WO2003066565A1 - Derives biphenyle deuterises - Google Patents
Derives biphenyle deuterises Download PDFInfo
- Publication number
- WO2003066565A1 WO2003066565A1 PCT/DE2003/000367 DE0300367W WO03066565A1 WO 2003066565 A1 WO2003066565 A1 WO 2003066565A1 DE 0300367 W DE0300367 W DE 0300367W WO 03066565 A1 WO03066565 A1 WO 03066565A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- trideuteromethyl
- deuterated
- biphenyl
- tetrazole
- group
- Prior art date
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 150000003536 tetrazoles Chemical group 0.000 claims description 24
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 15
- -1 sulfhydroxy groups Chemical group 0.000 claims description 14
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- JEVYUPNXQZXXPA-UHFFFAOYSA-N trimethyl(pyrazol-1-yl)stannane Chemical group C[Sn](C)(C)N1C=CC=N1 JEVYUPNXQZXXPA-UHFFFAOYSA-N 0.000 claims description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- IDXMMWSJDMRAMN-AAYPNNLASA-N 2,3,4,5-tetradeuterio-6-[4-(trideuteriomethyl)phenyl]benzamide Chemical compound [2H]C1=C(C(=C(C(=C1[2H])[2H])[2H])C1=CC=C(C=C1)C([2H])([2H])[2H])C(=O)N IDXMMWSJDMRAMN-AAYPNNLASA-N 0.000 claims description 2
- IDXMMWSJDMRAMN-DMONGCNRSA-N 2-[2,3,5,6-tetradeuterio-4-(trideuteriomethyl)phenyl]benzamide Chemical compound [2H]C1=C(C(=C(C(=C1[2H])C([2H])([2H])[2H])[2H])[2H])C=1C(=CC=CC=1)C(=O)N IDXMMWSJDMRAMN-DMONGCNRSA-N 0.000 claims description 2
- ZSTUEICKYWFYIC-DMONGCNRSA-N 2-[2,3,5,6-tetradeuterio-4-(trideuteriomethyl)phenyl]benzoic acid Chemical compound [2H]C1=C(C(=C(C(=C1[2H])C([2H])([2H])[2H])[2H])[2H])C=1C(=CC=CC=1)C(=O)O ZSTUEICKYWFYIC-DMONGCNRSA-N 0.000 claims description 2
- ZGQVZLSNEBEHFN-DMONGCNRSA-N 2-[2,3,5,6-tetradeuterio-4-(trideuteriomethyl)phenyl]benzonitrile Chemical compound [2H]C1=C(C(=C(C(=C1[2H])C([2H])([2H])[2H])[2H])[2H])C=1C(=CC=CC1)C#N ZGQVZLSNEBEHFN-DMONGCNRSA-N 0.000 claims description 2
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims description 2
- JUNZDJNCZJUDRU-DDIXUHJNSA-N 4,4-dimethyl-2-[2,3,4,5-tetradeuterio-6-[4-(trideuteriomethyl)phenyl]phenyl]-5h-1,3-oxazole Chemical compound N=1C(C)(C)COC=1C1=C([2H])C([2H])=C([2H])C([2H])=C1C1=CC=C(C([2H])([2H])[2H])C=C1 JUNZDJNCZJUDRU-DDIXUHJNSA-N 0.000 claims description 2
- ZSBYTGRKIKIRRJ-XJOUZFRTSA-N 5-[2-[2,3,5,6-tetradeuterio-4-(trideuteriomethyl)phenyl]phenyl]-1-trityltetrazole Chemical compound [2H]C1=C([2H])C(C([2H])([2H])[2H])=C([2H])C([2H])=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZSBYTGRKIKIRRJ-XJOUZFRTSA-N 0.000 claims description 2
- VWOJMXKARYCRCC-DMONGCNRSA-N 5-[2-[2,3,5,6-tetradeuterio-4-(trideuteriomethyl)phenyl]phenyl]-2h-tetrazole Chemical compound [2H]C1=C([2H])C(C([2H])([2H])[2H])=C([2H])C([2H])=C1C1=CC=CC=C1C1=NNN=N1 VWOJMXKARYCRCC-DMONGCNRSA-N 0.000 claims description 2
- 235000013877 carbamide Nutrition 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- OWEDFWZJRNPJIV-UHICTDSJSA-N tert-butyl 2-[2,3,5,6-tetradeuterio-4-(trideuteriomethyl)phenyl]benzoate Chemical compound C(C)(C)(C)OC(=O)C=1C(=CC=CC=1)C1=C(C(=C(C(=C1[2H])[2H])C([2H])([2H])[2H])[2H])[2H] OWEDFWZJRNPJIV-UHICTDSJSA-N 0.000 claims description 2
- ZSBYTGRKIKIRRJ-ZUXMIVTESA-N 5-[2,3,4,5-tetradeuterio-6-[4-(trideuteriomethyl)phenyl]phenyl]-1-trityltetrazole Chemical compound N=1N=NN(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C1=C([2H])C([2H])=C([2H])C([2H])=C1C1=CC=C(C([2H])([2H])[2H])C=C1 ZSBYTGRKIKIRRJ-ZUXMIVTESA-N 0.000 claims 1
- VWOJMXKARYCRCC-AAYPNNLASA-N 5-[2,3,4,5-tetradeuterio-6-[4-(trideuteriomethyl)phenyl]phenyl]-2h-tetrazole Chemical compound N1=NNN=C1C1=C([2H])C([2H])=C([2H])C([2H])=C1C1=CC=C(C([2H])([2H])[2H])C=C1 VWOJMXKARYCRCC-AAYPNNLASA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- POCFBDFTJMJWLG-UHFFFAOYSA-N dihydrosinapic acid methyl ester Natural products COC(=O)CCC1=CC(OC)=C(O)C(OC)=C1 POCFBDFTJMJWLG-UHFFFAOYSA-N 0.000 claims 1
- FLHJONIUHKDYJT-LCETYNOGSA-N trimethyl-[5-[2,3,4,5-tetradeuterio-6-[4-(trideuteriomethyl)phenyl]phenyl]tetrazol-1-yl]stannane Chemical compound N=1N=NN([Sn](C)(C)C)C=1C1=C([2H])C([2H])=C([2H])C([2H])=C1C1=CC=C(C([2H])([2H])[2H])C=C1 FLHJONIUHKDYJT-LCETYNOGSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 206010020772 Hypertension Diseases 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 208000019622 heart disease Diseases 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-DYCDLGHISA-N Deuterium chloride Chemical compound [2H]Cl VEXZGXHMUGYJMC-DYCDLGHISA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- ZSTUEICKYWFYIC-UHFFFAOYSA-N 2-(4-methylphenyl)benzoic acid Chemical class C1=CC(C)=CC=C1C1=CC=CC=C1C(O)=O ZSTUEICKYWFYIC-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- OSJRGDBEYARHLX-UHFFFAOYSA-N azido(trimethyl)stannane Chemical compound [N-]=[N+]=[N-].C[Sn+](C)C OSJRGDBEYARHLX-UHFFFAOYSA-N 0.000 description 2
- 125000005997 bromomethyl group Chemical group 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SEXZHJJUKFXNDY-UHFFFAOYSA-N 1-(bromomethyl)-2-phenylbenzene Chemical group BrCC1=CC=CC=C1C1=CC=CC=C1 SEXZHJJUKFXNDY-UHFFFAOYSA-N 0.000 description 1
- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical class CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 description 1
- ZGDUNGBWVZKWGE-UHFFFAOYSA-N 2-(2-methoxyphenyl)-4,4-dimethyl-5h-1,3-oxazole Chemical class COC1=CC=CC=C1C1=NC(C)(C)CO1 ZGDUNGBWVZKWGE-UHFFFAOYSA-N 0.000 description 1
- ZGQVZLSNEBEHFN-UHFFFAOYSA-N 2-(4-methylphenyl)benzonitrile Chemical class C1=CC(C)=CC=C1C1=CC=CC=C1C#N ZGQVZLSNEBEHFN-UHFFFAOYSA-N 0.000 description 1
- CTTUUXGJIWMJHV-UHFFFAOYSA-N 2-methyl-6-phenylbenzonitrile Chemical compound CC1=CC=CC(C=2C=CC=CC=2)=C1C#N CTTUUXGJIWMJHV-UHFFFAOYSA-N 0.000 description 1
- JUNZDJNCZJUDRU-UHFFFAOYSA-N 4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5h-1,3-oxazole Chemical class C1=CC(C)=CC=C1C1=CC=CC=C1C1=NC(C)(C)CO1 JUNZDJNCZJUDRU-UHFFFAOYSA-N 0.000 description 1
- ZSBYTGRKIKIRRJ-UHFFFAOYSA-N 5-[2-(4-methylphenyl)phenyl]-1-trityltetrazole Chemical class C1=CC(C)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZSBYTGRKIKIRRJ-UHFFFAOYSA-N 0.000 description 1
- VWOJMXKARYCRCC-UHFFFAOYSA-N 5-[2-(4-methylphenyl)phenyl]-2h-tetrazole Chemical class C1=CC(C)=CC=C1C1=CC=CC=C1C1=NN=NN1 VWOJMXKARYCRCC-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical class COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 238000006887 Ullmann reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 150000004074 biphenyls Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 150000005342 methoxybenzoic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002918 oxazolines Chemical class 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/33—Polycyclic acids
- C07C63/331—Polycyclic acids with all carboxyl groups bound to non-condensed rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/12—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
-
- 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
- C07F7/22—Tin compounds
- C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Definitions
- the invention relates to deuterated biphenyl derivatives and deuterated precursors for the preparation of these compounds.
- Deuterated biphenyl derivatives are important intermediates for the synthesis of drugs, in particular the so-called “- sartans", which can be used, for example, for the treatment of circulatory disorders, high blood pressure and heart diseases.
- the Ullmann reaction can be used to produce symmetrically and asymmetrically substituted biphenyls.
- halogen aryl compounds preferably iodine compounds, are used in the presence of copper at high
- the object of the present invention is therefore to provide deuterated biphenyl derivatives which can be used in particular in the manufacture of deuterated medicaments.
- R 1 is independently of one another H or D
- R 2 is C-C3-al yl or Ci-Cs-alkyl substituted by one or more halogen atoms, hydroxy groups, sulfhydroxy groups, phosphate groups or sulfate groups, which can be partially or completely deuterated
- R 3 is a carboxyl or deuterated carboxyl group, a carbamide or deuterated carbamide group, a cyano group, an oxazoline group, a tetrazole group, a deuterated tetrazole group, a substituted tetrazole group, N- (trimethylstannyl) pyrazole group, a deuterated N- (trimethylstannyl) ) pyrazole group, a pyrazole group, a deuterated pyrazole group or a pyrazole group substituted with a triphenylmethyl group or with a deuterated triphenylmethyl group, these groups in turn being substituted by one or more C 1 -C 3 -alkyl groups, halogen atoms, hydroxyl groups, sulfhydroxy groups, phosphate groups or sulfate groups -Ca-alkyl, which can be partially or completely deuterated and wherein at least one of the radicals R 1 to
- Deuterated biphenyl derivatives of the general formula I in which R 1 is independently H or D, R 2 is trideuteromethyl and R 3 is a carbamide group or a deuterated carbamide group are particularly preferred.
- Deuterated biphenyl derivatives of the general formula I in which R 1 is independently H or D, R 2 is trideuteromethyl and R 3 is an N- (trimethylstannyl) pyrazole group are particularly preferred.
- Deuterated biphenyl derivatives of the general formula I in which R 1 is independently H or D, R 2 is trideuteromethyl and R 3 is a pyrazole group or a deuterated pyrazole group are advantageous.
- Deuterated biphenyl derivatives of the general formula I in which R 1 is independently H or D, R 2 is trideuteromethyl and R 3 is a pyrazole group which is substituted by a triphenylmethyl group are particularly advantageous.
- Deuterated biphenyl derivatives of the general formula I in which R 1 is independent of one another H or D, R 2 is a bromideideuteromethyl group are particularly advantageous and R 3 represents a pyrazole group substituted by a triphenylmethyl group.
- the object of the invention is achieved by the provision of
- the deuterated acid chloride is generated and this is reacted with 2-amino-2-methyl-l-propanol to give the deuterated 4,4-dimethyl-2- (2-methoxyphenyl) oxazoline.
- This oxazoline is further processed with deuterated 4-methylphenyl-Grignard reagent, obtained from deuterated 4-bromotoluene, to give deuterated 2- (4'-methylbiphenyl-2-yl) -4, 4-dimethyloxazoline.
- deuterated 4'-methyl-2-biphenylcarboxylic acid is obtained from this by heating in deuterium chloride solution.
- the deuterated 4'-methyl-2-biphenylcarboxylic acid is converted to deuterated 4'-methyl-2-biphenylnitrile via the acid amide which is obtained from the acid chloride with ammonium hydroxide solution.
- Methyl 2-biphenyl nitrile with trimethyltin azide obtained N-trimethylstannyl-5- (4'-methylbiphenyl-2-yl) etrazole.
- the tetrazole group is subsequently protected by reaction with trityl chloride and the deuterated N-triphenylmethyl-5- (4'-methylbiphenyl-2-yl) tetrazole obtained is converted into the deuterated (bromomethyl) biphenyl derivative with N-bromosuccinimide.
- the product is prepared by dissolving 33 g of N-trimethylstannyl-5- (dll-4 '- methylbiphenyl-2-yl) tetrazole in a mixture of toluene and tetrahydrofuran and so long dry deuterium chloride at room temperature through the solution is blown until a clear solution is obtained.
- the product crystallizes out of the solution and is obtained
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU2003227005A AU2003227005A1 (en) | 2002-02-07 | 2003-02-06 | Deuterated biphenyl derivatives |
Applications Claiming Priority (2)
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DE10205336.7 | 2002-02-07 | ||
DE10205336A DE10205336A1 (de) | 2002-02-07 | 2002-02-07 | Deuterierte Biphenylderivate |
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WO2003066565A1 true WO2003066565A1 (fr) | 2003-08-14 |
Family
ID=27618480
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PCT/DE2003/000367 WO2003066565A1 (fr) | 2002-02-07 | 2003-02-06 | Derives biphenyle deuterises |
Country Status (3)
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AU (1) | AU2003227005A1 (fr) |
DE (1) | DE10205336A1 (fr) |
WO (1) | WO2003066565A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7674796B2 (en) | 2002-12-20 | 2010-03-09 | Pfizer Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0291969A2 (fr) * | 1987-05-22 | 1988-11-23 | E.I. Du Pont De Nemours And Company | Dérivés de tétrazole comme produits intermédiaires pour composés anti-hypertensifs |
-
2002
- 2002-02-07 DE DE10205336A patent/DE10205336A1/de not_active Withdrawn
-
2003
- 2003-02-06 WO PCT/DE2003/000367 patent/WO2003066565A1/fr not_active Application Discontinuation
- 2003-02-06 AU AU2003227005A patent/AU2003227005A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0291969A2 (fr) * | 1987-05-22 | 1988-11-23 | E.I. Du Pont De Nemours And Company | Dérivés de tétrazole comme produits intermédiaires pour composés anti-hypertensifs |
Non-Patent Citations (3)
Title |
---|
CARINI D J ET AL: "NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS: THE DISCOVERY OF A SERIES OF N-(BIPHENYLYLMETHYL)IMIDAZOLES AS POTENT, ORALLY ACTIVE ANTIHYPERTENSIVES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 8, 1 August 1991 (1991-08-01), pages 2525 - 2547, XP000674205, ISSN: 0022-2623 * |
DUNCIA, J.V. ET AL.: "Three synthetic routes to a sterically hindered tetrazole. A new one-step mild conversion of an amide into a tetrazole", J. ORG. CHEM., vol. 56, 1991, pages 2395 - 2400, XP002243982 * |
MANTLO N B ET AL: "POTENT, ORALLY ACTIVE IMIDAZOU4,5-BPYRIDINE-BASED ANGIOTENSIN II RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 9, 1 September 1991 (1991-09-01), pages 2919 - 2922, XP000674665, ISSN: 0022-2623 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7674796B2 (en) | 2002-12-20 | 2010-03-09 | Pfizer Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
US7741336B2 (en) | 2002-12-20 | 2010-06-22 | Pfizer Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
Also Published As
Publication number | Publication date |
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DE10205336A1 (de) | 2003-08-21 |
AU2003227005A1 (en) | 2003-09-02 |
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