CN1044649A - 萘衍生物及其合成的中间体的制备方法 - Google Patents
萘衍生物及其合成的中间体的制备方法 Download PDFInfo
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- CN1044649A CN1044649A CN90100376A CN90100376A CN1044649A CN 1044649 A CN1044649 A CN 1044649A CN 90100376 A CN90100376 A CN 90100376A CN 90100376 A CN90100376 A CN 90100376A CN 1044649 A CN1044649 A CN 1044649A
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- 150000002790 naphthalenes Chemical class 0.000 title claims abstract description 14
- 239000000543 intermediate Substances 0.000 title description 8
- 238000002360 preparation method Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 32
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 21
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000002587 enol group Chemical group 0.000 claims description 8
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical class C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 241000790917 Dioxys <bee> Species 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 4
- 239000003524 antilipemic agent Substances 0.000 abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- -1 phenyl aldehyde Chemical class 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000011097 chromatography purification Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010306 acid treatment Methods 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- UTXBJOTXFNNRDN-UHFFFAOYSA-N CC(C)(C)[Si](C)(C)[O] Chemical compound CC(C)(C)[Si](C)(C)[O] UTXBJOTXFNNRDN-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229940059936 lithium bromide Drugs 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- VTBHBNXGFPTBJL-UHFFFAOYSA-N 4-tert-butyl-1-sulfanylidene-2,6,7-trioxa-1$l^{5}-phosphabicyclo[2.2.2]octane Chemical compound C1OP2(=S)OCC1(C(C)(C)C)CO2 VTBHBNXGFPTBJL-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KSGUUTWSWMLVHG-UHFFFAOYSA-N N.OOO Chemical compound N.OOO KSGUUTWSWMLVHG-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910001513 alkali metal bromide Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000006307 alkoxy benzyl group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- LDDQLRUQCUTJBB-UHFFFAOYSA-N ammonium fluoride Chemical compound [NH4+].[F-] LDDQLRUQCUTJBB-UHFFFAOYSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- HXLVDKGPVGFXTH-UHFFFAOYSA-N butyl(dimethyl)silane Chemical group CCCC[SiH](C)C HXLVDKGPVGFXTH-UHFFFAOYSA-N 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-N butynedioic acid Chemical compound OC(=O)C#CC(O)=O YTIVTFGABIZHHX-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- LDCRTTXIJACKKU-ARJAWSKDSA-N dimethyl maleate Chemical compound COC(=O)\C=C/C(=O)OC LDCRTTXIJACKKU-ARJAWSKDSA-N 0.000 description 1
- 238000006253 efflorescence Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910001512 metal fluoride Inorganic materials 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- URXNVXOMQQCBHS-UHFFFAOYSA-N naphthalene;sodium Chemical compound [Na].C1=CC=CC2=CC=CC=C21 URXNVXOMQQCBHS-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- GTDKXDWWMOMSFL-UHFFFAOYSA-M tetramethylazanium;fluoride Chemical compound [F-].C[N+](C)(C)C GTDKXDWWMOMSFL-UHFFFAOYSA-M 0.000 description 1
- 229910021558 transition metal bromide Inorganic materials 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Moulding By Coating Moulds (AREA)
- Water Treatment By Sorption (AREA)
- Furan Compounds (AREA)
Abstract
本发明涉及一种制备萘衍生物的方法,式中R1和R2是低级烷氧基羰基或者两者可结合在一起形成式为:的基团;R3和R4中的一个是氢原子或低级烷氧基,另一个是低级烷氧基,环A是取代或非取代的苯环,该萘衍生物作为降血脂剂是有用的。本发明也涉及一种下式的新颖的中间体:
(其中R1、R2、R3、R4和环A的定义同上)
Description
本发明涉及作为降血脂剂是有用的萘衍生物的制备方法。本发明也涉及它们的合成中间体。
1-(3-和/或4-低级烷氧基苯基)-2,3-二(低级烷氧基羰基)-4-羟基萘化合物和1-(3-和/或4-低级烷氧基苯基)-3-羟甲基-4-羟基-2-萘甲酸内酯化合物是有用的降血脂剂。
到目前为止,已知将2-(α-羟基-3和/或4-低级烷氧基苄基)苯甲醛或它的二-低级烷基乙缩醛与乙炔二羧酸二低级烷酯反应,并且如果需要,再使产物进行还原内酯化反应可以制得这些化合物[日本专利第一公报(Kokai)第267541/1986]。
本发明者经细致的研究并实现了一种新颖的萘衍生物的制备方法,其中的合成途经与常规方法完全不同。
根据本发明,采用下列步骤可以制备下式的萘衍生物:
(其中R1和R2是低级烷氧基羰基或者两者结合在一起形成结构式为:
的基团;R3和R4中的一个是氢原子或低级烷氧基,另一个是低级烷氧基;环A是取代或未被取代的苯环):
A.使下式的三种化合物进行反应:
(其中R5是羟基的保护基团,R1,R2,R3,R4和环A的定义同上),
B.将产物用酸处理给出下式的被护的含氧基-四氢化萘化合物:
(其中R1,R2,R3,R4,R5和环A的定义同上),
C.用氟离子给予体处理化合物(Ⅴ)或其盐给出下式氧代-四氢化萘化合物:
(其中R1,R2,R3,R4和环A的定义同上),
D.进一步使化合物(Ⅵ)或它的烯醇式互变异构体氧化。
在碱性物质的存在下使起始化合物(Ⅱ)、(Ⅲ)和(Ⅳ)的反应。碱性物质可以是任何常用的碱性物质,较好地可采用氨基化锂(例如二异丙氨基化锂)、芳基锂(例如苯基锂)或烷基锂(例如正丁基锂)。在被护含氧基乙腈化合物(Ⅱ)中用作羟基的保护基团(R5)可以是任何用来保护羟基的常规保护基团,较好地可采用单-、双-或三-低级烷基甲硅烷基(例如,甲基甲硅烷基、二甲基甲硅烷基、三甲基甲硅烷基、叔丁基二甲基甲硅烷基)、低级烷氧基-低级烷基(例如,甲氧基甲基)、低级烷氧基-低级烷氧基-低级烷基(例如,甲氧基乙氧基甲基)或苯基低级烷基(例如苄基)。当在取代的乙烯化合物(Ⅲ)中的R1和R2是低级烷氧基羰基时,可采用它们的反式取代化合物或顺式取代化合物。该反应较好地在冷却下,例如-78℃至-40℃下进行。所述的反应能在适当的溶剂中进行。作为溶剂,可以采用常规的有机溶剂,例如,四氢呋喃、醚、二甘醇二甲醚、己烷、甲苯、二甲苯。在进行所述的反应时,较好地是当被护的含氧基乙腈化合物(Ⅱ)与被取代的乙烯化合物(Ⅲ)反应后再将醛化合物(Ⅳ)加入反应体系中。
采用常规的方法对产物进行酸处理。作为酸可采用有机酸或无机酸,而采用有机酸(例如,三氟乙酸、甲磺酸、甲苯磺酸)则更为优选。可在室温下或加热时,例如10℃-50℃下进行酸处理。所述的反应可在合适的溶剂内进行,作为溶剂,较好地采用与三种化合物(Ⅱ)、(Ⅲ)和(Ⅳ)的上述反应中所采用的相同的溶剂。
用氟离子供体对被保护的含氧基-四氢化萘化合物(Ⅴ)或其盐进行随后的处理可以采用常规方法。作为氟离子供体可采用任何常规的氟离子供体,较好地是采用氟化物与酸的化合物。氟化物包括碱金属氟化物(例如氟化钾)、氟化铵和四-(低级)烷基铵氟化物(例如,四甲基氟化铵、四丁基氟化铵),酸包括,例如乙酸、三氟乙酸、甲磺酸、甲苯磺酸。较好的氟离子供体也包括氟化氢之类。所述的反应在周围温度下于合适的溶剂中可有效地进行。溶剂包括任何常规有机溶剂,例如二氯甲烷或氯仿。
这样得到的氧基-四氢化萘化合物(Ⅵ)或其烯醇式互变异构体的氧化反应可用常规方法进行。通过将化合物(Ⅵ)或其互变异构体用氧化剂处理或者用卤化剂处理后再用碱处理来进行所述的氧化反应。可采用常规的氧化剂,较好地是使用二氧化硒、2,3-二氯-4,5-二氰基苯醌、氧气或空气。另一方面,常规的卤化剂可以用作卤化剂,较好地是使用有碱金属溴化物(例如溴化镁、溴化钠)存在的过渡金属溴化物(例如,溴化铜)。有机碱或无机碱可用作碱,较好地是使用三乙胺、三丁胺、1,8-二氮杂双环[5,4,0]十一碳-7-烯、碱金属氢氧化物或碱金属碳酸盐。根据所采用的氧化方法,化合物(Ⅵ)的氧化反应可在冰冷却下进行或加热下进行,用卤化剂的反应在加热下较好地在50℃-80℃下进行,而用碱进行的随后处理可在冰冷却下进行或在氛围温度下进行,例如,在0℃-25℃下进行。两种反应较好地在合适的溶剂中进行。溶剂包括任何常规的有机溶剂,例如,乙腈、丙腈和氯仿。
在上述反应中,起始化合物(Ⅱ)(其中环A是被羟基取代的苯环)、中间体(Ⅴ)和(Ⅳ)以及中间产物(Ⅵ)的烯醇式互变异构体所应用的盐可以是碱金属盐、碱土金属盐等等。这些盐可如同用在化合物相应游离形式的反应中的相同的方法被用来进行反应。
由于中间体(Ⅴ)和(Ⅵ)依次有4和3个不对称碳原子故它们可以有非对映异构体,任何异构体或其混合物可用于本发明的方法中。
根据本发明的方法,日本专利公报(公开篇)第267541/1986中揭示的萘衍生物不论其环A的种类都可以以工业规模进行有利地制备。例如,可以有利地制得化合物(Ⅰ)(式中环A是未被取代的苯环,低级亚烷基二氧基所取代的苯环或有1-3个取代基的苯环,该取代基选自由低级烷氧基、低级烷基、苯基-低级烷氧基、羟基和卤原子所组成的组)以及萘衍生物(Ⅰ)[其中R1和R2是低级烷氧基羰基,R3和R4是低级烷氧基,环A是下式的取代的苯环:
其中Rd,Re和Rf是低级烷基。
通过用碱金属氢化物、碱金属氢氧化物、碱土金属氢氧化物、铵氢氧化物等来适当地处理这样得到的萘衍生物(Ⅰ)可任选地转变成其药学上可接受的化合物(Ⅰ)。
本发明的方法是通过新颖的反应来进行的,其中的合成途径与常规方法的合成途径完全不同。本发明的方法有一个工业上的优点即中间体氧代-四氢化萘化合物(Ⅴ)可通过将三种起始化合物(Ⅱ)、(Ⅲ)和(Ⅳ)在一简单过程中反应制得结果作为降血脂剂是有用的萘衍生物可在简单的反应过程中得到。
在本发明中作为中间体而得到的氧代-四氢化萘化合物(Ⅵ)在溶剂中与其烯醇式互变异构体有着如下式所示的平衡:
其中R1,R2,R3,R4和环A的定义同上,它们两者都可用于本发明中。
中间体(Ⅵ)是新颖的化化合物,只要在式中环A是被低级亚烷基二氧基取代的苯基,R1和R2结合在一起形成结构式为
的基团,R3和R4是低级烷氧基。
将下式的苯甲醛化合物:
(其中环A的定义同上),与碱金属氰化物及式为:R5-X(Ⅷ)(其中X是卤素原子,R5的定义同上)在路易斯酸[例如碘化锌(Ⅱ)]的存在下进行反应可以制得本发明的起始化合物(Ⅱ)。
本发明通过下列实施例进行阐述,但本发明不被它们所限制。
实施例1
(1-a)将3,4,5-三甲氧基苯甲醛(50克)溶于乙腈(与五氧化二磷在一起蒸馏制得)(250毫升)中。向该溶液中加入氰化钾(24.9克)、碘化锌(Ⅱ)(8.1克)和氯化叔丁基二甲基甲硅烷(46.1克),使混合物在室温下搅拌过夜。从反应混合物中蒸去乙腈,向残留物中加入二乙醚并滤去不溶物质。滤液用水洗涤、干燥并减压浓缩。所得的残留物用硅胶柱色谱层析纯化[溶剂∶正己烷/乙酸乙酯(3∶1)]并用正己烷和异丙醚混合物重结晶给出(3,4,5-三甲氧基苯基)(叔丁基二甲基甲硅烷基氧基)乙腈的无色晶体(67克)。
得率:78%
熔点:43℃
(1-b)用与上述方法(1-a)中相同的方法处理3,4,5-三甲氧基苯甲醛、乙腈、氰化钾、碘化锌(Ⅱ)和三甲基甲硅烷基氯化物给出(3,4,5-三甲氧基苯基)(三甲基甲硅烷基氧基)乙腈的油状产物。
沸点:145-147℃(1mmHg)
(2-a)将上述步骤(1-a)中所得的产物(10克)在四氢呋喃(20毫升)中的溶液于-70℃下滴加至二异丙基氨基化锂溶液[在1.6M正丁基锂的正己烷溶液(20.4毫升)中制得]中,让混合物在同样的温度下搅拌约5分钟。向该混合物中滴加入3,4-二甲氧基苯甲醛(4.93克)在四氢呋喃(20毫升)中的溶液,然后将乙酸(3.7毫升)和水(50毫升)和混合物加至反应混合物中。在室温下用乙酸乙酯萃取混合物。萃取液用水洗涤并干燥。蒸去溶剂,残留物用硅胶柱色谱层析纯化[溶剂∶正己烷/乙酸乙酯(2∶1)]。浓缩洗脱液,将残留物溶于乙酸酐(20毫升)中并使之在室温下搅拌2小时。进一步地,将三氟乙酸(10毫升)加至混合物中并让它静置过夜。将反应溶液浓缩,用氯仿萃取残留物。将萃取液洗涤,干燥,然后蒸去溶剂。残留物用异丙醚结晶,滤去不溶物质给出γ-1-(3,4-二甲氧基苯基)-t-2-甲氧基羰基-c-3-甲氧基羰基-4-氰基-4-(叔丁基二甲基甲硅烷基氧基)-6,7,8-三甲氧基-1,2,3,4-四氢化萘的无色晶体12.9克)。
得率:69%
熔点:162-163℃
(2-b)用与上述步骤(2-a)的相同方法来处理在上述步骤(1-b)中所得的产物、马来酸二甲酯和3,4-二甲氧基苯甲醛给出r-1-(3,4-二甲氧基苯基)-t-2-甲氧基羰基-c-3-甲氧基羰基-4-氰基-4-(三甲基甲硅烷基氧基)-6,7,8-三甲氧基-1,2,3,4-四氢化萘的油状产物。
(3-a)将上述步骤(2-a)中所得的产物(10.1克)溶于二氯甲烷(100毫升)中。向该溶液内加入四正丁基氟化铵溶液(17毫升)和乙酸(1.2毫升),并使混合物在室温下搅拌2小时。反应溶液用水洗涤,干燥,然后蒸去溶剂。残留物用硅胶柱色谱层析纯化[溶剂∶正己烷/乙酸乙酯(2∶1)]。浓缩洗脱液,用二乙醚使残留物结晶给出r-1-(3,4-二甲氧基苯基)-t-2-甲氧基羰基-3-甲氧基羰基-4-羟基-6,7,8-三甲氧基-1,2-二氢化萘的无色晶体(2.1克)。
得率:27%
熔点:132-134℃
NMR(CDCl3,δ):3.4-4.0(m,23H),4.5(d,1H,J=2Hz),6.5-7.0(m,4H)
在溶剂中该产物与r-1-(3,4-二甲氧基苯基)-t-2-甲氧基羰基-c-3-甲氧基羰基-4-氧基-6,7,8-三甲氧基-1,2,3,4-四氢化萘以平衡混合物的形式存在。
将母液进一步浓缩得到r-1-(3,4-二甲氧基苯基)-t-2-甲氧基羰基-c-3-甲氧基羰基-4-氧代-6,7,8-三甲氧基-1,2,3,4-四氢化萘的浆状物质(4.8克)。
得率:61%
(3-b)用与步骤(3-a)相同的方法处理上述步骤(2-b)中得到的产物给出r-1-(3,4-二甲氧基苯基)-t-2-甲氧基羰基-c-3-甲氧基羰基-4-氧基-6,7,8-三甲氧基-1,2,3,4-四氢化萘。
该产物的物理化学性质与上述步骤(3-a)中所得产物的物理化学性质相同。
(4)将在步骤(3-a)或(3-b)(4-氧基化合物)所得的产物(2.0克)、溴化铜(1.83克)、溴化锂(356毫克)和乙腈(50毫升)的混合物加热回流4小时。从反应溶液中蒸去乙腈,将氯仿加至残留物中。混合物经硅胶柱色谱层析纯化[溶剂∶氯仿/乙酸乙酯(1∶1)]。浓缩洗脱液,使残留物溶于氯仿中,然后向其中加入三乙胺(10毫升)。让混合物在室温下静置1小时。溶液用浓盐酸进行酸化,收集氯仿层。氯仿层用水洗涤,干燥,然后蒸去溶剂。将甲醇加至残留物中,通过过滤收集析出的结晶给出1-(3,4-二甲氧基苯基)-2,3-二(甲氧基羰基)-4-羟基-6,7,8-三甲氧基萘的无色棱晶(1.1克)。
得率:55%
熔点:178-179℃
(5)在室温及搅拌下将上述步骤(4)所得产物(4.86克)在四氢呋喃(100毫升)中的溶液,加到62.5%氢化钠(0.387克)在四氢呋喃(10毫升)中的溶液内,并让混合物在相同的温度下搅拌1小时。反应后,在30℃下减压蒸去溶剂。所得的残留物用石油醚使其粉化给出1-(3,4-二甲氧基苯基)-2,3-二(甲氧基羰基)-4-羟基-6,7,8-三甲氧基萘钠盐的粉末(4.8克)。
IRν KBr(cm-1):1710,1680,1600
最大值
实施例2
(1)在-70℃下将(3,4,5-三甲氧基苯基)(叔丁基二甲基甲硅烷基氧基)乙腈(10克)在四氢呋喃(20毫升)中的溶液滴加到二异丙基氨基化锂溶液内[从二异丙基胺(3.0克)在四氢呋喃(50毫升)中的溶液和1.6M正丁基锂的正己烷溶液(2.04毫升)在干冰冷却下制得]。使混合物在相同的温度下搅拌约5分钟,在20分钟内向其中滴加2-氧基-2,5-二氢呋喃(2.49克)在四氢呋喃(50毫升)中的溶液。进一步地,向其中加入3,4-二甲氧基苯甲醛(4.93克)在四氢呋喃(20毫升)中的溶液。将乙酸(3.7毫升)和水(50毫升)的混合物加至反应混合物中,在室温下用乙酸乙酯进行萃取。萃取液用水洗涤,干燥并蒸去溶剂。将所得的残留物溶于二氯甲烷(20毫升)中并向其中加入三氟乙酸。让混合物在室温下静置过夜。反应溶液用二氯甲烷稀释并用水洗涤,然后蒸去溶剂。残留物用硅胶柱色谱层析(溶液∶氯仿)进行纯化。从洗脱液中得到的浆状物用异丙醚结晶给出r-1-(3,4-二甲氧基苯基)-c-3-羟甲基-4-氰基-4-(叔丁基二甲基甲硅烷基氧基)-6,7,8-三甲氧基-1,2,3,4-四氢化萘-t-2-羧酸内酯的无色晶体(12.7克)。
得率:75%
熔点:132-135℃
(2)将上述步骤(1)中得到的产物(5.0克)溶于二氯甲烷(50毫升)中。向该溶液内加入1M四正丁基氟化铵(10.5毫升)和乙酸(791毫克),让混合物在室温下搅拌5分钟。反应溶液用水洗涤,干燥,然后蒸去溶剂。将所得的残留物溶于二乙醚中并用冰冷却。通过过滤收集析出的结晶给出r-1-(3,4-二甲氧基苯基)-c-3-羟甲基-4-氧基-6,7,8-三甲氧基-1,2,3,4-四氢化萘2-羧酸内酯的无色晶体(2.33克)。
得率:62%
(3)将上述步骤(2)中得到的产物(1.0克)、溴化铜(1.04克)、溴化锂(203毫克)和乙腈(25毫升)的混合物回流加热8小时。从反应溶液中蒸去乙腈,将氯仿加至残留物中并再经硅胶柱色谱层析[溶剂∶氯仿/乙酸乙酯(1∶1)]纯化。浓缩洗脱液并将残留物溶于氯仿中。在冰冷却下向其中加入三甲胺(5毫升)、让混合物在室温下静置1小时。用浓盐酸酸化溶液并收集氯仿层。氯仿层用水洗涤,干燥,然后蒸去溶剂。将所得的残留物溶于甲醇中并用冰冷却。通过过滤收集析出的结晶给出1-(3,4-二甲氧基苯基)-3-羟甲基-4-羟基-6,7,8-三甲氧基-2-萘甲酸内酯的无色晶体(520毫克)。
得率:54%
熔点:261℃(分解)
实施例3和4
(1)用与实施例1-(1-a)相同的方法处理相应的起始化合物给出下表1中的化合物
*:TBPS表示下式的基团
(后面相同)
(2)用与实施例1-(2-a)相同的方法处理上述步骤(1)的产物给出下表2的化合物。
注解1:r-1-1(3,4-二甲氧基苯基)-t-2-甲氧基羰基-c-3-甲氧基羰基化合物(下面相同)
(3)用与实施例1-(3-a)相同的方法处理上述步骤(2)的产物给出下表3的化合物。
(4)用与实施例1-(4)相同的方法处理上述步骤(3)的产物给出下表4的化合物。
实施例5和6
(1)用与实施例2-(1)相同的方法处理相应的起始化合物给出下列表5的化合物。
注解2:r-1-(3,4-二甲氧基苯基)-c-3-3-羟甲基-t-2-羧酸内酯化合物
(2)用与实施例2-(2)相同的方法处理上述步骤(1)中的产物给出下表6的化合物。
(3)用与实施例2-(3)相同的方法处理上述步骤(2)中的产物给出下表7的化合物。
实施例7-23
用与实施例1中相同的方法来处理相应的起始化合物给出下面表8和表9的化合物。
-下续-
*:Bzl表示苄基
实施例24-36
用与实施例2相同的方法处理相应的起始化合物给出下表10的化合物。
-后续-
Claims (8)
2、一种制备下式萘衍生物或其药学上可接受的盐的方法:
(其中R1和R2是低级烷氧基羰基或者两者可结合在一起形成式为
的基团;R3和R4中的一个是氢原子或低级烷氧基,另一个是低级烷氧基;环A是取代或非取代苯环),其特征在于该方法包括下列步骤:
A.用氟离子供体处理下式的被保护的含氧基-四氢化萘化合物或其药学上可接受的盐:
(其中R5是用于羟基的保护基团;R1、R2、R3、R4和环A的定义同上),给出下式氧代-四氢化萘化合物:
(其中R1、R2、R3、R4和环A的定义同上),
B.将上述的氧代-四氢化萘化合物、它的烯醇式互变异构体或它的盐进行氧化,
C.如果需要,再将产物转变成其药学上可接受的盐。
3、一种制备下式萘衍生物或其药学上可接受的盐的方法:
A.使下式的三种化合物进行反应:
(其中R5是用于羟基的保护基团,R1、R2、R3、R4和环A的定义同上),
B.再用酸处理产物给出下式被保护的含氧基-四氢化萘化合物:
(其中R1、R2、R3、R4、R5和环A的定义同上),
C.用氟离子供体处理该产物或它的盐给出下式氧代-四氢化萘:
(其中R1、R2、R3、R4和环A的定义同上),
D.将上述的氧代-四氢化萘化合物,其烯醇式互变异构体或它的盐进行氧化反应,
E.如果需要,将产物转变成其药学上可接受的盐。
4、根据权利要求1、2或3所述的方法,其特征在于其中的环A是非取代的苯环;低级亚烷基二氧基取代的苯环或者是被1-3个取代基所取代的苯环,其中取代基选自由低级烷氧基、低级烷基、苯基-低级烷氧基、羟基和卤原子所组成的组。
7、根据权利要求6所述的化合物,其特征在于其中环A是非取代苯环或者被1-3个取代基所取代的苯环,该取代基选自由低级烷氧基、低级烷基、苯基-低级烷氧基、羟基和卤原子所组成的组。
Applications Claiming Priority (2)
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JP26416/89 | 1989-02-03 | ||
JP2641689 | 1989-02-03 |
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CN1044649A true CN1044649A (zh) | 1990-08-15 |
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CN90100376A Pending CN1044649A (zh) | 1989-02-03 | 1990-01-20 | 萘衍生物及其合成的中间体的制备方法 |
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US (1) | US5003087A (zh) |
EP (1) | EP0380982A3 (zh) |
JP (1) | JPH02288845A (zh) |
CN (1) | CN1044649A (zh) |
AU (1) | AU625546B2 (zh) |
BG (1) | BG51155A3 (zh) |
CA (1) | CA2007580A1 (zh) |
FI (1) | FI900529A0 (zh) |
HU (1) | HU207279B (zh) |
IL (1) | IL93070A0 (zh) |
NO (1) | NO171974C (zh) |
PH (1) | PH27104A (zh) |
PT (1) | PT92834A (zh) |
ZA (1) | ZA9076B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106317161A (zh) * | 2015-06-29 | 2017-01-11 | 深圳翰宇药业股份有限公司 | 一种氟甲基酮肽系列化合物的制备方法 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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IE911919A1 (en) * | 1990-06-21 | 1992-01-01 | Zeneca Ltd | Bicyclic heterocyclic compounds |
EP0501578A1 (en) * | 1991-02-28 | 1992-09-02 | Merck Frosst Canada Inc. | Pyranylphenyl hydroxyalkylnaphthoic acids as inhibitors of leukotriene biosynthesis |
US5281720A (en) * | 1991-02-28 | 1994-01-25 | Merck Frosst Canada, Inc. | Pyranylphenyl hydroxyalkylnaphthoic acids as inhibitors of leukotriene biosynthesis |
US5227399A (en) * | 1991-02-28 | 1993-07-13 | Merck Frosst Canada, Inc. | Pyranylphenyl naphthalene lactones as inhibitors of leukotriene biosynthesis |
EP0501579A1 (en) * | 1991-02-28 | 1992-09-02 | Merck Frosst Canada Inc. | Naphthalene lactones as inhibitors of leukotriene biosynthesis |
US5308852A (en) * | 1992-06-29 | 1994-05-03 | Merck Frosst Canada, Inc. | Heteroarylnaphthalenes as inhibitors of leukotriene biosynthesis |
US5428060A (en) * | 1992-08-27 | 1995-06-27 | Merck Frosst Canada, Inc. | Heteroarylnaphthalene lactones as inhibitors of leukotriene biosynthesis |
US5252599A (en) * | 1992-08-27 | 1993-10-12 | Merck Frosst Canada, Inc. | Heteroarylnaphthalene hydroxy acids as inhibitors of leukotriene biosynthesis |
US5350744A (en) * | 1992-08-27 | 1994-09-27 | Merck Frosst Canada, Inc. | Phenylnaphthalene lactones as inhibitors of leukotriene biosynthesis |
US5426109A (en) * | 1992-08-27 | 1995-06-20 | Merck Frosst Canada, Inc. | Phenylnaphthalene hydroxy acids |
CA2121060C (en) * | 1993-04-16 | 2004-04-06 | Sachio Mori | Preparation of lignan analogues |
ID18046A (id) * | 1996-08-20 | 1998-02-19 | Takeda Chemical Industries Ltd | Senyawa siklik campuran, pembuatan dan penngunaannya. |
CN1980657A (zh) * | 2004-05-05 | 2007-06-13 | 耶鲁大学 | 新颖的抗病毒赛菊宁黄质类似物 |
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NO170760C (no) * | 1985-01-10 | 1992-12-02 | Tanabe Seiyaku Co | Analogifremgangsmaate for fremstilling av terapeutisk aktive nafthalenderivater |
US4728740A (en) * | 1985-04-12 | 1988-03-01 | Bristol-Myers Company | Intermediates for the production of epipodophylotoxin and related compounds and processes for the preparation and use thereof |
MY105057A (en) * | 1989-01-27 | 1994-07-30 | Tanabe Seiyaku Co | A process for preparing naphthalene derivatives |
-
1990
- 1990-01-05 ZA ZA9076A patent/ZA9076B/xx unknown
- 1990-01-05 US US07/461,506 patent/US5003087A/en not_active Expired - Fee Related
- 1990-01-10 PT PT92834A patent/PT92834A/pt unknown
- 1990-01-11 CA CA002007580A patent/CA2007580A1/en not_active Abandoned
- 1990-01-16 IL IL93070A patent/IL93070A0/xx unknown
- 1990-01-18 AU AU48590/90A patent/AU625546B2/en not_active Ceased
- 1990-01-19 EP EP19900101092 patent/EP0380982A3/en not_active Ceased
- 1990-01-20 CN CN90100376A patent/CN1044649A/zh active Pending
- 1990-01-31 JP JP2023444A patent/JPH02288845A/ja active Pending
- 1990-02-02 PH PH39989A patent/PH27104A/en unknown
- 1990-02-02 FI FI900529A patent/FI900529A0/fi not_active Application Discontinuation
- 1990-02-02 NO NO900513A patent/NO171974C/no unknown
- 1990-02-02 BG BG091104A patent/BG51155A3/xx unknown
- 1990-02-02 HU HU90658A patent/HU207279B/hu not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106317161A (zh) * | 2015-06-29 | 2017-01-11 | 深圳翰宇药业股份有限公司 | 一种氟甲基酮肽系列化合物的制备方法 |
CN106317161B (zh) * | 2015-06-29 | 2020-05-15 | 深圳翰宇药业股份有限公司 | 一种氟甲基酮肽系列化合物的制备方法 |
Also Published As
Publication number | Publication date |
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NO171974B (no) | 1993-02-15 |
FI900529A0 (fi) | 1990-02-02 |
HU207279B (en) | 1993-03-29 |
US5003087A (en) | 1991-03-26 |
HU900658D0 (en) | 1990-04-28 |
AU4859090A (en) | 1990-08-09 |
CA2007580A1 (en) | 1990-08-03 |
HUT53588A (en) | 1990-11-28 |
JPH02288845A (ja) | 1990-11-28 |
NO900513D0 (no) | 1990-02-02 |
PT92834A (pt) | 1990-08-31 |
NO171974C (no) | 1993-05-26 |
AU625546B2 (en) | 1992-07-16 |
EP0380982A3 (en) | 1990-11-28 |
NO900513L (no) | 1990-08-06 |
EP0380982A2 (en) | 1990-08-08 |
IL93070A0 (en) | 1990-11-05 |
BG51155A3 (en) | 1993-02-15 |
PH27104A (en) | 1993-03-16 |
ZA9076B (en) | 1990-10-31 |
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