CN108069997A - 一种托格列净中间体及其制备方法 - Google Patents
一种托格列净中间体及其制备方法 Download PDFInfo
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- CN108069997A CN108069997A CN201610978191.8A CN201610978191A CN108069997A CN 108069997 A CN108069997 A CN 108069997A CN 201610978191 A CN201610978191 A CN 201610978191A CN 108069997 A CN108069997 A CN 108069997A
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- ZXOCGDDVNPDRIW-NHFZGCSJSA-N Tofogliflozin Chemical compound O.C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 ZXOCGDDVNPDRIW-NHFZGCSJSA-N 0.000 title claims abstract description 22
- 229950006667 tofogliflozin Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 229940125904 compound 1 Drugs 0.000 claims abstract description 21
- 239000003223 protective agent Substances 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000006884 silylation reaction Methods 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims abstract description 5
- 150000002367 halogens Chemical group 0.000 claims abstract description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 125000006239 protecting group Chemical group 0.000 claims description 19
- 239000000758 substrate Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 10
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical group C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical group [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 7
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 7
- 229910052710 silicon Inorganic materials 0.000 claims description 7
- 239000010703 silicon Substances 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 5
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- 239000003205 fragrance Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 0 *C[C@]([C@@](*)[C@@](*)[C@@]1*)OC1=O Chemical compound *C[C@]([C@@](*)[C@@](*)[C@@]1*)OC1=O 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- -1 bis- bromo- -2 propyl Chemical group 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000012209 glucono delta-lactone Nutrition 0.000 description 2
- 229960003681 gluconolactone Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- RXEQQBIEGNVBPM-UHFFFAOYSA-N CC(C)(OC)Oc(cc(cc1)Br)c1Br Chemical compound CC(C)(OC)Oc(cc(cc1)Br)c1Br RXEQQBIEGNVBPM-UHFFFAOYSA-N 0.000 description 1
- CTQJHRSGDPCBNB-XXEPRFFLSA-N CCc1ccc(C(C(C2)=CC=C(CO3)C2[C@@]3([C@@H](C2=O)O)O[C@H](CO)[C@H]2O)O)cc1 Chemical compound CCc1ccc(C(C(C2)=CC=C(CO3)C2[C@@]3([C@@H](C2=O)O)O[C@H](CO)[C@H]2O)O)cc1 CTQJHRSGDPCBNB-XXEPRFFLSA-N 0.000 description 1
- VWVKUNOPTJGDOB-BDHVOXNPSA-N CCc1ccc(Cc2cc([C@]([C@@H]([C@H]3O)O)(OC4)O[C@H](CO)[C@H]3O)c4cc2)cc1 Chemical compound CCc1ccc(Cc2cc([C@]([C@@H]([C@H]3O)O)(OC4)O[C@H](CO)[C@H]3O)c4cc2)cc1 VWVKUNOPTJGDOB-BDHVOXNPSA-N 0.000 description 1
- PLQVDNBZYCMIHQ-ARQDHWQXSA-N C[SiH2]C(=O)[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O Chemical compound C[SiH2]C(=O)[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O PLQVDNBZYCMIHQ-ARQDHWQXSA-N 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- QVMHBCYOURAVBN-UHFFFAOYSA-L [Li+].[Cl-].CCC[Mg]Cl Chemical compound [Li+].[Cl-].CCC[Mg]Cl QVMHBCYOURAVBN-UHFFFAOYSA-L 0.000 description 1
- WDCNLMFEFWDYAV-UHFFFAOYSA-M [Mg].C(CCC)[Mg]Cl Chemical compound [Mg].C(CCC)[Mg]Cl WDCNLMFEFWDYAV-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BULOCEWDRJUMEL-UHFFFAOYSA-N benzene formaldehyde Chemical compound C=O.C1=CC=CC=C1.C=O BULOCEWDRJUMEL-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- MPOOBUXJJDKJOG-UHFFFAOYSA-M lithium;chloride;hydrochloride Chemical compound [Li+].Cl.[Cl-] MPOOBUXJJDKJOG-UHFFFAOYSA-M 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- DQZLQYHGCKLKGU-UHFFFAOYSA-N magnesium;propane Chemical compound [Mg+2].C[CH-]C.C[CH-]C DQZLQYHGCKLKGU-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/05—Preparation of ethers by addition of compounds to unsaturated compounds
- C07C41/06—Preparation of ethers by addition of compounds to unsaturated compounds by addition of organic compounds only
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/48—Preparation of compounds having groups
- C07C41/50—Preparation of compounds having groups by reactions producing groups
- C07C41/54—Preparation of compounds having groups by reactions producing groups by addition of compounds to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/17—Unsaturated ethers containing halogen
- C07C43/174—Unsaturated ethers containing halogen containing six-membered aromatic rings
- C07C43/1742—Unsaturated ethers containing halogen containing six-membered aromatic rings with halogen atoms bound to the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/30—Compounds having groups
- C07C43/313—Compounds having groups containing halogen
-
- 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
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
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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)
- Chemical Kinetics & Catalysis (AREA)
Abstract
本发明公开了一种托格列净新中间体,如式(I)化合物,为化合物1与保护剂在催化剂作用下反应得到,使用如式(I)化合物来制备托格列净,具有反应选择性高、收率高、产品便于分离提纯、操作简便、成本低等优点,利于工业化生产,
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种用于治疗糖尿病的原料药的中间体及其合成方法。
背景技术
托格列净是一种螺缩酮衍生物,不但具有降血糖的作用,而且具有药效持续性、代谢稳定性或安全性。可用于胰岛素依赖性糖尿病(I型糖尿病)、非胰岛素依赖型糖尿病(II型糖尿病)等糖尿病、糖尿病并发症、肥胖症等起因于高血糖症的疾病的预防或治疗。
目前文献报道托格列净的合成方法有以下几种:
专利CN200980119081、EP2308886公开报道了以2,4-溴苄醇为原料与2-甲氧基丙烯发生加成反应制得2,4-二溴-3-甲氧基-2-甲基-2丙烷基苯醚,然后与2,3,4,6-四-O-三甲基硅基-D-葡萄糖酸内酯缩合反应,再与4-乙基苯甲醛缩合,然后还原,上保护,脱保护制得目标化合物。反应路线如下所示:
其中nBuLi是正丁基锂,Pd/C是鈀碳。
此路线的原料2,4-二溴苄醇价格昂贵,需要两次使用正丁基锂,反应可控性差,危险性高,反应体系较杂,不易纯化,而且需要长时间超低温反应,不适宜工业化生产。
WO 2006/080421、WO2009/154276、EP1852439等专利公开了如下路线:
其中TFA是三氟乙酸。
此路线中原料1来源不易得,且价格昂贵,化合物6氧化时引入重金属,不利于目标化合物的质量控制;且需要两次使用正丁基锂,危险性大;需要长时间使用超低温设备,对工业生产设备要求较高;危险性较高,不利于工业生产。
上述技术方案虽各自有其优点,但存在使用昂贵的原料,反应条件苛刻,环境污染严重,收率低,成本较高,不利于工业化生产的缺陷。鉴于托格列净良好的药物前景,因此需要开发一种原料廉价易得、反应安全性高、成本低、易于工业化的工艺路线。
发明内容
本发明的目的是克服上述现有技术中起始原料价格昂贵,所用试剂毒害大,分离纯化困难,不易工业化等缺点,提供一种反应步骤简短、反应条件温和、操作简便、对环境友好的托格列净及其中间体的合成方法。
一种式(I)的托格列净中间体,结构为
R代表硅烷基或烷基醚基,X代表卤素,为碘、溴或氯,R可以为三甲基硅基、三乙基硅基、叔丁基或2-甲氧基-2丙烷基。
式(I)化合物的制备方法,包含如下步骤:化合物1在催化剂作用下与保护剂反应得到
其中R代表硅烷基或烷基醚基,X代表卤素,碘、溴或氯,优选碘。
保护剂为三甲基氯硅烷、三乙基氯硅烷、异丁烯、2-甲氧基丙烯,相应的保护基R为三甲基硅基、三乙基硅基、叔丁基、2-甲氧基-2丙烷基,保护剂优选三甲基氯硅烷和2-甲氧基丙烯;保护剂与化合物1的当量比为:当保护剂为硅烷基时,保护剂与化合物1的当量比为1.1~1.5∶1.0,优选1.2∶1.0;当催化剂为烷基或烷基醚时,保护剂与化合物1的当量比为2.0~5.0∶1.0,优选3.0∶1.0。
催化剂为三乙胺、咪唑、N-甲基吗啉、吡啶等有机碱或对甲苯磺酸吡啶、4-二甲氨基吡啶,优选三乙胺与对甲苯磺酸吡啶。
式(I)化合物的制备方法中,当保护基为硅烷基时,催化剂与化合物1的当量比为1.5~2.0∶1.0,优选1.5∶1.0,当保护基为烷基或烷基醚基时,催化剂与化合物1的当量比为0.1~0.2∶1.0,优选0.15∶1.0。
本发明所述托格列净中间体的制备方法,反应所用溶剂为芳香烃类溶剂或醚类溶剂;芳香烃类溶剂可以是苯或甲苯,醚类溶剂可以是四氢呋喃或甲基叔丁基醚苯甲醚或1,4二氧六环;优选四氢呋喃。
式(I)化合物的制备方法,当保护基为硅烷基时,保护剂与化合物1的当量比为1.1~1.5∶1.0,当保护基为烷基或烷基醚基时,保护剂与化合物1的当量比为2.0~5.0∶1.0。
本发明所述的式(I)化合物的制备方法,反应温度为0℃~25℃。
本发明的式(I)化合物,按如下步骤制备托格列净
其中TMS为三甲基硅基。
本发明的式(I)化合物,到托格列净的制备方法,其式(I)化合物到托格列净的缩合反应中,缩合试剂为正丁基锂、仲丁基锂、叔丁基锂、异丙基氯化镁氯化锂、正丁基氯化镁,反应温度为-80℃~-10℃。
下面对上述反应作具体说明:
本发明步骤化合物1到式(I)化合物可按照如下步骤进行,其中操作如下:化合物1经保护得到式(I)化合物,在0℃~30℃下反应1~16小时,萃取,浓缩,得到化合物。
进一步的,所述的式(I)化合物的制备方法,其中保护剂选自三甲基氯硅烷、三乙基氯硅烷、2-甲氧基丙烯、异丁烯等一切在有机酸或无机酸中易脱去的保护剂。
进一步的,上述羟基保护剂为三甲基氯硅烷或三乙基氯硅烷时,操作如下:化合物1,四氢呋喃和碱混合,滴加三甲基氯硅烷或三乙基氯硅烷,反应10~16小时,萃取,浓缩,得到式(I)化合物;上保护基时所用的碱为三乙胺,咪唑,N-甲基吗啉,吡啶等弱碱,投料摩尔比为化合物1∶三甲基氯硅烷∶碱=1.0∶1.2~2.0∶2.0~5.0,优选比为1.0∶1.5~2.0∶2.3~3.5。
式(I)化合物在三甲基硅基或三乙基硅基为保护基时结构式如下:
进一步的,上述羟基保护剂为2-甲氧基丙烯或异丁烯时,操作如下:化合物1、四氢呋喃、保护剂混合,分批加入催化剂,0~5℃下反应1~3小时,萃取,浓缩,得到式(I)化合物。上述所述催化剂甲苯磺酸吡啶鎓或路易斯酸,投料摩尔比为化合物1∶异丁烯∶催化剂=1.0∶1.5~10.0∶0.05~0.2,优选1.0∶1.5~3.0∶0.05~0.1。
式(I)化合物在2-甲氧基丙烯或异丁烯为保护基时结构式如下:
本发明制备托格列净步骤可按照如下步骤进行,其操作流程如下:
将通式(I)化合物加成至葡萄糖内酯上,优选化合物结构式为的化合物与葡萄糖内酯加成。
根据上述流程,由式(I)化合物开始,将对应的有机金属化合物通过卤素-金属交换,或通过将金属插入碳-卤素键而制得。与式(I)化合物进行卤素-金属交换时,所用试剂为正丁基锂或仲丁基锂或叔丁基锂,交换后得到锂化芳香基。类似的镁化物也可以通过异丙基氯化镁氯化锂或二异丙基氯化镁氯化锂等格式试剂,进行卤素-金属交换。该反应优选在乙醚、四氢呋喃、甲苯、己烷、甲基叔丁基醚等惰性溶剂或其混合溶剂中进行,在0℃~-80℃进行,优选-10℃~-80℃中进行。
进一步的,卤素-金属交换后加入酸,10℃~30℃反应10~12小时,萃取,浓缩,结晶得目标化合物。上述所述的酸可以为甲磺酸、甲苯磺酸、乙酸、盐酸甲醇溶液、盐酸乙醇溶液等,优选甲磺酸。
本发明给出的合成托格列净中间体的新工艺,有益效果为:本发明所操作过程无需低温或使用低温设备时间减少,减少了危险试剂丁基锂类的使用,安全性增加,降低了成本;另外,本发明中不再使用昂贵的起始原料,降低了成本;由于反应后粗品含量较高,终成品易于纯化。因此,本发明托格列净的制备方法具有反应条件温和、操作简便、对环境友好、生产成本低等优点,适合于工业化生产。
具体实施方式
通过下述实施例更具体的阐述本发明,然而,所述实施例并不意味着限制本发明的范围。
实施例1 式(I)化合物的合成(保护基为三甲基硅基)
向反应瓶中,加入化合物1(1g,0.003mmol)加入到三口瓶中,加入咪唑(0.67g,0.0098mol)和四氢呋喃降温到5℃,滴加三甲基氯硅烷(0.53g,0.0049mol),滴加完毕,室温反应12小时,加入水(200mL)和乙酸乙酯(200mL),分层,弃去下层,纯化水洗涤上层,无水硫酸镁干燥。旋干溶剂得产品,得无色油体1.08g,收率85.7%。1H NMR(400MHz,CDCl3):δ0.08(s,9H),1.22-1.24(m,3H),2.53-2.59(m,2H),5.03(s,2H),6.90-7.21(m,7H),MS(M+1)+=377.1。
实施例2 式(I)化合物的合成(保护基为三乙基硅基)
向反应瓶中,加入化合物1(1g,0.003mmol)加入到三口瓶中,加入三乙胺(0.99g,0.0098mol)和四氢呋喃降温0~5℃,滴加三乙基氯硅烷(0.73g,0.0049mol),滴加完毕,室温反应12小时,加入水(200mL)和乙酸乙酯(200mL),分层,弃去下层,纯化水洗涤上层,无水硫酸镁干燥。旋干溶剂得产品,得无色油体1.11g,收率90.2%。1H NMR(400MHz,CDCl3):δ0.85-0.91(m,9H),δ0.08(s,9H),1.23(s,3H),δ2.57-2.64(m,2H),δ3.81(s,2H)5.05(s,2H),6.89-7.21(m,7H),MS(M+1)+=419.1。
实施例3 式(I)化合物的合成(保护基为2-甲氧基-2-丙烷基)
向反应瓶中,加入化合物1(1g,0.003mol)加入到三口瓶中,加入2-甲氧基丙烯(0.71g,0.0098mol)和四氢呋喃,降温0~5℃,加入甲苯磺酸吡啶(0.07g,0.0003mol),滴加完毕,保温反应2小时,加入水(200mL)和乙酸乙酯(200mL),分层,弃去下层,纯化水洗涤上层,无水硫酸镁干燥。旋干溶剂得产品,得无色油体1.1g,收率80.6。1H NMR(400MHz,CDCl3):δ1.20-1.24(m,3H),1.40(m,6H),2.53-2.59(m,2H),3.24(s,3H),3.80(s,2H),4.62(s,2H),6.90-7.21(m,7H),MS(M+1)+=425.1。
实施例4 托格列净的合成(以式(I)化合物,保护基为三甲基硅基为例)
氮气保护下,将式(I)化合物1.08g加入到100ml三口瓶中,加入甲基叔丁基醚∶四氢呋喃=2∶1的溶剂30ml,降温-30℃以下,滴加正丁基锂(2.5M,1.4ml,0.003mol),滴加完毕,控温于-30℃以下,将该反应体系滴加到化合物2(0.009mol)中,加毕室温反应过夜。滴加氯化铵水溶液淬灭反应,分层,水相用乙酸乙酯提取,合并有机相,干燥浓缩,加入丙酮,析出固体,抽滤,得引湿性白色固体1.2g。1H NMR(400MHz,CDCl3):δ1.12-1.16(m,3H),2.51-2.58(m,2H),3.16-3.21(m,1H),3.31-3.41(m,1H),3.51-3.61(m,4H),3.92(s,2H),4.37(s,1H),4.52(s,1H),4.85(s,1H),4.94-5.01(m,3H),7.09-7.22(m,7H),MS(M+1)+=409.17。
实施例5 托格列净的合成(以式(I)化合物,保护基为三乙基硅基为例)
氮气保护下,将式(I)化合物1.0g加入到100ml三口瓶中,加入四氢呋喃20ml,降温-5℃~0℃,滴加异丙基氯化镁氯化锂(1.3M,5.1ml0.0066mol),滴加完毕,保温反应1小时,控温与-10℃以下,滴加化合物2的四氢呋喃溶液(1.7g,0.0036mol),滴加完毕,保温0℃~5℃反应1小时。控温于10℃以下滴加甲磺酸0.5ml(0.009mol),加毕室温反应过夜。滴加氯化铵水溶液淬灭反应,分层,水相用乙酸乙酯提取,合并有机相,干燥浓缩,加入丙酮析出固体,抽滤,得白色固体1.08g。1H NMR(400MHz,CDCl3):δ1.12-1.16(m,3H),2.49-2.58(m,2H),3.16-3.21(m,1H),3.31-3.41(m,1H),3.50-3.59(m,4H),3.92(s,2H),4.37(s,1H),4.50(s,1H),4.85(s,1H),4.94-5.01(m,3H),7.1-7.21(m,7H),MS(M+1)+=409.17。
实施例6 托格列净的合成(以式(I)化合物,保护基为三甲基硅基为例)
氮气保护下,将式(I)化合物1.1g加入到100ml三口瓶中,加入四氢呋喃20ml,降温-5℃~0℃,滴加异丙基氯化镁氯化锂(1.3M,5.6ml0.0073mol),滴加完毕,保温反应1小时,控温与-10℃以下,滴加化合物2的四氢呋喃溶液(1.7g,0.0036mol),滴加完毕,保温0℃~5℃反应1小时。控温于10℃以下滴加甲磺酸0.5ml(0.009mol),加毕室温反应过夜。滴加氯化铵水溶液淬灭反应,分层,水相用乙酸乙酯提取,合并有机相,干燥浓缩,加入丙酮析出固体,抽滤,得白色固体1.08克。1H NMR(400MHz,CDCl3):δ1.12-1.16(m,3H),2.49-2.58(m,2H),3.16-3.21(m,1H),3.31-3.41(m,1H),3.51-3.61(m,4H),3.92(s,2H),4.37(s,1H),4.52(s,1H),4.85(s,1H),4.94-5.01(m,3H),7.1-7.21(m,7H),MS(M+1)+=409.17。
Claims (12)
1.一种式(I)的托格列净中间体,结构为
R代表硅烷基或烷基醚基,X代表卤素,为碘、溴或氯。
2.如权利要求1所述的式(I)化合物,其特征在于:R为三甲基硅基、三乙基硅基、叔丁基或2-甲氧基-2丙烷基。
3.根据权利要求1所述的式(I)化合物的制备方法,包含如下步骤:化合物1在催化剂作用下与保护剂反应得到
R代表硅烷基或烷基醚基,X代表卤素,碘、溴或氯。
4.根据权利要求3所述的式(I)化合物的制备方法,其特征在于:保护剂为三甲基氯硅烷、三乙基氯硅烷、异丁烯、2-甲氧基丙烯,相应的保护基R为三甲基硅基、三乙基硅基、叔丁基、2-甲氧基-2丙烷基。
5.根据权利要求3所述的式(I)化合物的制备方法,其特征在于:所述催化剂为三乙胺、咪唑、N-甲基吗啉、吡啶、对甲苯磺酸吡啶、4-二甲氨基吡啶。
6.根据权利要求3所述的式(I)化合物的制备方法,其特征在于:当保护基为硅烷基时,催化剂与化合物1的当量比为1.5~2.0∶1.0,当保护基为烷基或烷基醚基时,催化剂与化合物1的当量比为0.1~0.2∶1.0。
7.根据权利要求3所述的式(I)化合物的制备方法,其特征在于:当保护基为硅烷基时,保护剂与化合物1的当量比为1.1~1.5∶1.0,当保护基为烷基或烷基醚基时,保护剂与化合物1的当量比为2.0~5.0∶1.0。
8.根据权利要求3所述的式(I)化合物的制备方法,其特征在于:反应所用溶剂为芳香烃类溶剂或醚类溶剂,芳香烃类溶剂选自苯、甲苯,醚类溶剂选自四氢呋喃、甲基叔丁基醚苯甲醚、1,4二氧六环。
9.根据权利要求8所述的式(I)化合物的制备方法,其特征在于:反应所用溶剂为四氢呋喃。
10.根据权利要求3所述的式(I)化合物的制备方法,其特征在于:反应温度为0℃~25℃。
11.根据权利要求1所述的式(I)化合物,按如下步骤制备托格列净
其中TMS为三甲基硅基。
12.根据权利要求11所述的托格列净的制备方法,其特征在于:式(I)化合物到托格列净的缩合反应中,缩合试剂为正丁基锂、仲丁基锂、叔丁基锂、异丙基氯化镁氯化锂、正丁基氯化镁,反应温度为-80℃~-10℃。
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