US20080114035A1 - Novel intermediate compounds useful in the preparation of oxazoles and pharmaceutical actives for the regulation of lipid and glucose metabolism - Google Patents
Novel intermediate compounds useful in the preparation of oxazoles and pharmaceutical actives for the regulation of lipid and glucose metabolism Download PDFInfo
- Publication number
- US20080114035A1 US20080114035A1 US11/928,117 US92811707A US2008114035A1 US 20080114035 A1 US20080114035 A1 US 20080114035A1 US 92811707 A US92811707 A US 92811707A US 2008114035 A1 US2008114035 A1 US 2008114035A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- aryl
- alkylene
- substituted
- group
- 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.)
- Abandoned
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000002916 oxazoles Chemical class 0.000 title abstract description 11
- 230000004153 glucose metabolism Effects 0.000 title abstract description 4
- 230000028503 regulation of lipid metabolic process Effects 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 47
- 229910052801 chlorine Inorganic materials 0.000 claims description 47
- 229910052794 bromium Inorganic materials 0.000 claims description 46
- 229910052731 fluorine Inorganic materials 0.000 claims description 40
- 229910052740 iodine Inorganic materials 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 150000001204 N-oxides Chemical class 0.000 claims description 18
- -1 ammonium ions Chemical class 0.000 claims description 18
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 14
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 239000012454 non-polar solvent Substances 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 11
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 abstract description 7
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 abstract description 7
- 239000000556 agonist Substances 0.000 abstract description 5
- 239000013543 active substance Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000356 contaminant Substances 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 230000037356 lipid metabolism Effects 0.000 abstract description 2
- 150000002632 lipids Chemical class 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 0 [1*]C.[2*]C.[3*]C.[4*]C1=C(C([5*])([6*])[7*])[N+]([O-])=C(C2=[W]C=CC=C2)O1 Chemical compound [1*]C.[2*]C.[3*]C.[4*]C1=C(C([5*])([6*])[7*])[N+]([O-])=C(C2=[W]C=CC=C2)O1 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- RXVSHJATYXGFHA-UHFFFAOYSA-N 2-(3-methoxyphenyl)-4-methyl-3-oxido-5-propan-2-yl-1,3-oxazol-3-ium Chemical compound COC1=CC=CC(C2=[N+](C(C)=C(C(C)C)O2)[O-])=C1 RXVSHJATYXGFHA-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- ZUHYKTUQKCGVMF-UHFFFAOYSA-N 2-(3-methoxyphenyl)-4,5-dimethyl-3-oxido-1,3-oxazol-3-ium Chemical compound COC1=CC=CC(C2=[N+](C(C)=C(C)O2)[O-])=C1 ZUHYKTUQKCGVMF-UHFFFAOYSA-N 0.000 description 4
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 4
- VWFGBAZRKXYFCO-UHFFFAOYSA-N 4-(chloromethyl)-2-(3-methoxyphenyl)-5-methyl-1,3-oxazole Chemical compound COC1=CC=CC(C=2OC(C)=C(CCl)N=2)=C1 VWFGBAZRKXYFCO-UHFFFAOYSA-N 0.000 description 4
- IGRUGMIHUWOYDN-UHFFFAOYSA-N 4-(chloromethyl)-2-(3-methoxyphenyl)-5-methyl-1,3-oxazole;hydrochloride Chemical compound Cl.COC1=CC=CC(C=2OC(C)=C(CCl)N=2)=C1 IGRUGMIHUWOYDN-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
- 150000003934 aromatic aldehydes Chemical class 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- SNAKZQGNQQFDCV-UHFFFAOYSA-N 2-hydroxyimino-4-methylpentan-3-one Chemical compound CC(C)C(=O)C(C)=NO SNAKZQGNQQFDCV-UHFFFAOYSA-N 0.000 description 3
- UTGOXWRFDPYZIP-UHFFFAOYSA-N 4,5-dimethyl-2-(4-methylphenyl)-3-oxido-1,3-oxazol-3-ium;hydrochloride Chemical compound Cl.CC1=C(C)OC(C=2C=CC(C)=CC=2)=[N+]1[O-] UTGOXWRFDPYZIP-UHFFFAOYSA-N 0.000 description 3
- KXNUEXVTZGBAQF-UHFFFAOYSA-N 4-(chloromethyl)-2-(3-methoxyphenyl)-5-propan-2-yl-1,3-oxazole Chemical compound COC1=CC=CC(C=2OC(=C(CCl)N=2)C(C)C)=C1 KXNUEXVTZGBAQF-UHFFFAOYSA-N 0.000 description 3
- DQTOUJFUSUPWOK-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-2-(4-methylphenyl)-1,3-oxazole Chemical compound ClCC1=C(C)OC(C=2C=CC(C)=CC=2)=N1 DQTOUJFUSUPWOK-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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- JHWYQVITAXLLKM-UHFFFAOYSA-N CC1=CC=C(C2=[N+]([O-])C(C)=C(C)O2)C=C1 Chemical compound CC1=CC=C(C2=[N+]([O-])C(C)=C(C)O2)C=C1 JHWYQVITAXLLKM-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000008043 acidic salts Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003461 sulfonyl halides Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RGPUSZZTRKTMNA-UHFFFAOYSA-N 1-benzofuran-7-carbaldehyde Chemical compound O=CC1=CC=CC2=C1OC=C2 RGPUSZZTRKTMNA-UHFFFAOYSA-N 0.000 description 1
- NAOPGVBLRHCPHI-UHFFFAOYSA-N 2-(chloromethyl)-1,3-oxazole Chemical class ClCC1=NC=CO1 NAOPGVBLRHCPHI-UHFFFAOYSA-N 0.000 description 1
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 1
- SNAKZQGNQQFDCV-FNORWQNLSA-N C/C(=N\O)C(=O)C(C)C Chemical compound C/C(=N\O)C(=O)C(C)C SNAKZQGNQQFDCV-FNORWQNLSA-N 0.000 description 1
- PLFPKKJSGJEPNA-UHFFFAOYSA-N CS(=O)(=O)Cl.O=S(Cl)Cl Chemical compound CS(=O)(=O)Cl.O=S(Cl)Cl PLFPKKJSGJEPNA-UHFFFAOYSA-N 0.000 description 1
- HYTRYEXINDDXJK-UHFFFAOYSA-N Ethyl isopropyl ketone Chemical compound CCC(=O)C(C)C HYTRYEXINDDXJK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910015818 MPO4 Inorganic materials 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- FSEUPUDHEBLWJY-UHFFFAOYSA-N diacetylmonoxime Chemical compound CC(=O)C(C)=NO FSEUPUDHEBLWJY-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/40—One oxygen atom attached in position 4
-
- 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
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
Definitions
- the invention relates generally to intermediate compounds produced during the reaction sequence of a process for the preparation of pharmaceutical actives for the regulation of lipid and/or glucose metabolism.
- the intermediate compounds that are precursors to the final product are also useful in the improved methods for the preparation of oxazoles which results in higher yields with less impurities and contaminants.
- Oxazoles constitute valuable intermediates in the synthesis of pharmaceutically active substances such as, for example peroxisome proliferator activated receptor (PPAR) agonists.
- PPAR peroxisome proliferator activated receptor
- the intermediate compounds of the present invention allow for the preparation of oxazoles in high yield and great purity.
- Oxazoles constitute valuable intermediates in the synthesis of pharmaceutically active substances, for example PPAR agonists.
- PPAR agonists are described, inter alia, in WO 03/020269, WO 2004/075815, WO 2004/076447, WO 2004/076428, WO 2004/076426, WO 2004/076427, DE 102004039533.0, DE 102004039532.2, DE 102004039509.8, all of which are incorporated by reference herein.
- the latter are pharmaceutical actives which can have a positive influence both on lipid metabolism and on glucose metabolism.
- the invention relates to chemical intermediates prepared during the process for the preparation of oxazoles by the condensation of aldehydes with ⁇ -ketoximes to give N-oxides in the form of their salts or as free bases. These compounds are then subsequently reacted with activated acid derivatives to give oxazoles in the form of their salts or as free bases. More specifically, the present invention comprises a series of intermediate compounds produced during the condensation reaction between aromatic aldehydes and ⁇ -ketoximes followed by the reaction of inorganic thionyl halides or organic sulfonyl halides to produce higher, purer yields of chloromethyloxazoles.
- the present invention comprises intermediate compounds of formula III derived during the reaction steps of an improved process for the preparation of compounds of formula IV. This arises by means of conversion of aromatic aldehydes of the formula I using ⁇ -ketoximes of the formula II via N-oxides of the formula III to produce the halomethyloxazoles of the formula IV,
- R 5 and R 6 together are selected from the group consisting of (C4-C5)-alkylene, in which one —CH 2 group may be replaced by O, S, NH, N—CH 3 or N-benzyl;
- R 7 is selected from the group consisting of is H or (C1-C8)-alkyl
- HX 1 selected from the group consisting of HCl, HBr, H 2 SO 4 , H 3 PO 4 , HOOCCF 3 , HOOCCCl 3 , HO 3 SCF 3 , HO 3 SCH 3 , HO 3 SC 6 H 5 , HO 3 S—C 6 H 4 -p-CH 3 , HOOCH, to the N-oxides of the formula III
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and X 1 are each as defined above and n1 is 0, 1, 1 ⁇ 2 or 1 ⁇ 3; and wherein the latter is subsequently reacted with the reagent R 8 X 2 which is a compound selected from the group consisting of:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X 2 are each as defined above and
- X3 is Cl, Br, CH 3 SO 3 , CF3SO 3 , C 6 H 5 SO 3 or p-CH 3 —C 6 H 4 —SO 3 and
- n2 is 0 or 1.
- the invention relates to the compounds of the formula III in which:
- the invention further relates to compounds of formula III in which:
- the invention even more preferably relates to the compounds of formula III in which:
- the invention more preferably further relates to compounds of the formula III, in which:
- the invention more preferably also relates to a process for preparing the compounds of the formula III in which:
- R 2 H, CH 3 , OCH 3 , Br or Cl;
- R 3 H, CH 3 , OCH 3 , Br or Cl;
- R 4 CH 3 , CH 2 CH 3 or CH(CH 3 ) 2 ;
- R 5 H, CH 3 , CH 2 CH 3 or CH(CH 3 ) 2 ;
- R 6 H, CH 3 , CH 2 CH 3 or CH(CH 3 ) 2 ;
- X 3 Cl, CH 3 SO 3 or p-CH 3 —C 6 H 4 —SO 3 and
- n2 0 or 1.
- the un-substituted or substituted ammonium ions in the definition of R 9 are preferably each triethylammonium.
- the invention relates to a process for preparing compounds of the formula VIII,
- R 2 H or CH 3 ,
- R 3 H or OCH 3 ,
- R 4 CH 3 or CH(CH 3 ) 2 ,
- n2 0 or 1.
- the invention most preferably relates to a process in which the reagent R 8 X 2 has the structure:
- the invention relates to a process in which the reagent R 8 X 2 has either the structure SOCl—Cl (formula IX) or CH 3 SO 2 —Cl (formula X).
- N-oxide (formula II) may either be isolated or further reacted directly in solution.
- the N-oxide (formula II) or the oxazole (formula IV) is obtained as the salt (n1 ⁇ 0 or n2 ⁇ 0), it can be converted to the corresponding free base by treatment with a base such as aqueous solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate, for example.
- a base such as aqueous solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate, for example.
- hydrogen chloride will be selected.
- the reagent HX 1 can be used in stoichiometric amounts, based on the ⁇ -ketoxime (formula II), up to a high excess.
- a preferred working range is the use of stoichiometric amounts up to a 7-fold excess. Particular preference is given to a 1 to 6-fold excess.
- the solvents used may be protic polar solvents such as carboxylic acids, aprotic dipolar solvents such as sulfoxides, nitriles or ethers or polyethers, aprotic polar solvents such as halogenated aromatic and aliphatic hydrocarbons, or aprotic nonpolar solvents such as aromatic and aliphatic hydrocarbons, or a mixture of the solvent groups.
- protic polar solvents such as carboxylic acids
- aprotic dipolar solvents such as sulfoxides, nitriles or ethers or polyethers
- aprotic polar solvents such as halogenated aromatic and aliphatic hydrocarbons
- aprotic nonpolar solvents such as aromatic and aliphatic hydrocarbons
- useful solvents are formic acid, glacial acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether and higher homologs or dichloromethane and chlorobenzene or toluene, cyclohexane and n-heptane, in each case alone or in a mixture.
- the reaction is carried out in glacial acetic acid, in a mixture of glacial acetic acid and ethylene glycol dimethyl ether, or in a mixture of glacial acetic acid and toluene.
- reaction temperatures for the formation of the N-oxides can be varied within a wide range and depend upon factors including the solubility properties of the aldehydes (formula I) and ⁇ -ketoximes (formula II) to be converted.
- reaction temperatures of from minus 20° C. to 150° C. are possible, preference being given in general to reaction temperatures of from minus 10° C. to 90° C.
- reaction temperatures of from 0° C. to 60° C. will be selected.
- N-oxides (formula I+formula II ⁇ formula III) can be carried out either in a closed system under elevated pressure or else in an open system under standard pressure, i.e., for example, by introducing a hydrogen halide gas into the system open to the atmosphere or by using a hydrogen halide gas in an organic solvent.
- the product can be obtained as the acid derivative COX 2 or, after preceding hydrolysis by processes known in principle, as the free acid COOH by acidic or alkaline hydrolysis.
- the reagent R 8 X 2 may be used in stoichiometric amounts, based on the intermediate N-oxide (formula III), up to a high excess.
- the amount used is in stoichiometric amounts in a range is the use of amounts up to a 5-fold excess. Particular preference is given to a 1-4-fold excess.
- This introduces the X 2 moiety (of R 3 X 2 ) in formula IV in covalently bonded form and converts R 8 to HX 3 by hydrolysis.
- the solvents used may be aprotic dipolar solvents such as amides, sulfoxides, nitriles or ethers or polyethers, aprotic polar solvents such as halogenated aromatic and aliphatic hydrocarbons, or aprotic nonpolar solvents such as aromatic and aliphatic hydrocarbons, or a mixture of the solvent groups.
- aprotic dipolar solvents such as amides, sulfoxides, nitriles or ethers or polyethers
- aprotic polar solvents such as halogenated aromatic and aliphatic hydrocarbons
- aprotic nonpolar solvents such as aromatic and aliphatic hydrocarbons
- useful solvents are N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether and higher homologs, or dichloromethane and chlorobenzene or toluene, cyclohexane and n-heptane, in each case alone or in a mixture.
- the reaction is carried out in dichloromethane or toluene.
- the reaction may also be carried out without solvent in an excess of the thionyl chloride or methanesulfonyl chloride reagents.
- reaction temperatures for the formation of the halomethyloxazoles can be varied within a wide range and depend upon factors including the solubility properties for the aldehydes and ⁇ -ketoximes to be converted.
- reaction temperatures from minus 20° C. to 150° C. are possible, preference being given generally to reaction temperatures of from 20° C. to 120° C. In a particularly preferred embodiment, reaction temperatures of from 20° C. to 80° C. will be selected.
- Halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, bromine, more preferably chlorine or bromine, and most preferably chlorine.
- alkyl radical is understood to mean a straight-chain or branched hydrocarbon chain having from one to six carbons, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, neopentyl, tert-butyl.
- alkyl radicals may be mono-, di- or trisubstituted by suitable groups, for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C3-C8)-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl.
- suitable groups for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C3-C8)-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl.
- An aryl radical is understood to mean a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonyl, indanyl or indan-1-onyl radical.
- the aryl radicals may be mono-, di- or trisubstituted by suitable groups, for example: F, Cl, Br, I, CF3, NO2, SF5, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)alkyl]2, (C3-C8)-cycloalkyl, (C1-C10)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkyl, O—CO—(C6-C10)-aryl.
- suitable groups for example: F, Cl, Br, I, CF3, NO2, SF5, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)alkyl]
- a cycloalkyl radical is understood to mean a three- to eight-membered ring system which contains one or more rings and is present in saturated or partially unsaturated (with one or two double bonds) form which is composed exclusively of carbon atoms, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
- the cycloalkyl radicals may be mono-, di- or trisubstituted by suitable groups, for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)alkyl]2, (C3-C8)-cycloalkyl, (C1-C10)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkyl, O—CO—(C6-C10)-aryl.
- suitable groups for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)alkyl]2, (C
- a heteroaryl radical is understood to mean a C5-C6-heterocycle which may contain from 1 to 4 heteroatoms from the group O, N, S.
- Examples include furan, thiophene, pyrrole, pyridine, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, thiazole, isothiazole, furazan, tetrazole.
- inventive compounds of the formula IV can be reacted, for example, according to DE 102004040736.3 further to give pharmaceutically active substances, the PPAR agonists.
- the pH was adjusted to 10.6, for which 172 ml (1.930 mol) of 33% aqueous sodium hydroxide solution were required; the internal temperature was kept ⁇ 32° C. by external cooling. Two phases formed and were separated. The aqueous phase was extracted twice with 100 ml each time of toluene and subsequently discarded. The combined organic phases were concentrated under reduced pressure while distilling off 50 ml. The thus obtained toluenic solution (420 ml) was used directly for the synthesis of 4-chloromethyl-2-(3-methoxyphenyl)-5-methyloxazole hydrochloride.
- Example 2 The entire toluenic solution from Example 1 (420 ml) was admixed at 60° C. dropwise with 54.2 g (0.456 mol) of thionyl chloride and stirred at ⁇ 60° C. for up to 22 h. Subsequently, the mixture was concentrated by distilling off 229 ml. The suspension was cooled to ⁇ 20° C., and the product was isolated by filtration with suction, washed 3 times with 20 ml each time of toluene and dried at elevated temperature under reduced pressure.
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Abstract
The present invention is directed to compounds of Formula III
wherein the R1-R7 groups or substituents are defined herein. The present invention also comprises improved methods in the preparation of oxazoles in which the compounds of Formula III are intermediates and which results in higher yields with less impurities and contaminants. Oxazoles constitute valuable intermediates in the synthesis of pharmaceutically active substances such as, for example peroxisome proliferator activated receptor (PPAR) agonists which are pharmaceutical actives which can have a positive influence on both lipid and glucose metabolism.
Description
- This application is a continuation of patent application Ser. No. 11/754,477 filed on May 29, 2007 which is a continuation of International Patent Application No. PCT/EP2005/012800 filed on Dec. 1, 2005 which is incorporated herein by reference in its entirety which also claims the benefit of priority of German Patent Application No. 10/2004 060 227.1 filed on Dec. 15, 2004.
- The invention relates generally to intermediate compounds produced during the reaction sequence of a process for the preparation of pharmaceutical actives for the regulation of lipid and/or glucose metabolism. The intermediate compounds that are precursors to the final product are also useful in the improved methods for the preparation of oxazoles which results in higher yields with less impurities and contaminants. Oxazoles constitute valuable intermediates in the synthesis of pharmaceutically active substances such as, for example peroxisome proliferator activated receptor (PPAR) agonists.
- The intermediate compounds of the present invention allow for the preparation of oxazoles in high yield and great purity. Oxazoles constitute valuable intermediates in the synthesis of pharmaceutically active substances, for example PPAR agonists. Appropriate examples of PPAR agonists are described, inter alia, in WO 03/020269, WO 2004/075815, WO 2004/076447, WO 2004/076428, WO 2004/076426, WO 2004/076427, DE 102004039533.0, DE 102004039532.2, DE 102004039509.8, all of which are incorporated by reference herein. The latter are pharmaceutical actives which can have a positive influence both on lipid metabolism and on glucose metabolism.
- The condensation of aromatic aldehydes with α-ketoximes to give N-oxides and the subsequent reaction with activated acid derivatives to give oxazoles is a reaction well known in the art.
- For the conversion of the N-oxides to the oxazoles, the literature describes the reagents phosphorus (III) chloride (PCl3) and phosphorus oxychloride (POCl3) and, in one variant, acetic anhydride ((CH3COO)2O) (Y. Goto, M. Yamazaki, M. Hamana, Chem Pharm Bull. 19 (1971) 2050, and literature cited there). These reagents are not widely applicable and often lead to no products or to highly contaminated products which can only be obtained in sufficient purity with low yields in a costly and inconvenient manner, for example by chromatographic processes.
- The reaction conditions described require the isolation of the N-oxides. For N-oxides with exothermic decomposition potential, this constitutes a considerable safety risk and prevents the process from being practiced on the industrial scale.
- It has now been found that, surprisingly, the transformation of the N-oxides to the halomethyloxazoles proceeds unexpectedly smoothly with high yield and great purity with inorganic thionyl halides or organic sulfonyl halides.
- Although it was unexpected on the basis of the remarks in the literature, halomethyl-oxazoles in some cases precipitate cleanly directly out of the reaction mixture in the form of the free base or as salts.
- Unexpectedly, for N-oxides with exothermic decomposition potential, it has been possible to achieve both safe preparation in dilute solution and the further direct reaction of the solution to give the halo-methyloxazoles.
- The invention relates to chemical intermediates prepared during the process for the preparation of oxazoles by the condensation of aldehydes with α-ketoximes to give N-oxides in the form of their salts or as free bases. These compounds are then subsequently reacted with activated acid derivatives to give oxazoles in the form of their salts or as free bases. More specifically, the present invention comprises a series of intermediate compounds produced during the condensation reaction between aromatic aldehydes and α-ketoximes followed by the reaction of inorganic thionyl halides or organic sulfonyl halides to produce higher, purer yields of chloromethyloxazoles.
- The present invention comprises intermediate compounds of formula III derived during the reaction steps of an improved process for the preparation of compounds of formula IV. This arises by means of conversion of aromatic aldehydes of the formula I using α-ketoximes of the formula II via N-oxides of the formula III to produce the halomethyloxazoles of the formula IV,
- which comprises converting the aromatic aldehydes of the formula I using the α-ketoximes of the formula II
- in which:
- R1 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2—CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, wherein aryl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
- wherein
- R9 is selected from the group consisting of H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or tri-substituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,
- R10 and R11 are each independently selected from the group consisting of H, (C1-C5)-alkyl, phenyl or CH2-phenyl, wherein phenyl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
- or
- R10 and R11 together are (C4-C5)-alkylene, wherein one CH2 group may be replaced by O, S, NH, N—CH3 or N-benzyl;
- R2 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2—CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, wherein aryl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF3; and
- wherein R9, R10 and R11 are each as defined above;
- R3 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2-CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
where R9, R10 and R11 are each as defined above; and - W is CH or N, if o=1;
- W is O, S or NR12, if o=0;
- o is 0 or 1;
- R12 is selected from the group consisting of H, (C1-C6)-alkyl, (C1-C6)-alkylenephenyl, phenyl;
- (R4 is selected from the group consisting of H, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C3)-alkylene-(C3-C8)-cycloalkyl, phenyl, (C1-C3)-alkylenephenyl, (C5-C6)-heteroaryl, (C1-C3)-alkylene-(C5-C6)-heteroaryl or (C1-C3)-alkyl which is fully or partly substituted by F, or COOR9, CONR(10)R(11);
- wherein R9, R10 and R11 are each as defined above;
- R5 and R6 are each independently selected from the group consisting of (C1-C8)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, COOR9, CONR10R11, SH and NR10R11,
wherein R9, R10, R11 are each as defined above;
or, - in the presence of one or more acids HX1 selected from the group consisting of HCl, HBr, H2SO4, H3PO4, HOOCCF3, HOOCCCl3, HO3SCF3, HO3SCH3, HO3SC6H5, HO3S—C6H4-p-CH3, HOOCH,
to the N-oxides of the formula III - in which R1, R2, R3, R4, R5, R6, R7 and X1 are each as defined above and
n1 is 0, 1, ½ or ⅓;
and wherein the latter is subsequently reacted with the reagent R8X2 which is a compound selected from the group consisting of: - to give the halomethyloxazoles of the formula IV
- wherein R1, R2, R3, R4, R5, R6 and X2 are each as defined above and
- n2 is 0 or 1.
- Preferably, the invention relates to the compounds of the formula III in which:
- o=1.
- More preferably, the invention further relates to compounds of formula III in which:
- R1 is H;
- R2 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2-CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
- wherein
- R9 is selected from the group consisting of H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or trisubstituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,
- R10 and R11 are each independently is selected from the group consisting of H, (C1-C5)-alkyl, phenyl or CH2-phenyl,
- where phenyl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
- or
- R10 and R11 together are (C4-C5)-alkylene, in which one CH2 group may be replaced by O, S, NH, N—CH3 or N-benzyl;
- R3 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2-CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
where R9, R10 and R11 are each as defined above. - The invention even more preferably relates to the compounds of formula III in which:
- R1 is H;
- R2 is H;
- R3 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2-CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
- and wherein
- R9 is selected from the group consisting of H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or trisubstituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,
- R10 and R11 are each independently is selected from the group consisting of H, (C1-C5)-alkyl, phenyl or CH2-phenyl,
- Wherein if phenyl, the phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, i, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
- or
- R10 and R11 together are (C4-C5)-alkylene, in which one CH2 group may be replaced by O, S, NH, N—CH3 or N-benzyl.
- The invention more preferably further relates to compounds of the formula III, in which:
- R1, R2, R3 are each independently selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, OCF2—CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
- where
- R9 is H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or trisubstituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,
- R10 and R11 are each independently H, (C1-C5)-alkyl, phenyl or CH2-phenyl,
- where phenyl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
- or,
- R10 and R11 together are (C4-C5)-alkylene, in which one CH2 group may be replaced by O, S, NH, N—CH3 or N-benzyl.
- The invention more preferably also relates to a process for preparing the compounds of the formula III in which:
- o=1;
- n2=0 or 1.
- The un-substituted or substituted ammonium ions in the definition of R9 are preferably each triethylammonium.
- In particular, the invention relates to a process for preparing compounds of the formula VIII,
- in which
- n2=0 or 1.
- The invention most preferably relates to a process in which the reagent R8X2 has the structure:
-
SOCl—Cl, SOBr—Br, CH3SO2—Cl or p-CH3—C6H4—SO2—Cl. - In particular, the invention relates to a process in which the reagent R8X2 has either the structure SOCl—Cl (formula IX) or CH3SO2—Cl (formula X).
- The N-oxide (formula II) may either be isolated or further reacted directly in solution.
- When the N-oxide (formula II) or the oxazole (formula IV) is obtained as the salt (n1≠0 or n2≠0), it can be converted to the corresponding free base by treatment with a base such as aqueous solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate, for example.
- For the reaction to form the N-oxides (formula I+formula II→formula III), useful reagents HX1 are hydrogen halides, sulfuric acid and its acidic salt, phosphoric acid and its acidic salts, trifluoroacetic acid, trichloroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid and also HMSO4, H2 MPO4, HM2PO4 where M=Na, K, preference being given to hydrogen halides. In a particularly preferred embodiment, hydrogen chloride will be selected. In the case of sulfuric acid, hydrogen sulfates (n1=1) or sulfates (n1=½) can form; in the case of phosphoric acid, dihydrogenphosphates (n1=1), hydrogenphosphates (n1=½) or phosphates (n1=⅓) can form.
- The reagent HX1 can be used in stoichiometric amounts, based on the α-ketoxime (formula II), up to a high excess. A preferred working range is the use of stoichiometric amounts up to a 7-fold excess. Particular preference is given to a 1 to 6-fold excess.
- For the reaction to form the N-oxides (formula I+formula II→formula III), the solvents used may be protic polar solvents such as carboxylic acids, aprotic dipolar solvents such as sulfoxides, nitriles or ethers or polyethers, aprotic polar solvents such as halogenated aromatic and aliphatic hydrocarbons, or aprotic nonpolar solvents such as aromatic and aliphatic hydrocarbons, or a mixture of the solvent groups. For example, useful solvents are formic acid, glacial acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether and higher homologs or dichloromethane and chlorobenzene or toluene, cyclohexane and n-heptane, in each case alone or in a mixture. In a preferred form, the reaction is carried out in glacial acetic acid, in a mixture of glacial acetic acid and ethylene glycol dimethyl ether, or in a mixture of glacial acetic acid and toluene.
- The reaction temperatures for the formation of the N-oxides (formula I+formula II→formula III) can be varied within a wide range and depend upon factors including the solubility properties of the aldehydes (formula I) and α-ketoximes (formula II) to be converted. Thus, in principle, reaction temperatures of from minus 20° C. to 150° C. are possible, preference being given in general to reaction temperatures of from minus 10° C. to 90° C. In a particularly preferred embodiment, reaction temperatures of from 0° C. to 60° C. will be selected.
- The formation of the N-oxides (formula I+formula II→formula III) can be carried out either in a closed system under elevated pressure or else in an open system under standard pressure, i.e., for example, by introducing a hydrogen halide gas into the system open to the atmosphere or by using a hydrogen halide gas in an organic solvent.
- When a further function such as COOR9 which can react with activated acid derivatives is present among the R1 to R6 radicals, the product can be obtained as the acid derivative COX2 or, after preceding hydrolysis by processes known in principle, as the free acid COOH by acidic or alkaline hydrolysis.
- The reagent R8X2 may be used in stoichiometric amounts, based on the intermediate N-oxide (formula III), up to a high excess. Preferably, the amount used is in stoichiometric amounts in a range is the use of amounts up to a 5-fold excess. Particular preference is given to a 1-4-fold excess. This introduces the X2 moiety (of R3X2) in formula IV in covalently bonded form and converts R8 to HX3 by hydrolysis.
- For the reaction for the formation of the halomethyloxazoles (formula III→formula IV), the solvents used may be aprotic dipolar solvents such as amides, sulfoxides, nitriles or ethers or polyethers, aprotic polar solvents such as halogenated aromatic and aliphatic hydrocarbons, or aprotic nonpolar solvents such as aromatic and aliphatic hydrocarbons, or a mixture of the solvent groups. For example, useful solvents are N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether and higher homologs, or dichloromethane and chlorobenzene or toluene, cyclohexane and n-heptane, in each case alone or in a mixture. In a preferred form, the reaction is carried out in dichloromethane or toluene. The reaction may also be carried out without solvent in an excess of the thionyl chloride or methanesulfonyl chloride reagents.
- The reaction temperatures for the formation of the halomethyloxazoles (formula III→formula IV) can be varied within a wide range and depend upon factors including the solubility properties for the aldehydes and α-ketoximes to be converted. Thus, in principle, reaction temperatures from minus 20° C. to 150° C. are possible, preference being given generally to reaction temperatures of from 20° C. to 120° C. In a particularly preferred embodiment, reaction temperatures of from 20° C. to 80° C. will be selected.
- Halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, bromine, more preferably chlorine or bromine, and most preferably chlorine.
- An alkyl radical is understood to mean a straight-chain or branched hydrocarbon chain having from one to six carbons, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, neopentyl, tert-butyl.
- The alkyl radicals may be mono-, di- or trisubstituted by suitable groups, for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C3-C8)-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl.
- An aryl radical is understood to mean a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonyl, indanyl or indan-1-onyl radical.
- The aryl radicals may be mono-, di- or trisubstituted by suitable groups, for example: F, Cl, Br, I, CF3, NO2, SF5, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)alkyl]2, (C3-C8)-cycloalkyl, (C1-C10)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkyl, O—CO—(C6-C10)-aryl.
- A cycloalkyl radical is understood to mean a three- to eight-membered ring system which contains one or more rings and is present in saturated or partially unsaturated (with one or two double bonds) form which is composed exclusively of carbon atoms, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl. The cycloalkyl radicals may be mono-, di- or trisubstituted by suitable groups, for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)alkyl]2, (C3-C8)-cycloalkyl, (C1-C10)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O—(C1-C6)-alkyl, O—CO—(C1-C6)-alkyl, O—CO—(C6-C10)-aryl.
- A heteroaryl radical is understood to mean a C5-C6-heterocycle which may contain from 1 to 4 heteroatoms from the group O, N, S. Examples include furan, thiophene, pyrrole, pyridine, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, thiazole, isothiazole, furazan, tetrazole.
- The inventive compounds of the formula IV can be reacted, for example, according to DE 102004040736.3 further to give pharmaceutically active substances, the PPAR agonists.
-
- 15.2 g (0.150 mol) of 2,3-butanedione monoxime were initially charged and 260 ml of toluene, 22.1 g (0.157 mol) of 3-methoxybenzaldehyde and 70 ml (73.4 g, 1.224 mol) of glacial acetic acid were added with stirring. 27.3 g (0.749 mol) of hydrogen chloride gas were introduced with cooling at such a rate that the internal temperature was <22° C. Subsequently, the mixture was stirred for up to 16 h. With stirring, the reaction mixture was added to 600 ml of water (exothermic reaction). The pH was adjusted to 10.6, for which 172 ml (1.930 mol) of 33% aqueous sodium hydroxide solution were required; the internal temperature was kept <32° C. by external cooling. Two phases formed and were separated. The aqueous phase was extracted twice with 100 ml each time of toluene and subsequently discarded. The combined organic phases were concentrated under reduced pressure while distilling off 50 ml. The thus obtained toluenic solution (420 ml) was used directly for the synthesis of 4-chloromethyl-2-(3-methoxyphenyl)-5-methyloxazole hydrochloride.
- Yield: 32.9 g (100%) of 2-(3-methoxyphenyl)-4,5-dimethyloxazole 3-oxide,
- Not isolated, assumption for the calculation of the subsequent stage.
- The data which follow were measured on the pure substance which was obtained after the solvent of the organic phases had been distilled off completely.
- Melting point: 114° C.
- 1H NMR (CDCl3, 400 MHz) δ (ppm)=2.20 (s, 3H); 2.35 (s, 3H); 3.87 (s, 3H); 6.98 (m, 1H); 7.38 (m, 1H); 7.88 (m, 3H); 8.26 (m, 1H).
-
- The entire toluenic solution from Example 1 (420 ml) was admixed at 60° C. dropwise with 54.2 g (0.456 mol) of thionyl chloride and stirred at <60° C. for up to 22 h. Subsequently, the mixture was concentrated by distilling off 229 ml. The suspension was cooled to <20° C., and the product was isolated by filtration with suction, washed 3 times with 20 ml each time of toluene and dried at elevated temperature under reduced pressure.
- Yield: 23.2 g (56%) of 4-chloromethyl-2-(3-methoxyphenyl)-5-methyloxazole hydrochloride
- Melting point: 117° C.
- 1H NMR (CDCl3, 400 MHz) δ (ppm)=2.58 (s, 3H); 3.92 (s, 3H); 4.78 (s, 2H); 7.15 (m, 1H); 7.42 (m, 1H); 7.79 (m, 1H); 8.04 (m, 1H).
-
- 10.1 g (0.037 mol) of 4-chloromethyl-2-(3-methoxyphenyl)-5-methyloxazole hydrochloride were suspended in 100 ml of water and 75 ml of dichloromethane. With stirring, a pH of 12 was established in the water phase with 45 ml (0.023 mol) of aqueous sodium hydroxide solution. Subsequently, the phases were separated and the aqueous phase was discarded. The organic phase was concentrated by distillation completely under reduced pressure. The remaining oil crystallized through after the addition of seed crystals.
- Yield: 8.0 g (92%) of 4-chloromethyl-2-(3-methoxyphenyl)-5-methyloxazole
- Melting point: 46-50° C.
- 1H NMR (CDCl3, 400 MHz) δ (ppm)=2.43 (s, 3H); 3.88 (s, 3H); 4.56 (s, 2H); 6.99 (m, 1H); 7.35 (m, 1H); 7.54 (m, 1H); 7.60 (m, 1H).
-
- 100 g (979 mmol) of butane-2,3-dione monoxime were initially charged and dissolved in 500 ml of acetic acid. 120 g (979 mmol) of 4-methylbenzaldehyde were added. 100 g (2.74 mol) of hydrogen chloride gas were introduced at such a rate that an internal temperature of 40° C. was not exceeded. Subsequently, the mixture was stirred at 35-40° C. for a further 2-3 hours. With intensive cooling, 2 l of tert-butyl methyl ether were added. The reaction mixture was stirred at 10° C. for 1 hour. The product was isolated by filtration with suction, washed with tert-butyl methyl ether and dried at elevated temperature under reduced pressure.
- Yield: 213 g (91%) of 4,5-dimethyl-2-p-tolyloxazole 3-oxide hydrochloride
- Melting point: 101° C.
- 1H NMR (DMSO-D6, 500 MHz) δ (ppm)=10.30 (sbr, 1H), 8.17 (d, J=8.3 Hz; 2H), 7.47 (d, J=8.3 Hz; 2H), 2.44 (s, 3H), 2.42 (s, 3H)
-
- 32.8 g (137 mmol) of 4,5-dimethyl-2-p-tolyloxazole 3-oxide hydrochloride were suspended in 165 ml of dichloromethane. 17.5 g (151 mmol) of methanesulfonyl chloride were added. The reaction was stirred at reflux up to full conversion (HPLC). Subsequently, 200 ml of ethylene glycol dimethyl ether were added, and the dichloromethane was distilled off under reduced pressure. The reaction mixture was cooled to 15° C. and 250 ml of water were added. The mixture was stirred at 15° C. for 1 hour. The precipitated product was isolated by filtration with suction, washed with water and dried at elevated temperature under reduced pressure.
- Yield: 27.6 g (91%) of 4-chloromethyl-5-methyl-2-p-tolyloxazole
- Melting point: 95° C.
- 1H NMR (DMSO-D6, 500 MHz) δ (ppm)=7.82 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 4.74 (s, 2H), 2.43 (s, 3H), 2.37 (s, 3H)
-
- 100 g (948 mmol) of 2-methylpentan-3-one were dissolved in 400 ml of tert-butyl methyl ether. 50 g (274 mmol) of solution of hydrochloride in ethylene glycol dimethyl ether (20%) were added. Subsequently, a solution of 117 g (949 mmol) isoamyl nitrite in 150 ml of tert-butyl methyl ether was added dropwise within 60 minutes. The solvent was removed fully under reduced pressure. The residue was taken up in 300 ml of n-heptane and concentrated again under reduced pressure. After 200 ml of n-heptane had been added, extraction was effected with 522 ml of sodium hydroxide solution (2 molar). After phase separation, the aqueous phase was washed with n-heptane. The aqueous phase was acidified by adding conc. hydrochloric acid. The product was isolated by filtration with suction, washed with water and dried at elevated temperature under reduced pressure.
- Yield: 61.1 g (50%) of 4-methylpentane-2,3-dione 2-oxime
- Melting point: 94° C.
- 1H NMR (DMSO-D6, 500 MHz) δ (ppm)=12.3 (s, 1H), 3.54 (sept, J=6.9 Hz, 1H), 1.82 (2, 3H), 1.02 (s, 3H), 1.01 (s, 3H).
-
- 19.0 g (137 mmol) of 3-methoxybenzaldehyde were added to a solution of 18.0 g (137 mmol) of 4-methylpentane-2,3-dione 2-oxime in 30 g (99 mmol) of solution of hydrogen chloride in acetic acid (12%) and 30 g (164 mmol) of solution of hydrogen chloride in ethylene glycol dimethyl ether (20%). The reaction was stirred at 50-55° C. for 3 hours and at room temperature for 60 hours. Subsequently, 500 ml of water and 300 ml of tert-butyl methyl ether were added before a pH of 3-4 was established by adding sodium hydrogen carbonate. After phase separation, the aqueous phase was extracted twice with 100 ml each time of tert-butyl methyl ether. The combined organic phases were washed with 4×100 ml of water and concentrated fully under reduced pressure.
- Yield: 42.8 g (79% purity) (100%) of 5-isopropyl-2-(3-methoxyphenyl)-4-methyloxazole 3-oxide
- 1H NMR (DMSO-D6, 500 MHz) δ (ppm)=8.12 (m, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.06 (dd, J=2.4, 8.0 Hz, 1H), 3.82 (s, 3H), 3.16 (sept, J=7.0 Hz, 1H), 2.12 (s, 3H), 1.29 (d, J=7.0 Hz, 3H).
-
- 75 g (648 mmol) of methanesulfonyl chloride were added at a temperature of 20° C. to a solution of 135 g (435 mmol) of 5-isopropyl-2-(3-methoxyphenyl)-4-methyloxazole 3-oxide in 500 ml of dichloromethane. The reaction was stirred at 40-45° C. up to full conversion. 500 ml of tert-butyl methyl ether and 300 ml of water were added. Addition of 20% sodium hydroxide solution established a pH of 8. After phase separation, the organic phase was washed with 3×200 ml of water. The organic phase was concentrated fully under reduced pressure.
- Yield: 132 g (87% purity) (99%) of 4-chloromethyl-5-isopropyl-2-(3-methoxyphenyl)-oxazole
- 1H NMR (DMSO-D6, 500 MHz) δ (ppm)=7.55 (m, 1H), 7.45 (m, 2H), 7.10 (ddd, J=0.9, 2.7, 5.6 Hz, 1H), 4.77 (s, 2H), 3.85 (s, 3H), 3.33 (sept, 7.0 Hz, 1H), 1.30 (d, J=7.0 Hz, 6H).
Claims (13)
1. The compounds of formula III,
wherein:
R1 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SC2F5, OCF2—CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, wherein aryl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF3, and;
R9 is selected from the group consisting of H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or trisubstituted by (C1-C4)-alkyl, and is (C1-C8)-alkyl,
R10 and R11 are each independently selected from the group consisting of H, (C1-C5)-alkyl, phenyl or CH2-phenyl,
wherein phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF3;
or
R10 and R11 together are (C4-C5)-alkylene, in which one CH2 group may be replaced by O, S, NH, N—CH3 or N-benzyl;
R2 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C1-C8)-alkylene-H, CF3, OCF3, SCF3, SC2F5, OCF2—CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF3;
wherein R9, R10 and R11 are each as defined above;
R3 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SC2F3, SF5, OCF2—CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl and CF3;
wherein R9, R10 and R11 are each as defined above;
W is CH, N, if o=1;
W is O, S, NR12, if o=0;
o is 0 or 1;
R12 is H, (C1-C6)-alkyl, (C1-C6)-alkylenephenyl, phenyl;
R4 is selected from the group consisting of H, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C3)-alkylene-(C3-C8)-cycloalkyl, phenyl, (C1-C3)-alkylenephenyl, (C5-C6)-heteroaryl, (C1-C3)-alkylene-(C5-C6)-heteroaryl or (C1-C3)-alkyl which is fully or partly substituted by F, or COOR9, CONR(10)R(11);
wherein R9, R10 and R11 are each as defined above;
R5 and R6 are each independently selected from the group consisting of H, (C1-C8)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, COOR9, CONR10R11, SH or NR10R11,
wherein R9, R10, R11 are each as defined above;
or,
R5 and R6 together are (C4-C5)-alkylene, in which one CH2 group may be replaced by O, S, NH, N—CH3 or N-benzyl;
R7 is selected from the group consisting of H or (C1-C8)-alkyl;
and,
wherein R1, R2, R3, R4, R5, R6, R7 and X1 are each as defined above and
n1 is 0, 1, ½ or ⅓;
2. The compounds of formula III as recited in claim 1 , wherein:
W=CH and
o=1.
3. The compounds of formula III as recited in claim 2 , wherein:
R1 is H;
R2 is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C1-C8)-alkylene-H, CF3, OCF3, SCF3, SC2F5, OCF2—CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3; wherein
R9 is selected from the group consisting of H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or tri-substituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,
R10 and R11 are each independently H, (C1-C5)-alkyl, phenyl or CH2-phenyl, and wherein the phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
or
R10 and R11 together are (C4-C5)-alkylene, in which one CH2 group may be replaced by O, S, NH, N—CH3 or N-benzyl;
R3 is H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SC2F5, OCF2—CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
wherein R9, R10 and R11 are each as defined above.
4. The compounds of formula III as recited in claim 3 wherein:
R1 is H;
R2 is H;
R3 is H, (C1-C6)-alkyl, F, Cl, Br, I, O—(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2-CHF2, (C6-C10)-aryl, O—(C6-C10)-aryl, O—(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR9, CONR10R11, SH, or NR10R11, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
wherein
R9 is H, Li, Na, K, ½Mg, ½Ca, ammonium ions which are un-substituted or mono-, di- or tri-substituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,
R10 and R11 are each independently selected from the group consisting of H, (C1-C5)-alkyl, phenyl or CH2-phenyl,
wherein phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—(C1-C4)-alkyl or CF3;
or
R10 and R11 together form a (C4-C5)-alkylene, in which one CH2 group may be replaced by O, S, NH, N—CH3 or N-benzyl.
5. The compounds of formula III as recited in claim 4 , wherein:
W=CH;
o=1;
R1=H;
R2=H, CH3, OCH3, Br or Cl;
R3=H, CH3, OCH3, Br or Cl;
R4=CH3, CH2CH3 or CH(CH3)2;
R5=H, CH3, CH2CH3 or CH(CH3)2;
R6=H, CH3, CH2CH3 or CH(CH3)2;
X3=Cl, CH3SO3 or p-CH3—C6H4—SO3 and
n2=0 or 1.
7. A process for the preparation of compounds of formula III as recited in claim 1 , wherein the reaction temperature for the formation of the N-oxides as depicted by formula III from the reaction of compounds of formulae I and II is between about −20° C. and +150° C.
8. The process for the preparation of compounds of formula III as recited in claim 7 , wherein the reaction for the formation of the N-oxides as depicted by formula III is carried out in protic, polar, aprotic non-polar solvents or mixtures thereof.
9. The process for the preparation of compounds of the formula III as recited in claim 8 , wherein the reaction temperature for the formation of the halomethyloxazoles as depicted by formula IV from compounds of the formula III is from about −20° C. to +150° C.
10. The process for the preparation of compounds of formula III as recited in claim 8 wherein one or more of the compounds of formula I and II are used in the preparation thereof.
Priority Applications (2)
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US11/928,117 US20080114035A1 (en) | 2004-12-15 | 2007-10-30 | Novel intermediate compounds useful in the preparation of oxazoles and pharmaceutical actives for the regulation of lipid and glucose metabolism |
US12/509,853 US7825144B2 (en) | 2004-12-15 | 2009-07-27 | Method for the production of oxazoles by condensing aromatic aldehydes with α-ketoximes to N-oxides and then reacting the same with activated acid derivatives |
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DE102004060227.1 | 2004-12-15 | ||
DE102004060227A DE102004060227B3 (en) | 2004-12-15 | 2004-12-15 | Process for the preparation of oxazoles by condensation of aromatic aldehydes with α-ketoximes to N-oxides and subsequent reaction with activated acid derivatives |
PCT/EP2005/012800 WO2006066694A1 (en) | 2004-12-15 | 2005-12-01 | Method for the production of oxazoles by condensing aromatic aldehydes with a-ketoximes to n-oxides and then reacting the same with activated acid derivatives |
US11/754,477 US7544809B2 (en) | 2004-12-15 | 2007-05-29 | Method for the preparation of oxazoles by condensing aromatic aldehydes with α-ketoximes to form n-oxides and reacting same with activated acid derivatives |
US11/928,117 US20080114035A1 (en) | 2004-12-15 | 2007-10-30 | Novel intermediate compounds useful in the preparation of oxazoles and pharmaceutical actives for the regulation of lipid and glucose metabolism |
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US11/754,477 Continuation US7544809B2 (en) | 2004-12-15 | 2007-05-29 | Method for the preparation of oxazoles by condensing aromatic aldehydes with α-ketoximes to form n-oxides and reacting same with activated acid derivatives |
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US12/509,853 Continuation US7825144B2 (en) | 2004-12-15 | 2009-07-27 | Method for the production of oxazoles by condensing aromatic aldehydes with α-ketoximes to N-oxides and then reacting the same with activated acid derivatives |
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US11/928,117 Abandoned US20080114035A1 (en) | 2004-12-15 | 2007-10-30 | Novel intermediate compounds useful in the preparation of oxazoles and pharmaceutical actives for the regulation of lipid and glucose metabolism |
US12/509,853 Expired - Fee Related US7825144B2 (en) | 2004-12-15 | 2009-07-27 | Method for the production of oxazoles by condensing aromatic aldehydes with α-ketoximes to N-oxides and then reacting the same with activated acid derivatives |
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US (3) | US7544809B2 (en) |
EP (1) | EP1828149B1 (en) |
JP (1) | JP2008523124A (en) |
KR (1) | KR20070089165A (en) |
CN (1) | CN101080398A (en) |
AR (1) | AR052267A1 (en) |
AU (1) | AU2005318635A1 (en) |
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CA (1) | CA2590494A1 (en) |
DE (1) | DE102004060227B3 (en) |
MA (1) | MA29094B1 (en) |
MX (1) | MX2007006676A (en) |
NO (1) | NO20073144L (en) |
NZ (1) | NZ555670A (en) |
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TW (1) | TW200635907A (en) |
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US8722731B2 (en) | 2010-06-07 | 2014-05-13 | Novomedix, Llc | Furanyl compounds and the use thereof |
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US7816385B2 (en) * | 2002-12-20 | 2010-10-19 | High Point Pharmaceuticals, Llc | Dimeric dicarboxylic acid derivatives, their preparation and use |
DE102004060227B3 (en) * | 2004-12-15 | 2006-07-20 | Sanofi-Aventis Deutschland Gmbh | Process for the preparation of oxazoles by condensation of aromatic aldehydes with α-ketoximes to N-oxides and subsequent reaction with activated acid derivatives |
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US5036079A (en) * | 1989-12-07 | 1991-07-30 | Pfizer Inc. | Hypoglycemic thiazolidinedione derivatives |
AU2001284660A1 (en) * | 2000-08-23 | 2002-03-04 | Eli Lilly And Company | Oxazolyl-arylpropionic acid derivatives and their use as ppar agonists |
US7282501B2 (en) * | 2001-06-07 | 2007-10-16 | Eli Lilly And Company | Modulators of peroxisome proliferator activated receptors (PPAR) |
DE10308355A1 (en) * | 2003-02-27 | 2004-12-23 | Aventis Pharma Deutschland Gmbh | Aryl-cycloalkyl-substituted alkanoic acid derivatives, process for their preparation and their use as medicaments |
DE10308353A1 (en) * | 2003-02-27 | 2004-12-02 | Aventis Pharma Deutschland Gmbh | Diarylcycloalkyl derivatives, processes for their preparation and their use as medicines |
DE102004060227B3 (en) * | 2004-12-15 | 2006-07-20 | Sanofi-Aventis Deutschland Gmbh | Process for the preparation of oxazoles by condensation of aromatic aldehydes with α-ketoximes to N-oxides and subsequent reaction with activated acid derivatives |
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- 2005-12-13 AR ARP050105212A patent/AR052267A1/en not_active Application Discontinuation
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Cited By (3)
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US8722731B2 (en) | 2010-06-07 | 2014-05-13 | Novomedix, Llc | Furanyl compounds and the use thereof |
US9149527B2 (en) | 2010-06-07 | 2015-10-06 | Novomedix, Llc | Furanyl compounds and the use thereof |
US9663483B2 (en) | 2010-06-07 | 2017-05-30 | Novomedix, Llc | Furanyl compounds and the use thereof |
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BRPI0519918A2 (en) | 2009-04-07 |
WO2006066694A1 (en) | 2006-06-29 |
NZ555670A (en) | 2010-09-30 |
US20080058529A1 (en) | 2008-03-06 |
EP1828149B1 (en) | 2015-01-21 |
US7825144B2 (en) | 2010-11-02 |
CN101080398A (en) | 2007-11-28 |
AR052267A1 (en) | 2007-03-07 |
RU2007126844A (en) | 2009-01-27 |
UY29257A1 (en) | 2006-07-31 |
US20090286988A1 (en) | 2009-11-19 |
AU2005318635A1 (en) | 2006-06-29 |
RU2402537C2 (en) | 2010-10-27 |
KR20070089165A (en) | 2007-08-30 |
JP2008523124A (en) | 2008-07-03 |
US7544809B2 (en) | 2009-06-09 |
DE102004060227B3 (en) | 2006-07-20 |
ZA200704027B (en) | 2008-07-30 |
NO20073144L (en) | 2007-09-11 |
MA29094B1 (en) | 2007-12-03 |
MX2007006676A (en) | 2007-08-14 |
TW200635907A (en) | 2006-10-16 |
EP1828149A1 (en) | 2007-09-05 |
CA2590494A1 (en) | 2006-06-29 |
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