CN106146480B - A kind of preparation method of Itraconazole - Google Patents
A kind of preparation method of Itraconazole Download PDFInfo
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- CN106146480B CN106146480B CN201610566225.2A CN201610566225A CN106146480B CN 106146480 B CN106146480 B CN 106146480B CN 201610566225 A CN201610566225 A CN 201610566225A CN 106146480 B CN106146480 B CN 106146480B
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- compound
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- itraconazole
- trityl
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- VHVPQPYKVGDNFY-TUJWMRSMSA-N 2-[(2S)-butan-2-yl]-4-[4-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-TUJWMRSMSA-N 0.000 title claims abstract description 28
- 229960004130 itraconazole Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- -1 p-toluenesulfonyl Chemical group 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000004593 Epoxy Substances 0.000 claims abstract description 12
- 238000007259 addition reaction Methods 0.000 claims abstract description 12
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 12
- 239000011734 sodium Substances 0.000 claims abstract description 12
- 239000011630 iodine Substances 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 10
- 238000006884 silylation reaction Methods 0.000 claims abstract description 9
- 238000003379 elimination reaction Methods 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 150000001336 alkenes Chemical class 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 238000006264 debenzylation reaction Methods 0.000 claims abstract description 4
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 15
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- 238000003747 Grignard reaction Methods 0.000 claims description 7
- JBWKIWSBJXDJDT-UHFFFAOYSA-N Triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000003852 triazoles Chemical class 0.000 claims description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- OOCUOKHIVGWCTJ-UHFFFAOYSA-N chloromethyl(trimethyl)silane Chemical compound C[Si](C)(C)CCl OOCUOKHIVGWCTJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000004795 grignard reagents Chemical class 0.000 claims description 5
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- IRSVDHPYXFLLDS-UHFFFAOYSA-N 2,4-dichloro-1-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1Cl IRSVDHPYXFLLDS-UHFFFAOYSA-N 0.000 claims description 3
- RQNMYNYHBQQZSP-UHFFFAOYSA-M Methylmagnesium chloride Chemical compound C[Mg]Cl RQNMYNYHBQQZSP-UHFFFAOYSA-M 0.000 claims description 3
- CTKINSOISVBQLD-UHFFFAOYSA-N glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims description 3
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N Dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N Tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- QGBSISYHAICWAH-UHFFFAOYSA-N cyanoguanidine Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003700 epoxy group Chemical group 0.000 claims description 2
- 239000003999 initiator Substances 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- 239000001187 sodium carbonate Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 claims 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N Di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000002194 synthesizing Effects 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 230000004048 modification Effects 0.000 abstract description 2
- 238000006011 modification reaction Methods 0.000 abstract description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 230000003287 optical Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 229960004217 benzyl alcohol Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 2
- 229960000935 Dehydrated Alcohol Drugs 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 150000004862 dioxolanes Chemical class 0.000 description 2
- 201000009910 diseases by infectious agent Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 1
- CEOCVKWBUWKBKA-UHFFFAOYSA-N 2,4-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1Cl CEOCVKWBUWKBKA-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- IFCFLQDKQCOSRY-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CC1=CC=C(S(O)(=O)=O)C=C1 IFCFLQDKQCOSRY-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 210000002889 Endothelial Cells Anatomy 0.000 description 1
- FIVPIPIDMRVLAY-RBJBARPLSA-N Gliotoxin Chemical compound C1C2=CC=C[C@H](O)[C@H]2N2[C@]1(SS1)C(=O)N(C)[C@@]1(CO)C2=O FIVPIPIDMRVLAY-RBJBARPLSA-N 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical group [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940000406 drug candidates Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- 238000004156 green chemistry Methods 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 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
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 231100000224 toxic side effect Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
Abstract
The invention discloses a kind of preparation methods of Itraconazole; racemic modification (±)-epoxy prapanol for using raw material cheap and easy to get is raw material; it is used respectively after two terminal hydroxy group of trityl and benzyl protection with 2; 4- dichlorobenzoyl chloride is through being esterified; then use the addition reaction of silylation grignard and β-silylation alcohol elimination reaction by carbonyl reduction for carbon-carbon double bond; again through iodine to alkene addition reaction and stereoselectivity cyclization reaction, compound 9 is obtained with triazole sodium substitution, debenzylation, introducing p-toluenesulfonyl；Condensation reaction, which is carried out, with compound 10 generates Itraconazole；Entirely synthesis process not only pollutes small, and easy to handle, by-product is few, and reaction selectivity and purity is high, environmentally friendly, production cost is low, is suitble to industrialized production；Avoid that poor selectivity in the prior art, by-product is more, yield is lower, the drawbacks of avoiding using valuable catalyst and environmental pollution big reagent.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical fields, and in particular to a kind of preparation method of Itraconazole.
Background technique
Itraconazole is that current curative effect is preferable, a kind of lesser triazole type broad-spectrum antifungal drug of side effect, external anti-
Bacterium spectrum it is wider, but injection this arrive pulmonary infection position, for treating lung's aspergillin infection.Its English name is
Itraconazole, the Chinese cis- 4- of chemical name [4- [4- [4- [[- 2- (2,4- dichlorophenyl) -2- (1H-1,2,4- triazole -1-
Ylmethyl) -1,3- dioxolanes -4- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -2- [(2 ' S) -1- methyl-propyl] -1,
2,4- triazole -3- ketone.Its chemical structural formula is as follows:
Itraconazole has 3 asymmetric carbon atoms, shares 8 kinds of optical isomers, clinical use is dioxy penta in its structure
The mixture of 4 cis-isomers on alkane ring corresponds to the R- of 2S, 4R, 2 ' Itraconazole (A), the S- Itraconazole of 2S, 4R, 2 '
(C), the R- of 2R, 4S, 2 ' Itraconazole (B) and the S- of 2R, 4S, 2 ' Itraconazole (D), chemical structural formula is as follows:
The study found that there are larger differences for the bioactivity and toxic side effect of Itraconazole Isomers, such as
CN103263417A, which discloses itraconazole isomer composition, can be improved selectivity to fungi and endothelial cell, while be
It is the drug candidate with treatment fungi and relevant diseases of angiogenesis potentiality, the optical voidness Itraconazole of single configuration can also be shown
Writing reduces hepatotoxicity, can avoid side effect caused by Itraconazole.
The synthetic method of Itraconazole has been reported:
1, document Med.Chem.Lett.2010,1,155~159 and US20130102614All are reported more commonly used
Synthetic route, using chemical compounds I and compound ii as starting material, first cyclization obtains dioxolanes structural unit, by controlization
The chirality for closing object II, can obtain optically pure compound III, then be condensed to yield V optical voidness Yi Qu with optical voidness chemicals IV
Health azoles.The route is fairly simple, but the reaction critical materials compound III p-methyl benzenesulfonic acid glycerine esterification complicated component, purity and
The satisfactory p-methyl benzenesulfonic acid glyceride of optical voidness generally requires to customize, and the production cost is very high, is not easy to industrialize.
2, CN201510104731.5 discloses the synthesis technology of optical voidness Itraconazole: VI-a of chemical compounds I and compound
Or VI-b of compound under Catalyzed by p-Toluenesulfonic Acid under the action of carry out aldol reaction, obtain it is cis- based on key it is intermediate
With sodium benzoate substitution reaction occurs for body compound VII-a or VII-b, and basic hydrolysis is reacted with paratoluensulfonyl chloride, in highly basic
Catalysis under carry out condensation reaction, obtain optical voidness Itraconazole.Though but light simple in VII-a of compound or VII-b synthesis technology
It is lower (78-85%) to learn purity, also contains a large amount of transisomer impurity, needs chiral separation.
3, in patent US4101665, US5998413, EP0402989, US4267179 and document J.Med.chem, 1983,
26,611~613 and J.Med.chem is disclosed in 1984,27,894~900, wherein typical compound sulphonic acid ester
Synthetic route are as follows:
Above-mentioned synthetic method exists following insufficient: (1) complex operation is cumbersome, needs by first preparing triazole
Sodium, then be alkylated with cis-bromic ester N-, most triazole compounds, production cycle are synthesized through three steps such as sodium hydroxide alkali hydrolysis afterwards
It is long.(2) raw material cis-bromic ester price is more expensive.(3) yield lower only 50%~60%, isomer impurities content is higher,
15% or so, the related content of material that isomer impurities too high levels will lead to Itraconazole finished product is very high or even exceeded, seriously
Affect the Control of Internal Quality to Itraconazole product.
Summary of the invention
To solve above-mentioned technical problem of the existing technology, the present invention provides a kind of preparation method of Itraconazole,
Which obviate poor selectivity in the prior art, by-product is more, the more low disadvantage of yield.
Technical scheme is as follows:
A kind of preparation method of Itraconazole, it is characterised in that include the following steps:
1) using (R)-(+)-epoxy prapanol as raw material, (R)-(+)-trityl is obtained after protecting hydroxyl with trityl chloride
Glycidol ether (1)；
2) (R)-(+)-trityl glycidol ether (1) is obtained with benzyl alcohol progress epoxy ring opening reaction in the presence of alkali
To compound 2；
3) compound 2 and 2,4 dichlorobenzyl chloride esterification occur under the action of alkali and organic solvent obtain chemical combination
Object 3；
4) compound 3 carries out the addition reaction of silylation grignard and obtains compound 4；
5) compound 4 carries out β-silylation alcohol elimination reaction and removing trityl-protecting group obtains compound 5；
6) compound 5 carries out iodine and obtains compound 6 to alkene addition reaction and stereoselectivity cyclization reaction；
7) compound 6 and triazole sodium generation substitution reaction obtain compound 7；
8) compound 7 carries out debenzylation and obtains compound 8；
9) compound 8 introduces p-toluenesulfonyl and obtains compound 9；
10) compound 9 is reacted with compound 10 generates Itraconazole；Its synthetic route is as follows:
Preferably, in step 1), (R)-(+)-epoxy prapanol and trityl chloride in catalyst and triethylamine into
Row, the catalyst are 4- dimethylamino pyridine (DMAP), and reaction dissolvent is chloroform or methylene chloride；(R)-(+)-epoxy prapanol
Molar ratio with trityl chloride is 1:1-1.1.
Preferably, the alkali is NaH or NaOH in step 2)；；Reaction dissolvent is dimethylformamide (DMF), two
Methylacetamide, dimethyl sulfoxide or tetrahydrofuran, 15 DEG C -40 DEG C of reaction temperature, reaction time 12-18 hour.
Preferably, the alkali is pyridine, triethylamine, n,N-Dimethylaniline, N, N- dimethylamino pyrrole in step 3)
Pyridine, tetramethylethylenediamine or sodium carbonate；The organic solvent is DCM, THF, toluene or DMF；Compound 2,2,4 dichloro benzene first
The molar ratio of acyl chlorides and alkali is 1:1-1.2:1-3.
Preferably, grignard reaction is occurred into for chloromethyl trimethyl silane and magnesium and generates Grignard Reagent in step 4), it will
Obtained Grignard Reagent and compound 3 occurs addition reaction and generates compound 4；The grignard reaction uses and is dissolved in methyl- tert fourth
Iodine grain in base ether is as initiator；The grignard reaction and addition reaction be in the dicyandiamide solution of methyl tertiary butyl ether(MTBE) into
Row.
Preferably, compound 4 is dissolved in MTBE in step 5), enriching sulfuric acid disappears in 40~60 DEG C of temperature
Compound 5 is generated except reacting and removing trityl-protecting group.
Preferably, reaction dissolvent is acetonitrile, ethyl alcohol or THF in step 6)；Reaction temperature is -20 DEG C~-10 DEG C.
Preferably, in step 7), reaction dissolvent DMSO；Reaction temperature is 80 DEG C~100 DEG C；Compound 6 and three
The molar ratio of nitrogen azoles sodium is 1:1~6.
Preferably, making compound 7 slough benzyl in step 8) using palladium charcoal catalytic hydrogenation and obtaining compound 8；Chemical combination
Object 7, catalyst mass ratio be 1:0.05-0.1, preferably 1:0.1；Reaction dissolvent is methanol, ethyl alcohol, isopropanol one or two
More than, preferred methanol.
Compared with the existing technology, the present invention has the following beneficial effects:
1) innovative (R)-(+)-epoxy prapanol, benzyl alcohol and the 2,4 dichloro benzene cheap and easy to get using raw material of the present invention
Formyl chloride is raw material, carries out the synthesis of itraconazole key intermediate sulfonic acid ester, that is, compound 9: with racemic modification (±)-epoxy
Propyl alcohol is raw material, is obtained with 2,4- dichlorobenzoyl chloride through esterification after it to be used to two terminal hydroxy group of trityl and benzyl protection respectively
Compound 3；That then innovates uses the addition reaction of silylation grignard and β-silylation alcohol elimination reaction by carbonyl reduction for carbon
Carbon double bond obtains compound 5；Compound 6 is obtained to alkene addition reaction and stereoselectivity cyclization reaction through iodine again；With three nitrogen
The substitution of azoles sodium, debenzylation, introducing p-toluenesulfonyl obtain compound 9；Entire synthesis process not only pollutes small, easy to handle, pair
Product is few, and reaction selectivity and purity is high, environmentally friendly, production cost is low, is suitble to industrialized production；Avoid the prior art
In poor selectivity, by-product is more, yield is lower, avoids disadvantage using valuable catalyst and the big reagent of environmental pollution
End.
2) in the synthesis of compound 5, carbonyl is turned with silylation grignard reaction and β-silylation alcohol elimination reaction
It is melted into carbon-carbon double bond, economic and environment-friendly, post-processing is simple, meets the principle of Green Chemistry.The present invention selects chloromethyl trimethyl silicane
Alkane prepares Grignard Reagent, and the trimethyl silicon substrate of the compound 4 of generation is easy to act on the hydroxyl at ortho position, so that elimination reaction product
5 purity is higher, and product silanol has preferable stability.
3) the iodine cyclization in step 6), substrate are acted on elemental iodine under alkaline condition, are lured by substrate S or R configuration
It leads, generates a new S or R configuration iodine methylene structured product compound 6.Iodine replaces carbon atom on the dioxolanes of side
Chiral selectivity is substantially unaffected, diastereoisomer content≤1.5%.And when temperature is -20 DEG C~-10 DEG C, product
Purity it is higher, non-corresponding isomers product is less.
Specific embodiment
Content in order to better understand the present invention is described further combined with specific embodiments below, but specific
Embodiment be not the limitation that the contents of the present invention are done.
Embodiment 1-1: the synthesis of trityl-glycidol ether (1)
Trityl chloride (139.4g, 0.5mol) dissolves in 5000mL methylene chloride, be added 4- diamino-pyridine (DMAP, 3g,
25mmol) with triethylamine (100mL), the dichloromethane solution of lower drop (R)-(+)-epoxy prapanol (37g, 0.5mol) is stirred
(500mL) is reacted at room temperature 3 hours；A large amount of white solids are precipitated, filter out solid, solution is washed with saturated sodium chloride solution (300mL)
It washs, anhydrous sodium sulfate is dry, is recrystallized after concentration with dehydrated alcohol, dry white solid (109.6g, 1), yield 69.3%.
Embodiment 1-2: the synthesis of trityl-glycidol ether (1)
Trityl chloride (153.3g, 0.55mol) dissolves in 5000mL chloroform, be added 4- diamino-pyridine (DMAP, 3g,
25mmol) with triethylamine (120mL), the chloroformic solution (500mL) of lower drop (R)-(+)-epoxy prapanol (37g, 0.5mol) is stirred,
Room temperature reaction 5 hours；A large amount of white solids are precipitated, filter out solid, solution is washed with saturated sodium chloride solution (300mL), anhydrous
Sodium sulphate is dry, is recrystallized after concentration with dehydrated alcohol, dry white solid (119.0g, 1), yield 75.2%.
Embodiment 2-1: the preparation of compound 2
Sodium hydride (50% is dispersed in mineral oil, 0.7mol) is washed twice with 1 liter of hexane, is then dried under a nitrogen.
Dry dimethylformamide (0.5L) is added.Then 50 DEG C are maintained the temperature at hereinafter, benzylalcohol is added dropwise with certain rate
(140mL) is dripped in 2 hours.Compound 1 (110.7g, 0.35mol) is added dropwise 0.5 hour again, cooling to keep temperature to be lower than
It 40 DEG C, stirs 16 hours at 20 DEG C of temperature, then is stirred 2.5 hours at 50 DEG C.Be evaporated under reduced pressure and removes dimethyl formyl
Amine, with 1L ether dissolution oiliness residue, organic solution uses the water of 0.5L respectively, 2% hydrochloric acid solution of 0.5L, 0.5L's
1% sodium bicarbonate solution and the salt water washing of 0.35L, anhydrous sodium sulfate is dry, is concentrated to get brown oil (compound
2,104.5g), yield 70.5%.
Embodiment 2-2: the preparation of compound 2
Sodium hydroxide (32g, 0.8mol) heating, which is added, in dry dimethyl sulfoxide (0.5L) makes to dissolve.Then temperature is kept
At 50 DEG C hereinafter, benzylalcohol (140mL) is added dropwise with certain rate, dripped in 2 hours.Again compound 1 (110.7g,
0.35mol) it is added dropwise 0.5 hour, it is cooling to keep temperature lower than 40 DEG C, it is stirred 18 hours at 30 DEG C of temperature, then at 50 DEG C
Stirring 2.5 hours.Be evaporated under reduced pressure and remove dimethyl sulfoxide, with 1L ether dissolution oiliness residue, organic solution is used respectively
The water of 0.5L, 2% hydrochloric acid solution of 0.5L, 1% sodium bicarbonate solution of 0.5L and the salt water washing of 0.35L, anhydrous sulphur
Sour sodium is dry, is concentrated to get brown oil (compound 2,112.4g), yield 75.8%.
Embodiment 3-1: the preparation of compound 3
Under the conditions of being stirred at room temperature, to 1000mL methylene chloride, compound 2 (110.1g, 0.26mol) and 70mL triethylamine
54.5g2 is added dropwise in the mixture of (0.5mol), 4- dichlorobenzoyl chloride (0.26mol), about 30min is added, 50 DEG C are warming up to,
Continue to stir 30min.Then 500mL water is added, separates organic layer, it is dry, methylene chloride is removed under reduced pressure, obtains compound 3
(147.6g), yield 95.2%.
Embodiment 3-2: the preparation of compound 3
Under the conditions of being stirred at room temperature, to 1000mL toluene, compound 2 (110.1g, 0.26mol) and 63mL pyridine
65.4g2 is added dropwise in the mixture of (0.78mol), 4- dichlorobenzoyl chloride (0.312mol), about 30min is added, and is warming up to 50
DEG C, continue to stir 30min.Then 500mL water is added, separates organic layer, it is dry, methylene chloride is removed under reduced pressure, obtains compound 3
(154.3g), yield 99.5%.
Embodiment 4: the preparation of compound 5
N2Magnesium powder (14.6g, 0.6mol) and dry methyl tertiary butyl ether(MTBE) is added into the dry there-necked flask of 1L under protection
(MTBE, 100mL) is heated to flowing back.It is added iodine grain (1.27g, 5mmol), chloromethyl trimethyl silane is added dropwise into reaction solution
(6mL, 0.05mol)/MTBE (20mL) solution.After reaction to be determined causes, continue to be added dropwise chloromethyl trimethyl silane (50mL,
0.4mol)/MTBE (150mL) solution.Drop finishes, and reacts 2h at 0~56 DEG C.It is cooled to -10~0 DEG C, the dropwise additionization into reaction flask
Object 3 (150.0g, 0.2mol)/MTBE (100mL) solution is closed, -10 DEG C of process temperature control~10 DEG C are added dropwise, after being added dropwise, transfer
5h is reacted to 10~30 DEG C, TLC (solvent: PE) monitors raw material after completion of the reaction, and 4N hydrochloric acid (1500mL) is added and terminates instead
It answers, stirs 30min, stand 10min, extraction, water phase is extracted with MTBE (200mL), merges MTBE layers, and concentration obtains g light yellow liquid
Body compound 4 is direct plungeed into and is reacted in next step.
Compound 4 obtained above is dissolved in MTBE (0.5L), is added dropwise the concentrated sulfuric acid (55mL, 1mol), temperature control 25~30
DEG C, it is added dropwise, is warming up to 40~60 DEG C, react 3.5h, TLC monitors raw material after completion of the reaction, is cooled to 20 DEG C, adds water
(400mL) terminates reaction, and after liquid separation, organic layer successively uses 9%NaHCO3(200mL) solution, water (200mL), saturated salt solution
(200mL) washing, it is dry, 54.5g dark red solution compound 5, yield 80.5% is concentrated under reduced pressure to obtain at 40~45 DEG C.
Embodiment 5-1: the preparation of compound 6
Compound 5 (50.7g, 0.15mol) and EA (400mL) are sequentially added into 1L there-necked flask, stirring is cooled to -15
~-20 DEG C, I is added2(114.2g, 0.45mol), NaHCO3(33.6g, 0.4mol) reacts 5~6h, TLC (PE/EA=3:1)
Monitoring raw material has reacted.10%Na is added dropwise2SO3(500mL) stops reaction, liquid separation, and water phase is extracted with EA (200mL), merges EA,
Use 10%Na2SO3Solution (200mL), H2O (200mL) respectively washed once, and be concentrated, dry, obtains the orange-yellow oily materialization of 60.9g and closes
Object 6, yield 86.8%, purity 99.3%, non-corresponding isomers impurity is less than 0.5%.
Following instance operation is identical as embodiment 5-1, and reaction raw materials are identical, reaction dissolvent, reaction time, reaction temperature etc.
Variant, experimental result see the table below:
| Sequence | Solvent | Reaction temperature | Non-corresponding isomers | Purity | Yield |
| Embodiment 5-2 | Ethyl alcohol | - 20~-25 DEG C | 2.4% | 96.6% | 83.1% |
| Embodiment 5-3 | Ethyl alcohol | - 10~-15 DEG C | 0.6% | 99.2% | 88.4% |
| Embodiment 5-4 | Ethyl alcohol | - 5~-10 DEG C | 2.3% | 97.1% | 74.5% |
| Embodiment 5-5 | Acetonitrile | - 10~-15 DEG C | 0.5% | 98.9% | 87.2% |
| Embodiment 5-6 | THF | - 15~-20 DEG C | 0.8% | 98.6% | 85.3% |
Embodiment 6-1: the preparation of compound 7
Compound 6 (55.7g, 0.12mol) and dry DMSO (400mL), triazole sodium are added into 500mL there-necked flask
(45.5g, 0.5mol), stirs 1h at room temperature, is warming up to 80-100 DEG C of reaction for 24 hours, and HPLC detection raw material has reacted (<
1.5%).Saturation brine ice (600mL) is added after being cooled to room temperature in reaction solution, and stirring is extracted, water with EA (250mL × 2)
(250mL) is washed, concentrated by rotary evaporation, obtains 45.9g yellow oily compounds 7, yield 92.8%, purity 98.6%.
Embodiment 6-2: the preparation of compound 7
Compound 6 (55.7g, 0.12mol) and dry DMSO (400mL), triazole sodium are added into 500mL there-necked flask
(22.8g, 0.25mol), stirs 1h at room temperature, is warming up to 80-100 DEG C of reaction for 24 hours, and HPLC detection raw material has reacted (<
1.5%).Saturation brine ice (600mL) is added after being cooled to room temperature in reaction solution, and stirring is extracted, water with EA (250mL × 2)
(250mL) is washed, concentrated by rotary evaporation, obtains 43.0g yellow oily compounds 7, yield 86.8%, purity 98.3%.
Embodiment 7: the preparation of compound 8
By compound 7 (40.6g, 0.1mol), palladium carbon catalyst Pd-C4.0g, refrigerated methanol 350mL, concentrated hydrochloric acid 8.4mL,
It is successively put into high pressure resistant bottle, is evacuated to -0.08Mpa, be flushed with hydrogen gas to 0.2Mpa, react at room temperature 18 hours, filtering, filtrate
45 DEG C of decompressions are dense dry, and pure water 36.5mL, isopropanol 36.5mL, stirring heating dissolved clarification, filtering, 60~70 DEG C of filtrate temperature control drops are added
Add isopropanol 164.3mL, drip off slow cooling, white solid is precipitated, is cooled to -10 DEG C of suction filtrations, 50 DEG C of decompression dryings of filter cake
30.3g obtains compound 8, yield 95.3%, purity 99.4%.
Embodiment 8: the preparation of compound 9
Compound 8 (25.3g, 0.08mol) is added into 250mL there-necked flask, DCM (250mL) stirs dissolved clarification.Reaction solution
It is cooled to -15~0 DEG C, triethylamine (15.2g, 0.15mol), TsCl (15.3g, 0.08mol), 10~30 DEG C of stirrings are slowly added dropwise
20min is warming up to reflux, and for 24 hours, TLC detection (DCM:MeOH=25:1) raw material reacts completely for reaction.10% hydrochloric acid is added
(50mL), 9%NaHCO3The washing of (50mL), water (50mL), liquid separation obtain organic phase, are concentrated to give faint yellow solid.Into concentrate
It is added DCM (20mL), is added dropwise normal heptane (180mL), 0 DEG C of crystallization 1h, filter, vacuum drying obtains 30.5g compound as white solid
9, yield 80.6%, purity 99.5%.
Embodiment 10: the synthesis of Itraconazole
With stirring, air inlet pipe, thermometer, condenser pipe four-hole bottle in, in N2Protection under be added 20g4- [4- [4-
(hydroxy phenyl) -1- piperazinyl] phenyl] -2,4- dihydro -2- (1- methyl-propyl) -3H-l, 2,4- triazole -one (compound 10,
0.05mol), 2.6g sodium hydrate solid, 0.3mL80% hydrazine hydrate and 150mLDMF.Stirring is warming up to 40 DEG C and reacts 40 minutes,
Then 23.6g compound 9 (0.05mol) is added, and is heated to 60 DEG C, react 1.5 hours, TLC is monitored without piperazine oxazolone
As reaction end.After reaction, 20 DEG C are cooled to, reaction solution is poured into 200mL10% sodium hydroxide solution, is added
300mL methylene chloride is simultaneously layered in separatory funnel, and organic layer is washed with 200mL10% sodium hydroxide solution, is washed with water into
Property, anhydrous magnesium sulfate are dried, filtered, are drained, filter cake 10mL eluent methylene chloride, concentrate the filtrate to dry, obtain crude product.Then
100mL toluene is added, heat up stirring and dissolving, and 50mL ethyl acetate is added, slowly cooling that 32g solid itraconazole, yield is precipitated
90.5%, purity 99.8%, quality meets European Pharmacopoeia standard.
Claims (10)
1. a kind of preparation method of Itraconazole, it is characterised in that include the following steps:
1) using (R)-(+)-epoxy prapanol as raw material, (R)-(+)-trityl is obtained after protecting hydroxyl with trityl chloride and is shunk
Glycerin ether (1)；
2) (R)-(+)-trityl glycidol ether (1) carries out epoxy ring opening reaction with benzyl alcohol in the presence of alkali
Close object 2；
3) compound 2 and 2,4 dichlorobenzyl chloride esterification occur under the action of alkali and organic solvent obtain compound 3；
4) generation addition reaction under the action of chloromethyl trimethyl silane and magnesium of compound 3 obtains compound 4；
5) compound 4 carries out β-silylation alcohol elimination reaction under the action of the concentrated sulfuric acid and removing trityl-protecting group obtains
Compound 5；
6) compound 5 carries out iodine and obtains compound 6 to alkene addition reaction and stereoselectivity cyclization reaction；
7) compound 6 and triazole sodium substitution reaction occur in DMSO obtain compound 7；
8) compound 7 carries out debenzylation and obtains compound 8；
9) compound 8 and TsCl obtain compound 9 under the action of DCM and TEA；
10) compound 9 and compound 10 carry out condensation reaction and generate Itraconazole；Its synthetic route is as follows:
2. preparation method as described in claim 1, it is characterised in that: in step 1), (R)-(+) -- epoxy prapanol and triphen first
Base chlorine carries out in catalyst and triethylamine, the catalyst be 4- dimethylamino pyridine (DMAP), reaction dissolvent be chloroform or
Methylene chloride；(R) molar ratio of-(+) -- epoxy prapanol and trityl chloride is 1:1-1.1.
3. preparation method as claimed in claim 2, it is characterised in that: in step 2), the alkali is NaH or NaOH；React molten
Agent is dimethylformamide (DMF), dimethyl acetamide, dimethyl sulfoxide or tetrahydrofuran, 15 DEG C -40 DEG C of reaction temperature, instead
12-18 hours between seasonable.
4. preparation method as claimed in claim 2, it is characterised in that: in step 3), the alkali is pyridine, triethylamine, N, N-
Dimethylaniline, N, N- dimethylamino naphthyridine, tetramethylethylenediamine or sodium carbonate；The organic solvent be DCM, THF, toluene or
DMF；The molar ratio of compound 2,2,4 dichlorobenzyl chloride and alkali is 1:1-1.2:1-3.
5. preparation method as described in claim 1, it is characterised in that: in step 4), chloromethyl trimethyl silane and magnesium are sent out
Raw grignard reaction generates Grignard Reagent, and addition reaction is occurred for obtained Grignard Reagent and compound 3 and generates compound 4；It is described
Grignard reaction is using the iodine grain being dissolved in methyl tertiary butyl ether(MTBE) as initiator；The grignard reaction and addition reaction are in first
It is carried out in the dicyandiamide solution of base tertbutyl ether.
6. preparation method as described in claim 1, it is characterised in that: in step 5), compound 4 is dissolved in MTBE, enriching
Sulfuric acid generates compound 5 in 40~60 DEG C of generation elimination reactions of temperature and removing trityl-protecting group.
7. preparation method as claimed in claim 6, it is characterised in that: in step 6), reaction dissolvent is acetonitrile, ethyl alcohol or THF；
Reaction temperature is -20 DEG C~-10 DEG C.
8. preparation method as described in claim 1, it is characterised in that: in step 7), reaction temperature is 80 DEG C~100 DEG C；Change
The molar ratio for closing object 6 and triazole sodium is 1:1~6.
9. preparation method as described in claim 1, it is characterised in that: in step 8), make compound 7 using palladium charcoal catalytic hydrogenation
It sloughs benzyl and obtains compound 8；Compound 7, catalyst mass ratio be 1:0.05-0.1；Reaction dissolvent is methanol, ethyl alcohol, different
Propyl alcohol is one or more kinds of.
10. preparation method as claimed in claim 9, it is characterised in that: in step 8), compound 7, catalyst mass ratio be
1:0.1；Reaction dissolvent is methanol.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4141908A (en) * | 1976-10-15 | 1979-02-27 | Janssen Pharmaceutica N.V. | 2-Aryl-1,3-dioxolanes |
| CN1047865A (en) * | 1989-06-09 | 1990-12-19 | 詹森药业有限公司 | The triazolone of antimycotic usefulness and the preparation method of imidazolones derivs |
| WO1993019061A1 (en) * | 1992-03-18 | 1993-09-30 | Janssen Pharmaceutica N.V. | Itraconazole and saperconazole stereoisomers |
| US5474997A (en) * | 1993-01-27 | 1995-12-12 | Sepracor, Inc. | Methods and compositions of (2R,4S) itraconazole for treating fungal yeast and dermatophyte infections |
| WO2000043390A1 (en) * | 1999-01-19 | 2000-07-27 | Korea Research Institute Of Chemical Technology | Antifungal azole derivatives having a fluorinated vinyl group and process for preparing same |
| US20130102614A1 (en) * | 2007-04-05 | 2013-04-25 | Jun O. Liu | Chirally pure isomers of itraconazole for use as angiogenesis inhibitors |
| CN104774195A (en) * | 2015-03-10 | 2015-07-15 | 扬州艾迪生物科技有限公司 | Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate |
-
2016
- 2016-07-18 CN CN201610566225.2A patent/CN106146480B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4141908A (en) * | 1976-10-15 | 1979-02-27 | Janssen Pharmaceutica N.V. | 2-Aryl-1,3-dioxolanes |
| CN1047865A (en) * | 1989-06-09 | 1990-12-19 | 詹森药业有限公司 | The triazolone of antimycotic usefulness and the preparation method of imidazolones derivs |
| WO1993019061A1 (en) * | 1992-03-18 | 1993-09-30 | Janssen Pharmaceutica N.V. | Itraconazole and saperconazole stereoisomers |
| US5474997A (en) * | 1993-01-27 | 1995-12-12 | Sepracor, Inc. | Methods and compositions of (2R,4S) itraconazole for treating fungal yeast and dermatophyte infections |
| WO2000043390A1 (en) * | 1999-01-19 | 2000-07-27 | Korea Research Institute Of Chemical Technology | Antifungal azole derivatives having a fluorinated vinyl group and process for preparing same |
| US20130102614A1 (en) * | 2007-04-05 | 2013-04-25 | Jun O. Liu | Chirally pure isomers of itraconazole for use as angiogenesis inhibitors |
| CN104774195A (en) * | 2015-03-10 | 2015-07-15 | 扬州艾迪生物科技有限公司 | Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate |
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