CN1642936A - 合成手性n-芳基哌嗪的方法 - Google Patents
合成手性n-芳基哌嗪的方法 Download PDFInfo
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- CN1642936A CN1642936A CNA038058413A CN03805841A CN1642936A CN 1642936 A CN1642936 A CN 1642936A CN A038058413 A CNA038058413 A CN A038058413A CN 03805841 A CN03805841 A CN 03805841A CN 1642936 A CN1642936 A CN 1642936A
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 230000002194 synthesizing effect Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- -1 2-aminopyridyl Chemical group 0.000 claims abstract description 31
- 239000000460 chlorine Substances 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000006371 dihalo methyl group Chemical group 0.000 claims description 2
- 125000004982 dihaloalkyl group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 2
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical group CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 1
- 125000005270 trialkylamine group Chemical group 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 210000003169 central nervous system Anatomy 0.000 abstract description 3
- 125000004193 piperazinyl group Chemical group 0.000 abstract description 3
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 abstract 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 abstract 1
- 238000006073 displacement reaction Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 4
- YWWMGXGZLQWZGA-UHFFFAOYSA-N 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-hydroxyethyl)amino]ethanol Chemical compound O1CCOC2=C1C=CC=C2N(CCO)CCO YWWMGXGZLQWZGA-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000003927 aminopyridines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000005690 diesters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- WOBXIZDZSBFOEN-UHFFFAOYSA-N aniline 2,3-dihydro-1,4-benzodioxine Chemical compound NC1=CC=CC=C1.O1CCOC2=C1C=CC=C2 WOBXIZDZSBFOEN-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- BKMMTJMQCTUHRP-GSVOUGTGSA-N (2r)-2-aminopropan-1-ol Chemical compound C[C@@H](N)CO BKMMTJMQCTUHRP-GSVOUGTGSA-N 0.000 description 1
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical compound CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 description 1
- JCBPETKZIGVZRE-UHFFFAOYSA-N 2-aminobutan-1-ol Chemical class CCC(N)CO JCBPETKZIGVZRE-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FCOPZNOYFMGOEO-UHFFFAOYSA-N C(CCC)O.NC1C(C(=O)O)=CC=CC1(C(=O)O)C Chemical class C(CCC)O.NC1C(C(=O)O)=CC=CC1(C(=O)O)C FCOPZNOYFMGOEO-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CLWRFNUKIFTVHQ-UHFFFAOYSA-N [N].C1=CC=NC=C1 Chemical group [N].C1=CC=NC=C1 CLWRFNUKIFTVHQ-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000005257 alkyl acyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940059936 lithium bromide Drugs 0.000 description 1
- ITYJDNHFRZSTJY-UHFFFAOYSA-N methanesulfonyl bromide Chemical compound CS(Br)(=O)=O ITYJDNHFRZSTJY-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
本发明涉及以下结构式表示的有手性侧链的N-芳基哌嗪的制备方法,以及制备其中间体化合物的方法(式I)。在本发明方法中,手性在哌嗪环形成步骤中被引入,以及通过取代反应引入2-氨基吡啶基取代基,得到的N,N’-二取代的哌嗪在中枢神经系统中作用于5HT受体。
Description
发明的领域
本发明涉及合成手性取代的N-芳基哌嗪及其中间体的方法的领域,所述化合物在中枢神经系统中能够结合5HT受体。
发明的背景
某些N,N′二取代哌嗪,特别是N-芳基取代的哌嗪,能够作用于中枢神经系统(例如结合5HT受体)。J.Med.Chem.(1995),38(20),4044-55和JP 61152655教导了合成芳基哌嗪核的方便的方法,包括苯胺和双(二氯乙基)胺反应,通过烷基化得到的仲胺加工得到哌嗪。
化学方法中的“反向”转化是可能的,在该方法中苯胺-类芥子气中间体和烷基胺反应,如J.Labeled Compounds和RadioPharm公开的((1986)Vol XXIV,No.4,351),但是与苯胺芥子气的一般可用性有关的双(2-氯乙基)胺盐酸盐是否能够买到使所述方法不很有利。
不对称的芳基哌嗪也可以通过哌嗪和三氟甲磺酸芳基酯或溴化物的偶合形成,Tetrahedron Letters(1998),39,2219指出该方法的产率很依赖于(芳基)底物,一般很低。
形成在氮原子上直接有手性中心的哌嗪是本发明的焦点,某些形成手性N-哌嗪的方法是公知的,一个公知的方法是拆分外消旋混合物,其缺点是浪费了一半的原料。
另一公知的方法是使用芳基哌嗪取代连接于手性中心的离去基团,但是取代受阻的离去基团的障碍是一个问题,提高离去基团的活性会产生另一个问题:JP 01125357教导苄基-(S)-溴代丙酸酯和1-苄基哌嗪反应能够得到预期的(R)异构体取代产品,羰基基团虽然活化了取代过程,但是在反应条件下也提高了邻近手性中心对于外消旋化的敏感性。
WO 95/33743报道了另一方法,通过使用手性环状氨基磺酸酯作为活性烷基化剂消除了活性中的外消旋化问题。
虽然环状氨基磺酸酯容易和哌嗪反应,氨基磺酸酯本身要求多步反应制备,例如当R=2-吡啶基时需要四个化学步骤或转化步骤。
已经报道了手性氨基酸和N-甲基-N,N-双(2-氯乙烷)的反应(ActaPoL Pharm.,56(1),41-47,1999),在反应期间和随后的合成操作期间羧酸官能基使手性中心对外消旋化很敏感。
在另一方法中(J.Med Chem.30(10),1779-87;1987)报道了手性苄基胺和各种(N-烷基和N-芳基)芥子气的反应,使用的手性胺经拆分得到。
WO94/24115教导了β-烷基(和芳基)氧基手性胺和芥子气反应形成哌嗪化合物。
至今许多合成N-芳基N′取代的哌嗪的方法包括预先形成N-芳基哌嗪,随后在N′上烷基化,这种方法对于制备很多化合物类型是有效的方法,但是实际上它限制了对于将手性α引入氮原子,这是因为它依赖于需要多步合成制备的手性烷基化剂。
发明的概述
本发明包括制备化合物式VII的方法
其中
R是C1-C3烷基,
Y是C1-C6烷氧基,C1-C6烷基,C3-C7环烷基或C3-C7环烷氧基,和
Ar是2,3-二氢-苯并二氧杂环己烯-5-基,或者是用直到三个独立地选自卤素,甲氧基,卤代甲基,二卤代甲基,三卤代甲基中的取代基任意取代的苯基,
所述方法包括:
a)化合物式III和手性2-氨基-1-(C3-C5)链烷醇在极性非质子溶剂中反应形成化合物IV
其中L表示选自Cl,Br,甲磺酸酯和甲苯磺酸酯的离去基团,*表示手性中心;
b)将化合物式IV转化为化合物式V:
其中X是Cl,Br,三氟甲磺酸酯,甲苯磺酸酯或甲磺酸酯;和
c)在非质子溶剂中用化合物式VI处理化合物式V:
其中M是碱金属(例如Na,Li,K)和Y表示选自C1-C6烷氧基,C1-C6烷基,C3-C7环烷基或C3-C7环烷氧基的部分。
本发明还包括制备化合物式IX的方法,包括上述步骤(a),(b)(c)和以下步骤:
(d)用质子酸处理化合物式VII形成化合物式VIII:
(e)在碱存在下用选自芳酰基氯,芳酰基溴,芳酰基酸酐的芳酰基化合物处理化合物式VIII,形成化合物式IX:
其中芳基表示被直到三个独立地选自以下的取代基任意取代的C6-C12芳基:卤素原子,烷基,烷氧基,烷氧羰基,硝基,氨基,烷基氨基,二烷基氨基,卤代烷基,二卤代烷基,三卤代烷基,氰基和酰胺基取代基,每个不多于6个碳原子。
发明的详细说明
本发明的优选实施方案是制备有手性N’-1-[苄酰基(2-吡啶基)氨基]-2-丙烷侧链的N-芳基哌嗪,它能够结合5HT受体。本发明的另一实施方案是制备其中间体化合物的方法,在本发明的方法中手性在哌嗪环形成步骤中引入。
在本发明的优选实施方案中,合成方法是首先通过使用氯乙醇二烷基化苯胺式I形成二醇式II开始,制备出二甲磺酸酯化合物式III。另外,二醇化合物式II还可以通过使用卤代乙酸烷基酯二烷基化苯胺,随后还原制备,两个羟基能够方便地转化为合适的离去基团,例如甲磺酸酯离去基:
二甲磺酸酯和手性2-氨基-1-丙醇(氨基丙醇)反应得到所需的哌嗪。在本发明的另一实施方案中,手性氨基化合物是2-氨基-1-丁醇,2-氨基-1-戊醇,或2-氨基-3-甲基-1-丁醇。在实施本发明时可以使用除了甲磺酸酯以外的其它离去基团,包括甲苯磺酸酯,氯和溴,胺组份的手性在过程中被保留。在环化期间不需要保护的醇基团对于进一步结构加工是不变,得到的伯醇例如使用甲基磺酰基氯或甲基磺酰基溴处理进行活化,以便进行取代反应。确信反应形成了作为过度中间体的甲磺酸酯后,最终得到化合物式V。
在本发明优选实施方案中,化合物式V和从2-(t-Boc)-氨基吡啶得到的阴离子反应,引入氨基吡啶基侧链,并且产生化合物式VII。
使用其它基团代替叔丁氧基也属于本发明的范围,合适的基团包括C1-C6烷氧基,C1-C6烷基,C3-C7环烷基和C3-C7环烷氧基。当所述基团是上述环状基团之一时,可以有一个或多个环外的碳原子,例如环己基甲氧基或乙基环戊基。
化合物式VII能够进一步反应形成化合物式VIII和化合物式IX,优选t-Boc保护基使用HCl/EtOH除去,形成式VIII胺的盐酸盐,其盐能够直接用于游离NH基团的官能化。虽然以下实施方案是用芳酰基氯进行酰基化反应,在实施本发明时也可以使用其它酰基衍生物。
因为本发明的合成在形成哌嗪步骤中引入手性,手性胺总是需要的,惊奇地发现甚至在存在邻近的游离羟基时,反应仍然有效(例如III,IV)。
然后羟基能够用于通过取代反应引入氨基吡啶基官能基。表面上或者从现有技术还没有明显看出上述副反应能够怎样严重地损害使用的取代反应,更多的是依赖于烷基化试剂。在WO9703982中氨基吡啶VIa在非特定条件下能够和通式化合物Va反应,其中X离去基团,得到VIIa。在开发本发明的过程中,我们观察到当和V(X=Cl)反应时,烷基酰基化合物(例如VIb)在吡啶氮原子上进行了大量(约20%)不需要的烷基化,形成化合物X。在本发明优选实施方案中Y是烷氧基。
本发明提供N-芳基哌嗪的有用的合成方法,其中手性是在哌嗪环形成步骤被引入,以及2-氨基吡啶的取代是通过取代反应引入的。
如本发明所述,t-Boc 2-氨基吡啶VI的使用大大抑制了形成类似副产品的数量(<7%),提高了所需化合物式VII的比例,如前一段所述,t-Boc保护基很容易除去,然后将游离胺酰基化。
在全部说明书和随后的权利要求书中,除了另外指出以外,术语卤素是指F,Cl和Br,术语烷基,烷,链烷醇和烷氧基包括直链和支链的两种烷基基团。
以下实施例用于说明本发明的某些实施方案,但是不构成对本发明范围的限制。
实施例1
2-[(2,3-二氢-苯并[1,4]二氧杂环己烯-5-基)-(2-羟基乙基)-氨基]-乙醇(II)
2,3-二氢-苯并[1,4]二氧杂环己烯-5-基胺(31.1g,0.2mol)和2-氯乙醇(210mL,3.1mol)和Hunigs碱(105mL,0.6mol)混合,得到的暗色溶液加热到120℃,于该温度继续搅拌,并且用HPLC监视,12.5小时以后停止反应,加入乙酸乙酯(300mL),溶液用稀盐水洗涤(1×250mL),再用盐水洗涤(2×75mL),合并全部水相,用K2CO3调节到pH 7,溶液用乙酸乙酯(2×100mL)反洗,合并全部有机相,使用2N HCl(3×150mL)萃取,得到的水溶液用固体K2CO3中和到pH 7并且用乙酸乙酯(3×100mL)萃取,有机相用MgSO4干燥,浓缩和用于甲苯驱赶(2×50mL)除去残留的氯乙醇,得到39.6g(80%)粗产品,是暗色油状物,94面积%(LC-MS)纯度。
1H NMR(CDCl3)δ6.88-6.70(m,3H),4.34-4.22(m,4H),3.54(t,J=7.5Hz,4H),3.18(t,J=7.5Hz,4H).
实施例2
甲烷磺酸2-[(2,3-二氢-苯并[1,4]二氧杂环己烯-5-基)-(2-甲烷磺酰基氧基-乙基)-氨基]-乙酯(III)
往在冰浴中冷却到5℃的11(39.6g,0.165mol)和三乙胺(69mL,0.5mol)的二氯甲烷(250mL)溶液中加入甲基磺酰基氯(38mL,0.5mol)的二氯甲烷(50mL)溶液,在不超过18℃和0.5小时内完成,移去冰浴,得到的悬浮液于室温搅拌1小时以后TLC和HPLC显示原料消失。反应混合物用水(1×150mL)和5%NaHCO3水溶液(1×150mL)洗涤,MgSO4干燥,浓缩得到III,为红色油状物,粗产品产率67.0g(102%)。
1H NMR(CDCl3)δ6.85(m,1H),6.63(m,2H),4.28(m,8H),3.55(t,J=7.5Hz,4H),2.97(s,6H).
实施例3
2-[4-(2,3-二氢-苯并[1,4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙-1-醇(IV)
二甲磺酸酯III(67.0g,0.17mol),D-丙氨醇(D-alaninol 14.0g,0.19mol),溴化锂(31.0g,0.35mol),和碳酸钾(74.8g,0.54mol)使用乙腈(750mL)混合在一起,得到的悬浮液回馏(82℃)27小时同时用HPLC监视,冷却反应混合物,过滤,不溶解的残留物用乙腈洗涤,将母液浓缩到小体积,通过200cm3的硅胶过滤,用1.5L EtOAc中的10%MeOH洗脱,用旋转蒸发器除去溶剂以后残留物再溶解于EtOAc(200mL)中,溶液用水(2×50mL)洗涤,MgSO4干燥,浓缩得到IV,为黏稠金色油状物,静置后慢慢结晶,产率29.4g(63%),纯度88.3面积%(LC-MS)。熔点=91-92℃。
1H NMR(CDCl3)δ6.78(t,J=7.5Hz,1H),6.55(m,2H),4.29(m,4H),3.45(dd,J=11,5Hz,1H),3.38(t,J=11Hz,1H),3.10(br m,4H),2.86(m,3H),2.63(m,2H),0.96(d,J=7.5Hz,3H).
实施例4
6-(2,3-二氢-苯并[1,4]二氧杂环己烯-5-基)-1-甲基-6-氮杂-3-氮鎓螺[2.5]辛烷氯化物(V)
粗化合物IV(29.4g,0.106mol)和三乙胺(16.2mL,0.116mol)溶解在CH2Cl2(150mL)中,往溶液中加入甲基磺酰基氯(8.6mL,0.111mol)的CH2Cl2(50mL)溶液,于冷却到5-15℃进行0.5小时,室温继续搅拌过夜,得到清澈红色溶液,用水(1×100mL)和5%NaHCO3水溶液(1×100mL)洗涤,合并水层用CH2Cl2(2×50mL)反洗,有机层用MgSO4干燥,浓缩得到V,为黏稠红色油状物,产率31.6g(101%)。
1H NMR(CDCl3)δ6.76(t,J=7.5Hz,1H),6.55(m,2H),4.27(m,4H),4.11(m,1H),3.10(m,4H),2.8-2.64(m,5H),2.54(dd,J=7.5,15Hz,1H),1.55(d,3H).
实施例5
{2-[4-(2,3-二氢-苯并[1,4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-吡啶-2-基氨基甲酸叔丁基酯(VII)
t-Boc-2-氨基吡啶(24.7g,0.127mol)和叔丁醇钠(19.3g,0.2mol)使用THF(250mL)混合,于室温搅拌0.5小时,在THF(100mL)中的氯化物V(31.6g,0.106mol)加入到混合物中,随后加入固体K2CO3(23.4g,0.17mol),将反应混合物加热到回馏(68℃),回馏时搅拌,同时用TLC(EtOAc/己烷3∶2,V/V)监视,97小时以后原料全部消失,将反应混合物冷却,用EtOAc(400mL)稀释,用水(3×150mL)和盐水(1×100mL)洗涤,水相用EtOAc(2×75mL)反洗,合并有机溶液用MgSO4干燥,浓缩得到49g粗油状物,含有(LC-MS)67.9%VII(产率-69%)和10.8%V。
1H NMR(CDCl3)δ8.35(m,1H),7.66-7.45(m,2H),7.00(m,1H),6.75(t,J=7.5H,1H),6.55(br d,1H),6.4(br d,1H),4.3-4.15(m,6H),3.82(dd,J=7,14Hz,1H),2.88(m,2H),2.70(m,4H),2.50(m,2H),1.50(s,9H),0.94(d,J=7.5,3H).
实施例6
{2-[4-(2,3-二氢-苯并[1,4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-吡啶-2-基-胺(VIII)
化合物VII作为粗油状物(49.0g,0.106mol)溶解在乙醇(150mL)中,往该溶液中加入乙醇中的1N HCl溶液(212mL),将得到的溶液回馏18小时,真空浓缩到小体积(约100mL),直到产品开始结晶。往得到的浆状物中分步慢慢加入乙醚(100mL),混合物于室温搅拌2小时,过滤亮灰色的结晶,用乙醇/乙醚的混合物(50∶50)洗涤,得到22.2g化合物VIII(49%,3步总产率),LC-MS方法测定的纯度是97.9%,该批产品从甲醇(150mL)和乙醚(200mL)中重结晶,得到19.3g VIII,纯度99%。
1H NMR(CD3OD)δ8.01(m,2H),7.30(d,J=9Hz,1H),7.08(t,J=7.4Hz,1H),6.82(t,J=8.1Hz,1H),6.63(m,2H),4.30(m,4H),4.10(m,1H),3.80-2.90(m,9H),1.55(d,J=6.2Hz,3H).MP=245-248℃.
实施例7
4-氰基-N-{2-[4-(2,3-二氢-苯并[1,4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-N-吡啶-2-基-苯甲酰胺(IXa)
于0-5℃将化合物VIII(18.7g,0.044mol)加入到K2CO3(21.2g,0.15mol)于75mL水中的溶液中,其中混合了90mL EtOAc,搅拌得到的两相体系0.5小时,直到固体溶解,然后于5-7℃和15分钟内加入p-氰基苯甲酰基氯(8.0g,0.048mol)的EtOAc(35mL)溶液,移去冷却浴,于室温搅拌反应混合物1小时,通过TLC测定确认反应完成。
分离有机层,用水(1×50mL)和盐水(1×50mL)洗涤,合并的水层用EtOAc(1×60mL)反洗,合并的EtOAc溶液用MgSO4干燥,过滤,使用活性炭Darco(2g)再回馏0.5小时,通过硅藻土过滤,母液用庚烷(90mL)稀释,用硅胶(20g)成浆2小时,过滤硅胶以后浓缩滤液得到IXa的游离碱,为黏稠油状物,LC纯度是94.5%。
将该油状物溶解在EtOAc(100mL)中,用37mL 1.2N HCl的EtOAc溶液于20-25℃处理,过滤收集沉淀的盐酸盐,为白色固体,于50℃真空干燥得到IX 20.8g(91%,该步骤,19.4%从步骤1共7步)。
1H NMR(CD3OD)δ8.59(m,1H),7.72(m,1H),7.66(d,J=8.3Hz,2H),7.53(d,J=8.3Hz,2H),7.36(m,1H),7.03(d,J=8.3Hz,1H),6.83(m,1H),6.66(m,2H),4.52(m,1H),4.30(m,5H),3.90(m,1H),3.72(m,4H),3.61(m,4H),3.45(m,1H),3.20(m,2H),1.50(d,J=7Hz,3H).
实施例8:
苯并二噁烷苯胺烷基化为二酯
苯并二噁烷苯胺(3.0g,20mmol),溴代乙酸乙酯(7.5mL,68mmol),Hunig′s碱(12.5mL,72mmol)和NaI(0.3g,2.0mmol)在甲苯(30mL)中的混合物加热到回馏,23小时以后将反应混合物冷却到室温,加入水(25mL),两相分离。水层用甲苯(25mL)萃取,合并的有机层用Na2SO4干燥,过滤,真空浓缩得到6.5g(100%)二酯,为棕色油状物。
1H NMR(CDCl3)δ6.70(t,J=8.1Hz,1H),6.3-6.6(m,2H),4.1-4.3(m,12H),1.2-1.3(m,6H).
实施例9:
苯并二噁烷二酯还原为二醇
二酯(24g,74.3mmol)在THF(240mL)中的混合物冷却到0-5℃,然后慢慢加入LAH垫衬(9.9g,260mmol),同时维持反应温度在10℃以下,加入LAH以后移去冷却浴,于室温继续搅拌,搅拌18小时以后将反应混合物在干冰/IPA浴中冷却到0±5℃,往反应混合物中慢慢加入水(10mL),再加入15%氢氧化钠水溶液(10mL)和水(30mL),将得到的混合物搅拌30分钟然后过滤,固体用THF(100ML)洗涤,真空浓缩滤液得到14.5g(81%)二醇式IV,为黏稠清澈油状物,98面积%(LC-MS)纯度。
1H NMR(CDCl3)δ6.88-6.70(m,3H), 4.34-4.22(m,4H),3.54(t,J=7.5Hz,4H),3.18(t,J=7.5Hz,4H).
本文没有说明的本发明的许多变化对于本领域的技术人员是明显的,本发明不限于上述实施方案和本说明书的记载,而包括随后权利要求书和等同物范围中的全部主题。
Claims (9)
1.制备化合物式VII的方法
其中
R是C1-C3烷基,
Y表示选自C1-C6烷氧基,C1-C6烷基,C3-C7环烷基和C3-C7环烷氧基的部分,和
Ar是2,3-二氢-苯并二氧杂环己烯-5-基,或者是用直到三个独立地选自卤素,甲氧基,卤代甲基,二卤代甲基,三卤代甲基中的取代基任意取代的苯基,
所述方法包括:
a)化合物式III和手性2-氨基-1-(C3-C5)链烷醇在极性非质子溶剂中反应形成化合物IV
其中L表示选自Cl,Br,甲磺酸酯,三氟甲磺酸酯和甲苯磺酸酯的离去基团,*表示手性中心;
b)将化合物式IV转化为化合物式V:
其中X是Cl或Br,
c)在非质子溶剂中用化合物式VI处理化合物式V:
其中M是碱金属。
2.按照权利要求1的方法,还包括用质子酸处理化合物式VII形成化合物式VIII。
3.按照权利要求2的方法,还包括在碱存在下用芳酰基氯,芳酰基溴,芳酰基酸酐处理化合物式VIII,形成化合物式IX:
其中芳基表示被直到三个独立地选自以下的取代基任意取代的C6-C12芳基:卤素原子,烷基,烷氧基,烷氧羰基,硝基,氨基,烷基氨基,二烷基氨基,卤代烷基,二卤代烷基,三卤代烷基,氰基和酰胺基取代基,每个不多于6个碳原子。
4.按照权利要求3的方法,其中芳基是4-氰基苯基。
6.按照权利要求1-5中的任何一项的方法,其中Y是C1-C6烷氧基。
7.按照权利要求1-6中的任何一项的方法,其中Y是叔丁氧基。
8.按照权利要求1-7中的任何一项的方法,其中Ar是2,3-二氢-苯并二氧杂环己烯-5-基。
9.按照权利要求1-8中的任何一项的方法,其中手性2-氨基-1-(C3-C5)链烷醇是D-2-氨基-1-丙醇和R是甲基。
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US7504395B2 (en) * | 2001-07-20 | 2009-03-17 | Psychogenics, Inc. | Treatment for attention-deficit hyperactivity disorder |
US7361773B2 (en) * | 2002-03-12 | 2008-04-22 | Wyeth | Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines |
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ES2329122T3 (es) | 2009-11-23 |
ATE439356T1 (de) | 2009-08-15 |
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BR0308377A (pt) | 2005-01-11 |
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US20030187265A1 (en) | 2003-10-02 |
JP4391241B2 (ja) | 2009-12-24 |
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AR038930A1 (es) | 2005-02-02 |
US6713626B2 (en) | 2004-03-30 |
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RU2004130300A (ru) | 2005-04-10 |
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KR20040105765A (ko) | 2004-12-16 |
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