CN113354625B - Synthesis process of voriconazole - Google Patents
Synthesis process of voriconazole Download PDFInfo
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- CN113354625B CN113354625B CN202110666581.2A CN202110666581A CN113354625B CN 113354625 B CN113354625 B CN 113354625B CN 202110666581 A CN202110666581 A CN 202110666581A CN 113354625 B CN113354625 B CN 113354625B
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- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 title claims abstract description 53
- 229960004740 voriconazole Drugs 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000008569 process Effects 0.000 title claims abstract description 28
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 17
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 17
- BZYVJTMKMDGJRN-UHFFFAOYSA-N 2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol Chemical compound C=1C=C(F)C=C(F)C=1C(O)(CO)CN1C=NC=N1 BZYVJTMKMDGJRN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract description 4
- 239000002608 ionic liquid Substances 0.000 claims description 18
- -1 epoxypropane compound Chemical class 0.000 claims description 17
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011830 basic ionic liquid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical group [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 claims description 3
- 229910001950 potassium oxide Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- AYZDRTRWCASUFO-UHFFFAOYSA-N 4-ethyl-5-fluoropyrimidine Chemical compound CCC1=NC=NC=C1F AYZDRTRWCASUFO-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- AQZGPSLYZOOYQP-UHFFFAOYSA-N Diisoamyl ether Chemical compound CC(C)CCOCCC(C)C AQZGPSLYZOOYQP-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 229910052814 silicon oxide Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- JLYBWFXORSYMEO-UHFFFAOYSA-N 4-ethyl-2-fluoropyrimidine Chemical class CCC1=CC=NC(F)=N1 JLYBWFXORSYMEO-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006298 dechlorination reaction Methods 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 abstract description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000007810 chemical reaction solvent Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940121375 antifungal agent Drugs 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000000843 anti-fungal effect Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000011261 inert gas Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 2
- UIXQTZYZQHYHRL-UHFFFAOYSA-N 1-[[2-(2,4-difluorophenyl)oxiran-2-yl]methyl]-1,2,4-triazole Chemical compound FC1=CC(F)=CC=C1C1(CN2N=CN=C2)OC1 UIXQTZYZQHYHRL-UHFFFAOYSA-N 0.000 description 2
- BXIHJVDQQNZXBD-UHFFFAOYSA-N 4-(1-bromoethyl)-5-fluoropyrimidine Chemical compound CC(Br)C1=NC=NC=C1F BXIHJVDQQNZXBD-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- POEDHWVTLBLWDA-UHFFFAOYSA-N 1-butylindole-2,3-dione Chemical compound C1=CC=C2N(CCCC)C(=O)C(=O)C2=C1 POEDHWVTLBLWDA-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- FUJCRWPEOMXPAD-UHFFFAOYSA-N lithium oxide Chemical compound [Li+].[Li+].[O-2] FUJCRWPEOMXPAD-UHFFFAOYSA-N 0.000 description 1
- 229910001947 lithium oxide Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 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
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 229910021426 porous silicon Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 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
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- 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)
Abstract
The invention discloses a synthesis process of voriconazole bulk drug, comprising the following steps: preparing halogenated ethyl fluoro pyrimidine and carrying out Grignard reaction; oxidizing 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazol-1-yl) -1, 2-propanediol to obtain a glycidoxane compound; and mixing the Grignard reagent with a glycidoxane compound for reaction to obtain voriconazole. The synthesis process provided by the invention can simplify the reaction steps, does not need to use palladium carbon for dechlorination and hydrogenolysis, shortens the reaction period, saves energy consumption, reduces cost and obtains voriconazole and racemate thereof with higher yield.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a synthesis process of voriconazole bulk drug, and especially relates to preparation of voriconazole and racemate thereof.
Background
Voriconazole (VRC, UK 109496), which is chemically named (2 r,3 s) -2- (2, 4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol, is a novel antifungal agent synthesized by american-type febrile corporation on the basis of fluconazole and is mainly used in progressive, fatal-risk immunocompromised patients. The voriconazole sleep antifungal has wide antifungal spectrum, strong antibacterial efficacy and good safety, and the demand of antifungal drugs in the domestic market is rapidly increased, so the voriconazole sleep antifungal has great market prospect.
The existing method or process for synthesizing voriconazole generally takes 2R,3S/2S,3R racemate as a key intermediate, and uses specific chiral resolution reagents, such as 1R- (-) -10-camphorsulfonic acid, to obtain the voriconazole by salt formation resolution. However, the conventional processes for preparing voriconazole or an intermediate thereof generally have problems of low yield, low purity of the product, and the like.
Therefore, there is a need for a synthesis process of voriconazole bulk drug which is easy to operate, controllable in process, high in yield, high in purity, and suitable for industrial production, thereby preparing voriconazole and racemate thereof which meet the requirements.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a synthesis method process of voriconazole bulk drug or racemate thereof, which takes specific haloalkyl-fluoropyrimidine and difluorophenyl-triazolyl propylene glycol compounds as raw materials to prepare the voriconazole racemate in the presence of ionic liquid, thus obtaining the voriconazole racemate by synthesis.
In order to achieve the above object, in a first aspect, the present invention provides a method for preparing a voriconazole racemate, comprising:
step 1, preparing halogenated ethyl fluoro pyrimidine and carrying out Grignard reaction;
step 2, oxidizing 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazole-1-yl) -1, 2-propanediol to obtain an epoxypropane compound;
and step 3, mixing the Grignard reagent obtained in the step 1 with a glycidoxide compound, and reacting to obtain voriconazole.
In a second aspect, the present invention provides a voriconazole or racemate thereof, prepared synthetically by the process of the first aspect.
The synthesis process of voriconazole provided by the invention has the following beneficial effects:
(1) According to the invention, 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazole-1-yl) -1, 2-propanediol is used as a reaction raw material to directly generate the voriconazole racemate, so that the reaction steps can be simplified, palladium carbon is not required to be used for dechlorination and hydrogenolysis, the reaction period is shortened, the energy consumption can be saved, the cost can be reduced, and the yield of the voriconazole racemate can be improved;
(2) The post-treatment is washing and filtering, the operation is simple and convenient, and complex processes such as extraction and the like are not needed;
(3) The voriconazole racemate can be directly used for preparing voriconazole without further purification, so that the material cost and the time cost are saved, the purity of the obtained voriconazole is high, and the quality standard of the medicament is met;
(4) The method has the advantages of simple operation, high yield, high process safety, no need of introducing a large amount of auxiliary agents and solvents, energy conservation, environmental protection and the like, and is suitable for industrialization.
Drawings
FIG. 1 is a mass spectrum of voriconazole according to example 2 of the present invention.
Detailed Description
The following detailed description of the preferred embodiments of the invention is provided to enable those skilled in the art to more readily understand the advantages and features of the invention and to make a clear and concise definition of the scope of the invention.
According to a first aspect of the present invention there is provided a process for the synthesis of voriconazole, the process comprising the steps of:
step 1, preparing halogenated ethyl fluoro pyrimidine and carrying out Grignard reaction.
In the present invention, the halogenated ethyl fluoropyrimidine is preferably 4- (1-halogenated ethyl) -5-fluoropyrimidine, and the halogenated group may be any one of Cl-, br-, I-, preferably Br-. The 4- (1-bromoethyl) -5-fluoropyrimidine is commercially available, such as Hubei Yongku technology Co., ltd, or Hubei zifei pharmaceutical chemicals Co., ltd, and can be obtained by reacting low-cost and easily available 4-ethyl-5-fluoropyrimidine with a common brominating agent, such as N-bromosuccinimide (NBS).
According to the invention, 4- (1-halogenated ethyl) -5-fluoropyrimidine and magnesium metal undergo Grignard reaction to obtain magnesium halide Grignard reagent, and the reaction process is as follows:
in a preferred embodiment of the invention, in step 1, the magnesium metal used is magnesium turnings.
The inventors have found that the choice of magnesium is important. Because magnesium powder can lead the reaction to be violent, or an oxide film is easy to form on the surface of the magnesium powder to prevent the reaction from proceeding, and the magnesium powder is not easy to purify. Therefore, the invention selects magnesium chips as raw materials.
In a preferred embodiment of the invention, the magnesium turnings need to be pretreated before the reaction, comprising: firstly, washing magnesium chips with dilute acid, and carrying out suction filtration; washing with acetone, vacuum drying, wrapping with aluminum foil, and placing in N 2 Or under an inert gas.
In the present invention, the reaction solvent I used in step 1 is an ether and/or a tertiary amine, preferably, the ether is at least one selected from the group consisting of propyl ether, butyl ether, pentyl ether, isopropyl ether, isopentyl ether, anisole, phenetole, methyl tert-butyl ether, tetrahydrofuran and methyl tetrahydrofuran, and the tertiary amine is selected from the group consisting of N, N-dimethylaniline and/or pyridine. More preferably, the reaction solvent I is selected to be tetrahydrofuran and/or methyltetrahydrofuran, for example methyltetrahydrofuran.
Among them, methyltetrahydrofuran has a high boiling point (80 ℃) and can increase the reaction rate, fewer by-products are produced, and the loss during solvent condensation recovery is reduced. Methyl tetrahydrofuran has a lower solubility in water than tetrahydrofuran, and thus it is easier to include the grignard reagent therein separately, while recovering dried methyl tetrahydrofuran. In addition, methyltetrahydrofuran has clearer phase separation capability, so that methyltetrahydrofuran is preferably selected as the reaction solvent I.
Tetrahydrofuran has a boiling point of 66 ℃, which may produce dibenzyl as a by-product when used as a solvent, but the reaction is easily initiated. In the reaction, the reaction may be initiated with tetrahydrofuran followed by the addition of methyltetrahydrofuran.
Wherein, the reaction solvent I may be pretreated before the reaction. The pretreatment process is to add KOH into the reaction solvent I for drying for 3-5 days, and then to distill to obtain anhydrous reaction solvent I.
In a preferred embodiment of the invention, the molar ratio of 4- (1-haloethyl) -5-fluoropyrimidine to reaction solvent I is 1: (8-20), preferably 1: (10 to 16), more preferably 1:15.
According to the invention, when the molar ratio of 4- (1-haloethyl) -5-fluoropyrimidine to reaction solvent I is 1: in the case of (8-20), the production of by-product dibenzyl can be reduced by controlling the amount of the above-mentioned compound to be added.
Among these, the reaction temperature is critical for the preparation of grignard reagents. If the temperature is too high, a coupling reaction may occur, and if the temperature is too low, it may not be initiated. Thus, the reaction temperature is preferably 35 to 60 ℃, preferably 45 to 55 ℃, for example 50 ℃.
According to the present invention, the reaction can be optimized when the reaction temperature is 45 to 55 ℃.
Wherein, a trace amount of moisture can inhibit the initiation of the reaction and decompose the formed grignard reagent to affect the yield. Meanwhile, if no nitrogen or inert gas is adopted for replacement in the reaction vessel, a large amount of inflammable gas is generated by evaporation of the solvent in the reaction vessel, and the inflammable gas is mixed with air to form explosive mixed gas, so that the explosion is easy. Therefore, before the reaction proceeds, nitrogen or an inert gas such as helium, neon, argon, etc. is introduced into the reaction vessel to remove air from the reaction vessel so that the reaction proceeds under a nitrogen or inert gas atmosphere.
Illustratively, in step 1, the addition of a small amount of initiator may also be included in order to shorten the initiation time. Preferably, the initiator is selected from iodine or methylene chloride, for example by adding 1-2 particles of iodine.
And 2, oxidizing 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazole-1-yl) -1, 2-propanediol to obtain the epoxypropane compound.
In the present invention, the 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazol-1-yl) -1, 2-propanediol is commercially available, such as Guangzhou brand biotechnology limited or American QCC, and can be prepared according to the method of the document Keiji Tamura et al Journal of Organic Chemistry,2014,79 (7), 3272-3278.
The reaction process of the step is as follows:
in a preferred embodiment of the present invention, in step 2, the catalyst used is a supported catalyst, wherein the catalyst support is selected from at least one of alumina, silica, activated carbon and zeolite molecular sieves; the supporting substance is an alkali metal soluble salt or an alkali metal oxide, preferably at least one selected from lithium oxide, sodium oxide and potassium oxide.
Wherein, the methods for preparing the supported catalyst by different carriers and different supported substances are similar. Illustratively, the supported catalyst may be prepared as follows:
(1) Preparing an impregnating solution, preparing a solution of alkali metal soluble salt or alkali metal oxide with a certain concentration, for example 8-12 wt%;
(2) And (3) placing the carrier in impregnating solution, impregnating for a period of time (for example, 7-10 h), filtering, drying and roasting to obtain the supported catalyst.
In the present invention, the reaction is carried out by using the supported catalyst, and the side reaction possibly caused by the strong oxidizing agent can be avoided. The reaction can be carried out by using a small amount of supported catalyst, and the catalyst is cheap and easy to obtain, so that the reaction cost can be reduced.
Preferably, in step 2, the molar ratio of 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazol-1-yl) -1, 2-propanediol to supported catalyst is (2-10): 1, preferably (3 to 7): 1.
preferably, in step 2, the reaction temperature is 30 to 80 ℃, preferably 50 to 70 ℃; and/or the reaction pressure is-15 to 5MPa, preferably-5 to 2MPa.
In the present invention, the reaction temperature and the reaction pressure need to be kept within a range such that an epoxy compound is produced. If the reaction temperature is too high or the pressure is too high, the raw materials are easily oxidized further to obtain ketone compounds, and if the reaction temperature is too low or the pressure is too low, the reaction is not easy to proceed. In the present invention, the use of the supported catalyst in the above-described range results in a higher conversion of the raw material and fewer by-products.
And step 3, mixing the Grignard reagent obtained in the step 1 with the epoxypropane compound obtained in the step 2, and reacting to obtain voriconazole.
In a preferred embodiment of the present invention, step 3 may specifically comprise the following sub-steps:
and 3-1, dissolving the epoxypropane compound in the ionic liquid.
Preferably, the ionic liquid is an alkaline ionic liquid.
And step 3-2, dropwise adding the Grignard reagent obtained in the step 1, and reacting to obtain the voriconazole racemate.
The reaction process of the step is as follows:
wherein X represents any one of Cl-, br-, and I-.
According to the invention, the dropping speed should be slower, so that the Grignard reagent can be completely dissolved in the alkaline ionic liquid. Preferably, the drop velocity is 1 to 2 drops/s.
In the invention, in the alkaline ionic liquid, grignard reagent can form carbanion to attack carbon on epoxy with smaller steric hindrance in the epoxypropane compound, so that the epoxy can be opened to form the voriconazole racemate. Wherein the amount of voriconazole (2 r,3 s) -2- (2, 4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol can be controlled between 70 and 90%.
In a preferred embodiment of the invention, the basic ionic liquid is selected from a supported basic ionic liquid or a silica-supported basic ionic liquid. Specifically, the structural formula is represented as follows:
in the invention, the supported alkaline ionic liquid is preferably an alkaline ionic liquid supported by polystyrene resin.
In the invention, the silica branch-supported alkaline ionic liquid can be prepared according to the following process:
(1) Adding porous silicon dioxide into an acetone solution of polypropylene trimethoxysilane for reaction;
(2) Adding imidazole into the solution in the step 1 to react;
(3) And (3) adding sodium hydroxide into the solution obtained in the step (2) to react, and performing post-treatment to obtain the silica branch-supported alkaline ionic liquid.
According to the invention, the ionic liquid with the introduced basic functional group has higher catalytic activity than inorganic base or organic base and can be recycled. It makes asymmetric addition easier due to its molecular structure of larger size.
In a preferred embodiment of the present invention, the molar ratio of the epoxypropane compound to the basic ionic liquid is 1: (5-20).
According to the invention, the molar ratio of the epoxypropane compound to the alkaline ionic liquid is in a certain range, and if the molar ratio is smaller, the reaction speed is too high, and the ratio of voriconazole is reduced. If the molar ratio is large, the reaction speed is small, and the reaction time and the reaction cost are increased. In the present invention, when the molar ratio is 1: when (5-20), preferably (10-15), the yield of voriconazole is between 80 and 90%.
In the invention, the ionic liquid with the alkaline functional group is used as the alkaline catalyst, the reaction conversion rate is high, the condition is mild, the product is easy to separate, and the ionic liquid can be recycled.
In a preferred embodiment of the invention, the molar ratio of grignard reagent to the epoxypropane compound is 1: (1-3).
In the present invention, the molar amount of the epoxypropane compound is slightly larger, which is advantageous in that the whole addition of the Grignard reagent is enabled, and the solution of the Grignard reagent is gradually added dropwise, which enables the suitability of the reaction rate, thereby enabling the generated voriconazole to occupy a relatively large amount.
In the invention, the synthesis process further comprises the following steps: the voriconazole racemate is resolved to obtain voriconazole, and the resolving agent is preferably an optically active acid including, but not limited to, (+) -tartaric acid, (+) -camphoric acid, L- (+) -glycine or L-camphor-10-sulfonic acid and addition salts thereof.
According to a second aspect of the present invention there is provided voriconazole or a racemate thereof, obtainable by the synthesis process or method of the above first aspect.
For a further understanding of the present invention, voriconazole provided by the present invention is described below with reference to examples, the scope of the present invention not being limited by the following examples.
Example 1
In a flask equipped with a two-neck adapter, 4.8g of magnesium turnings were placed. The front opening of the interface is provided with a dropping funnel, and the side opening is provided with a reflux condensing pipe of a calcium chloride drying pipe. Dropwise adding a mixed solution of 0.2mol of 4- (1-bromoethyl) -5-fluoropyrimidine and 302mL of methyltetrahydrofuran into a bottle, and heating in a water bath at the temperature of 50 ℃ to obtain a methyltetrahydrofuran solution of a Grignard reagent;
weighing 0.2mol of 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazole-1-yl) -1, 2-propanediol and 0.05mol of potassium oxide-silica supported catalyst (wherein the supporting amount of potassium oxide is 12 wt%), wherein the reaction temperature is 65 ℃ and the reaction pressure is 2MPa; obtaining 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazol-1-yl) -1, 2-epoxypropane;
dissolving 0.1mol of the prepared 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazol-1-yl) -1, 2-epoxypropane in 1.2mol of silica branch-supported alkaline ionic liquid, dropwise adding 100mL of the prepared Grignard reagent methyltetrahydrofuran solution, and washing with acetone or ethanol for multiple times after the reaction is finished to obtain 32.8g of voriconazole racemate with the yield of 93.7%.
Example 2
0.05mol of the voriconazole racemate obtained in example 1 was dissolved in 73.7mL of acetone, and 13.9g of L- (-) -10-camphorsulfonic acid dissolved in 24mL of methanol was added thereto. Refluxing the obtained mixture for 1h, slowly cooling to room temperature, crystallizing, filtering and drying to obtain camphorsulfonate of voriconazole;
the camphorsulfonate salt of voriconazole was added to 100mL of a mixture of water and dichloromethane in a volume ratio of 1:1, and 40% sodium hydroxide solution was slowly added thereto, to adjust to ph=11-12. The organic layer was separated, dried, the organic solvent was removed under reduced pressure, crystallized with isopropyl alcohol, and dried to give 13.7g of voriconazole as white in 92% yield, and the mass spectrum of the obtained voriconazole was shown in fig. 1.
The invention has been described in detail in connection with the specific embodiments and exemplary examples thereof, but such description is not to be construed as limiting the invention. It will be understood by those skilled in the art that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, and these fall within the scope of the present invention.
Claims (8)
1. The synthesis process of voriconazole is characterized by comprising the following steps of:
step 1, preparing 4- (1-halogenated ethyl) -5-fluoropyrimidine, and carrying out Grignard reaction, wherein halogenated groups are any one of Cl-, br-and I-, and metal used in the Grignard reaction is magnesium;
step 2, oxidizing 2- (2, 4-difluorophenyl) -3- (1, 2, 4-triazole-1-yl) -1, 2-propanediol, and obtaining a glycidoxane compound by using a supported catalyst, wherein the used carrier is silicon oxide and the supported substance is potassium oxide;
step 3, mixing the Grignard reagent obtained in the step 1 with the epoxypropane compound, and reacting to obtain voriconazole;
step 3 comprises the following sub-steps:
step 3-1, dissolving the epoxypropane compound in an ionic liquid, wherein the ionic liquid is silica branch-supported alkaline ionic liquid,
step 3-2, dropwise adding the Grignard reagent obtained in step 1, wherein the molar ratio of the Grignard reagent to the epoxypropane compound is 1: (1-3) reacting to obtain voriconazole raceme, and splitting the voriconazole raceme to obtain voriconazole.
2. The synthesis process according to claim 1, wherein, in step 1,
the 4- (1-halogenated ethyl) -5-fluoropyrimidine is obtained by reacting 4-ethyl-5-fluoropyrimidine with NBS;
the magnesium metal is magnesium scraps and is pretreated.
3. The synthesis process according to claim 1, wherein, in step 1,
the solvent I is ethers and/or tertiary amines, the solvent I is pretreated before the reaction,
the reaction temperature is 35-60 ℃, and an initiator is added in the reaction.
4. A synthesis process according to claim 3, wherein, in step 1,
the solvent I is selected from at least one of propyl ether, butyl ether, amyl ether, isopropyl ether, isoamyl ether, anisole, phenetole, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran, N-dimethylaniline and pyridine,
the reaction temperature is 45-55 ℃.
5. The synthesis process according to any one of claims 1 to 4, wherein in step 2, the reaction temperature is 30 to 80 ℃; and/or
The reaction pressure is-15-5 MPa.
6. The synthesis process according to claim 5, wherein in step 2, the reaction temperature is 50-70 ℃; and/or
The reaction pressure is-5-2 MPa.
7. The synthesis process according to claim 1, wherein the molar ratio of the epoxypropane compound to the basic ionic liquid is 1: (5-20).
8. The synthetic process of claim 1 wherein the resolving agent is (+) -tartaric acid, (+) -camphoric acid, L- (+) -glycine or L-camphor-10-sulfonic acid and addition salts thereof.
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| CN101773822A (en) * | 2009-01-14 | 2010-07-14 | 中国科学院大连化学物理研究所 | Catalyst used in preparation of propylene epoxide by utilizing 1,2-propylene glycol gas dehydration and application |
| JP2015059086A (en) * | 2013-09-17 | 2015-03-30 | 公益財団法人微生物化学研究会 | Compound and method for manufacturing the same, and method for manufacturing voriconazole |
| CN106432198A (en) * | 2016-09-08 | 2017-02-22 | 浙江华海药业股份有限公司 | Method for preparing voriconazole resolution intermediate |
| CN111018839A (en) * | 2019-12-02 | 2020-04-17 | 中国人民解放军第二军医大学 | Triazole alcohol derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101773822A (en) * | 2009-01-14 | 2010-07-14 | 中国科学院大连化学物理研究所 | Catalyst used in preparation of propylene epoxide by utilizing 1,2-propylene glycol gas dehydration and application |
| JP2015059086A (en) * | 2013-09-17 | 2015-03-30 | 公益財団法人微生物化学研究会 | Compound and method for manufacturing the same, and method for manufacturing voriconazole |
| CN106432198A (en) * | 2016-09-08 | 2017-02-22 | 浙江华海药业股份有限公司 | Method for preparing voriconazole resolution intermediate |
| CN111018839A (en) * | 2019-12-02 | 2020-04-17 | 中国人民解放军第二军医大学 | Triazole alcohol derivative and preparation method and application thereof |
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