CN114829354A - Recovery method of voriconazole enantiomer - Google Patents
Recovery method of voriconazole enantiomer Download PDFInfo
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- CN114829354A CN114829354A CN201980103211.9A CN201980103211A CN114829354A CN 114829354 A CN114829354 A CN 114829354A CN 201980103211 A CN201980103211 A CN 201980103211A CN 114829354 A CN114829354 A CN 114829354A
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- 238000000034 method Methods 0.000 title claims abstract description 41
- BCEHBSKCWLPMDN-HWPZZCPQSA-N (2s,3r)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol Chemical compound C1([C@@H](C)[C@@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-HWPZZCPQSA-N 0.000 title claims abstract description 37
- 238000011084 recovery Methods 0.000 title claims description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 239000000126 substance Substances 0.000 claims abstract description 25
- 238000000926 separation method Methods 0.000 claims abstract description 22
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 14
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 159
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical class C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 239000012141 concentrate Substances 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims 1
- 238000003756 stirring Methods 0.000 abstract description 28
- 150000001875 compounds Chemical class 0.000 abstract description 21
- 238000001816 cooling Methods 0.000 abstract description 11
- 238000000967 suction filtration Methods 0.000 abstract description 11
- 239000002699 waste material Substances 0.000 abstract description 7
- 230000007613 environmental effect Effects 0.000 abstract description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 20
- 229960004740 voriconazole Drugs 0.000 description 14
- 239000007788 liquid Substances 0.000 description 13
- -1 1H-1,2, 4-triazolyl Chemical group 0.000 description 10
- AYZDRTRWCASUFO-UHFFFAOYSA-N 4-ethyl-5-fluoropyrimidine Chemical compound CCC1=NC=NC=C1F AYZDRTRWCASUFO-UHFFFAOYSA-N 0.000 description 10
- 229960001701 chloroform Drugs 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 5
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- 239000000047 product Substances 0.000 description 3
- 241000228212 Aspergillus Species 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical class C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 description 1
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 description 1
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 description 1
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 description 1
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 description 1
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 description 1
- 241000235645 Pichia kudriavzevii Species 0.000 description 1
- 241001495452 Podophyllum Species 0.000 description 1
- 241000222126 [Candida] glabrata Species 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 208000032343 candida glabrata infection Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 238000012994 industrial processing Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 description 1
- 229940058690 lanosterol Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method for recovering voriconazole enantiomer comprises the following steps: mixing voriconazole enantiomer with a reaction solvent containing an alkaline substance A, after the reaction is finished, concentrating under reduced pressure, adding an organic solvent A and water, stirring for dissolving, separating, collecting an oil layer, continuously adding water, adjusting the pH value of the solution with an acidic substance, separating, concentrating the oil layer, adding a separation solvent, stirring for dissolving, cooling, crystallizing, and performing suction filtration to obtain a compound shown in formula II; and adding an organic solvent B into the collected water layer, adjusting the pH value of the solution by using an alkaline substance B, separating the solution, distilling the organic solvent layer under reduced pressure, and then heating and distilling under reduced pressure to obtain the formula III. The method has the advantages of simple process route, convenient operation in the treatment process, small harm to human bodies, repeated utilization of wastes, environmental friendliness, no waste of resources and the like.
Description
The invention relates to the field of medicinal chemistry, and particularly relates to a recovery method of voriconazole enantiomer.
Voriconazole (voriconazole) is a triazole antifungal and a second-generation synthetic derivative of fluconazole, a first-line therapeutic for invasive aspergillus infection and candida krusei infection. The action mechanism of the compound plays a role in resisting fungi by inhibiting cytochrome P450(CYP450) end-dependent demethylation of lanosterol 14 alpha, which is a crucial step in the synthesis of membrane ergosterol of fungi. In vitro tests have shown that voriconazole has a broad spectrum antifungal effect, has an antibacterial effect on all candida species (including fluconazole-resistant strains of candida krusei, candida glabrata and candida albicans), has a bactericidal effect on all detected aspergillus fungi, and furthermore, voriconazole has a bactericidal effect in vitro on other pathogenic fungi including those less sensitive to existing antifungal agents, such as podophyllum and fusarium. Voriconazole has the advantages of wide antibacterial spectrum and strong antibacterial efficacy, and especially has good curative effect on invasive aspergillus soaking infection.
Voriconazole has the following structural formula:
voriconazole (2R,3S) is a chiral compound with two chiral centers in the structure, with two diastereomers (2R,3R/2S,3S) and one enantiomer (2S, 3R). Wherein the diastereoisomers generally have different physicochemical properties and are easy to separate and remove in the production process. The enantiomer has the same physical and chemical properties with voriconazole in an achiral environment, and is difficult to separate and remove in a production process.
The reported voriconazole is generally obtained by resolving voriconazole racemate (2R,3S/2S,3R) by using a chiral resolving agent, and the chiral resolving agent is simple to recover and can be generally used repeatedly. The yield of voriconazole (2R,3S) obtained after the resolution by using a resolving agent is about 40%, and the voriconazole enantiomer (2S,3R) obtained by the resolution has two processing methods, one is to convert the voriconazole isomer (2S,3R) into voriconazole, but four isomers, 2S,3R, 2R,3S, 2R,3R and 2S,3S, can be obtained because the voriconazole isomer (2S,3R) contains two chiral centers which are overturned to carry out the conversion of the isomers, and the obtained voriconazole has low conversion efficiency after the four isomers are separated and resolved, and meanwhile, the process flow is relatively complex and is not suitable for industrial production; the other method is to treat the voriconazole enantiomer directly as waste, so that the method not only causes environmental pollution, but also increases the production cost. Therefore, a method suitable for industrial processing of voriconazole isomer is urgently needed.
Disclosure of Invention
In order to solve the problems of the two methods for treating the voriconazole enantiomer, the invention discloses a recovery method of the voriconazole enantiomer, which has the advantages of simple process route, convenient operation in the treatment process, small harm to human bodies, repeated utilization of wastes, environmental friendliness, no waste of resources and the like because substances used in the reaction process are common substances in experiments, and the substances obtained by the reaction can be used as starting materials for preparing the voriconazole again.
The recovery method of voriconazole enantiomer comprises the following steps of mixing voriconazole enantiomer with a reaction solvent containing alkaline substance A, heating to temperature I for reaction, and obtaining formula II and formula III after the reaction is finished, wherein the reaction is as follows:
after the reaction is finished, decompressing and concentrating, adding the organic solvent A and water into a concentrate, recovering and separating the separated formula III from a water layer, and recovering the formula II from an oil layer.
According to the recovery method of voriconazole enantiomer, the organic solvent A and water are added into the concentrate, the mixture is stirred and dissolved, then liquid separation is carried out, an oil layer is collected, water is continuously added into the oil layer, the pH value of the solution is adjusted by using an acidic substance, liquid separation is carried out, and the oil layer and a water layer are collected.
Concentrating the collected oil layer, adding a separation solvent, stirring for dissolving, cooling to a temperature II, stirring for crystallization, and performing suction filtration to obtain a formula II; and adding an organic solvent B into the collected water layer, adjusting the pH value of the solution by using an alkaline substance B, separating the solution, collecting the organic solvent layer, removing the organic solvent by reduced pressure distillation, heating to the temperature III, and carrying out reduced pressure distillation to obtain the formula III.
The recovery method of voriconazole enantiomer comprises the following steps that the mass ratio of voriconazole enantiomer shown in formula I to reaction solvent is 1: 3-1: 8, and the mass ratio of voriconazole enantiomer shown in formula I to alkaline substance A is 3: 1-7: 1.
According to the recovery method of voriconazole enantiomer, the reaction solvent is one or two of methanol, ethanol, propanol, isopropanol, acetone and n-butanol, the alkaline substance A is a strong alkaline substance, and the strong alkaline substance is one or two of lithium hydroxide, sodium hydroxide and potassium hydroxide.
According to the recovery method of voriconazole enantiomer, the reaction temperature I of voriconazole enantiomer shown in formula I and alkaline substance A is 60-85 ℃, and the reaction time is 10-20 hours.
According to the recovery method of voriconazole enantiomer, the organic solvent A is one or two of toluene, dichloromethane and chloroform, the acidic substance is one or two of hydrochloric acid, sulfuric acid, nitric acid and acetic acid, and the pH value of the solution is 1-5.
According to the recovery method of voriconazole enantiomer, the separation solvent is one or two of acetone, methyl acetate, ethyl acetate, diethyl ether and phenol; the temperature II is 0-10 ℃.
According to the recovery method of voriconazole enantiomer, the alkaline substance B is one or two of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, lithium hydroxide, sodium hydroxide and potassium hydroxide, the organic solvent B is one or two of toluene, dichloromethane and trichloromethane, and the pH value of the solution is 8-12.
The recovery method of voriconazole enantiomer has the temperature III of 70-90 ℃ and the pressure of-0.085 to-0.095 MPa.
According to the recovery method of voriconazole enantiomer, the yield of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone (formula II) is 86% -95%, and the yield of the 6-ethyl-5-fluoropyrimidine (formula III) is 85% -92%.
The method has the advantages of simple process route, convenient operation in the treatment process, small harm to human bodies due to the fact that substances used in the reaction process are common substances in experiments, recycling of wastes, environmental friendliness, no waste of resources and the like, the yield of the product obtained by the method is over 85 percent, and the yield of the product can reach over 90 percent partially, the product is simple to separate, and the substance prepared by the reaction can be used as a starting material for preparing the voriconazole.
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail. The reagents used in the present invention are either commercially available or can be prepared by methods known in the art or by methods described herein.
In the present invention, the term "DEG C" means "centigrade degree, g means" g ", MPa means" MPa ", and h means" hour ".
Example 1
100g of voriconazole enantiomer, 400g of reaction solvent methanol and 20g of lithium hydroxide are added into a reaction bottle, and the temperature is increased to 65 ℃ for reaction for 10 hours. And after the reaction is finished, carrying out reduced pressure concentration to recover methanol, adding 400g of organic solvent A trichloromethane and 200g of water into the concentrate, stirring and dissolving, standing and separating, collecting a trichloromethane layer of the organic solvent A, continuously adding 200g of water into the collected trichloromethane layer, adjusting the pH to 1 by using concentrated sulfuric acid, separating, and collecting an oil layer and a water layer.
And (3) concentrating the chloroform layer of the finally collected organic solvent A to dryness, adding 200g of methyl acetate serving as a separation solvent, stirring and dissolving, cooling to 3 ℃, stirring and crystallizing for 4H, and performing suction filtration to obtain a crude product (the compound shown in the formula II) of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 86.29%.
Adding 200g of organic solvent B trichloromethane into a water layer, adjusting the pH value to 8 by using a sodium acetate solution, separating liquid, collecting the trichloromethane layer of the organic solvent B, distilling at 30 ℃ under reduced pressure to remove the trichloromethane of the organic solvent B, reducing the pressure at 70 ℃ to-0.095 Mpa, and distilling to obtain 6-ethyl-5-fluoropyrimidine (a compound shown in a formula III), wherein the yield is 85.33%.
Example 2
100g of voriconazole enantiomer, 400g of reaction solvent acetone and 20g of potassium hydroxide are added into a reaction bottle, and the temperature is raised to 75 ℃ for reflux reaction for 20 hours. And after the reaction is finished, concentrating under reduced pressure to recover acetone, adding 400g of organic solvent A toluene and 200g of water into the concentrate, stirring and dissolving, standing and separating, collecting a toluene layer of the organic solvent A, continuously adding 200g of water into the toluene layer, adjusting the pH value to 5 by using concentrated nitric acid, separating, and collecting an oil layer and a water layer.
And (3) concentrating the finally collected organic solvent A toluene layer to dryness, adding 200g of separation solvent diethyl ether, stirring and dissolving, cooling to 8 ℃, stirring and crystallizing for 4H, and performing suction filtration to obtain a crude product (the compound shown in the formula II) of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 88.27%.
Adding 200g of organic solvent B toluene into the water layer, adjusting the pH value to 12 by using 25% potassium hydroxide solution, separating liquid, collecting the organic solvent B toluene layer, distilling at 30 ℃ under reduced pressure to remove the organic solvent B toluene, then distilling at 90 ℃ under reduced pressure to-0.085 Mpa to obtain 6-ethyl-5-fluoropyrimidine (the compound shown in the formula III), wherein the yield is 87.52%.
Example 3
100g of voriconazole enantiomer, 400g of reaction solvent ethanol and 20g of sodium hydroxide are added into a reaction bottle, and the temperature is increased to 85 ℃ for reflux reaction for 15 hours. After the reaction is finished, decompressing and concentrating to recover ethanol, adding 400g of organic solvent A dichloromethane and 200g of water into the concentrate, stirring and dissolving, standing and separating liquid, collecting the dichloromethane layer of the organic solvent A, continuously adding 200g of water into the dichloromethane layer, adjusting the pH value to 3 by using concentrated hydrochloric acid, separating liquid, and collecting an oil layer and a water layer.
And (3) concentrating the finally collected dichloromethane layer of the organic solvent A to dryness, adding 200g of ethyl acetate serving as a separation solvent, stirring and dissolving, cooling to 3 ℃, stirring and crystallizing for 4H, and performing suction filtration to obtain a crude product (the compound shown in the formula II) of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 93.84%.
Adding 200g organic solvent B dichloromethane into water layer, adjusting pH to 10 with 25% sodium hydroxide solution, separating, collecting dichloromethane layer, distilling at 30 deg.C under reduced pressure to remove dichloromethane, and distilling at 80 deg.C under reduced pressure to-0.09 Mpa to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III) with yield of 91.37%.
Example 4
100g of voriconazole enantiomer, 400g of reaction solvent methanol and 20g of sodium carbonate are added into a reaction bottle, and the temperature is increased to 65 ℃ for reflux reaction for 10 hours. After the reaction, the methanol is recovered by concentration under reduced pressure, 400g of organic solvent A dichloromethane and 200g of water are added into the concentrate, the mixture is stirred and dissolved, then the mixture is kept stand for liquid separation, a dichloromethane layer of the organic solvent A is collected, 200g of water is continuously added into the dichloromethane layer, the pH value is adjusted to 1 by concentrated sulfuric acid, liquid separation is carried out, and an oil layer and a water layer are collected.
And (3) concentrating the finally collected dichloromethane layer of the organic solvent A to dryness, adding 200g of ethyl acetate serving as a separation solvent, stirring and dissolving, cooling to 0 ℃, stirring and crystallizing for 4H, and performing suction filtration to obtain a crude product (the compound shown in the formula II) of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 50.96%.
Adding 200g organic solvent B dichloromethane into water layer, adjusting pH to 9 with 25% sodium hydroxide solution, separating, collecting dichloromethane layer, distilling at 30 deg.C under reduced pressure to remove dichloromethane, and distilling at 70 deg.C under reduced pressure to-0.095 Mpa to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III) with yield of 43.58%.
Example 5
100g of voriconazole enantiomer, 400g of reaction solvent ethanol and 20g of sodium acetate are added into a reaction bottle, and the temperature is increased to 80 ℃ for reflux reaction for 15 h. After the reaction is finished, concentrating under reduced pressure to recover ethanol, adding 400g of organic solvent A dichloromethane and 200g of water into the concentrate, stirring and dissolving, standing and separating, collecting the dichloromethane layer of the organic solvent A, continuously adding 200g of water into the dichloromethane layer, adjusting the pH to 3 by using concentrated sulfuric acid, separating, and collecting an oil layer and a water layer.
And (3) concentrating the finally collected dichloromethane layer of the organic solvent A to dryness, adding 200g of ethyl acetate serving as a separation solvent, stirring and dissolving, cooling to 3 ℃, stirring and crystallizing for 4H, and performing suction filtration to obtain a crude product (the compound shown in the formula II) of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 41.78%.
Adding 200g of organic solvent B dichloromethane into the water layer, adjusting the pH value to 12 by using a sodium acetate solution, separating liquid, collecting a dichloromethane layer, distilling at 30 ℃ under reduced pressure to remove dichloromethane, reducing the pressure at 80 ℃ to-0.09 Mpa, and distilling to obtain 6-ethyl-5-fluoropyrimidine (a compound shown in a formula III), wherein the yield is 37.62%.
Example 6
100g of voriconazole enantiomer, 400g of reaction solvent methanol and 20g of sodium hydroxide are added into a reaction bottle, and the temperature is increased to 30 ℃ for reflux reaction for 15 h. After the reaction is finished, concentrating under reduced pressure to recover ethanol, adding 400g of organic solvent A dichloromethane and 200g of water into the concentrate, stirring and dissolving, standing and separating, collecting the dichloromethane layer of the organic solvent A, continuously adding 200g of water into the dichloromethane layer, adjusting the pH to 3 by using concentrated sulfuric acid, separating, and collecting an oil layer and a water layer.
Concentrating the finally collected dichloromethane layer of the organic solvent A to dryness, adding 200g of ethyl acetate as a separation solvent, stirring for dissolving, cooling to 3 ℃, stirring for crystallization for 4 hours, and performing suction filtration to obtain a crude product (the compound of the formula II) of 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 39.84%.
Adding 200g organic solvent B dichloromethane into water layer, adjusting pH to 9 with 25% sodium hydroxide solution, separating, collecting dichloromethane layer, distilling at 30 deg.C under reduced pressure to remove dichloromethane, and distilling at 70 deg.C under reduced pressure to-0.095 Mpa to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III) with yield of 33.71%.
Example 7
100g of voriconazole enantiomer, 400g of reaction solvent methanol and 20g of sodium hydroxide are added into a reaction bottle, and the temperature is increased to 50 ℃ for reflux reaction for 15 h. After the reaction, the methanol is recovered by concentration under reduced pressure, 400g of organic solvent A dichloromethane and 200g of water are added into the concentrate, the mixture is stirred and dissolved, then the mixture is kept stand for liquid separation, a dichloromethane layer of the organic solvent A is collected, 200g of water is continuously added into the dichloromethane layer, the pH value is adjusted to 3 by concentrated sulfuric acid, liquid separation is carried out, and an oil layer and a water layer are collected.
And (3) concentrating the finally collected dichloromethane layer of the organic solvent A to dryness, adding 200g of ethyl acetate serving as a separation solvent, stirring and dissolving, cooling to 3 ℃, stirring and crystallizing for 4H, and performing suction filtration to obtain a crude product (the compound shown in the formula II) of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 58.64%.
Adding 200g organic solvent B dichloromethane into water layer, adjusting pH to 12 with 25% sodium hydroxide solution, separating, collecting dichloromethane layer, distilling at 30 deg.C under reduced pressure to remove dichloromethane, and distilling at 80 deg.C under reduced pressure to-0.09 Mpa to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III) with yield of 51.47%.
Example 8
100g of voriconazole enantiomer, 400g of reaction solvent ethanol and 20g of sodium hydroxide are added into a reaction bottle, and the temperature is increased to 20 ℃ for reflux reaction for 15 h. After the reaction, the methanol is recovered by concentration under reduced pressure, 400g of organic solvent A dichloromethane and 200g of water are added into the concentrate, the mixture is stirred and dissolved, then the mixture is kept stand for liquid separation, a dichloromethane layer of the organic solvent A is collected, 200g of water is continuously added into the dichloromethane layer, the pH value is adjusted to 3 by concentrated sulfuric acid, liquid separation is carried out, and an oil layer and a water layer are collected.
And (3) concentrating the finally collected dichloromethane layer of the organic solvent A to dryness, adding 200g of ethyl acetate serving as a separation solvent, stirring and dissolving, cooling to 3 ℃, stirring and crystallizing for 4H, and performing suction filtration to obtain a crude product (the compound shown in the formula II) of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 38.71%.
Adding 200g organic solvent B dichloromethane into water layer, adjusting pH to 12 with 25% sodium hydroxide solution, separating, collecting dichloromethane layer, distilling at 30 deg.C under reduced pressure to remove dichloromethane, and distilling at 80 deg.C under reduced pressure to-0.09 Mpa to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III) with yield of 33.71%.
Example 9
100g of voriconazole enantiomer, 400g of reaction solvent ethanol and 20g of sodium hydroxide are added into a reaction bottle, and the temperature is increased to 40 ℃ for reflux reaction for 15 h. After the reaction is finished, concentrating under reduced pressure to recover ethanol, adding 400g of organic solvent A dichloromethane and 200g of water into the concentrate, stirring and dissolving, standing and separating, collecting an organic solvent A dichloromethane layer, continuously adding 200g of water into the dichloromethane layer, adjusting the pH to 3 with concentrated nitric acid, separating, and collecting an oil layer and a water layer.
And (3) concentrating the finally collected dichloromethane layer of the organic solvent A to dryness, adding 200g of ethyl acetate serving as a separation solvent, stirring and dissolving, cooling to 3 ℃, stirring and crystallizing for 4H, and performing suction filtration to obtain a crude product (the compound shown in the formula II) of the 2, 4-difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the yield is 49.21%.
Adding 200g organic solvent B dichloromethane into water layer, adjusting pH to 10 with 25% sodium hydroxide solution, separating, collecting dichloromethane layer, distilling at 30 deg.C under reduced pressure to remove dichloromethane, and distilling at 70 deg.C under reduced pressure to-0.095 Mpa to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III) with yield of 43.85%.
Claims (10)
- A method for recovering voriconazole enantiomers is characterized by comprising the following steps of mixing voriconazole enantiomers with a reaction solvent containing a basic substance A, heating to a temperature I for reaction, and obtaining a formula II and a formula III after the reaction is finished, wherein the reaction is specifically as follows:
- the method for recovering voriconazole enantiomers as claimed in claim 1, wherein after the reaction is finished, the reaction is concentrated under reduced pressure, the concentrate is added with organic solvent A and water, separated formula III is recovered from the water layer, and formula II is recovered from the oil layer.
- The method for recovering voriconazole enantiomers as claimed in claim 2, wherein the concentrate is added with organic solvent A and water, stirred to dissolve, then separated, the oil layer is collected, water is further added to the oil layer, the pH value of the solution is adjusted by acidic substance, separated, and the oil layer and the water layer are collected.
- The recovery method of voriconazole enantiomer according to claim 3, wherein the collected oil layer is concentrated, added with a separation solvent, stirred for dissolution, cooled to temperature II, stirred for crystallization, and then filtered with suction to obtain formula II; and adding an organic solvent B into the collected water layer, adjusting the pH value of the solution by using an alkaline substance B, separating the solution, collecting the organic solvent layer, removing the organic solvent by reduced pressure distillation, heating to the temperature III, and carrying out reduced pressure distillation to obtain the formula III.
- The recovery method of voriconazole enantiomer according to claim 4, wherein the mass ratio of voriconazole enantiomer of formula I to reaction solvent is 1: 3-1: 8, and the mass ratio of voriconazole enantiomer of formula I to alkaline substance A is 3: 1-7: 1; or the reaction temperature I of the voriconazole enantiomer of the formula I and the alkaline substance A is 60-85 ℃, and the reaction time is 10-20 hours.
- The method for recovering voriconazole enantiomers as claimed in claim 5, wherein the reaction solvent is one or two of methanol, ethanol, propanol, isopropanol, acetone and n-butanol, the basic substance A is a strong basic substance, and the strong basic substance is one or two of lithium hydroxide, sodium hydroxide and potassium hydroxide.
- The method for recovering voriconazole enantiomers as claimed in any of claims 1 to 6, wherein the organic solvent A is one or two of toluene, dichloromethane and chloroform, the acidic substance is one or two of hydrochloric acid, sulfuric acid, nitric acid and acetic acid, and the pH value of the solution is 1 to 5.
- The method for recovering voriconazole enantiomers as claimed in any of claims 1 to 6, wherein the separation solvent is one or two of acetone, methyl acetate, ethyl acetate, diethyl ether and phenol, and the temperature II is 0-10 ℃.
- The method for recovering voriconazole enantiomers as claimed in any of claims 1 to 6, wherein the basic substance B is one or two of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, lithium hydroxide, sodium hydroxide and potassium hydroxide, the organic solvent B is one or two of toluene, dichloromethane and chloroform, and the pH value of the solution is 8 to 12.
- The method for recovering voriconazole enantiomers as claimed in any of claims 1 to 6, wherein the temperature III is 70 ℃ to 90 ℃ and the pressure is-0.085 MPa to-0.095 MPa.
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|---|---|---|---|---|
| WO2011096697A2 (en) * | 2010-02-04 | 2011-08-11 | Dongkook Pharmaceutical Co., Ltd. | Process for preparing voriconazole by using new intermediates |
| CN106117186A (en) * | 2016-06-12 | 2016-11-16 | 重庆莱美隆宇药业有限公司 | A kind of voriconazole and the preparation method of intermediate thereof |
| CN107827876A (en) * | 2017-10-27 | 2018-03-23 | 江苏理工学院 | A kind of preparation method of voriconazole raceme |
| CN109705102A (en) * | 2019-02-19 | 2019-05-03 | 浙江华海立诚药业有限公司 | The preparation method of voriconazole and its intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011096697A2 (en) * | 2010-02-04 | 2011-08-11 | Dongkook Pharmaceutical Co., Ltd. | Process for preparing voriconazole by using new intermediates |
| CN106117186A (en) * | 2016-06-12 | 2016-11-16 | 重庆莱美隆宇药业有限公司 | A kind of voriconazole and the preparation method of intermediate thereof |
| CN107827876A (en) * | 2017-10-27 | 2018-03-23 | 江苏理工学院 | A kind of preparation method of voriconazole raceme |
| CN109705102A (en) * | 2019-02-19 | 2019-05-03 | 浙江华海立诚药业有限公司 | The preparation method of voriconazole and its intermediate |
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| Title |
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| 段玺玉 等: "HPLC法测定伏立康唑冻干眼用制剂中的有关物质" * |
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