CN1232023A - 异羟肟酸的制备方法 - Google Patents
异羟肟酸的制备方法 Download PDFInfo
- Publication number
- CN1232023A CN1232023A CN99104834A CN99104834A CN1232023A CN 1232023 A CN1232023 A CN 1232023A CN 99104834 A CN99104834 A CN 99104834A CN 99104834 A CN99104834 A CN 99104834A CN 1232023 A CN1232023 A CN 1232023A
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- CN
- China
- Prior art keywords
- aryl
- heteroaryl
- alkyl
- alkoxyl group
- amino
- Prior art date
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- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 239000002253 acid Substances 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims description 82
- 125000001072 heteroaryl group Chemical group 0.000 claims description 53
- -1 silyl halides Chemical class 0.000 claims description 38
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 20
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 9
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 6
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000003141 primary amines Chemical class 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 2
- 125000003277 amino group Chemical group 0.000 abstract 1
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- 239000000243 solution Substances 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- 239000000203 mixture Substances 0.000 description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 39
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 32
- 238000005406 washing Methods 0.000 description 22
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000012141 concentrate Substances 0.000 description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 229940124761 MMP inhibitor Drugs 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 10
- 238000010790 dilution Methods 0.000 description 10
- 239000012895 dilution Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 7
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 235000019260 propionic acid Nutrition 0.000 description 7
- 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 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- KHBRCHARZCVROM-UHFFFAOYSA-N benzyl 4-aminooxane-4-carboxylate Chemical compound C=1C=CC=CC=1COC(=O)C1(N)CCOCC1 KHBRCHARZCVROM-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- DNBHXBWIWOADBL-UHFFFAOYSA-N benzyl cyclopentanecarboxylate Chemical compound C1CCCC1C(=O)OCC1=CC=CC=C1 DNBHXBWIWOADBL-UHFFFAOYSA-N 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
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- PDAYRCHIAPCRRD-UHFFFAOYSA-N 4-(4-fluorophenoxy)benzenesulfonyl chloride Chemical compound C1=CC(F)=CC=C1OC1=CC=C(S(Cl)(=O)=O)C=C1 PDAYRCHIAPCRRD-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001447 alkali salts Chemical class 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
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- 230000002829 reductive effect Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000018594 Tumour necrosis factor Human genes 0.000 description 3
- 108050007852 Tumour necrosis factor Proteins 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 208000007474 aortic aneurysm Diseases 0.000 description 3
- KFNIDRLZPBRDNJ-UHFFFAOYSA-N benzyl 2-(benzhydrylideneamino)acetate Chemical compound C=1C=CC=CC=1COC(=O)CN=C(C=1C=CC=CC=1)C1=CC=CC=C1 KFNIDRLZPBRDNJ-UHFFFAOYSA-N 0.000 description 3
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- 238000003818 flash chromatography Methods 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
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- 125000004076 pyridyl group Chemical group 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
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- 235000011121 sodium hydroxide Nutrition 0.000 description 3
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- 125000001544 thienyl group Chemical group 0.000 description 3
- HGMRCAGQEDXAGL-UHFFFAOYSA-N 1-[(3-ethoxy-3-oxopropyl)-[4-(4-fluorophenoxy)phenyl]sulfonylamino]cyclopentane-1-carboxylic acid Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)N(CCC(=O)OCC)C1(C(O)=O)CCCC1 HGMRCAGQEDXAGL-UHFFFAOYSA-N 0.000 description 2
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
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- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
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- 239000002798 polar solvent Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
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- 125000003373 pyrazinyl group Chemical group 0.000 description 2
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- SZXIMJCHKWYCHX-UHFFFAOYSA-N 2-aminoethyl propanoate Chemical compound CCC(=O)OCCN SZXIMJCHKWYCHX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- QAMMMKJJVLYVAR-UHFFFAOYSA-N 4-(4-fluorophenoxy)benzenethiol Chemical compound C1=CC(F)=CC=C1OC1=CC=C(S)C=C1 QAMMMKJJVLYVAR-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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Abstract
本发明涉及一种由羧酸中间体制备异羟肟酸的方法,其中所述羧酸中间体不具有活性取代基例如羟基或氨基。
Description
本发明涉及一种由羧酸中间体制备异羟肟酸的方法,其中所述羧酸中间体不具有活性取代基例如羟基或氨基。
众所周知,基质金属蛋白酶(MMP)抑制剂可用于治疗下列病症,所述病症包括关节炎(例如骨关节炎和类风湿性关节炎)、肠炎疾病、节段性回肠炎、肺气肿、急性呼吸窘迫综合症、哮喘、慢性梗阻性肺病、早老性痴呆、器官移植毒性、恶病质、过敏反应、过敏接触型超敏反应、癌症、组织溃疡、再狭窄、牙周疾病、大疱性表皮松懈、骨质疏松症、人工关节植入松弛、动脉粥样硬化(包括动脉粥样硬化斑破裂)、主动脉瘤(包括腹主动脉瘤和颅内主动脉瘤)、充血性心力衰竭、心肌梗塞形成、中风、大脑缺血、脑外伤、脊髓损伤、神经变性疾病(急性和慢性)、自身免疫疾病、亨廷顿舞蹈病、帕金森病、偏头痛、抑郁症、外周神经病变、疼痛、大脑淀粉样血管病、向精神性或认知增强、肌萎缩性侧索硬化、多发性硬化、眼血管发生、角膜损伤、黄斑变性、非正常伤口愈合、烧伤、糖尿病、肿瘤侵袭、肿瘤生长、肿瘤转移、角膜伤疤、巩膜炎、艾滋病、脓毒病、败血病性休克以及具有抑制金属蛋白酶或ADAM(包括TNF-α)表达特征的其他疾病。另外,由本发明所述化合物和方法制备的所述产物可以与常规非类固醇类抗炎药(下文称作NSAID)、COX-2抑制剂和用于治疗关节炎的镇痛剂一起以结合治疗方式使用,并且在治疗癌症中,可以与细胞毒素药物例如阿霉素、柔毛霉素、顺铂、依托赛特、紫杉醇、taxotere和生物碱例如长春新碱结合使用。
基质金属蛋白酶抑制剂在文献中早已公知。特别是,公开于1996年10月24日的PCT申请公开WO 96/33172涉及用作MMP抑制剂的环状芳基磺酰氨基异羟肟酸类化合物。美国专利5,672,615、PCT申请公开WO 97/20824、PCT申请公开WO 98/08825、PCT申请公开WO 98/27069和公开于1998年8月13日的名称为“芳基磺酰基异羟肟酸衍生物”的PCT申请公开WO 98/34918均涉及用作MMP抑制剂的环状异羟肟酸类化合物。分别公开于1996年3月7日和1998年2月26日的PCT申请公开WO 96/27583和WO 98/07697涉及芳基磺酰基异羟肟酸类化合物。公开于1998年1月29日的PCT申请公开WO 98/03516涉及具有MMP活性的磷酸酯。公开于1998年8月13日、名称为“N-羟基-β-磺酰基丙酰胺衍生物”的PCT申请公开WO 98/34915涉及用作MMP抑制剂的丙酰基异羟肟酸类化合物。公开于1998年8月6日、名称为“芳基磺酰氨基异羟肟酸衍生物”的PCT申请公开WO 98/33768涉及N-未被取代的芳基磺酰氨基异羟肟酸类化合物。公开于1998年6月16日、名称为“环状砜衍生物”的PCT申请公开WO 98/30566涉及用作MMP抑制剂的环状砜异羟肟酸类化合物。1997年8月8日提交的美国临时专利申请60/55208涉及用作MMP抑制剂的二芳基异羟肟酸类化合物。1997年8月8日提交、名称为“芳氧基芳基磺酰氨基异羟肟酸衍生物”的美国临时专利申请60/55207涉及用作MMP抑制剂的芳氧基芳基磺酰基异羟肟酸类化合物。上述每一篇相关公开内容和申请全文作为本文参考文献。
本发明涉及一种含异羟肟酸基团的分子的制备方法,所述方法包括在碱存在下,将羟胺或其盐与((C1-C6)烷基)3甲硅烷基卤化物,优选((C1-C6)烷基)3甲硅烷基氯化物反应,随后与含酰卤化物的分子反应,随后与酸反应,条件是所述含酰卤化物的分子不含羟基、伯胺、仲胺或巯基。
Z是>CH2或>NR1;
Q是(C1-C6)烷基、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳氧基(C1-C6)烷基、(C6-C10)芳氧基(C6-C10)芳基、(C6-C10)芳氧基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C2-C9)杂芳基、(C6-C10)芳基(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C6-C10)芳基(C2-C9)杂芳基、(C2-C9)杂芳基(C1-C6)烷基、(C2-C9)杂芳基(C6-C10)芳基、(C2-C9)杂芳基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C2-C9)杂芳基、(C2-C9)杂芳氧基(C1-C6)烷基、(C2-C9)杂芳氧基(C6-C10)芳基、(C2-C9)杂芳氧基(C2-C9)杂芳基、(C2-C9)杂芳基(C1-C6)烷氧基(C1-C6)烷基、(C2-C9)杂芳基(C1-C6)烷氧基(C6-C10)芳基或(C2-C9)杂芳基(C1-C6)烷氧基(C2-C9)杂芳基;
其中所述(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳氧基(C1-C6)烷基、(C6-C10)芳氧基(C6-C10)芳基、(C6-C10)芳氧基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C2-C9)杂芳基、(C6-C10)芳基(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C6-C10)芳基(C2-C9)杂芳基、(C2-C9)杂芳基(C1-C6)烷基、(C2-C9)杂芳基(C6-C10)芳基、(C2-C9)杂芳基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C2-C9)杂芳基、(C2-C9)杂芳氧基(C1-C6)烷基、(C2-C9)杂芳氧基(C6-C10)芳基、(C2-C9)杂芳氧基(C2-C9)杂芳基、(C2-C9)杂芳基(C1-C6)烷氧基(C1-C6)烷基、(C2-C9)杂芳基(C1-C6)烷氧基(C6-C10)芳基或(C2-C9)杂芳基(C1-C6)烷氧基(C2-C9)杂芳基中的每个(C6-C10)芳基或(C2-C9)杂芳基基团可以任选地在能另外成键的所述环碳原子上每个环被独立地选自下列的一个或多个取代基任意取代,所述取代基选自氟、氯、溴、(C1-C6)烷基、(C1-C6)烷氧基、全氟代(C1-C3)烷基、全氟代(C1-C3)烷氧基和(C6-C10)芳氧基;
R1是氢、(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷基、(C2-C9)杂芳基(C1-C6)烷基或下式基团
其中所述星号表示R2和R3的共用碳原子;
而R4是(C1-C6)烷基;
n是1-6的整数;
所述方法包括:
a)在第一种碱(优选吡啶、2,6-二甲基吡啶或二异丙基乙基胺)存在下,于溶剂(优选吡啶)中,将羟胺或其盐与((C1-C6)烷基)3甲硅烷基卤化物,优选三甲基甲硅烷基氯化物反应,就地形成((C1-C6)烷基)3甲硅烷基化的羟胺,
b)将所述就地形成的((C1-C6)烷基)3甲硅烷基化的羟胺与下式化合物反应
其中R7是((C1-C6)烷基)3-Si-而R8是氢或((C1-C6)烷基)3-Si-,和
c)用酸水解所述式Ⅵ化合物。
本文所用术语“烷基”,除非另有说明,包括含有直链、支链或环状或者其组合的饱和一价烃基基团。
本文所用术语“烷氧基”包括其中“烷基”如上定义的0-烷基基团。
本文所用术语“芳基”,除非另有说明,包括由芳香烃通过除去一个氢衍生的有机基团,例如苯基或萘基。
本文所用术语“杂芳基”,除非另有说明,包括由芳族杂环化合物通过除去一个氢衍生的有机基团,例如吡啶基、呋喃基、吡咯基、噻吩基、异噻唑基、咪唑基、苯并咪唑基、四唑基、吡嗪基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吡唑基、吲哚基、异吲哚基、嘌呤基、咔唑基、异噁唑基、噻唑基、噁唑基、苯并噻唑基或苯并噁唑基。优选的杂芳基包括吡啶基、呋喃基、噻吩基、异噻唑基、吡嗪基、嘧啶基、吡唑基、异噁唑基、噻唑基或噁唑基。最优选的杂芳基包括吡啶基、呋喃基或噻吩基。
本文所用术语“酰基”,除非另有说明,包括通式R-(C=O)-基团,其中R是烷基、烷氧基、芳基、芳烷基或芳烷氧基并且所述术语“烷基”或“芳基”如上定义。
本文所用术语“酰氧基”包括O-酰基基团,其中“酰基”如上定义。
所述式Ⅰ-Ⅵ化合物可能含有手性中心并因此可以以不同的非对映异构体或对映体形式存在。本发明涉及所有式Ⅰ-Ⅵ化合物的光学异构体和立体异构体及其混合物。优选的是,式Ⅰ’化合物以下式外型异构体形式存在
下列反应路线阐明了本发明所述化合物的制备方法。除非另有说明,反应路线及下文讨论部分中n、R1、R2、R3、R4、R5、Q和Z如上定义。
反应路线2
反应路线1涉及式Ⅰ基质金属蛋白酶化合物的制备。
如反应路线1所示,式Ⅰ化合物可由式Ⅷ羟胺(其中R9是氯化氢、硫化氢或者R9不存在)制备。具体地讲,在碱存在下,将式Ⅷ化合物与((C1-C4)烷基)3甲硅烷基卤化物反应,就地形成式Ⅶ化合物,其中R7是((C1-C6)烷基)3-Si-而R8是氢或((C1-C6)烷基)3-Si-。适宜的((C1-C6)烷基)3甲硅烷基卤化物包括三甲基甲硅烷基氯化物、三乙基甲硅烷基氯化物、三甲基甲硅烷基碘化物、三乙基甲硅烷基碘化物、三甲基甲硅烷基溴化物、叔丁基二甲基甲硅烷基氯化物或三乙基甲硅烷基溴化物,优选三甲基甲硅烷基氯化物。适宜的碱包括吡啶、2,6-二甲基吡啶或二异丙基乙基胺,优选吡啶。所述反应在约0℃至约22℃(例如室温)温度下进行约1小时至约12小时,优选约1小时。
然后,在碱存在下,将就地形成的式Ⅶ化合物与反应路线2所得式Ⅱ化合物或式Ⅴ化合物的酰氯化物反应,就地形成式Ⅵ化合物,其中R2、R3、R7、R8和Q如上定义并且Z是>NR1。适宜的碱包括吡啶、2,6-二甲基吡啶或二异丙基乙基胺,优选吡啶。所述反应在约0℃至约22℃(例如室温)温度下进行约1小时至约12小时,优选约1小时。
通过酸水解,将式Ⅵ化合物转变成式Ⅰ化合物,其中Z是>NR1。适宜的酸包括盐酸或硫酸,优选盐酸。所述反应在约0℃至约22℃(例如室温)温度下进行约1小时至约12小时,优选约1小时。
另外,其中Z是-(CH2)-的式Ⅰ化合物可通过将下式化合物与式Ⅶ化合物反应制备
其中R2和R3和Q如上定义。式Ⅸ化合物可通过本领域普通技术人员公知的方法制备。
反应路线2涉及在反应路线1所述方法中用作制备式Ⅰ化合物中间体的式Ⅱ化合物的制备。
如反应路线2所示,在惰性溶剂例如二氯甲烷或甲苯中,通过与草酰氯或亚硫酰氯,优选草酰氯,和催化剂,优选约2%N,N-二甲基甲酰胺反应,由其中R10是氢的式Ⅲ化合物制得式Ⅱ化合物。上述反应在约0℃(例如室温)至约70℃,优选约20℃至约50℃,最优选约20℃温度下进行。上述反应进行约1-7小时,优选约2小时。
其中R10是氢的式Ⅲ化合物可通过在极性溶剂中的还原反应由其中R6是任意取代的苄基的式Ⅳ化合物制备。适宜的还原剂包括钯催化还原反应例如氢/钯、氢/钯/碳或氢氧化钯/碳,优选氢/钯/碳。适宜的溶剂包括四氢呋喃、甲醇、乙醇和异丙醇及其混合物,优选乙醇。上述反应在约22℃(即室温)温度下进行1-7天,优选约2天。
式Ⅲ化合物(其中R10不为氢,例如质子化的胺(如质子化的伯胺、仲胺或叔胺)、碱金属或碱土金属)可通过用含可接受的阳离子(例如钠、钾、二环己基胺、钙和镁,优选二环己基胺)的水溶液或碱性溶液处理,然后将所得溶液蒸发至干,优选在减压条件下或者过滤沉淀物,优选的是二环己基胺盐沉淀,由式Ⅲ化合物(其中R10是氢)制备。
式Ⅳ化合物可通过在碱存在下于极性溶剂中丙炔酸酯的迈克尔加成反应由式Ⅴ化合物(其中R6是被任意取代的苄基)制备。适宜的丙炔酯是式H-C≡C-CO2R4(其中R4是(C1-C6)烷基)化合物。适宜的碱包括四丁基氟化铵、碳酸钾、叔胺和碳酸铯,优选四丁基氟化铵。适宜溶剂包括四氢呋喃、乙腈、叔丁醇、叔戊醇和N,N-二甲基甲酰胺,优选四氢呋喃。上述反应在约-10℃至约60℃,优选0℃至约22℃(即室温)温度范围内进行。式Ⅳ化合物可以烯烃双键的几何异构体混合物形式获得;不必分离异构体。
式Ⅴ化合物(其中R2和R3是四氢吡喃-4-基或下式双环
其中所述星号表示R2和R3的共用碳原子)可按照实施例3和4所述相似方法制备。
式Ⅴ化合物(其中R6是被任意取代的苄基)可按照本领域公知方法制备。此类制备方法的实例包括在下列公开文件和申请文件中。基质金属蛋白酶抑制剂是文献中早已公知的。特别是,公开于1996年10月24日的PCT申请公开WO 96/33172涉及用作MMP抑制剂的环状芳基磺酰氨基异羟肟酸类化合物。美国专利5,672,615、PCT申请公开WO 97/20824、PCT申请公开WO 98/08825、PCT申请公开WO 98/27069和公开于1998年8月13日、名称为“芳基磺酰基异羟肟酸衍生物”的PCT申请公开WO 98/34918均涉及用作MMP抑制剂的环状异羟肟酸类化合物。分别公开于1996年3月7日和1998年2月26日的PCT申请公开WO 96/27583和WO 98/07697涉及芳基磺酰基异羟肟酸类化合物。公开于1998年1月29日的PCT申请公开WO 98/03516涉及具有MMP活性的磷酸酯。公开于1998年8月13日、名称为“N-羟基-β-磺酰基丙酰胺衍生物”的PCT申请公开WO 98/34915涉及用作MMP抑制剂的丙酰基异羟肟酸类化合物。公开于1998年8月6日、名称为“芳基磺酰氨基异羟肟酸衍生物”的PCT申请公开WO 98/33768涉及N-未被取代的芳基磺酰氨基异羟肟酸类化合物。公开于1998年7月16日、名称为“环状砜衍生物”的PCT申请公开WO 98/30566涉及用作MMP抑制剂的环状砜异羟肟酸类化合物。1997年8月8日提交的美国临时专利申请60/55208涉及用作MMP抑制剂的二芳基异羟肟酸类化合物。1997年8月8日提交、名称为“芳氧基芳基磺酰氨基异羟肟酸衍生物”的美国临时专利申请60/55207涉及用作MMP抑制剂的芳氧基芳基磺酰基异羟肟酸类化合物。上述每一篇相关公开和申请全文作为本文参考文献。
实际上为碱性的式Ⅰ化合物可与各种无机酸或有机酸形成各种不同类型的盐。尽管此类盐对于给动物施用时必须是药物上可接受的,但实际上通常希望由反应混合物中开始分离出的式Ⅰ化合物是非药物上可接受的盐,然后通过用碱性试剂处理将后者很容易地转变成游离碱化合物,随后再将所述游离碱转变成药物上可接受的酸加成盐。本发明碱性化合物的酸加成盐通过在含水溶剂介质或者适宜的有机溶剂例如甲醇或乙醇中,用基本上等量的所选用的无机酸或有机酸处理所述碱性化合物容易地制备。小心地将溶剂蒸发后,可得到所需固体盐。
可用于制备本发明所述碱性化合物药物上可接受的酸加成盐的酸是那些可形成无毒酸加成盐的酸,即含生理上可接受的阴离子盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐或硫酸氢盐、磷酸盐或酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐或酸式柠檬酸盐、酒石酸盐或酒石酸氢盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、甲磺酸盐和扑酸盐(pamoate)[即1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐)]。
实际上也可以是酸性的式Ⅰ化合物能与各种生理上可接受的阳离子形成碱盐。此类盐的实例包括碱金属或碱土金属盐并且特别是钠盐和钾盐。此类盐均可通过常规方法制备。可用于制备本发明药物上可接受的碱盐的化学碱试剂是可与本文所述式Ⅰ酸性化合物形成无毒碱盐的试剂。这些无毒碱盐包括由例如钠、钾、钙和镁等药理上可接受的阳离子衍生的盐。这些盐可以通过用含所需药理上可接受的阳离子的水溶液处理相应的酸性化合物,然后优选在减压下将所得溶液蒸干很容易地制备。另外,它们也可以通过将所述酸性化合物的低级链烷醇溶液与所需链烷醇碱金属盐混合,然后如上述相同方法将所得溶液蒸干制得。在每一种情况下,为了确保反应完全以及产生最多的产物,优选使用化学计算量的试剂。
式Ⅰ化合物或其药物上可接受的盐(下文称作活性化合物)可抑制基质金属蛋白酶或者肿瘤坏死因子(TNF)的产生,并因此表明,它们可有效地治疗本领域普通技术人员按照公知的体外试验确定的以基质金属蛋白酶或者肿瘤坏死因子产生为特征的各种疾病。
下列实施例阐明了本发明所述化合物的制备方法。熔点未校正。NMR数据以每百万分之几(δ)计并且相应于样品溶剂(氘代氯仿,除非另有所指)氘锁峰信号。市售试剂无需纯化使用。THF指四氢呋喃。DMF指N,N-二甲基甲酰胺。色谱法指用32-63mm硅胶并在氮气压(快速色谱)条件下进行的柱色谱。室温或环境温度指20-25℃。为了方便并且为了获得最大产率,所有无水反应均在氮气氛下进行。减压浓缩是指用旋转蒸发仪进行。实施例1
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)-氨基]-丙酸
A)1-[4-(4-氟苯氧基)苯磺酰基氨基]环戊烷羧酸苄基酯
向12.41g(0.032mol)1-氨基环戊烷羧酸苄基酯、甲苯-4-磺酸盐(可按照美国专利4,745,124中所述方法制备)和10.0g(0.035mol,1.1当量)4-(4-氟苯氧基)苯磺酰氯在113ml甲苯中的混合物中加入11.0ml(0.079mol,2.5当量)三乙胺。反应混合物于环境温度下搅拌过夜,用2N盐酸(2×100ml)和盐水(100ml)洗涤,用硫酸钠干燥并浓缩至30ml。在3小时内滴加149ml己烷,得到固体沉淀,将其在0℃下制粒1小时并过滤,得到12.59g(85%)1-[4-(4-氟苯氧基)苯磺酰基氨基]环戊烷羧酸苄基酯。
1H NMR(CDCl3)δ7.78-7.82(m,2H),7.30-7.39(m,5H),7.06-7.12(m,2H),6.99-7.04(m,2H),6.93-6.97(m,2H),5.15(s,1H),5.02(s,2H),2.04-2.13(m,2H),1.92-1.98(m,2H),1.62-1.69(m,4H).
将4.0g样品在4ml乙酸乙酯和40ml己烷的混合物中制粒过夜,得到3.72g(回收率93%)浅褐色固体状1-[4-(4-氟苯氧基)苯磺酰基氨基]环戊烷羧酸苄基酯,mp 97.0-97.5℃。
B)1-{(2-乙氧羰基乙烯基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-环戊烷-羧酸苄基酯
将25.0g(53.2mmol)1-[4-(4-氟苯氧基)苯磺酰基氨基]环戊烷羧酸苄基酯和10.8ml(106mmol,2当量)丙炔酸乙酯的200ml无水四氢呋喃溶液于1℃下用53.2ml(53.2mmol,1当量)的四丁基氟化铵的四氢呋喃溶液(1M)处理45分钟。令所得溶液缓慢温热至环境温度并搅拌过夜。减压下用甲苯替代四氢呋喃并将甲苯溶液用水和盐水洗涤,用甲苯稀释至600ml,与90g硅胶一起搅拌3小时,过滤并浓缩,得到25.14g(83%)橙色油状1-{(2-乙氧羰基乙烯基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-环戊烷羧酸苄基酯。1H NMR(CDCl3)表明反/顺比为1.5∶1。
反式δ7.74-7.78(m,2H),7.72(d,J=14Hz,1H),7.26-7.36(m,5H),6.96-7.12(m,4H),6.78-6.84(m,2H),5.44(d,J=14Hz,1H),5.11(s,2H),4.12(q,J=7.1 Hz,2H),2.08-2.43(m,4H),1.63-1.80(m,4H),1.24(t,J=7.1Hz,3H).顺式δ7.68-7.72(m,2H),7.26-7.36(m,5H),6.96-7.12(m,4H),6.86-6.91(m,2H),6 47(d,J=8.1Hz,1H),5.90(d,J=8.1Hz,1H),5.11(s,2H),3.93(q,J=7.2 Hz,2H),2.08-2.43(m,4H),1.63-1.80(m,4 H),1.1 7(t,J=7.2Hz,3H).
C)1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-环戊烷-羧酸
将2.50g(4.4mmol)1-{(2-乙氧羰基乙烯基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸苄基酯的25ml乙醇溶液用2.5g 50%水润湿的10%钯/碳催化剂处理并在53psi氢气压下振荡21小时。滤除催化剂并用乙醇(4×25ml)洗涤。将滤液和洗液合并并真空浓缩,得到1.74g(82%)粘性油状1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸粗产物。
1H NMR(CDCl3)δ7.78-7.82(m,2H),6.94-7.09(m,6H),4.09(q,J=7.2Hz,2H).3.56-3.60(m,2H),2.75-2.79(m,2H),2.33-2.39(m,2H),1.93-2.03(m,2H),1.69-1.76(m,2H),1.56-1.63(m,2H),1.22(t,J=7.2Hz,3H).
D)1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-环戊烷-羧酸,二环己基铵盐
于环境温度下,将3.10g(6.5mmol)1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸粗产物的30ml乙醇溶液用1.28ml(6.5mmol,1当量)二环己基胺处理,5分钟内有固体生成。将此混合物于环境温度下搅拌过夜并于0℃下搅拌5小时。过滤分离出白色固体,用10ml冷乙醇洗涤并空气干燥,得到2.89g(67%)1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸,二环己基铵盐。
1H NMR(CDCl3)δ7.86-7.91(m,2H),6.99-7.09(m,4H),6.90-6.94(m,2H),5.3(brs,2H),4.07(q,J=7.1Hz,2H),3.54-3.59(m,2H),2.88-2.95(m,4H),2.31-2.38(m,2H),1.95-2.22(m,6H),1.68-1.77(m,6H),1.53-1.60(m,4H),1.40-1.50(m,4H),1.21(t,J=7.1Hz,3H),1.14-1.22(m,6H).Mp164.5-165.9℃.
E)1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-环戊烷-羧酸
于环境温度下,将3.0g(4.5mmol)1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸,二环己基铵盐的30ml二氯甲烷溶液用30ml 2N盐酸处理,立即生成固体沉淀。将此混合物于环境温度下搅拌3小时。将固体过滤,水相用二氯甲烷萃取,并将合并的有机相用水洗涤,硫酸钠干燥,并真空浓缩,得到2.2g(100%)透明油状1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸。
1H NMR(DMSO-d6)δ12.68(bs,1H),7.76-7.80(m,2H),7.25-7.31(m,2H),7.16-7.21(m,2H),7.03-7.08(m,2H),4.01(q,J=7.1Hz,2H),3.48-3.54(m,2H),2.64-2.70(m,2H),2.13-2.21(m,2H),1.90-1.98(m,2H),1.52-1.59(m,4H),1.14(t,J=7.1Hz,3H).
F)3-{(1-氯羰基环戊基)-[4-(4-氟苯氧基)苯磺酰基]氨基}丙酸乙酯
于环境温度下,将7.26g(15.1mmol)1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸的73ml二氯甲烷溶液用1.4ml(17mmol,1.1当量)草酰氯和0.02ml(0.3mmol,0.02当量)二甲基甲酰胺处理,产生一些气泡,并搅拌过夜。无需分离,将所得3-{(1-氯羰基环戊基)-[4-(4-氟苯氧基)苯磺酰基]氨基}丙酸乙酯用于制备3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯。
将用相似方法制备的3-{(1-氯羰基环戊基)-[4-(4-氟苯氧基)苯磺酰基]氨基}丙酸乙酯溶液真空浓缩,得到一油状物。
1H NMR(CDCl3)δ7.84-7.87(m,2H),6.97-7.12(m,6H),4.10(q,J=7.2Hz,2H),3.55-3.59(m,2H),2.68-2.72(m,2H),2.47-2.53(m,2H),1.95-2.02(m,2H),1.71-1.76(m,4H),1.24(t,J=7.2Hz,3H).
G)3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯
于0℃下,将1.37g(19.7mmol,1.3当量)羟胺盐酸盐的9.2ml(114mmol,7.5当量)无水吡啶溶液用5.8ml(45mmol,3.0当量)三甲基甲硅烷基氯化物处理,沉淀出白色固体,并令其温热至环境温度过夜。将此混合物冷却至0℃并用如上所述无需分离制备的7.54g(15.1mmol)3-{(1-氯羰基环戊基)-[4-(4-氟苯氧基)苯磺酰基]氨基}丙酸乙酯的73ml二氯甲烷溶液处理,引起放热至8℃。将此混合物于0℃下搅拌30分钟并于环境温度下搅拌1小时,之后用50ml 2N盐酸水溶液处理并于环境温度下搅拌1小时。水相用二氯甲烷萃取,合并的有机相用2N盐酸水溶液(2×50ml)和水(50ml)洗涤。无需分离,将此3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯的二氯甲烷溶液用于制备3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸。将一等分式样浓缩,得到一泡沫状物。
1H NMR(DMSO-d6)δ10.37(s,1H),8.76(s,1H),7.74-7.79(m,2H),7.24-7.30(m,2H),7.14-7.20(m,2H),7.01-7.05(m,2H),3.99(q,J=7.1Hz,2H),3.42-3.47(m,2H),2.62-2.67(m,2H),2.16-2.23(m,2H),1.77-1.85(m,2H),1.43-1.52(m,4H),1.13(t,J=7.1Hz,3H).
将相似方法制备的溶液真空浓缩,得到6.71g(89%)干硬的泡沫状3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯。
H)3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸
将7.48g(15.1mmol)3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯的二氯甲烷溶液在加入75ml甲苯后进行旋转蒸发浓缩。此溶液用75ml水处理,冷却至0℃并在剧烈搅拌下用6.05g(151mmol,10当量)氢氧化钠颗粒处理10分钟。将混合物于0℃下搅拌15分钟并在1小时内温热至环境温度。分离水相,用7.5ml四氢呋喃稀释,冷却至0℃并用33ml 6N盐酸水溶液处理20分钟。在0℃至环境温度下,将此混合物与75ml乙酸乙酯一起搅拌,分离出乙酸乙酯相并用水洗涤。于环境温度下,将乙酸乙酯溶液缓慢地用150ml己烷处理,有固体沉淀生成,并搅拌过夜。过滤,得到5.0lg白色固体状3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸(由1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸开始所得产率为71%)。
1H NMR(DMSO-d6)δ12.32(s,1H).10.43(s,1H),8.80(s,1H),7.82(d,J=8.6Hz,2H),7.28-7.35(m,2H),7.20-7.26(m,2H),7.08(d,J=8.9Hz,2H),3.44-3.49(m,2H),2.61-2.66(m,2H),2.24-2.29(m,2H),1.86-1.90(m,2H),1.54-1.55(m,4H).Mp162.9-163.5℃(dec).实施例2
3-[[4-(4-氟苯氧基)苯磺酰基]-(4-羟基氨基甲酰基四氢吡喃-4-基)氨基]丙酸
A)4-[N-(二苯亚甲基)氨基]四氢吡喃-4-羧酸苄基酯
于0℃下,经滴液漏斗向氢化钠(6.56g,0.164mol)的乙二醇二甲醚(150ml)悬浮液中滴加N-(二苯亚甲基)甘氨酸苄基酯(0.07398mol)乙二醇二甲醚(50ml)溶液。然后在约5分钟内,以每10ml一份向所述乙二醇二甲醚溶液中加入2-溴乙醚(23.21g,0.090mol)的乙二醇二甲醚(50ml)溶液。除去冰浴,反应在室温下搅拌16小时。混合物用乙醚稀释并用水洗涤,水层用乙醚萃取。合并的有机萃取液用盐水洗涤,硫酸镁干燥并浓缩,得到粗产物。于硅胶上进行色谱纯化,首先用4L 5%乙酸乙酯/己烷洗脱,然后用4L 10%乙酸乙酯/己烷洗脱,得到透明黄色油状4-[N-(二苯亚甲基)氨基]四氢吡喃-4-羧酸苄基酯。
B)4-氨基四氢吡喃-4-羧酸苄基酯
向4-[N-(二苯亚甲基)氨基]四氢吡喃-4-羧酸苄基酯(16.0g,0.047mol)的乙醚(120ml)溶液中加入1M盐酸水溶液(100ml)。混合物于室温下剧烈搅拌16小时,分层并将水层用乙醚洗涤。水层用稀氢氧化铵水溶液调至pH10并用二氯甲烷萃取。将有机萃取液用硫酸钠干燥并浓缩,得到4-氨基四氢吡喃-4-羧酸苄基酯。
C)4-[4-(4-氟苯氧基)苯磺酰基氨基]四氢吡喃-4-羧酸苄基酯
向4-氨基四氢吡喃-4-羧酸苄基酯(0.0404mol)的N,N-二甲基甲酰胺(40ml)溶液中加入三乙胺(5.94ml,0.043mol)。向上述溶液中分批加入4-(4-氟苯氧基)苯磺酰氯固体(12.165g,0.0424mol),所得混合物于室温下搅拌16小时并在真空下蒸发除去大部分溶剂。残余物于饱和碳酸氢钠溶液和二氯甲烷之间配分,分出水层并用二氯甲烷萃取。合并的有机层用盐水洗涤并用硫酸钠干燥。真空蒸除溶剂,得到4-[4-(4-氟苯氧基)苯磺酰基氨基]四氢吡喃-4-羧酸苄基酯粗产物。于硅胶上进行快速色谱纯化,用25%乙酸乙酯/己烷,随后用50%乙酸乙酯/己烷洗脱,得到4-[4-(4-氟苯氧基)苯磺酰基氨基]四氢吡喃-4-羧酸苄基酯。
D)4-{(2-乙氧羰基乙烯基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-四氢吡喃-4-羧酸苄基酯
将上述步骤所述产物(53.2mmol)和10.8ml(106mmol,2当量)丙炔酸乙酯的200ml无水四氢呋喃溶液于1℃下用53.2ml(53.2mmol,1当量)的四丁基氟化铵的四氢呋喃溶液(1M)处理45分钟。令所得溶液缓慢温热至环境温度并搅拌过夜。减压下用甲苯替代四氢呋喃并将甲苯溶液用水和盐水洗涤,用甲苯稀释至600ml,与90g硅胶一起搅拌3小时,过滤并浓缩,得到所述标题化合物。
E)4-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-四氢吡喃-4-羧酸
将步骤D所述产物(4.4mmol)的25ml乙醇溶液用2.5g 50%水润湿的10%钯/碳催化剂处理并在53psi氢气压下振荡21小时。滤除催化剂并用乙醇(4×25ml)洗涤。将滤液和洗液合并并真空浓缩,得到粗产物。
F)3-{(4-氯羰基四氢吡喃-4-基)-[4-(4-氟苯氧基)苯磺酰基]氨基}丙酸乙酯
于环境温度下,将步骤E所述产物(15.1mmol)的73ml二氯甲烷溶液用1.4ml(17mmol,1.1当量)草酰氯和0.02ml(0.3mmol,0.02当量)二甲基甲酰胺处理,产生一些气泡,并搅拌过夜。无需分离,将所得所述标题化合物溶液用于下一步骤。
G)3-[[4-(4-氟苯氧基)苯磺酰基]-(4-羟基氨基甲酰基四氢吡喃-4-基)氨基]丙酸乙酯
于0℃下,将羟胺盐酸盐(19.7mmol,1.3当量)的9.2ml(114mmol,7.5当量)无水吡啶溶液用5.8ml(45mmol,3.0当量)三甲基甲硅烷基氯化物处理,沉淀出白色固体,并令混合物温热至环境温度过夜。然后将此混合物冷却至0℃并用步骤F所述产物(15.1mmol)的73ml二氯甲烷溶液处理,引起放热至8℃。将此混合物于0℃下搅拌30分钟并于环境温度下搅拌约1小时,然后用50ml2N盐酸水溶液处理并于环境温度下搅拌1小时。水相用二氯甲烷萃取,合并的有机相用2N盐酸水溶液(2×50ml)和水(50ml)洗涤。将所述标题化合物的此二氯甲烷溶液用于下一步骤。
H)3-[[4-(4-氟苯氧基)苯磺酰基]-(4-羟基氨基甲酰基四氢吡喃-4-基)氨基]丙酸
将步骤G所述产物(15.1mmol)的二氯甲烷溶液在加入75ml甲苯后进行旋转蒸发浓缩。此溶液用75ml水处理,冷却至0℃并在剧烈搅拌下用6.05g(151mmol,10当量)氢氧化钠颗粒处理10分钟。将混合物于0℃下搅拌1 5分钟并在1小时内温热至环境温度。分离水相,用7.5ml四氢呋喃稀释,冷却至0℃并用33ml 6N盐酸水溶液处理20分钟。在0℃至环境温度下,将此混合物与75ml乙酸乙酯一起搅拌,分离出乙酸乙酯相并用水洗涤。将乙酸乙酯溶液浓缩,得到所述标题化合物。实施例3
3-[[4-(4-氟苯氧基)苯磺酰基]-(3-羟基氨基甲酰基-8-氧杂-双环[3.2.1]辛-3-基)氨基]丙酸
A)3-(二苯亚甲基氨基)-8-氧杂双环[3.2.1]辛烷-3-羧酸苄基酯
于0℃下,向氢化钠(0.41g,17.1mmol)的N,N-二甲基甲酰胺(50ml)悬浮液中滴加N-(二苯亚甲基)甘氨酸苄基酯(7.8mmol)的N,N-二甲基甲酰胺(50ml)溶液。于室温下搅拌30分钟后,滴加顺-2,5-双(羟甲基)四氢呋喃二甲苯磺酸酯(4.1g,9.3mmol)(按照文献中所述方法制备,例如JOC,47,2429-2435(1982)所述方法)的N,N-二甲基甲酰胺(50ml)溶液。在油浴中将反应混合物逐渐加热至100℃并在此温度下搅拌过夜。真空蒸除溶剂并将残余物溶于水,用乙醚萃取两次。合并的有机萃取液用盐水洗涤,硫酸镁干燥并浓缩,得到粗产物。
B)3-氨基-8-氧杂双环[3.2.1]辛烷-3-羧酸苄基酯盐酸盐
将3-(二苯亚甲基氨基)-8-氧杂双环[3.2.1]辛烷-3-羧酸苄基酯(3.9mmol)的1N盐酸水溶液(100ml)和乙醚(100ml)的两相混合物于室温下搅拌过夜。将水层浓缩,得到所述标题化合物。
C)3-外-[4-(4-氟苯氧基)苯磺酰基氨基]-8-氧杂双环[3.2.1]辛烷-3-羧酸苄基酯
将3-氨基-8-氧杂双环[3.2.1]辛烷-3-羧酸苄基酯盐酸盐(2.9mmol)、4-(4-氟苯氧基)苯磺酰氯(923mg,3.2mmol)和三乙胺(0.9ml,6.5mmol)的N,N-二甲基甲酰胺(45ml)溶液于室温下搅拌过夜。真空下除去溶剂并将残余物溶于饱和碳酸氢钠水溶液。用二氯甲烷萃取两次后,合并的有机层用盐水洗涤,硫酸镁干燥并浓缩,得到一褐色油状物。用1%甲醇的二氯甲烷溶液作洗脱剂,在硅胶上经色谱法分离,得到所述标题化合物。
D)3-{(2-乙氧羰基乙烯基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-8-氧杂双环[3.2.1]辛烷-3-羧酸苄基酯
将上述步骤所述产物的溶液(53.2mmol)和10.8ml(106mmol,2当量)丙炔酸乙酯的200ml无水四氢呋喃溶液于1℃下用53.2ml(53.2mmol,1当量)的四丁基氟化铵的四氢呋喃溶液(1M)处理45分钟。令所得溶液缓慢温热至环境温度并搅拌过夜。减压下用甲苯替代四氢呋喃并将甲苯溶液用水和盐水洗涤,用甲苯稀释至600ml,与90g硅胶一起搅拌3小时,过滤并浓缩,得到所述标题化合物。
E)3-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-8-氧杂双环[3.2.1]辛烷-3-羧酸
将步骤D所述产物(4.4mmol)的25ml乙醇溶液用2.5g 50%水润湿的10%钯/碳催化剂处理并在53psi氢气压下振荡48小时。滤除催化剂并用乙醇(4×25ml)洗涤。将滤液和洗液合并并真空浓缩,得到粗产物。
F)3-{(3-氯羰基-8-氧杂双环[3.2.1]辛-3-基)-[4-(4-氟苯氧基)苯磺酰基]氨基}丙酸乙酯
于环境温度下,将步骤E所述产物(15.1mmol)的73ml二氯甲烷溶液用1.4ml(17mmol,1.1当量)草酰氯和0.02ml(0.3mmol,0.02当量)二甲基甲酰胺处理,产生一些气泡,并搅拌过夜。无需分离,将所得所述标题化合物溶液用于下一步骤。
G)3-[[4-(4-氟苯氧基)苯磺酰基]-(3-羟基氨基甲酰基-8-氧杂双环[3.2.1]辛-3-基)氨基]丙酸乙酯
于0℃下,将羟胺盐酸盐(19.7mmol,1.3当量)的9.2ml(114mmol,7.5当量)无水吡啶溶液用5.8ml(45mmol,3.0当量)三甲基甲硅烷基氯化物处理,沉淀出白色固体。令混合物温热至环境温度过夜,然后将此混合物冷却至0℃并用步骤F所述产物(15.1mmol)的73ml二氯甲烷溶液处理,引起放热至8℃。将此混合物于0℃下搅拌30分钟并于环境温度下搅拌约1小时,然后用50ml2N盐酸水溶液处理并于环境温度下搅拌1小时。水相用二氯甲烷萃取,合并的有机相用2N盐酸水溶液(2×50ml)和水(50ml)洗涤。将所述标题化合物的此二氯甲烷溶液用于下一步骤。
H)3-[[4-(4-氟苯氧基)苯磺酰基]-(3-羟基氨基甲酰基-8-氧杂双环[3.2.1]辛-3-基)氨基]丙酸
将步骤G所述产物(15.1mmol)的二氯甲烷溶液在加入75ml甲苯后进行旋转蒸发浓缩。此溶液用75ml水处理,冷却至0℃并在剧烈搅拌下用6.05g(15lmmol,10当量)氢氧化钠颗粒处理10分钟。将混合物于0℃下搅拌15分钟并在1小时内温热至环境温度。分离水相,用7.5ml四氢呋喃稀释,冷却至0℃并用33ml 6N盐酸水溶液处理20分钟。在0℃至环境温度下,将此混合物与75ml乙酸乙酯一起搅拌,分离出乙酸乙酯相并用水洗涤。将乙酸乙酯溶液浓缩,得到所述标题化合物。
实施例4
3-外-[4-(4-氟苯氧基)苯磺酰基甲基]-8-氧杂双环[3.2.1]辛烷-3-羧酸羟基酰胺
A)8-氧杂双环[3.2.1]辛烷-3,3-二羧酸二乙酯
将氢化钠(2.28g,95mmol)分批加入到搅拌下的丙二酸二乙酯(15ml,99mmol)的N,N-二甲基甲酰胺(400ml)溶液中。将混合物搅拌45分钟,此时氢释放完全。然后滴加顺-2,5-双(羟甲基)四氢呋喃二苯磺酸酯(19.0g,43mmol)的N,N-二甲基甲酰胺(400ml)溶液,混合物于油浴中于140℃下加热过夜。冷却至室温后,通过加入饱和氯化铵水溶液使混合物骤冷并真空浓缩。将残余的油状物溶于水并用乙醚萃取。有机萃取液用水和盐水洗涤,硫酸镁干燥并浓缩,得到一油状物。
B)3-外-羟甲基-8-氧杂双环[3.2.1]辛烷-3-羧酸乙酯
于-40℃下,将1.2M二异丁基氢化铝的甲苯溶液(75mmol)滴加到8-氧杂双环[3.2.1]辛烷-3,3-二羧酸二乙酯(30mmol)的甲苯(80ml)溶液中。于搅拌下3小时内将混合物温热至0℃,然后令其冷却至-15℃并在保持该温度下缓慢加入乙醇(8ml)。于-15℃下搅拌1小时后,加入硼氢化钠(1.1g,30mmol),将混合物于室温下搅拌过夜并通过滴加饱和硫酸钠水溶液使其骤冷。加入乙酸乙酯,搅拌20分钟后,经硅藻土(CeliteTM)过滤除去不溶物。滤液用盐水洗涤,硫酸镁干燥并浓缩,得到透明油状所述标题化合物。
C)3-外-羟甲基-8-氧杂双环[3.2.1]辛烷-3-羧酸
将氢氧化锂水合物(59.5mmol)加入到3-外-羟甲基-8-氧杂双环[3.2.1]辛烷-3-羧酸乙酯(23.8mmol)的甲醇(25ml)、四氢呋喃(25ml)和水(2.5ml)混合物溶液中。将混合物回流加热过夜,冷却并通过加入Amberlite IR-120TM离子交换树脂使其骤冷。搅拌20分钟后,滤除树脂,用四氢呋喃洗涤。蒸除溶剂并用乙醚研制所述残余物,得到所述标题化合物。
D)3’,8二氧杂螺[双环[3.2.1]辛烷-3,1’-环丁烷]-2’-酮
于0℃下,将苯磺酰氯(13.5mmol)滴加到3-外-羟甲基-8-氧杂双环[3.2.1]辛烷-3-羧酸(12.3mmol)、三乙胺(24.7mmol)和4-二甲氨基吡啶(2.5mmol)的二氯甲烷(50ml)溶液中。混合物于0℃下搅拌1小时,用二氯甲烷稀释并用1N盐酸水溶液、饱和碳酸氢钠水溶液和盐水洗涤。用硫酸镁干燥后,蒸除溶剂,得到所述标题化合物。
E)3-外-[4-(4-氟苯氧基)苯硫基甲基]-8-氧杂双环[3.2.1]辛烷-3-羧酸
于-10℃下,将4-(4-氟苯氧基)硫酚(10mmol)的四氢呋喃(10ml)溶液滴加到氢化钠(11.3mmol)的四氢呋喃(20ml)浆状物中。令混合物温热至室温,同时搅拌30分钟。再次冷却至-10℃后,滴加3’,8二氧杂螺[双环[3.2.1]辛烷-3,1’-环丁烷]-2’-酮(10mmol)的四氢呋喃(20ml)溶液。除去冷却浴并于室温下继续搅拌2小时,之后混合物用1N盐酸水溶液骤冷并用二氯甲烷萃取两次。合并的有机萃取液用水和盐水洗涤,硫酸镁干燥并浓缩,得到一固体。
F)3-[4-(4-氟苯氧基)苯硫基甲基]-8-氧杂双环[3.2.1]辛烷-3-甲酰氯
于环境温度下,将步骤E所述产物(15.1mmol)的73ml二氯甲烷溶液用1.4ml(17mmol,1.1当量)草酰氯和0.02ml(0.3mmol,0.02当量)二甲基甲酰胺处理,产生一些气泡,并搅拌过夜。无需分离,将所得所述标题化合物溶液用于下一步骤。
G)3-[4-(4-氟苯氧基)苯硫基甲基]-8-氧杂双环[3.2.1]辛烷-3-羧酸羟基酰胺
于0℃下,将羟胺盐酸盐(19.7mmol,1.3当量)的9.2ml(114mmol,7.5当量)无水吡啶溶液用5.8ml(45mmol,3.0当量)三甲基甲硅烷基氯化物处理,沉淀出白色固体。令混合物温热至环境温度过夜,然后将此混合物冷却至0℃并用步骤F所述产物(15.1mmol)的73ml二氯甲烷溶液处理,引起放热至8℃。将此混合物于0℃下搅拌30分钟并于环境温度下搅拌约1小时,然后反应用50ml 2N盐酸水溶液处理并于环境温度下搅拌1小时。水相用二氯甲烷萃取,合并的有机相用2N盐酸水溶液(2×50ml)和水(50ml)洗涤。将有机相浓缩,得到所述标题化合物
H)3-[4-(4-氟苯氧基)苯磺酰基甲基]-8-氧杂双环[3.2.1]辛烷-3-羧酸羟基酰胺
将过硫酸氢钾制剂(OxoneTM)(8.63mmol)加入到上述步骤所述产物(3.63mmol)的水(30ml)、甲醇(40ml)和四氢呋喃(12ml)混合物溶液中。所得混合物于室温下搅拌过夜,用水稀释并用乙酸乙酯萃取两次。合并的有机萃取液用盐水洗涤,硫酸镁干燥并浓缩,得到所述标题化合物。
实施例5
4-[4-(4-氟苯氧基)苯磺酰基氨基]-四氢吡喃-4-羧酸羟基酰胺
A)4-[N-(二苯亚甲基)氨基]四氢吡喃-4-羧酸苄基酯
于0℃下,经滴液漏斗向氢化钠(6.56g,0.164mol)的乙二醇二甲醚(150ml)悬浮液中滴加N-(二苯亚甲基)甘氨酸苄基酯(0.07398mol)乙二醇二甲醚(50ml)溶液。然后在约5分钟内,以每10ml一份向所述乙二醇二甲醚溶液中加入2-溴乙醚(23.21g,0.090mol)的乙二醇二甲醚(50ml)溶液。除去冰浴,反应在室温下搅拌16小时。混合物用乙醚稀释并用水洗涤,水层用乙醚萃取。合并的有机萃取液用盐水洗涤,硫酸镁干燥并浓缩,得到粗产物。于硅胶上进行色谱纯化,首先用4L 5%乙酸乙酯/己烷洗脱,然后用4L 10%乙酸乙酯/己烷洗脱,得到透明黄色油状4-[N-(二苯亚甲基)氨基]四氢吡喃-4-羧酸苄基酯。
B)4-氨基四氢吡喃-4-羧酸苄基酯
向4-[N-(二苯亚甲基)氨基]四氢吡喃-4-羧酸苄基酯(16.0g,0.047mol)的乙醚(120ml)溶液中加入1M盐酸水溶液(100ml)。混合物于室温下剧烈搅拌16小时,分层并将水层用乙醚洗涤。水层用稀氢氧化铵水溶液调至pH10并用二氯甲烷萃取。将有机萃取液用硫酸钠干燥并浓缩,得到4-氨基四氢吡喃-4-羧酸苄基酯。
C)4-[4-(4-氟苯氧基)苯磺酰基氨基]四氢吡喃-4-羧酸苄基酯
向4-氨基四氢吡喃-4-羧酸苄基酯(0.0404mol)的N,N-二甲基甲酰胺(40ml)溶液中加入三乙胺(5.94ml,0.043mol)。向上述溶液中分批加入4-(4-氟苯氧基)苯磺酰氯固体(12.165g,0.0424mol),所得混合物于室温下搅拌16小时并在真空下蒸发除去大部分溶剂。残余物于饱和碳酸氢钠溶液和二氯甲烷之间分配,分出水层并用二氯甲烷萃取。合并的有机层用盐水洗涤并用硫酸钠干燥。真空蒸除溶剂,得到4-[4-(4-氟苯氧基)苯磺酰基氨基]四氢吡喃-4-羧酸苄基酯粗产物。于硅胶上进行快速色谱纯化,用25%乙酸乙酯/己烷,随后用50%乙酸乙酯/己烷洗脱,得到4-[4-(4-氟苯氧基)苯磺酰基氨基]四氢吡喃-4-羧酸苄基酯。
D)4-{(2-乙氧羰基乙烯基)-[4-(4-氟苯氧基)苯磺酰基]氨基}-四氢吡喃-4-羧酸苄基酯
将上述步骤所述产物(53.2mmol)和10.8ml(106mmol,2当量)丙炔酸乙酯的200ml无水四氢呋喃溶液于1℃下用53.2ml(53.2mmol,1当量)的四丁基氟化铵的四氢呋喃溶液(1M)处理45分钟。令所得溶液缓慢温热至环境温度并搅拌过夜。减压下用甲苯替代四氢呋喃并将甲苯溶液用水和盐水洗涤,用甲苯稀释至600ml,与90g硅胶一起搅拌3小时,过滤并浓缩,得到所述标题化合物。
E)4-[4-(4-氟苯氧基)苯磺酰基氨基]-四氢吡喃-4-甲酰氯
于环境温度下,将4.40kg(11.13mol)4-[4-(4-氟苯氧基)苯磺酰基氨基]-四氢吡喃-4-羧酸的40L二氯甲烷溶液用19ml二甲基甲酰胺和1.075L(12.32mol,1.1当量)草酰氯处理,并搅拌16小时。无需分离,将所得所述标题化合物溶液用于下列步骤F。
F)4-[4-(4-氟苯氧基)苯磺酰基氨基]四氢吡喃-4-羧酸羟基酰胺
于0-10℃下,将1.160kg(16.69mol,1.5当量)羟胺盐酸盐的6.8L(84.08mol,7.5当量)吡啶溶液用2.8L(22.06mol,20当量)三甲基甲硅烷基氯化物处理,沉淀出白色固体。将此混合物于0-2℃下搅拌4小时,之后用步骤E产物的二氯甲烷溶液处理,引起放热。将混合物于0-2℃下搅拌1小时,然后在20℃下搅拌1.5小时。反应混合物用132L 2N盐酸水溶液处理并于环境温度下搅拌1小时。水相用乙酸乙酯(3×100L)萃取,合并的有机相用水(2×130L)洗涤并浓缩至17L。所得悬浮液于0℃下搅拌3小时,过滤,得到4.068kg(89%)灰白色固体状所述标题化合物。
Claims (8)
1.一种制备含异羟肟酸基团的分子的方法,所述方法包括在碱存在下,将羟胺或其盐与甲硅烷基卤化物反应,随后与含酰卤化物的分子反应,再与酸反应,条件是所述含酰氯化物的分子不含羟基、伯胺、仲胺或巯基。
Z是>CH2或>NR1;
Q是(C1-C6)烷基、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳氧基(C1-C6)烷基、(C6-C10)芳氧基(C6-C10)芳基、(C6-C10)芳氧基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C2-C9)杂芳基、(C6-C10)芳基(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C6-C10)芳基(C2-C9)杂芳基、(C2-C9)杂芳基(C1-C6)烷基、(C2-C9)杂芳基(C6-C10)芳基、(C2-C9)杂芳基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C2-C9)杂芳基、(C2-C9)杂芳氧基(C1-C6)烷基、(C2-C9)杂芳氧基(C6-C10)芳基、(C2-C9)杂芳氧基(C2-C9)杂芳基、(C2-C9)杂芳基(C1-C6)烷氧基(C1-C6)烷基、(C2-C9)杂芳基(C1-C6)烷氧基(C6-C10)芳基或(C2-C9)杂芳基(C1-C6)烷氧基(C2-C9)杂芳基;
其中所述(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳氧基(C1-C6)烷基、(C6-C10)芳氧基(C5-C10)芳基、(C6-C10)芳氧基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C2-C9)杂芳基、(C6-C10)芳基(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C6-C10)芳基(C2-C9)杂芳基、(C2-C9)杂芳基(C1-C6)烷基、(C2-C9)杂芳基(C6-C10)芳基、(C2-C9)杂芳基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C2-C9)杂芳基、(C2-C9)杂芳氧基(C1-C6)烷基、(C2-C9)杂芳氧基(C6-C10)芳基、(C2-C9)杂芳氧基(C2-C9)杂芳基、(C2-C9)杂芳基(C1-C6)烷氧基(C1-C6)烷基、(C2-C9)杂芳基(C1-C6)烷氧基(C6-C10)芳基或(C2-C9)杂芳基(C1-C6)烷氧基(C2-C9)杂芳基中的每个(C6-C10)芳基或(C2-C9)杂芳基基团可以任选地在能另外成键的所述环碳原子上每个环被独立地选自下列的一个或多个取代基任意取代,所述取代基选自氟、氯、溴、(C1-C6)烷基、(C1-C6)烷氧基、全氟代(C1-C3)烷基、全氟代(C1-C3)烷氧基和(C6-C10)芳氧基;
其中所述星号表示R2和R3的共用碳原子;
而R4是(C1-C6)烷基;
n是1-6的整数;
所述方法包括:
a)在第一种碱存在下,将羟胺或其盐与((C1-C6)烷基)3甲硅烷基卤化物反应,就地形成((C1-C6)烷基)3甲硅烷基化的羟胺,
其中R7是((C1-C6)烷基)3-Si-而R8是氢或((C1-C6)烷基)3-Si-;和
c)用酸水解所述式Ⅵ化合物。
3.权利要求2所述方法,其中所述第一种碱是吡啶、2,6-二甲基吡啶或二异丙基乙基胺。
4.权利要求2所述方法,其中所述第一种碱是吡啶。
5.权利要求2所述方法,其中所述((C1-C6)烷基)3甲硅烷基卤化物是三甲基甲硅烷基氯化物。
6.权利要求2所述方法,其中所述第二种碱是吡啶、2,6-二甲基吡啶或二异丙基乙基胺。
7.权利要求2所述方法,其中所述第二种碱是吡啶。
8.权利要求2所述方法,其中所述溶剂是吡啶。
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