JP5295103B2 - オキシインドールジオキサン誘導体の合成において適当な中間体である化合物の合成法 - Google Patents
オキシインドールジオキサン誘導体の合成において適当な中間体である化合物の合成法 Download PDFInfo
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- JP5295103B2 JP5295103B2 JP2009512182A JP2009512182A JP5295103B2 JP 5295103 B2 JP5295103 B2 JP 5295103B2 JP 2009512182 A JP2009512182 A JP 2009512182A JP 2009512182 A JP2009512182 A JP 2009512182A JP 5295103 B2 JP5295103 B2 JP 5295103B2
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- 150000001875 compounds Chemical class 0.000 title claims description 80
- 238000000034 method Methods 0.000 title claims description 42
- -1 oxindole dioxane derivatives Chemical class 0.000 title description 16
- 239000000543 intermediate Substances 0.000 title description 4
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052987 metal hydride Inorganic materials 0.000 claims description 3
- 150000004681 metal hydrides Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical group [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 3
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims 1
- 229940125890 compound Ia Drugs 0.000 claims 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 229960003638 dopamine Drugs 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 201000000980 schizophrenia Diseases 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000004031 partial agonist Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 102000007527 Autoreceptors Human genes 0.000 description 5
- 108010071131 Autoreceptors Proteins 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 125000005233 alkylalcohol group Chemical group 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- 108050004812 Dopamine receptor Proteins 0.000 description 3
- 102000015554 Dopamine receptor Human genes 0.000 description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 239000003880 polar aprotic solvent Substances 0.000 description 3
- 230000001242 postsynaptic effect Effects 0.000 description 3
- 239000003586 protic polar solvent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 2
- XJNPNXSISMKQEX-UHFFFAOYSA-N 4-nitrocatechol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1O XJNPNXSISMKQEX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 0 O=C(C1)Nc(cc2)c1c1c2OCC(C*=I)O1 Chemical compound O=C(C1)Nc(cc2)c1c1c2OCC(C*=I)O1 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000000561 anti-psychotic effect Effects 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000001259 mesencephalon Anatomy 0.000 description 2
- 125000005905 mesyloxy group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000015883 synaptic transmission, dopaminergic Effects 0.000 description 2
- OTKMWYJAIRWTNV-UHFFFAOYSA-N (6-nitro-2,3-dihydro-1,4-benzodioxin-3-yl)methanol Chemical compound C1=C([N+]([O-])=O)C=C2OC(CO)COC2=C1 OTKMWYJAIRWTNV-UHFFFAOYSA-N 0.000 description 1
- YUGDKEWUYZXXRU-UHFFFAOYSA-N 2-(4-chlorophenoxy)acetonitrile Chemical compound ClC1=CC=C(OCC#N)C=C1 YUGDKEWUYZXXRU-UHFFFAOYSA-N 0.000 description 1
- PGPJPQIRYVCQDI-UHFFFAOYSA-N 2-[3-(hydroxymethyl)-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetonitrile Chemical compound C1=C([N+]([O-])=O)C(CC#N)=C2OC(CO)COC2=C1 PGPJPQIRYVCQDI-UHFFFAOYSA-N 0.000 description 1
- AWYUNLPLBYUNSH-UHFFFAOYSA-N 2-[3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetonitrile Chemical compound O1C2=C(CC#N)C([N+](=O)[O-])=CC=C2OCC1CNCC1=CC=CC=C1 AWYUNLPLBYUNSH-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 208000017194 Affective disease Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 238000006343 Makosza Vicarious substitution reaction Methods 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- DYJIKHYBKVODAC-UHFFFAOYSA-N aplindore Chemical compound N1C(=O)CC(C=2O3)=C1C=CC=2OCC3CNCC1=CC=CC=C1 DYJIKHYBKVODAC-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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- GRSGMANVXQJXHY-UHFFFAOYSA-N methyl 2-[3-[(benzylamino)methyl]-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetate Chemical compound C1OC2=CC=C([N+]([O-])=O)C(CC(=O)OC)=C2OC1CNCC1=CC=CC=C1 GRSGMANVXQJXHY-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000008062 neuronal firing Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 210000001009 nucleus accumben Anatomy 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 150000002918 oxazolines Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Classifications
-
- 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
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Neurology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
本願は、2006年5月25日に出願した米国仮特許出願番号60/808,394(その全体が出典明示により本明細書の一部を構成する)に基づく優先権を主張する。
本発明は、シナプス後ドーパミンD2受容体でのドーパミン自己受容体アゴニストおよび部分アゴニストとして有用な化合物およびその誘導体の合成方法、ならびにその中間体に関する。
Raは、−(CH2)nフェニルであり;
nは、1または2である)。
本発明の方法および中間体は、例えばStack, et alの名における米国特許番号第5,756,532号(その全体が出典明示により本明細書の一部を構成する)に記載されるような化合物の製造に有用である。本発明の合成法は、容易に入手可能な試薬を使用してかかる化合物を大規模に製造するという利点がある。特定の実施態様では、本発明の化合物は、下記スキームIに従って一般的に製造される:
(a)式E:
および
(b)適当な塩基の存在下にて式Eで示される化合物を式:
で示される化合物で処理する工程
を含む方法を提供する。
で示される化合物の製造方法であって、
(a)式D:
および
(b)式Dで示される化合物の遊離ヒドロキシル基を適当な脱離基に変換して式Cで示される化合物を得る工程
を含む方法を提供する。
(a)式C:
で示される化合物を準備する工程;
および
(b)式Cで示される化合物をベンジルアミンで処理する工程
を含む方法を提供する。
で示される化合物の製造方法であって、
(a)化合物B:
および
(b)該化合物Bのニトリル基を加水分解して式Aで示される化合物を得る工程
を含む方法を提供する。
Claims (20)
- R1がハロゲンまたはフェノキシ基(ここで、フェニル環は、1つまたはそれ以上のハロゲン、ニトロ、またはエステル基で置換されていてもよい)である、請求項1記載の方法。
- R1がハロゲンで置換されているフェノキシ基である、請求項2記載の方法。
- 工程(b)での適当な塩基が強塩基である、請求項1〜3いずれか1項記載の方法。
- 強塩基が金属アルコキシドまたは金属の水素化物である、請求項4記載の方法。
- 強塩基がカリウムtert−ブトキシドである、請求項5記載の方法。
- LG2がトシルである、請求項7記載の方法。
- 式Dで示される化合物の遊離ヒドロキシル基を適当な脱離基に変換する工程が適当な塩基の存在下で行われる、請求項8記載の方法。
- 適当な塩基がトリエチルアミンである、請求項9記載の方法。
- 式Cで示される化合物が1〜5当量のベンジルアミンで処理される、請求項11記載の方法。
- R2が置換されていてもよいC1-6 脂肪族基または置換されていてもよいアリールである、請求項13記載の方法。
- R2がメチル、エチル、プロピル、またはイソプロピルである、請求項14記載の方法。
- 還元が適当な触媒の存在下における水素添加によって行われる、請求項16記載の方法。
- 適当な触媒が白金触媒、Fe/HClまたはSn/HClである、請求項17記載の方法。
- 適当な触媒が酸化白金である、請求項18記載の方法。
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Application Number | Priority Date | Filing Date | Title |
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US80839406P | 2006-05-25 | 2006-05-25 | |
US60/808,394 | 2006-05-25 | ||
PCT/US2007/012622 WO2007139998A2 (en) | 2006-05-25 | 2007-05-25 | Synthesis of a compound which is a suitable intermediate in the synthesis of oxindoledioxane derivatives |
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JP2009538324A JP2009538324A (ja) | 2009-11-05 |
JP5295103B2 true JP5295103B2 (ja) | 2013-09-18 |
Family
ID=38569786
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JP2009512182A Active JP5295103B2 (ja) | 2006-05-25 | 2007-05-25 | オキシインドールジオキサン誘導体の合成において適当な中間体である化合物の合成法 |
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US (1) | US7662979B2 (ja) |
EP (1) | EP2046771B1 (ja) |
JP (1) | JP5295103B2 (ja) |
CN (1) | CN101448814B (ja) |
AR (1) | AR061125A1 (ja) |
AU (1) | AU2007267799B2 (ja) |
BR (1) | BRPI0712608B8 (ja) |
CA (1) | CA2652800C (ja) |
CL (1) | CL2007001498A1 (ja) |
ES (1) | ES2387901T3 (ja) |
IL (1) | IL195226A0 (ja) |
MX (1) | MX2008014789A (ja) |
PE (1) | PE20080178A1 (ja) |
TW (1) | TW200811182A (ja) |
WO (1) | WO2007139998A2 (ja) |
ZA (1) | ZA200809966B (ja) |
Families Citing this family (2)
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WO2005044262A1 (en) | 2003-10-29 | 2005-05-19 | Wyeth | Sustained release pharmaceutical compositions comprising aplindore and derivatives thereof |
WO2008118935A1 (en) * | 2007-03-26 | 2008-10-02 | Neurogen Corporation | Compounds and processes for preparing substituted aminomethyl-2,3,8,9-tetrahydro-7h-1,4-dioxino[2,3-e]indol-8-ones |
Family Cites Families (19)
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US4314944A (en) * | 1980-08-22 | 1982-02-09 | Smithkline Corporation | 4-Aminoalkyl-7-hydroxy-2(3H)-indolones |
JPH05505599A (ja) | 1990-03-15 | 1993-08-19 | ジ・アップジョン・カンパニー | 治療上有用な複素環インドール化合物類 |
US5126366A (en) * | 1991-06-21 | 1992-06-30 | American Home Products Corporation | Aminophenoxyalkyl derivatives of benzodioxan |
US5166367A (en) * | 1991-06-21 | 1992-11-24 | American Home Products Corporation | Antipsychotic benzodioxan derivatives |
US5189171A (en) * | 1991-06-21 | 1993-02-23 | American Home Products Corporation | Antipsychotic benzodioxan derivatives |
DE4135474A1 (de) | 1991-10-28 | 1993-04-29 | Bayer Ag | 2-aminomethyl-chromane |
DE4140540A1 (de) * | 1991-12-09 | 1993-06-17 | Bayer Ag | Neue azaheterocyclylmethyl-chromane |
US5235055A (en) * | 1992-09-02 | 1993-08-10 | American Home Products Corporation | Antipsychotic quinoline derivatives of benzodioxanmethylamine |
US5245051A (en) * | 1992-09-03 | 1993-09-14 | American Home Products Corporation | Antipsychotic chroman derivatives of benzodioxanmethylamine |
EP0939135A1 (en) * | 1992-12-21 | 1999-09-01 | Duphar International Research B.V | Substantially pure hetero-bicyclic alcohol enantiomers |
PT707007E (pt) | 1994-10-14 | 2002-06-28 | Merck Patent Gmbh | Derivados amino(tio)eter como agentes activos no snc |
US5756532A (en) | 1995-11-06 | 1998-05-26 | American Home Products Corporation | Aminomethyl-2 3 8 9-tetrahydro-7H-1 4-dioxino 2 3-E!-indol-8-ones and derivatives |
IL119483A (en) | 1995-11-06 | 1999-06-20 | American Home Prod | 2-(Aminomethyl)-3,4,7,9- tetrahydro- 2H-pyrano-2[3,3-e]indol-8-ones their derivatives and pharmaceutical compositions containing them |
US5869490A (en) * | 1996-10-15 | 1999-02-09 | American Home Products Corporation | Azaheterocyclymethyl derivatives of 2,3,8,9-tetrahydro-7h-1,4-dioxino (2,3-e) indol-8-one |
US5750556A (en) * | 1996-10-30 | 1998-05-12 | American Home Products Corporation | 2-(aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano- 2,3-E!indol-8-ones and derivatives |
MXPA04003085A (es) * | 2001-10-05 | 2004-09-06 | Wyeth Corp | Proceso estereoespecifico para sintesis de derivados de 2-il cromano. |
EP1432695A1 (en) * | 2001-10-05 | 2004-06-30 | Wyeth | A process for the stereoselective synthesis of 2-hydroxymethyl-chromans |
US7135479B2 (en) * | 2002-09-12 | 2006-11-14 | Wyeth | Antidepressant azaheterocyclylmethyl derivatives of heterocycle-fused benzodioxans |
ES2277546B1 (es) | 2005-11-21 | 2008-06-16 | Natraceutical, S.A. | Procedimiento microbiano de produccion de isomeros especificos de acidos linoleicos conjugados. |
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- 2007-05-23 PE PE2007000641A patent/PE20080178A1/es not_active Application Discontinuation
- 2007-05-24 AR ARP070102253A patent/AR061125A1/es unknown
- 2007-05-24 CL CL2007001498A patent/CL2007001498A1/es unknown
- 2007-05-25 WO PCT/US2007/012622 patent/WO2007139998A2/en active Application Filing
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Also Published As
Publication number | Publication date |
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CA2652800A1 (en) | 2007-12-06 |
PE20080178A1 (es) | 2008-04-16 |
US20070293686A1 (en) | 2007-12-20 |
CN101448814A (zh) | 2009-06-03 |
CA2652800C (en) | 2014-05-13 |
TW200811182A (en) | 2008-03-01 |
ZA200809966B (en) | 2009-09-30 |
EP2046771B1 (en) | 2012-07-11 |
AU2007267799B2 (en) | 2013-09-12 |
WO2007139998A3 (en) | 2008-01-31 |
CN101448814B (zh) | 2013-04-24 |
MX2008014789A (es) | 2008-11-28 |
EP2046771A2 (en) | 2009-04-15 |
BRPI0712608B1 (pt) | 2020-09-08 |
AR061125A1 (es) | 2008-08-06 |
BRPI0712608B8 (pt) | 2021-05-25 |
JP2009538324A (ja) | 2009-11-05 |
WO2007139998A2 (en) | 2007-12-06 |
CL2007001498A1 (es) | 2008-01-18 |
AU2007267799A1 (en) | 2007-12-06 |
BRPI0712608A8 (pt) | 2018-12-11 |
US7662979B2 (en) | 2010-02-16 |
ES2387901T3 (es) | 2012-10-03 |
BRPI0712608A2 (pt) | 2012-08-14 |
IL195226A0 (en) | 2009-08-03 |
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