CN115448911A - Preparation method of posaconazole intermediate - Google Patents
Preparation method of posaconazole intermediate Download PDFInfo
- Publication number
- CN115448911A CN115448911A CN202211248020.1A CN202211248020A CN115448911A CN 115448911 A CN115448911 A CN 115448911A CN 202211248020 A CN202211248020 A CN 202211248020A CN 115448911 A CN115448911 A CN 115448911A
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- China
- Prior art keywords
- chloride
- combination
- ligand
- sodium
- reaction
- Prior art date
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- Pending
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 28
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 65
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 239000003054 catalyst Substances 0.000 claims abstract description 50
- 230000008569 process Effects 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims description 42
- 239000003446 ligand Substances 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- -1 m-trimethylphenyl Chemical group 0.000 claims description 22
- 229910052751 metal Inorganic materials 0.000 claims description 22
- 239000002184 metal Substances 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000013522 chelant Substances 0.000 claims description 20
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 108090000790 Enzymes Proteins 0.000 claims description 13
- 102000004190 Enzymes Human genes 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 238000006555 catalytic reaction Methods 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000011630 iodine Substances 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
- 239000002841 Lewis acid Substances 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 150000001299 aldehydes Chemical class 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- 150000007517 lewis acids Chemical class 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000003429 antifungal agent Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 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 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229940121375 antifungal agent Drugs 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- 229910021555 Chromium Chloride Inorganic materials 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 5
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 claims description 5
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 5
- 229940046892 lead acetate Drugs 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 5
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 239000004246 zinc acetate Substances 0.000 claims description 5
- 108090001060 Lipase Proteins 0.000 claims description 4
- 239000004367 Lipase Substances 0.000 claims description 4
- 102000004882 Lipase Human genes 0.000 claims description 4
- SLSGHPNWPPHNHN-UHFFFAOYSA-M [Br-].FC1=CC=C([Mg+])C(F)=C1 Chemical compound [Br-].FC1=CC=C([Mg+])C(F)=C1 SLSGHPNWPPHNHN-UHFFFAOYSA-M 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 235000019421 lipase Nutrition 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- OAWXYINGQXLWOE-UHFFFAOYSA-N (2-acetyloxybenzoyl) 2-acetyloxybenzoate Chemical compound CC(=O)OC1=CC=CC=C1C(=O)OC(=O)C1=CC=CC=C1OC(C)=O OAWXYINGQXLWOE-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 3
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 3
- 229910004373 HOAc Inorganic materials 0.000 claims description 3
- 108090000604 Hydrolases Proteins 0.000 claims description 3
- 102000004157 Hydrolases Human genes 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 235000019800 disodium phosphate Nutrition 0.000 claims description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 3
- XMGMFRIEKMMMSU-UHFFFAOYSA-N phenylmethylbenzene Chemical group C=1C=CC=CC=1[C]C1=CC=CC=C1 XMGMFRIEKMMMSU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-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
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- UYXAHRLPUPVSNJ-UHFFFAOYSA-N sodium;2h-triazole Chemical compound [Na].C=1C=NNN=1 UYXAHRLPUPVSNJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940014800 succinic anhydride Drugs 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 3
- 235000019801 trisodium phosphate Nutrition 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000006880 cross-coupling reaction Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 6
- 230000003287 optical effect Effects 0.000 abstract description 3
- 238000012216 screening Methods 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 70
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- 239000000047 product Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 12
- 229940125898 compound 5 Drugs 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 229940126214 compound 3 Drugs 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- DFWVLCJRFGIRAK-KKSFZXQISA-N [(3s,5r)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@H]1C[C@](CN2N=CN=C2)(C=2C(=CC(F)=CC=2)F)OC1 DFWVLCJRFGIRAK-KKSFZXQISA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- MGHBDQZXPCTTIH-UHFFFAOYSA-N 1-bromo-2,4-difluorobenzene Chemical compound FC1=CC=C(Br)C(F)=C1 MGHBDQZXPCTTIH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 150000005690 diesters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UOORRWUZONOOLO-UHFFFAOYSA-N 1,3-dichloropropene Chemical compound ClCC=CCl UOORRWUZONOOLO-UHFFFAOYSA-N 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229910010084 LiAlH4 Inorganic materials 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001361 allenes Chemical class 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
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- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 2
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 238000012803 optimization experiment Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- FALCMQXTWHPRIH-UHFFFAOYSA-N 2,3-dichloroprop-1-ene Chemical compound ClCC(Cl)=C FALCMQXTWHPRIH-UHFFFAOYSA-N 0.000 description 1
- JONDTFNGQQZTDO-UHFFFAOYSA-N 2-(2,4-difluorophenyl)prop-2-en-1-ol Chemical compound OCC(=C)C1=CC=C(F)C=C1F JONDTFNGQQZTDO-UHFFFAOYSA-N 0.000 description 1
- QZELMXYYONEIDT-UHFFFAOYSA-N 3,3-diacetylpentane-2,4-dione Chemical compound CC(=O)C(C(C)=O)(C(C)=O)C(C)=O QZELMXYYONEIDT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 208000037026 Invasive Fungal Infections Diseases 0.000 description 1
- 108010084311 Novozyme 435 Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 238000006202 Sharpless epoxidation reaction Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000656145 Thyrsites atun Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000004697 chelate complex Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- WDAXFOBOLVPGLV-UHFFFAOYSA-N isobutyric acid ethyl ester Natural products CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- MLTFKRDFAJSIEX-UHFFFAOYSA-N lithium;1,3-oxazolidin-2-one Chemical compound [Li].O=C1NCCO1 MLTFKRDFAJSIEX-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940099075 noxafil Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000246 remedial effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000002602 strong irritant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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Abstract
The invention discloses a preparation method of a posaconazole intermediate shown in a formula I, which has the advantages of low material cost, simple and convenient process, no need of harsh reaction conditions, short process route compared with other traditional processes, simple and efficient reaction process, and capability of obtaining the posaconazole intermediate with the optical purity of 99.99 percent by screening chiral catalysts.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of a posaconazole intermediate.
Background
Posaconazole (trade name: noxafil) is a broad-spectrum triazole antifungal drug with wide prospect, and shows good antifungal activity in vitro and in vivo, especially against some drug-resistant strains. The medicine can be used for treating various complicated rare fungal infectious diseases, has strong activity and quick response, can be clinically used as remedial treatment of refractory invasive fungal infection, has ideal safety and tolerance, has small toxicity to liver and kidney, and is suitable for patients with long-term treatment.
The ((3S, 5R) -5- ((1H-1, 2, 4-triazole-1-yl) methyl) -5- (2, 4-difluorophenyl) tetrahydrofuran-3-yl) methyl 4-methylbenzenesulfonate is used as a key intermediate for synthesizing the posaconazole, and the Active pharmaceutical ingredient of the posaconazole can be obtained through two-step reaction.
With respect to the synthesis method of ((3s, 5r) -5- ((1H-1, 2, 4-triazol-1-yl) methyl) -5- (2, 4-difluorophenyl) tetrahydrofuran-3-yl) methyl 4-methylbenzenesulfonate, there have been disclosed mainly reports of:
patent nos. 08/055, 268 and WO89/04829 disclose preparation methods of sulfonate intermediates, in which 2' -chloro-2,4-difluoroacetophenone is subjected to wittig reaction, nucleophilic substitution and hydrolysis reaction to obtain 2- (2 ',4' -difluorophenyl) -2-propenol, and then subjected to Sharpless epoxidation, nucleophilic substitution and other 11 steps to obtain the sulfonate intermediate, which is relatively complex in process and fails to completely solve the chiral problem of two carbons on the furan ring.
Patent documents US5403937 and (Saksena, a.r; girijavauabhan, wans, I; liu, y.i; pike, R; gansuIy, a.r. tetrahedron lett, 1996, 37, 5657-5660) report the synthesis of the sulfonate intermediate using a chiral prosthetic group, but this process requires the use of the relatively dangerous strong base n-butyl lithium for the preparation of the lithium 2-oxazolidinone salt, which is prepared by reaction at an ultra-low temperature of-78 ℃ and is not suitable for large-scale production.
Patent EP2789610 (A1), world patent WO2011144653 (A1), WO2011144656 (A1) and WO 2011144657 (A1) all disclose methods for synthesizing the intermediate from 1, 3-difluorobenzene, which involve the use of expensive (CH) catalysts 3 ) 3 Si-CH 2 MgCl, resulting in 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl]The production cost of the 1, 3-malonic acid is high; in addition, the method also needs to use a strong irritant compound chloroacetyl chloride, has the disadvantages of large pollution, strict requirements on reaction conditions, difficult operation, high production cost and difficult realization of industrial production.
In addition, european patent EP075902B1 reports that 2- [2' - (2 ',4' -difluorophenyl) propenyl ] -1, 3-malonic acid diester as an intermediate of posaconazole is synthesized in one step by using 2, 4-difluorobromobenzene, malonic acid diester and allene as raw materials and using a palladium complex as a catalyst under alkaline conditions. Although the process has few steps, the process adopts an expensive target catalyst, and the allene is extremely active and generates a plurality of impurities, so that the separation of the product is complicated, and the yield is low. The specific route is as follows:
the literature (Synthetic Communications,2015,45 (6): 734-740) discloses a method for synthesizing posaconazole intermediate 2- [2- (2, 4-difluorophenyl) propenyl ] -1, 3-diethyl malonate by using 2, 3-dichloropropene and diethyl malonate as raw materials, firstly methylating the raw materials, then reducing the raw materials by using LiAlH4, then acylating the reduced products by using acetic anhydride, and finally synthesizing the posaconazole intermediate diethyl 2- [2- (2, 4-difluorophenyl) propenyl ] -1, 3-malonate in one step by using ferric triacetylacetonate as a catalyst under alkaline conditions, wherein although the steps are relatively few, liAlH4 and acetic anhydride are used in the reaction process, the LiAlH4 is inflammable and explosive when meeting water, and the acetic anhydride is easy to tear during the use process, so the reaction conditions are harsh and are not favorable for industrial production; the ferric triacetylacetonate used as the catalyst for the Grignard reaction is difficult to avoid generating fluorine-removed impurities in the process, and the fluorine-removed impurities are extremely difficult to remove in the subsequent reaction process and post-treatment and are finally transferred to a final product, so that the reaction yield is reduced. It is therefore desirable to select a less expensive catalyst that avoids or reduces fluorine generation.
Therefore, a preparation method of posaconazole intermediate with low raw material cost, simple process and high yield is needed to be provided.
Disclosure of Invention
The invention aims to provide a method for synthesizing a posaconazole intermediate ((3S, 5R) -5- ((1H-1, 2, 4-triazol-1-yl) methyl) -5- (2, 4-difluorophenyl) tetrahydrofuran-3-yl) methyl 4-methylbenzenesulfonate, and also provides front-end intermediates II, III, IV and V in the synthesis process of the posaconazole intermediate.
The purpose of the invention is realized by the following technical scheme:
in a first aspect, the invention provides a preparation method of a posaconazole intermediate shown in a formula I,
((3S, 5R) -5- ((1H-1, 2, 4-triazol-1-yl) methyl) -5- (2, 4-difluorophenyl) tetrahydrofuran-3-yl) methyl 4-methylbenzenesulfonate
The synthetic route is as follows:
the method is characterized by comprising the following steps:
(1) Compound A
X 1 、X 2 Independently selected from F, br, cl, I,
with compounds B
R 1 、R 2 Independently selected from methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, benzyl,
reacting under the action of alkali and a catalyst to obtain an intermediate I, wherein the structural formula of the intermediate I is shown as follows:
(2) Reducing the intermediate I by a reducing agent, and condensing the intermediate I and an aldehyde (ketone) reagent under the catalysis of protonic acid or Lewis acid to obtain an intermediate II, wherein the structural formula of the intermediate II is shown as follows:
Wherein Y is 1 、Y 2 Independently selected from H, -CH 3 、-C 2 H 5 T-butyl, phenyl, benzyl, p-methoxyphenyl, p-methylphenyl, p-nitrophenyl, m-trimethylphenyl, diphenylmethylene, or Y 1 、Y 2 And C5-C7 cycloalkyl with C atoms in between.
In a specific embodiment of the present invention, said Y is 1 、Y 2 is-CH 3 The structure of intermediate II is as follows:
in the technical scheme provided by the invention, 5- (2-chloroallyl) -2, 2-dimethyl-1, 3-dioxane is used as a key intermediate for the first time in the preparation of the posaconazole intermediate.
(3) And (3) carrying out cross coupling on the intermediate II and 2, 4-difluorophenyl magnesium bromide under the catalysis of Cat. I to obtain an intermediate III, wherein the structural formula of the intermediate III is shown as follows:
(4) Adding alkali into the intermediate III and an acylation reagent to obtain an intermediate IV under the catalysis of enzyme, wherein the structural formula of the intermediate IV is shown as follows:
Wherein R is 6 Selected from ethyl, propyl, isopropyl, butyl, benzyl, acetyl phenyl; in a preferred embodiment of the invention, R 6 Is isopropyl, and the structural formula of the intermediate IV is as follows:
(S) -4- (2, 4-difluorophenyl) -2- (hydroxymethyl) pent-4-en-1-ylpropionate
(5) And (3) catalyzing the intermediate IV and iodine by Cat. II to obtain an intermediate V, wherein the structural formula of the intermediate V is shown as follows:
Wherein R is 6 Selected from ethyl, propyl, isopropyl, butyl, benzyl, acetyl phenyl; in a preferred embodiment of the invention, R 6 Is isopropyl, the structural formula of the intermediate V is as follows:
5 ((3S, 5R) -5- (2, 4-difluorophenyl) -5- (iodomethyl) tetrahydrofuran-3-yl) methyl isobutyrate
(6) And (3) reacting the intermediate V with sodium triazole, dropwise adding a sodium hydroxide aqueous solution after the reaction is finished, cooling, and adding p-toluenesulfonyl chloride to react to obtain the compound shown in the formula I.
In a specific embodiment of the present invention, X in step (1) 1 、X 2 Is Cl, R 1 、R 2 Selected from methyl.
Preferably, the base in step (1) is one or a combination of more than two of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
The catalyst in the step (1) is one or a combination of more than two of cuprous chloride, cuprous iodide and ferric chloride (II).
In the step (2), the solvent for the reduction reaction is preferably one or a combination of two or more selected from methanol, ethanol, tetrahydrofuran, isopropanol and butanol.
The reducing agent is selected from one or a combination of more than two of sodium borohydride, potassium borohydride and lithium aluminum hydride.
The catalyst in the step (2) is one or two of protonic acid or Lewis acidWherein the protonic acid is selected from sulfuric acid, p-TsOH, CSA, HClO 4 One or a combination of two or more of HOAc; the Lewis acid is selected from CuSO 4 、ZnCl 2 、AlCl 3 、FeCl 3 、SnCl 4 、CoCl 2 、TiCl 4 One or a combination of two or more of them.
The aldehyde (ketone) reagent is selected from one or a combination of more than two of P1-P7 compounds, and the P1-P7 compounds have the following structures:
wherein R is 3 、R 4 、R 5 Independently selected from H, C1-C10 straight chain/branched chain alkyl, phenyl and benzyl.
In a particular embodiment of the invention, the aldehyde (ketone) reagent is acetone.
Preferably, the condensation reaction solvent is one or a combination of two or more selected from ethyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether.
In step (3), preferably, the solvent used is one or a combination of two or more selected from tetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, toluene, and 1, 4-dioxane.
The catalyst Cat. I is a chelate product of a metal salt and a ligand I, wherein the ligand I is one or a combination of more than two of the following compounds:
the metal salt is selected from one or the combination of more than two of chromium chloride, nickel chloride, copper chloride and cobalt chloride.
In a particular embodiment of the invention, the catalyst Cat. I is a chelate product of copper chloride with ligand I-2.
In step (4), the acylating agent is one or a combination of two or more selected from acetic anhydride, propionic anhydride, succinic anhydride, benzoic anhydride and acetylsalicylic anhydride.
The alkali in the step (4) is selected from one or the combination of more than two of sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium hydrogen phosphate, potassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, triethylamine and pyridine.
The enzyme is one or the combination of two of lipase and amino acid hydrolase, in the preferred embodiment of the invention, the enzyme is fixed on an enzyme carrier, and the enzyme carrier is one or the combination of two of alumina, diatomite, titanium dioxide, cellulose, DEAE glucose gel, gelatin and activated carbon.
In the step (5), the catalyst Cat. II is a chelate product of a metal salt and a ligand II.
The metal salt in the step (5) is selected from one or a combination of more than two of zinc chloride, copper chloride, cobalt chloride, aluminum chloride, rhodium chloride, copper acetate, zinc acetate and lead acetate.
The ligand II has a structure shown in a formula II:
wherein R is 7 And R 8 Independently selected from C1-C6 linear/branched alkyl, benzyl, tolyl, hydroxyphenyl, and hydroxynaphthyl.
Preferably, the ligand II is selected from one or more of the following compounds:
in a particular embodiment of the invention, the catalyst Cat. II is a chelate product of cobalt chloride with ligand II-1.
The solvent used in the reaction in the step (5) is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, n-butanol, 1, 4-dioxane, acetonitrile and toluene.
In a second aspect, the present invention provides a compound of formula I prepared by the above process.
In a third aspect, the invention provides the use of a compound of formula i prepared by the above process for the preparation of the antifungal agent posaconazole.
In a fourth aspect, the present invention provides a process for the preparation of intermediate II, said process being prepared by the following route:
(1) Reacting the compound A with the compound B under the action of alkali and a catalyst to obtain an intermediate I;
(2) The intermediate I is reduced by a reducing agent and then condensed with an aldehyde (ketone) reagent under the catalysis of protonic acid or Lewis acid to obtain an intermediate II.
X 1 、X 2 Independently selected from F, br, cl, I;
R 1 、R 2 independently selected from methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, phenyl and benzyl;
Y 1 、Y 2 independently selected from H, -CH 3 、-C 2 H 5 Tert-butyl, phenyl, benzyl, p-methoxyphenyl, p-methylphenyl, p-nitrophenyl, m-trimethylphenyl, diphenylmethylene, or Y 1 、Y 2 And C5-C7 cycloalkyl with C atoms in between.
In a specific embodiment of the present invention, X in step (1) 1 、X 2 Is Cl, R 1 、R 2 Selected from methyl, Y 1 、Y 2 is-CH 3 。
Preferably, the base in step (1) is one or a combination of more than two of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
The catalyst in the step (1) is one or a combination of more than two of cuprous chloride, cuprous iodide and ferric chloride (II).
In the step (2), the solvent for the reduction reaction is preferably one or a combination of two or more selected from methanol, ethanol, tetrahydrofuran, isopropanol and butanol.
The reducing agent is selected from one or a combination of more than two of sodium borohydride, potassium borohydride and lithium aluminum hydride.
The catalyst in the step (2) is one or the combination of two of protonic acid or Lewis acid, wherein the protonic acid is selected from sulfuric acid, p-TsOH, CSA and HClO 4 One or a combination of two or more of HOAc; the Lewis acid is selected from CuSO 4 、ZnCl 2 、AlCl 3 、FeCl 3 、SnCl 4 、CoCl 2 、TiCl 4 Or a combination of two or more thereof.
The aldehyde (ketone) reagent is selected from one or a combination of more than two of P1-P7 compounds, and the P1-P7 compounds have the following structures:
wherein R is 3 、R 4 、R 5 Independently selected from H, C1-C10 straight chain/branched chain alkyl, phenyl and benzyl.
In a particular embodiment of the invention, the aldehyde (ketone) reagent is acetone.
Preferably, the condensation reaction solvent is one or a combination of two or more selected from ethyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether.
In a fifth aspect, the present invention provides an intermediate II prepared according to the process as described above.
In a sixth aspect, the present invention provides the use of intermediate II prepared according to the process as described above for the preparation of the antifungal agent posaconazole.
In a seventh aspect, the present invention provides a method for preparing intermediate iii, wherein the preparation route of the method is as follows:
wherein, the intermediate II is prepared according to the method of the invention, and the intermediate II is cross-coupled with 2, 4-difluorophenyl magnesium bromide under the catalysis of Cat.I to obtain an intermediate III.
Preferably, the solvent used is one or a combination of two or more selected from tetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, toluene and 1, 4-dioxane.
The catalyst Cat. I is a chelate product of a metal salt and a ligand I, wherein the ligand I is one or a combination of more than two of the following compounds:
the metal salt is selected from one or the combination of more than two of chromium chloride, nickel chloride, copper chloride and cobalt chloride.
In a specific embodiment of the invention, the catalyst Cat. I is a chelate product of copper chloride with ligand I-2.
In an eighth aspect, the present invention provides an intermediate iii prepared according to the process as described above.
In a ninth aspect, the present invention provides the use of intermediate iii, prepared according to the process as described above, for the preparation of the antifungal agent posaconazole.
In a tenth aspect, the present invention provides a preparation method of an intermediate iv, wherein the preparation route of the method is as follows:
wherein R is 6 Selected from ethyl, propyl and isopropylThe intermediate III is prepared by the method, and the intermediate IV is obtained by adding alkali and an acylation reagent into the intermediate III under the catalysis of enzyme.
The acylating reagent is one or the combination of more than two of acetic anhydride, propionic anhydride, succinic anhydride, benzoic anhydride and acetylsalicylic anhydride.
The alkali is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium hydrogen phosphate, potassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, triethylamine and pyridine.
The enzyme is one or the combination of two of lipase and amino acid hydrolase, in the preferred embodiment of the invention, the enzyme is fixed on an enzyme carrier, and the enzyme carrier is one or the combination of two of alumina, diatomite, titanium dioxide, cellulose, DEAE glucose gel, gelatin and activated carbon.
In an eleventh aspect, the present invention provides an intermediate iv prepared according to the process as described above.
In a twelfth aspect, the present invention provides the use of intermediate iv prepared according to the process as described above for the preparation of the antifungal agent posaconazole.
In a thirteenth aspect, the present invention provides a preparation method of intermediate v, wherein the preparation route of the method is as follows:
wherein R is 6 Selected from ethyl, propyl, isopropyl, butyl, benzyl and acetyl phenyl, the intermediate IV is prepared according to the method of the invention, and the intermediate IV and iodine are catalyzed by Cat. II to obtain the intermediate V.
The catalyst Cat. II is a chelate product of a metal salt and a ligand II.
Wherein the metal salt is selected from one or more of zinc chloride, copper chloride, cobalt chloride, aluminum chloride, rhodium chloride, copper acetate, zinc acetate, and lead acetate.
The ligand II is shown as a formula II:
wherein R is 7 And R 8 Independently selected from C1-C6 linear/branched alkyl, benzyl, hydroxyphenyl, and hydroxy naphthyl.
Preferably, the ligand II is selected from one or more than two of the following compounds:
in a particular embodiment of the invention, the catalyst Cat. II is a chelate product of cobalt chloride with ligand II-1.
The solvent used in the reaction is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, n-butanol, 1, 4-dioxane, acetonitrile and toluene.
In a fourteenth aspect, the present invention provides an intermediate v prepared according to the process as described above.
In a fifteenth aspect, the present invention provides the use of intermediate v, prepared according to the process as described above, for the preparation of the antifungal agent posaconazole.
In a sixteenth aspect, the invention provides the use of a catalyst cat. I for the preparation of intermediate iii, having the formula:
The catalyst Cat. I is a chelate product of a metal salt and a ligand I, wherein the ligand I is one or a combination of more than two of the following compounds:
the metal salt is selected from one or the combination of more than two of chromium chloride, nickel chloride, copper chloride and cobalt chloride.
In a specific embodiment of the invention, the catalyst Cat. I is a chelate product of copper chloride with ligand I-2.
In a seventeenth aspect, the invention provides application of a catalyst Cat. II in preparation of an intermediate V, wherein the structural formula of the intermediate V is shown as follows
The catalyst Cat. II is a chelate product of a metal salt and a ligand II, wherein the ligand II is selected from one or more than two of the following compounds:
wherein the metal salt is selected from one or more of zinc chloride, copper chloride, cobalt chloride, aluminum chloride, rhodium chloride, copper acetate, zinc acetate, and lead acetate.
The ligand II has a structure shown in a formula II:
wherein R is 7 And R 8 Independently selected from C1-C6 linear/branched alkyl, benzyl, tolyl, hydroxyphenyl, and hydroxynaphthyl.
Preferably, the ligand II is selected from one or more of the following compounds:
in a particular embodiment of the invention, the catalyst cat. Ii is a chelate product of cobalt chloride with ligand ii-1.
The preparation method of the posaconazole intermediate provided by the invention has the advantages of low material cost, simple and convenient process, no need of excessively harsh reaction conditions, shorter process route than other traditional processes, and concise and efficient reaction process, and the preparation method is already in industrial production, and the obtained products are all sold in the market.
Drawings
FIG. 1 preparation of intermediate II 1 H nuclear magnetic resonance atlas
FIG. 2 of posaconazole intermediates of formula I 1 H nuclear magnetic resonance atlas
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
EXAMPLE 1 preparation of posaconazole intermediates of formula I
A scheme was prepared as follows:
the preparation method comprises the following steps:
174kg of toluene was charged into a reaction vessel, and 150kg of dimethyl malonate, 50kg of 1, 3-dichloro-1-propene and 25kg of sodium methoxide were charged into the reaction vessel. After the addition, the reaction is kept at 50-55 ℃ for 7h. Cooling to 25-35 ℃, filtering, slowly dripping prepared sodium hydroxide solution (2M, 3.4eq) into the filtrate, simultaneously monitoring whether the reaction is complete by TLC, separating liquid, washing the organic phase once by 50kg of water, separating liquid, and concentrating to remove the solvent; 90kg of the indicated compound 1 are obtained and the product obtained is used directly in the next reaction.
Adding 59.5kg of ethanol into a reaction kettle, adding 17kg of compound 1, adding sodium borohydride (total 6.22 kg) in batches, controlling the temperature to be 20-25 ℃, reacting for 1h at room temperature after the addition is finished, dropwise adding 16.3kg of concentrated hydrochloric acid, quenching and filtering. The filtrate was extracted with 34.02kg of ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give the product, which was used directly in the next reaction.
47.14kg of dichloromethane, 11.76kg of the product obtained in the previous step, 1.19kg of zinc chloride and 9.23kg of acetone are added into the reaction solution in a dropwise manner, and the reaction is carried out for 2h. The reaction solution was filtered, and the filtrate was collected and concentrated to obtain 14.0kg of an oily compound, which was used in the next reaction.
12.42kg of tetrahydrofuran and 21.39kg of 1-bromo-2, 4-difluorobenzene are added into a reaction kettle (1), nitrogen is replaced, then nitrogen is protected, the temperature is reduced to 0 ℃, 37.03L of isopropyl magnesium chloride (2M) is added dropwise, and the temperature is kept for 2h after the dropwise addition.
Adding 24.84L of tetrahydrofuran, 0.46kg of copper chloride and 0.51kg of 2,2' -bipyridyl into the reaction kettle (2), replacing with nitrogen, then carrying out nitrogen protection, stirring for 30min at room temperature, adding 14.0kg of compound 2, stirring for 30min at room temperature, cooling to-10-5 ℃, slowly adding the reaction liquid in the reaction kettle (1) into the reaction kettle (2), and keeping the temperature for 3h after the addition is finished.
Dropwise adding 1M hydrochloric acid, controlling the temperature to be 5-10 ℃, adjusting the pH value, separating liquid, adding a sodium bicarbonate solution into an organic phase, stirring, separating liquid, washing the organic phase with 15kg of water for three times, combining the aqueous phases, extracting with 30kg of methyl tert-ether until no product residue exists, combining the organic phases, drying with anhydrous sodium sulfate, and concentrating to obtain 14.86kg of a light yellow semisolid compound, wherein the yield is 88.7%, and the purity of a crude product is 96.5%.
Adding 56.1kg of acetonitrile, 7.65kg of sodium bicarbonate, 0.68kg of lipase, 1.27kg of molecular sieve and 3.0 kg of compound into a reaction kettle (1), carrying out nitrogen substitution, cooling to-3-8 ℃, slowly dripping 10.2kg of isobutyric anhydride after temperature control and pH value adjustment after diluting with 30.6kg of acetonitrile, controlling the temperature to-3-8 ℃, keeping the temperature for 30min after finishing the addition, carrying out TLC monitoring, filtering when the reaction is finished, leaching a filter cake with pre-cooled 5kg of acetonitrile, collecting filtrate, wherein the filtrate product is compound 4 and about 80L, and detecting the chiral purity of the reaction solution to be 99.5%.
Adding 8L of acetonitrile, 1.4kg of 2- (penta) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol and 0.4kg of cobalt chloride into the reaction kettle (2), stirring for 30min, dropwise adding the filtrate obtained from the reaction kettle (1), replacing nitrogen for protection, stirring for 30min at room temperature, cooling to-15 to-20 ℃, adding iodine (7.78kg and 0.5eq in total) in batches at intervals of 15min, and keeping the temperature for reaction for 1h after the addition is finished. TLC monitoring, reaction, adding sodium sulfite (0.3eq, 7.65kg) solution for washing, separating, extracting the aqueous phase with 25kg ethyl acetate for three times, combining the organic phases, adjusting the pH value to 7 with saturated sodium bicarbonate solution, separating, washing the organic phase with saturated 15kg of saline solution again, separating, drying the organic phase with anhydrous sodium sulfate, concentrating to obtain 22.14kg of compound 5 oily matter, detecting the chiral purity to be 98.6%, and using the compound in the next reaction.
Adding 80kg of DMSO and 20kg of compound 5 into a reaction kettle, replacing with nitrogen, then carrying out nitrogen protection, stirring for 30min at room temperature, adding 6.44kg of sodium triazole under the nitrogen protection, heating to 90-95 ℃, reacting for 15-20h, monitoring by TLC, cooling to below room temperature after the reaction is finished, dropwise adding a sodium hydroxide aqueous solution (2M, 1.5eq), controlling the temperature to be 20-30 ℃, completing dropwise adding, stirring for 2h at room temperature, then adding 2.3kg of sodium hydroxide, cooling to 0 ℃ under the nitrogen protection, adding p-toluenesulfonyl chloride (7.7 kg) in batches, keeping the temperature for 2h after the addition is finished, addingThe mixture was washed twice with 10kg of water, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give an oil which was purified by low temperature crystallization in a 20kg ethyl acetate-n-heptane system to give 12.17kg of a white solid with a yield of 83.5% and a chiral purity of 99.99%. Of the white compound 1 The H NMR spectrum is shown in FIG. 2, and it can be confirmed that the white compound is a compound represented by formula I, which is posaconazole intermediate ((3S, 5R) -5- ((1H-1, 2, 4-triazol-1-yl) methyl) -5- (2, 4-difluorophenyl) tetrahydrofuran-3-yl) methyl 4-methylbenzenesulfonate.
Comparative example 1
Compound 3 according to the invention is prepared according to the method of patent CN 102643194A, by the following steps:
under the protection of nitrogen, 10.6g of magnesium chips and a catalytic amount of iodine particles are added into 35mL of anhydrous THF, 81.3g of 2, 4-difluorobromobenzene is dropwise added at room temperature, and the dropping speed is 40-50 ℃ of the system. After the magnesium chips had completely disappeared, it was cooled to room temperature and then 21mmol of 2- (2' -chloropropenyl) -1, 3-propanediol diacetate 100g and iron (III) tris (acetylacetonate) [ Fe (acac) 3], 4.47g and THF (600 ml) were added to a reaction flask and stirred to form a mixed solution, 400ml of NMP was added to 600ml of the above 2, 4-difluorophenyl magnesium bromide and added dropwise thereto at-5 ℃ for 1.5 hours. Stirring was continued at this temperature for 30 minutes of cooling and the reaction mixture was then quenched with 1M hydrochloric acid. After separation of the organic layer, the aqueous layer was extracted with dichloromethane (2X 800 ml). The combined organic layers were washed with saturated brine. After drying and concentration over anhydrous sodium sulfate, 97.6g of intermediate 2- [2' - (2 ',4' -difluorophenyl) propenyl ] -1, 3-propanediol diacetate was obtained as a brown yellow oil in a yield of 71%.
114.2g of brown yellow oily matter of the intermediate 2- [2' - (2 ',4' -difluorophenyl) propenyl ] -1, 3-propanediol diacetate is added into 600ml of absolute ethyl alcohol and stirred for dissolution at room temperature, then 20% sodium hydroxide aqueous solution (2.6 eq) is added and stirred for 5 at the temperature of 35-25 ℃, the disappearance of the raw materials is monitored, the mixture is concentrated under reduced pressure at the temperature of 50-55 ℃ to obtain a residue, the aqueous phase is back extracted by MTBE (1.5V/W) until no product residue exists in the aqueous phase, and then the dried organic phase is concentrated to obtain 343.6g of brown oily matter compound, the yield of the two steps is 45%, and the purity of the crude product is 41.2%.
It was found by control experiments that the catalyst added at this stage of the Grignard coupling had a greater influence on the yield and purity of the reaction. The catalyst of ferric triacetylacetone in the patent CN 102643194A is used for replacing the catalyst Cat. I (copper chloride +2,2' -bipyridyl) provided by the invention, the yield of the compound 3 is reduced to 45 percent from 88.7 percent, the product purity is reduced to 41.2 percent from 96.5 percent, and the yield and the product purity are obviously reduced.
At the same time, the skilled person found that compound 3 prepared according to the process provided in patent CN 102643194A also had a significant increase in the appearance of the pigment. If the compound 3 has lower purity and deeper pigment, the activity of the next enzyme reaction is reduced, so that a large amount of raw materials are remained in the next step, and the generation of by-product diester is more, so that the yield and chirality of the next compound 4 are reduced, and finally the iodine ring closing step is influenced. In addition, the preparation of compound 3 according to the method provided by patent CN 102643194A requires a single step of reaction to remove acetyl protecting group, and the operation is more complicated.
Comparative example 2
Compound 5 according to the present invention is prepared according to the method provided in patent CN201180024632, and the preparation process is as follows:
20g of the compound produced in comparative example 1 was taken out and dissolved in 800ml of toluene, and the reaction solution was cooled to-15 ℃. Then 15g of sodium bicarbonate, 1g of the enzyme Novozym 435 and 16ml of isobutyric anhydride were added and stirring was continued for 24 hours at constant temperature-15 ℃. The solid was then filtered off and the filtrate washed with 5% (w/v) aqueous sodium bicarbonate, then washed with water, separated dried and concentrated to give 27g crude tan oil compound 4 with a chiral purity of 89.7% with 15% by-product diester and 26% by weight starting material. 27g of the crude product of the obtained compound 4 was dissolved in 160ml of ethyl acetate and cooled to-15 ℃ and 40g of iodine (2.5 eq) and 14g of sodium hydrogencarbonate were added, and after the obtained suspension was stirred at-15 ℃ for 5 hours, 1.5L of a 10% (w/v) aqueous solution of sodium sulfite was added to the reaction solution to quench. The organic layer was washed with 300ml of a 10% (w/v) aqueous sodium sulfite solution and water, respectively. The solvent of the washed organic layer thus obtained was removed by distillation under the reduced pressure to obtain 20.4g of a brown oily compound 5 as an oil 19g, in 54.6% yield and 85% chiral purity by detection.
It is found by comparing example 2 that the reaction conditions of compound 3 for the enzyme reaction are harsh, the reaction environment has a large influence on the reaction, such as Ph, temperature, solvent, and small amount of residual solvent and pigment in compound 3 all affect the catalytic activity of the enzyme, resulting in the yield of the product compound 5 decreasing from 83.5% to 54.6% and the optical purity decreasing from 99.99% to 83.5%. Therefore, it is important to improve the quality of the reaction raw material compound 3.
In addition, the technical personnel of the invention find that if the compound 4 prepared by the method disclosed in the patent CN201180024632 is not subjected to column chromatography purification, the remaining raw materials directly affect the selectivity of the iodine ring closing step and the optical purity of iodine ring closing; the by-product diester will not participate in the reaction at this step and will further affect the yield of iodine ring closure. In addition, in the method disclosed in patent CN201180024632, the amount of iodine (2.5 eq) used in the iodine ring closing step is relatively large, and the addition of the amount of iodine will substitute for one fluorine on the benzene ring, resulting in one fluorine-removed impurity, which is very difficult to remove in the subsequent reaction, thereby resulting in the reduction of yield and purity of the iodine ring closing step and the subsequent steps.
Screening optimization experiment of catalyst Cat. II
The purpose of the experiment is as follows: the chiral catalyst which is most suitable for the invention is obtained by the screening of optimization experiments.
The experimental method comprises the following steps: the compound 4 prepared by the invention is used as a starting material, and the compound 5 is prepared by changing the type of a catalyst.
50ml of acetonitrile, 1.8g of 2- (penta) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyl imino methylphenol and 0.5g of cobalt chloride are added into a reaction bottle, stirred for 30min, 20g of the compound 4 is dissolved by 100ml and then dripped into the reaction bottle, nitrogen is replaced for nitrogen protection, the mixture is stirred for 30min at room temperature, the temperature is reduced to-15 to-20 ℃, iodine (0.97 g in total) is added in batches, the time interval between each batch is 15min, and after the addition is finished, the mixture is subjected to heat preservation reaction for 1h. TLC monitoring, reaction completed, sodium sulfite (0.3 eq,) solution was added for washing, liquid separation, aqueous phase extraction with 50ml ethyl acetate three times, organic phase combination, saturated sodium bicarbonate solution to adjust pH value to 7, liquid separation, organic phase washing with saturated 50ml brine again, liquid separation, organic phase drying with anhydrous sodium sulfate and concentration to obtain compound 5 oil 24.2g, chiral purity was 98.6%.
Experiment 2
The reaction materials and conditions were the same as in experiment 1 except that the catalyst "1.8g of 2- (pentane) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol and 0.5g of cobalt chloride" were replaced with 1.8g of N1, N1, N2-trimethylethane-1, 2-diamine and 0.5g of cobalt chloride. 26.0g of compound 5 was prepared as an oil with a chiral purity of 95.1% as determined.
Experiment 3
The reaction materials and conditions were the same as in experiment 1 except that the catalyst "1.8g of 2- (pentane) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol and 0.5g of cobalt chloride" were replaced with 1.8g of 1, 3-bis (2, 6-diisopropylphenyl) -4, 5-dihydro-1H-imidazole-3-ammonium chloride and 0.5g of cobalt chloride ". Compound 5 was prepared as an oil 24.2g with a chiral purity of 95.6% by assay.
Experiment 4
The reaction materials and conditions were the same as those in experiment 1 except that the catalyst "1.8g of 2- (pentane) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol and 0.5g of cobalt chloride" were replaced with 1.8g of 2- (pentane) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol and 0.5g of copper chloride ". Compound 5 was prepared as an oil 24.8g with a chiral purity of 95.6% by assay.
Experiment 5
The reaction materials and conditions were the same as those in experiment 1 except that the catalyst "1.8g of 2- (pentane) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol and 0.5g of cobalt chloride" were replaced with 1.8g of 2- (pentane) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol and 0.5g of iron chloride ". 25.8g of compound 5 was prepared as an oil with a chiral purity of 96.0% by assay.
As a result of comparative experiments 1 to 3, it was found that when the metal salt was cobalt chloride, the chelate complex formed using 2- (penta) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol as a ligand was more effective in catalyzing the reaction. As a result of comparing experiments 1 and 4 to 5, it was found that when the ligand was 2- (penta) - (1S, 2R) -1, 2-diphenyl-2-p-tolylsulfinylethyliminomethylphenol, the catalytic effect of selecting cobalt chloride as the metal salt was the best as compared with iron chloride and copper chloride.
The above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same. Those of ordinary skill in the art will understand that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (29)
1. A process for preparing posaconazole intermediate of formula I,
characterized in that the method comprises the following steps:
(1) Compound A
X 1 、X 2 Independently selected from F, br, cl, I,
with compounds B
R 1 、R 2 Independently selected from methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, benzyl,
reacting under the action of alkali and a catalyst to obtain an intermediate I, wherein the structural formula of the intermediate I is shown as follows:
(2) Reducing the intermediate I by a reducing agent, and condensing the intermediate I and an aldehyde (ketone) reagent under the catalysis of protonic acid or Lewis acid to obtain an intermediate II, wherein the structural formula of the intermediate II is shown as follows:
wherein Y is 1 、Y 2 Independently selected from-H, methyl, ethyl, t-butyl, phenyl, benzyl, p-methoxyphenyl, p-methylphenyl, p-nitrophenyl, m-trimethylphenyl, diphenylmethylene, or Y 1 、Y 2 A C5-C7 cycloalkyl group with a C atom in between;
(3) And (3) carrying out cross coupling on the intermediate II and 2, 4-difluorophenyl magnesium bromide under the catalysis of Cat. I to obtain an intermediate III, wherein the structural formula of the intermediate III is shown as follows:
(4) Adding alkali into the intermediate III and an acylation reagent to obtain an intermediate IV under the catalysis of enzyme, wherein the structural formula of the intermediate IV is as follows:
wherein R is 6 Selected from ethyl, propyl, isopropyl, butyl, benzeneMethyl, acetyl phenyl;
(5) And (3) catalyzing the intermediate IV and iodine by Cat. II to obtain an intermediate V, wherein the structural formula of the intermediate V is shown as follows:
(6) And (3) reacting the intermediate V with sodium triazole, dropwise adding a sodium hydroxide aqueous solution after the reaction is finished, cooling, and adding p-toluenesulfonyl chloride to react to obtain the compound shown in the formula I.
2. The method according to claim 1, wherein the base in step (1) is one or a combination of two or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
3. The method of claim 1, wherein the catalyst in step (1) is one or more selected from cuprous chloride, cuprous iodide, and ferric chloride (II).
4. The preparation method according to claim 1, wherein the reducing agent in step (2) is selected from one or a combination of two or more of sodium borohydride, potassium borohydride and lithium aluminum hydride; the solvent for reduction reaction is one or more selected from methanol, ethanol, tetrahydrofuran, isopropanol and butanol.
5. The method of claim 1, wherein the catalyst in step (2) is one or a combination of two of protonic acid and Lewis acid, wherein protonic acid is selected from sulfuric acid, p-TsOH, CSA, HClO 4 One or a combination of two or more of HOAc; the Lewis acid is selected from CuSO 4 、ZnCl 2 、AlCl 3 、FeCl 3 、SnCl 4 、CoCl 2 、TiCl 4 One or a combination of two or more of them.
6. The method according to claim 1, wherein the aldehyde (ketone) reagent in step (2) is selected from one or a combination of two or more of P1-P7 compounds, and the P1-P7 compounds have the following structures:
wherein R is 3 、R 4 、R 5 Independently selected from H, C1-C10 straight chain/branched chain alkyl, phenyl and benzyl.
7. The method according to claim 1, wherein the condensation reaction solvent in step (2) is one or more selected from the group consisting of ethyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, and methyl t-butyl ether.
8. The method according to claim 1, wherein the solvent used in step (3) is one or a combination of two or more selected from tetrahydrofuran, N-methylpyrrolidone, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, methyl tert-butyl ether, toluene, and 1, 4-dioxane.
9. The process according to claim 1, wherein the catalyst cat. I in step (3) is a chelate product of a metal salt and a ligand i selected from one or a combination of two or more of the following compounds:
the metal salt is selected from one or the combination of more than two of chromium chloride, nickel chloride, copper chloride and cobalt chloride.
10. The process according to claim 9, wherein the catalyst cat. I is a chelate product of copper chloride with the ligand i-2.
11. The method according to claim 1, wherein the acylating agent in step (4) is selected from one or more of acetic anhydride, propionic anhydride, succinic anhydride, benzoic anhydride, and acetylsalicylic anhydride.
12. The method according to claim 1, wherein the base in step (4) is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium hydrogen phosphate, potassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, triethylamine, and pyridine.
13. The method according to claim 1, wherein the enzyme in step (4) is one or a combination of two of lipase and amino acid hydrolase.
14. The preparation method according to claim 1, wherein in the step (5), the catalyst Cat. II is a chelate product of a metal salt and a ligand II, wherein the metal salt is selected from one or a combination of more than two of zinc chloride, copper chloride, cobalt chloride, aluminum chloride, rhodium chloride, copper acetate, zinc acetate and lead acetate;
the ligand II has a structure shown in a formula II:
wherein R is 7 And R 8 Independently selected from C1-C6 linear/branched alkyl, benzyl, tolyl, hydroxyphenyl, and hydroxynaphthyl.
15. The method according to claim 14, wherein the ligand ii is selected from one or a combination of two or more of the following compounds.
16. The process of claim 15, wherein the catalyst cat. Ii is a chelate product of cobalt chloride and ligand ii-1.
17. The method according to claim 1, wherein the solvent used in the reaction of step (5) is one or a combination of two or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, n-butanol, 1, 4-dioxane, acetonitrile and toluene.
18. The method according to claim 1, wherein X in the step (1) 1 、X 2 Is Cl, R 1 、R 2 Is selected from methyl, said Y 1 、Y 2 is-CH 3 The structure of intermediate II is as follows:
19. a process for producing an intermediate II, characterized in that it is as shown in steps (1) to (2) in the production process according to any one of claims 1 to 7.
20. An intermediate II prepared according to the process of claim 19.
21. Use of intermediate II prepared according to the process of claim 19 for the preparation of the antifungal agent posaconazole.
22. A process for producing an intermediate iii, characterized in that it is as shown in steps (1) to (3) in the production process according to any one of claims 1 to 10.
23. A method for producing an intermediate iv, characterized in that steps (1) to (4) of the production method according to any one of claims 1 to 13 are included.
24. A process for the preparation of intermediate V, characterized in that it is as described in any one of claims 1 to 17 in steps (1) to (5).
25. Use of a catalyst cat. I in the preparation of intermediate iii having the formula:
the catalyst Cat. I is a chelate product of a metal salt and a ligand I, wherein the ligand I is selected from one or more than two of the following compounds:
the metal salt is selected from one or the combination of more than two of chromium chloride, nickel chloride, copper chloride and cobalt chloride.
26. Use according to claim 25, wherein the catalyst cat. I is a chelate product of copper chloride with ligand i-2.
27. The application of a catalyst Cat. II in the preparation of an intermediate V, wherein the structural formula of the intermediate V is shown as follows
The catalyst Cat. II is a chelate product of a metal salt and a ligand II,
wherein the metal salt is selected from one or more of zinc chloride, copper chloride, cobalt chloride, aluminum chloride, rhodium chloride, copper acetate, zinc acetate, and lead acetate.
The ligand II is shown as a formula II:
wherein R is 7 And R 8 Independently selected from C1-C6 linear/branched alkyl, benzyl, tolyl, hydroxyphenyl, and hydroxynaphthyl.
28. The use according to claim 27, wherein the ligand ii is selected from one or a combination of two or more of the following compounds.
29. Use according to claim 28, wherein the catalyst cat. Ii is a chelate product of cobalt chloride with ligand ii-1.
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