物在室温搅拌。在反应结束时,将水加入至混合物中并滤出不溶性杂质。将滤液残余物用甲苯洗涤,分离滤液的各相,将有机相蒸发。将粗产物通过使用己烷:乙酸乙酯混合物作为洗脱剂的硅胶柱色谱纯化。
收率:1515g(91%)淡棕色油。
NMR数据:
(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;5.575 ppm(H-7,1),t,J=1.7Hz;5.00-4.90ppm(H-15,2),m,(在:4.97ppm(H-15a,1), dq,J~10.2Hz和1.6Hz;4.94ppm(H-15b,1),dq,J~16.9Hz和1.8Hz);4.55 ppm(H-17,1),m;3.87-3.73ppm(H-12两种非对映异构体,H-16和H-21a,5), m,(在: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,(在: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;1.86-1.73 ppm(H-11和H-19a,3),m,(在: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-19bés H-20, 4),m,(在: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):157.47 ppm(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66.13 ppm(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)。
2f.)制备(9R)-9-[叔丁基(二甲基)甲硅烷基]氧基-5-甲氧基-1-(3-四氢吡喃 -2-基氧基丙基)-3,3a,4,9-四氢环戊二烯并[b]萘-2-酮(MPK-5)
在惰性气氛中将1427g MPK-4溶解在11.5l二甲氧基乙烷中,然后加入1070g八羰基二钴。将反应混合物在室温搅拌2.5小时,然后将其加热至 60-70℃并搅拌3小时。在反应结束时,使空气通过混合物鼓泡。鼓泡持续过夜。然后将反应混合物过滤,用乙酸乙酯洗涤并蒸发。将粗产物通过使用己烷:二异丙基醚混合物作为洗脱剂的硅胶柱色谱纯化。
收率:1363g(90%)淡棕色油。
NMR数据:
(CDCl3),1H NMR(500MHz):7.22ppm(H-22,1),t,J=7.9Hz;6.96-6.87 ppm(H-23,1),m(在: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(在:3.81 ppm(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(在: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(在:3.52ppm (H-4a,0.5),dd,J=17.1Hz和7.4Hz;3.51ppm(H-4a,0.5),dd,J=17.0and 7.4 Hz);3.43-3.27ppm(H-9,H-15b,H-28b,2.5),m(在: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);3.06 ppm(H-15b,0.5),ddd,J=9.5Hz,8.6Hz和4.8Hz;2.745-2.65ppm(H-10a,1),m (在: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(在: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(在:2.212ppm(H-10b,0.5),dd,J=18.8Hz和1.3 Hz;2.210ppm(H-10b,0.5),dd,J=18.8Hz和1.3Hz);2.175-2.07ppm(H-4b,1), m(在:2.13ppm(H-4b,0.5),dd,J=17.1Hz和8.9Hz;2.115ppm(H-4b,0.5),dd, J=17.1and 8.9Hz);1.875-1.72ppm(H-14a和H-26,2),m(在: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(在: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(在:1.53ppm(H-25b,1),m;1.51 ppm(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)(在: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(在: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125.10 ppm(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),25.77 ppm(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)。
2g.)制备(9aS)-5-甲氧基-1-(3-四氢吡喃-2-基氧基丙基)-1,3,3a,4,9,9a-六氢环戊二烯并[b]萘-2-酮(MPK-6)
将1363g MPK-5溶解于5.5l乙醇中,加入60g碳酸钠和480g 10% Pd(C)催化剂,并且在适当的惰性化之后,将反应混合物在6巴氢气压下在室温搅拌。在反应结束时,将催化剂滤出,用乙醇洗涤并将滤液溶液蒸发。将粗产物通过使用己烷:乙酸乙酯混合物作为洗脱剂的硅胶柱色谱纯化。
收率:703g(70%)淡棕色油。
NMR数据:
(CDCl3),1H NMR(500MHz):7.10ppm(H-22,1),t,J=7.9Hz,6.74-6.64 ppm(H-21和H-23,2),m(在: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(在: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(在:3.51 ppm(H-28b,1),m;3.44ppm(H-15b,1),m),2.95ppm(H-4a,1),m(dd),J=18.3 Hz和7.4Hz,2.80ppm(H-4b,1),d,J=18.2Hz;2.77-2.625ppm(H-7a和H-9,2), m(在: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(在: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(在: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(在: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(在: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),41.86 ppm(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)。
2h.)制备(1R,2R,9aS)-5-甲氧基-1-(3-四氢吡喃-2-基氧基丙基)-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-醇(MPK-7)
将703g MPK-6溶解于14l乙醇中,将溶液冷却并在(-)15-(-)10℃加入 42g硼氢化钠。将反应混合物搅动。在反应结束时,将混合物用乙酸淬灭并蒸馏除去乙醇。在加入水和乙酸乙酯后,分离各相,将水相用乙酸乙酯萃取。将合并的有机相用1M NaHCO3溶液和水洗涤,干燥,过滤并蒸发。将粗产物未经纯化地转移至下一步骤中。
收率:636g(90%)淡棕色油。
NMR数据:
(CDCl3),1H NMR(500MHz):7.125-7.04ppm(H-22,1),m(在: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(在: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(在: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);3.87 ppm(H-28a,0.5),m(ddd);3.84-3.67ppm(H-2,H-11,H-15a和H-28a,5.5),m (在: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(在:3.50ppm(H-28b,0.5),m;3.48ppm(H-28b, 0.5),m);3.46-3.36ppm(H-15b,1),m(在: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(在: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(在: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;2.455 ppm(H-7b,1),dd,J=14.3Hz和6.4Hz);2.30-2.04ppm(H-9,H-10和OH-11, 2.5),m(在: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,7.1 Hz和6.3Hz;2.15ppm(OH-11,0.5),宽峰);2.00ppm(OH-11,0.5),1.93-1.64 ppm(H-8,H-14,H-25a和H-26a,5),m(在: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(在: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);1.38-1.20 ppm(H-12,1),m(在: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(在: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),108.43 ppm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41.53 ppm(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19.69 ppm(C-26)。
2i.)制备4-苯基苯甲酸[(1R,9aS)-5-甲氧基-1-(3-四氢吡喃-2-基氧基丙基)-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(MPK-8)
在惰性气氛中将636g MPK-7溶解于1.4l吡啶中并将508g对苯基苯甲酰氯加入至溶液中。将反应混合物在50-60℃搅拌。在反应结束时,加入水和叔丁基甲基醚,分离各相,将水相用叔丁基甲基醚萃取。将合并的有机相接连用NaHSO4溶液、K2CO3溶液和水洗涤,干燥,过滤和蒸发。将粗产物通过使用己烷:乙酸乙酯混合物作为洗脱剂的硅胶色谱纯化。
收率:763g(80%)白色晶体。Mp:140-143℃。
NMR数据:
(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(在: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;7.14 ppm(H-22,1),t,J=7.8Hz;6.82ppm(H-23,1),m(d/d宽峰),J=7.4Hz;6.77 ppm(H-21,1),d,J=8.2Hz;5.03ppm(H-11,1),td,J=8.4Hz和6.3Hz;4.565 ppm(H-24,1),m;3.895-3.79ppm(H-2和H-28a,4),m(在:3.85ppm(H-28a,1),m;3.82ppm(H-2,3),s);3.79-3.72ppm(H-15a,1),m(在: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);3.48 ppm(H-28b,1),m;3.45-3.375ppm(H-15b,1),m(在: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(在:2.91ppm(H-4a,1),dd,J=14.9Hz和6.2 Hz;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(在:2.589ppm(H-7b,0.5),m(dd),J=14.4Hz和6.9Hz;2.587 ppm(H-7b,0.5),m(dd),J=14.6Hz和7.0Hz;2.535ppm(H-4b,1),dd,J=14.9 Hz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(在: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(125.8 MHz):166.44ppm(C-29),156.64ppm(C-3),145.64ppm(C-33),140.26ppm (C-6);140.21ppm(C-34),130.20ppm(C-31és C-31’,2),129.44ppm(C-30), 129.03ppm(C-36和C-36’,2),128.21ppm(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),120.58 ppm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),25.92 ppm(C-4),25.61ppm(C-27),19.81ppm和19.80ppm(C-26)。
2j.)制备4-苯基苯甲酸[(1R,2R,9aS)-1-(3-羟基丙基)-5-甲氧基 -2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(MPK-9)
将574g MPK-8溶解于1.2l四氢呋喃中。加入4.6L甲醇,然后小心地加入145ml浓盐酸和145ml水的混合物。在反应结束时,将混合物用1M NaHCO3溶液淬灭并蒸馏除去溶剂。将残余的水相用乙酸乙酯萃取,将合并的有机相用水洗涤,干燥,过滤并蒸发。将蒸发的粗产物通过硅胶色谱纯化。
收率:376g(78%)无色油。
NMR数据:
(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(在: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;7.14 ppm(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(在: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(在: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(在: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(在: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),120.58 ppm(C-23),108.45ppm(C-21),79.86ppm(C-11),63.29ppm(C-15),55.65 ppm(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)。
2k.)制备4-苯基苯甲酸[(1R,9aS)-5-甲氧基-1-(3-氧代丙基)-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(MPK-10)
在惰性气氛中将140ml草酰氯溶解于4.2l二氯甲烷中。将溶液冷却至 (-)-60℃并加入227ml二甲基亚砜在1130ml二氯甲烷中的溶液,然后在搅拌后加入376g MPK-9在690ml二氯甲烷中的溶液。搅拌在(-)-60℃继续进行。在反应结束时,通过加入830ml三乙胺淬灭混合物。将混合物在未冷却的情况下搅动1小时,然后将温度升高至10℃并加入1M NaHSO4溶液。将水相用二氯甲烷萃取,将合并的有机相用水洗涤,干燥并蒸发。将粗产物首先通过使用己烷:乙酸乙酯混合物作为洗脱剂的硅胶柱色谱纯化,然后通过从甲苯:己烷混合物结晶来纯化。
收率:374g(100%)白色晶体。Mp:94-96℃。
NMR数据:
(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(在: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;7.39 ppm(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=8.3 Hz和6.3Hz;3.82ppm(H-2,3),s;2.935-2.79ppm(H-4a和H-7a,2),m(在:2.865ppm(H-4a,1),dd,J=14.9Hz和6.1Hz;2.835ppm(H-7a,1),dd,J=14.4 Hz和6.3);2.65-2.53ppm(H-4b,H-7b和H-14,4),m(在: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(在: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(在:2.02ppm(H-8,1),m,1.94ppm (H-13a,1),m);1.85-1.73ppm(H-12和H-13b,2),m(在: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),37.91 ppm(C-10),33.53ppm(C-9),33.29ppm(C-7),25.73ppm(C-4),24.69ppm (C-13)。
2l1.)制备4-苯基苯甲酸[(1R,2R,9aS)-1-[(3S)-3-羟基辛基]-5-甲氧基 -2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(PPB-TREP-14)
在惰性气氛中向4.5l蒸馏过的甲苯中加入7.5g MIB*催化剂,然后加入1800ml二戊基锌。将混合物在室温搅动。搅动1小时后,在室温加入300 g MPK-10在1.5l蒸馏过的甲苯中的溶液并搅拌混合物,直到偶联反应进行。然后,在强烈搅动下,将反应混合物倒在盐酸溶液上。持续搅拌,直到锌盐的完全分解,然后用乙酸乙酯萃取产物。将有机相用水和饱和氯化钠溶液洗涤,然后蒸发。将粗产物通过使用甲苯:叔丁基甲基醚混合物作为洗脱剂的硅胶柱梯度色谱法纯化。
收率:300g(86%)黄色油。
NMR数据:
(CDCl3),1H NMR(500MHz):8.05ppm(H-31和H-31’,2),m(d),J=8.3 Hz;7.68-7.53ppm(H-32,H-32’,H-35和H-35’,4),m(在: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),7.46 ppm(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,5.05ppm(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(在: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(在:2.585ppm(H-7b,1),dd,J=14.5 Hz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(在:2.47ppm(H-10a,1),ddd,J=12.3Hz,7.6Hz和6.4Hz;2.41 ppm(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(在:1.675ppm(H-13a,1),m;1.62 ppm(H-14a,1),m;1.59ppm(H-13b,1),m;1.545ppm(H-14b,1),m);1.48-1.33 ppm(H-10b,H-16,H-17a and OH-15,5),m(在:1.43ppm(H-16a,1),m;1.41 ppm(H-17a,1),m;1.40ppm(H-16b,1),m;1.39ppm(H-10b,1),m),1.33-1.17 ppm(H-17b,H-18和H-19,5),m(在: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),140.21 ppm/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),120.60 ppm(C-23),108.45ppm(C-21),79.83ppm(C-11),73.13ppm(C-15),55.66 ppm(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),14.16 ppm(C-20)。
*MIB催化剂:(2S)-3-外-(吗啉代)异冰片,M:239.35,C14H25NO2
制备二戊基锌
向550g凡士林中加入267g锌-铜合金(alloy)(10%铜,90%锌)。在惰性气氛中将混合物加热至约60℃,然后开始搅动并将混合物加热至160℃。在持续回流和强烈冷却的条件下,加入188ml 1-戊基碘和186ml 1-戊基溴的混合物。在加入后,在保持该温度的条件下,将搅动持续1小时。然后将混合物冷却至约60℃。在0.5-1.5毫巴真空下在110-150℃的内部温度蒸馏出产物。
2l.2)制备4-苯基苯甲酸[(1R,2R,9aS)-1-[(3S)-3-羟基辛基]-5-甲氧基-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-基]酯(PPB-TREP-14)
将溶解1.3ml Ti(OiPr)4在16ml二氯甲烷中,并在冷却至(-)70℃后将1.1 ml(2.2mmol)戊基溴化镁(2M在乙醚中的溶液)加入至混合物中。将100mg (0.22mmol)MPK-10、10mg(R)-(+)-1,1′-二(2-萘酚)和0.4ml Ti(OiPr)4溶解在 4ml二氯甲烷中,将溶液冷却至0/+5℃并将戊基溴化镁试剂溶液加入其中。在0/+5℃持续搅拌。在反应结束时,小心地加入2ml 1:1盐酸-水混合物。分离各相,将有机相用5ml水洗涤,干燥和蒸发。粗产物含有0-20%的15- 表-PPB-TREP-14异构体。将产物通过使用己烷:乙酸乙酯混合物作为洗脱剂的硅胶色谱纯化。
收率:90mg(77%)黄色油。
2m.)制备(1R,2R,3aS,9aS)-1-[(3S)-3-羟基辛基]-5-甲氧基-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[b]萘-2-醇(TREP-14)
将250g PPB-TREP-14溶解在1l四氢呋喃中,向溶液中加入2.5l甲醇和150g碳酸钠并将混合物在45℃搅拌。在反应结束时,用稀磷酸将混合物的pH设定为2-4,滤出析出的晶体并用甲醇洗涤。将滤液溶液浓缩,向浓缩的产物溶液中加入乙酸乙酯,分离各相,将水相用乙酸乙酯萃取,将合并的有机相用氯化钠溶液洗涤并蒸发。将粗产物通过使用己烷:乙酸乙酯混合物作为洗脱剂的硅胶柱色谱纯化。将蒸发的主要级分在二异丙基醚:己烷混合物中结晶。
收率:125g(76%)白色晶体。Mp:71-72℃。
Claims (60)
1.用于制备式I的曲前列尼尔及其与碱的无定形盐形式、盐无水物以及盐的一水合物和多水合物的方法,
其特征在于,
使通式XVII的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,
前提条件是R1保护基必须可选择性地从R2和R4移除,
x表示0或2-
和通式XVI的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团并且n表示1、2、3、4-
a1.)在格氏试剂的存在下反应,并且将所得到的通式XV的化合物
-其中在该式中x、R1和R2具有如上面所定义的含义-
氧化,
将所得到的通式XIV的化合物
-其中在该式中x、R1和R2具有如上面所定义的含义-
选择性地还原,或
a2.)在手性碱和锌盐的存在下反应,和
将步骤a1.)或a2.)中获得的通式XIII的化合物
-其中在该式中x、R1和R2具有如上面所定义的含义-
与适合于引入基团R3的化合物反应
-其中R3表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-或C1-13酰基-基团-,
b.)使所得到的通式XII的化合物
-其中在该式中x、R1、R2和R3具有如上面所定义的含义-
经历分子内环化,
c.)将所得到的通式XI的化合物
-其中在该式中x、R1、R2和R3具有如上面所定义的含义-
催化氢化,并且在其中x=0的情况下,将其异构化,
d.)将所得到的通式Xa.或Xb.的化合物
-其中在该式中R1、R2具有如上面所定义的含义,并且在式Xa.的化合物中x=0,在式Xb.的化合物中x=2-,
还原,
e.)将所得到的通式IX的化合物
-其中在该式中x、R1和R2具有如上面所定义的含义-
与适合于引入基团R4的化合物反应
-其中R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,并且R1必须可选择性地从R4移除,
f.)在酸性介质中从所得到的通式VIII的化合物
-其中在该式中x、R1、R2和R4具有如上面所定义的含义-
裂解R1保护基,
g.)将所得到的通式VII的化合物
-其中在该式中x、R2和R4具有如上面所定义的含义-
氧化,
h.)将所得到的通式VI的化合物
-其中在该式中x、R2和R4具有如上面所定义的含义-
h1.)在其中x表示0的情况下,与以下通式化合物在Wittig反应中反应
CH3-(CH2)4-CO-CH2-PO(OR6)2
-其中R6表示C1-4烷基-或苯基-基团-,和
将所得到的通式V的化合物
-其中在该式中R2和R4具有如上面所定义的含义-
选择性地还原,和
将所得到的通式IVa.的化合物的R4保护基
-其中在该式中R2和R4具有如上面所定义的含义-
R4移除,和
将所得到的通式III的化合物
-其中在该式中R2具有如上面所定义的含义-
氢化,或
h2.)在其中x表示2的情况下,在手性催化剂的存在下与有机金属试剂反应,和
将所得到的通式IVb.的化合物的保护基R4
-其中在该式中R2和R4具有如上面所定义的含义-
R4移除,
i)将步骤h1.)或h2.)中获得的通式II的化合物
-其中在该式中R2具有如上面所定义的含义-
通过已知方法转化为式I的曲前列尼尔,并且如果需要的话,转化为其与碱的盐。
2.如权利要求1中定义的方法,其特征在于,作为R1保护基,应用甲氧基甲基-、甲氧基乙氧基甲基-或四氢吡喃基-基团;作为R2保护基,应用甲基基团;作为R3保护基,应用含有硅原子的保护基,优选叔丁基二甲基甲硅烷基基团;作为R4保护基,应用对苯基苯甲酰基基团。
3.如权利要求1a1中定义的方法,其特征在于,作为格氏试剂,应用甲基-、乙基-、丙基-、丁基-、环己基-溴化镁,优选甲基溴化镁。
4.如权利要求1a1中定义的方法,其特征在于,式XV的化合物的氧化用氯铬酸吡啶鎓进行。
5.如权利要求1a1中定义的方法,其特征在于,式XV的化合物的氧化通过Swern氧化进行。
6.如权利要求1a1中定义的方法,其特征在于,还原在手性氧氮硼杂环戊烷催化剂的存在下用硼烷化合物进行。
7.如权利要求6中定义的方法,其特征在于,作为硼烷化合物,应用硼烷-二甲基硫醚络合物、儿茶酚硼烷或硼烷-二乙基苯胺络合物,优选硼烷-二甲基硫醚络合物。
8.如权利要求1a2中定义的方法,其特征在于,作为手性碱,应用手性氨基醇或二胺,优选(+)-N-甲基麻黄碱。
9.如权利要求1a2中定义的方法,其特征在于,作为锌盐,应用三氟甲磺酸锌。
10.如权利要求1b中定义的方法,其特征在于,分子内环化通过Pauson-Khand环化方法进行。
11.如权利要求10中定义的方法,其特征在于,Pauson-Khand环化通过使用八羰基二钴进行。
12.如权利要求11中定义的方法,其特征在于,八羰基二钴以等摩尔量或小于等摩尔量或大于等摩尔量应用。
13.如权利要求10-12中定义的方法,其特征在于,反应在一氧化碳气氛下进行。
14.如权利要求10-13中定义的方法,其特征在于,反应在乙酸乙酯中进行。
15.如权利要求1c中定义的方法,其特征在于,对于式XI.的化合物的氢化,作为催化剂,应用Pd/C或氧化铂催化剂,优选Pd/C催化剂。
16.如权利要求1d中定义的方法,其特征在于,式X的化合物的还原用二异丁基氢化铝、氢化铝锂、异丙醇铝或硼氢化钠,优选硼氢化钠进行。
17.如权利要求1e中定义的方法,其特征在于,作为适合于引入基团R4的化合物,应用对苯基苯甲酰氯。
18.如权利要求1f中定义的方法,其特征在于,含有硅原子的R1保护基是苯基二甲基甲硅烷基-、三乙基甲硅烷基-、三异丙基甲硅烷基-、叔丁基二甲基甲硅烷基-或叔丁基二苯基甲硅烷基-基团。
19.如权利要求1g中定义的方法,其特征在于,式VII的化合物的氧化在Swern条件下进行,或用TEMPO进行,或在Pfitzner-Moffat条件下进行。
20.根据权利要求1h1的方法,其特征在于,式V.的化合物的还原在氧氮硼杂环戊烷催化剂的存在下用硼烷化合物进行。
21.如权利要求20中定义的方法,其特征在于,作为硼烷化合物,应用儿茶酚硼烷、硼烷-二乙基苯胺络合物、硼烷-二甲基硫醚络合物,优选硼烷-二甲基硫醚络合物。
22.如权利要求1h2中定义的方法,其特征在于,作为有机金属试剂,应用二戊基锌或戊基溴化镁。
23.如权利要求1h2中定义的方法,其特征在于,作为手性催化剂,应用(2S)-3-外-(吗啉代)异冰片。
24.根据权利要求1i的方法,其特征在于,通式III.的化合物的氢化在催化剂的存在下进行。
25.根据权利要求24的方法,其特征在于,应用的催化剂是氧化铂催化剂、Pd/C催化剂,优选Pd/C催化剂。
26.根据权利要求1i的方法,其特征在于,R4保护基为含有硅原子的保护基(苯基二甲基甲硅烷基-、三乙基甲硅烷基-、三异丙基甲硅烷基-、叔丁基二甲基甲硅烷基-或叔丁基二苯基甲硅烷基-基团)、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,并且R1必须可选择性地从R4移除。
27.根据权利要求1i的方法,其特征在于,R4保护基的裂解通过在碱的存在下的甲醇解进行。
28.用于制备式I的曲前列尼尔与碱的无定形形式、无水物盐及其一水合物和多水合物的方法
其特征在于,将曲前列尼尔溶解于极性溶剂中,将碱加入该溶液中,搅动反应混合物,在盐形成结束时,将溶液过滤,浓缩,将浓缩物的溶剂交换为结晶的有机溶剂,并结晶曲前列尼尔盐。
29.如权利要求1和28中定义的用于制备式I的曲前列尼尔与碱的盐的方法,其特征在于,作为极性溶剂,应用C1-5开链或支链有机醇,优选乙醇。
30.如权利要求1和28中定义的用于制备式I的曲前列尼尔与碱的盐的方法,其特征在于,对于碱而言,应用含有期望的盐的阳离子的无溶剂的有机或无机碱。
31.如权利要求30中定义的用于制备式I的曲前列尼尔与碱的盐的方法,其特征在于,对于碱而言,应用含有碱金属或碱土金属阳离子的有机或无机碱。
32.如权利要求31中定义的用于制备式I的曲前列尼尔与碱的盐的方法,其特征在于,对于碱而言,应用碳酸钠一水合物、碳酸氢钠、甲醇钠,优选碳酸钠水合物。
33.如权利要求1和28中定义的用于制备式I的曲前列尼尔与碱的盐的方法,其特征在于,将反应混合物在惰性气氛中搅动直到盐形成进行。
34.如权利要求1和28中定义的用于制备式I的曲前列尼尔与碱的盐的方法,其特征在于,作为结晶的有机溶剂,应用醚-、酯-或酮-型溶剂。
35.如权利要求1和28中定义的用于制备式I的曲前列尼尔与碱的盐的方法,其特征在于,作为醚-型溶剂,应用支链或开链简单或混合醚,优选叔丁基甲基醚。
36.如权利要求1和28中定义的用于制备式I的曲前列尼尔与碱的一水合物盐的方法,其特征在于,在50℃-(-40℃)的温度,优选在室温进行结晶。
37.如权利要求36中定义的用于制备式I的曲前列尼尔的一水合物盐的方法,其特征在于,在20-50℃的温度在真空中干燥晶体。
38.如权利要求34和37中定义的用于制备式I的曲前列尼尔的一水合物盐的方法,其特征在于,结晶的有机溶剂是已经用水饱和的有机溶剂。
39.如权利要求34和37中定义的用于制备式I的曲前列尼尔与碱的无定形盐的方法,其特征在于,结晶的有机溶剂是无水的有机溶剂。
40.如权利要求1和28中定义的用于制备式I的曲前列尼尔与碱的无水物盐的方法,其特征在于,在60-100℃的温度在真空中干燥晶体。
41.如权利要求1和28中定义的用于制备式I的曲前列尼尔与碱的多水合物盐的方法,其特征在于,将晶体保持在20-80%水含量的气氛下至少48小时,或在空气中保持5-10天。
42.通式III的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团并且n表示1、2、3、4-,前提条件是-COOR5中的R5不能表示C1-4烷基。
43.通式IV的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,n表示1、2、3、4,
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,和
虚线表示单键或双键。
44.通式V的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,n表示1、2、3、4,和
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除。
45.上述通式VI的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,和
x表示0或2。
46.通式VII的化合物
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,和
x表示0或2。
47.通式VIII的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,和
x表示0或2。
48.通式IX的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,和
x表示0或2。
49.通式X的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,和
x表示0或2。
50.通式XI的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,
R3表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-或C1-13酰基-基团,和
x表示0或2。
51.通式XII的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,
R3表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-或C1-13酰基-基团,和
x表示0或2。
52.通式XIII的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,和
x表示0或2。
53.通式XIV的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,和
x表示0或2。
54.通式XV的化合物
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,和
x表示0或2。
55.式I的曲前列尼尔的钠盐一水合物。
56.式I的曲前列尼尔的无定形钠盐。
57.式I的曲前列尼尔的钠盐无水物。
58.式I的曲前列尼尔的钠盐多水合物(3-5mol水含量)。
59.通式III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV和XV的曲前列尼尔中间体
-其中在该式中
R1表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-基团,前提条件是R1保护基必须可选择性地从R2和R4移除,
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,
n表示1、2、3、4,
R3表示含有硅原子的保护基、四氢吡喃基-、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-、苄基氧基甲基-或C1-13酰基-基团,
R4表示含有硅原子的保护基、三苯甲基-、甲氧基三苯甲基-、对甲氧基苄基-、甲氧基甲基-、乙氧基甲基-、甲氧基乙氧基甲基-、甲硫基甲基-、苄基氧基甲基-或C1-13酰基-基团,前提条件是R4保护基必须可选择性地从R2移除,
x表示0或2,和
虚线表示单键或双键,前提条件是在通式III的化合物中,Y不能表示腈或-COOR5,其中R5表示C1-4烷基。
60.根据权利要求1的方法,其特征在于,通式II的化合物的R2基团的移除在碱卤化物的存在下用十二烷基硫醇进行
-其中在该式中
R2表示-(CH2)nY,其中
Y表示氢原子、卤素原子、苯基-、腈-、-OR5或-COOR5基团,其中
R5表示C1-4烷基-、四氢吡喃基-、三(C1-4)烷基甲硅烷基-或(C1-4)烷基-二(C6-10)芳基甲硅烷基-基团,和
n表示1、2、3、4。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110561010.2A CN113292419A (zh) | 2014-10-08 | 2015-09-28 | 用于制备曲前列尼尔的方法 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU1400475A HU231186B1 (hu) | 2014-10-08 | 2014-10-08 | Új eljárás treprostinil és sói előállítására |
HUP1400475 | 2014-10-08 | ||
PCT/HU2015/000065 WO2016055819A1 (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110561010.2A Division CN113292419A (zh) | 2014-10-08 | 2015-09-28 | 用于制备曲前列尼尔的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107001221A true CN107001221A (zh) | 2017-08-01 |
CN107001221B CN107001221B (zh) | 2021-05-25 |
Family
ID=89991608
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110561010.2A Pending CN113292419A (zh) | 2014-10-08 | 2015-09-28 | 用于制备曲前列尼尔的方法 |
CN201580066416.6A Active CN107001221B (zh) | 2014-10-08 | 2015-09-28 | 用于制备曲前列尼尔的方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110561010.2A Pending CN113292419A (zh) | 2014-10-08 | 2015-09-28 | 用于制备曲前列尼尔的方法 |
Country Status (14)
Country | Link |
---|---|
US (3) | US10322990B2 (zh) |
EP (1) | EP3204349A1 (zh) |
JP (2) | JP6820255B2 (zh) |
KR (2) | KR102651020B1 (zh) |
CN (2) | CN113292419A (zh) |
AU (1) | AU2015329740B2 (zh) |
CA (1) | CA2963844C (zh) |
HU (2) | HU231186B1 (zh) |
IL (1) | IL251613B (zh) |
MX (1) | MX2017004672A (zh) |
RU (1) | RU2709200C2 (zh) |
SG (1) | SG11201702790YA (zh) |
TW (2) | TWI761299B (zh) |
WO (1) | WO2016055819A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111801313A (zh) * | 2018-03-09 | 2020-10-20 | 奇诺因药物和化学工厂私人有限公司 | 用于制备曲前列环素二乙醇胺盐的多晶型b的方法 |
WO2020233588A1 (zh) * | 2019-05-21 | 2020-11-26 | 江苏众强药业有限公司 | 曲前列尼尔钠盐新晶型及制备方法 |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9505737B2 (en) | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
EP3712142B1 (en) | 2013-01-11 | 2022-07-06 | Corsair Pharma, Inc. | Prodrugs of treprostinil |
US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
US9394227B1 (en) | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
ES2909890T3 (es) | 2016-01-27 | 2022-05-10 | Emcure Pharmaceuticals Ltd | Proceso de preparación de derivados de prostaciclina |
KR101830693B1 (ko) * | 2016-04-28 | 2018-02-21 | 연성정밀화학(주) | 트레프로스티닐의 제조방법 및 이를 위한 중간체 |
US20180153847A1 (en) | 2016-09-26 | 2018-06-07 | United Therapeutics Corporation | Treprostinil prodrugs |
KR102084044B1 (ko) * | 2018-12-24 | 2020-03-03 | 주식회사 세미부스터 | 인산용액 중의 실리콘 농도 분석방법 |
EP4017588A1 (en) | 2019-08-23 | 2022-06-29 | United Therapeutics Corporation | Treprostinil prodrugs |
US10781160B1 (en) * | 2019-10-04 | 2020-09-22 | Chirogate International Inc. | Hexadecyl Treprostinil crystals and methods for preparation thereof |
US11339110B2 (en) * | 2019-12-19 | 2022-05-24 | Chirogate International Inc. | Efficient crystallization process for preparing ultrapure Treprostinil and crystal prepared therefrom |
IL296567A (en) | 2020-04-17 | 2022-11-01 | United Therapeutics Corp | Terfostinil for use in the treatment of interstitial lung disease |
CA3180230A1 (en) | 2020-06-09 | 2021-12-16 | Hitesh Batra | Fumaryl diketopiperidine prodrugs of treprostinil |
US11447440B2 (en) * | 2020-10-29 | 2022-09-20 | Chirogate International Inc. | Treprostinil monohydrate crystals and methods for preparation thereof |
WO2022132655A1 (en) | 2020-12-14 | 2022-06-23 | United Therapeutics Corporation | Methods of treating disease with treprostinil prodrugs |
CN117479946A (zh) | 2021-03-03 | 2024-01-30 | 联合治疗公司 | 含曲前列环素及其前药并还包含(e)-3,6-双[4-(n-羰基-2-丙烯基)酰胺丁基]-2,5-二酮哌嗪(fdkp)的干粉组合物 |
WO2023154705A1 (en) | 2022-02-08 | 2023-08-17 | United Therapeutics Corporation | Treprostinil iloprost combination therapy |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1283184A (zh) * | 1997-10-24 | 2001-02-07 | 联合治疗公司 | 前列环素衍生物的立体选择合成方法 |
US20090163738A1 (en) * | 2007-12-17 | 2009-06-25 | United Therapeutics Corporation | Process to prepare treprostinil, the active ingredient in remodulin |
WO2009158010A1 (en) * | 2008-06-27 | 2009-12-30 | Concert Pharmaceuticals, Inc. | Prostacyclin analogs |
CN102015613A (zh) * | 2008-05-08 | 2011-04-13 | 联合治疗公司 | 曲前列素一水合物 |
WO2012009816A1 (en) * | 2010-07-22 | 2012-01-26 | Alphora Research Inc. | Synthesis of treprostinil and intermediates useful therein |
WO2012088607A1 (en) * | 2010-12-30 | 2012-07-05 | Alphora Research Inc. | Process for treprostinil salt preparation |
CN102952157A (zh) * | 2011-08-24 | 2013-03-06 | 佳和桂科技股份有限公司 | 用于合成苯并茚前列腺素的中间体和其制备 |
CN103261142A (zh) * | 2010-06-03 | 2013-08-21 | 联合治疗公司 | 曲前列环素的制备 |
WO2013174848A2 (en) * | 2012-05-23 | 2013-11-28 | Scipharm Sàrl | Improved process for the preparation of treprostinil and derivatives thereof |
US20140275616A1 (en) * | 2013-03-15 | 2014-09-18 | United Therapeutics Corporation | Salts of treprostinil |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4338457A (en) | 1980-02-28 | 1982-07-06 | The Upjohn Company | Composition and process |
CA1313670C (en) | 1980-02-28 | 1993-02-16 | Robert Charles Kelly | Carbacyclin analogs |
US6441245B1 (en) | 1997-10-24 | 2002-08-27 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
EP1045695B1 (en) | 1997-11-14 | 2004-03-24 | United Therapeutics Corporation | Use of 9-deoxy-2', 9-alpha-methano-3- oxa-4,5,6- trinor-3, 7-(1',3'-interphenylene) -13,14-dihydro- prostaglandin f 1? to treat peripheral vascular disease |
EP2792353B1 (en) * | 2003-05-22 | 2018-02-28 | United Therapeutics Corporation | Polymorph of Treprostinil diethanolamine salt |
JP5038031B2 (ja) | 2006-07-11 | 2012-10-03 | キヤノン株式会社 | 放射線撮影装置、その駆動方法及び放射線撮影システム |
CN102040618B (zh) | 2009-04-30 | 2013-09-04 | 上海天伟生物制药有限公司 | 一种PGF2a类似物的制备方法及其相关中间体 |
CN102906520B (zh) | 2010-11-19 | 2014-11-12 | 岛产业株式会社 | 干燥减容处理装置 |
EP2495235B1 (en) * | 2011-03-04 | 2015-08-05 | Newchem S.p.A. | Process for the synthesis of prostaglandins and intermediates thereof |
CN103193627B (zh) * | 2012-01-10 | 2016-04-20 | 上海天伟生物制药有限公司 | 一种前列腺素类似物的晶型及其制备方法和用途 |
CN110590547A (zh) * | 2012-12-07 | 2019-12-20 | 开曼化学股份有限公司 | 前列环素衍生物的合成方法 |
EP3712142B1 (en) * | 2013-01-11 | 2022-07-06 | Corsair Pharma, Inc. | Prodrugs of treprostinil |
EP3169660A1 (en) * | 2014-07-16 | 2017-05-24 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
-
2014
- 2014-10-08 HU HU1400475A patent/HU231186B1/hu unknown
- 2014-10-08 HU HU1900346A patent/HU231184B1/hu unknown
-
2015
- 2015-09-28 KR KR1020177012210A patent/KR102651020B1/ko active IP Right Grant
- 2015-09-28 CN CN202110561010.2A patent/CN113292419A/zh active Pending
- 2015-09-28 AU AU2015329740A patent/AU2015329740B2/en active Active
- 2015-09-28 CA CA2963844A patent/CA2963844C/en active Active
- 2015-09-28 RU RU2017115930A patent/RU2709200C2/ru active
- 2015-09-28 SG SG11201702790YA patent/SG11201702790YA/en unknown
- 2015-09-28 KR KR1020247009377A patent/KR20240046264A/ko active Search and Examination
- 2015-09-28 MX MX2017004672A patent/MX2017004672A/es unknown
- 2015-09-28 JP JP2017518846A patent/JP6820255B2/ja active Active
- 2015-09-28 WO PCT/HU2015/000065 patent/WO2016055819A1/en active Application Filing
- 2015-09-28 US US15/518,096 patent/US10322990B2/en active Active
- 2015-09-28 EP EP15787660.8A patent/EP3204349A1/en active Pending
- 2015-09-28 CN CN201580066416.6A patent/CN107001221B/zh active Active
- 2015-10-06 TW TW104132764A patent/TWI761299B/zh active
- 2015-10-06 TW TW108142477A patent/TWI761731B/zh active
-
2017
- 2017-04-06 IL IL251613A patent/IL251613B/en active IP Right Grant
-
2019
- 2019-04-29 US US16/397,139 patent/US11098001B2/en active Active
- 2019-09-11 JP JP2019165225A patent/JP6898401B2/ja active Active
-
2021
- 2021-07-15 US US17/377,125 patent/US11724979B2/en active Active
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1283184A (zh) * | 1997-10-24 | 2001-02-07 | 联合治疗公司 | 前列环素衍生物的立体选择合成方法 |
US20090163738A1 (en) * | 2007-12-17 | 2009-06-25 | United Therapeutics Corporation | Process to prepare treprostinil, the active ingredient in remodulin |
CN102015613A (zh) * | 2008-05-08 | 2011-04-13 | 联合治疗公司 | 曲前列素一水合物 |
WO2009158010A1 (en) * | 2008-06-27 | 2009-12-30 | Concert Pharmaceuticals, Inc. | Prostacyclin analogs |
CN103261142A (zh) * | 2010-06-03 | 2013-08-21 | 联合治疗公司 | 曲前列环素的制备 |
WO2012009816A1 (en) * | 2010-07-22 | 2012-01-26 | Alphora Research Inc. | Synthesis of treprostinil and intermediates useful therein |
WO2012088607A1 (en) * | 2010-12-30 | 2012-07-05 | Alphora Research Inc. | Process for treprostinil salt preparation |
CN102952157A (zh) * | 2011-08-24 | 2013-03-06 | 佳和桂科技股份有限公司 | 用于合成苯并茚前列腺素的中间体和其制备 |
WO2013174848A2 (en) * | 2012-05-23 | 2013-11-28 | Scipharm Sàrl | Improved process for the preparation of treprostinil and derivatives thereof |
EP2674413A1 (en) * | 2012-06-15 | 2013-12-18 | SciPharm SàRL | Process for the preparation of treprostinil and derivatives thereof |
US20140275616A1 (en) * | 2013-03-15 | 2014-09-18 | United Therapeutics Corporation | Salts of treprostinil |
Non-Patent Citations (2)
Title |
---|
ROBERT M. MORIARTY等: "The Intramolecular Asymmetric Pauson -Khand Cyclization as a Novel and General Stereoselective Route to Benzindene Prostacyclins:Synthesis of UT-15 (Treprostinil)", 《J. ORG. CHEM.》 * |
SORBERA L A ET AL: "UT-15 TREATMENT OF PULMONARY HYPERTENSION TREATMENT OF PERIPHERAL VASCULAR DISEASE", 《DRUGS OF THE FUTURE》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111801313A (zh) * | 2018-03-09 | 2020-10-20 | 奇诺因药物和化学工厂私人有限公司 | 用于制备曲前列环素二乙醇胺盐的多晶型b的方法 |
CN111801313B (zh) * | 2018-03-09 | 2023-08-29 | 奇诺因药物和化学工厂私人有限公司 | 用于制备曲前列环素二乙醇胺盐的多晶型b的方法 |
WO2020233588A1 (zh) * | 2019-05-21 | 2020-11-26 | 江苏众强药业有限公司 | 曲前列尼尔钠盐新晶型及制备方法 |
CN112313202A (zh) * | 2019-05-21 | 2021-02-02 | 江苏众强药业有限公司 | 曲前列尼尔钠盐新晶型及制备方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107001221A (zh) | 用于制备曲前列尼尔的方法 | |
CN106831680B (zh) | 一种制备曲前列尼尔的中间体、其制备方法以及通过其制备曲前列尼尔的方法 | |
JPH11508271A (ja) | 5−ホルミル吉草酸の調製法 | |
CN112110951B (zh) | 一类草苔虫素c环骨架化合物、其合成方法及用途 | |
Vargas-Díaz et al. | Synthesis of acyldodecaheterocycles derived from (1R)-(–)-myrtenal and evaluation as chiral auxiliaries | |
Stewart et al. | Synthesis of 1, 3-divinylcyclopentane derivatives from platina (IV) cyclobutane complexes | |
WO2020163295A1 (en) | Chiral-substituted poly-n-vinylpyrrolidinones and complexes with bimetallic nanoclusters and uses thereof in asymmetric oxidation reactions | |
JP3410492B2 (ja) | 7−オクチン−1−エン誘導体およびその製造方法 | |
WO1999043641A1 (fr) | Composes intermediaires entrant dans la synthese de la fraction cyclique de derives 2-substitues de la vitamine d | |
Hoather | Towards the total synthesis of Diaporthichalasin | |
JPH0753537A (ja) | 光学活性化合物とその製造法 | |
Aimon | A NHK approach towards the total synthesis of the cornexistins | |
Hamme II | Mechanistic probing of helical equilibration and self-immolation of chirality in squarate ester cascades. Synthetic efforts toward linear triquinane natural products | |
Vidal | Rhodium-catalyzed silylformylation, silylcarbocyclization, silylcarbobicyclization, cyclohydrocarbonylation, and some applications to the synthesis of piperidine alkaloids | |
Geng | Synthetic and mechanistic investigations of the Wittig rearrangements and synthetic studies toward amphidinolide A | |
Samy | Diastereoselective total synthesis of indole alkaloids and asymmetric induction in radical cyclizations | |
Allen | The Lewis acid ene reaction in kinetic resolution, molecular symmetry breaking, and natural product synthesis | |
JPS5953464A (ja) | プロスタグランディンe,f類の製造法 | |
WO2007066512A1 (ja) | トリアザスマネン類、及び、その製造方法 | |
JP2003261513A (ja) | インデン誘導体およびその中間体並びにそれらの製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |