CN114516831A - Preparation method of miglitol - Google Patents
Preparation method of miglitol Download PDFInfo
- Publication number
- CN114516831A CN114516831A CN202210073219.9A CN202210073219A CN114516831A CN 114516831 A CN114516831 A CN 114516831A CN 202210073219 A CN202210073219 A CN 202210073219A CN 114516831 A CN114516831 A CN 114516831A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- formula
- compound
- substituted
- benzoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 title abstract description 41
- 229960001110 miglitol Drugs 0.000 title abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims abstract description 34
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000006239 protecting group Chemical group 0.000 claims abstract description 11
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 43
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 20
- 150000003254 radicals Chemical class 0.000 claims description 19
- 125000003170 phenylsulfonyl group Chemical class C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- -1 isobutyryl Chemical group 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 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 description 9
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003903 2-propenyl group Chemical class [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 238000010306 acid treatment Methods 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- MFIGJRRHGZYPDD-UHFFFAOYSA-N n,n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)NCCNC(C)C MFIGJRRHGZYPDD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 9
- 238000006243 chemical reaction Methods 0.000 abstract description 40
- 239000002994 raw material Substances 0.000 abstract description 14
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 230000006103 sulfonylation Effects 0.000 abstract 1
- 238000005694 sulfonylation reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000003729 cation exchange resin Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 238000002425 crystallisation Methods 0.000 description 14
- 230000008025 crystallization Effects 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- LXBIFEVIBLOUGU-JGWLITMVSA-N duvoglustat Chemical compound OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O LXBIFEVIBLOUGU-JGWLITMVSA-N 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000036983 biotransformation Effects 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 238000004042 decolorization Methods 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- LXBIFEVIBLOUGU-UHFFFAOYSA-N Deoxymannojirimycin Natural products OCC1NCC(O)C(O)C1O LXBIFEVIBLOUGU-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- RHHHLFPLFQGJHF-KEWYIRBNSA-N (3R,4R,5S,6R)-3-amino-2-(2-hydroxyethyl)-6-(hydroxymethyl)oxane-2,4,5-triol Chemical compound OCCC1(O)[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO RHHHLFPLFQGJHF-KEWYIRBNSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 238000009631 Broth culture Methods 0.000 description 1
- 102100024452 DNA-directed RNA polymerase III subunit RPC1 Human genes 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 101000689002 Homo sapiens DNA-directed RNA polymerase III subunit RPC1 Proteins 0.000 description 1
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 description 1
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012770 industrial material Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical class [H]C([H])([H])OC([H])([H])* 0.000 description 1
- HOVAGTYPODGVJG-ZFYZTMLRSA-N methyl alpha-D-glucopyranoside Chemical compound CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HOVAGTYPODGVJG-ZFYZTMLRSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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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)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of miglitol. Specifically, the method takes the compound in the formula VI as a raw material, performs substitution reaction with ethanolamine after sulfonylation, then removes a protecting group, and finally performs hydrogenation cyclization to prepare miglitol. The method has the advantages of simple steps, mild reaction conditions, high total yield, high product purity and the like, and is very suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry synthesis. In particular to a preparation method of a hypoglycemic drug miglitol, an intermediate compound and a preparation method thereof.
Background
Miglitol (Miglitol) is an antidiabetic drug marketed by bayer corporation in 1997. It is a novel intestinal alpha-glucosidase inhibitor found in a bacillus broth culture medium, is a parent modification product of 1-deoxynojirimycin,belongs to the type of N-substituted-1-deoxynojirimycin, and has a structure similar to that of glucose. The chemical name is (2R,3R,4R,5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3,4, 5-piperidinetriol, the melting point is 146 ℃, and the optical rotation is alpha]D20＝-8(C,1,CH3OH), structural formula as follows:
as a novel alpha-glucosidase inhibitor, miglitol competitively inhibits alpha-glucosidase, reduces the metabolism of carbohydrate compounds, and reduces the absorption of carbohydrates in the small intestine, thereby stabilizing the postprandial plasma glucose concentration. The medicine is safe and effective, has good tolerance generally, and has become a common medicine for treating type II diabetes.
The current preparation methods of miglitol are mainly divided into two modes of chemical synthesis and chemical-biological enzymatic synthesis.
The first way is chemical synthesis:
the literature Carbohydrate Research,2016,435,1-6 discloses a method for the synthesis of miglitol based solely on a chemical process. However, this method has disadvantages that diastereomer impurities are difficult to control and the total yield is low.
The documents Yunnan chemical industry, 2010(2),14-17 also give a method for preparing miglitol, and the preparation process is as follows: methyl-alpha-D-glucoside is used as a raw material, a series of chemical modifications are carried out to obtain a lipophilic derivative of a key intermediate 1-deoxynojirimycin, and a series of substitution reactions are carried out to obtain miglitol. However, this method is complicated in steps, produces many by-products, and is difficult to purify.
Another way is chemo-bio enzymatic synthesis:
patent CN105968042B discloses a method for preparing a final product by using glucose and ethanolamine as raw materials, performing catalytic hydrogenation under the condition of high pressure hydrogen to prepare an intermediate hydroxyethylglucosamine, then performing biological oxidation by gluconic acid oxidizing bacteria, performing catalytic hydrogenation under the condition of high pressure hydrogen to prepare a miglitol crude product, and then performing purification and crystallization refining. The reaction conditions are harsh, the cost of thallus culture and the cost of biotransformation are high, and the thallus is not easy to recycle, so that the commercial application of the thallus is limited.
Patent CN101029321A discloses a method for preparing miglitol by using 1-hydroxyethylamino-1-deoxy-D-sorbitol as raw material, performing fermentation reaction by using bacterial-containing microcapsules prepared from polymeric ionic membrane containing gluconic acid oxidizing bacteria to prepare 1-hydroxyethylamino-1-deoxy-D-sorbose, performing catalytic hydrogenation, refining with resin, and concentrating and crystallizing. The method has the defects of harsh reaction conditions, difficult raw material acquisition, complicated reaction steps and the like, and is not beneficial to industrial production.
Patent CN107746385A discloses a method for preparing miglitol by using 6-deoxy-6-hydroxyethyl amino-alpha-L-sorbose cell resting liquid as a raw material. The method has the defects of harsh reaction conditions, difficult raw material purchase, complicated reaction steps and the like, and is not beneficial to industrial production.
Patent CN101302549B discloses a method for preparing miglitol (HPLC 99.0%) by screening miglitol production strains, performing biotransformation, microfiltration, ultrafiltration, nanofiltration and activated carbon decolorization on a substrate to obtain a miglitol intermediate, and then performing hydrogenation purification. However, the route has the defects of difficult culture and separation of miglitol production strains, low recycling rate, small yield and the like, and the industrial development of the miglitol production strains is restricted.
Patent EP0008031B1 discloses a method for preparing miglitol by using 6-amino-6-deoxy-L-sorbitol as a raw material and performing amino protection, microbial oxidation, catalytic hydrogenation, and reaction with ethylene oxide. However, in this route, the cost for culturing cells and the cost for biotransformation are high, and the cells collected by centrifugation have a large loss, and thus the method is not suitable for industrial mass production.
Patent CN1328270C discloses that furan ring derivative is used as raw material and catalyst RaNi, 1% -5% Pd/C or Pd-CaCO are used3A method for preparing miglitol by catalytic hydrogenation. In the patent, the purity of the refined miglitol product prepared by the method is only 98.9 percent, which can not meet the requirements of the preparation market, and the patent does not give a synthetic route which can be used as a raw material for reference, which necessarily limits the development of the route.
In summary, the existing synthetic routes are classified into two categories, one is the preparation of miglitol by a chemical synthesis method; the other is the preparation of miglitol by microbial fermentation or by chemical synthesis followed by microbial fermentation. However, the two preparation methods have the problems of complicated steps, harsh synthesis conditions, difficult raw material acquisition or difficult product purity adaptation to market requirements and the like. Therefore, a synthetic method for preparing high-quality miglitol by taking simple and easily-obtained industrial materials as raw materials through simple and conveniently-operated steps is required to be developed, so that the requirement of industrial large-scale production is met.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the existing synthesis method and provide a novel miglitol preparation method which is more beneficial to industrial production.
Specifically, the invention provides a preparation method of miglitol of a formula I, which comprises the following steps:
step (1): removing a protecting group R from the compound shown in the formula IV to obtain a compound shown in the formula III;
step (2): removing a protecting group from the compound of the formula III through acid treatment to obtain a compound of a formula II;
and (3): catalytically hydrogenating the compound of formula II in the presence of a catalyst to obtain a compound of formula I;
wherein R is a hydroxyl protecting group;
alternatively, the compound of formula IV is deprotected directly in the presence of the acid described in step (2) to give a compound of formula II, followed by step (3).
In one embodiment, R is selected from C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkylcarbonyl, halo C1-8Alkylcarbonyl, benzoyl, C1-8Alkyl-substituted benzoyl, halo-C1-8Alkyl-substituted benzoyl, benzenesulfonyl, C1-8Alkyl substituted benzenesulfonyl, halo C1-8Alkyl-substituted phenylsulfonyl, benzyl, C1-8Alkyl-substituted benzyl, C1-8Alkoxy-substituted benzyl, halogen-substituted benzyl, halogeno-C1-8Alkyl-substituted benzyl, allyl, C1-8alkoxy-C1-8Alkyl radical, C1-8alkoxy-C1-8alkoxy-C1-8Alkyl, benzyloxy-C1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups, e.g. t-BuMe2Si、t-BuPh2Si、(i-Pr)3Si、Et3Si or Me3Si。
Preferably, R is selected from C1-8Alkyl radical, C1-8An alkylcarbonyl group,Benzoyl, benzyl, C1-8Alkyl-substituted benzyl, C1-8Alkoxy-substituted benzyl, halogen-substituted benzyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyran-2-yl or a silicon protecting group.
More preferably, R is selected from benzyl, C1-8Alkyl-substituted benzyl, C1-8Alkoxy-substituted benzyl, halogen-substituted benzyl, t-BuMe2Si、t-BuPh2Si、(i-Pr)3Si、Et3Si or Me3Si。
Most preferably, R is selected from benzyl, C1-8Alkyl substituted benzyl, t-BuMe2Si、t-BuPh2Si、(i-Pr)3Si、Et3Si or Me3Si。
In the step (1), the hydroxyl-protecting group R can be deprotected under basic conditions, acidic conditions or catalytic hydrogenation conditions.
When R is C1-8Alkylcarbonyl, halo C1-8Alkylcarbonyl, benzoyl, C1-8Alkyl-substituted benzoyl, phenylsulfonyl or C1-8In the case of an alkyl-substituted benzenesulfonyl group, the hydroxyl protecting group is removed in the presence of a base, for example, an alkali metal hydroxide or carbonate, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
When R is C1-8Alkyl radical, C1-8alkoxy-C1-8Alkyl, benzyloxy-C1-8In the case of alkyl, 2-tetrahydropyranyl or a silicon protecting group, the compound of formula IV may be deprotected in the presence of an acid to give a compound of formula III, followed by step (2), or the compound of formula IV may be deprotected directly in the presence of an acid to give a compound of formula II, followed by step (3).
The acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid or trifluoroacetic acid, or a mixture of two or more of the above.
When R is benzyl or C1-8When the benzyl group is substituted by alkyl or the benzyl group is substituted by halogen atom, the protecting group can be removed by catalytic hydrogenation. Catalytic hydrogenation plantThe catalyst used is selected from Pd/C, Pd (OH)2、Pd(OAc)2、PdCl2Pd and Ni, the pressure of the hydrogen used is 0.5-3.0 MPa, and the reaction time is 4-24 hours.
The reaction solvent of step (1) is an alcohol, an ester or an ether, or a mixture of any two or more thereof.
The alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, cyclohexanol, benzyl alcohol, etc.
The ester is selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate and isopropyl acetate.
The ether is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, anisole, tetrahydrofuran, methyl tetrahydrofuran and 1, 4-dioxane.
In step (2), the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid or trifluoroacetic acid, or a mixture of two or more thereof.
In step (3), the catalyst is selected from Pd/C, Pd (OH)2、Pd(OAc)2、PdCl2Pd or Ni, for example RaNi.
The hydrogen pressure in the step (3) is 0-4 MPa, preferably 1.0-3 MPa, and more preferably 2.0-2.5 MPa.
The reaction temperature in the step (3) is 0-30 ℃, and the reaction time is 4-24 hours.
In a preferred embodiment, said step (3) further comprises obtaining the compound of formula I by cation exchange resin. The cation exchange resin is selected from strong acid cation exchange resin D001, strong acid cation exchange resin HD-8, strong acid cation exchange resin JK006, strong acid cation exchange resin JK001, strong acid cation exchange resin DOWEX 50X 8-100, cation exchange resin CG50, strong acid cation exchange resin HZ002, strong acid cation exchange resin HZ016, strong acid cation exchange resin C145, strong acid cation exchange resin C150 or strong acid cation exchange resin C160.
In a further preferred embodiment, said step (3) further comprises purifying the crude compound of formula I by crystallization in an organic solvent or a mixture of an organic solvent and water after treatment with a cation exchange resin. The organic solvent may be selected from methanol, ethanol, n-propanol, isopropanol, or a mixture of two or more thereof.
In a second aspect, the present invention provides a process for the preparation of a compound of formula IV, comprising the steps of:
and (4): reacting a compound of formula VI with R1Reacting Cl in the presence of a base to prepare a compound of formula V;
and (5): reacting the compound of formula V with ethanolamine to prepare a compound of formula IV;
wherein R is as defined above for the first aspect, and R1Is C1-8Alkanoyl radical, C1-8Alkylsulfonyl, arylsulfonyl, C1-8Alkyl-substituted arylsulfonyl, benzoyl or substituted benzoyl.
Preferably, R is1Selected from formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl or p-toluenesulfonyl.
Preferably, the base is selected from an inorganic or organic base, such as an alkali metal hydroxide or carbonate or bicarbonate, for example sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diisopropylethylenediamine, diisopropylamine, piperidine, morpholine, pyridine or 2-methylpyridine.
In a preferred embodiment, in the step (4), the temperature is controlled to be-5 to 30 ℃, and the compound of the formula VI reacts with R in a low-polarity solvent in the presence of a base1And (4) reacting Cl. After the reaction is finished, the reaction solution can be directly subjected to the reaction in the step (5) after simple treatment.
The low-polarity solvent is selected from dichloromethane, trichloromethane, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane or acetonitrile, or a mixture of two or more of the two.
The simple treatment is that the reaction solution is washed and extracted by water to remove salts generated by the reaction.
In a preferred embodiment, in the step (5), the temperature is controlled to be 40-100 ℃, and the compound of formula V is reacted with ethanolamine in an organic solvent. And after the reaction is finished, cooling to room temperature, adjusting to be alkaline, further cooling for crystallization, and optionally crystallizing in an organic solvent or a mixture of the organic solvent and water to obtain the compound shown in the formula IV.
The base is selected from inorganic or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide.
The organic solvent used for the reaction is selected from dichloromethane, trichloromethane, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile or a mixture of two or more of the two.
The organic solvent used for crystallization is selected from dichloromethane, trichloromethane, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile or a mixture of two or more of the two.
In a third aspect, the present invention provides a novel intermediate compound of formula IV
Wherein R is selected from C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkylcarbonyl, halo C1-8Alkylcarbonyl, benzoyl, C1-8Alkyl-substituted benzoyl, halo-C1-8Alkyl-substituted benzoyl, benzenesulfonyl radicals、C1-8Alkyl substituted benzenesulfonyl, halo C1-8Alkyl-substituted phenylsulfonyl, benzyl, C1-8Alkyl-substituted benzyl, C1-8Alkoxy-substituted benzyl, halogen-substituted benzyl, halogeno-C1-8Alkyl-substituted benzyl, allyl, C1-8alkoxy-C1-8Alkyl radical, C1-8alkoxy-C1-8alkoxy-C1-8Alkyl, benzyloxy-C1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups, e.g. t-BuMe2Si、t-BuPh2Si、(i-Pr)3Si、Et3Si or Me3Si。
In a fourth aspect, the invention provides a method for synthesizing miglitol of formula I, which comprises the steps of taking a compound of formula VI as a raw material, carrying out protecting group application, substitution reaction, protecting group removal and catalytic hydrogenation cyclization reaction to obtain miglitol, and optionally carrying out recrystallization purification to obtain a final product.
Specifically, the invention provides a method for synthesizing miglitol of formula I, which comprises the following steps (4), (5), (1), (2) and (3):
wherein R and R1As defined above.
In a preferred embodiment, the conditions of steps (4) and (5) are as described in the second aspect of the invention. In another preferred embodiment, the conditions of steps (1), (2) and (3) are as described in the first aspect of the invention. Alternatively, the compound of formula IV is deprotected directly in the presence of the acid described in step (2) to give a compound of formula II, followed by step (3).
In a more preferred embodiment, the conditions of steps (4) and (5) are as described in the second aspect of the invention and the conditions of steps (1), (2) and (3) are as described in the first aspect of the invention, or the compound of formula IV is deprotected directly in the presence of an acid as described in step (2) to give the compound of formula II, followed by step (3).
Compared with the prior art, the invention has the following advantages:
1. the diastereoisomer impurities generated by the method can be effectively controlled to be below 0.1 percent;
2. the method for preparing miglitol by using the compound of the formula VI as a raw material has high yield which reaches 48.5-51.5%;
3. the purity of the miglitol prepared by the method reaches 99.9 percent, thereby providing reliable quality assurance for the preparation.
The invention overcomes the problems of low total yield, difficult control of diastereoisomer impurities, low product purity and the like in the prior art, and is suitable for industrial large-scale production.
Defining:
for the purpose of interpreting this specification, the following definitions will be used, and terms used in the singular may also include the plural and vice versa, as appropriate. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
The term "halogen" or "halo" as used herein refers to F, Cl, Br or I. Furthermore, the term "halogen-substituted" group is intended to include monohalogenated or polyhalogenated groups in which one or more of the same or different halogens substitute for one or more hydrogens in the group.
The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, e.g., 1 to 8, 1 to 6, 1 to 5,1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "C1-8Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms, and examples thereof are methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl and the like.
The term "halo C" as used herein1-8Alkyl "refers to C as described above1-8Alkyl, one or more of which (e.g. 1, 2, 3,4 or 5)The hydrogen atom is replaced by a halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different carbon atoms. "halo C1-8Examples of alkyl include-CH2F、-CHF2、-CF3、-CCl3、-C2F5、-C2Cl5、-CH2CF3、-CH2Cl、-CH2CH2CF3or-CF (CF)3)2And the like.
The term "alkoxy", alone or in combination with other groups, denotes the group Ry-O-wherein RyIs an alkyl group as described above. "C1-8Alkoxy "denotes the radical Ry-O-wherein RyIs C as described above1-8An alkyl group.
"aryl" refers to a monocyclic or fused bicyclic aromatic ring consisting of carbon and hydrogen atoms. "C6-10Aryl "means an aryl group containing 6 to 10 carbon atoms. For example, aryl may be phenyl or naphthyl.
"aralkyl" refers to an alkyl group as described above substituted with an aryl group as described above, for example benzyl.
"aralkoxy" means an alkoxy group as described above substituted with an aryl group as described above, e.g., benzyloxy.
"acyl" means the group-CO-RxWherein R isxIs an alkyl, aryl or aralkyl group as described above, for example an alkanoyl or aralkanoyl group, for example benzoyl.
The aryl groups described above, either as groups per se or as part of other groups such as aralkyl, aralkoxy, acyl groups, may be optionally substituted with one or more substituents. When said aryl group is substituted, said substituent is selected from C1-6Alkyl radical, C1-6Alkoxy, halo C1-8Alkyl, halogen, aryl and nitro, more preferably methoxy, ethoxy, halogen or phenyl. For example, substituted benzoyl means that the substituents on the phenyl ring are selected from C1-6Alkyl radical, C1-6Alkoxy, halo C1-8Alkyl, halogen or aryl benzoyl.
Detailed Description
The process of the present invention is further illustrated by the following examples. It should be understood that the following examples are provided only for the purpose of enabling a better understanding of the present invention, and are not intended to limit the scope of the present invention in any way.
Preparation of Compounds of formula IV
Example 1:
adding 1870g of dichloromethane and 269g of the compound of formula VI-a into a reaction bottle, stirring, cooling to 0-5 ℃, adding 125g of triethylamine, stirring for 10 minutes, slowly adding 220g of paratoluensulfonyl chloride, keeping the reaction at a low temperature for 30 minutes, heating to 25 ℃, keeping the temperature for reaction, adding 400g of water, stirring for 30 minutes, standing and layering. A solution of the compound of formula V-a in dichloromethane was obtained and used in the next reaction without further work-up.
Adding 120g of ethanolamine into a dichloromethane solution of the compound shown in the formula V-a, and stirring and heating to reflux; after the temperature is raised, controlling the internal temperature to be 90-95 ℃, and carrying out heat preservation reaction for 5-7 hours; after the reaction is finished, cooling to the internal temperature of 20-30 ℃; adding 200g of water, then dropwise adding a proper amount of 10% NaOH, adjusting the pH to be more than or equal to 12, and stirring and reacting for 12 hours at the temperature of 20-30 ℃; after the reaction is finished, cooling to 0-5 ℃, stirring for crystallization for 2 hours, and performing suction filtration; soaking and washing a filter cake with a small amount of purified water; suction filtration and drying of the filter cake are carried out to obtain 262g of the compound shown in the formula IV. Yield: 85.4%, purity: 99 percent.1H NMR(600MHz,DMSO-d6)δ7.35(h,J＝5.9Hz,4H),7.32–7.25(m,1H),4.58(q,J＝12.2Hz,2H),4.50(t,J＝5.3Hz,1H),4.33(s,1H),4.15(td,J＝5.4,2.8Hz,1H),4.02(d,J＝2.8Hz,1H),3.63(d,J＝10.7Hz,1H),3.56(d,J＝10.7Hz,1H),3.43(q,J＝5.0Hz,2H),3.34(s,1H),2.84(dd,J＝12.4,5.2Hz,1H),2.74(dd,J＝12.4,5.7Hz,1H),2.58(td,J＝5.6,2.5Hz,2H),1.40(s,3H),1.29(s,3H)；13C NMR(151MHz,DMSO)δ138.74,128.72,127.87,127.74,113.49,111.37,85.54,80.27,75.22,73.17,70.93,60.73,52.35,48.20,27.92,26.95。
Example 2:
adding 1870g of dichloromethane and 254g of the compound of formula VI-b into a reaction bottle, stirring, cooling to 0-5 ℃, adding 115g of triethylamine, stirring for 10 minutes, slowly adding 220g of methanesulfonyl chloride, keeping the reaction at low temperature for 30 minutes after the addition is finished, heating to 25 ℃, keeping the temperature for reaction, adding 400g of water, stirring for 30 minutes, standing and layering. A solution of the compound of formula V-b in dichloromethane was obtained and used in the next reaction without further work-up.
Adding 120g of ethanolamine into a dichloromethane solution of the compound shown in the formula V-b, stirring, heating, preserving heat and reacting for 5-7 hours; after the reaction is finished, cooling to the internal temperature of less than 20 ℃; adding 200g of water, then dropwise adding a proper amount of 10% NaOH, adjusting the pH to be more than or equal to 12, and stirring and reacting for 12 hours at the temperature of 20-30 ℃; after the reaction is finished, cooling to 0-5 ℃, stirring for crystallization for 2 hours, and performing suction filtration; soaking and washing a filter cake with a small amount of purified water; suction filtration and drying of the filter cake gave 227.6g of compound of formula IV-b. Yield: 78.1%, purity: 98.5 percent.
Preparation of Compounds of formula III
Example 3:
adding 240g of the compound shown in the formula IV-a and 1440mL of methanol into an autoclave, adding 36g of 10% palladium/carbon into the autoclave, replacing with nitrogen and hydrogen, stirring, heating to 50 ℃ of internal temperature and 0.9-1.0 MPa of hydrogen pressure, reacting for 4 hours under heat preservation, performing pressure filtration, and concentrating the filtrate under reduced pressure to obtain 175.2g of the compound shown in the formula III. Yield: 98.0 percent.1H NMR(600MHz,DMSO-d6)δ4.46–3.78(m,6H),3.60–3.32(m,4H),2.84(dd,J＝12.4,5.2Hz,1H),2.75(dd,J＝12.6,5.8Hz,1H),2.59(s,2H),1.34(d,J＝59.4Hz,6H)；13C NMR(151MHz,DMSO)δ114.60,111.12,85.25,80.06,75.21,62.43,60.59,52.26,48.18,27.95,27.10。
Preparation of Compounds of formula I
Example 4:
and (3) adding 175.2g of the compound shown in the formula III into a reaction bottle, dropwise adding 200g of concentrated hydrochloric acid, controlling the internal temperature to be 20-40 ℃ until the reaction is finished, and adding 60g of sodium hydroxide to adjust the alkali to obtain the compound water solution shown in the formula II. And transferring the compound water solution in the formula II into a high-pressure reaction kettle, adding 20g (wet weight and water content of 60%) of 10% palladium/carbon into the high-pressure reaction kettle, replacing 3 times with nitrogen and hydrogen respectively, and controlling the pressure of the hydrogen to be 1.0-3.0 MPa. After the reaction, filtering, and recycling the filter cake catalyst. And (3) putting the filtrate on a cation exchange resin column, dissociating with purified water and ammonia water after all the materials are put on the column, collecting the ammonia water dissociation solution, and concentrating under reduced pressure under the condition of controlling the external temperature to be 60-65 ℃. After the concentration is finished, adding absolute ethyl alcohol for crystallization, stirring for 2 hours at 50-55 ℃, slowly cooling to-5-0 ℃ for crystallization for 2 hours, and performing suction filtration. The filter cake was dried to obtain 117.2g of miglitol crude product. Yield: 85.0 percent.
Adding 117.2g of miglitol crude product, purified water and ethanol into a reaction bottle, stirring and heating to 50-55 ℃, adding 10g of activated carbon for decolorization after 1 hour, and performing suction filtration after 1 hour. And leaching the filter cake with hot absolute ethyl alcohol, combining the filtrates, and stirring at 50-55 ℃ for 2 hours. Slowly cooling to 25 ℃ for crystallization for 2 hours, cooling to-5-0 ℃, stirring for crystallization for 3-5 hours. Suction filtration and drying of filter cakes are carried out, thus obtaining 105.6g of miglitol. Yield: 90.1%, purity: 99.9 percent.
Example 5:
227.6g of the compound shown in the formula IV-b is added into a reaction bottle, 300g of concentrated hydrochloric acid is dripped, the internal temperature is controlled to be 20-40 ℃ until the reaction is finished, 60g of sodium hydroxide is added for alkali adjustment, and the compound water solution shown in the formula II is obtained after the adjustment is finished. And transferring the compound water solution in the formula II into a high-pressure reaction kettle, adding 20g (wet weight and water content of 60%) of 10% palladium/carbon into the high-pressure reaction kettle, replacing 3 times with nitrogen and hydrogen respectively, and controlling the pressure of the hydrogen to be 1.0-3.0 MPa. After the reaction, filtering, and recycling the filter cake catalyst. And (3) putting the filtrate on an cation exchange resin column, dissociating the filtrate by using purified water and ammonia water after all the materials are put on the column, collecting the ammonia water dissociation solution, and carrying out reduced pressure concentration under the condition of controlling the external temperature to be 60-65 ℃. After the concentration is finished, adding absolute ethyl alcohol for crystallization, stirring for 2 hours at 50-55 ℃, slowly cooling to-5-0 ℃ for crystallization for 2 hours, and performing suction filtration. And drying the filter cake to obtain 100g of miglitol crude product.
Adding 100g of miglitol crude product, purified water and ethanol into a reaction bottle, stirring and heating to 50-55 ℃, adding 10g of activated carbon for decolorization after 1 hour, and performing suction filtration after 1 hour. And leaching the filter cake with hot absolute ethyl alcohol, combining the filtrates, and stirring at 50-55 ℃ for 2 hours. Slowly cooling to 25 ℃ for crystallization for 2 hours, cooling to-5-0 ℃, stirring for crystallization for 3-5 hours. And (4) carrying out suction filtration, and drying a filter cake to obtain 78-83 g of miglitol. The total yield of miglitol prepared from the compound of formula VI-b is 42.5-45.3%, and the purity is as follows: 99.9 percent.
Claims (11)
1. A process for the preparation of a compound of formula I, comprising the steps of:
step (1): removing a protecting group R from the compound shown in the formula IV to obtain a compound shown in the formula III;
step (2): removing a protecting group from the compound of the formula III through acid treatment to obtain a compound of a formula II;
and (3): catalytically hydrogenating the compound of formula II in the presence of a catalyst to obtain a compound of formula I;
wherein R is a hydroxyl protecting group;
alternatively, the compound of formula IV is deprotected directly in the presence of the acid described in step (2) to give a compound of formula II, followed by step (3).
2. The method of claim 1, whereinR is selected from C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkylcarbonyl, halo C1-8Alkylcarbonyl, benzoyl, C1-8Alkyl-substituted benzoyl, halo-C1-8Alkyl-substituted benzoyl, benzenesulfonyl, C1-8Alkyl substituted benzenesulfonyl, halo C1-8Alkyl-substituted phenylsulfonyl, benzyl, C1-8Alkyl-substituted benzyl, C1-8Alkoxy-substituted benzyl, halogen-substituted benzyl, halogeno-C1-8Alkyl-substituted benzyl, allyl, C1-8alkoxy-C1-8Alkyl radical, C1-8alkoxy-C1-8alkoxy-C1-8Alkyl, benzyloxy-C1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups, e.g. t-BuMe2Si、t-BuPh2Si、(i-Pr)3Si、Et3Si or Me3Si。
3. The method of any one of claims 1-2, wherein R is selected from C1-8Alkyl radical, C1-8Alkylcarbonyl, benzoyl, benzyl, C1-8Alkyl-substituted benzyl, C1-8Alkoxy-substituted benzyl, halogen-substituted benzyl, tetrahydropyran-2-yl, or silicon protecting groups, e.g. t-BuMe2Si、t-BuPh2Si、(i-Pr)3Si、Et3Si or Me3Si。
4. The process of any one of claims 1-3, wherein the acid of step (2) is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, or trifluoroacetic acid, or a mixture of two or more thereof.
5. The process according to any one of claims 1 to 4, wherein the catalyst of step (3) is selected from Pd/C, Pd (OH)2、Pd(OAc)2、PdCl2Pd or Ni, for example RaNi.
6. The process of claims 1-5, wherein in step (1) by catalysisRemoving the protecting group R by hydrogenation, wherein the catalyst used is selected from Pd/C, Pd (OH)2、Pd(OAc)2、PdCl2Pd, Ni, such as Rani.
7. A process for the preparation of a compound of formula IV comprising the steps of:
and (4): reacting a compound of formula VI with R1Reacting Cl in the presence of a base to prepare a compound of formula V;
and (5): reacting the compound of formula V with ethanolamine to prepare a compound of formula IV;
wherein R is as defined in any of claims 1-3, and R1Is C1-8Alkanoyl radical, C1-8Alkylsulfonyl, arylsulfonyl, C1-8Alkyl-substituted arylsulfonyl, benzoyl or substituted benzoyl.
8. The method of claim 7, wherein R1Selected from formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl or p-toluenesulfonyl.
9. The process according to claim 7 or 8, wherein the base of step (4) is selected from inorganic or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diisopropylethylenediamine, diisopropylamine, piperidine, morpholine, pyridine or 2-methylpyridine.
10. A compound of formula IV
Wherein R is selected from C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkylcarbonyl, halo C1-8Alkylcarbonyl, benzoyl, C1-8Alkyl-substituted benzoyl, halo-C1-8Alkyl-substituted benzoyl, benzenesulfonyl, C1-8Alkyl substituted benzenesulfonyl, halo C1-8Alkyl-substituted phenylsulfonyl, benzyl, C1-8Alkyl-substituted benzyl, C1-8Alkoxy-substituted benzyl, halogen-substituted benzyl, halogeno-C1-8Alkyl-substituted benzyl, allyl, C1-8alkoxy-C1-8Alkyl radical, C1-8alkoxy-C1-8alkoxy-C1-8Alkyl, benzyloxy-C1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups, e.g. t-BuMe2Si、t-BuPh2Si、(i-Pr)3Si、Et3Si or Me3Si。
11. A process for the preparation of a compound of formula I, comprising the steps of:
and (4): reacting a compound of formula VI with R1Reacting Cl in the presence of a base to prepare a compound of formula V;
and (5): reacting the compound of formula V with ethanolamine to prepare a compound of formula IV;
step (1): removing a protecting group R from the compound shown in the formula IV to obtain a compound shown in the formula III;
step (2): removing a protecting group from the compound of the formula III through acid treatment to obtain a compound of a formula II; and
and (3): catalytically hydrogenating the compound of formula II in the presence of a catalyst to obtain a compound of formula I;
or, directly deprotecting the compound of formula IV in the presence of the acid of step (2) to give a compound of formula II, and then performing step (3);
wherein R is selected from C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkylcarbonyl, halo C1-8Alkylcarbonyl, benzoyl, C1-8Alkyl-substituted benzoyl, halo-C1-8Alkyl-substituted benzoyl, benzenesulfonyl, C1-8Alkyl substituted benzenesulfonyl, halo C1-8Alkyl-substituted phenylsulfonyl, benzyl, C1-8Alkyl-substituted benzyl, C1-8Alkoxy-substituted benzyl, halogen-substituted benzyl, halogeno-C1-8Alkyl-substituted benzyl, allyl, C1-8alkoxy-C1-8Alkyl radical, C1-8alkoxy-C1-8alkoxy-C1-8Alkyl, benzyloxy-C1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups, e.g. t-BuMe2Si、t-BuPh2Si、(i-Pr)3Si、Et3Si or Me3Si；
And R is1Is C1-8Alkanoyl radical, C1-8Alkylsulfonyl, arylsulfonyl, C1-8Alkyl-substituted arylsulfonyl, benzoyl or substituted benzoyl.
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| CN105968042A (en) * | 2016-07-15 | 2016-09-28 | 四川维奥制药有限公司 | Preparation method of migltol |
| CN112142648A (en) * | 2019-06-28 | 2020-12-29 | 鲁南制药集团股份有限公司 | Preparation method of miglitol |
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| US4429117A (en) * | 1979-09-07 | 1984-01-31 | Bayer Aktiengesellschaft | Process for the production of known and new 6-amino-6-desoxy-2,3-O-isopropylidene-α-L-sorbofuranose derivatives, and intermediate products of the process |
| US4405714A (en) * | 1980-10-15 | 1983-09-20 | Bayer Aktiengesellschaft | Production of N-substituted derivatives of 1-desoxynojirimicin |
| CN105968042A (en) * | 2016-07-15 | 2016-09-28 | 四川维奥制药有限公司 | Preparation method of migltol |
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Cited By (1)
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| WO2023138099A1 (en) * | 2022-01-21 | 2023-07-27 | 浙江奥翔药业股份有限公司 | Preparation method for miglittol |
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