CN1364153A - 取代的苯氧基乙酸 - Google Patents
取代的苯氧基乙酸 Download PDFInfo
- Publication number
- CN1364153A CN1364153A CN00809446A CN00809446A CN1364153A CN 1364153 A CN1364153 A CN 1364153A CN 00809446 A CN00809446 A CN 00809446A CN 00809446 A CN00809446 A CN 00809446A CN 1364153 A CN1364153 A CN 1364153A
- Authority
- CN
- China
- Prior art keywords
- fluoro
- acetate
- phenoxy group
- formyl radical
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical class OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 238000000034 method Methods 0.000 claims abstract description 37
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 421
- -1 wherein Chemical group 0.000 claims description 140
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 78
- 239000000460 chlorine Substances 0.000 claims description 75
- 239000001257 hydrogen Substances 0.000 claims description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims description 70
- 229910052736 halogen Inorganic materials 0.000 claims description 65
- 150000002367 halogens Chemical class 0.000 claims description 65
- 239000011737 fluorine Substances 0.000 claims description 61
- 229910052731 fluorine Inorganic materials 0.000 claims description 61
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 39
- 229910052801 chlorine Inorganic materials 0.000 claims description 39
- 229910052760 oxygen Inorganic materials 0.000 claims description 38
- 239000001301 oxygen Substances 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- 150000001721 carbon Chemical group 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 19
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 18
- 150000003254 radicals Chemical class 0.000 claims description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 125000005605 benzo group Chemical group 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 239000005864 Sulphur Chemical group 0.000 claims description 12
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 12
- 208000002249 Diabetes Complications Diseases 0.000 claims description 11
- 206010012655 Diabetic complications Diseases 0.000 claims description 11
- 239000002532 enzyme inhibitor Substances 0.000 claims description 11
- 229940125532 enzyme inhibitor Drugs 0.000 claims description 11
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Chemical group 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 238000011161 development Methods 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 6
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 108010007859 Lisinopril Proteins 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 229960000830 captopril Drugs 0.000 claims description 4
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 4
- 229960002394 lisinopril Drugs 0.000 claims description 4
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 claims description 4
- 229940043232 butyl acetate Drugs 0.000 claims description 3
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 150000004866 oxadiazoles Chemical class 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 230000002981 neuropathic effect Effects 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 28
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 6
- 229960002909 spirapril Drugs 0.000 claims 6
- 108700035424 spirapril Proteins 0.000 claims 6
- HRWCVUIFMSZDJS-SZMVWBNQSA-N spirapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2(C1)SCCS2)C(O)=O)CC1=CC=CC=C1 HRWCVUIFMSZDJS-SZMVWBNQSA-N 0.000 claims 6
- NVXFXLSOGLFXKQ-JMSVASOKSA-N (2s)-1-[(2r,4r)-5-ethoxy-2,4-dimethyl-5-oxopentanoyl]-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)[C@H](C)C[C@@H](C)C(=O)OCC)[C@H](C(O)=O)CC2=C1 NVXFXLSOGLFXKQ-JMSVASOKSA-N 0.000 claims 3
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 claims 3
- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-N 0.000 claims 3
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical group C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 claims 3
- IFYLTXNCFVRALQ-OALUTQOASA-N Ceronapril Chemical compound O([C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)P(O)(=O)CCCCC1=CC=CC=C1 IFYLTXNCFVRALQ-OALUTQOASA-N 0.000 claims 3
- 108010061435 Enalapril Proteins 0.000 claims 3
- UWWDHYUMIORJTA-HSQYWUDLSA-N Moexipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC(OC)=C(OC)C=C2C1)C(O)=O)CC1=CC=CC=C1 UWWDHYUMIORJTA-HSQYWUDLSA-N 0.000 claims 3
- XRKXJJYSKUIIEN-LLVKDONJSA-N Pivopril Chemical compound CC(C)(C)C(=O)SC[C@@H](C)C(=O)N(CC(O)=O)C1CCCC1 XRKXJJYSKUIIEN-LLVKDONJSA-N 0.000 claims 3
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 claims 3
- 229950007884 alacepril Drugs 0.000 claims 3
- 229960004530 benazepril Drugs 0.000 claims 3
- 229960004067 benazeprilat Drugs 0.000 claims 3
- MADRIHWFJGRSBP-ROUUACIJSA-N benazeprilat Chemical compound C([C@H](N[C@H]1CCC2=CC=CC=C2N(C1=O)CC(=O)O)C(O)=O)CC1=CC=CC=C1 MADRIHWFJGRSBP-ROUUACIJSA-N 0.000 claims 3
- 229950005749 ceronapril Drugs 0.000 claims 3
- 229960005227 delapril Drugs 0.000 claims 3
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 claims 3
- 229960000873 enalapril Drugs 0.000 claims 3
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims 3
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- AXTCRUUITQKBAV-KBPBESRZSA-N libenzapril Chemical compound OC(=O)CN1C(=O)[C@@H](N[C@@H](CCCCN)C(O)=O)CCC2=CC=CC=C21 AXTCRUUITQKBAV-KBPBESRZSA-N 0.000 claims 3
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- 229950008492 pentopril Drugs 0.000 claims 3
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- 229960001455 quinapril Drugs 0.000 claims 3
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 claims 3
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- FLSLEGPOVLMJMN-YSSFQJQWSA-N quinaprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)C(O)=O)CC1=CC=CC=C1 FLSLEGPOVLMJMN-YSSFQJQWSA-N 0.000 claims 3
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- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 claims 3
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- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 claims 3
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 2
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 claims 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- PWSBNTOBQBTNEJ-UHFFFAOYSA-N thieno[2,3-b]pyridine Chemical compound C1=C[CH]C2=C=CSC2=N1 PWSBNTOBQBTNEJ-UHFFFAOYSA-N 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 abstract description 6
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- 235000011152 sodium sulphate Nutrition 0.000 description 36
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 31
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- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 11
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明公开了用于治疗由糖尿病引起的慢性并发症的取代的苯氧基乙酸。本发明还公开了药物组合物,其单独地包含所述化合物,或者与其它治疗剂结合,本发明还公开了采用所述化合物和药物组合物进行治疗的方法,以及它们的合成方法。
Description
发明背景
本申请所要保护的优先权文件为U.S.临时申请号60/141,068(申请日1999年6月25日),将其引入本文作为参考。
发明领域
本发明涉及取代的苯氧基乙酸和包含该类化合物的药物组合物。本发明还涉及所述化合物在治疗或预防由糖尿病引起的慢性并发症中的用途。
相关技术描述
用于治疗慢性糖尿病并发症的醛糖还原酶(ARIs)是公知的。由于组织如神经、肾、视网膜和晶状体中葡萄糖水平升高会造成并发症,所述葡萄糖进入多元醇途径并经醛糖还原酶转化成山梨醇。由于山梨醇难于穿越细胞膜,其会在某些细胞中积聚,导致渗透压变化,从而改变吡啶核苷酸的氧化还原态(即增加NADH/NAD+比)并减少肌醇的细胞内含量。这些与糖尿病并发症相关的生物化学变化可通过醛糖还原酶抑制剂进行控制。
已有许多文献综述了采用醛糖还原酶抑制剂用来治疗慢性糖尿病并发症,参见;(a)糖尿病教科书(Textbook of Diabetes),第2版;Pickup,J.C.和Williams,G.(Eds.);Blackwell Science,Boston,MA 1997.;(b)Larson,E.R.;Lipinski,C.A.和Sarges,R.,Medicinal ResearchReviews,1988,8(2),159-198;(c)Dvornik,D.醛糖还原酶抑制(Aldose Reductase Inhibition).Porte,D.(ed),BiomedicalInformation Corp.,New York,NY.Mc Graw Hill 1987;(d)Petrash,J.M.,Tarle,I.,Wilson,D.K.Quiocho.F.A.糖尿病透视(Perspectives in Diabetes),醛糖还原酶催化和结晶学(AldoseReductase Catalysis和Crystalography):酶结构和功能的最新进展,糖尿病(Insights From Recent Advances in Enzyme Structure和Function,Diabetes),1994,43,955;(e)Aotsuka,T.;Abe,N.;Fukushima,K.;Ashizawa,N.和Yoshida,M.,Bioorg. & Med.Chem.Letters,1997,7,1677,(f),T.,Nagaki,Y.;Ishii,A.;Konishi,Y.;Yago,H;Seishi,S.;Okukado,N.;Okamoto,K.,J.Med.Chem.,1997,40,684;(g)Ashizawa,N.;Yoshida,M.;Sugiyama,Y.;Akaike,N.;Ohbayashi,S.;Aotsuka,T.;Abe,N.;Fukushima,K.;Matsuura,A,Jpn.J.Pharmacol.1997,73,133;(h)Kador,P.F.;Sharpless,N.E.,Molecular Pharmacology,1983,24,521;(I)Kador,P.F.;Kinoshita,J.H.;Sharpless,N.E.,J.Med.Chem.1985,28(7),841;(j)Hotta,N.,Biomed. & Pharmacother.1995,5,232;(k)Mylar,B.;Larson,E.R.;Beyer,T.A.;Zembrowski,W.J.;Aldinger,C.E.;Dee,F.D.;Siegel,T.W.;Singleton,D.H.,J.Med.Chem.1991,34,108;(1)Dvornik,D.Croatica Chemica Acta 1996,69(2),613。
下述专利公开了一些具有醛糖还原酶抑制剂活性的化合物:U.S.专利5,700,819;4,868,301;和4,734,419。虽然已开发了许多醛糖还原酶抑制剂,但还未找到一种在人体的临床试验中具有充分的功效且无显著副反应。因此,在美国还没有醛糖还原酶抑制剂被批准作为治疗剂,所以,仍希望开发出新的有效且安全的用于治疗糖尿病并发症的药物。
发明概述
其中A为共价键,C1-C4亚烷基,其可被C1-C2烷基取代或未取代或被卤素,优选氟或氯单或二取代;
X为氧、硫或NR6,其中,每一个R6为氢,氰基或具有1-6个碳原子烷基(其可被一个或多个卤素取代);
R1、R2、R3和R4彼此独立地为氢,卤素,硝基或具有1-6个碳原子烷基(其可被一个或多个卤素取代);
OR7、SR7、S(O)R7、S(O)2R7、C(O)N(R7)2或N(R7)2,其中,每一个R7独立地为氢、具有1-6个碳原子的烷基(其可被一个或多个卤素取代)或苄基,其中,苯基部分被至多三个取代基取代或未取代,取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨基;
苯基或杂芳基如2-、3-或4-咪唑基或2-、3-或4-吡啶基,每一个苯基或杂芳基被至多三个取代基取代或未取代,取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨基;
苯氧基,其中,苯基部分可被至多3个基团取代或未取代,所述取代基独立地选自卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨基;或
其中
J为单键、CH2、氧或氮;和
每一个r独立地为2或3;
R5为羟基或前药基团;和
Ar表示芳基或杂芳基,每一个基团可被至多5个基团取代或未取代。
另一方面,本发明提供了制备这些化合物的方法。
本发明的化合物可抑制醛糖还原酶。由于醛糖还原酶对于糖尿病患者个体中产生高含量山梨醇来说是关键所在,因此,醛糖还原酶抑制剂可用于预防和/或治疗各种与糖尿病相关的并发症。因此,本发明的化合物可有效地治疗糖尿病并发症,因其能够抑制醛糖还原酶。
所以,另一方面,本发明提供了治疗和/或预防与糖尿病相关的慢性并发症的方法,包括糖尿病性白内障、视网膜病、肾病和神经病。
另一方面,本发明提供了治疗和/或预防与糖尿病相关的慢性并发症的方法,包括糖尿病性白内障、视网膜病、角膜病、创伤愈合、糖尿病性眼色素层炎、糖尿病性心肌病、肾病和神经病。
本发明的化合物可促进哺乳动物创伤愈合。在优选的方面,本发明的化合物可用于促进患有糖尿病的哺乳动物创伤愈合。因此,本发明的化合物可用于治疗哺乳动物,特别是人类,更优选糖尿病患者的创伤。
另一方面,本发明提供了式I的化合物在制备用于治疗如上所列出的疾病或异常(a)或(b)相关的糖尿病并发症的药物中的用途。
ACE抑制剂以治疗有效长期给药可能有害于或会造成某些患者的副作用,例如,可能会导致肾功能的显著衰退,造成血钾过高,中性白细胞减少症,血管神经病性水肿,皮疹或腹泻或引起干咳。本发明提供了联合治疗方法,包括使式I的化合物与血管舒张药,优选ACE抑制剂一起给药。这种给药方式降低了给药血管舒张剂如ACE抑制剂相关可能产生的问题,所述问题是由于单独给药这些试剂中的一种造成的。因此,糖尿病并发症涉及了复杂或大量的机理,其开始于生物化学交替的级联,其又会造成结构变化。这些可导致变化多的患者人口。因而,本发明提供了其它的优选,允许对特定的患者人口进行人体治疗。
在此方面,本发明提供了一种药物组合物,其包含通式I的化合物和血管舒张剂,优选ACE抑制剂,以及一种可药用载体和/或稀释剂。此外,本发明还提供了治疗与葡萄糖升的血浆水平有亲的疾病或异常的方法,包括与糖尿病和高血压和/或充血性心力衰竭有并的并发症。
这些方法包括向需要此种治疗的患者,如患有糖尿病或高血压的患者或可能感染这些疾病的患者给药有效量的式I的化合物与血管舒张化合物,优选ACE抑制剂。
在相关的方面,本发明提供了治疗、预防或逆转与损害神经元的传导速率有关的疾病的发展的方法。这些方法包括向患有或证实发展这种疾病的患者给药有效量的式I化合物及有效量的血管舒张化合物,如血管紧张素转化酶抑制剂。
进而,本发明提供了治疗或预防糖尿病性神经病的方法,包括向患有或证实发展这种疾病的患者给药有效量的式I化合物。
另一方面,本发明提供了包含式I的化合物的药物组合物。
另一方面,本发明提供了用于制备式I化合物的中间体以及用于制备这种化合物和中间体的合成方法。发明详述式I化合物的编号方式如下:
如上所述,本发明提供了可用于治疗和/或预防与患有糖尿病的患者中与葡萄糖水平升高相关或由其引起的并发症的新的取代的苯氧基乙酸。
这些化合物由如上的式I表示。
在式I的优选化合物中,以及在式II和III的化合物中,X为氧。
在式I的化合物中,由Ar表示的芳基和杂芳基包括:
苯基,其中
(i)苯基可被至多3个基团取代或未取代,所述取代基独立地选自:
卤素,具有1-6个碳原子的烷基(其可被一个或多个卤素取代),
硝基,OR7、SR7、S(O)R7、S(O)2R7、C(O)N(R7)2或N(R7)2,其中,每
一个R7独立地为氢、具有1-6个碳原子的烷基(其可被一个或多
个卤素取代)或苄基,其中,苯基部分被至多三个取代基取代或
未取代,取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨
基和单或二(C1-C6)烷氨基;
(ii)如上(i)所述苯基被选择性地单取代和被C1-C5亚烷基二取代,
形成与苯基稠合的环烷基,其中,C1-C5亚烷基进一步被下述基
团单或二取代:羟基、卤素、C1-C2烷基、C1-C2烷氧基、氨基或
单或二(C1-C2)烷氨基,其中,C1-C5亚烷基选择性地包含一个或
两个选自氧、氮和硫的杂原子;或
(iii)如上(i)所述苯基被至多三个基团选择性地取代和进一步与
苯并基团稠合,其中、苯并基团被下述一个或两上基团取代或未
取代:卤素、氰基、硝基、三氟甲基、全氟乙基、三氟乙酰基或
(C1-C6)烷酰基、羟基、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷
硫基、三氟甲氧基、三氟甲硫基、(C1-C6)烷基亚磺酰基、(C1-C6)
烷基磺酰基;
杂环5-元环,其具有一个氮、氧或硫,两个氮,其中之一可被氧或硫代替,或三个氮,其中之一可被氧或硫代替,所述的杂环5-元环被下述基团取代:一或两个氟、氯、(C1-C6)烷基或苯基,或与苯并基团稠合,或者被下述基团之一取代:吡啶基、呋喃基或噻吩基,所述的苯基或苯并基团可被下述基团取代或未取代:碘、氰基、硝基、全氟乙基、三氟乙酰基或(C1-C6)烷酰基,一个或两个氟、氯、溴、羟基、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、三氟甲氧基、三氟甲硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基或三氟甲基,或两个氟或两个三氟甲基与一个羟基羟基或一个(C1-C6)烷氧基,或一个,或优选两个氟和一个三氟甲基,或三个氟,所述的吡啶基、呋喃基或噻吩基在3-位上被下述基团取代或未取代:氟、氯、溴、(C1-C6)烷基或(C1-C6)烷氧基;
杂环6-元环,其具有1-3个氮原子,或者1个或2个氮原子,和1个氧或硫,所述的杂环6-元环被1或2个(C1-C6)烷基或苯基取代,或与苯并基团稠合,或被吡啶基、呋喃基或噻吩基之一取代,所葶苯基或苯并基团被下述基团之一取代或未取代:碘或三氟甲硫基,或1个或2个氟、氯、溴、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基或三氟甲基,所述的吡啶基、呋喃基或噻吩基在其3-位上被下述基团取代或未取代:氟、氯、(C1-C6)烷基或(C1-C6)烷氧基;所述的苯并基团稠合的杂环5-元或6-元环在其杂环5-元或6-元环上被下
述取代基之一取代或未取代:氟、氯、溴、甲氧基或三氟甲基;恶唑或噻唑,与包含1或2个氮原子的6-元芳族基团稠合,与噻吩或与
呋喃稠合,每一种被下述基团之一取代或未取代:氟、氯、溴、三氟
甲基、甲硫基或甲基亚磺酰基;咪唑并吡啶或三唑并吡啶,被下述基团之一取代或未取代:三氟甲基、三
氟甲硫基、溴或(C1-C6)烷氧基,或被氟或氯中的两个取代;噻吩并噻吩或噻吩并呋喃,被下述基团之一取代或未取代:氟、氯或三氟
甲基;噻吩并三唑,被下述基团之一取代或未取代:氯或三氟甲基;萘并噻唑;萘并恶唑;或噻吩并异噻唑。
杂环5-元和6-元环可如上所述被单取代或未取代,并可进一步用C1-C5亚烷基二取代,形成与杂环稠合的环烷基,其中,C1-C5亚烷基进一步选择性地被下述基团单或二取代:羟基、卤素、C1-C2烷基、C1-C2烷氧基、氨基或单或二(C1-C2)烷氨基,其中,C1-C5亚烷基选择性地包含1或2个选自氧、氮和硫的杂原子。
本发明更具体的化合物为以下的式I化合物,其中,Ar为取代或未取代的苯并噻唑基、苯并恶唑基、异喹啉基、苯并噻吩基、苯并呋喃基或苯并咪唑基,或取代的恶二唑基或吲哚基。其它更具体的式I化合物为以下的化合物,其中,A为共价键或CH2,R5为羟基,每一个R1-R4独立地为氢,卤素,更优选溴,氯或氟,C1-C6,更优选,C1-C2烷基,苯氧基,苄氧基,或C1-C6,更优选,C1-C2烷氧基。在式I化合物中,R1和R4更优选氢或C1-C3烷基,首选氢。同时,更优选的式I化合物为以下的化合物,其中,R2和R3独立地为氢,卤素,更优选氯或氟,C1-C6烷基,更优选甲基或乙基,C1-C6烷氧基,更优选甲氧基或乙氧基,氨基,单或二(C1-C3)烷氨基,吗啉基,哌啶-1-基或哌嗪-1-基。
本发明优选的化合物为以下的化合物,其中,A为亚甲基,R5为羟基,Ar为取代或未取代的苯并噻唑-2-基、苯并噻唑-5-基、苯并异噻唑-3-基、苯并恶唑-2-基、2-喹啉基、2-喹喔啉基、恶唑并[4,5b]吡啶-2-基、苯并噻吩-2-基、苯并呋喃-2-基或噻唑并[4,5b]吡啶-2-基、噻吩并[2,3-b]吡啶-2-基、咪唑并[1,5-a]吡啶-2-基或吲哚-2-基、或取代的1,2,4-恶二唑-3-基、1,2,4-恶二唑-5-基,异噻唑-5-基、异噻唑-4-基、1,3,4-恶二唑-5-基、1,2,5-噻二唑-3-基、恶唑-2-基、噻唑-2-基或噻唑-4-基,R1-R4独立地为氢,卤素,更优选溴,氯或氟,C1-C2烷基,苯氧基,苄氧基或苯基,其中,每一个苯基部分被下述基团取代或未取代:C1-C6烷基、卤素、C1-C6烷氧基、羟基、氨基或单或二(C1-C6)烷氨基。优选地,在本发明的化合物中,R1和R4为氢或C1-C3烷基,更优选氢。
本发明其它更具体的化合物为以下的化合物,其中,A为亚甲基,R5为羟基,Ar为选择性地4、5、6或7苯并-取代的苯并噻唑基、苯并恶唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基或吲哚基,或者Ar为2-苯并噻唑基,在其苯并基团上被1个三氟乙酰基或三氟甲硫基取代,或被下述基团之一或之二取代:氟、氯、溴、羟基、甲基、甲氧基、三氟甲基、三氟甲氧基、三氟甲硫基,或者被1个,优选2个氟和1个三氟甲基取代,或者被两个氟或两个三氟甲基和一个甲氧基取代,或者被3个氟取代,或者被6,7苯并基团取代。优选地,在本发明的化合物中,R1和R4为氢或C1-C3烷基,更优选氢。
本发明优选的化合物包括以下的化合物,其中,式I中的Ar为取代的苯基,即式II的化合物:其中
A为被C1-C2烷基取代或未取代的C1-C4亚烷基;
X为氧、硫或NR6,其中,每一个R6为氢、氰基具有1-6个碳原子的烷基(其可被一个或多个卤素取代);
R1、R2、R3和R4彼此独立地为氢、卤素、具有1-6个碳原子的烷基(其可被一个或多个卤素取代)、硝基、OR7、SR7、S(O)R7、S(O)2R7、C(O)N(R7)2或N(R7)2,其中,每一个R7独立地为氢、具有1-6个碳原子的烷基(其可被一个或多个卤素取代)或苄基,其中,苯基部分可被至多3个基团取代或未取代,所述取代基独立地选自:卤素,C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨基;
苯基或杂芳基如2-、3-或4-咪唑基或2-、3-或4-吡啶基,每一个苯基或杂芳基可被至多3个基团取代或未取代,所述取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨基;
苯氧基,其中,苯基部分可被至多3个基团取代或未取代,所述取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨基;或
下式的基团
其中
J为单键、CH2、氧或氮;和
每一个r独立地为2或3;R5为羟基、1-6个碳原子的烷氧基或O-M+,其中,M+为形成可药用盐的阳
离子;和R8、R9、R10、R11和R12组合表示氢,或1-3个选自氟、氯、
溴、三氟甲基或硝基的基团。
其中
A为共价键,被C1-C2烷基取代或未取代的C1-C4亚烷基;
X为氧、硫或NR6,其中,每一个R6为氢、氰基、具有1-6个碳原子的烷基(其可被一个或多个卤素取代);
R1、R2、R3和R4彼此独立地为氢、卤素、具有1-6个碳原子的烷基(其可被一个或多个卤素取代)、硝基、OR7、SR7、S(O)R7、S(O)2R7、C(O)N(R7)2或N(R7)2,其中,每一个R7独立地为氢、具有1-6个碳原子的烷基(其可被一个或多个卤素取代)或苄基,其中,苯基部分可被至多3个基团取代或未取代,所述取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨基;
苯基或杂芳基如2-、3-或4-咪唑基或2-、3-或4-吡啶基,每一个苯基或杂芳基可被至多3个基团取代或未取代,所述取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨基;
其中
J为单键、CH2、氧或氮;和
每一个r独立地为2或3;
R5为羟基、C1-C6烷氧基,或-O-M+,其中,M+为形成可药用盐的阳离子;和R13、R14、R15和R16独立地为氢、卤素、硝基、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、三氟甲基、三氟甲氧基、C1-C6烷基亚磺酰基或C1-C6烷基磺酰基。
在优选的式III化合物中,R13、R14、R15和R16取代基组合表示溴、氰基或硝基之一,氟、氯、羟基、(C1-C6)烷基、(C1-C6)烷氧基或三氟甲基之一或之二,或两个氟或两个甲基与一个羟基或一个(C1-C6)烷氧基,或一个,优选两个氟和一个甲基,或三个氟基团。特别优选的R13、R14、R15和R16取代基独立地为氟、氯、硝基和三氟甲基。
在式II和III的优选化合物中,A优选为亚甲基,被甲基取代的亚甲基或亚乙基。
按照如上所述式II的优选化合物包括以下的化合物,其中,R8为氟,R10为溴和R9,R11和R12为氢;或以下的化合物,其中,R8、R10、R11和R12为氢和R9为硝基。式II的其它优选化合物包括以下的化合物,其中,R2和R3独立地为氢,卤素,更优选氯或氟,C1-C6烷基,更优选甲基或乙基,烷氧基,更优选甲氧基或乙氧基,氨基,单或二(C1-C3烷基)氨基,吗啉基,哌啶-1-基,或哌嗪-1-基;R8为氟,R10为溴和R9,R11和R12为氢;或以下的化合物,其中,R2和R3独立地为氢,卤素,更优选氯或氟,C1-C6烷基,更优选甲基或乙基,烷氧基,更优选甲氧基或乙氧基,氨基,单或二(C1-C3烷基)氨基,吗啉基,哌啶-1-基,或哌嗪-1-基;R8、R10、R11和R12为氢,和R9为硝基。
上式III的优选化合物为以下的化合物,其中,苯并噻唑部分被下述基团取代,硝基,1、2或3个氟,1或2个氯,或者1个三氟甲基。更优选的式II化合物为以下的化合物,其中,A为亚甲基,和R5为羟基或C1-C6烷氧基。其它更优选的式III化合物为以下的化合物,其中,R2和R3独立地为氢,卤素,更优选氯或氟,C1-C6烷基,更优选甲基或乙基,烷氧基,更优选甲氧基或乙氧基,氨基,单或二(C1-C3烷基)氨基,吗啉基,哌啶-1-基,或哌嗪-1-基。
更为优选的式III化合物为以下的化合物,其中,R13、R14和R16为氟,R15为氢。
术语“前药基团”是指会在体内转化成式I活性化合物的部分,其中,R5为羟基。该基团通常是现有技术中公知的,包括成酯基团,形成酯前药,如苄氧基,二(C1-C6)烷氨基乙氧基,乙酰氧基甲基,新戊酰氧基甲基,邻苯二甲酰氧基,乙氧羰基氧基乙基,5甲基-2-氧代-1,3-间二氧杂环戊烯-4-基甲基和(C1-C8),优选C1-C6,更优选C1-C3烷氧基,其选择性地被N-吗啉代基团和成酰胺基团如二(C1-C6)烷氨基取代。优选的前药基团包括C1-C6烷氧基,首选C1-C2烷氧基和O-M+,其中,M+表示阳离子。优选的阳离子包括钠、钾、铵、镁和钙。其中,当M为二价阳离子如镁或钙时,可以理解,这种阳离子将与超过一个,通常为两个由式I的化合物形成的羧酸根阴离子结合。
在某些情形下,式I的化合物可包含一个或多个不对称碳原子,从而化合物可以不同的立体异构体形式存在。这些化合物例如可以是外消旋体或旋光形式。在这些情形下,单一的旋光对映体即旋光形式可以纯化合物获得,或者以对称体过量的方式通过不对称合成或通过外消旋体拆分的方式获得。外消旋体的拆分例如可通过常规方法完成,如在拆分试剂存在下进行结晶,或者采用例如手性HPLC柱进行色谱处理。
本发明的代表性化合物包括所述化合物的可药用酸加成盐,其中,R5含碱性氮原子,即烷氨基或吗啉代基团。此外,如果本发明的化合物或其前药是以酸加成盐获得的,则游离碱可通过对酸性盐的溶液进行碱化获得。与此相反,如果前药为游离碱,则加成盐,特别是可药用加成盐可通过将游离碱溶解于适宜的有机溶剂中,用酸对溶液进行处理,以由碱性化合物制备酸加成盐的常规方法生产。
无毒的药用盐包括酸如盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸如乙酸、HOOC-(CH2)n-COOH的盐,其中,n为0-4等。无毒药用碱加成盐包括碱如钠、钾、钙、铵、镁等的盐。本领域的技术人员公知各种无毒的可药用加成盐。
本文中所述用术语2-苯并噻唑基和苯并噻唑-2-基是同义的。
包括以下的基团,其中,J为氧和每一个r为2(吗啉基),J为氮和每一个r为2(哌嗪基)或一个r为2和另一个为3(高哌嗪基),或J为CH2和每一个r为2(哌啶基)或一个r为2和另一个为3(高哌啶基)。
该式的优选基团为吗啉基和哌嗪基。这些基团中的任一种可在其碳原子上选择性地被C1-C6烷基取代。
具有1-3个氮原子,其中之一可被氧或硫代替的杂环5-元环包括咪唑基、恶唑基、噻唑基、吡唑基、恶二唑基、噻二唑基和三唑基。
具有1-3个氮原子,其中之一或之二可被氧或硫代替的杂环6-元环包括三嗪基、嘧啶基、哒嗪基、恶嗪基和三嗪基。
杂环可与苯并基团稠合,从而所述的环在两个邻的碳原子处连接而形成苯基。这种苯并杂环可连接至A上,或者通过杂环基团,或者通过苯并杂环的苯并基团。其中杂环为与苯并基团稠合的杂环的化合物的代表性实例包括苯并恶唑基,喹唑啉-2-基,2-苯并咪唑基,喹唑啉-4-基和苯并噻唑基。包含1个或2个氮原子并与6-元芳族基团稠合的恶唑或噻唑包括位置异构体,如恶唑并[4,5-b]吡啶-2-基,噻唑并[4,5-b]吡啶-2-基,恶唑并[4,5-c]吡啶-2-基,噻唑并[4,5-c]吡啶-2-基,恶唑并[5,4-b]吡啶-2-基,噻唑并[5,4-b]吡啶-2-基,恶唑并[5,4-c]吡啶-2-基和噻唑并[5,4-c]吡啶-2-基。5-或6-元杂环优选通过在杂环上的碳原子共价键合至A基团,更优选通过2个杂原子间的碳原子。
所谓“杂芳基”是指一种芳环体系,其包含1、2或3个环,每个环具有5、6、7或8个原子,至少一个芳环包含至少一个且至多四个选自氮、氧或硫的杂原子。这种杂芳基的实例包括噻吩基、呋喃基、噻唑基、咪唑基、异恶唑基、恶唑基、吡啶基、嘧啶基、异喹啉基、喹啉基、萘啶基、苯并噻唑基、苯并咪唑基和苯并恶唑基。优选地,杂芳基通过在杂芳基基团上的碳原子连接至母分子部分上。其中,杂芳基通过氮与母部分相连,相邻的X基团将为亚烷基。优选的杂芳基为单环基团,其中,环具有5或6环原子,并包含1或2个氮原子,或者为二环,其中,一个环具有5或6个环原子,并包含1或2个氮原子,第二个环具有5、6或7个环原子,并包含0、1或2个氮原子。优选的杂芳基为苯并咪唑基、咪唑并吡啶基、苯并噻唑基和咪唑并吡嗪基。
提供以下的本发明的化合物以使读者了解本发明所包含的化合物:
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸
[5-氯-2-(3-三氟甲基-苄基氨基甲酰基)-苯氧基]-乙酸
[2-(3-硝基-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸
[5-氯-2-(3-氟-5-三氟甲基-苄基氨基甲酰基)-苯氧基]-酸
[5-氯-2-(3,4-二氯-苄基氨基甲酰基)-苯氧基-乙酸
[2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-氯-苯氧基]-乙酸
[4-溴-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-氟-苯氧基]-乙酸
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-甲基-苯氧基]-乙酸
[4-硝基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸
[2-(3-硝基-苄基氨基甲酰基)-4-甲基-苯氧基]-乙酸
[2-(3-硝基-苄基氨基甲酰基)-4-三氟甲氧基-苯氧基]-乙酸
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-苯氧基]-乙酸
[5-氟-2-(4-甲基-3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸
[2-(4-溴-2-氟-苄基氨基甲酰基)-4,5-二氟-苯氧基]-乙酸
[5-氟-2-(3-硝基-苄硫基氨基甲酰基)-苯氧基]-乙酸
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-5-氟-苯氧基]-乙酸
[4-溴-2-(4-溴-2-氟-苄硫基氨基甲酰基)-苯氧基]-乙酸
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-4-三氟甲氧基-苯氧基]-乙酸
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-4,5-二氟-苯氧基]-乙酸
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸
[2-(3-硝基-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸
[2-(3-硝基-苄硫基氨基甲酰基)-5-氟-4-甲基-苯氧基-乙酸
[2-(3-硝基-苄基氨基甲酰基)-4-溴-5-氟-苯氧基]-乙酸
[5-硝基-苄基氨基甲酰基)-2-氟-联苯基-4-基氧基]-乙酸
[5-(3-硝基-苄硫基氨基甲酰基)-2-氟-联苯基-4-基氧基]-乙酸
[2-(3-硝基-苄基氨基甲酰基)-4-氰基-5-氟-苯氧基]-乙酸
[2-(3-硝基-苄基氨基甲酰基)-5-氟-4-吗啉-4-基-苯氧基]-乙酸
{5-氟-2[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-酸
{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)硫代氨基甲酰基]-苯氧基}-乙酸
{5-氟-2-[(5-三氟甲基-苯并噻唑-2-基甲基)-氨基甲酰基]-苯氧基}-乙酸
{5-氯-2-[(5-三氟甲基-苯并噻唑-2-基甲基)-氨基甲酰基]-苯氧基}-乙酸
上述化合物会在实施例和本发明的其它描述中进一步说明,但它们并非对本发明范围的限制。
本发明的化合物可单独给药于需要治疗的患者,或者与其它具有类似或不同生理学活性的化合物一起组合使用。例如,本发明的化合物可以联合治疗方式给药,即以单次或多次剂量形式同时给药,或者在几个小时或几天内以多次剂量形式给药。这种联合治疗的实例包括使式I的化合物与其它用于治疗高血糖、高血脂和糖尿病并发症的其它试剂一起给药。
适用于联合治疗的化合物包括
对高血糖:
胰岛素
甲福明
曲格列酮
吡格列酮
罗格列酮(Rosiglitazone)
达格列酮
磺酰基脲如格列吡嗪和格列美脲
瑞格列奈
α-糖苷酶抑制剂如阿卡波糖,米格列醇
对糖尿病并发症:
ACE抑制剂:卡托普利,赖诺普利,omaprilat
血管紧张素II受体拮抗剂(AT1-受体)如坎地沙坦(candesartan),洛沙坦,埃比沙坦(irbesartan)和缬沙坦
MMP抑制剂
蛋白激酶C抑制剂
对降血脂:
他汀类药(Statin)如阿伐他汀(Atorvastatin),昔伐他汀,普伐他汀,氟伐他汀,洛伐他汀,舍伐他汀
贝特类药(Fibrates)如非诺贝特,苯扎贝特,环丙贝特,吉非贝齐
这种联合治疗例如可包括同时以分开的药物组合物给药血管舒张药,优选ACE抑制剂和式I的化合物,给药同时包含血管舒张药优选ACE抑制剂和式I的化合物的药物组合物,或者在不同的时间给药两类化合物。本领域的技术人员知道实现例如与ACE抑制剂和式I化合物进行联合治疗的其它方式。
通式I的化合物可采用的给药方式可以为,口服、局部给药、非肠道给药、吸入法或喷雾法给药或直肠给药,剂量单元制剂包含常规无毒可药用载体、助剂和赋形剂。本文中术语非肠道包括皮下注射、静脉内注射、肌内注射、胸骨内注射或输注。此外,也提供了药物制剂,其包含通式I的化合物和可药用载体。一种或多种通式I的化合物可与一种或多种无毒可药用载体和/或稀释剂和/或助剂一起存在,如果需要的话,还可包含其它活性成分。包含通式I的化合物的药物组合物可为适用于口服的形式,例如片剂、糖锭、锭剂、水或油悬浮液、分散粉末或颗粒、乳剂、硬或软胶囊或糖浆或酏剂。
准备用于口服使用的组合物可按照本领域技术人员公知的生产药物组合物的方法生产,这种组合物可包含一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的试剂,以提供可药学上优雅和适口的制剂。片剂包含活性成分和适用于生产片剂的无毒可药用赋形剂。这些的赋形剂的实例可为惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒和崩解剂,如玉米淀粉或藻酸;粘合剂,如淀粉、明胶或阿拉伯胶,以及润滑剂,如硬脂酸镁、硬脂酸或滑石。片剂可为未包衣片,或者可按照公知技术进行包衣以延迟在胃肠中的崩解和吸收,从而在较长的时间内提供缓释作用。例如,可采用延时物质如甘油单硬脂酸酯或甘油二硬脂酸酯。
口服制剂也可为硬胶囊,其中,活性成分与惰性的固体稀释剂混合,所述稀释剂例如为碳酸钙、磷酸钙或高岭土,或者为软胶囊,其中,活性成分与水或油性介质混合,例如花生油、液体石蜡或橄榄油。
含水悬浮液包含活性物质和适用于生产含水悬浮液的赋形剂。这种赋形剂为悬浮剂,如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯基吡咯烷酮、黄芪胶和阿拉伯胶;分散剂或润滑剂可为天然磷脂,如卵磷脂或氧化烯与脂肪酸的缩合产物,如聚氧乙烯硬脂酸酯或环氧乙烷与长链脂肪醇的缩合产物,如十七烷基亚氧乙基鲸蜡醇(heptadecaethyleneoxycetanol),或环氧乙烷与来自脂肪酸与己糖醇的部分酯如聚氧亚乙基山梨醇单油酸酯的缩合产物,或环氧乙烷与来自脂肪酸与己糖醇酸酐的部分酯如聚亚乙基脱水山梨醇单油酸酯的缩合产物。含水悬浮液也可包含一种或多种防腐剂,如对羟基苯甲酸乙酯或正丙酯,一种或多种着色剂,一种或多种矫味剂和一种或多种甜味剂,如蔗糖或糖精。
油性悬浮液是将活性成分悬浮于植物油或矿物油中配制而成的,所述植物油例如为花生油、橄榄油、芝麻油或椰子油,矿物油例如为液体石蜡。油性悬浮液可包含一种增稠剂,如蜂蜡、硬石蜡或鲸蜡醇。还可加入如上所述的甜味剂和矫味剂以提供适口的口服制剂。这些组合物可通过加入抗氧化剂如抗坏血酸进行防腐。
适用于通过加入水而制备水性悬浮液的可分散粉末和颗粒提供了与分散剂或润湿剂、悬浮剂和一种或多种防腐剂混合在一起的活性成分。适宜的分散剂或润滑剂和悬浮剂的实例为如上提及的那些。也可存在其它赋形剂,如甜味剂、矫味剂和着色剂。
本发明的药物组合物也可为水包油乳剂。油相可为植物油如橄榄油、花生油或矿物油如液体石蜡或其混合物。适宜的乳化剂可为天然胶质,如阿拉伯胶或黄芪胶,天然磷脂,如大豆,卵磷脂和来自脂肪酸与己糖醇,酸酐的酯或部分酯,如脱水山梨醇单油酸酯,和所述部分酯与环氧乙烷的缩合物,如聚氧亚乙基脱水山梨醇单油酸酯。乳剂也可包含甜味剂和矫味剂。
糖浆和酏剂可用甜味剂配制,如甘油、聚乙二醇、山梨醇或蔗糖。这种制剂也可包含缓和剂,防腐剂和矫味剂及着色剂。药物组合物可为无菌注射用水质或油质悬浮液。这种悬浮液可按照公知常识,采用如上所提及的分散剂或润湿剂和悬浮剂来配制。无菌注射制剂也可为在无毒可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如在1,3-丁二醇中的溶液。在可以采用的可接受的赋形剂和溶剂中,可采用水,林格氏溶液和等渗氯化钠溶液。
此外,无菌的固定油常规用作溶剂或悬浮介质。为此,任何温和的固定油可采用,包括合成单或二甘油酸酯。此外,脂肪酸如油酸可用于制备注射制剂。
通式I的化合物也可以用于药物直肠给药的栓剂形式给药。这些组合物的制备过程是,将药物与适宜的无刺激性赋形剂混合,所述赋形剂在常温下为固体,但在直肠温度下为液体,从而在直肠内熔化释放出药物。这种物质为椰子油和聚乙二醇。
通式I的化合物可以无菌培养基经非肠道给药。根据所采用的赋形剂和浓度,药物可悬浮或溶解于赋形剂中。有利地,可在赋形剂中溶解助剂如局部麻醉剂,防腐剂和缓冲剂。
在治疗上述疾病中可采用的剂量水平大体为约0.1-140mg/kg体重/天(约0.5mg-7g/患者/天)。可与载体物质合并以产生单一剂型的活性成分的量取决于治疗的疾病和具体的给药方式。单次剂量通常包含约1mg-1000mg的活性成分。
但是,可以理解,对于特定的患者来说,具体的剂量可取决于各种因素,包括所采用的具体化合物的活性,年龄,体重,健康状况,性别,膳食,给药时间,给药方式和排泄率,药物组合及所治疗具体疾病的严重程度。
本发明的化合物可采用常规化学反应和过程制备。以下给出合成合成化合物的一般方法。可以理解,对所期望的目标化合物所需的取代基的性质经常决定了合成的优选方法。如果未进行具体说明的话,这些方法的所有可变基团均在一般描述中说明。在以下的实验部分显示出对具体实施例更详细的过程。
制备方法
通常,其中X为氧或硫的式I的化合物可便利地采用以下给出的一般反应路线A由取代的水杨酸制备。反应路线A
在该方法中,取代的水杨酸部分IV被活化和与胺偶联。活化方法的实例对本领域的技术人中来说是公知的,包括形成酰氯或混合酸酐,并使用偶联剂如1,3-二环己基碳化二亚胺(DCC)。该方法的综述性文章可参看下述文献:Bodanszky,M.肽合成原理(Principles of PeptideSynthesis);Springer-Verlag:New York,1984。可以理解,选择所采用的偶联方法将取决于诸如官能团相容性和所需规模等因素。通常,当采用未保护的水杨酸时,采用亚硫酰氯来形成酰氯是便利的。随后,在胺碱如三乙胺或吡啶存在下,在质子惰性溶剂如二氯甲烷存在下加成胺V,得到酰胺VI。或者,可采用含水或二相性的反应条件,采用无机碱如氢氧化钠或碳酸钾。这种被称之为萧顿-包曼反应的反应在下述文献中有说明Bioorg.Med.Chem.Letters 1994,4,335。引入乙酸部分以提供苯氧基乙酸衍生物VII通常是采用烷基化试剂如溴代乙酸乙酯或2-氯乙酸钠在具有碱如碳酸钾的含水丙酮溶液中完成的。其它采用无水反应条件的方法也可采用,有机合成领域的技术人员对此也是公知的。如果希望酰胺产物VIII,可将酯中间体VII水解成酸,可采用含水酸或碱条件。硫代酰胺衍生物X可由相应的酰胺IX制备,即在质子惰性溶剂如甲苯中用诸如五硫代磷的试剂进行处理。硫代酰胺产物X可以与酰胺产物VIII类似的方式获得。酯中间体IX可水解成酸,采用含水酸或碱条件。
如果所需的取代的水杨酸难于获得,可采用公知方法制备。一种有用的方法示于反应路线B,其中,2-氟苯甲酸XI用一种碱如氢氧化钠在1,3-二甲基-2-咪唑啉酮(DMI)中在升高的温度下(优选约135℃)处理。反应路线B
通常,中间体化合物IV,其中R1-4为芳基或杂芳基,可采用公知的过渡金属催化的偶联反应如Suzuki and Stille反应进行合成。应当理解,根据所采用的具体化学,可能需要保护基团P。这些一般方法的应用在下述文献中有述:有机合成中的保护基团(Protective Groups in OrganicSynthesis),第二版,T.W.Green和P.G.M.Wuts,John Wiley和Sons,New York,1991。
在Suzuki反应中,如反应路线C所示,取代或未取代的芳基卤化物XII可用芳基或杂芳基硼酸和钯催化剂处理,以提供取代的水杨酸衍生物XIII。这些反应经常在醚或醇溶剂与含水碱的混合物中,在钯催化剂存在下进行,所述催化剂如如Pd(OAc)2、Pd(OAc)2w/PPh或Pd(PPh3)4,如下述文献所述:Tetrahedron Lett.1998,39,4467,J.Org.Chem.1999,64,1372和Heterocycles 1992,34,1395。如果需要的话,采用公知的方法进行脱保护以得到中间体XIV。有关硼酸与芳基卤化物进行Suzuki交联反应的一般性综述参见下述文献:Miyaura,N;Suzuki,A.Chem.Rev.1995,95,2457。反应路线C
此外,Stille反应也用作用于取代水杨酸中间体XIV的区位控制合成的一般方法,如以下的反应路线D所示。在该方法中,水杨酸部分可用作有机锡部分或芳基卤化物。锡烷基水杨酸衍生物XV可方便地由相应的芳基溴化物Ar-Br(XII)制备,即用六甲基二锡(HMDT)和钯催化剂如Pd(PPh3)4进行处理。随后,将这种锡中间体用各种合作试剂(即乙烯基/烯丙基卤,三氟甲磺酸乙烯基酯,芳基/杂芳基卤化物和酰卤,XVI)在钯催化剂存在下处理,得到所需的芳基或杂芳基偶联的水杨酸中间体(XIII)。相反,卤代的水杨酸衍生物(XII)可用各种锡试剂在Stille条件下处理,得到所需的取代的水杨酸(XIII)。有关的综述性文献可参见:(a)Heterocycles 1988,27,1585,(b)Synth.Comm 1992,22,1627,(c)Synnlett1993,771,(d)Helv.Chim.Acta 1993,76,2356(e)J.Org.Chem.,1994,59,4250和Farina,V.;Krishnamurthy,V;Scott,W.,Organic Rections,1998,50,1-652。反应路线D
过渡金属催化的反应也可用于偶联芳基或杂芳基卤化物与胺、醇和含硫化合物,从而形成相应的芳基和杂芳基苯胺,醚和硫醚衍生物。以下的反应路线E给出了合成中间体化合物的一般过程,其中,R1-4之一为-N(H)R7。通常,芳基溴或氯XII用含杂原子的中间体XV,碱如叔丁醇钾或碳酸铯,钯催化剂如Pd2(dba)3或(DPPF)PdCl2和配位体如BINAP或DPPF在甲苯或四氢呋喃中,在升高的温度(通常为50-150℃)下处理,产生所需的中间体XVI。反应路线E
有关该化学过程的更详细描述可参见:(a)J.Chem.Soc.,PerkinTrans.1,1998,2615,(b)Acc.Chem.Res.1998,31,805,(c)Tetrahedron Letters,1997,38,6359。
除了合成取代的水杨酸中间体外,过渡金属催化的偶联反应也可用来由高级中间体制备目标化合物。例如,如反应路线F所示,用芳基或杂芳基硅酸或锡中间体,R-M,处理中间体溴化物XVII,采用Pd-介层的偶联条件,得到所需的芳基和杂芳基产物XVIII。通常,该方法的实用性是由易于合成XVII型高级中间体及可获得芳基和杂芳基硼酸和锡衍生物来确定的。反应路线F
通过下述实施例的说明,本领域的技术人员可以理解,可以改变原料和反应条件,改变反应的顺序,用于产生本发明范围内的其它化合物。在某些情形下,对一些活泼官能团进行保护可能是必要的,以实现上述中的某些转化。通常,有机合成领域的技术人员公知这种保护基的需求以及必须连接或除去这些基团的条件。
在本申请中提及的所有文章和参考文献包括专利在内均引入本文作为参考。
本发明化合物的制备进一步通过下述实施例说明,但这些实施例并非对本发明保护范围的限制。
步骤1:N-(4-溴-2-氟-苄基)-4-氯-2-羟基-苯甲酰胺:
将5-氯-2-羟基-苯甲酸(20.0g,116mmol)的庚烷(232mL,0.5M)溶解用亚硫酰氯(25.4mL,348mmol)处理,并在60℃下加热6小时。在冷却至室温后,将溶液进行减压浓缩,得到5-氯-2-羟基苯甲酰氯,为一种浑浊的黄色油(22g),其不进行纯化即可使用。
将5-氯-2-羟基-苯甲酰氯(4.00g,23.2mmol)的二氯甲烷(46mL,0.5M)溶液用三乙胺(6.46mL,46.4mmol)和4-溴-2-氟苄基胺(6.10g,30.1mmol)处理。在室温下搅拌16小时后,将溶液依次用2N盐酸和饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩。用MPLC纯化(10-50%乙酸乙酯的庚烷溶液,23mL/分钟,70分钟),给出N-(4-溴-2-氟-苄基)-4-氯-2-羟基-苯甲酰胺,为一种白色结晶固体(4.4g,53%):mp159-161?;Rf0.49(30%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ12.56(br s,1H),9.28(br t,J=5.4Hz,1H),7.88(d,J=6.0Hz,1H),7.50(dd,J1=9.9Hz,J2=1.8Hz,1H),7.37(dd,J1=8.4Hz,J1=1.8Hz,1H),7.33(dd,J1=15.9Hz,J2=8.1Hz,1H),6.99-6.93(m,2H),4.50-4.46(m,2H)。ESI-LC/MS m/z计算值C14H10BrClFNO2:358.6;实测值360.0(M+1)+。分析计算值C14H10BrClFNO2:C,46.89;H,2.81;N,3.91;Cl,19.78。实测值C,46.89;H,2.81;N,3.90;Cl,19.73。
步骤2:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸乙酯
将N-(4-溴-2-氟-苄基)-4-氯-2-羟基-苯甲酰胺(3.25g,9.06mmol)的丙酮(45mL,0.2M)溶液用碳酸钾水溶液(2M,6.8mL,14mmol)和溴乙酸乙酯(1.2mL,11mmol)处理。在50℃下加热8小时后,将溶液冷却至室温和减压浓缩,直至除去大多数丙酮。将溶液酸化至pH1-2,采用2N盐酸,用乙酸乙酯稀释和用饱和氯化钠水溶液洗涤。有机层用硫酸钠干燥,过滤和浓缩。用MPLC纯化(10-60%乙酸乙酯的庚烷溶液,23 mL/分钟,70分钟),给出[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸乙酯,为一种白色结晶固体(3.78g,94%):mp 126-127?;Rf0.61(50%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ8.90(t,J=6Hz,1H),7.82(d,J=8.4Hz,1H),7.52-7.47(m,1H),7.39-7.31(m,2H),7.28(d,J=1.8Hz,1H),7.14(dd,J1=8.4Hz,J2=1.8Hz,1H),5.00(s,2 H),4.49(d,J=6Hz,2 H),4.16(q,J=7.2Hz,2H),1.18(t,J=6.6Hz,3H)。ESI-LC/MS m/z计算值C18H16BrClFNO4:444.7;实测值446.0(M+1)+。分析计算值C18H16BrClFNO4:C,48.62;H,3.63;N,3.15;Cl,15.95;实测值C,48.57;H,3.63;N,3.11;Cl,16.00。
步骤3:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸
将[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸乙酯(3.20g,7.20mmol)的乙醇(36mL,0.2 M)溶液冷却至0?和用氢氧化钠水溶液(1.25M,28.8mL,36.0mmol)处理。在搅拌30分钟后,将溶液升温至室温和再搅拌4小时。然后,将溶液酸化至pH 1-2,采用2N盐酸,用乙酸乙酯稀释和用饱和氯化钠水溶液洗涤。有机层用硫酸钠干燥,过滤和浓缩,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸,为一种白色结晶固体(2.9 g,97%):mp 184-185?;Rf0.31(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.40(br s,1H),9.05,(t,J=5.7Hz.1H),7.83,(d,J=8.4Hz,1H),7.48(d,J=10.5Hz,1Hz),7.38-7.32(m,2H),7.26(d,J=1.8 Hz,1 H),7.13(dd,J1=8.4Hz,J2=1.5Hz,1H),4.91(s,2H),4.49(d,J=5.7Hz,2H)。ESI-LC/MS m/z计算值C16H12BrClFNO4:416.6;实测值418.0(M+1)+。分析计算值C16H12BrClFNO4:C,46.13;H,2.90;N,3.36;Cl,17.02;实测值C,46.04;H,2.89;N,3.31;Cl,17.09。
实施例2
按照与实施例1所述类似的方式制备(2-苄基氨基甲酰基-5-氯-苯氧基)-乙酸,只是苄基胺用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp145-146?;Rf0.48(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6300 MHz)δ13.37(s,1H),9.09(t,J=6.0Hz,1H),7.86(d,J=8.4Hz,1H),7.34-7.18(m,6H),7.14(dd,J1=8.4Hz,J2=1.8Hz,1H),4.92(s,2H),4.50(d,J=6.0Hz,2H)。ESI-LC/MS m/z计算值C16H14ClNO4:319.74;实测值318.0(M-1)-。分析计算值C16H14ClNO4:C,60.10;H,4.41;N,4.38;Cl,11.09;实测值C,60.03;H,4,49;N,4.36;Cl,11.05。
实施例3
[5-氯-2-(3-氟-苄基氨基甲酰基)-苯氧基]-乙酸
按照与实施例1所述类似的方式制备[5-氯-2-(3-氟-苄基氨基甲酰基)-苯氧基]-乙酸,只是3-氟苄基胺用于代替步骤1中的4溴-2-氟苄基胺盐酸盐:mp 155?;Rf0.43(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6300MHz)δ10.81(br s,1H),7.73(d,J=9.0Hz,1H),7.34-7.27(m,1H),7.19-7.11(m,2H),7.05(dd,J1=8.3Hz,J2=1.7Hz,1 H),6.99(dt,J1=8.3Hz,J2=2.0Hz,1H),4.51-4.47(m,4H)。ESI-LC/MS m/z计算值C16H13ClFNO4:337.7;实测值336,338.0(M-1,M+1)-。分析计算值C16H15ClFNO5:C,54.02;H,4.25;N,3.94;Cl,9.97;实测值C,53.94;H,3.75;N,3.91;Cl,9.99。
实施例4
按照与实施例1所述类似的方式制备[5-氯-2-(3-三氟甲基-苄基氨基甲酰基)-苯氧基]-乙酸,只是3-(三氟甲基)-苄基胺用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 179-181?;Rf0.76(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.36(br s,1H),9.17(t,J=6.2Hz,1H),7.84(d,J=8.1Hz,1H),7.67-7.52(m,4 H),7.27(d,J=1.8Hz,1H),7.15(dd,J1=8.3Hz,J2=2.0Hz,1H),4.93(s,2H),4.59(d,J=6Hz,2H)。ESI LC/MS m/z计算值C17H15ClF3NO4:387.7;实测值388.0(M+1)+。分析计算值C17H15ClF3NO4:C,52.66;H,3.38;N,3.61;Cl,9.14;实测值C,52.57;H,3.39;N,3.55;Cl,9.21。
实施例5
[2-(3-硝基-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸
按照与实施例1所述类似的方式制备[2-(3-硝基-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸,只是3-硝基苄基胺盐酸盐用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 200?;Rf0.25(20%甲醇的二氯甲烷溶液);1HNMR(DMSO-d6 300MHz)δ13.35(br s,1 H),9.21(br t,J=5.4Hz,1H),8.18(br s,1H),8.05-8.07(m,1H),7.82(d,J=8.4Hz,1H),7.81(t,J=9.3Hz,1H),7.60(t,J=7.8Hz,1H),7.25(d,J=2.1Hz,1H),7.13(dd,J1=8.4Hz,J2=1.8Hz,1H),4.91(s,2 H),4.61(d,J=6.3Hz,2H)。ESI-LC/MS m/z计算值C16H13ClN2O6:364.1;实测值365.0(M+1)+。分析计算值C16H13ClN2O6:C,52.96;H,3.59;N,7.68;Cl,9.72;实测值C,52.63;H,3.64;N,7.60;Cl,9.81。
实施例6
按照与实施例1所述类似的方式制备[5-氯-2-(4-氯-苄基氨基甲酰基)-苯氧基]-乙酸,只是4-氯苄基胺用于代替步骤1中的4溴-2-氟苄基胺盐酸盐:mp 184-186?;Rf0.49(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.34(br s,1H),9.10(t,J=6.2Hz,1H),7.84(d,J=8.4 Hz,1H),7.35(s,4H),7.25(d,J=1.8Hz,1 H),7.13(dd,J1=8.3Hz,J2=2.0Hz,1H),4.91(s,2H),4.48(d,J=6Hz,2H)。ESI-LC/MS m/z计算值C16H13Cl2NO4:354.2;实测值354.0,355.0(M,M+1)+。分析计算值C16H13Cl2NO4:C,54.26;H,3.70;N,3.95;Cl,20.02;实测值C,54.30;H,3.74;N,3.90;Cl,20.10。
实施例7
按照与实施例1所述类似的方式制备[2-(4-溴-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸,只是4-溴苄基胺盐酸盐用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 172173?;Rf0.63(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.10(t,J=5.6Hz,1H),7.84(d,J=8.4Hz,1 H),7.50-7.46(m,2H),7.30-7.24(m,3H),7.13(dd,J1=8.4Hz,J2=2.0Hz,1H),4.91(s,2H),4.46(d,J=5.7Hz,2H)。ESI-LC/MS m/z计算值C16H13BrClNO4:398.6;实测值399.0(M+1)+,400(M+2)+。分析计算值C16H13BrClNO4:C,48.21;H,3.29;N,3.51;Cl,17.79;Br,40.09;实测值C,48.53;H,3.70;N,3.21;Cl,17.89;Br,40.32。
实施例8
[5-氯-2-(4-甲氧基-苄基氨基甲酰基)-苯氧基1-乙酸
按照与实施例1所述类似的方式制备[5-氯-2-(4-甲氧基-苄基氨基甲酰基)-苯氧基]-乙酸,只是4-甲氧基苄基胺盐酸盐用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 178-179?;Rf0.80(20%甲醇的二氯甲烷溶液);1H NMR(丙酮-d6 300MHz)δ9.02(br s,1H),8.09(d,J=8.4Hz,1H),7.32(d,J=8.7Hz,2H),7.25(d,J=2.1Hz,1H),7.15(dd,J1=8.6Hz,J2=1.8Hz,1H),6.85(dd,J1=6.6Hz,J2=2.1Hz,2H),5.0(s,2H),4.54(d,J=6Hz,2 H),3.76(s,3H)。ESI-LC/MS m/z计算值C20H22ClNO5:349.8;实测值350.0(M+1)+。分析计算值C20H22ClNO5:C,58.38;H,4.61;N,4.00;实测值C,58.35;H,4.75;N,3.87。
实施例9
按照与实施例1所述类似的方式制备[5-氯-2-(4-三氟甲氧基-苄基氨基甲酰基)-苯氧基]-乙酸,只是(4-三氟甲氧基)-苄基胺用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 184-185?;Rf0.41(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.18(t,J=6Hz,1H),7.85(J=8.4Hz,1H),7.47-7.42(m,2H),7.32-7.26(m,3H),7.14(dd,J,=8.4Hz,J2=1.8Hz,1H),4.92(s,2H),4.53(d,J=6Hz,2H)。ESI-LC/MS m/z计算值C17H13ClF3NO5:403.7;实测值404.0(M+1)+。
实施例10
按照与实施例1所述类似的方式制备[5-氯-2-(2,6-二氟-苄基氨基甲酰基)-苯氧基]-乙酸,只是2,6-二氟苄基胺盐酸盐用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 188-190?;Rf0.76(20%甲醇的二氯甲烷溶液);1H NMR(丙酮-d6 300MHz)δ8.86(br s,1H),8.07(d,J=8.4Hz,1H),7.37(dt,J1=7.2Hz,,J2=1.8Hz,1H),7.24(d,J=1.5Hz,1H),7.15(dd,J1=8.6Hz,J,=1.5 Hz,1H),6.99(t,J=7.8Hz,1H),4.97(s,2H),4.69(d,J=5.1Hz,2H)。ESI-LC/MSm/z计算值C16H12ClF2NO4:355.72;实测值356(M+1)+。分析计算值C16H12ClF2NO4:C,54.02;H,3.40;N,3.94;Cl,9.97;实测值C,53.43;H,3.46;N,3.83;Cl,9.82。
实施例11
按照与实施例1所述类似的方式制备[5-氯-2-(3-氟-5-三氟甲基-苄基氨基甲酰基)-苯氧基]-乙酸,只是3-氟-5-(三氟甲基)-苄基胺用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 160-162?;Rf0.42(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.34(br s,1H),9.16(t,J=6Hz,1H),7.83(d,J=8.7Hz,1H),7.55-7.47(m,3 H),7.27(d,J=2.1Hz,1H),7.14(dd,J1=8.4Hz,J2=1.8Hz,1H),4.93(s,2 H),4.59(d,J=6.3Hz,2H)。ESI-LC/MS m/z计算值C17H12CLF4NO4:405.73;实测值406.0(M+1)+。分析计算值C17H12ClF4NO4:C,50.32;H,2.98;N,3.45;Cl,8.74;实测值C,50.28;H,3.01;N,3.40;Cl,8.79。
实施例12
[2-(3,5-二三氟甲基-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸
按照与实施例1所述类似的方式制备[2-(3,5-二三氟甲基-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸,只是3,5-(二三氟甲基)苄基胺用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 191-193?;Rf0.23(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.34(br s,1H),9.20(t,J=6Hz,1H),8.01-7.97(m,3H),7.80(d,J=3Hz,1H),7.26(d,J=1.8Hz,1H),7.14(dd,J1=8.7Hz,J2=2.1Hz,1H),4.92(s,2H),4.67(d,J=6Hz,2H)。ESI LC/MS m/z计算值C18H12ClF6NO4:455.7;实测值456.0(M+1)+。分析计算值C18H12ClF6NO4:C,47.44;H,2.65;N,3.07;Cl,7.78;实测值C,47.53;H,2.72;N,3.06;Cl,7.86。
实施例13
[5-氯-2-(3,5-二甲氧基-苄基氨基甲酰基)-苯氧基]-乙酸
按照与实施例1所述类似的方式制备[5-氯-2-(3,5-二甲氧基-苄基氨基甲酰基)-苯氧基]-乙酸,只是3,5-二甲氧基苄基胺用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 163?;Rf0.57(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.39(br s,1H),9.04(t,J=6.2Hz,1H),7.86(d,J=8.2Hz,1H),7.25(d,J=1.9Hz,1H),7.14(dd,J1=8.2Hz,J2=1.9Hz,1H),6.49(d,J=2.2Hz,2H),6.34(t,J=2.4Hz,1H),4.93(s.2H),4.43(d,J=6Hz,2H),3.69(s,6H)。ESI-LC/MS m/z计算值C18H18ClNO6:379.8;实测值380.0(M+1)+。分析计算值C18H18ClNO6:C,56.92;H,4.78;N,3.69;Cl,9.33;实测值:C,56.93;H,4.84;N,3.76;Cl,9.25。
实施例14
按照与实施例1所述类似的方式制备[5-氯-2-(3,4-二氯-苄基氨基甲酰基)-苯氧基]-乙酸,只是3,4-二氯苄基胺用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 177-178?;Rf0.39(20%甲醇的二氯甲烷溶液);1HNMR(DMSO-d6 300MHz)δ9.19(t,J=6.0Hz,1H),7.81(d,J=8.1Hz,1H),7.55(d,J=8.1Hz,1H),7.55,(d,J=1.8Hz,1H),7.31(dd,J1=8.1Hz,J2=2.1Hz,1H),7.25(d,J=1.8Hz,1H),7.12(dd,J1=8.4Hz,J2=1.8Hz,1H),4.90(s,2H),4.48(d,J=6.0Hz,2H)。ESI-LC/MS m/z计算值C16H12Cl3NO4:387.0;实测值388.0(M+1)+。分析计算值C16H12Cl3NO4:C,49.45;H,3.11;N,3.60;Cl,27.37;实测值C,49.36;H,3.16;N,3.53;Cl,27.25。
实施例15
{2-[(苯并[1,3]间二氧杂环戊烯-5-基甲基)-氨基甲酰基]-5-氯-苯氧
按照与实施例1所述类似的方式制备{2-[(苯并[1,3]间二氧杂环戊烯-5-基甲基)-氨基甲酰基]-5-氯-苯氧基}-乙酸,只是胡椒基胺用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 208-209?;Rf0.25(10%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.38(br s,1H),9.02(t,J=6.0Hz,1H),7.84(d,J=8.4Hz,1H),7.24(d,J=1.2Hz,1H),7.13(dd,J1=8.1Hz,=0.9Hz,1H),6.87(s,1H),6.83-6.73(m,2H),5.94(s,2H),4.9(s,2H),4.39(d,J=6.0Hz,2H)。ESI-LC/MS m/z计算值C17H14ClNO6:363.1;实测值362.0(M-1)-。分析计算值C17H14ClNO6:C,56.13;H,3.88;N,3.85;Cl,9.75;实测值C,56.24;H,3.88;N,3.82;Cl,9.84。
实施例16
步骤1:3-(4-溴-2-氟-苄基)-7-甲氧基苯并[e][1,3]恶嗪-2,4-二酮:
将2-羟基-4-甲氧基苯甲酸(2.04g,12.2mmol)的四氢呋喃(20mL,0.6M)溶液冷却至0?。在用二异丙基胺(4.4mL,25.3mmol)和氯代甲酸乙酯(2.4mL,25.1mmol)处理后,将混合物在室温下搅拌1小时,随后再用2-氟-4-溴苄基胺(2.92g,12.1mmol)和二异丙基胺(4.4mL,25.3mmol)的四氢呋喃(15mL)溶液处理。在室温下搅拌22小时后,将反应混合物用乙酸乙酯稀释,依次用2N盐酸,饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩。将粗固体用庚烷和乙酸乙酯进行重结晶,得到3-(4-溴-2-氟-苄基)-7-甲氧基苯并[e][1,3]恶嗪-2,4-二酮(1.68g,36%):1H NMR(DMSO-d6 300MHz)δ7.87(d,J=8.4Hz,1H),7.53(dd,J1=10.5Hz,J2=1.1Hz,1H),7.33-7.34(m,2H),7.03-6.99(m,2H),5.02(s,2H),3.87(s,3H)。
步骤2:N-(4-溴-2-氟-苄基)-2-羟基-4-甲氧基-苯甲酰胺:
将3-(4-溴-2-氟-苄基)-7-甲氧基苯并[e][1,3]恶嗪-2,4-二酮(1.67g,4.4mmol)的乙醇(80mL,0.06M)溶液冷却至0?和用氯化钾水溶液(0.673g,11.9mmol,1.2M)处理。在3小时后,将反应物酸化至pH1-2,采用2N HCl,用乙酸乙酯萃取3次。将合并后的有机萃取液用饱和氯化钠水溶液洗涤,用硫酸钠干燥,过滤和浓缩。将粗固体用庚烷和乙酸乙酯进行重结晶,得到N-(4-溴-2-氟-苄基)-2-羟基-4-甲氧基-苯甲酰胺,为一种白色结晶固体(1.10g,71%):mp 128-129.5?;Rf0.28(25%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ12.70(br s,1H),9.14(brt,J=5.2Hz,1H),7.80(d,J=8.5Hz,1H),7.50(d,J=8.5Hz,1H),7.40-7.25(m,2H),6.50-6.48(m,2H),4.45(d,J=5.2Hz,2H),3.75(s,3H)。ESI-LC/MS m/z计算值C15H13BrFNO2:353.0;实测值352.0(M-1)-。分析计算值C15H13BrFNO2:C,50.87;H,3.70;N,3.95;实测值C,50.70;H,3.73;N,3.91。
步骤3:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲氧基-苯氧基-乙酸乙酯
将N-(4-溴-2-氟-苄基)-2-羟基-4-甲氧基-苯甲酰胺(2.33g,6.9mmol)的丙酮(35mL,0.2M)溶液用碳酸钾水溶液(2M,5.0mL,10.0mmol)和溴代乙酸乙酯(0.9mL,8.1mmol)处理。在50?下加热2.5小时后,将溶液冷却至室温和减压浓缩,直至大多数的丙酮除去。将溶液酸化至pH1-2,采用2N盐酸,用乙酸乙酯稀释和用饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩。用MPLC纯化(10-60%乙酸乙酯的庚烷溶液,23mL/分钟,70分钟),给出[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸乙酯,为一种粗白色固体(2.86g,97%):1H NMR(DMSO-d6 300MHz)δ8.85(br t,J=6.0Hz,1H),7.85(d,J=9.0Hz,1H),7.50(dd,J1=9.7Hz,J2=1.7Hz,1H),7.38-7.28(m,3H),6.68-6.65(m,1H),4.96(s,2H),4.49(d,J=6.0Hz,2 H),4.16(q,J2=14.3Hz,J2=1.7Hz,2 H),3.79(s,3H),1.18(t,J=6.6Hz,3H)。
步骤4:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲氧基-苯氧基]-乙酸
将[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸乙酯(1.23g,2.8mmol)的乙醇(16mL,0.18M)溶液冷却至0?,用氢氧化钠水溶液(1.25M,7.0mL,8.7mmol)处理。在搅拌2.5小时后,将溶液升温至室温,再搅拌24小时。然后,将溶液酸化至pH1-2,采用2N盐酸,用乙酸乙酯稀释和用饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲氧基-苯氧基]-乙酸,为一种白色固体(1.03g,89%):mp 203-204?;Rf0.10(10%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.02(br t,J=5.9Hz,1H),7.84,(d,J=8.2Hz,1H),7.50,(br d,J=8.7Hz,1H),7.48-7.29(m,2H),6.69-6.80(m,2H),4.87(s,2H),4.49(d,J=5.8Hz,2H),3.79(s,3H)。ESI-LC/MS m/z计算值C17H15BrFNO5:411.0;实测值412.0(M+1)-。分析计算值C17H15BrFNO5:C,49.53;H,3.67;N,3.40;实测值C,49.48;H,3.68;N,3.39。
实施例17
按照与实施例16所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-4-氯-苯氧基]-乙酸,只是5-氯水杨酸用于代替步骤1中的2-羟基-4-甲氧基苯甲酸:Rf0.10(10%乙酸乙酯的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.13(br t,J=5.7Hz,1H),7.76(d,J=2.7Hz,1H),7.55-7.46(m,2H),7.42-7.30(m,2H),7.16(d,J=8.7Hz,1H),4.86(s,J=6.3Hz,2H),4.49(d,J=6.3Hz,2H)。ESI LC/MS m/z计算值C16H12BrClFNO4:415.0实测值416.5(M+1)-。
实施例18
按照与实施例1所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-4-氟-苯氧基]乙酸,只是5-氟水杨酸用于代替步骤1中的4-氯水杨酸:mp 145-146?;1H NMR(DMSO-d6 300MHz)δ9.22(br t,J=5.7Hz,1 H),7.56(dd,J1=9.3Hz,J2=3.6Hz,1H),7.49(br dd,J1=9.0Hz,J2=1.5Hz,1H),7.41-7.29(m,3H),7.16(dd,J=9.3Hz,J2=4.2Hz,1H),4.84(s,2H),4.50(d,J=5.4Hz,2H)。ESI LC/MS m/z计算值C16H12BrFNO4:399.0;实测值400.0(M+1)+。分析计算值C16H10BrFNO4:C,48.02;H,3.02;N,3.50实测值C,48.09;H,3.05;N,3.43。
实施例19
按照与实施例1所述类似的方式制备[4-溴-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸,只是5-溴-2-羟基-苯甲酸用于代替步骤1中的4-氯-2-羟基-苯甲酸:mp 153-155?;Rf0.29(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.10(t,J=12.3Hz,1H),7.88(dd,J1=1.5Hz,J2=2.4Hz,1H),7.64(ddd,J1=8.7Hz,J2=2.7Hz,J3=1.2Hz,1H),7.51(d,J=9.3Hz,1H),7.37-7.53(m,2H),7.10(dd,J1=8.7Hz,J2=2.1Hz,1H),4.86(s,2H),4.48(d,J=6.0Hz,2H);ESI-LC/MS m/z计算值C17H15Br2FNO4:458.9.实测值462.0,(M+3)+。分析计算值C17H15Br2FNO4:C,41.68;H,2.62;Br,34.66;N,3.04.实测值C,41.82;H,2.71;Br,34.38;N,2.92。
实施例20
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-甲基-苯氧基]-乙酸
按照与实施例16所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-4-甲基-苯氧基]-乙酸,只是2-羟基-4-甲基苯甲酸用于代替步骤1中的2-羟基-4-甲氧基苯甲酸:mp 145-146℃;Rf0.11(10%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.10(br t,J=6.0Hz,1H),7.49(br,dd,J1=9.0Hz,J2=2.6Hz,1H),7.40-7.31(m,3H),7.26(dd,J1=8.7Hz,J2=2.6Hz,1H),7.00(d,J=9.0Hz,1H),4.80(s,2H),4.49(d,J=6.0Hz,2H),2.25(s,3H).ESI-LC/MS m/z计算值C17H15BrFNO4:395.0实测值394.0(M-1)-。分析计算值C17H15BrFNO4:C,51.53;H,3.82;N,3.54实测值C,51.06;H,3.88;N,3.47。
实施例21
步骤1:N-(4-溴-2-氟-苄基)-2-羟基-5-硝基-苯甲酰胺:
按照与实施例1所述类似的方式制备该化合物,只是2-羟基-5-硝基苯甲酸用于代替步骤1中的4-氯水杨酸:1H NMR(DMSO-d6 300MHz)δ9.56(br t,J=5.5Hz,1H),8.83(s,1H),8.26(dd,J1=9.2Hz,J2=2.7Hz,1H),7.53(br d,J=9.8Hz,1H),7.43-7.31(m,2H),7.11(d,J=9.1Hz,1h),4.52(d,J=5.5Hz,2H)。
步骤2:[2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]-乙酸叔丁酯:
将N-(4-溴-2-氟-苄基)-2-羟基-5-硝基-苯甲酰胺(0.95g,2.6mmol)的丙酮(15mL,0.2M)溶液用碳酸钾水溶液(2M,1.9mL,3.8mmol)和溴代乙酸叔丁酯(2.2mL,8.4mmol)处理。在50℃下加热30小时后,将反应的酸化至pH1-2,采用2N HCl,用乙酸乙酯萃取3次。将合并后的有机萃取液用饱和氯化钠水溶液洗涤,用硫酸钠干燥,过滤和浓缩。将粗油用庚烷和乙酸乙酯结晶,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]-乙酸叔丁酯,为一种白色结晶固体(1.21g,97%):1H NMR(DMSO-d6 300MHz)δ9.01(br t,J=5.7Hz,1H),8.58(d,J=3.0Hz,1H),8.33(dd,J1=9.0Hz,J2=3.0Hz,1H),7.51(br d,J=9.6Hz,1H),7.42-7.34(m,2H),7.32(d,J=9.3Hz,1H),4.99(s,2H),4.52(d,J=5.7Hz,2H),1.40(s,9H)。
步骤3:[2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]乙酸
将[2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]-乙酸叔丁酯的二氯甲烷(11mL,0.2M)溶液用三氟乙酸(3.0mL,4.44g.39.0mmol)处理,搅拌24小时。将反应物用水稀释,用乙酸乙酯萃取3次。将合并后的有机萃取液用水洗涤2次,用饱和氯化钠水溶液洗涤,用硫酸镁干燥,过滤和浓缩,得到一种粗固体,将其用庚烷和乙酸乙酯进行重结晶,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]-乙酸,为一种白色结晶固体(0.98g,92%);Rf0.10(10%乙酸乙酯的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.14(br t,J=6.0Hz,1H),8.58(d,J=3.3Hz,1H),8.34(dd,J1=9.0Hz,J2=3.0Hz,1H),7.52(br dd,J1=9.3Hz,J2=3.0Hz,1H),7.43-7.32(m,3H),5.02(s,2H),4.52(d,J=6.0Hz,2H)。ESI-LC/MS m/z计算值C16H12BrFN2O6:426.0实测值427.0(M+1)+。分析计算值C16H12BrFN2O6:C,44.99;H,2.83;N,6.56;实测值C,44.97;H,2.83;N,6.47。
实施例22
按照与实施例16所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基-苯氧基]-乙酸,只是2-羟基-4-甲基苯甲酸用于代替步骤1中的2-羟基-4-甲氧基苯甲酸:mp188-189℃;Rf0.10(10%乙酸乙酯的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ8.89(br t,J=6.0Hz,1H),7.57(d,J=7.8Hz,1H),7.30(dd,J1=10.5Hz,J2=1.5Hz,1H),7.20-7.08(m,2H),6.76(s,1H),6.69(d,J=8.1Hz,1H),4.64(s,2H),4.29(d,J=6.0Hz,2H),2.12(s,3H)。ESI LC/MSm/z计算值C17H15BrFNO4:395.0实测值394.0(M-1)-。分析计算值C17H15BrFNO4:C,51.53;H,3.82;N,3.54;实测值C,51.42;H,3.88;N,3.53。
实施例23
[2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
按照与实施例16所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸,只是水杨酸用于代替步骤1中的2-羟基-4甲氧基苯甲酸:mp144-145℃;Rf0.10(10%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6300MHz)δ9.11(br t,J=6.0Hz,1H),7.84(dd,J1=7.8Hz,J2=1.8Hz,1H),7.54-7.43(m,3H),7.41-7.32(m,1H),7.08(dd,J1=14.1Hz,J2=7.5Hz,2H),4.86(s,2H),4.50(d,J=5.7Hz,2H)。ESI-LC/MS m/z计算值C16H13BrFNO4:381.0实测值382.0(M+1)-。分析计算值C16H13BrFNO4:C,50.28;H,3.43;N,3.66;实测值C,50.36;H,3.49;N,3.62。
实施例24
步骤1:N-(4-溴-2-氟-苄基)-2-甲氧基-4-甲基硫烷基-苯甲酰胺:
将2-甲氧基-4-(甲硫基)苯甲酸(5.0g,25.2mmol)的二氯甲烷(50mL)溶液冷却至0℃,用草酰氯(6.6mL,75.6mmol)处理。加入一滴N,N-二甲基甲酰胺,将反应混合物加热至温和回流2小时。在冷却至室温后,将溶液真空浓缩除去过量的草酰氯,用二氯甲烷(53mL)洗涤,冷却至0℃。将形成的溶液用N,N二异丙基胺(11.6mL,67mmol)和4-溴-2氟苄基胺盐酸盐(9.7g,40.2mmol)处理。将形成的溶液在室温下过夜搅拌,真空浓缩,用乙酸乙酯稀释,依次用2N HCl和饱和氯化钠洗涤。有机层用硫酸镁干燥,过滤和浓缩。Rf0.43(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ8.63(t,J=6Hz,1H),7.70(d,J=8.1Hz,1H),7.50(dd,J1=9.6Hz,J2=2.1Hz,1H),7.38(dd,J1=8.4Hz,J2=2.0Hz,1H),7.28(t,J=8.4Hz,1H),6.94(br s,1H),6.89(dd,J,=5.7Hz,J2=1.7Hz,1H),4.46(d,J=6Hz,2H),3.91(s,3H),2.51(s,3H)。
步骤2:N-(4-溴-2-氟-苄基)-2-羟基-4-甲基硫烷基-苯甲酰胺:
将N-(4-溴-2-氟-苄基)-2-甲氧基-4-甲基硫烷基-苯甲酰胺(11g粗品,来自步骤1)溶解于25%HBr的冰醋酸溶液(400mL)中,在100℃下加热4小时。将溶液用乙酸乙酯稀释(750mL)和用饱和氯化钠(500mL)洗涤。有机层用硫酸镁干燥,过滤和浓缩。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),给出N-(4-溴-2-氟-苄基)-2-羟基-4-甲基硫烷基-苯甲酰胺(5.0g,50%)。Rf0.57(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ12.57(s,1H),9.22(t,J=5.4Hz,1H),7.78(d,J=8.4Hz,1H),7.52(dd,J1=9.8Hz,J2=1.7Hz,1H),7.40-7.27(m,2H),6.77-6.71(m,2H),4.46(d,J=5.7Hz,2H),2.46(s,3H)。
步骤3:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸乙酯:
将N-(4-溴-2-氟-苄基)-2-羟基-4-甲基硫烷基-苯甲酰胺(5.0g,13.5mmol)的丙酮(27mL)溶液用2N碳酸钾(10mL,20.3mmol)和溴代乙酸乙酯(2.2mL,20.3mmol)处理。将反应混合物在50℃下加热4小时,冷却至室温和酸化至pH1,采用2N盐酸。将产物用乙酸乙酯萃取和用饱和氯化钠洗涤。有机层用硫酸镁干燥,过滤和浓缩。将浅褐色固体悬浮于的庚烷和二氯甲烷中。将固体用庚烷洗涤,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸乙酯(5.3g,86%):Rf0.45(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ8.90(t,J=6Hz,1H),7.80(d,J=8.4Hz,1H),7.50(dd,J,=9.9Hz,J2=1.7Hz,1H),7.397.29(m,2H),6.97-6.93(m,2H),5.0(s,2H),4.50(d,J=6.0Hz,2H),4.17(q,J=7.1Hz,2H),1.18(t,J=7.2Hz,3H)。
步骤4:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸:
将[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸乙酯(1.0g,2.19mmol)的乙醇(11mL)悬浮液用2N氢氧化钠(6.6mL,13.2mmol)处理。将反应混合物在室温下搅拌2小时,真空浓缩和采用2N HCl水溶液酸化至pH1。将混合物用乙酸乙酯稀释和用饱和氯化钠洗涤。有机层用硫酸镁干燥,过滤和浓缩,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸(0.8g,85%),为一种白色结晶固体:mp196-199℃;Rf0.3(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.16(t,J=6.0Hz,1H),7.79(d,J=8.7Hz,1H),7.48(dd,J=8.7Hz,J2=1.5Hz,1H),7.36-7.32(m,2H),6.95-6.90(m,2H),4.87(s,2H),4.48(d,J=3.3Hz,2H),2.49(s,3H)。ESI-LC/MS m/z计算值C17H15BrFNO4S:428.3;实测值427.0(M-1)-。分析计算值C17H15BrFNO4S:C,47.68;H,3.53;N,3.27;S,7.49;实测值C,47.70;H,3.47;N,3.22;S,7.38。
实施例25
按照与实施例1所述类似的方式制备[2-(3-硝基-苄基氨基甲酰基)-4-甲基-苯氧基]-乙酸,只是5-甲基水杨酸用于代替步骤1中的4-氯水杨酸;和3-硝基苄基胺盐酸盐用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 193-194℃;Rf0.48(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.37(br s,1H),9.26(t,J=6Hz,1H),8.18(t,J=1.8Hz,1H),8.09(ddd,J1=8.3Hz,J2=2.3Hz,J3=1.0Hz,1H),7.79(d,J=7.5Hz,1H),7.65-7.58(m,2H),7.26(ddd,J1=8.4Hz,J2=2.4Hz,J3=0.6Hz,1H),7.00(d,J=8.1Hz,1H),4.82(s,2H),4.62(d,J=6Hz,2 H),2.25(s,3H)。ESI-LC/MSm/z计算值C17H16N2O6:344.3;实测值345.0(M+1)+。分析计算值C17H16N2O6:C,59.30;H,4.68;N,8.14;实测值C,59.10;H,4.78;N,7.90。
实施例26
向搅拌中的NaOH(8.15g,203.8mmol)水(35mL,5.8M)溶液中加入硝酸银水溶液(17.3g,101.9mmol,35mL水,2.9M)。形成褐色固体。将烧瓶置于冰浴中,向搅拌中的悬浮液中以500mg一份加入2-羟基-5-三氟甲氧基苯甲醛(10.0g,48.5mmol)。加完后,将反应混合物在冰浴中搅拌10分钟,将混合物过滤,用热水洗涤褐色沉淀物。将合并后的洗涤液用浓HCl酸化至pH1,通过真空过滤收集沉淀。然后,将固体溶解于乙酸乙酯。将乙酸乙酯溶液用饱和氯化钠水溶液洗涤,用硫酸钠干燥,过滤。再将水层用乙酸乙酯萃取。将有机层用饱和氯化钠水溶液洗涤,用硫酸钠干燥,过滤和浓缩,得到2-羟基-5-三氟甲氧基-苯甲酸(9.8g,91%),为一种白色固体:Rf0.38(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ10.30(bs,1H),7.79(d,J=3.0Hz,1H),7.41(dd,J1=9.3Hz,J2=3.0Hz,1H),7.05(d,J=9.0Hz,1H)。
步骤2:[2-(3-硝基-苄基氨基甲酰基)-4-三氟甲氧基-苯氧基]-乙酸
按照与实施例1所述类似的方式制备[2-(3-硝基-苄基氨基甲酰基)-4-三氟甲氧基-苯氧基]-乙酸,只是在步骤1中,2-羟基-5三氟甲氧基-苯甲酸用于代替步骤1中的4-氯-2羟基-苯甲酸和3-硝基苄基胺盐酸盐用于代替步骤1中的4-溴-2-氟苄基胺盐酸盐:mp 154-156℃;Rf0.38(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.30(t,J=6.0Hz,1H),8.20(s,1H),8.10(ddd,J1=8.1Hz,J2=3.3Hz,J3=1.2Hz,1H),7.81(d,J=7.8Hz,1H),7.74(dd,J1=3.6Hz,J2=0.06Hz,1H),7.62(t,J=7.8Hz,1H),7.51(ddd,J,=9.6Hz,J2=3.2Hz,J3=0.6Hz,1H),7.24(d,J=9.0Hz,1H),4.92(s,2H),4.63(d,J=6.3Hz,2H);ESI-LC/MS m/z计算值C17H13F3N2O7:414.07。实测值413(M-1)-。分析计算值C17H13F3N2O7:C,49.28;H,3.16;N,6.76;实测值C,49.19;H,3.23;N,6.67。
实施例27
步骤1:4-氟-2-羟基-苯甲酸:
将2,4-二氟苯甲酸(100g,0.63mol)的1,3-二甲基-2-咪唑啉酮(1,400mL,0.45M)溶液用氢氧化钠(88g,2.2mol)处理和并加热至135℃,在搅拌4小时后,将溶液冷却至0℃,溶解于水(100mL)中,转移至5L的锥形瓶中,小心地用HCl水溶液(2,800mL,2N)处理。在滤出粗产物后,将沉淀溶解于乙酸乙酯中,用硫酸钠和脱色炭干燥,过滤。将溶液进行减压浓缩和采用乙酸乙酯和庚烷进行重结晶,得到4-氟水杨酸(2crops,67g,68%),为一种灰白色针状物。mp:188-189℃;Rf0.26(20%甲醇的二氯甲烷溶液)。
步骤2:4-氟-2-羟基-苯甲酰氯:
将4-氟-2-羟基-苯甲酸(15g,96.1mmol)的庚烷(190mL)悬浮液用亚硫酰氯(21mL,288mmol)以滴加的方式处理30分钟。加入一滴N,N-二甲基甲酰胺,将溶液在60℃下加热4小时。减压滤除过量的亚硫酰氯。将其余的溶液冷却至室温,过滤和浓缩,得到4-氟-2-羟基-苯甲酰氯,为一种浅黄色结晶固体(14.2g,85%)。
步骤3:4-氟-2-羟基-N-(3-硝基-苄基)-苯甲酰胺:
将4-氟水杨酰氯(12.3g,70.3mmol)的二氯甲烷(140mL)溶液冷却至0℃,用N,N-二异丙基乙基胺(31.0mL,175mmol)和3-硝基苄基胺盐酸盐(16g,84.6mmol)处理。在室温下搅拌24小时后,将溶液真空浓缩和用乙酸乙酯稀释。有机层依次用2N HCl水溶液和饱和氯化钠水溶液洗涤,用硫酸镁干燥,过滤和浓缩。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),得到4-氟-2-羟基-N-(3-硝基-苄基)-苯甲酰胺,为一种黄色固体(13.7g,67%):1H NMR(DMSO-d6 300MHz)δ12.75(s,1H),9.43(t,J=6.0Hz,1H),8.11(ddd,J1=8.3,J2=2.1Hz,J3=1.2Hz,1H),8.18(t,J=1.5Hz,1H),7.94(dd,J1=8-9Hz,J2=6.5Hz,1H),7.78(td,J1=7.8Hz,J2=1.4Hz,1H),7.63(t,J=8.0Hz,1H),6.81-6.72(m,2H),4.61(d,J=5.7Hz,2H)。
步骤4:[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯:
将4-氟-2-羟基-N-(3-硝基-苄基)-苯甲酰胺(5.00g,17.2mmol)的丙酮(86.0mL)溶液用2N碳酸钾(13.0mL,25.8mmol)和溴代乙酸乙酯(1.50mL,9.66mmol)处理,在50℃下加热2小时。将溶液冷却至0℃和采用2N盐酸酸化至pH1。将溶液用乙酸乙酯稀释和用饱和氯化钠水溶液洗涤。有机层用硫酸镁干燥,过滤和浓缩。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),得到[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯,为-种浅黄色固体(6g,93%):mp 78-80℃;Rf0.26(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ9.01(t,J=6Hz,1H),8.19(t,J=1.8Hz,1H),8.10(dd,J1=8.1Hz,J2=1.5Hz,1H),7.89(dd,J1=8.7 Hz,J2=6.9Hz,1H),7.79(d,J=7.5Hz,1H),7.61(t,J=8.1Hz,1H),7.11(dd,J=11.1Hz,J2=2.4Hz,1H),6.92(dt,J1=8.4Hz,J2=2.4Hz,1H),5.0(s,2H),4.63(d,J=6.3Hz,2H),4.15(q,J=7.2Hz,2H)1.17(t,J 6.5Hz,3H)。ESI-LC/MS m/z计算值C18H17FN2O6:376.4;实测值377.0(M+1)+。分析计算值C18H17FN2O6:C,57.45;H,4.55;N,7.44;实测值:C,57.47;H,4.64;N,7.28。
步骤5:[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸:
将[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(3.3g,8.77mmol)的乙醇(40mL)溶液用2 N氢氧化钠水溶液(24mL,47.8mmol)处理。在搅拌4小时后,将溶液真空浓缩直至除去大多数乙醇,将混合物采用2N盐酸酸化至pH1。在用乙酸乙酯萃取后,有机层用饱和氯化钠水溶液洗涤,用硫酸镁干燥和浓缩,得到[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸,为一种灰白色固体(3.00g,98%):mp 148-151℃;Rf0.39(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.20(t,J=6.3Hz,1H)8.18(s,1H),8.09(dd,J1=7.2Hz,J2=2.7Hz,1H),7.90(dd,J1=8.7Hz,J2=7.0Hz,1H),7.79(d,J=7.5Hz,1H),7.61(t,J=7.8Hz,1H),7.08(dd,J1=10.8Hz,J2=2.1Hz,1H),6.91(dt,J1=8.7Hz,J2=2.4Hz,1H),4.89(s,2H),4.62(d,J=6Hz,2H)。ESI-LC/MS m/z计算值C16H13FN2O6:348.3;实测值347.0(M-1)-。分析计算值C16H13FN2O6:C,55.18;H,3.76;N,8.04;实测值C,55.02;H,3.79;N,7.98。
实施例28
按照与实施例1所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-苯氧基]-乙酸,只是4-氟水杨酸(实施例27)用于代替步骤1中的4-氯水杨酸:mp143145℃;Rf0.43(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.37(br s,1H),9.03(t,J=6Hz,1H),7.91(dd,J1=8.6Hz,J2=7.1Hz,1H),7.50(d,J=9.9Hz,1H),7.37-7.36(m,2H),7.09(dd,J1=11.0Hz,J2=2.4Hz,1H),6.92(dt,J1=8.4Hz,J2=2.4Hz,1H),4.90(s,2H),4.50(d,J=5.4Hz,2H)。ESI-LC/MS m/z计算值C16H12BrF2NO4:400.2;实测值400.5,402.0(M,M+2)+。分析计算值C16H12BrF2NO4:C,48.02;H,3.02;N,3.50;实测值:C,48.07;H,3.08;N,3.41。
实施例29
按照与实施例1所述类似的方式制备[5-氟-2-(4-甲基-3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸,只是4-氟水杨酸(实施例27)用于代替4-氯水杨酸;和4-甲基-3-硝基苄基胺用于代替步骤1中的4-溴-2氟苄基胺盐酸盐:mp 159-160℃;Rf0.48(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.37(br s,1H),9.12(t,J=5.9Hz,1H),7.92-7.87(m,2H),7.58(d,J=8.7Hz,1H),7.43(d,J=8.1Hz,1H),7.07(d,J=10.8Hz,1H),6.91(t,J=8.6Hz,1H),4.89(s,2H),4.55(d,J=6Hz,2H),2.46(s,3H)。ESI-LC/MS m/z计算值C17H16FN2O6:362.3;实测值361.0(M-1)-。分析计算值C17H15FN2O6C,56.36;H,4.17;N,7.73;实测值:C,56.18;H,4.22;N,7.60。
实施例30
按照与实施例27所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-4,5-二氟-苯氧基]-乙酸,只是2,4,5-三氟水杨酸用于代替步骤1中的2,4-二氟水杨酸;和4-溴-2-氟苄基胺盐酸盐用于代替步骤3中的3-硝基苄基胺盐酸盐:mp 156-158℃;Rf0.26(20%甲醇的二氯甲烷溶液);1HNMR(DMSO-d6 300MHz)δ9.11(t,J=5.6Hz,1H),7.80(dd,J1=11.4Hz,J2=9.6Hz,1H),7.50(dd,J1=9.6Hz,J2=1.8Hz,1H),7.447.34(m,3H),4.87(s,2H),4.49(d,J=5.7Hz,2H)。ESI LC/MS m/z计算值C16H11BrF3NO4:418.2;实测值417.0(M-1)-。分析计算值C16H11BrF3NO4:C,45.96;H,2.65;N,3.35。实测值:C,45.96;H,2.65;N,3.35。
实施例31
[2-(4-溴-2-氟-苄基氨基甲酰基)-3,5-二氟-苯氧基]-乙酸
按照与实施例27所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-3,5-二氟-苯氧基]-乙酸,只是2,4,6-三氟水杨酸用于代替步骤1中的2,4-二氟水杨酸;和4-溴-2-氟苄基胺盐酸盐用于代替步骤3中的3-硝基苄基胺盐酸盐:mp 158-159℃;分析计算值C16H11BrF3NO4:C,45.96;H 2.65;N,3.35;实测值:C,46.05;H,2.61;N,3.45。
实施例32
步骤1:[5-氟-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸乙酯:
在氮气氛下,在一个火焰干燥的烧瓶中,将五硫化磷(0.77g,1.73mmol)的吡啶(6.9mL)悬浮液用[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(实施例27,1.3g,3.45mmol)处理,在11℃下加热4小时。在冷却至室温后,将混合物用水和乙酸乙酯稀释。有机层依次用2N盐酸和饱和氯化钠洗涤,用硫酸镁干燥,浓缩。通过短硅胶热滤出深橙色固体,再次浓缩,得到[5-氟-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸乙酯,为一种橙色固体(1.2g,89%):mp 118℃;Rf0.43(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ10.71(s,1H),8.23(s,1H),8.12(d,J=8.1Hz,1H),7.83(d,J=7.8Hz,1H),7.71-7.60(m,2H),7.04(dd,J1=11.1Hz,J2=2.4Hz,1H),6.87(dt,J1=8.4Hz,J2=2.4Hz,1H),5.07(d,J=3.3Hz,2H),4.89(s,2H),4.13(q,J=6.7Hz,2H),1.17(t,J=5.7Hz,3H)。ESI-LC/MSm/z计算值C18H17FN2O5S:394.1;实测值393.0(M+1)+。分析计算值C18H17FN2O5S:C,55.09;H,4.37;N,7.14;实测值C,54.98;H,4.36;N,7.08。
步骤2:[5-氟-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸:
将[5-氟-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸乙酯(4.39g,11.2mmol)的乙醇(40mL)悬浮液用2N氢氧化钠(11mL,22.4mmol)的水溶液处理。在搅拌4小时后,将溶液进行真空浓缩,直至除去大多数的乙醇,将混合物用2N HCl酸化至pH1。在用乙酸乙酯萃取后,有机层用饱和氯化钠水溶液洗涤,用硫酸镁干燥,浓缩,得到[5-氟-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸(4.0g,98%),为一种灰白色固体:mp 147-150℃;Rf0.27(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.23(s,1H),10.79(t,J=5.7Hz,1H),8.23(t,J=1.8Hz,1H),8.11(ddd,J1=8.3Hz,J2=2.7Hz,J3=1.2Hz,1H),7.85(br d,J=7.5Hz,1H),7.73(dd,J1=8.9Hz,J2=7.1Hz,1H),7.63(t,J=8.1Hz,1H),7.03(dd,J1=11.4Hz,J2=2.4Hz,1H),6.86(dt,J,=8.4Hz,J2=2.4Hz,1H),5.07(d,J=5.7Hz,2H),4.83(s,2H)。ESI-LC/MS m/z计算值C16H13FN2O5S:364.4;实测值363.0(M-1)-。分析计算值C16H13FN2O5S:C,52.74:小时,3.60;N,7.69;实测值C,52.65;H,3.62;N,7.58。
实施例33
按照与实施例32所述类似的方式制备[2-(4-溴-2-氟-苄基硫代氨基甲酰基)-5-氟-苯氧基]-乙酸,只是[5-氟-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(实施例28)用于代替步骤1中的[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯:mp 154-157℃;Rf0.46(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.29(br s,1H),10.66(t,J=5.7Hz,1H),7.73(dd,J1=8.9Hz,J2=6.8Hz,1H),7.52(dd,J1=9.9Hz,J2=1.5Hz,1H),7.46-7.36(m,2H),7.04(dd,J1=11.3Hz,J2=2.3Hz,1H),6.86(dt,J1=8.4Hz,J2=2.4Hz,1H),4.90(d,J=5.7Hz,2H),4.81(s,2H)。ESI-LC/MS m/z计算值C16H12BrF2NO3S:415.0;实测值416.0(M+1)+。分析计算值C16H12BrF2NO3S:C,46.17;H,2.91;N,3.37;S,7.70;Br,19.20;实测值:C,46.17;H,2.90;N,3.33;S,7.62;Br,19.31。
实施例34
按照与实施例32所述类似的方式制备[4-溴-2-(4-溴-2-氟-苄基硫代氨基甲酰基)-苯氧基]-乙酸,只是[4-溴-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(实施例19)用于代替步骤1中的[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯:Rf0.30(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ10.78(t,J=5.9Hz,1H),7.68(t,J=2.4Hz,1H),7.56-7.51(m,2H),7.46-7.37(m,2H),7.04(d,J=9.0Hz,1H),4.87(bd s,2H),4.76(s,2H);ESI-LC/MS m/z计算值C16H12Br2FNO3S:474.9;实测值478(M+3)+。分析计算值C16H12Br2FNO3S:C,40.28;H,2.53;Br,33.49;N,2.94;S,6.72。实测值C,40.42;H,2.53;Br,33.31;N,2.84;S,6.61。
实施例35
按照与实施例32所述类似的方式制备[2-(3-硝基-苄基硫代氨基甲酰基)-4-三氟甲氧基-苯氧基]-乙酸,只是[2-(3-硝基-苄基氨基甲酰基)-4-三氟甲氧基-苯氧基]-乙酸乙酯(实施例26)用于代替步骤1中的[5-氟-2-(3-硝基-苄基氨基甲酰基-苯氧基]-乙酸乙酯:mp 158-161℃;Rf0.40(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ10.95(t,J=4.4Hz,1H),8.24(s,1H),8.12(dd,J1=7.8Hz,J2=2.4Hz,1H),7.85(d,J=7.8Hz,1H),7.64(d,J=8.0Hz,1H),7.55(d,J=3.0Hz,1H),7.40(dd,J1=8.7Hz,J2=3.0Hz,1H),7.16(d,J=9.0Hz,1H),5.07(d,J=5.7Hz,2H),4.81(s,2H);ESI-LC/MSm/z计算值C17H13F3N2O6S:430.04;实测值431.0(M+1)+。分析计算值C17H13F3N2O6S:C,47.44;N,6.51;H,3.04;S,7.45;实测值C,47.16;N,6.37;H,3.11;S,7.58。
实施例36
按照与实施例32所述类似的方式制备[2-(4-溴-2-氟-苄基硫代氨基甲酰基)-4,5-二氟-苯氧基]-乙酸,只是[4,5-二氟-2-(4-溴-2氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(实施例30)用于代替步骤1中的(5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯:mp 206-209℃;Rf0.5(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ10.8(br s,1H),7.70(dt,J1=9.3Hz,J2=2.1Hz,1H),7.52(dd,J1=9,9Hz,J2=2.1Hz,1H),7.45-7.30(m,3H),4.88(br s,2H),4.79(s,2H)。ESI-LC/MS m/z计算值C16H11BrF3NO3S:434.2;实测值432.0,433.0(M-2,M-1)-。分析计算值C16H11BrF3NO3S:C,44.26;H,2.55;N,3.23;S,7.38;实测值C,44.43;H,2.64;N,3.12;S,7.23。
实施例37
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸
步骤1:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸乙酯
在55℃下,向搅拌中的[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸乙酯(实施例24,2.0g,4.38mmol)的冰醋酸(44mL,0.1M)溶液中加入过硼酸钠(NaBO3á4水,16.9g,109.6mmol),将反应混合物搅拌过夜。然后,将反应混合物冷却至室温,用50mL乙酸乙酯稀释。有机层用水(3×50mL)和饱和氯化钠水溶液(50mL)洗涤。将有机层用硫酸钠干燥,过滤和减压浓缩。将形成的油用硅胶填料纯化(5%甲醇的二氯甲烷溶液)。将滤液浓缩,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸乙酯,为一种白色固体(1.56g,73%):mp140-143℃;Rf0.11(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ9.01(t,J=6.2Hz,1H),7.92(d,J=8.7Hz,1 H),7.61-7.58(m,2H),7.52(d,J=10.8Hz,1H),7.39-7.37(m,2H),5.02(s,2H),4.49(d,J=5.7Hz,2H),4.18(q,J=7.1Hz,2H),3.24(s,3H),1.19(t,J=7.1Hz,3H);分析计算值C11H19BrFNO6S:C,46.73;H,3.92;Br,16.36;N,2.87;S,6.57;实测值C,46.85;H,3.89;Br,16.48;N,2.98;S,6.48。
步骤2:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸
按照与实施例1步骤3所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸,只是[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸乙酯用于代替[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸乙酯,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸,为一种白色固体:mp 193194℃;Rf0.19(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.13(t,J=6.0Hz,1H),7.94(d,J=8.1Hz,1H),7.61-7.58(m,2H),7.51(d,J=10.8Hz,1H),7.40-7.38(m,2H),4.99(s,2H),4.49(d,J=6.0Hz,2H),3.24(s,3H);ESI-LC/MS m/z计算值C17H15BrFNO6S:458.98;实测值460.0(M+1)+;分析计算值C17H15BrFNO6Sá0.5水:C,43.51;H,3.44;N,2.98;S,6.83;实测值C,43.43;H,3.34;N,2.90;S,6.59。
实施例38
将(2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]-乙酸(1.10g,2.76mmol)溶解于乙醇(40mL,0.1M)中,用10%Pd/炭(Degussa,0.10g)处理,并置于氢气球下12小时。将反应混合物用硅藻土进行过滤,浓缩,得到一种粗固体,将其用庚烷和乙酸乙酯重结晶,得到[4-氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸(0.79g,66%):mp 204℃(分解);Rf0.10(10%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.16(brt,J=6.3Hz,1H),7.85(d,J=2.7Hz,1H),7.46-7.11(m,5H),4.91(s,2H),4.57(br d,J=3.6Hz,2H)。ESI-LC/MS m/z计算值C16H14BrFN2O4:396.0实测值395.0(M-1)-。分析计算值C16H14BrFN2O4:C,48.38;H,3.55;N,7.05。实测值C,48.05;H,4.02;N,6.94。
实施例39
步骤1:[4-氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸烯丙基酯:
将[4-氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸(0.62g,1.56mmol)溶解于烯丙醇(15mL,0.1M)中。将溶液用7滴浓硫酸处理,在室温下搅拌48小时。将反应混合物浓缩,再溶解于乙酸乙酯中,用水,饱和氯化钠水溶液(3x)洗涤,用硫酸钠干燥和过滤。将滤液用脱色炭处理,沸腾10分钟,冷却至室温,过滤和浓缩。将粗固体用庚烷和乙酸乙酯进行重结晶,得到[4-氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸烯丙基酯,为一种淡橙色固体(0.13g,20%)。1H NMR(DMSO-d6 300MHz)δ8.92(br t,J=5.4Hz,1H),7.49-7.80(m,4H),6.84(d,J=8.7Hz,1H),6.63(br dd,J1=8.7Hz,J2=2.7Hz,1H),5.95-5.79(m,1H),5.29(br d,J=17.1Hz,1H),5.19(br d,J=10.5Hz,1H),4.91(br s,1H),4.83(br s,2H),4.61(br d,J=5.4Hz,1H)。
步骤2:[4-乙酰基氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸烯丙基酯
将[4-氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸烯丙基酯(0.13g,0.30mmol)溶解于四氢呋喃(2mL,0.2M)和吡啶(0.05mL,0.05g,0.61mmol)中。将混合物冷却至0℃,之后用乙酸酐(0.10mL,0.098g,0.95mmol)处理。在室温下搅拌24小时后,将反应混合物用乙酸乙酯稀释,依次用2N盐酸,饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到[4-乙酰基氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸烯丙基酯(0.125g,87%):1H NMR(DMSO-d6 300MHz)δ9.95(br s,1H),8.94(br t,J=5.7Hz,1H),7.98(d,J=2.7Hz,1H),7.74(dd,J1=9.0Hz,J2=3.0Hz,1H),7.42-7.24(m,2H),7.22-7.02(m,2H),5.88(m,1H),5.30(dd,J1=17.1Hz,J2=1.8Hz,1H),5.21(dd,J1=9.0Hz,J2=1.8hz,1H),4.97(s,2H),4.64(br d,J=5.4Hz,2H),4.55(br d,J=6.0Hz,2H),2.00(s,3H)。
步骤3:[4-乙酰基氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
将[4-乙酰基氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸烯丙基酯(0.114g,0.24mmol)在10%水的1,4-二恶烷(8mL,0.03M)溶液用比咯烷(pyrollidine)(0.05mL,0.60mmol)和[(C6H5)3P]4Pd(0.01g,3.6mol%)处理,搅拌6小时。将反应混合物用乙酸乙酯稀释,用2NHCl(3x),水(2x),饱和氯化钠水溶液洗涤,用硫酸镁干燥,过滤,浓缩,用庚烷和乙酸乙酯重结晶,得到[4-乙酰基氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸(0.055g,52%),为一种白色固体:mp 235℃;1HNMR(DMSO-d6 300MHz)δ9.93(br s,1H),9.16(br t,1H),7.98(br d,J=2.7Hz,1H),7.73(br dd,J1=9.0Hz,J2=2.7Hz,1H),7.44-7.20(m,2H),7.20-7.00(m,2H),4.80(s,2H),4.54(brd,J=4.5Hz,2H),1.99(s,3H)。
实施例40
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-三氟甲基-苯氧基]-乙酸
按照与实施例31所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-4-三氟甲基-苯氧基]-乙酸,只是2-氟-4-(三氟甲基)-苯甲酸用于代替步骤1中的2,4,6-三氟苯甲酸:mp 169-170℃;1H NMR(DMSO-d6 300MHz)δ9.12(br t,J=6.5Hz,1H),7.94(d,J=7.5Hz,1H),7.54-7.34(m,5H),4.98(s,2H),4.49(d,J=5.7Hz,2H);分析计算值C17H12BrF4NO4:C,45.36;H,2.69;N,3.11;实测值C,45.55;H,2.76;N,3.12。
实施例41
[4-烯丙氧基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
步骤1:5-烯丙氧基-2-羟基-苯甲酸甲酯:
将2,4-二羟基苯甲酸甲酯(8.60g,51.2mmol)溶解于丙酮(125mL,0.4M)中,然后用碳酸钾(27.2g,196.8mmol)和烯丙基溴(6.0mL,8.39g,69.3mmol)处理。将反应混合物在60℃下加热20小时,然后酸化至pH1-2,采用2N盐酸,用乙醚萃取4次。将合并后的萃取液用饱和氯化钠水溶液洗涤(2x),用硫酸钠干燥,过滤和浓缩,得到5-烯丙氧基-2-羟基-苯甲酸甲酯,为一种粗黄色油(6.11g,57%):1H NMR(DMSO-d6 300MHz)δ10.74(s,1H),7.69(d,J=8.4Hz,1H),(m,2H),6.08-5.94(m,1H),5.38(dd,J1=1.8Hz,J2=16.8Hz,2H),4.61(d,J=5.4Hz,2H),3.81(s,3H)。
步骤2:2-羟基-5-丙氧基-苯甲酸:
将5-烯丙氧基-2-羟基-苯甲酸甲酯(6.10g,29.30mmol)溶解于甲醇(25.0mL,1.2M)中。将溶液用氢氧化钠水溶液(75mL,1.33M,100mmol)处理,在室温下搅拌48小时。将反应混合物酸化至pH1-2,采用浓HCl,用乙酸乙酯萃取4次。将合并后的有机萃取液用水洗涤2次,用饱和氯化钠水溶液洗涤,用硫酸钠干燥,过滤和浓缩,得到2-羟基-5-丙氧基-苯甲酸(5.30g,91%),为一种浅黄色固体:分析计算值C10H10O4:C,61.85;H,5.19。实测值:C,62.06;H,5.27。
步骤3:[4-烯丙氧基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
按照与实施例1所述类似的方式制备[4-烯丙氧基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸,只是5-烯丙氧基-2-羟基-苯甲酸用于代替步骤1中的4-氯水杨酸。1H NMR(DMSO-d6 300MHz)δ13.33(br s,1H),9.03(t,J=5.7Hz,1H),7.83(d,J=9.0Hz,1H),7.48(d,J=9.6Hz,1H),7.38-7.28(m,2H),6.70-6.65(m,2H),6.10-5.94(m,1H),5.39(d,J=17.1Hz,1H),5.25(d,J=10.5Hz,1H),4.85(s,2H),4.61(dd,J1=1.5Hz,J2=5.4Hz,2H),4.48(d,J=6.0Hz,2H)。ESI-LC/MS m/z计算值C19H17BrFNO5:437.0;实测值438.0(M+1)+。分析计算值C19H17BrFNO5:C,52.07;H,3.91;N,3.20。实测值:C,52.12;H,3.95;N,3.19。
实施例42
将[4-烯丙氧基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(1.02g,2.40mmol)和Pd(Ph3)4(15mg,1.4mol%)在1,4-二恶烷溶液(10mL,95%1,4-二oxane)中的溶液用吡咯烷(0.45mL,5.39mmol)以滴加的方式处理。在室温下搅拌2小时后,将溶液用乙酸乙酯稀释和用10%HCl水溶液,饱和氯化钠水溶液洗涤,用硫酸钠干燥,过滤和浓缩。将形成的粗固体用乙酸乙酯和庚烷重结晶,得到[4-羟基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(0.780g,76%),为一种白色结晶固体。
步骤2:[4-羟基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
将[4-羟基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(0.773g,1.83mmol)的乙醇(10mL,0.18M)溶液冷却至0℃,用KOH水溶液(5mL,1.25M)处理,升温至室温。将溶液酸化至pH1-2,用乙酸乙酯稀释和用饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到[4-羟基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸,为一种白色结晶固体:mp 244分解;1H NMR(DMSO-d6 300MHz)δ10.14(brs,1H),8.97(t,J=5.4Hz,1H),7.75(dd,J1=8.4Hz,J2=0.3Hz,1H),7.48(d,J=9.6Hz,1H),7.37-7.26(m,2H),6.46(dd,J1=8.7Hz,J2=2.1Hz,1H),6.40(s,1H),4.77(s,2H),4.47(d,J=5.4Hz,2Hz)。分析计算值C16H13BrFNO5,:C,48.26;H,3.29;N,3.52;实测值C,48.19;H,3.52;N,3.32。
实施例43
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-丙氧基-苯氧基]-乙酸
按照与实施例1所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-4-丙氧基-苯氧基]乙酸,只是2-羟基-5-丙氧基-苯甲酸用于代替步骤1中的4-氯水杨酸:1H NMR(DMSO-d6 300MHz)δ。ESI-LC/MS m/z计算值C19H19BrFNO5:439.0;实测值440.0(M+1)+。
实施例44
步骤1:[4-丙氧基-2-(2-氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯
将[4-烯丙氧基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯(0.998g,2.35mmol)的乙醇(150mL)和乙酸乙酯(5mL)溶液脱气,置于氮气氛下。加入钯催化剂(10%Pd/C,Degussa),将烧瓶抽空,用氢气(气球)处理。在过夜搅拌后,将溶液用硅胶垫过滤和用甲醇洗涤。在将溶液浓缩后,将粗产物用快速柱色谱纯化(30%庚烷的乙酸乙酯溶液),得到[4-丙氧基-2-(2-氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯。
步骤2:[4-丙氧基-2-(2-氟-苄基氨基甲酰基)-苯氧基]-乙酸
将[4-丙氧基-2-(氟-苄基氨基甲酰基)-苯氧基]-乙酸乙酯的乙醇(20mL)溶液冷却至0℃,用有KOH水溶液(7.5mL,1.25M)处理,升温至室温。将溶液酸化至pH1-2,用乙酸乙酯稀释,用饱和氯化钠水溶液搅拌。将有机层用硫酸钠干燥,过滤和浓缩,得到[4-羟基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸,为一种白色结晶固体:1H NMR(DMSO-d6 300MHz)δ13.34(br s,1H),9.03(s,1H),7.85(dd,J1=9Hz,J2=2.1Hz,1H),7.40-7.12(m,4H),6.62(s,2H),4.84(s,2H),4.54(s,2H),3.96(t,J=6.3Hz,2H),1.78-1.63(m,2H),0.98-0.91(m,3H)。
实施例45
步骤1:1-氟-5-甲氧基-2-甲基-4-硝基-苯:
在氮气氛下,在一个nalgene瓶中,将搅拌中的吡啶(17.1mL,3.2M,-70℃)用HF-吡啶(51.91mL)滴加处理。然后,加入5-甲氧基-2-甲基-4-硝基苯基胺(10.0g,54.9nmol),再加入亚硝酸钠(6.4g,92.76mmol)。除去干冰/丙酮浴,使反应混合物升温至室温。然后,将溶液在60℃下加热2小时(或直至氮气释放停止)。在冷却至室温后,将nalgene瓶置于浴浴中,向溶液中缓慢地加入375mL水。通过抽滤收集形成的橙色沉淀,用到1-氟-5-甲氧基-2-甲基-4-硝基-苯(7.69g,76%),为一种淡橙色固体:mp 71-74?;Rf0.56(30%乙酸乙酯的庚烷溶液);1H NMR(CDCl3 300MHz)δ7.82(d,J=7.5Hz,1H),6.75(d,J=10.5Hz,1H),3.93(s,3H),2.25(d,J=2.1Hz,3H);ESI-LC/MS m/z计算值C8H8FNO3:185.1;实测值186.0(M+1)+。分析计算值C8H8FNO3:C,51.90;H,4.36;实测值C,52.11;H,4.47。
步骤2:4-氟-2-甲氧基-5-甲基-苯基胺:
将1-氟-5-甲氧基-2-甲基-4-硝基-苯(5.5g,29.3mmol)和10%Pd-C(1.56g)的乙醇(300mL,0.1M)溶液在1大气压下氢化。在搅拌过夜后,将溶液通过硅胶垫冲洗,用400mL乙醇作为洗脱液。将滤液进行减压浓缩,得到4-氟-2-甲氧基-5-甲基-苯基胺(4.5g,99%),为一种浅紫外固体:mp 108-110?;Rf0.35(30%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ6.62(d,J=11.4Hz,1H),6.43(d,J=7.8Hz,1H),3.70(s,3H),2.02(d,J=1.8Hz,3H);ESI-LC/MS m/z计算值C8H10FNO:155.1;实测值156.0(M+1)+。分析计算值C8H10FNO:C,61.92;H,6.50;实测值:C,61.64;H,6.53。
步骤3:1-溴-4-氟-2-甲氧基-5-甲基-苯:
将4-氟-2-甲氧基-5-甲基-苯基胺(25.75g,0.17mol)在180mLHBr(48%,0.9M)中的悬浮液于冰浴上用亚硝酸钠水溶液(12.6g,0.18mol,3.6M)进行滴加处理。释放出褐色气体,检测反应的温度,从而使其内部温度不升温至10℃。在此期间,将CuBr(13.1g,0.09mol)在6.5mL HBr(48%,13.9M)中的悬浮液加热至110?。然后,将0℃下的溶液缓慢地倒入(在20分钟内)搅拌中的CuBr悬浮液中。将合并后的反应混合物在110℃下加热2.5小时。在冷却至室温后,将溶液用乙酸乙酯稀释和用硫酸水溶液(50%v/v)处理。分离有机层,依次用水,硫酸,水,1.25M氢氧化钠,水和饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和减压浓缩。将形成的褐色油进行硅胶快速色谱纯化(5%乙酸乙酯的庚烷溶液),得到1-溴-4-氟-2-甲氧基-5-甲基-苯(17.1g,47%),为一种澄清液体:Rf0.70(30%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ7.34(d,J=8.4Hz,1H),6.61(d,J=10.8Hz,1H),3.85(s,3H),2.18(d,J=1.8Hz,3H);分析计算值C8H8BrFO:C,43.86;H,3.68;Br,36.48;实测值C,44.01;H,3.68;Br,36.57。
步骤4:4-氟-2-甲氧基-5-甲基-苯甲腈:
将1-溴-4-氟-2-甲氧基-5-甲基-苯(5.0g,22.8mmol)的DMF(100mL,0.2M)溶液用CuCN(4.7g,52.5mmol)处理。备有回收冷凝器,将反应混合物在160℃下加热20小时。在冷却至室温后,将溶液倒入2L的锥形瓶中。向溶液中加入乙酸乙酯(400mL),饱和氯化锂水溶液(100mL),1N盐酸(100mL),11g氯化铁(III)六水合物和15mL浓HCl。将这种绿色的混合物在70℃下加热2小时(或直至乳状液消失)。在冷却至室温后,将混合物倒入分离漏斗中,用乙酸乙酯(总共600mL)萃取。将合并后的有机层用1N HCl(200mL),饱和氯化锂(2×200mL)和饱和氯化钠水溶液(100mL)洗涤。将有机层用硫酸钠干燥,过滤,减压浓缩。将形成的粉末溶解于乙酸乙酯(50mL)中,再用饱和氯化锂(3×30mL)洗涤,用硫酸钠干燥,过滤,减压浓缩,得到4-氟-2-甲氧基-5-甲基-苯甲腈(3.25g,86%),为一种米色粉末:mp 99-101℃;Rf0.53(30%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ7.39(d,J=8.1Hz,1 H),6.65(d,J=11.1Hz,1H),3.89(d,J=0.9Hz,3H),2.21(s,3 H);分析计算值C9H8FNO:C,65.45;H,4.88;实测值C,65.17;H,4.97。
步骤5:4-氟-2-甲氧基-5-甲基-苯甲酸:
将4-氟-2-甲氧基-5-甲基-苯甲腈(3.0g,18.2mmol)的2N氢氧化钠(300mL,0.06M)中的悬浮液于90℃下加热19小时。然后滤出沉淀,回收0.86g的4-氟-2-甲氧基-5-甲基-苯甲腈。将水层酸化至pH1,采用浓HCl。将混浊的水层用乙酸乙酯(2×250mL)萃取。将合并后的有机层用硫酸钠干燥,过滤和浓缩,得到4-氟-2-甲氧基-5甲基-苯甲酸,为一种白色粉末(2.28g,96%,基于回收的原料):mp 125-127?;Rf0.15(40%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ10.20(s,1H),8.05(d,J=9.0Hz,1H),6.74(d,J=10.8Hz,1H),4.04(s,3H),2.25(d,J=1.8Hz,3H);ESI-LC/MS m/z计算值C9H9FO3:184.1;实测值185.0(M+1)+。分析计算值C9H9FO3:C,58.70;H,4.93;实测值C,58.58;H,4.97。步骤6:N-(4-溴-2-氟-苄基)-4-氟-2-甲氧基-5-甲基-苯甲酰胺
在干燥的氮气氛下,将4-氟-2-甲氧基-5-甲基-苯甲酸(1.19g,6.47mmol)的二氯甲烷(16mL,0.5M)溶液用草酰氯(1.7mL,19.4mmol)和一滴DMF在0℃下处理。将混合物逐渐升温至室温,然后浓缩,得到一种黄色粉末。将粉末溶解于二氯甲烷(16mL,0.5M)中。在0℃下,向搅拌中的溶液中加入二异丙基胺(2.8mL,16.2mmol),随后加入4-溴-2-氟苄基胺盐酸盐(2.34g,9.71mmol)。在氮气氛下搅拌,将混合物逐渐升温至室温。21小时后,将反应混合物依次用1N盐酸(3×50mL)和饱和氯化钠水溶液(50mL)洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到N-(4-溴-2-氟-苄基)-4-氟-2-甲氧基-5-甲基-苯甲酰胺(2.33g,97%),为一种褐色油,其可不经纯化直接使用:Rf0.40(30%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ8.17(bd s,1H),8.06(d,J=9.3Hz,1H),7.33-7.22(m,3H),6.65(d,J=11.1Hz,1H),4.63(d,J=6.3Hz,2H),3.92(s,3H),2.23(bd d,J=1.8Hz,3H)。
步骤7:N-(4-溴-2-氟-苄基)-4-氟-2-羟基-5-甲基-苯甲酰胺
将搅拌中的N-(4-溴-2-氟-苄基)-4-氟-2-甲氧基-5-甲基-苯甲酰胺(2.32g,6.51mmol)在25%HBr的乙酸溶液(60mL,0.11M)中的悬浮液配备回流冷凝器,并在120℃下加热3.5小时。将混合物冷却,加入饱和氯化钠水溶液(50mL)和乙酸乙酯(50mL)。使两层分离,收集有机层。水层用乙酸乙酯(2×50mL)萃取。将合并后的有机层用硫酸钠干燥,过滤和浓缩,得到得到一种橙色粉末。对固体进地硅胶快速色谱纯化(30%乙酸乙酯的庚烷溶液),得到N-(4-溴-2-氟-苄基)-4-氟-2-羟基-5-甲基-苯甲酰胺(1.69,73%),为一种白色粉末:mp 149-150?;Rf0.51(30%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ12.20(d,J=1.5,1H),7.30-7.29(m,2H),7.26(s,1H),7.14(d,J=8.1Hz,1H),6.64(d,J=10.8,1H),6.48(bd s,1H),4.62(d,J=5.7Hz,2H),2.19(s,3 H);ESI-LC/MS m/z计算值
C15H12BrF2NO2:355.0;实测值354.0(M-1)-。分析计算值C15H12BrF2NO2:C,50.58;H,3.40;N,3.93;实测值C,50.65;H,3.47;N,3.87。
步骤8:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯
将搅拌中的N-(4-溴-2-氟-苄基)-4-氟-2-羟基-5-甲基-苯甲酰胺(1.69g,4.76mmol)的丙酮(24mL,0.2M)溶液用碳酸钾水溶液(3.6mL,2M,7.12mmol)和溴代乙酸乙酯(0.63mL,5.69mmol)的丙酮(24mL,0.2M)溶液处理,在50℃下加热2.5小时。在冷却至室温后,将溶液浓缩,酸化至pH1,采用2N盐酸,用乙酸乙酯稀释(100mL),用50mL饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯(1.95,93%),为一种白色固体:mp 128-129?;Rf0.42(30%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ8.79(bd t,J=4.5Hz,1H),8.10(d,J=9.0Hz,1H),7.34(t,J=8.3Hz,1H),7.267.23(m,1H),7.21(t,J=2.3Hz,1H),6.53(d,J=10.5Hz,1H),4.66(d,J=3.9Hz,1H),4.65(s,2H),4.28(q,J=7.2Hz,2H),2.23(bd d,J=1.5Hz,3H),1.30(t,J=7.2Hz,3H);分析计算值C19H18BrF2NO4:C,51.60;H,4.10;N,3.17;实测值C,51.65;H,4.19;N,3.10。
步骤9:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸
将搅拌中的[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯(0.72g,1.62mmol)的乙醇(8.1mL,0.2M)溶液置于冰浴中,用氢氧化钠水溶液(1.25M,7.8mL,9.73mmol)处理。将混合物逐渐升温至室温,2小时后,将混合物进行减压浓缩,用乙酸乙酯稀释,用2N HCl(10mL)处理。将分离出的有机层用饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸(0.66g,98%),为一种白色固体:mp169?;Rf0.22(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.00(bd t,J=5.3Hz,1H),7.76(d,J=9.6Hz,1H),7.49(d,J=9.6Hz,1H),7.39-7.33(m,2H),7.04(dd,=11.4Hz,J2=1.4Hz,1H),4.84(d,J=1.8Hz,2H),4.48(bd s,2H),2.17(s,3H);ESI-LC/MS m/z计算值C17H14BrF2NO4:413.0;实测值412(M-1)-。分析计算值C17H14BrF2NO4:C,49.30;H,3.41;N,3.38;实测值C,49.32;H,3.43;Br,3.32。
实施例46
步骤1:[2-(4-溴-2-氟-苄基硫代氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯
将搅拌中的[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯(0.816g,1.83mmol)的吡啶(3.7mL,0.5M)溶液用五硫化磷(0.41g,0.92mmol)处理,在115℃下加热3小时。将混合物逐渐升温至室温,用乙酸乙酯稀释,依次用1M HCl和饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和减压浓缩。将形成的褐色油溶解于少量二氯甲烷中,采用硅胶填料冲洗,使用40%乙酸乙酯的庚烷溶液作为洗脱液。将滤液浓缩,得到[2-(4-溴-2-氟-苄基硫代氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯(0.75g,89%),为一种黄色固体:mp 98-100?;Rf0.45(30%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ10.15(bs,1H),8.26(d,J=8.4Hz,1H),7.38(t,J=8.4Hz,1H),7.26-7.23(m,2H),6.53(d,J=10.8Hz,1H),5.08(d,J=5.4Hz,2H),4.67(s,3H),4.20(q,J=7.2Hz,2H),2.23(s,2H),1.27(dt,J1=6.8 Hz,J2=0.6Hz,3H)。
步骤2:[2-(4-溴-2-氟-苄基硫代氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸
将搅拌中的[2-(4-溴-2-氟-苄基硫代氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯(0.79g,1.53mmol)的乙醇(7.6mL,0.2M)溶液用氢氧化钠水溶液(2N,7.4mL,9.15mmol)以与实施例45,步骤9类似的方式处理,得到[2-(4-溴-2-氟-苄基硫代氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸(0.65g,98%),为一种黄色固体:mp 162-164?;Rf0.41(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ10.64(t,J=5.0Hz,1H),7.61(d,J=9.0Hz,1H),7.52(dd,J1=9.6Hz,J2=1.7Hz,1H),7.45-7.36(m,2H),7.00(d,J=11.4Hz,1H),4.89(bd d,J=5.1Hz,2H),4.78(s,2H),2.15(d,J=1.2Hz,3H);ESI-LC/MS m/z计算值C17H14BrF2NO3S:428.98;实测值428.0(M-1)-;分析计算值C17H14BrF2NO3S:C,47.45;H,3.28;N,3.26;S,7.45;实测值C,47.54;H,3.19;N,3.11;S,7.33。
实施例47
[2-(3-硝基-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸
按照与实施例45所述类似的方式制备[5-氟-4-甲基-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸,只是2,3-硝基苄基胺盐酸盐用于代替步骤6中的4-溴-2-氟苄基胺盐酸盐:mp 177-179?;Rf0.28(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.14(t,J=6.2Hz,1H),8.17(s,1H),8.09(dd,J1=8.4Hz,J2=1.2Hz,1H),7.79-7.75(m,2H),7.60(t,1H),7.04(d,J=5.9Hz,1H),4.87(s,2H),4.62(d,J=4.2Hz,2H),2.17(s,3H);ESI-LC/MS m/z计算值C17H15FN2O6:362.1;实测值363.0(M+1)+。分析计算值C17H15FN2O6:C,56.36;H,7.73;N,4.17;实测值C,56.45;H,7.64;N,4.19。
实施例48
[2-(3-硝基-苄基硫代氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸
按照与实施例46所述类似的方式制备[5-氟-4-甲基-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸,只是[5-氟-4-甲基-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯用于代替步骤1中的[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯:mp 137-139℃;Rf0.29(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6,300MHz)δ10.81(bds,1H),8.23(s,1H),8.12(dd,J1=7.8Hz,J2=2.0Hz,1H),8.84(d,J=7.5Hz,1H),7.65-7.60(m,2H),6.99(d,J=11.4Hz,1H),5.07(bd d,J=3.6Hz,2H),4.79(3,2H),2.15(d,J=1.5Hz,3H);ESI-LC/MS m/z计算值C17H15FN2O5S:378.1;实测值377.0(M-1)-。分析计算值C17H15FN2O5S:C,53.96;H,4.00;N,7.4;S,8.47;实测值C,53.97;H,4.02;N,7.33;S,8.40。
实施例49
[4-溴-5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸
步骤1:5-溴-4-氟-2-羟基-苯甲酸
向搅拌中的4-氟-2-羟基-苯甲酸(5.58g,35.7mmol)的二甲基甲酰胺(72mL,0.5M)溶液中加入N-溴琥珀酰亚胺(7.08g,39.3mmol)。将混合物在室温下搅拌24小时。然后,将混合物用300mL的乙酸乙酯稀释,依次用水(3×330mL)和饱和氯化锂水溶液(4×200mL)洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到5-溴-4-氟-2-羟基-苯甲酸(8.1g,96%),为一种米色粉末。请注意,产物包含高达20%的二溴化杂质,在与苄基胺偶联或经甲基化反应(实施例50)后,可将这种杂质从目的产物中分离出去:Rf0.32(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ8.00(d,J=8.1Hz,1H),7.05(d,J=10.5Hz,1H)。
步骤2:[4-溴-5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸
按照与实施例1所述类似的方式制备[4-溴-5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸,只是在步骤1中,5-溴-4-氟-2羟基-苯甲酸用于代替4-氯-2-羟基苯甲酸和3-硝基苄基胺盐酸盐用于代替4-溴-2-氟苄基胺盐酸盐:mp 169-172℃;Rf0.28(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.17(bt,J=4.5,1H),8.19(s,1H),8.11(d,J=8.1Hz,1H),8.05(d,J=8.4Hz,1H),7.80(d,J=7.8Hz,1H),7.62(t,J=8.1Hz,1H),7.35(d,J=10.5Hz,1H),4.93(s,2H),4.63(d,J=5.7Hz,2H);ESI-LC/MS m/z计算值C16H12BrFN2O6:426.0;实测值427.0(M+1)+。分析计算值C16H12BrFN2O6:C,44.99;H,2.83;N,6.56;Br,18.71;实测值C,44.87;H,2.87;N,6.46;Br,18.59。
实施例50
[5-(3-硝基-苄基氨基甲酰基)-2-氟-联苯基-4-基氧基]-乙酸
步骤1:5-溴-4-氟-2-甲氧基-苯甲酸甲酯
将搅拌中的5-溴-4-氟-2-羟基-苯甲酸(15.0g,63.8mmol)的丙酮(128mL,0.5M)溶液用无水碳酸钾(19.4g,140.4mmol)和碘代甲烷(24.0mL,383.0mmol)处理。备有回流冷凝器,将混合物在60℃下加热过夜。根据TLC在无原料存在后,将反应混合物冷却至室温,浓缩,用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,70分钟),得到5-溴4-氟-2-甲氧基-苯甲酸甲酯(13.52g,80%),为一种白色固体:mp xx℃;Rf0.56(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ8.05(d,J=7.8Hz,1H),6.76(d,J=10.5Hz,1H),3.89(s,3H),3.88(s,3H)。
步骤2:6-氟-4-甲氧基-bi苯基-3-甲酸甲酯
向包含脱气的甲苯(15.2mL,0.5M)的火焰干燥的烧瓶中加入5-溴-4-氟-2-甲氧基-苯甲酸甲酯(2.0g,7.6mmol),无水碳酸钾(2.1g,15.2mmol),苯基硼酸(3.7g,30.4mmol),和Pd(PPh3)4(0.88g,0.76mmol)。采用回流冷凝器,将搅拌的混合物于110℃下加热3.5小时。然后,将混合物冷却至室温,置于冰浴中,缓慢地加入H2O2(30%,10mL)。除去冰浴,将反应混合物在室温下搅拌1小时。然后,用乙醚稀释混合物,依次用2N HCl和饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到一种褐色油。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),得到6-氟-4甲氧基-联苯基-3-甲酸甲酯(1.8g,91%),为一种浅黄色固体:Rf0.5(40%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ8.00(d,J=9.0Hz,1H),7.53-7.33(m,5H),6.79(d,J=12.6Hz,1H),3.94(s,3H),3.89(s,3H)。
步骤3:6-氟-4-甲氧基-联苯基-3-甲酸
向搅拌中的6-氟-4-甲氧基-联苯基-3-甲酸甲酯(0.5g,2.3mmol)的二恶烷(8mL,0.3M)溶液中加入2N氢氧化钠(6.0mL,12mmol)。在室温下1小时后,将反应混合物浓缩,加入2N盐酸。将水层用乙醚稀释。分离出有机层,用硫酸钠干燥,过滤和浓缩,得到6-氟-4-甲氧基-联苯基-3-甲酸(0.55g,96%),为一种浅黄色粉末:Rf0.18(5%甲醇的二氯甲烷溶液);1H NMR(CDCl3,300MHz)δ8.35(d,J=9.0Hz,1H),7.55-7.52(m,2H),7.48-7.38(m,3H),6.89(d,J=11.7Hz,1H),4.12(s,3H)。
步骤4:6-氟-4-甲氧基-联苯基-3-甲酸3-硝基-苄基酰胺
将搅拌中的6-氟-4-甲氧基-联苯基-3-甲酸(1.0g,4.06mmol)的二氯甲烷(8.2mL,0.5M)浆液用草酰氯(1.1mL,12.2mmol)和DMF(1滴)处理。将混合物加热至40℃直到溶液澄清(1-2小时)。然后,将混合物冷却至室温,减压浓缩,然后用二氯甲烷(8.2mL,0.5M)稀释。向在0℃下搅拌中的混合物中加入二异丙基胺(1.8mL,10.2mmol),随后加入3-硝基苄基胺盐酸盐(1.2g,6.1mmol)。在氮气氛下搅拌下,将溶液逐渐升温至室温,搅拌过夜。然后,将混合物用二氯甲烷稀释,再用2N盐酸(2×50mL)和饱和氯化钠水溶液(1×100mL)洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到一种黄色油。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),得到6-氟-4-甲氧基-联苯基-3-甲酸3-硝基-苄基酰胺(1.0g,65%),为一种黄色固体:Rf0.33(50%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ8.90(bd t,J=6.2Hz,1H),8.10(dd,J1=7.2 Hz,J2=2.4Hz,1H),7.84(d,J=9.3Hz,1H),7.79(d,J=7.5Hz,1H),7.63(t,J=8.0Hz,1H),7.52-7.43(m,5H),7.40-7.34(m,1H),7.20(d,J=12.9Hz,1H),4.61(d,J=6.0Hz,2H),3.96(s,3H)。
步骤5:6-氟-4-羟基-联苯基-3-甲酸3硝基-苄基酰胺
将-78℃下搅拌中的6-氟-4-甲氧基-联苯基-3-甲酸3-硝基-苄基酰胺(2.18g,5.7mmol)的二氯甲烷(150mL,0.4M)溶液用BBr3(27mL,27mmol)处理。将混合物在-78℃下搅拌45分钟,然后用100mL甲醇使反应停止。将混合物升温至室温,浓缩,和用硅胶填料过滤,采用50%乙酸乙酯作为洗脱液。将滤液浓缩,得到6-氟-4-羟基-联苯基-3-甲酸3-硝基苄基酰胺(2.1g,100%),为一种黄色粉末:Rf0.68(50%乙酸乙酯的庚烷溶液);1H NMR(CDCl3,300MHz)δ12.29(bd s,1H),8.14-8.09(m,2H),7.65(d,J=7.2Hz,1H),7.48(t,J=8.0Hz,1H),7.38-7.29(m,5H),6.74(d,J=11.4Hz,1H),6.60(bd s,1H),4.68(d,J=6.0Hz,2H)。
步骤6:[2-氟-5-(3-硝基-苄基氨基甲酰基)-联苯基-4-基氧基]-乙酸
按照与实施例45(步骤8-9)所述类似的方式制备[2-氟-5-(3-硝基-苄基氨基甲酰基)-联苯基-4-基氧基]-乙酸,只是6-氟-4-羟基-联苯基-3-甲酸3-硝基-苄基酰胺用于代替步骤8中的N-(4-溴-2-氟-苄基)-4-氟-2-羟基-5-甲基-苯甲酰胺:mp 210-211℃;Rf0.53(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.18(t,J=5.9Hz,1H),8.20(s,1H),8.11(dd,J1=8.1Hz,J2=1.1Hz,1H),7.96(d,J=9.3Hz,1H),7.81(d,J=8.1Hz,1H),7.62(t,J=7.8Hz,1H),7.52-7.35(m,5H),7.22(d,J=12.3Hz,1H),4.96(s,2H),4.64(d,J=6.3Hz,2H);ESI-LC/MS m/z计算值C22H17FN2O6:424.1;实测值423.0(M-1)-。分析计算值C22H17FN2O6:C,62.26;N,6.60;H,4.04;实测值C,62.18;N,6.47;H,4.14。
实施例51
按照与实施例46所述类似的方式制备[2-氟-5-(3-硝基-苄基硫代氨基甲酰基)-联苯基-4-基氧基]-乙酸,只是在步骤1中,[2-氟-5-(3硝基-苄基氨基甲酰基)-联苯基-4-基氧基]-乙酸乙酯用于代替[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯:mp 177-179?;Rf0.46(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ10.85(bds,1H),8.26(d,J=3.0Hz,1H),8.12(d,J=8.4Hz,1H),7.86(d,J=6.6Hz,1H),7.82(d,J=9.3Hz,1H),7.64(t,J=8.0Hz,1H),7.51-7.36(m,5H),7.18(d,J=12.6Hz,1H),5.10(bd d,J=6.0Hz,2H),4.89(s,2H);ESI-LC/MS m/z计算值C22H17FN2O5S:440.1;实测值439.0(M-1)-。分析计算值C22H17FN2O5S:C,59.99;N,6.36;H,3.89;实测值C,59.79;N,6.12;H,4.11。
实施例52
[2-(3-硝基-苄基氨基甲酰基)-4-氰基-5-氟-苯氧基]-乙酸
步骤1:5-氰基-4-氟-2-甲氧基-苯甲酸甲酯
将搅拌中的5-溴-4-氟-2-甲氧基-苯甲酸甲酯(5.0g,10.0mmol)的DMF(38mL,0.5M)溶液用CuCN(3.92g,43.7mmol)处理。备有回流冷凝器,将混合物于150℃下加热24小时。在冷却后,将反应混合物倒入2L的锥形瓶中。向溶液中加入乙酸乙酯(400mL),饱和氯化锂水溶液(100mL),1N盐酸(100mL),11g氯化铁(III)六水合的和15mL的浓盐酸。将这种绿色的混合物在70℃下加热2小时(或直至乳状液消失)。在冷却至室温后,将混合物倒入分离漏斗中,用乙酸乙酯(总共600mL)萃取。将合并后的有机层用1N HCl(200mL),饱和氯化锂(2×200mL)和饱和氯化钠水溶液(100mL)洗涤。将有机层用硫酸钠干燥,过滤,减压浓缩。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),得到5氰基-4-氟-2-甲氧基-苯甲酸甲酯(2.98g,75%),为一种白色结晶固体:1H NMR(CDCl3,300MHz)δ8.15(d,J=7.5Hz,1H),6.80(d,J=11.1Hz,1H),3.97(s,3H),3.90(s,3H)。
步骤2:5-氰基-4-氟-2-甲氧基-苯甲酸
将搅拌中的5-氰基-4-氟-2-甲氧基苯甲酸甲酯(2.98g,14.25mmol)的乙醇(30mL,0.5M)溶液用1.25M氢氧化钠(68mL,85.5mmol)处理。在10分钟内,溶液澄清,通过TLC,所有的原料被消耗。将溶液浓缩,然后用2N盐酸处理,直至pH为1。通过抽滤收集形成的白色沉淀,将其溶解于二恶烷中,有饱和氯化钠水溶液洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到5-氰基-4-氟-2-甲氧基-苯甲酸(1.9g,70%),为一种白色固体。Rf=0.34(20%甲醇的二氯甲烷溶液);1H NMR(CDCl3,300MHz)δ8.13(d,J=8.1Hz,1H),7.36(d,J=12.0Hz,1H),3.90(s,3H)。
步骤3:[5-氰基-4-氟-2-甲氧基-N-(3-硝基-苄基)-苯甲酰胺
向搅拌中的5-氰基-4-氟-2-甲氧基-苯甲酸(1.92g,9.8mmol)的二氯甲烷(20mL,0.5M)浆液中加入草酰氯(2.57mL,29.5mmol)和DMF(1滴)。将混合物加热到40℃直至溶液澄清(1-2小时)。然后,将混合物冷却至室温,减压浓缩,然后用二氯甲烷(20mL,0.5M)稀释。向在0℃下搅拌中的混合物中加入二异丙基胺(4.3mL,24.6mmol),随后加入3-硝基苄基胺盐酸盐(2.78g,14.8mmol)。在氮气氛下搅拌下,将溶液逐渐升温至室温,搅拌过夜。然后,将混合物用二氯甲烷稀释,再用2N盐酸(3×25mL)和饱和氯化钠水溶液(2×25mL)洗涤。将有机层用硫酸钠干燥,过滤和浓缩,得到一种黄色油。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),得到[5-氰基-4-氟-2-甲氧基-N-(3-硝基-苄基)-苯甲酰胺(2.0g,63%),为一种黄色固体:1H NMR(DMSO-d6 300MHz)δ8.55(d,J=7.5Hz,1H),8.19(s,1H),8.15(d,J=8.4Hz,1H),7.96(bd s,1H),7.70(d,J=6.3Hz,1H),7.54(t,J=8.0Hz,5H),6.86(d,J=10.5Hz,1H),4.76(d,J=5.4Hz,1H),4.07(d,J=1.2Hz,3H)。
步骤4:5-氰基-4-氟-2-羟基-N-(3-硝基-苄基)-苯甲酰胺
将-78℃下搅拌中的[5-氰基-4-氟-2-甲氧基-N-(3-硝基-苄基)-苯甲酰胺(1.5g,4.6mmol)的二氯甲烷(200mL,0.3M)溶液用BBr3(2l.5mL,21.4mmol)处理。将混合物在-78℃下搅拌45分钟,然后除去干冰/丙酮浴,使溶液升温至室温。然后,再将溶液冷却至-78℃,然后用100mL甲醇使反应停止。将混合物升温至室温,浓缩,用MPLC纯化(10-100%乙酸乙酯,23mL/分钟,75分钟),得到5-氰基-4-氟-2羟基-N-(3-硝基-苄基)-苯甲酰胺(0.85g,59%),为一种米色粉末:Rf0.37(70%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ9.50(bd s,1H),8.39(d,J=7.5Hz,1H),8.20(s,1H),8.12(d,J=9.3Hz,1H),7.80(d,J=7.2Hz,1H),7.63(t,J=7.8Hz,1H),7.04(d,J=11.1Hz,1H),4.62(s,2H)。步骤5:[4-氰基-5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸
按照与实施例45(步骤8-9)所述类似的方式制备[4-氰基-5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸,只是在步骤8中,5-氰基4-氟-2-羟基-N-(3-硝基-苄基)-苯甲酰胺用于代替N-(4-溴-2-氟苄基)-4-氟-2-羟基-5-甲基-苯甲酰胺。在步骤9中,在水解[4-氰基-5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯时须特别小心。水解是在二恶烷中进行,而非在乙醇中进行,在15分钟后停止反应以防止氰基官能团水解:mp 179-180?;Rf0.22(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.12(t,J=6.0Hz,1H),8.21(d,J=7.8Hz,1H),8.19(s,1H),8.10(dd,J1=8.4Hz,J2=2.6Hz,1H),7.80(d,J=8.4Hz,1H),7.61(t,J=8.0Hz,1H),7.45(d,J=11.4Hz,1H),4.99(s,2H),4.61(d,J=6.0Hz,2H);ESI-LC/MS m/z计算值C17H12FN3O6:373.1;实测值472.0(M-1)-。分析计算值C17H12FN3O6:C,54.70;N,11.26;H,3.24;实测值C,54.43;N,11.07;H,3.32。
实施例53
步骤1:4-氟-2-甲氧基-5-吗啉-4-基-苯甲酸甲酯
在火焰干燥的烧瓶中,在氮气氛下,将干透的碳酸铯(4.33g,13.3mmol)与乙酸钯(85.3mg,0.380mmol)和R-(+)-2,2’-二(联苯基膦基(phosphino))-1,1’-联萘(0.355g,0.570mmol)合并。在稳定的氮气流下,将混合物溶解于甲苯(0.76mL)中,用5-溴-4-氟-2-甲氧基-苯甲酸甲酯(2.50g,9.50mmol)和吗啉(0.995mL,11.4mmol)处理。在100℃下加热24小时后,将反应混合物冷却至室温,用乙醚稀释,过滤和浓缩。用MPLC纯化(乙酸乙酯的庚烷溶液),得到4-氟-2-甲氧基-5吗啉-4-基-苯甲酸甲酯(1.20g,47%)1H NMR(DMSO-d6 300MHz)δ7.33(d,J=9.9Hz,1H),7.08(d,J=14.4Hz,1H),3.76(s,3H),3.75(s,3H),3.70(t,J=4.7Hz,4H),2.90(t,J=4.5Hz,4H)。步骤2:4-氟-2-甲氧基-5-吗啉-4-基-苯甲酸:
钭4-氟-2-甲氧基-5-吗啉-4-基苯甲酸甲酯(1.20g,4.46mmol)的乙醇(22.0mL)悬浮液用2N氢氧化钠水溶液(13mL,26.7mmol)处理。将混合物在室温下搅拌2小时,浓缩直至大多数乙醇除去,用2N盐酸酸化至pH1。在用乙酸乙酯萃取后,将有机层用饱和氯化钠水溶液洗涤,用硫酸镁干燥和浓缩,得到4-氟-2-甲氧基-5-吗啉-4-基苯甲酸(0.90g,79%):1H NMR(DMSO-d6 300MHz)δ12.62(s,1H),7.34(d,J=10.5Hz,1H),7.04(d,J=14.7Hz,1H),3.76(s,3H),3.70(t,J=4.7Hz,4H),2.90(t,J=4.7Hz,4H)。
步骤3:N-(4-溴-2-氟-苄基)-4-氟-2-甲氧基-5-吗啉-4-基-苯甲酰胺:
将4-氟-2-甲氧基-5-吗啉-4-基-苯甲酸(0.90g,3.53mmol)的二氯甲烷(7.0mL)溶液冷却至0?,用草酰氯(0.90mL,10.6mmol)处理,用催化量的N,N-二甲基甲酰胺(1滴)催化。30分钟后,将反应混合物在40℃下加热1小时,冷却至室温和浓缩。将形成的褐色固体再溶解于的二氯甲烷(7.0mL)中,冷却至0?,用N,N二异丙基胺(3.0mL,17.6mmol)和5-溴-2氟-苄基胺盐酸盐(1.0g,5.29mmol)处理。将混合物在室温下过夜搅拌。通过过滤分离出沉淀的固体。将其余的滤液用水洗涤,再用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用硫酸镁干燥,浓缩和用MPLC纯化(乙酸乙酯的庚烷溶液)。将形成的产物与初始沉淀的产物合并,得到N-(4-溴-2-氟-苄基)-4-氟-2-甲氧基-5-吗啉-4-基-苯甲酰胺(0.94g,68%);1H NMR(DMSO-d6 300MHz)δ8.84(t,6Hz,1H),8.18(s,1H),8.09(dd,J1=8.3Hz,2=2.3Hz,1H),7.77(d,J=7.8Hz,1H),7.61(t,J=8.0Hz,1H),7.46(d,J=10.2Hz,1H),7.10(d,J=14.4Hz,1H),4.58(d,J=6Hz,2H),3.87(s,3H),3.71(t,J=4.7Hz,4H),2.90(t,J=4.7Hz,4H)。
步骤4:N-(4-溴-2-氟-苄基)-4-氟-2-羟基-5-吗啉-4-基-苯甲酰胺:
将N-(4-溴-2-氟-苄基)-4-氟-2-甲氧基-5-吗啉-4-基-苯甲酰胺(0.94g,24.1mmol)在25%HBr/AcOH溶液(25mL)中的溶液在100?下加热6小时,冷却至室温,用乙酸乙酯萃取。将粗产的通过硅胶短垫过滤,浓缩,得到固体N-(4-溴-2-氟-苄基)-4氟-2-羟基-5-吗啉-4-基-苯甲酰胺(0.8g,88%):1H NMR(DMSO-d6 300MHz)δ12.4(s,1H),9.34(br s,1H),8.12(s,1H),8.05(d,J=8.1Hz,1H),7.72(d,J=4.5Hz,1H),7.56(t,J=8.1Hz,1H),7.47(d,J=9.6Hz,1H),6.69(d,J=13.2Hz,1H),4.56(d,J=6Hz,2H),3.65(br d,J=3Hz,4H),2.84(br d,J=3Hz,4H)。
步骤5:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-吗啉-4-基-苯氧基]-乙酸乙酯:
将N-(4-溴-2-氟-苄基)-4-氟-2-羟基-5-吗啉-4-基-苯甲酰胺(0.8g,2.13mmol)的丙酮(11mL)溶液用2N碳酸钾水溶液(1.6mL,3.20mmol)和溴代乙酸乙酯(0.35mL,3.20mmol)处理,并加热至50?。在搅拌30分钟后,将反应混合物冷却至室温和用2N盐酸酸化至酸化至pH7。将形成的溶液用乙酸乙酯萃取,再用饱和氯化钠洗涤。有机层用硫酸镁干燥,过滤和浓缩,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-吗啉-4-基-苯氧基]-乙酸乙酯(0.8g,81%):1H NMR(DMSO-d6 300MHz)δ9.05(t,J=6Hz,1H),8.18(d,J=2.1Hz,1H),8.09(ddd,J1=8.4Hz,J2=2.4Hz,J3=0.9Hz,1H),7.79(d,J=7.8Hz,1H),7.61(t,J=8.0Hz,1H),7.54(d,J=10.2Hz,1H),7.15(d,J=14.1Hz,1H),4.94(s,2H),4.63(d,J=6Hz,2H),4.14(q,J=7.2Hz,2H),3.71(t,J=4.7Hz,4H),2.92(t,J=4.7Hz,4H),1.16(t,J=7.2Hz,3H)。
步骤6:[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-吗啉-4-基-苯氧基]-乙酸
将[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-吗啉-4-基-苯氧基]-乙酸乙酯(0.8g,1.73mmol)的乙醇(9mL)悬浮液用2N氢氧化钠水溶液(5.0mL,10.4mmol)处理。在搅拌30分钟后,将反应混合物进行真空浓缩,直至大多数乙醇除去。将混合物用2N盐酸酸化至pH3,用乙酸乙酯萃取,用饱和氯化钠洗涤。有机层用硫酸镁干燥,过滤和浓缩,得到[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-吗啉-4-基-苯氧基]-乙酸(0.7g,93%),为一种白色结晶固体:mp 180?;Rf0.17(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.21(t,J=5.4Hz,1H),8.17(s,1H),8.09(dd,J1=8.1Hz,J2=2.4Hz,1H),7.78(d,J=7.5Hz,1H),7.65-7.52(m,2H),7.13(d,J=13.8Hz,1H),4.85(s,2H),4.62(d,J=6Hz,2H),3.71(t,J=4.7Hz,4H),2.91(t,J=4.8Hz,4H)。分析计算值C20H20FN3O7:C,55.43;H,4.65;N,9.70;实测值C,55.49;H,4.68;N,9.60。
实施例54
{5-氟-2[(4,5,7-tri氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-
步骤1:2,3,5,6-四氟乙酰苯胺
将2,3,5,6-四氟苯胺(200g,1.21mol)的无水吡啶(103mL,1.27mol)溶液用乙酸酐(120mL,1.27mol)处理,在120℃下加热2小时。在冷却至室温后,将溶液倒入冰冷却的水(500mL)中。将形成的沉淀过滤,溶解于乙酸乙酯中,用硫酸镁干燥,过滤和浓缩。将固体物质用庚烷(200mL)洗涤,干燥,得到2,3,5,6-四氟乙酰苯胺,为一种白色结晶固体(206g,82%):mp 136-137?;Rf0.48(50%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6300MHz)δ10.10(s,1H),7.87-7.74(m,1H),2.09(s,3H)。分析计算值C8H5F4NO:C,46.39;H,2.43;N,6.67;实测值C,46.35;H,2.39;N,6.68。
步骤2:2,3,5,6-四氟硫代乙酰苯胺
在火焰干燥的4颈5,000mL圆底烧瓶中加入五硫化磷(198g,0.45mol),用无水苯(3,000mL,0.34M)稀释。一次性加入2,3,5,6-四氟乙酰苯胺(185g,0.89mol),将亮黄色悬浮液加热,温和回流3小时。将溶液冷却至0?,过滤。将不溶性物质用乙醚(2×250mL)洗涤,将合并后的滤液用10%氢氧化钠水溶液(750mL,500mL)萃取。在将水层冷却至0℃后,小心地用浓盐酸酸化(pH2-3)。过滤收集沉淀出的产物,用水(500mL)洗涤。将黄色-橙色物质溶解于乙酸乙酯(1,000mL),用硫酸镁和活性炭(3g)干燥,用硅胶短垫(50g)过滤,浓缩。将形成的固体用庚烷(500mL)研制,过滤,得到2,3,5,6-四氟硫代乙酰苯胺(174.9g,88%):mp:103-104?;Rf0.67(50%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ11.20(s,1H),8.00-7.88(m,1H),2.66(s,3H)。分析计算值C8H5F4NS:C,43.05;H,2.26;N,6.28;实测值C,43.10;H,2.23;N,6.19。
步骤3:4,5,7-三氟-2-甲基苯并噻唑
在火焰干燥的备有顶部搅拌器的5,000mL圆底烧瓶中加入氢化钠(15.9g,0.66mol),用无水甲苯(3,000mL,0.2M)洗涤。将悬浮液冷却至0?,和一次性用2,3,5,6-四氟硫代乙酰苯胺(134g,0.60mol)处理。将溶液在1小时内升温至室温,然后加热进行温和回流。在30分钟后,小心地加入N,N-二甲基甲酰胺(400mL),将混合物再搅拌2小时。将溶液冷却至0?,再加至冰-水(2,000mL)中。将溶液用乙酸乙酯(1,500mL)萃取,用饱和氯化钠水溶液(1,000mL)洗涤。将有机层浓缩至干,再用庚烷稀释,依次用水(300mL)和饱和氯化钠水溶液(1,000mL)洗涤。有机层用硫酸镁干燥,过滤和浓缩,得到4,5,7-三氟-2-甲基苯并噻唑(116.8g,96%),为一种淡褐色固体:mp:91-92?;Rf0.56(30%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ7.76-7.67(m,1H),2.87(s,3H);.分析计算值C8H4F3NS:C,47.29;H,1.98;N,6.82;S,15.78;实测值C,47.56;H,2.07;N,6.82;S,15.59。
步骤4:2-氨基-3,4,6-三氟苯硫酚盐酸盐
将4,5,7-三氟-2-甲基苯并噻唑(25.0g,123mmol)的乙二醇(310mL,0.4M)和30%氢氧化钠水溶液(310mL,0.4M)的溶液用氮气流脱气,随后加热进行温和回流(125℃)3小时。将溶液冷却至0?和用浓盐酸(约200mL)酸化至pH3-4。将溶液用乙醚(750mL)萃取,用水(200mL)洗涤。将有机层用硫酸钠干燥,过滤和用2,2-二-叔丁基-4-甲基苯酚(0.135g,0.5mol%)处理。在浓缩至干后,将粗产的溶解于无水甲醇(200mL)中,再用HCl的1,4-二恶烷(37mL,4N,148mmol)溶液处理。将形成的混合物浓缩至干,用异丙基醚(100mL)研制,过滤,得到2-氨基-3,4,6-三氟苯硫酚盐酸盐(19.3g,73%),为一种淡褐色固体,其可不经纯化而使用。mp.121-124?;Rf0.43(30%乙酸乙酯的庚烷溶液);分析计算值C6H5ClF3NS:C,33.42;H,2.34;N,6.50;S,14.87;实测值C,33.45;H,2.27;N,6.48;S,14.96。
步骤5:N-氰基甲基-4-氟-2-羟基-苯甲酰胺:
将4-氟水杨酸氯化物(实施例1,10g,57.3mmol)的二氯甲烷(114mL)溶液用N,N-二异丙基乙基胺(25mL,143mmol)和乙腈盐酸盐(7.95g,85.9mmol)处理。在35℃下搅拌24小时后,将溶液进行减压浓缩,用乙酸乙酯稀释,依次用2N盐酸和饱和氯化钠水溶液稀释剂。将形成的溶液用硫酸镁干燥,过滤和浓缩。将形成的固体悬浮于二氯甲烷中,过滤和用庚烷漂法,得到N-氰基甲基-4-氟-2-羟基-苯甲酰胺(7.20g,65%):1H NMR(DMSO-d6 300MHz)δ12.16(br s,1H),9.17(t,J=5.3Hz,1H),7.88(dd,J1=8.7Hz,2=6.3Hz,1H),6.81-6.73(m,2H),4.32(d,J=5.7Hz,2H)。
步骤6:4-氟-2-羟基-N-(4,5,7,-三氟-苯并噻唑-2-基甲基)-苯甲酰胺:
将N-氰基甲基-4-氟-2-羟基-苯甲酰胺(2.93g,13.6mmol)和2-氨基-4,5,7-三氟苯硫酚盐酸盐(6.64g,13.6mmol)的乙醇(27.2mL)溶液加热回流24小时。在冷却至室温后,将混合物真空浓缩,用水稀释,用乙酸乙酯萃取。有机层用饱和氯化钠水溶液洗涤,用硫酸镁干燥,过滤和浓缩。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),得到4-氟-2-羟基-N-(4,5,7-三氟-苯并噻唑-2-基甲基)-苯甲酰胺(1.00g,21%),为一种白色结晶固体:1H NMR(DMSO-d6 300MHz)δ12.35(brs,1H),9.70(t,J=5.4Hz,1H),7.95(dd,J1=8.9Hz,J2=6.8Hz,1H),7.80-7.70(m,1H),(m,2H),4.94(t,J=3Hz,2H)。
步骤7:{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-乙酸乙酯:
将4-氟-2-羟基-N-(4,5,7,-三氟-苯并噻唑-2-基甲基)-苯甲酰胺(1.0g,2.8mmol)的丙酮(14mL)溶液用2 N碳酸钾水溶液(2.1mL,4.2mmol)和溴代乙酸乙酯(2mL,19mmol)处理,在45℃下加热5小时。在冷却至室温后,用2N盐酸将溶液酸化至pH1,将形成的溶液用乙酸乙酯稀释和用饱和氯化钠洗涤。有机层用硫酸镁干燥,过滤和浓缩。用MPLC纯化(10-100%乙酸乙酯的庚烷溶液23mL/分钟,75分钟),得到{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-乙酸乙酯(1.0g,81%),为一种白色结晶固体:1H NMR(DMSO-d6 300MHz)δ9.32(t,J=5.9Hz,1H),7.94(dd,J1=9.0Hz,J2=7.2Hz,1H),7.80-7.70(m,1H),7.13(dd,J1=11.1Hz,J2=2.4Hz,1H),6.95(dt,J1=8.4Hz,J2=2.5Hz,1H),5.02(s,2H),4.94(d,J=6Hz,2H),4.17(q,J=7.2Hz,2H),1.18(t,J=7.1Hz,3H)。步骤8:{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-乙酸:
将{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-乙酸乙酯(1g,2.3mmol)的乙醇(11mL)溶液用2 N氢氧化钠水溶液(6.8mL,14mmol)处理,在室温下搅拌。在搅拌1小时后,将溶液真空浓缩和酸化至pH1,采用2N盐酸。半形成的溶液用乙酸乙酯稀释和用饱和氯化钠洗涤。有机层用硫酸镁干燥,过滤和浓缩,得到{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-乙酸(0.68g,73%),为一种白色结晶固体。mp 172-174?;Rf0.38(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.25(br s,1H),9.49(t,J=6Hz,1H),7.95(dd,J1=9Hz,J2=7.2Hz,1H),7.78-7.69(m,1H),7.11(dd,J1=11.0Hz,J2=2.3Hz,1H),6.94(dd,J,=8.4Hz,J2=2.4Hz,1H),4.94-4.92(m,4H)。ESI-LC/MS m/z计算值C17H10F4N2O4S:414.3;实测值413.0(M-1)-。分析计算值C17H10F4N2O4SC,49.28;H,2.43;N,6.76;实测值C,49.26;H,2.47;N,6.68。
实施例55
{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)-硫代氨基甲酰基]-苯氧
基}-乙酸
步骤1:{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)-硫代氨基甲酰基]-苯氧基}-乙酸乙酯:
在火焰干燥的烧瓶中,在氮气氛下,将五硫化磷(2.9g,6.4mmol)的吡啶(26mL)悬浮液用{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-乙酸乙酯(实施例54,5.7g,13mmol)处理,在115℃下加热4小时。在冷却至室温后,将混合物用水和乙酸乙酯稀释,将有机层依次用2N盐酸(2x)和饱和氯化钠洗涤,用硫酸镁干燥,浓缩。将形成的褐色油用MPLC进行色谱纯化(10-100%乙酸乙酯的庚烷溶液,23mL/分钟,75分钟),得到{5-氟-2-[(4,5,7-三氟苯并噻唑-2-基甲基)-硫代氨基甲酰基]-苯氧基}-乙酸乙酯(2.0g,34%):1H NMR(DMSO-d6 300MHz)δ10.98(br s,1H),7.79(br t,J=6.0Hz,2H),7.06(br d,J=11.1Hz,1H),6.90(br t,J=9Hz,1H),5.38(br s,2H),4.89(s,2H),4.12(q,J=7.2Hz,2H),1.16(t,J=7.13H)。
步骤2:{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)-硫代氨基甲酰基]-苯氧基}-乙酸:
将(5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)-硫代氨基甲酰基]-苯氧基}-乙酸乙酯(2.0g,4.3mmol)的乙醇(22 mL)悬浮液用2N氢氧化钠水溶液(13mL,26mmol)处理。在搅拌2小时后,将溶液真空浓缩以除去大多数乙醇,酸化至pH1,采用2N盐酸。将产物用乙酸乙酯萃取,用饱和氯化钠洗涤。有机层用硫酸镁干燥,过滤和浓缩,得到{5-氟-2-[(4,5,7-三氟苯并噻唑-2-基甲基)-硫代氨基甲酰基]-苯氧基}-乙酸,为一种橙色固体(1.05g,57%):mp 150?;Rf0.50(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.76(br s,1H),7.83(br t,J=8.0Hz,1H),7.79-7.70(m,1H),7.14(dd,J,=11.1Hz,J2=2.4Hz,1H),6.84(dt,J1=8.4Hz,J2=2.4Hz,1H),5.37(d,J=5.7Hz,2H),4.58(s,2H)。ESI-LC/MS m/z计算值C17H10F4N2O3S2:430.4;实测值429.0(M-1)-。分析计算值C17H10F4N2O3S2:C,47.44;H,2.34;N,6.51;S,14.90。实测值C,46.72;H,2.81;N,5.85:S,12.02。乙醇和水仍可存在于样品中,应从分析中除去。
实施例56
{5-氟-2-[(5-三氟甲基-苯并噻唑-2-基甲基)-氨基甲酰基]-苯氧基}-
按照与实施例54(步骤5-8)所述类似的方式制备{5-氟-2-[(5-三氟甲基-苯并噻唑-2-基甲基)-氨基甲酰基]-苯氧基}-乙酸,只是5-氨基-3-(三氟甲基)苯硫酚盐酸盐用于代替步骤6中的2-氨基-4,5,7-三氟苯硫酚盐酸盐:mp 206-208?;Rf0.32(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ13.36(s,1H),9.45(t,J=6Hz,1H),8.30-8.28(m,2H),7.96(dd,J1=9Hz,J2=7.2Hz,1H),7.73(dd,J,=8.4Hz,J2=2.0Hz,1H),7.11(dd,J1=11.1Hz,J2=2.4Hz,1H),6.94(dt,J1=8.4Hz,J2=2.4Hz,1H),4.95-4.93(m,4H)。ESI-LC/MSm/z计算值C19H13F4NO4S:428.4;实测值428.0,429.0(M,M+1)+。分析计算值C19H13F4NO4S:C,50.47;H,2.82;N,6.54;实测值C,50.54;H,2.79;N,6.57。
实施例57
{5-氯-2-[(5-三氟甲基-苯并噻唑-2-基甲基)-氨基甲酰基]-苯氧基}-
按照与实施例54(步骤5-8)所述类似的方式制备{5-氯-2-[(5-三氟甲基-苯并噻唑-2-基甲基)-氨基甲酰基]-苯氧基}-乙酸,只是4-氯水杨酸用于代替步骤5中的4-氟水杨酸;和5-氨基-3-(三氟甲基)苯硫酚盐酸盐用于代替步骤6中的2-氨基-4,5,7-三氟苯硫酚盐酸盐:mp 225-227?;Rf0.44(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.49(t,J=6.2Hz,1H),8.30-8.28(m,2H),7.89(d,J=8.7Hz,1H),7.73(dd,J1=8.7Hz,J2=1.8Hz,1H),7.29(d,J=1.8Hz,1H),7.17(dd,J1=8.3Hz,J2=2.0Hz,1H),4.98(s,2H),4.94(d,J=6Hz,2H)。ESI-LC/MS m/z计算值C18H12ClF3N2O4S:444.8;实测值443.0(M-1)-。分析计算值C18H12ClF3N2O4S:C,48.60;H,2.72;N,6.30;Cl,7.97;实测值:C,48.47;H,2.68;N,6.20;Cl,8.12。
实施例58
按照与实施例54(步骤1-4)所述类似的方式制备[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸苄酯,只是氯代乙酸苄酯用于代替步骤3中的溴代乙酸乙酯:mp 95-98℃;Rf0.30(40%乙酸乙酯的庚烷溶液);1HNMR(DMSO-d6 300MHz)δ8.90(br,t,J=6.2Hz,1H),8.16(s,1H),8.08(br d,J=7.8Hz,1H),7.88(dd,J1=8.7Hz,J2=7.2Hz,1H),7.76(d,J=7.8Hz,1H),6.59(t,J=7.9Hz,1H),7.36-7.32(m,5H),7.12(dd,J1=10.9Hz,J2=2.4Hz,1H),5.08(s,2H),4.6(d,J=6Hz,2H)。ESI-LC/MS m/z计算值C23H19FN2O6:438.4;实测值439.1(M+1)+。分析计算值C23H19FN2O6:C,63.01;H,4.37;N,6.39;实测值:C,63.09;H,4.40;N,6.40。
实施例59
按照与实施例54(步骤1-4)所述类似的方式制备[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸3-甲基-丁酯,只是氯代乙酸异戊酯用于代替步骤3中的溴代乙酸乙酯:mp 65-68?;Rf0.33(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ9.0(t,J=6Hz,1H),8.19(s,1H),8.10(d,J=7.2Hz,1H),7.89(dd,J1=8.9Hz,J2=7.1Hz,1H),7.79(d,J=7.2Hz,1H),7.61(t,J=7.8Hz,1H),7.11(dd,J1=11.3Hz,J2=2.4Hz,1H),6.91(dt,J1=8.4Hz,J,=2.4Hz,1H),5.01(s,2H),4.63(d,J=6Hz,2H),4.13(t,J=6.8Hz,2H),1.58(br spt,J=6.6Hz,1H),1.42(q,J=6.6Hz,2H),0.83(s,3H),0.81(s,3H)。ESI-LC/MS m/z计算值C21H23FN2O6:418.4;实测值419.0(M+1)+。分析计算值C21H23FN2O6:C,60.28;H,5.54;N,6.70;实测值C,60.16;H,5.47;N,6.63。
实施例60
按照与实施例54(步骤1-4)所述类似的方式制备[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸,只是氯代乙酸辛酯用于代替步骤3中的溴代乙酸乙酯:mp 72-74?;Rf0.36(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ9.0(br t,J=6.3Hz,1H),8.19(s,1H),8.10(d,J=8.4Hz,1H),7.89(dd,J1=8.7Hz,J2=7.2Hz,1H),7.79(d,J=7.5Hz,1H),7.61(t,J=8.0Hz,1H),7.17(dd,J1=11.0Hz,J,=2.3Hz,1H),6.92(dt,J1=8.4Hz,J2=2.4Hz,1H),5.01(s,2H),4.63(d,J=6Hz,2H),4.09(t,J=6.6Hz,2H),1.51(br t,J=6Hz,2H),1.25-1.10(m,10H),0.82(t,J=6.6Hz,3 H)。ESI-LC/MS m/z计算值C24H29FN2O6:460.5;实测值461.0(M+1)+。分析计算值C24H29FN2O6:C,62.60;H,6.35;N,6.08;实测值C,62.68;H,6.41;N,6.11。
实施例61
按照与实施例54(步骤1-4)所述类似的方式制备[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸丁酯,只是氯代乙酸丁酯用于代替步骤3中的溴代乙酸乙酯:mp 80-81?;Rf0.36(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ9.0(br t,J=6Hz,1H),8.19(s,1H),8.09(d,J=8.1Hz,1H),7.89(dd,J1=9Hz,J2=7.2Hz,1H),7.79(d,J=7.5Hz,1H),7.61(t,J=8Hz,1H),7.11(dd,J1=11Hz,J2=2.4Hz,1H),6.92(dt,J1=8.4Hz,J2=2.4Hz,1H),5.01(s,2H),4.63(d,J=6Hz,2H),4.10(t,J=6.6Hz,2H),1.51(qnt,J=7.1Hz,2H),1.25(sx,J=7.5Hz,2H),0.82(t,J=7.2Hz,3H)。ESI-LC/MS m/z计算值C20H21FN2O6:404.4;实测值405.0(M+1)+。分析计算值C20H21FN2O6:C,59.40;H,5.23;N,6.93;实测值C,59.49;H,5.28;N,6.90。
实施例62
按照与实施例54(步骤1-4)所述类似的方式制备[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸环己基酯,只是氯代乙酸环己基酯用于代替步骤3中的溴代乙酸乙酯:mp 87-90?;Rf0.39(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ9.01(br t,J=6Hz,1H),8.19(s,1H),8.10(dd,J1=7.5Hz,J2=1.5Hz,1H),7.90(dd,J1=9.0Hz,J2=71Hz,1H),7.79(d,J=7.5Hz,1H),7.61(t,J=8Hz,1H),7.10(dd,J1=11Hz,J2=2.3Hz,1H),6.92(dt,J1=8.4Hz,J2=2.4Hz,1H),4.99(s,2H),4.78-4.72(m,1H),4.63(d,J=6.3Hz,2H),1.72(br s,2H),1.57(br d,J=5.4Hz,2H),1.44-1.15(m,6H)。ESI-LC/MS m/z计算值C22H23FN2O6:430.4;实测值431.0(M+1)+。分析计算值C22H23FN2O6:C,61.39;H,5.39;N,6.51;实测值C,61.48;H,5.43;N,6.57。
实施例63
按照与实施例54(步骤1-4)所述类似的方式制备[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-乙基-己酯,只是氯代乙酸2-乙基己酯用于代替步骤3中的溴代乙酸乙酯:mp 59-60?;Rf0.46(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ8.99(t,J=6Hz,1H),8.19(s,1H),8.09(br d,J=8.1Hz,1H),7.89(dd,J1=7.8Hz,J2=7.2Hz,1H),7.79(d,J=7.5Hz,1H),7.61(t,J=8Hz,1H),7.11(dd,J1=11.2Hz,J2=2.3Hz,1H),6.91(dt,J1=8.4Hz,J2=2.3Hz,1H),5.04(s,2H),4.63(br d,J=3.6Hz,2H),4.01(dd,J1=5.4Hz,J2=1.1Hz,2H),1.50-1.44(m,1H),1.25-1.15(m,8H),0.82-0.70(m,6H)。ESI-LC/MS m/z计算值C24H29FN2O6:460.5;实测值461.0(M+1)+。分析计算值C24H29FN2O6:C,62.60;H,6.35;N,6.08;实测值C,62.66;H,6.34;N,6.05。
实施例64
按照与实施例54(步骤1-4)所述类似的方式制备[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-甲氧基-乙酯,只是氯代乙酸2-甲氧基乙酯用于代替步骤3中的溴代乙酸乙酯:mp 112-115?;Rf0.14(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ9.0(br t,J=6Hz,1H),8.19(br s,1H),8.11(br dd,J1=8.1Hz,J2=0.9Hz,1H),7.89(dd,J1=8.7Hz,J2=6.9Hz,1H),7.80(d,J=7.5Hz,1H),7.62(t,J=8Hz,1H),7.11(dd,J1=11.4Hz,J2=2.4Hz,1H),6.93(dt,J1=8.4Hz,J2=2.4Hz,1H),5.04(s,2H),4.63(d,J=6Hz,2H),4.25(t,J=4.7Hz,2H),3.52(t,J=4.5Hz,2H),3.22(s,3H)。ESI-LC/MS m/z计算值C19H19FN2O7:406.4;实测值407.0(M+1)+。分析计算值C19H19FN2O7,:C,56.16;H,4.71;N,6.89;实测值C,56.13;H,4.73;N,6.94。
实施例65
[5-氟-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸辛酯
按照与实施例32所述类似的方式制备[5-氟-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸辛酯,只是[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸辛酯(实施例60)用于代替步骤1中的[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯:mp 69-72?;Rf0.60(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ10.70(br s,1H),8.23(s,1H),8.15(dd,J1=8.1Hz,J,2.1Hz,1H),7.83(d,J=7.5Hz,1H),7.72-7.59(m,2H),7.03(dd,J1=11.4Hz,J2=2.4Hz,1H),6.86(dt,J1=8.4Hz,J2=2.4Hz,1H),5.06(br s,2H),4.07(t,J=6.6Hz,2H),1.54-1.48(m,2H),1.28-1.16(m,10H),0.83(br t,J=6.6Hz,3H)。ESI-LC/MS m/z计算值C24Hz9FN2O5S:476.6;实测值477.0(M+1)+。分析计算值C24H29FN2O5S:C,60.49;H,6.13;N,5.88;S,6.73;实测值C,60.25;H,6.03;N,5.79;S,6.58。
实施例66
按照与实施例32所述类似的方式制备[5-氟-2-(3-硝基-苄基硫代氨基甲酰基)-苯氧基]-乙酸3-甲基-丁酯,只是[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸3-甲基-丁酯(实施例59)用于代替步骤1中的[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯:mp 56-58 C.Rf0.59(40%乙酸乙酯的庚烷溶液);1H NMR(DMSO-d6 300MHz)δ10.68(brs,1H),8.23(s,1H),8.16(d,J=8.1Hz,1H),7.83(d,J=7.8Hz,1H),7.72-7.60(m,2H),7.03(d,J=8.7Hz,1H),6.86(dt,J1=8.4Hz,J2=2.1Hz,1H),5.06(br s,2H),4.90(s,2H),4.11(t,J=6.6Hz,2H),1.58(br spt,J=6.5,1H),1.43(q,J=6.7Hz,2H),0.84(s,3H),0.82(s,3H)。ESI-LC/MS m/z计算值C21H23FN2O5S:434.5;;实测值435.0(M+1)+。分析计算值C21H23FN2O5S:C,58,05;H,5.34;N,6.45;S,7.38;实测值C,58,09;H,5.26;N,6.41;S,7.31。
实施例67
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-二乙基铵-乙酯
将[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸(实施例32,2.0g,5.74mmol)的乙腈(150mL)溶液用CsF-Celite1(1.9g,8.61mmol)和2-溴-N,N-二乙基乙基胺氢溴酸盐(3.0g,11.5mmol)处理。将悬浮液加热回流24小时,冷却至室温和浓缩。将混合物用乙酸乙酯稀释和过滤,除去不溶性盐。将滤液依次用2N碳酸钾水溶液和饱和氯化钠洗涤。机层用硫酸镁干燥,过滤和浓缩。随后,将浑浊的油用无水的1.0M HCl的乙醚溶液(6mL,1当量)处理,得到[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-二乙基铵-乙酯盐酸盐(1.2g,43%):mp 96-100?;Rf0.35(10%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ10.50(brs,1H),9.01(t,J=6.2Hz,1H),8.19(s,1H),8.10(br d,J=7.8Hz,1H),7.88-7.79(m,2H),7.62(t,J=7.8Hz,1H),7.19(dd,J1=11.1Hz,J2=2.4Hz,1H),6.92(dt,J1=8.1Hz,J2=2.2Hz,1H),5.09(s,2H),4.62(d,J=6.3Hz,2H),4.48(t,J=5.1Hz,2H),3.38-3.35(m,2H),3.13-3.08(m,4H),1.18(t,J=7.2Hz,6H)。ESI-LC/MS m/z计算值C22H26FN3O6:447.5;实测值448(M+1)+。
实施例68
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-三甲基氯化铵-
将[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸(1.4g,4.02mmol)的乙腈(300mL)溶液用CsF-Celite1(1.30g,6.03mmol)和(2-溴乙基)三甲基溴化铵(1.99g,8.04mmol)处理。将悬浮液加热回流24小时,冷却和浓缩。将混合物用乙酸乙酯稀释和过滤,除去不溶性盐。将滤液浓缩,随后通过反相HPLC纯化(10-90%乙腈,含0.05%HCl,10mL/分钟,35分钟),得到[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-三甲基氯化铵-乙酯(0.5g,26%)。mp 100-105?;Rf0.30(20%甲醇的二氯甲烷溶液);1H NMR(DMSO-d6 300MHz)δ9.00(t,J=5.9Hz,1H),8.20(s,1H),8.12(br d,J=8.1Hz,1H),7.88-7.79(m,2H),7.63(t,J=8.0Hz,1H),7.14(dd,J1=11.1Hz,J2=2.4Hz,1H),6.95(dt,J1=8.4Hz,J2=2.4Hz,1H),5.05(s,2H),4.63(d,J=6Hz,2H),4.57(br s,2H),3.69-3.66(m,2H),3.10(s,9H)。ESI-LC/MS m/z计算值C21H25ClFN3O6:469.90;实测值434.0(M-35.5-氯化物)+。
实施例69
按照与实施例54(步骤5-8)所述类似的方式制备[2-(4-溴-2-氟-苄基氨基甲酰基)-4-甲氧基-苯氧基]-乙酸,只是2-羟基-5-甲氧基-苯甲酸用于代替步骤1中的4-氯水杨酸:Rf0.11(10%甲醇的二氯甲烷溶液);1HNMR(DMSO-d6 300MHz)δ9.23(br t,J=6.1Hz,1H),7.50(br d,J=9.1Hz,1H),7.40-4.34(m,3H),7.1 1-7.00(m,2H),4.79(s,2H),4.49(d,J=5.6Hz,2H),3.71(s,3H)。ESI-LC/MS m/z计算值C17H15BrFNO5:411.01;实测值XX(M+1)-。分析计算值C17H15BrFNO5:C,49.53;H,3.67;N,3.40;实测值C,49.47;H,3.65;N,3.33。
对本发明的代表性化合物作为人醛糖还原酶抑制剂的效力、选择性和功效进行测试。采用类似于下述文献所述的方法测试化合物的效力或醛糖还原酶抑制作用:Butera等,J.Med.Chem.1989,32,757。采用该试验,测量由50%(IC50)表示的需抑制人醛糖还原酶活性(hALR2)的浓度。
在第二个试验中,对大量的相同化合物进行试验,测量它们抑制作为结构化相关酶的醛还原酶(hALR1)的能力。所采用的试验方法基本如下述文献所述:Ishii等,J.Med.Chem.1996 39:1924。采用该试验,测量由50%(IC50)表示的需抑制人醛还原酶活性的浓度。
由这些数据,测量hALR1/hALR2比值。由于希望试验的化合物作为醛糖还原酶抑制剂的高效力,因此,寻求较低的hALR2 IC50值。另一方面,由于不希望试验的化合物作为醛还原酶抑制剂的高效力,因此,寻求较高的hALR1 IC50值。因此,hALR1/hALR2比值用于确定试验化合物的选择性。这种选择性的重要性如以下文献所述:Kotani等,J.Med.Chem.40:684,1997。
在下表1中显示了所有这些试验结果。
Ex.# | hALR2(aldose)(IC50) | hALR1(aldehyde)(IC50) | hALR1/hALR2 |
1 | 30nM | 14,000nM | 470 |
4 | 39nM | ||
5 | 6nM | 19%@25μM | >4,200 |
11 | 29nM | ||
14 | 34nM | 18,000nM | 530 |
17 | 46nM | 18,000nM | 390 |
18 | 150nM | ||
19 | 64nM | ||
20 | 69nM | 11,000nM | 160 |
21 | 200nM |
23 | 180nM | ||
24 | 83nM | ||
25 | 11nM | 48%@100μM | >9,100 |
26 | 9nM | ||
27 | 8nM | 34,000nM | 4,300 |
28 | 55nM | 6,600nM | 120 |
29 | 8nM | ||
30 | 37nM | ||
32 | 6nM | 35,000nM | 5,800 |
33 | 34nM | 33,000nM | 970 |
34 | 37nM | ||
35 | 12nM | ||
36 | 33nM | ||
45 | 24nM | 5,800nM | 240 |
46 | 24nM | 31,000nM | 1,300 |
47 | 8nM | ||
48 | 7nM |
以上描述了本发明优选的实施方案,在不背离本发明的精神实质或范围的前提下可作为如权利要求所提出的修改。为特别指出和严格限制本发明所涉及的主题,以下的权利要求结束了说明书。
Claims (57)
氟或氯单或二取代;X为氧、硫或NR6,其中,每一个R6为氢,氰基或具有1-6个碳原子的烷
基(其可被一个或多个卤素取代);R1、R2、R3和R4彼此独立地为
氢,卤素,硝基或具有1-6个碳原子的烷基(其可被一个或多个卤素
取代);
OR7、SR7、S(O)R7、S(O)2R7、C(O)N(R7)2或N(R7)x2,其中,每一个R7独
立地为氢、具有1-6个碳原子的烷基(其可被一个或多个卤素取
代)或苄基,其中,苯基部分被至多三个取代基取代或未取代,
取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单
或二(C1-C6)烷氨基;
苯基或杂芳基如2-、3-或4-咪唑基或2-、3-或4-吡啶基,每一个苯
基或杂芳基被至多三个取代基取代或未取代,取代基独立地选
自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷氨
基;
苯氧基,其中,苯基部分可被至多3个基团取代或未取代,所述取代
基独立地选自卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)
其中
J为单键、CH2、氧或氮;和
每一个r独立地为2或3;
R5为羟基或前药基团;和
Ar表示芳基或杂芳基,每一个基团可被至多5个基团取代或未取代。
2.根据权利要求1的化合物,其中,Ar为取代或未取代的苯并噻唑基、苯并恶唑基、异喹啉基、苯并噻吩基、苯并呋喃基或苯并咪唑基,或取代的恶二唑基或吲哚基。
3.根据权利要求1的化合物,其中,A为共价键或CH2;R5为羟基;和每一个R1-R4独立地为氢,卤素,更优选溴,氯或氟,C1-C2烷基,苯氧基,苄氧基,或C1-C2烷氧基。
4.根据权利要求2的化合物,其中,A为共价键或CH2;R5为羟基;和每一个R1-R4独立地为氢、卤素、C1-C2烷基、苯氧基、苄氧基、或C1-C2烷氧基。
5.根据权利要求2的化合物,其中,R1和R4为氢、甲基或乙基;和R2和R3独立地为氢、溴、氯、氟、C1-C2烷基、苯氧基、苄氧基、C1-C2烷氧基、氨基、单或二(C1-C3烷基)氨基、吗啉基、哌啶-1-基或哌嗪-1-基。
6.根据权利要求5的化合物,其中,至少R2和R3之一为氢,且R1和R4均为氢。
7.根据权利要求1的化合物,其中
A为亚甲基;
R5为羟基;
Ar为取代或未取代的苯并噻唑-2-基、苯并噻唑-5-基、苯并异噻唑-3-基、苯并恶唑-2-基、2喹啉基、2-喹喔啉基、恶唑并[4,5-b]吡啶-2-基、苯并噻吩-2-基、苯并呋喃-2-基或噻唑并[4,5b]-吡啶-2-基、噻吩并[2,3-b]吡啶2-基、咪唑并[1,5-a]吡啶-2-基或吲哚-2-基,或取代的1,2,4-恶二唑-3-基、1,2,4-恶二唑-5-基、异噻唑-5-基、异噻唑-4-基、1,3,4-恶二唑-5-基、1,2,5-噻二唑-3-基、恶唑-2-基、噻唑-2-基或噻唑-4-基;和
R1-R4独立地为氢,卤素,更优选溴,氯或氟,C1-C2烷基,苯氧基,苄氧基或苯基,其中,每一个苯基部分被下述基团取代或未取代:C1-C6烷基、卤素、C1-C6烷氧基、羟基、氨基或单或二(C1-C6)烷氨基。
8.根据权利要求2的化合物,其中,R1和R4均为氢、甲基或乙基;和R2和R3独立地为氢、溴、氯、氟、C1-C2烷基、苯氧基、苄氧基、C1-C2烷氧基、氨基、单或二(C1-C3烷基)氨基、吗啉基、哌啶-1-基或哌嗪-1-基。
9.根据权利要求1的化合物,其中
A为亚甲基;
R5为羟基;
Ar为选择性地4、5、6或7-取代的苯并噻唑基、苯并恶唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基或吲哚基,或
Ar为2-苯并噻唑基,在其苯并基团上被1个三氟乙酰基或三氟甲硫基取代,或被下述基团之一或之二取代:氟、氯、溴、羟基、甲基、甲氧基、三氟甲基、三氟甲氧基、三氟甲硫基,或者被1个,优选2个氟和1个三氟甲基取代,或者被两个氟或两个三氟甲基和一个甲氧基取代,或者被3个氟取代,或者被6,7苯并基团取代。
10.根据权利要求7的化合物,其中,R1和R4均为氢或C1-C3烷基。
11.根据权利要求10的化合物,其中,至少R2和R3之一为氢,R1和R4均为氢。
可被一个或多个卤素取代);R1、R2、R3和R4彼此独立地为
氢、卤素、具有1-6个碳原子的烷基(其可被一个或多个卤素取代)、
硝基、OR7、SR7、S(O)R7、S(O)2R7、C(O)N(R7)2或N(R7)2,其中,每
一个R7独立地为氢、具有1-6个碳原子的烷基(其可被一个或多
个卤素取代)或苄基,其中,苯基部分可被至多3个基团取代或
未取代,所述取代基独立地选自:卤素,C1-C6烷基、C1-C6烷氧
基、氨基和单或二(C1-C6)烷氨基;苯基或杂芳基如2-、3-或4-咪唑基或2-、3-或4-吡啶基,每一个苯
基或杂芳基可被至多3个基团取代或未取代,所述取代基独立地
选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷
氨基;苯氧基,其中,苯基部分可被至多3个基团取代或未取代,所述取代
基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二
其中
J为单键、CH2、氧或氮;和
每一个r独立地为2或3;R5为羟基、1-6个碳原子的烷氧基或O-M+,其中,M+为形成可药用盐的阳
离子;和R8、R9、R10、R11和R12组合表示氢,或1-3个选自氟、氯、溴、三氟甲基或
硝基的基团。
13.根据权利要求12的化合物,其中,R1和R4均为氢、甲基或乙基;和R2和R3独立地为氢、溴、氯、氟、C1-C2烷基、苯氧基、苄氧基、C1-C2烷氧基、氨基、单或二(C1-C3烷基)氨基、吗啉基、哌啶-1-基或哌嗪-1-基。
14.根据权利要求13的化合物3,其中,R8-R12表示1个三氟乙酰基或三氟甲硫基取代,或1个或2个氟、氯、溴、羟基、甲基、甲氧基、三氟甲基、三氟甲氧基、三氟甲硫基,或者1个,或者优选2个氟和1个三氟甲基,或者氟或1个三氟甲基和1个甲氧基,或3个氟。
15.根据权利要求12的化合物,其中,R1和R4均为氢、甲基或乙基;和R2和R3独立地为氢、溴、氯、氟、C1-C2烷基、苯氧基、苄氧基、C1-C2烷氧基、氨基、单或二(C1-C3烷基)氨基、吗啉基、哌啶-1-基或哌嗪-1-基。
16.根据权利要求15的化合物,其中,R1和R4均为氢或C1-C3烷基。
17.根据权利要求16的化合物,其中,至少R2和R3之一氢,和R1和R4均为氢。
基(其可被一个或多个卤素取代);R1、R2、R3和R4彼此独立地为
氢、卤素、具有1-6个碳原子的烷基(其可被一个或多个卤素取代)、
硝基、OR7、SR7、S(O)R7、S(O)2R7、C(O)N(R7)2或N(R7)2,其中,每
一个R7独立地为氢、具有1-6个碳原子的烷基(其可被一个或多
个卤素取代)或苄基,其中,苯基部分可被至多3个基团取代或
未取代,所述取代基独立地选自:卤素、C1-C6烷基、C1-C6烷氧
基、氨基和单或二(C1-C6)烷氨基;苯基或杂芳基如2-、3-或4-咪唑基或2-、3-或4-吡啶基,每一个苯
基或杂芳基可被至多3个基团取代或未取代,所述取代基独立地
选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二(C1-C6)烷
氨基;苯氧基,其中,苯基部分可被至多3个基团取代或未取代,所述取代
基独立地选自:卤素、C1-C6烷基、C1-C6烷氧基、氨基和单或二
其中
J为单键、CH2、氧或氮;和
每一个r独立地为2或3;R5为羟基、C1-C6烷氧基,或-O-M+,其中,M+为形成可药用盐的阳离子;和R13、R14、R15和R16独立地为氢、卤素、硝基、羟基、C1-C6烷基、C1-C6烷氧
基、C1-C6烷硫基、三氟甲基、三氟甲氧基、C1-C6烷基亚磺酰基或C1-C6
烷基磺酰基。
19.根据权利要求18的化合物,其中,R13、R14、R15和R16组合表示1个溴、氰基或硝基,1个或2个氟、氯、羟基、(C1-C6)烷基、(C1-C6)烷氧基之,或三氟甲基,或2个氟或2个甲基与1个羟基或1个(C1-C6)烷氧基,或2个氟和1个甲基,或3个氟基团。
20.根据权利要求18的化合物,其中,R13、R14、R15和R16独立地表示氟、氯、硝基和三氟甲基。
21.根据权利要求19的化合物,其中,A为亚甲基,被甲基取代的或亚乙基。
22.根据权利要求21的化合物,其中,R13、R14、R15和R16独立地表示硝基,1、2或3个氟,1或2个氯,或1个三氟甲基。
23.根据权利要求22的化合物,其中,A为亚甲基,和R5为羟基或C1-C6烷氧基。
24.根据权利要求23的化合物,其中,R2和R3独立地为氢、卤素、C1-C6烷基、烷氧基、氨基、单或二(C1-C3烷基)氨基、吗啉基、哌啶-1-基或哌嗪-1-基。
25.根据权利要求24的化合物,其中,R13、R14和R16均为氟和R15为氢。
26.根据权利要求18的化合物,其中,R1和R4均为氢、甲基或乙基;和R2和R3独立地为氢、溴、氯、氟、C1-C2烷基、苯氧基、苄氧基、C1-C2烷氧基、氨基、单或二(C1-C3烷基)氨基、吗啉基、哌啶-1-基或哌嗪-1-基。
27.根据权利要求2的化合物6,其中,R8-R12表示1个三氟乙酰基或三氟甲硫基取代,或1个或2个氟、氯、溴、羟基、甲基、甲氧基、三氟甲基、三氟甲氧基、三氟甲硫基,或者1个,或者优选2个氟和1个三氟甲基,或者氟或1个三氟甲基和1个甲氧基,或3个氟。
28.根据权利要求27的化合物,其中,R1和R4均为氢、甲基或乙基;和R2和R3独立地为氢、溴、氯、氟、C1-C2烷基、苯氧基、苄氧基、C1-C2烷氧基、氨基、单或二(C1-C3烷基)氨基、吗啉基、哌啶-1-基或哌嗪-1-基。
29.根据权利要求28的化合物,其中,R1和R4均为氢或C1-C3烷基。
30.根据权利要求29的化合物,其中,至少R2和R3之一为氢,并且R1和R4均为氢。选自:
31.根据权利要求1的化合物,其为:
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸乙酯;
(2-苄基氨基甲酰基-5-氯-苯氧基)-乙酸;
[5-氯-2-(3-氟-苄基氨基甲酰基)-苯氧基]-乙酸;
[5-氯-2-(3-三氟甲基-苄基氨基甲酰基)-苯氧基]-乙酸;
[2-(3-硝基-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸;
[5-氯-2-(4-氯-苄基氨基甲酰基)-苯氧基]-乙酸;
[2-(4-溴-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸;
[5-氯-2-(4-甲氧基-苄基氨基甲酰基)-苯氧基]-乙酸;或
[5-氯-2-(4-三氟甲氧基-苄基氨基甲酰基)-苯氧基]-乙酸。
32.根据权利要求1的化合物,其为:
[5-氯-2-(2,6-二氟-苄基氨基甲酰基)-苯氧基]-乙酸;
[5-氯-2-(3-氟-5-三氟甲基-苄基氨基甲酰基)-苯氧基]-乙酸;
[2-(3,5-二三氟甲基-苄基氨基甲酰基)-5-氯-苯氧基]-乙酸;
[5-氯-2-(3,5-二甲氧基-苄基氨基甲酰基)-苯氧基]-乙酸;
[5-氯-2-(3,4-二氯-苄基氨基甲酰基)-苯氧基]-乙酸;
{2-[(苯并[1,3]间二氧杂环戊烯-5-基甲基)-氨基甲酰基]-5-氯-苯氧基}-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲氧基-苯氧基]-乙酸;或
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲氧基-苯氧基-乙酸乙酯。
33.根据权利要求1的化合物,其为:
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-氯-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-氟-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-氟-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-甲基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]-乙酸叔丁酯;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-硝基-苯氧基]-乙酸;或
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基-苯氧基]-乙酸。
34.根据权利要求1的化合物,其为:
[2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸乙酯;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲基硫烷基-苯氧基]-乙酸;
[2-(3-硝基-苄基氨基甲酰基)-4-甲基-苯氧基]-乙酸;
[2-(3-硝基-苄基氨基甲酰基)-4-三氟甲氧基-苯氧基]-乙酸;
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸;或
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸乙酯。
35.根据权利要求1的化合物,其为:
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-苯氧基]-乙酸;
[5-氟-2-(4-甲基-3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4,5-二氟-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-3,5-二氟-苯氧基]-乙酸;
[5-氟-2-(3-硝基-苄硫基氨基甲酰基)-苯氧基]-乙酸;
[5-氟-2-(3-硝基-苄硫基氨基甲酰基)-苯氧基]-乙酸乙酯;
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-5-氟-苯氧基]-乙酸;或
[4-溴-2-(4-溴-2-氟-苄硫基氨基甲酰基)-苯氧基]-乙酸。
36.根据权利要求1的化合物,其为:
[2-(3-硝基-苄硫基氨基甲酰基)-4-三氟甲氧基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-4,5-二氟-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸乙酯;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-甲磺酰基-苯氧基]-乙酸;
[4-氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-甲氧基-苯氧基]-乙酸;或
[4-氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸烯丙酯。
37.根据权利要求1的化合物,其为:
[4-乙酰氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸烯酯;
[4-乙酰氨基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-三氟甲基-苯氧基]-乙酸;
[4-烯丙氧基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸;
[4-烯丙氧基-2-(4-溴-2-氟-苄基氨基甲酰基)-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-羟基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-丙氧基-苯氧基]-乙酸;或
[2-(2-氟-苄基氨基甲酰基)-4-丙氧基-苯氧基]-乙酸。
38.根据权利要求1的化合物,其为:
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯;
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸乙酯;
[2-(4-溴-2-氟-苄硫基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸;
[2-(3-硝基-苄基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸;
[2-(3-硝基-苄硫基氨基甲酰基)-5-氟-4-甲基-苯氧基]-乙酸;或
(4-溴-5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸。
39.根据权利要求1的化合物,其为:
[4-溴-5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸;
[5-(3-硝基-苄基氨基甲酰基)-2-氟-联苯基-4-基氧基]-乙酸;
[5-(3-硝基-苄硫基氨基甲酰基)-2-氟-联苯基-4-基氧基]-乙酸;
[2-(3-硝基-苄基氨基甲酰基)-4-氰基-5-氟-苯氧基]-乙酸;
[2-(3-硝基-苄基氨基甲酰基)-5-氟-4-吗啉-4-基-苯氧基]-乙酸;
[2-(4-溴-2-氟-苄基氨基甲酰基)-5-氟-4-吗啉-4-基-苯氧基]-乙酸乙酯;
{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-乙酸;或
{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)氨基甲酰基]-苯氧基}-乙酸乙酯。
40.根据权利要求1的化合物,其为:
{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)硫代氨基甲酰基]-苯氧基}-乙酸;
{5-氟-2-[(4,5,7-三氟-苯并噻唑-2-基甲基)硫代氨基甲酰基]-苯氧基}-乙酸乙酯;
{5-氟-2-[(5-三氟甲基-苯并噻唑-2-基甲基)-氨基甲酰基]-苯氧基}-乙酸;
{5-氯-2-[(5-三氟甲基-苯并噻唑-2-基甲基)-氨基甲酰基]-苯氧基}-乙酸;
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸苄酯;
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸3-甲基-丁酯;
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸辛酯;或
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸丁酯。
41.根据权利要求1的化合物,其为:
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸环己酯;
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-乙基-己酯;
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-甲氧基-乙基酯;
[5-氟-2-(3-硝基-苄硫基氨基甲酰基)-苯氧基]-乙酸辛酯;
[5-氟-2-(3-硝基-苄硫基氨基甲酰基)-苯氧基]-乙酸3-甲基-丁酯;
[5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-二乙基铵-乙基酯盐酸盐;
5-氟-2-(3-硝基-苄基氨基甲酰基)-苯氧基]-乙酸2-三甲基氯化铵-乙酯;或
[2-(4-溴-2-氟-苄基氨基甲酰基)-4-甲氧基-苯氧基]-乙酸。
42.一种药物组合物,其包含可药用载体和预定量的权利要求1的化合物。
43.根据权利要求42的药物组合物,进一步包含血管紧张素转化酶抑制剂。
44.根据权利要求43的药物组合物,其中,血管紧张素转化酶抑制剂选自贝那普利、贝那普利拉(benazeprilar)、卡托普利、地拉普利、芬替普利(fentiapril)、福辛普利、利本普利(libenzapril)、莫西普利、喷托普利、哌汀多普利(petindopril)、匹伏普利、喹那普利、喹那普利特、雷米普利、螺普利、螺普利特、佐芬普利、塞罗普利、依那普利、吲哚普利、奥马普利特(omaprilat)、赖诺普利、阿拉普利、西拉普利和其可药用盐。
45.权利要求1的化合物和血管紧张素转化酶抑制剂在制备用于治疗糖尿病并发症的药物组合物中的用途。
46.权利要求1的化合物和血管紧张素转化酶抑制剂在生产用于治疗或预防与损害神经元传导速率有关的疾病发展的药物中的用途。
47.权利要求1的化合物和血管紧张素转化酶抑制剂在生产用于逆转损害神经元传导速率的药物中的用途。
48.权利要求1的化合物和血管紧张素转化酶抑制剂在生产用于治疗糖尿病性神经病的药物中的用途。
49.根据权利要求43的药物组合物,其中,血管紧张素转化酶抑制剂选自贝那普利、贝那普利拉(benazeprilar)、卡托普利、地拉普利、芬替普利(fentiapril)、福辛普利、利本普利(libenzapril)、莫西普利、喷托普利、哌汀多普利(petindopril)、匹伏普利、喹那普利、喹那普利特、雷米普利、螺普利、螺普利特、佐芬普利、塞罗普利、依那普利、吲哚普利、奥马普利特(omaprilat)、赖诺普利、阿拉普利、西拉普利和其可药用盐。
50.一种治疗糖尿病并发症的方法,包括向患有此并发症的患者给药有效量的权利要求1的化合物。
51.根据权利要求50的方法,其中,将所述化合物以包含权利要求1的化合物与可药用载体的药物组合物给药于患者。
52.根据权利要求51的方法,其中,药物组合物进一步包含一种血管紧张素转化酶抑制剂。
53.一种治疗或预防与损害神经元传导速率相关的疾病的方法,包括向如患有或证实发展此种并发症的患者给药有效量的权利要求1的化合物。
54.一种治疗或预防糖尿病性神经病的方法,包括向如患有或证实发展此种并发症的患者给药有效量的权利要求1的化合物。
55.根据权利要求54的方法,其中,将所述化合物以包含权利要求1的化合物与可药用载体的药物组合物给药于患者。
56.根据权利要求55的方法,其中,药物组合物进一步包含一种血管紧张素转化酶抑制剂。
57.根据权利要求56的方法,其中,血管紧张素转化酶抑制剂选自贝那普利、贝那普利拉(benazeprilar)、卡托普利、地拉普利、芬替普利(fentiapril)、福辛普利、利本普利(libenzapril)、莫西普利、喷托普利、哌汀多普利(petindopril)、匹伏普利、喹那普利、喹那普利特、雷米普利、螺普利、螺普利特、佐芬普利、塞罗普利、依那普利、吲哚普利、奥马普利特(omaprilat)、赖诺普利、阿拉普利、西拉普利和其可药用盐。
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Cited By (3)
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US6958355B2 (en) | 2000-04-24 | 2005-10-25 | Aryx Therapeutics, Inc. | Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis |
US6784199B2 (en) | 2000-09-21 | 2004-08-31 | Aryx Therapeutics | Isoxazolidine compounds useful in the treatment of diabetes, hyperlipidemia, and atherosclerosis in mammals |
US6680387B2 (en) | 2000-04-24 | 2004-01-20 | Aryx Therapeutics | Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis |
US6768008B2 (en) | 2000-04-24 | 2004-07-27 | Aryx Therapeutics | Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis |
KR100356374B1 (ko) * | 2000-09-14 | 2002-10-19 | 사회복지법인삼성생명공익재단(삼성서울병원) | 안지오텐신 전환효소 억제제의 부작용으로 발생하는마른기침을 저해하기 위한 철분을 포함하는 기침 저해조성물 |
IL159002A0 (en) * | 2001-06-07 | 2004-05-12 | Lilly Co Eli | Modulators of peroxisome proliferator activated receptors (ppar) |
WO2004073606A2 (en) | 2003-02-14 | 2004-09-02 | Eli Lilly And Company | Sulfonamide derivatives as ppar modulators |
JP2006525329A (ja) * | 2003-04-30 | 2006-11-09 | ジ インスチチュート フォー ファーマシューティカル ディスカバリー、エルエルシー | 置換カルボン酸類 |
EP1750862B1 (en) | 2004-06-04 | 2011-01-05 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical composition containing irbesartan |
AU2005302475A1 (en) * | 2004-10-28 | 2006-05-11 | The Institutes For Pharmaceutical Discovery, Llc | Substituted phenylalkanoic acids |
GB0427603D0 (en) * | 2004-12-16 | 2005-01-19 | Novartis Ag | Organic compounds |
US10640457B2 (en) | 2009-12-10 | 2020-05-05 | The Trustees Of Columbia University In The City Of New York | Histone acetyltransferase activators and uses thereof |
US9969677B2 (en) | 2010-12-22 | 2018-05-15 | The Trustees Of Columbia University In The City Of New York | Histone acetyltransferase modulators and uses thereof |
WO2018002673A1 (en) | 2016-07-01 | 2018-01-04 | N4 Pharma Uk Limited | Novel formulations of angiotensin ii receptor antagonists |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986005779A1 (en) | 1985-04-03 | 1986-10-09 | Yamanouchi Pharmaceutical Co., Ltd. | Phenylene derivatives |
JPH04297466A (ja) * | 1990-06-22 | 1992-10-21 | Nippon Shinyaku Co Ltd | テトラゾール誘導体及び医薬 |
AU5334594A (en) * | 1992-10-16 | 1994-05-09 | Byk Nederland Bv | Substituted ethanolamine esters |
GB9511694D0 (en) * | 1995-06-09 | 1995-08-02 | Fujisawa Pharmaceutical Co | Benzamide derivatives |
EE200100708A (et) * | 1999-06-25 | 2003-02-17 | The Institutes For Pharmaceutical Discovery, Llc | Asendatud fenoksüäädikhapped |
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- 2000-06-23 SK SK1915-2001A patent/SK19152001A3/sk unknown
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- 2000-06-23 IL IL14719700A patent/IL147197A0/xx unknown
- 2000-06-23 TN TNTNSN00139A patent/TNSN00139A1/fr unknown
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- 2000-06-23 KR KR1020017016636A patent/KR20020013936A/ko not_active Application Discontinuation
- 2000-06-23 US US09/603,817 patent/US6420426B1/en not_active Expired - Fee Related
- 2000-06-23 AU AU58869/00A patent/AU5886900A/en not_active Abandoned
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109289696A (zh) * | 2018-10-29 | 2019-02-01 | 天津先光化工有限公司 | 一种咪唑啉两性表面活性剂的制备方法 |
CN109289696B (zh) * | 2018-10-29 | 2022-03-22 | 天津先光化工有限公司 | 一种咪唑啉两性表面活性剂的制备方法 |
CN114790133A (zh) * | 2021-01-26 | 2022-07-26 | 江苏中旗科技股份有限公司 | 一种以2-氯-4-氨基苯腈为原料合成2-氯-4-氟苯甲酸的方法 |
CN114790139A (zh) * | 2021-01-26 | 2022-07-26 | 江苏中旗科技股份有限公司 | 一种以2-氯-4-氨基溴苯为原料合成2-氯-4-氟苯甲酸的方法 |
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TNSN00139A1 (fr) | 2005-11-10 |
AU5886900A (en) | 2001-01-31 |
US7189749B2 (en) | 2007-03-13 |
WO2001000566A3 (en) | 2002-02-07 |
NZ516290A (en) | 2004-03-26 |
ZA200200300B (en) | 2003-08-27 |
US20070161631A1 (en) | 2007-07-12 |
BR0011928A (pt) | 2002-04-09 |
MXPA02003123A (es) | 2003-08-20 |
EE200100708A (et) | 2003-02-17 |
KR20020013936A (ko) | 2002-02-21 |
US6420426B1 (en) | 2002-07-16 |
JP2003503381A (ja) | 2003-01-28 |
US20030036558A1 (en) | 2003-02-20 |
CZ20014637A3 (cs) | 2002-04-17 |
IL147197A0 (en) | 2002-08-14 |
AP2001002377A0 (en) | 2001-12-31 |
HUP0202384A2 (hu) | 2002-11-28 |
PL355857A1 (en) | 2004-05-31 |
SK19152001A3 (sk) | 2002-06-04 |
WO2001000566A2 (en) | 2001-01-04 |
EP1198451A2 (en) | 2002-04-24 |
HUP0202384A3 (en) | 2003-03-28 |
NO20016272D0 (no) | 2001-12-20 |
NO20016272L (no) | 2002-01-17 |
US20050239849A1 (en) | 2005-10-27 |
TR200200619T2 (tr) | 2003-01-21 |
OA11972A (en) | 2006-04-18 |
BG106351A (bg) | 2002-09-30 |
CA2385798A1 (en) | 2001-01-04 |
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