CN1205213C - 制备咪唑并[1,2－c][2,3]苯并二氮杂䓬的方法以及该方法中的新中间产物 - Google Patents
制备咪唑并[1,2－c][2,3]苯并二氮杂䓬的方法以及该方法中的新中间产物 Download PDFInfo
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- CN1205213C CN1205213C CNB018139876A CN01813987A CN1205213C CN 1205213 C CN1205213 C CN 1205213C CN B018139876 A CNB018139876 A CN B018139876A CN 01813987 A CN01813987 A CN 01813987A CN 1205213 C CN1205213 C CN 1205213C
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- halogen
- alkoxyl group
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- hydroxyl
- alkyl
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 title abstract 3
- 239000000543 intermediate Substances 0.000 title abstract 2
- JENALEDAZIFLGS-UHFFFAOYSA-N 3h-imidazo[1,2-c][2,3]benzodiazepine Chemical class C1=NN2CC=NC2=CC2=CC=CC=C21 JENALEDAZIFLGS-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 229940049706 benzodiazepine Drugs 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- -1 phenylethyl acetic ester Chemical compound 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 12
- 125000005605 benzo group Chemical group 0.000 claims description 12
- 229910021529 ammonia Inorganic materials 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229960003424 phenylacetic acid Drugs 0.000 claims description 9
- 239000003279 phenylacetic acid Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 125000005418 aryl aryl group Chemical group 0.000 claims description 6
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 235000019439 ethyl acetate Nutrition 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000006698 hydrazinolysis reaction Methods 0.000 claims description 3
- 150000002916 oxazoles Chemical class 0.000 claims description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 2
- 150000007978 oxazole derivatives Chemical class 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims 3
- 239000011877 solvent mixture Substances 0.000 claims 1
- 150000001557 benzodiazepines Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 239000002585 base Substances 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 238000009838 combustion analysis Methods 0.000 description 5
- 150000005826 halohydrocarbons Chemical class 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- OSARRPBJIYFICJ-UHFFFAOYSA-N 2-benzyl-4,5-dimethyl-1,3-oxazole Chemical class O1C(C)=C(C)N=C1CC1=CC=CC=C1 OSARRPBJIYFICJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- ROWKJAVDOGWPAT-UHFFFAOYSA-N Acetoin Chemical compound CC(O)C(C)=O ROWKJAVDOGWPAT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RPBDCDQMCRHNLM-UHFFFAOYSA-N C1=NNC=C2C=CC=CC2=C1 Chemical compound C1=NNC=C2C=CC=CC2=C1 RPBDCDQMCRHNLM-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 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
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 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
- 150000007857 hydrazones Chemical class 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
本发明涉及通式(1)化合物的制备方法。本发明还涉及通式(5)和(6)的新化合物，它们可作为制备式(1)苯并二氮杂䓬的中间体。
Description
本发明涉及制备通式(1)之咪唑并[1，2-c][2，3]苯并二氮杂的新方法以该方法中的新中间产物：
其中：
R1＝氢、C1-C6烷基、硝基、卤素、氰基、C1-C4烷氧基、-CF3、羟基或C1-C6烷酰基氧基，
R2和R3可相同或不同并代表氢、卤素、C1-C6烷氧基、羟基、氰基、C1-C6烷酰基、C2-C6炔基、C2-C6烯基，任选被卤素、羟基或C1-C6烷氧基取代的C1-C6烷基，C3-C7环烷基，或者任选被卤素、C1-C4烷氧基或C1-C4烷基取代的芳基或杂芳基；
X＝氢或卤素，
Y＝C1-C6烷氧基，或者
X和Y一起代表-O-(CH2)n-O-，其中n＝1、2或3。
本发明还包括通式5的苯基乙酸衍生物，其可作为制备药理活性化合物的中间产物：
其中：
R1＝氢、C1-C6烷基、硝基、卤素、氰基、C1-C4烷氧基、-CF3、羟基或C1-C6烷酰基氧基，
R2和R3可相同或不同并代表氢、卤素、C1-C6烷氧基、羟基、氰基、C1-C6烷酰基、C2-C6炔基、C2-C6烯基，任选被卤素、羟基或C1-C6烷氧基取代的C1-C6烷基，C3-C7环烷基，或者任选被卤素、C1-C4烷氧基或C1-C4烷基取代的芳基或杂芳基；
X＝氢或卤素，
Y＝C1-C6烷氧基，或者
X和Y一起代表-O-(CH2)n-O-，其中n＝1、2或3；
以及通式6的噁唑衍生物：
其中：
R1＝氢、C1-C6烷基、硝基、卤素、氰基、C1-C4烷氧基、-CF3、羟基或C1-C6烷酰基氧基，
R2和R3可相同或不同并代表氢、卤素、C1-C6烷氧基、羟基、氰基、C1-C6烷酰基、C2-C6炔基、C2-C6烯基，任选被卤素、羟基或C1-C6烷氧基取代的C1-C6烷基，C3-C7环烷基，或者任选被卤素、C1-C4烷氧基或C1-C4烷基取代的芳基或杂芳基；
X＝氢或卤素，
Y＝C1-C6烷氧基，或者
X和Y-起代表-O-(CH2)n-O-，其中n＝1、2或3。
上述通式中的基团具有以下含意：
C1-C6烷基分别定义为直链或支链烷基，如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、戊基、异戊基或己基。
R2和R3中的C2-C6烯基分别包含至少一个双键，例如是乙烯基、丙烯基、丁烯-1-基、异丁烯基、戊烯-1-基、2，2-二甲基-丁烯-1-基、3-甲基丁烯-1-基、或者己烯-1-基。
如果R2和R3代表C2-C6炔基，则至少存在一个叁键，例如是乙炔基、丙炔基、丁炔-1-基、丁炔-2-基、戊炔-1-基、戊炔-2-基、3-甲基丁炔-1-基、或者己炔-1-基。上述烯基或炔基也可任选被卤原子取代。如果存在卤代烷基，则可在一个或者多个位置处被卤化，而且或可被全卤化，例如-CF3。
在上述基团中，卤素定义为氟、氯、溴和碘。
R2和R3中的芳基和杂芳基可任选地在一个、二个或者三个位置处被卤素、C1-4烷氧基、或者C1-4烷基取代；任何的取代置换都是可能的。
芳基和杂芳基可为单环或者二环化合物，并包含5-12个环原子、优选5-9个环原子，例如，芳基例如是苯基、联苯基、萘基、或者茚基，而杂芳基例如是噻吩基、呋喃基、吡喃基、吡咯基、吡唑基、吡啶基、嘧啶基、哒嗪基、噁唑基、异噁唑基、噻唑基、异噻唑基、1，3，4-恶二唑-2-基、1，2，4-恶二唑-5-基、1，2，4-恶二唑-3-基、喹啉基、异喹啉基、苯并[1]噻吩基、或者苯并呋喃基，其包含1-3个杂原子，例如硫、氧和/或氮。优选的基团是2-噻吩基、3-噻吩基、吡啶-2-基、吡啶-3-基、吡啶-4-基和苯基。
R2和R3定义中的C3-C8环烷基例如是环丙基、环丁基、环戊基、环己基和环庚基。
对于直链或支链脂族羧酸中的C1-C6烷酰基，合适的有甲酰基、乙酰基、丙酰基、丁酰基、异丙基羰基、己酰基、戊酰基、或三甲基乙酰基。
R1优选代表氢、氯、硝基、甲氧基；R2和R3优选代表氢、或C1-4烷基或苯基；X和Y优选一起代表-O-CH2-O-。
制备通式1化合物的方法描述于WO 97/28163中。
本发明的目的是提供一种制备通式1化合物的新合成方法。本发明的目的还在于通式5和6之新的中间产物，这些产物是在上述合成方法框架中处理的，而且其本身或者衍生物可用作合成目标分子的起始物。
与现有技术中的已知合成方法相比，根据本发明的方法需要更少的中间步骤，纯制步骤的数目显著减少，而且总产率增加。根据本发明的方法还使工业规模地制造通式1化合物成为可能。
因此，本发明包括制备通式1之咪唑并[1，2-c][2，3]苯并二氮杂的方法，其中R1、R2和R3以及X和Y的定义如上所述，该方法是由通式4的苯基乙酸起始，
其中X、Y和R1的定义如上所述，
a)用式5a的醇进行酯化，
形成通式5的苯基乙基乙酸酯，
其中：X、Y、R1、R2和R3的定义如上所述，
b)与氨或氨供体进行缩合，形成通式6的噁唑，
其中：X、Y、R1、R2和R3的定义如上所述，随后进行肼解形成通式1的化合物。
通式1的咪唑并[1，2-c][2，3]苯并二氮杂是根据以下合成路线1来合成的。
合成路线1
通式2化合物反应形成通式3化合物是根据本领域已知的Friedel-Crafts反应方法实施的(例如J.Chem.Soc.，Perkin Trans.l 1991，169-173)。例如，通式2的化合物在Lewis酸(如四氯化锡、三氯化铝、四氯化钛)以及酰化剂(如苯甲酰氯、苯甲酸酐或其他活化羧酸衍生物)存在下进行反应。如果在反应混合物中添加额外的N，N-二甲基乙酰胺，则可显著增加产率。作为溶剂，例如可以使用卤代烃，如二氯甲烷或二氯乙烷以及他们的混合物。反应在-30至50℃的温度范围内进行，优选温度范围是0-25℃。
通式3化合物反应形成通式4化合物是根据本领域已知的皂化反应法实施的。例如，通式3的化合物在碱(如碱金属氢氧化物，优选氢氧化钠)存在下于溶剂(如低级醇，优选伯醇，或者水或者他们的混合物)中加热。反应温度范围可为25-150℃，但优选为70-110℃。
通式4化合物反应形成通式5化合物是根据本领域已知的酯化反应法实施的。例如，在活化试剂如羰基二咪唑以及式(5a)醇如3-羟基-2-丁酮存在下，使通式4的化合物反应。
作为溶剂，可使用卤代烃，如二氯甲烷或二氯乙烷，以及THF和他们的混合物。反应温度范围可以是-20℃至100℃，但优选为0-25℃。
R2和R3可根据标准方法在通式5的化合物中进行改变，这对于本领域技术人员是已知的。这可通过在酯化步骤中使用其他的醇来实施，不过也可通过重新酯化已经存在的酯来实施。R2和R3因此可代表以下基团：氢、卤素、烷氧基、羟基、氰基、烷酰基、任选取代的炔基、任选取代的烯基，任选被卤素、羟基、或者烷氧基取代的烷基，环烷基，或者任选取代的芳基或杂芳基。
通式5化合物反应形成通式6化合物是根据本领域已知的通过缩合羰基和氨制备噁唑类化合物的方法实施的。例如，在乙酸铵、氨、氨溶液或者其他氨供体(如乙酰胺或者甲酰胺)存在下，在乙酸存在下使通式5的化合物反应。作为溶剂，可以使用卤代烃，如二氯甲烷或二氯乙烷；有机酸，如甲酸或乙酸；以及低级醇，如甲醇或乙醇，但还可使用乙二醇以及他们的混合物。反应温度范围是0-150℃，优选的温度范围是50-100℃。
通式6化合物反应形成通式1化合物是根据本领域已知的肼解或者形成腙的方法实施的。例如，通式6的化合物在肼或者水合肼存在下反应。作为溶剂，可以使用卤代烃，如二氯甲烷或二氯乙烷；有机酸，如甲酸或乙酸；以及低级醇，如甲醇或乙醇，但还可使用乙二醇以及他们的混合物。反应温度范围是0-200℃，优选为80-120℃。在高压釜中的反应过程是可行的。
通式5化合物反应形成通式1化合物也可在单罐反应中进行。例如，在乙酸铵、氨、氨溶液或者其他氨供体(如乙酰胺或者甲酰胺)存在下，在乙酸存在下使通式5的化合物反应。作为溶剂，可以使用卤代烃，如二氯甲烷或二氯乙烷；有机酸，如甲酸或乙酸；以及低级醇，如甲醇或乙醇，但还可使用乙二醇以及他们的混合物。反应温度范围是0-150℃，优选为50-100℃。该反应完成后，在反应混合物中添加肼或水合肼。反应温度范围是0-200℃，优选为80-120℃。在高压釜中的反应过程是可行的。
如果未描述起始化合物的制备，则该化合物是已知的或者可按照类似于已知的方法或者在此描述的方法来制备。以下将通过实施例进一步说明根据本发明的方法。
实施例
2-苯甲酰基-4，5-(亚甲二氧基)-苯基乙酸甲酯(3)
在室温下使79ml的四氯化锡和25ml的N，N′-二甲基乙酰胺在270ml的二氯甲烷中与39ml的苯甲酰氯混合。于0℃下向该混合物中滴加44g的4，5-(亚甲二氧基)-苯基乙酸甲酯(2)，并在室温下搅拌该溶液12小时。处理时，在-15℃下添加660ml的水，然后用二氯甲烷萃取含水相。收集的有机相用6N氢氧化钠水溶液洗涤，然后在旋转蒸发器中彻底蒸发浓缩。由乙醇中结晶出粗产物3(74g)。
1H-NMR(CDCl3)δ＝3.61(s，3H，OMe)，3.80(s，2H，苄基CH2)，6.03(s，2H，OCH2O)，6.84和6.88(2s 1H，3-和6-H芳基)，7.43-7.80(m，5H，PhCO)
熔点：74-76℃ 燃烧分析：计算C68.45 H4.73
实测C68.53 H4.59
类似地制备以下化合物：
2-(4-氯-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸甲酯
2-(4-硝基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸甲酯
2-(4-甲氧基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸甲酯
2-(4-甲基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸甲酯
2-(4-氰基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸甲酯
2-苯甲酰基-4，5-(亚甲二氧基)-苯基乙酸(4)
使10g化合物2在50ml的1N氢氧化钠水溶液中的悬浮液回流2小时。然后添加10ml的1N硫酸水溶液，过滤出沉淀的固体，并用水重新洗涤。真空干燥产物4(8.3g)，而且无需纯制即用于以下步骤中。
1H-NMR(DMSO)δ＝3.68(s，2H，苄基CH2)，6.12(s，2H，OCH2O)，6.86和7.03(2s 1H，3-和6-H芳基)，7.50-7.73(m，5H，PhCO)，12，18(brs，1H，COOH)
熔点：185-189℃，燃烧分析：计算C67.60 H4.25
实测C67.66 H4.20
类似地制备以下化合物：
2-(4-氯-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸
2-(4-硝基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸
2-(4-甲氧基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸
2-(4-甲基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸
2-(4-氰基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸
2-苯甲酰基-4，5-(亚甲二氧基)-苯基乙酸-(3-氧代-丁-2-基酯)(5)
将50g的化合物4、19g的3-羟基-2-丁酮和32g的N，N′-羰基二咪唑在室温下溶解于500ml的二氯甲烷中，然后搅拌3天。处理时，与200ml的VE水混合，然后用二氯甲烷萃取。收集的有机相在旋转蒸发器中蒸发浓缩。由甲醇(2×)中结晶出粗产物，并得到45g的化合物5。
1H-NMR(CDCl3)δ＝1.32(d，3H，J＝6.9，CH3C-O)，2.11(s，3H，CH3C＝O)，3.88(s，2H，苄基CH2)，5.03(q，1H，J＝6.9，CH-O)，6.04(s，2H，OCH2O)，6.87和6.90(2s 1H，3-和6-H芳基)，7.42-7.74(m，5H，PhCO)
熔点：81-83℃ 燃烧分析：计算C67.79 H5.12
实测C67.83 H5.04
类似地制备以下化合物：
2-(4-氯-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸-(3-氧代-丁-2-基酯)
2-(4-硝基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸-(3-氧代-丁-2-基酯)
2-(4-甲氧基-苯甲酰基)-4，5-(亚甲二氧基)-苯基乙酸-(3-氧代-丁-2-基酯)
2-苯甲酰基-4，5-(亚甲二氧基)-苯基乙酸-(4-氧代-己-3-基酯)
2-苯甲酰基-4，5-(亚甲二氧基)-苯基乙酸-(2-氧代-1，2-二苯基-乙-1-基酯)
2-苯甲酰基-4，5-(亚甲二氧基)苄基-4，5-二甲基-噁唑(6)
将14ml的浓乙酸添加至10g的化合物5和19g的乙酸铵在200ml的1，2-二氯乙烷中的溶液内，然后加热回流该混合物6小时。接着，添加100ml的1N氢氧化钠水溶液，并用二氯甲烷萃取。合并的有机相在旋转蒸发器中旋转蒸发，并在硅胶上过滤粗产物(己烷∶乙酸乙酯9∶1-8∶2)。得到6.9g的纯化合物6(粘稠油状物)。
1H-NMR(CDCl3)δ＝1.94和2.03(2s 3H，2CH3)，4.13(s，2H，苄基CH2)，6.01(s，2H，OCH2O)，6.83和6.86(2s 1H，3-和6-H芳基)，7.41-7.80(m，5H，PhCO)
燃烧分析：计算C71.63 H5.11 N4.18
实测C71.47 H5.04 N3.97
类似地制备以下化合物：
2-(4-氯-苯甲酰基)-4，5-(亚甲二氧基)-苄基-4，5-二甲基-噁唑
2-(4-硝基-苯甲酰基)-4，5-(亚甲二氧基)-苄基-4，5-二甲基-噁唑
2-(4-甲氧基-苯甲酰基)-4，5-(亚甲二氧基)-苄基-4，5-二甲基-噁唑
2-苯甲酰基-4，5-(亚甲二氧基)-苄基-4，5-二乙基-噁唑
2-苯甲酰基-4，5-(亚甲二氧基)-苄基-4，5-二苯基-噁唑
2，3-二甲基-6-苯基-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c] [2，3]苯并二杂(1)
在高压釜中，将0.5ml的水合肼添加至2g化合物6在18ml乙二醇和2ml浓乙酸中的溶液内。加热12小时至120℃，然后在室温下使反应混合物与2N氢氧化钠水溶液混合。用乙酸乙酯萃取多次，然后在旋转蒸发器中彻底蒸发浓缩合并的有机相。粗产物用柱色谱纯制(己烷∶乙酸乙酯9∶1-8∶2)，得到1.2g的纯化合物1。
1H-NMR(DMSO)δ＝2.01和2.20(2s 3H，2 CH3)，3.82(brs，2H，苄基CH2)，6.08(s，2H，OCH2O)，6.55和7.15(2s 1H，2芳基-H)，7.48-7.72(m，5H，PhCO)
熔点：177℃
燃烧分析：计算C72.49 H5.18 N12.88
实测C72.33 H5.31 N12.46
类似地制备以下化合物：
2，3-二甲基-6-(4-氯-苯基)-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂
2，3-二甲基-6-(4-硝基-苯基)-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂草
2，3-二甲基-6-(4-甲氧基-苯基)-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂
2，3-二乙基-6-苯基-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂草
2，3-二苯基-6-苯基-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂
Claims (5)
1、制备通式1之咪唑并[1，2-c][2，3]苯并二氮杂的方法，
其中：
R1＝氢、C1-C6烷基、硝基、卤素、氰基、C1-C4烷氧基、-CF3、羟基或C1-C6烷酰基氧基，
R2和R3可相同或不同并代表氢、卤素、C1-C6烷氧基、羟基、氰基、C1-C6烷酰基、C2-C6炔基、C2-C6烯基，任选被卤素、羟基或C1-C6烷氧基取代的C1-C6烷基，C3-C7环烷基，或者任选被卤素、C1-C4烷氧基或C1-C4烷基取代的芳基或杂芳基，所述芳基或杂芳基为包含5-12个环原子的单环或二环基团，而且所述杂芳基中的环原子有1-3个是选自于硫、氧和氮的杂原子；
X＝氢或卤素，
Y＝C1-C6烷氧基，或者
X和Y一起代表-O-(CH2)n-O-，其中n＝1、2或3；
该方法是由通式4的苯基乙酸起始，
其中X、Y和R1的定义如上所述，
a)用式5a的醇进行酯化，
形成通式5的苯基乙基乙酸酯，
其中：X、Y、R1、R2和R3的定义如上所述，
b)与氨或氨供体进行缩合，形成通式6的噁唑，
其中：X、Y、R1、R2和R3的定义如上所述，随后进行肼解形成通式1的化合物：
其中：X、Y、R1、R2和R3的定义如上所述。
2、如权利要求1所述的方法，其中通式5的化合物在溶剂或溶剂混合物中于乙酸铵和氨或氨供体存在下使用单罐反应法在0-150℃的温度下反应，然后在0-200℃下与肼反应，任选在高压釜中，得到通式1的化合物。
3、如权利要求1或2所述的方法，其是制备以下化合物：
2，3-二甲基-6-苯基-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂
2，3-二甲基-6-(4-氯-苯基)-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂
2，3-二甲基-6-(4-硝基-苯基)-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂
2，3-二甲基-6-(4-甲氧基-苯基)-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂
2，3-二乙基-6-苯基-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂
2，3-二苯基-6-苯基-(12H)-[1，3]间二氧杂环戊烯并[4，5-h]咪唑并[1，2-c][2，3]苯并二杂。
4、通式5的苯基乙酸酯：
其中：
R1＝氢、C1-C6烷基、硝基、卤素、氰基、C1-C4烷氧基、-CF3、羟基或C1-C6烷酰基氧基，
R2和R3可相同或不同并代表氢、卤素、C1-C6烷氧基、羟基、氰基、C1-C6烷酰基、C2-C6炔基、C2-C6烯基，任选被卤素、羟基或C1-C6烷氧基取代的C1-C6烷基，C3-C7环烷基，或者任选被卤素、C1-C4烷氧基或C1-C4烷基取代的芳基或杂芳基，所述芳基或杂芳基为包含5-12个环原子的单环或二环基团，而且所述杂芳基中的环原子有1-3个是选自于硫、氧和氮的杂原子；
X＝氢或卤素，
Y＝C1-C6烷氧基，或者
X和Y一起代表-O-(CH2)n-O-，其中n＝1、2或3。
5、通式6的噁唑衍生物：
其中：
R1＝氢、C1-C6烷基、硝基、卤素、氰基、C1-C4烷氧基、-CF3、羟基或C1-C6烷酰基氧基，
R2和R3可相同或不同并代表氢、卤素、C1-C6烷氧基、羟基、氰基、C1-C6烷酰基、C2-C6炔基、C2-C6烯基，任选被卤素、羟基或C1-C6烷氧基取代的C1-C6烷基，C3-C7环烷基，或者任选被卤素、C1-C4烷氧基或C1-C4烷基取代的芳基或杂芳基，所述芳基或杂芳基为包含5-12个环原子的单环或二环基团，而且所述杂芳基中的环原子有1-3个是选自于硫、氧和氮的杂原子；
X＝氢或卤素，
Y＝C1-C6烷氧基，或者
X和Y一起代表-O-(CH2)n-O-，其中n＝1、2或3。
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|---|---|---|---|
| DE10041671.3 | 2000-08-10 | ||
| DE10041671A DE10041671C1 (de) | 2000-08-10 | 2000-08-10 | Verfahren zur Herstellung von Imidazo[1,2-c][2,3]benzodiazepinen sowie Phenylessigsäureester und Oxazol-Derivate als Zwischenprodukte bei deren Herstellung |
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| KR200453637Y1 (ko) * | 2009-06-23 | 2011-05-19 | (주)대양스톤 | 씽크대용 볼 고정장치 |
| CN104498543B (zh) * | 2015-01-22 | 2017-10-31 | 中国石油大学(华东) | 一种脂肪酶催化合成乙偶姻脂肪酸酯的方法 |
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| HUP9701325A1 (hu) | 1997-07-31 | 2000-08-28 | Gyógyszerkutató Intézet Kft. | Új 2,3-benzodiazepin-származékok |
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