JP2009040763A - Method for producing silanol compound - Google Patents
Method for producing silanol compound Download PDFInfo
- Publication number
- JP2009040763A JP2009040763A JP2008161259A JP2008161259A JP2009040763A JP 2009040763 A JP2009040763 A JP 2009040763A JP 2008161259 A JP2008161259 A JP 2008161259A JP 2008161259 A JP2008161259 A JP 2008161259A JP 2009040763 A JP2009040763 A JP 2009040763A
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- JP
- Japan
- Prior art keywords
- group
- compound
- added
- ethyl acetate
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 silanol compound Chemical class 0.000 title claims abstract description 199
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 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
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 4
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 4
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 148
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 210
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 147
- 238000005160 1H NMR spectroscopy Methods 0.000 description 63
- 230000015572 biosynthetic process Effects 0.000 description 63
- 238000003786 synthesis reaction Methods 0.000 description 63
- 239000000243 solution Substances 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 53
- 239000000203 mixture Substances 0.000 description 49
- 239000002904 solvent Substances 0.000 description 41
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 37
- 238000010898 silica gel chromatography Methods 0.000 description 37
- 229910052938 sodium sulfate Inorganic materials 0.000 description 37
- 235000011152 sodium sulphate Nutrition 0.000 description 37
- 238000001035 drying Methods 0.000 description 36
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 33
- 239000012230 colorless oil Substances 0.000 description 33
- 238000000746 purification Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 239000012043 crude product Substances 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 235000019270 ammonium chloride Nutrition 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000010791 quenching Methods 0.000 description 9
- 230000000171 quenching effect Effects 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- ITKVLPYNJQOCPW-UHFFFAOYSA-N chloro-(chloromethyl)-dimethylsilane Chemical compound C[Si](C)(Cl)CCl ITKVLPYNJQOCPW-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 235000011056 potassium acetate Nutrition 0.000 description 6
- ZVGZRYXBRJWDDT-UHFFFAOYSA-N C[SiH](C)C(C(Br)=CC(CCl)=C1)=C1C(O)=O Chemical compound C[SiH](C)C(C(Br)=CC(CCl)=C1)=C1C(O)=O ZVGZRYXBRJWDDT-UHFFFAOYSA-N 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- KJJBSBKRXUVBMX-UHFFFAOYSA-N magnesium;butane Chemical compound [Mg+2].CCC[CH2-].CCC[CH2-] KJJBSBKRXUVBMX-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- MLKGCZSRAYXENL-UHFFFAOYSA-N C[SiH](C)C(C(CCl)=CC=C1)=C1C(O)=O Chemical compound C[SiH](C)C(C(CCl)=CC=C1)=C1C(O)=O MLKGCZSRAYXENL-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 4
- CAURZYXCQQWBJO-UHFFFAOYSA-N bromomethyl-chloro-dimethylsilane Chemical compound C[Si](C)(Cl)CBr CAURZYXCQQWBJO-UHFFFAOYSA-N 0.000 description 4
- CRWHUKCWLNKYTF-UHFFFAOYSA-N chloromethyl-[4-[chloromethyl(dimethyl)silyl]phenyl]-dimethylsilane Chemical compound ClC[Si](C)(C)C1=CC=C([Si](C)(C)CCl)C=C1 CRWHUKCWLNKYTF-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- OURXRFYZEOUCRM-UHFFFAOYSA-N 4-hydroxymorpholine Chemical compound ON1CCOCC1 OURXRFYZEOUCRM-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- MRYPXAIOXXDUDQ-UHFFFAOYSA-N C[SiH](C)C(C(CCl)=CC(CCl)=C1)=C1C(O)=O Chemical compound C[SiH](C)C(C(CCl)=CC(CCl)=C1)=C1C(O)=O MRYPXAIOXXDUDQ-UHFFFAOYSA-N 0.000 description 3
- PSRPFIKGYKBONK-UHFFFAOYSA-N C[SiH](C)C(C(CCl)=CC([Si](C)(C)C)=C1)=C1C(O)=O Chemical compound C[SiH](C)C(C(CCl)=CC([Si](C)(C)C)=C1)=C1C(O)=O PSRPFIKGYKBONK-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QZHDNICXKYAEKK-UHFFFAOYSA-N diazomethyl(trimethyl)silane;hexane Chemical compound CCCCCC.C[Si](C)(C)C=[N+]=[N-] QZHDNICXKYAEKK-UHFFFAOYSA-N 0.000 description 3
- YBNBOGKRCOCJHH-UHFFFAOYSA-N hydroxy-[4-[hydroxy(dimethyl)silyl]phenyl]-dimethylsilane Chemical compound C[Si](C)(O)C1=CC=C([Si](C)(C)O)C=C1 YBNBOGKRCOCJHH-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- VOIZNVUXCQLQHS-UHFFFAOYSA-N 3-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC(Br)=C1 VOIZNVUXCQLQHS-UHFFFAOYSA-N 0.000 description 2
- LXWLEQZDXOQZGW-UHFFFAOYSA-N 3-bromofuran Chemical compound BrC=1C=COC=1 LXWLEQZDXOQZGW-UHFFFAOYSA-N 0.000 description 2
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 2
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 2
- OQCYTKZPQPKJFO-UHFFFAOYSA-N C[SiH](C)C1=C(C=CC(=C1)CCl)C(=O)O Chemical compound C[SiH](C)C1=C(C=CC(=C1)CCl)C(=O)O OQCYTKZPQPKJFO-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 2
- 229940077239 chlorous acid Drugs 0.000 description 2
- GWIVSKPSMYHUAK-UHFFFAOYSA-N ethoxy-[ethoxy(dimethyl)silyl]-dimethylsilane Chemical compound CCO[Si](C)(C)[Si](C)(C)OCC GWIVSKPSMYHUAK-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000006138 lithiation reaction Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 description 1
- NHDODQWIKUYWMW-UHFFFAOYSA-N 1-bromo-4-chlorobenzene Chemical compound ClC1=CC=C(Br)C=C1 NHDODQWIKUYWMW-UHFFFAOYSA-N 0.000 description 1
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 1
- SFTFNJZWZHASAQ-UHFFFAOYSA-N 3,5-dibromobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC(Br)=C1 SFTFNJZWZHASAQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- IOXZOXCGCJKYBC-UHFFFAOYSA-N NC(=O)C1=CC=CC=C1[SiH3] Chemical compound NC(=O)C1=CC=CC=C1[SiH3] IOXZOXCGCJKYBC-UHFFFAOYSA-N 0.000 description 1
- 238000006137 acetoxylation reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 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
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012776 electronic material Substances 0.000 description 1
- CWAFVXWRGIEBPL-UHFFFAOYSA-N ethoxysilane Chemical compound CCO[SiH3] CWAFVXWRGIEBPL-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- HTDJPCNNEPUOOQ-UHFFFAOYSA-N hexamethylcyclotrisiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O1 HTDJPCNNEPUOOQ-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000004819 silanols Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Abstract
Description
本発明は、新規なアリールシラノール化合物、及び芳香族複素環シラノール化合物の製造方法に関する。 The present invention relates to a novel arylsilanol compound and a method for producing an aromatic heterocyclic silanol compound.
種々のビアリール化合物は、医薬品、農薬及び電子材料などの機能性材料に広く使用されているが、その主たる製造方法のひとつとして、パラジウム触媒存在下に、アリールシラノール化合物又は芳香族複素環シラノール化合物と、芳香族臭化物又は芳香族ヨウ化物とのクロス−カップリング反応（炭素−炭素結合反応）が知られている（例えば、非特許文献１）。そこで、目的のビアリール化合物を得るための製造原料として、所望のアリールシラノール化合物、又は芳香族複素環シラノール化合物を、経済的かつ安全で、効率的に得ることは重要な課題のひとつとなっている。 Various biaryl compounds are widely used in functional materials such as pharmaceuticals, agricultural chemicals, and electronic materials. As one of the main production methods, an arylsilanol compound or an aromatic heterocyclic silanol compound is used in the presence of a palladium catalyst. A cross-coupling reaction (carbon-carbon bond reaction) with an aromatic bromide or aromatic iodide is known (for example, Non-Patent Document 1). Thus, obtaining a desired arylsilanol compound or aromatic heterocyclic silanol compound as a production raw material for obtaining the target biaryl compound is one of the important issues to obtain economically, safely and efficiently. .
非特許文献２には、芳香族臭化物にｎ−ブチルリチウムを反応させた（金属−ハロゲン交換反応）後、ヘキサメチルシクロトリシロキサンを反応させて芳香族シラノール化合物を得る反応例が記載されている。しかしこの反応では金属−ハロゲン交換反応の際、ハロゲン原子、低級アルキル基で保護されたカルボキシル基等の置換基を含む基質では該置換基との副反応が生じるため、反応に適用できる基質に限界がある。即ち低級アルキル基、低級アルコキシ基等の置換基に限られる。 Non-Patent Document 2 describes a reaction example in which aromatic bromide is reacted with n-butyllithium (metal-halogen exchange reaction), and then hexamethylcyclotrisiloxane is reacted to obtain an aromatic silanol compound. . However, in this reaction, a substrate containing a substituent such as a halogen atom or a carboxyl group protected by a lower alkyl group undergoes a side reaction with the substituent during the metal-halogen exchange reaction, so that the substrate applicable to the reaction is limited. There is. That is, it is limited to substituents such as a lower alkyl group and a lower alkoxy group.
一方、非特許文献３には芳香族臭化物にパラジウム触媒、ホスフィンリガンド、塩基存在下１,２−ジエトキシ−１,１,２,２−テトラメチルジシランを反応させた後、得られたシリルエチルエーテル体を加水分解させて芳香族シラノール化合物を得る反応例が記載されている。この反応においては、高価な１,２−ジエトキシ−１,１,２,２−テトラメチルジシランや、触媒量ではあるが高価な（２−ビフェニル）ジｔｅｒｔ−ブチルホスフィンを使用すること、またシリルエチルエーテルを加水分解させる際に、基質によってはシラノール２量体が副生することなど、工業的に有利な製法とは言い難い。 On the other hand, Non-Patent Document 3 discloses a silylethyl ether obtained by reacting aromatic bromide with 1,2-diethoxy-1,1,2,2-tetramethyldisilane in the presence of a palladium catalyst, a phosphine ligand and a base. The reaction example which hydrolyzes a body and obtains an aromatic silanol compound is described. In this reaction, the use of expensive 1,2-diethoxy-1,1,2,2-tetramethyldisilane or a catalytic but expensive (2-biphenyl) ditert-butylphosphine is used. When hydrolyzing ethyl ether, it is difficult to say that it is an industrially advantageous production method, such as silanol dimer by-product depending on the substrate.
本発明の課題は高価な試薬を必要とせず、経済的かつ安全で効率的に式（２）で表されるアリールシラノール化合物及び芳香族複素環シラノール化合物を製造する方法を提供することにある。 An object of the present invention is to provide a method for producing an arylsilanol compound and an aromatic heterocyclic silanol compound represented by the formula (2) economically, safely and efficiently without requiring an expensive reagent.
本発明は式（１）で表されるシリル化合物に酸化剤を反応させることを特徴とする、式（２）で表されるシラノール化合物の製造方法に係る。 This invention relates to the manufacturing method of the silanol compound represented by Formula (2) characterized by making an oxidizing agent react with the silyl compound represented by Formula (1).
本発明者らは、アリールシリル化合物及び芳香族複素環シリル化合物に酸化剤を反応させることにより、アリールシラノール化合物及び芳香族複素環シラノール化合物を与えることを見出し、本発明の新規反応に到達した。 The present inventors have found that an arylsilanol compound and an aromatic heterocyclic silanol compound can be obtained by reacting an arylsilyl compound and an aromatic heterocyclic silyl compound with an oxidizing agent, and have reached the novel reaction of the present invention.
本発明は高価な試薬を必要とせず、経済的かつ安全で、効率的に式（２）で表されるアリールシラノール化合物及び芳香族複素環シラノール化合物を製造する方法を提供することができる。 The present invention can provide a method for producing an arylsilanol compound and an aromatic heterocyclic silanol compound represented by the formula (2) efficiently and safely without requiring an expensive reagent.
式（１）中、Ｒ１で示される「置換基を有していてもよいアリール基」の「アリール基」とは、炭素数６〜１４のアリール基を示し、フェニル基、ナフチル基が例示され、好ましくはフェニル基である。 In formula (1), the “aryl group” of the “aryl group optionally having substituent (s)” represented by R 1 represents an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. Preferably, it is a phenyl group.
式（１）中、Ｒ１で示される「置換基を有していてもよい芳香族複素環基」の「芳香族複素環基」とは、窒素原子、酸素原子及び硫黄原子から選ばれる原子を１〜３個含む、５〜６員の単環性又は２環性の芳香族複素環基を示し、フラニル基、チオフェニル基、ピロリル基、チアゾリル基、オキサゾリル基、イミダゾリル基、ピラゾリル基、チアジアゾリル基、オキサジアゾリル基、トリアゾリル基等の５員環基、ピリジル基、ピリミジル基、トリアジル基等の６員環基、ベンゾフラニル基、ベンゾチオフェニル基、インドリル基、ベンズイミダゾリル基、インダゾリル基、ベンゾチアジアゾリル基、ベンゾオキサゾリル基、キノリル基、イソキノリル基等の２環性基が例示され、好ましくはフラニル基、チオフェニル基である。 In the formula (1), the “aromatic heterocyclic group” of the “optionally substituted aromatic heterocyclic group” represented by R 1 is an atom selected from a nitrogen atom, an oxygen atom and a sulfur atom 5 to 6-membered monocyclic or bicyclic aromatic heterocyclic group containing 1 to 3, furanyl group, thiophenyl group, pyrrolyl group, thiazolyl group, oxazolyl group, imidazolyl group, pyrazolyl group, thiadiazolyl Group, 5-membered ring group such as oxadiazolyl group and triazolyl group, 6-membered ring group such as pyridyl group, pyrimidyl group and triazyl group, benzofuranyl group, benzothiophenyl group, indolyl group, benzimidazolyl group, indazolyl group, benzothiadiazo Bicyclic groups such as a ryl group, a benzoxazolyl group, a quinolyl group, and an isoquinolyl group are exemplified, and a furanyl group and a thiophenyl group are preferred.
式（１）中、Ｒ２、Ｒ３で示される「低級アルキル基」とは、炭素数１〜６の直鎖状又は分枝状アルキル基であり、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ｎ−ヘキシル基等が例示され、好ましくはメチル基である。 In the formula (1), the “lower alkyl group” represented by R 2 and R 3 is a linear or branched alkyl group having 1 to 6 carbon atoms, and includes a methyl group, an ethyl group, and an n-propyl group. , An isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-hexyl group and the like, preferably a methyl group.
式（１）中、Ｘで示される「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が例示され、好ましくは塩素原子、臭素原子である。
式（１）中、Ｒ４、Ｒ５、Ｒ６で示される「低級アルキル基」としては、上記のアルキル基が例示され、好ましくはメチル基である。
In the formula (1), examples of the “halogen atom” represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a chlorine atom and a bromine atom.
In the formula (1), examples of the “lower alkyl group” represented by R 4 , R 5 and R 6 include the above alkyl groups, and a methyl group is preferable.
式（１）中、Ｒ１で示される「置換基を有していてもよいアリール基」の「置換基」としては、保護基で保護されていてもよい水酸基、ハロゲン原子、低級アルキル基、低級アルコキシ基、フェノキシ基、低級アルキル基で保護されていてもよいカルボキシル基、シアノ基が例示され、好ましくは、ハロゲン原子、低級アルコキシ基、低級アルキル基で保護されていてもよいカルボキシル基であり、より好ましくは臭素原子、塩素原子、メトキシ基、メトキシカルボニル基、カルボキシル基である。該置換基の個数は１〜３個であり、好ましくは１個である。 In the formula (1), as the “substituent” of the “aryl group optionally having substituent (s)” represented by R 1 , a hydroxyl group, halogen atom, lower alkyl group, which may be protected with a protecting group, Examples thereof include a carboxyl group which may be protected with a lower alkoxy group, a phenoxy group and a lower alkyl group, and a cyano group, preferably a carboxyl group which may be protected with a halogen atom, a lower alkoxy group or a lower alkyl group. More preferably, they are a bromine atom, a chlorine atom, a methoxy group, a methoxycarbonyl group, and a carboxyl group. The number of the substituents is 1 to 3, and preferably 1.
式（１）中、Ｒ１で示される「置換基を有していてもよい芳香族複素環基」の「置換基」としては、上記の置換基が例示される。置換基の個数は１又は２個である。 In the formula (1), examples of the “substituent” of the “aromatic heterocyclic group which may have a substituent” represented by R 1 include the above-mentioned substituents. The number of substituents is 1 or 2.
式（１）中、Ｒ１が置換基としても有していてもよい「置換基を有していてもよいフェニルアミノカルボニル基」の「置換基」としては、上記の置換基が例示され、好ましくは低級アルキル基で保護されていてもよいカルボキシル基であり、より好ましくは、メチル基又はエチル基で保護されていてもよいカルボキシル基であり、特に好ましくはカルボキシル基である。該置換基の個数は１又は２個であり、好ましくは１個である。 In the formula (1), examples of the “substituent” of the “optionally substituted phenylaminocarbonyl group” that R 1 may have as a substituent include the above substituents, A carboxyl group that may be protected with a lower alkyl group is preferable, a carboxyl group that may be protected with a methyl group or an ethyl group is more preferable, and a carboxyl group is particularly preferable. The number of the substituents is 1 or 2, and preferably 1.
式（１）中、Ｒ４、Ｒ５、Ｒ６で示される「置換基を有していてもよい低級アルキル基」の「置換基」としては、上記の置換基が例示され、好ましくはハロゲン原子、保護基で保護されていてもよい水酸基であり、より好ましくは、テトラヒドロピラニル基により保護されていてもよい水酸基である。該置換基の個数は１又は２個であり、好ましくは１個である。
式（１）中、Ｒ６が置換基として有していてもよい「保護基により保護されていてもよい水酸基」の「保護基」としては、通常水酸基の保護基として用いられる保護基であれば特に制限はないが、アセチル基、トリメチルシリル基、ｔｅｒｔ−ブチルジメチルシリル基、テトラヒドロピラニル基、ベンジル基等が例示される。
式（１）中、ｎは１〜３であり、好ましくは１又は２である。
In the formula (1), examples of the “substituent” of the “lower alkyl group optionally having substituent (s)” represented by R 4 , R 5 and R 6 include the above substituents, preferably halogen It is a hydroxyl group that may be protected by an atom or a protecting group, and more preferably a hydroxyl group that may be protected by a tetrahydropyranyl group. The number of the substituents is 1 or 2, and preferably 1.
In the formula (1), the “protecting group” of the “hydroxy group optionally protected by a protecting group” that R 6 may have as a substituent may be a protecting group usually used as a protecting group for a hydroxyl group. Examples thereof include, but are not limited to, acetyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tetrahydropyranyl group, and benzyl group.
In formula (1), n is 1-3, Preferably it is 1 or 2.
本発明の製造方法を、以下の反応式を参照して説明する。 The production method of the present invention will be described with reference to the following reaction formula.
式（１）で表されるアリールシリル化合物及び芳香族複素環シリル化合物は市販されているものを入手するか、或いは公知の方法により製造することができる。例えば、アリールシリルメタノール化合物、芳香族複素環シリルメタノール化合物は特願２００７−１５４７４６号記載の方法により得られるハロゲノメチル（ジ低級アルキル）シリル化合物のハロゲンを、通常公知の方法によりアセトキシ化後、通常公知の方法で加水分解することにより、製造することができる。
式（１）の化合物としては、３−ヒドロキシメチルジメチルシリル安息香酸メチルエステル、４−ヒドロキシメチルジメチルシリル安息香酸メチルエステル、３−ブロモ−５−ヒドロキシメチルジメチルシリル安息香酸メチルエステル、４−（３−ヒドロキシメチルジメチルシリル−５−トリメチルシリルベンズアミド）安息香酸、４−（３,５−ジ−ヒドロキシメチルジメチルシリルベンズアミド）安息香酸、４−（３−ヒドロキシメチルジメチルシリル−５−テトラヒドロピラノキシメチルジメチルシリルベンズアミド）安息香酸、４−ヒドロキシメチルジメチルシリルアニソール、４−ヒドロキシメチルジメチルシリル−クロロベンゼン、１,４−ビス（ヒドロキシメチルジメチルシリル）ベンゼン、２−ヒドロキシメチルジメチルシリルチオフェン、３−ヒドロキシメチルジメチルシリルフラン、４−クロロメチルジメチルシリル安息香酸メチルエステル、４−ブロモメチルジメチルシリル安息香酸メチルエステル、４−クロロメチルジメチルシリルアニソール、４−ブロモメチルジメチルシリルアニソール、４−クロロメチルジメチルシリル−クロロベンゼン、４−ブロモメチルジメチルシリル−クロロベンゼン、３−クロロメチルジメチルシリルフラン、３−ブロモメチルジメチルシリルフラン等が例示される。
As the arylsilyl compound and the aromatic heterocyclic silyl compound represented by the formula (1), commercially available ones can be obtained or can be produced by a known method. For example, an arylsilylmethanol compound and an aromatic heterocyclic silylmethanol compound are usually obtained by acetoxylation of a halogen of a halogenomethyl (di-lower alkyl) silyl compound obtained by the method described in Japanese Patent Application No. 2007-154746, by a generally known method. It can manufacture by hydrolyzing by a well-known method.
Examples of the compound of the formula (1) include 3-hydroxymethyldimethylsilylbenzoic acid methyl ester, 4-hydroxymethyldimethylsilylbenzoic acid methyl ester, 3-bromo-5-hydroxymethyldimethylsilylbenzoic acid methyl ester, 4- (3 -Hydroxymethyldimethylsilyl-5-trimethylsilylbenzamide) benzoic acid, 4- (3,5-di-hydroxymethyldimethylsilylbenzamide) benzoic acid, 4- (3-hydroxymethyldimethylsilyl-5-tetrahydropyranoxymethyldimethyl) Silylbenzamide) benzoic acid, 4-hydroxymethyldimethylsilylanisole, 4-hydroxymethyldimethylsilyl-chlorobenzene, 1,4-bis (hydroxymethyldimethylsilyl) benzene, 2-hydroxymethyldimethylsilyl Thiophene, 3-hydroxymethyldimethylsilylfuran, 4-chloromethyldimethylsilylbenzoic acid methyl ester, 4-bromomethyldimethylsilylbenzoic acid methyl ester, 4-chloromethyldimethylsilylanisole, 4-bromomethyldimethylsilylanisole, 4- Examples include chloromethyldimethylsilyl-chlorobenzene, 4-bromomethyldimethylsilyl-chlorobenzene, 3-chloromethyldimethylsilylfuran, 3-bromomethyldimethylsilylfuran and the like.
式（１）で表されるアリールシリル化合物及び芳香族複素環シリル化合物に、必要により溶媒中で、酸化剤を作用させることにより、式（２）で表されるアリールシラノール化合物及び芳香族複素環シラノール化合物を得ることが出来る。 The arylsilanol compound and aromatic heterocycle represented by the formula (2) are allowed to act on the arylsilyl compound and aromatic heterocyclic silyl compound represented by the formula (1), if necessary, in a solvent. A silanol compound can be obtained.
酸化剤は、一般的にアルコール類をアルデヒド類、ケトン類、カルボン酸類に酸化する酸化剤が使用できるが、三酸化硫黄ピリジン錯体；Ｎ，Ｎ−ジメチルスルホキシド（ＤＭＳＯ）／オキザリクロライド／トリエチルアミン；次亜塩素酸ナトリウム／２,２,６,６―テトラメチルピペリジン−Ｎ−オキシド（ＴＥＭＰＯ）；クロロクロム酸ピリジニウム；二クロム酸ピリジニウム；トリメチルアミンＮ−オキシド（ＴＭＡＮＯ）、モルフォリンＮ−オキシド等のアミンＮ−オキシドが例示される。Ｘが水酸基の場合には、好ましくは次亜塩素酸ナトリウム／ＴＥＭＰＯ、三酸化硫黄ピリジン錯体であり、より好ましくはコスト、環境への配慮から次亜塩素酸ナトリウム／ＴＥＭＰＯである。Ｘがハロゲン原子の場合には、ＴＭＡＮＯ、モルフォリンＮ−オキシド等のアミンＮ−オキシドであり、より好ましくはコスト、環境への配慮からＴＭＡＮＯである。酸化剤の等量数は０.８等量〜１０等量であり、好ましくは１.０等量〜４.０等量である。反応溶媒は、反応に影響を及ぼさず、通常用いられる溶媒であれば特に制限はないが、酸化剤として次亜塩素酸ナトリウム／ＴＥＭＰＯを用いる場合にはアセトン、塩化メチレンが例示され、好ましくはアセトンである。酸化剤としてトリメチルアミンＮ−オキシド、モルフォリンＮ−オキシド等のアミンＮ−オキシドを用いる場合にはジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリル等が例示され、好ましくはジメチルスルホキシドである。反応時間は５分〜２４時間であり、好ましくは１０分〜１８時間である。反応温度は０℃〜７０℃であり、好ましくは５℃〜６０℃である。反応後の後処理としては通常知られた方法で行うが、例えば、濃縮後、酢酸エチル、ジクロルメタン等の有機溶媒で抽出し、硫酸ナトリウム、硫酸マグネシウム等で乾燥後、濃縮して目的物の式（２）で表されるアリールシラノール化合物及び芳香族複素環シラノール化合物が得られる。得られた化合物は必要に応じて通常の方法で精製してもよく、精製方法としては再結晶、カラムクロマトグラフィーが例示される。 As the oxidizing agent, an oxidizing agent that generally oxidizes alcohols to aldehydes, ketones, and carboxylic acids can be used. However, sulfur trioxide pyridine complex; N, N-dimethylsulfoxide (DMSO) / oxalichloride / triethylamine; Sodium hypochlorite / 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO); pyridinium chlorochromate; pyridinium dichromate; trimethylamine N-oxide (TMANO), morpholine N-oxide, etc. Amine N-oxide is exemplified. When X is a hydroxyl group, sodium hypochlorite / TEMPO or sulfur trioxide pyridine complex is preferable, and sodium hypochlorite / TEMPO is more preferable in consideration of cost and environment. When X is a halogen atom, it is an amine N-oxide such as TMANO or morpholine N-oxide, and more preferably TMANO in consideration of cost and environment. The equivalent number of the oxidizing agent is 0.8 equivalents to 10 equivalents, preferably 1.0 equivalents to 4.0 equivalents. The reaction solvent does not affect the reaction and is not particularly limited as long as it is a commonly used solvent. However, when sodium hypochlorite / TEMPO is used as the oxidizing agent, acetone and methylene chloride are exemplified, and preferably acetone. It is. When amine N-oxides such as trimethylamine N-oxide and morpholine N-oxide are used as the oxidizing agent, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile and the like are exemplified, and dimethyl sulfoxide is preferred. The reaction time is 5 minutes to 24 hours, preferably 10 minutes to 18 hours. The reaction temperature is 0 ° C to 70 ° C, preferably 5 ° C to 60 ° C. The post-treatment after the reaction is carried out by a generally known method. For example, after concentration, the mixture is extracted with an organic solvent such as ethyl acetate or dichloromethane, dried over sodium sulfate, magnesium sulfate or the like, and then concentrated to obtain the formula of the target product. The arylsilanol compound and aromatic heterocyclic silanol compound represented by (2) are obtained. The obtained compound may be purified by a conventional method as necessary, and examples of the purification method include recrystallization and column chromatography.
以下、実施例を挙げて本発明を具体的に説明するが、本発明は実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to an Example.
実施例１
３−クロロメチルジメチルシリル安息香酸（１ａ）の合成
アルゴン気流下、３−ブロモ安息香酸５.０ｇ（２４.９ｍｍｏｌ）を乾燥テトラヒドロフラン２５０ｍＬに溶解し、−１５℃で１ｍｏｌ／Ｌのジブチルマグネシウムヘプタン溶液１３.７ｍＬを滴下した。同温で２０分撹拌後、−３０℃で１.５８ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液１７.３ｍＬを徐々に滴下し、同温で３０分撹拌後、クロロメチルジメチルシリルクロリド３.９３ｍＬを滴下した。−３０℃で３０分撹拌後、室温で終夜撹拌した。次に氷冷下に飽和塩化アンモニウム水溶液１０ｍＬでクエンチし反応液を濃縮した。残渣に水３００ｍＬを加え、２Ｎ塩酸で水層のｐＨを２〜３とした後、酢酸エチル（３００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物を７.１８ｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２０：８０で溶出）で精製し、白色固体の表題化合物１.１９ｇ（収率：２１％）を得た。融点：９９〜１００℃
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
１０.７１（１Ｈ、ｂｒｓ）、８.２９（１Ｈ、ｓ）、８.１５（１Ｈ、ｄ、Ｊ＝７.７Ｈｚ）、７.８０（１Ｈ、ｄ、Ｊ＝７.２Ｈｚ）、７.５０（１Ｈ、ｄｄ、Ｊ＝７.７Ｈｚ、Ｊ＝７.２Ｈｚ）、２.９８（２Ｈ、ｓ）、０.４７（６Ｈ、ｓ）
ＦＡＢＭＳ：２２７（Ｍ−Ｈ）
Example 1
Synthesis of 3-chloromethyldimethylsilylbenzoic acid (1a) Under an argon stream, 5.0 g (24.9 mmol) of 3-bromobenzoic acid was dissolved in 250 mL of dry tetrahydrofuran, and a 1 mol / L dibutylmagnesium heptane solution at −15 ° C. 13.7 mL was added dropwise. After stirring for 20 minutes at the same temperature, 17.3 mL of a 1.58 mol / L n-butyllithium hexane solution was gradually added dropwise at −30 ° C., and after stirring for 30 minutes at the same temperature, 3.93 mL of chloromethyldimethylsilyl chloride was added. It was dripped. After stirring at −30 ° C. for 30 minutes, the mixture was stirred at room temperature overnight. Next, the reaction solution was concentrated by quenching with 10 mL of saturated aqueous ammonium chloride solution under ice-cooling. 300 mL of water was added to the residue, and the pH of the aqueous layer was adjusted to 2 to 3 with 2N hydrochloric acid, followed by extraction with ethyl acetate (300 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 7.18 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 20: 80) gave 1.19 g (yield: 21%) of the title compound as a white solid. Melting point: 99-100 ° C
1 H-NMR (CDCl 3 , δ ppm):
10.71 (1H, brs), 8.29 (1H, s), 8.15 (1H, d, J = 7.7 Hz), 7.80 (1H, d, J = 7.2 Hz), 7. 50 (1H, dd, J = 7.7 Hz, J = 7.2 Hz), 2.98 (2H, s), 0.47 (6H, s)
FABMS: 227 (M-H)
３−クロロメチルジメチルシリル安息香酸メチルエステル（１ｂ）の合成
化合物（１ａ）９７３ｍｇをメタノール１０ｍＬ、トルエン４０ｍＬに溶解し、室温で２ｍｏｌ／Ｌのトリメチルシリルジアゾメタンヘキサン溶液３.１９ｍＬを加え１５分撹拌した。次に反応系の色が消失するまで酢酸を加え、溶媒を留去し粗生成物を１.１２ｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１０：９０で溶出）で精製し、無色油状の表題化合物９４８ｍｇ（収率：９２％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２０（１Ｈ、ｓ）、８.０７（１Ｈ、ｄ、Ｊ＝７.７Ｈｚ）、７.７４（１Ｈ、ｄ、Ｊ＝７.２Ｈｚ）、７.４６（１Ｈ、ｄｄ、Ｊ＝７.７Ｈｚ、Ｊ＝７.２Ｈｚ）、３.９３（３Ｈ、ｓ）、２.９７（２Ｈ、ｓ）、０.４５（６Ｈ、ｓ）
ＦＡＢＭＳ：２４３（Ｍ＋Ｈ）
Synthesis of 3-chloromethyldimethylsilylbenzoic acid methyl ester (1b) 973 mg of compound (1a) was dissolved in 10 mL of methanol and 40 mL of toluene, and 3.19 mL of a 2 mol / L trimethylsilyldiazomethanehexane solution was added at room temperature and stirred for 15 minutes. Next, acetic acid was added until the color of the reaction system disappeared, and the solvent was distilled off to obtain 1.12 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 10: 90) gave 948 mg (yield: 92%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.20 (1H, s), 8.07 (1H, d, J = 7.7 Hz), 7.74 (1H, d, J = 7.2 Hz), 7.46 (1H, dd, J = 7) 0.7 Hz, J = 7.2 Hz), 3.93 (3H, s), 2.97 (2H, s), 0.45 (6H, s)
FABMS: 243 (M + H)
３−アセトキシメチルジメチルシリル安息香酸メチルエステル（１ｃ）の合成
化合物（１ｂ）８８２ｍｇをジメチルホルムアミド１８ｍＬに溶解し、酢酸カリウム１.４３ｇを加え７０℃で４時間撹拌した。次に水６０ｍＬを加え、酢酸エチル：ヘキサン＝１：２混合溶媒（６０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物９３４ｍｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１０：９０で溶出）で精製し、無色油状の表題化合物７９８ｍｇ（収率：８２％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２１（１Ｈ、ｓ）、８.０６（１Ｈ、ｄ、Ｊ＝７.７Ｈｚ）、７.７２（１Ｈ、ｄ、Ｊ＝７.２Ｈｚ）、７.４５（１Ｈ、ｄｄ、Ｊ＝７.７Ｈｚ、Ｊ＝７.２Ｈｚ）、３.９７（３Ｈ、ｓ）、３.９３（２Ｈ、ｓ）、０.３９（６Ｈ、ｓ）
ＦＡＢＭＳ：２６７（Ｍ＋Ｈ）
Synthesis of 3-acetoxymethyldimethylsilylbenzoic acid methyl ester (1c) Compound (1b) (882 mg) was dissolved in dimethylformamide (18 mL), potassium acetate (1.43 g) was added, and the mixture was stirred at 70 ° C. for 4 hours. Next, 60 mL of water was added, and the mixture was extracted with a mixed solvent of ethyl acetate: hexane = 1: 2 (60 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 934 mg of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 10: 90) gave 798 mg (yield: 82%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.21 (1H, s), 8.06 (1H, d, J = 7.7 Hz), 7.72 (1H, d, J = 7.2 Hz), 7.45 (1H, dd, J = 7) 0.7 Hz, J = 7.2 Hz), 3.97 (3H, s), 3.93 (2H, s), 0.39 (6H, s)
FABMS: 267 (M + H)
３−ヒドロキシメチルジメチルシリル安息香酸メチルエステル（１ｄ）の合成
化合物（１ｃ）７７４ｍｇをメタノール１４ｍＬに溶解し、炭酸カリウム４０２ｍｇを加え室温で３時間撹拌した。次に水５０ｍＬを加え、酢酸エチル（５０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物を６３８ｍｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１６：８４で溶出）で精製し、無色油状の表題化合物５５３ｍｇ（収率：８５％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２３（１Ｈ、ｓ）、８.０５（１Ｈ、ｄ、Ｊ＝７.７Ｈｚ）、７.７６（１Ｈ、ｄ、Ｊ＝７.２Ｈｚ）、７.４５（１Ｈ、ｄｄ、Ｊ＝７.７Ｈｚ、Ｊ＝７.２Ｈｚ）、３.９２（３Ｈ、ｓ）、３.６１（２Ｈ、ｓ）、１.１０（１Ｈ、ｂｒｓ）、０.３９（６Ｈ、ｓ）
ＦＡＢＭＳ：２２５（Ｍ＋Ｈ）
Synthesis of 3-hydroxymethyldimethylsilylbenzoic acid methyl ester (1d) Compound (1c) (774 mg) was dissolved in methanol (14 mL), potassium carbonate (402 mg) was added, and the mixture was stirred at room temperature for 3 hr. Next, 50 mL of water was added and extracted with ethyl acetate (50 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 638 mg of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 16: 84) gave 553 mg (yield: 85%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.23 (1H, s), 8.05 (1H, d, J = 7.7 Hz), 7.76 (1H, d, J = 7.2 Hz), 7.45 (1H, dd, J = 7) 0.7 Hz, J = 7.2 Hz), 3.92 (3H, s), 3.61 (2H, s), 1.10 (1H, brs), 0.39 (6H, s)
FABMS: 225 (M + H)
３−ヒドロキシジメチルシリル安息香酸メチルエステル（１）の合成
化合物（１ｄ）３６４ｍｇをアセトン１０.８ｍＬに溶解し、氷冷下２,２,６,６−テトラメチルピペリジン−Ｎ−オキシド（以下ＴＥＭＰＯと略す）２５.３ｍｇ、臭化カリウム１９.３ｍｇを加え、５％次亜塩素酸ナトリウム４.８２ｇを０.５ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液１０.８ｍＬに溶解した溶液を順次加え室温で１時間撹拌した。次に飽和塩化アンモニウム水溶液１０.８ｍＬを加え、酢酸エチル（３０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物を３６６ｍｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：３で溶出）で精製し、無色油状の表題化合物３００ｍｇ（収率：８８％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２４（１Ｈ、ｓ）、８.０３（１Ｈ、ｄ、Ｊ＝７.７Ｈｚ）、７.７７（１Ｈ、ｄ、Ｊ＝７.４Ｈｚ）、７.４３（１Ｈ、ｄｄ、Ｊ＝７.７Ｈｚ、Ｊ＝７.４Ｈｚ）、３.９１（３Ｈ、ｓ）、２.６３（１Ｈ、ｂｒｓ）、０.４２（６Ｈ、ｓ）
ＦＡＢＭＳ：２１１（Ｍ＋Ｈ）
Synthesis of 3-hydroxydimethylsilylbenzoic acid methyl ester (1) 364 mg of compound (1d) was dissolved in 10.8 mL of acetone, and 2,2,6,6-tetramethylpiperidine-N-oxide (hereinafter referred to as TEMPO) was cooled with ice. Abbreviated) 25.3 mg and 19.3 mg of potassium bromide were added, and a solution prepared by dissolving 4.82 g of 5% sodium hypochlorite in 10.8 mL of a 0.5 mol / L aqueous sodium hydrogen carbonate solution was sequentially added and stirred at room temperature for 1 hour did. Next, 10.8 mL of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (30 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 366 mg of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 1: 3) gave 300 mg (yield: 88%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.24 (1H, s), 8.03 (1H, d, J = 7.7 Hz), 7.77 (1H, d, J = 7.4 Hz), 7.43 (1H, dd, J = 7 0.7 Hz, J = 7.4 Hz), 3.91 (3H, s), 2.63 (1H, brs), 0.42 (6H, s)
FABMS: 211 (M + H)
実施例２
４−クロロメチルジメチルシリル安息香酸（２ａ）の合成
４−ブロモ安息香酸５.０ｇを用いて化合物（１ａ）と同様の方法でリチウム化後、クロロメチルジメチルシリルクロリド７.５４ｍＬを反応させ、同様の処理により無色油状の表題化合物４.９２ｇ（収率：８６％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.１０（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、７.６７（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、２.９７（２Ｈ、ｓ）、０.４８（６Ｈ、ｓ）
ＦＡＢＭＳ：２２７（Ｍ−Ｈ）
Example 2
Synthesis of 4-chloromethyldimethylsilylbenzoic acid (2a) After lithiation in the same manner as compound (1a) using 5.0 g of 4-bromobenzoic acid, 7.54 mL of chloromethyldimethylsilyl chloride was reacted, and the same As a result, 4.92 g (yield: 86%) of the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.10 (2H, d, J = 7.9 Hz), 7.67 (2H, d, J = 7.9 Hz), 2.97 (2H, s), 0.48 (6H, s)
FABMS: 227 (M-H)
４−クロロメチルジメチルシリル安息香酸メチルエステル（２ｂ）の合成
化合物（２ａ）１.９４ｇを用いて化合物（１ｂ）と同様の反応を実施し、無色油状の表題化合物１.３３ｇ（収率：６５％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.０２（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、７.６２（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、３.９２（３Ｈ、ｓ）、２.９６（２Ｈ、ｓ）、０.４４（６Ｈ、ｓ）
ＦＡＢＭＳ：２４３（Ｍ＋Ｈ）
Synthesis of 4-chloromethyldimethylsilylbenzoic acid methyl ester (2b) Using 1.94 g of compound (2a), a reaction similar to that of compound (1b) was carried out to give 1.33 g of the title compound as a colorless oil (yield: 65 %).
1 H-NMR (CDCl 3 , δ ppm):
8.02 (2H, d, J = 7.9 Hz), 7.62 (2H, d, J = 7.9 Hz), 3.92 (3H, s), 2.96 (2H, s), 0.8 44 (6H, s)
FABMS: 243 (M + H)
４−アセトキシメチルジメチルシリル安息香酸メチルエステル（２ｃ）の合成
化合物（２ｂ）１.２４ｇを用いて化合物（１ｃ）と同様の反応を実施し、無色油状の表題化合物１.２０ｇ（収率：８８％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.０１（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、７.６１（２Ｈ、ｄ、Ｊ＝７.１Ｈｚ）、３.９７（２Ｈ、ｓ）、３.９２（３Ｈ、ｓ）、２.０２（３Ｈ、ｓ）、０.３８（６Ｈ、ｓ）
ＦＡＢＭＳ：２６５（Ｍ−Ｈ）
Synthesis of 4-acetoxymethyldimethylsilylbenzoic acid methyl ester (2c) Using 1.24 g of compound (2b), a reaction similar to that of compound (1c) was carried out to give 1.20 g of the title compound as a colorless oil (yield: 88 %).
1 H-NMR (CDCl 3 , δ ppm):
8.01 (2H, d, J = 8.1 Hz), 7.61 (2H, d, J = 7.1 Hz), 3.97 (2H, s), 3.92 (3H, s), 2. 02 (3H, s), 0.38 (6H, s)
FABMS: 265 (M-H)
４−ヒドロキシメチルジメチルシリル安息香酸メチルエステル（２ｄ）の合成
化合物（２ｃ）１.０６ｇを用いて化合物（１ｄ）と同様の反応を実施し、無色油状の表題化合物７４６ｍｇ（収率：８４％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.０１（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、７.６４（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、３.９１（３Ｈ、ｓ）、３.５９（２Ｈ、ｓ）、１.３５（１Ｈ、ｂｒｓ）、０.３７（６Ｈ、ｓ）
ＦＡＢＭＳ：２２５（Ｍ＋Ｈ）
Synthesis of 4-hydroxymethyldimethylsilylbenzoic acid methyl ester (2d) Using 1.06 g of compound (2c), a reaction similar to that of compound (1d) was carried out to give 746 mg (yield: 84%) of the title compound as a colorless oil. Got.
1 H-NMR (CDCl 3 , δ ppm):
8.01 (2H, d, J = 7.9 Hz), 7.64 (2H, d, J = 7.9 Hz), 3.91 (3H, s), 3.59 (2H, s), 1. 35 (1H, brs), 0.37 (6H, s)
FABMS: 225 (M + H)
４−ヒドロキシジメチルシリル安息香酸メチルエステル（２）の合成
化合物（２ｄ）３００ｍｇを用いて化合物（１）と同様の反応を実施し、無色油状の表題化合物２３２ｍｇ（収率：８２％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.９６（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、７.６３（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、３.８９（３Ｈ、ｓ）、３.００（１Ｈ、ｂｒｓ）、０.３９（６Ｈ、ｓ）
ＦＡＢＭＳ：２１１（Ｍ＋Ｈ）
Synthesis of 4-hydroxydimethylsilylbenzoic acid methyl ester (2) Using 300 mg of compound (2d), a reaction similar to that of compound (1) was carried out to obtain 232 mg (yield: 82%) of the title compound as a colorless oil. .
1 H-NMR (CDCl 3 , δ ppm):
7.96 (2H, d, J = 7.9 Hz), 7.63 (2H, d, J = 7.9 Hz), 3.89 (3H, s), 3.00 (1H, brs), 0.8. 39 (6H, s)
FABMS: 211 (M + H)
実施例３
３−ブロモ−５−クロロメチルジメチルシリル安息香酸（３ａ）の合成
アルゴン気流下、３,５−ジブロモ安息香酸２１.３ｇを乾燥テトラヒドロフラン３００ｍＬに溶解し、−１５℃で１ｍｏｌ／Ｌのジブチルマグネシウムヘプタン溶液４１.８ｍＬを滴下した。同温で４０分撹拌後、−３０℃で１.５８ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液５３ｍＬを徐々に滴下し、同温で１時間撹拌後、クロロメチルジメチルシリルクロリド２３ｍＬを滴下した。−３０℃で３０分撹拌後、室温で４時間撹拌した。次に氷冷下に飽和塩化アンモニウム水溶液でクエンチ後、反応液を濃縮した。残渣に飽和塩化アンモニウム水溶液８００ｍＬを加え酢酸エチル（１０００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物３３.４９ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１６：８４で溶出）で精製し、表題化合物１２.１ｇ（収率：５１％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２６（１Ｈ、ｄｄ、Ｊ＝１.７Ｈｚ Ｊ＝１.７Ｈｚ）、８.１８（１Ｈ、ｄｄ、Ｊ＝１.７Ｈｚ Ｊ＝１.７Ｈｚ）、７.８８（１Ｈ、ｍ）、２.９７（２Ｈ、ｓ）、０.４７（６Ｈ、ｓ）
Example 3
Synthesis of 3-bromo-5-chloromethyldimethylsilylbenzoic acid (3a) In an argon stream, 21.3 g of 3,5-dibromobenzoic acid was dissolved in 300 mL of dry tetrahydrofuran, and 1 mol / L dibutylmagnesium heptane at -15 ° C. 41.8 mL of the solution was added dropwise. After stirring at the same temperature for 40 minutes, 53 mL of a 1.58 mol / L n-butyllithium hexane solution was gradually added dropwise at −30 ° C., and after stirring at the same temperature for 1 hour, 23 mL of chloromethyldimethylsilyl chloride was added dropwise. After stirring at −30 ° C. for 30 minutes, the mixture was stirred at room temperature for 4 hours. Next, after quenching with a saturated aqueous solution of ammonium chloride under ice cooling, the reaction solution was concentrated. To the residue was added 800 mL of saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (1000 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 33.49 g of a crude product. Purification by silica gel column chromatography (eluted with ethyl acetate: hexane = 16: 84) gave 12.1 g (yield: 51%) of the title compound.
1 H-NMR (CDCl 3 , δ ppm):
8.26 (1H, dd, J = 1.7 Hz J = 1.7 Hz), 8.18 (1H, dd, J = 1.7 Hz J = 1.7 Hz), 7.88 (1H, m), 2 .97 (2H, s), 0.47 (6H, s)
３−ブロモ−５−クロロメチルジメチルシリル安息香酸メチルエステル（３ｂ）の合成
化合物（３ａ）８.９０ｇをメタノール３０ｍＬ、トルエン１２０ｍＬに溶解し、氷冷下に２ｍｏｌ／Ｌのトリメチルシリルジアゾメタンヘキサン溶液２５ｍＬを加え、同温で３０分、室温で３０分撹拌した。次に反応系の色が消失するまで酢酸を加え溶媒を留去し粗生成物８.６１ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２０で溶出）で精製し、無色油状の表題化合物７.４６ｇ（収率：８０％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.１９（１Ｈ、ｓ）、８.１０（１Ｈ、ｓ）、７.８１（１Ｈ、ｓ）、３.９４（３Ｈ、ｓ）、２.９６（２Ｈ、ｓ）、０.４６（６Ｈ、ｓ）
Synthesis of 3-bromo-5-chloromethyldimethylsilylbenzoic acid methyl ester (3b) 8.90 g of the compound (3a) was dissolved in 30 mL of methanol and 120 mL of toluene, and 25 mL of a 2 mol / L trimethylsilyldiazomethanehexane solution was added under ice cooling. In addition, the mixture was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. Next, acetic acid was added until the color of the reaction system disappeared, and the solvent was distilled off to obtain 8.61 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 1: 20) gave 7.46 g (yield: 80%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.19 (1H, s), 8.10 (1H, s), 7.81 (1H, s), 3.94 (3H, s), 2.96 (2H, s), 0.46 (6H) , S)
３−ブロモ−５−アセトキシメチルジメチルシリル安息香酸メチルエステル（３ｃ）の合成
化合物（３ｂ）７.４４ｇをジメチルホルムアミド１２０ｍＬに溶解し、酢酸カリウム９.０８ｇ）を加え、９０℃で３時間撹拌した。次に水１２０ｍＬを加え、酢酸エチル：ヘキサン＝１：２混合溶媒（１５０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物７.３２ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：８で溶出）で精製し、淡黄色油状の表題化合物４.６８ｇ（収率：５９％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.１８（１Ｈ、ｓ）、８.１０（１Ｈ、ｓ）、７.８０（１Ｈ、ｓ）、３.９５（２Ｈ、ｓ）、３.９３（３Ｈ、ｓ）、２.０４（３Ｈ、ｓ）、０.３９（６Ｈ、ｓ）
Synthesis of 3-bromo-5-acetoxymethyldimethylsilylbenzoic acid methyl ester (3c) Compound (3b) (7.44 g) was dissolved in dimethylformamide (120 mL), potassium acetate (9.08 g) was added, and the mixture was stirred at 90 ° C. for 3 hours. . Next, 120 mL of water was added, and the mixture was extracted with a mixed solvent of ethyl acetate: hexane = 1: 2 (150 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 7.32 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 1: 8) gave 4.68 g (yield: 59%) of the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 , δ ppm):
8.18 (1H, s), 8.10 (1H, s), 7.80 (1H, s), 3.95 (2H, s), 3.93 (3H, s), 2.04 (3H) , S), 0.39 (6H, s)
３−ブロモ−５−ヒドロキシメチルジメチルシリル安息香酸メチルエステル（３ｄ）の合成
化合物（３ｃ）４.６６ｇをメタノール９０ｍＬに溶解し、炭酸カリウム２.０５ｇを加え、室温で３.５時間撹拌した。次に水１５０ｍＬを加え、酢酸エチル（１５０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物３.３０ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：８で溶出）で精製し、無色油状の表題化合物２.０９ｇ（収率：５１％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.１７（１Ｈ、ｓ）、８.１３（１Ｈ、ｓ）、７.８５（１Ｈ、ｓ）、３.９３（３Ｈ、ｓ）、３.６２（２Ｈ、ｄ、Ｊ＝４.６Ｈｚ）０.９７（１Ｈ、ｔ、Ｊ＝４.３Ｈｚ）、０.３８（６Ｈ、ｓ）
Synthesis of 3-bromo-5-hydroxymethyldimethylsilylbenzoic acid methyl ester (3d) 4.66 g of compound (3c) was dissolved in 90 mL of methanol, 2.05 g of potassium carbonate was added, and the mixture was stirred at room temperature for 3.5 hours. Next, 150 mL of water was added and extracted with ethyl acetate (150 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 3.30 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 1: 8) gave 2.09 g (yield: 51%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.17 (1H, s), 8.13 (1H, s), 7.85 (1H, s), 3.93 (3H, s), 3.62 (2H, d, J = 4.6 Hz) 0.97 (1H, t, J = 4.3 Hz), 0.38 (6H, s)
３−ブロモ−５−ヒドロキシジメチルシリル安息香酸メチルエステル（３）の合成
化合物（３ｄ）３０２ｍｇをアセトン６.６ｍＬに溶解し、氷冷下ＴＥＭＰＯ１５.６ｍｇ、臭化カリウム１１.９ｍｇを加え、５％次亜塩素酸ナトリウム２.９７ｇを０.５ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液６.６ｍＬに溶解した溶液を順次加え、室温で１時間撹拌した。次に飽和塩化アンモニウム水溶液６.６ｍＬを加え、酢酸エチル（３０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物２５９ｍｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４で溶出）で精製し、無色油状の表題化合物２１２ｍｇ（収率：７４％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.１７（１Ｈ、ｓ）、８.１５（１Ｈ、ｓ）、７.８７（１Ｈ、ｓ）、３.９３（３Ｈ、ｓ）、２.１３（１Ｈ、ｂｒｓ）、０.４３（６Ｈ、ｓ）
Synthesis of 3-bromo-5-hydroxydimethylsilylbenzoic acid methyl ester (3) 302 mg of compound (3d) was dissolved in 6.6 mL of acetone, and 15.6 mg of TEMPO and 11.9 mg of potassium bromide were added under ice cooling to add 5% A solution prepared by dissolving 2.97 g of sodium hypochlorite in 6.6 mL of a 0.5 mol / L aqueous sodium hydrogen carbonate solution was sequentially added, and the mixture was stirred at room temperature for 1 hour. Next, 6.6 mL of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (30 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 259 mg of a crude product. Purification by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 4) gave 212 mg (yield: 74%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.17 (1H, s), 8.15 (1H, s), 7.87 (1H, s), 3.93 (3H, s), 2.13 (1H, brs), 0.43 (6H , S)
実施例４
３―クロロメチルジメチルシリル−５−トリメチルシリル安息香酸（４ａ）の合成
アルゴン気流下、化合物（３ａ）１２.１ｇを乾燥テトラヒドロフラン２０ｍＬに溶解し、−１５℃で１ｍｏｌ／Ｌのジブチルマグネシウムヘプタン溶液２１.６ｍＬを滴下した。同温で４０分撹拌後、−３０℃で１.５８ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液２７.４ｍＬを徐々に滴下し、同温で１時間撹拌後、トリメチルシリルブロミド１１.９ｍＬを滴下した。同温で３０分撹拌後、室温で終夜撹拌した。次に氷冷下に飽和塩化アンモニウム水溶液でクエンチ後反応液を濃縮した。残渣に飽和塩化アンモニウム水溶液３４０ｍＬを加え酢酸エチル（８００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し表題化合物１０.２ｇ（収率：８６％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２８（１Ｈ、ｄｄ、Ｊ＝１.６Ｈｚ Ｊ＝１.６Ｈｚ）、８.２４（１Ｈ、ｄｄ、Ｊ＝１.６Ｈｚ、Ｊ＝１.６Ｈｚ）、７.９１（１Ｈ、ｄｄ、Ｊ＝１.６Ｈｚ、Ｊ＝１.６Ｈｚ）、２.９９（２Ｈ、ｓ）、０.４７（６Ｈ、ｓ）、０.３２（９Ｈ、ｓ）
Example 4
Synthesis of 3-chloromethyldimethylsilyl-5-trimethylsilylbenzoic acid (4a) In an argon stream, 12.1 g of compound (3a) was dissolved in 20 mL of dry tetrahydrofuran, and a 1 mol / L dibutylmagnesium heptane solution at -15 ° C. 21. 6 mL was added dropwise. After stirring for 40 minutes at the same temperature, 27.4 mL of a 1.58 mol / L n-butyllithium hexane solution was gradually added dropwise at −30 ° C., and after stirring for 1 hour at the same temperature, 11.9 mL of trimethylsilyl bromide was added dropwise. After stirring at the same temperature for 30 minutes, the mixture was stirred at room temperature overnight. Next, after quenching with a saturated aqueous solution of ammonium chloride under ice cooling, the reaction solution was concentrated. To the residue was added 340 mL of saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (800 mL × 3). After drying over sodium sulfate, the solvent was distilled off to obtain 10.2 g (yield: 86%) of the title compound.
1 H-NMR (CDCl 3 , δ ppm):
8.28 (1H, dd, J = 1.6 Hz J = 1.6 Hz), 8.24 (1H, dd, J = 1.6 Hz, J = 1.6 Hz), 7.91 (1H, dd, J = 1.6 Hz, J = 1.6 Hz), 2.99 (2H, s), 0.47 (6H, s), 0.32 (9H, s)
４−（３−クロロメチルジメチルシリル−５−トリメチルシリルベンズアミド）安息香酸エチルエステル（４ｂ）の合成
化合物（４ａ）１０.２ｇをアセトニトリル１７０ｍＬに溶解し、ｐ−アミノ安息香酸エチルエステル６.７２ｇ、ピリジン２.７３ｍＬ、オキシ塩化リン１.６３ｍＬを加えて２時間還流した。冷後、水３００ｍＬを加え酢酸エチル（３００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：９で溶出）で精製し、白色固体の表題化合物５.８９ｇ（収率：３９％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.０６（２Ｈ、ｄ、Ｊ＝８.７Ｈｚ）、７.９９―８.００（３Ｈ、ｍ）７.８６（１Ｈ、ｄｄ、Ｊ＝１.０Ｈｚ、Ｊ＝１.０Ｈｚ）、７.７５（２Ｈ、ｄ、Ｊ＝８.７Ｈｚ）、４.３８（２Ｈ、ｑ、Ｊ＝７.３Ｈｚ）、２.９９（２Ｈ、ｓ）、１.４０（３Ｈ、ｔ、Ｊ＝７.３Ｈｚ）０.４７（６Ｈ、ｓ）、０.３２（９Ｈ、ｓ）
Synthesis of 4- (3-chloromethyldimethylsilyl-5-trimethylsilylbenzamide) benzoic acid ethyl ester (4b) 10.2 g of compound (4a) was dissolved in 170 mL of acetonitrile, and 6.72 g of p-aminobenzoic acid ethyl ester was added to pyridine. 2.73 mL and 1.63 mL of phosphorus oxychloride were added and refluxed for 2 hours. After cooling, 300 mL of water was added and extracted with ethyl acetate (300 mL × 3). After drying over sodium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 9) to give 5.89 g of the title compound as a white solid (yield: 39%) )
1 H-NMR (CDCl 3 , δ ppm):
8.06 (2H, d, J = 8.7 Hz), 7.9-8.00 (3H, m) 7.86 (1H, dd, J = 1.0 Hz, J = 1.0 Hz), 7. 75 (2H, d, J = 8.7 Hz), 4.38 (2H, q, J = 7.3 Hz), 2.99 (2H, s), 1.40 (3H, t, J = 7.3 Hz) ) 0.47 (6H, s), 0.32 (9H, s)
４−（３−アセトキシメチルジメチルシリル−５−トリメチルシリルベンズアミド）安息香酸エチルエステル（４ｃ）の合成
化合物（４ｂ）５.８６ｇをジメチルホルムアミド２００ｍＬに溶解し、酢酸カリウム５.１３ｇを加えて、７０℃で５時間撹拌した。冷後、水３００ｍＬを加え、酢酸エチル：ヘキサン＝１：２（３００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２：８で溶出）で精製し、白色固体の表題化合物４.８２ｇ（収率：７８％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.１３（１Ｈ、ｂｒｓ）、８.０８（２Ｈ、ｄ、Ｊ＝８.６Ｈｚ）、８.００―８.０２（２Ｈ、ｍ）、７.８４（１Ｈ、ｄｄ、Ｊ＝１.２Ｈｚ、Ｊ＝１.２Ｈｚ）、７.８０（２Ｈ、ｄ、Ｊ＝８.６Ｈｚ）、４.３８（２Ｈ、ｑ、Ｊ＝７.１Ｈｚ）、４.０９（２Ｈ、ｓ）、２.００（３Ｈ、ｓ）、１.４１（３Ｈ、ｔ、Ｊ＝７.１Ｈｚ）、０.４１（６Ｈ、ｓ）、０.３２（９Ｈ、ｓ）
Synthesis of 4- (3-acetoxymethyldimethylsilyl-5-trimethylsilylbenzamide) benzoic acid ethyl ester (4c) 5.86 g of compound (4b) was dissolved in 200 mL of dimethylformamide, and 5.13 g of potassium acetate was added thereto. For 5 hours. After cooling, 300 mL of water was added, and the mixture was extracted with ethyl acetate: hexane = 1: 2 (300 mL × 3). After drying over sodium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 2: 8) to give 4.82 g of the title compound as a white solid (yield: 78%). )
1 H-NMR (CDCl 3 , δ ppm):
8.13 (1H, brs), 8.08 (2H, d, J = 8.6 Hz), 8.00-8.02 (2H, m), 7.84 (1H, dd, J = 1.2 Hz) , J = 1.2 Hz), 7.80 (2H, d, J = 8.6 Hz), 4.38 (2H, q, J = 7.1 Hz), 4.09 (2H, s), 2.00 (3H, s), 1.41 (3H, t, J = 7.1 Hz), 0.41 (6H, s), 0.32 (9H, s)
４−（３−ヒドロキシメチルジメチルシリル−５−トリメチルシリルベンズアミド）安息香酸（４ｄ）の合成
化合物（４ｃ）４.８２ｇをメタノール２００ｍＬと水５０ｍＬの混液に溶解し、２Ｎ水酸化ナトリウム溶液１７.９ｍＬを加えて、５０℃で３時間撹拌した。冷後、メタノールを留去し後、２Ｎ塩酸１７.９ｍＬで中和し析出物を濾取した。メタノール／水から再結晶し白色固体の表題化合物２.５４ｇ（収率：６２％）を得た。融点：２１７〜２１８℃
1Ｈ−ＮＭＲ（ＤＭＳＯｄ６、δｐｐｍ）：
１２.７７（１Ｈ、ｂｒｓ）、１０.５１（１Ｈ、ｓ）、７.８８―８.０４（７Ｈ、ｍ）、４.１９（１Ｈ、ｂｒｓ）、３.４０（２Ｈ、ｓ）、０.３２（１５Ｈ、ｓ）
ＬＣ−ＭＳ：ｍ／ｚ＝４００（ネガチブ）
Synthesis of 4- (3-hydroxymethyldimethylsilyl-5-trimethylsilylbenzamide) benzoic acid (4d) 4.82 g of compound (4c) was dissolved in a mixture of 200 mL of methanol and 50 mL of water, and 17.9 mL of 2N sodium hydroxide solution was added. In addition, the mixture was stirred at 50 ° C. for 3 hours. After cooling, the methanol was distilled off, neutralized with 17.9 mL of 2N hydrochloric acid, and the precipitate was collected by filtration. Recrystallization from methanol / water gave 2.54 g (yield: 62%) of the title compound as a white solid. Melting point: 217-218 ° C
1 H-NMR (DMSOd 6 , δ ppm):
12.77 (1H, brs), 10.51 (1H, s), 7.88-8.04 (7H, m), 4.19 (1H, brs), 3.40 (2H, s), 0 .32 (15H, s)
LC-MS: m / z = 400 (negative)
４−（３−ヒドロキシジメチルシリル−５−トリメチルシリルベンズアミド）安息香酸（４）の合成
化合物（４ｄ）２００ｍｇをジメチルスルホキシド３ｍＬに溶解し、トリエチルアミン０.４５ｍＬ、三酸化硫黄ピリジン錯体２３８ｍｇを加えて、室温で３０分撹拌した。水４０ｍＬを加え、更に２Ｎ塩酸で反応液のｐＨを１〜２に調整後、酢酸エチル（４０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝４：６で溶出）で精製し、白色固体の表題化合物５２.５ｍｇ（収率：２６％）を得た。融点：１１０〜１１１℃
1Ｈ−ＮＭＲ（ＤＭＳＯｄ６、δｐｐｍ）：
１２.７５（１Ｈ、ｂｒｓ）１０.５３（１Ｈ、ｓ）、７.８５―８.０８（７Ｈ、ｍ）、６.０５（１Ｈ、ｂｒｓ）、０.３１（１５Ｈ、ｓ）
ＬＣ−ＭＳ：ｍ／ｚ＝３８６（ネガチブ）
Synthesis of 4- (3-hydroxydimethylsilyl-5-trimethylsilylbenzamide) benzoic acid (4) 200 mg of the compound (4d) was dissolved in 3 mL of dimethyl sulfoxide, 0.45 mL of triethylamine and 238 mg of sulfur trioxide pyridine complex were added, and For 30 minutes. 40 mL of water was added, and the pH of the reaction solution was adjusted to 1 to 2 with 2N hydrochloric acid, followed by extraction with ethyl acetate (40 mL × 3). After drying over sodium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 4: 6) to give 52.5 mg (yield: 26%) of the title compound as a white solid. ) Melting point: 110-111 ° C
1 H-NMR (DMSOd6, δ ppm):
12.75 (1H, brs) 10.53 (1H, s), 7.85-8.08 (7H, m), 6.05 (1H, brs), 0.31 (15H, s)
LC-MS: m / z = 386 (negative)
実施例５
４−（３−ヒドロキシジメチルシリル−５−トリメチルシリルベンズアミド）安息香酸（４）の合成
化合物（４ｄ）３００ｍｇをアセトン５ｍＬに溶解し、氷冷下ＴＥＭＰＯ１１.７ｍｇ、臭化カリウム８.９ｍｇ、５％次亜塩素酸２.２２ｇ／０.５ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液５ｍＬの混液を加えて、室温で１時間撹拌した。水４０ｍＬを加え更に２Ｎ塩酸で反応液のｐＨを４〜５に調整後、酢酸エチル（４０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１で溶出）で精製し、表題化合物２８８ｍｇ（収率：９９％）を得た。なお、物性値（1Ｈ−ＮＭＲ、ＬＣ−ＭＳ、融点）は実施例４に一致した。
Example 5
Synthesis of 4- (3-hydroxydimethylsilyl-5-trimethylsilylbenzamide) benzoic acid (4) 300 mg of the compound (4d) was dissolved in 5 mL of acetone, 11.7 mg of TEMPO, 8.9 mg of potassium bromide, 5% A mixture of 2.22 g of chlorous acid / 0.5 mol / L aqueous sodium hydrogen carbonate solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. 40 mL of water was added and the pH of the reaction solution was adjusted to 4-5 with 2N hydrochloric acid, followed by extraction with ethyl acetate (40 mL × 3). After drying with sodium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 1) to obtain 288 mg (yield: 99%) of the title compound. The physical property values ( 1 H-NMR, LC-MS, melting point) corresponded to those in Example 4.
実施例６
３,５−ジクロロメチルジメチルシリル安息香酸（６ａ）の合成
アルゴン気流下、化合物（３ａ）３.３ｇを乾燥テトラヒドロフラン６０ｍＬに溶解し、−１０℃で１ｍｏｌ／Ｌのジブチルマグネシウムヘプタン溶液５.５８ｍＬを滴下した。４０分撹拌後、−２０℃で１.５８ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液８.１４ｍＬを徐々に滴下し、同温で１時間撹拌後、クロロメチルジメチルシリルクロリド３.２４ｍＬを滴下した。−１５℃で３０分撹拌後、室温で終夜撹拌した。次に氷冷下に飽和塩化アンモニウム水溶液でクエンチ後、反応液を濃縮した。希塩酸で酸性とした後、酢酸エチル（５０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し表題化合物４.５３ｇを得た。精製する事なく次の反応に使用した。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.９２（２Ｈ、ｓ）、７.９６（１Ｈ、ｓ）、２.９８（４Ｈ、ｓ）、０.４７（１２Ｈ、ｓ）
Example 6
Synthesis of 3,5-dichloromethyldimethylsilylbenzoic acid (6a) In an argon stream, 3.3 g of compound (3a) was dissolved in 60 mL of dry tetrahydrofuran, and 5.58 mL of a 1 mol / L dibutylmagnesium heptane solution was added at −10 ° C. It was dripped. After stirring for 40 minutes, 8.14 mL of a 1.58 mol / L n-butyllithium hexane solution was gradually added dropwise at −20 ° C., and after stirring for 1 hour at the same temperature, 3.24 mL of chloromethyldimethylsilyl chloride was added dropwise. After stirring at −15 ° C. for 30 minutes, the mixture was stirred at room temperature overnight. Next, after quenching with a saturated aqueous solution of ammonium chloride under ice cooling, the reaction solution was concentrated. After acidifying with dilute hydrochloric acid, the mixture was extracted with ethyl acetate (50 mL × 3). After drying over sodium sulfate, the solvent was distilled off to obtain 4.53 g of the title compound. Used in the next reaction without purification.
1 H-NMR (CDCl 3 , δ ppm):
8.92 (2H, s), 7.96 (1H, s), 2.98 (4H, s), 0.47 (12H, s)
４−（３,５−ジクロロメチルジメチルシリルベンズアミド）安息香酸エチルエステル（６ｂ）の合成
化合物（６ａ）６.７２ｇ、ｐ−アミノ安息香酸エチルエステル３.２５ｇ、ピリジン１.４４ｍＬ、アセトニトリル１２０ｍＬの混液にオキシ塩化リン０.８６ｍＬを加えて１時間還流した。冷後、水５０ｍＬを加え酢酸エチル（７０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１６：８４で溶出）で精製し、アモルファスの表題化合物２.０９ｇ（収率：２２％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.０９（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、８.０３（２Ｈ、ｓ）、７.９１（１Ｈ、ｓ）、７.８８（１Ｈ、ｓ）、７.７４（２Ｈ、ｄ、Ｊ＝８.６Ｈｚ）、４.３９（２Ｈ、ｑ、Ｊ＝７.３Ｈｚ）、３.００（４Ｈ、ｓ）、１.４１（３Ｈ、ｔ、Ｊ＝７.１Ｈｚ）、０.４８（１２Ｈ、ｓ）
Synthesis of 4- (3,5-dichloromethyldimethylsilylbenzamide) benzoic acid ethyl ester (6b) Compound (6a) 6.72 g, p-aminobenzoic acid ethyl ester 3.25 g, pyridine 1.44 mL, acetonitrile 120 mL To the mixture, 0.86 mL of phosphorus oxychloride was added and refluxed for 1 hour. After cooling, 50 mL of water was added and extracted with ethyl acetate (70 mL × 3). After drying over sodium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 16: 84) to give 2.09 g (yield: 22%) of the amorphous title compound. Got.
1 H-NMR (CDCl 3 , δ ppm):
8.09 (2H, d, J = 8.4 Hz), 8.03 (2H, s), 7.91 (1H, s), 7.88 (1H, s), 7.74 (2H, d, J = 8.6 Hz), 4.39 (2H, q, J = 7.3 Hz), 3.00 (4H, s), 1.41 (3H, t, J = 7.1 Hz), 0.48 ( 12H, s)
４−（３,５−ジアセトキシメチルジメチルシリルベンズアミド）安息香酸エチルエステル（６ｃ）の合成
化合物（６ｂ）２.０８ｇをジメチルホルムアミド１００ｍＬに溶解し、酢酸カリウム２.９６ｇを加えて、１００℃で２.５時間撹拌した。冷後、水２００ｍＬを加え酢酸エチル：ヘキサン＝１：２（１００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１７：８３で溶出）で精製し、白色固体の表題化合物２.２３ｇ（収率：９８％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.３３（１Ｈ、ｓ）、８.００−８.０２（４Ｈ、ｍ）、７.８２−７.８６（３Ｈ、ｍ）、４.３８（２Ｈ、ｑ、Ｊ＝７.１Ｈｚ）、２.０１（４Ｈ、ｓ）、１.４１（３Ｈ、ｔ、Ｊ＝７.１Ｈｚ）、０.４１（６Ｈ、ｓ）、０.４１（１２Ｈ、ｓ）
Synthesis of 4- (3,5-diacetoxymethyldimethylsilylbenzamide) benzoic acid ethyl ester (6c) Compound (6b) (2.08 g) was dissolved in dimethylformamide (100 mL), and potassium acetate (2.96 g) was added. Stir for 2.5 hours. After cooling, 200 mL of water was added, and the mixture was extracted with ethyl acetate: hexane = 1: 2 (100 mL × 3). After drying over sodium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 17: 83) to give 2.23 g of the title compound as a white solid (yield: 98%). )
1 H-NMR (CDCl 3 , δ ppm):
8.33 (1H, s), 8.00-8.02 (4H, m), 7.82-7.86 (3H, m), 4.38 (2H, q, J = 7.1 Hz), 2.01 (4H, s), 1.41 (3H, t, J = 7.1 Hz), 0.41 (6H, s), 0.41 (12H, s)
４−（３,５−ジヒドロキシメチルジメチルシリルベンズアミド）安息香酸（６ｄ）の合成
化合物（６ｃ）２.２３ｇをメタノール５５ｍＬに溶解し、１Ｎ水酸化ナトリウム溶液２１ｍＬを加えて、室温で６時間撹拌した。更に１Ｎ水酸化ナトリウム溶液１２.６ｍＬを加えて５時間、室温で撹拌した。メタノールを留去した後、氷冷下に１Ｎ塩酸３３.６ｍＬで中和し析出物を濾取した。メタノール／水から再結晶後、シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９１：９で溶出）で精製し、白色固体の表題化合物７０６ｍｇ（収率：４０％）を得た。融点：２１７〜２２０℃
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
１２.７１（１Ｈ、ｂｒｓ）、１０.５０（１Ｈ、ｓ）、８.０５（２Ｈ、ｓ）、７.８６−７.９６（５Ｈ、ｍ）、４.１８（２Ｈ、ｓ）、３.４０（４Ｈ、ｓ）、０.３１（１２Ｈ、ｓ）
ＬＣ−ＭＳ：ｍ／ｚ＝４１８（ポジティブ）
Synthesis of 4- (3,5-dihydroxymethyldimethylsilylbenzamide) benzoic acid (6d) Compound (6c) (2.23 g) was dissolved in methanol (55 mL), 1N sodium hydroxide solution (21 mL) was added, and the mixture was stirred at room temperature for 6 hours. . Further, 12.6 mL of 1N sodium hydroxide solution was added and stirred at room temperature for 5 hours. After distilling off methanol, the mixture was neutralized with 33.6 mL of 1N hydrochloric acid under ice cooling, and the precipitate was collected by filtration. After recrystallization from methanol / water, the residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 91: 9) to obtain 706 mg (yield: 40%) of the title compound as a white solid. Melting point: 217-220 ° C
1 H-NMR (CDCl 3 , δ ppm):
12.71 (1H, brs), 10.50 (1H, s), 8.05 (2H, s), 7.86-7.96 (5H, m), 4.18 (2H, s), 3 .40 (4H, s), 0.31 (12H, s)
LC-MS: m / z = 418 (positive)
４−（３,５―ジヒドロキシジメチルシリルベンズアミド）安息香酸（６）の合成
化合物（６ｄ）５５ｍｇをアセトン１.５ｍＬに溶解し、氷冷下ＴＥＭＰＯ２.０６ｍｇ、臭化カリウム１.５７ｍｇ、５％次亜塩素酸７８６ｍｇ／０.５ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液１.５ｍＬの混液を加えて、室温で２時間撹拌した。水１０ｍＬを加え更に１Ｎ塩酸で反応液のｐＨを４〜５に調整後、酢酸エチル（８ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９：１で溶出）で精製し、表題化合物３８.６ｍｇ（収率：７５％）を得た。融点：１５６〜１５７℃
1Ｈ−ＮＭＲ（ＤＭＳＯｄ６、δｐｐｍ）：
１０.５４（１Ｈ、ｂｒｓ）、８.１４―８.０５（２Ｈ、ｍ）、８.００―７.８５（５Ｈ、ｍ）、６.０４（２Ｈ、ｂｒｓ）、０.３１（１２Ｈ、ｓ）
Synthesis of 4- (3,5-dihydroxydimethylsilylbenzamide) benzoic acid (6) 55 mg of the compound (6d) was dissolved in 1.5 mL of acetone, 2.06 mg of TEMPO, 1.57 mg of potassium bromide, 5% A mixed solution of 786 mg of chlorous acid / 0.5 mol / L aqueous sodium hydrogen carbonate solution (1.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. 10 mL of water was added and the pH of the reaction solution was adjusted to 4-5 with 1N hydrochloric acid, followed by extraction with ethyl acetate (8 mL × 3). After drying over sodium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 9: 1) to give 38.6 mg (yield: 75%) of the title compound. . Melting point: 156-157 ° C
1 H-NMR (DMSOd 6 , δ ppm):
10.54 (1H, brs), 8.14-8.05 (2H, m), 8.00-7.85 (5H, m), 6.04 (2H, brs), 0.31 (12H, s)
実施例７
４−（３−アセトキシメチルジメチルシリル−５−ヒドロシメチルジメチルシリルベンズアミド）安息香酸エチルエステル（７ａ）の合成
化合物（６ｃ）２.３８ｇをエタノール５６ｍＬに溶解し、炭酸カリウム６２１ｍｇを加えて、室温で１.５時間撹拌した。飽和塩化アンモニウム２５ｍＬを加えてエタノールを留去し後、酢酸エチル（１００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２で溶出）で精製し、白色固体の表題化合物１.０５ｇ（収率：４８％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２７（１Ｈ、ｓ）、８.０１−８.１２（４Ｈ、ｍ）、７.８９（１Ｈ、ｓ）、７.８０（２Ｈ、ｄ、Ｊ＝８.６Ｈｚ）、４.３４（２Ｈ、ｑ、Ｊ＝７.１Ｈｚ）、４.０８（２Ｈ、ｓ）、３.６３（２Ｈ、ｓ）、２.００（３Ｈ，ｓ）、１.４１（３Ｈ、ｔ、Ｊ＝７.１Ｈｚ）、１.２３（１Ｈ、ｂｒｓ）、０.４１（６Ｈ，ｓ）、０.３９（６Ｈ、ｓ）
Example 7
Synthesis of 4- (3-acetoxymethyldimethylsilyl-5-hydroxymethyldimethylsilylbenzamide) benzoic acid ethyl ester (7a) Compound (6c) 2.38 g was dissolved in ethanol 56 mL, potassium carbonate 621 mg was added, and For 1.5 hours. Saturated ammonium chloride (25 mL) was added and ethanol was distilled off, followed by extraction with ethyl acetate (100 mL × 3). After drying over sodium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2) to give 1.05 g (yield: 48%) of the title compound as a white solid. )
1 H-NMR (CDCl 3 , δ ppm):
8.27 (1H, s), 8.01-8.12 (4H, m), 7.89 (1H, s), 7.80 (2H, d, J = 8.6 Hz), 4.34 ( 2H, q, J = 7.1 Hz), 4.08 (2H, s), 3.63 (2H, s), 2.00 (3H, s), 1.41 (3H, t, J = 7. 1Hz), 1.23 (1H, brs), 0.41 (6H, s), 0.39 (6H, s)
４−（３−アセトキシメチルジメチルシリル−５−テトラヒドロピラノキシメチルジメチルシリルベンズアミド）安息香酸エチルエステル（７ｂ）の合成
化合物（７ａ）１.０ｇ、ジヒドロピラン２０４μＬ、ｐ−トルエンスルホン酸・１水和物３９ｍｇを塩化メチレン２５ｍＬ中、室温で１.０時間撹拌した。飽和炭酸水素ナトリウム水溶液１０ｍＬを加えて塩化メチレン（１００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し淡黄色油状の表題化合物１.１８ｇ（収率：１００％）を得た。精製することなく次の反応に用いた。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.０２−８.２１（５Ｈ、ｍ）、７.９１（１Ｈ、ｓ）、７.８０（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、４.４９（１Ｈ、ｍ）、４.３８（２Ｈ、ｑ、Ｊ＝７.１Ｈｚ）、４.０７（２Ｈ、ｓ）、３.７５（１Ｈ、ｄ、Ｊ＝１３.１Ｈｚ）、３.６８−３.７９（１Ｈ、ｍ）、３.４２―３.５３（１Ｈ、ｍ）、３.２１（１Ｈ、ｄ、Ｊ＝１３.１Ｈｚ）、２.０１（３Ｈ、ｓ）、１.４０−１.８７（６Ｈ、ｍ）、１.４１（３Ｈ、ｔ、Ｊ＝７.１Ｈｚ）、０.４１（６Ｈ、ｓ）、０.３９（６Ｈ、ｓ）
Synthesis of 4- (3-acetoxymethyldimethylsilyl-5-tetrahydropyranoxymethyldimethylsilylbenzamide) benzoic acid ethyl ester (7b) Compound (7a) 1.0 g, dihydropyran 204 μL, p-toluenesulfonic acid, 1 water 39 mg of the Japanese product was stirred in 25 mL of methylene chloride at room temperature for 1.0 hour. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (100 mL × 3). After drying over sodium sulfate, the solvent was distilled off to obtain 1.18 g (yield: 100%) of the title compound as a pale yellow oil. Used in the next reaction without purification.
1 H-NMR (CDCl 3 , δ ppm):
8.02-8.21 (5H, m), 7.91 (1H, s), 7.80 (2H, d, J = 8.4 Hz), 4.49 (1H, m), 4.38 ( 2H, q, J = 7.1 Hz), 4.07 (2H, s), 3.75 (1H, d, J = 13.1 Hz), 3.68-3.79 (1H, m), 3. 42-3.53 (1H, m), 3.21 (1H, d, J = 13.1 Hz), 2.01 (3H, s), 1.40-1.87 (6H, m), 1. 41 (3H, t, J = 7.1 Hz), 0.41 (6H, s), 0.39 (6H, s)
４−（３−ヒドロキシメチルジメチルシリル−５−テトラヒドロピラノキシメチルジメチルシリルベンズアミド）安息香酸（７ｃ）の合成
化合物（７ｂ）１.１２ｇをメタノール２０ｍＬ、水５ｍＬに溶解し、２Ｎ水酸化ナトリウム溶液３.４３ｍＬを加えて、５０℃で１.５時間撹拌した。次に氷冷下に２Ｎ塩酸３.４３ｍＬで中和し酢酸エチル（７０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し淡黄色油状の表題化合物９９８ｍｇ（収率：１００％）を得た。精製することなく次の反応に用いた。
1Ｈ−ＮＭＲ（ＤＭＳＯｄ６、δｐｐｍ）：
１２.６１（１Ｈ、ｂｒｓ）、１０.５３（１Ｈ、ｓ）、７.８５―８.１１（７Ｈ、ｍ）、４.４５（１Ｈ、ｍ）、４.２０（１Ｈ、ｂｒｓ）、３.６４（１Ｈ、ｄ、Ｊ＝１３.０Ｈｚ）、３.５８−３.６８（１Ｈ、ｍ）、３.４０（２Ｈ、ｓ）、３.３３（１Ｈ、ｍ）、３.１７（２Ｈ、ｄ、Ｊ＝１３.２Ｈｚ）、１.３０−１.７７（６Ｈ、ｍ）、０.３６（６Ｈ、ｓ）、０.３１（６Ｈ、ｓ）
Synthesis of 4- (3-hydroxymethyldimethylsilyl-5-tetrahydropyranoxymethyldimethylsilylbenzamide) benzoic acid (7c) 1.12 g of compound (7b) was dissolved in 20 mL of methanol and 5 mL of water, and 2N sodium hydroxide solution. 3.43 mL was added and stirred at 50 ° C. for 1.5 hours. Next, the mixture was neutralized with 3.43 mL of 2N hydrochloric acid under ice cooling, and extracted with ethyl acetate (70 mL × 3). After drying over sodium sulfate, the solvent was distilled off to obtain 998 mg (yield: 100%) of the title compound as a pale yellow oil. Used in the next reaction without purification.
1 H-NMR (DMSOd 6 , δ ppm):
12.61 (1H, brs), 10.53 (1H, s), 7.85-8.11 (7H, m), 4.45 (1H, m), 4.20 (1H, brs), 3 .64 (1H, d, J = 13.0 Hz), 3.58-3.68 (1H, m), 3.40 (2H, s), 3.33 (1H, m), 3.17 (2H , D, J = 13.2 Hz), 1.30-1.77 (6H, m), 0.36 (6H, s), 0.31 (6H, s)
４−（３−ヒドロキシジメチルシリル−５−テトラヒドロピラノキシメチルジメチルシリルベンズアミド）安息香酸（７ｄ）の合成
化合物（７ｃ）７７.２ｍｇをジメチルスルホキシド２ｍＬに溶解し、トリエチルアミン０.１４ｍＬ、三酸化硫黄ピリジン錯体７３.５ｍｇを加えて、室温で１５分撹拌した。飽和塩化アンモニウム水溶液１ｍＬを加え更に２Ｎ塩酸で反応液のｐＨを２〜３に調整後、酢酸エチル（３０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し淡黄色油状の表題化合物８４.３ｍｇ（収率：１００％）を得た。精製することなく次の反応に用いた。
1Ｈ−ＮＭＲ（ＤＭＳＯｄ６、δｐｐｍ）：
１２.６９（１Ｈ、ｂｒｓ）、１０.５５（１Ｈ、ｓ）、７.８７―８.０９（７Ｈ、ｍ）、６.０５（１Ｈ、ｓ）、４.４５（１Ｈ、ｍ）、３.６４（１Ｈ、ｄ、Ｊ＝１２.８Ｈｚ）、３.５７−３.６７（１Ｈ、ｍ）、３.３６（１Ｈ、ｍ）、３.１７（１Ｈ、ｄ、Ｊ＝１３.０Ｈｚ）、１.３０−１.７５（６Ｈ、ｍ）、０.３６（６Ｈ、ｓ）、０.３１（６Ｈ、ｓ）
Synthesis of 4- (3-hydroxydimethylsilyl-5-tetrahydropyranoxymethyldimethylsilylbenzamide) benzoic acid (7d) Compound (7c) 77.2 mg was dissolved in dimethyl sulfoxide 2 mL, triethylamine 0.14 mL, sulfur trioxide. 73.5 mg of pyridine complex was added and stirred at room temperature for 15 minutes. 1 mL of a saturated aqueous ammonium chloride solution was added, and the pH of the reaction solution was adjusted to 2 to 3 with 2N hydrochloric acid, followed by extraction with ethyl acetate (30 mL × 3). After drying over sodium sulfate, the solvent was distilled off to obtain 84.3 mg (yield: 100%) of the title compound as a pale yellow oil. Used in the next reaction without purification.
1 H-NMR (DMSOd 6 , δ ppm):
12.69 (1H, brs), 10.55 (1H, s), 7.87-8.09 (7H, m), 6.05 (1H, s), 4.45 (1H, m), 3 .64 (1H, d, J = 12.8 Hz), 3.57-3.67 (1H, m), 3.36 (1H, m), 3.17 (1H, d, J = 13.0 Hz) 1.30-1.75 (6H, m), 0.36 (6H, s), 0.31 (6H, s)
４−（３−ヒドロキシジメチルシリル−５−ヒドロキシメチルジメチルシリルベンズアミド）安息香酸（７）の合成
化合物（７ｄ）８２３ｍｇをメタノール３０ｍＬに溶解し、ｐ−トルエンスルホン酸・１水和物３２ｍｇを加えて、室温で３.５時間攪拌後、更に３５℃で２.５時間撹拌した。水４０ｍＬを加え、酢酸エチル（４０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝７５：２５で溶出）で精製し、白色固体の表題化合物１９４ｍｇ（収率：２８％）を得た。融点：１７１〜１７２℃
1Ｈ−ＮＭＲ（ＤＭＳＯｄ６、δｐｐｍ）：
１２.７０（１Ｈ、ｂｒｓ）、１０.５３（１Ｈ、ｓ）、７.８６―８.０７（７Ｈ、ｍ）、６.０４（１Ｈ、ｂｒｓ）、４.１９（１Ｈ、ｂｒｓ）、３.４０（２Ｈ、ｓ）、０.３１（１２Ｈ、ｓ）
ＬＣ−ＭＳ：ｍ／ｚ＝４０２（ネガチブ）
Synthesis of 4- (3-hydroxydimethylsilyl-5-hydroxymethyldimethylsilylbenzamide) benzoic acid (7) 823 mg of the compound (7d) was dissolved in 30 mL of methanol, and 32 mg of p-toluenesulfonic acid monohydrate was added. The mixture was stirred at room temperature for 3.5 hours, and further stirred at 35 ° C. for 2.5 hours. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). After drying over sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 75: 25) to give 194 mg (yield: 28%) of the title compound as a white solid. Got. Melting point: 171-172 ° C
1 H-NMR (DMSOd 6 , δ ppm):
12.70 (1H, brs), 10.53 (1H, s), 7.86-8.07 (7H, m), 6.04 (1H, brs), 4.19 (1H, brs), 3 .40 (2H, s), 0.31 (12H, s)
LC-MS: m / z = 402 (negative)
実施例８
４−クロロメチルジメチルシリルアニソール（８ａ）の合成
アルゴン気流下、４−ブロモアニソール５.０ｇを乾燥テトラヒドロフラン１２０ｍＬに溶解し、−５０℃で１.５８ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液１８.６ｍＬを徐々に滴下し、同温で３０分撹拌後、クロロメチルジメチルシリルクロリド４.２２ｍＬを滴下した。−３０℃で３０分撹拌後、室温に戻した。次に氷冷下に飽和塩化アンモニウム水溶液１０ｍＬでクエンチし反応液を濃縮した。残渣に水３００ｍＬを加え、酢酸エチル（３００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物６.４７ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝４：９６で溶出）で精製し、白色固体の表題化合物５.５２ｇ（収率：９６％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４７（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、６.９３（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、３.８１（３Ｈ、ｓ）、２.９２（２Ｈ、ｓ）、０.３９（６Ｈ、ｓ）
Example 8
Synthesis of 4-chloromethyldimethylsilylanisole (8a) Under an argon stream, 5.0 g of 4-bromoanisole was dissolved in 120 mL of dry tetrahydrofuran, and 18.6 mL of a 1.58 mol / L n-butyllithium hexane solution at −50 ° C. Was gradually added dropwise and stirred at the same temperature for 30 minutes, and then 4.22 mL of chloromethyldimethylsilyl chloride was added dropwise. After stirring at -30 ° C for 30 minutes, the temperature was returned to room temperature. Next, the reaction solution was concentrated by quenching with 10 mL of saturated aqueous ammonium chloride solution under ice-cooling. 300 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (300 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 6.47 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 4: 96) gave 5.52 g (yield: 96%) of the title compound as a white solid.
1 H-NMR (CDCl 3 , δ ppm):
7.47 (2H, d, J = 8.4 Hz), 6.93 (2H, d, J = 8.4 Hz), 3.81 (3H, s), 2.92 (2H, s), 0.8 39 (6H, s)
４−アセトキシメチルジメチルシリルアニソール（８ｂ）の合成
化合物（８ａ）５.２２ｇをジメチルホルムアミド８０ｍＬに溶解し、酢酸カリウム２.８６ｇを加え、９０℃で３時間撹拌した。次に水２００ｍＬを加え、酢酸エチル：ヘキサン＝１：２混合溶媒（２００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物５.８３ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１０：９０で溶出）で精製し、無色油状の表題化合物５.２０ｇ（収率：９０％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４６（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、６.９２（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、３.９３（２Ｈ、ｓ）、３.８２（３Ｈ、ｓ）、２.０２（３Ｈ、ｓ）、０.３３（６Ｈ、ｓ）
ＦＡＢＭＳ：２７７（Ｍ＋Ｋ）ＫＩ添加
Synthesis of 4-acetoxymethyldimethylsilylanisole (8b) 5.22 g of the compound (8a) was dissolved in 80 mL of dimethylformamide, 2.86 g of potassium acetate was added, and the mixture was stirred at 90 ° C. for 3 hours. Next, 200 mL of water was added, and the mixture was extracted with a mixed solvent of ethyl acetate: hexane = 1: 2 (200 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 5.83 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 10: 90) gave 5.20 g (yield: 90%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.46 (2H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.4 Hz), 3.93 (2H, s), 3.82 (3H, s), 2. 02 (3H, s), 0.33 (6H, s)
FABMS: 277 (M + K) KI addition
４−ヒドロキシメチルジメチルシリルアニソール（８ｃ）の合成
化合物（８ｂ）４.８５ｇをメタノール８０ｍＬに溶解し、炭酸カリウム２.８１ｇを加え、室温で２.５時間撹拌した。次に水１５０ｍＬを加え、酢酸エチル（１５０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物３.９１ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２０：８０で溶出）で精製し、無色油状の表題化合物３.１６ｇ（収率：７９％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５０（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、６.９４（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、３.８２（３Ｈ、ｓ）、３.５５（２Ｈ、ｓ）、１.１１（１Ｈ、ｂｒｓ）、０.３４（６Ｈ、ｓ）
ＦＡＢＭＳ：２３５（Ｍ＋Ｋ）ＫＩ添加
Synthesis of 4-hydroxymethyldimethylsilylanisole (8c) 4.85 g of the compound (8b) was dissolved in 80 mL of methanol, 2.81 g of potassium carbonate was added, and the mixture was stirred at room temperature for 2.5 hours. Next, 150 mL of water was added and extracted with ethyl acetate (150 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 3.91 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 20: 80) gave 3.16 g (yield: 79%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.50 (2H, d, J = 8.4 Hz), 6.94 (2H, d, J = 8.4 Hz), 3.82 (3H, s), 3.55 (2H, s), 1. 11 (1H, brs), 0.34 (6H, s)
FABMS: 235 (M + K) KI addition
４−ヒドロキシジメチルシリルアニソール（８）の合成
化合物（８ｃ）９３.６ｍｇをアセトン２.０ｍＬに溶解し、氷冷下ＴＥＭＰＯ ７.５ｍｇ、臭化カリウム５.７ｍｇを加え、５％次亜塩素酸ナトリウム８５２ｍｇを０.５ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液２.０ｍＬに溶解した溶液を順次加え、室温で３時間撹拌した。次に飽和塩化アンモニウム水溶液２.０ｍＬを加え、酢酸エチル（１５ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物９６.３ｍｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４で溶出）で精製し、無色油状の表題化合物７１.３ｍｇ（収率：８２％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５２（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、６.９２（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、３.８２（３Ｈ、ｓ）、１.９２（１Ｈ、ｂｒｓ）、０.３８（６Ｈ、ｓ）
ＦＡＢＭＳ：１８１（Ｍ−Ｈ）
Synthesis of 4-hydroxydimethylsilylanisole (8) 93.6 mg of the compound (8c) was dissolved in 2.0 mL of acetone, and 7.5 mg of TEMPO and 5.7 mg of potassium bromide were added under ice cooling, and 5% hypochlorous acid. A solution prepared by dissolving 852 mg of sodium in 2.0 mL of a 0.5 mol / L aqueous sodium hydrogen carbonate solution was sequentially added, and the mixture was stirred at room temperature for 3 hours. Next, 2.0 mL of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (15 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 96.3 mg of a crude product. Purification by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 4) gave 71.3 mg (yield: 82%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.52 (2H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.4 Hz), 3.82 (3H, s), 1.92 (1H, brs), 0.7. 38 (6H, s)
FABMS: 181 (M-H)
実施例９
４−クロロメチルジメチルシリル−クロロベンゼン（９ａ）の合成
４−ブロモ−クロロベンゼン４.９１ｇを用いて化合物（８ａ）と同様の反応を実施し、無色油状の表題化合物４.８１ｇ（収率：７４％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４７（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、７.３５（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、２.９３（２Ｈ、ｓ）、０.４１（６Ｈ、ｓ）
Example 9
Synthesis of 4-chloromethyldimethylsilyl-chlorobenzene (9a) The same reaction as that of the compound (8a) was carried out using 4.91 g of 4-bromo-chlorobenzene, and 4.81 g of the title compound as a colorless oil (yield: 74%) )
1 H-NMR (CDCl 3 , δ ppm):
7.47 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 2.93 (2H, s), 0.41 (6H, s)
４−アセトキシメチルジメチルシリル−クロロベンゼン（９ｂ）の合成
化合物（９ａ）３.５７ｇを用いて化合物（８ｂ）と同様の反応を実施し、無色油状の表題化合物３.８１ｇ（収率：９６％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４６（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、７.３５（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、３.９４（２Ｈ、ｓ）、２.０２（３Ｈ、ｓ）、０.３５（６Ｈ、ｓ）
ＦＡＢＭＳ：２８１（Ｍ＋Ｋ）ＫＩ添加
Synthesis of 4-acetoxymethyldimethylsilyl-chlorobenzene (9b) Using 3.57 g of the compound (9a), the same reaction as that of the compound (8b) was carried out to give 3.81 g of the title compound as a colorless oil (yield: 96%) Got.
1 H-NMR (CDCl 3 , δ ppm):
7.46 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 3.94 (2H, s), 2.02 (3H, s), 0.0 35 (6H, s)
FABMS: 281 (M + K) KI added
４−ヒドロキシメチルジメチルシリル−クロロベンゼン（９ｃ）の合成
化合物（９ｂ）３.３７ｇを用いて化合物（８ｃ）と同様の反応を実施し、無色油状の表題化合物２.４４ｇ（収率：８７％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４９（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、７.３５（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、３.５７（２Ｈ、ｓ）、０.９９（１Ｈ、ｓ）、０.３４（６Ｈ、ｓ）
ＦＡＢＭＳ：１９９（Ｍ−Ｈ）
Synthesis of 4-hydroxymethyldimethylsilyl-chlorobenzene (9c) The same reaction as that of the compound (8c) was carried out using 3.37 g of the compound (9b) to give 2.44 g of the title compound as a colorless oil (yield: 87%). Got.
1 H-NMR (CDCl 3 , δ ppm):
7.49 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 3.57 (2H, s), 0.99 (1H, s), 0.5. 34 (6H, s)
FABMS: 199 (MH)
４−ヒドロキシジメチルシリル−クロロベンゼン（９）の合成
化合物（９ｃ）３６３ｍｇを用いて化合物（８）と同様の反応を実施し、無色油状の表題化合物２６８ｍｇ（収率：７９％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４９（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、７.３４（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、２.２８（１Ｈ、ｓ）、０.３７（６Ｈ、ｓ）
Synthesis of 4-hydroxydimethylsilyl-chlorobenzene (9) 363 mg of the compound (9c) was used to carry out a reaction similar to that of the compound (8) to obtain 268 mg (yield: 79%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.49 (2H, d, J = 8.1 Hz), 7.34 (2H, d, J = 8.1 Hz), 2.28 (1H, s), 0.37 (6H, s)
実施例１０
１,４−ビス（クロロメチルジメチルシリル）ベンゼン（１０ａ）の合成
アルゴン気流下、１,４―ジブロモベンゼン４.６２ｇを乾燥テトラヒドロフラン１３８ｍＬに溶解し、−７８℃で１.５８ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液２７.３ｍＬを徐々に滴下し、同温で３０分撹拌後、クロロメチルジメチルシリルクロリド６.１９ｍＬを滴下した。−７８℃で３０分撹拌後、室温に戻した。次に氷冷下に飽和塩化アンモニウム水溶液１０ｍＬでクエンチし反応液を濃縮した。残渣に水３００ｍＬを加え、酢酸エチル（３００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物７.０２ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝４：９６で溶出）で精製し、白色固体の表題化合物４.３８ｇ（収率：７７％）を得た。融点：５７〜５８℃
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５７（４Ｈ、ｓ）、２.９６（４Ｈ、ｓ）、０.４３（１２Ｈ、ｓ）
Example 10
Synthesis of 1,4-bis (chloromethyldimethylsilyl) benzene (10a) Under an argon stream, 4.62 g of 1,4-dibromobenzene was dissolved in 138 mL of dry tetrahydrofuran, and 1.58 mol / L of n- at −78 ° C. 27.3 mL of butyllithium hexane solution was gradually added dropwise, stirred at the same temperature for 30 minutes, and then 6.19 mL of chloromethyldimethylsilyl chloride was added dropwise. After stirring at −78 ° C. for 30 minutes, the temperature was returned to room temperature. Next, the reaction solution was concentrated by quenching with 10 mL of saturated aqueous ammonium chloride solution under ice-cooling. 300 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (300 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 7.02 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 4: 96) gave 4.38 g (yield: 77%) of the title compound as a white solid. Melting point: 57-58 ° C
1 H-NMR (CDCl 3 , δ ppm):
7.57 (4H, s), 2.96 (4H, s), 0.43 (12H, s)
１,４−ビス（アセトキシメチルジメチルシリル）ベンゼン（１０ｂ）の合成
化合物（１０ａ）３.８０ｇをジメチルホルムアミド６５ｍＬに溶解し、酢酸カリウム３.５７ｇを加え、９０℃で３時間撹拌した。次に水２００ｍＬを加え、酢酸エチル：ヘキサン＝１：２混合溶媒（２００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物４.４２ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１０：９０で溶出）で精製し、無色固体の表題化合物４.０７ｇ（収率：９２％）を得た。融点：４０〜４２℃
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５４（４Ｈ、ｓ）、３.９６（４Ｈ、ｓ）、２.０３（６Ｈ、ｓ）、０.３６（１２Ｈ、ｓ）
ＦＡＢＭＳ：３９９（Ｍ＋Ｈ）
Synthesis of 1,4-bis (acetoxymethyldimethylsilyl) benzene (10b) 3.80 g of the compound (10a) was dissolved in 65 mL of dimethylformamide, 3.57 g of potassium acetate was added, and the mixture was stirred at 90 ° C. for 3 hours. Next, 200 mL of water was added, and the mixture was extracted with a mixed solvent of ethyl acetate: hexane = 1: 2 (200 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 4.42 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 10: 90) gave 4.07 g (yield: 92%) of the title compound as a colorless solid. Melting point: 40-42 ° C
1 H-NMR (CDCl 3 , δ ppm):
7.54 (4H, s), 3.96 (4H, s), 2.03 (6H, s), 0.36 (12H, s)
FABMS: 399 (M + H)
１,４−ビス（ヒドロキシメチルジメチルシリル）ベンゼン（１０ｃ）の合成
化合物（１０ｂ）３.５８ｇをメタノール５０ｍＬに溶解し、炭酸カリウム２.９３ｇを加え、室温で２時間撹拌した。次に水１５０ｍＬを加え、酢酸エチル（１５０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物２.６７ｇを得た。シリカゲルカラムクロマトグラフィー（メタノール：クロロホルム＝５：９５で溶出）で精製し、白色固体の表題化合物１.９４ｇ（収率：７２％）を得た。融点：１３６〜１３８℃
1Ｈ−ＮＭＲ（ＣＤＣｌ３，δｐｐｍ）：
７.５８（４Ｈ、ｓ）、３.５９（４Ｈ、ｄ、Ｊ＝４.６Ｈｚ）、０.８９（２Ｈ、ｔ、Ｊ＝４.６Ｈｚ）、０.３５（１２Ｈ、ｓ）
ＦＡＢＭＳ：２９３（Ｍ＋Ｋ）ＫＩ添加
Synthesis of 1,4-bis (hydroxymethyldimethylsilyl) benzene (10c) 3.58 g of the compound (10b) was dissolved in 50 mL of methanol, 2.93 g of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. Next, 150 mL of water was added and extracted with ethyl acetate (150 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 2.67 g of a crude product. Purification by silica gel column chromatography (eluting with methanol: chloroform = 5: 95) gave 1.94 g (yield: 72%) of the title compound as a white solid. Melting point: 136-138 ° C
1 H-NMR (CDCl 3 , δ ppm):
7.58 (4H, s), 3.59 (4H, d, J = 4.6 Hz), 0.89 (2H, t, J = 4.6 Hz), 0.35 (12H, s)
FABMS: 293 (M + K) KI addition
１,４−ビス（ヒドロキシジメチルシリル）ベンゼン（１０）の合成
化合物（１０ｃ）３６２ｍｇをアセトン９.５ｍＬに溶解し、氷冷下ＴＥＭＰＯ ２２.２ｍｇ、臭化カリウム１６.９ｍｇを加え、５％次亜塩素酸ナトリウム８.４６ｇを０.５ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液９.５ｍＬに溶解した溶液を順次加え、室温で１時間撹拌した。次に飽和塩化アンモニウム水溶液９.５ｍＬを加え、酢酸エチル（３０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物３４０ｍｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２で溶出）で精製し、白色固体の表題化合物２６９ｍｇ（収率：８４％）を得た。融点：１３６〜１３７℃
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５３（４Ｈ、ｓ）、５.８７（２Ｈ、ｓ）、０.２４（１２Ｈ、ｓ）
ＦＡＢＭＳ：１９９（Ｍ−Ｈ）
Synthesis of 1,4-bis (hydroxydimethylsilyl) benzene (10) 362 mg of the compound (10c) was dissolved in 9.5 mL of acetone, and 22.2 mg of TEMPO and 16.9 mg of potassium bromide were added under ice cooling, followed by 5% A solution prepared by dissolving 8.46 g of sodium chlorite in 9.5 mL of a 0.5 mol / L aqueous sodium bicarbonate solution was sequentially added, and the mixture was stirred at room temperature for 1 hour. Next, 9.5 mL of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (30 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 340 mg of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 1: 2) gave 269 mg (yield: 84%) of the title compound as a white solid. Melting point: 136-137 ° C
1 H-NMR (CDCl 3 , δ ppm):
7.53 (4H, s), 5.87 (2H, s), 0.24 (12H, s)
FABMS: 199 (MH)
実施例１１
２−クロロメチルジメチルシリルチオフェン（１１ａ）の合成
アルゴン気流下、２−ブロモチオフェン４.０１ｇを乾燥テトラヒドロフラン１２５ｍＬに溶解し、−７８℃で１.５８ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液１７.１ｍＬを徐々に滴下し、同温で３０分撹拌後、クロロメチルジメチルシリルクロリド３.８９ｍＬを滴下した。同温で３０分撹拌後、室温に戻した。次に氷冷下に飽和塩化アンモニウム水溶液１０ｍＬでクエンチし反応液を濃縮した。残渣に水３００ｍＬを加え、酢酸エチル（３００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物４.８７ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１０：９０で溶出）で精製し、白色油状の表題化合物３.５４ｇ（収率：７５％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.６５（１Ｈ、ｄ、Ｊ＝４.５Ｈｚ）、７.３５（１Ｈ、ｄ、Ｊ＝３.０Ｈｚ）、７.２２（１Ｈ、ｄｄ、Ｊ＝４.５、Ｊ＝３.０Ｈｚ）、２.９５（２Ｈ、ｓ）、０.４７（６Ｈ、ｓ）
Example 11
Synthesis of 2-chloromethyldimethylsilylthiophene (11a) Under an argon stream, 4.01 g of 2-bromothiophene was dissolved in 125 mL of dry tetrahydrofuran, and 17.1 mL of a 1.58 mol / L n-butyllithium hexane solution at -78 ° C. Was gradually added dropwise, and after stirring at the same temperature for 30 minutes, 3.89 mL of chloromethyldimethylsilyl chloride was added dropwise. After stirring for 30 minutes at the same temperature, the temperature was returned to room temperature. Next, the reaction solution was concentrated by quenching with 10 mL of saturated aqueous ammonium chloride solution under ice-cooling. 300 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (300 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 4.87 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 10: 90) gave 3.54 g (yield: 75%) of the title compound as a white oil.
1 H-NMR (CDCl 3 , δ ppm):
7.65 (1H, d, J = 4.5 Hz), 7.35 (1H, d, J = 3.0 Hz), 7.22 (1H, dd, J = 4.5, J = 3.0 Hz) 2.95 (2H, s), 0.47 (6H, s)
２−アセトキシメチルジメチルシリルチオフェン（１１ｂ）の合成
化合物（１１ａ）２.９９ｇを用いて化合物（８ｂ）と同様の反応を実施し、無色油状の表題化合物２.１７ｇ（収率：６４％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.６４（１Ｈ、ｄ、Ｊ＝４.５Ｈｚ）、７.３３（１Ｈ、ｄ、Ｊ＝２.９Ｈｚ）、７.２１（１Ｈ、ｄｄ、Ｊ＝４.５、Ｊ＝２.９Ｈｚ）、３.９５（２Ｈ、ｓ）、２.０５（３Ｈ、ｓ）、０.４１（６Ｈ、ｓ）
Synthesis of 2-acetoxymethyldimethylsilylthiophene (11b) Using 2.99 g of the compound (11a), the same reaction as that of the compound (8b) was carried out to give 2.17 g (yield: 64%) of the title compound as a colorless oil. Obtained.
1 H-NMR (CDCl 3 , δ ppm):
7.64 (1H, d, J = 4.5 Hz), 7.33 (1H, d, J = 2.9 Hz), 7.21 (1H, dd, J = 4.5, J = 2.9 Hz) 3.95 (2H, s), 2.05 (3H, s), 0.41 (6H, s)
２−ヒドロキシメチルジメチルシリルチオフェン（１１ｃ）の合成
化合物（１１ｂ）１.７０ｇを用いて化合物（８ｃ）と同様の反応を実施し、無色油状の表題化合物３１１ｍｇ（収率：２３％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.６５（１Ｈ、ｄ、Ｊ＝４.５Ｈｚ）、７.３５（１Ｈ、ｄ、Ｊ＝３.０Ｈｚ）、７.２３（１Ｈ、ｄｄ、Ｊ＝４.５、Ｊ＝３.０Ｈｚ）、３.５７（２Ｈ、ｓ）、０.９８（１Ｈ、ｂｒｓ）、０.４０（６Ｈ、ｓ）
Synthesis of 2-hydroxymethyldimethylsilylthiophene (11c) The same reaction as that of the compound (8c) was performed using 1.70 g of the compound (11b) to obtain 311 mg (yield: 23%) of the title compound as a colorless oil. .
1 H-NMR (CDCl 3 , δ ppm):
7.65 (1H, d, J = 4.5 Hz), 7.35 (1H, d, J = 3.0 Hz), 7.23 (1H, dd, J = 4.5, J = 3.0 Hz) 3.57 (2H, s), 0.98 (1H, brs), 0.40 (6H, s)
２−ヒドロキシジメチルシリルチオフェン（１１）の合成
化合物（１１ｃ）１６２ｍｇを用いて化合物（８）と同様の反応を実施し、淡黄色油状の表題化合物１１１ｍｇ（収率：７４％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.６４（１Ｈ、ｄ、Ｊ＝４.５Ｈｚ）、７.３７（１Ｈ、ｄ、Ｊ＝３.０Ｈｚ）、７.２１（１Ｈ、ｄｄ、Ｊ＝４.５、Ｊ＝３.０Ｈｚ）、１.９９（１Ｈ、ｂｒｓ）、０.４７（６Ｈ、ｓ）
Synthesis of 2-hydroxydimethylsilylthiophene (11) Using 162 mg of compound (11c), the same reaction as compound (8) was carried out to obtain 111 mg (yield: 74%) of the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 , δ ppm):
7.64 (1H, d, J = 4.5 Hz), 7.37 (1H, d, J = 3.0 Hz), 7.21 (1H, dd, J = 4.5, J = 3.0 Hz) 1.99 (1H, brs), 0.47 (6H, s)
実施例１２
３−クロロメチルジメチルシリルフラン（１２ａ）の合成
アルゴン気流下、３−ブロモフラン５.３２ｇを乾燥ジエチルエーテル１５０ｍＬに溶解し、化合物（１０ａ）と同様の反応を行い、粗生成物７.２２ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１０：９０で溶出）で精製し、白色油状の表題化合物５.００ｇ（収率：７９％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５２（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝１.３Ｈｚ）、７.４５（１Ｈ、ｄｄ、Ｊ＝１.３、Ｊ＝０.８Ｈｚ）、６.４２（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝０.８Ｈｚ）、２.８９（２Ｈ、ｓ）、０.３５（６Ｈ、ｓ）
Example 12
Synthesis of 3-chloromethyldimethylsilylfuran (12a) Under an argon stream, 5.32 g of 3-bromofuran was dissolved in 150 mL of dry diethyl ether, and a reaction similar to that of the compound (10a) was performed to obtain 7.22 g of a crude product. It was. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 10: 90) gave 5.00 g (yield: 79%) of the title compound as a white oil.
1 H-NMR (CDCl 3 , δ ppm):
7.52 (1H, dd, J = 1.6, J = 1.3 Hz), 7.45 (1H, dd, J = 1.3, J = 0.8 Hz), 6.42 (1H, dd, J = 1.6, J = 0.8 Hz), 2.89 (2H, s), 0.35 (6H, s)
３−アセトキシメチルジメチルシリルフラン（１２ｂ）の合成
化合物（１２ａ）４.９５ｇを用いて化合物（８ｂ）と同様の反応を実施し、無色油状の表題化合物５.３３ｇ（収率：９５％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５１（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝１.３Ｈｚ）、７.４２（１Ｈ、ｄｄ、Ｊ＝１.３、Ｊ＝０.８Ｈｚ）、６.４０（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝０.８Ｈｚ）、３.９０（２Ｈ、ｓ）、２.０４（３Ｈ、ｓ）、０.３０（６Ｈ、ｓ）
Synthesis of 3-acetoxymethyldimethylsilylfuran (12b) Using 4.95 g of the compound (12a), the same reaction as that of the compound (8b) was carried out to obtain 5.33 g (yield: 95%) of the title compound as a colorless oil. Obtained.
1 H-NMR (CDCl 3 , δ ppm):
7.51 (1H, dd, J = 1.6, J = 1.3 Hz), 7.42 (1H, dd, J = 1.3, J = 0.8 Hz), 6.40 (1H, dd, J = 1.6, J = 0.8 Hz), 3.90 (2H, s), 2.04 (3H, s), 0.30 (6H, s)
３−ヒドロキシメチルジメチルシリルフラン（１２ｃ）の合成
化合物（１２ｂ）４.３５ｇを用いて化合物（８ｃ）と同様の反応を実施し、無色油状の表題化合物２.８２ｇ（収率：８３％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５２（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝１.５Ｈｚ）、７.４４（１Ｈ、ｄｄ、Ｊ＝１.５、Ｊ＝０.８Ｈｚ）、６.４２（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝０.８Ｈｚ）、３.５１（２Ｈ、ｓ）、１.０６（１Ｈ、ｓ）、０.２９（６Ｈ、ｓ）
Synthesis of 3-hydroxymethyldimethylsilylfuran (12c) Using 4.35 g of the compound (12b), the same reaction as the compound (8c) was carried out to obtain 2.82 g (yield: 83%) of the title compound as a colorless oil. Obtained.
1 H-NMR (CDCl 3 , δ ppm):
7.52 (1H, dd, J = 1.6, J = 1.5 Hz), 7.44 (1H, dd, J = 1.5, J = 0.8 Hz), 6.42 (1H, dd, J = 1.6, J = 0.8 Hz), 3.51 (2H, s), 1.06 (1H, s), 0.29 (6H, s)
３−ヒドロキシジメチルシリルフラン（１２）の合成
化合物（１２ｃ）３０１ｍｇを用いて化合物（８）と同様の反応を実施し、無色油状の表題化合物７３.６ｍｇ（収率：２７％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５１（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝１.３Ｈｚ）、７.４６（１Ｈ、ｄｄ、Ｊ＝１.３、Ｊ＝０.８Ｈｚ）、６.４４（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝０.８Ｈｚ）、２.０８（１Ｈ、ｂｒｓ）、０.３６（６Ｈ、ｓ）
Synthesis of 3-hydroxydimethylsilylfuran (12) Using 301 mg of the compound (12c), the same reaction as that of the compound (8) was carried out to obtain 73.6 mg (yield: 27%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.51 (1H, dd, J = 1.6, J = 1.3 Hz), 7.46 (1H, dd, J = 1.3, J = 0.8 Hz), 6.44 (1H, dd, J = 1.6, J = 0.8 Hz), 2.08 (1H, brs), 0.36 (6H, s)
実施例１３
３−ブロモメチルジメチルシリル安息香酸（１３ａ）の合成
アルゴン気流下、３−ブロモ安息香酸３.００ｇ（１４.９ｍｍｏｌ）を乾燥テトラヒドロフラン７５ｍＬに溶解し、−１５℃で１ｍｏｌ／Ｌのジブチルマグネシウムヘプタン溶液８.２１ｍＬを滴下した。同温で２０分撹拌後、−３０℃で１.６５ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液９.９５ｍＬを徐々に滴下し、同温で３０分撹拌後、ブロモメチルジメチルシリルクロリド４.６３ｍＬを滴下した。−３０℃で３０分撹拌後、室温で終夜撹拌した。次に氷冷下に飽和塩化アンモニウム水溶液２０ｍＬでクエンチし反応液を濃縮した。残渣に水２００ｍＬを加え、２Ｎ塩酸で水層のｐＨを２〜３とした後、酢酸エチル（２００ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物を８.５０ｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３３：６７で溶出）で精製し、白色固体の表題化合物３.０７ｇ（収率：７５％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２９（１Ｈ、ｓ）、８.１５（１Ｈ、ｄｄｄ、Ｊ＝７.９Ｈｚ、Ｊ＝１.３Ｈｚ、Ｊ＝１.３Ｈｚ）、７.８０（１Ｈ、ｄｄｄ、Ｊ＝７.４Ｈｚ、Ｊ＝１.３Ｈｚ、Ｊ＝１.３Ｈｚ）、７.５０（１Ｈ、ｄｄ、Ｊ＝７.９Ｈｚ、Ｊ＝７.４Ｈｚ）、２.６６（２Ｈ、ｓ）、０.４９（６Ｈ、ｓ）
Example 13
Synthesis of 3-bromomethyldimethylsilylbenzoic acid (13a) Under an argon stream, 3.00 g (14.9 mmol) of 3-bromobenzoic acid was dissolved in 75 mL of dry tetrahydrofuran, and a 1 mol / L dibutylmagnesium heptane solution at −15 ° C. 8.21 mL was added dropwise. After stirring at the same temperature for 20 minutes, 9.95 mL of a 1.65 mol / L n-butyllithium hexane solution was gradually added dropwise at −30 ° C., and after stirring at the same temperature for 30 minutes, 4.63 mL of bromomethyldimethylsilyl chloride was added. It was dripped. After stirring at −30 ° C. for 30 minutes, the mixture was stirred at room temperature overnight. Next, the reaction solution was concentrated by quenching with 20 mL of saturated aqueous ammonium chloride solution under ice cooling. 200 mL of water was added to the residue, and the pH of the aqueous layer was adjusted to 2 to 3 with 2N hydrochloric acid, followed by extraction with ethyl acetate (200 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 8.50 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 33: 67) gave 3.07 g (yield: 75%) of the title compound as a white solid.
1 H-NMR (CDCl 3 , δ ppm):
8.29 (1H, s), 8.15 (1H, ddd, J = 7.9 Hz, J = 1.3 Hz, J = 1.3 Hz), 7.80 (1H, ddd, J = 7.4 Hz, J = 1.3 Hz, J = 1.3 Hz), 7.50 (1H, dd, J = 7.9 Hz, J = 7.4 Hz), 2.66 (2H, s), 0.49 (6H, s )
３−ブロモメチルジメチルシリル安息香酸メチルエステル（１３ｂ）の合成
化合物（１３ａ）２.０９ｇをメタノール１０ｍＬ、トルエン４０ｍＬに溶解し、室温で２ｍｏｌ／Ｌのトリメチルシリルジアゾメタンヘキサン溶液５.７０ｍＬを加え１５分撹拌した。次に反応系の色が消失するまで酢酸を加え、溶媒を留去し粗生成物を２.１９ｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝５：９５で溶出）で精製し、無色油状の表題化合物１.３７ｇ（収率：６２％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２０（１Ｈ、ｍ）、８.０６（１Ｈ、ｄｄｄ、Ｊ＝７.７Ｈｚ、Ｊ＝１．６Ｈｚ、Ｊ＝１．３Ｈｚ）、７.７３（１Ｈ、ｄｄｄ、Ｊ＝７.４Ｈｚ、Ｊ＝１．３Ｈｚ、Ｊ＝１．３Ｈｚ）、７.４３（１Ｈ、ｄｄ、Ｊ＝７.７Ｈｚ、Ｊ＝７.４Ｈｚ）、３.９３（３Ｈ、ｓ）、２.６５（２Ｈ、ｓ）、０.４７（６Ｈ、ｓ）
Synthesis of 3-bromomethyldimethylsilylbenzoic acid methyl ester (13b) 2.09 g of compound (13a) was dissolved in 10 mL of methanol and 40 mL of toluene, and 5.70 mL of a 2 mol / L trimethylsilyldiazomethanehexane solution was added at room temperature and stirred for 15 minutes. did. Next, acetic acid was added until the color of the reaction system disappeared, and the solvent was distilled off to obtain 2.19 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 5: 95) gave 1.37 g (yield: 62%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.20 (1H, m), 8.06 (1H, ddd, J = 7.7 Hz, J = 1.6 Hz, J = 1.3 Hz), 7.73 (1H, ddd, J = 7.4 Hz, J = 1.3 Hz, J = 1.3 Hz), 7.43 (1H, dd, J = 7.7 Hz, J = 7.4 Hz), 3.93 (3H, s), 2.65 (2H, s ), 0.47 (6H, s)
３−ヒドロキシジメチルシリル安息香酸メチルエステル（１３）の合成
化合物（１３ｂ）１８３ｍｇをジメチルスルホキシド（以下ＤＭＳＯと略す）３ｍＬに溶解し、室温にてトリメチルアミンＮ−オキシド（以下ＴＭＡＮＯと略す）１９１ｍｇを加え室温で終夜撹拌した。次に水２０ｍＬを加え、酢酸エチル（２０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物を１３６ｍｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２で溶出）で精製し、無色油状の表題化合物３５ｍｇ（収率：２６％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.２４（１Ｈ、ｓ）、８.０３（１Ｈ、ｄ、Ｊ＝７.７Ｈｚ）、７.７７（１Ｈ、ｄ、Ｊ＝７.４Ｈｚ）、７.４３（１Ｈ、ｄｄ、Ｊ＝７.７Ｈｚ、Ｊ＝７.４Ｈｚ）、３.９１（３Ｈ、ｓ）、２.６３（１Ｈ、ｂｒｓ）、０.４２（６Ｈ、ｓ）
Synthesis of 3-hydroxydimethylsilylbenzoic acid methyl ester (13) 183 mg of compound (13b) was dissolved in 3 mL of dimethyl sulfoxide (hereinafter abbreviated as DMSO), and 191 mg of trimethylamine N-oxide (hereinafter abbreviated as TMANO) was added at room temperature. And stirred overnight. Next, 20 mL of water was added and extracted with ethyl acetate (20 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 136 mg of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 1: 2) gave 35 mg (yield: 26%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
8.24 (1H, s), 8.03 (1H, d, J = 7.7 Hz), 7.77 (1H, d, J = 7.4 Hz), 7.43 (1H, dd, J = 7 0.7 Hz, J = 7.4 Hz), 3.91 (3H, s), 2.63 (1H, brs), 0.42 (6H, s)
実施例１４
４−ブロモメチルジメチルシリル安息香酸（１４ａ）の合成
４−ブロモ安息香酸３．０１ｇを用いて化合物（１３ａ）と同様の方法でリチウム化後、ブロモメチルジメチルシリルクロリド４.５９ｍＬを反応させ、同様の処理により白色固体の表題化合物６８７ｍｇ（収率：１７％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.１０（２Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、７.６６（２Ｈ、ｄ、Ｊ＝８.２Ｈｚ）、２.６５（２Ｈ、ｓ）、０.４８（６Ｈ、ｓ）
Example 14
Synthesis of 4-bromomethyldimethylsilylbenzoic acid (14a) After lithiation in the same manner as compound (13a) using 3.01 g of 4-bromobenzoic acid, 4.59 mL of bromomethyldimethylsilyl chloride was reacted, and the same Gave 687 mg (yield: 17%) of the title compound as a white solid.
1 H-NMR (CDCl 3 , δ ppm):
8.10 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz), 2.65 (2H, s), 0.48 (6H, s)
４−ブロモメチルジメチルシリル安息香酸メチルエステル（１４ｂ）の合成
化合物（１４ａ）６８５ｍｇを用いて化合物（１３ｂ）と同様の反応を実施し、無色油状の表題化合物４７０ｍｇ（収率：６５％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
８.０２（２Ｈ、ｄ、Ｊ＝８.２Ｈｚ）、７.６２（２Ｈ、ｄ、Ｊ＝８.２Ｈｚ）、３.９２（３Ｈ、ｓ）、２.６４（２Ｈ、ｓ）、０.４６（６Ｈ、ｓ）
Synthesis of 4-bromomethyldimethylsilylbenzoic acid methyl ester (14b) Using 685 mg of compound (14a), the same reaction as compound (13b) was carried out to obtain 470 mg (yield: 65%) of the title compound as a colorless oil. It was.
1 H-NMR (CDCl 3 , δ ppm):
8.02 (2H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.2 Hz), 3.92 (3H, s), 2.64 (2H, s), 0.8 46 (6H, s)
４−ヒドロキシジメチルシリル安息香酸メチルエステル（１４）の合成
化合物（１４ｂ）１６１ｍｇを用いて化合物（１３）と同様の反応を実施し、無色油状の表題化合物８０ｍｇ（収率：６７％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.９６（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、７.６３（２Ｈ、ｄ、Ｊ＝７.９Ｈｚ）、３.８９（３Ｈ、ｓ）、３.００（１Ｈ、ｂｒｓ）、０.３９（６Ｈ、ｓ）
Synthesis of 4-hydroxydimethylsilylbenzoic acid methyl ester (14) Using 161 mg of compound (14b), a reaction similar to that of compound (13) was carried out to obtain 80 mg (yield: 67%) of the title compound as a colorless oil. .
1 H-NMR (CDCl 3 , δ ppm):
7.96 (2H, d, J = 7.9 Hz), 7.63 (2H, d, J = 7.9 Hz), 3.89 (3H, s), 3.00 (1H, brs), 0.8. 39 (6H, s)
実施例１５
４−ブロモメチルジメチルシリルアニソール（１５ａ）の合成
アルゴン気流下、４−ブロモアニソール１.０ｇを乾燥テトラヒドロフラン２４ｍＬに溶解し、−７８℃で１.６５ｍｏｌ／Ｌのｎ−ブチルリチウムヘキサン溶液３.５６ｍＬを徐々に滴下し、同温で３０分撹拌後、ブロモメチルジメチルシリルクロリド０.８７ｍＬを滴下した。０℃で３０分撹拌後、飽和塩化アンモニウム水溶液１０ｍＬでクエンチし反応液を濃縮した。残渣に水５０ｍＬを加え、酢酸エチル（５０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物１.５２ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝５：９５で溶出）で精製し、無色油状の表題化合物５３６ｍｇ（収率：３９％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４８（２Ｈ、ｄ、Ｊ＝８.７Ｈｚ）、６.９４（２Ｈ、ｄ、Ｊ＝８.７Ｈｚ）、３.８２（３Ｈ、ｓ）、２.６２（２Ｈ、ｓ）、０.４２（６Ｈ、ｓ）
Example 15
Synthesis of 4-bromomethyldimethylsilylanisole (15a) Under an argon stream, 1.0 g of 4-bromoanisole was dissolved in 24 mL of dry tetrahydrofuran, and 3.56 mL of a 1.65 mol / L n-butyllithium hexane solution at -78 ° C. Was gradually added dropwise, and after stirring at the same temperature for 30 minutes, 0.87 mL of bromomethyldimethylsilyl chloride was added dropwise. After stirring at 0 ° C. for 30 minutes, the reaction solution was concentrated by quenching with 10 mL of saturated aqueous ammonium chloride solution. 50 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (50 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 1.52 g of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 5: 95) gave 536 mg (yield: 39%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.48 (2H, d, J = 8.7 Hz), 6.94 (2H, d, J = 8.7 Hz), 3.82 (3H, s), 2.62 (2H, s), 0.8 42 (6H, s)
４−ヒドロキシジメチルシリルアニソール（１５）の合成
化合物（１５a）１５４ｍｇをＤＭＳＯ３.０ｍＬに溶解し、室温にてＴＭＡＮＯ１７８ｍｇを加え、室温で終夜撹拌した。次に水２０ｍＬを加え、酢酸エチル（２０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物を１１１ｍｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：３で溶出）で精製し、無色油状の表題化合物６９ｍｇ（収率：６４％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５２（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、６.９２（２Ｈ、ｄ、Ｊ＝８.４Ｈｚ）、３.８２（３Ｈ、ｓ）、１.９２（１Ｈ、ｂｒｓ）、０.３８（６Ｈ、ｓ）
Synthesis of 4-hydroxydimethylsilylanisole (15) 154 mg of the compound (15a) was dissolved in 3.0 mL of DMSO, 178 mg of TMANO was added at room temperature, and the mixture was stirred at room temperature overnight. Next, 20 mL of water was added and extracted with ethyl acetate (20 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 111 mg of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 1: 3) gave 69 mg (yield: 64%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.52 (2H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.4 Hz), 3.82 (3H, s), 1.92 (1H, brs), 0.7. 38 (6H, s)
実施例１６
４−クロロメチルジメチルシリル−クロロベンゼン（１６ａ）の合成
４−ブロモ−クロロベンゼン４.９１ｇを用いて化合物（１５ａ）と同様に、ブロモメチルジメチルシリルクロリドの代わりにクロロメチルジメチルシリルクロリドを用いて反応を実施することにより、無色油状の表題化合物４.１８ｇ（収率：７４％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４７（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、７.３５（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、２.９３（２Ｈ、ｓ）、０.４１（６Ｈ、ｓ）
４−ヒドロキシジメチルシリル−クロロベンゼン（１６）の合成
化合物（１６ａ）２１９ｍｇをＤＭＳＯ５.０ｍＬに溶解し、室温にてＮ−メチルモルホリンＮ−オキシド４６９ｍｇを加え、６０℃で３２時間撹拌した。次に室温まで冷却後、水２０ｍＬを加え、酢酸エチル（２０ｍＬ×３）で抽出した。硫酸ナトリウムで乾燥後、溶媒を留去し粗生成物を２０３ｍｇ得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４で溶出）で精製し、無色油状の表題化合物１３１ｍｇ（収率：７０％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.４９（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、７.３４（２Ｈ、ｄ、Ｊ＝８.１Ｈｚ）、２.２８（１Ｈ、ｓ）、０.３７（６Ｈ、ｓ）
Example 16
Synthesis of 4-chloromethyldimethylsilyl-chlorobenzene (16a) Using 4.91 g of 4-bromomethylchlorosilyl, the reaction was carried out using chloromethyldimethylsilyl chloride instead of bromomethyldimethylsilyl chloride in the same manner as compound (15a). As a result, 4.18 g (yield: 74%) of the title compound as a colorless oil was obtained.
1 H-NMR (CDCl 3 , δ ppm):
7.47 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 2.93 (2H, s), 0.41 (6H, s)
Synthesis of 4-hydroxydimethylsilyl-chlorobenzene (16) 219 mg of the compound (16a) was dissolved in 5.0 mL of DMSO, 469 mg of N-methylmorpholine N-oxide was added at room temperature, and the mixture was stirred at 60 ° C. for 32 hours. Next, after cooling to room temperature, 20 mL of water was added and extracted with ethyl acetate (20 mL × 3). After drying with sodium sulfate, the solvent was distilled off to obtain 203 mg of a crude product. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 1: 4) gave the title compound (131 mg, yield: 70%) as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.49 (2H, d, J = 8.1 Hz), 7.34 (2H, d, J = 8.1 Hz), 2.28 (1H, s), 0.37 (6H, s)
実施例１７
３−ブロモメチルジメチルシリルフラン（１７ａ）の合成
アルゴン気流下、３−ブロモフラン１.７９ｇを乾燥ジエチルエーテル４０ｍＬに溶解し、化合物（１６ａ）と同様の反応を行い、粗生成物３.０１ｇを得た。シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１０：９０で溶出）で精製し、白色油状の表題化合物２.１７ｇ（収率：８１％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５２（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝１.３Ｈｚ）、７.４５（１Ｈ、ｄｄ、Ｊ＝１.３、Ｊ＝０.８Ｈｚ）、６.４３（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝０.８Ｈｚ）、２.５８（２Ｈ、ｓ）、０.３７（６Ｈ、ｓ）
Example 17
Synthesis of 3-bromomethyldimethylsilylfuran (17a) Under an argon stream, 1.79 g of 3-bromofuran was dissolved in 40 mL of dry diethyl ether, and a reaction similar to that of the compound (16a) was performed to obtain 3.01 g of a crude product. It was. Purification by silica gel column chromatography (eluting with ethyl acetate: hexane = 10: 90) gave 2.17 g (yield: 81%) of the title compound as a white oil.
1 H-NMR (CDCl 3 , δ ppm):
7.52 (1H, dd, J = 1.6, J = 1.3 Hz), 7.45 (1H, dd, J = 1.3, J = 0.8 Hz), 6.43 (1H, dd, J = 1.6, J = 0.8 Hz), 2.58 (2H, s), 0.37 (6H, s)
２−ヒドロキシジメチルシリルフラン（１７）の合成
化合物（１７ａ）２１９ｍｇを用いて化合物（１５）と同様の反応を実施し、無色油状の表題化合物１００ｍｇ（収率：７０％）を得た。
1Ｈ−ＮＭＲ（ＣＤＣｌ３、δｐｐｍ）：
７.５１（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝１.３Ｈｚ）、７.４６（１Ｈ、ｄｄ、Ｊ＝１.３、Ｊ＝０.８Ｈｚ）、６.４４（１Ｈ、ｄｄ、Ｊ＝１.６、Ｊ＝０.８Ｈｚ）、２.０８（１Ｈ、ｂｒｓ）、０.３６（６Ｈ、ｓ）
Synthesis of 2-hydroxydimethylsilylfuran (17) 219 mg of the compound (17a) was used to carry out a reaction similar to the compound (15) to obtain 100 mg (yield: 70%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 , δ ppm):
7.51 (1H, dd, J = 1.6, J = 1.3 Hz), 7.46 (1H, dd, J = 1.3, J = 0.8 Hz), 6.44 (1H, dd, J = 1.6, J = 0.8 Hz), 2.08 (1H, brs), 0.36 (6H, s)
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013170123A (en) * | 2012-02-17 | 2013-09-02 | National Institute Of Advanced Industrial Science & Technology | Method for producing silanol under anhydrous condition |
| JP2020002121A (en) * | 2018-05-07 | 2020-01-09 | 達興材料股▲ふん▼有限公司 | Silicon-containing compound, and liquid-crystal composition and liquid-crystal display using the same |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013170123A (en) * | 2012-02-17 | 2013-09-02 | National Institute Of Advanced Industrial Science & Technology | Method for producing silanol under anhydrous condition |
| JP2020002121A (en) * | 2018-05-07 | 2020-01-09 | 達興材料股▲ふん▼有限公司 | Silicon-containing compound, and liquid-crystal composition and liquid-crystal display using the same |
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