CN110683998A - Preparation method of empagliflozin intermediate - Google Patents
Preparation method of empagliflozin intermediate Download PDFInfo
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- CN110683998A CN110683998A CN201911140208.2A CN201911140208A CN110683998A CN 110683998 A CN110683998 A CN 110683998A CN 201911140208 A CN201911140208 A CN 201911140208A CN 110683998 A CN110683998 A CN 110683998A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 title claims description 8
- 229960003345 empagliflozin Drugs 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 239000002994 raw material Substances 0.000 claims abstract description 27
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims abstract description 26
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims abstract description 18
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 claims abstract description 18
- WWCNXHYRAKUQDB-JTQLQIEISA-N [(3s)-oxolan-3-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@@H]1COCC1 WWCNXHYRAKUQDB-JTQLQIEISA-N 0.000 claims abstract description 15
- 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 abstract description 13
- 238000000297 Sandmeyer reaction Methods 0.000 claims abstract description 11
- 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 claims abstract description 10
- 230000009471 action Effects 0.000 claims abstract description 9
- 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 abstract description 7
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- -1 4-iodo-2- (4-methoxybenzyl) aniline Chemical compound 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- 239000002841 Lewis acid Substances 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 150000007517 lewis acids Chemical class 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 9
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 9
- 229940045803 cuprous chloride Drugs 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- JVROQQAZKZLCHH-UHFFFAOYSA-N 1-chloro-4-iodo-2-[(4-methoxyphenyl)methyl]benzene Chemical compound C1=CC(OC)=CC=C1CC1=CC(I)=CC=C1Cl JVROQQAZKZLCHH-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 230000001335 demethylating effect Effects 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 20
- 239000007810 chemical reaction solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000010520 demethylation reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- YLUHNGIWRCCQMQ-INIZCTEOSA-N (3s)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]oxolane Chemical compound ClC1=CC=C(I)C=C1CC(C=C1)=CC=C1O[C@@H]1COCC1 YLUHNGIWRCCQMQ-INIZCTEOSA-N 0.000 description 2
- GEBYSTBEDVQOTK-UHFFFAOYSA-N 2-chloro-5-iodobenzoic acid Chemical compound OC(=O)C1=CC(I)=CC=C1Cl GEBYSTBEDVQOTK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 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 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- KNYGUQLVFSPVRI-UHFFFAOYSA-N (2-chloro-5-iodophenyl)-(4-fluorophenyl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CC(I)=CC=C1Cl KNYGUQLVFSPVRI-UHFFFAOYSA-N 0.000 description 1
- HUNLNKBDQXGMAP-INIZCTEOSA-N (3s)-3-[4-[(5-bromo-2-chlorophenyl)methyl]phenoxy]oxolane Chemical compound ClC1=CC=C(Br)C=C1CC(C=C1)=CC=C1O[C@@H]1COCC1 HUNLNKBDQXGMAP-INIZCTEOSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CRBYUOHFEZMJTE-UHFFFAOYSA-N 2-chloro-5-iodobenzoyl chloride Chemical compound ClC(=O)C1=CC(I)=CC=C1Cl CRBYUOHFEZMJTE-UHFFFAOYSA-N 0.000 description 1
- SSIMHHUMYMHNID-UHFFFAOYSA-N 4-(chloromethyl)phenol Chemical compound OC1=CC=C(CCl)C=C1 SSIMHHUMYMHNID-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- YVBSAPDHRXHFHV-UHFFFAOYSA-N [chloro(methoxy)methyl]benzene Chemical compound COC(Cl)C1=CC=CC=C1 YVBSAPDHRXHFHV-UHFFFAOYSA-N 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000030558 renal glucose absorption Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an engelizin intermediate, which comprises the steps of using p-methoxybenzyl chloride and p-iodoaniline as starting raw materials, obtaining a compound IV through substitution, then obtaining a compound III through diazotization and Sandmeyer reaction, further removing methyl under the action of boron tribromide to obtain a compound II, and finally condensing with (S) -3-p-toluenesulfonyloxy tetrahydrofuran to obtain a target compound I, wherein the purity of the product is more than or equal to 99.0%. The preparation method has the advantages of simple and easily obtained raw materials, low cost, simple operation steps, simple and convenient post-treatment, high product yield and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of an engelizin intermediate- (S) -3- (4- (5-iodine-2-chlorobenzyl) phenoxy) tetrahydrofuran, belonging to the technical field of organic synthesis.
Background
Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by a defect in insulin secretion or an impaired biological action, or both. Hyperglycemia occurring in the long term of diabetes results in chronic damage to, and dysfunction of, various tissues, particularly the eyes, kidneys, heart, blood vessels, nerves.
Engelizin is a type 2 sodium glucose cotransporter inhibitor developed by bouling invager and lilac co. The SGLT-2 inhibitor is a novel hypoglycemic agent, mainly reduces glucose reabsorption by the kidney and increases glucose excretion in urine by inhibiting SGLT-2 expressed in the kidney, thereby reducing plasma glucose level, and the hypoglycemic effect is independent of beta cell function and insulin resistance. The product is approved for the first time by European drug administration (EMA) in 5 months in 2014, and approved for marketing by FDA in U.S. 8 months in 2014, and is used for treating type 2 diabetes.
The (S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) tetrahydrofuran is a key intermediate for preparing the empagliflozin, and the synthesis method mainly comprises the following two methods:
patent documents CN102574829A and CN102549005A disclose a synthetic method of an engagliflozin intermediate, and the synthetic route thereof is shown as follows.
In the synthetic route, 2-chloro-5-iodobenzoic acid is used as a starting material, reacts with oxalyl chloride under the catalysis of fluorobenzene and DMF to generate 2-chloro-5-iodobenzoyl chloride, then performs Friedel-crafts reaction with fluorobenzene to generate (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone, then performs substitution reaction with (S) -3-hydroxytetrahydrofuran to generate a compound 2, and finally performs carbonyl reduction to obtain a (S) -3- [4- (5-iodo-2-chlorobenzyl) phenoxy ] tetrahydrofuran compound 3. The synthesis route adopts expensive starting material 2-chloro-5-iodobenzoic acid, and earlier uses expensive (S) -3-hydroxytetrahydrofuran, which causes higher cost, and in addition, a large amount of highly toxic oxalyl chloride is used, and the post-treatment is complex and is not suitable for industrial production.
Chinese patent CN108178751A reports that 4-hydroxybenzyl chloride is used as a starting material, and reacts with methylsulfonyl chloride and (S) -3-hydroxytetrahydrofuran in sequence to obtain a compound 4, then reacts with 4-iodoaniline to obtain a compound 5, and finally reacts with cuprous chloride after diazotization to obtain (S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran.
In the above synthetic route, (S) -3-hydroxytetrahydrofuran, which is a starting material, is used earlier, resulting in high starting material costs.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a preparation method of an empagliflozin intermediate. The method has less pollution, and the (S) -3-hydroxytetrahydrofuran which is a raw material with higher price is introduced in the last step, so that the method has low cost and high purity of the final product.
In order to achieve the purpose, the invention adopts the following technical scheme:
the chemical structural formula of the empagliflozin intermediate is as follows:
the method comprises the steps of using p-methoxybenzyl chloride and p-iodoaniline as starting raw materials, obtaining a compound IV through substitution, then obtaining a compound III through diazotization and Sandmeyer reaction, further obtaining a compound II through demethylation under the action of boron tribromide, and finally condensing with (S) -3-p-toluenesulfonyloxy tetrahydrofuran to obtain an engelazin intermediate compound I.
The method specifically comprises the following steps:
1) taking p-methoxybenzyl chloride and p-iodoaniline as raw materials, and carrying out substitution reaction to obtain a compound 4-iodo-2- (4-methoxybenzyl) aniline shown in a formula IV:
taking p-methoxybenzyl chloride and p-iodoaniline as raw materials, dissolving the raw material p-methoxybenzyl chloride in a solvent, adding the raw materials p-iodoaniline and Lewis acid, and carrying out heating reflux reaction to obtain a compound shown in a formula IV, wherein the reaction formula is as follows:
the solvent is selected from any one of ethyl acetate, carbon disulfide or nitrobenzene;
the Lewis acid is selected from any one of zinc chloride, anhydrous aluminum chloride and titanium tetrachloride;
2) diazotizing the compound shown as IV and carrying out Sandmeyer reaction to obtain a compound 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene shown as a formula III:
adding the compound IV into concentrated hydrochloric acid, cooling, dropwise adding an ice water solution of sodium nitrite, and continuously controlling the temperature to be-10-0 ℃ for reaction after dropwise adding is finished; and (3) after the reaction is finished, adding a hydrochloric acid solution of cuprous chloride for reaction to obtain a compound shown in a formula III, wherein the reaction formula is as follows:
the cooling temperature is-15 to-10 ℃;
the temperature of the Sandmeyer reaction is 70-80 ℃;
3) demethylating the compound shown in the formula III to obtain the compound 4- (2-chloro-5-iodophenyl) phenol shown in the formula II:
adding the compound III into a dichloromethane solvent under the protection of nitrogen, adding a catalyst boron tribromide, and stirring at a reaction temperature of-25 to-15 ℃ to obtain a compound shown in a formula II, wherein the reaction formula is as follows:
4) and (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran which is a compound shown in the formula I is obtained by the condensation reaction of the compound shown in the formula II and (S) -3-p-toluenesulfonyloxy tetrahydrofuran:
adding the compound II into a reaction solvent, adding a raw material (S) -3-p-toluenesulfonyloxy tetrahydrofuran, alkali and a catalyst, uniformly stirring, and heating to react to obtain a compound shown as a formula I, namely a target product of the invention, wherein the reaction formula is as follows:
the reaction temperature is 50-55 ℃;
the reaction solvent is any one selected from N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1, 4-dioxane, toluene and the like;
the alkali is selected from any one of potassium carbonate, sodium carbonate, potassium tert-butoxide, triethylamine and diisopropylethylamine;
the catalyst is any one selected from potassium iodide and potassium bromide.
Preferably, the molar ratio of the p-methoxybenzyl chloride to the p-iodoaniline to the Lewis acid in the step 1) is 1 (1.0-1.1) to (1.1-2.0).
Preferably, in the step 2), the temperature is controlled to be-10-0 ℃ in the dropping process.
Preferably, in the step 2), the cuprous chloride hydrochloric acid solution is added, and then the reaction is performed for a certain time at room temperature, about 1.0-2.5 hours, and then the reaction is continued for 1.0-2.5 hours at a temperature of 70-80 ℃.
Preferably, the molar ratio of the compound III in the step 3) to the boron tribromide catalyst is 1 (1.1-2.0).
Preferably, in the condensation reaction in the step 4), the molar ratio of the compound II (S) -3-p-toluenesulfonyloxy tetrahydrofuran to the alkali to the catalyst is 1 (1.05-1.2) to (1.5-3.0) to (0.02-0.08).
The invention has the beneficial effects that:
compared with the prior art, the method selects the p-methoxybenzyl chloride with low price as the starting raw material, and introduces the (S) -3-hydroxytetrahydrofuran with the highest cost ratio in the last step, so that the cost of the raw material is reduced by about 30 percent; in addition, high-toxicity oxalyl chloride is avoided, and environmental pollution is low; and the post-treatment is simple, and the method is suitable for industrial production.
Drawings
FIG. 1 shows the reaction of Compound I in CDCl3In1H-NMR spectrum
FIG. 2 shows the reaction of Compound I in CDCl3In (1)13C-NMR spectrum
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
In the examples of the present disclosure, other values or other solvents within the ranges may be implemented in the raw material ratio selection, solvent selection, reaction temperature and reaction time selection, and the like.
Example 1
The invention provides a preparation method of an engletin intermediate, which uses p-methoxybenzyl chloride and p-iodoaniline as starting raw materials, obtains a compound IV through substitution, then obtains a compound III through diazotization and Sandmeyer reaction, further obtains a compound II through demethylation under the action of boron tribromide, and finally obtains the engletin intermediate compound I through condensation with (S) -3-p-toluenesulfonyloxy tetrahydrofuran, and specifically comprises the following steps:
1) taking p-methoxybenzyl chloride and p-iodoaniline as raw materials, and carrying out substitution reaction to obtain a compound 4-iodo-2- (4-methoxybenzyl) aniline shown in a formula IV:
2) diazotizing the compound shown as IV and carrying out Sandmeyer reaction to obtain a compound 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene shown as a formula III:
3) demethylating the compound shown in the formula III to obtain the compound 4- (2-chloro-5-iodophenyl) phenol shown in the formula II:
4) and (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran which is a target compound of the invention and is shown in the formula I is obtained by the condensation reaction of the compound shown in the formula II and (S) -3-p-toluenesulfonyloxy tetrahydrofuran:
the invention discloses a method for preparing (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran, which has the advantages that the price of the starting raw material is low, the (S) -3-hydroxytetrahydrofuran with the highest cost ratio is introduced in the last step, the cost of the raw material is reduced by about 30 percent, the environmental pollution of the whole process is small, the post-treatment is simple, and the industrialization is facilitated.
In the embodiment of the invention, p-methoxybenzyl chloride and p-iodoaniline are used as raw materials to obtain a compound 4-iodo-2- (4-methoxybenzyl) aniline shown in a formula IV through a substitution reaction, wherein the reaction formula is as follows:
the preparation method of the compound 4-iodo-2- (4-methoxybenzyl) aniline shown in IV comprises the following steps: dissolving a raw material p-methoxybenzyl chloride in a solvent, adding the raw material p-iodoaniline and Lewis acid, and carrying out reflux reaction for 7-9 h to prepare 4-iodo-2- (4-methoxybenzyl) aniline. Wherein, the solvent is selected from any one of ethyl acetate, carbon disulfide or nitrobenzene; the Lewis acid is selected from any one of zinc chloride, anhydrous aluminum chloride and titanium tetrachloride; the reflux temperature varies depending on the solvent used. The present invention can treat the obtained reaction solution according to the post-treatment method well known to those skilled in the art, and the amount of the extraction solvent is not limited: after the reaction is finished, cooling to room temperature, adding water, adjusting the pH value to 8-9, extracting by using a solvent, washing to be neutral by using water, drying by using anhydrous sodium sulfate, filtering, cooling the filtrate to 0 ℃, stirring for crystallization, filtering and drying to obtain a product IV.
In the embodiment of the invention for preparing the compound 4-iodo-2- (4-methoxybenzyl) aniline represented by the formula IV, the molar ratio of p-methoxybenzyl chloride to p-iodoaniline is 1: 1.0-1.1; the molar ratio of the methoxybenzyl chloride to the Lewis acid is 1: 1.1-2.0 respectively.
In the embodiment of the invention, the compound shown in the formula IV is subjected to diazotization and Sandmeyer reaction to obtain a compound 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene shown in the formula III, wherein the reaction formula is as follows:
the preparation method of the compound 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene shown in the formula III comprises the following steps: adding the compound shown in the formula IV into concentrated hydrochloric acid, cooling to-15-10 ℃, dropwise adding an ice water solution of sodium nitrite, controlling the temperature to be-10-0 ℃ in the dropwise adding process, and continuously controlling the temperature to be-10-0 ℃ after the dropwise adding is finished to react for 2.0-3.5 h; and after the reaction is finished, adding a hydrochloric acid solution of cuprous chloride to carry out a sandmeyer reaction to prepare the 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene. Wherein, the cuprous chloride hydrochloric acid solution is added to react for 1.0 to 2.5 hours at room temperature, and then the mixture is heated to 70 to 80 ℃ to continue to react for 1.0 to 2.5 hours. The present invention may treat the obtained reaction solution according to a post-treatment manner well known to those skilled in the art: after the Sandmeyer reaction is finished, extracting a reaction product by using a solvent, washing an extract liquor to be neutral, drying the extract liquor by using anhydrous sodium sulfate, filtering, adding petroleum ether into a filtrate for recrystallization to obtain a compound shown in a formula III, wherein the extraction solvent can be ethyl acetate.
In the embodiment of the invention, the compound shown in the formula III is subjected to demethylation reaction to obtain the compound 4- (2-chloro-5-iodophenyl) phenol shown in the formula II, wherein the reaction formula is as follows:
the preparation method of the compound 4- (2-chloro-5-iodophenyl) phenol shown in the formula II comprises the following steps: adding the compound shown in the formula III into a dichloromethane solvent under the protection of nitrogen, adding a catalyst of boron tribromide, and stirring to react at the temperature of-25 to-15 ℃ for 1.0 to 2.5 hours to obtain the compound shown in the formula II. Wherein the molar ratio of the compound III to the boron tribromide catalyst is 1: 1.1-2.0. The present invention may treat the obtained reaction solution according to a post-treatment manner well known to those skilled in the art: after the reaction is finished, pouring the solution into water, extracting with a solvent, washing an organic layer with a saturated sodium bicarbonate solution and a saturated salt solution sequentially until the organic layer is neutral, drying with anhydrous magnesium sulfate, filtering, and evaporating the solvent to obtain the compound shown in the formula II. Wherein the extraction solvent is dichloromethane or ethyl acetate, and the dosage of the extraction solvent is not required.
In the embodiment of the invention, the compound shown in the formula II and (S) -3-p-toluenesulfonyloxy tetrahydrofuran are subjected to condensation reaction to obtain the compound (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran shown in the formula I, wherein the reaction formula is as follows:
the preparation method of the compound (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran shown in the formula I comprises the following steps: adding the compound shown in the formula II into a reaction solvent, adding the raw material (S) -3-p-toluenesulfonyloxy tetrahydrofuran, alkali and a catalyst, uniformly stirring, and heating to 50-55 ℃ for reaction to obtain the compound shown in the formula I. Wherein, the mixture is heated to 50-55 ℃ after being uniformly stirred and reacts overnight; the reaction solvent is any one selected from N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1, 4-dioxane, toluene and the like; the alkali is selected from any one of potassium carbonate, sodium carbonate, potassium tert-butoxide, triethylamine and diisopropylethylamine; the catalyst is selected from any one of potassium iodide or potassium bromide; the molar ratio of the (S) -3-p-toluenesulfonyloxy tetrahydrofuran of the compound II is 1: 1.05-1.2; the molar ratio of the compound II to the alkali is 1: 1.5-3.0; the molar ratio of the compound II to the catalyst is 1: 0.02-0.08. The present invention may treat the obtained reaction solution according to a post-treatment manner well known to those skilled in the art: after the reaction is finished, decompressing and concentrating to remove the reaction solvent, then adding water and dichloromethane with the same proportion, extracting the water phase for 1 time by using dichloromethane, combining the organic phases, washing the organic phases for 1 time by using saturated salt solution, drying the organic phases by using sodium sulfate, concentrating the organic phases and recrystallizing the organic phases by using the solvent to obtain the compound shown in the formula I. Wherein, the organic solvent is recrystallized, preferably, the mixed solvent of petroleum ether and ethyl acetate is recrystallized.
EXAMPLE 2 preparation of 4-iodo-2- (4-methoxybenzyl) aniline, a compound of formula IV
Raw materials: 60kg (0.383kmol) of p-methoxybenzyl chloride, 88.11kg (0.402kmol) of p-iodoaniline;
as the Lewis acid in this example, zinc chloride is selected as an example, 78.32kg (0.575kmol) of zinc chloride;
the reaction solvent in this example is ethyl acetate;
the selection of any lewis acid and any reaction solvent can be carried out, and the reaction formula is as follows:
the method specifically comprises the following steps: 60kg (0.383kmol) of p-methoxybenzyl chloride is dissolved in 120kg of ethyl acetate, 88.11kg (0.402kmol) of p-iodoaniline is added, 78.32kg (0.575kmol) of zinc chloride is added, heating reflux reaction is carried out for about 7 hours, the temperature is reduced to room temperature after the reaction is finished, 240kg of water is added, the pH value of a sodium bicarbonate solution is adjusted to 8-9, ethyl acetate is used for extraction, the solution is washed to be neutral, anhydrous sodium sulfate is used for drying, filtering is carried out, the filtrate is cooled to 0 ℃, stirring is carried out for crystallization, filtering and drying are carried out, 104kg of light yellow solid is obtained, and the yield is 80.03%.
EXAMPLE 3 preparation of 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene, a compound of formula III
Raw materials: 100kg of the compound of formula IV prepared in example 1 as a pale yellow solid;
the reaction formula is as follows:
taking 100kg of compound IV, adding 300kg of concentrated hydrochloric acid, cooling to-10 ℃, dropwise adding an ice water solution of sodium nitrite (20.34kg of sodium nitrite and 120kg of ice water), controlling the temperature to be-10-0 ℃ in the dropwise adding process, and continuously controlling the temperature to be-10-0 ℃ after the dropwise adding is finished to react for 2.5 hours; after the reaction is finished, adding a hydrochloric acid solution of cuprous chloride (35.02kg of cuprous chloride, 70kg of 10% hydrochloric acid), reacting at room temperature for 1.5h, and then heating to 70-80 ℃ for reacting for 1.5 h; after the reaction is finished, ethyl acetate is added for extraction, the mixture is washed to be neutral by water, dried by anhydrous sodium sulfate, filtered, and added with petroleum ether for recrystallization to obtain 89.3kg of white solid with the yield of 84.46 percent.
EXAMPLE 4 preparation of 4- (2-chloro-5-iodophenyl) phenol, a compound of formula II
Raw materials: 88kg (0.245kmol) of the compound of formula III prepared in example 2 was taken as a white solid;
the reaction solvent in this example was dichloromethane;
the catalyst of this example was boron tribromide, 67.62kg (0.270 kmol);
the extraction solvent in this example was dichloromethane;
the reaction formula is as follows:
under the protection of nitrogen, 88kg of compound III is added into 704kg of dichloromethane solvent, 67.62kg of catalyst boron tribromide is added, the mixture is stirred and reacted for 1.5h at-l 5 ℃, and after the reaction is finished, the solution is poured into water and is extracted by dichloromethane solvent; the organic layer was washed with saturated sodium bicarbonate solution and saturated brine to neutrality, dried over anhydrous magnesium sulfate, filtered, and the dichloromethane solvent was evaporated to give 71.2kg of a white solid with a yield of 84.20%.
EXAMPLE 5 preparation of (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran, a Compound of formula I
Raw materials: the compound of formula II prepared in example 3, a white solid, 70kg (0.203 kmol); (S) -3-p-toluenesulfonyloxy tetrahydrofuran, 54.14kg (0.223kmol)
The base used in this example was DIEA (diisopropylethylamine), 52.51kg (0.406 kmol);
acetonitrile is selected as an example of the reaction solvent in the embodiment, and 350kg of the reaction solvent is selected;
in the present example, potassium iodide was selected as an example, 1.69kg (0.010 kmol);
this example can be performed by selecting either one of the bases, or either one of the catalysts, or either one of the reaction solvents, and the reaction formula is as follows:
adding 70kg of compound II (0.203kmol) into 350kg of acetonitrile solvent, adding 54.14kg (0.223kmol) of raw material S-3-p-toluenesulfonyloxy tetrahydrofuran, 52.51kg (0.406kmol) of alkali DIEA and 1.69kg (0.010kmol) of catalyst potassium iodide, stirring uniformly, heating to 50-55 ℃ for reacting overnight, and directly decompressing and concentrating to remove part of solvent acetonitrile after the reaction is finished; then adding 350kg of water and 350kg of dichloromethane solvent for extraction, extracting the water phase for 1 time by using 175kg of dichloromethane solvent, combining organic phases, washing the organic phases for 1 time by using 350kg of saturated common salt, drying the organic phases by using anhydrous sodium sulfate, performing vacuum concentration, and recrystallizing the dried organic phases by using a mixed solvent of petroleum ether and ethyl acetate to obtain 76.65kg of white solid, namely the exellen intermediate (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran, of which the yield is 90.1%.
The structure of the compound of the formula I obtained by the invention is confirmed by nuclear magnetic hydrogen spectrum and carbon spectrum, and the result is as follows:1H-NMR(500MHz,CDCl3)：δ＝2.129-2.239(m,2H),3.887-3.929(m,1H),3.965-4.021(m,5H),4.924-4.895(m,1H),6.798-6.827(m,2H),7.087-7.109(m,3H),7.462-7.485(t,2H)。
13C-NMR(500MHz,CDCl3)：δ＝33.257，38.262，67.454，73.377，77.526，91.906，115.711，130.237，131.196，131.447，134.440，136.834，139.762，141.616，141.616，156.303。
from the above examples, it can be seen that in the examples of the present invention, p-methoxybenzyl chloride and p-iodoaniline are used as starting materials, and are substituted to obtain compound IV, and then are diazotized and sandmeyer reacted to obtain compound III, and further are demethylated under the action of boron tribromide to obtain compound II, and finally, the compound II is condensed with (S) -3-p-toluenesulfonyloxy tetrahydrofuran to obtain engelazin intermediate compound I. The preparation method has the advantages of cheap and easily-obtained raw materials, high yield, 40-60% of total molar yield, over 99% of chemical purity and less than or equal to 0.15% of isomer.
The above description is not intended to limit the present invention, and any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention should be considered within the scope of the present invention.
Claims (9)
1. A preparation method of an empagliflozin intermediate, which is characterized in that:
(1) the chemical structural formula of the empagliflozin intermediate is as follows:
(2) the preparation method of the empagliflozin intermediate comprises the following steps:
(a) synthesizing a compound 4-iodo-2- (4-methoxybenzyl) aniline represented by a formula IV by using p-methoxybenzyl chloride and p-iodoaniline as starting raw materials;
(b) diazotizing a compound 4-iodine-2- (4-methoxybenzyl) aniline shown as a formula IV under the action of sodium nitrite and hydrochloric acid, and performing a Sandmeyer reaction under the action of cuprous chloride to obtain a compound 1-chlorine-4-iodine-2- (4-methoxybenzyl) benzene shown as a formula III;
(c) demethylating 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene shown in formula III under the action of boron tribromide to obtain 4- (2-chloro-5-iodophenyl) phenol shown in formula II;
(d) condensing 4- (2-chloro-5-iodophenyl) phenol shown as a formula II and (S) -3-p-toluenesulfonyloxy tetrahydrofuran to obtain (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran shown as a formula I.
2. The preparation method according to claim 1, wherein the step (a) is specifically: heating and refluxing p-methoxybenzyl chloride and p-iodoaniline under the action of Lewis acid in a solvent to react to obtain a compound shown as a formula IV; the solvent is selected from any one of ethyl acetate, carbon disulfide or nitrobenzene; the Lewis acid is selected from any one of zinc chloride, anhydrous aluminum chloride and titanium tetrachloride.
3. The preparation method according to claim 1, wherein concentrated hydrochloric acid is selected for the diazotization reaction of the compound IV in the step (b), and the reaction temperature is-10-0 ℃; and (3) carrying out a Sandmeyer reaction on the diazotization reaction product in a hydrochloric acid solution of cuprous chloride at the reaction temperature of 70-80 ℃ to obtain the compound shown in the formula III.
4. The method according to claim 1, wherein the step (c) is specifically: under the protection of nitrogen, reacting the compound III in a dichloromethane solvent under the action of boron tribromide as a catalyst at the reaction temperature of-25 to-l 5 ℃ to obtain the compound shown in the formula II.
5. The method according to claim 1, wherein the step (d) is specifically: carrying out condensation reaction on the compound II and (S) -3-p-toluenesulfonyloxy tetrahydrofuran in a solvent at 50-55 ℃ in the presence of alkali and a catalyst to obtain a compound shown in a formula I; the solvent is selected from any one of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1, 4-dioxane, toluene and the like; the alkali is selected from any one of potassium carbonate, sodium carbonate, potassium tert-butoxide, triethylamine and diisopropylethylamine; the catalyst is selected from any one of potassium iodide and potassium bromide.
6. The method according to claim 2, wherein the molar ratio of p-methoxybenzyl chloride to p-iodoaniline to Lewis acid in step (a) is 1 (1.0-1.1) to (1.1-2.0).
7. The preparation method according to claim 1 or 3, wherein the compound of formula IV in the step (b) is added into concentrated hydrochloric acid, cooled to-15 to-10 ℃, and then added with an ice water solution of sodium nitrite, wherein the temperature is controlled to-10 to 0 ℃ during the adding process.
8. The preparation method according to claim 1 or 4, wherein the molar ratio of the compound III to the boron tribromide in the step (c) is 1 (1.1-2.0).
9. The process according to claim 1 or 5, wherein the molar ratio of the compound II (S) -3-p-toluenesulfonyloxy tetrahydrofuran to the base to the catalyst in the step (d) is 1 (1.05 to 1.2) to (1.5 to 3.0) to (0.02 to 0.08).
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