CN106188190B - Preparation method of tolgliflozin monohydrate - Google Patents
Preparation method of tolgliflozin monohydrate Download PDFInfo
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- CN106188190B CN106188190B CN201610598721.6A CN201610598721A CN106188190B CN 106188190 B CN106188190 B CN 106188190B CN 201610598721 A CN201610598721 A CN 201610598721A CN 106188190 B CN106188190 B CN 106188190B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 150000004682 monohydrates Chemical class 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- -1 torsemide monohydrate Chemical class 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 229960005461 torasemide Drugs 0.000 claims abstract description 6
- WWYFPDXEIFBNKE-UHFFFAOYSA-N 4-(hydroxymethyl)benzoic acid Chemical compound OCC1=CC=C(C(O)=O)C=C1 WWYFPDXEIFBNKE-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 51
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 24
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 21
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 10
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Substances CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 10
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 9
- 239000007818 Grignard reagent Substances 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 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
- 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 7
- 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 7
- 150000004795 grignard reagents Chemical class 0.000 claims description 7
- 229910015900 BF3 Inorganic materials 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 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
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical group CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 5
- DLMONAQGOXNQGP-UHFFFAOYSA-N 4-(acetyloxymethyl)benzoic acid Chemical compound CC(=O)OCC1=CC=C(C(O)=O)C=C1 DLMONAQGOXNQGP-UHFFFAOYSA-N 0.000 claims description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 239000005051 trimethylchlorosilane Substances 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 claims description 4
- 239000012336 iodinating agent Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 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
- 230000021736 acetylation Effects 0.000 claims description 3
- 238000006640 acetylation reaction Methods 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 239000012345 acetylating agent Substances 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 229940007550 benzyl acetate Drugs 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 238000005831 deiodination reaction Methods 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical group COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 230000002083 iodinating effect Effects 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
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- FUNMSHCNGVSXHD-UHFFFAOYSA-N tetramethylammonium dichloroiodate(i) Chemical compound Cl[I-]Cl.C[N+](C)(C)C FUNMSHCNGVSXHD-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 claims 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 239000002516 radical scavenger Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 18
- 125000002346 iodo group Chemical group I* 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000006722 reduction reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000000543 intermediate Substances 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
- DKWYZBFGYJOCJX-UHFFFAOYSA-N [iodo(phenyl)methyl]benzene Chemical group C=1C=CC=CC=1C(I)C1=CC=CC=C1 DKWYZBFGYJOCJX-UHFFFAOYSA-N 0.000 abstract description 2
- 230000010933 acylation Effects 0.000 abstract description 2
- 238000005917 acylation reaction Methods 0.000 abstract description 2
- 125000006840 diphenylmethane group Chemical group 0.000 abstract description 2
- 239000002360 explosive Substances 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000003756 stirring Methods 0.000 description 52
- 238000007792 addition Methods 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 22
- 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
- 239000007787 solid Substances 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- WPOPPYYDVYDYLJ-UHFFFAOYSA-N [4-(4-ethylbenzoyl)-2-iodophenyl]methyl acetate Chemical compound CCc1ccc(cc1)C(=O)c1ccc(COC(C)=O)c(I)c1 WPOPPYYDVYDYLJ-UHFFFAOYSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 239000012141 concentrate Substances 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- YYIHNJLQJXDLPQ-UHFFFAOYSA-N 4-(acetyloxymethyl)-3-iodobenzoic acid Chemical compound CC(=O)OCC1=CC=C(C(O)=O)C=C1I YYIHNJLQJXDLPQ-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000010792 warming 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
- 238000004440 column chromatography Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VXEVXBMLHQPKGA-UHFFFAOYSA-N (2,4-dibromophenyl)methanol Chemical compound OCC1=CC=C(Br)C=C1Br VXEVXBMLHQPKGA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 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
- 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 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 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
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 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
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 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
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of torsemide monohydrate. The route takes p-hydroxymethylbenzoic acid as an initial material, an iodo diphenylmethane skeleton is obtained through acylation, iodo, Friedel-crafts and reduction reactions, splicing of the diphenylmethane skeleton and a sugar ring is realized under mild conditions by utilizing the active characteristic of iodo matters and the action of isopropyl magnesium chloride lithium chloride, and the eleven-step total yield is 22%. The method has the advantages of high yield, good selectivity, low production cost, mild reaction conditions, no use of flammable, explosive and highly toxic reagents, easy purification of products and intermediates, and suitability for industrial production.
Description
Technical Field
The invention relates to a novel preparation method of torsemide monohydrate, belonging to the field of pharmaceutical chemicals.
Background
The torsagliflozin monohydrate was developed by the combination of Chinese and foreign pharmaceuticals, cenofine-amphetate and japan, and was marketed in japan in 2014. The novel SGLT2 inhibitor has the advantages of higher drug selectivity, capability of reducing blood sugar and reducing body weight, and no obvious side effect.
The literature on synthesis disclosed at present is all published by the pharmaceutical companies in China and abroad, and the specific details are as follows:
(1) the synthetic route of trogliflozin is published by the pharmaceutical company in China and China in Japan for the first time in 2006 (EP1852439A1), and the synthetic route takes 2-bromoterephthalic acid as a starting material and obtains a product through eight steps of reduction, hydroxyl protection, addition, ring closure, oxidation, addition, reduction and hydrogenolysis. The process route mainly has the following defects: the yield is low, the yield of the second step and the fifth step is only 18 percent and 33 percent, and the total yield is only 1.6 percent; secondly, all intermediates and products need to be purified by column chromatography, and are not suitable for industrial production; palladium carbon is used in the reaction, which is expensive, and palladium belongs to a class of metal and is not beneficial to product quality control; fourthly, butyl lithium is used in the addition of the gluconolactone derivative and the benzene ring in the third step, the reaction temperature is required to be-78 ℃, the reaction is an ultralow temperature reaction, the conditions are harsh, the butyl lithium is extremely flammable, and a large potential safety hazard exists; boron trifluoride used in the reaction is decomposed into extremely toxic fluoride smoke in the air, which is not favorable for labor protection.
(2) A new synthetic method of the trogliflozin monohydrate (EP2308886A1) is developed in the year of the Chinese and foreign pharmaceutical company, namely, the 2009, and the new synthetic method takes 2, 4-dibromobenzyl alcohol as a starting material and obtains a product through eight steps of hydroxyl protection, addition, ring closure, reduction and the like. Compared with the first route, all intermediates and products in the first route do not need column chromatography purification, and the yield is improved to 68 percent; the use of high-risk reagent boron trifluoride is avoided, and the production process is safer. However, the metal-halogen exchange reaction in the route still needs to be carried out at-78 ℃, so that the production process is not easy to be amplified, and meanwhile, the price of 2, 4-dibromobenzyl alcohol is high, and the use of noble metals such as Pd/C and the like causes high production cost, so that the method is not suitable for industrial production.
Disclosure of Invention
In view of the disadvantages of the above processes, it is an object of the present invention to provide an economical and environmentally friendly process for the preparation of torsemide monohydrate.
The technical scheme of the invention is as follows: cheap and easily available p-hydroxymethylbenzoic acid is used as a starting material, an iodo diphenylmethane skeleton is obtained through acylation, iodo, Friedel-crafts and reduction reactions, meanwhile, the active characteristic of an iodo substance is utilized, a Grignard reagent isopropyl magnesium chloride/lithium chloride is used for replacing butyl lithium, the diphenylmethane skeleton and a sugar ring can be spliced at the temperature of minus 20 ℃, a crude product of the tolgliflozin is prepared through cyclization and deprotection, and then the refined product is obtained through two-step purification. The synthesis process comprises the following steps:
a. p-hydroxymethylbenzoic acid is taken as a raw material, and is subjected to acetylation and hydrolysis under the action of an acid-binding agent to obtain p-acetoxymethylbenzoic acid of a compound shown in a formula I;
in this step, the acetylating agent is usually acetic anhydride or acetyl chloride, preferably acetic anhydride. Mixed acid anhydride is generated in the reaction, and water is added in the post-treatment process to hydrolyze the mixed acid anhydride into acid.
b. Dissolving a compound p-acetoxymethyl benzoic acid shown in the formula I in a solvent, and obtaining a compound 4-acetoxymethyl-3-iodine-benzoic acid shown in the formula II under the action of an iodinating reagent;
in this step, the iodo group of the aromatic ring has multiple iodo reagents, such as N-iodosuccinimide and sodium iodide, tetramethylammonium dichloroiodate, KI/KIO3/H+、HIO4/H2SO4And the like. It was found through research that a relatively ideal iodination effect can be obtained by using an acetic acid/acetic anhydride mixture as a reaction solvent, an iodinating agent as a mixture of iodine and sodium periodate as iodinating agents.
c. Preparing acyl chloride from a compound 4-acetoxymethyl-3-iodine-benzoic acid shown in a formula II and a chlorinating agent, and performing Friedel-crafts reaction with ethylbenzene under the action of Lewis acid to generate a compound 4- (4-ethylbenzoyl) -2-iodine benzyl acetate shown in a formula III;
in the step, the chlorination reagent is thionyl chloride, so that the use and the post-treatment are convenient; the catalyst Lewis acid used in the Friedel-crafts reaction adopts aluminum trichloride, and the optimal molar ratio of a substrate compound to the aluminum trichloride is 1: 2.2; the molar ratio of the substrate to the ethylbenzene used in the reaction in the step is 1: 1.5-1: 4.5, and the optimal molar ratio is 1: 3.5; the reaction temperature in this step is 0-40 ℃, and the optimal reaction temperature is 40 ℃.
d. Dissolving a compound 4- (4-ethylbenzoyl) -2-iodobenzyl acetate in a solvent, reducing the solution under the action of a reducing agent, and hydrolyzing the solution under the action of inorganic base to obtain a compound 4- (4-ethylbenzyl) -2-iodobenzyl methanol in a formula IV;
in the step, the reducing agent is selected from aluminum trichloride/triethylsilane, boron trifluoride/triethylsilane, aluminum trichloride/1, 1,3, 3-tetramethyldisiloxane; preferably, aluminum trichloride/1, 1,3, 3-tetramethyldisiloxane is used as a reducing agent; the molar ratio of the aluminum trichloride to the compound shown in the formula III is 1:2-1:3, and the optimal molar ratio is 1:3.
e. Dissolving the compound 4- (4-ethylbenzyl) -2-iodophenyl methanol in the formula IV in a solvent, and reacting with trimethylchlorosilane to obtain the compound 4- (4-ethylbenzyl) -2-iodobenzyloxy trimethylsilane in the formula V, wherein the compound is directly used in the step f;
according to the preferable technical scheme of the step, the optimal molar ratio of the compound (IV) to the trimethylchlorosilane is 1: 1.5.
f. Dissolving the compound 4- (4-ethylbenzyl) -2-iodobenzyloxy trimethyl silane in the formula V obtained in the step e in a solvent, dropwise adding a Grignard reagent at a controlled temperature for deiodination, and then reacting with a gluconolactone derivative to prepare a compound (3R,4S,5R,6R) -2- (5- (4-ethylbenzyl) -2- (trimethylsiloxymethyl) phenyl) -3,4, 5-tris (trimethylsiloxy) -6-trimethylsiloxymethyl tetrahydropyran-2-ol in a formula VI, wherein the compound is directly used in the step g;
in this step, the grignard reagent is a konichel type grignard reagent selected from isopropyl magnesium chloride/lithium chloride, diisopropyl magnesium chloride/lithium chloride, and the like. Preferably an isopropyl magnesium chloride/lithium chloride complex. The reaction temperature in this step is-30 to 0 ℃, and the optimal temperature is-20 ℃. Experiments show that the element iodine connected with the aromatic ring is changed into bromine, and the reaction can be carried out only by ultralow temperature of-78 ℃ and strong alkali n-butyl lithium reducing agent.
g. Dissolving the compound (3R,4S,5R,6R) -2- (5- (4-ethylbenzyl) -2- (trimethylsiloxymethyl) phenyl) -3,4, 5-tri (trimethylsiloxy) -6-trimethylsiloxymethyl tetrahydropyran-2-alcohol in the formula VI obtained in the step f into a solvent, and carrying out deprotection ring closure under the catalytic action of an acid to generate an oily compound in the formula VII; the catalytically acting acid is selected from methanesulfonic acid. Because the crude product of the tobermiflozin obtained in the step contains more impurities, direct crystallization is very difficult. The crude product VII needs to be firstly derivatized into a compound VIII which is easy to crystallize and purify, and then is deprotected to obtain a product with higher purity.
VII Togliflozin crude product
h. Dissolving the oily matter in the formula VII obtained in the step g in a solvent, and reacting the oily matter with methyl chloroformate in the presence of an acid binding agent to obtain a compound (1S,3' R,4' S,5' S,6' R) -6- (4-ethylphenyl) -6' - (methoxycarbonyloxymethyl) -3',4',5',6' -tetrahydro-3 ',4',5' -trimethoxy formyloxy-3H-spiro [ isobenzofuran-1, 2' -pyran ];
in the preparation of the formula VIII, methyl chloroformate is adopted properly, the obtained product is easy to crystallize and has high purity, and other derivative reagents (ethyl chloroformate, isopropyl chloroformate and acetic anhydride) are poor in crystallization, so that the obtained product has poor purity. The acid-binding agent is selected from 1-methylimidazole; the solvent is selected from the group consisting of ethanol, isopropanol, and methyl tert-butyl ether. Refining to obtain the formula (VIII) with higher purity.
i. Dissolving the compound of the formula VIII obtained in the step h in a solvent, and adding an alkali for hydrolysis to obtain the torsemide monohydrate, wherein the solvent is diethylene glycol dimethyl ether;
dissolving the obtained solid compound formula (VIII) in a solvent, adding alkali for hydrolysis, extracting and concentrating after hydrolysis to obtain an oily substance, and adding a mixed solvent of acetone and water for refining to obtain the tongliflozin monohydrate.
The specific reaction route is as follows:
has the advantages that: the invention has the advantages that the initial raw materials are cheap and easy to obtain, the novel route of the invention avoids the need of using noble metal palladium as a catalyst in the prior patent documents, the total yield can reach 21.6 percent, and the production cost is greatly reduced; in the metal-halogen exchange process in the step f, the reaction temperature does not need to reach-78 ℃ reported in the literature, and the reaction can be realized at-20 ℃, so that the amplification production is easy to carry out; in the step f, flammable and explosive reagents such as n-butyllithium and the like and reagents with high boron trifluoride toxicity are avoided, and the operation is easy to control and safe; the product and the intermediate are easy to purify and suitable for industrial production.
Example 1: preparation of Paraacetoxymethylbenzoic acid (Compound I)
To a 3000mL three-necked flask, 91.5g (0.601mol) of p-hydroxymethylbenzoic acid was added at room temperature, and 600mL of chloroform, 300mL of acetic anhydride and 10mL of pyridine were sequentially added. Heating and refluxing until the system is clear, and continuing stirring for 2h at the temperature. After the reaction, the solvent was distilled off, about 2000mL of water was added and the mixture was refluxed for 2 h. After the TLC detection reaction is finished, cooling to 0 ℃ and continuing stirring for 2 h. Suction filtration is carried out, and the filter cake is washed by 600mL of clear water and then dried for 8h at 60 ℃ to obtain 103.9g of white solid with the yield of 89%.
1H NMR(400MHz,CDCl3)8.12(d,J＝7.8Hz,2H)，7.46(d，J＝7.8Hz,2H)，5.19(s,2H)，2.15(s,2H)。13C NMR(100MHz,CDCl3)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。
Example 2: preparation of 4-acetoxymethyl-3-iodo-benzoic acid (Compound II)
38.8g (0.181mol) of sodium periodate, 30.7g (0.121mol) of iodine, 63.0g (0.324mol) of p-acetoxymethylbenzoic acid, 252mL of glacial acetic acid, and 126mL of acetic anhydride were sequentially added to a 2000mL three-necked flask at room temperature. The temperature is reduced to 5 ℃ by stirring, and 246.9g (2.469mol) of concentrated sulfuric acid is slowly added dropwise. After the addition was complete, the temperature was raised to 25 ℃ and stirring was continued at this temperature for 20 h. The reaction was poured into 420g of crushed ice and 420mL of 10% sodium sulfite solution was added. Stirring at room temperature for 0.5h, filtering, washing the filter cake with 220mL of water, and drying at 60 ℃ for 8h to obtain 94.5g of white-like solid with a yield of 91%.
1H NMR(400MHz,CDCl3)8.58(s,1H)，8.09(d,J＝8.0Hz,1H),7.48(d,J＝8.0Hz,1H),5.17(s,1H),2.19(s,1H)。13C NMR(100MHz,CDCl3)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。
Example 3: preparation of 4- (4-ethylbenzoyl) -2-iodobenzyl acetate (Compound III)
To a 250mL three-necked flask were added 9.0g (0.028mol) of 4-acetoxymethyl-3-iodo-benzoic acid, 75mL of dichloromethane, and 0.1mL of DMF in this order at room temperature. And cooling to 0-5 ℃ while stirring, and slowly dropwise adding 8.3g (0.070mol) of thionyl chloride. After the addition was complete, the temperature was raised to reflux and stirring was continued at this temperature for 3 h. The solvent was distilled off under reduced pressure and the product obtained was used in the next step without purification.
The above product was dissolved in 60mL of methylene chloride, and 12.0mL (0.098mol) of ethylbenzene was added. The temperature is reduced to 0 ℃ by stirring, 8.2g (0.062mol) of aluminium trichloride is added in batches at the temperature below 10 ℃, and the stirring is continued for 4 hours at the temperature of 0 ℃ after the addition is finished. The reaction mixture was poured into 10mL of ice-water and extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and concentrated. To the concentrate were added 45mL of isopropanol and 15mL of water, and after warming to reflux and clearing, the mixture was slowly cooled to room temperature and stirred for an additional 2 h. After filtration, the filter cake was washed with 9mL of isopropanol/water (v/v ═ 2:1) and dried at 50 ℃ for 8 hours to give 5.7g of an off-white solid with a yield of 50% in two steps.
1H NMR(400MHz，CDCl3)8.26(s,1H)，7.76-7.72(m,3H)，7.47(d,J＝7.9Hz,1H)，7.32(d,J＝7.8Hz,2H)，5.18(s,2H),，2.75(q,J＝7.6Hz,2H)，2.19(s,3H)，1.29(t,J＝7.6Hz,3H)。13C NMR(100MHz,CDCl3)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。
Example 4: preparation of 4- (4-ethylbenzoyl) -2-iodobenzyl acetate (Compound III)
To a 250mL three-necked flask were added 9.0g (0.028mol) of 4-acetoxymethyl-3-iodo-benzoic acid, 75mL of dichloromethane, and 0.1mL of DMF in this order at room temperature. And cooling to 0-5 ℃ while stirring, and slowly dropwise adding 8.3g (0.070mol) of thionyl chloride. After the addition was complete, the temperature was raised to reflux and stirring was continued at this temperature for 3 h. The solvent was distilled off under reduced pressure and the product obtained was used in the next step without purification.
The above product was dissolved in 60mL of dichloromethane, and 5.1mL (0.042mol) of ethylbenzene was added. The temperature is reduced to 0 ℃ by stirring, 8.2g (0.062mol) of aluminium trichloride is added in batches at the temperature below 10 ℃, and the stirring is continued for 4 hours at the temperature of 0 ℃ after the addition is finished. The reaction mixture was poured into 10mL of ice-water and extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and concentrated. To the concentrate were added 45mL of isopropanol and 15mL of water, and after warming to reflux and clearing, the mixture was slowly cooled to room temperature and stirred for an additional 2 h. After filtration, the filter cake was washed with 9mL of isopropanol/water (v/v ═ 2:1) and dried at 50 ℃ for 8 hours to give 4.6g of an off-white solid with a yield of 40% in two steps.
Example 5: preparation of 4- (4-ethylbenzoyl) -2-iodobenzyl acetate (Compound III)
To a 250mL three-necked flask were added 9.0g (0.028mol) of 4-acetoxymethyl-3-iodo-benzoic acid, 75mL of dichloromethane, and 0.1mL of DMF in this order at room temperature. And cooling to 0-5 ℃ while stirring, and slowly dropwise adding 8.3g (0.070mol) of thionyl chloride. After the addition was complete, the temperature was raised to reflux and stirring was continued at this temperature for 3 h. The solvent was distilled off under reduced pressure and the product obtained was used in the next step without purification.
The above product was dissolved in 60mL of methylene chloride, and 15.4mL (0.126mol) of ethylbenzene was added. The temperature is reduced to 0 ℃ by stirring, 8.2g (0.062mol) of aluminium trichloride is added in batches at the temperature below 10 ℃, and the stirring is continued for 4 hours at the temperature of 0 ℃ after the addition is finished. The reaction mixture was poured into 10mL of ice-water and extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and concentrated. To the concentrate were added 45mL of isopropanol and 15mL of water, and after warming to reflux and clearing, the mixture was slowly cooled to room temperature and stirred for an additional 2 h. After filtration, the filter cake was washed with 9mL of isopropanol/water (v/v ═ 2:1) and dried at 50 ℃ for 8 hours to give 4.7g of an off-white solid with a yield of 41% in two steps.
Example 6: preparation of 4- (4-ethylbenzoyl) -2-iodobenzyl acetate (Compound III)
To a 2000mL three-necked flask were added 90g (0.281mol) of 4-acetoxymethyl-3-iodo-benzoic acid, 750mL of dichloromethane, and 0.5mL of DMF in this order at room temperature. Stirring and cooling to 0-5 ℃, and slowly dropwise adding 83.4g (0.701mol) of thionyl chloride. After the addition was complete, the temperature was raised to reflux and stirring was continued at this temperature for 3 h. The solvent was distilled off under reduced pressure and the product obtained was used in the next step without purification.
The above product was dissolved in 600mL of dichloromethane, and 120mL (0.983mol) of ethylbenzene was added. The temperature is reduced to 0 ℃ by stirring, 82.4g (0.618mol) of aluminum trichloride is added in batches at the temperature of below 10 ℃, the temperature is raised to reflux after the addition is finished, and the stirring is continued for 0.5h at the temperature. The reaction mixture was poured into 1000mL of ice-water and extracted with ethyl acetate (600 mL. times.3). The organic phases were combined and concentrated. To the concentrate were added 450mL of isopropanol and 150mL of water, and after warming to reflux and clearing, the mixture was slowly cooled to room temperature and stirred for an additional 2 h. Filtration was carried out, and the filter cake was washed with 90mL of isopropanol/water (v/v ═ 2:1) and dried at 50 ℃ for 8 hours to give 71.2g of off-white solid with a yield of 62% in two steps.
Example 7: preparation of 4- (4-ethylbenzyl) -2-iodophenylmethanol (Compound IV)
To a 500mL three-necked flask were added 25.0g (0.061mol) of 4- (4-ethylbenzoyl) -2-iodo-benzyl acetate, 183mL of methylene chloride, 183mL of acetonitrile, and 14.2g (0.122mol) of triethylsilane in this order at room temperature. The mixture was stirred and cooled to 0 ℃ and 17.3g (0.122mol) of boron trifluoride ether solution was added dropwise. After the addition was complete, the temperature was raised to room temperature and stirring was continued at this temperature for 20 h. After TLC detection, the reaction mixture was poured into 500mL of ice-water and extracted with ethyl acetate (100 mL. times.3), and the organic phases were combined and concentrated under reduced pressure. The product was used in the next step without purification.
The above product was dissolved in 80mL of tetrahydrofuran and 80mL of methanol, and 80mL of 7.5% aqueous sodium hydroxide solution was added. After the addition, the mixture was stirred at room temperature for 2 hours. Filtering, washing a filter cake by using 100mL of water, and drying at 70 ℃ for 8 hours to obtain 17.5g of white solid with the yield of two steps of 81 percent.
1H NMR(400MHz,CDCl3)7.67(s,1H),7.34(d,J＝7.8Hz,1H),7.18(d,J＝7.8Hz,1H),7.13(d,J＝7.7Hz,2H),7.08(d,J＝7.7Hz,2H),4.64(s,2H),3.89(s,2H),2.62(q,J＝7.6Hz,2H),1.86(br s,1H),1.22(t,J＝7.6Hz,3H)。13C NMR(100MHz,CDCl3)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。HRMScalculated for C16H21INO[M+NH4]+:370.0662,Found:370.0662。
Example 8: preparation of 4- (4-ethylbenzyl) -2-iodophenylmethanol (Compound IV)
To a 200mL three-necked flask were added 5.0g (0.012mol) of 4- (4-ethylbenzoyl) -2-iodo-benzyl acetate, 40mL of dichloromethane, 40mL of acetonitrile, and 2.8g (0.024mol) of triethylsilane in this order at room temperature. The temperature is reduced to 0 ℃ by stirring, and 4.9g (0.037mol) of aluminum trichloride is added in portions. After the addition was complete, the temperature was raised to room temperature and stirring was continued at this temperature for 20 h. After TLC detection, the reaction mixture was poured into 100mL of ice-water and extracted with ethyl acetate (100 mL. times.3), and the organic phases were combined and concentrated under reduced pressure. The product was used in the next step without purification.
The above product was dissolved in 15mL of tetrahydrofuran and 15mL of methanol, and 15mL of 7.5% aqueous sodium hydroxide solution was added. After the addition, the mixture was stirred at room temperature for 2 hours. After the solvent was spin-dried under reduced pressure, the crude product was purified by column chromatography to obtain 1.8g of a white solid with a yield of 42% in two steps.
Example 9: preparation of 4- (4-ethylbenzyl) -2-iodophenylmethanol (Compound IV)
To a 200mL three-necked flask were added 5.0g (0.012mol) of 4- (4-ethylbenzoyl) -2-iodo-benzyl acetate, 40mL of methylene chloride, 40mL of acetonitrile, and 3.3g (0.024mol) of 1,1,3, 3-tetramethyldisiloxane in this order at room temperature. The mixture is stirred and cooled to 0 ℃, and 3.2g (0.024mol) of aluminum trichloride is added in batches. After the addition was complete, the temperature was raised to room temperature and stirring was continued at this temperature for 20 h. After TLC detection, the reaction mixture was poured into 100mL of ice-water and extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined and concentrated under reduced pressure. The product was used in the next step without purification.
The above product was dissolved in 15mL of tetrahydrofuran and 15mL of methanol, and 15mL of a 15% aqueous solution of sodium hydroxide was added. After the addition, the mixture was stirred at room temperature for 4 hours. Filtering, washing a filter cake by using 20mL of water, and drying at 70 ℃ for 8h to obtain 3.5g of white solid with the yield of two steps being 82%.
Example 10: preparation of 4- (4-ethylbenzyl) -2-iodophenylmethanol (Compound IV)
To a 1000mL three-necked flask were added 50.0g (0.122mol) of 4- (4-ethylbenzoyl) -2-iodo-benzyl acetate, 366mL of methylene chloride, 366mL of acetonitrile, and 32.8g (0.244mol) of 1,1,3, 3-tetramethyldisiloxane, in that order, at room temperature. The temperature is reduced to 0 ℃ while stirring, and 48.8g (0.366mol) of aluminum trichloride is added in portions. After the addition was complete, the temperature was raised to room temperature and stirring was continued at this temperature for 20 h. After completion of the TLC detection, the reaction solution was poured into 1000mL of ice water and extracted with ethyl acetate (200 mL. times.3), and the organic phases were combined and concentrated under reduced pressure. The product was used in the next step without purification.
The above product was dissolved in 160mL of tetrahydrofuran and 160mL of methanol, and 160mL of 15% aqueous sodium hydroxide solution was added. After the addition, the mixture was stirred at room temperature for 4 hours. Filtering, washing a filter cake by using 200mL of water, and drying at 70 ℃ for 8 hours to obtain 39.2g of white solid with the yield of 91 percent in two steps.
Example 11: preparation of 4- (4-ethylbenzyl) -2-iodobenzyloxytrimethylsilane (Compound V)
21.2g (0.060mol) of 4- (4-ethylbenzyl) -2-iodophenylmethanol, 200mL of tetrahydrofuran and 12.1g (0.120mol) of triethylamine were added in this order to a 500mL three-necked flask at room temperature, and while stirring, 9.8g (0.090mol) of trimethylchlorosilane was slowly added dropwise thereto while cooling to 0 ℃. After the addition, the temperature was raised to 25 ℃ and stirring was continued for 1 hour. 240mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (240 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, 25.5g of oil was obtained in 98% yield. The product was used in the next step without purification.
Example 12: preparation of (3R,4S,5R,6R) -2- (5- (4-ethylbenzyl) -2- (trimethylsiloxymethyl) phenyl) -3,4, 5-tris (trimethylsiloxy) -6-trimethylsiloxymethyl-tetrahydropyran-2-ol (Compound VI)
At room temperature, 25.5g (0.059mol) of oily 4- (4-ethylbenzyl) -2-iodobenzyloxy-trimethylsilane is dissolved in 56mL of anhydrous tetrahydrofuran, stirred under nitrogen and cooled to 0 ℃, 50.0mL (0.065mol) of isopropyl magnesium chloride lithium chloride (1.3M tetrahydrofuran solution) is slowly added dropwise, and stirring is continued for 20min at the temperature after the addition is finished. 33.6g (0.072mol) of (3R,4S,5R,6R) -3,4, 5-trisiloxy-6-trimethylsiloxymethyltetrahydro-2H-pyran-2-one was slowly added dropwise at a temperature below 0 ℃. After the addition was complete, stirring was continued for 1h at 0 ℃. After the TLC detection reaction, 120mL of 10% ammonium chloride aqueous solution was added dropwise to the reaction system, and after the addition, the reaction system was warmed to room temperature and stirred for 0.5h, and extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a pale yellow oil which was used in the next step without purification.
Example 13: preparation of a crude product of tolgliflozin
The oil obtained in example 12 was dissolved in 150mL of tetrahydrofuran at room temperature, cooled to 0 ℃ with stirring and a solution of methanesulfonic acid in methanol (0.24g of methanesulfonic acid in 50mL of methanol) was slowly added dropwise. Stirring was continued at this temperature for 15h after the addition was complete. To the reaction mixture was added 400mL of a saturated sodium bicarbonate solution, and most of tetrahydrofuran was distilled off under reduced pressure, followed by addition of 200mL of ethylene glycol dimethyl ether, 200mL of water and 300mL of n-hexane in this order. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain the crude product of the tolgliflozin, wherein the product is directly used in the next step without purification.
Example 14: preparation of (1S,3' R,4' S,5' S,6' R) -6- (4-ethylphenyl) -6' - (methoxycarbonyloxymethyl) -3',4',5',6' -tetrahydro-3 ',4',5' -trimethoxyformyloxy-3H-spiro [ isobenzofuran-1, 2' -pyran ] (Compound VIII)
The oil obtained in example 13 was dissolved in 90mL of acetone at room temperature and 49.44g (0.602mol) of 1-methylimidazole was added. The temperature was reduced to 0 ℃ with stirring, and 37.2g (0.394mol) of methyl chloroformate was slowly added dropwise. After the addition was complete, the temperature was raised to 25 ℃ and stirring was continued at this temperature for 1 h. 120mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and concentrated under reduced pressure. To the concentrate were added 120mL of ethanol, 20mL of methyl t-butyl ether, and 30mL of isopropanol in this order. Heating, refluxing and dissolving, slowly cooling to 25 ℃ and continuously stirring for 2 h. The mixture was filtered, and the filter cake was washed with 10mL of an ethanol/isopropanol mixture (v/v ═ 3:1) and dried at 50 ℃ for 6 hours to obtain 12.6g of a white solid with a yield of 34% in four steps.
1H NMR(400MHz,CDCl3)7.31(s,1H),7.20(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.12-7.07(m,4H),5.51(t,J＝9.6Hz,1H),5.41(d,J＝9.9Hz,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＝7.5Hz,2H),1.20(t,J＝7.6Hz,3H)。13C NMR(100MHz,CDCl3)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。
Example 15: preparation of (3R,4S,5R,6R) -2- (5- (4-ethylbenzyl) -2- (trimethylsiloxymethyl) phenyl) -3,4, 5-tris (trimethylsiloxy) -6-trimethylsiloxymethyl-tetrahydropyran-2-ol (Compound VI)
At room temperature, 25.5g (0.059mol) of 4- (4-ethylbenzyl) -2-iodobenzyloxy-trimethyl silane is dissolved in 56mL of anhydrous tetrahydrofuran, stirred under nitrogen protection and cooled to-30 ℃, 50.0mL (0.065mol) of isopropyl magnesium chloride lithium chloride (1.3M tetrahydrofuran solution) is slowly added dropwise, and stirring is continued for 40min at the temperature after the addition is finished. 33.6g (0.072mol) of (3R,4S,5R,6R) -3,4, 5-trisiloxy-6-trimethylsiloxymethyltetrahydro-2H-pyran-2-one is slowly added dropwise at a temperature below-15 ℃. After the addition was complete, the temperature was raised to 0 ℃ and stirring was continued at this temperature for 1 h. After the TLC detection reaction, 120mL of 10% ammonium chloride aqueous solution was added dropwise to the reaction system, and after the addition, the reaction system was warmed to room temperature and stirred for 0.5h, and extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a pale yellow oil which was used in the next step without purification.
Example 16: preparation of a crude product of tolgliflozin
The oil obtained in example 15 is dissolved in 150mL of tetrahydrofuran at room temperature, stirred and cooled to 0 ℃ and a solution of methanesulfonic acid in methanol (0.24g of methanesulfonic acid in 50mL of methanol) is slowly added dropwise. Stirring was continued at this temperature for 15h after the addition was complete. To the reaction mixture was added 400mL of a saturated sodium bicarbonate solution, and most of tetrahydrofuran was distilled off under reduced pressure, followed by addition of 200mL of ethylene glycol dimethyl ether, 200mL of water and 300mL of n-hexane in this order. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain the crude product of the tolgliflozin, wherein the product is directly used in the next step without purification.
Example 17: preparation of (1S,3' R,4' S,5' S,6' R) -6- (4-ethylphenyl) -6' - (methoxycarbonyloxymethyl) -3',4',5',6' -tetrahydro-3 ',4',5' -trimethoxyformyloxy-3H-spiro [ isobenzofuran-1, 2' -pyran ] (Compound VIII)
The oil obtained in example 16 was dissolved in 90mL of acetone at room temperature and 49.44g (0.602mol) of 1-methylimidazole was added. The temperature was reduced to 0 ℃ with stirring, and 37.2g (0.394mol) of methyl chloroformate was slowly added dropwise. After the addition was complete, the temperature was raised to 25 ℃ and stirring was continued at this temperature for 1 h. 120mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and concentrated under reduced pressure. To the concentrate were added 120mL of ethanol, 20mL of methyl t-butyl ether, and 30mL of isopropanol in this order. Heating, refluxing and dissolving, slowly cooling to 25 ℃ and continuously stirring for 2 h. The mixture was filtered, and the filter cake was washed with 10mL of an ethanol/isopropanol mixture (v/v ═ 3:1) and dried at 50 ℃ for 6 hours to obtain 21.6g of a white solid, which was 58% in yield in four steps.
Example 18: preparation of (3R,4S,5R,6R) -2- (5- (4-ethylbenzyl) -2- (trimethylsiloxymethyl) phenyl) -3,4, 5-tris (trimethylsiloxy) -6-trimethylsiloxymethyl-tetrahydropyran-2-ol (Compound VI)
At room temperature, 25.5g (0.059mol) of 4- (4-ethylbenzyl) -2-iodobenzyloxy-trimethyl silane is dissolved in 56mL of anhydrous tetrahydrofuran, stirred under the protection of nitrogen and cooled to-20 ℃, 50.0mL (0.065mol) of isopropyl magnesium chloride lithium chloride (1.3M tetrahydrofuran solution) is slowly added dropwise, and stirring is continued for 0.5h at the temperature after the addition is finished. 33.6g (0.072mol) of (3R,4S,5R,6R) -3,4, 5-trisiloxy-6-trimethylsiloxymethyltetrahydro-2H-pyran-2-one is slowly added dropwise at a temperature below-15 ℃. After the addition was complete, the temperature was raised to 0 ℃ and stirring was continued at this temperature for 1 h. After the TLC detection reaction, 120mL of 10% ammonium chloride aqueous solution was added dropwise to the reaction system, and after the addition, the reaction system was warmed to room temperature and stirred for 0.5h, and extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a pale yellow oil which was used in the next step without purification.
Example 19: preparation of a crude product of tolgliflozin
The oil obtained in example 18 was dissolved in 150mL of tetrahydrofuran at room temperature, cooled to 0 ℃ with stirring and a solution of methanesulfonic acid in methanol (0.24g of methanesulfonic acid in 50mL of methanol) was slowly added dropwise. Stirring was continued at this temperature for 15h after the addition was complete. To the reaction mixture was added 400mL of a saturated sodium bicarbonate solution, and most of tetrahydrofuran was distilled off under reduced pressure, followed by addition of 200mL of ethylene glycol dimethyl ether, 200mL of water and 300mL of n-hexane in this order. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 mL. times.3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain the crude product of the tolgliflozin, wherein the product is directly used in the next step without purification.
Example 20: preparation of (1S,3' R,4' S,5' S,6' R) -6- (4-ethylphenyl) -6' - (methoxycarbonyloxymethyl) -3',4',5',6' -tetrahydro-3 ',4',5' -trimethoxyformyloxy-3H-spiro [ isobenzofuran-1, 2' -pyran ] (Compound VIII)
The oil obtained in example 19 was dissolved in 90mL of acetone at room temperature and 49.44g (0.602mol) of 1-methylimidazole was added. The temperature was reduced to 0 ℃ with stirring, and 37.2g (0.394mol) of methyl chloroformate was slowly added dropwise. After the addition was complete, the temperature was raised to 25 ℃ and stirring was continued at this temperature for 1 h. 120mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL. times.3). The organic phases were combined and concentrated under reduced pressure. To the concentrate were added 120mL of ethanol, 20mL of methyl t-butyl ether, and 30mL of isopropanol in this order. Heating, refluxing and dissolving, slowly cooling to 25 ℃ and continuously stirring for 2 h. The mixture was filtered, and the filter cake was washed with 10mL of an ethanol/isopropanol mixture (v/v ═ 3:1) and dried at 50 ℃ for 6 hours to obtain 22.7g of a white solid with a yield of 61% in four steps.
Example 21: preparation of tolagliflozin monohydrate
To a 250mL three-necked flask were added (1S,3' R,4' S,5' S,6' R) -6- (4-ethylphenyl) -6' - (methoxycarbonyloxymethyl) -3',4',5',6' -tetrahydro-3 ',4',5' -trimethoxyformyloxy-3H-spiro [ isobenzofuran-1, 2' -pyran ]15.0g (0.024mol), ethylene glycol dimethyl ether 90mL, and 16% aqueous sodium hydroxide 72mL in this order at room temperature. Stirring for 3h at room temperature, adding hydrochloric acid to adjust the pH value of the reaction system to 6-7, and extracting with ethyl acetate (60mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foamy solid.
The solid was dissolved in 30mL of acetone and stirred to dissolve. 120mL of water was slowly added dropwise at 20 ℃ over a controlled period of time (about 2 hours), and after the addition was complete, 0.1g of seed crystals were added to the reaction solution and stirring was continued at that temperature for 1 hour. Slowly cooling to 0 ℃ and continuing stirring for 2 h. Filtering, washing a filter cake with purified water, and performing vacuum drying at 30 ℃ for 10 hours to obtain 7.7g of white solid with the yield of two steps of 79%.
1H NMR(400MHz,MeOD)7.23-7.18(m,3H),7.12-7.08(m,4H),5.13(d,J＝12.4Hz,1H),5.07(d,J＝12.4Hz,1H),3.96(s,2H),3.83-3.73(m,4H),3.65(dd,J＝11.9,5.5Hz,1H),3.41-3.47(m,1H),2.59(q,J＝7.6Hz,2H),1.19(t,J＝7.6Hz,3H)。13C NMR(100MHz,MeOD)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 (9)
1. A preparation method of the torsemide monohydrate is characterized by comprising the following steps:
a. p-hydroxymethylbenzoic acid is taken as a raw material, and is subjected to acetylation and hydrolysis under the action of an acid-binding agent to obtain p-acetoxymethylbenzoic acid of a compound shown in a formula I; wherein the acetylation reagent is selected from acetic anhydride or acetyl chloride;
b. dissolving a compound p-acetoxymethyl benzoic acid shown in the formula I in a solvent, and obtaining a compound 4-acetoxymethyl-3-iodine-benzoic acid shown in the formula II under the action of an iodinating reagent; wherein the iodinating agent is selected from the group consisting of N-iodosuccinimide, sodium iodide, tetramethylammonium dichloroiodate, KI/KIO3/H+、HIO4/H2SO4And iodine and sodium periodate mixtures;
c. preparing acyl chloride from a compound 4-acetoxymethyl-3-iodine-benzoic acid shown in a formula II and a chlorinating agent, and performing Friedel-crafts reaction with ethylbenzene under the action of Lewis acid to generate a compound 4- (4-ethylbenzoyl) -2-iodine benzyl acetate shown in a formula III; wherein the chlorination reagent is selected from thionyl chloride, the Lewis acid is selected from aluminum trichloride, and the molar ratio of the compound II to the aluminum trichloride is 1: 2.2; the molar ratio of the compound II to ethylbenzene is 1: 1.5-1: 4.5, and the reaction temperature is 0-40 ℃;
d. dissolving a compound 4- (4-ethylbenzoyl) -2-iodobenzyl acetate in a solvent, reducing the solution under the action of a reducing agent, and hydrolyzing the solution under the action of inorganic base to obtain a compound 4- (4-ethylbenzyl) -2-iodobenzyl methanol in a formula IV; the reducing agent is selected from aluminum trichloride/triethylsilane, boron trifluoride/triethylsilane, aluminum trichloride/1, 1,3, 3-tetramethyldisiloxane;
e. dissolving the compound 4- (4-ethylbenzyl) -2-iodophenyl methanol in the formula IV in a solvent, and reacting with trimethylchlorosilane to obtain the compound 4- (4-ethylbenzyl) -2-iodobenzyloxy trimethylsilane in the formula V, wherein the compound is directly used in the step f;
f. dissolving the compound 4- (4-ethylbenzyl) -2-iodobenzyloxy trimethyl silane in the formula V obtained in the step e in a solvent, dropwise adding a Grignard reagent at a controlled temperature for deiodination, and then reacting with a gluconolactone derivative to prepare a compound (3R,4S,5R,6R) -2- (5- (4-ethylbenzyl) -2- (trimethylsiloxymethyl) phenyl) -3,4, 5-tris (trimethylsiloxy) -6-trimethylsiloxymethyl tetrahydropyran-2-ol in a formula VI, wherein the compound is directly used in the step g; the Grignard reagent is a Konchel type Grignard reagent selected from isopropyl magnesium chloride/lithium chloride and diisopropyl magnesium/lithium chloride, and the reaction temperature is-30-0 ℃;
g. dissolving the compound (3R,4S,5R,6R) -2- (5- (4-ethylbenzyl) -2- (trimethylsiloxymethyl) phenyl) -3,4, 5-tri (trimethylsiloxy) -6-trimethylsiloxymethyl tetrahydropyran-2-alcohol in the formula VI obtained in the step f into a solvent, and carrying out deprotection ring closure under the catalytic action of an acid to generate an oily compound in the formula VII; the catalytically acting acid is selected from methanesulfonic acid;
h. dissolving the oily matter in the formula VII obtained in the step g in a solvent, and reacting the oily matter with methyl chloroformate in the presence of an acid binding agent to obtain a compound (1S,3' R,4' S,5' S,6' R) -6- (4-ethylphenyl) -6' - (methoxycarbonyloxymethyl) -3',4',5',6' -tetrahydro-3 ',4',5' -trimethoxyformyloxy-3H-spiro [ isobenzofuran-1, 2' -pyran ] in the formula VIII;
i. dissolving the compound of the formula VIII obtained in the step h in a solvent, and adding an alkali for hydrolysis to obtain the torsemide monohydrate, wherein the solvent is diethylene glycol dimethyl ether;
2. the process according to claim 1, wherein the acetylating agent in the step of preparing the compound of formula I is acetic anhydride.
3. The process according to claim 1, wherein in the step of preparing the compound of formula II, the solvent is an acetic acid/acetic anhydride mixture; the iodinating agent is a mixture of iodine and sodium periodate.
4. The method according to claim 1, wherein in the step of preparing the compound of formula III, the molar ratio of the compound of formula II to ethylbenzene is 1: 3.5; the reaction temperature was 40 ℃.
5. The method of claim 1, wherein the compound of formula III is dissolved in a solvent in step d, and the reducing agent is selected from the group consisting of aluminum trichloride/1, 1,3, 3-tetramethyldisiloxane; the molar ratio of the aluminum trichloride to the compound of the formula III is 1:2-1: 3.
6. The method of claim 1, wherein the compound of formula III is dissolved in a solvent in step d, and the reducing agent is selected from the group consisting of aluminum trichloride/1, 1,3, 3-tetramethyldisiloxane; the molar ratio of aluminum trichloride to the compound of formula III is 1:3.
7. The preparation method of claim 1, wherein in the step e, the molar ratio of the compound IV to the trimethylchlorosilane is 1: 1.5.
8. The method according to claim 1, wherein in the step f, the Grignard reagent is selected from isopropyl magnesium chloride/lithium chloride complex, and the reaction temperature is-20 ℃.
9. The process of claim 1, wherein in the step of preparing formula VIII, the acid scavenger is 1-methylimidazole.
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