CN106188190A - A kind of preparation method of the clean monohydrate of Tuo Gelie - Google Patents
A kind of preparation method of the clean monohydrate of Tuo Gelie Download PDFInfo
- Publication number
- CN106188190A CN106188190A CN201610598721.6A CN201610598721A CN106188190A CN 106188190 A CN106188190 A CN 106188190A CN 201610598721 A CN201610598721 A CN 201610598721A CN 106188190 A CN106188190 A CN 106188190A
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- Prior art keywords
- compound
- formula
- preparation
- acid
- solvent
- Prior art date
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 150000004682 monohydrates Chemical class 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 15
- 125000002346 iodo group Chemical class I* 0.000 claims abstract description 11
- MGMNPSAERQZUIM-UHFFFAOYSA-N 2-(hydroxymethyl)benzoic acid Chemical compound OCC1=CC=CC=C1C(O)=O MGMNPSAERQZUIM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 58
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 42
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 27
- 229910052740 iodine Inorganic materials 0.000 claims description 22
- 239000011630 iodine Substances 0.000 claims description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000377 silicon dioxide Substances 0.000 claims description 17
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- -1 Acyloxymethyl benzoic acid Chemical compound 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- 229940007550 benzyl acetate Drugs 0.000 claims description 12
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 239000004519 grease Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 239000007818 Grignard reagent Substances 0.000 claims description 8
- AOKMFXQCRBQJOP-UHFFFAOYSA-N benzyl trimethylsilyl ether Chemical compound C[Si](C)(C)OCC1=CC=CC=C1 AOKMFXQCRBQJOP-UHFFFAOYSA-N 0.000 claims description 8
- KWEKXPWNFQBJAY-UHFFFAOYSA-N (dimethyl-$l^{3}-silanyl)oxy-dimethylsilicon Chemical compound C[Si](C)O[Si](C)C KWEKXPWNFQBJAY-UHFFFAOYSA-N 0.000 claims description 7
- 150000004795 grignard reagents Chemical class 0.000 claims description 7
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- 229910015900 BF3 Inorganic materials 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical group CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 5
- NGSQAGKATGKVIC-UHFFFAOYSA-N [4-[(4-ethylphenyl)methyl]-2-iodophenyl]methanol Chemical compound CCc1ccc(Cc2ccc(CO)c(I)c2)cc1 NGSQAGKATGKVIC-UHFFFAOYSA-N 0.000 claims description 5
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 4
- BCLPLXPYKPSXAN-UHFFFAOYSA-N 3-acetyl-2-methylbenzoic acid Chemical compound CC(=O)C1=CC=CC(C(O)=O)=C1C BCLPLXPYKPSXAN-UHFFFAOYSA-N 0.000 claims description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- GHICCUXQJBDNRN-UHFFFAOYSA-N 4-iodobenzoic acid Chemical compound OC(=O)C1=CC=C(I)C=C1 GHICCUXQJBDNRN-UHFFFAOYSA-N 0.000 claims description 3
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical class OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims description 3
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 238000005957 chlorosulfonylation reaction Methods 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical group COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 230000026045 iodination Effects 0.000 claims description 2
- 238000006192 iodination reaction Methods 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- DQZLQYHGCKLKGU-UHFFFAOYSA-N magnesium;propane Chemical compound [Mg+2].C[CH-]C.C[CH-]C DQZLQYHGCKLKGU-UHFFFAOYSA-N 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910001629 magnesium chloride Inorganic materials 0.000 claims 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000006722 reduction reaction Methods 0.000 abstract description 6
- 125000006840 diphenylmethane group Chemical group 0.000 abstract description 4
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 3
- 239000002360 explosive Substances 0.000 abstract description 2
- 239000002574 poison Substances 0.000 abstract 1
- 231100000614 poison Toxicity 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 239000000047 product Substances 0.000 description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 208000035126 Facies Diseases 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 238000010792 warming Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000000376 reactant Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 230000006837 decompression Effects 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 150000007984 tetrahydrofuranes Chemical class 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 238000010583 slow cooling Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- OPGQKSHKFCOBGF-UHFFFAOYSA-N methanesulfonic acid;methanol Chemical compound OC.CS(O)(=O)=O OPGQKSHKFCOBGF-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- QPBGNSFASPVGTP-UHFFFAOYSA-N 2-bromoterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(Br)=C1 QPBGNSFASPVGTP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 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 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052752 metalloid Inorganic materials 0.000 description 1
- 150000002738 metalloids Chemical class 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- HQTJYTVKYNLWBJ-UHFFFAOYSA-N silane trimethyl-lambda3-chlorane Chemical compound [SiH4].CCl(C)C HQTJYTVKYNLWBJ-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
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Abstract
The present invention relates to the preparation method of the clean monohydrate of a kind of Tuo Gelie.This route with to hydroxymethyl-benzoic acid as starting material; the diphenyl-methane skeleton of iodo is obtained by acylated, iodo, Fu Ke and reduction reaction; utilize the characteristic that iodo thing is active; effect by isopropylmagnesium chloride lithium chloride; achieving diphenyl-methane skeleton and the splicing of sugar ring in a mild condition, 11 step total recoverys are 22%.This route productivity is high, and selectivity is good, and production cost is low, and reaction condition is gentle, does not use inflammable and explosive high poison reagent, and product and intermediate are prone to purify, and are suitable for industrialized production.
Description
Technical field
The present invention relates to relate to the preparation method of the clean hydrate novel of a kind of Tuo Gelie, belong to field of medicine and chemical technology.
Background technology
The clean monohydrate of Tuo Gelie is developed jointly by Chugai, Sanofi-Aventis and Japan Xinghe, and 2014 in day
This listing.The advantage of this novel SGLT2 inhibitor is that the selectivity of medicine is higher, and while reducing blood glucose also
Can lose weight, the most there is not apparent side effect.
At present, disclosed about synthesis document, be entirely by Japan Choongwae Pharmacutical Corp disclosed in, specific as follows:
(1) Choongwae Pharmacutical Corp of Japan within 2006, disclose first clean for Tuo Gelie synthetic route (EP 1852439A1),
This route with 2-bromo terephthalic acid as starting material, through reduction, hydroxyl protection, addition, closed loop, oxidation, addition, reduction,
Hydrogenolysis totally eight steps obtain product.This process route is primarily present following shortcoming: 1. yield is on the low side, and second step and the 5th step are received
Rate only has 18% and 33%, and total recovery is only 1.6%；The most all intermediate and product are both needed to, through column chromatography purification, be not suitable for industry
Metaplasia is produced；3. using palladium carbon in reaction, the most expensive but also palladium belongs to a metalloid, is unfavorable for control of product quality；④
Butyl lithium is used in 3rd step gluconic acid lactone derivant and phenyl ring addition, it is desirable to reaction temperature-78 DEG C, reacts for ultralow temperature,
Condition is harsh, and butyl lithium easily fires, and there is bigger potential safety hazard；5. the boron trifluoride used in reaction can divide in atmosphere
Solving is severe toxicity fluoride smog, is unfavorable for labor protection.
(2) Choongwae Pharmacutical Corp's public affairs have opened a kind of new Tuo Gelie clean monohydrate synthetic method for 2009
(EP2308886A1), this route is with 2, and 4-dibromobenzene methanol is starting material, through hydroxyl protection, addition, closed loop, reduction etc.
Eight steps obtain product.Compared with route one, all intermediate of this route and product all need not column chromatography and purify, and yield carries
High to 68%；Avoid the use of high-risk reagent boron trifluoride, make production process safer.But, the metal-halogen in this route
Element exchange reaction still needs to carry out at-78 DEG C, is difficult to implement production technology and amplifies, simultaneously 2,4-dibromobenzene methanol prices expensive with
And the use of the noble metal such as Pd/C causes production cost higher, thus be not suitable for industrialized production.
Summary of the invention
In view of the shortcoming of above method, it is an object of the invention to provide a kind of clean monohydrate system of economic and environment-friendly Tuo Gelie
Preparation Method.
The technical scheme is that with cheap and easily-available to hydroxymethyl-benzoic acid as starting material, by acylated, iodine
Generation, Fu Ke and reduction reaction obtain the diphenyl-methane skeleton of iodo, utilize the characteristic that iodo thing is active simultaneously, use Grignard reagent
Isopropylmagnesium chloride/lithium chloride replaces butyl lithium, can make diphenyl-methane skeleton and sugar ring splicing at-20 DEG C, then through cyclization,
Deprotection prepares the clean crude product of Tuo Gelie, purifies by two steps and obtains fine work.Building-up process comprises the following steps:
A, with to hydroxymethyl-benzoic acid for raw material under the effect of acid binding agent through acetylation, hydrolysis obtain compound of formula I to second
Acyloxymethyl benzoic acid；
I
In this step, acetylation reagent is often acetic anhydride, chloroacetic chloride, preferably acetic anhydride.Mixed acid anhydride can be generated in the reaction, after
Processing procedure adds water can make it be hydrolyzed into acid.
B, acetyl-o-methyl benzoic acid is dissolved in solvent by compound of formula I, under iodo reagent effect, obtains Formula II
The compound 4-iodo-benzoic acid of acetyl-o-methyl-3-；
II
In this step, the iodo of aromatic ring has multiple iodo reagent, such as N-chlorosuccinimide and sodium iodide, two chlorosulfonylations four
Ammonium methyl, KI/KIO3/H+、HIO4/H2SO4Deng.Found by research, with acetic acid/acetic anhydride mixture as reaction dissolvent, with iodine
Change reagent and be iodine and sodium metaperiodate mixture is made iodination reagent and can be obtained more satisfactory iodo effect.
C. the Formula II compound 4-iodo-benzoic acid of acetyl-o-methyl-3-and chlorination reagent are made acyl chlorides, under lewis acid effect
Formula III compound 4-(4-ethylamino benzonitrile acyl group)-2-iodine benzyl acetate is generated with ethylbenzene generation Friedel-Crafts reaction；
III
In this step, chlorination reagent used is thionyl chloride, uses and convenient post-treatment；Friedel-Crafts reaction used catalyst Louis
Acid uses aluminum chloride, substrate compoundsIt is 1:2.2 with aluminum chloride optimum mole ratio；Substrate and this step reaction ethylbenzene used
Mol ratio be 1:1.5 ~ 1:4.5, optimum mole ratio is 1:3.5；This step reaction temperature is 0 ~ 40 DEG C, and optimal reaction temperature is 40
℃。
D, formula III compound 4-(4-ethylamino benzonitrile acyl group)-2-iodine benzyl acetate is dissolved in solvent, under reducing agent effect
Reduction, then hydrolysis obtains formula IV compound 4-(4-Ethylbenzyl)-2-iodophenyl methanol under the effect of inorganic base；
IV
In this step, go back original reagent and be selected from aluminum chloride/triethyl silicane, boron trifluoride/triethyl silicane, aluminum chloride/1,
1,3,3-tetramethyl disiloxane；Preferably aluminum chloride/1,1,3,3-tetramethyl disiloxane makees reducing agent；Aluminum chloride used
Being 1:2 ~ 1:3 with the mol ratio of formula III compound, optimum mole ratio is 1:3.
E, formula IV compound 4-(4-Ethylbenzyl)-2-iodophenyl methanol is dissolved in solvent, and trim,ethylchlorosilane reaction system
Obtain Formula V compound 4-(4-Ethylbenzyl)-2-iodine benzyloxy trimethyl silane, be directly used in step f；
V
The preferred technical scheme of this step, compound (), trim,ethylchlorosilane optimum mole ratio be 1:1.5.
F, step e gained Formula V compound 4-(4-Ethylbenzyl)-2-iodine benzyloxy trimethyl silane is dissolved in solvent, temperature control
Dropping grignard reagent takes off iodine, then prepares Formula IV compound (3 with gluconic acid lactone derivatives reactionR,4S,5R,6R)-2-
(5-(4-Ethylbenzyl)-2-(trimethyl silica methyl) phenyl)-3,4,5-three (trimethylsiloxy group)-6-trimethyl silica first
Base Pentamethylene oxide .-2-alcohol, is directly used in step g；
VI
In this step, described grignard reagent is Konchel type Grignard reagent, selected from isopropylmagnesium chloride/lithium chloride, diisopropyl
Magnesium/lithium chloride etc..Preferably isopropylmagnesium chloride/lithium chloride complex.This step reaction temperature is-30 ~ 0 DEG C, and optimum temperature is-20
℃.Through experiment, the elemental iodine that aromatic ring connects is become bromine, need ultralow temperature-78 DEG C and highly basic n-BuLi reducing agent ability anti-
Should.
G, by step f gained Formula IV compound (3R, 4S, 5R, 6R)-2-(5-(4-Ethylbenzyl)-2-(trimethyl silica methyl)
Phenyl)-3,4,5-tri-(trimethylsiloxy group)-6-trimethyl silica methyl Pentamethylene oxide .-2-alcohol is dissolved in solvent, urging of acid
Under change effect, deprotection closed loop generates oily Formula VII compound；The acid of described catalytic action is selected from methanesulfonic acid.Due to this step
The Tuo Gelie clean crude product crude product obtained contains more impurity, and direct crystallize is extremely difficult.Need crude product VII first derivative chemical conversion
The easily compound VIII of crystallize purification, then deprotection obtains the product that purity is higher.
The clean crude product of VII Tuo Gelie
H, step g is obtained Formula VII grease it is dissolved in solvent, react with methylchloroformate in the presence of acid binding agent and obtain formula
VIII compound (1S, 3'R, 4'S, 5'S, 6'R)-6-(4-ethylphenyl)-6'-(methoxycarbonyl oxygen methyl)-3', 4', 5',
6'-tetrahydrochysene-3', 4', 5'-trimethoxy formyloxy-3H-spiral shell [isobenzofuran-1,2'-pyrans；
VIII
The preparation of formula VIII, uses methylchloroformate proper, and the product obtained is easier crystallize, and purity is high, and other spread out
Raw reagent (ethyl chloroformate, isopropyl chlorocarbonate, acetic anhydride) then crystallize is bad, obtains product purity poor.Acid binding agent is selected from
1-Methylimidazole.；Solvent selected from ethanol, isopropanol, the mixture of methyl tertiary butyl ether(MTBE).Obtain, after refined, the formula that purity is higher
(Ⅷ)。
I, step h gained Formula VIII compound being dissolved in alkaline hydrolysis in solvent, the clean monohydrate of get Tuo Gelie, described solvent is
Diethylene glycol dimethyl ether；
Gained solid chemical compound formula (VIII) is dissolved in alkaline hydrolysis in solvent, is concentrated to give grease through extraction after hydrolysis, then adds
Enter acetone and water mixed solvent is refining to obtain the clean monohydrate of Tuo Gelie.
Concrete reaction scheme is as follows:
Beneficial effect: the invention has the beneficial effects as follows that initiation material is cheap and easily-available, before avoiding due to the variation route of the present invention specially
Profit document needs to use precious metal palladium to make catalyst, and total recovery can reach 21.6%, significantly reduces production cost；In step
In rapid f metal-halogen exchange process, reaction temperature need not reach to report in document-78 DEG C, can realize at-20 DEG C, easily
It is amplified producing；Making of the inflammable and explosive reagent such as n-BuLi and the higher reagent of boron trifluoride toxicity is avoided in step f
With, easy controlled operation and safety；Product and intermediate are prone to purify, and are suitable for industrialized production.
Embodiment 1: to acetyl-o-methyl benzoic acid (compound) preparation
Under room temperature, add in 3000 mL there-necked flasks hydroxymethyl-benzoic acid 91.5 g (0.601 mol), and be sequentially added into chlorine
Imitative 600 mL, acetic anhydride 300 mL and pyridine 10 mL.It is heated to reflux to system molten clearly, and continues stirring 2 h at such a temperature.
Solvent is evaporated off after completion of the reaction, adds water about 2000 mL temperature rising reflux 2 h.TLC detects after completion of the reaction, is cooled to 0 DEG C
And continue to stir 2 h.Sucking filtration, filter cake obtains white solid 103.9 g after 60 DEG C are dried 8 h after 600 mL clear water washings, receives
Rate 89%.
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8
Hz, 2H), 5.19 (s, 2H), 2.15 (s, 2H)。13C NMR (100 MHz, CDCl3) δ 171.8, 170.8,
141.9, 130.4, 129.0, 127.7, 65.4, 20.8。HRMS calculated for C10H14NO4 [M+NH4]+:
212.0917, Found: 212.0905。
Embodiment 2:4-acetyl-o-methyl-3-iodo-benzoic acid (compound) preparation
Under room temperature, in 2000 mL there-necked flasks, it is sequentially added into sodium metaperiodate 38.8 g (0.181 mol), iodine 30.7 g
(0.121mol) with to acetyl-o-methyl benzoic acid 63.0 g (0.324mol), glacial acetic acid 252 mL and acetic anhydride 126 mL.Stir
Mix and be cooled to 5 DEG C, be slowly added dropwise concentrated sulphuric acid 246.9 g (2.469 mol).Finish and be warming up to 25 DEG C and continue at such a temperature
Stir 20 h.Reactant is poured in 420 g trash ices, and add 10% sodium sulfite solution 420 mL.After 0.5 h is stirred at room temperature
Filter, be dried 8 h through 60 DEG C after filter cake water 220 mL washing and obtain off-white color solid 94.5 g, yield 91%.
1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.48
(d, J = 8.0 Hz, 1H), 5.17 (s, 1H), 2.19 (s, 1H)。13C NMR (100 MHz, CDCl3) δ
170.4, 169.5, 144.2, 141.0, 130.2, 130.0, 128.5, 96.9, 69.6, 20.8。HRMS
calculated for C10H13INO4 [M+NH4]+: 337.9884, Found: 337.9875。
Embodiment 3:4-(4-ethylamino benzonitrile acyl group)-2-iodine benzyl acetate (compound) preparation
Under room temperature, be sequentially added in 250 mL there-necked flasks 4-acetyl-o-methyl-3-iodo-benzoic acid 9.0 g (0.028mol), two
Chloromethanes 75 mL and DMF 0.1 mL.Stirring is cooled to 0 ~ 5 DEG C, is slowly added dropwise thionyl chloride 8.3 g (0.070mol).Finish
It is warming up to backflow and continues stirring 3 h at such a temperature.Decompression steams solvent, and products therefrom is the most purified, is directly used in next
Step.
Above-mentioned product is dissolved in 60 mL dichloromethane, adds ethylbenzene 12.0 mL (0.098 mol).Stirring is cooled to 0
DEG C, temperature control less than 10 DEG C adds aluminum chloride 8.2 g (0.062 mol) in batches, finishes and continues stirring 4 h at 0 DEG C.Will
Reactant mixture is poured in 10 mL frozen water and is extracted with ethyl acetate (60 mL × 3).Merge organic facies and concentrate.To concentrate
Middle addition isopropanol 45 mL and water 15 mL, be heated to reflux molten clear after, be slowly dropped to room temperature and continue to stir 2 h.Filter, filter cake
It is dried 8 h through 50 DEG C after washing with isopropanol/water (v/v=2:1) 9 mL and obtains off-white color solid 5.7 g, two step yields 50%.
1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.76-7.72 (m, 3H), 7.47 (d, J
= 7.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 5.18 (s, 2H), 2.75 (q, J = 7.6 Hz,
2H), 2.19 (s, 3H), 1.29 (t, J = 7.6 Hz, 3H)。 13C NMR (100 MHz, CDCl3) δ 194.1,
170.3, 149.9, 142.1, 140.4, 139.1, 134.3, 130.3, 129.6, 128.4, 127.9, 97.2,
69.5, 28.9, 20.8, 15.1。HRMS calculated for C18H18IO3 [M+H]+: 409.0295, Found:
409.0287。
Embodiment 4:4-(4-ethylamino benzonitrile acyl group)-2-iodine benzyl acetate (compound) preparation
Under room temperature, be sequentially added in 250 mL there-necked flasks 4-acetyl-o-methyl-3-iodo-benzoic acid 9.0 g (0.028mol), two
Chloromethanes 75 mL and DMF 0.1 mL.Stirring is cooled to 0 ~ 5 DEG C, is slowly added dropwise thionyl chloride 8.3 g (0.070mol).Finish
It is warming up to backflow and continues stirring 3 h at such a temperature.Decompression steams solvent, and products therefrom is the most purified, is directly used in next
Step.
Above-mentioned product is dissolved in 60 mL dichloromethane, adds ethylbenzene 5.1 mL (0.042mol).Stirring is cooled to 0
DEG C, temperature control less than 10 DEG C adds aluminum chloride 8.2 g (0.062 mol) in batches, finishes and continues stirring 4 h at 0 DEG C.Will
Reactant mixture is poured in 10 mL frozen water and is extracted with ethyl acetate (60 mL × 3).Merge organic facies and concentrate.To concentrate
Middle addition isopropanol 45 mL and water 15 mL, be heated to reflux molten clear after, be slowly dropped to room temperature and continue to stir 2 h.Filter, filter cake
It is dried 8 h through 50 DEG C after washing with isopropanol/water (v/v=2:1) 9 mL and obtains off-white color solid 4.6 g, two step yields 40%.
Embodiment 5:4-(4-ethylamino benzonitrile acyl group)-2-iodine benzyl acetate (compound) preparation
Under room temperature, be sequentially added in 250 mL there-necked flasks 4-acetyl-o-methyl-3-iodo-benzoic acid 9.0 g (0.028mol), two
Chloromethanes 75 mL and DMF 0.1 mL.Stirring is cooled to 0 ~ 5 DEG C, is slowly added dropwise thionyl chloride 8.3 g (0.070mol).Finish
It is warming up to backflow and continues stirring 3 h at such a temperature.Decompression steams solvent, and products therefrom is the most purified, is directly used in next
Step.
Above-mentioned product is dissolved in 60 mL dichloromethane, adds ethylbenzene 15.4 mL (0.126mol).Stirring is cooled to 0
DEG C, temperature control less than 10 DEG C adds aluminum chloride 8.2 g (0.062 mol) in batches, finishes and continues stirring 4 h at 0 DEG C.Will
Reactant mixture is poured in 10 mL frozen water and is extracted with ethyl acetate (60 mL × 3).Merge organic facies and concentrate.To concentrate
Middle addition isopropanol 45 mL and water 15 mL, be heated to reflux molten clear after, be slowly dropped to room temperature and continue to stir 2 h.Filter, filter cake
It is dried 8 h through 50 DEG C after washing with isopropanol/water (v/v=2:1) 9 mL and obtains off-white color solid 4.7 g, two step yields 41%.
Embodiment 6:4-(4-ethylamino benzonitrile acyl group)-2-iodine benzyl acetate (compound) preparation
Under room temperature, be sequentially added in 2000 mL there-necked flasks 4-acetyl-o-methyl-3-iodo-benzoic acid 90 g (0.281mol), two
Chloromethanes 750 mL and DMF 0.5 mL.Stirring is cooled to 0 ~ 5 DEG C, is slowly added dropwise thionyl chloride 83.4 g (0.701mol).Add
Finish and be warming up to backflow and continue stirring 3 h at such a temperature.Decompression steams solvent, and products therefrom is the most purified, is directly used in down
One step.
Above-mentioned product is dissolved in 600 mL dichloromethane, adds ethylbenzene 120 mL (0.983mol).Stirring is cooled to 0
DEG C, temperature control less than 10 DEG C adds aluminum chloride 82.4 g (0.618 mol) in batches, finishes and is warming up to backflow and in this temperature
Lower continuation stirs 0.5 h.Reactant mixture poured in 1000 mL frozen water and be extracted with ethyl acetate (600 mL × 3).Merge
Organic facies also concentrates.In concentrate, add isopropanol 450 mL and water 150 mL, be heated to reflux molten clear after, be slowly dropped to room temperature
And continue to stir 2 h.Filter, be dried 8 h through 50 DEG C after filter cake isopropanol/water (v/v=2:1) 90 mL washing and obtain off-white color
Solid 71.2 g, two step yields 62%.
Embodiment 7:4-(4-Ethylbenzyl)-2-iodophenyl methanol (compound) preparation
Under room temperature, in 500 mL there-necked flasks, it is sequentially added into 4-(4-ethylamino benzonitrile acyl group)-2-iodo-benzyl acetate 25.0 g
(0.061 mol), dichloromethane 183 mL, acetonitrile 183 mL and triethyl silicane 14.2 g (0.122 mol).Stirring is cooled to
0 DEG C, dropping boron trifluoride ether solution 17.3 g (0.122 mol).Finish and be warming up to room temperature and continue stirring at such a temperature
20 h.TLC detects after completion of the reaction, is poured into by reactant liquor in 500 mL frozen water and is extracted with ethyl acetate (100 mL × 3), closes
And organic facies concentrating under reduced pressure.Products therefrom is the most purified, is directly used in next step.
Above-mentioned product is dissolved in 80 mL oxolanes and 80 mL methanol, and adds the sodium hydrate aqueous solution 80 of 7.5%
mL.Finish and be stirred at room temperature 2 h.Filtering, filter cake is dried 8 h with 100 mL water washings by 70 DEG C and obtains white solid 17.5
G, two step yields 81%.
1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.18
(d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.7 Hz, 2H), 7.08 (d, J = 7.7 Hz, 2H), 4.64
(s, 2H), 3.89 (s, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.86 (br s, 1H), 1.22 (t, J
= 7.6 Hz, 3H)。13C NMR (100 MHz, CDCl3) δ 142.9, 142.2, 140.3, 139.4, 137.3,
129.1, 128.7, 128.5, 128.0, 97.8, 69.0, 40.5, 28.4, 15.5。HRMS calculated for
C16H21INO [M+NH4]+: 370.0662, Found: 370.0662。
Embodiment 8:4-(4-Ethylbenzyl)-2-iodophenyl methanol (compound) preparation
Under room temperature, in 200 mL there-necked flasks, it is sequentially added into 4-(4-ethylamino benzonitrile acyl group)-2-iodo-benzyl acetate 5.0 g
(0.012 mol), dichloromethane 40 mL, acetonitrile 40 mL and triethyl silicane 2.8 g (0.024 mol).Stirring is cooled to 0
DEG C, add aluminum chloride 4.9 g (0.037 mol) in batches.Finish and be warming up to room temperature and continue stirring 20 h at such a temperature.
TLC detects after completion of the reaction, is poured into by reactant liquor in 100 mL frozen water and is extracted with ethyl acetate (100 mL × 3), being associated with
Machine the most also concentrating under reduced pressure.Products therefrom is the most purified, is directly used in next step.
Above-mentioned product is dissolved in 15 mL oxolanes and 15 mL methanol, and adds the sodium hydrate aqueous solution 15 of 7.5%
mL.Finish and be stirred at room temperature 2 h.After decompression is spin-dried for solvent, crude product obtains white solid 1.8 g through column chromatography purification, and two steps are received
Rate 42%.
Embodiment 9:4-(4-Ethylbenzyl)-2-iodophenyl methanol (compound) preparation
Under room temperature, in 200 mL there-necked flasks, it is sequentially added into 4-(4-ethylamino benzonitrile acyl group)-2-iodo-benzyl acetate 5.0 g
(0.012 mol), dichloromethane 40 mL, acetonitrile 40 mL and 1,1,3,3-tetramethyl disiloxane 3.3 g (0.024 mol).
Stirring is cooled to 0 DEG C, adds aluminum chloride 3.2 g (0.024 mol) in batches.Finish and be warming up to room temperature at such a temperature
Continue stirring 20 h.TLC detects after completion of the reaction, is poured into by reactant liquor in 100 mL frozen water and is extracted with ethyl acetate (50mL
× 3), organic facies concentrating under reduced pressure are merged.Products therefrom is the most purified, is directly used in next step.
Above-mentioned product is dissolved in 15 mL oxolanes and 15 mL methanol, and adds the sodium hydrate aqueous solution 15 of 15%
mL.Finish and be stirred at room temperature 4 h.Filtering, filter cake is dried 8 h with 20 mL water washings by 70 DEG C and obtains white solid 3.5 g,
Two step yields 82%.
Embodiment 10:4-(4-Ethylbenzyl)-2-iodophenyl methanol (compound) preparation
Under room temperature, in 1000 mL there-necked flasks, it is sequentially added into 4-(4-ethylamino benzonitrile acyl group)-2-iodo-benzyl acetate 50.0 g
(0.122 mol), dichloromethane 366 mL, acetonitrile 366 mL and 1,1,3,3-tetramethyl disiloxane 32.8 g (0.244
mol).Stirring is cooled to 0 DEG C, adds aluminum chloride 48.8 g (0.366 mol) in batches.Finish and be warming up to room temperature and at this
At a temperature of continue stirring 20 h.TLC detects after completion of the reaction, is poured into by reactant liquor in 1000 mL frozen water and extracts by ethyl acetate
Take (200 mL × 3), merge organic facies concentrating under reduced pressure.Products therefrom is the most purified, is directly used in next step.
Above-mentioned product is dissolved in 160 mL oxolanes and 160 mL methanol, and adds the sodium hydrate aqueous solution of 15%
160 mL.Finish and be stirred at room temperature 4 h.Filtering, filter cake is dried 8 h with 200 mL water washings by 70 DEG C and obtains white solid
39.2 g, two step yields 91%.
Embodiment 11:4-(4-Ethylbenzyl)-2-iodine benzyloxy trimethyl silane (compound) preparation
Under room temperature, in 500 mL there-necked flasks, it is sequentially added into 4-(4-Ethylbenzyl)-2-iodophenyl methanol 21.2 g (0.060
Mol), oxolane 200 mL and triethylamine 12.1 g (0.120 mol), stirring be cooled to 0 DEG C, be slowly added dropwise trimethyl chlorine
Silane 9.8 g (0.090 mol).Finish and be warming up to 25 DEG C and continue to stir 1 h.In reactant liquor, add water 240 mL and use
Ethyl acetate extraction (240 mL × 3).Merge organic facies and be dried with anhydrous sodium sulfate.Filter, after concentrating under reduced pressure, obtain grease
25.5 g, yield 98%.Products therefrom is the most purified, is directly used in next step.
Embodiment 12:(3R,4S,5R,6R)-2-(5-(4-Ethylbenzyl)-2-(trimethyl silica methyl) phenyl)-3,4,
5-tri-(trimethylsiloxy group)-6-trimethyl silica methyl Pentamethylene oxide .-2-alcohol (compound) preparation
Under room temperature, grease 4-(4-Ethylbenzyl)-2-iodine benzyloxy trimethyl silane 25.5 g (0.059 mol) is dissolved in 56
In mL anhydrous tetrahydro furan, stirred under nitrogen atmosphere is cooled to 0 DEG C, is slowly added dropwise isopropylmagnesium chloride lithium chloride (1.3 M tetra-
Hydrogen tetrahydrofuran solution) 50.0 mL (0.065 mol), finish and continue stirring 20 min at such a temperature.Control temperature less than 0 DEG C
It is slowly added dropwise (3R,4S,5R,6R)-3,4,5-three or three silyloxy-6-front three silica methyl tetrahydrochysene-2H-pyran-2-one 33.6
g ( 0.072 mol).At 0 DEG C, stirring 1 h is continued after finishing.TLC detects after completion of the reaction, drips in reaction system
10% aqueous ammonium chloride solution 120 mL, finishes and is warmed to room temperature continuation stirring 0.5 h and is extracted with ethyl acetate (60 mL × 3).Close
And organic facies being dried with anhydrous sodium sulfate.Filtering, obtain pale yellow oil after concentrating under reduced pressure, this product is not required to purification, directly
For next step.
The preparation of the clean crude product of embodiment 13: Tuo Gelie
Under room temperature, being dissolved in 150 mL oxolanes by gained grease in embodiment 12, stirring is cooled to 0 DEG C and slowly drips
Add methanesulfonic acid methanol solution (0.24 g methanesulfonic acid is dissolved in 50 mL methanol).Finish and continue stirring 15 h at such a temperature.To reaction
Liquid adds 400 mL saturated sodium bicarbonate solutions and after decompression steams major part oxolane, be sequentially added into glycol dimethyl ether
200 mL, water 200 mL and normal hexane 300 mL.Separating organic facies, aqueous phase is extracted with ethyl acetate (200 mL × 3).It is associated with
Machine phase is also dried with anhydrous sodium sulfate.Filtering, the clean crude product of get Tuo Gelie after concentrating under reduced pressure, this product is not required to purification, is directly used in
Next step.
Embodiment 14:(1S,3'R,4'S,5'S,6'R)-6-(4-ethylphenyl)-6'-(methoxycarbonyl oxygen methyl)-3',
4', 5', 6'-tetrahydrochysene-3', 4', 5'-trimethoxy formyloxy-3H-spiral shell [isobenzofuran-1,2'-pyrans] (compound VIII)
Preparation
Under room temperature, gained grease in embodiment 13 is dissolved in 90 mL acetone and adds 1-Methylimidazole. 49.44 g (0.602
mol).Stirring is cooled to 0 DEG C, is slowly added dropwise methylchloroformate 37.2 g (0.394 mol).Finish and be warming up to 25 DEG C and at this
At a temperature of continue stirring 1 h.In reactant liquor, add water 120 mL and be extracted with ethyl acetate (60 mL × 3).Merge organic facies
And concentrating under reduced pressure.Ethanol 120 mL, methyl tertiary butyl ether(MTBE) 20 mL and isopropanol 30 mL it is sequentially added in concentrate.Heat back
Flow molten clear after, slow cooling to 25 DEG C room temperature also continues to stir 2 h.Filter, filter cake ethanol/isopropanol mixed liquor (v/v=3:
1) rear 50 DEG C of dry 6 h of 10 mL washings obtain white solid 12.6 g, four step yields 34%.
1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.14
(d, J = 8.0 Hz, 1H), 7.12-7.07 (m, 4H), 5.51 (t, J = 9.6 Hz, 1H), 5.41 (d, J
= 9.9 Hz, 1H), 5.21-5.10 (m, 3H), 4.39-4.36 (m, 1H), 4.35-4.31 (m, 1H), 4.25-
4.22 (m, 1H), 3.96 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.50
(s, 3H), 2.60 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H)。13C NMR (100 MHz,
CDCl3) δ 155.3, 154.9, 154.7, 154.4, 141.9, 141.4, 138.0, 137.9, 135.2,
131.0, 128.7, 127.9, 123.2, 120.9, 108.4, 75.5, 74.6, 73.1, 72.6, 69.4, 65.6,
55.3, 55.1, 54.9, 54.9, 41.3, 28.3, 15.5。HRMS calculated for C30H38NO14 [M+NH4
]+: 636.2287, Found: 636.2280。
Embodiment 15:(3R,4S,5R,6R)-2-(5-(4-Ethylbenzyl)-2-(trimethyl silica methyl) phenyl)-3,4,
5-tri-(trimethylsiloxy group)-6-trimethyl silica methyl Pentamethylene oxide .-2-alcohol (compound) preparation
Under room temperature, 4-(4-Ethylbenzyl)-2-iodine benzyloxy trimethyl silane 25.5 g (0.059 mol) is dissolved in 56 mL without
In water oxolane, stirred under nitrogen atmosphere is cooled to-30 DEG C, is slowly added dropwise isopropylmagnesium chloride lithium chloride (1.3 M tetrahydrochysenes
Tetrahydrofuran solution) 50.0 mL (0.065 mol), finish and continue stirring 40 min at such a temperature.Control temperature less than-15 DEG C to delay
Slow dropping (3R,4S,5R,6R)-3,4,5-three or three silyloxy-6-front three silica methyl tetrahydrochysene-2H-pyran-2-one 33.6 g
(0.072 mol).Finish and be warming up to 0 DEG C and continue stirring 1 h at such a temperature.TLC detects after completion of the reaction, to reaction system
Middle dropping 10% aqueous ammonium chloride solution 120 mL, finish be warmed to room temperature continuation stirring 0.5 h and be extracted with ethyl acetate (60 mL ×
3).Merge organic facies and be dried with anhydrous sodium sulfate.Filtering, obtain pale yellow oil after concentrating under reduced pressure, this product is not required to purification,
It is directly used in next step.
The preparation of the clean crude product of embodiment 16: Tuo Gelie
Under room temperature, being dissolved in 150 mL oxolanes by gained grease in embodiment 15, stirring is cooled to 0 DEG C and slowly drips
Add methanesulfonic acid methanol solution (0.24 g methanesulfonic acid is dissolved in 50 mL methanol).Finish and continue stirring 15 h at such a temperature.To reaction
Liquid adds 400 mL saturated sodium bicarbonate solutions and after decompression steams major part oxolane, be sequentially added into glycol dimethyl ether
200 mL, water 200 mL and normal hexane 300 mL.Separating organic facies, aqueous phase is extracted with ethyl acetate (200 mL × 3).It is associated with
Machine phase is also dried with anhydrous sodium sulfate.Filtering, the clean crude product of get Tuo Gelie after concentrating under reduced pressure, this product is not required to purification, is directly used in
Next step.
Embodiment 17:(1S,3'R,4'S,5'S,6'R)-6-(4-ethylphenyl)-6'-(methoxycarbonyl oxygen methyl)-3',
4', 5', 6'-tetrahydrochysene-3', 4', 5'-trimethoxy formyloxy-3H-spiral shell [isobenzofuran-1,2'-pyrans] (compound VIII)
Preparation
Under room temperature, gained grease in embodiment 16 is dissolved in 90 mL acetone and adds 1-Methylimidazole. 49.44 g
(0.602 mol).Stirring is cooled to 0 DEG C, is slowly added dropwise methylchloroformate 37.2 g (0.394 mol).Finish and be warming up to 25
DEG C and at such a temperature continue stirring 1 h.In reactant liquor, add water 120 mL and be extracted with ethyl acetate (60 mL × 3).Close
And organic facies concentrating under reduced pressure.Ethanol 120 mL, methyl tertiary butyl ether(MTBE) 20 mL and isopropanol 30 it is sequentially added in concentrate
mL.Be heated to reflux molten clear after, slow cooling to 25 DEG C room temperature also continues to stir 2 h.Filter, filter cake ethanol/isopropanol mixing
Rear 50 DEG C of dry 6 h of liquid (v/v=3:1) 10 mL washing obtain white solid 21.6 g, four step yields 58%.
Embodiment 18:(3R,4S,5R,6R)-2-(5-(4-Ethylbenzyl)-2-(trimethyl silica methyl) phenyl)-3,4,
5-tri-(trimethylsiloxy group)-6-trimethyl silica methyl Pentamethylene oxide .-2-alcohol (compound) preparation
Under room temperature, it is anhydrous that 4-(4-Ethylbenzyl)-2-iodine benzyloxy trimethyl silane 25.5 g (0.059 mol) is dissolved in 56 mL
In oxolane, stirred under nitrogen atmosphere is cooled to-20 DEG C, is slowly added dropwise isopropylmagnesium chloride lithium chloride (1.3 M tetrahydrochysene furans
Mutter solution) 50.0 mL (0.065 mol), finish and continue stirring 0.5 h at such a temperature.Control temperature less than-15 DEG C slow
Dropping (3R,4S,5R,6R)-3,4,5-three or three silyloxy-6-front three silica methyl tetrahydrochysene-2H-pyran-2-one 33.6 g
(0.072 mol).Finish and be warming up to 0 DEG C and continue stirring 1 h at such a temperature.TLC detects after completion of the reaction, to reactant
System drips 10% aqueous ammonium chloride solution 120 mL, finishes and be warmed to room temperature continuation stirring 0.5 h and be extracted with ethyl acetate (60 mL
×3).Merge organic facies and be dried with anhydrous sodium sulfate.Filtering, obtain pale yellow oil after concentrating under reduced pressure, this product is not required to pure
Change, be directly used in next step.
The preparation of the clean crude product of embodiment 19: Tuo Gelie
Under room temperature, being dissolved in 150 mL oxolanes by gained grease in embodiment 18, stirring is cooled to 0 DEG C and slowly drips
Add methanesulfonic acid methanol solution (0.24 g methanesulfonic acid is dissolved in 50 mL methanol).Finish and continue stirring 15 h at such a temperature.To reaction
Liquid adds 400 mL saturated sodium bicarbonate solutions and after decompression steams major part oxolane, be sequentially added into glycol dimethyl ether
200 mL, water 200 mL and normal hexane 300 mL.Separating organic facies, aqueous phase is extracted with ethyl acetate (200 mL × 3).It is associated with
Machine phase is also dried with anhydrous sodium sulfate.Filtering, the clean crude product of get Tuo Gelie after concentrating under reduced pressure, this product is not required to purification, is directly used in
Next step.
Embodiment 20:(1S,3'R,4'S,5'S,6'R)-6-(4-ethylphenyl)-6'-(methoxycarbonyl oxygen methyl)-3',
4', 5', 6'-tetrahydrochysene-3', 4', 5'-trimethoxy formyloxy-3H-spiral shell [isobenzofuran-1,2'-pyrans] (compound VIII)
Preparation
Under room temperature, gained grease in embodiment 19 is dissolved in 90 mL acetone and adds 1-Methylimidazole. 49.44 g
(0.602 mol).Stirring is cooled to 0 DEG C, is slowly added dropwise methylchloroformate 37.2 g (0.394 mol).Finish and be warming up to 25
DEG C and at such a temperature continue stirring 1 h.In reactant liquor, add water 120 mL and be extracted with ethyl acetate (60 mL × 3).Close
And organic facies concentrating under reduced pressure.Ethanol 120 mL, methyl tertiary butyl ether(MTBE) 20 mL and isopropanol 30 it is sequentially added in concentrate
mL.Be heated to reflux molten clear after, slow cooling to 25 DEG C room temperature also continues to stir 2 h.Filter, filter cake ethanol/isopropanol mixing
Rear 50 DEG C of dry 6 h of liquid (v/v=3:1) 10 mL washing obtain white solid 22.7 g, four step yields 61%.
The preparation of the clean monohydrate of embodiment 21: Tuo Gelie
Under room temperature, in 250 mL there-necked flasks, it is sequentially added into (1S,3'R,4'S,5'S,6'R)-6-(4-ethylphenyl)-6'-(first
Oxygen methanoyl methyl)-3', 4', 5', 6'-tetrahydrochysene-3', 4', 5'-trimethoxy formyloxy-3H-spiral shell [isobenzofuran-1,2'-
Pyrans] 15.0 g (0.024 mol), glycol dimethyl ether 90 mL and 16% sodium hydrate aqueous solution 72 mL.3 hs are stirred at room temperature
After, add hydrochloric acid regulation pH value of reaction system and be 6 ~ 7 and be extracted with ethyl acetate (60 mL × 3).Merge organic facies and use anhydrous sulfur
Acid sodium is dried, and obtains off-white color foaming solid after concentrating under reduced pressure.
Above-mentioned solid is dissolved in 30 mL acetone stir molten clearly.Temperature control is slowly added dropwise water 120 mL(about 2 h) at 20 DEG C,
Finish and backward reactant liquor adds crystal seed 0.1 g and continues stirring 1 h at such a temperature.Slow cooling is to 0 DEG C and continues stirring
2 h.Filter, after the washing of filter cake pure water, obtain white solid 7.7 g, two step yields 79% through 30 DEG C of vacuum drying 10 h.
1H NMR (400 MHz, MeOD) δ 7.23-7.18 (m, 3H), 7.12-7.08(m, 4H), 5.13
(d, J = 12.4 Hz, 1H), 5.07 (d, J = 12.4 Hz, 1H), 3.96 (s, 2H), 3.83-3.73 (m,
4H), 3.65 (dd, J = 11.9, 5.5 Hz, 1H), 3.41-3.47 (m, 1H), 2.59 (q, J = 7.6 Hz,
2H), 1.19 (t, J = 7.6 Hz, 3H)。 13C NMR (100 MHz, MeOD) δ 143.2, 142.6, 140.2,
139.9, 139.7, 131.2, 129.9, 128.9, 123.6, 121.8, 111.6, 76.4, 76.2, 74.9,
73.4, 71.9, 62.8, 42.3, 29.5, 16.3。HRMS calculated for C22H27O6 [M+H]+:
387.1802, Found: 387.1805。
Claims (10)
1. the preparation method of the clean monohydrate of Yi Zhong Tuo Gelie, it is characterised in that comprise the following steps:
A, with to hydroxymethyl-benzoic acid for raw material under the effect of acid binding agent through acetylation, hydrolysis obtain compound of formula I to second
Acyloxymethyl benzoic acid；Wherein, acetylation reagent is selected from acetic anhydride or chloroacetic chloride；
I
B, acetyl-o-methyl benzoic acid is dissolved in solvent by compound of formula I, under iodo reagent effect, obtains Formula II compound
The iodo-benzoic acid of 4-acetyl-o-methyl-3-；Wherein, iodo reagent is selected from N-chlorosuccinimide and sodium iodide, two chlorosulfonylations
Tetramethyl-ammonium, KI/KIO3/H+、HIO4/H2SO4；
II
C. the Formula II compound 4-iodo-benzoic acid of acetyl-o-methyl-3-and chlorination reagent are made acyl chlorides, under lewis acid effect
Formula III compound 4-(4-ethylamino benzonitrile acyl group)-2-iodine benzyl acetate is generated with ethylbenzene generation Friedel-Crafts reaction；Wherein, chlorination
Reagent is selected from thionyl chloride, and lewis acid is selected from aluminum chloride, compoundIt is 1:2.2 with the mol ratio of aluminum chloride；CompoundBeing 1:1.5 ~ 1:4.5 with the mol ratio of ethylbenzene, reaction temperature is 0 ~ 40 DEG C；
III
D, formula III compound 4-(4-ethylamino benzonitrile acyl group)-2-iodine benzyl acetate is dissolved in solvent, under reducing agent effect
Reduction, then hydrolysis obtains formula IV compound 4-(4-Ethylbenzyl)-2-iodophenyl methanol under the effect of inorganic base；Also original reagent
Selected from aluminum chloride/triethyl silicane, boron trifluoride/triethyl silicane, aluminum chloride/1,1,3,3-tetramethyl disiloxane；
IV
E, formula IV compound 4-(4-Ethylbenzyl)-2-iodophenyl methanol is dissolved in solvent, and trim,ethylchlorosilane reaction system
Obtain Formula V compound 4-(4-Ethylbenzyl)-2-iodine benzyloxy trimethyl silane, be directly used in step f；
V
F, step e gained Formula V compound 4-(4-Ethylbenzyl)-2-iodine benzyloxy trimethyl silane is dissolved in solvent, temperature control
Dropping grignard reagent takes off iodine, then prepares Formula IV compound (3R, 4S, 5R, 6R)-2-with gluconic acid lactone derivatives reaction
(5-(4-Ethylbenzyl)-2-(trimethyl silica methyl) phenyl)-3,4,5-three (trimethylsiloxy group)-6-trimethyl silica first
Base Pentamethylene oxide .-2-alcohol, is directly used in step g；Described grignard reagent is Konchel type Grignard reagent, selected from isopropyl chlorination
Magnesium/lithium chloride, diisopropyl magnesium/lithium chlorides etc., reaction temperature is-30 ~ 0 DEG C；
VI
G, by step f gained Formula IV compound (3R, 4S, 5R, 6R)-2-(5-(4-Ethylbenzyl)-2-(trimethyl silica methyl)
Phenyl)-3,4,5-tri-(trimethylsiloxy group)-6-trimethyl silica methyl Pentamethylene oxide .-2-alcohol is dissolved in solvent, urging of acid
Under change effect, deprotection closed loop generates oily Formula VII compound；The acid of described catalytic action is selected from methanesulfonic acid；
The clean crude product of VII Tuo Gelie
H, step g is obtained Formula VII grease it is dissolved in solvent, react with methylchloroformate in the presence of acid binding agent and obtain formula
VIII compound (1S, 3'R, 4'S, 5'S, 6'R)-6-(4-ethylphenyl)-6'-(methoxycarbonyl oxygen methyl)-3', 4', 5',
6'-tetrahydrochysene-3', 4', 5'-trimethoxy formyloxy-3H-spiral shell [isobenzofuran-1,2'-pyrans；
VIII
I, step h gained Formula VIII compound being dissolved in alkaline hydrolysis in solvent, the clean monohydrate of get Tuo Gelie, described solvent is
Diethylene glycol dimethyl ether；
。
2., according to preparation method described in claim 1, it is characterised in that in the preparation process of compound of formula I, acylating reagent is
Acetic anhydride.
3., according to preparation method described in claim 1, it is characterised in that in the preparation process of Formula II compound, solvent is second
Acid/acetic anhydride mixture；Iodination reagent is iodine and sodium metaperiodate mixture.
4. according to preparation method described in claim 1, it is characterised in that formulaIn the preparation process of compound, Formula II compound:
The mol ratio of ethylbenzene is 1:3.5；Reaction temperature is 40 DEG C.
5. according to preparation method described in claim 1, it is characterised in that by formula described in Step dCompound is dissolved in solvent,
Reducing agent is selected from aluminum chloride/1,1,3,3-tetramethyl disiloxane；The mol ratio of aluminum chloride and formula III compound be 1:2 ~
1:3。
6. according to preparation method described in claim 1, it is characterised in that by formula described in Step dCompound is dissolved in solvent,
Reducing agent is selected from aluminum chloride/1,1,3,3-tetramethyl disiloxane；Aluminum chloride is 1:3 with the mol ratio of formula III compound.
7. according to preparation method described in claim 1, it is characterised in that in step e, compound (), trim,ethylchlorosilane
Good mol ratio is 1:1.5.
8. according to preparation method described in claim 1, it is characterised in that in f step, Grignard reagent selected from isopropylmagnesium chloride/
Lithium chloride complex, reaction temperature is-20 DEG C.
9. according to preparation method described in claim 1, it is characterised in that formulaPreparation process in, described acid is methanesulfonic acid.
10., according to preparation method described in claim 1, it is characterised in that in the preparation process of formula VIII, described acid binding agent is 1-
Methylimidazole..
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| CN113480497A (en) * | 2021-07-27 | 2021-10-08 | 山东铂源药业有限公司 | Synthesis method of empagliflozin key intermediate |
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