CN116239643A - Engliflozin intermediate compound - Google Patents
Engliflozin intermediate compound Download PDFInfo
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- CN116239643A CN116239643A CN202111516828.9A CN202111516828A CN116239643A CN 116239643 A CN116239643 A CN 116239643A CN 202111516828 A CN202111516828 A CN 202111516828A CN 116239643 A CN116239643 A CN 116239643A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 63
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 23
- 230000008569 process Effects 0.000 claims abstract description 6
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 claims abstract description 4
- 229950002375 englitazone Drugs 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 49
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 20
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 10
- KCWYOFZQRFCIIE-UHFFFAOYSA-N ethylsilane Chemical compound CC[SiH3] KCWYOFZQRFCIIE-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 3
- -1 (S) -4- ((tetrahydrofuran-3-yl) oxy) benzoyl chloride Chemical compound 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000012074 organic phase Substances 0.000 description 58
- 239000000203 mixture Substances 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- 239000002904 solvent Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 239000000243 solution Substances 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000002274 desiccant Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 17
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 230000009471 action Effects 0.000 description 9
- 239000012300 argon atmosphere Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 230000020477 pH reduction Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 238000010606 normalization Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 4
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 229940126208 compound 22 Drugs 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 2
- 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 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
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- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
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- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- DCHYHZGBCSNKQN-UHFFFAOYSA-L lithium zinc dibromide Chemical compound [Br-].[Zn+2].[Br-].[Li+] DCHYHZGBCSNKQN-UHFFFAOYSA-L 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
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- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
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- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- FGERXQWKKIVFQG-UHFFFAOYSA-N 5-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Cl FGERXQWKKIVFQG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 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
- 239000007818 Grignard reagent Substances 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
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 108091006269 SLC5A2 Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 1
- WWCNXHYRAKUQDB-SNVBAGLBSA-N [(3r)-oxolan-3-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1COCC1 WWCNXHYRAKUQDB-SNVBAGLBSA-N 0.000 description 1
- KYOIPUDHYRWSFO-UHFFFAOYSA-N [Br].[Li] Chemical group [Br].[Li] KYOIPUDHYRWSFO-UHFFFAOYSA-N 0.000 description 1
- NJHPWOQALXDSNZ-UHFFFAOYSA-N [Mg].[Br] Chemical group [Mg].[Br] NJHPWOQALXDSNZ-UHFFFAOYSA-N 0.000 description 1
- PGTXKIZLOWULDJ-UHFFFAOYSA-N [Mg].[Zn] Chemical group [Mg].[Zn] PGTXKIZLOWULDJ-UHFFFAOYSA-N 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HHHPKVLNNLPPKL-UHFFFAOYSA-N benzene;hydrofluoride Chemical compound F.C1=CC=CC=C1 HHHPKVLNNLPPKL-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 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 description 1
- 229960003345 empagliflozin Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004795 grignard reagents Chemical group 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 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
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to an englitazone intermediate compound. The invention takes (S) -4- ((tetrahydrofuran-3-yl) oxy) benzoyl chloride as an initial material to react with a compound III to obtain a new intermediate compound V of the engagliflozin. The invention also provides a method for preparing the englitjing by deprotection and reduction of the novel intermediate compound. The new intermediate provided by the invention has the advantages of simple synthesis method, short synthesis route for preparing the englitjing by using the new intermediate, high yield, mild reaction conditions and stable process, and is suitable for mass industrialized production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to an englitazone intermediate compound.
Background
Engliflozin (empagliflozin), chemical name (2S, 3R,4R,5S, 6R) -2- [3- [4- [ (S) -tetrahydrofurane-3-yloxy ] benzyl ] -4-chlorophenyl ] -6-hydroxymethyl-epoxyhexane-3, 4, 5-triol, co-developed by Boringer' S Johner company and Gift, first approved by European drug administration (EMA) for 5 months in 2014, is an SGLT2 hypoglycemic drug which effectively reduces blood glucose, improves insulin sensitivity and islet beta cell function by a mechanism independent of insulin secretion and insulin action, and can reduce cardiovascular disease risk, heart disease and stroke for the first time, and has molecular weight: 450.91, CAS registry number 864070-44-0, having the following structural formula:
the literature reports a large number of synthetic methods for enggliflozin, but the ideas are about the same, and mainly include the following:
the method comprises the following steps: U.S. Pat. No. 3, 11406971 uses compound 2, D-glucolactone as raw material, and reacts with trimethylchlorosilane under the catalysis of N-methylmorpholine to obtain key intermediate 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone. 5-bromo-2-chlorobenzoic acid is used as a raw material, and reacts with oxalyl chloride under the catalysis of N, N-dimethylformamide to obtain a compound 7, the compound 7 directly undergoes a friedel-crafts acylation reaction with anisole to obtain a compound 8, the compound 8 is reduced in a solution system of triethylsilane and boron trifluoride diethyl ether to obtain a compound 9, the compound 9 is demethylated to obtain a compound 10, and the compound 10 is subjected to the action of triethylamine and 4-dimethylaminopyridine, and TMS is used for protecting the hydroxyl of the compound 10 to obtain a compound 11. Under the protection of argon, carrying out lithium-bromine exchange on a compound 11 and tertiary butyl lithium at-80 ℃ and then carrying out nucleophilic substitution reaction on the compound 11 and tertiary butyl lithium and an intermediate 3, removing TMS protecting groups under an acidic condition to obtain two configuration products 12, removing methoxy groups of the 12 to obtain a compound 13, acetylating the compound 13 by acetic anhydride and then recrystallizing the compound 13 in ethanol to obtain a pure beta conformation product 14, deacetylating the compound 14 under a strong base condition to obtain a compound 15, and carrying out SN (R) -3- (4-methylbenzenesulfonyloxy) tetrahydrofuran on the compound 15 under the action of cesium carbonate 2 Substitution reaction to obtain the target product Engliflozin I, wherein the synthetic route is as follows:
the method has long synthetic route and complex operation; the dangerous reagent n-butyllithium is used, the TMS protected glucolactone is unstable, anhydrous and anaerobic conditions are required to be strictly controlled, and the reaction conditions are very harsh; the epimer generated by the route needs to be purified twice, has lower yield and is not beneficial to industrial production.
The second method is as follows: U.S. patent US14770415 and chinese patent application CN1051531374, namely alpha-D-glucose is taken as a raw material, under the protection of nitrogen, pivaloyl chloride and lithium bromide react to generate pivaloyl bromide, and zinc bromide and a compound 4 are added to react to obtain a key intermediate 2,3,4, 6-O-tetrapivaloyl-alpha-D-bromopyranose 5. Obtaining an intermediate 8 according to the route of the first method, reducing the intermediate 8 by sodium borohydride/aluminum trichloride to obtain a compound 9, reacting the compound 9 with an organometallic reagent n-hexyl n-dibutyl magnesium lithium to realize selective magnesium-bromine exchange, then carrying out magnesium-zinc exchange with zinc bromide-lithium bromide, finally carrying out coupling reaction with the compound 5 to obtain an intermediate 16, demethylating the intermediate 16 under the action of boron tribromide to obtain a compound 17, and carrying out SN (N) reaction between the compound 17 and (R) -3-iodotetrahydrofuran under alkaline conditions 2 Substitution reaction to obtain the target I:
the method has the advantages of short synthetic route, low-cost and easily-obtained raw materials, mild reaction conditions, good stereoselectivity when pivaloyl is used for protecting, and high yield, but the organic metal reagent n-hexyl n-dibutyl magnesium lithium is not easily obtained.
And a third method: chinese patent application CN105399735 takes compound 18, namely 5-iodine-2-chlorobenzoic acid as raw material, and under the catalysis of DMF, the compound 18 reacts with oxalyl chloride to obtain compound 19, the compound 19 reacts with fluorinated benzene under the participation of Lewis acid aluminum trichloride to generate Friedel-crafts acylation reaction to obtain compound 20, and the compound 20 reacts with (S) -3-hydroxytetrahydrofuran under the action of strong alkali potassium tert-butoxide to generate SN 2 Nucleophilic substitution reaction to obtain compound 21, reducing the compound 21 by sodium borohydride-aluminum trichloride system to obtain compound 22, reacting the compound 22 with n-butyllithium and zinc bromide-lithium bromide, coupling with compound 5 to selectively generate beta conformational product 23, and removing pivaloyl from the compound 23 under sodium methoxide condition to obtain the target compound I. The method has the advantages of short synthetic route, mild reaction conditions, good stereoselectivity when pivaloyl is used for protection, high yield, but high price of (S) -3-hydroxytetrahydrofuran, and increased cost:
the method four: under the acidic condition, the compound 21 undergoes a reduction reaction in a 1, 3-tetramethyl disilyl ether and aluminum trichloride system to obtain a compound 22, the compound 22 undergoes a Grignard reagent exchange reaction with isopropyl magnesium chloride/lithium chloride and then undergoes a nucleophilic addition reaction with an intermediate 3 to obtain a compound 24 under the action of citric acid, the compound 24 undergoes a reaction under the condition of hydrochloric acid-methanol solution to obtain a compound 25, and the compound 25 undergoes a demethoxy reaction under the action of triethylsilane-aluminum trichloride to obtain the target compound:
the method has the advantages of short synthetic route, high yield and mild reaction conditions. However, the (S) -3-hydroxytetrahydrofuran is relatively expensive, the synthesis cost is increased, and the post-treatment of the route is relatively complicated.
And a fifth method: patent WO2015101916 takes compound 26, namely 5-iodine (or bromine) -2-chlorobenzaldehyde, and under the protection of nitrogen, n-butyllithium hexane solution is added to realize lithium-halogen exchange, and then the compound is subjected to coupling reaction with compound 27, namely (S) -3- (4-bromophenoxy) tetrahydrofuran to obtain compound 28; or the compound 26 reacts with oxalyl chloride under the catalysis of DMF to obtain a compound 32, the compound 32 reacts with benzene fluoride under the action of Lewis acid aluminum trichloride to obtain a compound 33, and the compound 33 reacts with (S) -3-hydroxytetrahydrofuran under the action of strong alkali potassium tert-butoxide to generate SN 2 Nucleophilic substitution reaction and reduction by sodium borohydride to give compound 28. Triethylamine is used as an acid binding agent, and trimethyl chlorosilane is used for protecting the hydroxyl of the compound 28 to obtain a compound 29; or compound 28 and methanesulfonic acid react to obtain compound 34, at-70 ℃, compound 29 (or compound 34) firstly undergoes lithium-halogen exchange with n-butyllithium, then undergoes nucleophilic addition with compound 3 to obtain compound 30, and the hydroxyl group of compound 30 (or compound 35) is converted into methyl ether by using methanol solution of methanesulfonic acid to obtain compound 31The compound 31 is subjected to removal of two methoxy groups in a triethylsilane and boron trifluoride diethyl etherate solution system to obtain a target compound:
the method has the advantages of longer synthetic route, more used reagents, complicated post-treatment, very harsh reaction conditions and no contribution to industrial production.
In view of the problems in the existing preparation of Engliclazide, the research and search of a route which is suitable for industrial production and has the advantages of mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost is the problem to be solved at present.
Disclosure of Invention
In order to overcome the defects of the prior art, solve the problems of low reaction temperature and difficult control of sugar and side chains, and effectively remove alpha-configuration impurities in the product to obtain a process more suitable for industrial production, the invention provides a novel Engliflozin intermediate compound and a novel method for preparing Engliflozin by using the novel intermediate.
The specific technical content of the invention is as follows:
in a first aspect, the present invention provides a novel englitjing intermediate compound having the structure shown in formula V:
the second aspect of the invention provides a preparation method of the englitjing intermediate compound V: the preparation method of the englitjing intermediate compound V comprises the following steps: adding the compound III and the compound IV into the organic solvent A, and controlling the temperature T under the protection of inert gas 1 Stirring for reaction, adding aluminium trichloride in batches, heating to room temperature for reaction until the reaction is finished, and post-treatingObtaining a compound V:
preferably, the organic solvent A is selected from one or a combination of dichloromethane, carbon tetrachloride, chloroform and 1, 2-dichloroethane.
Preferably, the feeding mole ratio of the compound III, the compound IV and the aluminum trichloride is 1:1.0 to 2.0:1.0 to 2.0, preferably 1:1.05:1.2.
Preferably, the reaction temperature T 1 Is at a temperature of between-5 and 5 ℃.
In a preferred scheme, after the reaction is finished, the post-treatment is required, and the specific steps are as follows: after the reaction, 1M diluted hydrochloric acid is added for acidification, an organic phase is separated, an acid water layer is extracted by dichloromethane, the organic layers are combined, the organic layers are washed by water, saturated saline water, dried by anhydrous sodium sulfate, filtered and the solvent is distilled off under reduced pressure, so that the compound V is obtained.
Wherein compound III is prepared as follows:
step 1: adding a compound SM-1, magnesium chips and an organic solvent B into two bottles, stirring and reacting under the protection of inert gas at a low temperature T2, slowly adding a compound IV, and stirring at a temperature of 0 ℃ after adding until the reaction is finished to obtain a compound II;
step 2: adding the compound II, methanesulfonic acid and absolute methanol into a single-neck flask, and stirring at room temperature until the reaction is finished to obtain a compound III:
the synthetic route is as follows:
preferably, the organic solvent B in step 1 is selected from one of diethyl ether, tetrahydrofuran and n-hexane.
Preferably, the molar ratio of the compound IV, the compound SM-1 and the magnesium turnings in the step 1 is as follows: 1:1.0 to 1.8:1.0 to 2.0, particularly preferred: 1.0:1.1:1.3.
Preferably, the low temperature T in step 1 2 The method comprises the following steps: -30 to-10 ℃.
Preferably, the molar ratio of the compound II to the methanesulfonic acid in the step 2 is as follows: 1.0:0.08 to 0.5, preferably 1.0:0.1.
In a preferred scheme, after the reaction is finished, the post-treatment is needed, and the post-treatment in the step 1 is as follows: after the reaction, a saturated aqueous ammonium chloride solution was slowly added to quench, ethyl acetate was added, the organic phase was separated, the aqueous phase was extracted with diethyl ether, the organic phases were combined, the organic phase was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove the drying agent, concentrating under reduced pressure, and evaporating solvent to obtain the compound II.
The post-treatment of the step 2 is as follows: after the reaction, adding sodium bicarbonate, stirring, adding anhydrous sodium sulfate, drying, filtering to remove a drying agent, concentrating under reduced pressure, and evaporating to remove the solvent to obtain a yellow solid compound III.
In a third aspect, the present invention provides a process for the preparation of englitjing, using the novel intermediate compound V:
a preparation method of englitjing, comprising the following steps:
step 1: adding a compound V and tetrabutylammonium fluoride into a single-neck flask at room temperature, adding an organic solvent D, and reacting at room temperature until the reaction is finished to obtain a compound VI;
step 2: adding a mixed solvent of a compound VI and dried dichloromethane/acetonitrile into a single-neck flask, and controlling the temperature T 3 And adding ethyl silane and boron fluoride diethyl ether complex, heating to 0 ℃, and stirring until the reaction is finished to obtain the engagliflozin.
Preferably, the organic solvent D in step 1 is selected from one of dry tetrahydrofuran, diethyl ether, acetonitrile and dichloromethane.
Preferably, the molar ratio of the compound V to tetrabutylammonium fluoride in the step 1 is as follows: 1:4.0.0 to 5.0, of which 1 is particularly preferred: 4.2.
preferably, the molar ratio of the compound VI, the ethylsilane and the fluorinated boron diethyl ether complex in the step 2 is as follows: 1:3.5 to 4.5:2.5 to 3.5, of which particular preference is given: 1.0:4.0:3.0.
Preferably, the temperature T in step 2 3 Is at a temperature of between-20 and 0 ℃.
In a preferred scheme, after the reaction is finished, the post-treatment is required, and the specific steps of the step 1 are as follows: after the reaction, the solvent was distilled off by concentrating under reduced pressure, and the crude product was recrystallized from a mixture of ethanol and ethyl acetate (volume ratio 1:1) to give a pale yellow solid compound VI.
The post-treatment specific steps of the step 2 are as follows: after the reaction, the mixture was quenched by slowly adding a saturated aqueous sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove the drying agent, concentrating under reduced pressure, evaporating to remove the solvent, and recrystallizing the crude product with a mixed solution of ethanol and ethyl acetate (volume ratio 1:1) to obtain the engagliflozin.
Compared with the prior art, the invention has the technical effects that:
1. provides a new intermediate compound of the enggliflozin, and simultaneously provides a simple and efficient method for preparing the enggliflozin by using the new intermediate, the whole synthesis method has simple and convenient operation, avoids the use of dangerous chemicals such as n-butyl and the like, and has high reaction yield;
2. the process can solve the problems of low reaction temperature and difficult control of sugar and side chains, and effectively remove alpha-configuration impurities in the product;
3. the enggliflozin obtained by the technology has higher purity and yield, and is suitable for industrialized amplified production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The structure of the compound obtained by the invention is confirmed:
HPLC peak area normalization method:
chromatographic column: YMC-Triart C 18 Columns (4.6 mm. Times.250 mm,5 μm);
mobile phase: acetonitrile: water (80:20);
column temperature: 30 ℃;
detection wavelength: 210nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 16.5min.
High resolution mass spectrum of compound II: ESI-HRMS: m/z=748.7482 [ M+H ]] + ,mp 213~216℃, 1 H-NMR(400MHz,DMSO-d 6 )δ:7.38(d,2H),7.36(d,2H),5.12(br,1H),4.08(d,1H),4.03(d,1H),3.77(d,1H),3.70(dd,1H),3.60(m,2H),0.98(s,36H),0.21(s,24H); 13 C-NMR(100MHz,DMSO-d 6 )δ:137.7,131.5,128.7,128.6,127.8,127.7,113.8,85.6,80.6,79.2,73.0,63.9,30.9,30.7,30.6,30.5,25.9,25.8,25.7,25.6;
Characterization of compound III:
HPLC peak area normalization method:
chromatographic column: YMC-Triart C 18 Columns (4.6 mm. Times.250 mm,5 μm);
mobile phase: acetonitrile: water (80:20);
column temperature: 30 ℃;
detection wavelength: 210nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 13.0min.
ESI-HRMS(m/z):784.7745[M+Na] + .mp 215~218℃; 1 H-NMR(400MHz,DMSO-d 6 )δ:7.38(d,2H),7.37(d,2H),4.28(d,1H),4.03(d,1H),3.77(d,1H),3.70(dd,1H),3.60(m,2H),3.30(s,3H),0.98(s,36H),0.21(s,24H); 13 C-NMR(100MHz,DMSO-d 6 )δ:137.7,131.5,128.7,128.6,127.8,127.7,121.5,83.1,80.9,79.5,73.0,63.9,30.9,30.7,30.6,30.5,25.9,25.8,25.7,25.6.
HPLC peak area normalization method:
chromatographic column: YMC-Triart C18 column (4.6 mm. Times.250 mm,5 μm);
mobile phase: acetonitrile: water (80:20);
column temperature: 30 ℃;
detection wavelength: 210nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 12.5min.
ESI-HRMS:m/z=974.9732[M+Na] + ,mp 235~238℃, 1 H-NMR(400MHz,DMSO-d 6 )δ:7.77(s,1H),7.73(d,2H),7.56(d,1H),7.55(d,1H),7.03(d,2H),4.28(d,1H),4.25(d,1H),4.05(m,1H),4.03(d,1H),4.00(d,1H),3.80(t,1H),3.77(d,1H),3.70(m,2H),3.60(m,2H),3.30(s,3H),2.36(dt,1H),2.11(dt,1H),0.98(s,36H),0.21(s,24H); 13 C-NMR(100MHz,DMSO-d 6 )δ:196.3,161.1,137.4,136.5,136.2,131.4,131.0,130.9,130.8,130.0,127.2,121.5,114.1,114.0,83.1,80.9,80.8,79.6,79.5,73.0,67.5,63.9,52.4,32.2,30.9,30.2,25.9,25.6.
HPLC peak area normalization method:
chromatographic column: YMC-Triart C18 column (4.6 mm. Times.250 mm,5 μm);
mobile phase: acetonitrile: water (80:20);
column temperature: 30 ℃;
detection wavelength: 210nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 19.5min.
ESI-HRMS:m/z=495.9207[M+H] + ,mp 280~283℃, 1 H-NMR(400MHz,DMSO-d 6 )δ:7.78(s,1H),7.70(d,2H),7.56(d,1H),7.55(d,1H),7.03(d,2H),4.28(d,1H),4.25(d,1H),4.05(m,1H),4.03(d,1H),4.00(d,1H),3.80(t,1H),3.77(d,1H),3.70(m,2H),3.60(m,2H),3.30(s,3H),2.36(dt,1H),2.11(dt,1H),0.98(s,36H),0.21(s,24H); 13 C-NMR(100MHz,DMSO-d 6 )δ:196.3,161.1,137.4,136.5,136.2,131.4,131.0,130.9,130.8,130.0,127.2,121.5,114.1,114.0,83.1,80.9,80.8,79.6,79.5,73.0,67.5,63.9,52.4,32.2,30.9,30.2,25.9,25.6.
HPLC peak area normalization method:
chromatographic column: YMC-Triart C18 column (4.6 mm. Times.250 mm,5 μm);
mobile phase: a: acetonitrile, B: gradient elution (0- > 10min: A40%, 10- > 30min: A40% -90%);
column temperature: 35 ℃;
detection wavelength: 224nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 16.80min.
ESI-HRMS:m/z=451.9212[M+H] + ,mp149~152℃, 1 H NMR(400MHz,MeOD)δ:7.36(d,2H),7.28(dd,1H),7.13(d,2H),6.81-6.89(m,2H),4.87-4.94(m,1H),4.11(d,1H),4.00(d,1H),3.95(ddd,5H),3.68(dd,1H),3.36-3.53(m,3H),3.24-3.35(m,2H),2.18(dtd,1H),1.98-2.13(m,1H)。 13 C NMR(400MHz,MeOD)δ:154.9,143.2,137.7,133.1,130.7,130.6,129.1,128.9,128.8,125.4,115.0,114.9,84.8,80.8,79.6,78.7,75.0,71.5,70.2,67.5,62.2,36.5,32.2.
Preparation of Compound II
Example 1
SM-1 (52.46 g,0.22 mol), magnesium turnings (6.41 g,0.26 mol) and dehydrated ether (110 mL) were added to a two-necked flask, and reacted at-20℃for 3 hours under argon atmosphere, compound IV (127.03 g,0.20mol, dissolved in 200mL of dry tetrahydrofuran) was slowly added, and after the addition was completed, the mixture was stirred at constant temperature of 0℃for 4 hours. After the completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was slowly added to quench, ethyl acetate (100 mL) was added, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is evaporated by decompression concentration, and the compound II is obtained with the yield of 98.4 percent and the HPLC purity of 99.92 percent.
Example 2
SM-1 (47.58 g,0.2 mol), magnesium turnings (6.41 g,0.26 mol) and anhydrous tetrahydrofuran (110 mL) were added to a two-necked flask, and the mixture was reacted at-30℃for 3 hours under argon atmosphere, compound IV (127.03 g,0.20mol, dissolved in 200mL of dry tetrahydrofuran) was slowly added, and after the addition was completed, the mixture was stirred at constant temperature of 0℃for 4 hours. After the completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was slowly added to quench, ethyl acetate (100 mL) was added, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure to give compound II in 94.5% yield and 99.62% purity by HPLC.
Example 3
SM-1 (85.64 g,0.36 mol), magnesium turnings (6.41 g,0.26 mol) and anhydrous n-hexane (180 mL) were added to a two-necked flask, and reacted at-10℃for 3 hours under argon atmosphere, compound IV (127.03 g,0.20mol, dissolved in 200mL of dry tetrahydrofuran) was slowly added, and after the addition was completed, the mixture was stirred at constant temperature of 0℃for 4 hours. After the completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was slowly added to quench, ethyl acetate (100 mL) was added, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is evaporated by vacuum concentration, and the compound II is obtained with the yield of 94.8 percent and the HPLC purity of 99.48 percent.
Example 4
SM-1 (52.46 g,0.22 mol), magnesium turnings (4.86 g,0.2 mol) and anhydrous tetrahydrofuran (110 mL) were added to a two-necked flask, and the mixture was reacted at-30℃for 3 hours under argon atmosphere, compound IV (127.03 g,0.20mol, dissolved in 200mL of dry tetrahydrofuran) was slowly added, and after the addition was completed, the mixture was stirred at constant temperature of 0℃for 4 hours. After the completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was slowly added to quench, ethyl acetate (100 mL) was added, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is evaporated by vacuum concentration, and the compound II is obtained with the yield of 94.5% and the HPLC purity of 99.45%.
Example 5
SM-1 (52.46 g,0.22 mol), magnesium turnings (9.72 g,0.4 mol) and tetrahydrofuran (110 mL) were added to a two-necked flask, and reacted at-10℃for 3 hours under argon, compound IV (127.03 g,0.20mol, dissolved in 200mL of dry tetrahydrofuran) was slowly added, and after the addition, the mixture was stirred at constant temperature of 0℃for 4 hours. After the completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was slowly added to quench, ethyl acetate (100 mL) was added, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by vacuum concentration, and the compound II is obtained with the yield of 95.5 percent and the HPLC purity of 99.32 percent.
Example 6
SM-1 (95.16 g,0.4 mol), magnesium turnings (10.69 g,0.44 mol) and dehydrated ether (200 mL) were added to a two-necked flask, and reacted at-20℃for 3 hours under argon atmosphere, compound IV (127.03 g,0.20mol, dissolved in 200mL of dry tetrahydrofuran) was slowly added, and after the addition was completed, the mixture was stirred at constant temperature of 0℃for 4 hours. After the completion of the reaction, a saturated aqueous ammonium chloride solution (250 mL) was slowly added to quench, ethyl acetate (100 mL) was added, the organic phase was separated, the aqueous phase was extracted with diethyl ether (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by concentration under reduced pressure, and the compound II is obtained with the yield of 88.6% and the HPLC purity of 98.87%.
Preparation of Compound III
Example 7
To a single vial was added compound II (112.16 g,0.15 mol), methanesulfonic acid (1.44 g,15 mmol) and anhydrous methanol (75 mL) and dissolved with stirring, and reacted at room temperature for 2 hours. After the reaction, sodium hydrogencarbonate (1.3 g) was added and stirred for 30 minutes, then anhydrous sodium sulfate was added and dried, the drying agent was removed by filtration, and the solvent was distilled off by concentration under reduced pressure to obtain compound III in a yield of 98.9% and an HPLC purity of 99.89%.
Example 8
To a single vial was added compound II (112.16 g,0.15 mol), methanesulfonic acid (1.15 g,12 mmol) and anhydrous methanol (75 mL) and the mixture was dissolved with stirring and reacted at room temperature for 2 hours. After the reaction, sodium hydrogencarbonate (1.2 g) was added and stirred for 30 minutes, then anhydrous sodium sulfate was added and dried, the drying agent was removed by filtration, and the solvent was distilled off by concentration under reduced pressure to obtain compound III in a yield of 94.6% and an HPLC purity of 99.63%.
Example 9
To a single vial was added compound II (112.16 g,0.15 mol), methanesulfonic acid (7.2 g,75 mmol) and anhydrous methanol (120 mL) and the mixture was dissolved with stirring and reacted at room temperature for 2 hours. After the reaction, sodium bicarbonate (1.2 g) was added and stirred for 30 minutes, then anhydrous sodium sulfate was added and dried, the drying agent was removed by filtration, and the solvent was distilled off by concentration under reduced pressure to obtain compound III in a yield of 95.3% and an HPLC purity of 99.55%.
Example 10
To a single vial was added compound II (112.16 g,0.15 mol), methanesulfonic acid (0.86 g,9.0 mmol) and anhydrous methanol (75 mL) and the mixture was dissolved with stirring and reacted at room temperature for 2 hours. After the reaction, sodium hydrogencarbonate (0.76 g) was added and stirred for 30 minutes, then anhydrous sodium sulfate was added and dried, the drying agent was removed by filtration, and the solvent was distilled off by concentration under reduced pressure to give compound III in 88.9% yield and 98.69% purity by HPLC.
Example 11
To a single flask, compound II (112.16 g,0.15 mol), methanesulfonic acid (2.55 g,105 mmol) and anhydrous methanol (75 mL) were added and dissolved with stirring, and reacted at room temperature for 2 hours. After the reaction, sodium hydrogencarbonate (8.82 g) was added and stirred for 30 minutes, then anhydrous sodium sulfate was added and dried, the drying agent was removed by filtration, and the solvent was distilled off by concentration under reduced pressure to give compound III in a yield of 84.7% and an HPLC purity of 98.23%.
Preparation of Compound V
Example 12
To a two-port flask, compound III (76.18 g,0.10 mol), compound IV (23.37 g,0.105 mol) and dry dichloromethane (150 mL) were added, and the mixture was stirred at 0℃for 30 minutes under argon atmosphere, aluminum trichloride (16.00 g,0.12 mol) was added in portions, and after the addition was completed, the mixture was allowed to stand at room temperature for 5 hours. After the reaction, 1.0mol/L dilute hydrochloric acid (100 mL) was added for acidification, the organic phase was separated, the acid-water layer was extracted with dichloromethane (150 mL. Times.3), the organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent, to give Compound V in 98.9% yield and 99.95% HPLC purity.
Example 13
To a two-port flask, compound III (76.18 g,0.10 mol), compound IV (22.60 g,0.10 mol) and dry carbon tetrachloride (150 mL) were added, and the mixture was stirred at-5℃under argon for 30 minutes, aluminum trichloride (16.00 g,0.12 mol) was added in portions, and after the addition was completed, the mixture was warmed to room temperature and reacted for 5 hours. After the reaction, 1.0mol/L dilute hydrochloric acid (100 mL) was added for acidification, the organic phase was separated, the aqueous acid layer was extracted with dichloromethane (150 mL. Times.3), the organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent, to give Compound V in a yield of 94.1% and an HPLC purity of 99.51%.
Example 14
To a two-port flask, compound III (76.18 g,0.10 mol), compound IV (45.2 g,0.20 mol) and dried chloroform (150 mL) were added, and the mixture was stirred at 5℃for 30 minutes under argon atmosphere, aluminum trichloride (16.00 g,0.12 mol) was added in portions, and after the addition was completed, the mixture was warmed to room temperature and reacted for 5 hours. After the reaction, 1.0mol/L dilute hydrochloric acid (100 mL) was added for acidification, the organic phase was separated, the acid-water layer was extracted with dichloromethane (150 mL. Times.3), the organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent, to give Compound V in a yield of 95.2% and an HPLC purity of 99.40%.
Example 15
To a two-port flask, compound III (76.18 g,0.10 mol), compound IV (23.37 g,0.105 mol) and dry 1, 2-dichloroethane (150 mL) were added, and under argon, aluminum trichloride (15.14 g,0.1 mol) was added in portions with stirring at-5℃for 30 minutes, and after the addition was completed, the reaction was allowed to proceed to room temperature for 5 hours. After the reaction, 1.0mol/L dilute hydrochloric acid (100 mL) was added for acidification, the organic phase was separated, the acid-water layer was extracted with dichloromethane (150 mL. Times.3), the organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent, to give Compound V in a yield of 93.9% and an HPLC purity of 99.65%.
Example 16
To a two-port flask, compound III (76.18 g,0.10 mol), compound IV (23.37 g,0.105 mol) and dry dichloromethane (180 mL) were added, and the mixture was stirred at 5℃for 30 minutes under argon atmosphere, aluminum trichloride (30.28 g,0.2 mol) was added in portions, and after the addition was completed, the mixture was warmed to room temperature and reacted for 5 hours. After the reaction, 1.0mol/L dilute hydrochloric acid (100 mL) was added for acidification, the organic phase was separated, the acid-water layer was extracted with dichloromethane (150 mL. Times.3), the organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent, to give Compound V in a yield of 94.1% and an HPLC purity of 99.44%.
Example 17
To a two-port flask, compound III (76.18 g,0.10 mol), compound IV (49.73 g,0.22 mol) and dried dichloromethane (200 mL) were added, and under argon atmosphere, the mixture was stirred at 10℃for 30 minutes, aluminum trichloride (33.30 g,0.22 mol) was added in portions, and after the addition was completed, the mixture was warmed to room temperature and reacted for 5 hours. After the reaction, 1.0mol/L dilute hydrochloric acid (100 mL) was added for acidification, the organic phase was separated, the acid-water layer was extracted with dichloromethane (150 mL. Times.3), the organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent, to give Compound V in a yield of 88.1% and an HPLC purity of 98.84%.
Preparation of Compound VI
Example 18
To a single-port flask, compound IV (47.60 g,0.05 mol), tetrabutylammonium fluoride (210 mL,0.21mol,1mol/LTHF solution) and dry tetrahydrofuran (100 mL) were added, and after the reaction was completed, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from a mixture of ethanol and ethyl acetate (volume ratio 1:3) to give Compound IV as a pale yellow solid, yield 99.8% and HPLC purity 99.94%.
Example 19
To a single-port flask, compound IV (47.60 g,0.05 mol), tetrabutylammonium fluoride (200 mL,0.20mol,1mol/LTHF solution) and dry diethyl ether (100 mL) were added, and after the reaction was completed at room temperature for 1 hour, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from a mixture of ethanol and ethyl acetate (volume ratio 1:3) to give Compound IV as a pale yellow solid, yield 98.2% and HPLC purity 99.89%.
Example 20
To a single-port flask, compound IV (47.60 g,0.05 mol), tetrabutylammonium fluoride (250 mL,0.25mol,1mol/LTHF solution) and dry acetonitrile (100 mL) were added, and after the reaction was completed at room temperature for 1 hour, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from a mixture of ethanol and ethyl acetate (volume ratio 1:3) to give Compound IV as a pale yellow solid in 96.4% yield with a HPLC purity of 99.65%.
Example 21
To a single-port flask, compound IV (47.60 g,0.05 mol), tetrabutylammonium fluoride (175 mL,0.175mol,1mol/LTHF solution) and dried dichloromethane (100 mL) were added, and after the reaction was completed at room temperature for 1 hour, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from a mixture of ethanol and ethyl acetate (volume ratio 1:3) to give Compound IV as a pale yellow solid in a yield of 88.9% and an HPLC purity of 98.85%.
Example 22
To a single-port flask, compound IV (47.60 g,0.05 mol), tetrabutylammonium fluoride (275 mL,0.275mol,1mol/LTHF solution) and dried dichloromethane (100 mL) were added, and after the reaction was completed, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from a mixture of ethanol and ethyl acetate (volume ratio 1:3) to give Compound IV as a pale yellow solid in a yield of 89.3% and an HPLC purity of 98.66%.
Preparation of Engliflozin
Example 23
To a single vial was added compound VI (9.89 g,0.02 mol) with dry dichloromethane and acetonitrile (V Dichloromethane (dichloromethane) ∶V Acetonitrile Dissolving with stirring (1:1, 50 mL), cooling to-10deg.C, sequentially adding ethyl silane (4.81 g,0.08 mol), boron trifluoride diethyl etherate (8.51 g,0.06 mol), slowly raising to 0deg.C, and reacting at constant temperature for 5 hr. After completion of the reaction, the mixture was quenched by slowly adding a saturated aqueous sodium hydrogencarbonate solution (150 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by decompression concentration, and the crude product is recrystallized by mixed solution of ethanol and ethyl acetate (volume ratio is 1:1) to obtain the Enagliflozin with the yield of 99.5 percent and the HPLC purity of 99.98 percent.
Example 24
To a single vial was added compound VI (9.89 g,0.02 mol) with dry dichloromethane and acetonitrile (V Dichloromethane (dichloromethane) ∶V Acetonitrile Dissolving with stirring (1:1, 50 mL), cooling to-20deg.C, adding ethyl silane (4.21 g,0.07 mol) and boron trifluoride diethyl etherate (7.10 g,0.05 mol) in sequence, slowly raising to 0deg.C, and reacting at constant temperature for 5 hours. After completion of the reaction, the mixture was quenched by slowly adding a saturated aqueous sodium hydrogencarbonate solution (150 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by decompression concentration, and the crude product is recrystallized by mixed solution of ethanol and ethyl acetate (volume ratio is 1:1) to obtain the Enagliflozin with the yield of 96.1 percent and the HPLC purity of 99.62 percent.
Example 25
To a single vial was added compound VI (9.89 g,0.02 mol) with dry dichloromethane and acetonitrile (V Dichloromethane (dichloromethane) ∶V Acetonitrile Stirring and dissolving the mixture, cooling the mixture to 0 ℃, adding ethyl silane (5.42 g,0.09 mol) and boron trifluoride diethyl etherate (9.94 g,0.07 mol) in sequence, slowly raising the mixture to 0 ℃, and reacting the mixture at constant temperature for 5 hours. After the reaction, a saturated aqueous sodium hydrogencarbonate solution (150 mL) was slowly added to quench the reaction, and the organic phase was separatedThe aqueous phase was extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, each washed once with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by decompression concentration, and the crude product is recrystallized by mixed solution of ethanol and ethyl acetate (volume ratio is 1:1) to obtain the Enagliflozin with the yield of 96.8 percent and the HPLC purity of 99.58 percent.
Example 26
To a single vial was added compound VI (9.89 g,0.02 mol) with dry dichloromethane and acetonitrile (V Dichloromethane (dichloromethane) ∶V Acetonitrile Stirring and dissolving the mixture, cooling the mixture to-25 ℃, sequentially adding ethyl silane (3.61 g,0.06 mol) and boron trifluoride diethyl etherate (5.68 g,0.04 mol), slowly raising the temperature to 0 ℃, and reacting the mixture at constant temperature for 5 hours. After completion of the reaction, the mixture was quenched by slowly adding a saturated aqueous sodium hydrogencarbonate solution (150 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by decompression concentration, and the crude product is recrystallized by mixed solution of ethanol and ethyl acetate (volume ratio is 1:1) to obtain the Enagliflozin with the yield of 88.8 percent and the HPLC purity of 98.88 percent.
Example 27
To a single vial was added compound VI (9.89 g,0.02 mol) with dry dichloromethane and acetonitrile (V Dichloromethane (dichloromethane) ∶V Acetonitrile Stirring and dissolving the mixture, cooling the mixture to 5 ℃, adding ethyl silane (6.01 g,0.1 mol) and boron trifluoride diethyl etherate (11.35 g,0.08 mol) in sequence, slowly raising the temperature to 0 ℃ and reacting the mixture at constant temperature for 5 hours. After completion of the reaction, the mixture was quenched by slowly adding a saturated aqueous sodium hydrogencarbonate solution (150 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, each of the organic phases was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by decompression concentration, and the crude product is recrystallized by mixed solution of ethanol and ethyl acetate (volume ratio is 1:1) to obtain the Enagliflozin with the yield of 89.4 percent and the HPLC purity of 98.45 percent.
Claims (10)
2. a process for the preparation of the engagliflozin intermediate compound V according to claim 1, comprising the steps of: adding the compound III and the compound IV into the organic solvent A, and controlling the temperature T under the protection of inert gas 1 Stirring for reaction, adding aluminum trichloride in batches, reacting at room temperature until the reaction is finished, and performing post-treatment on the reaction to obtain a compound V:
the synthetic route is as follows:
3. the preparation method according to claim 2, wherein the organic solvent A is selected from one or a combination of dichloromethane, carbon tetrachloride, chloroform and 1, 2-dichloroethane.
4. The preparation method according to claim 2, wherein the feeding molar ratio of the compound III, the compound IV and the aluminum trichloride is 1:1.0 to 2.0:1.0 to 2.0; the reaction temperature T 1 Is at a temperature of between-5 and 5 ℃.
5. The preparation method according to claim 2, wherein the preparation method of the compound III comprises the steps of:
step 1: adding compound SM-1, magnesium chips and organic solvent B into two bottles, and under the protection of inert gas, performing low-temperature T 2 Stirring for reaction under the condition, slowly adding the compound IV, and controlling the temperature to be 0 ℃ after the addition is finished, and stirring until the reaction is finished to obtain a compound II;
step 2: adding the compound II, methanesulfonic acid and absolute methanol into a single-neck flask, and stirring at room temperature until the reaction is finished to obtain a compound III:
the synthetic route is as follows:
6. the preparation method according to claim 5, wherein the compound IV, the compound SM-1 and the magnesium chips in the step 1 are fed in a molar ratio of: 1:1.0 to 1.8:1.0 to 2.0; the feeding mole ratio of the compound II to the methanesulfonic acid in the step 2 is as follows: 1.0:0.08-0.5.
7. The preparation method according to claim 5, wherein the organic solvent B in the step 1 is selected from one of diethyl ether, tetrahydrofuran and n-hexane; the low temperature T in step 1 2 The method comprises the following steps: -30 ℃ to-10 ℃.
8. Use of an englitazone intermediate compound of claim 1 for the preparation of englitazone.
9. Use of an england intermediate compound of claim 8 for the preparation of england, characterized in that the preparation process comprises the steps of:
step 1: adding a compound V and tetrabutylammonium fluoride into a single-neck flask at room temperature, adding an organic solvent D, and reacting at room temperature until the reaction is finished to obtain a compound VI;
step 2: adding a mixed solvent of a compound VI and dried dichloromethane/acetonitrile into a single-neck flask, and controlling the temperature T 3 Adding ethyl silane and boron fluoride diethyl ether complex, heating to 0 ℃, stirring until the reaction is finished, and obtaining the englitjing:
10. the use according to claim 9, wherein the compound V, tetrabutylammonium fluoride in step 1 is fed in a molar ratio of: 1:4.0.0-5.0; the feeding mole ratio of the compound VI, the ethyl silane and the boron fluoride diethyl ether complex in the step 2 is as follows: 1:3.5-4.5:2.5-3.5; the organic solvent D in the step 1 is selected from one of dry tetrahydrofuran, diethyl ether, acetonitrile and dichloromethane; the temperature T in step 2 3 Is at a temperature of between-20 and 0 ℃.
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