CN111840271B - Novel application of glycoside derivative - Google Patents
Novel application of glycoside derivative Download PDFInfo
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- CN111840271B CN111840271B CN201910336845.0A CN201910336845A CN111840271B CN 111840271 B CN111840271 B CN 111840271B CN 201910336845 A CN201910336845 A CN 201910336845A CN 111840271 B CN111840271 B CN 111840271B
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- 229930182470 glycoside Natural products 0.000 title claims abstract description 36
- 150000002338 glycosides Chemical class 0.000 title claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 291
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 124
- 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
- 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 5
- 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 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
- CBLVVOJERODGMF-RXFVIIJJSA-N (2S,3R,4R,5S,6R)-2-[3-fluoro-4-[[4-(4-fluorophenoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound FC=1C=C(C=CC1CC1=CC=C(C=C1)OC1=CC=C(C=C1)F)[C@@H]1O[C@@H]([C@H]([C@@H]([C@H]1O)O)O)CO CBLVVOJERODGMF-RXFVIIJJSA-N 0.000 claims description 4
- PJRAFZKHHNTEBJ-IFPLKCGESA-N (2S,3R,4R,5S,6R)-2-[4-[(3,4-diethoxyphenyl)methyl]-2,6-difluorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound C(C)OC=1C=C(CC2=CC(=C(C(=C2)F)[C@@H]2O[C@@H]([C@H]([C@@H]([C@H]2O)O)O)CO)F)C=CC1OCC PJRAFZKHHNTEBJ-IFPLKCGESA-N 0.000 claims description 4
- UUIUTZHTKWFNCY-ADAARDCZSA-N (2S,3R,4R,5S,6R)-2-[4-[(4-ethoxyphenyl)methyl]-3-fluorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound C(C)OC1=CC=C(CC2=C(C=C(C=C2)[C@@H]2O[C@@H]([C@H]([C@@H]([C@H]2O)O)O)CO)F)C=C1 UUIUTZHTKWFNCY-ADAARDCZSA-N 0.000 claims description 4
- NVWPSZGMTHYECS-BDHVOXNPSA-N (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-[4-[(4-propan-2-yloxyphenyl)methyl]-2-(trifluoromethyl)phenyl]oxane-3,4,5-triol Chemical compound C(C)(C)OC1=CC=C(CC2=CC(=C(C=C2)[C@@H]2O[C@@H]([C@H]([C@@H]([C@H]2O)O)O)CO)C(F)(F)F)C=C1 NVWPSZGMTHYECS-BDHVOXNPSA-N 0.000 claims description 3
- RNFFCCYTUQXHMF-RQXATKFSSA-N (2S,3R,4R,5S,6R)-2-[4-[(4-ethoxyphenyl)methyl]-2,6-dihydroxyphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound C(C)OC1=CC=C(CC2=CC(=C(C(=C2)O)[C@@H]2O[C@@H]([C@H]([C@@H]([C@H]2O)O)O)CO)O)C=C1 RNFFCCYTUQXHMF-RQXATKFSSA-N 0.000 claims description 3
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 224
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 193
- 239000000243 solution Substances 0.000 description 189
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 172
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 52
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- 125000000217 alkyl group Chemical group 0.000 description 39
- 238000002953 preparative HPLC Methods 0.000 description 38
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
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- 239000000706 filtrate Substances 0.000 description 32
- 150000002431 hydrogen Chemical group 0.000 description 32
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 26
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 26
- 125000003545 alkoxy group Chemical group 0.000 description 25
- 239000008280 blood Substances 0.000 description 25
- 210000004369 blood Anatomy 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 24
- 229910052736 halogen Inorganic materials 0.000 description 23
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- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 21
- 125000001072 heteroaryl group Chemical group 0.000 description 21
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- 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 18
- 239000004480 active ingredient Substances 0.000 description 18
- 239000008103 glucose Substances 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 206010012601 diabetes mellitus Diseases 0.000 description 14
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- 239000012300 argon atmosphere Substances 0.000 description 13
- 241000700159 Rattus Species 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 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
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
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- 125000005842 heteroatom Chemical group 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 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 8
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- 230000004060 metabolic process Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001019 normoglycemic effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 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
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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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- 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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- 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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- 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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Abstract
The invention belongs to the field of chemical medicines, and particularly relates to a novel application of a glycoside derivative. The glycoside derivative is a compound shown in a formula I or pharmaceutically acceptable salt thereof: Formula I. Compared with the prior art, the novel glycoside derivative has excellent treatment effect on the type II diabetes no matter in high, medium and low doses.
Description
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a novel application of a glycoside derivative.
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; type II diabetes is a chronic metabolic disease characterized by relative insulin deficiency and hyperglycemia, and can induce a series of complications. 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. At present, common type II diabetes therapeutic drugs include sulfonylureas, alpha-carbosidase inhibitors, biguanides, insulins and the like, and although the drugs have good blood sugar control effects, various adverse reactions exist. Thus, researchers are still looking for and developing therapeutic drugs with novel mechanisms of action and little toxic and side effects.
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 cotransporter (SGLTs) is saturated, a large amount of glucose is discharged along with urine, currently SGLTs has become a hot therapeutic target for diabetes, and the number of human SGLT protein families has been 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, while SGLT1 has a main function of absorption of glucose from the gastrointestinal tract and distribution in a plurality of organs such as the heart and brain, but inhibition of SGLT1 may cause serious side effects such as diarrhea and other gastrointestinal problems, so that the research on SGLT1 inhibitors has been slow until now, and SGLT-2 inhibitors have been rapidly developed. There are 6 SGLT-2 inhibitors already marketed abroad, but both are in clinical research phase at home. In view of this, there is a need in the marketplace to develop novel and efficient drugs as SGLT-2 target inhibitors to treat type I and type II diabetes.
Disclosure of Invention
In order to solve the technical problems, the invention provides a glycoside derivative, and a preparation method and application thereof.
The first object of the present invention is to provide a glycoside derivative, which is a compound represented by 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,R2,R3,R4,R5,R6 is independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, -CN, alkoxyalkoxy or-NR 7R7a or a 3-14 membered heterocycle containing 1-4 heteroatoms N, O, S, SO and/or SO 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 7、R7a groups are independently hydrogen atoms or alkyl groups.
In the glycoside derivative, as a preferred embodiment, in the compound represented by the formula I, R 2 is hydrogen, hydroxy, -O-aryl, -OCH 2 -aryl, alkoxy, alkyl, aryl, heteroaryl, -CF 3, or halogen.
In the glycoside derivative, as a preferred embodiment, in the compound represented by the formula I, R 4,R5 is independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, or-CN; r 4,R5 are identical or different.
In the glycoside derivative, as a preferred embodiment, in the compound represented by the formula I, R 6 is hydrogen, hydroxy, carboxyl, alkoxy, alkyl, cycloalkyl, -CF 3、-OCHF2、-OCF3, halogen, or-CN.
Among the glycoside derivatives, 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.
The second object of the present invention is to provide a preparation method of the glycoside derivative, wherein the compound shown in the formula I is prepared by deprotection reaction of the compound shown in the 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,R2,R3,R4,R5,R6 is independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, -CN, alkoxyalkoxy or-NR 7R7a or a 3-14 membered heterocycle containing 1-4 heteroatoms N, O, S, SO and/or SO 2;
r 9 is TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
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 7、R7a groups are independently hydrogen atoms or alkyl groups.
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,R2,R3,R4,R5,R6 is independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, -CN, alkoxyalkoxy or-NR 7R7a or a 3-14 membered heterocycle containing 1-4 heteroatoms N, O, S, SO and/or SO 2;
r 9 is TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
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 7、R7a groups are independently hydrogen atoms or alkyl groups.
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,R2,R3,R4,R5,R6 is independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, -CN, alkoxyalkoxy or-NR 7R7a or a 3-14 membered heterocycle containing 1-4 heteroatoms N, O, S, SO and/or SO 2;
R 8 is-H, -F, -Cl, -Br, -I, -OMs, -OTs, -OTf;
r 9 is TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
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 7、R7a groups are independently hydrogen atoms or alkyl groups.
The third object of the invention is to provide an application of the glycoside derivative in the medicine for preventing and/or treating type II diabetes.
The fourth object of the invention is to provide an application of the glycoside derivative in the preparation of drugs for preventing and/or treating type II diabetes induced by high-fat and high-sugar food.
A fifth object of the present invention is to provide a pharmaceutical composition of the above glycoside derivative, which comprises: the compound shown in the formula I or pharmaceutically acceptable salt thereof is used as an active ingredient and at least one pharmaceutically acceptable auxiliary material; preferably, the composition is administered orally, by injection, transdermally, nasally, mucosally, by inhalation; more preferably, the composition is in a conventional dosage form, a slow release, controlled release, localized or immediate release dosage form.
Compared with the prior art, the invention has the following technical effects:
1. compared with the prior art, the glycoside derivative has excellent treatment effect on the type II diabetes no matter in high, medium and low doses.
2. The preparation method of the glycoside derivative adopts cheap and easily available chemical products as the starting materials, and the synthesis yield of each step is higher, so that the preparation method has lower production cost and 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).
Detailed Description
The glycoside derivative of the present application, 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 application only and are not to be construed as limiting the scope of the application. It is to be understood that various changes and modifications may be made by those skilled in the art after reading the disclosure herein, and that such equivalents are intended to fall within the scope of the application as defined by the appended claims.
A glycoside derivative is a compound shown in a formula I or 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,R2,R3,R4,R5,R6 is 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.), -O-heteroaryl (-O-heteroaryl is illustratively Etc.), -OCH 2 -aryl (-OCH 2 -aryl is exemplified by PhCH 2 O-),Etc.), -OCH 2 -heteroaryl (-OCH 2 -heteroaryl 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, orEtc.), heteroaryl (illustratively, heteroaryl is Etc.), -CF 3、-OCHF2、-OCF3, halogen (illustratively halogen is fluorine, chlorine, bromine, or iodine), -CN, alkoxyalkoxy (illustratively alkoxyalkoxy is methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy, isopropoxymethoxy, n-propoxyethoxy, isopropoxyethoxy, orEtc.), an ester group (illustratively, an ester group isEtc.) or-NR 7R7a (illustratively, -NR 7R7a is amino,Etc.) or 3-14 membered heterocyclic ring containing 1-4 heteroatoms N, O, S, SO and/or SO 2 (illustrativelyEtc.);
R 7、R7a is independently a hydrogen atom or an alkyl group (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes a straight chain alkyl or branched alkyl, illustratively, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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.
Preferably, R 2 is hydrogen, hydroxy, -O-aryl, -OCH 2 -aryl, alkoxy, alkyl, aryl, heteroaryl, -CF 3, or halogen.
Preferably, R 4,R5 is independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, or-CN; r 4,R5 are identical or different.
Preferably, R 6 is hydrogen, hydroxy, carboxy, alkoxy, alkyl, cycloalkyl, -CF 3、-OCHF2、-OCF3, halogen, or-CN.
The preparation method of the glycoside derivative is as follows, and the compound shown in the formula I is prepared by deprotection reaction of the compound shown in the 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,R2,R3,R4,R5,R6 is independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, -CN, alkoxyalkoxy or-NR 7R7a or a 3-14 membered heterocycle containing 1-4 heteroatoms N, O, S, SO and/or SO 2;
r 9 is TMS- (trimethylsilyl), bn- (benzyl), ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (tert-butyldimethylsilyl);
The R 7、R7a is independently a hydrogen atom or an alkyl group;
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.
Illustratively, when R 9 is TMS-or TBDMS-, the deprotecting reagent is TBAF; when R 9 is Bn-, the deprotection reaction conditions are H 2/Pd-C、H2/Pt-C, H 2/Pd(OH)2 -C, etc.; when R 9 is Ac-, the deprotection reaction conditions are strong base conditions (such as aqueous sodium hydroxide or aqueous potassium hydroxide) or strong acid conditions; when R 9 is THP-or MOM-, the deprotection reaction conditions are acidic conditions (such as aqueous hydrochloric acid, ethyl hydrogen chloride solution (HCl (g)/EtOAc), methanol hydrogen chloride solution (HCl (g)/CH 3 OH), ethanol hydrogen chloride solution (HCl (g)/EtOH), or dioxane hydrogen chloride solution (HCl (g)/dioxane)).
Further, the compound shown in the formula II is prepared from a compound shown in the 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,R2,R3,R4,R5,R6 is independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, -CN, alkoxyalkoxy or-NR 7R7a or a 3-14 membered heterocycle containing 1-4 heteroatoms N, O, S, SO and/or SO 2;
r 9 is TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
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 7、R7a groups are independently hydrogen atoms or alkyl groups.
Illustratively, the reaction conditions for preparing the compound of formula II from the compound of formula III are BF 3.Et2 O.
Further, the compound shown in the formula III is prepared by reacting a compound shown in the formula IV with a compound shown in the 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,R2,R3,R4,R5,R6 is independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3、-OCHF2、-OCF3, halogen, -CN, or-NR 7R7a or a 3-to 14-membered heterocycle containing 1-4 heteroatoms N, O, S, SO and/or SO 2;
R 8 is-H, -F, -Cl, -Br, -I, -OMs, -OTs, -OTf;
r 9 is TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
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 7、R7a groups are independently hydrogen atoms or alkyl groups.
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.
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
(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, cs 2CO3 g (994 mmol,2 eq), cuI 28.4g (149.2 mmol,0.3 eq) and isobutyl nitrite 30.8g (298 mmol,0.6 eq) were added successively to the above solution at 20℃and then stirred for 12h at 100 ℃. 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
To the above solution, 165.0mL of redistilled tetrahydrofuran was added, 71.3mL (2.0M, 1.5 eq) of an LDA (lithium diisopropylamide) solution was added dropwise at-70℃under N 2, and the above mixture was stirred at-70℃under nitrogen for 0.5 hours, followed by dropwise addition of a tetrahydrofuran (redistilled THF,100.0 mL) solution of 1-4.2 g (95.1 mmol,1.0 eq) of the compound under nitrogen for 1 hour. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 46.0g of pure compound 1-5 as a colorless oil with a yield of 61.3%.
(3) Preparation of intermediate Compounds 1-6
1-5.0 G (59.2 mmol,1.0 eq) of compound was weighed, 320.0mL of methylene chloride was added, and Et 3 SiH 8.2g (70.0 mmol,1.2 eq) was added to the above solution under nitrogen at 20 ℃; cooling to 0 ℃, then adding BF 3.Et2.0 g (70.0 mmol,1.2 eq) dropwise, further heating to 20 ℃ and stirring 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 C18.50 mm. Times.10 um; mobile phase: water (0.1% TFA) -ACN; B%:30% -80%,20 min) to give 4.6g of the objective compound 1 as a white solid in 33.3% yield.
1H NMR(400MHz,CD3OD),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).
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
(1) Preparation of intermediate Compounds 2-3
Weighing 2-1 g (213.4 mmol,1.0 eq) of compound, adding 265mL of redistilled tetrahydrofuran, dropwise adding 106.6mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution to the solution at-70 ℃ under N 2, stirring for 0.5h at-70 ℃ under nitrogen, then dropwise adding 2-2 115g (213.4 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,106.0 mL) solution, and stirring for 1h at-70 ℃ under nitrogen. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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, giving 105.0g of pure compound 2-3 as a colorless oil in 62.5% yield.
(2) Preparation of intermediate Compounds 2-4
2-3.0 G (133.4 mmol,1.0 eq) of compound was weighed, 735.0mL of methylene chloride was added, 18.6g (160 mmol,1.2 eq) of Et 3 SiH was added to the above solution under nitrogen at 20℃and cooled to 0℃and 22.75g (160 mmol,1.2 eq) of BF 3.Et2 O was added dropwise, followed by heating to 20℃and stirring 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 C18.250 mm x 10um; mobile phase: water (0.1% tfa) -ACN, B%:25% -53%,30 min) to give 15g of the objective compound 2 as a white solid in 41.5% yield.
1H NMR(400MHz,CD3OD),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 DMA (dimethylacetamide), compound 3-2.35.90 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 670.0mL, and the reaction system was reacted at 20℃for 10 hours. After completion of the TLC detection reaction, 200.0mL of a saturated aqueous Na 2SO3 solution was added to the reaction solution at 10℃and extracted with MTBE (300.0 mL), then the organic phase was extracted with a saturated aqueous sodium carbonate solution and a saturated brine, respectively, and the organic phase was collected and concentrated to obtain 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, cooling to 0 ℃ and adding 300.0mL of saturated NH 4 Cl aqueous solution into the reaction solution, adding MTBE for extraction, 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 10:1, giving 55.0g of compound 3-6 as a pale yellow oil in 74.8% yield.
1HNMR(400MHz,CDCl3)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
Weigh compound 3-6.0 g (122.10 mmol,1.00 eq), add redistilled 700mL THF, drop wise to the above solution at-70 ℃ under N 2, 48.84mL (2.5 m,1.00 eq) of N-BuLi (N-butyllithium) in tetrahydrofuran, and stir at-70 ℃ under nitrogen for 0.2h, then drop wise add compound 3-6.77 g (122.10 mmol,1.00 eq) of tetrahydrofuran (redistilled THF,100.0 mL), then stir at-70 ℃ under nitrogen for 1h. The reaction solution was poured into saturated aqueous NH 4 Cl solution, then extracted with MTBE, and the 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, 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 methylene chloride was added, et 3 SiH (13.3 g,114.3mmol,1.20 eq) was added to the above solution under nitrogen at 20deg.C, the temperature was lowered to 0deg.C, BF 3.Et2 O6.5 g (45.7 mmol,1.2 eq) was added dropwise, then the temperature was raised to 20deg.C and stirred for 2h. After the reaction was completed, the reaction solution was poured into a saturated 200.0mL aqueous NaHCO 3 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=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, the filtrate was suction filtered, and concentrated, and the concentrate was subjected to prep.SFC (preparative SFC) (column: CHIRALPAK IC-H250: 30mm i.d.5u; mobile phase: A phase CO 2, B phase IPA (isopropylamine) (0.1% NH 3.H2 O); gradient: B% = 45%; flow rate: 73g/min; detection wavelength: 220nm; column temperature: 40 ℃ and pressure: 100 bar) to give 9.22g of the objective compound 3 as a white solid.
1HNMR(400MHz,CD3OD)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 DCM and 0.1mL DMF were added, 17.8g (140.2 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 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 0℃under nitrogen was added 15.5g (127.4 mmol,1.00 eq) of ethoxybenzene, followed by addition of 3 17.0.0 g (127.4 mmol,1.00 eq) of AlCl in portions, and after the addition was completed, the reaction mixture was warmed to 20℃for 3 hours. After the reaction, the reaction solution is cooled to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, an organic phase is collected, anhydrous Na 2SO4 is dried, filtered, and the filtrate is distilled and concentrated under reduced pressure to obtain a 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,CDCl3)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 of acetonitrile was added, 59.9g (515.3 mmol,5.00 eq) of Et 3 SiH was added under nitrogen at 20℃and then 29.3g (206.1 mmol,2.00 eq) of BF 3.Et2 O was added dropwise under nitrogen at 25℃and the above mixture was reacted for 12h at 25 ℃. After the reaction, 300.0mL of saturated NaHCO 3 aqueous solution is added into the reaction solution, then MTBE is added for extraction, the organic phase is extracted by saturated saline water, the organic phase is collected, dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and a crude product is obtained. 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,CDCl3)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, 560mL of redistilled THF was added, 34.4mL (2.5M, 1.00 eq) of N-BuLi in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, and stirred under nitrogen at-70℃for 0.2h, then 4-5.3 g (86.0 mmol,1.00 eq) of 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 aqueous NH 4 Cl solution, then extracted with MTBE, and the 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 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, 390.0mL of methylene chloride was added, et 3 SiH 9.95g (85.6 mmol,1.20 eq) was added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O12.1 g (85.6 mmol,1.20 eq) was added dropwise followed by heating to 20℃and stirring 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
(1) Preparation of intermediate Compounds 5-3
To the above solution, 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 added 500mL of dimethylformamide, followed by addition of Cs 2CO3 g (992 mmol,2 eq) at 20℃and stirring at 100℃under nitrogen for 12 hours. 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
180.0ML of redistilled tetrahydrofuran was added to 5-3.3 g (124 mmol,1.0 eq) of compound, 148.8mL (2.5M, 3 eq) of a solution of N-butyllithium in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, the above mixture was stirred under nitrogen at-70℃for 0.5h, then 5-4.66.7 g (124 mmol,1.0 eq) of a solution of tetrahydrofuran (redistilled THF,150.0 mL) was added dropwise, and stirring was carried out under nitrogen at-70℃for 1h. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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
5-5.6 G (40.3 mmol,1.0 eq) of compound was weighed, 350.0mL of methylene chloride was added, and 5.6g (48.36 mmol,1.2 eq) of Et 3 SiH was added to the above solution under nitrogen at 20 ℃; cooling to 0 ℃, then adding BF 3.Et2 O3.5 g (48.36 mmol,1.2 eq) dropwise, further heating to 20 ℃ and stirring 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 objective compound 5 as a white solid in a yield of 30.1%.
1H NMR(400MHz,CD3OD),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 0℃under nitrogen, followed by addition of 3 30.7.7 g (230.4 mmol,1.00 eq) of AlCl in portions, and after the addition was completed, the reaction mixture was warmed to 20℃for 3 hours. After the reaction, the reaction solution is cooled to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, an organic phase is collected, anhydrous Na 2SO4 is dried, filtered, and the filtrate is distilled and concentrated under reduced pressure to obtain a 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 g (186.4 mmol,1.00 eq) was taken, 350.0mL acetonitrile was added, et 3 SiH 108.3g (932 mmol,5.00 eq) was added under nitrogen at 20deg.C, and BF 3.Et2 O106 g (745.6 mmol,4.00 eq) was then added dropwise under nitrogen at 25deg.C, the above mixture was reacted for 12h. After the reaction, 300.0mL of saturated NaHCO 3 aqueous solution is added into the reaction solution, then MTBE is added for extraction, the organic phase is extracted by saturated saline water, the organic phase is collected, dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and a crude product is obtained. 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
Weigh 6-4.4 g (171.5 mmol,1.0 eq) of compound, add 300mL of redistilled tetrahydrofuran, add 205.8mL (2.5M, 3.0 eq) of N-butyllithium in tetrahydrofuran solution dropwise to the above solution at-70℃under N 2, and stir for 0.5h at-70℃under nitrogen, then add 6-5.92 g (171.5 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) dropwise, and stir for 1h at-70℃under nitrogen. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 40.3g of pure compound 6-6 in 30% yield.
(5) Preparation of intermediate Compounds 6-7
6-6.3 G (51.45 mmol,1.0 eq) of compound was weighed, 300.0mL of methylene chloride was added, et 3 SiH 7.16g (61.74 mmol,1.2 eq) was added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O8.8 g (61.74 mmol,1.2 eq) was added dropwise, followed by heating to 20℃and stirring 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 pure compound 6-7 as a white solid 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 C18.250 mm x 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
(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
To the above solution, 800mL of dioxane was added 100g (383 mmol,1 eq) of compound 7-3, 60.2g (compound 7-4, 463.2mmol,1.2 eq), followed by Cs 2CO3 252g (772 mmol,2 eq), cuI 22g (115.8 mmol,0.3 eq), isobutyl nitrite 23.9g (231.6 mmol,0.6 eq) and stirring at 100deg.C for 12 hours. 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 the compound 7-7 were taken, 200.0mL of redistilled tetrahydrofuran was added, 144.6mL (2.0M, 1.5 eq) of a solution of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, the above mixture was stirred for 0.5h under nitrogen at-70℃and then 103.9g (193 mmol,1.0 eq) of a solution of tetrahydrofuran (redistilled THF,200.0 mL) was added dropwise, and stirred for 1h under nitrogen at-70 ℃. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 95.1g of pure compound 7-7 with a yield of 58.3%.
(4) Preparation of intermediate Compounds 7-8
To the above solution was weighed 7-8.1 g (112.5 mmol,1.0 eq), 500.0mL of methylene chloride was added, and 15.6g (135 mmol,1.2 eq) of Et 3 SiH was added under nitrogen at 20 ℃; cooling to 0 ℃, then adding BF 3.Et2 O9.6 g (135 mmol,1.2 eq) dropwise, further heating to 20 ℃ and stirring 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,CD3OD),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 g (227 mmol,1.0 eq), adding 300mL of redistilled tetrahydrofuran, dropwise adding 226.8mL (2.0M, 2.0 eq) of LDA tetrahydrofuran solution to the solution at-70 ℃ under N 2, stirring for 0.5h at-70 ℃ under nitrogen, then dropwise adding compound 8-2.122.3 g (227 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) and stirring for 1h at-70 ℃ under nitrogen. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 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, 800.0mL of methylene chloride was added, et 3 SiH 18.7g (160.7 mmol,1.2 eq) was added to the above solution under nitrogen at 20deg.C, the temperature was lowered to 0deg.C, BF 3.Et2 O22.8 g (160.7 mmol,1.2 eq) was added dropwise, then the temperature was raised to 20deg.C 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,CD3OD),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
Weighing 50g (171.2 mmol,1.0 eq) of compound 9-1, adding 200mL of redistilled tetrahydrofuran, dropwise adding 85.5mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution to the solution at-70 ℃ under N 2, stirring for 0.5h at-70 ℃ under nitrogen, then dropwise adding 9-2.92.3 g (171.2 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) solution, and stirring for 1h at-70 ℃ under nitrogen. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 2:1, yielding 92.3g of pure compound 9-3 as a colorless oil in 65% yield.
(2) Preparation of intermediate Compounds 9-4
9-3.3 G (111.3 mmol,1.0 eq) of compound was weighed, 700.0mL of methylene chloride was added, 15.6g (133.6 mmol,1.2 eq) of Et 3 SiH was added to the above solution under nitrogen at 20℃and cooled to 0℃and 19g (133.6 mmol,1.2 eq) of BF 3.Et2 O was added dropwise, followed by heating to 20℃and stirring 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 C18.250 x100 mm x10 um; 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,CD3OD),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, 91.1mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution at-70℃under N 2, and stirred under nitrogen at-70℃for 0.2 hours, then 10-2.98.2 g (182.4 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, and stirred under nitrogen at-70℃for 1 hour after the completion of the dropwise addition. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 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
10-3.5 G (106.6 mmol,1.0 eq) of compound was weighed, 700.0mL of methylene chloride was added, 14.9g (127.9 mmol,1.2 eq) of Et 3 SiH was added to the above solution under nitrogen at room temperature, the temperature was lowered to 0℃and 18.2g (127.9 mmol,1.2 eq) of BF 3.Et2 O was added dropwise, then the temperature was raised 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. The crude product is passed through a silica gel column, and 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 C18.250 mm x 10um; mobile phase: water (0.1% hcooh) -ACN, B%:25% -70%,30 min) to give 13g of the objective compound 10 as a white solid in 42% yield.
1H NMR(400MHz,CD3OD),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 0℃under nitrogen was added 16.7g (137 mmol,1.00 eq) of ethoxybenzene, followed by addition of 3 18.3.3 g (137 mmol,1.00 eq) of AlCl in portions, and after the addition was completed, the reaction mixture was warmed to room temperature and reacted for 3 hours. After the reaction, the reaction solution is cooled to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, an organic phase is collected, anhydrous Na 2SO4 is dried, filtered, distilled and concentrated under reduced pressure, and a concentrate is obtained. 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 of acetonitrile was added, et 3 SiH 18g (154.65 mmol,1.5 eq) was added under nitrogen at 20deg.C, and BF 3.Et2 O29.3 g (206.1 mmol,2.00 eq) was then added dropwise under nitrogen at 25deg.C, and the above mixture was reacted at 25deg.C for 12h. After the reaction, 300.0mL of saturated NaHCO 3 aqueous solution is added into the reaction solution, then MTBE is added for extraction, the organic phase is extracted by saturated saline water, the organic phase is collected and dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated 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 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, 600mL of redistilled THF was added, 36.7mL (2.5M, 1.00 eq) of N-BuLi in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, and stirred under nitrogen at-70℃for 0.2h, then 10-5.49.4 g (91.8 mmol,1.00 eq) of 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 aqueous NH 4 Cl solution, then extracted with MTBE, and the 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 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, 400.0mL of methylene chloride was added, et 3 SiH 9.6g (82.62 mmol,1.20 eq) was added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O11.7 g (82.62 mmol,1.20 eq) was added dropwise followed by heating to 20℃and stirring 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 C18.50 mm. Times.10 um; 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 0℃under nitrogen, followed by addition of 3 18.3.3 g (137 mmol,1.00 eq) of AlCl in portions, and after the addition was completed, the reaction mixture was warmed to 20℃for reaction for 5 hours. After the reaction, the reaction solution is cooled to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, an organic phase is collected, anhydrous Na 2SO4 is dried, filtered, and the filtrate is distilled and concentrated under reduced pressure to obtain a 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 12-3.45.3 g (116.4 mmol,1.00 eq) was taken, 400.0mL of acetonitrile was added, et 3 SiH 40.6g (349.2 mmol,3.00 eq) was added under nitrogen at 20deg.C, and BF 3.Et2 O33 g (232.8 mmol,2.00 eq) was then added dropwise under nitrogen at 25deg.C, the above mixture was reacted for 12h at 25deg.C. After the reaction, 300.0mL of saturated NaHCO 3 aqueous solution is added into the reaction solution, then MTBE is added for extraction, the organic phase is extracted by saturated saline water, the organic phase is collected, dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and a crude product is obtained. 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, 600mL of redistilled THF was added, 42.4mL (2.5M, 1.00 eq) of N-BuLi in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, and stirred under nitrogen at-70℃for 0.2h, then 12-5 57g (105.9 mmol,1.00 eq) of tetrahydrofuran (redistilled THF,150.0 mL) was added dropwise, and then stirred under nitrogen at-70℃for 1h. The reaction solution was poured into saturated aqueous NH 4 Cl solution, then extracted with MTBE, and the 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 4:1, yielding 66.2g of pure compound 12-6 in 75% yield.
(5) Preparation of intermediate Compounds 12-7
12-6.2 G (79.4 mmol,1.00 eq) of compound are weighed, 400.0mL of methylene chloride is added, et 3 SiH 11g (95.3 mmol,1.20 eq) is added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O13.5 g (95.3 mmol,1.20 eq) is added dropwise, then the temperature is raised 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 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 the dichloromethane solution of compound 13-2 obtained in step (1) was added 13-330.7g (137 mmol,1.00 eq) at 0deg.C under nitrogen, followed by addition of AlCl 3 18.3.3 g (137 mmol,1.00 eq) in portions, and after the addition was completed, the reaction mixture was warmed to 20deg.C for reaction for 5 hours. After the reaction, the reaction solution is cooled to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, an organic phase is collected, anhydrous Na 2SO4 is dried, filtered, and the filtrate is distilled and concentrated under reduced pressure to obtain a 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 of acetonitrile was added, et 3 SiH 39g (336.9 mmol,3.00 eq) was added under nitrogen at 20℃and BF 3.Et2 O31.8 g (224.6 mmol,2.00 eq) was then added dropwise under nitrogen at 25℃and the above mixture was reacted for 12h at 25 ℃. After the reaction, 300.0mL of saturated NaHCO 3 aqueous solution is added into the reaction solution, then MTBE is added for extraction, the organic phase is extracted by saturated saline water, the organic phase is collected and dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated 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 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, 600mL of redistilled THF was added, 41.4mL (2.5M, 1.00 eq) of N-BuLi in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, and stirred under nitrogen at-70℃for 0.2h, then 13-6.6 g (103.3 mmol,1.00 eq) of tetrahydrofuran (redistilled THF,150.0 mL) was added dropwise, and then stirred under nitrogen at-70℃for 1h. The reaction solution was poured into saturated aqueous NH 4 Cl solution, then extracted with MTBE, and the 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=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, 400.0mL of methylene chloride was added, et 3 SiH 9.6g (83 mmol,1.20 eq) was added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O11.8 g (83 mmol,1.20 eq) was added dropwise, followed by heating to 20℃and stirring 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 C18250 x 50mm x 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 chemical combination object 14 preparation: (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 14-127.5g (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 the dichloromethane solution of compound 13-2 obtained in step (2) was added 14-323.7g (137 mmol,1.00 eq) under nitrogen at 0 ℃ and then added in portions AlCl 3 18.3.3 g (137 mmol,1.00 eq) and after the addition was completed, the reaction mixture was warmed to 20 ℃ for reaction for 5 hours. After the reaction, the reaction solution is cooled to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, an organic phase is collected, anhydrous Na 2SO4 is dried, filtered, and the filtrate is distilled and concentrated under reduced pressure to obtain a 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 of acetonitrile was added, et 3 SiH 40.4g (349.2 mmol,3.00 eq) was added under nitrogen at 20deg.C, and BF 3.Et2 O33 g (224.6 mmol,2.00 eq) was then added dropwise under nitrogen at 25deg.C, the above mixture was reacted at 25deg.C for 12h. After the reaction, 300.0mL of saturated NaHCO 3 aqueous solution is added into the reaction solution, then MTBE is added for extraction, the organic phase is extracted by saturated saline water, the organic phase is collected and dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated 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 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, 600mL of redistilled THF was added, 41.4mL (2.5M, 1.00 eq) of N-BuLi in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, and stirred under nitrogen at-70℃for 0.2h, then 14-6.6 g (103.3 mmol,1.00 eq) of tetrahydrofuran (redistilled THF,150.0 mL) was added dropwise, and then stirred under nitrogen at-70℃for 1h. The reaction solution was poured into saturated aqueous NH 4 Cl solution, then extracted with MTBE, and the 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=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, 400.0mL of methylene chloride was added, et 3 SiH 9.3g (80.4 mmol,1.20 eq) was added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O11.4 g (80.4 mmol,1.20 eq) was added dropwise, followed by heating to 20℃and stirring 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
15-313.8G (86.6 mmol,1.00 eq) of compound 15-2 obtained in step (1) was added to a dichloromethane solution of compound 15-2 at 0℃under nitrogen, followed by addition of 3 11.6.6 g (86.6 mmol,1.00 eq) of AlCl in portions, and after the addition was completed, the reaction mixture was allowed to react at room temperature for 6 hours. After the reaction, the reaction solution is cooled to 0 ℃, 200mL of diluted hydrochloric acid is added, then saturated saline water is added for extraction, an organic phase is collected, anhydrous Na 2SO4 is dried, filtered, and the filtrate is distilled and concentrated under reduced pressure to obtain a 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
15-4.8 G (69.3 mmol,1.00 eq) of compound was taken, 200.0mL of acetonitrile was added, and Et 3 SiH 24g (207.9 mmol,3.00 eq) was added under nitrogen at 20℃followed by dropwise addition of BF 3.Et2 O39.2 g (277.2 mmol,4.00 eq) under nitrogen at 25℃and the above mixture was reacted for 12h at 25 ℃. After the reaction, 100.0mL of saturated NaHCO 3 aqueous solution is added into the reaction solution, then MTBE is added for extraction, the organic phase is extracted by saturated saline water, the organic phase is collected and dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated 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 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, 300mL of redistilled THF was added, 47.2mL (2.5M, 2.00 eq) of N-BuLi in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, and stirred under nitrogen at-70℃for 0.3h, then 15-6.7 g (58.9 mmol,1.00 eq) of tetrahydrofuran (redistilled THF,50.0 mL) was added dropwise, and then stirred under nitrogen at-70℃for 1h. The reaction solution was poured into saturated aqueous NH 4 Cl solution, then extracted with dichloromethane, and the 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=10:1 to 1:1, yielding 24.6g of pure compound 15-7 in 52% yield.
(5) Preparation of intermediate Compounds 15-8
15-7.6 G (30.6 mmol,1.00 eq) of compound was weighed, 200.0mL of methylene chloride was added, 4.2g (36.7 mmol,1.20 eq) of Et 3 SiH was added to the above solution under nitrogen at 20℃and the temperature was lowered to 0℃and 13g (91.8 mmol,3.0 eq) of BF 3.Et2 O was added dropwise, followed by warming to room temperature and stirring 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/C4.5 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, 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
Weighing 16-1 g (67.3 mmol,1.0 eq) of compound, adding 100mL of redistilled tetrahydrofuran, dropwise adding 100.8mL (2.0M, 3.0 eq) of LDA tetrahydrofuran solution to the solution at-70 ℃ under N 2, stirring for 1h at-70 ℃ under nitrogen, then dropwise adding 16-2.36.2 g (67.3 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) solution, and stirring for 1h at-70 ℃ under nitrogen. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 16.3g of pure compound 16-3 as a colorless oil in a yield of 32%.
(2) Preparation of intermediate Compound 16-4
16-3.3 G (21.5 mmol,1.0 eq) of compound 16-3 was weighed, 200.0mL of methylene chloride was added, et 3 SiH 3g (25.8 mmol,1.2 eq) was added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O3.7 g (25.8 mmol,1.2 eq) was added dropwise, followed by heating to 20℃and stirring 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 C18.250 mm x 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,CD3OD),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 having the structural formula
(1) Preparation of intermediate Compound 17-3
Weighing 17-1 g (68 mmol,1.0 eq) of compound, adding 150mL of redistilled tetrahydrofuran, dropwise adding 34mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution to the solution at-70 ℃ under N 2, stirring for 0.5h at-70 ℃ under nitrogen, then dropwise adding 17-2.6 g (68 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,50.0 mL) solution, and stirring for 1h at-70 ℃ under nitrogen. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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, giving 33.4g of pure compound 17-3 in 59% yield.
(2) Preparation of intermediate Compound 17-4
17-3.4 G (40.1 mmol,1.0 eq) of compound was weighed, 150.0mL of methylene chloride was added, 5.6g (48.1 mmol,1.2 eq) of Et 3 SiH was added to the above solution under nitrogen at 20℃and cooled to 0℃and 6.8g (48.1 mmol,1.2 eq) of BF 3.Et2 O was added dropwise, followed by heating to 20℃and stirring 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 C18.100 mm. Times.10 um; mobile phase: water (0.1% TFA) -ACN; B%:20% -80%,30 min) to give 4.05g of the objective compound 17 as a white solid in 37% yield.
1H NMR(400MHz,CD3OD),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 was added to the dichloromethane solution of compound 18-2 obtained in step (1) at 0deg.C under nitrogen, then 3 18.3.3 g (137 mmol,1.00 eq) of AlCl was added in portions, and after the addition was completed, the reaction mixture was warmed to room temperature 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, an organic phase is collected, anhydrous Na 2SO4 is dried, filtration is carried out, and the filtrate is distilled and concentrated under reduced pressure, thus obtaining 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 of acetonitrile was added, et 3 SiH 53g (515.3 mmol,4.00 eq) was added under nitrogen at 20deg.C, and BF 3.Et2 O32.3 g (227.4 mmol,2.00 eq) was then added dropwise under nitrogen at 25deg.C, the above mixture was reacted at 25deg.C for 12h. After the reaction, 300.0mL of saturated NaHCO 3 aqueous solution is added into the reaction solution, then MTBE is added for extraction, the organic phase is extracted by saturated saline water, the organic phase is collected and dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated 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 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, 550mL of redistilled THF was added, 35.6mL (2.5M, 1.00 eq) of N-BuLi in tetrahydrofuran was added dropwise to the above solution at-70℃under N 2, and stirred under nitrogen at-70℃for 0.3h, then 18-6.53.2 g (98.9 mmol,1.00 eq) of 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 aqueous NH 4 Cl solution, then extracted with MTBE, and the 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 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, 400.0mL of methylene chloride was added, 10.3g (89 mmol,1.20 eq) of Et 3 SiH was added to the above solution under nitrogen at room temperature, the temperature was lowered to 0℃and 12.6g (89 mmol,1.20 eq) of BF 3.Et2 O was added dropwise, then the temperature was raised 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 title 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 compound, adding 100mL of redistilled tetrahydrofuran, dropwise adding 82mL (2.0M, 3.0 eq) of a tetrahydrofuran solution of N-butyllithium to the solution at-70 ℃ under N 2, stirring for 0.5h at-70 ℃ under nitrogen, then dropwise adding 19-2.30.3 g (54.8 mmol,1.0 eq) of a tetrahydrofuran (redistilled THF,50.0 mL) solution, and stirring for 1h at-70 ℃ under nitrogen. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 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, 200.0mL of methylene chloride was added, et 3 SiH 4.4g (38.2 mmol,1.2 eq) was added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O5.4 g (38.2 mmol,1.2 eq) was added dropwise followed by heating to 20℃and stirring 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 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 C18.100 mm. Times.10 um; mobile phase: water (0.1% TFA) -ACN; B%:20% -80%,40 min) to give 3g of the objective compound 19 as a white solid in 37% yield.
1H NMR(400MHz,CD3OD),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
Weigh 20-1 g (213.4 mmol,1.0 eq) of compound, add 265mL of redistilled tetrahydrofuran, add 106.6mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution drop-wise to the above solution at-70℃under N 2, stir 0.5h under nitrogen at-70℃and then add 20-2 118g (213.4 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) drop-wise and stir 1h under nitrogen at-70 ℃. The reaction solution was poured into saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, and the 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 109.5g of pure compound 20-3 in 64% yield.
(2) Preparation of intermediate Compound 20-4
20-3.5 G (136.6 mmol,1.0 eq) of compound was weighed, 700.0mL of methylene chloride was added, et 3 SiH 19g (163.9 mmol,1.2 eq) was added to the above solution under nitrogen at 20℃and cooled to 0℃and BF 3.Et2 O23.3 g (163.9 mmol,1.2 eq) was added dropwise, followed by heating to 20℃and stirring 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 C18.250 mm x10 um; mobile phase: water (0.1% tfa) -ACN, B%:25% -53%,30 min) to give 15.02g of the title compound 20 as a white solid in 43% yield.
1H NMR(400MHz,CD3OD),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 for 7d continuously, and the fasting blood glucose concentration (FGB) (i.e., blood glucose value after administration) of the mice was measured by a rapid glucometer 1h after administration on day 7, and the results are expressed in units of mmol.l -1, and 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: p < 0.01 compared with the blank group; ②: p < 0.05 compared with the model group; ③: 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.
Test example 2 therapeutic Effect of the glycoside derivative of the present invention on type II diabetes
The experiment adopts a method of preparing a type II diabetes rat model by adopting a high-fat diet to induce rat insulin resistance and injecting low-dose Streptozotocin (STZ) to damage islets and cause blood sugar rise, so that the pathogenesis of human type II diabetes can be simulated. Streptozotocin has highly selective toxic effect on islet beta cells, and causes dysfunction by damaging islet beta cells through free radicals, reduces insulin synthesis, and causes diabetes.
The specific experiment is as follows:
After one week of adaptive feeding, the rats were given high-fat high-sugar feed, and after 4 weeks of feeding, the rats were fasted without water withdrawal for 12 hours and were intraperitoneally injected with 2% stz solution at a dose of 30 mg/kg. After the high-fat and high-sugar feed is fed for 3 days, the feeding is fasted for 12 hours, 200 mu L of blood is taken from the inner canthus vein of the rat by adopting a capillary glass tube (or 200 mu L of blood is taken from the tail vein of the rat by adopting a disposable blood taking needle), the fasting blood glucose value (FBG) of the rat (namely the blood glucose value before administration) is measured by adopting a rapid blood glucose meter, and the fasting blood glucose value is 16.7 mmol.L -1～25mmol·L-1 which is used as a judging standard for judging the successful modeling of the immune model of the type II diabetes.
Randomly selecting model II diabetes rats with successful modeling, and dividing the model II diabetes rats into 29 groups of 4 animals each, wherein the male and female parts are half; the model group G2, the dapagliflozin group G3 (positive control group) and the glycoside derivatives of the invention are respectively administered groups G4 to G30, and the blank control group G1 (4 healthy and normoglycemic mice fed with the same basic feed batch are used as the blank control group G1). Wherein, the glycoside derivatives of the invention are respectively administered in groups G4-G30 and dapagliflozin group G3 rats, and the corresponding doses of the drugs are administered by lavage every day (dissolved in 0.4% CMCNA), and the blank control group G1 and the group G2 rats of type II diabetes mellitus model are administered by lavage every day with 0.4% CMCNA with the same volume, and are administered for 1 time every day, and are continuously administered for 2 weeks, and the blood glucose values after administration for 1 week and 2 weeks are respectively measured, and the measurement results are shown in Table 2:
table 2: the glycoside derivative has the therapeutic effect on type II diabetes
Note that: compared to the blank: ◆P＜0.05;◆◆ P is less than 0.01; compared with the model group: ▼P＜0.05;▼▼ P < 0.01.
From the results, it can be seen that the high-fat high-sugar feed combined with streptozotocin can be used for constructing a rat type II diabetes model, all rats have extremely obvious differences in blood sugar rise, and no statistically significant differences exist between groups after grouping. After 1 week and 2 weeks of administration, compared with the model group G2, the glycoside derivative has the effect of obviously reducing blood sugar in high, medium and low dose groups; in comparison to dapagliflozin group G3, after 1 week of administration, all doses of compound 1, compound 2, compound 6, compound 9, high dose of compound 3, high and medium dose of compound 4, high and medium dose of compound 11, high and medium dose of compound 12, high and medium dose of blood glucose levels and high dose of compound 17 were lower than in dapagliflozin group; after 2 weeks of administration, the high and medium doses of the compound 1, the medium and low doses of the compound 2, the medium doses of the compound 6, the high and medium doses of the compound 9, the high and medium doses of the compound 11, the high and medium doses of the compound 12 and the high doses of the compound 17 are lower than the dapagliflozin group, so that the glucoside derivative has the effect of reducing blood sugar in the blood sugar rise caused by type II diabetes.
Claims (2)
1. An application of a glycoside derivative in preparing a medicament for preventing and/or treating type II diabetes mellitus, wherein the glycoside derivative is a compound shown in a formula I or pharmaceutically acceptable salt thereof:
Selected from: (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- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethyloxybenzyl) -2, 6-difluorophenyl) -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-isopropoxybenzyl) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol.
2. Use of the glycoside derivative according to claim 1 for the preparation of a medicament for the prophylaxis and/or treatment of high-fat and high-sugar food-induced type II diabetes.
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| WO1998031697A1 (en) * | 1997-01-15 | 1998-07-23 | Sankyo Company, Limited | Aryl c-glycoside compounds and sulfated esters thereof |
| CN1407990A (en) * | 1999-10-12 | 2003-04-02 | 布里斯托尔-迈尔斯斯奎布公司 | C-aryl glucoside sgltz inhibitors |
| CN101103013A (en) * | 2005-01-07 | 2008-01-09 | 大正制药株式会社 | 1-Thio-D-glucitol derivatives |
| WO2013134415A1 (en) * | 2012-03-07 | 2013-09-12 | Vertex Pharmaceuticals Incorporated | Mannose derivatives for treating bacterial infections |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1998031697A1 (en) * | 1997-01-15 | 1998-07-23 | Sankyo Company, Limited | Aryl c-glycoside compounds and sulfated esters thereof |
| CN1407990A (en) * | 1999-10-12 | 2003-04-02 | 布里斯托尔-迈尔斯斯奎布公司 | C-aryl glucoside sgltz inhibitors |
| CN101103013A (en) * | 2005-01-07 | 2008-01-09 | 大正制药株式会社 | 1-Thio-D-glucitol derivatives |
| WO2013134415A1 (en) * | 2012-03-07 | 2013-09-12 | Vertex Pharmaceuticals Incorporated | Mannose derivatives for treating bacterial infections |
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