RU2388747C2 - Способы получения производных бицикло [3.1.0]гексана и промежуточные соединения для этой цели - Google Patents
Способы получения производных бицикло [3.1.0]гексана и промежуточные соединения для этой цели Download PDFInfo
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- RU2388747C2 RU2388747C2 RU2006119924/04A RU2006119924A RU2388747C2 RU 2388747 C2 RU2388747 C2 RU 2388747C2 RU 2006119924/04 A RU2006119924/04 A RU 2006119924/04A RU 2006119924 A RU2006119924 A RU 2006119924A RU 2388747 C2 RU2388747 C2 RU 2388747C2
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- Prior art keywords
- formula
- compound
- alkyl
- compounds
- halogen
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 142
- 238000000034 method Methods 0.000 title claims abstract description 55
- 238000003786 synthesis reaction Methods 0.000 title abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 15
- JAPMJSVZDUYFKL-UHFFFAOYSA-N bicyclo[3.1.0]hexane Chemical class C1CCC2CC21 JAPMJSVZDUYFKL-UHFFFAOYSA-N 0.000 title abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- 150000002118 epoxides Chemical class 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 238000007254 oxidation reaction Methods 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 239000002841 Lewis acid Substances 0.000 claims description 8
- 150000007517 lewis acids Chemical class 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- FSJSYDFBTIVUFD-XHTSQIMGSA-N (e)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C/C(C)=O.C\C(O)=C/C(C)=O FSJSYDFBTIVUFD-XHTSQIMGSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 238000007059 Strecker synthesis reaction Methods 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 11
- 230000001590 oxidative effect Effects 0.000 claims 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 150000002367 halogens Chemical group 0.000 abstract description 20
- 239000000556 agonist Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 70
- 238000005481 NMR spectroscopy Methods 0.000 description 49
- 239000000203 mixture Substances 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 17
- 239000000460 chlorine Substances 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- -1 (+) - (1R, 2S, 5S, 6S) -2-amino-6-fluoro-4-oxobicyclo [3.1.0] hexane hydrochloride salt Chemical compound 0.000 description 14
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 14
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 14
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- 0 C*(*)C[C@]1C=CC[C@@]1O Chemical compound C*(*)C[C@]1C=CC[C@@]1O 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 11
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- KFAGJPNFERWZJA-JKBXLQNXSA-N (1r,2s,5s,6s)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound OC(=O)[C@]1(N)CC(=O)[C@H]2[C@@](C(O)=O)(F)[C@@H]12 KFAGJPNFERWZJA-JKBXLQNXSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 6
- 239000007800 oxidant agent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 229910018540 Si C Inorganic materials 0.000 description 5
- 239000005708 Sodium hypochlorite Substances 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000006735 epoxidation reaction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000003840 hydrochlorides Chemical class 0.000 description 5
- PMDKYLLIOLFQPO-UHFFFAOYSA-N monocyclohexyl phthalate Chemical compound OC(=O)C1=CC=CC=C1C(=O)OC1CCCCC1 PMDKYLLIOLFQPO-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000004593 Epoxy Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- FSJSYDFBTIVUFD-SUKNRPLKSA-N (z)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FSJSYDFBTIVUFD-SUKNRPLKSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 125000005219 aminonitrile group Chemical group 0.000 description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229930195712 glutamate Natural products 0.000 description 3
- 150000001469 hydantoins Chemical class 0.000 description 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- DFLPBQREGPOGIO-UHFFFAOYSA-N 6-fluorobicyclo[3.1.0]hexan-2-amine Chemical class NC1CCC2C(F)C12 DFLPBQREGPOGIO-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000007844 bleaching agent Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000003944 halohydrins Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 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
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- VXUPYTFAUWLDDY-WYUUTHIRSA-N methyl (1r,4r,5s,6r)-4-[tert-butyl(dimethyl)silyl]oxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate Chemical compound [C@H]1([C@@H](CC2=O)O[Si](C)(C)C(C)(C)C)[C@@H]2[C@@H]1C(=O)OC VXUPYTFAUWLDDY-WYUUTHIRSA-N 0.000 description 2
- KRZJIMWVVHBTIE-JSKYLQRQSA-N methyl (1r,5s,6r)-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylate Chemical compound C1=CC(=O)[C@H]2[C@H](C(=O)OC)[C@H]21 KRZJIMWVVHBTIE-JSKYLQRQSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
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- C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C61/08—Saturated compounds having a carboxyl group bound to a six-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
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- 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
- C07D317/72—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 spiro-condensed with carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms
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- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Epoxy Compounds (AREA)
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| WO (1) | WO2005047215A2 (enExample) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5309680B2 (ja) * | 2008-05-09 | 2013-10-09 | 大正製薬株式会社 | フッ素化エステル化合物の製造方法及びその中間体 |
| WO2009142184A1 (ja) * | 2008-05-21 | 2009-11-26 | 大正製薬株式会社 | 酵素を用いたビシクロ［３．１．０］ヘキサン誘導体の製造方法 |
| US8742161B2 (en) * | 2009-11-18 | 2014-06-03 | Taisho Pharmaceutical Co., Ltd | Process for producing optically active bicyclo [3.1.0] hexane derivative using enzyme |
| CN112074505B (zh) | 2018-03-08 | 2024-04-05 | 因赛特公司 | 作为PI3K-γ抑制剂的氨基吡嗪二醇化合物 |
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2152925C1 (ru) * | 1994-08-12 | 2000-07-20 | Эли Лилли Энд Компани | Производные аминобицикло[3.1.0]гексан-2,6-дикарбоновой кислоты и фармацевтическая композиция |
| US6160009A (en) * | 1997-05-14 | 2000-12-12 | Eli Lilly And Company | Excitatory amino acid receptor modulators |
| US6333428B1 (en) * | 1998-08-31 | 2001-12-25 | Taisho Pharmaceutical Co., Ltd. | 6-fluorobicyclo[3.1.0]hexane derivatives |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5661184A (en) | 1994-08-12 | 1997-08-26 | Eli Lilly And Company | Psychiatric agents |
| JP2000072731A (ja) * | 1998-08-31 | 2000-03-07 | Taisho Pharmaceut Co Ltd | ４−置換−２−アミノビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸誘導体及び製薬用組成物 |
| JP4194715B2 (ja) * | 1998-08-31 | 2008-12-10 | 大正製薬株式会社 | ６−フルオロビシクロ［３．１．０］ヘキサン誘導体 |
| PE20001236A1 (es) | 1998-11-13 | 2000-11-10 | Lilly Co Eli | Moduladores del receptor de aminoacidos excitadores |
| US6479674B1 (en) * | 1999-03-25 | 2002-11-12 | Taisho Pharmaceutical Co., Ltd. | Carboxylic acid derivatives and process for producing same |
| AU6785501A (en) | 2000-06-28 | 2002-01-08 | Taisho Pharmaceutical Co Ltd | Intermediate and process for producing fluorinated carboxylic acid derivative from the same |
| CA2441127A1 (en) * | 2001-03-14 | 2002-09-19 | Taisho Pharmaceutical Co., Ltd. | Process for producing bicyclocarboxylic acid derivative |
-
2004
- 2004-11-03 US US10/578,476 patent/US7786314B2/en not_active Expired - Fee Related
- 2004-11-03 CN CNB2004800381879A patent/CN100475800C/zh not_active Expired - Fee Related
- 2004-11-03 CA CA2544560A patent/CA2544560C/en not_active Expired - Fee Related
- 2004-11-03 WO PCT/US2004/036574 patent/WO2005047215A2/en not_active Ceased
- 2004-11-03 CN CN2009100086868A patent/CN101654410B/zh not_active Expired - Fee Related
- 2004-11-03 EP EP04800646A patent/EP1689727A4/en not_active Withdrawn
- 2004-11-03 AU AU2004289652A patent/AU2004289652B8/en not_active Ceased
- 2004-11-03 KR KR1020067011065A patent/KR101204145B1/ko not_active Expired - Fee Related
- 2004-11-03 JP JP2006538449A patent/JP4742239B2/ja not_active Expired - Fee Related
- 2004-11-03 RU RU2006119924/04A patent/RU2388747C2/ru not_active IP Right Cessation
- 2004-11-05 TW TW093133900A patent/TWI347316B/zh not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2152925C1 (ru) * | 1994-08-12 | 2000-07-20 | Эли Лилли Энд Компани | Производные аминобицикло[3.1.0]гексан-2,6-дикарбоновой кислоты и фармацевтическая композиция |
| US6160009A (en) * | 1997-05-14 | 2000-12-12 | Eli Lilly And Company | Excitatory amino acid receptor modulators |
| US6333428B1 (en) * | 1998-08-31 | 2001-12-25 | Taisho Pharmaceutical Co., Ltd. | 6-fluorobicyclo[3.1.0]hexane derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1689727A2 (en) | 2006-08-16 |
| US20070112030A1 (en) | 2007-05-17 |
| CA2544560C (en) | 2014-01-07 |
| JP4742239B2 (ja) | 2011-08-10 |
| CA2544560A1 (en) | 2005-05-26 |
| HK1096971A1 (en) | 2007-06-15 |
| RU2006119924A (ru) | 2007-12-27 |
| EP1689727A4 (en) | 2008-12-31 |
| TW200530178A (en) | 2005-09-16 |
| KR101204145B1 (ko) | 2012-11-22 |
| WO2005047215A2 (en) | 2005-05-26 |
| CN100475800C (zh) | 2009-04-08 |
| JP2007513070A (ja) | 2007-05-24 |
| CN101654410B (zh) | 2013-03-06 |
| CN1898224A (zh) | 2007-01-17 |
| AU2004289652B8 (en) | 2011-01-20 |
| CN101654410A (zh) | 2010-02-24 |
| TWI347316B (en) | 2011-08-21 |
| US7786314B2 (en) | 2010-08-31 |
| AU2004289652A1 (en) | 2005-05-26 |
| KR20060131771A (ko) | 2006-12-20 |
| HK1139124A1 (en) | 2010-09-10 |
| AU2004289652B2 (en) | 2010-09-16 |
| WO2005047215A3 (en) | 2005-07-14 |
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| MM4A | The patent is invalid due to non-payment of fees |
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