CN104045513A - 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene, its preparation method and application as intermediate in preparation of anti-type II diabetes drugs - Google Patents
4-substituted-1-chloro-2-(4-fluorobenzyl)benzene, its preparation method and application as intermediate in preparation of anti-type II diabetes drugs Download PDFInfo
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- CN104045513A CN104045513A CN201310080816.5A CN201310080816A CN104045513A CN 104045513 A CN104045513 A CN 104045513A CN 201310080816 A CN201310080816 A CN 201310080816A CN 104045513 A CN104045513 A CN 104045513A
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- benzene
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- -1 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene Chemical class 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 241000486679 Antitype Species 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 10
- 229940079593 drug Drugs 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 18
- 230000000694 effects Effects 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 72
- 150000001875 compounds Chemical class 0.000 claims description 69
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000002585 base Substances 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 11
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007818 Grignard reagent Substances 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 239000000010 aprotic solvent Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 claims description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 6
- 239000003921 oil Substances 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000007259 addition reaction Methods 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 239000003849 aromatic solvent Substances 0.000 claims description 4
- 229910052728 basic metal Inorganic materials 0.000 claims description 4
- 150000003818 basic metals Chemical class 0.000 claims description 4
- 229910000085 borane Inorganic materials 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 claims description 4
- 229940055742 indium-111 Drugs 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000005062 perfluorophenyl group Chemical group FC1=C(C(=C(C(=C1F)F)F)F)* 0.000 claims description 4
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- UIDUKLCLJMXFEO-UHFFFAOYSA-N propylsilane Chemical compound CCC[SiH3] UIDUKLCLJMXFEO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000077 silane Inorganic materials 0.000 claims description 4
- 238000006884 silylation reaction Methods 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims description 4
- 229940094989 trimethylsilane Drugs 0.000 claims description 4
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 150000004795 grignard reagents Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims description 2
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- VXHYMZHKGHLQNO-UHFFFAOYSA-N methanesulfonic acid;toluene Chemical compound CS(O)(=O)=O.CC1=CC=CC=C1 VXHYMZHKGHLQNO-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical class [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical group [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 abstract description 6
- 229960003345 empagliflozin Drugs 0.000 abstract description 6
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 239000001301 oxygen Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- LSQARZALBDFYQZ-UHFFFAOYSA-N 4,4'-difluorobenzophenone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CC=C(F)C=C1 LSQARZALBDFYQZ-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229910052774 Proactinium Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000694440 Colpidium aqueous Species 0.000 description 1
- OBWASQILIWPZMG-UHFFFAOYSA-N Empagliflozin Chemical compound OC1C(O)C(O)C(CO)OC1C1=CC=C(Cl)C(CC=2C=CC(OC3COCC3)=CC=2)=C1 OBWASQILIWPZMG-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a compound 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene shown as formula V, its preparation method and application as an intermediate in preparation of anti-type II diabetes drugs, and especially discloses the compound 4-substituted-1-chloro-2-(4-fluorobenzyl)benzene shown as formula V and its application as an intermediate in preparation of anti-type II diabetes drug Empagliflozin shown as formula I. The method provided by the invention has the advantages of relatively cheap raw material and reagent, low cost, simple and safe operation, good yield, small environmental pollution, and very good economic effect, thus being suitable for industrial production.
Description
Technical field
The present invention relates to a kind of suc as formula the chloro-2-of compound 4-replacement-1-(4-luorobenzyl) benzene shown in V and preparation method thereof with as intermediate application in anti-type ii diabetes medicine in preparation, particularly relate to a kind of suc as formula the chloro-2-of compound 4-replacement-1-(4-luorobenzyl) benzene shown in V and as intermediate for the preparation of the anti-type ii diabetes medicine Empagliflozin suc as formula described in I.
Technical background
Empagliflozin(is as shown in the formula shown in I, CAS:864070-44-0) Shi You Boehringer Ingelheim company develops, be called as sodium glucose co-transporter 2 white-2(SGLT-2) a kind of in the compound of new generation of inhibitor, the effect of the reduction blood high glucose level (hyperglycemia) that does not rely on Regular Insulin can be provided, thereby its mechanism of action be blocking-up glucose kidney heavily absorb body in too much glucose via urine, discharge, reach and fall the hypoglycemic while and further alleviate patient's body weight.
Boehringer Ingelheim company discloses respectively two kinds of new preparation technologies of above-mentioned formula I compound in patent WO2006120208A, WO2011039108A.Yet up to the present, the route of synthesis of this compound is also more limited.
Summary of the invention
It is a kind of suc as formula the chloro-2-of compound 4-replacement-1-(4-luorobenzyl) benzene shown in V and preparation method thereof that technical problem to be solved by this invention is to provide, and this compound as intermediate for the preparation of the anti-type ii diabetes medicine Empagliflozin suc as formula described in I.The inventive method desired raw material and reagent price are relatively cheap, with low cost, safety simple to operation, and yield is good, and environmental pollution is simultaneously little, has good economic benefits, suitable industrial production.
The described chloro-2-of formula V compound 4-replacement-1-(4-luorobenzyl) benzene, its structural formula is as follows:
Wherein, X is halogen, preferably bromine or iodine.
The preparation method of described formula V compound, comprises the following steps: take formula VI compound as starting raw material (this compou nd synthesis is referring to patent WO2006120208A), under reductive agent effect, carbonyl reduction makes formula V compound.Reaction formula is as follows:
Wherein, described reductive agent is selected from: 1) silane of C1-C3 is as triethyl silicane, trimethyl silane, three n-propyl silane, or tri isopropyl silane; 2) hydroborate is as sodium borohydride, POTASSIUM BOROHYDRIDE, or borine; Or 3) alanate is as lithium aluminum hydride; Above system is reduced under lewis acidic existence, and described Lewis acid is selected from: boron trifluoride diethyl etherate, three perfluorophenyl borines, trifluoroacetic acid, hydrogenchloride and solution, hydrogen bromide and solution thereof, aluminum chloride, or Indium-111 chloride; Described reaction is carried out in aprotic solvent, and aprotic solvent is selected from: methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene, acetonitrile, tetrahydrofuran (THF), normal hexane, sherwood oil, normal heptane, or any two or more mixed solvent wherein; Temperature of reaction is-20～130 ℃, preferably 20～100 ℃.
The above-mentioned formula V compound of take is key intermediate, is used for synthesizing suc as formula the anti-type ii diabetes medicine Empagliflozin described in I, specifically comprises the following steps:
1) formula V compound and formula VII compound carry out addition reaction by basic metal reagent, obtain formula IV compound subsequently in C1-C3 alcoholic solution through acid catalysis;
2) formula IV compound is reduced to obtain formula III compound under the effect of reductive agent and acid additives;
3) formula III compound reacts to obtain formula II compound with formula VIII compound under basic cpd effect;
4) formula II compound Deprotection under the effect of metal catalyst obtains formula I compound, or formula II compound Deprotection under acid effect obtains formula I compound.
Reaction formula is as follows:
X is bromine or iodine, R
1for C1-C6 silylation protecting group or benzyl class protecting group, R
2for C1-C3 alkyl.
Preferably, described C1-C6 silylation protecting group as: trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, or t-Butyldimethylsilyl; Described benzyl class protecting group is as trityl Trity, benzyl Bn, 4-methoxy-benzyl PMB, 4-methyl-benzyl, 4-nitrobenzyl, 2,4-dimethoxy-benzyl DMB, carbobenzoxy-(Cbz) Cbz, 4-methoxyl group benzyloxy carbonyl, or 4-methyl carbobenzoxy-(Cbz); Described C1-C3 alkyl is as methyl, ethyl, n-propyl, or sec.-propyl.
Wherein, in step 1), described basic metal reagent is selected from: a) alkyl lithium reagents is as n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, and b) Grignard reagent is as sec.-propyl Grignard reagent, or c) mixed system of normal-butyl Grignard reagent and lithium chloride; Described addition reaction is carried out in organic solvent, organic solvent is selected from: C2-C8 ether or its inertia aromatic solvents, wherein C2-C8 ether is as tetrahydrofuran (THF), dioxane, ether, methyl tertiary butyl ether, or methyl-phenoxide, and aromatic solvents is as benzene,toluene,xylene or their mixed solution; Temperature of reaction is-90～140 ℃, preferably-80～80 ℃; Described C1-C3 alcoholic solution is methyl alcohol, ethanol, n-propyl alcohol, or Virahol; Described acid catalyst is as: methylsulfonic acid, benzene methanesulfonic acid, to methylbenzene methylsulfonic acid, trifluoromethanesulfonic acid, or hydrogenchloride and solution thereof.
Step 2) in, described reductive agent is selected from: a) silane of C1-C3 is as triethyl silicane, trimethyl silane, three n-propyl silane, or tri isopropyl silane; B) hydroborate is as sodium borohydride, POTASSIUM BOROHYDRIDE, or borine; Or c) alanate is as lithium aluminum hydride; Described acid additives is as boron trifluoride diethyl etherate, three perfluorophenyl borines, trifluoroacetic acid, hydrogenchloride and solution, hydrogen bromide and solution thereof, aluminum chloride, or Indium-111 chloride; Described reaction is carried out in aprotic solvent, and aprotic solvent is selected from: methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene, acetonitrile, tetrahydrofuran (THF), normal hexane, sherwood oil, normal heptane, or any two or more mixed solvent wherein; Temperature of reaction is-20～130 ℃, preferably 20～100 ℃.
In step 3), described basic cpd is selected from: the alcohol alkali of C1-C8 or phenol alkali, carbonic acid alkali, alkali metal hydroxide, the tertiary amine of C1-C3, or other nitrogenous class organic basess, for example: potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diisopropyl ethyl amine, hexamethyldisilane base sodium amide, hexamethyldisilane base Lithamide, hexamethyldisilane base potassium amide, 1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylene diamine (DABCO) or their mixture, preferred potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide and composition thereof, the consumption of described basic cpd is 1-5 times of formula III compound mol ratio, and preferably 1-1.5 doubly.The consumption of formula VIII compound is 1-3 times of formula III compound mol ratio, and preferably 1-1.3 doubly; Reaction solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, or dimethyl sulfoxide (DMSO); Temperature of reaction is-20～80 ℃, preferably-10～30 ℃.
In step 4), described metal catalyst is selected from Ni/C, Pd/C, or Pt/C class catalyzer, in wherein said Ni/C catalyzer, Ni content is 2-20%, preferably 5-10%, Ni/C consumption is the 5-50wt% of formula II compound, preferred 20-30%, temperature of reaction is 0～100 ℃, preferably 20-80 ℃, hydrogenation pressure is 0.1-25MPa, preferably 10-15MPa; Described Pd/C Palladium Content in Catalyst is 5-10%, and Pd/C usage quantity is the 10-50% of formula II compound, preferably 20-30%; Reaction solvent is selected from: C1-C4 alkyl alcohol is as methyl alcohol, ethanol, Virahol, butanols, or C1-C4 alkyl oxide is as ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl-phenoxide, and acetonitrile, benzene, toluene, dimethylbenzene.
Described Pd/C catalyzer can be used jointly with LiCl, and wherein LiCl consumption is the 5-50% of formula II compound molar weight, preferably 10-20%; Or described Pd/C catalyzer can use jointly with formiate, to avoid using hydrogen, wherein formate is potassium formiate or ammonium formiate, the consumption of formate be formula II compound mol ratio 4-10 doubly.
In step 4), described acid is organic acid or mineral acid, wherein organic carboxyl acid is as citric acid, oxalic acid, acetic acid, methylsulfonic acid, benzene methanesulfonic acid, trifluoromethanesulfonic acid, or tosic acid, mineral acid is as hydrogenchloride and solution, hydrogen bromide and solution thereof, sulfuric acid, or phosphoric acid, temperature of reaction is-10～60 ℃, preferably 20-30 ℃.
The present invention is usingd formula V and is synthesized suc as formula the anti-type ii diabetes medicine Empagliflozin shown in I as key intermediate, desired raw material and reagent price are relatively cheap, with low cost, operational path section, safety simple to operation, yield is good, and environmental pollution is simultaneously little, there are good economic benefits, suitable industrial production.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is described in further detail, but described embodiment does not limit the scope of the invention.Should be noted that, following examples are only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement the technical scheme of invention, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in claim scope of the present invention.
Synthesizing of the chloro-2-of the bromo-1-of example 14-(4-luorobenzyl) benzene (Va)
In 500mL there-necked flask, add (the bromo-2-chloro-phenyl-of 5-) (4-fluorophenyl) ketone (VIa, 31.3g, 100mmol) with methylene dichloride 190mL, under room temperature, after stirring and dissolving, be down to 0～5 ℃, slowly drip triethyl silicane (44.2g, 380mmol), control afterwards temperature and between 0～5 ℃, slowly drip boron trifluoride diethyl etherate (51.8g, 365mmol), rise again to 20～30 ℃ of reactions 4～6 hours, HPLC tracks to raw material residue <3%.In reaction flask, add 150mL saturated sodium bicarbonate aqueous solution, stir separatory 30 minutes.Organic phase is concentrated into without cut and flows out, and adds 230g deionized water, is stirred to solid and separates out, and filters.Solid dissolves with 110mL acetonitrile, drips 110mL2% aqueous sodium hydroxide solution, stirs, and system is filtered, and filter cake, with after little water washing, is dried, and obtains off-white color solid, i.e. the chloro-2-of the bromo-1-of compound 4-(4-luorobenzyl) benzene (Va) (25.1g, yield 84%).
MS(ESI)301.0(M+H
+，100%)
Synthesizing of the chloro-2-of example 21-(4-luorobenzyl)-4-iodobenzene (Vb)
In 500mL there-necked flask, add (the chloro-5-iodophenyl of 2-) (4-fluorophenyl) ketone (VIb, 36.1g, 100mmol) with acetonitrile 180mL, under room temperature, after stirring and dissolving, be down to 0～5 ℃, slowly drip triethyl silicane (44.2g, 380mmol), control afterwards and at 0～5 ℃ of temperature, slowly drip boron trifluoride diethyl etherate (51.8g, 365mmol), rise again to 20-30 ℃ of reaction 4-6 hour, HPLC tracks to raw material residue and is less than 3%.In reaction flask, add 150mL saturated sodium bicarbonate aqueous solution, stir separatory 30 minutes.Organic phase is concentrated into 95～110mL, adds 230g deionized water, is stirred to solid and separates out, and filters.The system drip washing (100mL) of acetonitrile/water for solid=1/3, dries, and obtains off-white color solid, i.e. the chloro-2-of compound 1-(4-luorobenzyl)-4-iodobenzene (Vb) (27.4g, yield 79%).
MS(ESI)347.0(M+H
+，100%)
Example 3 (2S, 3R, 4S, 5R, 6R)-3,4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group tetrahydrochysene-2H-pyrans (IVa) synthetic
Method 1): in there-necked flask, add the bromo-1-of 4-chloro-2-(4-luorobenzyl) benzene (Va, 3g, 10mmol) and 15mL THF; nitrogen protection borehole cooling, to-78 ℃, slowly drips the n-heptane solution (10mL, 10mmol) of n-Butyl Lithium; dropwise-78 ℃ of insulated and stirred 1 hour.At-78 ℃, drip (3R, 4S, 5R, 6R)-3,4, the THF solution of 5-tri-(benzyloxy)-6-(benzyloxymethyl) tetrahydrochysene-2H-pyran-2-one (10mmol, is dissolved in 6mL THF for VIIa, 5.4g), system is reacted 1 hour at-78 ℃.Add afterwards the methanol solution 20mL containing 1.5mL methylsulfonic acid, system is risen again to stirred overnight at room temperature.In system, add saturated sodium bicarbonate aqueous solution cancellation reaction, separatory, water extracts at twice by 50mL ethyl acetate, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, concentrate to obtain yellow oil 5.4g, be compound (2S, 3R, 4S, 5R, 6R)-3,4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group tetrahydrochysene-2H-pyrans (IVa) (crude product yield 70%).
MS(ESI)773.3(M+H
+，100%)
Method 2): use the chloro-2-of 1-(4-luorobenzyl)-4-iodobenzene (Vb) as starting raw material, other operation stepss are with method 1), obtain dark oily matter 6g, be compound (2S, 3R, 4S, 5R, 6R)-3,4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group tetrahydrochysene-2H-pyrans (IVa) (crude product yield 77%).
MS(ESI)773.3(M+H
+，100%)
Synthesizing of example 4 ((2S, 3R, 4S, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) Trimethoxy silane (IVb)
Method 1): in the there-necked flask of nitrogen protection, add the chloro-2-of 1-(4-luorobenzyl)-4-iodobenzene (Vb; 6.9g; 20mmol) and 15mLTHF; control temperature between-20 to-10 ℃; the mixing solutions (10mL Grignard reagent dissolves in 0.85g Lithium chloride (anhydrous)) that drips sec.-propyl Grignard reagent and Lithium chloride (anhydrous), drips rear reaction system insulation reaction 1.5h at-20～-10 ℃.Slowly drip afterwards (3R, 4S, 5R, 6R)-3,4, the THF solution (VIIb of 5-tri-(trimethylsiloxy group)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyran-2-one, 9.3g, 20mmol, is dissolved in 15mLTHF), insulation reaction 0.5-1h at-10～-5 ℃.Aqueous citric acid solution 30mL to adding 10% in system, rises again to stirring at room 2h, separatory, and ethyl acetate 50mL extraction twice for water, merges organic phase, saturated common salt water washing, organic phase anhydrous sodium sulfate drying, concentrates and to obtain oily matter.In this oily matter, add 20mL dissolve with methanol, slowly add the HCl methanol solution 2mL of 1.25N under room temperature, system reaction is spent the night, and concentrated organic phase is also with three times with methylene dichloride 20mL * 3 are de-.Add afterwards 30mL methylene dichloride, system is cooled to 0～10 ℃, to system, add 12g(118mmol) triethylamine, and slowly drip TMSCl(12g, 111mmol), system, to room temperature reaction 2h, filters out white solid, filtrate is used saturated aqueous common salt washed twice, anhydrous sodium sulfate drying, concentrates to obtain dark oily matter 8.5g, i.e. compound ((2S, 3R, 4S, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) Trimethoxy silane (IVb) (crude product yield 61%).
MS(ESI)701.3(M+H
+，100%)
Method 2): use the bromo-1-of 4-chloro-2-(4-luorobenzyl) benzene (Va) as starting raw material, other operation stepss are with method 1), obtain dark oily matter 7.5g, be compound ((2S, 3R, 4S, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) Trimethoxy silane (IVb) (crude product yield 54%).
MS(ESI)701.3(M+H
+，100%)
Example 5 (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-luorobenzyl) phenyl) tetrahydrochysene-2H-pyrans (IIIa) synthetic
In there-necked flask, add (2S, 3R, 4S, 5R, 6R)-3,4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group tetrahydrochysene-2H-pyrans crude product (IVa, 5g, 6.5mmol) and 20mL methylene dichloride, be cooled between-10～-5 ℃, to system, drip 4.5mL triethyl silicane, keep afterwards this temperature, drip 1.2mL boron trifluoride diethyl etherate.Reaction system is reacted 4h between-5～0 ℃.To system, add 5% sodium bicarbonate aqueous solution 30mL, stir separatory after 0.5h, water dichloromethane extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, filtering and concentrating obtains faint yellow oily matter 3.8g, be compound (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-luorobenzyl) phenyl) tetrahydrochysene-2H-pyrans (IIIa) (yield 80%.）。
MS(ESI)743.3(M+H
+，100%)
Synthesizing of example 6 ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) trimethicone (IIIb)
With ((2S, 3R, 4S, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-2-methoxyl group-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) Trimethoxy silane (IVb) is starting raw material, the similar example 5 of synthetic operation, obtain yellow oil, i.e. compound ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-tri-bases) trimethicone (IIIb), yield 74%.
MS(ESI)671.3(M+H
+，100%)
Example 7 (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa) synthetic
In there-necked flask, add (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-luorobenzyl) phenyl) tetrahydrochysene-2H-pyrans (IIIa, 7.4g, 10mmol) and 20mL THF, at 10～20 ℃, add (S)-3-hydroxyl tetrahydrofuran (VIII, 0.9g, 11mmol), at this temperature, continue to add solid potassium tert-butoxide (1.3g, 12mmol), system at room temperature stirs 1 hour.In system, add 20mL water, stir 15 minutes, separate organic phase, water is extracted with ethyl acetate three times, merges organic phase, concentrated rear column chromatography for separation (PE/EA=2/1), obtain off-white color solid 7.0g, be compound (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa) (yield 86%).
MS(ESI)811.3(M+H
+，100%)
Example 8 ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) trimethoxy siloxane (IIb) is synthetic
With ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-luorobenzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-bases) trimethicone (IIIb) is starting raw material, the similar example 7 of synthetic operation, obtain white solid, i.e. compound ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-tri-bases) trimethoxy siloxane (IIb), yield 80%.
MS(ESI)739.3(M+H
+，100%)
Example 9 (1S)-1, the chloro-3-[[4-[[(3S of 5-dehydration-1-C-[4-)-tetrahydrochysene-3-furyl] oxygen base] phenyl] methyl] phenyl]-D-Glucose alcohol (I) synthetic
Method 1): in autoclave, add (2R, 3R, 4R, 5S, 6S)-3,4, the methanol solution (methyl alcohol 20mL) of 5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa, 5g, 6.2mmol), add 10%Pa/C(1.5g, 30%wt) and lithium chloride (0.5g, 10%wt), system is at 20～25 ℃, under 0.1-0.3MPa hydrogen pressure, react 24h, filtration system, concentrated rear column chromatography (DCM/EA=5/1), obtains white solid, be formula I compound (1.7g, yield 61%).
Method 2): in autoclave, add (2R, 3R, 4R, 5S, 6S)-3,4,5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa, 5g, 6.2mmol) methanol solution (methyl alcohol 20mL), add 10%Ni/C(1.5g, 30%wt), system, at 40～50 ℃, is reacted 12h under 20～25MPa pressure, filters, column chromatography (DCM/EA=5/1) after concentrated, obtain white solid, i.e. formula I compound (2.5g, yield 89%).
Method 3): in there-necked flask, add (2R, 3R, 4R, 5S, 6S)-3,4, the tetrahydrofuran solution (tetrahydrofuran (THF) 20mL) of 5-tri-(benzyloxy)-2-(benzyloxymethyl)-6-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl) tetrahydrochysene-2H-pyrans (IIa, 5g, 6.2mmol), add 10%Pa/C(1.5g, 30%wt), add ammonium formiate (3.89g, 62mmol), system backflow 4h, cooled and filtered, column chromatography (DCM/EA=5/1) after filtrate is concentrated, obtains white solid, be formula I compound (2.0g, yield 71%).
MS(ESI)451.2(M+H
+，100%)
Example 10 (1S)-1, the chloro-3-[[4-[[(3S of 5-dehydration-1-C-[4-)-tetrahydrochysene-3-furyl] oxygen base] phenyl] methyl] phenyl]-D-Glucose alcohol (I) synthetic
In reaction flask, add ((2S, 3S, 4R, 5R, 6R)-2-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyrans-3,4,5-tri-bases) trimethoxy siloxane (IIb, 7.4g, 10mmol) and 25mL ethanol, hierarchy of control temperature 10-20 ℃, to system, slowly drip 10% HCl ethanolic soln 5mL, system at room temperature stirs 2h, and phase system adds saturated sodium bicarbonate to adjust pH to 6.5～7.5, to system, add 20mL ethyl acetate, separatory.Water is extracted with ethyl acetate three times, merges organic phase, and concentrated rear column chromatography (DCM/EA=5/1), obtains white solid, i.e. formula I compound (3.6g, yield 85%).
MS(ESI)451.2(M+H
+，100%)
Claims (10)
1. as shown in the formula the chloro-2-of compound 4-replacement-1-(4-luorobenzyl) benzene shown in V,
Wherein, X is bromine or iodine.
2. the preparation method of formula V compound claimed in claim 1, is characterized in that, comprises the following steps: the formula VI compound of take is starting raw material, carbonyl reduction preparation formula V compound under reductive agent effect; Reaction formula is as follows:
Wherein, described reductive agent is selected from: 1) silane of C1-C3 is as triethyl silicane, trimethyl silane, three n-propyl silane, or tri isopropyl silane; 2) hydroborate is as sodium borohydride, POTASSIUM BOROHYDRIDE, or borine; Or 3) alanate is as lithium aluminum hydride; Above system is reduced under lewis acidic existence, and described Lewis acid is selected from: boron trifluoride diethyl etherate, three perfluorophenyl borines, trifluoroacetic acid, hydrogenchloride and solution, hydrogen bromide and solution thereof, aluminum chloride, or Indium-111 chloride; Described reaction is carried out in aprotic solvent, and aprotic solvent is selected from: methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene, acetonitrile, tetrahydrofuran (THF), normal hexane, sherwood oil, normal heptane, or any two or more mixed solvent wherein; Temperature of reaction is-20～130 ℃.
3. suc as formula a preparation method for the anti-type ii diabetes medicine described in I, it is characterized in that, the formula V compound of usining synthesizes as key intermediate, specifically comprises the following steps:
1) formula V compound and formula VII compound carry out addition reaction by basic metal reagent, obtain formula IV compound subsequently in C1-C3 alcoholic solution through acid catalysis;
2) formula IV compound is reduced to obtain formula III compound under the effect of reductive agent and acid additives;
3) formula III compound reacts to obtain formula II compound with formula VIII compound under basic cpd effect;
4) formula II compound Deprotection under the effect of metal catalyst obtains formula I compound, or formula II compound Deprotection under acid effect obtains formula I compound; Reaction formula is as follows:
Wherein X is bromine or iodine, and R1 is C1-C6 silylation protecting group or benzyl class protecting group, and R2 is C1-C3 alkyl.
4. method according to claim 3, is characterized in that, described C1-C6 silylation protecting group as: trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, or t-Butyldimethylsilyl; Described benzyl class protecting group is as trityl Trity, benzyl Bn, 4-methoxy-benzyl PMB, 4-methyl-benzyl, 4-nitrobenzyl, 2,4-dimethoxy-benzyl DMB, carbobenzoxy-(Cbz) Cbz, 4-methoxyl group benzyloxy carbonyl, or 4-methyl carbobenzoxy-(Cbz); Described C1-C3 alkyl is as methyl, ethyl, n-propyl, or sec.-propyl.
5. method according to claim 3, it is characterized in that, in step 1), described basic metal reagent is selected from: a) alkyl lithium reagents is as n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, b) Grignard reagent is as sec.-propyl Grignard reagent, or c) mixed system of normal-butyl Grignard reagent and lithium chloride; Described addition reaction is carried out in organic solvent, organic solvent is selected from: C2-C8 ether or its inertia aromatic solvents, wherein C2-C8 ether is as tetrahydrofuran (THF), dioxane, ether, methyl tertiary butyl ether, or methyl-phenoxide, and aromatic solvents is as benzene,toluene,xylene or their mixed solution; Temperature of reaction is-90～140 ℃; Described C1-C3 alcoholic solution is methyl alcohol, ethanol, n-propyl alcohol, or Virahol; Described acid catalyst is as: methylsulfonic acid, benzene methanesulfonic acid, to methylbenzene methylsulfonic acid, trifluoromethanesulfonic acid, or hydrogenchloride and solution thereof.
6. method according to claim 3, is characterized in that step 2) in, described reductive agent is selected from: a) silane of C1-C3 is as triethyl silicane, trimethyl silane, three n-propyl silane, or tri isopropyl silane; B) hydroborate is as sodium borohydride, POTASSIUM BOROHYDRIDE, or borine; Or c) alanate is as lithium aluminum hydride; Described acid additives is as boron trifluoride diethyl etherate, three perfluorophenyl borines, trifluoroacetic acid, hydrogenchloride and solution, hydrogen bromide and solution thereof, aluminum chloride, or Indium-111 chloride; Described reaction is carried out in aprotic solvent, and aprotic solvent is selected from: methylene dichloride, 1,2-ethylene dichloride, benzene,toluene,xylene, acetonitrile, tetrahydrofuran (THF), normal hexane, sherwood oil, normal heptane, or any two or more mixed solvent wherein; Temperature of reaction is-20～130 ℃.
7. method according to claim 3, it is characterized in that, in step 3), described basic cpd is selected from: potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diisopropyl ethyl amine, hexamethyldisilane base sodium amide, hexamethyldisilane base Lithamide, hexamethyldisilane base potassium amide, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), triethylene diamine (DABCO), or their mixture; The consumption of described basic cpd is 1-5 times of formula III compound mol ratio; The consumption of formula VIII compound is 1-3 times of formula III compound mol ratio; Reaction solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, or dimethyl sulfoxide (DMSO); Temperature of reaction is-20～80 ℃.
8. method according to claim 3, is characterized in that, in step 4), described metal catalyst is selected from Ni/C, Pd/C, or Pt/C class catalyzer; In wherein said Ni/C catalyzer, Ni content is 2-20wt%, and Ni/C consumption is the 5-50wt% of formula II compound, and temperature of reaction is 0～100 ℃, and hydrogenation pressure is 0.1-25MPa; Described Pd/C Palladium Content in Catalyst is 5-10wt%, and Pd/C usage quantity is the 10-50wt% of formula II compound; Reaction solvent is selected from: methyl alcohol, ethanol, Virahol, butanols, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl-phenoxide, acetonitrile, benzene, toluene, or dimethylbenzene.
9. method according to claim 3, is characterized in that, in step 4), described Pd/C catalyzer can be used jointly with LiCl, and wherein LiCl consumption is the 5-50% of formula II compound molar weight; Or described Pd/C catalyzer can use jointly with formiate, to avoid using hydrogen, wherein formate is potassium formiate or ammonium formiate, the consumption of formate be formula II compound mol ratio 4-10 doubly.
10. method according to claim 3, it is characterized in that, in step 4), described acid is organic acid or mineral acid, wherein organic carboxyl acid is as citric acid, oxalic acid, acetic acid, methylsulfonic acid, benzene methanesulfonic acid, trifluoromethanesulfonic acid, or tosic acid, and mineral acid is as hydrogenchloride and solution, hydrogen bromide and solution thereof, sulfuric acid, or phosphoric acid, temperature of reaction is-10～60 ℃.
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| CN104877136A (en) * | 2015-04-30 | 2015-09-02 | 大连理工大学 | Long-branched-chain polysulfone anionic membrane and preparation method thereof |
| CN106117192A (en) * | 2016-06-23 | 2016-11-16 | 甘肃成纪生物药业有限公司 | The synthetic method that a kind of En Gelie is clean |
| CN106336403A (en) * | 2015-07-14 | 2017-01-18 | 江苏豪森药业集团有限公司 | Industrial preparation method for empagliflozin |
| CN106674080A (en) * | 2015-11-10 | 2017-05-17 | 南京卡文迪许生物工程技术有限公司 | Synthesis method of panobinostat |
| CN108752170A (en) * | 2018-07-20 | 2018-11-06 | 中山大学 | A method of catalysis benzalcohol derivatives etherificate |
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| CN104877136A (en) * | 2015-04-30 | 2015-09-02 | 大连理工大学 | Long-branched-chain polysulfone anionic membrane and preparation method thereof |
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| CN106336403A (en) * | 2015-07-14 | 2017-01-18 | 江苏豪森药业集团有限公司 | Industrial preparation method for empagliflozin |
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| CN106117192A (en) * | 2016-06-23 | 2016-11-16 | 甘肃成纪生物药业有限公司 | The synthetic method that a kind of En Gelie is clean |
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| CN108752170A (en) * | 2018-07-20 | 2018-11-06 | 中山大学 | A method of catalysis benzalcohol derivatives etherificate |
| CN111410639A (en) * | 2020-04-14 | 2020-07-14 | 天津法莫西医药科技有限公司 | Preparation method of empagliflozin intermediate impurity |
| CN117800939A (en) * | 2022-09-23 | 2024-04-02 | 浙江宏元药业股份有限公司 | Characteristic impurities in empagliflozin raw materials or preparations and their applications |
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