CN102159586A - C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof - Google Patents
C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof Download PDFInfo
- Publication number
- CN102159586A CN102159586A CN201080002682XA CN201080002682A CN102159586A CN 102159586 A CN102159586 A CN 102159586A CN 201080002682X A CN201080002682X A CN 201080002682XA CN 201080002682 A CN201080002682 A CN 201080002682A CN 102159586 A CN102159586 A CN 102159586A
- Authority
- CN
- China
- Prior art keywords
- protective embankment
- embankment base
- naphthalene
- aryl
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229930182478 glucoside Natural products 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 23
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 125000001424 substituent group Chemical group 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 230000001681 protective effect Effects 0.000 claims description 247
- 125000003118 aryl group Chemical group 0.000 claims description 75
- -1 nitro, hydroxyl Chemical group 0.000 claims description 73
- 125000001072 heteroaryl group Chemical group 0.000 claims description 61
- 150000001875 compounds Chemical class 0.000 claims description 57
- 125000000623 heterocyclic group Chemical group 0.000 claims description 50
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 26
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 26
- 150000002118 epoxides Chemical class 0.000 claims description 21
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 21
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 16
- 206010022489 Insulin Resistance Diseases 0.000 claims description 15
- 229910052710 silicon Inorganic materials 0.000 claims description 15
- 239000010703 silicon Substances 0.000 claims description 15
- 208000011580 syndromic disease Diseases 0.000 claims description 15
- 201000001320 Atherosclerosis Diseases 0.000 claims description 13
- 206010020772 Hypertension Diseases 0.000 claims description 13
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 13
- 125000001931 aliphatic group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 235000011187 glycerol Nutrition 0.000 claims description 13
- 201000001421 hyperglycemia Diseases 0.000 claims description 13
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 13
- 150000002790 naphthalenes Chemical class 0.000 claims description 13
- 208000009928 nephrosis Diseases 0.000 claims description 13
- 231100001027 nephrosis Toxicity 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 13
- 208000002249 Diabetes Complications Diseases 0.000 claims description 12
- 206010012655 Diabetic complications Diseases 0.000 claims description 12
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 12
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 12
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 12
- 208000008589 Obesity Diseases 0.000 claims description 12
- 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 12
- 201000008980 hyperinsulinism Diseases 0.000 claims description 12
- 235000020824 obesity Nutrition 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 235000000346 sugar Nutrition 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 210000002700 urine Anatomy 0.000 claims description 7
- 150000001263 acyl chlorides Chemical group 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 150000001555 benzenes Chemical class 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 3
- 238000011287 therapeutic dose Methods 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 2
- 230000001934 delay Effects 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 224
- 238000006243 chemical reaction Methods 0.000 description 172
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
- 239000000243 solution Substances 0.000 description 104
- 238000003756 stirring Methods 0.000 description 101
- 239000000047 product Substances 0.000 description 82
- 238000001914 filtration Methods 0.000 description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 71
- 239000000706 filtrate Substances 0.000 description 71
- 239000012074 organic phase Substances 0.000 description 69
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 67
- 239000007787 solid Substances 0.000 description 64
- JTPNRXUCIXHOKM-UHFFFAOYSA-N 1-chloronaphthalene Chemical compound C1=CC=C2C(Cl)=CC=CC2=C1 JTPNRXUCIXHOKM-UHFFFAOYSA-N 0.000 description 63
- 238000005481 NMR spectroscopy Methods 0.000 description 54
- 239000003480 eluent Substances 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- 238000010898 silica gel chromatography Methods 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 32
- 239000007864 aqueous solution Substances 0.000 description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 26
- 239000007788 liquid Substances 0.000 description 25
- 239000012046 mixed solvent Substances 0.000 description 25
- 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 22
- 239000008103 glucose Substances 0.000 description 22
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 21
- 235000011167 hydrochloric acid Nutrition 0.000 description 21
- 239000008346 aqueous phase Substances 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000008280 blood Substances 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 9
- 238000002955 isolation Methods 0.000 description 9
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 108091006269 SLC5A2 Proteins 0.000 description 7
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 7
- 239000011630 iodine Substances 0.000 description 7
- 229910052740 iodine Inorganic materials 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 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 6
- 210000003734 kidney Anatomy 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 6
- 150000003222 pyridines Chemical class 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- SPEHEHYVDRYEDX-UHFFFAOYSA-N 3-methyloxan-2-one Chemical compound CC1CCCOC1=O SPEHEHYVDRYEDX-UHFFFAOYSA-N 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229910001623 magnesium bromide Inorganic materials 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000003472 antidiabetic agent Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical class [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical class CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 229910001947 lithium oxide Inorganic materials 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- DUKJZYZDOKKAMU-UHFFFAOYSA-N 1-chloronaphthalene-2-carbaldehyde Chemical compound C1=CC=C2C(Cl)=C(C=O)C=CC2=C1 DUKJZYZDOKKAMU-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XCCPULNRTZPSPC-UHFFFAOYSA-N C1CC1C2=CC=C(C=C2)CC3=CC=CC4=CC=CC=C43 Chemical compound C1CC1C2=CC=C(C=C2)CC3=CC=CC4=CC=CC=C43 XCCPULNRTZPSPC-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
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- 230000000977 initiatory effect Effects 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 210000005239 tubule Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CPIQIFZUPSNWNR-UHFFFAOYSA-N 1-chloronaphthalene-2-carboxylic acid Chemical compound C1=CC=CC2=C(Cl)C(C(=O)O)=CC=C21 CPIQIFZUPSNWNR-UHFFFAOYSA-N 0.000 description 2
- MFJNOXOAIFNSBX-UHFFFAOYSA-N 1-fluoro-3-methoxybenzene Chemical class COC1=CC=CC(F)=C1 MFJNOXOAIFNSBX-UHFFFAOYSA-N 0.000 description 2
- RPEPGIOVXBBUMJ-UHFFFAOYSA-N 2,3-difluorophenol Chemical class OC1=CC=CC(F)=C1F RPEPGIOVXBBUMJ-UHFFFAOYSA-N 0.000 description 2
- CKKOVFGIBXCEIJ-UHFFFAOYSA-N 2,6-difluorophenol Chemical class OC1=C(F)C=CC=C1F CKKOVFGIBXCEIJ-UHFFFAOYSA-N 0.000 description 2
- ORPYLLUOBDZSEX-UHFFFAOYSA-N 2-bromo-1-chloronaphthalene Chemical compound C1=CC=C2C(Cl)=C(Br)C=CC2=C1 ORPYLLUOBDZSEX-UHFFFAOYSA-N 0.000 description 2
- HFHFGHLXUCOHLN-UHFFFAOYSA-N 2-fluorophenol Chemical compound OC1=CC=CC=C1F HFHFGHLXUCOHLN-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof, especially C-aryl glucoside derivatives presented by formula (I), pharmaceutical salts and stereoisomers thereof, methods for their preparation, or pharmaceutical compositions containing the derivatives, and their use as a therapeutic agent, especially use as drugs for treating diabetes and related diseases, in which each substituent group of formula (I) is defined in the specification.
Description
C- aryl glucosides derivative, its preparation method and its in applied technical field pharmaceutically
The present invention relates to a kind of formula（I the derivatives of C- aryl glucosides shown in) or its pharmaceutically useful salt or its all stereoisomer, its preparation method and the pharmaceutical composition containing the derivative, and it is used as therapeutic agent especially as the purposes of the medicine of the treatment relevant disease such as diabetes.N J5 graves are not
Early stage in treatment diabetes mellitus, diet control and kinesiatrics are essential two methods.When these methods are not enough to symptom management, it is necessary to treated using insulin or OHA.At present, the medicine as hypoglycemic agent comes out, such as biguanide compound, sulfonyl urea compound, agent for amelioration of insulin resistance and Alpha-glucosidase inhibitor etc..But these antidiabetic drugs limit its application because of its various side effect, for example, biguanide compound easily causes lactic acidosis, sulfonyl urea compound can cause conspicuousness hypoglycemia, agent for amelioration of insulin resistance easily causes oedema and heart failure, and Alpha-glucosidase inhibitor can cause stomachache, abdominal distension, diarrhoea.In view of the foregoing, people place hope on develop it is a kind of new, it is safer, and can effectively reduce the Remedies for diabetes of blood glucose.
Transhipment regulation of the cell to glucose passes through to promoting GLUT (passively) (GLUTs) and Na-dependent glucose (active) corotation transporter（SGLTs) the regulation of function realizes that wherein SGLTs family members play during enteron aisle glucose absorption and kidney glucose reabsorption particularly important effect, thus become control blood glucose and then treat the promising target of diabetes.
Plasma glucose can generally pass through the glomerulus of kidney, actively be attached to renal cells and then by reabsorption.In kidney, 90% glucose reuptake occurs in the S1 fragment epithelial cells of cortex renis proximal tubule epithelium, and SGLT2 may be the major transporter for causing the reuptake.SGLT2 is 672 amino acid proteins containing 14 transmembrane segments, and it is mainly expressed before kidney nearly tubule in S1 sections.SGLT2 substrate specificity, sodium dependence and localization are consistent with being characterized as high power capacity, low compatibility, the property of sodium dependent glucose transport protein in the previously described nearly tubule of people's cortex renis.In addition, hybridization missing research shows, it is main Na+/glucose cotransporter in nearly tubule S1 sections SGLT2, because actually all sodium dependent glucose transport activities encoded in renal cortex of rats mRNA are suppressed by the specific ASONs of rat SGLT2.
In case of human, SGLT2 variation and the heredity of renal glucosuria are relevant, and this main function just for SGLT2 in kidney reuptake glucose provides further evidence.Thus develop it is a kind of can reabsorption of the selective depression kidney to glucose, while strengthening the excretion of glucose, and then realize the blood sugar reducing function of long period, become control blood glucose, treat the ideal medicament of diabetes.
Research finds that C- aryl glucosides class SGLT2 inhibitor is made like that with Orally active antidiabetic medicine
With.Specifically, it was found that these C- aryl glucoside SGL T 2 inhibitors can be used for treating or delay breaking-out or the progress of diabetes, especially I types and type ii diabetes, including diabetic complication such as retinopathy, neuropathy, nephrosis or retardance wound healing, and relevant disease such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, high fat of blood fat acid or glycerine level, it is fat, hyperlipemia includes hypertriglyceridemia, X syndromes, hypertension, atherosclerosis and relevant disease, and for improving high density lipid level.X syndromes are described later in detail in Johammsson, J Clin. Endrocrinol. Metal, 82,727-34 (1997).
This C- aryl glucoside SGL T 2s give as security preparation and can be used alone or be used in combination with existing medicine, and the medicine includes sulfonamide, thiazole protective embankment diketone, melbine and insulin, to avoid taking the potential side effect of these other drugs.About the more detailed content of C- aryl glucosides and its derivative visible CN1989132A, CN1671682A and CN1829729A, its all disclosure is incorporated herein by reference.
To sum up, SGLT inhibitor compounds, particularly SGLT2 inhibitor compound, are most to be hopeful that the medicine of anti-diabetic can be used for.
It is an object of the invention to provide a kind for the treatment of or medicine of palliative for having and preferably suppressing SGLT2 activity and can be used for treating diabetes or similar disease.' the content of the invention
In order to overcome the deficiencies in the prior art part, it is an object of the invention to provide a kind of formula（I the compound shown in), and their dynamic isomer, enantiomer, diastereomer, raceme and pharmaceutically useful salt, and metabolite and metabolic precursor thereof or prodrug.
Wherein:
Rl、R2、R3And R4It is each independently selected from hydrogen atom, protective embankment base, aryl, fragrant protective embankment base ,-C (0) RaOr-C (0) ORa, wherein the alkyl, aryl or aralkyl are optionally further replaced by one or more substituents selected from halogen, nitro, hydroxyl, cyano group, protective embankment epoxide or aryl；
R5And R6It is each independently selected from hydrogen atom, halogen, nitro, hydroxyl, cyano group, protective embankment base, alkoxy ,-CF3Or-OCF3, preferably hydrogen atom or halogen；
R7And R8It is each independently selected from hydrogen atom, halogen, nitro, hydroxyl, cyano group, alkyl, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 - NHC(0)Ra、 -NH-S(0)ORaOr-C (0) NRbRe, wherein the alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optionally further by it is one or more selected from halogen, nitro, cyano group, protective embankment base, hydroxyl, protective embankment epoxide, cycloalkyl,
Aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、
-N bRcOr-C (0) NRbReSubstituent replaced；
R9Selected from hydrogen atom, halogen, nitro, hydroxyl, cyano group, protective embankment base, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORaOr-C (0) NRbRc, wherein the protective embankment base, ring protective embankment base, Heterocyclylalkyl, aryl or heteroaryl optionally further by it is one or more selected from halogen, nitro, cyano group, protective embankment base, hydroxyl, protective embankment epoxide, cycloalkyl, aryl, heteroaryl,
-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr
-C(0)NRbReSubstituent replaced；
RaSelected from protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl, aralkyl or heteroaryl, wherein the protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl are optionally further selected from halogen, nitro, hydroxyl, cyano group, protective embankment base, alkoxy, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or mored、 -C(0)OH、
-C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；
RbAnd ReBe each independently selected from hydrogen atom, protective embankment base, ring protective embankment base, Heterocyclylalkyl, aryl or heteroaryl, wherein the protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl or heteroaryl optionally further by it is one or more selected from halogen, nitro, hydroxyl, cyano group, alkyl, protective embankment epoxide, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl ' ,-ORd、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；
Or, RbAnd Re3 ~ 8 circle heterocycles bases are formed together with the atom being connected, wherein described 3 ~ 8 circle heterocycles base contains one or more N, 0 or S atom, and 3 ~ 8 circle heterocycles bases are appointed to select into a Walk and are selected from halogen, nitro, hydroxyl, cyano group, alkyl, alkoxy, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl ,-OR by one or mored、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；
RdSelected from protective embankment base, ring protective embankment base, Heterocyclylalkyl, aryl, fragrant protective embankment base or heteroaryl；
ReAnd RfIt is each independently selected from hydrogen atom, protective embankment base, cycloalkyl, aryl or heteroaryl；
N is 0,1 or 2.Formula（I) compound can contain asymmetric carbon atom, therefore can exist or exist as mesomer compound using in the form of optically pure diastereomer, non-enantiomer mixture, diastereomer racemic modification, the mixture of diastereomeric racemic modification.The present invention includes all these forms.The mixture of non-enantiomer mixture, diastereomeric racemic modification or diastereomeric racemic modification can be separated by conventional method such as by column chromatography, thin-layered chromatography and HPLC≤Formula of the present invention（I the preferred compound shown in) includes, but are not limited to:
(2 & 3i,4/,5S,6i) -2- [the chloro- 3- of 4- (4- ethyoxyls -2,6-
12 diiluoro-benzyls)-naphthalene-1-yl]-6- methylols-oxinane
- 3,4,5- triols
(2S,3i,4 , 5 ＆ 6W) and -2- [4- chloro- 3- (4- ethyoxyls -3,5-
13 diiluoro-benzyls)-naphthalene -1- bases] -6- methylols-oxinane
- 3,4,5- triols
(2 & 3i, 45 ＆ 6/) -2- { 4- chloro- 3- [4- (tetrahydrofurans
14-3- oxygen)-benzyl] the small base of-naphthalene }-6- methylols-oxinane
- 3,4,5- triols or its pharmaceutically useful salt or its all stereoisomer.Another aspect of the present invention is related to formula (IA) compound or its pharmaceutically useful salt or its stereoisomer, its as formula (：I) the intermediate of compound synthesis：
R^R9As defined in logical formula (I);
R1()Selected from hydrogen atom or alkyl.Formula of the present invention（I A) shown in preferred compound include, but are not limited to-compound
Structure is named
Numbering
(2 & 3 4 & 5i, 6i)-3,4,5- tri- benzyloxy-6- benzyloxy li methyl-2- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene-1-yl]-oxinane-2- alcohol
(2 & 3i,4 & 5 6i) three benzyloxy -6- benzyloxies of -3,4,5-
2c methyl-2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene-1-yl]-oxinane-2- alcohol
(2&3 4 & 5i,6i) three benzyloxy -6- benzyloxies of -3,4,5-
3c methyl _2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene-1-base oxinane-2- alcohol
(2 & 3/, 4S, 5 6/) three benzyloxy -6- benzyloxies of -3,4,5-
4e methyl -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3,5- bis-)-naphthalene -1- bases]-oxinane -2- alcohol
(2 & 3 ,4S,5 6 ) -3,4,5- tri- benzyloxy -6- benzyloxies
5e methyl -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2,3- bis-)-naphthalene -1- bases]-oxinane -2- alcohol
(2 & 37,4 & 5S,6i) -2- [the chloro- 3- of 4- (the fluoro- 4- hydroxyls-benzyls of 3-
6d yls)-naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans
- 3,4,5- triols
(2S,3 ,4 & 5i, 6i) -3,4,5- tri- benzyloxy -6- benzyloxies
7f methyl-2- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene-1-yl]-oxinane-2- alcohol
(2 & 3i,4S,5 & 6i) -2- [the chloro- 3- of 4- (4- methylsulfanies-benzyl
8e yls)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydro pyrans
- 3,4,5- triols
(2 & 3 ,4 & 5S,6i) -2- [the chloro- 3- of 4- (4- methoxyl groups-benzyl
9c yls)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydro pyrans
The $ of -3,4,5- three
(2 & 3 4 & 5 & 6i)-2- [the chloro- 3- of 4- (4- cyclopropyl-benzyl lOd yls)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydro pyrans
- 3,4,5- triols
(2 & 3 4 & 5 & 6i)-2- [the chloro- 3- of 4- (4- ethyoxyl-2,3- llf diiluoro-benzyls)-naphthalene-1-yl]-6- methylols-oxinane
-2,3,4,5-01
(2 & 3i,4 & 5 & 6i) -2- [the chloro- 3- of 4- (4- ethyoxyls -2,6-
12f diiluoro-benzyls)-naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans -3,4,5- triols
(2&3 45,5i,6i) -3,4,5- tri- benzyloxy -6- benzyloxies
13f methyl -2- [the chloro- 3- of 4- (4- ethyoxyls -3,5- diiluoro-benzyl)-naphthalene -1- bases]-oxinane -2- alcohol
(2S,3i,4 & 5S,6i) -2- [the chloro- 3- of 4- (4- Hydroxy-benzvls) -
14c naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans
- 3,4,5- triols
Or its pharmaceutically useful salt or its all stereoisomer.The present invention relates to formula（I) the preparation method of compound, this method includes:
Formula (IA) compound dehydroxylation or protective embankment epoxide generation formula（I) compound；
R'~R9Definition as described in logical formula (I);.
RIQDefinition as described in formula (IA).The present invention relates to formula（IA) the preparation method of compound, this method includes:
Amino and the naphthalene compound of cyano group substitution react with halogen, generate halo naphthalene compound;
K N
Amino on halo naphthalene compound generates R after diazotising with nucleopilic reagent5Substituted naphthalene compound;
R5The naphthalene compound of acidifying generation carboxyl substitution after cyano group on substituted naphthalene compound is hydrolyzed in the basic conditions;
The naphthalene derivatives of carboxyl substitution reacts the naphthalene derivatives of generation acyl chlorides substitution with oxalyl chloride in the basic conditions;
The naphthalene derivatives that acyl chlorides replaces is subjected to acylation reaction with substituted benzene under catalytic condition and generates assimilation compound;
Carbonyl in assimilation compound is reduced into methylene;
( 1A )
The methylene reduzate of generation and substitution lactone coupling generation formula (IA) compound；
Wherein：
R'~R9Definition as described in logical formula (I)；
R10Definition as described in formula (IA)；
X is halogen；
R^ R14It is each independently selected from hydrogen atom, alkyl, aryl, fragrant protective embankment base, silylation ,-C (0) RaOr-C (0) ORa, replaced wherein the protective embankment base, aryl or fragrant protective embankment base appoint to select into a Walk by one or more substituents selected from halogen, nitro, hydroxyl, cyano group, protective embankment epoxide or aryl；
RaSelected from alkyl, ring protective embankment base, heterocycle protective embankment base, aryl, aralkyl or heteroaryl, wherein the protective embankment base, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl are optionally further selected from halogen, nitro, hydroxyl, cyano group, alkyl, alkoxy, ring institute base, heterocycle protective embankment, aryl, heteroaryl ,-OR by one or mored、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；
RbAnd ReHydrogen atom, protective embankment base, ring protective embankment base, Heterocyclylalkyl, aryl or heteroaryl are each independently selected from, wherein the protective embankment base, cycloalkyl, heterocycle protective embankment base, aryl or heteroaryl are optionally further selected from halogen, nitro, hydroxyl, cyano group by one or more：Protective embankment base, protective embankment epoxide, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl ,-ORd、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；
Or, RbAnd ReA 38 circle heterocycles bases are formed together with the atom being connected, wherein described 3 ~ 8 circle heterocycles base contains one or more N, 0 or S atom, and 3 ~ 8 circle heterocycles bases are optionally further selected from halogen, nitro, hydroxyl, cyano group, alkyl, protective embankment epoxide, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl ,-OR by one or mored、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；
RdSelected from alkyl, ring protective embankment base, Heterocyclylalkyl, aryl, fragrant protective embankment base or heteroaryl；
ReAnd RfIt is each independently selected from hydrogen atom, protective embankment base, ring protective embankment base, aryl or heteroaryl；
N is 0,1 or 2.Jin mono- Walk, the present invention relates to formula（I compound or its pharmaceutically useful salt or its all stereoisomer described in) are preparing the purposes in being used to treat or delay the medicine of following advancing of disease or breaking-out, wherein the disease is selected from elevated level, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine.
The invention further relates to a kind of method for treating diabetes, diabetic retinopathy, elevated levels of the Tang urine Bing Zhong through disease, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or hypertension, methods described includes giving the formula for the effective therapeutic dose of patient for needing to treat（I compound or its pharmaceutically useful salt or its stereoisomer described in).
The invention further relates to formula（I the compound or its pharmaceutically useful salt or its stereoisomer described in) are as the medicine for treating or delaying following advancing of disease or breaking-out, wherein the disease is selected from elevated level, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine.
Further, the present invention relates to a kind of pharmaceutical composition, described composition includes the formula of effective dose（I compound or its pharmaceutically useful salt or its all stereoisomer and pharmaceutically useful carrier described in).The pharmaceutical composition is preparing the purposes in being used to treat or delay the medicine of following advancing of disease or breaking-out, wherein the disease is selected from elevated level, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, the plain mass formed by blood stasis in island of high-recruiting, aliphatic acid or glycerine.
The invention further relates to a kind of method of elevated level for treating diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or hypertension, methods described, which includes giving, needs the effective therapeutic dose of patient treated to contain formula（I the pharmaceutical composition described in).
The invention further relates to contain formula by（I the medicine of following advancing of disease or breaking-out is treated or delayed to the pharmaceutical composition described in) is, wherein the disease is selected from elevated level, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine.
Detailed description of the invention
Unless stated to the contrary, it is following that there are following implications with term in the specification and in the claims.
" protective embankment base " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.The alkyl of 1 to 10 carbon atom is preferably comprised, such as methyl, ethyl, propyl group, 2- propyl group, normal-butyl, isobutyl group, the tert-butyl group, amyl group.Low alkyl group more preferably containing 1 to 4 carbon atom, such as methyl, ethyl, propyl group, 2- propyl group, normal-butyl, isobutyl group or the tert-butyl group.Protective embankment base can be substituted or unsubstituted, and when substituted, substituent is preferably one or more, independently selected from halogen, nitro, hydroxyl, amino, protective embankment epoxide, cyano group, protective embankment base, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr-C (0) NRbRc。
" cycloalkyl " refers to non-aromatic monocyclic or polycyclic ring-type system, and it includes 3 to 20 carbon atoms, preferably
Including 3 to 10 carbon atoms, more preferably ring protective embankment basic ring includes 3 to 8 carbon atoms.The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexadienyl, cycloheptyl protective embankment base, cycloheptatriene base etc..Polycyclic ring protective embankment base includes the cycloalkyl of loop coil, condensed ring and bridged ring, and non-limiting example includes 1- naphthalanes base, norborny, Buddha's warrior attendant protective embankment base and similar group.Cycloalkyl can be substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkoxy, halogen, hydroxyl, nitro, cyano group, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr-C (0) NRbRc。
" heterocycle protective embankment base " refers to the monocyclic or polycyclic ring-type system of non-aromatic, and it includes 3 to 20 annular atoms, and wherein one or more annular atoms are selected from nitrogen, oxygen or S (0) n (whereinnInteger 0 to 2) hetero atom, but do not include -0-0-, -0-S- or-S-S- loop section, remaining annular atom is carbon.It is preferred that heterocycle protective embankment base includes 3 10 annular atoms, wherein 14 are hetero atoms, more preferably heterocycle protective embankment base includes 38 annular atoms.The non-limiting example of monocyclic heterocycloalkyl includes pyrroles's protective embankment base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc., and polycyclic Heterocyclylalkyl includes the heterocycle protective embankment base of bicyclic or polycyclic loop coil, condensed ring and bridged ring.Heterocycle protective embankment base can be substituted or unsubstituted.When substituted, substituent is preferably one or more following groups, is independently selected from alkyl, alkoxy, halogen, hydroxyl, nitro, cyano group, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S'(0)nR\ -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr-C (0) NRbRc。
" 38 circle heterocycles base ", which refers to, constitutes the quantity of annular atom for 38 yuan, constitute and contain one or more N, 0 or S (〇) n hetero atoms in the atom of ring, 12 double bonds can be contained in ring, for the ring group of monocyclic or bicyclic non-aromatic, when constituting in the atom of ring containing nitrogen-atoms, associative key can be stretched out from nitrogen-atoms.Preferably 46 circle heterocycles bases, more preferably 56 yuan, such as pyrroles's protective embankment base, piperidyl or piperazinyl.38 circle heterocycles bases can be substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, protective embankment epoxide, halogen, hydroxyl, nitro, cyano group, carbonyl, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr-C (0) NRbRc。
" aryl " refers to that 6 to 14 yuan of full carbon are monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, polycyclic (i.e. its ring for the carrying phase adjacency pair carbon atom) group of pi-electron system with conjugation, preferably 6 to 10 yuan, such as phenyl, naphthyl.Aryl can be substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, protective embankment epoxide, halogen, hydroxyl, nitro, cyano group, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl ,-ORa、 -C(0)OH、- C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr-C (0) NRbRc。
" heteroaryl " refers to comprising 1 to 4 hetero atom, and the heteroaromatic system of 5 to 14 annular atoms, wherein hetero atom include oxygen, sulphur and nitrogen.It is 5 yuan or 6 unit's heteroaryls that heteroaryl, which is preferably,.Such as furyl, thienyl, pyridine radicals, pyrrole radicals, N- protective embankment bases pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical.Heteroaryl can be substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, independently selected from protective embankment base, alkoxy, halogen, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle protective embankment base, aryl,
Heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr-C (0) NRbRc。
The protective embankment base that " aralkyl " is substituted with aryl comprising finger, fragrant protective embankment base preferably is, with the aryl lower aralkyl being connected with the protective embankment base containing 16 carbon atoms, to be more preferably attached to " phenyl Asia protective embankment base " in the protective embankment base section with 13 carbon atoms.For example, benzyl, 1- phenethyls, 2- phenethyls, 1- naphthyl methyls, preferably 2- naphthyl methyls, benzyl.Aryl in described aralkyl can be substituted or unsubstituted, and when substituted, substituent is preferably protective embankment base, alkoxy, halogen, hydroxyl, nitro, cyano group, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr-C (0) NRbRc。
" protective embankment epoxide " refers to-C protective embankments base) and -0- (unsubstituted cycloalkyl).Representative example includes but is not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..Alkoxy can be substituted or unsubstituted, and when substituted, substituent is preferably one or more, independently selected from protective embankment base, halogen, nitro, hydroxyl, amino, cyano group, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr TC (0) NRbRc。
" halogen " refers to fluorine, chlorine, bromine or iodine.
" nitro " refers to-N02。 ·
" hydroxyl " refers to-OH.
" amino " refers to-N.
" cyano group " refers to-CN.
" pharmaceutical composition " represents one or more compounds described herein or its physiologically/pharmaceutically useful salt or pro-drug and the mixture of other chemical constituents, other components such as physiology/pharmaceutically useful carrier and excipient.The purpose of pharmaceutical composition is to promote the administration of compound on organism body.
It is referred to as " X syndromes ", also referred to as the illness of metabolic syndrome, disease and illness, is specified in Johannsson J. Clin. Endocrinol. Metab., 1997;In 82,727-734.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes the event or environment occurs or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " mean alkyl can with but necessarily exist, the explanation includes the situation that the situation that is replaced by protective embankment base of heterocyclic group and heterocyclic group are not replaced by protective embankment base.
Wherein Ra〜ReDefinition as described in logical formula (I).The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention is adopted the following technical scheme that：
Formula of the present invention（I the preparation method of compound or its pharmaceutically useful salt or its all stereoisomer described in), comprises the following steps：
Amino and the naphthalene compound of cyano group substitution react with halogen, generate halo naphthalene derivatives；Amino on halo naphthalene derivatives generates R after diazotising with nucleopilic reagent5Substituted naphthalene compound； R5The naphthalene derivatives of acidifying generation carboxyl substitution after cyano group on substituted naphthalene derivatives is hydrolyzed in the basic conditions；Generates acyl chlorides to the naphthalene derivatives of carboxyl substitution with oxalyl chloride reaction in the basic conditions!The naphthalene derivatives in ^ generations；The naphthalene derivatives that acyl chlorides replaces is subjected to acylation reaction with substituted benzene under catalytic condition and generates ketone derivatives；
Carbonyl in ketone derivatives is reduced into methylene；The methylene product of generation and substitution lactone compound coupling generation formula (IA) compound；Formula (IA) compound dehydroxylation or alkoxy generation formula（I) compound.Brief description of the drawings
Fig. 1 is the blood glucose fall time of compound 1,10.
Fig. 2 is row's sugar amount time diagram of compound 1,10.Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments not limit the scope of the present invention.
' embodiment
The structure of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum（MS) determine.NMR displacements (δ) are provided with the unit of hundred a ten thousandths (ppm).NMR measure is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl sulfoxide（DMSOO deuterochloroforms (CDC13), deuterated methanol (CH30D), inside it is designated as tetramethylsilane（), tMS chemical shift is with l (T6(ppm) provided as unit.
MS measure is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model： Finnigan LCQ advantage MAX).
HPLC measure uses Agilent 1200DAD high pressure liquid chromatographs（Sunfire C18 150x4.6mm chromatographic columns) and Waters 2695-2996 high pressure liquid chromatographs (Gimini C18 150x4.6mm chromatographic columns).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and the specification that the silica gel plate that thin-layered chromatography (tLC) is used is used is the mm of 0.15 mm 0.2, and thin-layer chromatography isolates and purifies product use
Specification be the mm of 0.4 mm 0.5.
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200 ~ 300.
The initiation material of the present invention is known, and can commercially it buy, buy from ABCR GmbH ＆ Co. KG, Acros Organics, Aldrich Chemical Company, splendid remote chemical standing grain bucket skill (Accela-ChemBio Inc), up to companies such as auspicious chemicals, or can use or oneself knows according to this area method is synthesized.
Without specified otherwise in embodiment, reaction is carried out under argon atmospher or blanket of nitrogen.
Argon atmospher or blanket of nitrogen are the argon gas or nitrogen balloon that Yuh reaction bulbs connect about 1 L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of about 1 L volume.
Pressure hydration reaction using Parr 3916EK types hydrogenation instrument and clear indigo plant QL-500 types hydrogen generator or
HC2-SS types hydrogenate instrument.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Microwave reaction uses the type microwave reactors of CEM Discover-S 908860.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 201 30 °C.
The monitoring of reaction process in embodiment uses thin-layered chromatography（TLC), there be the system of solvent used in reacting：Dichloromethane protective embankment and methanol system, just own protective embankment and ethyl acetate system, the volume ratio of solvent are adjusted according to the polarity difference of compound.
The system of the eluant, eluent of column chromatography includes： A:Dichloromethane protective embankment and methanol system； B:' just own protective embankment and ethyl acetate system； C:Dichloromethane protective embankment; D:N-hexane：The own protective embankment system of dichloro； E:Just own protective embankment system.The volume ratio of solvent is different and be adjusted according to the polarity of compound, can also add a small amount of ammoniacal liquor and acetic acid etc. and be adjusted
Embodiment 1
qS,3ig,4i,5S,6i) -2- " the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases 1-6- methylols-oxinane -3,4,5- triols
The first step
Bromo- naphthalene -2- the nitriles of 1- amino -4-
Amino-naphthalene -2- nitriles la (840 mg, 5 mmol) is dissolved in 24 mL methanol and glacial acetic acid (V: V = 5 :1) in the mixed solvent, ice bath is cooled to 0 V, and bromine (0.3 mL, 6 mmol), stirring reaction 3 hours is added dropwise.It is concentrated under reduced pressure, adds 5 mL methanol, filter cake is collected in filtering, and vacuum drying obtains title product 1- amino -4- bromonaphthalene -2- nitriles lb (1.04 g, faint yellow solid), yield： 84.2%.
MS m/z (ESI): 246.8 [M-l]
Ή NMR (400 MHz, DMSO-c/6, ppm):δ 8.42 (d, 1H), 8.03 (d, 1H), 7.78 (t, 1 H), 7.72 (s, 1 H), 7.62 (t, 1H), 7.15 (br.s, 2H)
Second step
Chloro- naphthalene -2- the nitriles of the bromo- 1- of 4-
By anhydrous cupric chloride (6.9 g, 5.15 mmol) it is dissolved in 200 mL acetonitriles, add nitrite tert-butyl (7.6 mL, 64.5 mmol), stirring reaction 10 minutes, 1-amino-4- bromonaphthalene-2- nitriles lb (10.6 g are added portionwise, 43 mmol), continue stirring reaction 1 hour, in the hydrochloric acid of 400 mL 20% that reaction solution is poured into cooling, filtering, filter cake is collected, vacuum drying obtains the chloro- naphthalene-2- nitriles lc of the bromo- 1- of title product 4- (l l g, gray solid), yield： 96.5%.
Ή NMR (400 MHz, DMSO-i 6, ppm): δ 8.34 (m, 2Η), 8.28 (d, 1H), 7.95 (m, 2H)
3rd step
Chloro- naphthalene -2- the formic acid of the bromo- 1- of 4-
Chloro- naphthalene -2- nitriles the lc of the bromo- 1- of 4- (7.72 g, 29 mmol) are dissolved in 40 mL second alcohol and waters (V: V = 3 :1) in the mixed solvent, stirring is lower to add potassium hydroxide (8.14 g, 145 mmol), and back flow reaction 8 hours adds 50 mL 2M hydrochloric acid, and solid is collected in filtering, is recrystallized with ethyl acetate/just own protective embankment, is obtained title product 4-
The small chloro- naphthalene -2- formic acid ld (5.0 g, yellow solid) of bromine, yield： 60.4%.
MS m/z (ESI): 284.6 [M-l]
Ή NMR (400 MHz, CD3OD, ppm):δ 8.51 (dd, 1H), 8.30 (m, 1H), 8.13 (s, 1H), 7.80 (m, 2H)
4th step
Chloro- naphthalene -2- the formyls of the bromo- 1- of 4- are chloro- '
By chloro- naphthalene -2- formic acid ld (860 mg of the bromo- 1- of 4-, 3 mmol) it is dissolved in 15 mL dichloromethane, 0.1 mL DMFs are added dropwise, reaction bulb is placed in room-temperature water bath, it is slowly added to oxalyl chloride (0.3 mL, 3.6 mmol), stirring reaction 3 hours is concentrated under reduced pressure to give chloro- naphthalene -2- formyl chlorides le (900 mg of the bromo- 1- of title product 4-, yellow solid), product is directly used in next step reaction without isolation.
5th step
(4- bromo- 1-chloro- naphthalene-2- bases)-(4- ethyoxyls-phenyl)-ketone
By chloro- naphthalene -2- formyl chlorides le (910 mg of the bromo- 1- of 4-, 3 mmol) it is dissolved in 15 mL dichloromethane protective embankments, add phenetole (366.5 mg, 3 mmol), reaction bulb is placed in room-temperature water bath, alchlor (360 mg, 2.7 mmol) is slowly added to, is reacted 12 hours at room temperature.The M hydrochloric acid of 20 mL 1 is added dropwise into reaction bulb, extracted with dichloromethane (50 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls-phenyl)-ketone lf (1.0 g, yellow orange solid), yield： 86.2%.
MS m/z (ESI): 390.9 [M+l]
Ή NMR (400 MHz, DMSO- 6, ppm):6 8.30 (d, 1H), 8.28 (d, 1H), 8.00 (s, 1H), 7.85 (d, 2H), 7.74 (m, 2H), 7.05 (d, 2H), 4.13 (q, 2H), 1.34 (t, 3H)
6th step
The chloro- 2- of the bromo- 1- of 4- (4- ethyoxyls-benzyl)-naphthalene
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls-phenyl)-ketone lf (1.0 g, 2.56 mmol) is dissolved in 15 mL acetonitriles and dichloromethane (V: V = 2:1) in the mixed solvent, reaction bulb is placed in room-temperature water bath, adds triethyl silicane (1.0 mL, 6.16 mmol) and BFEE (0.5 mL, 3.85 mmol), at room temperature stirring reaction 12 hours.Potassium hydroxide solution (0.6 g, 3 mL) is added, 5 mL water is added, (20 mL is extracted with ether><3), merge organic phase, washed with saturated nacl aqueous solution (20 mL), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain small chloro- 2- (4- ethyoxyls-benzyl)-naphthalene lg (500 mg of title product 4- bromines, white solid), yield： 52.1%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.35 (d, 1 Η), 8.19 (d, 1H), 7.61 (m, 3H), 7.13 (d, 2H), 6.83 (d, 2H), 4.23 (s, 2H), 4.00 (q, 2H), 1.39 (t, 3H)
7th step
(2S,3i,4S,5i,6i) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases]-oxinane -2- alcohol
By the chloro- 2- of the bromo- 1- of 4- (4- ethyoxyls-benzyl)-naphthalene lg(1.8 g, 4.8 mmol) are dissolved in 25 mL tetrahydrofurans, under dry ice-propanone bath, are cooled to the hexamethylene protective embankment solution (2.12 that 2.5 M n-BuLis are slowly added dropwise after -78
ML, 5.3 mmol), react 30 minutes, by (3/,4 & 5 6/) -3,4,5- tri- benzyloxy -6- benzyloxymethyls-oxinane -2- ketone lh (2.84 g, 5.3 mmol, using known method "Rbo/2_y Res., 260 (1994), 243-250 " are prepared) it is dissolved in 10 mL tetrahydrofurans, instill in reaction solution, reacted 3 hours in -78 °C, be warming up to 0 V.10 mL saturated nacl aqueous solutions are added dropwise, add 10 mL water, extracted with ether (30 mLx3), merge organic phase, washed with saturated nacl aqueous solution (15 mL), anhydrous magnesium sulfate is dried, filtering, it is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (2 ＆ 3^,4＆5 6-3, 4, 5- tri- benzyloxy -6- benzyloxy plug methyl -2- [the chloro- 3- of 4- (4- ethyoxyls-benzyl) the small base of-naphthalene]-oxinane -2- alcohol li (1.9 g, pale yellow oil), yield： 47.5ό/ο。
MS m/z (LC-MS): 819.2 [M-17]
8th step
(2i,3/, 45 ＆ 6S) and -3,4,5- tri- benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases]-oxinane
By (2 ＆ 3i,4 & 5 6/) -3,4, benzyloxy -6- benzyloxymethyls-the 2- of 5- tri- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases]-oxinane -2- alcohol li (1.9 g, 2.27 mmol) it is dissolved in 15 mL dichloromethane protective embankments, reaction bulb is placed in room-temperature water bath, triethyl group silicon protective embankment (0.47 mL, 2.96 mmol) and three is added and establishes (change borate ether (0.35 mL, 2.73 mmol), stirring reaction 12 hours at room temperature.15 mL saturated nacl aqueous solutions are added, 10 mL water are added, (30 mLx2) is extracted with dichloromethane protective embankment, merges organic phase, (10 mL is washed with saturated nacl aqueous solution；), anhydrous magnesium sulfate dry, filtering, be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product (2i,3i, 4i, 5 ＆ 65) and -3,4,5- tri- benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases]-oxinane lj (1.5 g, white solid), yield： 80.6%.
Ή NMR (400 MHz, CDC13, ppm):(the d of δ 8.39, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 7.28 (s, 10H), 7.25 (s, 5H), 7.09 (d, 3H), 6.99 (m, 2H), 6.73 (d, 2H), 6.50 (d, 2H), 4.90 (m, 3H), 4.85 (m, 1H), 4.70 (d, 1H), 4.61 (d, 1H), 4.51 (d, 1H), 4.30 (d, 1H), 4.16 (m, 2H), 3.94 (m, 3H), 3.84 (m, 3H), 3.75 (d, 1H), 3.65 (d, 1H), 3.48 (d, 1 H), 1.36 (t, 3H)
9th step
(2 & 3i, 4, 5 ＆ 6/) -2- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols general (2/,3 47Benzyloxy -2- benzyloxymethyls-the 6- of 5 ＆ ^- tri- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases]-oxinane lj (1.5 g, 1.83 mmol) it is dissolved in 12 mL chloroforms, add 6 mL mercaptan and BFEE (3.48 mL, 27.45 mmol), stirring reaction 72 hours.Jian Ya Nong Shrink, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product crude product (2 ＆ 3/,4i,5S,6/) -2- [the chloro- 3- of 4- (4- ethyoxyls-benzyl) the small base of-naphthalene] -6- methylols-oxinane -3,4,5- triols lk (600 mg, white solid), yield： 71.5%.
MS m/z (LC-MS): 476.2 [M+18]
Tenth step
(2 ,3 4 , 5 ＆ 6S) and -3,4,5- triacetoxyl groups -6- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases]-oxinane -2- acetic acid methyl esters
By crude product (2 ＆ 3/,-the 2- of 45 ＆ 6 [the chloro- 3- of 4- (4- ethyoxyls-benzyl) the small base of-naphthalene] -6- methylols-tetrahydrochysene pyrrole
- 3,4, the 5- triol lk (458 mg, 1 mmol) that mutter are dissolved in 6mL pyridines and dichloromethane protective embankment (V: V = 1：5) in the mixed solvent, add acetic anhydride (0.9 mL, 9 mmol) and DMAP (6.1 mg, 0.05 mmol), stirring reaction 12 hours, be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (2,3/,4/, 5 ＆ 65) and -3,4,5- triacetoxyl group -6- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases]-oxinane -2- acetic acid methyl ester l m (500 mg, white solid), yield： 79.7%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.38 (dd, IH), 8.15 (dd, IH), 7.59 (m, 2H), 7.43 (m, IH), 7.12 (dd, 2H), 6.81 (dd, 2H), 5.43 (m, 2H), 5.32 (m, IH), 5.07 (m, IH), 4.25 (m: 3H), 4.18(dd, IH), 4.00 (q, 2H), 3.97 (m, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H), 1.47 (s, 3H), 1.39 (t, 3H)
11st step
(2S,3 4i,5S,6i) -2- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- the bases] -6- methylols-generals of oxinane -3,4,5- three (2,3/,4i5 ＆ 65) -3,4,5- triacetoxyl group -6- [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases]-m of oxinane -2- acetic acid methyl esters 1 (400 mg, 0.64 mmol) is dissolved in 6 mL tetrahydrofurans, first alcohol and water (V: V： V = 2: 3：1) in the mixed solvent, sequentially adds a hydronium(ion) lithia (32 mg, 0.77 mmol) and 5 mL dichloromethane protective embankments, stirs anti-and answers 12 hours.Be concentrated under reduced pressure reaction solution, adds 5 mL water, and (10 mLx3) is extracted with acetic acid second tenth of the twelve Earthly Branches purport, merge organic phase, washed with saturated nacl aqueous solution (5 mL), anhydrous slufuric acids a unit of weight used in ancient China, equal to six liang is dried, filtering, is concentrated under reduced pressure, obtains title product (2 ＆ 3 47,-the 2- of 5 ＆ 6 [the chloro- 3- of 4- (4- ethyoxyls-benzyl)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triol lC290 mg, white solid), yield： 100%.
MS m/z (LC-MS): 476.3 [M+18]
Ή NMR (400 MHz, CD3OD, ppm):δ 8.34 (d, 2H), 7.61-7.52 (m, 3H), 7.14 (d, 2H), 6.79 (m, 2H), 4.87 (d, IH), 4.27 (dd, 2H), 3.98 (dd, 2H), 3.88 (d, 1H), 3.74 (m, 2H), -3.60 (t, IH), 3.52 (m, 2H), 1.34 (t, 3H) embodiments 2
(2S,3 4 5S,6i) " the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene -1- bases foretell 6- methylols-oxinane to -2-
- 3,4,5- triols
The first step
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(the fluoro- 4- methoxyl groups-phenyl of 3-)-ketone is by small chloro- naphthalene -2- formyl chlorides le (2.2 g of 4- bromines, 6.83 mmol) it is dissolved in 30 mL dichloromethane, add fluoro- 2- methoxybenzenes (0.76 mL of 1-, 6.83 mmol), alchlor (820 mg are added portionwise, 6.15 mmol), stirring reaction 12 hours.Add the M hydrochloric acid of 20 mL 1, with dichloromethane protective embankment extractive reaction liquid (20 mLx3), organic phase is washed (20 mL) with saturated nacl aqueous solution, anhydrous acid magnesium is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained it is residual>, obtain（Chloro- naphthalene -2- the bases of the bromo- 1- of 4-)-(the fluoro- 4- methoxyl groups-phenyl of 3-)-ketone 2a (1.86 g, yellow solid), yield： ' 69.4%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.34-8.31 (η τ, 2 Η), 7.78-7.74 (m, 3 Η), 7.66-7.63 (dd, 1 Η), 7.57-7.52 (m, 1H), 6.98 (t, 1H), 3.97 (s, 3H)
Second step
The chloro- 2- of the bromo- 1- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene
(the bromo- chloro- naphthalene -2- bases of 4-)-(the fluoro- 4- methoxyl groups-phenyl of 3-)-ketone 2a (1.85 g, 4.70 mmol) is dissolved in 30 mL acetonitriles and dichloromethane protective embankment (V: V = 2:1) in the mixed solvent, sequentially add triethyl silicane (2.4 mL, 15 mmol) and BFEE (1.19 mL, 9.4 mmol), stirring reaction 12 hours, 1.5 g potassium hydroxide are dissolved in 30 mL water and are made into potassium hydroxide solution, it is added in reaction solution and reaction is quenched, extracted with ether (30 mLx3), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the chloro- 2- of the bromo- 1- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene 2b (1.37 g, yellow solid), yield： 77.1%.
Ή NMR (400 MHz, CDC13, ppm): δ 8.33 (dd, 1Η), 8.21 (m, 1H), 7.66-7.59 (m, 3H), 6.96-6.85 (m, 3H), 4.21 (s, 2H), 3.86 (s, 3H)
3rd step
(2 & 3/, 4 ＆ 57,6 ) three benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalenes of -3,4,5-
- 1- bases]-oxinane -2- alcohol
By the chloro- 2- of the bromo- 1- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene 2b (758 mg, 2 mmol) it is dissolved in 10 mL tetrahydrofurans, in hexamethylene protective embankment solution (0.8 mL that 2.5 M n-BuLis are added dropwise under -78 °C, 2 mmol), in -78 °C of lower stirring reactions 30 minutes, (3 are added dropwise；, 4 ＆ 5/,6i) -3,4,5- tri- benzyloxy -6- benzyloxymethyls-oxinane -2- ketone lh (1.18 g, 2.2 mmol) 5 mL tetrahydrofuran solutions continue stirring reaction 2 hours in -78 times.10 mL saturated nacl aqueous solutions are added, are extracted with ether (10 mLx3), merges organic phase, uses saturated sodium-chloride
Solution wash (10 mL), anhydrous magnesium sulfate dry, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain（2 & 3 4&5 ,6/) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene -1- bases]-oxinane -2- alcohol 2c (700 mg, yellow solid), yield： 41.7%.
1H NMR (400 MHz, CDC13, ppm):δ 8.61 (d, 1H), 8.36 (d, 1H), 7.77 (s, 1H), 7.52 (t, 1H), 7.30 (m, 16H), 7.10-6.90 (m, 6H), 6.65 (m, 2H), 4.96 (d, 1H), 4.88 (dd, 2H), 4.75 (d, 1H), 4.55 (d, 1H), 4.48 (d, 1H), 4.31-4.12 (m, 3H), 3.93-3.64 (m, 9H), 3.40 (d, 1H)
- the four step
(2/,3i,4i, 5＆65) and three benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (3- Gas -4- methyoxy-benzyls)-naphthalenes of -3,4,5-
- 1- bases]-oxinane
By (2 ＆ 3i,4S,5i,6/) -3,4, benzyloxy -6- benzyloxymethyls-the 2- of 5- tri- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene -1- bases]-oxinane -2- alcohol 2c (500 mg, 0.60 mmol) it is dissolved in 6 mL dichloromethane, triethyl silicane (124 L are sequentially added under ice bath, 0.77 mmol) and BFEE (91 μ, 0.72 mmol), at room temperature stirring reaction 2 hours.Add 5 mL saturated sodium carbonate solutions, (10 mLx3 merging organic phases are extracted with dichloromethane protective embankment, washed (10 mL) with Bao and Lvization Na Qi liquid, anhydrous sulphur ferment magnesium is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system C purify gained residue, obtain (2/,3 47, 5,＆65 3,4, the benzyloxy -2- benzyloxymethyls -6- of 5- tri- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene -1- bases]-oxinane 2d (321 mg, white solid), yield： 65.6%.
Ή NMR (400 MHz, CDC13, ppm): δ 8.38 (d, 2H), 7.58 (m, 1H), 7.43 (m, 2H), 7.28 (m, 15H), 7.10-6.90 (m, 6H), 6.50 (m, 2H), 4.91 (m, 3H), 4.82 (m, 1H), 4.70 (d, 1H), 4.61 (d, 1H), 4.29 (d, 1H), 4.31-4.12 (m, 3H), 3.93-3.64 (m, 9H), 3.50 (d, 1H)
5th step
(2 & 3i,4 5 & 6 )-2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene-1-yl]-6- methylols-oxinane
- 3,4,5- triols
By (2 3/45 ＆ 65 3,4, benzyloxy -2- benzyloxymethyls-the 6- of 5- tri- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-)-naphthalene -1- bases]-oxinane 2dC450 mg, 0.55 mmol) it is dissolved in 4 mL chloroforms, add 2 mL ethyl mercaptans and BFEE G.04 mL, 8.2 mmol), stirring reaction 5 hours.Be concentrated under reduced pressure reaction solution, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain（2&37,4i,5 & 67) -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3-) the small base of-naphthalene] -6- methylols-oxinane -3,4,5- triols 2 (130 mg, white solid), yield： 51.6%.
MS m/z (LC-MS): 480.3 [M+18]
1H NMR (400 MHz, CD3OD, ppm):δ 8.38 (d, 2H), 7.66-7.58 (m, 3H), 7.10-6.98 (m, 3H), 4.93 (d, 1H), 4.32 (dd, 2H), 3.94 (d, 2H), 3.86 (s, 1H), 3.77 (m, 2H), 3.64 (t, 1H), 3.57 (m, 2H) embodiment 3
(2S,3 4 5&67) the fluoro- 4- methyoxy-benzyls of the chloro- 3-G- of -2- Γ 4-) the small base 1-6- methylols-oxinane of-naphthalene
- 3,4,5- triols
The first step
(the small chloro- naphthalene -2- bases of 4- bromines)-(the fluoro- 4- methoxyl groups-phenyl of 2-)-ketone is by the small chloro- naphthalene of 4- bromines:2- formyl chlorides le (2.0 g, 6.58 mmol) is dissolved in 35 mL dichloromethane protective embankments, is added:- fluoro- 3- methoxyl groups (0.8 mL, 7 mmol), alchlor (840 mg, 6.3 mmol), stirring reaction 12 hours is added portionwise.The reaction of the M hydrochloric acids of 20 mL 1 is added, point liquid, aqueous phase is extracted (50 mLx3) with dichloromethane, merge organic phase, dried without magnesium sulfate forever, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product（Chloro- naphthalene -2- the bases of the bromo- 1- of 4-)-(the fluoro- 4- methoxyl groups-phenyl of 2-)-ketone 3a (1.12 g, white solid), yield： 43.3%.
MS m/z (LC-MS): 394.1 [M+1] '
1H NMR (400 MHz, CDC13, ppm):δ 8.35-8.34 (d, 1H), 8.33-8.32 (d, 1H), 7.87-7.85 (t, 1H), 7.83-7.76 (m, 3H), 6.84-6.83 (d, 1H), 6.63-6.60 (d, 1H), 3.94-3.91 (s, 3H)
Second step
The chloro- 2- of the bromo- 1- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(the fluoro- 4- methoxyl groups-phenyl of 2-)-ketone 3a (560 mg, 1.42 mmol) is dissolved in 15 mL acetonitriles and dichloromethane (V: V = 2:1) in the mixed solvent, sequentially adds triethyl group silicon protective embankment (0.68 mL, 4.26 mmol) and BFEE (0.36 mL, 2.84 mmol), stirring reaction 4 hours.Potassium hydroxide solution (500 mg, 10 mL) is added in the reaction, and (30 mL are extracted with ether><3), merge organic phase, it is washed with water (15 mL), anhydrous magnesium sulfate is dried, filtering, Jian Ya Nong Shrink filtrates, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the chloro- 2- of the bromo- 1- of title product 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene 3b (520 mg, white solid), yield： 96.5%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.24-8.21 (t, 1H), 8.19 (d, 1H), 7.69-7.56 (m, 3H), 7.05-6.99 (m, 1H), 6.67-6.57 (m, 2H), 4.31-4.23 (d, 2H), 3.77-3.74 (s, 3H)
Tri- Walk
(2 & 3 4 & 5i,6i) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-) the small base of-naphthalene]-oxinane -2- alcohol
By small chloro- 2- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene 3b (520 mg of 4- bromines, 1.36 mmol) it is dissolved in 10 mL tetrahydrofurans, in hexamethylene protective embankment solution (0.55 mL that 2.5 M n-BuLis are added dropwise under -78 °C, 1.36 mmol), in -78 °C of lower stirring reactions 30 minutes, (3 are added dropwise,4S,5i, 6W) -3,4,5- tri- benzyloxy -6- benzyloxymethyls-oxinane -2- ketone lh (808 mg, 1.5 mmol) 6 mL tetrahydrofuran solutions, under -78 °C continue react 2 hours.Add 5 mL saturated nacl aqueous solutions, it is extracted with ethyl acetate (30 mLx3), merge organic phase, it is washed with water (15 mL), anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product（2&3 4 & 5i,6/) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene -1- bases]-oxinane -2- alcohol 3c (635 mg, pale yellow oil), yield： 55.6%.
4th step
(2i,3i,4 , the benzyloxy -2- benzyloxymethyls -6- of 5 ＆, 65 3,4,5- tri- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalenes
- 1- bases]-oxinane
By (2 ＆ 3i,4 & 5i, 6i) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-) the small base of-naphthalene]:Oxinane -2- alcohol 3c (630 mg, 0.75 mmol) is dissolved in 13 mL acetonitriles and dichloromethane (V: V = 5 ;'-- ' in λ bonding solvents, sequentially add triethyl group silicon protective embankment (0.6 mL, 1.88 mmol) and BFEE (0.31 mL, 1.5 mmol), stirring reaction 4 hours.Add 2 mL triethylamines, be concentrated under reduced pressure reaction solution, add 40 mL ethyl acetate, organic phase washed with water washs (10 mL), washed with saturated nacl aqueous solution (10 mL), anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains title product (2i, 3i,4i, the benzyloxy-2- benzyloxymethyls-6- of 5 ＆ 6-3,4,5- tri- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene-1- bases]-oxinane 3d (610 mg, yellow solid), yield： 98.8%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.37 (d, 2H), 7.60-7.57 (t, 1 H), 7.45-7.41 (m, 2H), 7.36-7.30 (s, 20H), 7.10-7.06 (t, 1 H), 7.01-6.95 (m, 2H), 6.59-6.47 (m, 3H), 4.91-4.88 (t, 3H), 4.71-4.68 (d, 1H), 4.62-4.59 (d, 1H), 4.52-4.49 (d, 1H), 4.31-4.12 (m, 3H)
3.90-3.77 (m, 2H), 3.74-3.64 (s, 3H), 3.52-3.49 (d, 1H), 1.25-1.22 (s, 2H)
The step of ' the 5th
(2 3/,4 , 5 ＆ 6S) and-3,4,5- triacetoxyl groups-6- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene-1-yl]-oxinane-2- acetic acid methyl esters
By (2i,3 4i5 ＆ 65)-3,4, benzyloxy-2- benzyloxymethyls-the 6- of 5- tri- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene-1-yl]-oxinane 3d (600 mg, 0.73 mmol) it is dissolved in 10 mL chloroforms, 5 mL ethyl mercaptans are added, BFEE (1.84 mL are added dropwise, 14.5 mmol), stirring reaction 5 hours.Add 2 mL triethylamines, be concentrated under reduced pressure reaction solution, add 80 mL dichloromethane dissolving residue, it is washed with water (15 mL), anhydrous magnesium sulfate is dried, filtering, depressurize dense filtrate, vacuum drying, residue is dissolved in 5 mL pyridines, add acetic anhydride (0.47 mL, 7.28 mmol), stirring reaction 12 hours, be concentrated under reduced pressure reaction solution, add 100 mL ethyl acetate, (10 mLx2) is washed with copper/saturated copper sulphate solution successively, it is washed with water (10 mL), anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product（2/,3 , 45 ＆ 6S) and -3,4,5- orchid acetoxyl group -6- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene-I-yl]-oxinane -2- acetic acid methyl esters 3e (280 mg, white solid), yield： 61.0%.
MS m/z (LC-MS): 647.8 [M+18]
'H NMR (400 MHz, CDC13, ppm): δ 8.38-8.36 (d, 1H), 8.15-7.61 (m, 1H), 7.57-7.49 (m:2H), 7.41-7.39 (m, 1H), 6.98-6.66 (t, 1H), 6.63-6.58 (m, 2H), 5.41-5.28 (m, 3H), 5.14-5.01 (m, 2H), 4.29-4.15 (m, 3H), 3.94-3.92 (m, 1H), 3.77 (s, 3H), 2.22-1.66 (m, 12H)
6th step
(2 & 3 4 5 & 6i) -2- [4- chloro- 3 (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene -1- bases] -6- methylols-oxinane
- 3,4,5- triols
By (2/, 3i,4 5 ＆ 6-3,4,5- triacetoxyl group-6- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene-1- bases]-oxinane-2- acetic acid methyl esters 3e (164 mg, 0.26 mmol) is dissolved in 6 mL tetrahydrofurans, first alcohol and water (V: V： V = 2: 3：1) in the mixed solvent, sequentially adds a hydronium(ion) lithia (13.09 mg, 0.31 mmol) and 10 mL dichloromethane protective embankments, stirring reaction 4 hours.Be concentrated under reduced pressure reaction solution, adds 15 mL water, is extracted with ethyl acetate (30 mLx3), merges organic phase, and anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, obtains title product (2 3 4/,5 & 6i) -2- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 2-)-naphthalene -1- bases] -6- methylol-oxinanes -；5;4,5- triols 3 (130 mg, white solid), yield： 100%.
MS m/z (LC-MS): 480.3 [M+18]
Ή NMR (400 MHz, CD3OD, ppm):δ 8.36-8.33 (d, 2H), 7.60-7.53 (m, 3H), 7.02-6.97 (t, 1H), 6.70-6.67 (d, 1H), 6.63-6.60 (d, 1H), 4.87-4.85 (d, 1H), 4.32-4.23 (t, 2H), 4.12-4.07 (m, 1H), 3.91-3.88 (d, 2H), 3.77-3.73 (s, 3H), 3.72-3.61 (m, 2H), 3.57-3.47 (m, 2H), 1.33-1.22 (m, 3H) embodiment 4
(2S,3i,4 , 5S, the small base fore-telling 6- methylols-oxinane of the chloro- 3- of 6WV2-r4- (the fluoro- 4- methyoxy-benzyls of 3,5- bis-)-naphthalene
- 3.4,5- triols
The first step
1,3- difluoro-2-methoxies
2,6- difluoro-phenols 4a (4.8 g, 36.9 mmol) is dissolved in 37 mL acetone, sequentially add iodine first protective embankment (3.44 mL, 55.3 mmol) ^l potassium carbonate (8.66 g, 62.7 mmol), stirring reaction 36 hours.Cross;Be concentrated under reduced pressure filtrates, with 50 mL ether dissolution residues, is washed with water (15 mL), washed with saturated nacl aqueous solution (15 mL), anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, obtain title product 1,3- difluoro-2-methoxies 4b (3.2 g, yellow oil), yield： 60.4%.
Ή NMR (400 MHz, CDC13, ppm): δ 6.91 (m, 3Η), 3.99 (s, 3H)
Second step
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(the fluoro- 4- methoxyl groups-phenyl of 3,5- bis-)-ketone is by the bromo- 1- chlorine of 4-:Naphthalene -2- formyl chlorides le (1.06 g, 3.5 mmol) it is dissolved in 20 mL dichloromethane, add 1,3- difluoro-2-methoxies 4b (504 mg, 3.5 mmol), alchlor (420 mg, 3.15 mmol) is added portionwise, is reacted 12 hours under 25 °C.Add 20 mL l M hydrochloric acid, divide liquid, aqueous phase extracts (20 mLx2) with dichloromethane protective embankment, merges organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system D purify obtained by residue, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(3, the fluoro- 4- methoxyl groups-phenyl of 5- bis-)-ketone 4c (380 mg, white solid), yield： 26.4%.
Ή NMR (400 MHz, CDC13, ppm): δ 8.38-8.32 (m, 2H), 7.79-7.74 (m, 2H), 7.70 (s, 1H); 7.43-7.36 (m, 2H), 4.14-4.11 (s, 3H)
3rd step
Small chloro- 2- (the fluoro- 4- methyoxy-benzyls of the 3,5- bis-)-naphthalene of 4- bromines
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(the fluoro- 4- methoxyl groups-phenyl of 3,5- bis-)-ketone 4c (540 mg, 1.3 mmol) is dissolved in 24 mL acetonitriles and dichloromethane protective embankment (V: V = 2:1) in the mixed solvent, sequentially adds triethyl group silicon protective embankment (0.83 mL, 5.1 mmol) and BFEE (0.64 mL, 5.1 mmol), in reaction 12 hours under 30 °C.Potassium hydroxide solution (500 mg, 10 mL) is added into reaction solution, be concentrated under reduced pressure reaction solution, residue is dissolved with 30 mL dichloromethanes protective embankments, is washed with water (10 mLx2), merges organic phase, anhydrous magnesium sulfate is dried, and is filtered, decompression
Concentrate filtrate, with silica gel column chromatography with eluant, eluent system D purify obtained by residue, obtain the chloro- 2- of the bromo- 1- of title product 4- (3,5- bis- fluoro- 4- methyoxy-benzyls)-naphthalene 4d (170 mg, white solid), yield： 32.9%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.36-8.34 (dd, 1 Η), 8.24-8.22 (dd, 1 Η), 7.69-7.62 (m, 2H), 7.60 (s, 1H), 6.78-6.72 (m, 2H), 4.21 (s, 2H), 3.96 (s, 3H)
4th step
(2&3i4 ＆ 5^6/ -3,4, benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- (3 of 4- of 5- tri-, the fluoro- 4- methyoxy-benzyls of 5- bis-)-' the small base of naphthalene]-oxinane -2- alcohol-by the chloro- 2- (3 of the bromo- 1- of 4-, the fluoro- 4- methyoxy-benzyls of 5- bis-)-naphthalene 4d (170 mg, 0.43 mmol) be dissolved in 10 mL tetrahydrochysenes ' mutter, in cyclohexane solution (0.17 mL that 2.5 M n-BuLis are added dropwise under -78 °C, 0.43 mmol), in being reacted 30 minutes under -78 °C, by (3i,4 & 5i,6 ) -3, 4, benzyloxy -6- the benzyloxymethyls of 5- tri--oxinane -2- ketone lh (255 mg, 0.47 mmol) it is dissolved in 5 mL tetrahydrofurans, in instilling reaction solution under -78 °C, in -78 °C of lower stirring reactions 2.5 hours, it is warmed to room temperature, add 10 mL saturated ammonium chlorides, add 10 mL ethyl acetate, divide liquid, aqueous phase is extracted with ethyl acetate (10 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product（2 3 ,4 & 5i,6 ) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (3,5- bis- fluoro- 4 methyoxy-benzyl)-naphthalene -1- bases]-oxinane -2- alcohol 4e (200 mg, colorless oil), rate： 54.3%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.64-8.62 (dd, 1 Η), 8.37-8.35 (dd, 1 Η), 7.71 (s, 1H), 7.56-7.52 (m, 1H), 7.09-7.05 (m, 1H), 6.99-6.95 (m, 2H), 6.75-6.73 (m, 2H), 6.64-6.62 (m, 2H), 6.33-6.20 (m, 16H), 4.98-4.86 (m, 3H), 4.77-4.52 (m, 3H), 4.32-4.04 (m, 9H), 3.96 (s, 3H), 3.74-3.72 (m, 1H)
5th step
(2/,3/, 4, 5S, 65 3,4,5- tri- benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls) -- naphthalene -1- bases]-oxinane
By (2 ＆ 3i,4S,5i, 6/) -3,4, benzyloxy -6- benzyloxymethyls-the 2- of 5- tri- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls)-naphthalene -1- bases]-oxinane -2- alcohol 4e (200 mg, 0.23 mmol) is dissolved in 9 mL dichloromethanes protective embankments and acetonitrile (V: V = 2：1) in the mixed solvent, instills triethyl silicane (0.11 mL, 0.7 mmol) and BFEE (0.09 mL, 0.7 mmol), stirring reaction 1.5 hours successively.Add 5 mL saturated sodium carbonate solutions and reaction is quenched, be concentrated under reduced pressure reaction solution, residue (10 mLx2) is extracted with ethyl acetate, merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains title product (2i, 3, 4i, 5 6S) and -3,4,5- tri- benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls)-naphthalene -1- bases]-oxinane 4f (200 mg, white solid), yield：>100%, next step reaction is directly used in without isolation.
Ή NMR (400 MHz, CDC13, ppm):δ 8.42-8.33'(m, 2 Η), 7.61-7.59 (m, 1 Η), 7.47-7.44 (m, 2H), 7.40-7.10 (m, 15H), 7.10-7.06 (m, 1H), 6.99-6.96 (m, 2H), 6.75-6.70 (m, 2H), 6.50-6.47 (m, 2H), 4.96-4.85 (m, 3H), 4.77-4.51 (m, 3H), 4.30-4.03 (m, 10H), 3.96 (s, 3H), 3.74-3.71 (m, 1H)c
6th step
(2&3 , 4, 5S, 6i) -2- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls)-naphthalene -1- bases] -6- methylols-oxinane
- 4,5- triols
By (2/,3 ,4/5S, 65 3,4,5- tri- benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls)-naphthalene -1- bases]-oxinane 4f (200 mg, 0.24 mmol) it is dissolved in 5 mL chloroforms, 3 mL mercaptan and BFEE (0.45 mL, 3.57 mmol), stirring reaction 4 hours are sequentially added under stirring.Add 5 mL saturated sodium carbonate solutions, it is concentrated under reduced pressure, 5 mL saturated nacl aqueous solutions are added into residue, extracted with dichloromethane (5 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains title product crude product (2 ＆ 3i,4i,5 & 6 ) -2- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols 4g (114 mg, colorless oil), yield： 100%.'
7th step
(2i,3i, 45 6S) and -3,4,5- triacetoxyl groups -6- [the chloro- 3- of 4- (the fluoro- 4- methyoxy-benzyls of 3,5- bis-)-naphthalene -1- bases]-oxinane -2- acetic acid methyl esters
By crude product (2 ＆ 34, 5 ＆ 6i) -2- [the chloro- 3- (3 of 4-, the fluoro- 4- methyoxy-benzyls of 5- bis-)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols 4g (115 mg, 0.24 mmol) it is dissolved in 5 mL pyridines, add acetic anhydride (0.23 mL, 2.4 mmol), stirring reaction 12 hours.It is concentrated under reduced pressure, adds 20 mL acetic acid esters, washed with copper/saturated copper sulphate solution (5 mLx3), anhydrous slufuric acid U.S. is dried, filtering, pressure concentration filtrate, glue column chromatography purifies gained residue with eluant, eluent system Α, obtains (2 3i,4i, 5 65) -3,4,5- triacetyl oxygen -6- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls)-naphthalene -1- bases]-oxinane -2- acetic acid methyl esters 4h (80 mg, white solid), yield： 51.4%.
MS m/z (ESI): 666.0 [M+18]
8th step
(2 & 3i,4i,5 & 6i) -2- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls) the small base of-naphthalene] -6- methylols-oxinane
- 3,4,5- triols
By (2/, 3 4/5 ＆ 65)-3,4,5- triacetoxyl groups-6- [the chloro- 3- (3 of 4-, the fluoro- 4- methyoxy-benzyls of 5- bis-)-naphthalene-1-yl]-oxinane-2- base acetoxymethyl esters 4h (80 mg, 0.12 mmol) is dissolved in 5 mL tetrahydrofurans, and hydronium(ion) lithia (8.77 mg are sequentially added under stirring, 0.21 mmol) and 1 mL water, stirring reaction 12 hours.It is concentrated under reduced pressure, adds 10 mL dichloromethanes protective embankments and 5 mL saturated nacl aqueous solutions, (5 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains title product (2 ＆ 3i,4i,5S,6i) -2- [the chloro- 3- of 4- (3,5- bis- fluoro- 4- methyoxy-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols (40 1^, white solid), yield： 66.7%.
MS m/z (ESI): 498.0 [M+l 8]
Ή NMR (400 MHz, CD3OD, ppm):δ 8.37-8.34 (m, 2H), 7.63-7.55 (m, 3H), 6.87-6.82 (m, 2H), 4.92-4.90 (d, 1H), 4.34-4.25 (m, 2H), 3.93-3.89 (m, 4H), 3.76-3.70 (m, 2H), 3.63-3.55 (m, 3H) embodiment 5
OS, 3,4 5S,6/V2- " the fluoro- 4- methyoxy-benzyls of the chloro- 3- 3- bis- of 4-) the small base fore-telling 6- methylols-oxinane of-naphthalene
- 3,4,5- triols
The first step
1,2- bis- fluoro- 3- methoxybenzenes
2,3- difluorophenols 5a (5 g, 38.5 mmol) is dissolved in 38 mL acetone, iodomethane (3.59 mL, 57.7 mmol) and potassium carbonate (9.04 g, 65.4 τ η ψ ο), stirring reaction is sequentially added ":When the 1st,.Filtering, be concentrated under reduced pressure filtrate, with 50 mL ether dissolution residues, (15 mL) saturated nacl aqueous solution washing (15 mE) is washed with water in solution successively, and anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains title product 1, fluoro- 3- methoxybenzenes 5b (4.49 g of 2- bis-, colourless liquid), yield： 80.9%.
Ή NMR (400 MHz, CDC13, ppm): δ 7.03 (m, 1Η), 6.80 (m, 2H), 3.94 (s, 3H)
Second step
(4- bromo- 1-chloro- naphthalene-2- bases)-(2, the fluoro- 4- methoxyl groups-phenyl of 3- bis-)-ketone is by chloro- naphthalene-2- formyl chlorides le (1.0 g of the bromo- 1- of 4-, 3.3 mmol) it is dissolved in 15 mL dichloromethane, add 1, the fluoro- 3- methoxybenzenes 5b of 2- bis- (510 mg, 3.5 mmol), are added portionwise alchlor (430 mg, 3.9 mmol), stirring reaction 12 hours.Add the M hydrochloric acid of 10 mL 1, (50 mLx2) is extracted with dichloromethane protective embankment, merge organic phase, washed with saturated nacl aqueous solution (30 mL), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(2,3- bis- fluoro- 4- methoxyl groups-phenyl)-ketone 5c (380 mg, yellow solid), yield： 29.2%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.37-8.36 (d, 1H), 8.32-8.30 (d, 1H), 7.77-7.70 (m, 3H), 7.61-7.57 (m, 1H), 6.86-6.82 (t, 1H), 3.99 (s, 3H)
3rd step
The bromo- 1- of 4- are chloro-2-(2,3- two is fluoro-4- methyoxy-benzyl)-naphthalene
By (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(2, the fluoro- 4- methoxyl groups-phenyl of 3- bis-)-ketone 5c (380 mg, 0.92 mmol) it is dissolved in 4 mL dichloromethane, add 8 mL acetonitriles, triethyl group silicon protective embankment (0.67 mL, 4.12 mmol) and BFEE (0.47 mL, 3.72 mmol) are sequentially added at room temperature, finish, in reaction 22 hours under 30 °C.Potassium hydroxide solution (500 mg, 10 mL) will be added in reaction solution, with absolute ether extractive reaction liquid (30 mLx3), merge organic phase, be washed with water (15 mL), merge organic phase, anhydrous magnesium sulfate is dried, filtering, is concentrated under reduced pressure
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For 1, divide liquid, aqueous phase is extracted (20 mLx3) with dichloromethane, merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, title product 4- (4- bromo- 1-chloro- naphthalene-2- ylmethyls) fluoro- phenol 6a of-2- (2.3 g, yellow solid) are obtained, product is directly used in next step reaction without isolation.
Bis- Walk
[4- (the small chloro- naphthalene -2- ylmethyls of 4- bromines) the fluoro- phenoxy groups of -2-]-tert-butyI-dimethyl-silicon protective embankment is by 4- (the small chloro- naphthalene -2- ylmethyls of 4- bromines) fluoro- phenol 6a (2.3 g of -2-, 6.3 mmol) it is dissolved in 30 mL dichloromethane protective embankments, owe to add triethylamine (0.95 g according to ＞, 9.45 mmol), dimethylamino naphthyridine (38 mg, 0.32 mmol) and tert-butyldimethylsilyl chloride silicon protective embankment (1.04 g, 6.93 mmol), stirring reaction 16 hours.Reaction solution is successively with 1 M salt acid elution (20 mLx2), washed with saturated sodium bicarbonate solution (15 mL), anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system E purify gained residue, obtain title product [4- (the chloro- naphthalene -2- ylmethyls of the bromo- 1- of 4-) the fluoro- phenoxy groups of -2-]-tert-butyI-dimethyl-silicon protective embankment 6b (2.76 g, white solid), yield： 91.4%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.35 (dd, 1 Η), (dd of δ 8.22,1H), 7.64 (m, 2H), 7.59 (s, 1H), 6.91 (d, 1H), 6.85 (m, 2H), 4.21 (s, 2H), 1.00 (s, 9H), 0.18 (s, 6H)
3rd step
(2 & 3i,4 & 5 & 6i)-2- [the chloro- 3- of 4- (the fluoro- 4- Hydroxy-benzvls of 3-)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydro pyrans-3,4,5- triols
By [4- (4- bromo- 1-chloro- naphthalene-2- ylmethyls) the fluoro- phenoxy groups of-2-]-tert-butyI-dimethyl-silicon protective embankment 6b (2.75 g, 5.73 mmol) it is dissolved in 25 mL tetrahydrofurans, the V of temperature control-78, cyclohexane solution (2.75 mL of 2.5 M n-BuLis are added dropwise, 6.88 mmol), in-78 °C of lower stirring reactions 1 hour, 10 mL (3 are instilled,45,5i,6i) -3,4,5- tri--trimethylsiloxy group -6- trimethylsiloxy group methyl-tetrahydro pyran-2-one 6c (2.67 g, 5.73 mmol, are prepared using known method " patent CN1653075 ") tetrahydrochysene furan Pj | solution, drop finishes in -78 times stirring reactions 2 hours, add the methanol solution of the M methanesulfonic acids of 25 mL 0.6, stirring reaction 16 hours at room temperature, be concentrated under reduced pressure reaction solution, obtains title product (2 ＆ 3i,4 & 5 & 6 )-2- [the chloro- 3- of 4- (the fluoro- 4- Hydroxy-benzvls of 3-)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydro pyrans-3,4,5- triols 6d (650 riig, white solid), yield： 23.7%.
1H NMR (400 MHz, CDC13, ppm): δ 8.94 (br.s, 1Η), 8.34 (dd, 2H), 7.72 (br.s, 1H), 7.52 (m, 2H), 6.86 (m, 3H), 4.40 (d, 1H), 4.19 (d, 1H), 3.92 (m, 3H), 3.55 (m, 3H), 3.16 (s, 3H)
4th step
(2S, 3i,4i, 5S, 6i) -2- [the chloro- 3- of 4- (the fluoro- 4- Hydroxy-benzvls of 3-) the small base of-naphthalene] -6- methylols-oxinane -3,4,5- triols
By (2 ＆ 3/,4S,5 & 6 ) -2- [the chloro- 3- of 4- (the fluoro- 4- Hydroxy-benzvls of 3-)-naphthalene -1- bases] -6- methylols -2- methoxyl groups-oxinane -3,4,5- triols 6d (650 mg, 1.36 mmol) is dissolved in 15 mL acetonitriles and dichloromethane protective embankment (V: V = 2：1) in the mixed solvent, adds triethyl silicane (0.6 mL, 1.5 mmol) and BFEE (0.3 mL, 1.5 mmol), stirring reaction 16 hours.15 mL saturated sodium bicarbonate solutions are added dropwise, it is concentrated under reduced pressure, residue (30 mLx3) is extracted with ethyl acetate, merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product
(2 & 3/,4 5 & 6/) -2- [the chloro- 3- of 4- (the fluoro- 4- Hydroxy-benzvls of 3-)-naphthalene-yl] -6- methylols-oxinane -3,4,5- triols 6e (470 mg, white solid), yield： 77.0%.
MS m/z (ESI): 466.2 [M+18]
1H NMR (400 MHz, CDC13, ppm):δ 8.33 (dd, 2H), 7.60 (m, 3H), 6.86 (m, 3H), 4.90 (d, 1H), 4.26 (m, 2H), 3.90 (m, 1H), 3.74 (m, 2H), 3.55 (m, 3H)
5th step
(2 & 3i,4/,5 & 6i) -2- [the chloro- 3- of 4- (the fluoro- benzyls of 4- ethyoxyls -3-) the small base of-naphthalene] -6- methylols-oxinane
- 3,4,5- triols
By (the ＆ 6/ of 2 ＆ 345) -2- [the fluoro- 4- Hydroxy-benzvls of the chloro- 3- 3- of 4-)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols 6e (224 mg, 0.5 mmol) it is dissolved in 5 mL Ν, in Ν-dimethylformamide, cesium carbonate (179.2 mg, 0.55 mmol) and iodine second protective embankment (44 L are added, 0.55 mmol), in 50 °C of lower stirring reactions 4 hours.Be concentrated under reduced pressure reaction solution, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (2 ＆ 3i,4i,5 & 6；) -2- [the chloro- 3- of 4- (the fluoro- benzyls of 4- ethyoxyls -3-)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols 6 (140 mg, white solid), yield： 58.7%.
MS m/z (ESI): 494.1 M+.l 8]
Ή NMR (400 MHz, CDC13, ppm):δ 8.33 (dd, 2H), 7.60 (m, 3H), 6.96 (m, 3H), 4.90 (d, 1H), 4.26 (m, 2H), 4.05 (q, 2H), 3.90 (m, 1H), 3.74 (m, 2H), 3.55 (m, 3H), 1.38 (t, 3H) embodiment 7
(2S, 3 4i,5S,6i) -2- " the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases 6- methylols-oxinane -3,4,5- triols
Mono- Walk
Chloro- naphthalene -2- the formaldehyde of the bromo- 1- of 4-
By small chloro- naphthalene -2- nitriles lc (2.66 g of 4- bromines, 10 mmol) it is dissolved in 20 mL toluene, 20 mL diisobutyl aluminium hydrides (10 mL are added under ice bath, 11 mmol) toluene solution, stirring reaction 2 hours under ice bath, add 20 mL toluene and methanol (V: V=l :1) mixed solvent and the M hydrochloric acid of 20 mL 2, are stirred 30 minutes, filtering, filter cake is eluted with 50 mL ethyl acetate, 20 mL water are added, are extracted with ethyl acetate (20 mLx2), organic phase is washed (20 mL) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, Jian Ya Nong Shrink filtrates obtain chloro- naphthalene -2- formaldehyde 7a (1.7 g of the bromo- 1- of title product 4-, yellow solid), yield： 63.2%.
Ή NMR (400 MHz, CDC13, ppm): 5 10.70(s, 1Η), 8.5 l(d, 1H), 8.3 l(d, 1H), 8.23(d, 1H), 7.83(m, 1H), 7.76(m, 1H)
Second step
L- (4- Ethyl-phenyls) magnesium bromide
By the bromo- 4- ethyls of 1--benzene 7b (1.66 g, 8.97 mmol) it is dissolved in 15 mL tetrahydrofurans, 7b tetrahydrofuran solution is made, by magnesium (218 mg, 8.97 mmol) it is put into reaction bulb, add iodine (catalytic amount) and a small amount of 7b tetrahydrofuran solution, heat initiation reaction, continue dropwise addition 7b tetrahydrofuran solution, drop finishes return stirring and reacted 30 minutes, title product 1- (4- Ethyl-phenyls) magnesium bromide 7c is obtained, next step reaction is directly used in.
3rd step
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- Ethyl-phenyls)-methanol
Chloro- naphthalene -2- formaldehyde the 7a of the bromo- 1- of 4- (410 mg, 1.52 mmol) are dissolved in 5 mL tetrahydrofurans, added
1-(4- Ethyl-phenyls) magnesium bromide 7c (1.87 g, 8.97 mmol), in 30 °C of lower stirring reactions 2 hours.5 mL saturated nacl aqueous solutions are added, the M hydrochloric acid of l mL 2 is added, (10 mL is extracted with ethyl acetate><3) organic phase, is merged, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, pure with eluent system B with silica gel column chromatography
Change gained residue, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- Ethyl-phenyls)-methanol 7d (330 mg, yellow oil), yield： 57.7%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.29 (m, 1H), 8.2 l (m, 1H), 7.92 (s, 1H), 7.61 (m, 2H), 7.33 (d, 2H), 7.14 (d, 2H), 6.45 (s, 1H), 2.61 (q, 2H), 1.19 (t, 3H)
4th step
The chloro- 2- of the bromo- 1- of 4- (4- ethyl-benzyls)-naphthalene
By (the bromo- chloro- naphthalene -2- bases of 4-)-(4- Ethyl-phenyls)-methanol 7d (290 mg, 0.77 mmol) it is dissolved in 8 mL ' dichloromethane, triethyl silicane (0.37 mL is added under ice bath, 2.32 mmol) and BFEE (0.20 mL, 1.54 mmol), stirring reaction 30 minutes.Add 5 mL saturated sodium carbonate solutions, it is extracted with ethyl acetate (10 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains the chloro- 2- of the bromo- 1- of title product 4- (4- ethyl-benzyls)-naphthalene 7e (270 mg, yellow solid), yield： 97.5%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.33 (d, 1 Η), 8.20 (d, 1H), 7.65-7.41 (m, 3H), 7.16-7.08 (m, 4H), 4.26 (s, 2H), 2.6 l (q, 2H), 1.21 (t, 3H)
5th step
(all ^5i of 2＆3,6i) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases]-oxinane -2- alcohol
By the chloro- 2- of the bromo- 1- of 4- (4- ethyl-benzyls)-naphthalene 7e (370 mg, 1.03 mmol) it is dissolved in 8 mL tetrahydrofurans, in hexamethylene protective embankment solution (0.41 mL that 2.5 M n-BuLis are instilled under -78 °C, 1.03mmol), stirring 30 minutes, adds 2 mL (3i,4 & 5i,6i) three benzyloxy -6- benzyloxymethyls of -3,4,5--oxinane -2- ketone lh (610 mg, 1.13 mmol), -78 ° of temperature control 〇 stirring reactions 2 hours.A small amount of saturated nacl aqueous solution is added, ethyl acetate extractive reaction liquid (20 mLx3) is added, organic phase is collected, anhydrous sodium sulfate drying, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography purify gained residue, obtain title product (2 ＆ 3i,4 & 5i,6i) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases]-oxinane -2- alcohol 7f (400 mg, yellow oil), yield： 47.4%.
Ή NMR (400 MHz, CDC13, ppm):L (the d of δ 8.6, 1 Η), 8.35 (d, 1H), 7.77 (s, 1H), 7.52 (t, 1H), 7.36-7.22 (m, 16H), 7.14-6.96 (m, 7H), 6.65 (d, 2H), 4.96 (d, 1H), 4.89 (q, 2H), 4.76 (d, 1H), 4.57 (d, 1H), 4.45 (d, 1H), 4.36 (d, 1H), 4.24-4.12 (m, 5H), 3.97 (d, 1H), 3.72 (d, 1H), 3.60 (d, 1H), 3.41 (s, 1H), 2.58 (q, 2H), 1.19 (t, 3H)
6th step
(2i,3i,4i, 5 ＆ 65) and -3,4,5- three benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases]-oxinane
By (the ＆ 5 6/ of 2 ＆ 34) -3,4, benzyloxy -6- benzyloxymethyls-the 2- of 5- tri- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases]-oxinane -2- alcohol 7f (390 mg, 0.48 mmol) it is dissolved in 5 mL dichloromethane protective embankments, triethyl silicane (0.22 mL is sequentially added under ice bath, 1.43 mmol) and BFEE (0.12 mL, 0.95 mmol), at room temperature stirring reaction 48 hours.5 mL saturated sodium carbonate solutions are added, (20 mL are extracted with ethyl acetate><3), organic phase is washed (10 mL) with saturated nacl aqueous solution, anhydrous magnesium sulfate dry, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product
(2 3i, 4W, 5 ＆ 65) and -3,4,5- tri- benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene-yl]-oxinane 7g(210 mg, yellow oil), yield： 55.0%.
Ή NMR (400 MHz, CDC13, ppm):(the m of δ 8.39, 2 Η), 7.58 (t, 1H), 7.49 (s, 1H), 7.43 (t, 1H), 7.31-7.23 (m, 15H), 7.12-6.97 (m, 7H), 6.50 (d, 2H), 4.92-4.89 (m, 3H), 4.8 l (s, 1H), 4.69 (d, 1H), 4.6 l (d, 1H), 4.5 l (d, 1H), 4.35 (d, 1H), 4.20 (d, 1H), 4.15 (d, 1H), 3.86-3.82 (m, 4H), 3.76 (d, 1H), 3.68 (d, 1H), 3.49 (d, 1H), 2.57 (q, 2H), 1.17 (t, 3H)
The 7th step
(2 & 3i,4i,5 & 6i) -2- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols are by (2i,3/,4i5 ＆ 65) -3,4,5- tri- benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases]-oxinane 7g (210 mg, 0.26 mmol) it is dissolved in 3 mL chloroforms, sequentially add 2 mL ethyl mercaptans and BFEE (0.5 mL, 3.92 mmol), stirring reaction 16 hours.5 mL saturated sodium carbonate solutions are added, be concentrated under reduced pressure reaction solution, add 5 mL water, it is extracted with ethyl acetate (10 mLx4), merges organic phase, anhydrous magnesium sulfate is dried, filtering, Jian Ya Nong Shrink filtrates obtain title product (2 ＆ 3 4/,5 & 6/) -2- [the small base of the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalenes] -6- methylols-oxinane -3,4,5- triols 7h (220 mg, white solid), be directly used in without isolation next step reaction.
MS m/z (ESI): 460.0 [M+l 8]
8th step
(2i,3i,4i, 5 ＆ 6S) and -3,4,5- triacetoxyl group -6- [the small base of the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalenes]-oxinane -2- acetic acid methyl esters
By (2 ＆ 3i,4 ,5 & 6i) -2- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols 7h (220 mg, 0.26 mmol) it is dissolved in 5 mL pyridines, add acetic anhydride (0.25 mL, 2.6 mmol), stirring reaction 16 hours.Be concentrated under reduced pressure reaction solution, add 30 mL ethyl acetate, organic phase washs (10 mLx2) with copper/saturated copper sulphate solution successively, washed with saturated nacl aqueous solution (10 mL), anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (2 3,4i, 5 ＆ 65) and -3,4,5- triacetoxyl group -6- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases]-oxinane -2- acetic acid methyl esters 7i (120 mg, white solid), yield： 75%. - 'H NMR (400 MHz, CDC13, ppm): δ 8.38(d, 1Η), 8.15(d, 1H), 7.58(m, 2H), 7.44(s, 1H): 7.11(m, 4H), 5.42(m, 2H), 5.30(m, 1H), 5.07(s, 1H), 4.33-4.25(m, 3H), 4.17(d, 1H), 3.96-3.93(m, 1H), 2.60(q, 2H), 2.07(d, 6H), 2.00(s, 3H), 1.44(s, 3H), 1.20(t, 3H)
9th step
(2 & 3/,4i,5S,6i) -2- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols general (2 3/,4/5＆65) -3,4,5- triacetoxyl group -6- [the small base of the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalenes]-oxinane -2- acetic acid methyl esters 7i (110 mg, 0.18 mmol) is dissolved in 6 mL methanol, dichloromethane protective embankment and water (V: V： V=3 : 2：1) in the mixed solvent, adds a hydronium(ion) lithia (15 mg, 0.36 mmol), stirring reaction 16 hours.Be concentrated under reduced pressure reaction solution, adds 5 mL water, is extracted with ethyl acetate (10 mLx4), organic phase is washed (10 mL) with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains title product (2＆3 4/,5 & 6i) -2- [the chloro- 3- of 4- (4- ethyl-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols
7 (70 mg, yellow solid), yield： 87.5%.
MS m/z (ESI): 460.1 [M+18]
Ή NMR (400 MHz, CDC13, ppm):δ 8.33 (d, 1H), 8.08 (d, 1H), 7.47 (t, 1H), 7.40 (m, 2H);6.99 (q, 4H), 4.70 (d, 1H), 4.18 (q, 2H), 3.7 l (d, 1H), 3.69-3.50 (m, 5H), 2.47 (q, 2K), 1.10 (t, 3H) embodiments 8
(~2&3/, 45 ＆ 6W) and -2- " the small base 1-6- methylols-oxinane -3,4,5- three of the chloro- 3- of 4- (4- methylsulfanies-benzyl)-naphthalene
Mono- Walk
1 one (4- methylsulfanies-phenyl) magnesium bromides
By 1-bromo- 4- methylsulfanies benzene 8a (2.03 g, 10 mmol) it is dissolved in 10 mL tetrahydrofurans, 8a tetrahydrofuran solution is made, by magnesium (243 mg, 10 mmol) it is put into reaction bulb, add iodine (catalytic amount), add a small amount of 8a tetrahydrofuran solution, heat initiation reaction, continue dropwise addition 8a tetrahydrofuran solution, drop finishes back flow reaction 30 minutes, obtains title product 1- (4- methylsulfanies-phenyl) magnesium bromide 8b, is directly used in next step reaction.
Second step
(4- bromo- 1-chloro- naphthalene-2- bases)-(4- methylsulfanies-phenyl)-methanol
By the chloro- naphthalene -2- formaldehyde 7a (808mg of the bromo- 1- of 4-, 3 mmol) it is dissolved in 10 mL tetrahydrofurans, 1- (4- methylsulfanies-phenyl) magnesium bromide 8b (10 mL, 10 mmol), stirring reaction 2 hours are added under ice bath.Add a small amount of saturated nacl aqueous solution, add lO mL I M hydrochloric acid, with-ethyl acetate extraction (20 mLx3), organic phase is washed (20 mL) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- methylsulfanies-phenyl)-methanol 8c (490 mg, yellow solid), yield： 41.5%.
1H NMR (400 MHz, CDC13, ppm):The l of δ 8.3 (m, 1H), 8.24 (m, 1H), 8.09 (s, 1H), 7.63 (m, 2H), 7.36 (d, 2H), 7.22 (d, 2H), 6.46 (s, 1H), 2.45 (s, 3H)
Tri- Walk
4- bromo- 1-chloro- 2- (4- methylsulfanies-benzyl)-naphthalene
By (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- methylsulfanies-phenyl)-methanol 8c (490 mg, 1.24 mmol) it is dissolved in 20 mL dichloromethane, triethyl group silicon protective embankment (0.59 mL is sequentially added under ice bath, 3.72 mmol) and BFEE (0.31 mL, 2.49 mmol), stirring reaction 1.5 hours.Add 10 mL saturated sodium carbonate solutions, extracted with dichloromethane (20 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, gained residue is purified with eluant, eluent system B with ' silica gel column chromatography, obtain title product 4- bromo- 1-chloro- 2- (4- methylsulfanies-benzyl)-naphthalene 8d (440 mg, white solid), yield： 94.2%.
Ή NMR (400 MHz, CDC13, ppm): δ 8.33(d, 1Η), 8.2 l(d, 1H), 7.63(m, 3H), 7.2 l(d, 2H);7.19 (d, 2H), 4.26 (s, 2H), 2.46 (s, 3H)
4th step
(2 & 3i,4S,5 & 6/)-2- [the chloro- 3- of 4- (4- methylsulfanies-benzyl)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydro pyrans-3,4,5- triols
By small chloro- 2- (4- methylsulfanies-benzyl)-naphthalene 8d (440 mg of 4- bromines, 1.16 mmol) it is dissolved in 10 mL tetrahydrofurans, in hexamethylene protective embankment solution (0.52 mL, 1 that 2.5 M n-BuLis are added under -78 °C:28 mmol), stirring reaction 30 minutes, in adding 10 mL (3i under -78 °C, 4 ＆ 5^6i) -3,4, Hydrogen pyran-2-ones 6c (542 mg of 5- tri- - trimethylsiloxy group -6- trimethylsiloxy groups methyl - four, 1.16 mmol) tetrahydrofuran solution, -78 °C of stirring reactions are kept to add the methanol solution of the M methanesulfonic acids of 10 mL 0.6 after 2 hours, at room temperature stirring reaction 16 hours.Add 5 mL saturated sodium carbonate solutions, be concentrated under reduced pressure reaction solution, 10 mL water are added, are extracted with ethyl acetate (20 mLx4), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product (2S, 3i,4 & 5 & 6i)-2- [the chloro- 3- of 4- (4- methylsulfanies-benzyl)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydro pyrans-3,4,5- triols 8e (mg of l 70, white solid), yield： 29.8%.
MS m/z (ESI): 513.1 [M+23]
5th step
(2&3 ,-the 2- of 45 ＆ 6 [the chloro- 3- 4- methylsulfanies-benzyls of 4-) the small base of-naphthalene] -6- methylols-oxinane -3,4,5- three
Alcohol
By (the ＆ 6/ of 2 ＆, 34 ＆ 5)-2- [the chloro- 3- of 4- (4- methylsulfanies-benzyl)-naphthalene-1-yl]-6- methylols-2- methoxyl groups-oxinane-3,4,5- triols 8e (170 mg, 0.35 mmol) is dissolved in 6 mL acetonitriles and dichloromethane (V: V = 2 :1) in the mixed solvent, sequentially adds triethyl group silicon protective embankment (0.17 mL, 1.04 mmol) and BFEE (0.088 mL, 0.69 mmol), stirring reaction 16 hours,.5 mL saturated sodium carbonate solutions are added, are extracted with ethyl acetate (10 mLx4), merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filter, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (2 ＆ 3/,4i,5S,67) -2- [the chloro- 3- of 4- (4- methylsulfanies-benzyl) the small base of-naphthalene] -6- methylols-oxinane -3,4,5- triols 8 (130 mg, white solid), yield： 81.3%.
MS m/z (ESI): 478.0 [M+18]
Ή NMR (400 MHz, CD3OD, ppm): δ 8.36(d, 2H), 7.63-7.55(m, 3H), 7.19(s, 4H),
4.90 (d, 1H), 4.33 (q, 2H), 3.92 (d, 1H), 3.75 (m, 2H), 3.60 (t, 1H), 3.55 (m, 2H), 2.44 (s, 3H) embodiments 9
OS,3i,4 5S,6j) " the chloro- 3- of 4- (4- methyoxy-benzyls), the small base of naphthalene foretells 6- methylols-oxinane -3,4,5- triols to -2-
The first step
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- methoxyl groups-phenyl)-ketone
By chloro- naphthalene -2- formyl chlorides le (2.12 g of the bromo- 1- of 4-, 7 mmol) it is dissolved in 35 mL dichloromethane protective embankments, add methyl phenyl ethers anisole (0.76 mL, 7 mmol), alchlor (840 mg are added portionwise under room-temperature water bath, 6.3 mmol), power mouthful finishes stirring reaction 16 hours at room temperature, add the M hydrochloric acid of 20 mL 1, extracted with dichloromethane (100 mLx2), organic phase is washed (30 mL) with saturated nacl aqueous solution successively, it is washed with water (30 mL), anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (4- bromo- 1-chloro- naphthalene-2- bases)-(4- methoxyl groups-phenyl)-ketone 9a (1.5 g, yellow solid), yield： 57.3%. MS m/z (ESI): 377.1 [M+1]
Second step
The chloro- 2- of the bromo- 1- of 4- (4- methyoxy-benzyls)-naphthalene
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- methoxyl groups-phenyl)-ketone 9a (1.3 g, 3.46 mmol) is dissolved in 45 mL acetonitriles and dichloromethane (V: V = 2:1) in the mixed solvent, sequentially adds triethyl group silicon protective embankment (2.46 mL, 15.57 mmol) and BFEE (1.28 mL, 10.38 mmol), stirring reaction 4 hours.Be concentrated under reduced pressure reaction solution, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the chloro- 2- of the bromo- 1- of title product 4- (4- methyoxy-benzyls)-naphthalene 9b (630 mg, white solid), yield： 58.9%.
1H NMR (400 MHz, CDC13, ppm): δ 8.36-8.33 (d, 1H), 8.21 -8.19 (d, 1H), 7.66-7.58 (m, 3H), 7.16-7.13 (d, 2H), 6.86-6.82 (d, 2H), 4.24 (s, 2H), 3.78 (s, 3H)
Tri- Walk
(2S,3 4S,5 & 6i) -2- [the chloro- 3- of 4- (4- methyoxy-benzyls)-naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans
- 3,4,5- triols
By the chloro- 2- of the bromo- 1- of 4- (4- methyoxy-benzyls)-naphthalene 9b (620 mg, 1.99 mmol) it is dissolved in 20 mL tetrahydrofurans, in hexamethylene protective embankment solution (0.95 mL that 2.5 M n-BuLis are added dropwise under -78 °C, 2.38 mmol), in -78 °C of lower stirring reactions 1 hour, 10 mL (3i are added dropwise,4 & 5 6/) -3,4,5- tri--trimethylsiloxy group -6- trimethylsiloxy group methyl-tetrahydro pyran-2-ones 6c (930 mg, 1.99 mmol) tetrahydrofuran solution, -78 °C of temperature control lower stirring reaction 3 hours.The methanol solution of the M methanesulfonic acids of 3 mL 2 is added, at room temperature 16 ' hours of stirring reaction.15 mL saturated sodium bicarbonate solutions are added, are concentrated under reduced pressure；20 mL water are added, are extracted with ethyl acetate (30 mLx3), organic phase is washed with water (15 mL), merge organic phase, anhydrous magnesium sulfate is dried, filtering, ' be concentrated under reduced pressure filtrate, obtains title product (2 3i, 4S, 5S, 6i) -2- [the chloro- 3- of 4- (4- methyoxy-benzyls)-naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans -3,4,5- triols 9c (280 mg, white solid), yield： 29.6%.
4th step
(2S,3i,4 , the Α of 5 ＆ 6) and -2- [the chloro- 3- of 4- (4- methyoxy-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols are by (2 ＆ 3/- the 2- of 4＆5 ＆ 6 [the chloro- 3- of 4- (4- methyoxy-benzyls)--1- bases] -6- methylol -2- methoxy-tetrahydros pyrans -3,4,5- triols 9c (175 mg, 0.37 mmol) is dissolved in π acetonitriles and dichloromethane protective embankment (V: V = 3 :4) BFEE (0.94 mL, b.74 mmol) and triethyl silicane (0.18 mL, 1.12 mmol), stirring reaction 16 hours are sequentially added under in the mixed solvent, ice bath.Jian Ya Nong Shrink reaction solutions, with thin-layer chromatography eluant, eluent system A purify gained residue, obtain title product (2 ＆ 3i,4i,5 & 6i) -2- [the chloro- 3- of 4- (4- methyoxy-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols 9 (100 mg, faint yellow solid), yield： 61.0%. MS m/z (ESI): 462.1 [M+18]
Ή NMR (400 MHz, CD3OD, ppm):δ 8.35-8.32 (d, 2H), 7.60-7.52 (m, 3H), 7.16-7.13 (d, 2H), 6.82-6.79 (d, 2H), 4.88-4.84 (d, 1H), 4.32-4.22 (m, 3H), 3.91-3.88 (d, 2H), 3.88-3.70 (m, 5H), 3.61-3.57 (m, 2H), 3.52-3.47 (m, 3H) embodiment 10
(2 3 ,4/, 5＆67) -2- " the chloro- 3- of 4- (4- cyclopropyl-benzyl)-naphthalene -1- bases 6- methylols-oxinane -3,4,5- triols
The first step
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- cyclopropyl-phenyl)-ketone
By chloro- naphthalene -2- formyl chlorides le (1.7 g of the bromo- 1- of 4-, 5.6 mmol) it is dissolved in 40 mL dichloromethane protective embankments, add cyclopropyl-phenyl (0.7 mL, 5.6 mmol), alchlor (0.67 g is added under room-temperature water bath, 5 mmol), stirring reaction 64 hours.The M hydrochloric acid of 20 mL 2 is added dropwise under ice bath, (60 mLx3) is extracted with dichloromethane protective embankment, organic phase is washed with water (15 mL), anhydrous magnesium sulfate is dried, filtering, subtracts compression filtrates, with silica gel column chromatography with eluant, eluent system A purify gained residue, to title product (the small chloro- naphthalene -2- bases of 4 bromines)-(the third ' base of 4- rings-phenyl)-ketone 10a (1.36 g, yellow solid), yield： 63.0%.
Ή NMR (400 MHz, CDC13, ppm):δ 8.45-8.41 (d, 1 Η), 8.40-8.34 (d, 1H), 7.81-7.57 (d, 5H), 7.18-7.16 (d, 2H), 2.03-1.97 (m, 1H), 1.15-1.06 (m, 2H), 0.91-0.79 (d, 2H)
Second step
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- cyclopropyl-phenyl)-methanol
(the small chloro- naphthalene -2- bases of 4- bromines)-(4- cyclopropyl-phenyl)-ketone 10a (1.36 g, 3.52 mmol) is dissolved in 45 mL methanol and tetrahydrofuran (V: V = 5 :4) in the mixed solvent, is added portionwise potassium borohydride (284.8 mg, 5.28 mmol), finishes stirring reaction 2.5 hours.Add 15 mL l M hydrochloric acid, be concentrated under reduced pressure reaction solution, adds 15 mL water, is extracted with ethyl acetate (50 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, vacuum drying, title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- cyclopropyl-phenyl)-methanol 10b (1.36 g, brown oil) is obtained, next step reaction is directly used in without isolation.
3rd step
The chloro- 2- of the bromo- 1- of 4- (4- cyclopropyl-benzyl)-naphthalene
By (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- cyclopropyl-phenyl)-methanol 10b (1.36 g, 3.52 mmol) it is dissolved in 25 mL dichloromethane, add triethyl group silicon protective embankment (1.7 mL, 10.56 mmol) and BFEE (1.35 mL, 10.56 mmol), stirring reaction 16 hours.Add 15 ' iL saturated sodium carbonate solutions, 20 mL dichloromethane protective embankments are added, point liquid, aqueous phase extracts (30 mL) with dichloromethane protective embankment, merge organic phase, anhydrous acid magnesium is dried, filtering, and be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the chloro- 2- of the bromo- 1- of title product 4- (4- cyclopropyl-benzyl)-naphthalene 10c (750 mg, white solid), yield： 57.7%.
Ή NMR (400 MHz, CDC13, ppm): δ 8.42 (d, 1Η), 8.31 -8.28 (d, 1H), 7.72-7.64 (m, 3H), 7.23-7.21 (d, 2H), 7.11-7.09 (d, 2H), 2.00-1.93 (m, 1H), 1.06-0.98 (m, 2H),
0.83-0.77 (m, 2H)
4th step
(2 & 3/, 4＆5＆6/ ζ) and -2- [the chloro- 3- of 4- (4- cyclopropyl-benzyl)-naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans
- 3,4,5- triols
By the chloro- 2- of the bromo- 1- of 4- (4- cyclopropyl -- section base)-naphthalene 10c (750 mg, 2 mmol) it is dissolved in 20 mL tetrahydrofurans, in cyclohexane solution (1.5 mL that 1.6 M n-BuLis are added dropwise under -78 °C, 2.4 mmol), in -78 times stirring reactions .5 hours, 10 mL (3 are added dropwise,4S,5 ,6/) -3,4,5- tri--trimethylsiloxy group -6- trimethylsiloxy group methyl-tetrahydro pyran-2-one 6c (933 mg, 2 mmol) tetrahydrofuran solution, in -78 times stirring reactions 3.5 hours, the methanol solution of the M methanesulfonic acids of 10 mL 2 is added, reaction 16 hours is stirred at room temperature.20 mL saturated sodium bicarbonate solutions are added, are concentrated under reduced pressure, 20 mL water is added, is extracted with ethyl acetate (50 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains title product (2 ＆ 34 ＆ 5S, 6/) -2- [the chloro- 3- of 4- (4- cyclopropyl-benzyl)-naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans -3,4,5- triols 10 1 (400 1^, white solid), yield： 41.3%.
MS m/z (ESI): 507.3 [M+23]
5th step
(2 & 3/, 4i,5 & 6i)-', 2- [the chloro- 3- of 4- (4- cyclopropyl-benzyl)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols were by (2 ＆ 3i,4 & 5 & 67) -2- [the chloro- 3- of 4- (4- cyclopropyl-benzyl) the small base of-naphthalene] -6- methylol -2- methoxy-tetrahydro pyrans -3,4,5- triols 10d (400 mg, 0.83 mmol) is dissolved in 23 mL dichloromethanes protective embankments and acetonitrile (V: V = 2：1) stirring reaction 16 hours under triethyl silicane (0.3 mL, 1.8 mmol) and BFEE (0.5 mL, 4 mmol), ice bath are added under in the mixed solvent, ice baths.Be concentrated under reduced pressure reaction solution, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (the ＆ 6i of 2 ＆ 345) -2- [the chloro- 3- of 4- (4- cyclopropyl-benzyl) the small base of-naphthalene] -6- methylols-oxinane -3,4,5- triols 10 (261 mg, white solid), yield： 69.6%. MS m/z (ESI): 472.3 [M+l 8]
Ή NMR (400 MHz, CD3OD, ppm):δ 8.37-8.34 (d, 2H), 7.63-7.54 (m, 3H), 7.13-7.11 (d, 2H), 6.99-6.97 (d, 2H), 4.89-4.87 (s, 1H), 4.36-4.29 (m, 2H), 3.93-3.90 (d, 2H), 3.76-3.70 (m, 2H), 3.63-3.58 (m, 2H), 3.54-3.49 (m, 3H), 3.33-3.32 (d, 2H), 1.88-1.83 (m, 1H), 0.94-0.90 (m, 2H), 0.64-0.60 (m, 2H) embodiment 11
(2＆3 all 4/,5&6 ) -2- " the chloro- 3- of 4- (4- ethyoxyl -2,3- diiluoro-benzyls)-naphthalene -1- bases 1-6- methylols-oxinane
- 3,4,5- triols
The fluoro- benzene of 1- ethyoxyls -2,3- two
By 2,3- difluoro-phenols lla (6.5 g, 50 mmol) it is dissolved in 100 mL acetone, add potassium carbonate (10.3 g, 75 mmol) and iodoethane (5.2 mL, 65 mmol), stirring reaction 3 hours at room temperature, in 70 °C of lower back flow reactions 3 hours.Filtering reacting liquid, be concentrated under reduced pressure filtrate, obtains title product 1- ethyoxyls -2,3- bis- fluoro- benzene llb (7.8 g, yellow oil ^, yield： 98.7%.
Ή NMR (400 MHz, CDCI3, ppm) δ 7.03-6.17 (m,;1H), 6.82-6.75 (m, 2H), 4.19-4.13 (q
2H), 1.51-1.30 (t, 3H)
Second step
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -2,3- difluorophenyls)-ketone is by chloro- naphthalene -2- formyl chlorides le (2.23 g of the bromo- 1- of 4-, 7.36 mmol) it is dissolved in 30 mL dichloromethane protective embankments, add 1- ethyoxyls -2, fluoro- benzene llb (1.16 g of 3- bis-, 7.36 mmol) and alchlor (0.98 g, 7.36 mmol), stirring reaction 16 hours.The M hydrochloric acid of 20 mL 4 is added, point liquid, aqueous phase extracts (25 mL with dichloromethane protective embankment><3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -2,3- difluorophenyls)-ketone llc (1.47 g, yellow solid), yield： 47.0%.
Ή NMR (400 MHz, CDCI3, ppm): δ 8.41-8.33 (m, 2H), 7.81-7.73 (m, 3H), 7.62-7.58 (m, 1H), 6.87-6.83 (m, 1H), 4.27-4.22 (q, 2H), 1.55-1.47 (t, 3H)
3rd step
(the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -2,3- difluorophenyls)-methanol is by (the small chloro- naphthalene -2- bases of 4- bromines)-(4- ethyoxyls -2,3- difluorophenyls)-ketone llc (1.42 g, 3.34 mmol) is dissolved in 45 mL ethanol and tetrahydrofuran (V: V = 2:1) in the mixed solvent, is added portionwise potassium borohydride (270 mg, 5 mmol), finishes stirring reaction 2.5 hours.Add 20 mL l M hydrochloric acid, it is concentrated under reduced pressure and evaporates organic phase, aqueous phase extracts f20 mLx3 with dichloromethane protective embankment), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, vacuum drying, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -2,3- difluorophenyls)-methanol lld (1.37 g, yellow solid), yield： 95.8%.
4th step
Small chloro- 2- (4- ethyoxyls -2,3- diiluoro-benzyl)-naphthalene of 4- bromines
(the small chloro- naphthalene -2- bases of 4- bromines)-(4- ethyoxyls -2,3- difluorophenyl)-methanol lld (1.37 g, 3.2 mmol) is dissolved in 30 mL acetonitriles and dichloromethane protective embankment (V: V = 2:1) in the mixed solvent, adds triethyl silicane (1.6 mL, 10 mmol) and BFEE (1.27 mL, 6.6 mmol), stirring reaction 16 hours.1.5 g sodium hydroxides are dissolved in 20 mL water, reaction solution is instilled, point liquid, aqueous phase is extracted with ethyl acetate (30 mLx3), merge organic phase, no ice magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the chloro- 2- of the bromo- 1- of title product 4- (4- ethyoxyls -2,3- diiluoro-benzyl)-naphthalene lle (1.09 g, white solid), yield： 82.6%. '
Ή NMR (400 MHz, DMSO- , ppm):δ 8.33-8.20 (m, 1H), 8.20-8.18 (m, 1H), 7.86 (s, 1H), 7.83-7.77 (m, 2H), 6.97-6.89 (m, 2H), 4.30 (s, 2H), 4.13-4.08 (q, 2H), 1.35-1.32 (t, 3H)
5th step
(2 & 3i, S, 5 ＆ 6i) -2- [the chloro- 3- of 4- (4- ethyoxyl -2,3- diiluoro-benzyls) the small base of-naphthalene] -6- methylols-oxinane
- 2,3,4,5- tetrols
The chloro- 2- of the bromo- 1- of 4- (4- ethyoxyls -2,3- diiluoro-benzyl)-naphthalene lle (500 mg, 1.21 mmol) is dissolved in 15 mL tetrahydrofurans:In cyclohexane solution (0.79 mL, 1.27 that 1.6 M n-BuLis are added dropwise under -78 °C；Mmol), -78 °C ' lower stirring reaction 10 minutes, 10 mL. (3 are added dropwise,4 & 5i,6i) -3,4,5- tri--trimethylsiloxy group -6- trimethylsiloxy group methyl-tetrahydro pyran-2-one 6c (593 mg, 1.27 mmol) tetrahydrofuran solution, in -78 times stirring reactions 2 hours, naturally reaction 16 hours is warmed to room temperature, the M hydrochloric acid of 10 mL 2 is added, at room temperature stirring reaction 10 minutes.Divide liquid, aqueous phase is extracted with ethyl acetate (20 mLx4), merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, obtains title product (2 3/,4&5 & 6/)-2- [the chloro- 3- of 4- (4- ethyoxyls-2,3- diiluoro-benzyl)-naphthalene-1-yl]-6- methylols-oxinane-2,3,4,5- tetrol llf (460 mg, dark yellow oil thing), yield： 74.7%.
MS m/z (ESI): 493.1 [M-18]
6th step
(2 & 3i,4i,5S,6i)-2- [the chloro- 3- of 4- (4- ethyoxyl-2,3- diiluoro-benzyls)-naphthalene-1-yl]-6- methylols-oxinane
- 3,4,5- triols
By (2 ＆ 3,4 & 5 & 6i) -2- [4- chloro- 3- (4- ethyoxyls -2,3- diiluoro-benzyls)-naphthalene -1- bases] -6- methylols-oxinane -2,3,4,5- tetrols llf (460 mg, 0.9 mmol) is dissolved in 15 mL dichloromethane and acetonitrile (V: V = 1 :2) triethyl group silicon protective embankment (0.43 mL, 2.7 mmol) and BFEE (0.23 mL, 1.8 mmol) are added under in the mixed solvent, ice bath, at room temperature stirring reaction 3.5 hours.2 g potassium hydroxide are dissolved in 20 mL water, 3 mL are taken to instill in reaction solution, 10 mL water are added, point liquid, aqueous phase extracts (10 mLx3) with dichloromethane protective embankment, merge organic phase, ' anhydrous magnesium sulfate drying, filtering, be concentrated under reduced pressure filtrate, with thin-layered chromatography with solvent system A purify gained residue, title product (2 ＆ 3/ are prepared with HPLC,4i,5 & 6i) -2- [the chloro- 3- of 4- (4- ethyoxyls -2,3- diiluoro-benzyl)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols 11 (40 mg, yellow solid), yield： 9.0%.
MS m/z (ESI): 512.2 [M+18]
Ή NMR (400 MHz, CD3OD, ppm): δ 8.39-8.35 (t, 2H), 7.63-7.58 (m, 3H), 6.78-6.77
(m, 2H), 4.91 (m, 1H), 4.34-4.32 (d, 2H), 4.12-4.07 (q, 2H), 3.94-3.91 (dd, 1H):3.75-3.70 (m, 2H), 3.64-3.50 (m, 3H), 1.42-1.39 (t, 3H) embodiment 12
(2&37,/, 5＆67) the small base 1-6- methylols-oxinane of the chloro- 3- of -2- Γ 4- (- ethyoxyl -2,6- diiluoro-benzyls)-naphthalene
- 3,4,5- triols
The first step
The fluoro- benzene of 1- ethyoxyls -3,5- two
By 3,5- difluoro-phenols 12a (2.6 g, 20 mmol) it is dissolved in 30 mL acetone, add potassium carbonate (4.14 g, 30 mmol) and iodine second protective embankment (3.25 mL, 40 mmol), stirring reaction 16 hours, react 3 hours under 50 °C at room temperature.Filtering reacting liquid, eluted with 200 mL acetone, be concentrated under reduced pressure filtrate, add 200 mL ether dissolution residues, it is washed with water (50 mLx2), anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, obtain title product 1- ethyoxyls -3, the fluoro- benzene 12b of 5- bis- (2.2 g, pale yellow oil), yield： 69.6%.
Ή NMR (400 MHz, CDCla, ppm):δ 6.48-6.41 (m, 3 Η), 4.06-4.01 (q, 2H), 1.47-1.44 (t, 3H)
Second step
Chloro- naphthalene -2- formyl chlorides the le of the bromo- 1- of 4- (3.04 g, lO mmol) are dissolved in 50 mL dichloromethane protective embankments by (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -2,6- difluorophenyl)-ketone, are added
Alchlor (1.2 g, 9 mmol) is added under the fluoro- benzene 12b of 1- ethyoxyls -3,5- bis- (1.58 g, lO mmol), ice bath, is warmed to room temperature, stirring reaction 16 hours.Add the M hydrochloric acid of 20 mL 1, divide liquid, aqueous phase extracts (40 mLx2) with dichloromethane protective embankment, merge organic phase, washed with saturated nacl aqueous solution (40 mL), an anhydrous slufuric acid a unit of weight used in ancient China, equal to six liang is dried, filtering, be concentrated under reduced pressure filtrate, with silicagel column ' chromatography with eluant, eluent system D purify gained residue, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -2,6- difluorophenyl)-ketone 12c (980 mg, white solid), yield： 23.1%.
MS m/z (ESI): 427.0 [M+l]
1H NMR (400 MHz, CDC13, ppm): δ 8.46-8.43 (dd, 1H), 8.35-8.33 (dd, 1H), 7.95-7.94
(s, 1H), 7.80-7.73 (m, 2H), 6.54-6.49 (dd, 2H), 4.14-4.09 (q, 2H), the steps of 1.51-1.47 (t, 3H) the 3rd
(4- bromo- 1-chloro- naphthalene-2- bases)-(4- ethyoxyls-2,6- difluorophenyls)-methanol is by (the chloro- naphthalene-2- bases of the bromo- 1- of 4-)-(4- ethyoxyls-2,6- difluorophenyls)-ketone 12c (860 mg, 2.02 mmol) is dissolved in 40 mL methanol and tetrahydrofuran (V: V = l :1) in the mixed solvent, adds potassium borohydride (218 mg, 4.1 mmol), finishes stirring reaction 16 hours.Add 10 mL acetone, be concentrated under reduced pressure reaction solution, residue is dissolved with 50 mL dichloromethane, it is washed with water successively (50 mLx2), washed with saturated nacl aqueous solution (20 mL), anhydrous magnesium sulfate is dried, filtering, Jian Ya Nong Shrink filtrates, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -2,6- difluorophenyls)-methanol 12d (860 mg, faint yellow solid), next step reaction is directly used in without isolation.
4th step
The chloro- 2- of the bromo- 1- of 4- (4- ethyoxyl -2,6- diiluoro-benzyls)-naphthalene
By (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -2,6- difluorophenyls)-methanol 12d (855 mg, 2 mmol) it is dissolved in 20 mL dichloromethane protective embankments, add triethyl silicane (0.96 mL, 6 mmol) and BFEE (0.51 mL, 4 mmol), stirring reaction 16 hours.0.5 g sodium hydroxides are dissolved in 20 mL water, instill reaction solution, divide liquid, aqueous phase extracts (20 mL) with dichloromethane protective embankment, organic phase is washed (20 mL) with saturated nacl aqueous solution, merge organic phase, anhydrous acid magnesium is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography ' method with eluant, eluent system B purify obtained by residue, obtain the bromo- 1- of title product 4- chloro- 2- (4- ethyoxyls -2,6- diiluoro-benzyls)-naphthalene 12e (520 mg, white solid), yield： 63.2%.
5th step
(2 & 3i,4 & 5 & 6i) -2- [the chloro- 3- (4 of 4-：Ethyoxyl -2,6- diiluoro-benzyls)-naphthalene -1- bases] -6- methylols -2- methoxyl groups-oxinane -3,4,5- triols
By small chloro- 2- (the 4- ethyoxyls -2 of 4- bromines, 6- diiluoro-benzyls)-naphthalene 12e (520 mg, 1.26 mmol) it is dissolved in 20 mL tetrahydrofurans, in hexamethylene protective embankment solution (0.87 mL that 1.6 M n-BuLis are added dropwise under -78 °C, 1.4 mmol), in -78 °C of lower stirring reactions 30 minutes, 5 mL (3 are added dropwise,4 & 5i,6/) -3,4,5- tri--trimethylsiloxy group -6- trimethylsiloxy group methyl-tetrahydro pyran-2-one 6c (590 mg, 1.26 mmol) tetrahydrofuran solution, stirring reaction 3 hours under -78 V, the methanol solution of the M methanesulfonic acids of 5 mL 0.6 is added, is warmed to room temperature naturally, stirring reaction 16 hours.Add 10 mL saturated sodium bicarbonate solutions, be concentrated under reduced pressure reaction solution, 10 mL water and 30 mL ethyl acetate are added, point liquid, aqueous phase is extracted with ethyl acetate (30 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, with silica gel column chromatography with washing and dehydrating integrated machine system A purify gained residue, obtain title product (the ＆ 6i of 2 ＆, 34 ＆ 5) -2- [the chloro- 3- of 4- (4- ethyoxyls -2,6- diiluoro-benzyl)-naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans -3,4,5- triols 12f (130 mg, colorless oil), yield： 19.7%.
6th step
(2S,3i,4/, 5S, 6i) -2- [the chloro- 3- of 4- (4- ethyoxyl -2,6- diiluoro-benzyls)-naphthalene -1- bases] -6- methylols-oxinane
- 3,4,5- triols
By (2 ＆ 374＆5 ＆ 6W) -2- [4- chloro- 3- (4- ethyoxyls -2,6- diiluoro-benzyls) the small base of-naphthalene] -6- methylol -2- methoxy-tetrahydros pyrans -3,4,5- triols 12f (130 mg, 0.25 mmol) is dissolved in 20 mL dichloromethanes protective embankments and acetonitrile (V:
V = l :1) triethyl group silicon protective embankment (80 μ, 0.5 mmol) and BFEE (47 are added under in the mixed solvent, ice bath
0.37 mmol), stirring reaction 16 hours at room temperature.Add 10 mL saturated sodium carbonate solutions, stirring reaction 10 minutes, be concentrated under reduced pressure reaction solution, is extracted with ethyl acetate (30 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, and title product (2S, 3i are prepared with HPLC,4i,5S,6 ) -2- [the chloro- 3- of 4- (4- ethyoxyls -2,6- diiluoro-benzyl)-naphthalene -1- bases] -6- methylols-oxinane ' -3,4,5- triols 12 " (mg of ' 40, white solid), yield： 32.6%.
MS m/z (ESI): 512.0 [M+18]
Ή NMR (400 MHz, CD3OD, ppm):δ 8.36-8.33 (m, 2H), 7.60-7.54 (nl, 2H), 7.42 (s, 1H), 6.58-6.56 (dd, 2H), 4.80-4.78 (m, 1H), 4.29-4.27 (m, 2H), 4.05-4.00 (m, 2H), 3.91 (m, 1H), 3.70-3.66 (m, 2H), 3.56-3.45 (m, 3H), 1.41-1.34 (t, 3H) embodiment 13
(2&3 4/,5&6/) -2- " the small base 1-6- methylols-oxinanes of the chloro- 3- of 4- (4- ethyoxyl -3,5- diiluoro-benzyls)-naphthalenes
- 3,4,5- triols
The first step
The fluoro- benzene of 2- ethyoxyls -1,3- two
2,6- difluoro-phenols 13a (3.9 g, 30 mmol) is dissolved in 250 mL acetone, potassium carbonate (mmol of 6.2 g, 45) and iodine second protective embankment (5 mL, 60 mmol) is added, reacted 16 hours under 40 °C.Filtering reacting liquid, is eluted, be concentrated under reduced pressure filtrate with 200 mL acetone, adds 100 mL ether dissolution residues, it is washed with water (30 mLx2), anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtains the fluoro- benzene 13b (3.8 of title product 2- ethyoxyls -1,3- bis-
G, colorless oil；), yield： 80.2%.
'Η NMR (400 MHz, CDC13, ppm):6 6.96-6.86 (m, 3H), 4.23-4.17 (q, 2H), 1.41-1.37 (t, 3H)
Second step
(the small chloro- naphthalene -2- bases of 4- bromines)-(4- ethyoxyls -3,5- difluorophenyls)-ketone is by chloro- naphthalene -2- formyl chlorides le (3.5 g of the bromo- 1- of 4-, 11.5 mmol) it is dissolved in 50 mL dichloromethane protective embankments, add 2- ethyoxyls -1, fluoro- benzene 13b (1.82 g of 3- bis-, 11.5 mmol) and alchlor (1.38 g, 10.35 mmol), reacted 16 hours under 35 °C.Add 50 mL l M hydrochloric acid, divide liquid, water 4' mesh is extracted (100 mLx2) with dichloromethane, merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system D purify obtained by residue, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -3,5- difluorophenyls)-ketone 13c (1.37 g, faint yellow solid), yield： 28.0%.
1H NMR (400 MHz, CDC13, ppm): δ 8.41-8.34 (m, 2H), 7.79-7.76 (m, 2H), 7.72 (s, 1H): 7.42-7.40 (m, 2H), 4.42-4.36 (q, 2H), 1.46-1.42 (t, 3H)
3rd step
(4- bromo- 1-chloro- naphthalene-2- bases)-(4- ethyoxyl-3,5- difluorophenyls)-methanol
' (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(the fluoro- benzene ^ of 4- ethyoxyls -3,5- two)-ketones 13c (1.35 g, 3.2'mmol) are dissolved in 40 mL methanol and tetrahydrofuran (V: V = l :1) in the mixed solvent, adds potassium borohydride (24Mg, 6.4 mmol), finish stirring reaction 1 hour.Add 10 mL acetone, be concentrated under reduced pressure reaction solution, dissolves residue with 50 mL dichloromethane, is washed with water (50 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, obtain title product (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -3,5- difluorophenyls)-methanol 13d (1.3 g, yellow oil), next step reaction is directly used in without isolation.
4th step
The chloro- 2- of the bromo- 1- of 4- (4- ethyoxyls -3,5- diiluoro-benzyl)-naphthalene
By (the chloro- naphthalene -2- bases of the bromo- 1- of 4-)-(4- ethyoxyls -3,5- difluorophenyls)-methanol 13d (1.37 g, 3.2 mmol) it is dissolved in 30 mL dichloromethane protective embankments, add triethyl group silicon protective embankment (1.5 mL, 9.6 mmol) and BFEE (0.8 mL, 6.4 mmol), stirring reaction 16 hours.0.5 g sodium hydroxides are dissolved in 20 mL water, reaction solution is instilled, point liquid, aqueous phase is extracted (50 mLx2) with dichloromethane, merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system D purify gained residue, obtain small chloro- 2- (4- ethyoxyls -3,5- diiluoro-benzyl)-naphthalene 13e (1.05 g of title product 4- bromines, colorless oil), yield： 79.5%.
5th step
(2 & 3/,4 & 5i,6i) -3,4,5- three benzyloxy -6- epoxide methyl -2- [the chloro- 3- of 4- (4- ethyoxyl -3,5- diiluoro-benzyls) the small base of-naphthalene]-oxinane -2- alcohol
By small chloro- 2- (the 4- ethyoxyls -3 of 4- bromines, 5- diiluoro-benzyls)-naphthalene 13e (1.05 g, 2.55 mmol) it is dissolved in 30 mL tetrahydrofurans, in hexamethylene protective embankment solution (1.75 mL that 1.6 M n-BuLis are instilled under -78 °C, 2.8 mmol), stirring 20 minutes, adds 10 mL (3i, 4 ＆ 5i,6i) -3,4,5- tri- benzyloxy -6- benzyloxymethyls-oxinane -2- ketone lh (1.5 g, 2.8 mmol), the stirring reaction of temperature control -78 2 hours.20 mL saturated ammonium chloride solutions are added,
Divide liquid, aqueous phase is extracted with ethyl acetate (50 mLx2), merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (2＆3/,4 & 5/,6i) -3,4,5- tri- benzyloxy -6- benzyloxymethyls -2- [the chloro- 3- of 4- (4- ethyoxyls -3,5- diiluoro-benzyl)-naphthalene -1- bases]-oxinane -2- alcohol 13f (1.86 g, pale yellow oil), yield： 83.8%.
6th step
(2/,3i, 4 5S, 65) and -3,4,5- three benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (4- ethyoxyl -3,5- diiluoro-benzyls)-naphthalene -1- bases]-oxinane
By (2 ＆ 3i, 4 ＆ 5/,6/) -3,4, benzyloxy -6- benzyloxymethyls -2- [4- chloro- 3- (the 4- ethyoxyls -3 of 5- tri-, 5- diiluoro-benzyls)-naphthalene -1- bases]-oxinane -2- alcohol 13f (1.86 g, 2.14 mmol) it is dissolved in 20 mL dichloromethane protective embankments, triethyl group silicon protective embankment (0.41 mL, 2.57 mmol) and BFEE (0.3 mL are sequentially added under ice bath, 2.35 mmol), stirring reaction 3 hours at room temperature.Add 20 mL saturated sodium carbonate solutions, divide liquid, aqueous phase extracts (60 mLx2) with dichloromethane protective embankment, merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (2i,3i, 45 ＆ 65) and -3,4,5- three benzyloxy -2- benzyloxymethyls -6- [the chloro- 3- of 4- (4- ethyoxyl -3,5- diiluoro-benzyls) the small base of-naphthalene]-oxinane 13g(1.83 g, white solid), yield： 100%.
Ή NMR (400 MHz, CDC13, ppm): δ 8.41-8.39 (m, 2H), 7.64-7.62 (m, 1H), 7.45 (m, 2H), 7.32-7.26 (m, 15H), 7.01-7.00 (m, 3H), 6.75-6.73 (m, 2H), 6:51-6.49 (m, 2H), 4.95-4.91 (m, 2H), 4.62-4.53 (m, 4H), 4.26-4.13 (m, 6H), 3.89-3.79 (m, 6H), 3.55-3.53 (m, 1H), 1.48-1.34 (t, 3H)
7th step
(2 & 3i,4i,5S,6i) -2- [the chloro- 3- of 4- (4- ethyoxyl -3,5- diiluoro-benzyls) the small base of-naphthalene] -6- methylols-oxinane
- 3,4,5- triols
By (2/,4 , the benzyloxy -2- benzyloxymethyls -6- of 5 ＆ 65 3,4,5- tri- [the chloro- 3- of 4- (4- ethyoxyls -3,5- diiluoro-benzyl)-naphthalene -1- bases]-oxinane 13g(1.83 g, 2.14 mmol) are dissolved in 20 mL dichloromethane protective embankments, and BFEE (4.07 mL, 32.1 mmol) is added under ice bath, and 7 mL ethyl mercaptans, stirring reaction 16 hours are added dropwise.20 mL water are added, point liquid extracts (50 mLx2) with dichloromethane protective embankment, and anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate.Residue is dissolved in 20 mL pyridines, 26 mL acetic acid, stirring reaction 16 hours are added, Jian Ya Nong Shrink reaction solutions, the dissolving of 100 mL ethyl acetate is added, is washed with copper/saturated copper sulphate solution (50 mLx2), merges organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product (2S, 3i, 4i,5 & 6i) -2- [the chloro- 3- of 4- (4- ethyoxyls -3,5- diiluoro-benzyl)-naphthalene-yl] -6- methylols-oxinane -3,4,5- triols 13 (560 mg, white solid), yield： 52.8%.
MS m/z (ESI): 512.2 [M+18]
Ή NMR (400 MHz, CD3OD, ppm): δ 8.38-8.33 (m, 2H), 7.63-7.57 (m, 3H), 6.87-6.83 (m, 2H), 4.92-4.90 (d, 1H), 4.30-4.29 (m, 2H), 4.13-4.08 (m, 2H), 3.93-3.90 (dd, 1H), 3.74-3.70 (m, 2H), 3.61-3.53 (m, 3H), 1.34-1.26 (t, 3H)
Embodiment 14
(2S, 3 all 4i, 5 ＆ 6iV2--chloro- 3- Γ 4-^-tetrahydrofuran -3- epoxides)-benzyl 1- naphthalene -1- bases } -6- methylols-tetrahydrochysene
The first step
4- (the chloro- naphthalene -2- ylmethyls of the bromo- 1- of 4-)-phenol
By small chloro- 2- (4- methyoxy-benzyls)-naphthalene 9b (13.0 g of 4- bromines, 35.9 mmol) it is dissolved in 100 mL dichloromethane, 1 M Boron tribromides (9.9 g are slowly added dropwise under ice bath, 39.5 mmol) dichloromethane protective embankment solution, drop finishes stirring reaction 3 hours at room temperature, a small amount of saturated sodium carbonate solution is added under ice bath, concentrated hydrochloric acid, which is added dropwise, adjusts pH to be 1, add 200 mL water, divide liquid, aqueous phase extracts (150 mLx4) with dichloromethane protective embankment, merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtain title product 4- (the chloro- naphthalene -2- ylmethyls of the bromo- 1- of 4-)-phenol 14a (12.5 g, yellow solid), next step reaction is directly used in without isolation.
Second step
[4- (the small chloro- naphthalene -2- ylmethyls of 4- bromines)-phenoxy group]-tert-butyI-dimethyl-silicon protective embankment is by 4- (the chloro- naphthalene -2- ylmethyls of the bromo- 1- of 4-)-phenol 14a (12.5 g, 35.9 mmol) it is dissolved in 250 mL dichloromethane, add triethylamine (7.51 mL, 53.85 mmol) and DMAP (219 mg, 1.80 mmol), stirring reaction 15 minutes, add tert-butyl chloro-silicane (5.95 g, 39.5 mmol), stirring reaction 64 hours, add a small amount of 1 M hydrochloric acid, successively with 1 M hydrochloric acid washing reaction liquid (50 mLx2), washed with saturated sodium bicarbonate solution (50 mL), washed with saturated nacl aqueous solution (50 mL), merge organic phase, anhydrous magnesium sulfate is dried, filtering, Jian Ya Nong Shrink filtrates, with silica gel column chromatography with eluant, eluent system E purify gained residue, marked
Inscribe product [4- (the chloro- naphthalene -2- ylmethyls of the bromo- 1- of 4-)-phenoxy group]-t-butyl-dimethyI-sila 14b (16 g, faint yellow solid), yield： 96.5%.
3rd step
(2 & 3 4 & 5 & 6i)-2- [the chloro- 3- of 4- (4- Hydroxy-benzvls)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydro pyrans
-3;4,5- triols
By [4- (the chloro- naphthalene -2- ylmethyls of the bromo- 1- of 4-)-phenoxy group]-tert-butyI-dimethyl-silicon protective embankment 14b (600 mg, 1.3 mmol) it is dissolved in 20 mL tetrahydrofurans, hexamethylene protective embankment solution (0.9 mL of 1.6 M n-BuLis is added dropwise under -78 °C, 1.43 mmol), stirring reaction 40 minutes, adds 10 mL (3, 4S, 5i,6i) -3, 4, 5- tri--trimethylsiloxy group -6- trimethylsiloxy group methyl-tetrahydro pyran-2-one 6c (607 mg, 1.3 mmol) tetrahydrofuran solution, in -78 °C of lower stirring reactions 3 hours, add the methanol solution of the M methanesulfonic acids of 6 mL 0.6, stirring reaction 16 hours at room temperature, add 15 mL saturated sodium bicarbonate solutions, be concentrated under reduced pressure reaction solution, add 20 mL water, it is extracted with ethyl acetate (30 mLx3), organic phase is washed with water (10 mL), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, obtain title product (2 ＆ 37,4&5 & 67) -2- [the chloro- 3- of 4- (4- Hydroxy-benzvls)-naphthalene -1- bases] -6- methylol -2- methoxy-tetrahydro pyrans -3,4,5- triols 14c (400 mg, colorless oil), be directly used in without isolation next step reaction.
4th step
(2 & 3i,4i,5 & 6i) -2- [the chloro- 3- of 4- (4- Hydroxy-benzvls)-naphthyl] -6- methylols-oxinane -3,4,5- triols are by (the ＆ 67 of 2 ＆, 34 ＆ 5)-2- [the chloro- 3- of 4- (4- Hydroxy-benzvls)-naphthalene-1-yl]-6- methylol-2- methoxy-tetrahydros pyrans-3,4,5- triols 14c (400 mg, 0.3 mmol) is dissolved in 24 mL dichloromethane and acetonitrile (V: V = 2 :1) in the mixed solvent, BFEE (0.3 mL is added under 0 °C, 2.1 mmol) and triethyl group silicon protective embankment (0.3 mL, 1.8 mmol), stirring reaction 16 hours at room temperature, add 10 mL sodium bicarbonate solutions and reaction is quenched, be concentrated under reduced pressure reaction solution, aqueous phase is extracted with ethyl acetate (30 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (2S, 3R, 4R, 5S, 6R)-2- [the chloro- 3- of 4- (4- Hydroxy-benzvls)-naphthalene-1-yl]-6- methylols-oxinane-3, 4, 5- triols 14<1 (85 0, white solid), yield： 65.9%.
MS m/z (ESI): 431.1 [M+l]
5th step
(R) -4- sulfonic acid tetrahydrofuran -3- toluene base esters
By W tetrahydrofuran -3- alcohol 14e (705 mg, 8 mmol) it is dissolved in 8 mL pyridines, add paratoluensulfonyl chloride (1.83 g, 9.6 mmol), stirring reaction 16 hours, be concentrated under reduced pressure reaction solution, add the dissolving of 50 mL ethyl acetate, (20 mLx2) is washed with 1 M citric acid solutions successively, is washed with saturated nacl aqueous solution (20 mL), anhydrous magnesium sulfate is dried, filtering, be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product () -4- sulfonic acid tetrahydrofuran -3- toluene base esters 14f (1.72 g, white oil thing), yield： 88.7%.
Ή NMR (400 MHz, CDC13, ppm): δ 7.80 (d, 2Η), 7.35 (d, 2H), 5.12 (m, 1H), 3.91-3.78 (m, 4H), 2.46 (s, 3H), 2.12-2.06 (m, 2H)
6th step
(2 & 3i,4 5S,6i) -2- { the chloro- 3- of 4- [4- (tetrahydrofuran -3- oxygen)-benzyl] the small base of-naphthalene } -6- methylols-oxinane
- 3,4,5- triols
By (2 ＆ 3/,4/,5 & 6i) -2- [the chloro- 3- of 4- (4- Hydroxy-benzvls)-naphthalene -1- bases] -6- methylols-oxinane -3,4,5- triols 14d (100 mg, 0.23 mmol) is dissolved in 2 mL DMFs, add (/) -4- sulfonic acid tetrahydrofuran -3- toluene base ester 14f (84 mg, 0.35 mmol) and cesium carbonate (128 mg, 0.36 mmol), in 75 °C of lower stirring reactions 4 hours, add (R) -4- sulfonic acid tetrahydrofuran -3- toluene base ester 14f (84 mg, 0.35 mmol) and cesium carbonate (128 mg, 0.3 mmol), in 50 °C of lower stirring reactions 16 hours.Be concentrated under reduced pressure reaction solution, add 5 mL saturated nacl aqueous solutions, it is extracted with ethyl acetate (10 mLx3), merge organic phase, anhydrous magnesium sulfate is dried, filtering, and be concentrated under reduced pressure filtrate, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (2 ＆ 3i,4/,5 & 6i)-2- { the chloro- 3- of 4- [4- ((5)-tetrahydrofuran-3- epoxides)-benzyl]-naphthalene-1-yl }-6- methylols-oxinane-3,4,5- triols 14 (100 mg, white solid), yield： 86.2%.
MS m/z (ESI): 518.2 [M+18]
Ή NMR (400 MHz, CD3OD, ppm): δ 8.36 (d, 2H), 7.63-7.54 (m, 3H), 7.18 (d, 2H), 6.81 (d, 2H), 4.98-4.95 (m, 1Η);4.90 (d, 1H), 4.30 (dd, 2H), 3.84-3.81 (m, 5H), 3.74-3.69 (m, 2H), 3.60 (t, 1H), 3.52-3:48 (m, 2H)
Test case:The influence test objective to db/db mouse random blood sugars is administered in the compounds of this invention single oral：
Observe after embodiment 1, the administration of 10 compound single orals to type ii diabetes db/db mouse random blood sugars, while collecting mouse urine volume at times and detecting glucose in urine situation.Specify its duration of efficacy and dose-effect relationship.Experimental design
The db/db mouse of 78 week old, select the mouse of morbidity, blood glucose, insulin and body weight are divided into different compound groups, and set positive controls and solvent control group.After each group animal subcutaneous administrations, the blood glucose value of different time points after administration, and urine sugar value are determined.Observe the hypoglycemic effect of compound induction.
Animal subject
Kind, strain：Db/db mouse (B6.Cg-m+/+Leprdb/J), wild-type mice
Source：Introduce a fine variety in Jackson companies of the U.S.（Stock number 000697), by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences, conservation is bred, quality certification number：SCXK (Shanghai；) 2008-0017 body weight：Db/db mouse： 37.9±0.5g; '
The another ij of property:Db/db mouse：Male 6, female 6
Rearing conditions：SPF grades of Animal Houses are raised, temperature：22 24 °C, humidity：70 90%, illumination：
150 ~ 300Lx, day alternates with night within 12 hours (7:00〜 19:00 is daytime).
Tested material and control drug
Embodiment 1,10 compounds
Administering mode
It is administered orally, administration volume is 10 mL/kg.
Test method
' mouse, by non-mouse, it is grouped by non-fasting blood glucose and body weight, every group 6, respectively male and female half and half, blank control and different compound administration groups.Single oral gives test medicine and solvent to each group animal respectively, in before administration and 0.5,1 after administration, 2,4,6 hours survey blood glucose, ' the glucose in urine detection period be 03,36,6 12 and 12 24 j, when.Observation tested material is hypoglycemic to be promoted glucose in urine effect and holds time.
Result of the test：
The blood glucose rate of descent of compound 1,10 is shown in Table 1 and Fig. 1, and row's sugar amount is shown in Table 2 and Fig. 2.
The blood glucose fall time table of table 1
The row's sugar amount timetable of table 2
Claims (1)
- Claims：1st, formula（I compound or its pharmaceutically useful salt or its stereoisomer shown in):Wherein：R' R^R3And R4It is each independently selected from hydrogen atom, alkyl, aryl, fragrant protective embankment base ,-C (0) RaOr-C (0) ORa, wherein the protective embankment base, aryl or fragrant protective embankment base are optionally further replaced by one or more substituents selected from halogen, nitro, hydroxyl, cyano group, protective embankment epoxide or aryl；R5And R6It is each independently selected from hydrogen atom, halogen, nitro, hydroxyl, cyano group, alkyl, protective embankment epoxide ,-CF3Or-OCF3, choosing/hydrogen atom or halogen；R7And R8From being independently selected from hydrogen atom, i elements, nitro, hydroxyl, cyano group, protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nR\ -NHC(0)Ra、 -NH-S(0)ORaOr-C (0) NRbRe, wherein the protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl or heteroaryl are optionally further selected from halogen, nitro, cyano group, protective embankment base, hydroxyl, alkoxy, ring protective embankment base, aryl, heteroaryl ,-OR by one or morea、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -N bRcOr-CCC NRbRe substituent is replaced；R9Selected from hydrogen atom, halogen, nitro, hydroxyl, cyano group, protective embankment base, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa> -NHC(0)Ra、 -NH-S(0)ORaOr-C (0) NRbRe, wherein the alkyl, ring protective embankment base, Heterocyclylalkyl, aryl or heteroaryl optionally further by it is one or more selected from halogen, nitro, cyano group,：Protective embankment base, hydroxyl, protective embankment epoxide, ring protective embankment base, aryl, heteroaryl ,-ORa、 -C(0)OH、 -C(0)ORa、 -S(0)nRa、 -NHC(0)Ra、 -NH-S(0)ORa、 -NRbRcOr-C (0) NRbReSubstituent replaced；RaSelected from alkyl, cycloalkyl, heterocycle protective embankment base, aryl, fragrant protective embankment base or heteroaryl, wherein the alkyl, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl are optionally further selected from halogen, nitro, hydroxyl, cyano group, alkyl, protective embankment epoxide, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl ,-OR by one or mored、 -C(0)OH, -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced； ' 'RbAnd ReHydrogen atom, protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl or heteroaryl are each independently selected from, wherein the alkyl, ring protective embankment base, Heterocyclylalkyl, aryl or heteroaryl are optionally further selected from halogen, nitro, hydroxyl, cyano group, alkyl, protective embankment epoxide, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl ,-OR by one or mored、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced； Or, RbAnd Re3 ~ 8 circle heterocycles bases are formed together with the atom being connected, wherein described 38 circle heterocycles base contains one or more N, 0 or S atom, and 3 ~ 8 circle heterocycles bases optionally further by one or-multiple be selected from halogen, nitro, hydroxyl, cyano group, alkyl, protective embankment epoxide, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl, -0Rd、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；RdSelected from protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl, fragrant protective embankment base or heteroaryl；ReAnd RfIt is each independently selected from hydrogen atom, alkyl, ring protective embankment base, aryl or heteroaryl；N is 0,1 or 2.2nd, compound according to claim 1 or its pharmaceutically useful salt or its stereoisomer, wherein the compound is selected from：3rd, formula（I A) compound or its pharmaceutically useful salt or its stereoisomer, the compound is synthesizes formula as claimed in claim 1（I) the intermediate of compound：( IA )Wherein：R^R9As defined in claim 1,R1QSelected from hydrogen atom or protective embankment base.4th, compound according to claim 3 or its pharmaceutically useful salt or its stereoisomer, wherein the compound is selected from：；, one kind prepare formula as claimed in claim 1（I) the method for compound, this method includes：： ( IA )Formula (IA) compound dehydroxylation or protective embankment epoxide generation formula（I) compound；R^R9Definition as described in the appended claim 1；R10Definition such as ^ profits require described in 3.6th, the method that one kind prepares formula as claimed in claim 3 (Ι Α) compound, this method include-Amino and the naphthalene compound of cyano group substitution react with halogen, generate halo naphthalene derivatives;Amino on halo naphthalene compound generates R after diazotising with nucleopilic reagent5Substituted naphthalene derivatives;R5The naphthalene derivatives of acidifying generation carboxyl substitution after cyano group on substituted naphthalene compound is hydrolyzed in the basic conditions;The naphthalene derivatives of carboxyl substitution reacts the naphthalene derivatives of generation acyl chlorides substitution with oxalyl chloride in the basic conditions;The naphthalene derivatives that acyl chlorides replaces is subjected to acylation reaction with substituted benzene under catalytic condition and generates 1 | derivative;Carbonyl in assimilation compound is reduced into methylene；The methylene product of generation and lactone compound coupling generation formula (IA) compound；Wherein：R^R9Definition as described in the appended claim 1；R10Definition as claimed in claim 3；X is halogen；Ri'〜R'4It is each independently selected from hydrogen atom, alkyl, aryl, fragrant protective embankment base, silicon protective embankment base ,-C (0) RaOr-C (0) ORa, wherein the alkyl, aryl or aralkyl are optionally further replaced by one or more substituents selected from halogen, nitro, hydroxyl, cyano group, protective embankment epoxide or aryl；RaSelected from protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl, aralkyl or heteroaryl, wherein the alkyl, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl are optionally further selected from halogen, nitro, hydroxyl, cyano group, protective embankment base, alkoxy, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl ,-OR by one or mored、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；RbAnd ReHydrogen atom, protective embankment base, ring protective embankment base, Heterocyclylalkyl, aryl or heteroaryl are each independently selected from, wherein the protective embankment base, ring protective embankment base, heterocycle protective embankment base, aryl or heteroaryl are optionally further selected from halogen, nitro, hydroxyl, cyano group, alkyl, protective embankment epoxide, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl ,-OR by one or mored、 -C(0)OH、 -C(0)ORd、 -S(0)nRd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；Or, RbAnd Re3 ~ 8 circle heterocycles bases are formed together with the atom being connected, wherein described 3 ~ 8 circle heterocycles base contains one or more ^^, 0 or S atom, and 3 ~ 8 circle heterocycles bases optionally further by it is one or more selected from halogen, nitro, hydroxyl, cyano group, alkyl, alkoxy, ring protective embankment base, Heterocyclylalkyl, aryl, Heteroaryl ,-ORd、 -C(0)OH、 -C(0)ORd,-S (0), Rd、 -NHC(0)Rd、 -NH-S(0)ORd、 -NReRfOr-C (0) NReRfSubstituent replaced；RdSelected from alkyl, cycloalkyl, heterocycle protective embankment base, aryl, aralkyl or heteroaryl；ReAnd RfIt is each independently selected from hydrogen atom, protective embankment base, ring protective embankment base, aryl or heteroaryl；N is 0,1 or 2.7th, compound as claimed in claim 1 or 2 or its pharmaceutically useful salt or its stereoisomer are preparing the purposes in being used to treat or delay the medicine of following advancing of disease or breaking-out, wherein the disease is selected from elevated level, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine.8th, a kind of elevated level for treating diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetes complicated;F or Atherosclerosis 4fe or hypertension method, methods described include giving the compound according to claim 1 or ' 2 or its pharmaceutically useful salt or its stereoisomer for needing the patient treated effectively to treat i.9th, compound as claimed in claim 1 or 2 or its pharmaceutically useful salt or its stereoisomer are as the medicine for treating or delaying following advancing of disease or breaking-out, wherein the disease is selected from diabetes, diabetic retinopathy, elevated levels of the sugar urine disease Zhong through disease, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or hypertension.10th, a kind of pharmaceutical composition, described composition includes the compound as described in claim 1 or 2 or its pharmaceutically useful salt or its stereoisomer and pharmaceutically useful carrier for the treatment of effective dose.11st, pharmaceutical composition as claimed in claim 10 is preparing the purposes in being used to treat or delay the medicine of following advancing of disease or breaking-out, wherein the disease is selected from elevated level, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine.12nd, a kind of method of elevated level for treating diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or hypertension, methods described includes giving the medicine according to claim 10 for the effective therapeutic dose of patient for needing to treat Compositions.13, pharmaceutical composition as claimed in claim 10 is treatment or delays the medicine of following advancing of disease or breaking-out, wherein the disease is selected from elevated level, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine.
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| CN201080002682XA CN102159586B (en) | 2009-03-12 | 2010-03-10 | C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof |
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| CN200910047426A CN101830876A (en) | 2009-03-12 | 2009-03-12 | C-aryl glucoside derivative, preparation method thereof and application thereof in medicine |
| CN201080002682XA CN102159586B (en) | 2009-03-12 | 2010-03-10 | C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof |
| PCT/CN2010/000291 WO2010102512A1 (en) | 2009-03-12 | 2010-03-10 | C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof |
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| CN102159586B CN102159586B (en) | 2013-12-04 |
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| US9034921B2 (en) * | 2011-06-01 | 2015-05-19 | Green Cross Corporation | Diphenylmethane derivatives as SGLT2 inhibitors |
| CN104945363B (en) * | 2014-03-24 | 2017-09-12 | 天津药物研究院有限公司 | A kind of Preparation Method And Their Intermediate for preparing 3 deoxidation phenyl C glycoside SGLT2 inhibitors |
| CN105294785A (en) * | 2014-07-02 | 2016-02-03 | 上海阳帆医药科技有限公司 | C-benzo five-membered heteroaromatic aryl glucoside derivative as well as preparation method and application thereof |
| CN104710486A (en) * | 2015-04-07 | 2015-06-17 | 安润医药科技（苏州）有限公司 | Method for synthesizing SGLT2 inhibitor drugs |
| CN111471032B (en) * | 2019-01-24 | 2023-08-01 | 北京盈科瑞创新药物研究有限公司 | Synthesis method of glycoside derivative, intermediate and application thereof |
| CN111471031B (en) * | 2019-01-24 | 2023-05-16 | 北京盈科瑞创新药物研究有限公司 | Glycoside derivative and preparation method and application thereof |
| WO2020242253A1 (en) * | 2019-05-30 | 2020-12-03 | 동아에스티 주식회사 | Novel empagliflozin derivative which is sglt-2 inhibitor |
| CN114736099B (en) * | 2022-05-18 | 2023-06-06 | 江苏南大光电材料股份有限公司 | Preparation method of 1- (tertiary butyl) -3-chloronaphthalene |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004359630A (en) * | 2003-06-06 | 2004-12-24 | Yamanouchi Pharmaceut Co Ltd | Difluorodiphenylmethane derivative and its salt |
| US20050233988A1 (en) * | 2003-08-01 | 2005-10-20 | Tanabe Seiyaku Co., Ltd. | Novel compounds |
| CN1989132A (en) * | 2004-07-27 | 2007-06-27 | 中外制药株式会社 | Novel glucitol derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes |
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| US20080027014A1 (en) * | 2006-07-28 | 2008-01-31 | Tanabe Seiyaku Co., Ltd. | Novel SGLT inhibitors |
| CN101463055B (en) * | 2009-01-15 | 2010-12-08 | 天津药物研究院 | O-indican compounds, preparation and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080319047A1 (en) * | 1994-11-29 | 2008-12-25 | Hiroharu Matsuoka | Novel Glucitol Derivative, Prodrug Thereof And Salt Thereof, And Therapeutic Agent Containing The Same For Diabetes |
| JP2004359630A (en) * | 2003-06-06 | 2004-12-24 | Yamanouchi Pharmaceut Co Ltd | Difluorodiphenylmethane derivative and its salt |
| US20050233988A1 (en) * | 2003-08-01 | 2005-10-20 | Tanabe Seiyaku Co., Ltd. | Novel compounds |
| CN1989132A (en) * | 2004-07-27 | 2007-06-27 | 中外制药株式会社 | Novel glucitol derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes |
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| CN101830876A (en) | 2010-09-15 |
| CN102159586B (en) | 2013-12-04 |
| WO2010102512A1 (en) | 2010-09-16 |
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