JP6990183B2 - キラルスピロビインダン骨格化合物及びその製造方法 - Google Patents
キラルスピロビインダン骨格化合物及びその製造方法 Download PDFInfo
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- JP6990183B2 JP6990183B2 JP2018533768A JP2018533768A JP6990183B2 JP 6990183 B2 JP6990183 B2 JP 6990183B2 JP 2018533768 A JP2018533768 A JP 2018533768A JP 2018533768 A JP2018533768 A JP 2018533768A JP 6990183 B2 JP6990183 B2 JP 6990183B2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
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- OPELWUSJOIBVJS-UHFFFAOYSA-N 3,3'-spirobi[1,2-dihydroindene] Chemical compound C12=CC=CC=C2CCC11C2=CC=CC=C2CC1 OPELWUSJOIBVJS-UHFFFAOYSA-N 0.000 description 7
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- 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 4
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- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical class NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 3
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- VUTUHLLWFPRWMT-QMDOQEJBSA-M (1z,5z)-cycloocta-1,5-diene;rhodium;trifluoromethanesulfonate Chemical compound [Rh].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1.[O-]S(=O)(=O)C(F)(F)F VUTUHLLWFPRWMT-QMDOQEJBSA-M 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 1
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- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
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- 229910015900 BF3 Inorganic materials 0.000 description 1
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- TWXFKNVYLVBWIF-KXFASCEHSA-N CC(C1CC2(C3)C3[C@@H](CC3C4)c5ccccc5)([C@]23c2c4c(Br)ccc2OC)C(C)=CC=C1Br Chemical compound CC(C1CC2(C3)C3[C@@H](CC3C4)c5ccccc5)([C@]23c2c4c(Br)ccc2OC)C(C)=CC=C1Br TWXFKNVYLVBWIF-KXFASCEHSA-N 0.000 description 1
- MPTTVDDIJQYRAE-WAOMPPBFSA-N CC([C@@H]1CC2CCC3C4)=CC=CC(N=O)=C1[C@@]23C1=C4C=CC(C2)C12O Chemical compound CC([C@@H]1CC2CCC3C4)=CC=CC(N=O)=C1[C@@]23C1=C4C=CC(C2)C12O MPTTVDDIJQYRAE-WAOMPPBFSA-N 0.000 description 1
- VGGQPOGLTOSBBB-BMTNDILFSA-N COc(cc1C[C@H](CC(C[C@H]2Cc3cc(OC)ccc3[Br]=C)c3ccccc3)C2=O)ccc1Br Chemical compound COc(cc1C[C@H](CC(C[C@H]2Cc3cc(OC)ccc3[Br]=C)c3ccccc3)C2=O)ccc1Br VGGQPOGLTOSBBB-BMTNDILFSA-N 0.000 description 1
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- PDXOTPLEOMJPAA-ZGVDRVBQSA-N O[O](O[C@@H]1C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)=Cc2ccccc2C11)(Oc2c1c(cccc1)c1cc2-c1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O Chemical compound O[O](O[C@@H]1C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)=Cc2ccccc2C11)(Oc2c1c(cccc1)c1cc2-c1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O PDXOTPLEOMJPAA-ZGVDRVBQSA-N 0.000 description 1
- DSWRKOXBQCBDLU-IPEYFGQDSA-N Oc1c(C([C@@H](C2)C3)([C@@H](Cc4ccc5)CC3c3ccccc3)c4c5O)c2ccc1 Chemical compound Oc1c(C([C@@H](C2)C3)([C@@H](Cc4ccc5)CC3c3ccccc3)c4c5O)c2ccc1 DSWRKOXBQCBDLU-IPEYFGQDSA-N 0.000 description 1
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- JAZCEXBNIYKZDI-UHFFFAOYSA-N [Ir+] Chemical compound [Ir+] JAZCEXBNIYKZDI-UHFFFAOYSA-N 0.000 description 1
- 150000005325 alkali earth metal hydroxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- UCYRAEIHXSVXPV-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)indiganyl trifluoromethanesulfonate Chemical compound [In+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F UCYRAEIHXSVXPV-UHFFFAOYSA-K 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- RJJGBSLWQUNMMY-UHFFFAOYSA-N ctk1a3081 Chemical compound NP(Cl)Cl RJJGBSLWQUNMMY-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 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 compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052760 oxygen Inorganic materials 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
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical group [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/72—Spiro hydrocarbons
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/21—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing rings other than six-membered aromatic rings
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
- B01J31/182—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine comprising aliphatic or saturated rings
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
- B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
- B01J31/186—Mono- or diamide derivatives thereof
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- B01J31/189—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms containing both nitrogen and phosphorus as complexing atoms, including e.g. phosphino moieties, in one at least bidentate or bridging ligand
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- B01J31/2221—At least one oxygen and one phosphorous atom present as complexing atoms in an at least bidentate or bridging ligand
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Description
又は、R1、R4、R5及びR8はそれぞれ独立に水素、C1~C10アルキル基、C3~C10シクロアルキル基、C1~C4アルコキシ基、アリール基、フッ素、塩素、臭素、ヨウ素又はヒドロキシ基であり、R2及びR3はそれらに連結される分子骨格中の炭素原子とともに連結して芳香環を構成し、且つ該芳香環は「R2及びR3に連結される分子骨格中の炭素原子が所在するベンゼン環」とは縮合環構造となり、R6及びR7はそれらに連結される分子骨格中の炭素原子とともに連結して芳香環を構成し、且つ該芳香環は「R6及びR7に連結される分子骨格中の炭素原子が所在するベンゼン環」とは縮合環構造となる。
XはCY1Y2、NY1、O又はSであり、n=0~3である(ここで、Y1及びY2はそれぞれ独立に水素、C1~C10アルキル基、C3~C10シクロアルキル基、アリール基又はC1~C4アルコキシ基である。)。
且つ、前記式Iで示されるキラル縮合環スピロビインダン骨格化合物は式I-nで示される化合物ではない。)
前記R1’及びR2’はそれぞれ独立にC1~C10アルキル基又はC3~C10シクロアルキル基であり、又は前記R1’及びR2’はそれらに連結されるN原子とともに連結してC2~C10含窒素複素飽和環を構成する。)
下記式の反応経路で示されるように、化合物II-aの製造を例にして、本実施例で、本発明に記載のα,α’-ビス(アリーレン)ケトン化合物(一般式II)の典型的な製造方法を詳細に説明する。
反応基質である式2aで示される化合物における置換基を変更する以外、実施例1と同様な製造方法によって、下記α,α’-ビス(アリーレン)ケトン類化合物II-a~II-mをそれぞれ製造した。
黄色固体、92%.M.P.142-144℃,1H NMR(400MHz,CDCl3)δ7.91(s,2H),7.26-7.18(m,8H),2.77-2.75(m,4H),2.34(s,6H),1.73-1.67(m,2H),13C NMR(100MHz,CDCl3)δ190.4,137.9,136.7,136.0,135.1,130.1,129.0,128.4,125.3,28.4,23.5,20.0.IR(neat)ν2932,1664,1590,1463,1400,1277,1240,1195,1165,1138,1018,996,968,929,860,814,783,759,736,721,607cm-1.HRMS(ESI)m/z:calcd.for C22H23O+:303.1743,Found:303.1747([M+H]+).
黄色固体、収率85%、M.P.83-85℃,1H NMR(400MHz,CDCl3)δ7.77(s,2H),7.31-7.24(m,6H),7.16-7.14(m,2H),2.94-2.91(m,4H),2.38(s,6H),1.80-1.74(m,2H).13C NMR(100MHz,CDCl3)δ109.3,137.9,137.0,136.0,135.9,131.1,129.4,128.2,127.4,28.5,23.0,21.4.IR(neat)ν2939,1659,1597,1490,1428,1276,1227,1180,1162,1143,1072,1050,971,946,885,835,786,758,737,717,690,616cm-1.HRMS(ESI)m/z:calcd.for C22H23O+:303.1743,Found:303.1751([M+H]+).
黄色固体、収率90%.M.P.179-181℃,1H NMR(400MHz,CDCl3)δ7.78(s,2H),7.38(d,J=8.0Hz,4H),7.21(d,J=8.4Hz,4H),2.92(t,J=6Hz,4H),2.38(s,6H),1.81-1.75(m,2H).13C NMR(100MHz,CDCl3)δ190.4,138.8,136.8,135.4,133.1,130.4,129.1,28.5,23.0,21.4.IR(neat)ν2938,2915,1660,1598,1564,1507,1311,1266,1197,1154,1139,1016,958,935,867,817,757,729,706,660cm-1.HRMS(ESI)m/z:calcd.for C22H23O+:303.1743,Found:303.1749([M+H]+).
黄色固体、収率95%、1H NMR(400MHz,CDCl3)δ7.76(s,2H),7.32(t,J=8.0Hz,2H),7.06(d,J=7.6Hz,2H),6.99(s,2H),6.89(dd,J=8,2.4Hz,2H),3.83(s,6H),2.94-2.91(m,4H),1.81-1.75(m,2H).13C NMR(100MHz,CDCl3)δ190.3,159.4,137.2,136.8,136.4,129.3,122.8,115.7,114.2,55.2,28.4,22.9,IR(neat)ν2934,2834,1690,1601,1571,1491,1445,1426,1316,1270,1220,1185,1162,1094,1045,993,947,921,883,868,822,769,751,674,626cm-1.HRMS(ESI)m/z:calcd.for C22H23O3 +:335.1642,Found:335.1646([M+H]+).
黄色固体、収率90%、M.P.167-169℃、1H NMR(400MHz,CDCl3)δ7.76(s,2H),7.44(d,J=8.8Hz,4H),6.92(d,J=8.8Hz,4H),3.82(s,6H),2.89(t,J=5.2Hz,4H),1.83-1.75(m,2H).13C NMR(100MHz,CDCl3)δ190.0,159.8,136.4,134.2,132.1,128.6,113.8,55.2,28.4,22.9.IR(neat)ν2939,2829,1657,1591,1553,1505,1451,1416,1313,1301,1276,1247,1182,1159,1138,1112,1022,965,948,868,832,809,754,731,663cm-1.HRMS(ESI)m/z:calcd.for C22H23O3 +:335.1642,Found:335.1647([M+H]+).
アルゴンガス雰囲気下、水素化フラスコ(150-mL)を無水・無酸素条件下で処理した後、実施例2で製造された化合物II-h(0.1g、0.2mmol)、触媒A(0.002mmol)、及び無水ジクロロメタン(5mL)を投入した。グローブボックスにおいて水素化フラスコをオートクレーブに移して、水素ガスを3回置換した後、水素ガスを導入して、室温で12時間反応させた。ヒュームフードにおいて残留水素ガスを慎重に排出して、反応釜を開き、溶媒を減圧除去して、混合物をサンプリングして1H NMRにより、II-hの転化率と生成物III-hのシス-トランス比率(d.r.=anti/syn)を測定した。余剰混合物から溶媒を減圧除去して、残留物をシリカゲルカラムクロマトグラフィーにより分離精製して(石油エーテル/酢酸エチル20:1)、無色油状液体III-hを得て、生成物のee値とdr値はいずれも実施例3におけるキラル高速液体クロマトグラフィー方法によって測定された。触媒の種類と水素ガス圧力、生成物収率、dr値及びee値は表1に示される。
アルゴンガス雰囲気下、50-mLシュレンク管(Schlenk管)に化合物III-h(ee、>99%、247mg、0.5mmol)と無水ジクロロメタン(10mL)を投入して、溶液を氷浴中0℃に冷却させて、緩慢に触媒(本実施例では、触媒はTiCl4である)(0.11mL、1.0mmol)を加えて、0℃で30分間撹拌後、緩慢に室温に昇温して、5時間撹拌し続け、TLCにより検反応終了と検出されると、5mLの水を加えて反応をクエンチさせた。反応混合物をジクロロメタン(5mL×3)で3回抽出して、有機相を合併し、無水硫酸ナトリウムで乾燥させて、乾燥剤を濾過除去し、濾液から溶媒を減圧除去した後、残留物をシリカゲルカラムクロマトグラフィーにより分離精製して(石油エーテル/酢酸エチル=50:1)、白色固体(1S,2S,2’S)-I-hを得て、生成物のee値を、キラルHPLCにより測定した[Chiralcel OD-H column;移動相、イソプロパノール/ノルマルヘキサン=0:100、温度、室温.;移動相流速、0.8mL/min;紫外線-可視光検出波長λ=230nm;tR(major)=15.80min;tR(minor)=23.00min.]。
表3に示されるように、基質化合物III-hの使用量(本実施例では0.2mmol)、触媒の種類と使用量、溶媒の種類と使用量(本実施例では、溶媒の使用量はいずれも2.0mLである)、反応温度を変更する以外、実施例6と同様な方法によって実験を行い、収率とee値を表3に示す。表3中、モル当量は、化合物III-hのモル量に対する触媒のモル量の倍数である。表3中、ee値の欄において、「-」は測定不可を意味する。
表4に示されるように、基質化合物III-hの使用量(本実施例では0.2mmol)、触媒の種類と使用量、溶媒の種類と使用量(本実施例では、溶媒の使用量はいずれも2.0mLである)、反応温度を変更する以外、実施例6と同様な方法によって実験を行い、収率とee値を表4に示す。表4中、モル当量は、触媒のモル量の化合物III-hのモル量に対する倍数である。
化合物IIを原料として、不斉水素化と環化ワンポット法によって、中間体化合物IIIを分離せずに、水素化反応混合物に適量のTiCl4を加えて、化合物Iを合成した。本実施例では、化合物II-hのワンポット法による不斉水素化-環化反応を用いた化合物I-hの合成を例にして、化合物IIを出発材料としてワンポット法により化合物Iを合成する実験の典型的な操作方法を説明した。
実施例28と29の前記実験方法を参照して操作し、(R)-tBuPHOX/Ir(I)を不斉水素化触媒として、キラル縮合環スピロビインダン骨格ジフェノールI-pを得た。
実施例28と29の前記実験方法を参照して操作し、(R)-tBuPHOX/Ir(I)を不斉水素化触媒として、キラル縮合環スピロビインダン骨格ジフェノールI-qを得た。
実施例28と29の前記実験方法を参照して操作し、(R)-tBuPHOX/Ir(I)を不斉水素化触媒として、キラル縮合環スピロビインダン骨格ジフェノールI-rを得た。
実施例28と29の前記実験方法を参照して操作し、(R)-tBuPHOX/Ir(I)を不斉水素化触媒として、キラル縮合環スピロビインダン骨格ジフェノールI-sを得た。
Claims (18)
- 式Iで示されるキラル縮合環スピロビインダン骨格化合物、またはそのエナンチオマー若しくはジアステレオマー。
又は、R1、R4、R5及びR8はそれぞれ独立に水素、C1~C10アルキル基、C1~C4アルコキシ基、アリール基、又はヒドロキシ基であり、R2及びR3はそれらに連結される分子骨格中の炭素原子とともに連結して芳香環を構成し、且つ該芳香環は「R2及びR3に連結される分子骨格中の炭素原子が所在するベンゼン環」とは縮合環構造となり、R6及びR7はそれらに連結される分子骨格中の炭素原子とともに連結して芳香環を構成し、且つ該芳香環は「R6及びR7に連結される分子骨格中の炭素原子が所在するベンゼン環」とは縮合環構造となる。
XはCY1Y2 であり、n=0又は1である(ここで、Y1及びY2はそれぞれ独立に水素、C1~C10アルキル基又はアリール基である。)。) - 前記R1とR8は同じであり、及び/又は、前記R2とR7は同じであり、及び/又は、前記R3とR6は同じであり、及び/又は、前記R4とR5は同じであり、及び/又は、前記n=0又は1であることを特徴とする請求項1に記載の化合物。
- 前記R1、R2、R3、R4、R5、R6、R7及びR8がそれぞれ独立にC1~C10アルキル基
である場合、前記C1~C10アルキル基はC1~C6アルキル基であり、
前記R1、R2、R3、R4、R5、R6、R7及びR8がそれぞれ独立にC1~C4アルコキシ基である場合、前記C1~C4アルコキシ基はC1~C3アルコキシ基であり、
前記R1、R2、R3、R4、R5、R6、R7及びR8がそれぞれ独立にアリール基である場合、前記アリール基はC6~C20アリール基であり、
前記R2及びR3が、それらに連結される分子骨格中の炭素原子とともに連結して芳香環を構成する場合、前記芳香環はC6~C20芳香環であり、
前記R6及びR7が、それらに連結される分子骨格中の炭素原子とともに連結して芳香環を構成する場合、前記芳香環はC6~C20芳香環であり、
前記Y1及びY2がそれぞれ独立にC1~C10アルキル基である場合、前記C1~C10アルキル基はC1~C4アルキル基であり、
前記Y1及びY2がそれぞれ独立にアリール基である場合、前記アリール基はC6~C20アリール基であることを特徴とする請求項1又は2に記載の化合物。 - 前記R1、R2、R3、R4、R 5 、R6、R7及びR8がそれぞれ独立にC1~C6アルキル基である場合、前記C1~C6アルキル基はC1~C3アルキル基であり、
前記R1、R2、R3、R4、R5、R6、R7及びR8がそれぞれ独立にC1~C3アルコキシ基である場合、前記C1~C3アルコキシ基はメトキシ基、エトキシ基又はプロポキシ基であり、
前記R1、R2、R3、R4、R5、R6、R7及びR8がそれぞれ独立に前記C6~C20アリー
ル基である場合、前記C6~C20アリール基はC6~C12アリール基であり、
前記R2及びR3が、それらに連結される分子骨格中の炭素原子とともに連結して前記C6
~C20芳香環を構成する場合、前記C6~C20芳香環はC6~C12芳香環であり、
前記R6及びR7が、それらに連結される分子骨格中の炭素原子とともに連結してC6~C20芳香環を構成する場合、前記C6~C20芳香環はC6~C12芳香環であり、
前記Y1及びY2がそれぞれ独立にC1~C4アルキル基である場合、前記C1~C4アルキル基はメチル基、エチル基、プロピル基又はtert-ブチル基であり、
前記Y1及びY2がそれぞれ独立にC6~C20アリール基である場合、前記C6~C20アリール基はC6~C12アリール基であることを特徴とする請求項3に記載の化合物。 - 前記R1、R2、R3、R4、R5、R6、R7及びR8がそれぞれ独立にC1~C3アルキル基である場合、前記C1~C3アルキル基はメチル基、エチル基又はプロピル基であり、
前記R1、R2、R3、R4、R5、R6、R7及びR8がそれぞれ独立に前記C6~C12アリー
ル基である場合、前記C6~C12はフェニル基又はナフチル基であり、
前記R2及びR3が、それらに連結される分子骨格中の炭素原子とともに連結して前記C6
~C12芳香環を構成する場合、前記C6~C12芳香環はベンゼン環又はナフタレン環であ
り、
前記R6及びR7が、それらに連結される分子骨格中の炭素原子とともに連結してC6~C12芳香環を構成する場合、前記C6~C12芳香環はベンゼン環又はナフタレン環であり、
前記Y1及びY2がそれぞれ独立にC6~C12アリール基である場合、前記C6~C12アリール基はフェニル基又はナフチル基であることを特徴とする請求項4に記載の化合物。 - 前記R1’及びR2’がそれぞれ独立にC1~C10アルキル基である場合、前記C1~C10アルキル基はC1~C3アルキル基であり、
前記R1’及びR2’がそれぞれ独立にC3~C10シクロアルキル基である場合、前記C3~C10シクロアルキル基はC3~C6シクロアルキル基であり、
前記R1’及びR2’が、それらに連結されるN原子とともに連結してC2~C10含窒素複
素飽和環を構成する場合、前記C2~C10含窒素複素飽和環はC3~C6含窒素複素飽和環
であることを特徴とする請求項7に記載の式I’で示されるホスホロアミダイトリガンド、またはそのエナンチオマー若しくはジアステレオマー。 - 前記R1’及びR2’がそれぞれ独立にC1~C3アルキル基である場合、前記C1~C3アルキル基はメチル基、エチル基又はプロピル基であり、
前記R1’及びR2’がそれぞれ独立にC3~C6シクロアルキル基である場合、前記C3~
C6シクロアルキル基はシクロプロピル基であり、
前記R1’及びR2’が、それらに連結されるN原子とともに連結してC3~C6含窒素複素飽和環を構成する場合、前記C3~C6含窒素複素飽和環はピラゾリジンであることを特徴とする請求項8に記載の式I’で示されるホスホロアミダイトリガンド、またはそのエナンチオマー若しくはジアステレオマー。 - 前記ルイス酸は四塩化チタンであり、
及び/又は、前記式Iで示される化合物の製造方法はさらに、前記溶媒と前記式IIIで示される化合物を混合して、0℃条件において、前記触媒を添加して1~100分間反応させ、15℃~40℃に自然昇温して1~20時間引き続き反応させるステップを含み、及び/又は、前記分子内フリーデル・クラフツ反応は、無水・無酸素条件において行われ、
及び/又は、前記分子内フリーデル・クラフツ反応は、保護性ガスの存在下において行われ、
及び/又は、前記式IIIで示される化合物と前記触媒のモル比は100:1~1:100であり、
及び/又は、前記分子内フリーデル・クラフツ反応の溶媒は、芳香族炭化水素系溶媒、ハロゲン化炭化水素系溶媒、エーテル系溶媒、アルコール系溶媒、アミド系溶媒及びスルホキシド系溶媒のうちの1種又は複数種であり、
及び/又は、前記式IIIで示される化合物と前記分子内フリーデル・クラフツ反応の溶媒とのモル体積比は0.02mol/L~0.2mol/Lであり、
及び/又は、前記分子内フリーデル・クラフツ反応の温度は-40℃~100℃であり、及び/又は、前記分子内フリーデル・クラフツ反応の時間は0.1~48時間であることを特徴とする請求項11に記載の製造方法。 - 前記式Iで示される化合物の製造方法において、前記不斉水素化反応の触媒は、ルテニウム、ロジウム、イリジウム及びパラジウムの遷移金属錯体のうちの1種又は複数種であり、前記金属錯体はキラル又はアキラルであり、
及び/又は、前記式Iで示される化合物の製造方法において、前記不斉水素化反応の触媒と前記式IIで示される化合物とのモル比は0.0001~0.1であり、
及び/又は、前記式Iで示される化合物の製造方法において、前記不斉水素化反応の溶媒はハロゲン化炭化水素系溶媒、芳香炭化水素系溶媒、エーテル系溶媒、アルコール系溶媒、アミド系溶媒及びスルホキシド系溶媒のうちの1種又は複数種であり、
及び/又は、前記式Iで示される化合物の製造方法において、前記不斉水素化反応の溶媒と前記式IIで示される化合物との体積質量比は1ml/g~20ml/gであり、
及び/又は、前記式Iで示される化合物の製造方法において、前記不斉水素化反応の水素ガスの圧力は1~100atmであり、
及び/又は、前記式Iで示される化合物の製造方法において、前記不斉水素化反応の温度は-78~80℃であり、
及び/又は、前記式Iで示される化合物の製造方法において、前記不斉水素化反応の時間は1~48時間であり、
及び/又は、前記式Iで示される化合物の製造方法において、前記不斉水素化反応終了後、後処理を行わずに、反応系をそのまま、前記フリーデル・クラフツ反応の溶媒、触媒及び前記式IIIで示される化合物と混合して、前記分子内フリーデル・クラフツ反応を行うことを特徴とする請求項13に記載の製造方法。 - 前記アルドール縮合反応は、アルカリ性条件において行われ、
及び/又は、前記アルドール縮合反応の溶媒はアルコール系溶媒と水の混合溶媒であり、及び/又は、前記アルドール縮合反応の溶媒と前記式VIで示される化合物との体積モル比は10000ml/mol~1ml/molであり、
及び/又は、前記アルドール縮合反応の温度は10~35℃であることを特徴とする請求項15に記載の製造方法。 - 前記式I’で示される化合物の製造方法はさらに、アルカリ性条件において、前記式Iで示される化合物を前記溶媒と混合して、-40~10℃に冷却させ、次に前記式IVで示される化合物と混合し、温度を10~35℃に上げてから、前記置換反応を行うステップを含み、
及び/又は、前記置換反応は、無水・無酸素条件において行われ、
及び/又は、前記置換反応は、保護性ガスの存在下において行われ、
及び/又は、前記アルカリ性条件は、反応をアルカリの作用下で行うことであり、
及び/又は、前記置換反応の溶媒は、エーテル系溶媒、ハロ置換アルカン系溶媒及び芳香族炭化水素系溶媒のうちの1種又は複数種であり、
及び/又は、前記置換反応において、前記式Iで示される化合物と前記溶媒とのモル体積比は0.05mol/L~0.5mol/Lであり、
及び/又は、前記置換反応において、前記式Iで示される化合物と式IVで示される化合物とのモル比は1:1.1~1:3であり、
及び/又は、前記置換反応の温度は0~35℃であり、
及び/又は、前記置換反応の時間は1~12時間であることを特徴とする請求項17に記載の製造方法。
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