CN1014787B - 苯氧基乙酸衍生物的制备方法 - Google Patents
苯氧基乙酸衍生物的制备方法Info
- Publication number
- CN1014787B CN1014787B CN87106895A CN87106895A CN1014787B CN 1014787 B CN1014787 B CN 1014787B CN 87106895 A CN87106895 A CN 87106895A CN 87106895 A CN87106895 A CN 87106895A CN 1014787 B CN1014787 B CN 1014787B
- Authority
- CN
- China
- Prior art keywords
- compound
- pyrazolyl
- chloro
- preparation
- formula
- 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.)
- Expired
Links
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical class OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title abstract description 12
- -1 5-pyrazolyl Chemical group 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 51
- 238000002360 preparation method Methods 0.000 claims description 17
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 12
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 229920002554 vinyl polymer Polymers 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 6
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 150000002989 phenols Chemical class 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 239000002934 diuretic Substances 0.000 abstract description 6
- 230000001882 diuretic effect Effects 0.000 abstract description 6
- 230000003424 uricosuric effect Effects 0.000 abstract description 3
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 22
- 238000001819 mass spectrum Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 206010030113 Oedema Diseases 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 229940097420 Diuretic Drugs 0.000 description 4
- 208000004880 Polyuria Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000035619 diuresis Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 3
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229940116269 uric acid Drugs 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- YWGKOEQZKMSICW-UHFFFAOYSA-N 2-chloro-4-methoxybenzaldehyde Chemical class COC1=CC=C(C=O)C(Cl)=C1 YWGKOEQZKMSICW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical class CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- RSEBZFKHMOONCZ-UHFFFAOYSA-N bis(2-methylpyrazol-3-yl)methanone Chemical class Cn1nccc1C(=O)c1ccnn1C RSEBZFKHMOONCZ-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical class BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- WFPZPJSADLPSON-UHFFFAOYSA-N dinitrogen tetraoxide Chemical compound [O-][N+](=O)[N+]([O-])=O WFPZPJSADLPSON-UHFFFAOYSA-N 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 201000006334 interstitial nephritis Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 description 2
- BFNXYSZBURSNHS-UVJOBNTFSA-N (2s)-1-[(2s)-6-amino-2-[[(1s)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid;6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 BFNXYSZBURSNHS-UVJOBNTFSA-N 0.000 description 1
- GEORDJYJYUGGSO-UHFFFAOYSA-N 2,3-dichloro-4-hydroxybenzaldehyde Chemical class OC1=CC=C(C=O)C(Cl)=C1Cl GEORDJYJYUGGSO-UHFFFAOYSA-N 0.000 description 1
- ZMOMCILMBYEGLD-UHFFFAOYSA-N 2-chloro-4-hydroxybenzaldehyde Chemical class OC1=CC=C(C=O)C(Cl)=C1 ZMOMCILMBYEGLD-UHFFFAOYSA-N 0.000 description 1
- AQZMINLSVARCSL-UHFFFAOYSA-N 4-chloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound ClC1=CC(=O)C(C#N)=C(C#N)C1=O AQZMINLSVARCSL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 description 1
- UHBXGHADNVDXMM-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Li] Chemical compound C(C)(C)N(C(C)C)CC[Li] UHBXGHADNVDXMM-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000009447 Cardiac Edema Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000035220 Dyserythropoietic Congenital Anemia Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010025282 Lymphoedema Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940121792 Thiazide diuretic Drugs 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- PQFZWNNSXMOCAL-UHFFFAOYSA-N acetyl acetate;methylsulfinylmethane Chemical compound CS(C)=O.CC(=O)OC(C)=O PQFZWNNSXMOCAL-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 108010033243 lisinopril drug combination hydrochlorothiazide Proteins 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 208000002502 lymphedema Diseases 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 229910001512 metal fluoride Inorganic materials 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明揭示了一种由以下一般式表示的新颖的苯氧基乙酸衍生物及其盐以及其制备方法,
式中,A为取代或未取代5-吡唑基,R1为氢原子或低级烷基,R2为氢原子或低级链烯基,X为卤素原子,Z为氧原子或亚甲基,所说的衍生物(I)及其盐具有有效的利尿、排盐利尿及促尿酸尿的作用。
Description
本发明涉及苯氧基乙酸衍生物及其制备方法。更具体地说,本发明涉及由以下一般式表示的苯氧基乙酸衍生物,或者它们的盐,
式中,A为5-吡唑基或具有选自C1-10烷基或低级烷氧基-低级烷基的取代基的5-吡唑基,
R1为氢原子,
R2为氢原子,
X为卤素原子,
Z为氧原子或者亚甲基。
公知的利尿剂包含噻嗪类利尿剂,例如氯噻嗪或双氢氯噻嗪和袢性利尿剂,例如利尿磺胺或者利尿酸。这些利尿剂均用于通过抑制肾小管重吸收水和电解质来增加尿量和电解质排泄。然而,这些公知的利尿剂并不令人满意,因为它们易引起血尿酸过多,这往往会导致由于尿酸在活体组织中沉积而引起的间质性肾炎或者痛风。故而,人们业已着手研制不仅可促进水和电解质而且可促进尿酸排泄的利尿剂。
我们发现了苯氧基乙酸衍生物(Ⅰ)及其盐具有有效的利尿、排盐利尿以及促尿酸尿的作用。例如,当通过给盐水负荷的大鼠服用其羧甲基纤维素溶液(用量:100毫克/公斤)检验试验化合物对尿量的影响时,试验表明与对照组大鼠相比,尿量中[2,3-二氯-4-(1-
乙氧基甲基-5-吡唑基羰基)苯氧基]乙酸、[2,3-二氯-4-(1-甲氧基甲基-5-吡唑基羰基)苯氧基]乙酸、[2,3-二氯-4-(1-乙基-5-吡唑基羰基)苯氧基]乙酸以及[2,3-二氯-4-(1-异丙基-5-吡唑基羰基)苯氧基]乙酸中的每一种均增加100%以上。而且,与对照组大鼠相比,给所说的盐水负荷的大鼠口服[6-烯丙基-2,3-二氯-4-(1-甲基-5-吡唑基羰基)苯氧基]乙酸或者{2,3-二氯-4-[1-(1-甲基-5-吡唑基)乙烯基]苯氧基}乙酸,尿酸的排泄增加100%以上。
本发明的化合物的实例均含有由一般式(Ⅰ)表示的化合物,式中:A为5-吡唑基或者具有选自C1-10烷基如甲基、乙基、丙基、异丙基、丁基或戊基或低级烷氧基-低级烷基如甲氧甲基或乙氧甲基的一个取代基的5-吡唑基;R1为氢原子或者低级烷基,如甲基、乙基、丙基或丁基;R2为氢原子或者低级链烯基,如乙烯基、丙烯基或丁烯基;X为卤素原子,如氯、溴或碘;Z为氧原子或者亚甲基。
在本发明的化合物之中,优先采用的亚属是以一般式(Ⅰ)表示的化合物,式中:A为1-低级烷基-5-吡唑基,或者1-(低级烷氧基-低级烷基)-5-吡唑基;R1为氢原子;R2为氢原子;x为氯原子;Z为氧原子或者亚甲基。
本发明的苯氧基乙酸衍生物(Ⅰ)或者其盐可以用以下的步骤或几个步骤制备:
(A-Ⅰ)使由以下一般式表示的酚化合物
式中,A、R2、X和Z同上所述,与由以下一般式表示的乙酸化合物反应,
式中,Y为反应残基,R11为氢原子或低级烷基;或者
(A-Ⅱ)使由以下一般式表示的化合物
式中,A、R11、R2和X同上所述,氧化获得由以下一般式表示的化合物
式中,A、R11、R2和X同上所述;和
(B)当步骤(A-Ⅰ)或(A-Ⅱ)所得化合物的R11是低级烷基时,水解所述化合物,得到化合物(Ⅰ),和
(C)若有需要,再把产物转变成其盐。
起始化合物(Ⅲ)中反应残基Y的实例包括卤素原子,例如氯、溴或碘,甲苯磺酰氧基和甲磺酰氧基。
酚化合物(Ⅱ)与乙酸化合物(Ⅲ)的反应可以在有酸受体的溶剂中进行。酸受体包括碱金属氢氧化物,如氢氧化钠或氢氧化钾,碱土金属氢氧化物,如氢氧化钙或氢氧化钡,碱金属碳酸盐,如碳酸钠或碳酸钾,碱金属碳酸氢盐,如碳酸氢钠或碳酸氢钾,碱金属氢化物,如氢化钠或氢化钾,碱金属低级烷氧化合物,如乙醇钠或叔丁醇钾,二异丙基氨基化锂,氨基化钠,氨基化锂,碱金属氟化物,如氟化钾或氟化铯,或者有机碱,如三乙胺或三丁胺。优先采用低级链烷酮,例如丙酮或甲基乙基酮,低级链烷醇,如甲醇或乙醇,四氢呋喃,二噁烷,二甲基甲酰胺,二甲亚砜或者水和上述有机溶剂的混合物作为溶剂。反应优先在0到100℃下,特别在20到80℃下进行。
化合物(Ⅳ)的氧化可以用氧化剂在溶剂中处理来完成。优先采用二氯甲烷,氯仿,低级链烷酮,如丙酮或甲基乙基酮、苯、甲苯、己烷、石油醚、乙腈、二甲基甲酰胺、二甲亚砜、乙酸、四氢呋喃、二噁烷或者水和上述有机溶剂的混合物作为溶剂。氧化剂的合适实例包括二氧化锰、铬酐、高锰酸钾、乙酸酐-二甲亚砜、氯醌、2,3-二氯-5,6-二氰基苯醌、四氧化二氮。反应优先在-78到100℃下,特别在0到50℃下进行。
可以用惯用的方法,例如通过使所说的化合物在溶剂中与大体上等摩尔量的酸或者碱反应,将由上所得的本发明的化合物(Ⅰ)转变成它们的盐。
如本文上面所述,本发明的苯氧基乙酸衍生物(Ⅰ)及其盐具有有效的利尿、排盐利尿以及促尿酸尿的作用,并用于充血性心力衰竭、各种各样的水肿(例如,肝脏性水肿、肾脏性水肿、心脏性水肿、孕妇水肿(=怀孕期水肿)、淋巴性水肿、药物性水肿、肺水肿)、腹部积水、渗出性胸膜炎、间质性肾炎、痛风或者血尿酸过多的治疗和预防。
本发明的化合物(Ⅰ)可以游离状或其盐状用于药用。化合物(Ⅰ)的盐的实例包括碱金属盐,如钠盐或钾盐,碱土金属盐,如钙盐、无机酸加成盐,如氢氯化物或氢溴化物,有机酸加成盐,如甲磺酸盐或草酸盐,等等。
化合物(Ⅰ)或其盐可以口服或者非胃肠道使用。口服时,化合物(Ⅰ)或其盐可以固体剂型使用,如片剂、粉剂、胶囊剂或颗粒剂,它们可以含有通用的载体、粘合剂、稀释剂、崩解剂、湿润剂等等。它们还可以以液体状使用,如水剂或油混悬剂、溶液剂、糖浆剂或酏剂。另一方面,非胃肠道使用时,化合物(Ⅰ)或其盐可以注射剂或栓剂来应用。
化合物(Ⅰ)或其盐的用量可以在很大的范围内变动,取决于
疗程、病员的年令、体重或状况以及治疗疾病的种类和病情。然而,一般来说,化合物(Ⅰ)或其盐的一天用量最好采用0.3到200毫克/公斤/天,特别是1到100毫克/公斤/天。
伴随的情况是,其中Z为氧原子的起始化合物(Ⅱ)(所说的化合物在本文下面称之为化合物(Ⅱ-A)]可以通过用氢溴酸、碱金属氰化物、碱金属硫代乙酸盐、三溴化硼等处理由以下一般式表示的化合物,
式中,R3为低级烷基,A、R2和X同上所述,
或者通过使由以下一般式表示的化合物
式中,A、R2和X同上所述,
氧化来制备
其中Z为亚甲基的起始化合物(Ⅱ)可通过使由此获得的化合物(Ⅱ-A)与内鎓盐化合物(Ⅴ)反应制备。
另一方面,本发明的起始化合物(Ⅳ)可通过使化合物(Ⅶ)与乙酸化合物(Ⅲ)反应来制备。
在整篇说明书和权利要求书中,应当把“低级烷基”和“低级烷氧基”的术语分别认为是1到6个碳原子的烷基和1到6个碳原子的烷氧基。
实施例1
将0.63克2,3-二氯-4-(1-乙氧基甲基-5-吡唑基羰基)酚、0.58
克溴乙酸以及1.11克碳酸钾加入到40毫升丙酮中,混合物回流48小时。使反应混合物浓缩去除溶剂,把水加入到残留物中。用乙酸乙酯洗涤含水混合物,用10%盐酸酸化,然后用乙酸乙酯提取。用饱和氯化钠溶液洗涤提取液,干燥并蒸发去除溶剂。用水使残留物结晶,过滤分离结晶,依次用水和异丙醚洗涤,并干燥,获得0.42克[2,3-二氯-4-(1-乙氧基甲基-5-吡唑基羰基)苯氧基]乙酸。
熔点:148-149℃
质谱(m/e):372(M+)
核磁共振(CDCl3+DMSO-d6)δ:1.17(t,3H,J=7Hz)
3.61(q,2H,J=7Hz),4.76(s,2H),
5.90(s,2H),6.47(d,Ⅲ,J=2Hz),
6.84(d,1H,J=9Hz),7.32(d,1H,J=9Hz),
7.53(d,1H,J=2Hz).
一水化物钠盐:熔点194-196.5℃
实施例2
(1)将1.67克2,3-二氯-4-(1-乙氧基甲基-5-吡唑基羰基)酚、1.15克溴乙酸乙酯以及1.68克碳酸钾加入到60毫升丙酮中,混合物回流1小时。过滤反应混合物,使滤液蒸发去除溶剂。使残留物溶解在苯中,用活性碳处理溶液并蒸发获得一种油,然后由异丙醚使油结晶,获得1.89克[2,3-二氯-4-(1-乙氧基甲基-5-吡唑羰基)苯氧基]乙酸乙酯。
熔点:92-94℃
质谱(m/e):400(M+)
核磁共振(CDCl3)δ:1.14(t,3H,J=7Hz),
1.27(t,3H,J=7Hz),3.65(q,2H,J=7Hz),
4.32(q,2H,J=7Hz),4.80(s,2H),
5.92(s,2H),6.45(d,1H,J=2Hz),
6.79(d,1H,J=9Hz),7.33(d,1H,J=9Hz),
7.54(d,1H,J-2Hz)
(2)将0.9克[2,3-二氯-4-(1-乙氧基甲基-5-吡唑基羰基)苯氧基]乙酸乙酯混悬在20毫升乙醇中,再将10毫升10%氢氧化钠水溶液加入其中。该混合物于室温下搅拌1小时。将反应混合物浓缩以除去乙醇,并用10%盐酸调节至pH1-2。所得结晶经过滤收集,相继以水和异丙醚洗涤,并干燥,获得0.82克[2,3-二氯-4-(1-乙氧基甲基-5-吡唑基羰基)苯氧基]乙酸。
由此得到的产物的理化性质和实施例1所得化合物的理化性质相同。
实施例3到7
(1)用与实施例2(1)中所述的相同方法处理相应的酚衍生物和溴乙酸乙酯,获得如表1中所示的一些化合物。
在实施例6和7中,用乙醇作为结晶溶剂,代替实施例2(1)中的异丙醚。
表1
实施例 化合物(Ⅰ-a) 性质
序号 R
3(1) CH2OCH3熔点78-79℃
质谱(m/e):386(M+)
4(1) CH(CH3)2熔点79-80℃
质谱(m/e):384(M+)
油
IRν液体 max(cm-1):1755,1660,1580,
5(1) (CH2)5CH31550,1550.
质谱(m/e):426(M+)
熔点79-80℃
6(1) CH3质谱(m/e):356(M+)
熔点79-81℃
7(1) C2H5质谱(m/e):370(M+)
(2)用与实施例2(2)中所述的相同方法处理相应的苯氧基乙酸酯衍生物,获得如表2中所示一些化合物。
用异丙醚-已烷(实施例5)或乙酸乙酯(实施例6)作为结晶溶剂。
表2
实施例 化合物(Ⅰ-c) 性质
序号 R
熔点179-180.5℃
质谱(m/e):358(M+)
NMR(CDCl3+DMSO-d6)δ:3.37
(s,3H),4.81(s,2H),5.84(s,
3(2) CH2OCH32H).6.54(d,1H,J=2Hz),6.97
(d,1H,J=8.6Hz),7.39(d,1H,
J=8.6Hz),7.57(d,1H,J=
2Hz).
熔点223-225℃
质谱(m/e):356(M+)
NMR(CDCl3+DMSO-d6)δ:1.55
(d,6H,J6.6Hz),4.77(s,2H),
4(2) CH(CH3)25.52(sept.,1H,J=6.6Hz),6.39
(d,1H,J=2Hz),6.89(d,1H,J=
8.7Hz),7.34(d,1H,J=8.7Hz),
7.48(d,1H,J=2Hz),8.45(br s,
1H)
熔点114-115℃
5(2) (CH2)5CH3质谱(m/e):398(M+)
熔点230-231℃
6(2) CH3质谱(m/e):328(M+)
熔点203-204℃
质谱(m/e):342(M+)
NMR(CDCl3+DMSO-d6)δ:1.47
(t,3H,J=7Hz),4.63(q,2H,J=
7(2) C2H57Hz),4.81(s,2H),6.43(d,1H,
J=2Hz),6.97(d,1H,J=
8.5Hz,7.38(d,1H,J=8.5Hz),
7.45(d,1H,J=2Hz).
实施例8
将1.03克[2,3-二氯-4-(1-乙氧基甲基-5-吡唑基羰基)苯氧基]乙酸乙酯溶解在25毫升乙醇中,再加入6毫升浓盐酸。混合物在60-65℃下搅拌3.5小时。冷却反应混合物,通过在冰冷下添加饱和碳酸氢钠溶液把pH值调整到8-9,然后用乙酸乙酯提取。提取液依次用饱和碳酸氢钠溶液和水洗涤,经干燥和蒸发去除溶剂。残留物用硅胶柱色谱法(溶剂;苯-乙酸乙酯)提纯并用苯和氯仿的混合物结晶,获得0.54克[2,3-二氯-4-(5-吡唑基羰基)苯氧基]乙酸乙酯。
熔点:147-149℃
质谱(m/e):342(M+)
实施例9到11
(1)用与实施例2(1)所述的相同方法处理相应的苯酚衍生物和
溴乙酸乙酯,获得如表3中所示的一些化合物。
在实施例9中,用异丙醚和已烷的混合物作为结晶溶剂,代替实施例2(1)中的异丙醚。
表3
实施例 化合物(Ⅰ-b) 性质
序号 R
熔点88-89℃
9(1) CH3质谱(m/e):354(M+)
油
10(1) C2H5IRν液体 max(cm-1):1750
质谱(m/e:386(M+)
油
IRν液体 max(cm-1):
11(1) CH2OC2H51750,1620,1590,1560,1515
质谱(m/e:398(M+)
(2)用与实施例2(2)中所述的相同方法处理相应的苯氧基乙酸酯衍生物,获得如表4中所示的一些化合物。
在实施例11中,用乙醇-异丙醚作为结晶溶剂。
表4
实施例 化合物(Ⅰ-b) 性质
序号 R
熔点186.5-187.5℃
质谱(m/e):326(M+)
NMR(CDCl3+DMSO-d6)δ:3.75
(s,3H),4.71(s,2H),5.53(s-
9(2) CH3like,1H),5.61(s-like,1H),6.
03(d,1H,J=2Hz),6.79(d,1H,J
=8.5Hz),7.16(d,1H,J=8.
5Hz),7.38(d,1H,J=2Hz).
熔点151.5-153.5℃
质谱(m/e):370(M+)
NMR(CDCl3+DMSO-d6)δ:1.16
(t,3H,J=7Hz),3.6(q,2H,J=
10(2) CH2OC2H57Hz),4.72(s,2H),5.43(s,2H),
5,53(s-like,1H),5.97(s-like,
1H),6.83(d,1H,J=8.5Hz),7.
25(d,1H,J=8.5Hz),7.42(d-
like,2H).
熔点163.5-153.5℃
11(2) C2H5质谱(m/e):340(M+)
实施例12
(1)除了用异丙醚作为结晶溶剂之外,用与实施例8(1)中所述的相同方法处理1.10克{2,3-二氯-4-[1-(1-乙氧基甲基-5-吡唑基)乙烯基]苯氧基}乙酸乙酯,获得0.81克晶体状{2,3-二氯-4-[1-(5-吡唑基)乙烯基]苯氯基}乙酸乙酯。
熔点:110-112℃
质谱(m/e):340(M+)
NMR(CDCl3)δ:1.31(t,3H,J=7Hz),
4.31(q,2H,J=7Hz),4.75(s,2H),
5.24(s,1H)5.97(s,1H),
6.19(d,1H,J=2Hz),
6.81(d,1H,J=8.8Hz),
7.23(d,1H,J=8.5Hz),7.4(宽s,1H),
7.48(d,1H,J=2Hz),
实施例13
(1)用与实施例2(1)中所述的相同方法处理634毫克α-(1-乙氧基甲基-5-吡唑基)-2,3-二氯-4-羟基苄醇和367毫克溴乙酸乙酯,获得790毫克α(1-乙氧基甲基-5-吡唑基)-2,3-二氯-4-乙氧基羰基甲氧基苄醇。
IRν液体 最大(cm-1):3300-3200,1750,1590.
质谱(m/e):402(M+)
(2)使770毫克α-(1-乙氧基甲基-5-吡唑基)-2,3-二氯-4-乙氧基羰基甲氧基苄醇和1.66克二氧化锰悬浮在30毫升二氯甲烷中,在室温下使悬浮液搅拌24小时。过滤反应混合物,蒸发滤液去除溶剂。用异丙醚和已烷的混合物研磨残留物,获得703毫克晶体状[2,3-二氯-4-(1-乙氧基甲基-5-吡唑基羰基)苯氧基]乙酸乙酯。
由此获得的产物的物理化学性质与实施例2(1)中所得的化合
物的一样。
[起始化合物的制备]
制备1
(1)将己烷中有4.13毫升1.6Mn-丁基锂的溶液在-60℃、氩气气氛下一滴滴地加入到0.76克1-乙氧基甲基吡唑的四氢呋喃溶液中。混合物在-63到-50℃下搅拌1小时。把四氢呋喃中有1.23克2,3-二氯-4-甲氧基苯甲醛的溶液加入到该混合物中,混合物在-50℃到室温下搅拌1小时。把饱和氯化铵溶液和水在冰冷却下加入到混合物中,浓缩混合物去除四氢呋喃。用乙酸乙酯提取残留的含水层,提取液用水洗涤,经干燥且蒸发,获得无色晶体,然后用异丙醚洗涤该晶体,经干燥,获得1.62克α-(1-乙氧基甲基-5-吡唑基)-2,3-二氯-4-甲氧基-苯甲醇。
熔点:115-157℃
(2)将2.72克二氧化锰加入到二氯甲烷中有1.04克α-(1-乙氧基甲基-5-吡唑基)-2,3-二氯-4-甲氧基苯甲醇的溶液中,混合物在室温下搅拌27小时。过滤反应混合物,滤液凝集成油状残留物,然后由异丙醚使其结晶,获得0.93克(2,3-二氯-4-甲氧基苯基)(1-乙氧基甲基-5-吡唑基)甲酮。
熔点:74-76℃
(3)将9.45克硫代乙酸钾加入到二甲亚砜中有5.45克(2,3-二氯-4-甲氧基苯基)(1-乙氧基甲基-5-吡唑基)甲酮中,混合物在90-100℃氩气气氛中搅拌4小时。使溶液冷却之后,把冷水加入其中,用乙酸把混合物的pH值调整到5-6,然后用乙酸乙酯提取。提取液用水洗涤,经干燥且蒸发去除溶剂。用硅胶柱色谱法提纯残留物,获得3.72克2,3-二氯-4-(1-乙氧基甲基-5-吡唑基羰基)酚。
熔点:115-117℃
制备2
(1)用与制备1-(1)中所述的相同方法处理6.0克1-甲基吡唑。获得18.0克α-(1-甲基-5-吡唑基)-2,3-二氯-4-甲氧基苯甲醇。熔点:169-171℃
(2)使2.23克α-(1-甲基-5-吡唑基)-2,3-二氯-4-甲氧基苯甲醇溶解在乙酸、丙酮和水的混合物中,再把0.90克铬酸酸酐加入到该溶液中。混合物在室温下搅拌2.5小时,把异丙醇加入其中以分解过量的氧化剂。过滤混合物且蒸发滤液。把水加入到残留物中,用氯仿提取混合物。洗涤提取液,经干燥且蒸发去除溶剂。用甲醇使残留物结晶,获得2.07克(2,3-二氯-4-甲氧基苯基)(1-甲基-5-吡唑基)甲酮。
熔点:150-152℃
(3)将20毫升47%氢溴酸加入到1.0克(2,3-二氯-4-甲氧基苯基)(1-甲基-5-吡唑基)甲酮中,混合物回流4小时。蒸发反应混合物去溶剂,再把残留物溶解在10%氢氧化钠溶液中。过滤溶液,用乙酸把滤液的pH值调整到4-5。收集所得的晶体,用水洗涤且经干燥,获得0.88克2,3-二氯4(1-甲基吡唑基羰基)酚。
熔点:220-222℃
制备3-6
用与制备1或2中所述的相同方法处理相应的起始化合物,获得如表5中所示的一些化合物。
表5
实施例 化合物(Ⅱ-a) 熔点
序号 R
3 CH2OCH3134-135
4 CH(CH3)2191-192
5 (CH2)5CH3110-111.5
6 C2H5180-181
制备7
将在四氢呋喃-二甲亚砜中有2.71克2,3-二氯-4-(1-甲基-5-吡唑基羰基)酚的溶液一滴滴地加入到由在四氢呋喃-二甲亚砜中有8.57克甲基三苯基鏻溴化物和在己烷中有13.8毫升1.6Mn-丁基锂的溶液制备的内鎓盐溶液中。混合物在室温下搅拌18小时,再在65℃下搅拌2小时。把反应混合物倾倒入饱和氯化铵溶液中,然后用乙酸乙酯提取。用水洗涤提取液,经干燥且蒸发去除溶剂。用硅胶柱色谱法提纯残留物,获得2.41克2,3-二氯-4-[1-(1-甲基-5-吡唑基)乙烯基]酚。
熔点:185-186.5℃
制备8和9
用与制备7中所述的相同方法处理相应的酮化合物,获得以下化合物。
(8)2,3-二氯-4-[1-(1-乙基-5-吡唑基)乙烯基]酚
熔点:180-182.5℃
(9)2,3-二氯-4-[1-(1-乙氧基甲基-5-吡唑基)-乙烯基]酚
熔点:162-164℃
制备10
将在二氯甲烷中有5.51克三溴化硼的溶液一滴滴地加入到在二氯甲烷中有2.05克2,3-二氯-4-甲氧基苯甲醛的溶液中。混合物
在室温下搅拌4小时,倒入冰水中,然后用乙酸乙酯提取。用水洗涤提取液,经干燥且蒸发去除溶剂。把10%盐酸和甲醇加入到残留物中,混合物在冰冷却下搅拌3小时,再用乙酸乙酯提取。用水洗涤提取液,经干燥且蒸发去除溶剂。用异丙醚使残留物结晶,获得1.82克4-羟基-2,3二氯苯甲醛。
(2)将在己烷中有18.1毫升1.6Mn-丁基锂的溶液在-55到-53℃氩气气氛下加入到3.56克1-乙氧基甲基吡唑的四氢呋喃溶液中,混合物在同样温度下搅拌1小时。把在四氢呋喃中有2.45克2,3-二氯-4-羟基苯甲醛的溶液加入到上述的混合物中,反应混合物在-55到-60℃下搅拌3小时。然后加入4.9毫升六甲磷三酰胺,整个混合物在室温下搅拌16小时。加入饱和氯化铵溶液,用乙酸乙酯提取混合物。用水洗涤提取液,经干燥且蒸发去除溶剂。用硅胶柱色谱法提纯残留物,再用乙酸乙酯和异丙醚的混合物使之结晶,获得2.69克α-(1-乙氧基甲基-5-吡唑基)-2,3-二氯-4羟基苯甲醇。熔点:149.4-150℃
Claims (4)
1、一种由以下一般式表示的苯氧基乙酸衍生物或其药学上可接受的盐的制备方法,
式中,A为吡唑基,或为有取代基的5-吡唑基,取代基是选自由烷基(C1-10)和低级烷氧基-低级烷基所组成的组,
R1为氢原子,
R2为氢原子,
X为卤素原子,
Z为氧原子或亚甲基,
其特征在于所说的制备方法包括以下的步骤或者几个步骤:
(A-Ⅰ)使由以下一般式表示的酚化合物
式中,A、R2、X和Z同上所述,
与由以下一般式表示的乙酸化合物反应,
式中,Y为反应残基,R11是氢原子或低级烷基,或者
(A-Ⅱ)使由以下一般式表示的化合物:
式中,A、R11、R2和X同上所述,
氧化获得由以下一般式表示的化合物:
式中,A、R11、R2和X同上所述;以及
(B)当步骤(A-Ⅰ)或(A-Ⅱ)所得的化合物中R11是低级烷基时,使所述的化合物水解得到化合物(Ⅰ);以及
(C)如果需要,进一步将产物转化成药学上可接受的盐。
2、根据权利要求1所述的制备方法,其特征在于,在起始原料的一般式(Ⅱ)或一般式(Ⅳ)中,A为1-低级烷基-5-吡唑基或1-(低级烷氧基-低级烷基)-5-吡唑基。
3、根据权利要求2所述的制备方法,其特征在于,通过以下步骤制备[2,3-二氯-4-(1-乙基-5-吡唑基羰基)苯氧基]乙酸或其药学上可接受的盐:使2,3-二氯-4-(1-乙基-5-吡唑基)酚和溴乙酸乙酯反应,水解所得化合物,如果需要,进一步将产物转化成药学上可接受的盐。
4、根据权利要求2所述的制备方法,其特征在于,通过以下步骤制备{2,3-二氯-4-(1-乙基-5-吡唑基)乙烯基]苯氧基}乙酸或其药学上可接受的盐:使[2,3-二氯-4-(1-乙基-5-吡唑基)乙烯基]酚和溴乙酸乙酯反应,水解所得化合物,如果需要,进一步将产物转化成药学上可接受的盐。
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JPH01316317A (ja) * | 1988-03-10 | 1989-12-21 | Tanabe Seiyaku Co Ltd | 降圧剤 |
CA2036192A1 (en) | 1990-02-13 | 1991-08-14 | Nicholas Meanwell | Heterocyclic carboxylic acids and esters |
US4956379A (en) * | 1990-02-13 | 1990-09-11 | Bristol-Myers Squibb Company | Pyrazole carboxylic acids and esters and inhibition of blood platelet aggregation therewith |
US20040067531A1 (en) * | 1997-08-20 | 2004-04-08 | Sugen, Inc. | Methods of modulating protein tyrosine kinase function with substituted indolinone compounds |
EA005996B1 (ru) | 2000-02-15 | 2005-08-25 | Сьюджен, Инк. | Пирролзамещенный 2-индолинон, фармацевтическая композиция (варианты), способ модулирования каталитической активности протеинкиназы, способ лечения или профилактики нарушения в организме, связанного с протеинкиназой |
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FI874473A0 (fi) | 1987-10-12 |
IL84106A0 (en) | 1988-03-31 |
CN87106895A (zh) | 1988-04-20 |
IE872668L (en) | 1988-04-13 |
HUT50788A (en) | 1990-03-28 |
FI91402C (fi) | 1994-06-27 |
US4853404A (en) | 1989-08-01 |
HU202501B (en) | 1991-03-28 |
DE3776627D1 (de) | 1992-03-19 |
FI874473A (fi) | 1988-04-14 |
DK532987D0 (da) | 1987-10-12 |
AU7956387A (en) | 1988-04-14 |
FI91402B (fi) | 1994-03-15 |
IL84106A (en) | 1991-07-18 |
ES2032284T3 (es) | 1993-02-01 |
HK47193A (en) | 1993-05-21 |
AU595385B2 (en) | 1990-03-29 |
DK166879B1 (da) | 1993-07-26 |
KR920002296B1 (ko) | 1992-03-21 |
ATE72429T1 (de) | 1992-02-15 |
JPH0544944B2 (zh) | 1993-07-07 |
KR880005089A (ko) | 1988-06-28 |
JPS63225359A (ja) | 1988-09-20 |
GR3003727T3 (zh) | 1993-03-16 |
CA1311483C (en) | 1992-12-15 |
DK532987A (da) | 1988-04-14 |
EP0268800A1 (en) | 1988-06-01 |
IE60044B1 (en) | 1994-05-18 |
EP0268800B1 (en) | 1992-02-05 |
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