US20150239860A1 - Process for preparing morphine compounds - Google Patents
Process for preparing morphine compounds Download PDFInfo
- Publication number
- US20150239860A1 US20150239860A1 US14/628,333 US201514628333A US2015239860A1 US 20150239860 A1 US20150239860 A1 US 20150239860A1 US 201514628333 A US201514628333 A US 201514628333A US 2015239860 A1 US2015239860 A1 US 2015239860A1
- Authority
- US
- United States
- Prior art keywords
- compound
- formula
- nmepg
- wittig
- mmol
- 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
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 title abstract description 22
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 37
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 102
- 125000006239 protecting group Chemical group 0.000 claims description 18
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- 238000011905 homologation Methods 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- WVLOADHCBXTIJK-ZWUPXRALSA-N (4S,4aS,7aS,12bR)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound OC1=CC=C2C3=C1O[C@H]1[C@@]34CCN([C@H]([C@H]4CCC1=O)C2)C WVLOADHCBXTIJK-ZWUPXRALSA-N 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 238000006142 intramolecular cycloaddition reaction Methods 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 238000007239 Wittig reaction Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 6
- 230000000155 isotopic effect Effects 0.000 claims description 6
- 238000006751 Mitsunobu reaction Methods 0.000 claims description 5
- 229960001410 hydromorphone Drugs 0.000 claims description 5
- 238000006027 Birch reduction reaction Methods 0.000 claims description 4
- 230000033444 hydroxylation Effects 0.000 claims description 4
- 238000005805 hydroxylation reaction Methods 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 26
- 238000007115 1,4-cycloaddition reaction Methods 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 0 I.II.cc1-ccC2C([Y])/C=C3/C=CC(=O)C4(*O)OC1C2(CCC)C34.cc1-ccC=C(CCC)C1OC1(*O)C=C(/C=C/[Y])C=CC1=O Chemical compound I.II.cc1-ccC2C([Y])/C=C3/C=CC(=O)C4(*O)OC1C2(CCC)C34.cc1-ccC=C(CCC)C1OC1(*O)C=C(/C=C/[Y])C=CC1=O 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 229960005181 morphine Drugs 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- -1 dimethoxytrityl Chemical group 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 description 6
- PSMWZXVICITNAC-LEWJYISDSA-N N-[2-[(5S,6R)-5-[tert-butyl(dimethyl)silyl]oxy-6-hydroxycyclohexen-1-yl]ethyl]-N,4-dimethylbenzenesulfonamide Chemical compound C(C)(C)(C)[Si](O[C@H]1CCC=C([C@H]1O)CCN(S(=O)(=O)C1=CC=C(C=C1)C)C)(C)C PSMWZXVICITNAC-LEWJYISDSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- IJVCSMSMFSCRME-AROOSSJZSA-N (4S,4aS,7S,7aS,12bR)-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol Chemical compound CN1[C@@H]2[C@H]3CC[C@@H]([C@@H]4[C@@]3(CC1)C1=C(O4)C(=CC=C1C2)O)O IJVCSMSMFSCRME-AROOSSJZSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- UFDULEKOJAEIRI-UHFFFAOYSA-N (2-acetyloxy-3-iodophenyl) acetate Chemical compound CC(=O)OC1=CC=CC(I)=C1OC(C)=O UFDULEKOJAEIRI-UHFFFAOYSA-N 0.000 description 4
- PCIZWARERLOISH-UHFFFAOYSA-N *.CP([Y])(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound *.CP([Y])(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 PCIZWARERLOISH-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- WFZPKBVLFIQESA-RRLIAEKXSA-N [1-[(5S,6S)-5-[tert-butyl(dimethyl)silyl]oxy-6-[5-formyl-2-(methoxymethoxy)phenoxy]cyclohexen-1-yl]-4,4-dimethylpentan-3-yl] carbamate Chemical compound C(N)(OC(CCC1=CCC[C@@H]([C@H]1OC1=C(C=CC(=C1)C=O)OCOC)O[Si](C)(C)C(C)(C)C)C(C)(C)C)=O WFZPKBVLFIQESA-RRLIAEKXSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- XBINCGHENTZDPM-UHFFFAOYSA-N 3-hydroxy-4-(methoxymethoxy)benzaldehyde Chemical compound COCOC1=CC=C(C=O)C=C1O XBINCGHENTZDPM-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ANDFRJPTRKGNOT-JDXGNMNLSA-N N-[2-[(5S,6S)-5-[tert-butyl(dimethyl)silyl]oxy-6-[5-formyl-2-(methoxymethoxy)phenoxy]cyclohexen-1-yl]ethyl]-N,4-dimethylbenzenesulfonamide Chemical compound C(C)(C)(C)[Si](O[C@H]1CCC=C([C@@H]1OC1=C(C=CC(=C1)C=O)OCOC)CCN(S(=O)(=O)C1=CC=C(C=C1)C)C)(C)C ANDFRJPTRKGNOT-JDXGNMNLSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 3
- JNMXGGJQWFEHFN-UHFFFAOYSA-N (4-formyl-2-hydroxyphenyl) acetate Chemical compound CC(=O)OC1=CC=C(C=O)C=C1O JNMXGGJQWFEHFN-UHFFFAOYSA-N 0.000 description 2
- VYNIBXRGPHJFDC-RSBMDPRMSA-N (4S,4aS,7S,7aS,12bR)-7-[tert-butyl(dimethyl)silyl]oxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol Chemical compound C(C)(C)(C)[Si](O[C@@H]1[C@@H]2[C@]34CCN([C@H]([C@H]3CC1)CC1=CC=C(C(=C14)O2)O)C)(C)C VYNIBXRGPHJFDC-RSBMDPRMSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OVDHHRVCSZOEAF-UHFFFAOYSA-N 15-oxatetracyclo[10.2.1.05,14.08,13]pentadeca-1,3,5(14),6,8(13),9,11-heptaen-2-yl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(C=C1)S(=O)(=O)OC=1C=CC=2C=CC3=CC=CC=4OC1C2C43 OVDHHRVCSZOEAF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WSEYRYIQSMUYMG-UHFFFAOYSA-N [3-iodo-2-(2,2,2-trifluoroacetyl)oxyphenyl] 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OC1=CC=CC(I)=C1OC(=O)C(F)(F)F WSEYRYIQSMUYMG-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- FJPFUFWDADKKAP-UHFFFAOYSA-N furan-3-yl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1=COC=C1 FJPFUFWDADKKAP-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- DSNSMOCPDPSCDS-ZCYQVOJMSA-N tert-butyl N-[2-[(5S,6S)-5-[tert-butyl(dimethyl)silyl]oxy-6-(5-ethenyl-2-hydroxyphenoxy)cyclohexen-1-yl]ethyl]-N-methylcarbamate Chemical compound C(C)(C)(C)OC(N(C)CCC1=CCC[C@@H]([C@H]1OC1=C(C=CC(=C1)C=C)O)O[Si](C)(C)C(C)(C)C)=O DSNSMOCPDPSCDS-ZCYQVOJMSA-N 0.000 description 2
- LUZBHWRCEHMPHW-BDYUSTAISA-N tert-butyl N-[2-[(5S,6S)-5-[tert-butyl(dimethyl)silyl]oxy-6-[5-ethenyl-2-(methoxymethoxy)phenoxy]cyclohexen-1-yl]ethyl]-N-methylcarbamate Chemical compound C(C)(C)(C)OC(N(C)CCC1=CCC[C@@H]([C@H]1OC1=C(C=CC(=C1)C=C)OCOC)O[Si](C)(C)C(C)(C)C)=O LUZBHWRCEHMPHW-BDYUSTAISA-N 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
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical compound OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 1
- DJJXOIKCMROTBY-JWOZKIDPSA-N *.B.C.C.C=CC1=CC(C)(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2C)C(=O)C=C1.CCCC1=CCC[C@H](C)[C@H]1OC1(C)C=C(/C=C/[Y])C=CC1O.CCCC1=CCC[C@H](C)[C@H]1OC1=C(O)C=CC(/C=C/[Y])=C1.[H][C@@]12CC[C@H](C)[C@H]3OC4(C)C(=O)C=CC(=C[C@@H]1[Y])C4[C@]32CCC.[H][C@]12C=CC3=C4C(=C(O)C=C3)O[C@H]([C@@H](O)CC1)[C@]42CCNC.[H][C@]12CC=C3C=CC(=O)C4(C)O[C@H]([C@@H](C)CC1)[C@]2(CCN(C)C(=O)OC(C)(C)C)C34.[H][C@]12CCC(=O)[C@H]3OC4=C(O)C=CC5=C4[C@]31CCN(C)[C@H]2C5 Chemical compound *.B.C.C.C=CC1=CC(C)(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2C)C(=O)C=C1.CCCC1=CCC[C@H](C)[C@H]1OC1(C)C=C(/C=C/[Y])C=CC1O.CCCC1=CCC[C@H](C)[C@H]1OC1=C(O)C=CC(/C=C/[Y])=C1.[H][C@@]12CC[C@H](C)[C@H]3OC4(C)C(=O)C=CC(=C[C@@H]1[Y])C4[C@]32CCC.[H][C@]12C=CC3=C4C(=C(O)C=C3)O[C@H]([C@@H](O)CC1)[C@]42CCNC.[H][C@]12CC=C3C=CC(=O)C4(C)O[C@H]([C@@H](C)CC1)[C@]2(CCN(C)C(=O)OC(C)(C)C)C34.[H][C@]12CCC(=O)[C@H]3OC4=C(O)C=CC5=C4[C@]31CCN(C)[C@H]2C5 DJJXOIKCMROTBY-JWOZKIDPSA-N 0.000 description 1
- SZADDSGVKOTPER-XZYHWPERSA-N *.B.C.C.[2HH].[H][C@@]12CCC[C@@H]3OC4=CC=CC5=C4[C@@]31CCN(C)[C@@H]2C5 Chemical compound *.B.C.C.[2HH].[H][C@@]12CCC[C@@H]3OC4=CC=CC5=C4[C@@]31CCN(C)[C@@H]2C5 SZADDSGVKOTPER-XZYHWPERSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical class CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical compound COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- MKHGVMIXRPGHOO-UHFFFAOYSA-N 2-(benzenesulfonyl)-3-phenyloxaziridine Chemical compound C=1C=CC=CC=1S(=O)(=O)N1OC1C1=CC=CC=C1 MKHGVMIXRPGHOO-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- IJVCSMSMFSCRME-UHFFFAOYSA-N 3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol Chemical compound C12CCC(O)C3OC4=C5C32CCN(C)C1CC5=CC=C4O IJVCSMSMFSCRME-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- AVCIDFATNJNKLN-BVGQSLNGSA-N C/C1=C/C=C2/[C@H]3CC4=C5C(=C(O)C=C4)O[C@@H]1[C@]52CCN3C Chemical compound C/C1=C/C=C2/[C@H]3CC4=C5C(=C(O)C=C4)O[C@@H]1[C@]52CCN3C AVCIDFATNJNKLN-BVGQSLNGSA-N 0.000 description 1
- OYEAXTLLUCAWGX-PGRDOPGGSA-N C=CC1=CC(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2C)=C(C)C=C1 Chemical compound C=CC1=CC(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2C)=C(C)C=C1 OYEAXTLLUCAWGX-PGRDOPGGSA-N 0.000 description 1
- WYSJGRUOHLZFPH-HRAATJIYSA-N C=CC1=CC(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2C)=C(O)C=C1 Chemical compound C=CC1=CC(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2C)=C(O)C=C1 WYSJGRUOHLZFPH-HRAATJIYSA-N 0.000 description 1
- NWOCBYONMYMWGV-UHFFFAOYSA-N CC(Oc(cc(C=O)cc1)c1O)=O Chemical compound CC(Oc(cc(C=O)cc1)c1O)=O NWOCBYONMYMWGV-UHFFFAOYSA-N 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- VKUXPEDULFGYLF-UHFFFAOYSA-N CC1=C(C)C=C(C=O)C=C1.CC1=C(O)C=C(C=O)C=C1.CC1=C(O)C=CC(C=O)=C1.O=CC1=CC(O)=C(O)C=C1 Chemical compound CC1=C(C)C=C(C=O)C=C1.CC1=C(O)C=C(C=O)C=C1.CC1=C(O)C=CC(C=O)=C1.O=CC1=CC(O)=C(O)C=C1 VKUXPEDULFGYLF-UHFFFAOYSA-N 0.000 description 1
- DHVJHJQBQKKPNB-UHFFFAOYSA-N CC1=C(O)C=C(C=O)C=C1 Chemical compound CC1=C(O)C=C(C=O)C=C1 DHVJHJQBQKKPNB-UHFFFAOYSA-N 0.000 description 1
- BAKYASSDAXQKKY-UHFFFAOYSA-N CC1=C(O)C=CC(C=O)=C1 Chemical compound CC1=C(O)C=CC(C=O)=C1 BAKYASSDAXQKKY-UHFFFAOYSA-N 0.000 description 1
- PCPSGKMNDBTGAJ-LAUBAEHRSA-N CC1=C(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2C)C=C(C=O)C=C1 Chemical compound CC1=C(O[C@H]2C(CCN(C)C(=O)OC(C)(C)C)=CCC[C@@H]2C)C=C(C=O)C=C1 PCPSGKMNDBTGAJ-LAUBAEHRSA-N 0.000 description 1
- IECZBVFJTYLJJR-MNEFBYGVSA-N CC1=C2O[C@H]3/C(C)=C\C=C4\[C@H]5CC(=C2[C@]43CCN5C)C=C1 Chemical compound CC1=C2O[C@H]3/C(C)=C\C=C4\[C@H]5CC(=C2[C@]43CCN5C)C=C1 IECZBVFJTYLJJR-MNEFBYGVSA-N 0.000 description 1
- FZDNBRWKCLSRBT-YOEHRIQHSA-N CC1=CC=C(S(=O)(=O)N(C)CCC2=CCC[C@H](C)[C@@H]2O)C=C1 Chemical compound CC1=CC=C(S(=O)(=O)N(C)CCC2=CCC[C@H](C)[C@@H]2O)C=C1 FZDNBRWKCLSRBT-YOEHRIQHSA-N 0.000 description 1
- YMXAFWMAYMKSNO-NBGIEHNGSA-N CC1=CC=C(S(=O)(=O)N(C)CCC2=CCC[C@H](C)[C@H]2OC2=C(C)C=CC(C=O)=C2)C=C1 Chemical compound CC1=CC=C(S(=O)(=O)N(C)CCC2=CCC[C@H](C)[C@H]2OC2=C(C)C=CC(C=O)=C2)C=C1 YMXAFWMAYMKSNO-NBGIEHNGSA-N 0.000 description 1
- FMTYKTMYZXOJKS-UHFFFAOYSA-K CCCC1=CC(=O)CCC1.CCCC1=CC(OC)=CC=C1.CCCC1=CCCC(=O)C1C.CI.I[V](I)I.[V] Chemical compound CCCC1=CC(=O)CCC1.CCCC1=CC(OC)=CC=C1.CCCC1=CCCC(=O)C1C.CI.I[V](I)I.[V] FMTYKTMYZXOJKS-UHFFFAOYSA-K 0.000 description 1
- CVLCSDDTQVANDD-KSLYSKRISA-K CCCC1=CC(=O)CCC1.CCCC1=CC=CC(C)=C1.CCCC1=CCCC(=O)[C@@H]1O.CCCC1=CCCC(=O)[C@H]1O.CI.I[V](I)I.[V].[V] Chemical compound CCCC1=CC(=O)CCC1.CCCC1=CC=CC(C)=C1.CCCC1=CCCC(=O)[C@@H]1O.CCCC1=CCCC(=O)[C@H]1O.CI.I[V](I)I.[V].[V] CVLCSDDTQVANDD-KSLYSKRISA-K 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- ZKLXUUYLEHCAMF-UUWFMWQGSA-N Oripavine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ZKLXUUYLEHCAMF-UUWFMWQGSA-N 0.000 description 1
- ZKLXUUYLEHCAMF-UHFFFAOYSA-N Oripavine Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(O)C5=C4C23C1O5 ZKLXUUYLEHCAMF-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- NJBAOXQZYHLBHD-JUXKHHMRSA-N [H][C@@]12C=CC3=CC=C(C)C4=C3[C@]1(CCN(C)S(=O)(=O)C1=CC=C(C)C=C1)[C@H](O4)[C@@H](C)CC2 Chemical compound [H][C@@]12C=CC3=CC=C(C)C4=C3[C@]1(CCN(C)S(=O)(=O)C1=CC=C(C)C=C1)[C@H](O4)[C@@H](C)CC2 NJBAOXQZYHLBHD-JUXKHHMRSA-N 0.000 description 1
- BYBPWMHCMAHNPC-VFXZHPAVSA-N [H][C@@]12C=CC3=CC=C(C)C4=C3[C@]1(CCN(C)S(=O)(=O)C1=CC=C(C)C=C1)[C@H](O4)[C@@H](O)CC2 Chemical compound [H][C@@]12C=CC3=CC=C(C)C4=C3[C@]1(CCN(C)S(=O)(=O)C1=CC=C(C)C=C1)[C@H](O4)[C@@H](O)CC2 BYBPWMHCMAHNPC-VFXZHPAVSA-N 0.000 description 1
- LMOKDDNJOLPZDF-IVUQFNBUSA-N [H][C@@]12CC[C@H](C)[C@H]3OC4=C5C(=CC=C4O)C[C@@H]1N(C)CC[C@@]532 Chemical compound [H][C@@]12CC[C@H](C)[C@H]3OC4=C5C(=CC=C4O)C[C@@H]1N(C)CC[C@@]532 LMOKDDNJOLPZDF-IVUQFNBUSA-N 0.000 description 1
- AMVLYDOLEWRSRR-IZEDJZTJSA-N [H][C@]12CC=C3C=CC(=O)C4(C)O[C@H]([C@@H](C)CC1)[C@@]2(CCN(C)C(=O)OC(C)(C)C)C34 Chemical compound [H][C@]12CC=C3C=CC(=O)C4(C)O[C@H]([C@@H](C)CC1)[C@@]2(CCN(C)C(=O)OC(C)(C)C)C34 AMVLYDOLEWRSRR-IZEDJZTJSA-N 0.000 description 1
- WVLOADHCBXTIJK-CCTZJXECSA-N [H][C@]12CCC(=O)[C@H]3OC4=C(O)C=CC5=C4[C@]31CCN(C)C2C5 Chemical compound [H][C@]12CCC(=O)[C@H]3OC4=C(O)C=CC5=C4[C@]31CCN(C)C2C5 WVLOADHCBXTIJK-CCTZJXECSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000039 congener Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical group 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 229930013053 morphinan alkaloid Natural products 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006476 reductive cyclization reaction Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- IPMKAUAKEGAJNA-XSUJLISDSA-N solanapyrone g Chemical compound C1([C@H]2[C@@H]3CCCC[C@@H]3C=C[C@@H]2C)=CC(N)=C(C=O)C(=O)O1 IPMKAUAKEGAJNA-XSUJLISDSA-N 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- UIYOVVYZPVVUMJ-UHFFFAOYSA-N tert-butyl carbamoyl carbonate Chemical compound CC(C)(C)OC(=O)OC(N)=O UIYOVVYZPVVUMJ-UHFFFAOYSA-N 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229930003945 thebaine Natural products 0.000 description 1
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
-
- 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 System
- 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
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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 System
- 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
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Definitions
- the present application relates to processes for the preparation of morphine compounds.
- the present application relates to a novel process for forming the morphine skeleton using a [4+2] intramolecular cycloaddition reaction.
- the present application includes a process for the preparation of a compound of Formula I comprising treating a compound of Formula II under [4+2] intramolecular cycloaddition conditions:
- Y is H and X is NMePG 2 ;
- PG 1 and PG 2 are, independently, protecting groups; and LG is a leaving group, and one or more available hydrogens in the compounds of Formulae I and II is/are optionally replaced with F and/or one or more of available atoms in the compounds of Formulae I and II is/are optionally replaced with an isotopic label.
- the present application also includes any of the novel compounds disclosed herein.
- the present application includes compounds 5, 6, 17, 18, 19a, 19b, 20, 21, 23, 24, 25 and 26 as shown in Schemes 1 and 4 hereinbelow.
- the term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
- the foregoing also applies to words having similar meanings such as the terms “including”, “having” and their derivatives.
- the term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
- suitable means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions for the reaction to proceed to a sufficient extent to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.
- reaction or process/method steps proceed to an extent that conversion of the starting material or substrate to product is maximized. Conversion may be maximized when greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the starting material or substrate is converted to product.
- the second component as used herein is chemically different from the other components or first component.
- a “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.
- the compounds in the processes/methods described herein have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the processes/methods of the present application. It is to be further understood that while the stereochemistry of the compounds in the processes/methods may be as shown in any given compound listed herein, such compounds may also contain certain amounts (e.g. less than 20%, suitably less than 10%, more suitably less than 5%) of compounds having alternate stereochemistry.
- protecting refers to using a chemical moiety, i.e. a “protecting group” of “PG” which protects or masks a reactive portion of a molecule to prevent side reactions in that reactive portion of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule; i.e. the protected reactive portion of the molecule is “deprotected”.
- PG protecting group of “PG” which protects or masks a reactive portion of a molecule to prevent side reactions in that reactive portion of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule; i.e. the protected reactive portion of the molecule is “deprotected”.
- the selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting
- suitable protecting groups include, but are not limited to t-Boc, C 1-6 acyl, Ac, Ts, Ms, silyl ethers such as TMS, TBDMS, TBDPS, Tf, Ns, Bn, Fmoc, dimethoxytrityl, methoxyethoxymethyl ether, methoxymethyl ether, pivaloyl, p-methyoxybenzyl ether, tetrahydropyranyl, trityl, ethoxyethyl ethers, carbobenzyloxy, benzoyl and the like.
- LG refers to a group that is readily displaceable by a nucleophile, for example, under nucleophilic substitution reaction conditions.
- suitable leaving groups include, but are not limited to, halo, OMs, OTs, ONs, OTf, OC 1-6 acyl, and the like, including isotopically labeled versions thereof
- acyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated acyl groups.
- the number of carbon atoms that are possible in the referenced acyl group are indicated by the numerical prefix “C n1-n2 ”.
- C 1-6 acyl means an acyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
- halo refers to a halogen atom and includes F, Cl, Br and I.
- oxidizing agent means any compound or combination of compounds that oxidizes a desired functional group(s) but does not otherwise react with or degrade the substrate comprising the functional group(s). An oxidizing agent results in the overall loss of electrons, or in the case of organic chemistry, hydrogen atoms from the functional group.
- reducing agent means any compound or combination of compounds that reduces a desired functional group(s) but does not otherwise react with or degrade the substrate comprising the functional group(s).
- a reducing agent results in the overall gain of electrons, or in the case of organic chemistry, hydrogen atoms to the functional group. It is an embodiment of the application that the reducing agent is a metal hydride reducing agent.
- inert solvent means a solvent that does not interfere with or otherwise inhibit a reaction. Accordingly, the identity of the inert solvent will vary depending on the reaction being performed. The selection of inert solvent is within the skill of a person in the art. Examples of inert solvents include, but are not limited to, benzene, toluene, tetrahydrofuran, ethyl ether, ethyl acetate, dimethyl formamide (DMF), acetonitrile, C 1-6 alkylOH (e.g.
- DMSO dimethylslfoxide
- Further examples can include aqueous solutions, such as water and dilute acids and bases, and ionic liquids, provided that such solvents do not interfere with the reaction.
- alkyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups.
- the number of carbon atoms that are possible in the referenced alkyl group are indicated by the numerical prefix “C n1-n2 ”.
- C 1-6 alkyl means an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
- solvent includes both a single solvent and a mixture comprising two or more solvents.
- available refers to atoms that would be known to a person skilled in the art to be capable of replacement by either a fluorine atom (in the case of hydrogen atoms) or isotopic labels (in the case of all atoms) using methods known in the art.
- counteranion refers to a negatively charged species consisting of a single element, or a negatively charged species consisting of a group of elements connected by ionic and/or covalent bonds.
- t-Boc refers to the group t-butyloxycarbonyl.
- Ac as used herein refers to the group acetyl.
- Ts (tosyl) as used herein refers to the group p-toluenesulfonyl.
- Ms as used herein refers to the group methanesulfonyl.
- TBDMS as used herein refers to the group t-butyldimethylsilyl.
- TBDPS as used herein refers to the group t-butyldiphenylsilyl.
- TMS as used herein refers to the group trimethylsilyl.
- Tf as used herein refers to the group trifluoromethanesulfonyl.
- Ns as used herein refers to the group naphthalene sulphonyl.
- Bn as used herein refers to the group benzyl.
- Fmoc as used herein refers to the group fluorenylmethoxycarbonyl.
- morphine compound refers to a compound containing the 5 ring morphine skeleton as follows:
- the morphine compound is ent-hydromorphone or hydromorphone.
- oripavine refers to a compound of the following formula:
- hydromorphone refers to a compound of the following formula:
- ent-hydromorphone refers to a compound of the following formula:
- the term “thebaine” as used herein refers to a compound of the following formula:
- morphine refers to a compound of the following formula:
- the present application includes a process for the preparation of a compound of Formula I comprising treating a compound of Formula II under [4+2] intramolecular cycloaddition conditions:
- Y is H and X is NMePG 2 ;
- PG 1 and PG 2 are, independently, protecting groups; and LG is a leaving group, and one or more available hydrogens in the compounds of Formulae I and II is/are optionally replaced with F and/or one or more of available atoms in the compounds of Formulae I and II is/are optionally replaced with an isotopic label.
- the compound of Formula II is derived from the corresponding phenol by oxidative dearomatization using, for example, lead tetraacetate (Pb(OAc) 4 ), diacetoxyiodobenzene (DAIB), bis trifluoroacetoxyiodo benzene (PIFA) or Dess-Martin periodinane.
- the oxidative dearomatization comprises electrochemical anodic oxidation. The selection of suitable conditions for electrochemical anodic oxidation can be made by a person skilled in the art.
- the present application includes a process of preparing a compound of Formula I comprising converting a compound of Formula III into a compound of Formula II by oxidative dearomatization followed by treating the compound of Formula II under [4+2] intramolecular cycloaddition conditions to provide the compound of Formula I:
- Y is H and X is NMePG 2 ;
- PG 1 and PG 2 are, independently, protecting groups; and LG is a leaving group, and one or more available hydrogens in the compounds of Formulae I-III is/are optionally replaced with F and/or one or more of available atoms in the compounds of Formulae I-III is/are optionally replaced with an isotopic label.
- the compound of Formula III is available by reacting a compound of the Formula IV with a compound of the Formula V under Mitsunobu reaction conditions to provide a compound of the Formula VI followed by Wittig homologation of the CHO group and removal of PG 3 :
- Z represents a single or double bond
- Z is O when Z represents a double bond and Z is OPG 1 when Z represents a single bond; at least one of Y and X is NMePG 2 and the other is LG,
- Y is H and X is NMePG 2 ;
- PG 1 , PG 2 and PG 3 are, independently, protecting groups; and LG is a leaving group, and one or more available hydrogens in the compounds of Formulae III-VI is/are optionally replaced with F and/or one or more of available atoms in the compounds of Formulae III-VI is/are optionally replaced with an isotopic label.
- the Wittig homologation of CHO in the compound of Formula VI is performed by reacting a compound of the Formula VI with a Wittig reagent, for example, a compound of the Formula VII:
- a ⁇ is a suitable counteranion and Y is as defined above, under Wittig reaction conditions.
- the compound of the Formula III wherein Y is H is prepared by Wittig homologation of the CHO group in a compound of Formula X to provide a compound of Formula XI, followed by selective removal of PG 5 to provide a compound of Formula XII, then reacting the compound of Formula XII with a compound of Formula V under Mitsunobu reaction conditions and removal of PG 4 :
- Z represents a single or double bond
- Z is O when Z represents a double bond and Z is OPG 1 when Z represents a single bond; at least one of Y and X is NMePG 2 and the other is LG,
- Y is H and X is NMePG 2 ;
- PG 2 , PG 4 and PG 5 are, independently, protecting groups, wherein PG 4 and PG 5 are protecting groups that are removable under different conditions.
- the Wittig homologation of CHO in the compound of Formula X is performed by reacting a compound of the Formula X with a Wittig reagent, for example, a compound of the Formula VII:
- a ⁇ is a suitable counteranion and Y is as defined above, under Wittig reaction conditions.
- the present application therefore also includes a process for preparing a compound of the Formula V, wherein X is NMePG 2 or LG, Z is O, Z is a double bond and C C is a single bond comprising treating a compound of the Formula VIII under Birch reduction conditions to provide a compound of the Formula IX and treating the compound of the Formula IX under Davis hydroxylation conditions to provide the compound of the Formula V, wherein X is NMePG 2 or LG, Z is O, Z is a double bond and C C is a single bond:
- Z and C C both represent single bonds. Therefore, in an embodiment, Z is OPG 1 .
- Y is H and X is NMePG 2 .
- X is LG and Y is NMePG 2 .
- OR is OAc
- stereochemistry of the compounds of Formula II-XII is selected so that the compound of Formula I has the same stereochemistry as that found in hydromorphone. In an embodiment, the stereochemistry of the compounds of Formula II-XII is selected so that the compound of Formula I has the same stereochemistry as that found in ent-hydromorphone.
- the intramolecular cycloaddition conditions comprise heating a substrate, i.e. a compound comprising a diene and a dienophile such as a compound of Formula II, in an inert organic solvent, optionally in the presence of a catalyst.
- oxidative dearomatization conditions comprise treating an appropriate aromatic substrate with a suitable oxidizing agent, such as Pb(OAc) 4 , diacetoxyiodobenzene (DAIB), bis trifluoroacetoxyiodo benzene (PIFA) or Dess-Martin periodinane, in an inert organic solvent, optionally with heating.
- a suitable oxidizing agent such as Pb(OAc) 4 , diacetoxyiodobenzene (DAIB), bis trifluoroacetoxyiodo benzene (PIFA) or Dess-Martin periodinane
- the oxidative dearomatization to provide the compounds of Formula II and intramolecular cycloaddition are performed in a single step, wherein the compound of Formula II is formed in situ and converted, under the oxidative dearomatization conditions to a compound of the Formula I.
- the oxidizing agent is Pb(OAc) 4 .
- the Mitsunobu reaction conditions comprise treating the substrates in the presence of a trialkylphosphine, or a triarylphosphone, and an azodicarboxylate, such as tetramethylazodicarboxamide (TMAD), diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) in an inert organic solvent.
- TMAD tetramethylazodicarboxamide
- DEAD diethylazodicarboxylate
- DIAD diisopropylazodicarboxylate
- the reaction conditions optionally comprise heating or cooling depending on the substrates as would be known to a person skilled in the art.
- Wittig homologation refers to the conversion of an aldehyde to the next higher homolog (i.e. addition of one methylene unit) using Wittig reaction conditions.
- Wittig reaction conditions comprise reaction of an aldehyde-containing substrate with a Wittig reagent, for example a compound of the Formula VII as defined above at low temperature (for example, ⁇ 50° C. to ⁇ 100° C.) in an inert organic solvent, followed by warming to, for example room temperature or above,
- a Wittig reagent for example a compound of the Formula VII as defined above at low temperature (for example, ⁇ 50° C. to ⁇ 100° C.) in an inert organic solvent, followed by warming to, for example room temperature or above
- Birch reduction conditions comprise reaction of an aromatic substrate, such as a compound of Formula VIII, with anhydrous ammonia, t-BuOH and metals such as Na, Li etc. at low temperature (for example, ⁇ 50° C. to ⁇ 100° C.) in an inert organic solvent, followed by warming to, for example room temperature or above, and treating with a suitable acid to provide, for example, the desired enone IX.
- aromatic substrate such as a compound of Formula VIII
- metals such as Na, Li etc.
- Davis hydroxylation conditions comprise reaction of an enone, for example a compound of Formula IX, with metal bases at low temperature (for example, ⁇ 50° C. to ⁇ 100° C.) in an inert organic solvent, followed by reacting with Davis oxaziridine (or equivalent reagent) at low temperature (for example, ⁇ 50° C. to ⁇ 100° C.), quenching the reaction with a suitable acid to provide, for example, the desired alcohol V.
- metal bases at low temperature (for example, ⁇ 50° C. to ⁇ 100° C.) in an inert organic solvent
- Davis oxaziridine or equivalent reagent
- Standard methods and reactions are used to convert the compound of Formula I into morphine compounds.
- one of X and Y is NMePG 2 and the other is LG
- removal of PG 2 followed by nucleophilic displacement of the LG leads to the formation of the ring D of the morphine skeleton.
- formation of ring D is carried out using reductive cyclization, such as nitrogen centered radical cyclization. Oxidation and/or reduction of the various functional groups, such as the C6 OH group, as well as removal of protecting groups are performed to provide the desired morphine compound.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
Description
- The present application claims the benefit of priority from co-pending U.S. provisional application No. 61/943,556 filed on Feb. 24, 2014, the contents of which are incorporated herein by reference in their entirety.
- The present application relates to processes for the preparation of morphine compounds. In particular, the present application relates to a novel process for forming the morphine skeleton using a [4+2] intramolecular cycloaddition reaction.
- A truly practical synthesis of morphine and congeners has not yet appeared in spite of focused effort and many creative approaches having been published.1
- In one embodiment, the present application includes a process for the preparation of a compound of Formula I comprising treating a compound of Formula II under [4+2] intramolecular cycloaddition conditions:
- PG1 and PG2 are, independently, protecting groups; and
LG is a leaving group, and
one or more available hydrogens in the compounds of Formulae I and II is/are optionally replaced with F and/or one or more of available atoms in the compounds of Formulae I and II is/are optionally replaced with an isotopic label. - Processes for preparing compounds of Formula II, and precursors thereof, are described and included in the present application, as well as the conversion of the compounds of Formula I into various morphine compounds.
- It has been demonstrated that the process of the present application is enantiodivergent. For example, an enantiomer of hydromorphone (ent-hydromorphone) has been made and the other enantiomer is readily available using the same process.
- The present application also includes any of the novel compounds disclosed herein. In particular, the present application includes compounds 5, 6, 17, 18, 19a, 19b, 20, 21, 23, 24, 25 and 26 as shown in Schemes 1 and 4 hereinbelow.
- Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating embodiments of the application are given by way of illustration only and the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.
- Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.
- In understanding the scope of the present application, the term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms “including”, “having” and their derivatives. The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The term “consisting essentially of”, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and/or steps.
- The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions for the reaction to proceed to a sufficient extent to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.
- The expression “proceed to a sufficient extent” as used herein with reference to the reactions or process/method steps disclosed herein means that the reactions or process/method steps proceed to an extent that conversion of the starting material or substrate to product is maximized. Conversion may be maximized when greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the starting material or substrate is converted to product.
- Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.
- As used in this application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound or two or more additional compounds.
- In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.
- In embodiments of the present application, the compounds in the processes/methods described herein have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the processes/methods of the present application. It is to be further understood that while the stereochemistry of the compounds in the processes/methods may be as shown in any given compound listed herein, such compounds may also contain certain amounts (e.g. less than 20%, suitably less than 10%, more suitably less than 5%) of compounds having alternate stereochemistry.
- The term “protecting” as used herein refers to using a chemical moiety, i.e. a “protecting group” of “PG” which protects or masks a reactive portion of a molecule to prevent side reactions in that reactive portion of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule; i.e. the protected reactive portion of the molecule is “deprotected”. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J. F. W. Ed., Plenum Press, 1973, in Greene, T. W. and Wuts, P. G. M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas). Examples of suitable protecting groups include, but are not limited to t-Boc, C1-6acyl, Ac, Ts, Ms, silyl ethers such as TMS, TBDMS, TBDPS, Tf, Ns, Bn, Fmoc, dimethoxytrityl, methoxyethoxymethyl ether, methoxymethyl ether, pivaloyl, p-methyoxybenzyl ether, tetrahydropyranyl, trityl, ethoxyethyl ethers, carbobenzyloxy, benzoyl and the like.
- The term “leaving group” or “LG” as used herein refers to a group that is readily displaceable by a nucleophile, for example, under nucleophilic substitution reaction conditions. Examples of suitable leaving groups include, but are not limited to, halo, OMs, OTs, ONs, OTf, OC1-6acyl, and the like, including isotopically labeled versions thereof
- The term “acyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated acyl groups. The number of carbon atoms that are possible in the referenced acyl group are indicated by the numerical prefix “Cn1-n2”. For example, the term C1-6acyl means an acyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
- The term “halo” as used herein refers to a halogen atom and includes F, Cl, Br and I.
- The term “oxidizing agent” as used herein means any compound or combination of compounds that oxidizes a desired functional group(s) but does not otherwise react with or degrade the substrate comprising the functional group(s). An oxidizing agent results in the overall loss of electrons, or in the case of organic chemistry, hydrogen atoms from the functional group.
- The term “reducing agent” as used herein means any compound or combination of compounds that reduces a desired functional group(s) but does not otherwise react with or degrade the substrate comprising the functional group(s). A reducing agent results in the overall gain of electrons, or in the case of organic chemistry, hydrogen atoms to the functional group. It is an embodiment of the application that the reducing agent is a metal hydride reducing agent.
- The term “inert solvent” as used herein means a solvent that does not interfere with or otherwise inhibit a reaction. Accordingly, the identity of the inert solvent will vary depending on the reaction being performed. The selection of inert solvent is within the skill of a person in the art. Examples of inert solvents include, but are not limited to, benzene, toluene, tetrahydrofuran, ethyl ether, ethyl acetate, dimethyl formamide (DMF), acetonitrile, C1-6alkylOH (e.g. methanol, ethanol, n-propanol, 2-propanol, n-butanol, butan-2-ol and 2-methyl-1-propanol), diethylcarbonate, hexane and dimethylslfoxide (DMSO) including isotopically labeled versions thereof. Further examples can include aqueous solutions, such as water and dilute acids and bases, and ionic liquids, provided that such solvents do not interfere with the reaction.
- The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the numerical prefix “Cn1-n2”. For example, the term C1-6alkyl means an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
- The term “solvent” includes both a single solvent and a mixture comprising two or more solvents.
- The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by either a fluorine atom (in the case of hydrogen atoms) or isotopic labels (in the case of all atoms) using methods known in the art.
- The term “counteranion” as used herein refers to a negatively charged species consisting of a single element, or a negatively charged species consisting of a group of elements connected by ionic and/or covalent bonds.
- t-Boc as used herein refers to the group t-butyloxycarbonyl.
- Ac as used herein refers to the group acetyl.
- Ts (tosyl) as used herein refers to the group p-toluenesulfonyl.
- Ms as used herein refers to the group methanesulfonyl.
- TBDMS as used herein refers to the group t-butyldimethylsilyl.
- TBDPS as used herein refers to the group t-butyldiphenylsilyl.
- TMS as used herein refers to the group trimethylsilyl.
- Tf as used herein refers to the group trifluoromethanesulfonyl.
- Ns as used herein refers to the group naphthalene sulphonyl.
- Bn as used herein refers to the group benzyl.
- Fmoc as used herein refers to the group fluorenylmethoxycarbonyl.
- The term “morphine compound” as used herein refers to a compound containing the 5 ring morphine skeleton as follows:
- with optional substituents on one or more of the ring atoms and optional double bonds in ring C. In an embodiment, the morphine compound is ent-hydromorphone or hydromorphone.
- The term “oripavine” as used herein refers to a compound of the following formula:
- The term “hydromorphone” as used herein refers to a compound of the following formula:
- The term “ent-hydromorphone” as used herein refers to a compound of the following formula:
- The term “thebaine” as used herein refers to a compound of the following formula:
- The term “morphine” as used herein refers to a compound of the following formula:
- In the present application a strategy to construct the morphine skeleton by an intramolecular [4+2] cycloaddition reaction is reported. A schematic of a representative example of the overall strategy as it applies to the preparation of hydromorphine and ent-hydromorphine is shown in Scheme 1:
- Therefore, in one embodiment, the present application includes a process for the preparation of a compound of Formula I comprising treating a compound of Formula II under [4+2] intramolecular cycloaddition conditions:
- PG1 and PG2 are, independently, protecting groups; and
LG is a leaving group, and
one or more available hydrogens in the compounds of Formulae I and II is/are optionally replaced with F and/or one or more of available atoms in the compounds of Formulae I and II is/are optionally replaced with an isotopic label. - In an embodiment, the compound of Formula II is derived from the corresponding phenol by oxidative dearomatization using, for example, lead tetraacetate (Pb(OAc)4), diacetoxyiodobenzene (DAIB), bis trifluoroacetoxyiodo benzene (PIFA) or Dess-Martin periodinane. In another embodiment, the oxidative dearomatization comprises electrochemical anodic oxidation. The selection of suitable conditions for electrochemical anodic oxidation can be made by a person skilled in the art.
- Accordingly, in a further embodiment, the present application includes a process of preparing a compound of Formula I comprising converting a compound of Formula III into a compound of Formula II by oxidative dearomatization followed by treating the compound of Formula II under [4+2] intramolecular cycloaddition conditions to provide the compound of Formula I:
- PG1 and PG2 are, independently, protecting groups; and
LG is a leaving group, and
one or more available hydrogens in the compounds of Formulae I-III is/are optionally replaced with F and/or one or more of available atoms in the compounds of Formulae I-III is/are optionally replaced with an isotopic label. - In an embodiment, the compound of Formula III is available by reacting a compound of the Formula IV with a compound of the Formula V under Mitsunobu reaction conditions to provide a compound of the Formula VI followed by Wittig homologation of the CHO group and removal of PG3:
- PG1, PG2 and PG3 are, independently, protecting groups; and
LG is a leaving group, and
one or more available hydrogens in the compounds of Formulae III-VI is/are optionally replaced with F and/or one or more of available atoms in the compounds of Formulae III-VI is/are optionally replaced with an isotopic label. - In an embodiment, the Wittig homologation of CHO in the compound of Formula VI is performed by reacting a compound of the Formula VI with a Wittig reagent, for example, a compound of the Formula VII:
- wherein A− is a suitable counteranion and Y is as defined above, under Wittig reaction conditions.
- In another embodiment, the compound of the Formula III wherein Y is H is prepared by Wittig homologation of the CHO group in a compound of Formula X to provide a compound of Formula XI, followed by selective removal of PG5 to provide a compound of Formula XII, then reacting the compound of Formula XII with a compound of Formula V under Mitsunobu reaction conditions and removal of PG4:
- PG2, PG4 and PG5 are, independently, protecting groups, wherein PG4 and PG5 are protecting groups that are removable under different conditions.
- In an embodiment, the Wittig homologation of CHO in the compound of Formula X is performed by reacting a compound of the Formula X with a Wittig reagent, for example, a compound of the Formula VII:
- wherein A− is a suitable counteranion and Y is as defined above, under Wittig reaction conditions.
- Compounds of the Formula V, when X is NMePG2, Z is OPG1 and Z and CC are both single bonds, are available, for example, using methods known in the art, for example from (2-bromoethyl)benzene as described in the literature4,5 and as shown in Scheme 3 below. Alternatively, compounds of the Formula V, when Z is O, Z is a double bond and CC is a single bond, are prepared, for example, by the Birch reduction of a compound of the Formula VIII to provide a compound of the Formula IX, wherein X is as defined above. A Davis hydroxylation, which can be performed asymmetrically to provide either enantiomer, is then used to convert the compound of the Formula IX into the compound of the Formula V. The present application therefore also includes a process for preparing a compound of the Formula V, wherein X is NMePG2 or LG, Z is O, Z is a double bond and CC is a single bond comprising treating a compound of the Formula VIII under Birch reduction conditions to provide a compound of the Formula IX and treating the compound of the Formula IX under Davis hydroxylation conditions to provide the compound of the Formula V, wherein X is NMePG2 or LG, Z is O, Z is a double bond and CC is a single bond:
- Compounds of the Formula IV, are known and are prepared, for example, from 3,4-dihydroxylbenzaldyde as described in the literature2 and as shown in Scheme 2 below.
- Compounds of the Formula VII, VIII and X are either known in the art or are prepared using methods known in the art.
-
- In an embodiment, Y is H and X is NMePG2.
- In another embodiment, X is LG and Y is NMePG2.
- In an embodiment, OR is OAc.
- In an embodiment, the stereochemistry of the compounds of Formula II-XII is selected so that the compound of Formula I has the same stereochemistry as that found in hydromorphone. In an embodiment, the stereochemistry of the compounds of Formula II-XII is selected so that the compound of Formula I has the same stereochemistry as that found in ent-hydromorphone.
- In an embodiment, the intramolecular cycloaddition conditions comprise heating a substrate, i.e. a compound comprising a diene and a dienophile such as a compound of Formula II, in an inert organic solvent, optionally in the presence of a catalyst.
- In a further embodiment, oxidative dearomatization conditions comprise treating an appropriate aromatic substrate with a suitable oxidizing agent, such as Pb(OAc)4, diacetoxyiodobenzene (DAIB), bis trifluoroacetoxyiodo benzene (PIFA) or Dess-Martin periodinane, in an inert organic solvent, optionally with heating. In a further embodiment, the oxidative dearomatization to provide the compounds of Formula II and intramolecular cycloaddition are performed in a single step, wherein the compound of Formula II is formed in situ and converted, under the oxidative dearomatization conditions to a compound of the Formula I. In an embodiment, the oxidizing agent is Pb(OAc)4.
- In an embodiment, the Mitsunobu reaction conditions comprise treating the substrates in the presence of a trialkylphosphine, or a triarylphosphone, and an azodicarboxylate, such as tetramethylazodicarboxamide (TMAD), diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) in an inert organic solvent. The reaction conditions optionally comprise heating or cooling depending on the substrates as would be known to a person skilled in the art.
- In an embodiment, Wittig homologation refers to the conversion of an aldehyde to the next higher homolog (i.e. addition of one methylene unit) using Wittig reaction conditions.
- In an embodiment, Wittig reaction conditions comprise reaction of an aldehyde-containing substrate with a Wittig reagent, for example a compound of the Formula VII as defined above at low temperature (for example, −50° C. to −100° C.) in an inert organic solvent, followed by warming to, for example room temperature or above,
- In an embodiment, Birch reduction conditions comprise reaction of an aromatic substrate, such as a compound of Formula VIII, with anhydrous ammonia, t-BuOH and metals such as Na, Li etc. at low temperature (for example, −50° C. to −100° C.) in an inert organic solvent, followed by warming to, for example room temperature or above, and treating with a suitable acid to provide, for example, the desired enone IX.
- In an embodiment, Davis hydroxylation conditions comprise reaction of an enone, for example a compound of Formula IX, with metal bases at low temperature (for example, −50° C. to −100° C.) in an inert organic solvent, followed by reacting with Davis oxaziridine (or equivalent reagent) at low temperature (for example, −50° C. to −100° C.), quenching the reaction with a suitable acid to provide, for example, the desired alcohol V.
- Standard methods and reactions are used to convert the compound of Formula I into morphine compounds. For example, when one of X and Y is NMePG2 and the other is LG, removal of PG2 followed by nucleophilic displacement of the LG leads to the formation of the ring D of the morphine skeleton. In another example, when Y is H and X is NMePG2, formation of ring D is carried out using reductive cyclization, such as nitrogen centered radical cyclization. Oxidation and/or reduction of the various functional groups, such as the C6 OH group, as well as removal of protecting groups are performed to provide the desired morphine compound.
- The following non-limiting examples are illustrative of the present application:
- The reactions and numbering referred to in Examples 1 and 2 are depicted in Scheme 2:
-
- Aldehyde 152 (3.9 g, 28 mmol) was dissolved in THF and the solution was cooled to 0° C. Then a 2 N solution of NaOH in water (70 mmol) was added dropwise followed by the addition of acetic anhydride (3.2 mL, 34 mmol). The reaction mixture was stirred for 20 minutes, diluted with EtOAc, made acidic with 2.5 mL of con. HCl and 20 mL of phosphate buffer (pH=2.5). Then it was filtered through a pad of Celite™ and the organic phase was separated. The aqueous phase was washed 3 times with EtOAc, organic washes were combined, washed with brine, dried over Na2SO4 and solvent was evaporated under reduced pressure to obtain the crude product, which was purified by suction filtration chromatography on silica gel with [CH2Cl2/MeOH (98:2)→CH2Cl2/MeOH (95:5)] as eluent to provide 16 as a light yellow solid (4.2 g, 23.3 mmol, 84%). It was recrystallized from ether to provide colourless crystals.
- m.p. 88-91° C. (ether), [lit.3 87-89° C. (ether-light petrol)]; Rf=0.33 [CH2Cl2/MeOH (98:2)]; IR (CHCl3, cm−1) v 3564, 3374, 3028, 2838, 2737, 1773, 1696, 1607, 1509, 1441, 1371, 1296, 1277, 1172; 1H NMR (300 MHz, CDCl3) δ 9.78 (s, 1H), 7.69 (dd, J=8.4 Hz, 1.8, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 4.95 (bs, 1H), 2.33 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.8, 169.3, 155.4, 139.1, 129.6, 129.1, 124.0, 116.7, 19.2; MS (EI) m/z (%) 180 (11), 138 (65), 137 (55), 43 (100); HRMS (EI) calcd for C9H8O4: 180.0423. Found 180.0427; Anal. Calcd for C9H8O4: C, 60.00; H, 4.48. Found C, 60.24; H, 4.59.
-
- To a suspension of K2CO3 (2.3 g, 16.8 mmol) in DMF (30 mL) at 0° C. was added MOMCl (0.84 mL, 2 mmol) dropwise. Then a solution of 16 (1 g, 5.6 mmol) in DMF (30 mL) was added dropwise through an addition funnel. The reaction mixture was allowed to stir for another 30 minutes and was diluted with H2O (100 mL). It was then extracted three times with Et2O (75 mL), organic washes were combined, washed with brine solution, dried over Na2SO4, and the solvent was evaporated under reduced pressure to provide the crude acetate 17 which was taken to next step without further purification.
- A saturated solution of K2CO3 in MeOH (15 mL) was added to a solution of acetate 17 in MeOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 40 minutes, then the pH of the reaction mixture was adjusted to 7 using 1 N HCl and NH4Cl (saturated) solution. The aqueous layer was extracted with CH2Cl2 (3×100 mL), washed with brine, dried over Na2SO4, and the volatiles were removed in vacuo to provide crude product, which was filtered through a plug of silica using EtOAc to yield 18 (0.72 g, 3.95 mmol, 71% over two steps) as a colourless liquid.
- Rf=0.15 [hexane/EtOAc (80:20)]; IR (CHCl3, cm−1) v 3615, 3028, 3007, 2964, 2740, 1705, 1578, 1464; 1H NMR (CDCl3, 300 MHz) δ 9.79 (s, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.35 (dd, J=8.4, 1.8 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 5.26 (s, 2H), 3.47 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 191.4, 149.8, 146.7, 131.4, 124.3, 114.9, 114.3, 95.2, 56.6; MS (EI) m/z (%) 182 (13), 45 (100); HRMS-EI calcd for C9H10O4: 182.0579 found 182.0576.
- The reactions and numbering referred to in Examples 3-4 are depicted in Scheme 3:
- The synthesis of the homochiral subunit 13 was accomplished as shown in Scheme 3 and as previously described.4,5 Dihydroxylation of 8 by whole-cell fermentation with E. coli JM 109 (pDTG601A)6 yielded 9, which was immediately subjected to a selective reduction with potassium azodicarboxylate, followed by protection of the diol to give 10. Displacement of bromine in 10 with methylamine produced 11 (the tosylation of this compound could be used in the future to provide 14 and hence 19b, Scheme 4, in a more direct way). Hydrolysis of the acetonide with HCl was followed by protection of the secondary amine as a Boc carbamate to provide 12 in a one-pot operation; regioselective silylation of the distal hydroxyl then provided alcohol 13.
-
- To a solution of 13 (1 g, 2.59 mmol) in CH2Cl2 at 0° C. was added TFA (4 mL, 32 mmol) and was stirred for 20 minutes. Then the reaction mixture was diluted with CH2Cl2 (60 mL), then saturated NaHCO3 solution was added and pH was adjusted to −9. The organic layer was separated and the aqueous layer was washed with CH2Cl2 (3×30 mL), the organic washes were combined and were washed with brine solution, dried over Na2SO4 and solvent was evaporated under reduced pressure to provide crude product (540 mg). Then the aqueous phase was saturated with NaCl and was washed with CHCl3:EtOH (3:1) (3×30 mL), dried over Na2SO4 and solvent was evaporated under reduced pressure to provide another 200 mg of crude product. The crude material was taken to the next step without further purification.
- To a solution of crude product (740 mg, 2.6 mmol) in CH2Cl2 at 0° C. was added Et3N (0.47 mL, 3.37 mmol) followed by TsCl (593 mg, 3.1 mmol). The reaction mixture was slowly warmed to room temperature and was stirred for 3 hours. Then the solvent was evaporated under reduced pressure and column chromatography on silica gel using [hexane/EtOAc (90:10)→hexane/EtOAc (70:30)] to provide 14 (979 mg, 2.2 mmol, 86%) as a clear liquid.
- Rf=0.12 [hexane/EtOAc (70:30)]; [α]20 D=−30.0 (c=1.15, CHCl3); IR (CHCl3, cm−1) v 3550, 3028, 3008, 2954, 2930, 2885, 2859, 1690, 1598, 1462, 1373, 1339, 1160, 1088; 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 5.58 (bs, 1H), 3.92 (d, J=3.6 Hz, 1H), 3.83-3.78 (m, 1H), 3.35-3.26 (m, 1H), 3.00-2.93 (m, 1H), 2.70 (s, 3H), 2.39 (s, 4H), 2.30-2.23 (m, 1H), 2.21-1.88 (m, 3H), 1.80-1.67 (m, 1H), 1.56-1.52 (m, 1H), 0.89 (s, 9H), 0.14-0.09 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ 143.1, 134.8, 134.0, 129.6, 127.3, 127.2, 70.7, 68.7, 49.1, 34.6, 33.1, 25.8, 25.5, 23.9, 21.4, 18.0, −4.5, −4.9; MS (EI) m/z (%) 382 (4), 324 (8), 200 (10), 199 (25), 198 (100), 197 (86), 155 (67), 140 (21), 105 (15), 91 (58), 77 (13), 75 (81), 73 (30), 57 (16), 44 (35); HRMS (EI) calcd for C22H37NO4SSi (M+-C4H9): 382.1508. Found 382.1496; Anal. Calcd for C22H37NO4SSi: C, 60.10; H, 8.48. Found C, 59.92; H, 8.28.
- The reactions and numbering referred to in Examples 5-14 are depicted in Scheme 4:
-
- To a solution of alcohol 13 (3.19 g, 8.28 mmol) and phenol 18 (1.66 g, 9.11 mmol) in THF (30 mL) at −10° C. was added PBu3 (2.9 mL, 11.59 mmol) followed by tetramethylazodicarboxamide (TMAD) (1.9 g, 10.76 mmol). The reaction mixture was slowly warmed to room temperature and was stirred for 18 hours. Solvent was evaporated under reduced pressure and purified by flash column chromatography on silica gel using [hexane/EtOAc (90:10)] as eluent to isolate product 19a (3.7 g, 6.7 mmol, 81%) as a clear oil.
- Rf=0.39 [hexane/EtOAc (70:30)]; [α]20 D=−27.6 (c=1.48, CHCl3); IR (CHCl3, cm−1) v 3681, 3009, 2931, 1726, 1682, 1582, 1506, 1394, 1271, 1159; 1H NMR (CDCl3, 300 MHz) δ 9.86 (s, 1H), 7.70 (s, 1H), 7.44 (dd, J=8.1, 1.5 Hz, 1H), 7.28-7.24 (m, 1H), 5.69 (s, 1H), 5.29 (s, 2H), 4.75 (s, 1H), 4.11-4.06 (m, 1H), 3.49 (s, 3H), 3.25-3.17 (m, 2H), 2.72 (s, 3H), 2.35-2.04 (m, 4H), 1.93-1.86 (m, 1H), 1.79-1.70 (m, 1H), 1.41 (s, 9H), 0.81 (s, 9H), 0.00 (s, 3H), −0.09 (s, 3H); 13C NMR (CDCl3, 75 MHz, rotameric) δ 190.8, 155.7, 152.7, 149.8, 132.4, 131.1, 128.6, 125.8, 125.2, 115.5, 94.8, 80.3, 79.3, 70.4, 60.5, 56.5, 48.5, 34.5, 32.3, 31.7, 28.5, 25.8, 22.8, 18.0, −4.7, −4.8; MS (EI) m/z (%) 312 (37), 268 (50), 237 (29), 136 (34), 57 (51), 44 (100)); HRMS-EI calcd for C29H47NO7Si: 549.3122 found 549.3115; Anal. Calcd for C29H47NO7Si: C, 63.36; H, 8.62. Found C, 63.02; H, 8.61.
-
- To a solution of alcohol 14 (190 mg, 0.43 mmol) and phenol 18 (102 mg, 0.56 mmol) in THF (6 mL) at −10° C. was added PBu3 (0.15 mL, 0.65 mmol) followed by tetramethylazodicarboxamide (TMAD) (111 mg, 0.65 mmol). The reaction mixture was slowly warmed to room temperature and was stirred for 22 hours. Solvent was evaporated under reduced pressure and purified by flash column chromatography on silica gel using [hexane/EtOAc (80:20)→hexane/EtOAc (50:50)] as eluent to isolate product 19b (130 mg, 0.22 mmol, 50%) as a clear oil.
- Rf=0.34 [hexane/EtOAc (70:30)]; [α]20 D=−21.1 (c=1.5, CHCl3); IR (CHCl3, cm−1) v 3028, 3009, 2954, 2930, 2857, 1688, 1596, 1584, 1505, 1463, 1339, 1264, 1160, 1126, 1084; 1H NMR (CDCl3, 300 MHz) δ 9.87 (s, 1H), 7.69 (d, J=1.2 Hz, 1H), 7.55-7.45 (m, 3H), 7.28-7.23 (m, 3H), 5.75 (s, 1H), 5.31-5.26 (m, 2H), 4.72 (d, J=4.8 Hz, 1H), 4.14-4.05 (m, 1H), 3.48 (s, 3H), 3.05-3.01 (m, 1H), 2.94-2.88 (m, 1H), 2.62 (s, 3H), 2.50-2.40 (m, 4H), 2.36-2.26 (m, 1H), 2.19-2.13 (m, 2H), 1.89-1.87 (m, 1H), 1.85-1.83 (m, 1H), 0.80 (s, 9H), −0.00 (s, 3H), −0.11 (s, 3H); 13C NMR (CDCl3, 75 MHz, rotameric) δ 190.9, 152.8, 150.1, 149.4, 143.1, 134.6, 131.8, 130.9, 129.6, 128.9, 127.3, 125.4, 115.4, 115.1, 94.8, 79.9, 70.2, 60.4, 56.5, 49.4, 34.9, 32.4, 28.0, 25.7, 22.7, 21.5, 17.9, −4.9, −5.0; MS (EI) m/z (%) 546 (2), 199 (12), 198 (100), 155 (44), 91 (47), 75 (67), 45 (77); HRMS (EI) calcd for C31H45NO7SSi (M+-C4H9): 546.1982. Found 546.1976.
-
- To a suspension of Wittig salt CH3P+Ph3Br− (2.26 g, 6.3 mmol) in THF (20 mL) at −78° C., nBuLi (2.9 mL, 5.8 mmol) was added and the resulting yellow solution was stirred for 15 minutes. It was then warmed to 0° C., and aldehyde 19a (1.58 g, 2.9 mmol) in THF (20 mL) was cannulated into the reaction mixture, which was stirred for another 10 minutes at 0° C. The resulting yellow suspension was heated to reflux for 4 hours whereupon the solvent was evaporated under reduced pressure and column chromatography on silica gel using hexane/EtOAc (80:20) provided 20 (1.3 g, 2.37 mmol, 82%) as a colourless liquid.
- Rf=0.57 [hexane/EtOAc (70:30)]; [α]20 D=−9.4 (c=0.17, CHCl3); IR (CHCl3, cm−1) v 3009, 2954, 2930, 2898, 2857, 1683, 1601, 1577, 1506, 1261; 1H NMR (CDCl3, 300 MHz, rotameric) δ 7.21-7.20 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.01-6.93 (m, 1H), 6.67-6.57 (m, 1H), 5.67-5.58 (m, 2H), 5.20-5.13 (m, 3H), 4.57 (bs, 1H), 4.08 (bs, 1H), 3.48 (s, 3H), 3.20-3.16 (m, 2H), 2.73 (bs, 3H), 2.36-2.04 (m, 4H), 1.89-1.86 (m, 1H), 1.74-1.67 (m, 1H), 1.42 (s, 9H), 0.83 (s, 9H), −0.01 (s, 3H), −0.08 (s, 3H); 13C NMR (CDCl3, 75 MHz, rotameric) δ 155.6, 149.2, 147.2, 136.3, 132.6, 132.3, 128.2, 127.8, 119.7, 114.2, 113.7, 116.9, 114.2, 113.7, 112.4, 95.3, 79.9, 79.0, 69.6, 60.3, 56.0, 48.4, 47.7, 34.4, 32.6, 31.8, 28.4, 27.6, 25.7, 22.4, 20.9, 17.9, −4.8, −4.9; MS (EI) m/z (%) 312 (35), 268 (72), 237 (28), 225 (17), 180 (24), 136 (57), 109 (30), 75 (77), 57 (57), 45 (100); HRMS (EI) calcd for C30H49NO6Si: 547.3329. Found 547.3323; Anal. Calcd for C30H49NO6Si: C, 65.78; H, 9.02. Found C, 65.52; H, 8.85.
-
- To a solution of 20 (1.3 g, 2.4 mmol) in CH2Cl2 (25 mL) at 0° C. was added ZnBr2 (0.59 g, 2.6 mmol) followed by 1-dodecane thiol (1.1 mL, 4.8 mmol). Then the reaction mixture was stirred for 10 minutes, diluted with CH2Cl2 (60 mL), then NaHCO3 (sat) solution was added dropwise and the mixture was filtered through a pad of celite. The aqueous layer was separated and further extracted with CH2Cl2. The combined organic solution was dried with Na2SO4, volatiles were removed in vacuo to provide crude product and column chromatography on silica gel using [hexane/EtOAc (90:10)] provided 21 (1.12 g, 2.22 mmol, 93%) as a clear liquid.
- Rf=0.27 [hexane/EtOAc (80:20)]; [α]20 D=+1.0 (c=3.15, CHCl3); IR (CHCl3, cm−1) v 3535, 3297, 2955, 2930, 2858, 1684, 1605, 1508, 1396, 1268, 1161; 1H NMR (CDCl3, 300 MHz, rotameric) δ 7.06 (s, 1H), 6.92-6.86 (m, 2H), 6.60 (dd, J=17.4, 10.8 Hz, 1H), 5.65 (s, 1H), 5.56 (d, J=17.7 Hz, 1H), 5.09 (d, J=10.8 Hz, 1H), 4.58 (s, 1H), 4.10-4.06 (m, 1H), 3.71 (bs, 0.6H), 3.15 (bs, 0.8H), 2.95-2.91 (m, 0.6H), 2.75 (s, 3H), 2.33-1.95 (m, 4H), 1.70-1.68 (m, 2H), 1.43 (s, 9H), 0.86 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz, rotameric) δ 155.7, 146.8, 145.7, 136.7, 130.5, 129.2, 119.7, 115.3, 111.0, 109.8, 79.2, 78.7, 69.6, 68.7, 48.6, 47.6, 44.1, 33.8, 33.1, 31.2, 31.4, 29.6, 29.5, 29.3, 29.0, 28.4, 27.5, 26.7, 25.7, 22.7, 21.9, 17.9, −4.8; MS (EI) m/z (%) 312 (14), 268 (15), 237 (17), 228 (17), 136 (42), 109 (15), 105 (240), 83 (34), 75 (56), 57 (90), 44 (100); HRMS (EI) calcd for C28H45NO5Si: 503.3067. Found 503.3073; Anal. Calcd for C28H45NO5Si: C, 66.76; H, 9.00. Found C, 65.85; H, 9.07.
-
- A solution of lead tetraacetate (37.9 mg, 0.08 mmol) in DCE (1 mL) was added dropwise to a refluxing solution of 21 (43 mg, 0.08 mmol) in DCE (1 mL). The reaction mixture was stirred for another 4 hours, cooled to room temperature, and then passed through a plug of celite and solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography on silica gel using [hexane/EtOAc (90:10)→hexane/EtOAc (70:30)] as eluent to provide 6 (24 mg, 0.04 mmol, 50%) as a colourless liquid.
- Rf=0.46 [hexane/EtOAc (70:30)]; [α]20 D=−22.0 (c=1.2, CHCl3); IR (CHCl3, cm−1) v 3024, 3009, 2951, 2931, 2858, 1730, 1686, 1625, 1462, 1368, 1252, 1161; 1H NMR (300 MHz, CDCl3, rotameric) δ 7.06 (d, J=9.9 Hz, 1H), 6.47 (bt, J=3.6 Hz, 1H), 5.98 (d, J=9.9 Hz, 1H), 4.15-4.05 (m, 1H), 3.42-3.10 (m, 4H), 2.87 (s, 3H), 2.27-2.22 (m, 2H), 2.16 (bs, 1H), 2.13 (s, 3H), 2.04-2.02 (m, 2H), 1.72 (bs, 1H), 1.53-1.51 (m, 1H), 1.47 (s, 9H), 1.14-1.05 (m, 2H), 0.84 (s, 9H), −0.01 (s, 3H), −0.05 (s, 3H); 13C NMR (75 MHz, CDCl3, rotameric) δ88.2, 170.9, 155.4, 144.5, 139.0, 134.2, 122.7, 103.9, 90.6, 79.7, 74.2, 73.5, 52.0, 48.6, 45.9, 45.4, 40.7, 39.8, 38.6, 37.3, 34.4, 30.8, 29.4, 28.5, 25.8, 21.3, 20.6, 18.1, −4.6, −5.1; MS (EI) m/z (%) 388 (10), 345 (10), 313 (12), 287 (25), 171 (15), 83 (12), 75 (23), 73 (45), 59 (34), 57 (87), 44 (100); HRMS (EI) calcd for C30H47NO7Si (M+-C2H4O2): 501.2911. Found 501.2910; Anal. Calcd for C30H47NO7Si: C, 64.14; H, 8.43. Found C, 64.03; H, 8.45.
-
- A solution of 6 (16 mg, 0.028 mmol) in CH2Cl2 (1.5 mL) was cooled in an ice bath and TFA (0.5 mL) was added dropwise. The reaction mixture was stirred for 10 minutes, diluted with CH2Cl2 (4.5 mL) and the pH of the reaction mixture was adjusted to ˜7 using saturated Na2CO3 solution. The organic layer was separated, washed with water, dried over Na2SO4 and evaporated in vacuo to obtain the crude product (22) which was immediately taken to next step without further purification.
- To a solution of 22 in CH2Cl2 cooled in an ice bath, was added Et3N (6.3 μL, 0.045 mmol) and TsCl (8.6 mg, 0.045 mmol) and the resulting reaction mixture was stirred for 10 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using [hexane/EtOAc (90:10)→hexane/EtOAc (80:20)] as eluent to provide 23 (9 mg, 0.013 mmol, 46% over two steps) as a light yellow oil.
- Rf=0.47 [hexane/EtOAc (70:30)]; [α]20 D=−106.5 (c=0.42, CHCl3); IR (CHCl3, cm−1) v 3027, 2929, 2857, 1599, 1490, 1446, 1378, 1341, 1274, 1221, 1158; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.31-7.26 (m, 4H), 6.84 (d, J=8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 6.35 (d, J=9.6 Hz, 1H), 5.92 (dd, J=9.6, 5.7 Hz, 1H), 4.36 (d, J=6.9 Hz, 1H), 3.31-3.23 (m, 1H), 3.05-2.95 (m, 1H), 2.82-2.72 (m, 1H), 2.59 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H), 2.36-2.34 (m, 1H), 1.77-1.68 (m, 2H), 1.63-1.55 (m, 3H), 1.25-1.17 (m, 1H), 0.88 (s, 9H), 0.08 (s, 3H), −0.01 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 148.2, 145.3, 143.3, 134.6, 133.0, 132.8, 132.7, 129.7, 129.6, 129.2, 128.9, 128.8, 127.4, 124.1, 122.5, 117.7, 98.2, 73.9, 46.1, 44.7, 39.7, 35.8, 34.8, 29.8, 29.7, 26.6, 25.8, 21.7, 21.5, 18.1, −4.6, −5.0; MS (EI) m/z (%) 653 (3), 198 (34), 155 (12), 149 (19), 124 (28), 123 (13), 100 (42), 92 (17), 91 (58), 83 (16), 57 (35), 43 (100); HRMS (EI) calcd for C37H47NO7S2Si (M+-C4H9): 652.1859. Found 652.1852; Anal. Calcd for C37H47NO7S2Si: C, 62.59; H, 6.67. Found C, 62.52; H, 6.63.
-
- To a mixture of 23 (141 mg, 0.19 mmol) and THF (5 mL) at room temperature was added tetrabutylammonium fluoride (TBAF) solution in THF (0.34 mL, 0.34 mmol). The resulting mixture was stirred for 6 hours and the solvent was evaporated under reduced pressure to provide the crude product, which was purified by column chromatography on silica gel using [hexane/EtOAc (70:30)→hexane/EtOAc (50:50)] as eluent to provide 24 (101 mg, 0.17 mmol, 86%) as a clear oil.
- Rf=0.29 [hexane/EtOAc (50:50)]; [α]18 D=−20.4 (c=0.55, CHCl3); IR (CHCl3, cm−1) v 3518, 3033, 2926, 2861, 1597, 1489, 1445, 1335, 1191, 1177, 1088; 1H NMR (300 MHz, CDCl3) δ7.76 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.33-7.26 (m, 4H), 6.78 (d, J=8.1 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 6.35 (d, J=9.6 Hz, 1H), 5.93 (dd, J=9.6, 5.7 Hz, 1H), 4.48 (d, J=7.2 Hz, 1H), 3.08-2.98 (m, 2H), 2.84-2.74 (m, 1H), 2.57 (s, 3H), 2.47-2.36 (m, 8H), 1.88-1.56 (m, 4H), 1.27-1.15 (m, 1H), 0.89-0.76 (m, 1H); 13C NMR (75 MHz, CDCl3) δ47.9, 145.6, 143.4, 134.3, 133.0, 132.6, 129.7, 129.3, 129.1, 128.7, 127.4, 123.8, 122.5, 117.9, 98.0, 76.7, 72.9, 46.1, 44.7, 39.3, 35.2, 34.8, 27.8, 26.9, 21.7, 21.5; MS (EI) m/z (%) 595 (1), 440 (4), 384 (3), 229 (7), 198 (10), 155 (35), 139 (13), 124 (20), 97 (13), 92 (18), 91 (100), 69 (21), 57 (30); HRMS (EI) calcd for C31H33NO7S2: 595. 1698. Found 595. 1693.
-
- To a mixture of tBuOH (64 μL, 0.62 mmol) and THF (2 mL) at −78° C. was added liquid NH3 (˜15 mL) and Li wire (37 mg, 5.3 mmol). The resulting blue color reaction mixture was stirred for five minutes and 23 (35 mg, 0.05 mmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred for another 10 minutes while it remained blue in color. Then 2 g of NH4Cl was added as a solid, followed by 10 mL of MeOH and 20 mL of saturated NH4Cl solution. This mixture was then washed three times with CH2Cl2 (20 mL), the combined organic layers were washed with saturated NaCl solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure to provide the crude product, which was purified by column chromatography on silica gel using [CH2Cl2/MeOH (95:5)→CH2Cl2/MeOH (90:10)] as eluent to provide 25 (16 mg, 0.04 mmol, 82%) as a colourless oil.
- Rf=0.24 [CH2Cl2/MeOH (90:10)]; [α]20 D=+70.5 (c=0.8, CHCl3); IR (CHCl3, cm−1) v 3688, 3586, 2953, 2931, 2858, 1624, 1604, 1505, 1455, 1220, 1119, 1098; 1H NMR (600 MHz, CDCl3) δ 6.70 (d, J=8.4 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 4.91 (bs, 1H), 4.31 (d, J=6.6 Hz, 1H), 3.39-3.35 (m, 1H), 3.25 (d, J=2.4 Hz, 1H), 2.98 (d, J=18.6 Hz, 1H), 2.68 (dd, J=12, 4.2 Hz, 1H), 2.46 (s, 3H), 2.44-2.43 (m, 1H), 2.28-2.22 (m, 2H), 2.03 (s, 1H), 1.95-1.90 (m, 1H), 1.67-1.65 (m, 2H), 1.53-1.50 (m, 1H), 1.39-1.32 (m, 1H), 0.88 (s, 9H), 0.10 (s, 3H), 0.01 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 143.0, 139.9, 129.9, 124.5, 119.2, 117.0, 97.3, 73.7, 59.5, 46.9, 42.9, 42.2, 41.7, 34.7, 31.6, 25.8, 23.4, 20.4, 18.1, −4.5, −4.8; MS (EI) m/z (%) 401 (3), 120 (29), 118 (32), 87 (92), 85 (80), 83 (76), 60 (30), 47 (100), 43 (44); HRMS (EI) calcd for C23H35NO3Si: 401.2386. Found 401.2375.
-
- To a mixture of tBuOH (35 μL, 0.34 mmol) and THF (2 mL) at −78° C. was added liquid NH3 (˜15 mL) and Li wire (20 mg, 2.85 mmol). The resulting blue colour reaction mixture was stirred for five minutes and 24 (20 mg, 0.03 mmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred for another 10 minutes while the reaction mixture remained blue in color. Then 2 g NH4Cl was added as a solid, followed by 10 mL of MeOH and 20 mL of saturated NH4Cl solution. This mixture was then washed three times with CH2Cl2 (20 mL), the combined organic washes were washed with saturated NaCl solution and was further dried over Na2SO4. The solvent was evaporated under reduced pressure to provide the crude product, which was purified by column chromatography on silica gel using [CH2Cl2/MeOH (90:10)→CH2Cl2/MeOH (80:20)→MeOH] as eluent to provide 26 (9.1 mg, 0.03 mmol, 93%) as a white solid.
- m.p. >200° C.; Rf=0.15 [CH2Cl2/MeOH (80:20)]; [α]20 D=+57.0 (c=0.35, MeOH); IR (CHCl3, cm−1) v 3311, 2923, 1599, 1462, 1313, 1255, 1084; 1H NMR (600 MHz, MeOD) δ 6.71 (d, J=7.8 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 4.33 (d, J=6.6 Hz, 1H), 3.66 (s, 1H), 3.16 (d, J=19.2 Hz, 1H), 3.02 (d, J=11.4 Hz, 1H), 2.78 (s, 3H), 2.64-2.60 (m, 1H), 2.39 (d, J=9.6 Hz, 1H), 2.10-2.05 (m, 1H), 1.81 (d, J=10.6 Hz, 2H), 1.68-1.66 (m, 1H), 1.43-1.31 (m, 2H), 1.03-0.97 (m, 1H), 0.93-0.90 (m, 1H); 13C NMR (150 MHz, MeOD) δ 142.9, 140.9, 128.5, 122.1, 119.3, 117.5, 95.5, 72.1, 60.9, 47.2, 42.1, 40.6, 40.4, 33.2, 30.1, 22.9, 20.8; MS (EI) m/z (%) 287 (92), 286 (23), 230 (22), 228 (10), 164 (17), 149 (15), 97 (17), 84 (26), 70 (32), 57 (53), 43 (100); HRMS (EI) calcd for C17H21NO3: 287.1521. Found 287.1519.
-
- To a suspension of 26 (8 mg, 0.028 mmol) and benzophenone (10.2 mg, 0.056 mmol) in a mixture of toluene (1 mL) and DME (1 mL) was added potassium tert-butoxide (18 mg, 0.16 mmol) at room temperature. The resulting reaction mixture was heated at 85° C. for 8 hours and then the solvent was evaporated under reduced pressure to obtain the crude reaction mixture, which was purified by column chromatography on silica gel using [CH2Cl2/MeOH (95:5)→CH2Cl2/MeOH (90:10)] as eluent to provide 4 (3.5 mg, 0.012 mmol, 44%) as a white solid along with unreacted starting material 26 (4 mg, 0.014 mmol, 53%). The physical and spectral properties of 4 were matched with those given in the literature.7
- m.p. >200° C.; [lit.[3]m.p. 266-267° C. (ethanol)]; Rf=0.41 [CH2Cl2/MeOH (80:20)]; [α]20 D+190.0 (c=0.13, dioxane), [lit.[3] [α]25 D=−194 (c=0.98, dioxane); 1H NMR (300 MHz, MeOD) δ6.70 (dd, J=14.1, 8.4 Hz, 2H), 4.61 (s, 1H), 3.56 (bs, 1H), 3.14 (d, J=19.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.77-2.72 (m, 4H), 2.60-2.52 (m, 1H), 2.36-2.32 (m, 1H), 2.00-1.87 (m, 1H), 1.80 (dd, J=13.2, 2.7 Hz, 1H), 1.68 (dd, J=13.2, 2.4 Hz, 1H), 1.45-1.40 (m, 1H), 1.14-1.05 (m, 1H), 0.92-0.89 (m, 1H).
- All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.
-
- 1 For reviews of morphine alkaloid syntheses and discussion of strategies see: (a) U. Rinner, T. Hudlicky, Top. Curr. Chem. 2012, 309, 33-66; (b) J. Zezula, T. Hudlicky, Synlett 2005, 388-405; (c) D. F. Taber, T. D. Neubert, M. F. Schlecht, in Strategies and Tactics in Organic Synthesis, Vol. 5 (Ed.: H. Michael), Elsevier, London, 2004, pp. 353-389; (d) T. Hudlicky, J. Heterocyclic Chem. 2000, 37, 535-539; (e) B. H. Novak, T. Hudlicky, J. W. Reed, J. Mulzer, D. Trauner, Curr. Org. Chem. 2000, 4, 343-362; (f) T. Hudlicky, G. Butora, S. P. Fearnley, A. G. Gum, M. R. Stabile, in Studies in Natural Products Chemistry, Vol. 18, Part K (Ed.: R. Atta-ur), Elsevier, Amsterdam, 1995, pp. 43-154; (g) M. Maier, in Organic Synthesis Highlights II, (Ed.: H. Waldmann), VCH, Weinheim, 1995, pp. 357-369.
- 2 A. M. Sawayama, H. Tanaka, T. J. Wandless, J. Org. Chem. 2004, 69, 8810-8820.
- 3 J. G. Buchanan, D. G. Hill, R. H. Wightman, I. K. Boddy, B. D. Hewitt, Tetrahedron 1995, 51, 6033-6050.
- 4 H. Leisch, A. T. Omori, K. J. Finn, J. Gilmet, T. Bissett, D. Ilceski, T. Hudlicky, Tetrahedron 2009, 65, 9862-9875.
- 5 J. Duchek, T. G. Piercy, J. Gilmet, T. Hudlicky, Can. J. Chem. 2011, 89, 709-729.
- 6 G. J. Zylstra, D. T. Gibson, J. Biol. Chem. 1989, 264, 14940-14946.
- 7 H. Rapoport, R. Naumann, E. R. Bissell, R. M. Bonner, J. Org. Chem. 1950, 15, 1103-1107.
Claims (12)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/628,333 US9126965B1 (en) | 2014-02-24 | 2015-02-23 | Process for preparing morphine compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461943556P | 2014-02-24 | 2014-02-24 | |
US14/628,333 US9126965B1 (en) | 2014-02-24 | 2015-02-23 | Process for preparing morphine compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
US20150239860A1 true US20150239860A1 (en) | 2015-08-27 |
US9126965B1 US9126965B1 (en) | 2015-09-08 |
Family
ID=53881574
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/628,333 Expired - Fee Related US9126965B1 (en) | 2014-02-24 | 2015-02-23 | Process for preparing morphine compounds |
Country Status (2)
Country | Link |
---|---|
US (1) | US9126965B1 (en) |
CA (1) | CA2882694C (en) |
-
2015
- 2015-02-23 CA CA2882694A patent/CA2882694C/en active Active
- 2015-02-23 US US14/628,333 patent/US9126965B1/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
US9126965B1 (en) | 2015-09-08 |
CA2882694C (en) | 2022-02-15 |
CA2882694A1 (en) | 2015-08-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9777038B2 (en) | Process for preparing bile acid derivatives | |
Bravo et al. | New fluorinated chiral synthons | |
EP2958883B1 (en) | Cyclohexenone compositions and process for making thereof | |
US10538539B2 (en) | Method for preparing 3-((2S, 5S)-4-methylene-5-(3-oxopropyl)tetrahydrofurane-2-yl) propanol derivative, and intermediate therefor | |
KR100616029B1 (en) | Method for the Preparation of Aryl Ethers | |
IE883846L (en) | Propoxybenzene derivatives and process for preparing the same | |
US9126965B1 (en) | Process for preparing morphine compounds | |
US20100317868A1 (en) | Method of preparing taxane derivatives and intermediates used therein | |
Carretero | Stereodivergent Synthesis of (-)-and (+)-Slaframine from γ-Hydroxy-α, β-unsaturated Sulfones | |
US9701601B2 (en) | Optically active axially chiral alpha-allenic alcohol, synthesis method and use thereof | |
US11591280B2 (en) | Process and intermediates for the preparation of eldecalcitol | |
US20090234139A1 (en) | Novel Process | |
US6573388B1 (en) | Ethylaziridine derivatives and their preparation methods | |
Maciaszczyk et al. | Synthesis of aldopentapyranose-derived nitrones by silylation or Cu (II)-catalyzed aerobic oxidation of N-glycosylhydroxylamines | |
US6239296B1 (en) | Process for a phenylthiobutyl-isoquinoline and intermediates therefor | |
WO2006031179A1 (en) | Process for preparation of phtalimide | |
EP3287440B1 (en) | Pyrrolidine compound | |
Lohray et al. | Nucleophilic reaction of glycidol tosylate and the corresponding cyclic sulphate with various nucleophiles: A comparative study ǂ | |
US20230064920A1 (en) | Process of preparing arachidonoylethanolamine analogues | |
FR2681323A1 (en) | New amino-2-imidazole derivs. - are intermediates for e.g. girolline, keramadine, hymenidine and oroidine | |
US20150210665A1 (en) | Organocatalytic process for asymmetric synthesis of decanolides | |
KR950011743B1 (en) | The process for preparing the antibacterial benzoxazine derivatives using by novel propoxybenzene perivatives | |
EP2822927A1 (en) | PROCESS FOR PREPARATION OF PROSTAGLANDIN F2alpha ANALOGUES | |
MXPA01006680A (en) | Method for the preparation of aryl ethers | |
FR2470122A1 (en) | PROSTAGLANDIN / PROSTACYCLIN SYNTHESES CONTAINING NITROGEN AND PROCESS FOR PREPARING THE SAME |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BROCK UNIVERSITY, CANADA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HUDLICKY, TOMAS;VARGHESE, VIMAL;SIGNING DATES FROM 20150703 TO 20150715;REEL/FRAME:036184/0358 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2551); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY Year of fee payment: 4 |
|
FEPP | Fee payment procedure |
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
LAPS | Lapse for failure to pay maintenance fees |
Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20230908 |