CN111471040B - Synthesis method of glycoside derivative, intermediate and application thereof - Google Patents
Synthesis method of glycoside derivative, intermediate and application thereof Download PDFInfo
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- CN111471040B CN111471040B CN201910065966.6A CN201910065966A CN111471040B CN 111471040 B CN111471040 B CN 111471040B CN 201910065966 A CN201910065966 A CN 201910065966A CN 111471040 B CN111471040 B CN 111471040B
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- 229930182470 glycoside Natural products 0.000 title claims abstract description 23
- 150000002338 glycosides Chemical class 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 332
- 238000002360 preparation method Methods 0.000 claims abstract description 134
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- AIAWEAGMINBHLJ-ADAARDCZSA-N (2S,3R,4R,5S,6R)-2-[3-chloro-4-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound ClC=1C=C(C=CC1CC1=CC=C(C=C1)OCC)[C@@H]1O[C@@H]([C@H]([C@@H]([C@H]1O)O)O)CO AIAWEAGMINBHLJ-ADAARDCZSA-N 0.000 claims description 13
- ACMYKLBHDNJTQP-PKOFMYQESA-N (2S,3R,4R,5S,6R)-2-[4-(4-ethoxyphenoxy)-2,6-difluorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound C(C)OC1=CC=C(OC2=CC(=C(C(=C2)F)[C@@H]2O[C@@H]([C@H]([C@@H]([C@H]2O)O)O)CO)F)C=C1 ACMYKLBHDNJTQP-PKOFMYQESA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- YRVIRWSECSGEGM-OBKDMQGPSA-N (2S,3R,4R,5S,6R)-2-[3-chloro-4-(4-ethoxyphenoxy)phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound CCOC1=CC=C(C=C1)OC2=C(C=C(C=C2)[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)O)Cl YRVIRWSECSGEGM-OBKDMQGPSA-N 0.000 claims description 5
- HQWITGPSGDPCAS-RQXATKFSSA-N (2S,3R,4R,5S,6R)-2-[4-[(4-ethoxyphenyl)methyl]-2,6-difluorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound C(C)OC1=CC=C(CC2=CC(=C(C(=C2)F)[C@@H]2O[C@@H]([C@H]([C@@H]([C@H]2O)O)O)CO)F)C=C1 HQWITGPSGDPCAS-RQXATKFSSA-N 0.000 claims description 5
- 239000000543 intermediate Substances 0.000 abstract description 93
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 242
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 209
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 184
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 178
- 239000000243 solution Substances 0.000 description 178
- 238000006243 chemical reaction Methods 0.000 description 156
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 128
- 239000012043 crude product Substances 0.000 description 120
- 239000012071 phase Substances 0.000 description 109
- 229910052757 nitrogen Inorganic materials 0.000 description 92
- 235000019439 ethyl acetate Nutrition 0.000 description 81
- 239000003208 petroleum Substances 0.000 description 64
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 61
- 239000000741 silica gel Substances 0.000 description 61
- 229910002027 silica gel Inorganic materials 0.000 description 61
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 60
- 229910052739 hydrogen Inorganic materials 0.000 description 59
- 239000001257 hydrogen Substances 0.000 description 58
- 239000012074 organic phase Substances 0.000 description 58
- 125000000217 alkyl group Chemical group 0.000 description 56
- 229920006395 saturated elastomer Polymers 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000007787 solid Substances 0.000 description 50
- 239000012141 concentrate Substances 0.000 description 48
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 45
- 238000002953 preparative HPLC Methods 0.000 description 42
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 40
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
- -1 hydroxy,Carboxyl Chemical group 0.000 description 36
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 34
- 239000000706 filtrate Substances 0.000 description 32
- 150000002431 hydrogen Chemical group 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 125000003545 alkoxy group Chemical group 0.000 description 26
- 238000001816 cooling Methods 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 125000001072 heteroaryl group Chemical group 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 22
- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- 238000000605 extraction Methods 0.000 description 22
- 229910052736 halogen Inorganic materials 0.000 description 22
- 150000002367 halogens Chemical class 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 19
- 239000004480 active ingredient Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 241000699670 Mus sp. Species 0.000 description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 125000004093 cyano group Chemical group *C#N 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 239000012300 argon atmosphere Substances 0.000 description 13
- 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 12
- 239000000460 chlorine Substances 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 229910052717 sulfur Chemical group 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- 206010012601 diabetes mellitus Diseases 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 239000008280 blood Substances 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 6
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 125000004434 sulfur atom Chemical group 0.000 description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 4
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 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 4
- 239000003921 oil Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 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 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- ZDVSUWHZPOCHOW-IFPLKCGESA-N (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-[2-hydroxy-4-[(4-thiophen-2-ylphenyl)methyl]phenyl]oxane-3,4,5-triol Chemical compound OC1=C(C=CC(=C1)CC1=CC=C(C=C1)C=1SC=CC1)[C@@H]1O[C@@H]([C@H]([C@@H]([C@H]1O)O)O)CO ZDVSUWHZPOCHOW-IFPLKCGESA-N 0.000 description 3
- SPPBAJFZKFTSPC-BDHVOXNPSA-N (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-[4-[(4-pyrimidin-2-yloxyphenyl)methyl]phenyl]oxane-3,4,5-triol Chemical compound N1=C(N=CC=C1)OC1=CC=C(CC2=CC=C(C=C2)[C@@H]2O[C@@H]([C@H]([C@@H]([C@H]2O)O)O)CO)C=C1 SPPBAJFZKFTSPC-BDHVOXNPSA-N 0.000 description 3
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- WFSKHTCSXSNQCA-IFPLKCGESA-N (2S,3R,4R,5S,6R)-2-[2,6-difluoro-4-[4-(2-propan-2-yloxyethoxy)phenoxy]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound FC1=C(C(=CC(=C1)OC1=CC=C(C=C1)OCCOC(C)C)F)[C@@H]1O[C@@H]([C@H]([C@@H]([C@H]1O)O)O)CO WFSKHTCSXSNQCA-IFPLKCGESA-N 0.000 description 3
- QIOXHENARQYNAW-LHKMKVQPSA-N (2S,3R,4R,5S,6R)-2-[2,6-difluoro-4-[4-(trifluoromethyl)phenoxy]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound FC1=C(C(=CC(=C1)OC1=CC=C(C=C1)C(F)(F)F)F)[C@@H]1O[C@@H]([C@H]([C@@H]([C@H]1O)O)O)CO QIOXHENARQYNAW-LHKMKVQPSA-N 0.000 description 3
- ITQPRPLBUFEWEZ-FSMAJHIOSA-N (2S,3R,4R,5S,6R)-2-[2,6-dihydroxy-4-[[4-(oxolan-3-yloxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)thiane-3,4,5-triol Chemical compound OC1=C(C(=CC(=C1)CC1=CC=C(C=C1)OC1COCC1)O)[C@@H]1S[C@@H]([C@H]([C@@H]([C@H]1O)O)O)CO ITQPRPLBUFEWEZ-FSMAJHIOSA-N 0.000 description 3
- ZPUIAKSGRVCYAY-SJSRKZJXSA-N (2S,3R,4R,5S,6R)-2-[2-fluoro-4-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound FC1=C(C=CC(=C1)CC1=CC=C(C=C1)N1CCN(CC1)C)[C@@H]1O[C@@H]([C@H]([C@@H]([C@H]1O)O)O)CO ZPUIAKSGRVCYAY-SJSRKZJXSA-N 0.000 description 3
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- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
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- 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 belongs to the field of compound preparation and intermediates thereof, and particularly relates to a synthesis method of a glycoside derivative, an intermediate and application thereof. The intermediate compound is a compound shown in a formula III or a salt thereof:
formula III. The novel intermediate compound provided by the invention is used for synthesizing the glycoside derivative shown in the formula I, and the glycoside derivative with high purity can be prepared.
Description
Technical Field
The invention belongs to the field of compound preparation and intermediates thereof, and particularly relates to a synthesis method of a glycoside derivative, an intermediate and application thereof.
Background
Diabetes is an endocrine and metabolic disease that causes disturbances in the metabolism of sugar, fat and proteins due to relative or absolute hyposecretion of insulin in the body, or a decrease in its biological effects. The international diabetes association (IDF) predicts that the worldwide number of diabetics will reach 5.9 billion by 2035. Diabetes mellitus is classified into type I diabetes mellitus and type II diabetes mellitus; type I diabetes is an organ-specific autoimmune disease, and because of the life-long existence of the diabetes, the existing treatment method mainly comprises daily insulin injection and diet control, and patients are very painful; in recent years, a plurality of new breakthroughs are made for treating type I diabetes, such as chemical drug treatment and the like. Because of complex pathogenesis and long course of disease, the current therapeutic drugs are difficult to control blood sugar level, so that a novel hypoglycemic drug with a brand new action mechanism is urgently needed clinically.
Studies have shown that healthy adults have approximately 180g glucose per day filtered through the glomeruli, with > 99% of the glucose reabsorbed from the tubules. Under the condition of hyperglycemia, sodium-glucose cotransporters (SGLTs) are saturated, a large amount of glucose is excreted with urine, the SGLTs are currently hot targets for treating diabetes, and the number of human SGLT protein families is expanded to 12: SGLT1 to SGLT6 and another 6 SLC5A proteins, of which SGLT-1 and SGLT-2 play a dominant role. SGLT2 has a main function of reabsorption of glucose by the renal tubules, whereas SGLT1 has a main function of absorption of glucose from the gastrointestinal tract and distribution in various organs such as the heart and brain. In view of this, there is a need in the market to develop novel high-efficiency hypoglycemic agents for the treatment of type I diabetes.
Disclosure of Invention
In order to solve the technical problems, the invention provides a synthesis method of glycoside derivatives, an intermediate thereof and application thereof.
The first object of the present invention is to provide a preparation method of a glycoside derivative, wherein the glycoside derivative is a compound shown in formula I or a pharmaceutically acceptable salt thereof:
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 Independently is hydrogen, hydroxy,Carboxyl, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
In the above preparation method, as a preferred embodiment, in the compound represented by the formula I, the R 2 Is hydrogen, hydroxy, -O-aryl, -OCH 2 -aryl, alkoxy, alkyl, aryl, heteroaryl, -CF 3 Or halogen.
In the above preparation method, as a preferred embodiment, in the compound represented by the formula I, the R 4 ，R 5 Independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, or —cn; r is R 4 ，R 5 The same or different.
In the above preparation method, as a preferred embodiment, in the compound represented by the formula I, the R 6 Is hydrogen, hydroxy, carboxy, alkoxy, alkyl, cycloalkyl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, or —cn.
Further, R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 Independently hydrogen, hydroxy, carboxy, alkoxy (illustratively alkoxy is C1-C6 alkyloxy; C1-C6 alkyloxy is illustratively methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy)Oxy, isopentyloxy, n-hexyloxy, etc.), -O-aryl (illustratively, -O-aryl is
Etc.), the-O-heteroaryl (-O-heteroaryl is illustratively +.>
Etc. -OCH 2 -aryl (-OCH) 2 The aryl group is illustratively PhCH 2 O-、
Etc. -OCH 2 Heteroaryl (-OCH) 2 The heteroaryl group is illustratively +.>
Etc.), alkyl (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.), cycloalkyl (illustratively cycloalkyl is C3-C6 cycloalkyl; C3-C6 cycloalkyl includes substituted cycloalkyl or unsubstituted cycloalkyl, illustratively cyclopropyl, cyclobutyl,/- >
Cyclopentyl, or cyclohexyl, etc.), aryl (illustratively, aryl is phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl, or +.>
Etc.), heteroaryl (illustratively, heteroaryl is
Etc. -CF) 3 、-OCHF 2 、-OCF 3 Halogen (illustratively halogen is fluorine, chlorine, bromine, or iodine), -CN, alkoxyalkoxy (illustratively alkoxyalkoxy is methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy, isopropoxymethoxy, n-propoxyethoxy, isopropoxyethoxy, or +.>
Etc.), an ester group (illustratively, an ester group is +>
Etc.) or-NR 7 R 7a (illustratively, -NR) 7 R 7a Amino group, & lt>
Etc.) or contain 1 to 4N, O, S, SO and/or SO 2 3-14 membered heterocyclic ring (exemplified by +.>
Etc.);
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched chain alkyl, illustratively, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.);
wherein the alkyl, cycloalkyl, aryl, heteroaryl groups may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro.
In the above preparation method, as a preferred embodiment, the compound shown in the formula I is (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4-ethoxyphenoxy) -2H-pyran-3, 4, 5-triol, (2S, 5S, 6R) -2- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 4R, 6R) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 6- (4-ethoxybenzyl) -6R (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxy ethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4- (2, 4, 5-trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 5S, 6R) -2- (4-isobutoxy) phenyl) -6- (4-trifluoro-methyl) tetrahydro-2H-pyran-3, 5-triol, (2S, 3R,4R,5S, 6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol, or (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol.
In the above preparation method, as a preferred embodiment, the compound shown in formula I is prepared by deprotection reaction of a compound shown in formula II;
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
R 9 alkyl (illustratively, alkyl is C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched chain alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl, etc.), TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (t-butyldimethylsilyl);
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
The R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
Illustratively, when R is 9 In the case of TMS-or TBDMS-, the deprotecting reagent is TBAF; when R is 9 When Bn-, the deprotection reaction condition is H 2 /Pd-C、H 2 /Pt-C, or H 2 /Pd(OH) 2 -C, etc.; when R is 9 In the case of Ac-, the deprotection reaction conditions are strong alkali conditions (such as aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, etc.) or strong acid conditions; when R is 9 In the case of THP-or MOM-, the deprotection reaction conditions are acidic conditions (e.g., aqueous hydrochloric acid, ethyl hydrogen chloride (HCl (g)/EtOAc), methanolic hydrogen chloride (HCl (g)/CH) 3 OH), a hydrogen chloride ethanol solution (HCl (g)/EtOH), or a hydrogen chloride dioxane solution (HCl (g)/dioxane)); when R is 9 The deprotection reagent is concentrated hydrochloric acid, hydrobromic acid, concentrated sulfuric acid or boron tribromide.
In the above preparation method, as a preferred embodiment, the compound represented by formula II is prepared from a compound represented by formula III;
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
R 9 is alkyl, TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (tert-butyldi-methyl)A silyl group);
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
Illustratively, the reaction conditions for preparing a compound of formula II from a compound of formula III are BF 3 .Et 2 O。
In the above preparation method, as a preferred embodiment, the compound represented by formula III is prepared by reacting a compound represented by formula IV with a compound represented by formula V;
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
R 8 is-H, -F, -Cl, -Br, -I, -OMs, -OTs, -OTf;
R 9 alkyl, TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (tert-butyldimethylsilyl);
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
Illustratively, the reagent for preparing the compound of formula III from the compound of formula IV and the compound of formula V is LDA (lithium diisopropylamide), n-BuLi (n-butyllithium), or the like.
A second object of the present invention is to provide an intermediate compound which is a compound represented by formula III:
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
R 9 alkyl, TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (tert-butyldimethylsilyl);
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
Preferably, R 2 Is hydrogen, hydroxy, -O-aryl, -OCH 2 -aryl, alkoxy, alkyl, aryl, heteroaryl, -CF 3 Or halogen.
Preferably, R 4 ，R 5 Independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, or —cn; r is R 4 ，R 5 The same or different.
Preferably, R 6 Is hydrogen, hydroxy, carboxy, alkoxy, alkyl, cycloalkyl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, or —cn.
Further, R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 Independently hydrogen, hydroxy, carboxy, alkoxy (illustratively alkoxy is C1-C6 alkyloxy; C1-C6 alkyloxy is illustratively methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, and the like), -O-aryl (illustratively, -O-aryl is 
Etc.), the-O-heteroaryl (-O-heteroaryl is illustratively +.>
Etc. -OCH 2 -aryl (-OCH) 2 The aryl group is illustratively PhCH 2 O-、
Etc. -OCH 2 Heteroaryl (-OCH) 2 The heteroaryl group is illustratively +.>
Etc.), alkyl (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.), cycloalkyl (illustratively cycloalkyl is C3-C6 cycloalkyl; C3-C6 cycloalkyl includes substituted cycloalkyl or unsubstituted cycloalkyl, illustratively cyclopropyl, cyclobutyl,/->
Cyclopentyl, or cyclohexyl, etc.), aryl (illustratively, aryl is phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl, or +.>
Etc.), heteroaryl (illustratively, heteroaryl is
Etc. -CF) 3 、-OCHF 2 、-OCF 3 Halogen (illustratively halogen is fluorine, chlorine, bromine, or iodine), -CN, alkoxyalkoxy (illustratively alkoxyalkoxy is methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy, isopropoxymethoxy, n-propoxyethoxy, isopropoxyethoxy, or +. >
Etc.), an ester group (illustratively, an ester group is
Etc.) or-NR 7 R 7a (illustratively, -NR) 7 R 7a Amino group, & lt>
Etc.) or contain 1 to 4N, O, S, SO and/or SO 2 3-14 membered heterocyclic ring (exemplified by +.>
Etc.);
R 9 alkyl (illustratively, alkyl is C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched chain alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl, etc.), TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (t-butyldimethylsilyl);
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched chain alkyl, illustratively, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.);
wherein the alkyl, cycloalkyl, aryl, heteroaryl groups may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro.
Further, the compound shown in the formula III is:
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the third object of the invention is to provide an application of an intermediate compound in preparing the glycoside derivative, wherein the glycoside derivative is a compound shown in a formula I or pharmaceutically acceptable salt thereof, and the intermediate compound is a compound shown in a formula III.
Compared with the prior art, the invention has the following technical effects:
1. the invention provides a novel intermediate compound, which is used for synthesizing a glycoside derivative shown in a formula I and can prepare the glycoside derivative with high purity.
2. The preparation method of the novel intermediate compound adopts cheap and easily available chemical products as the initial raw materials, and the synthesis yield of each step is higher, so that the production cost is lower and the method is more suitable for industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (compound 1);
FIG. 2 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (compound 2);
FIG. 3 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 3);
FIG. 4 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 4);
FIG. 5 is a hydrogen spectrum of intermediate compounds 3-8 of example 3;
FIG. 6 is a High Performance Liquid Chromatography (HPLC) of intermediate compounds 4-6 of example 4.
Detailed Description
The glycoside derivative of the present invention, and the preparation method and application thereof are described below with reference to examples. It is to be understood that these examples are for the purpose of illustrating the invention only and are not to be construed as limiting the scope of the invention. It is to be understood that various changes and modifications may be made by one skilled in the art after reading the disclosure herein, and that such equivalents are intended to fall within the scope of the claims appended hereto.
The examples were conducted under conventional reaction conditions, where no specific conditions were noted. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 preparation of compound 1: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Route 1:
(1) Preparation of intermediate compound 1-3 (1- (4-ethoxyphenoxy) -3, 5-difluorobenzene)
100g of p-bromophenyl ethyl ether (compound 1-1, 496mmol,1 eq) and 97g of 3, 5-difluorophenol (compound 1-2, 746mmol,1.5 eq) were taken, 1000mL of dioxane was added, and Cs was added to the above solution in sequence at 20 ℃ 2 CO 3 324g (994 mmol,2 eq), cuI 28.4g (149.2 mmol,0.3 eq), isobutyl nitrite 30.8g (298 mmol,0.6 eq) and then stirred at 100℃for 12h. Cooling to 20 ℃ after the reaction is completed, then distilling under reduced pressure to obtain a concentrate, extracting the concentrate by adopting water-petroleum ether, collecting a petroleum ether phase, and distilling under reduced pressure to obtain a crude product; the crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 61.6g of pure compound 1-3 as a colorless oil in a yield of 24.8%.
(2) Preparation of intermediate Compounds 1-5
Taking compound 1-3.8 g (95.1 mmol,1.0 eq), adding 165.0mL of redistilled tetrahydrofuran at-70℃under N 2 71.3mL (2.0M, 1.5 eq) of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70deg.C for 0.5h, and then Compounds 1-4.51.2 were added dropwiseA solution of g (95.1 mmol,1.0 eq) in tetrahydrofuran (redistilled THF,100.0 mL) was stirred under nitrogen at-70℃for 1h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 46.0g of pure compound 1-5 as a colorless oil with a yield of 61.3%.
(3) Preparation of intermediate Compounds 1-6
Compound 1-5.0 g (59.2 mmol,1.0 eq) was weighed out, 320.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 8.2g (70.0 mmol,1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O5.0 g (70.0 mmol,1.2 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of a saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=1:0 to 10:1, yielding 26.0g of pure compound 1-6 as a colorless oil with a yield of 57.7%.
(4) Preparation of the target Compound 1 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
1-6.0 g (33.6 mmol,1.0 eq) of the compound was weighed, 200.0mL of methanol was added, 15.0g Pd/C (active material content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50psi of hydrogen for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 50mm, 10um; mobile phase water (0.1% tfa) -ACN, B%:30% -80%,20 min) to give 4.6g of the title compound 1 as a white solid in 33.3% yield.
1H NMR(400MHz，CD 3 OD)，δ：6.96-7.03(m,4H),6.45-6.49(m,2H),4.53(d,1H),4.06(q,2H),3.85-3.88(m,2H),3.65-3.75(m,1H),3.34-3.44(m,3H),1.41(t,3H)。
Route 2:
(1) Preparation of intermediate Compounds 1-8
Synthesis of 1-3 g (20 mmol) as illustrated in FIG. 1.
Compound 1-3.5 g (10 mmol,1.0 eq) was taken, to which was added 20mL of redistilled tetrahydrofuran at-70℃under N 2 7.5mL (2.0M, 1.5 eq) of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.5h, then 1-7.34 g (10 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,10 mL) was added dropwise and the mixture was stirred at-70℃for 1h under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, yielding 3.4g of pure compound 1-8 in 71% yield.
(2) Preparation of intermediate Compounds 1-9
Compound 1-8.4 g (7.1 mmol,1.0 eq) was weighed, 30mL of methylene chloride was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 1.0g (8.52 mmol,1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O0.6 g (8.52 mmol,1.2 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 20.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=1:0 to 6:1, yielding 2.16g of pure compound 1-9 in 65% yield.
(3) Preparation of the target Compound 1 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
Compound 1-9.16 g (4.6 mmol,1.0 eq) was weighed, 20mL of methylene chloride was added, 5.75g (23 mmol) of boron tribromide was added dropwise at 0deg.C, and stirred at 0deg.C for 2h. Pouring the mixture into ice water after the reaction is finished, adding dichloromethane for extraction, collecting an organic phase, and distilling under reduced pressure to obtain a concentrate; the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 18, 250, 50mm, 10um; mobile phase: water (0.1% TFA) -ACN, B%:30% -80%,20 min) to give 0.6g of the title compound 1 as a white solid in 32% yield.
Route 3:
(1) Preparation of intermediate Compounds 1-11
Synthesis of Compound 1-3.5 g (10 mmol,1.0 eq) by the preparation method of scheme 2, 20mL of redistilled tetrahydrofuran was added thereto, N at-70 ℃ 2 7.5mL (2.0M, 1.5 eq) of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.5h, then 1-10.7 g (10 mmol,1.0 eq) of a solution of the compound in tetrahydrofuran (redistilled THF,10 mL) was added dropwise, and the mixture was stirred at-70℃for 1h under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 4.4g of pure compound 1-11 in 62% yield.
(2) Preparation of intermediate Compounds 1-12
Compound 1-11.4 g (6.2 mmol,1.0 eq) was weighed, 40mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 0.87g (7.44 mmol,1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O0.5 g (7.44 mmol,1.2 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 20.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=1:0 to 8:1, yielding 2.74g of pure compound 1-12 in 63% yield.
(3) Preparation of the target Compound 1 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
Compound 1-12.74 g (3.9 mmol,1.0 eq) was weighed, 40mL tetrahydrofuran was added, 4.07g (15.6 mmol,4 eq) TBAF (tetrabutylammonium fluoride) was added, and the mixture was reacted at 40℃for 6h. After the reaction is finished, adding dichloromethane-saturated saline for extraction, collecting an organic phase, and distilling under reduced pressure to obtain a concentrate; the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 18, 250, 50mm, 10um; mobile phase: water (0.1% TFA) -ACN, B%:30% -80%,20 min) to give 0.67g of the title compound 1 as a white solid in 42% yield.
Example 2 preparation of compound 2: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
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(1) Preparation of intermediate Compounds 2-3
Compound 2-1 53g (213.4 mmol,1.0 eq) was weighed out, 265mL of redistilled tetrahydrofuran was added, and the mixture was taken at-70℃under N 2 106.6mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃for 0.5h, followed by dropwise additionA solution of compound 2-2 115g (213.4 mmol,1.0 eq) in tetrahydrofuran (redistilled THF,106.0 mL) was added dropwise and stirred at-70℃under nitrogen for 1h after the addition. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 105.0g of pure compound 2-3 as a colorless oil in 62.5% yield.
(2) Preparation of intermediate Compounds 2-4
Compound 2-3.0 g (133.4 mmol,1.0 eq) was weighed out, 735.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 18.6g (160 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O22.75 g (160 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, giving 68.0g of pure compound 2-4 as a white solid with a yield of 66.1%.
(3) Preparation of target Compound 2 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
2-4.0 g (88.2 mmol,1.0 eq) of the compound was weighed, 500.0mL of methanol was added, 22.0g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at 50℃under 50psi of hydrogen for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% tfa) -ACN, 25% -53% B%: 30 min) to give 15g of the objective compound 2 as a white solid in 41.5% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.08(dd,J＝8.8Hz,2H),6.82(dd,J＝8.4Hz,2H),6.76(d,2H),4.54(d,1H),3.99(q,2H),3.84-3.87(m,4H),3.61-3.63(m,1H),3.30-3.45(m,3H),1.35(t,3H)。
Example 3 preparation of compound 3: (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate compound 3-3 (4- (4-bromo-2-chlorophenoxy) benzaldehyde)
Compound 3-1.0 g (289.2 mmol,1.00 eq) was weighed out, 650.0mL of LDMA (dimethylacetamide), compound 3-2.90 g (289.2 mmol,1.00 eq) and potassium carbonate 42.37g (306.6 mmol,1.06 eq) were added and reacted under nitrogen at 100deg.C for 12h. After the reaction is completed, the temperature is reduced to room temperature, MTBE (methyl tert-butyl ether) (1.00L) is adopted for extraction, the organic phase MTBE is further adopted for extraction by saturated saline (1.00L), the organic phase is collected, the concentrate is obtained through reduced pressure distillation, the concentrate passes through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=40:1 to 3:1, giving 67.0g of compound 3-3 as a pale yellow oil in a yield of 72.1%.
1HNMR(400MHz，CDCl3)δ：9.66(s,1H),7.89(d,J＝8.8Hz,2H),7.69(d,J＝2.4Hz,1H),7.46(dd,J＝2.4Hz,J＝8.8Hz,1H),7.04(d,J＝0.8Hz,J＝8.8Hz,3H)。
(2) Preparation of intermediate Compounds 3-4
To the solution was added 58.0g (268.8 mmol, purity 80%,1.25 eq) of m-CPBA from 3-3.0 g (215.1 mmol,1.00 eq) of methylene chloride (670.0 mL), and the reaction system was reacted at 20℃for 10 hours. After completion of TLC detection, 200.0mL of saturated Na was added to the reaction solution at 10 ℃ 2 SO 3 Aqueous, MTBE (300.0 mL) extraction was performed, then the organic phase was extracted with saturated aqueous sodium carbonate and saturated brine, respectively, and the organic phase was collected and concentratedThe shrinkage afforded 70.0g of crude compound 3-4, which was used in the next step without purification.
(3) Preparation of intermediate Compounds 3-5
70.0g of crude compound 3-4 prepared in the step (2) is taken, 350mL of methanol and 0.5mL of concentrated hydrochloric acid (12M) are added, and the mixture is stirred for 2h at 20 ℃. After the reaction is finished, the crude product is obtained by reduced pressure distillation. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 67.0g of compound 3-5 as a pale yellow oil.
1HNMR(400MHz CDCl3)δ：7.60(d,J＝2.4Hz,1H),7.29(d,J＝2.4Hz,J＝8.8Hz,1H),6.91-6.93(m,2H),6.83-6.86(m,2H),6.75(d,J＝8.8Hz,1H)。
(4) Preparation of intermediate Compounds 3-6
Compound 3-5.0 g (1.00 eq) was taken, 450.0mL tetrahydrofuran was added, the temperature was reduced to 0℃and 16.5g NaH (purity 60%,2.4 eq) was added in portions, then 40.3g iodoethane (258.3 mmol,1.50 eq) was added dropwise, and the temperature was raised to 60℃for reaction for 12h. After the reaction is completed, the temperature is reduced to 0 ℃ and 300.0mL of saturated NH is added into the reaction solution 4 The Cl aqueous solution is added with MTBE for extraction, the organic phase is collected and concentrated to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 10:1, giving 55.0g of compound 3-6 as a pale yellow oil in 74.8% yield.
1HNMR(400MHz，CDCl 3 )δ：7.50(d,J＝2.4Hz,1H),7.17-7.20(m,1H),6.85-6.87(m,2H),6.79-6.85(m,2H),6.64(d,J＝8.4Hz,1H),3.94(q,J＝7.2Hz,J＝14.4Hz,2H),1.34(t,J＝7.2Hz,3H)。
(5) Preparation of intermediate Compounds 3-8
Weighing 3-6.0 g (122.10 mmol,1.00 eq) of compound, adding redistilled 700mLTHF at-70deg.C under N 2 Under the condition of48.84mL (2.5M, 1.00 eq) of a solution of n-BuLi (n-butyllithium) in tetrahydrofuran was added dropwise and stirred at-70℃under nitrogen for 0.2h, then a solution of 3-6.77 g (122.10 mmol,1.00 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise and stirred at-70℃under nitrogen for 1h. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 75.0g of pure compound 3-8 as a colorless oil.
1HNMR(400MHz，DMSO)δ：7.64(s,1H),7.34-7.32(d,J＝6.8Hz,1H),7.20-7.29(m,15H),6.92-6.93(m,6H),6.85(s,1H),4.75-4.80(m,3H),4.8-4.58(m,5H),3.96-4.02(m,4H),3.64-3.78(m,4H),1.30(t,J＝6.8Hz,3H)。
(6) Preparation of intermediate Compounds 3-9
Compound 3-8.0 g (95.3 mmol,1.00 eq) was weighed, 525.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH (13.3 g,114.3mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O6.5 g (45.7 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After completion of the reaction, the reaction mixture was poured into a saturated solution of 200.0mL NaHCO 3 Extracting in aqueous solution, collecting dichloromethane phase, and distilling under reduced pressure to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 52.0g of pure compound 3-9 as a white solid with a yield of 70.7%.
(7) Preparation of the target Compound 3 ((2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
3-9.0 g (57.0 mmol,1.00 eq) of the compound was weighed, 880.0mL of ethanol was added, pd/C11.0 g (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at 20℃under 30psi of hydrogen for 12 hours. After the reaction was completed, suction filtration was performed, the filtrate was concentrated, and the concentrate was subjected to prep.SFC (preparative SFC) (columnChiralpak IC-H250.30 mm i.d.5u; mobile phase A phase CO 2 Phase B IPA (isopropylamine) (0.1% NH) 3 .H 2 O); gradient B% = 45%; the flow rate is 73g/min; the detection wavelength is 220nm; column temperature is 40 ℃; pressure 100 bar) to give 9.22g of the title compound 3 as a white solid.
1HNMR(400MHz，CD 3 OD)δ：7.55(d,J＝2.0Hz,1H),7.28(dd,J＝2.0Hz,J＝8.4Hz,1H),6.83-6.89(m,5H),4.11(d,J＝8.8Hz,1H),4.06(q,2H),3.88(dd,J＝2.0Hz,J＝8.0Hz,1H),3.71(dd,J＝5.2Hz,J＝11.6Hz,1H),3.40-3.44(m,3H),3.30-3.31(m,1H),1.37(t,J＝6.8Hz,3H)。
Example 4 preparation of compound 4: (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula 
(1) Preparation of intermediate compound 4-2 (4-bromo-2-chlorobenzoyl chloride)
Compound 4-1.0 g (127.41 mmol,1.00 eq) was taken, 180.0mL of LDCM and 0.1mL of DMF were added, 17.8g (140.2 mmol,1.10 eq) of oxalyl chloride was added dropwise at 0℃and after the addition was completed, the temperature was raised to 20℃for reaction for 3h. After the reaction was completed, a dichloromethane solution of compound 4-2 was obtained and used directly in the next step without post-treatment.
(2) Preparation of intermediate Compounds 4-3
To a dichloromethane solution of compound 4-2 obtained in step (1) at 0deg.C under nitrogen, 15.5g (127.4 mmol,1.00 eq) of ethoxybenzene was added followed by the addition of AlCl in portions 3 17.0g (127.4 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to 20℃and reacted for 3h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase is collectedAnhydrous Na 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and dried under reduced pressure to give 35.0g of Compound 4-3 as a white solid in 80.9% yield.
1HNMR(400MHz，CDCl 3 )δ：7.74(dd,J＝7.2Hz,J＝9.2Hz,2H),7.63(m,1H),7.50(d,J＝2.0Hz,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),6.92(d,J＝8.8Hz,2H),4.11(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H)。
(3) Preparation of intermediate Compounds 4-4
Compound 4-3.0 g (103.1 mmol,1.00 eq) was taken, 350.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 59.9g (515.3 mmol,5.00 eq) and BF were then added dropwise under nitrogen at 25 ℃ 3 .Et 2 O29.3 g (206.1 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated brine, the organic phase is collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 33.0g of compound 4-4 as a pale yellow oil in 92.0% yield.
1HNMR(400MHz，CDCl 3 )δ：7.53(d,J＝2.0Hz,1H),7.29(d,J＝2.0Hz,J＝8.4Hz,1H),7.06(d,J＝8.8Hz,2H),6.98(d,J＝8.0Hz 1H),6.83(d,J＝8.4Hz,2H),3.98(q,J＝6.8Hz,2H),1.40(t,J＝6.8Hz,3H)。
(4) Preparation of intermediate Compounds 4-6
Compound 4-4.0 g (86.0 mmol,1.00 eq) was weighed out, 560mL of redistilled THF was added at-70℃under N 2 34.4mL (2.5M, 1.00 eq) of n-BuLi in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise additionA solution of compound 4-5.3 g (86.0 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise and then stirred under nitrogen at-70℃for 1h. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 56.0g of pure compound 4-6 as a colorless oil with a yield of 72.8%.
(5) Preparation of intermediate Compounds 4-7
Compound 4-6.0 g (71.3 mmol,1.00 eq) was weighed out, 390.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.95g (85.6 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O12.1 g (85.6 mmol,1.20 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of saturated aqueous sodium bicarbonate, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 55.0g of pure compound 4-7 as a colorless oil in a yield of 64.6%.
(6) Preparation of the target Compound 4 ((2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
41.2g (53.6 mmol,1.00 eq) of compound 4-7 and 800.0mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C8.00 g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at 20℃for 12 hours under 30psi of hydrogen. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 50mm, 10um; mobile phase: water (0.1% tfa) -ACN, B%:26% -46%,20 min) to give 7.7g of the title compound 4 as a white solid in 35.1% yield.
1HNMR(400MHz，DMSO)δ：7.37(s,1H),7.23(d,2H),7.08(d,J＝8.4Hz,2H),6.81(d,J＝8.4Hz,2H),4.7(br.s,4H),3.92-4.00(m,5H),3.60-3.66(m,1H),3.40-3.50(m,1H),3.05-3.24(m,4H),1.27(t,J＝7.2Hz,3H)。
Example 5 preparation of compound 5: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
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(1) Preparation of intermediate Compounds 5-3
69.4g (5-1, 496mmol,1 eq) of p-bromophenyl ethyl ether and 152.5g (744 mmol,1.5 eq) of compound 5-2 were taken, 500mL of dimethylformamide was added, cs was added to the above solution in sequence at 20 ℃ 2 CO 3 323g (992 mmol,2 eq) and then stirred for 12h under nitrogen at 100 ℃. Cooling to room temperature after the reaction is completed, then distilling under reduced pressure to obtain a concentrate, extracting the concentrate by adopting water-ethyl acetate, collecting an organic phase, and distilling under reduced pressure to obtain a crude product; the crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=40:1 to 5:1, giving 40.3g of pure compound 5-3 as a colorless oil in 25% yield.
(2) Preparation of intermediate Compounds 5-5
Taking 5-3.3 g (124 mmol,1.0 eq) of compound, adding 180.0mL of redistilled tetrahydrofuran at-70 ℃ under N 2 148.8mL (2.5M, 3 eq) of a tetrahydrofuran solution of n-butyllithium were added dropwise to the above solution under nitrogen at-70℃for 0.5h, followed by dropwise addition of a solution of 5-4.7 g (124 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,150.0 mL) of the compound under nitrogen at-70℃for 1h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate in Cl aqueous solutionThe organic phase was collected and distilled under reduced pressure to give crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 31.6g of pure compound 5-5 in 32.5% yield.
(3) Preparation of intermediate Compounds 5-6
Compound 5-5.6 g (40.3 mmol,1.0 eq) was weighed out, 350.0mL of dichloromethane was added, et was added to the above solution under nitrogen at 20 ℃ 3 SiH 5.6g (48.36 mmol,1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O3.5 g (48.36 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a saturated 200.0mL aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=1:0 to 10:1, yielding 18.8g of pure compound 5-6 in 61% yield.
(4) Preparation of the target Compound 5 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
5-6.8 g (24.5 mmol,1.0 eq) of the compound was weighed, 200.0mL of methanol was added, 17.0g Pd/C (active material content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50psi of hydrogen for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 50mm, 10um; mobile phase water (0.1% tfa) -ACN, B%:30% -80%,20 min) to give 3.0g of the target compound 5 as a white solid in a yield of 30.1%.
1H NMR(400MHz，CD 3 OD)，δ：6.96-7.03(m,4H),6.18(dd,2H),5.35(d,1H),4.53(q,2H),4.03-4.09(m,1H),3.85-3.88(m,2H),3.63-3.65(m,1H),3.34-3.44(m,3H),1.42(t,3H)。
Example 6 preparation of compound 6: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 6-2
Compound 6-1 60g (230.4 mmol,1.00 eq) was taken, 200.0mL DCM and 0.1mL DMF were added, 132.2g (253.4 mmol,1.10 eq) oxalyl chloride was added dropwise at 0deg.C, and after the addition was completed, the temperature was raised to 20deg.C for 3h. After the reaction was completed, a dichloromethane solution of compound 6-2 was obtained and used directly in the next step without post-treatment.
(2) Preparation of intermediate Compound 6-3
To a dichloromethane solution of compound 6-2 obtained in step (1) was added 28.0g (230.4 mmol,1.00 eq) of ethoxybenzene at 0deg.C under nitrogen, followed by the addition of AlCl in portions 3 30.7g (230.4 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to 20℃and reacted for 3h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate, and the mixture was stirred at 20℃for 2 hours, the solid was precipitated, collected by filtration, and dried under reduced pressure to give 68g of Compound 6-3 in 80.9% yield.
(3) Preparation of intermediate Compounds 6-4
Compound 6-3 68g (186.4 mmol,1.00 eq) was taken, 350.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 108.3g (932 mmol,5.00 eq) was then added dropwise under nitrogen at 25 ℃BF 3 .Et 2 O106 g (745.6 mmol,4.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated brine, the organic phase is collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 5:1, yielding 55.4g of compound 6-6 in 92.0% yield.
(4) Preparation of intermediate Compounds 6-6
Weighing 6-4.4 g (171.5 mmol,1.0 eq) of the compound, adding 300mL of redistilled tetrahydrofuran at-70deg.C under N 2 205.8mL (2.5M, 3.0 eq) of a tetrahydrofuran solution of n-butyllithium was added dropwise to the above solution under nitrogen at-70℃for 0.5h, followed by dropwise addition of a tetrahydrofuran (redistilled THF,100.0 mL) solution of compound 6-5 92g (171.5 mmol,1.0 eq) and stirring at-70℃for 1h under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 40.3g of pure compound 6-6 in 30% yield.
(5) Preparation of intermediate Compounds 6-7
Compound 6-6.3 g (51.45 mmol,1.0 eq) was weighed out, 300.0mL of dichloromethane was added, et was added to the above solution under nitrogen at 20 ℃ 3 SiH 7.16g (61.74 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O8.8 g (61.74 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of a saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, yielding 23.7g of purified productCompounds 6-7 were white solids in 60% yield.
(6) Preparation of the target Compound 6 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
Compound 6-7.7 g (30.87 mmol,1.0 eq) was weighed, 200.0mL of methanol was added, 12g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50psi of hydrogen for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% tfa) -ACN, B%:20% -60%,30 min) to give 3.7g of the target compound 6 as a white solid in 30% yield.
1H NMR(400MHz，DMSO)，δ：7.08(d,J＝8.8Hz,2H),6.82(d,J＝8.4Hz,2H),6.47(s,2H),4.53-4.56(m,1H),3.95-4.01(q,2H),3.84-3.87(m,4H),3.61-3.63(m,1H),3.30-3.35(m,3H),1.36(t,3H)。
Example 7 preparation of compound 7: (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxy ethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
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(1) Preparation of intermediate Compound 7-3
100g of p-bromophenol (compound 7-1, 578mmol,1 eq), compound 7-2.5 g (578 mmol,1 eq) and potassium carbonate 95.7g were taken, 1000mL of dioxane was added, and stirred at 60℃for 12h. After the reaction is completed, the reaction liquid is distilled under reduced pressure to obtain a concentrate, the concentrate is extracted by adopting saturated saline water-ethyl acetate, an organic phase is collected, and a crude product is obtained through reduced pressure distillation; the crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1, giving 104.8g of pure compound 7-3 in 70% yield.
(2) Preparation of intermediate Compounds 7-5
Taking 100g (383 mmol,1 eq) of compound 7-3, 60.2g (compound 7-4, 463.2mmol,1.2 eq) of 3, 5-difluorophenol, adding 800mL of dioxane, adding Cs sequentially to the above solution at 20deg.C 2 CO 3 252g (772 mmol,2 eq), cuI 22g (115.8 mmol,0.3 eq), isobutyl nitrite 23.9g (231.6 mmol,0.6 eq) and then stirred at 100℃for 12h. Cooling to 20 ℃ after the reaction is completed, then distilling under reduced pressure to obtain a concentrate, extracting the concentrate by adopting water-ethyl acetate, collecting an organic phase, and distilling under reduced pressure to obtain a crude product; the crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, yielding 59.4g of pure compound 7-5 in 50% yield.
(3) Preparation of intermediate Compounds 7-7
59.4g (193 mmol,1.0 eq) of Compound 7-7 was taken, 200.0mL of redistilled tetrahydrofuran was added at-70℃under N 2 144.6mL (2.0M, 1.5 eq) of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.5h, followed by dropwise addition of a solution of compound 7-6.9 g (193 mmol,1.0 eq) in tetrahydrofuran (redistilled THF,200.0 mL) under nitrogen at-70℃for 1h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 95.1g of pure compound 7-7 with a yield of 58.3%.
(4) Preparation of intermediate Compounds 7-8
Weigh 7-8.1 g (112).5mmol,1.0 eq) was added 500.0mL of dichloromethane and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 15.6g (135 mmol,1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O9.6 g (135 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a saturated 200.0mL aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=10:0 to 2:1, yielding 52.1g of pure compound 7-8 with a yield of 55.8%.
(5) Preparation of the target Compound 7 ((2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxyethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
To the above solution was weighed compound 7-8.1 g (62.8 mmol,1.0 eq), added 500.0mL of methanol, 28.0g Pd/C (active material content 10%) under argon atmosphere, and the reaction system was evacuated to fill hydrogen and reacted under 50psi hydrogen at 50℃for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 50mm, 10um; mobile phase: water (0.1% hcooh) -ACN, B%:30% -80%,20 min) to give 10.3g of the objective compound 7 as a white solid in 35% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.30(dd,2H),6.96(d,2H),6.87(dd,2H),4.54(d,1H),4.29(t,2H),4.03-4.09(m,2H),3.85(t,2H),3.65(m,1H),3.34-3.44(m,3H),3.11-3.13(m,1H),1.08(d,6H)。
Example 8 preparation of compound 8: (2S, 3R,4R,5S, 6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 8-3
Weighing compound 8-1 50g (227 mmol,1.0 eq), adding 300mL of redistilled tetrahydrofuran at-70deg.C under N 2 226.8mL (2.0M, 2.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃for 0.5h with stirring, and then 8-2.122.3 g (227 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise with stirring at-70℃for 1h under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 1:1, yielding 101.5g of pure compound 8-3 in 59% yield.
(2) Preparation of intermediate Compounds 8-4
Compound 8-3.5 g (133.9 mmol,1.0 eq) was weighed out, 800.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 18.7g (160.7 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O22.8 g (160.7 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 2:1, yielding 59.6g of pure compound 8-4 in 60% yield.
(3) Preparation of intermediate Compounds 8-5
Compound 8-4.6 g (80.3 mmol,1.0 eq) was weighed, 500mL of dichloromethane, 20.7g of DIPEA (160.6 mmol,2 eq), 35.5g of HATU (93.4 mmol,1.2 eq) were added, then 4.3g of formic acid (93.4 mmol,1.2 eq) was added dropwise, and after the addition was completed, stirring was carried out at room temperature for 2h. Extracting with saturated saline, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 10:1, yielding 45.3g of pure compound 8-5 in a yield of 72%.
(4) Preparation of target Compound 8 ((2S, 3R,4R,5S, 6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
8-5.0 g (57.8 mmol,1.0 eq) of the compound was weighed, 500.0mL of ethanol was added, 22.0g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at 50℃under 50psi of hydrogen for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% tfa) -ACN, B%:25% -70%,30 min) to give 9.5g of the title compound 8 as a white solid in 39% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.16(d,J＝8.8Hz,2H),6.87(d,J＝8.4Hz,2H),6.42(d,2H),4.57(d,1H),3.98(s,2H),3.86-3.89(m,4H),3.61(m,1H),3.30-3.35(m,1H),2.23(s,3H)。
Example 9 preparation of compound 9: (2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 9-3
50g (171.2 mmol,1.0 eq) of Compound 9-1 was weighed, 200mL of redistilled tetrahydrofuran was added, and the mixture was taken at-70℃under N 2 85.5mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70deg.C for 0.5h, followed by dropwise addition of 9-2.3 g (171.2 mmol,1.0 eq) of tetrahydrofuran A solution of the pyran (redistilled THF,100.0 mL) was stirred at-70℃under nitrogen for 1h after the addition. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 2:1, yielding 92.3g of pure compound 9-3 as a colorless oil in 65% yield.
(2) Preparation of intermediate Compounds 9-4
Compound 9-3.3 g (111.3 mmol,1.0 eq) was weighed out, 700.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 15.6g (133.6 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O19 g (133.6 mmol,1.2 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, giving 60.7g of pure compound 9-4 as a white solid in 67% yield.
(3) Preparation of target Compound 9 ((2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethyloxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
To the above solution was weighed compound 9-4.7 g (74.5 mmol,1.0 eq), added 500.0mL of methanol, 18.6g Pd/C (active ingredient content 10%) under argon atmosphere, and the reaction system was evacuated to fill hydrogen and reacted at 50℃under 50psi of hydrogen for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% hcooh) -ACN, B%:25% -60%,30 min) to give 15.2g of the objective compound 9 as a white solid in 45% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.05(s,1H),6.79(d,1H),6.70(d,1H),6.56(d,2H),4.53-4.56(m,1H),4.06(q,4H),3.97(s,2H),3.84-3.87(m,4H),3.60-3.63(m,2H),1.35(t,6H)。
Example 10 preparation of compound 10: (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 10-3
10-1 g (182.4 mmol,1.0 eq) of the compound was weighed, 200mL of redistilled tetrahydrofuran was added, and the mixture was taken at-70℃under N 2 91.1mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃for 0.2h with stirring, and then 10-2.98.2 g (182.4 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise with stirring at-70℃for 1h under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 2:1, yielding 86.5g of pure compound 10-3 as a colorless oil with a yield of 58.4%.
(2) Preparation of intermediate Compound 10-4
Compound 10-3.5 g (106.6 mmol,1.0 eq) was weighed out, 700.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at room temperature 3 SiH 14.9g (127.9 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O18.2 g (127.9 mmol,1.2 eq) then warmed to room temperature and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Crude product of desilicationThe gel column, the mobile phase is petroleum ether: ethyl acetate=100:1 to 3:1, yielding 56.8g of pure compound 10-4 as a white solid with a yield of 67%.
(3) Preparation of target Compound 10 ((2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
10-4.8 g (71.4 mmol,1.0 eq) of the compound was weighed, 500.0mL of ethyl acetate was added, 17.8g Pd/C (wet palladium on carbon, 5% active ingredient content) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50psi hydrogen at 50℃for 12 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% hcooh) -ACN, 25% -70% B%, 30 min) to give 13g of the title compound 10 as a white solid in 42% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.55(d,J＝8.8Hz,2H),7.32(d,J＝8.4Hz,2H),6.88(d,2H),4.53-4.56(m,1H),3.87-3.90(m,1H),3.80-3.82(m,2H),3.61-3.63(m,3H)。
Example 11 preparation of compound 11: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula 
(1) Preparation of intermediate Compound 11-2 (4-bromo-2-fluorobenzoyl chloride)
Compound 11-1.0 g (137 mmol,1.00 eq) was taken, 200.0mL DCM and 0.1mL DMF were added, and oxalyl chloride 19.1g (150.7 mmol,1.10 eq) was added dropwise at 0deg.C and reacted at room temperature for 5h. After the reaction was completed, a methylene chloride solution of the compound 11-2 was obtained, which was used in the next step without post-treatment.
(2) Preparation of intermediate Compound 11-3
To a dichloromethane solution of compound 11-2 obtained in step (1) at 0deg.C under nitrogen, 16.7g (137 mmol,1.00 eq) of ethoxybenzene was added followed by the addition of AlCl in portions 3 18.3g (137 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to room temperature and reacted for 3h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and the solid was dried under reduced pressure to give 33.3g of Compound 11-3 as a white solid in 75.2% yield.
(3) Preparation of intermediate Compound 11-4
Compound 11-3.3 g (103.1 mmol,1.00 eq) was taken, 350.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 18g (154.65 mmol,1.5 eq) and BF were then added dropwise under nitrogen at 25 ℃ 3 .Et 2 O29.3 g (206.1 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 28.4g of compound 11-4 in 89% yield.
(4) Preparation of intermediate Compounds 11-6
Compound 11-4.4 g (91.8 mmol,1.00 eq) was weighed out, 600mL of redistilled THF was added at-70℃under N 2 36.7mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran were added dropwise to the above solution under nitrogen at-70℃for 0.2h, thenA solution of compound 10-5.4 g (91.8 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise and then stirred under nitrogen at-70℃for 1h. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 3:1, yielding 52.9g of pure compound 11-6 in 75% yield.
(5) Preparation of intermediate Compounds 11-7
Compound 11-6.9 g (68.85 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.6g (82.62 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O11.7 g (82.62 mmol,1.20 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of saturated aqueous sodium bicarbonate, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, yielding 35.3g of pure compound 11-7 in 68% yield.
(6) Preparation of the target Compound 11 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
35.3g (46.8 mmol,1.00 eq) of 11-7 compound and 600.0mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C7.00 g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at 20℃under 30psi of hydrogen for 12 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 50mm, 10um; mobile phase: water (0.1% tfa) -ACN, B%:20% -60%,20 min) to give 6.8g of the objective compound 11 as a white solid in 37% yield.
1HNMR(400MHz，DMSO)δ：7.15(d,1H),7.14(d,2H),7.02(d,1H),6.89(d,2H),6.79(d,1H),4.7(br.s,4H),3.94-4.02(m,5H),3.61-3.67(m,1H),3.41-3.51(m,1H),3.06-3.25(m,4H),1.34D(t,3H)。
Example 12 preparation of compound 12: (2S, 3R,4R,5S, 6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate compound 12-2 (4-bromo-2-fluorobenzoyl chloride)
12-1.0 g (137 mmol,1.00 eq) of the compound was taken, 200.0mL of DCM and 0.1mL of DMF were added, 19.1g (150.7 mmol,1.10 eq) of oxalyl chloride was added dropwise at 0℃and after the addition was completed, the temperature was raised to 20℃for reaction for 3h. After the reaction was completed, a dichloromethane solution of compound 12-2 was obtained, which was used directly in the next step without post-treatment.
(2) Preparation of intermediate Compound 12-3
25.7g (137 mmol,1.00 eq) of p-fluorophenoxybenzene was added to a dichloromethane solution of compound 12-2 obtained in step (1) at 0deg.C under nitrogen, followed by the addition of AlCl in portions 3 18.3g (137 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to 20℃and reacted for 5h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and the solid was dried under reduced pressure to give 45.3g of compound 12-3 as a white solid in 85% yield.
(3) Preparation of intermediate Compound 12-4
Compound 12-3.3 g (116) was taken.4mmol,1.00 eq), 400.0mL acetonitrile and Et at 20℃under nitrogen 3 40.6g SiH (349.2 mmol,3.00 eq) were then added dropwise under nitrogen at 25℃with BF 3 .Et 2 O33 g (232.8 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated brine, the organic phase is collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 39.7g of compound 12-4 in 91.0% yield.
(4) Preparation of intermediate Compound 12-6
Compound 12-4.7 g (105.9 mmol,1.00 eq) was weighed out, 600mL of redistilled THF was added at-70℃under N 2 42.4mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise addition of 12-5 57g (105.9 mmol,1.00 eq) of a solution of the compound in tetrahydrofuran (redistilled THF,150.0 mL) and stirring at-70℃for 1h under nitrogen. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, yielding 66.2g of pure compound 12-6 in 75% yield.
(5) Preparation of intermediate Compounds 12-7
Compound 12-6.2 g (79.4 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, et was added to the above solution under nitrogen at 20 ℃ 3 SiH 11g (95.3 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O13.5 g (95.3 mmol,1.20 eq) and then warmed to 20℃and stirred for 2h. After the completion of the reaction, the reaction mixture was poured into 200.0mL of saturated aqueous sodium hydrogencarbonate, extracted, and the methylene chloride phase was collected and distilled under reduced pressureCrude products are obtained. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, yielding 39.6g of pure compound 12-7 in 61% yield.
(6) Preparation of the target Compound 12 ((2S, 3R,4R,5S, 6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
39.6g (48.4 mmol,1.00 eq) of the compound 12-7 and 800.0mL of ethyl acetate were taken and mixed uniformly under stirring, then 7.2g (active ingredient content 10%) of Pd/C was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30psi of hydrogen pressure for 12 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 50mm, 10um; mobile phase: water (0.1% tfa) -ACN, B%:20% -60%,30 min) to give 8.2g of the title compound 12 as a white solid in 37% yield.
1HNMR(400MHz，DMSO)δ：7.41(dd,2H),7.25(dd,2H),7.18(dd,2H),7.16(dd,2H),7.13(d,1H),6.99(d,1H),6.75(d,1H),3.95(s,2H),4.6(br.s,4H),3.91-4.04(m,3H),3.63-3.68(m,1H),3.42-3.51(m,3H),3.05-3.24(m,2H)。
Example 13 preparation of compound 13: (2S, 3R,4R,5S, 6R) -2- (4- (4- (2, 4, 5-Trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 13-2 (4-bromo-benzoyl chloride)
Compound 13-1.5 g (137 mmol,1.00 eq) was taken, 200.0mL DCM and 0.1mL DMF were added, and oxalyl chloride 19.1g (150.7 mmol,1.10 eq) was added dropwise at 0deg.C, after which the temperature was raised to 20deg.C for 3h. After the reaction was completed, a methylene chloride solution of the compound 13-2 was obtained, which was used in the next step without post-treatment.
(2) Preparation of intermediate Compound 13-4
To a dichloromethane solution of compound 13-2 obtained in step (1) at 0deg.C under nitrogen, 13-330.7g (137 mmol,1.00 eq) of compound was added followed by the addition of AlCl in portions 3 18.3g (137 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to 20℃and reacted for 5h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and the solid was dried under reduced pressure to give 45.7g of Compound 13-4 as a white solid in 82% yield.
(3) Preparation of intermediate Compound 13-5
Compound 13-4.7 g (112.3 mmol,1.00 eq) was taken, 400.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 39g (336.9 mmol,3.00 eq) and BF were then added dropwise under nitrogen at 25 ℃ 3 .Et 2 O31.8 g (224.6 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, yielding 40.6g of compound 13-5 in 92% yield.
(4) Preparation of intermediate Compounds 13-7
Compound 13-5.6 g (103.3 mmol,1.00 eq) was weighed out, 600mL of redistilled THF was added at-70℃under N 2 41.4mL (2.5M, 1.00 eq) n were added dropwise to the above solution under the conditionsA solution of BuLi in tetrahydrofuran was stirred at-70℃for 0.2h under nitrogen, then a solution of compound 13-6.6 g (103.3 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,150.0 mL) was added dropwise, followed by stirring at-70℃for 1h under nitrogen. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 3:1, yielding 59g of pure compound 13-7 in 67% yield.
(5) Preparation of intermediate Compounds 13-8
Compound 13-7 59g (69.2 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.6g (83 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O11.8 g (83 mmol,1.20 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of saturated aqueous sodium bicarbonate, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 4:1, yielding 34.2g of pure compound 13-8 in 59% yield.
(6) Preparation of the target Compound 13 ((2S, 3R,4R,5S, 6R) -2- (4- (4- (2, 4, 5-trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
34.2g (40.8 mmol,1.00 eq) of compound 13-8 and 800.0mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C6.1 g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30psi hydrogen pressure for 12 hours. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 50mm, 10um; mobile phase water (0.1% tfa) -MeOH, B%:20% -40%,30 min) to give 5.8g of the title compound 13 as a white solid in 30% yield.
1HNMR(400MHz，DMSO)δ：7.29(dd,2H),7.26(d,1H),7.25(dd,J＝8.4Hz,2H),7.19(dd,2H),7.16(dd,J＝8.4Hz,2H),6.68(t,1H),4.6(br.s,4H),4.05(d,1H),3.97(s,2H),3.63-3.68(m,1H),3.42-3.51(m,3H),3.05-3.24(m,2H)。
Example 14 preparation of compound 14: (2S, 3R,4R,5S, 6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 14-3
17.2g (150 mmol,1.00 eq) of 2-chloropyrimidine was taken, 100mL of DMF, 15.5g (165 mmol,1.100 eq) of phenol, 73.4g (225 mmol,1.5 eq) of cesium carbonate were added and reacted at 60℃for 12h; after the reaction is finished, extracting by adopting ethyl acetate and saturated saline water, collecting an organic phase, and concentrating to obtain a crude product; the crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, yielding 23.7g of compound 14-3 in 92% yield.
(2) Preparation of intermediate Compound 14-2 (4-bromo-benzoyl chloride)
Compound 14-1.5 g (137 mmol,1.00 eq) was taken, 200.0mL DCM and 0.1mL DMF were added, and oxalyl chloride 19.1g (150.7 mmol,1.10 eq) was added dropwise at 0deg.C, after which the temperature was raised to 20deg.C for 3h. After the reaction was completed, a dichloromethane solution of compound 14-2 was obtained, which was used directly in the next step without post-treatment.
(3) Preparation of intermediate Compound 14-4
To a dichloromethane solution of compound 13-2 obtained in step (2) at 0deg.C under nitrogen, 14-323.7g (137 mmol,1.00 eq) of compound was added followed by the addition of AlCl in portions 3 18.3g (137 mmol,1.00 eq) were addedAfter that, the reaction solution was heated to 20℃and reacted for 5 hours. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and the solid was dried under reduced pressure to give 41.3g of Compound 14-4 as a white solid in 85% yield.
(4) Preparation of intermediate Compound 14-5
Compound 14-4.3 g (116.4 mmol,1.00 eq) was taken, 400.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 40.4g of SiH (349.2 mmol,3.00 eq) were then added dropwise under nitrogen at 25℃with BF 3 .Et 2 O33 g (224.6 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, yielding 35.2g of compound 14-5 in 88.7% yield.
(5) Preparation of intermediate Compounds 14-7
Compound 14-5.2 g (103.3 mmol,1.00 eq) was weighed out, 600mL of redistilled THF was added at-70℃under N 2 41.4mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise addition of a solution of compound 14-6.6 g (103.3 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,150.0 mL) and stirring at-70℃for 1h under nitrogen. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column and flowsThe mobile phase is petroleum ether: ethyl acetate=50:1 to 2:1, yielding 53.7g of pure compound 14-7 in 65% yield.
(6) Preparation of intermediate Compounds 14-8
Compound 14-7.7 g (67 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.3g (80.4 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O11.4 g (80.4 mmol,1.20 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of saturated aqueous sodium bicarbonate, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 3:1, giving 33g of pure compound 14-8 in 63% yield.
(7) Preparation of the target Compound 14 ((2S, 3R,4R,5S, 6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
33g (42.2 mmol,1.00 eq) of compound 14-8 and 800.0mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C6.3 g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30psi hydrogen pressure for 12 hours. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 50mm, 10um; mobile phase water (0.1% tfa) -MeOH, B%:20% -50%,30 min) to give 6.3g of the title compound 14 as a white solid in 35% yield.
1HNMR(400MHz，DMSO)δ：8.35(d,2H),7.22(dd,2H),7.14(dd,J＝8.4Hz,2H),7.09(dd,2H),7.06(dd,J＝8.4Hz,2H),6.75(t,1H),4.5(br.s,4H),3.90-4.02(m,3H),3.61-3.66(m,1H),3.42-3.51(m,3H),3.03-3.21(m,2H)。
Example 15 preparation of compound 15: (2S, 3R,4R,5S, 6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 15-2
15-1 g (86.6 mmol,1.00 eq) of compound was taken, 200.0mL of DCM and 0.1mL of DMF were added, 12.1g (95.3 mmol,1.10 eq) of oxalyl chloride was added dropwise at 0℃and the reaction was carried out at room temperature for 2h after the addition was completed. After the reaction was completed, a dichloromethane solution of compound 15-2 was obtained, which was used directly in the next step without post-treatment.
(2) Preparation of intermediate Compounds 15-4
To a dichloromethane solution of compound 15-2 obtained in step (1) at 0deg.C under nitrogen, compound 15-313.8g (86.6 mmol,1.00 eq) was added followed by the addition of AlCl in portions 3 11.6g (86.6 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to room temperature and reacted for 6h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. Ethanol was added to the concentrate to precipitate a solid, and the solid was collected by filtration, and dried under reduced pressure to give 25.8g of compound 15-4 as a white solid in 80% yield.
(3) Preparation of intermediate Compounds 15-5
Compound 15-4.8 g (69.3 mmol,1.00 eq) was taken, 200.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 24g (207.9 mmol,3.00 eq) followed by dropwise addition of BF under nitrogen at 25 ℃ 3 .Et 2 O39.2 g (277.2 mmol,4.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 100.0mL of saturated NaHCO was added to the reaction mixture 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 10:1, yielding 20.3g of compound 15-5 in 85% yield.
(4) Preparation of intermediate Compounds 15-7
Compound 15-5.3 g (58.9 mmol,1.00 eq) was weighed out, 300mL of redistilled THF was added at-70℃under N 2 47.2mL (2.5M, 2.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.3h, followed by dropwise addition of a solution of 15-6.7 g (58.9 mmol,1.00 eq) of the compound in tetrahydrofuran (redistilled THF,50.0 mL) and stirring at-70℃for 1h under nitrogen. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, dichloromethane extraction is then adopted, an organic phase is collected, and reduced pressure distillation is carried out to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=10:1 to 1:1, yielding 24.6g of pure compound 15-7 in 52% yield.
(5) Preparation of intermediate Compounds 15-8
Compound 15-7.6 g (30.6 mmol,1.00 eq) was weighed out, 200.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 4.2g (36.7 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O13 g (91.8 mmol,3.0 eq) was then warmed to room temperature and stirred for 6h. After the reaction was completed, the reaction solution was poured into 100.0mL of saturated aqueous sodium hydrogencarbonate, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=10:1 to 3:1, yielding 11.6g of pure compound 15-8 in 48% yield 。
(6) Preparation of target Compound 15 ((2S, 3R,4R,5S, 6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
11.6g (14.7 mmol,1.00 eq) of the compound 15-8 and 200.0mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C4.5g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30psi hydrogen pressure for 12 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 50mm, 10um; mobile phase: water (0.1% hcooh) -MeOH, B%:20% -80%,30 min) to give 1.7g of the title compound 15 as a white solid in 27% yield.
1HNMR(400MHz，DMSO)δ：7.71(d,1H),7.67(dd,2H),7.42(d,1H),7.40(d,1H),7.31(dd,2H),7.18(t,1H),7.08(s,1H),6.75(d,1H),5.60(br.s,1H),4.7(br.s,4H),3.91-4.04(m,3H),3.64-3.69(m,1H),3.41-3.50(m,1H),3.21-3.32(m,3H),3.07-3.20(m,1H)。
Example 16 preparation of compound 16: (2S, 3R,4R,5S, 6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 16-3
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16-1 g (67.3 mmol,1.0 eq) of the compound was weighed, 100mL of redistilled tetrahydrofuran was added, and the mixture was evaporated at-70℃under N 2 100.8mL (2.0M, 3.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70deg.C for 1h, followed by dropwise addition of a solution of compound 16-2.36.2 g (67.3 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) after the addition was completed Stirring for 1h at-70℃under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 16.3g of pure compound 16-3 as a colorless oil in a yield of 32%.
(2) Preparation of intermediate Compound 16-4
Compound 16-3.3 g (21.5 mmol,1.0 eq) was weighed out, 200.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 3g (25.8 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O3.7 g (25.8 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 100.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, yielding 10.3g of pure compound 16-4 as a white solid in 65% yield.
(3) Preparation of the target Compound 16 ((2S, 3R,4R,5S, 6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
16-4.3 g (14 mmol,1.0 eq) of the compound was weighed, 100.0mL of methanol was added, 3.5g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50psi of hydrogen for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% tfa) -ACN, B%:20% -50%,30 min) to give 2.1g of the title compound 16 as a white solid in 40% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.21(dd,2H),7.10(dd,2H),6.50(d,2H),4.57(d,1H),3.98(s,2H),3.82-3.87(m,4H),3.54-3.63(m,2H)。
Example 17 preparation of compound 17: (2S, 3R,4R,5S, 6R) -2- (4- (4-isopropoxybenzyl)) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol of formula
(1) Preparation of intermediate Compound 17-3
17-1 g (68 mmol,1.0 eq) of the compound was weighed, 150mL of redistilled tetrahydrofuran was added, and the mixture was taken at-70℃under N 2 34mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃for 0.5h with stirring, and then 17-2.36.6 g (68 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,50.0 mL) was added dropwise with stirring at-70℃for 1h under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 33.4g of pure compound 17-3 in 59% yield.
(2) Preparation of intermediate Compound 17-4
Compound 17-3.4 g (40.1 mmol,1.0 eq) was weighed out, 150.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 5.6g (48.1 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O6.8 g (48.1 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 100.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 5:1, yielding 19.6g of pure compound 17-4 as a white solid in 60% yield.
(3) Preparation of target Compound 17 ((2S, 3R,4R,5S, 6R) -2- (4- (4-isopropoxybenzyl) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
17-4.6 g (24 mmol,1.0 eq) of the compound was weighed, 100.0mL of methanol was added, 6.0g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50psi of hydrogen for 12 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% tfa) -ACN, B%:20% -80%,30 min) to give 4.05g of the title compound 17 as a white solid in 37% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.42(s,1H),7.18(d,1H),7.16(d,1H),7.14(dd,2H),6.89(dd,2H),4.68-4.70(m,1H),4.53-4.56(m,1H),3.96(s,2H),3.54-3.79(m,6H),1.36(d,6H)。
Example 18 preparation of compound 18: (2S, 3R,4R,5S, 6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
/>
(1) Preparation of intermediate Compound 18-2
Compound 18-1.0 g (137 mmol,1.00 eq) was taken, 200.0mL DCM and 0.1mL DMF were added, and oxalyl chloride 19.1g (150.7 mmol,1.10 eq) was added dropwise at 0deg.C and reacted for 3h at room temperature after the addition was completed. After the reaction was completed, a dichloromethane solution of compound 18-2 was obtained, which was used directly in the next step without post-treatment.
(2) Preparation of intermediate Compound 18-4
24g (137 mmol,1.00 eq) of compound 18-3 are added to a dichloromethane solution of compound 18-2 obtained in step (1) at 0deg.C under nitrogen, followed by the addition of AlCl in portions 3 18.3g (137 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to room temperature and reacted for 5h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by reduced pressure distillation to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, drying under reduced pressure gave 42.8g of compound 18-4 as a white solid in 83% yield.
(3) Preparation of intermediate Compound 18-5
Compound 18-4.8 g (113.7 mmol,1.00 eq) was taken, 350.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 53g (515.3 mmol,4.00 eq) followed by dropwise addition of BF under nitrogen at 25 ℃ 3 .Et 2 O32.3 g (227.4 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 35.9g of compound 18-5 in a yield of 87.0%.
(4) Preparation of intermediate Compound 18-7
Compound 18-5.9 g (98.9 mmol,1.00 eq) was weighed out, 550mL of redistilled THF was added at-70℃under N 2 35.6mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran were added dropwise to the above solution under nitrogen at-70℃for 0.3h, followed by dropwise addition of compound 18-6.2 g (98)9mmol,1.00 eq) in tetrahydrofuran (redistilled THF,100.0 mL) and then stirred at-70℃under nitrogen for 1h. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 61g of pure compound 18-7 in 75% yield.
(5) Preparation of intermediate Compounds 18-8
Compound 18-7 61g (74.2 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at room temperature 3 SiH 10.3g (89 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O12.6 g (89 mmol,1.20 eq) then warmed to room temperature and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of saturated aqueous sodium bicarbonate, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 40.1g of pure compound 18-8 in 67% yield.
(6) Preparation of the target Compound 18 ((2S, 3R,4R,5S, 6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
40.1g (49.7 mmol,1.00 eq) of 18-8 mL of compound and 400.0mL of ethyl acetate were taken and mixed uniformly under stirring, then 7.4g of Pd/C (active ingredient content: 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at 20℃for 12 hours under 30psi of hydrogen. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 50mm, 10um; mobile phase: water (0.1% hcooh) -ACN, B%:20% -60%,30 min) to give 7.09g of the objective compound 18 as a white solid in 32% yield.
1HNMR(400MHz，DMSO)δ：7.17(d,1H),7.08(dd,2H),6.95(d,1H),6.72(d,1H),6.68(dd,2H),4.7(br.s,4H),3.92-4.00(m,1H),3.98(s,2H),3.60-3.69(m,5H),3.40-3.50(m,1H),3.34(t,4H),2.85(t,4H),2.28(s,3H)。
Example 19 preparation of compound 19: (2S, 3R,4R,5S, 6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 19-3
Weighing 19-1 g (54.8 mmol,1.0 eq) of the compound, adding 100mL of redistilled tetrahydrofuran at-70deg.C under N 2 82mL (2.0M, 3.0 eq) of a tetrahydrofuran solution of n-butyllithium was added dropwise to the above solution under nitrogen at-70℃for 0.5h, followed by dropwise addition of a tetrahydrofuran (redistilled THF,50.0 mL) solution of 19-2.3 g (54.8 mmol,1.0 eq) of the compound, and stirring at-70℃for 1h under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 26.7g of pure compound 19-3 in 58% yield.
(2) Preparation of intermediate Compound 19-4
Compound 19-3.7 g (31.8 mmol,1.0 eq) was weighed out, 200.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 4.4g (38.2 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O5.4 g (38.2 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 100.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Coarse sizeThe product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, yielding 14.4g of pure compound 19-4 as a white solid with a yield of 55%.
(3) Preparation of the target Compound 19 ((2S, 3R,4R,5S, 6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol)
To the above solution was weighed 14.4.4 g (17.5 mmol,1.0 eq) of the compound, 100.0mL of methanol was added, 4.3g Pd/C (active ingredient content 10%) was added under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at 50℃under 50psi of hydrogen for 12 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% tfa) -ACN, B%:20% -80%,40 min) to give 3g of the title compound 19 as a white solid in 37% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.12(dd,2H),6.86(dd,2H),6.47(d,2H),4.52-4.54(m,1H),4.28(d,2H),4.12-4.16(m,1H),3.98(s,2H),3.84-3.87(m,4H),3.80-3.82(m,2H),3.61-3.63(m,2H),2.60-2.65(m,2H)。
Example 20 preparation of compound 20: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 20-3
20-1 g (213.4 mmol,1.0 eq) of the compound was weighed out, 265mL of redistilled tetrahydrofuran was added, and the mixture was taken out at-70℃under N 2 106.6mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃with stirring 05h, then a solution of 20-2 118g (213.4 mmol,1.0 eq) of the compound in tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, and after the addition was stirred under nitrogen at-70℃for 1h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 109.5g of pure compound 20-3 in 64% yield.
(2) Preparation of intermediate Compound 20-4
Compound 20-3.5 g (136.6 mmol,1.0 eq) was weighed out, 700.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 19g (163.9 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O23.3 g (163.9 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, yielding 64.5g of pure compound 20-4 as a white solid in 60% yield.
(3) Preparation of target Compound 20 (((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol)
20-4.5 g (82 mmol,1.0 eq) of the compound was weighed, 500.0mL of methanol was added, 20g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50psi hydrogen at 50℃for 24 hours. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10um; mobile phase water (0.1% tfa) -ACN, 25% -53%,30 min) to give 15.02g of the title compound 20 as a white solid in 43% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.09(d,J＝8.8Hz,2H),6.83(d,J＝8.4Hz,2H),6.45(d,2H),4.52-4.54(m,1H),4.02(q,2H),3.98(s,2H),3.84-3.87(m,4H),3.61-3.63(m,2H),1.35(t,3H)。
In order to evaluate the efficacy of the glycoside derivative of the present invention, the following test examples were conducted.
Test example 1 therapeutic Effect of the glycoside derivative of the present invention on the model of type I diabetes in ICR mice induced by tetraoxypyrimidine
Healthy ICR mice are adaptively fed for 3d, fasted and not forbidden for 12-16 h on day 3, and the tail vein injection of tetraoxypyrimidine ALX (prepared in the prior art) is completed within 70.0mg/kg and 0.1mL/10g for 30s, so that an I-type diabetes animal model is induced, and normal non-modeling mice are injected with the same amount of physiological saline through tail vein injection. After injection, the mice are normally fed for 2d, the mice are fasted and not forbidden for 12-16 h, blood is taken from the tail tip after ALX is injected for 72h, the fast glucose meter with the trinoantine regulatory code is adopted to measure the fasting blood glucose concentration (FGB) (namely the blood glucose concentration before administration), and the FGB value is 11.1 mmol/L-25.0 mmol/L, which is regarded as the diabetic mice with successful modeling, and the mice are used for experiments.
Immediately after selecting diabetic mice with successful modeling, the diabetic mice are randomly grouped according to fasting blood glucose (FGB) of the mice, and the diabetic mice are divided into 22 groups of 4 mice each, wherein the diabetic mice are respectively grouped into a diabetes model group G2, a metformin group G3 (positive control, 200 mg/kg) and glycoside derivatives of the invention into groups G4-G23, and a control group G1 (4 healthy mice in the same batch and normal blood glucose mice are used as a blank control group G1), and the specific grouping conditions are shown in Table 1. Oral gavage administration was started the following day after grouping, 1 time a day, 7d continuously, and the fasting blood glucose concentration (FGB) (i.e., blood glucose value after administration) of mice was measured in mmol.L by using a rapid glucometer 1h after administration on day 7 -1 The specific test results are shown in Table 1.
Table 1: the glycoside derivative has the effect of treating ICR mouse type I diabetes model caused by tetraoxypyrimidine
Remarks: (1) the method comprises the following steps P < 0.01 compared with the blank group; (2) the method comprises the following steps P < 0.05 compared with the model group; (3) the method comprises the following steps P < 0.01 compared to model group.
As can be seen from the table, aiming at the ICR mouse type I diabetes model caused by the tetraoxypyrimidine, compared with a model group, a positive control metformin group and a glycoside derivative administration group have the effect of reducing blood sugar, have remarkable treatment effect, and part of the glycoside derivative administration group has the effect of reducing blood sugar better than the positive control group, so that the glycoside derivative has the treatment effect on type I diabetes.
Claims (3)
1. An intermediate compound, characterized in that the intermediate compound is a compound represented by formula III:
formula III; wherein the compound shown in the formula III is:
2. a process for the preparation of an intermediate compound according to claim 1, wherein the compound of formula III is prepared by reacting a compound of formula IV with a compound of formula V;
wherein the compound shown in the formula IV is:
/>
the compound shown in the formula V is:
3. the application of the intermediate compound in preparing glycoside derivatives, wherein the glycoside derivatives are compounds shown in a formula I or pharmaceutically acceptable salts thereof, and the compounds shown in the formula I are as follows:
(2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol;
The intermediate compound is a compound shown in a formula III, and the structural formula is as follows:
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| WO1998031697A1 (en) * | 1997-01-15 | 1998-07-23 | Sankyo Company, Limited | Aryl c-glycoside compounds and sulfated esters thereof |
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