CN1358176A - 制备2-杂环基甲基苯甲酸衍生物的方法 - Google Patents
制备2-杂环基甲基苯甲酸衍生物的方法 Download PDFInfo
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- CN1358176A CN1358176A CN00809503A CN00809503A CN1358176A CN 1358176 A CN1358176 A CN 1358176A CN 00809503 A CN00809503 A CN 00809503A CN 00809503 A CN00809503 A CN 00809503A CN 1358176 A CN1358176 A CN 1358176A
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- Prior art keywords
- sulfenyl
- methyl
- group
- alkyl
- amino
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- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- -1 formamyl Chemical group 0.000 claims description 123
- 239000002585 base Substances 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 26
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 26
- 239000000460 chlorine Substances 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 26
- 239000011737 fluorine Substances 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000003254 radicals Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 10
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000003368 amide group Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 7
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 7
- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- TWBIDQDUOXHFSN-UHFFFAOYSA-N C[CH]C=O Chemical compound C[CH]C=O TWBIDQDUOXHFSN-UHFFFAOYSA-N 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Chemical group 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000012752 auxiliary agent Substances 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 3
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- GYAPJISEIGCPQO-UHFFFAOYSA-N [O]C1CCC1 Chemical compound [O]C1CCC1 GYAPJISEIGCPQO-UHFFFAOYSA-N 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000006323 alkenyl amino group Chemical group 0.000 claims description 2
- 125000005108 alkenylthio group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- ZPFKRQXYKULZKP-UHFFFAOYSA-N butylidene Chemical group [CH2+]CC[CH-] ZPFKRQXYKULZKP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- RFPMGSKVEAUNMZ-UHFFFAOYSA-N pentylidene Chemical group [CH2+]CCC[CH-] RFPMGSKVEAUNMZ-UHFFFAOYSA-N 0.000 claims description 2
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 claims description 2
- UJKMGUWJWAGVTA-UHFFFAOYSA-N propan-2-ylperoxybenzene Chemical compound CC(C)OOC1=CC=CC=C1 UJKMGUWJWAGVTA-UHFFFAOYSA-N 0.000 claims description 2
- 125000006324 propenyl amino group Chemical group 0.000 claims description 2
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- CILIOFMUTCCCIW-UHFFFAOYSA-N CC=C[S] Chemical compound CC=C[S] CILIOFMUTCCCIW-UHFFFAOYSA-N 0.000 claims 1
- KWKGMWRBLLAJNV-UHFFFAOYSA-N [S]C1CC1 Chemical compound [S]C1CC1 KWKGMWRBLLAJNV-UHFFFAOYSA-N 0.000 claims 1
- 125000006309 butyl amino group Chemical group 0.000 claims 1
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims 1
- VCZIFQMEDXLHEA-UHFFFAOYSA-N cyclopentylperoxycyclohexane Chemical compound C1(CCCC1)OOC1CCCCC1 VCZIFQMEDXLHEA-UHFFFAOYSA-N 0.000 claims 1
- 125000006202 diisopropylaminoethyl group Chemical group [H]C([H])([H])C([H])(N(C([H])([H])C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 abstract 2
- 239000003085 diluting agent Substances 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 10
- 229910052700 potassium Inorganic materials 0.000 description 10
- 239000011591 potassium Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 6
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052728 basic metal Inorganic materials 0.000 description 3
- 150000003818 basic metals Chemical class 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 1
- KNCHDRLWPAKSII-UHFFFAOYSA-N 5-ethyl-2-methylpyridine Natural products CCC1=CC=NC(C)=C1 KNCHDRLWPAKSII-UHFFFAOYSA-N 0.000 description 1
- WAUHABGEEBVFTF-UHFFFAOYSA-N CCCC[S] Chemical group CCCC[S] WAUHABGEEBVFTF-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-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
- 206010013786 Dry skin Diseases 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- RPGRVGNMPNMFTJ-UHFFFAOYSA-N O=C1N(C)C(C(F)(F)F)=NN1CC1=CC=CC=C1C(O)=O Chemical compound O=C1N(C)C(C(F)(F)F)=NN1CC1=CC=CC=C1C(O)=O RPGRVGNMPNMFTJ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NRAINUFKKPBZQY-UHFFFAOYSA-N [O]C1CC1 Chemical compound [O]C1CC1 NRAINUFKKPBZQY-UHFFFAOYSA-N 0.000 description 1
- OEVDDQGQYDLCHU-UHFFFAOYSA-N [S]C1CCCCC1 Chemical compound [S]C1CCCCC1 OEVDDQGQYDLCHU-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000003916 acid precipitation Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical class [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910021518 metal oxyhydroxide Inorganic materials 0.000 description 1
- XRKQMIFKHDXFNQ-UHFFFAOYSA-N n-cyclohexyl-n-ethylcyclohexanamine Chemical compound C1CCCCC1N(CC)C1CCCCC1 XRKQMIFKHDXFNQ-UHFFFAOYSA-N 0.000 description 1
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002897 organic nitrogen compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003297 rubidium Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/30—Oxygen or sulfur atoms
- C07D233/42—Sulfur atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/26—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
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- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/04—1,2,3-Triazines
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
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Abstract
本发明涉及制备通式(I)的2-杂环基甲基苯甲酸衍生物的新的方法,其中n、X和Z具有说明书中给出的意义,该方法提供高收率和高纯度,其特征是,通式(II)的2-苯并[c]呋喃酮,其中n和x具有说明书中给出的含义,与通式(III)的氮杂环:H-Z,其中Z具有说明书中给出的意义,或与通式(II)的氮杂环的金属盐在质子惰性极性稀释剂中并任选在碱性反应助剂存在下反应。
Description
本发明涉及新的制备2-杂环基甲基-苯甲酸衍生物的方法,这些衍生物可用作制备药用和农用的活性化合物的中间体。
已知2-苯并呋喃-1(3H)-酮(“2-苯并[c]呋喃酮”)与邻苯二甲酰亚胺钾盐反应生成相应的N-(2-羧基-苄基)-邻苯二甲酰亚胺-衍生物(参见Organic Syntheses Coll.Vol.IV(1963),810-812;Arch.Pharm.318(1985),640-649;Synthetic Communications28(1998),4525-4530)。
但是2-苯并[c]呋喃酮与芳基烷基胺的反应不是按照相同的反应历程生成预期的2-芳基烷基氨基甲基-苯甲酸,而是得到N-芳基烷基-2-羟基甲基-苯甲酰胺衍生物也是已知的(参见Arch.Pharm.318(1985),640-649)。
n 为数字0、1、2或者3,
X 为硝基、氰基、氨基甲酰基、硫代氨基甲酰基、卤素、或者
各为任选取代的烷基、烷氧基、烷基硫基、烷基亚硫酰基、
烷基磺酰基、烷基氨基,二烷基氨基或者二烷基氨基磺酰基,
和
Z 为经N(氮)连接的杂环基。
n和X如上述定义,
与通式(III)氮杂环
H-Z (III)其中
Z 具有上述给出的含义,
- 或者与通式(II)氮杂环的金属盐-在质子惰性的极性稀释剂和任选在碱性反应助剂存在下反应时可获得高收率和高纯度。
尽管预期按上述现有技术在相对大的规模上作为副反应生成N-杂环基-2-羟基甲基-苯甲酰胺衍生物,但令人惊奇地按本发明方法可以高收率和高纯度地选择性获得通式(I)的2-杂环基甲基-苯甲酸衍生物。
本发明方法提供了一种易于工业规模实施的、基于按已知方法易于得到的2-苯并[c]呋喃酮的制备2-杂环基甲基-苯甲酸衍生物的方法。开环立即产生目的苯甲酸衍生物。
另一种通过2-卤代甲基苯甲酸酯与式(II)的氮杂环反应的合成需要合成2-甲基-苯甲酸酯其包括很多步骤且昂贵。相应的苯甲酸必需通过酯水解制备,但并不是所有其它的取代基在酯水解条件下都稳定。
上下文中所引用的式和基团的优选取代基或范围如下定义:
n 优选为数字0、1、2或3。
X 优选为硝基、氰基、氨基甲酰基、硫代氨基甲酰基、卤素,
各为任选被卤素、C1-C4-烷氧基、C1-C4-烷基硫基、C1-C4-烷
基亚硫酰基或者C1-C4-烷基磺酰基取代的且烷基基团中具有
最多4个碳原子的烷基、烷氧基、烷基硫基、烷基亚硫酰基
或者烷基磺酰基,或者为烷基基团具有最多4个碳原子的烷
Q 为氧或者硫,
R1为氢、羟基、巯基、氰基、卤素,各为任选被氰基、卤素、
C1-C4-烷氧基、C1-C4-烷基硫基、C1-C4-烷基亚硫酰基或者
C1-C4-烷基磺酰基取代的且烷基基团具有最多6个碳原子的
烷基、烷基羰基、烷氧基、烷氧基羰基、烷基硫基、烷基亚
硫酰基或者烷基磺酰基,各为任选被卤素取代的且烷基基团
具有最多6个碳原子的烷基氨基或者二烷基氨基,各为任选
被卤素取代的且各在链烯基或炔基基团中具有最多6个碳原
子的链烯基、炔基、链烯基氧基、链烯基硫基或者链烯基氨
基,各为任选被卤素取代的且在环烷基基团中各具有3~6个
碳原子和任选烷基部分中最多具有4个碳原子的环烷基、环
烷基氧基、环烷基硫基、环烷基氨基、环烷基烷基、环烷基
烷氧基、环烷基烷基硫基或者环烷基烷基氨基,或者各为任
选被卤素、C1-C4-烷基或者C1-C4-烷氧基取代的苯基、苯基氧
基、苯基硫基、苯基氨基、苄基、苄基氧基、苄基硫基或者
苄基氨基,或者如果两个相邻基团R1和R1位于双键上,则与
相邻的基团R1一起为苯并基团(Benzogruppierung),和
R2为氢、羟基、氨基、具有最多4个碳原子的亚烷基氨基,各
为任选被氰基、卤素或者C1-C4-烷氧基取代的且在烷基基团
中各具有最多6个碳原子的烷基、烷氧基、烷基氨基、二烷 基氨基或者烷酰基氨基,各为任选被卤素取代的且在链烯基或炔基基团中各具有最多6个碳原子的链烯基、炔基或者链烯基氧基,各为任选被卤素取代且在环烷基基团中各具有3~6个碳原子和在烷基部分任选含有最多3个碳原子的环烷基、环烷基烷基或者环烷基氨基,或者各为任选被卤素、C1-C4-烷基或者C1-C4-烷氧基取代的苯基或者苄基,或者与一个相邻的基团R1或者R2一起为任选被卤素或者C1-C4-烷基取代的具有3~5碳原子的亚烷基(Alkandiyl),其中单一基团R1和R2,如果多个这样的基团连接在相同的杂环基上时,它们可具有上述定义范围内相同或不同的含义。n 特别优选为数字0、1或者2。X 特别优选为硝基、氰基、氨基甲酰基、硫代氨基甲酰基、氟、氯、溴,各为任选被氟和/或者氯、甲氧基、乙氧基、正-或者异丙氧基、甲基硫基、乙基硫基、正-或者异丙基硫基、甲基亚硫酰基、乙基亚硫酰基、甲基磺酰基或者乙基磺酰基取代的甲基、乙基、正-或者异丙基、正-、异-、仲-或者叔丁基,各为任选被氟和/或者氯、甲氧基、乙氧基、正-或者异丙氧基取代的甲氧基、乙氧基、正-或者异丙氧基,各为任选被氟和/或者氯取代的甲基硫基、乙基硫基、正-或者异丙基硫基、甲基亚硫酰基、乙基亚硫酰基、正-或者异丙基亚硫酰基、甲基磺酰基、乙基磺酰基、正-或者异丙基磺酰基,或者为甲基氨基、乙基氨基、正-或者异丙基氨基、二甲基氨基、二乙基氨基、二甲基氨基磺酰基或者二乙基氨基磺酰基。Z 特别优选为下列杂环基之一: 其中各虚线键为单键或双键。
Q 为氧或者硫,
R1为氢、羟基、巯基、氰基、氟、氯、溴、碘,各为任选被氟、
氯、甲氧基、乙氧基、正-或者异丙氧基、正-、异-、仲-或
者叔丁氧基、甲基硫基、乙基硫基、正-或者异丙基硫基、正
-、异-、仲-或者叔丁基硫基、甲基亚硫酰基、乙基亚硫酰基
(sulfmyl)、正-或者异丙基亚硫酰基、甲基磺酰基、乙基
磺酰基、正-或者异丙基磺酰基取代的甲基、乙基、正-或者
异丙基、正-、异-、仲-或者叔丁基、甲氧基、乙氧基、正-
或者异丙氧基、正-、异-、仲-或者叔丁氧基、甲基硫基、乙
基硫基、正-或者异丙基硫基、正-、异-、仲-或者叔丁基硫
基、甲基亚硫酰基、乙基亚硫酰基、正-或者异丙基亚硫酰基、
甲基磺酰基、乙基磺酰基、正-或者异丙基磺酰基,为甲基氨
基、乙基氨基、正-或者异丙基氨基、正-、异-、仲-或者叔
丁基氨基、二甲基氨基、二乙基氨基、二正丙基氨基或者二
异丙基氨基,各为任选被氟和/或者氯取代的乙烯基、丙烯
基、丁烯基、乙炔基、丙炔基、丁炔基、丙烯基氧基、丁烯
基氧基、丙烯基硫基、丁烯基硫基、丙烯基氨基或者丁烯基
氨基,各为任选被氟和/或者氯取代的环丙基、环丁基、环戊
基、环己基、环丙基氧基、环丁基氧基、环戊基氧基、环己
基氧基、环丙基硫基、环丁基硫基、环戊基硫基、环己基硫
基、环丙基氨基、环丁基氨基、环戊基氨基、环己基氨基、
环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环丙
基甲氧基、环丁基甲氧基、环戊基甲氧基、环己基甲氧基、
环丙基甲基硫基、环丁基甲基硫基、环戊基甲基硫基、环己 基甲基硫基、环丙基甲基氨基、环丁基甲基氨基、环戊基甲基氨基或者环己基甲基氨基,或者各为任选被氟、氯、甲基、乙基、正-或者异丙基、正-、异-、仲-或者叔丁基、甲氧基、乙氧基、正-或者异丙氧基取代的苯基、苯基氧基、苯基硫基、苯基氨基、苄基、苄基氧基、苄基硫基或者苄基氨基,或者如果两个相邻基团R1和R1位于双键上,则与相邻的基团R1一起为苯并基团,和R2为氢、羟基、氨基,各为任选被氟和/或者氯、甲氧基或者乙氧基取代的甲基、乙基、正-或者异丙基、正-、异-或者仲丁基、甲氧基、乙氧基、正-或者异丙氧基、甲基氨基、乙基氨基或者二甲基氨基,各为任选被氟和/或者氯取代的乙烯基、丙烯基、乙炔基、丙炔基或者丙烯基氧基,各为任选被氟和/或者氯取代的环丙基、环丁基、环戊基、环己基、环丙基甲基、环丁基甲基、环戊基甲基或者环己基甲基,或者各为任选被氟、氯、甲基、乙基、正-或者异丙基、正-、异-、仲-或者叔丁基、甲氧基、乙氧基、正-或者异丙氧基取代的苯基或者苄基,或者与一个相邻的基团R1或者R2一起各为任选被甲基和/或者乙基取代的丙烷-1,3-二基(亚丙基)、丁烷-1,4-二基(亚丁基)或者戊烷-1,5-二基(亚戊基),其中单一基团R1和R2,如果多个这样的基团连接在相同的杂环基上时,它们可具有上述定义范围内相同或不同的含义。Z 特别优选为下列杂环基之一:其中Q、R1和R2如在特别优选的Z的定义中所定义。
在本发明方法中要求作为原料的通式(II)的2-苯并[c]呋喃酮是已知的和/或可按本身已知的方法制备(参见Heterocycles 31(1990),1261-1270;Synth.Commun.20(1990),2641-2652;J.Org.Chem.57(1992),2029-2033)。
在本发明方法中还要求作为原料的通式(III)的氮杂环是合成试剂,其中大多数是已知的。
适于用作通式(III)氮杂环的金属盐可优选用碱金属和碱土金属盐,如锂盐、钠盐、铷盐、铯盐、镁盐、钙盐和钡盐,最特别优选钠盐和钾盐。
用于制备通式(I)化合物的本发明方法在质子惰性的极性稀释剂中进行。这些极性溶剂包括,特别是,醚类,如二异丙基醚、二噁烷、四氢呋喃或者乙二醇二甲基-或者二乙基醚;酮类,如丙酮、丁酮、甲基异丙基酮或者甲基异丁基酮;腈类,如乙腈、丙腈或者丁腈;酰胺类,如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-N-甲酰苯胺、N-甲基-吡咯烷酮或者六甲基磷酸三酰胺;酯,如乙酸甲酯或者乙酸乙酯,亚砜类,如二甲基亚砜,及砜类,如亚丁基砜(四氢噻吩砜)。
酮类,如甲基异丁基酮,和酰胺类,如N,N-二甲基甲酰胺和N,N-二甲基乙酰胺,是最特别优选的稀释剂。
用于制备通式(I)化合物的本发明方法任选用碱性反应助剂进行。适用于本发明方法的反应助剂一般是常规无机或者有机碱或者酸接受剂。这些接受剂优选包括碱金属或者碱土金属的乙酸盐、氨化物、碳酸盐、碳酸氢盐、氢化物、氢氧化物或者烷酸盐,例如钠、钾或者钙的乙酸盐,锂、钠、钾或者钙的氨化物,钠、钾、或者钙的碳酸盐,钠、钾或者钙的碳酸氢盐,锂、钠、钾或者钙的氢化物,锂、钠、钾或者钙的氢氧化物,钠或者钾的甲醇盐、乙醇盐、正-或者异丙醇盐、正-、异-、仲-或者叔丁醇盐;此外还有碱性有机氮化合物,例如三甲胺、三乙胺、三丙胺、三丁基胺、乙基二异丙基胺、N,N-二甲基环己基胺、二环己基胺、乙基二环己基胺、N,N-二甲基苯胺、N,N-二甲基苄基胺、吡啶、2-甲基-、3-甲基-、4-甲基-、2,4-二甲基-、2,6-二甲基-、3,4-二甲基-和3,5-二甲基吡啶、5-乙基-2-甲基-吡啶、4-二甲基氨基吡啶、N-甲基-哌啶、1,4-二氮杂双环[2,2,2]-辛烷(DABCO)、1,5-二氮杂双环[4,3,0]-壬-5-烯(DBN)、或者1,8-二氮杂双环[5,4,0]-十一烷-7-烯(DBU)。
碱金属和碱土金属氢化物、氢氧化物和烷酸盐,如锂、钠、钾或者钙的氢化物,锂、钠、钾或者钙的氢氧化物,钠或者钾的甲醇盐、乙醇盐、正-或者异丙醇盐、正-、异-、仲-或者叔丁醇盐是最特别优选的碱性反应助剂。
实施本发明方法的反应温度可在较大的范围内变化。一般为0℃~200℃,优选10℃~180℃。
本发明方法一般在常压下进行,但也可在加压或减压下,一般在0.1bar~10bar下进行。
为实施本发明方法,一般1mol通式(II)的2-苯并[c]呋喃酮使用0.8~1.2mol,优选0.95~1.05mol的通式(III)的氮杂环或其盐。
在一优选的实施方案中,在室温或者在冷却下混合反应组份,然后优选在升高的温度下搅拌反应混合物直至反应完成。
后处理一般按常规方法进行,例如在减压下浓缩混合物,残余物用与水实际上不混溶的有机溶剂洗涤,然后用水处理,通过加入强酸,例如盐酸沉淀并通过抽滤分离产物(参见制备实施例)。
按本发明方法制备的通式(I)的2-杂环基甲基苯甲酸衍生物可用作制备药用和农用活性化合物的中间体(参见Arzneimittelforschung 27(1977),2364-2368-在Chem.Abstracts 88:98893中引用;GB-A-1427408;DE-A-198 33 360)。
制备实施例:
将10.0g(60mmol)4-甲基-5-三氟甲基-2,4-二氢-3H-1,2,4-三唑-3-酮加到100ml甲基异丁基酮中,并在搅拌下每次用少量的4.0g(60mmol)85%浓度的氢氧化钾处理。搅拌过夜后通过抽滤分离固体物质并在减压下、于80℃干燥。
将所得到的1.03g(5mmol)4-甲基-5-三氟甲基-2,4-二氢-3H-1,2,4-三唑-3-酮钾盐和0.67g(5mmol)2-苯并呋喃-1(3H)-酮(2-苯并[c]呋喃酮)加到8ml N,N-二甲基甲酰胺中,并回流加热反应混合物8小时,然后在水泵真空下浓缩,残余物用乙醚洗涤,溶于水中并用2N-盐酸酸化。所得结晶产物通过抽滤分离。
得到1.1g(理论量的74%)2-[(4-甲基-3-三氟甲基-5-氧代-4,5-二氢-1H-1,2,4-三唑-1-基)-甲基]-苯甲酸,熔点132℃。1H-NMR(CDCl3,δ):3.46(s),5.59(s),7.11(d),7.41(t),7.55(t),8.11(dd)。
将2.9g(20mmol)4-甲基-5-甲基硫代-2,4-二氢-3H-1,2,4-三唑-3-酮溶于60ml N,N-二甲基-甲酰胺中,并在加入0.88g(22mmol)氢化钠后在室温下(约20℃)搅拌混合物30分钟。随后加入2.68g(20mmol)2-苯并呋喃-1(3H)-酮(2-苯并[c]呋喃酮),并将反应混合物加热回流2小时。然后在水泵真空下浓缩混合物,残余物用乙醚洗涤,然后将其溶于水中并用2N-盐酸酸化。所得结晶产物通过抽滤分离。
得到3.5g(理论量的63%)2-[(4-甲基-3-甲基硫代-5-氧代-4,5-二氢-1H-1,2,4-三唑-1-基)-甲基]-苯甲酸,熔点122℃。1H-NMR(CDCl3,δ):2.55(s),3.25(s),5.44(s),7.18(d),7.39(dt),7.49(dt),7.99(dd)。
Claims (4)
2.权利要求1的方法,其特征是,该反应在0℃~200℃的温度下进行。
3.权利要求1或者2的方法,其特征是n 为数字0、1、2或者3,X 为硝基、氰基、氨基甲酰基、硫代氨基甲酰基、卤素,各为任选被卤素、C1-C4-烷氧基、C1-C4-烷基硫基、C1-C4-烷基亚硫酰基或者C1-C4-烷基磺酰基取代的且烷基基团中具有最多4个碳原子的烷基、烷氧基、烷基硫基、烷基亚硫酰基或者烷基磺酰基,或者为烷基基团具有最多4个碳原子的烷基氨基、二烷基氨基或者二烷基氨基磺酰基,Z 为下列的杂环基团之一 其中各虚线键为单键或者双键,和
Q 为氧或者硫,
R1为氢、羟基、巯基、氰基、卤素,各为任选被氰基、卤素、
C1-C4-烷氧基、C1-C4-烷基硫基、C1-C4-烷基亚硫酰基或者
C1-C4-烷基磺酰基取代的且烷基基团具有最多6个碳原子的
烷基、烷基羰基、烷氧基、烷氧基羰基、烷基硫基、烷基亚
硫酰基或者烷基磺酰基,各为任选被卤素取代的且烷基基团
具有最多6个碳原子的烷基氨基或者二烷基氨基,各为任选
被卤素取代的且各在链烯基或炔基基团中具有最多6个碳原
子的链烯基、炔基、链烯基氧基、链烯基硫基或者链烯基氨
基,各为任选被卤素取代的且在环烷基基团中各具有3~6个
碳原子和任选烷基部分中最多具有4个碳原子环烷基、环烷
基氧基、环烷基硫基、环烷基氨基、环烷基烷基、环烷基烷 氧基、环烷基烷基硫基或者环烷基烷基氨基,或者各为任选被卤素、C1-C4-烷基或者C1-C4-烷氧基取代的苯基、苯基氧基、苯基硫基、苯基氨基、苄基、苄基氧基、苄基硫基或者苄基氨基,或者如果两个相邻基团R1和R1位于双键上,则与相邻的基团R1一起为苯并基团,和R2为氢、羟基、氨基、具有最多4个碳原子的亚烷基氨基,各为任选被氰基、卤素或者C1-C4-烷氧基取代的且在烷基基团中各具有最多6个碳原子烷基、烷氧基、烷基氨基、二烷基氨基或者烷酰基氨基,各为任选被卤素取代的且在链烯基或炔基基团中各具有最多6个碳原子的链烯基、炔基或者链烯基氧基,各为任选被卤素取代的且在环烷基基团中各具有3~6个碳原子和在烷基部分任选最多3个碳原子的环烷基、环烷基烷基或者环烷基氨基,或者各为任选被卤素、C1-C4-烷基或者C1-C4-烷氧基取代的苯基或者苄基,或者与一个相邻的基团R1或者R2一起为任选被卤素或者C1-C4-烷基取代的具有3~5个碳原子的亚烷基,其中单一基团R1和R2,如果多个这样的基团连接在相同的杂环基上时,它们可具有上述定义范围内相同或不同的含义。
4.权利要求1~3任一项的方法,其特征是n 为数字0、1或者2。X 为硝基、氰基、氨基甲酰基、硫代氨基甲酰基、氟、氯、溴,各为任选被氟和/或者氯、甲氧基、乙氧基、正-或者异丙氧基、甲基硫基、乙基硫基、正-或者异丙基硫基、甲基亚硫酰基、乙基亚硫酰基、甲基磺酰基或者乙基磺酰基取代的甲基、乙基、正-或者异丙基、正-、异-、仲-或者叔丁基,各为任选被氟和/或者氯、甲氧基、乙氧基、正-或者异丙氧基取代的甲氧基、乙氧基、正-或者异丙氧基,各为任选被氟和/或者氯取代的甲基硫基、乙基硫基、正-或者异丙基硫基、甲基亚硫酰基、乙基亚硫酰基、正-或者异丙基亚硫酰基、甲基磺酰基、乙基磺酰基、正-或者异丙基磺酰基,或者为甲基氨基、乙基氨基、正-或者异丙基氨基、二甲基氨基、二乙基氨基、二甲基氨基磺酰基或者二乙基氨基磺酰基,Z 为下列杂环基之一: 其中各虚线键为单键或双键,
Q 为氧或者硫,
R1为氢、羟基、巯基、氰基、氟、氯、溴、碘,各为任选被氟、
氯、甲氧基、乙氧基、正-或者异丙氧基、正-、异-、仲-或
者叔丁氧基、甲基硫基、乙基硫基、正-或者异丙基硫基、正
-、异-、仲-或者叔丁基硫基、甲基亚硫酰基、乙基亚硫酰基、
正-或者异丙基亚硫酰基、甲基磺酰基、乙基磺酰基、正-或
者异丙基磺酰基取代的甲基、乙基、正-或者异丙基、正-、
异-、仲-或者叔丁基、甲氧基、乙氧基、正-或者异丙氧基、
正-、异-、仲-或者叔丁氧基、甲基硫基、乙基硫基、正-或
者异丙基硫基、正-、异-、仲-或者叔丁基硫基、甲基亚硫酰
基、乙基亚硫酰基、正-或者异丙基亚硫酰基、甲基磺酰基、
乙基磺酰基、正-或者异丙基磺酰基,为甲基氨基、乙基氨基、
正-或者异丙基氨基、正-、异-、仲-或者叔丁基氨基、二甲
基氨基、二乙基氨基、二正丙基氨基或者二异丙基氨基,各
为任选被氟和/或者氯取代的乙烯基、丙烯基、丁烯基、乙炔
基、丙炔基、丁炔基、丙烯基氧基、丁烯基氧基、丙烯基硫
基、丁烯基硫基、丙烯基氨基或者丁烯基氨基,各为任选被
氟和/或者氯取代的环丙基、环丁基、环戊基、环己基、环丙
基氧基、环丁基氧基、环戊基氧基、环己基氧基、环丙基硫
基、环丁基硫基、环戊基硫基、环己基硫基、环丙基氨基、 环丁基氨基、环戊基氨基、环己基氨基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环丙基甲氧基、环丁基甲氧基、环戊基甲氧基、环己基甲氧基、环丙基甲基硫基、环丁基甲基硫基、环戊基甲基硫基、环己基甲基硫基、环丙基甲基氨基、环丁基甲基氨基、环戊基甲基氨基或者环己基甲基氨基,或者各为任选被氟、氯、甲基、乙基、正-或者异丙基、正-、异-、仲-或者叔丁基、甲氧基、乙氧基、正-或者异丙氧基取代的苯基、苯基氧基、苯基硫基、苯基氨基、苄基、苄基氧基、苄基硫基或者苄基氨基,或者如果两个相邻基团R1和R1位于双键上,则与相邻的基团R1一起为苯并基团,和R2为氢、羟基、氨基,为各任选被氟和/或者氯、甲氧基或者乙氧基取代的甲基、乙基、正-或者异丙基、正-、异-或者仲丁基、甲氧基、乙氧基、正-或者异丙氧基、甲基氨基、乙基氨基或者二甲基氨基,各为任选被氟和/或者氯取代的乙烯基、丙烯基、乙炔基、丙炔基或者丙烯基氧基,各为任选被氟和/或者氯取代的环丙基、环丁基、环戊基、环己基、环丙基甲基、环丁基甲基、环戊基甲基或者环己基甲基,或者各为任选被氟、氯、甲基、乙基、正-或者异丙基、正-、异-、仲-或者叔丁基、甲氧基、乙氧基、正-或者异丙氧基取代的苯基或者苄基,或者与一个相邻的基团R1或者R2一起各为任选被甲基和/或者乙基取代的丙烷-1,3-二基(亚丙基)、丁烷-1,4-二基(亚丁基)或者戊烷-1,5-二基(亚戊基),其中单一基团R1和R2,如果多个这样的基团连接在相同的杂环基上时,它们可具有上述定义范围内相同或不同的含义。
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EP2440537A1 (en) | 2009-06-11 | 2012-04-18 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 based on the 1,3 -oxazinan- 2 -one structure |
US8883778B2 (en) | 2009-07-01 | 2014-11-11 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1 |
HUE035761T2 (en) | 2010-02-27 | 2018-05-28 | Bayer Ip Gmbh | Bisaryl-linked aryltriazolones and their use |
EP2582698B1 (en) | 2010-06-16 | 2016-09-14 | Vitae Pharmaceuticals, Inc. | Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use |
EP2585444B1 (en) | 2010-06-25 | 2014-10-22 | Boehringer Ingelheim International GmbH | Azaspirohexanones as inhibitors of 11-beta-hsd1 for the treatment of metabolic disorders |
DE102010040187A1 (de) | 2010-09-02 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Substituierte N-Phenethyl-triazolonacetamide und ihre Verwendung |
DE102010040924A1 (de) | 2010-09-16 | 2012-03-22 | Bayer Schering Pharma Aktiengesellschaft | Substituierte Phenylacet- und Phenylpropanamide und ihre Verwendung |
CN103179960A (zh) | 2010-11-02 | 2013-06-26 | 贝林格尔.英格海姆国际有限公司 | 治疗代谢疾病的药物组合 |
RS58049B1 (sr) | 2014-11-03 | 2019-02-28 | Bayer Pharma AG | Hidroksialkilom supstituisani derivati feniltriazola i njihova upotreba |
US9988367B2 (en) | 2016-05-03 | 2018-06-05 | Bayer Pharma Aktiengesellschaft | Amide-substituted pyridinyltriazole derivatives and uses thereof |
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DE19627901A1 (de) * | 1996-07-11 | 1998-01-15 | Bayer Ag | Substituierte aromatische Carbonylverbindungen und ihre Derivate |
DE19921732A1 (de) * | 1998-07-24 | 2000-01-27 | Bayer Ag | Substituierte Benzoylcyclohexandione |
-
1999
- 1999-06-26 DE DE19929348A patent/DE19929348A1/de not_active Withdrawn
-
2000
- 2000-06-13 CN CN00809503A patent/CN1358176A/zh active Pending
- 2000-06-13 IL IL14666200A patent/IL146662A0/xx unknown
- 2000-06-13 AU AU55325/00A patent/AU5532500A/en not_active Abandoned
- 2000-06-13 EP EP00940367A patent/EP1194419A1/de not_active Withdrawn
- 2000-06-13 WO PCT/EP2000/005412 patent/WO2001000595A1/de not_active Application Discontinuation
- 2000-06-13 MX MXPA01013263A patent/MXPA01013263A/es not_active Application Discontinuation
- 2000-06-13 BR BR0012451-6A patent/BR0012451A/pt not_active Application Discontinuation
- 2000-06-13 JP JP2001507005A patent/JP2003503396A/ja active Pending
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2003
- 2003-01-03 HK HK03100101.3A patent/HK1047932A1/zh unknown
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IL146662A0 (en) | 2002-07-25 |
MXPA01013263A (es) | 2002-06-21 |
JP2003503396A (ja) | 2003-01-28 |
HK1047932A1 (zh) | 2003-03-14 |
WO2001000595A1 (de) | 2001-01-04 |
DE19929348A1 (de) | 2000-12-28 |
BR0012451A (pt) | 2002-04-02 |
AU5532500A (en) | 2001-01-31 |
EP1194419A1 (de) | 2002-04-10 |
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