CN117777109A - Preparation method of voriconazole and intermediate thereof - Google Patents
Preparation method of voriconazole and intermediate thereof Download PDFInfo
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- CN117777109A CN117777109A CN202410006618.2A CN202410006618A CN117777109A CN 117777109 A CN117777109 A CN 117777109A CN 202410006618 A CN202410006618 A CN 202410006618A CN 117777109 A CN117777109 A CN 117777109A
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- 229960004740 voriconazole Drugs 0.000 title claims abstract description 57
- 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 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000010992 reflux Methods 0.000 claims abstract description 24
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003960 organic solvent Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 17
- 239000000725 suspension Substances 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 54
- 239000000543 intermediate Substances 0.000 claims description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 27
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 8
- 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 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 2
- 238000006298 dechlorination reaction Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims 1
- 239000002516 radical scavenger Substances 0.000 claims 1
- 239000002841 Lewis acid Substances 0.000 abstract description 6
- 150000007517 lewis acids Chemical class 0.000 abstract description 6
- 239000011701 zinc Substances 0.000 abstract description 6
- 229910052725 zinc Inorganic materials 0.000 abstract description 6
- 239000000010 aprotic solvent Substances 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 4
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- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 2
- 239000003999 initiator Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 238000001914 filtration Methods 0.000 description 17
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- 239000012074 organic phase Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 9
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- 238000002425 crystallisation Methods 0.000 description 7
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- XCHRPVARHBCFMJ-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone Chemical compound FC1=CC(F)=CC=C1C(=O)CN1N=CN=C1 XCHRPVARHBCFMJ-UHFFFAOYSA-N 0.000 description 6
- AAESVRBYUDTWKH-UHFFFAOYSA-N 4-(1-bromoethyl)-6-chloro-5-fluoropyrimidine Chemical compound CC(Br)C1=NC=NC(Cl)=C1F AAESVRBYUDTWKH-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
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- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
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- 239000007864 aqueous solution Substances 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 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 4
- WABPQHHGFIMREM-UHFFFAOYSA-N lead(0) Chemical compound [Pb] WABPQHHGFIMREM-UHFFFAOYSA-N 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 3
- 229960004884 fluconazole Drugs 0.000 description 3
- 239000011133 lead Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- PEUPUKDBCPLDIH-UHFFFAOYSA-N 1,2,4-triazole Chemical group C1=NC=N[N]1 PEUPUKDBCPLDIH-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- WAVYAFBQOXCGSZ-UHFFFAOYSA-N 2-fluoropyrimidine Chemical group FC1=NC=CC=N1 WAVYAFBQOXCGSZ-UHFFFAOYSA-N 0.000 description 1
- APSSAJKZELMQNM-UHFFFAOYSA-N 4-chloro-5-fluoropyrimidine Chemical compound FC1=CN=CN=C1Cl APSSAJKZELMQNM-UHFFFAOYSA-N 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
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- 229960004130 itraconazole Drugs 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
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- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of voriconazole and an intermediate thereof. The preparation method of the voriconazole intermediate II comprises the following steps: mixing zinc powder, trimethyl halosilane and an aprotic organic solvent to obtain a suspension, and heating to reflux; dripping 1, 2-dibromoethane into the suspension to carry out reflux reaction to obtain reaction liquid; and then sequentially adding a compound shown in a formula III and a compound shown in a formula IV for reaction to prepare the voriconazole intermediate II or the acid addition salt thereof. The invention uses trimethyl halosilane to remove water from aprotic solvent, and simultaneously activates zinc powder, thereby avoiding the use of highly toxic heavy metal lead. In addition, 1, 2-dibromoethane is used as an organic zinc reagent to prepare an initiator, so that the problems that the aprotic solvent required by the reaction cannot be directly used due to overhigh water content, and the reaction system is overhigh in water content due to easiness in moisture absorption of Lewis acid, so that the reaction is stopped and the like are solved. The method has high safety and is more suitable for industrial application.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of voriconazole and an intermediate thereof.
Background
Voriconazole (voriconazole) is a novel triazole antifungal agent developed by the institute of the american society of pyroxene, a structurally similar product of fluconazole, which differs from fluconazole mainly in that a methyl group is introduced into the propyl skeleton of the fluconazole structure, and a triazole ring is replaced with a fluoropyrimidine ring. In a comparative experiment of in vitro antimicrobial yeasts and aspergillus, the antimicrobial activity of voriconazole against most yeast-specific bacteria was the same as itraconazole, similar to amphotericin B, and superior to that of fluconazole. Meanwhile, voriconazole has wider antibacterial spectrum and better safety, and particularly has good curative effect on invasive aspergillus infiltration infection. Voriconazole is clinically used mainly for treating candida infections of deep subcutaneous tissue and abdomen, kidneys, bladder wall and wounds. The characteristics of high efficiency and low toxicity lead the voriconazole to have great economic value and market prospect.
The chemical name of voriconazole is (2R, 3S) -2- (2, 4-difluorophenyl) -3- (5-fluoro-4-pyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol, and the structural formula is shown in formula I.
The voriconazole intermediate II is a key intermediate of voriconazole, and has the chemical name of (2R, 3S/2S, 3R) -2- (2, 4-difluorophenyl) -3- (4-chloro-5-fluoropyrimidine) -1- (1H-1, 2, 4-triazole-1-yl) -2-butanoic acid hydrochloride, and the structural formula is shown in the formula II.
The current synthesis method of voriconazole intermediate II mainly adopts 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazole-1-yl) ethanone with a structural formula shown in III and 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine with a structural formula shown in IV to react in the presence of metallic zinc, lead, iodine or Lewis acid and aprotic organic solvent. The reaction mechanism is that zinc powder reacts with a compound shown in a formula IV to form an organic zinc reagent, and then the organic zinc reagent reacts with a compound shown in a formula III. The compounds of formula III and formula IV can be prepared from commercially available raw materials or by methods disclosed in the prior art.
However, this preparation method has certain drawbacks, such as: 1) Zinc powder is easy to oxidize when in contact with air, and the problems of initiation and activation exist in the process of preparing zinc reagent. In the method disclosed by the prior art, most of activated zinc powder relates to lead powder, lead is a highly toxic metal element, the preparation process of the raw material medicine is strictly controlled, the lead powder is used in the process, and the finished product has the risk of exceeding heavy metal standard, so that the method is not beneficial to large-scale industrial production. 2) The aprotic solvent required for the reaction often has the problem that the aprotic solvent cannot be directly used due to too high moisture and needs to be dried additionally. Meanwhile, iodine or Lewis acid is needed to be added as a reaction catalyst, and the Lewis acid commonly used in the reaction often causes overhigh water content of a reaction system due to easy moisture absorption, so that the reaction is stopped.
Therefore, there is a need to develop new methods to overcome the above-mentioned drawbacks of the prior art and to further synthesize high quality voriconazole intermediates ii and voriconazole.
Disclosure of Invention
In view of the above, one of the purposes of the present invention is to provide a preparation method of voriconazole intermediate ii or an acid addition salt thereof, wherein the present invention uses an excessive amount of trimethylhalosilane to remove water from an aprotic solvent, and hydrogen chloride generated by the solvent can activate zinc powder at the same time, thereby avoiding the use of lead powder and eliminating the risk of residue of highly toxic metals in a drug; meanwhile, 1, 2-dibromoethane is used as an organic zinc reagent to prepare an initiator, so that the use of Lewis acid is avoided. The invention provides technical support for the subsequent preparation of high-quality voriconazole.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the preparation method of the voriconazole intermediate II or the acid addition salt thereof comprises the steps of taking a compound shown in a formula III and a compound shown in a formula IV as raw materials, adopting an aprotic organic solvent as a solvent, and preparing the voriconazole intermediate II or the acid addition salt thereof under the action of zinc powder, trimethylhalosilane and 1, 2-dibromoethane; the trimethyl halosilane is used for removing water from the aprotic organic solvent and activating the zinc powder; the structural formula of the voriconazole intermediate II is shown in a formula II;
further, the method specifically comprises the following steps:
(1) Mixing the zinc powder, the trimethyl halosilane and the aprotic organic solvent to obtain a suspension, and heating to reflux;
(2) Dripping the 1, 2-dibromoethane into the suspension prepared in the step (1) to perform reflux reaction to obtain a reaction solution;
(3) Mixing the compound shown in the formula III with the aprotic organic solvent, adding the mixture into the reaction liquid obtained in the step (2), and stirring at a high speed to form a complex;
(4) And (3) mixing the compound shown in the formula IV with the aprotic organic solvent, and then adding the mixture into the complex obtained in the step (3) to react to obtain the voriconazole intermediate II or the acid addition salt thereof.
Further, the trimethylhalosilane comprises any one or more of trimethylchlorosilane, trimethylbromosilane and trimethyliodosilane.
Preferably, the trimethylhalosilane is trimethylchlorosilane.
Further, the aprotic organic solvent includes C 2 -C 10 Any one or more of a substituted or unsubstituted ether solvent, an alkane solvent, and an aromatic hydrocarbon solvent.
Preferably, the aprotic organic solvent is tetrahydrofuran
Further, the weight ratio of the trimethylhalosilane to the compound of formula III is 0.02-0.1:1, preferably 0.03-0.05:1, a step of; the molar ratio of the zinc powder to the 1, 2-dibromoethane to the compound shown in the formula III is 2.5-5.5:0.4-2.4:1, preferably 3.0-3.5:1.2-1.6:1.
further, in the step (2), 1, 2-dibromoethane and an aprotic organic solvent are prepared according to a mass ratio of 50-100:100 to obtain a mixed solution; and (3) dripping the mixed solution into the suspension prepared in the step (1) for reflux reaction. Preferably, the mass ratio of the 1, 2-dibromoethane to the aprotic organic solvent is 60-90:100.
Further, in the step (2), the reflux reaction time is 0.5 to 2 hours, more preferably 1 hour.
Further, in the step (3), the mass ratio of the compound represented by the formula III to the aprotic organic solvent is 1:4-8, preferably 7:40.
further, in the step (4), the mass ratio of the compound shown in the formula IV to the aprotic organic solvent is 0.8-1:1, preferably 0.95:1.
further, in the step (4), the reaction temperature is-20 ℃ to 50 ℃, preferably-10 ℃ to-5 ℃; the reaction time is 0.4h to 1h, preferably 0.5h.
Further, in the step (4), a 50% glacial acetic acid aqueous solution is used for quenching reaction.
Further, the voriconazole intermediate ii may be converted into its acid addition salt using any conventional method in the art.
Further, step (4) further comprises step (5): refining.
Further, the step (5) specifically comprises: filtering and concentrating the product under reduced pressure; adding dichloromethane and water into the concentrated residue, and adding ammonia water to adjust the pH of the system; separating liquid and collecting an organic phase; extracting the water phase with dichloromethane; combining the organic phases; concentrating under reduced pressure, dissolving the concentrated residue with acetone, adding hydrochloric acid at 40-45deg.C to form salt, cooling for crystallization, filtering, and vacuum drying to obtain voriconazole intermediate II or its acid addition salt.
The second object of the present invention is to provide a process for preparing the compound of formula V.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the preparation method of the compound shown in the formula V comprises the following steps:
(1) Preparing a voriconazole intermediate II or an acid addition salt thereof by adopting the method;
(2) The voriconazole intermediate II or acid addition salt thereof is subjected to hydrogenation dechlorination to prepare a compound shown in a formula V;
further, the step (2) specifically comprises:
adding dichloromethane and water into the voriconazole intermediate II or acid addition salt thereof, stirring and dissolving, adding sodium hydroxide to adjust the pH of a system to 10-11, performing liquid-separating extraction, concentrating under reduced pressure, and adding 95% ethanol for dissolving; adding anhydrous sodium acetate and wet palladium carbon into a hydrogenation kettle; 3 times of nitrogen replacement, pressurizing to 0.2MPa, and maintaining the pressure for 30min; replacing nitrogen with hydrogen for three times, pressurizing the hydrogen to 0.2MPa, controlling the temperature in the kettle to be 30-35 ℃, and stirring and reacting for 3-4h until the pressure in the kettle is unchanged for 30 min. Discharging and refining to obtain the compound shown in the formula V.
Further, the wet palladium carbon is 5% wet palladium carbon.
Further, the voriconazole intermediate ii or an acid addition salt thereof, methylene chloride and water have a mass ratio of 1:3.4-4.5:1.5-2.2, preferably 1:4:2.
further, the mass ratio of the voriconazole intermediate II or the acid addition salt thereof, the anhydrous sodium acetate and the wet palladium carbon is 1:0.2-0.3:0.04-0.06, preferably 1:0.25:0.05.
Further, in the hydrogen substitution process, if the pressure is reduced to 0.1MPa, the pressure is increased to 0.2MPa again.
The invention further aims to provide a preparation method of voriconazole.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the preparation method of voriconazole comprises the following steps:
(1) Preparing a compound shown in a formula V by adopting the method;
(2) Resolving the compound shown in the formula V by adopting L-camphorsulfonic acid to obtain a compound shown in the formula VI; the compound shown in the formula VI is subjected to alkali regulation and free recrystallization to prepare the voriconazole;
further, the chemical name of the compound of formula VI is (2R, 3S) -2- (2, 4-difluorophenyl) -3- (5-fluoro-4-pyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol levo-camphorsulfonate.
Further, the mass ratio of the compound represented by formula V to the L-camphorsulfonic acid is 1:0.7-1.0, preferably 1:0.77.
further, in the step (2), the reaction solvent is acetone and methanol.
Further, the mass ratio of the compound shown in the formula V, acetone and methanol is 25-35:8-12:1, preferably 30:10:1.
further, the step (2) is specifically as follows:
adding acetone and methanol into the compound shown in formula V, stirring and dissolving, adding L-camphorsulfonic acid, heating to reflux, refluxing for 30min, cooling to 30deg.C, maintaining the temperature and stirring for 1h, slowly cooling to 0-5deg.C, maintaining the temperature and crystallizing for 3h. Filtering, washing a filter cake with acetone, and vacuum drying to obtain a compound shown in a formula VI; dissolving the compound shown in the formula VI in dichloromethane, regulating the pH to 10-11, separating liquid, collecting an organic phase, concentrating under reduced pressure, adding isopropanol into concentrated residues, heating to reflux and stirring for 30min, slowly cooling to-5-0 ℃, preserving heat and crystallizing, filtering, and vacuum drying a filter cake to obtain voriconazole.
Further, in step (2), the base is preferably sodium hydroxide solution.
The invention aims at providing an application of trimethyl halosilane as a water removing agent and/or a zinc powder activating agent in preparation of voriconazole and intermediates thereof.
The invention has the beneficial effects that:
1. the invention provides a novel synthesis method of voriconazole and an intermediate thereof, which uses excessive trimethyl halosilane to remove water from aprotic organic solvent, and hydrogen chloride generated by the method can activate zinc powder at the same time, thereby avoiding using lead powder, eliminating the residual risk of highly toxic metal in medicines and having extremely high industrial application.
2. The invention uses 1, 2-dibromoethane to initiate the reaction, thereby avoiding the problem that the excessive water content of the system can cause the termination of the reaction due to the additional addition of Lewis acid.
3. The voriconazole and the intermediate thereof prepared by the method have higher yield and purity, and especially the final prepared voriconazole liquid phase purity can reach 100 percent.
Drawings
Figure 1 is a synthetic route diagram of voriconazole.
Detailed Description
The technical scheme of the present invention will be further clearly and completely described in connection with specific embodiments. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. Therefore, all other embodiments obtained by those skilled in the art without undue burden are within the scope of the invention based on the embodiments of the present invention.
In the embodiment of the invention, voriconazole and an intermediate thereof are prepared according to a synthetic route shown in fig. 1.
EXAMPLE 1 preparation of voriconazole intermediate II
Under the protection of nitrogen, 70g of zinc powder, 180g of tetrahydrofuran and 2.1g of trimethylchlorosilane are added into a clean and dry three-port bottle, the mixture is stirred at a high speed to form a suspension, and the temperature is raised to reflux. Slowly dripping a solution of 1, 2-dibromoethane/tetrahydrofuran prepared from 80g of 1, 2-dibromoethane and 100g of tetrahydrofuran, generating a large amount of bubbles in the reaction solution, continuously refluxing for 1H after the reaction is finished, cooling the system to 20 ℃, adding a solution prepared from 70g of 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazol-1-yl) ethanone and 400g of tetrahydrofuran, and stirring at a high speed to form a complex. A solution prepared from 95g of 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise at 15-20 ℃. After the dripping is finished, the reaction is carried out for 0.5H at 15-20 ℃, 42g of 50% glacial acetic acid aqueous solution is added for quenching reaction, filtration and reduced pressure concentration are carried out, 600g of dichloromethane and 200g of water are added into concentrated residues, ammonia water is added for regulating the pH value of the system to 10-11, liquid separation is carried out, organic phases are collected, aqueous phases are extracted by 200g of dichloromethane, organic phases are combined, after reduced pressure concentration, 390g of acetone is added into concentrated residues for dissolving, hydrochloric acid is added into the concentrated residues at 40-45 ℃ for forming salt, cooling crystallization is carried out, filtration and vacuum drying are carried out, thus obtaining 86.2g of (2R, 3S/2S, 3R) -2- (2, 4-difluorophenyl) -3- (4-chloro-5-fluoropyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol hydrochloride with the yield of 65.3%, and the liquid phase purity of 95.6%.
EXAMPLE 2 preparation of voriconazole intermediate II
Under the protection of nitrogen, 70g of zinc powder, 180g of tetrahydrofuran and 2.1g of trimethylchlorosilane are added into a clean and dry three-port bottle, the mixture is stirred at a high speed to form a suspension, and the temperature is raised to reflux. Slowly dripping a solution of 1, 2-dibromoethane/tetrahydrofuran prepared from 80g of 1, 2-dibromoethane and 100g of tetrahydrofuran, generating a large amount of bubbles in the reaction solution, continuously refluxing for 1H after the reaction is finished, cooling the system to 20 ℃, adding a solution prepared from 70g of 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazol-1-yl) ethanone and 400g of tetrahydrofuran, and stirring at a high speed to form a complex. A solution prepared from 95g of 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise at a reaction temperature of-10 to-5 ℃. After the dripping is finished, carrying out heat preservation reaction for 0.5H at the temperature of minus 10 ℃ to minus 5 ℃, adding 42g of 50% glacial acetic acid aqueous solution for quenching reaction, filtering, concentrating under reduced pressure, adding 600g of dichloromethane and 200g of water into concentrated residues, adding ammonia water to adjust the pH value of a system to 10-11, separating liquid, collecting organic phases, extracting aqueous phases by 200g of dichloromethane, combining the organic phases, concentrating under reduced pressure, adding 390g of acetone into concentrated residues for dissolving, adding hydrochloric acid at the temperature of 40-45 ℃ for salifying, cooling for crystallization, filtering, and carrying out vacuum drying to obtain 97.2g of (2R, 3S/2S, 3R) -2- (2, 4-difluorophenyl) -3- (4-chloro-5-fluoropyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol hydrochloride, wherein the yield is 73.6%, and the liquid phase purity is 97.2%.
EXAMPLE 3 preparation of voriconazole intermediate II
Under the protection of nitrogen, 70g of zinc powder, 180g of tetrahydrofuran and 1.4g of trimethylchlorosilane are added into a clean and dry three-port bottle, the mixture is stirred at a high speed to form a suspension, and the temperature is raised to reflux. Slowly dripping a solution of 1, 2-dibromoethane/tetrahydrofuran prepared from 80g of 1, 2-dibromoethane and 100g of tetrahydrofuran, generating a large amount of bubbles in the reaction solution, continuously refluxing for 1H after the reaction is finished, cooling the system to 20 ℃, adding a solution prepared from 70g of 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazol-1-yl) ethanone and 400g of tetrahydrofuran, and stirring at a high speed to form a complex. A solution prepared from 95g of 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise at 15-20 ℃. After the dripping is finished, the reaction is carried out for 0.5H at 15-20 ℃, 42g of 50% glacial acetic acid aqueous solution is added for quenching reaction, filtration and reduced pressure concentration are carried out, 600g of dichloromethane and 200g of water are added into concentrated residues, ammonia water is added for regulating the pH value of the system to 10-11, liquid separation is carried out, organic phases are collected, aqueous phases are extracted by 200g of dichloromethane, organic phases are combined, after reduced pressure concentration, 390g of acetone is added into concentrated residues for dissolving, hydrochloric acid is added into the concentrated residues at 40-45 ℃ for forming salt, cooling crystallization is carried out, filtration and vacuum drying are carried out, thus obtaining 84.8g of (2R, 3S/2S, 3R) -2- (2, 4-difluorophenyl) -3- (4-chloro-5-fluoropyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol hydrochloride, the yield is 64.2%, and the liquid phase purity is 94.6%.
EXAMPLE 4 preparation of voriconazole intermediate II
54g of zinc powder, 180g of tetrahydrofuran and 1.4g of trimethylchlorosilane are added into a clean and dry three-port bottle under the protection of nitrogen, the mixture is stirred at a high speed to form a suspension, and the suspension is heated to reflux. Slowly dripping a solution of 1, 2-dibromoethane/tetrahydrofuran prepared from 60g of 1, 2-dibromoethane and 100g of tetrahydrofuran, generating a large amount of bubbles in the reaction solution, continuously refluxing for 1H after the reaction is finished, cooling the system to 20 ℃, adding a solution prepared from 70g of 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazol-1-yl) ethanone and 400g of tetrahydrofuran, and stirring at a high speed to form a complex. A solution prepared from 95g of 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise at 15-20 ℃. After the dripping is finished, the reaction is carried out for 0.5H at 15-20 ℃, 42g of 50% glacial acetic acid aqueous solution is added for quenching reaction, filtration and reduced pressure concentration are carried out, 600g of dichloromethane and 200g of water are added into concentrated residues, ammonia water is added for regulating the pH value of the system to 10-11, liquid separation is carried out, organic phases are collected, aqueous phases are extracted by 200g of dichloromethane, organic phases are combined, after reduced pressure concentration, 390g of acetone is added into concentrated residues for dissolving, hydrochloric acid is added into the concentrated residues at 40-45 ℃ for forming salt, cooling crystallization is carried out, filtration and vacuum drying are carried out, thus obtaining 70.3g of (2R, 3S/2S, 3R) -2- (2, 4-difluorophenyl) -3- (4-chloro-5-fluoropyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol hydrochloride with the yield of 53.2%, and the liquid phase purity of 92.3%.
EXAMPLE 5 preparation of voriconazole intermediate II
Under the protection of nitrogen, 80g of zinc powder, 180g of tetrahydrofuran and 1.4g of trimethylchlorosilane are added into a clean and dry three-port bottle, the mixture is stirred at a high speed to form a suspension, and the temperature is raised to reflux. Slowly dripping a solution of 1, 2-dibromoethane/tetrahydrofuran prepared from 90g of 1, 2-dibromoethane and 100g of tetrahydrofuran, generating a large amount of bubbles in the reaction solution, continuously refluxing for 1H after the reaction is finished, cooling the system to 20 ℃, adding a solution prepared from 70g of 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazol-1-yl) ethanone and 400g of tetrahydrofuran, and stirring at a high speed to form a complex. A solution prepared from 95g of 4- (1-bromoethyl) -5-fluoro-6-chloropyrimidine and 100g of tetrahydrofuran was slowly added dropwise at a reaction temperature of-10 to-5 ℃. After the dripping is finished, carrying out heat preservation reaction for 0.5H at the temperature of minus 10 ℃ to minus 5 ℃, adding 42g of 50% glacial acetic acid aqueous solution for quenching reaction, filtering, concentrating under reduced pressure, adding 600g of dichloromethane and 200g of water into concentrated residues, adding ammonia water to adjust the pH value of a system to 10-11, separating liquid, collecting organic phases, extracting aqueous phases by 200g of dichloromethane, combining the organic phases, concentrating under reduced pressure, adding 390g of acetone into concentrated residues for dissolving, adding hydrochloric acid at the temperature of 40-45 ℃ for salifying, cooling for crystallization, filtering, and vacuum drying to obtain (2R, 3S/2S, 3R) -2- (2, 4-difluorophenyl) -3- (4-chloro-5-fluoropyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol hydrochloride (92.7 g, yield 70.2%), wherein the liquid phase purity is 96.8%.
EXAMPLE 6 preparation of the Compound of formula V
160g of dichloromethane, 80g of water and 40g of compound of formula II are added into a three-port bottle, stirred and dissolved, sodium hydroxide is added to adjust the pH of the system to 10-11, the solution is separated, the organic phase is collected, the aqueous phase is extracted with 120g of dichloromethane, and the organic phases are combined. Concentrating under reduced pressure, dissolving the concentrated residue with 120g of 95% ethanol, transferring to a hydrogenation kettle, adding 10g of anhydrous sodium acetate and 2g of 5% wet palladium on charcoal, replacing the reaction kettle with nitrogen for 3 times, pressurizing the nitrogen to 0.2MPa for 30min, maintaining the pressure for 30min, replacing the nitrogen with hydrogen for three times after no pressure change, pressurizing the hydrogen to 0.2MPa, controlling the temperature in the kettle to 30-35 ℃, stirring and reacting for 3-4h until the pressure in the kettle is unchanged (pressurizing to 0.2MPa again when the pressure is reduced to 0.1MPa in the reaction process). Discharging, concentrating under reduced pressure to dryness, adding 140g of water, pulping, filtering to obtain a crude product of the compound formula V, adding 40g of isopropanol into the crude product, heating to reflux, stirring for 30min, slowly cooling to-5-0 ℃, preserving heat, crystallizing for 2h, filtering, and vacuum drying a filter cake to obtain 29.4g of the compound formula V, wherein the yield is 88.2%, and the liquid phase purity is 99.9%.
EXAMPLE 7 preparation of voriconazole
600g of acetone, 200g of methanol and 20g of a compound shown in formula V are added into a three-port bottle, 15.4g of L-camphorsulfonic acid is added after stirring and dissolving, the mixture is heated to reflux for 30min, and the mixture is cooled to 30 ℃ for 1h, then cooled to 0-5 ℃ for heat preservation and crystallization for 3h. The mixture was filtered, and the filter cake was washed with acetone and dried in vacuo to give 15.9g of (2R, 3S) -2- (2, 4-difluorophenyl) -3- (5-fluoro-4-pyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol levo-camphorsulfonate in a yield of 47.7%. Dissolving the prepared (2R, 3S) -2- (2, 4-difluorophenyl) -3- (5-fluoro-4-pyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol levo camphorsulfonate in 110g of methylene dichloride, adding sodium hydroxide solution to adjust the pH of a system to 10-11, analyzing the solution, collecting an organic phase, concentrating under reduced pressure, adding 20g of isopropanol into the concentrated residue, heating to reflux and stirring for 30min, slowly cooling to-5-0 ℃, preserving heat and crystallizing for 2H, filtering, and drying a filter cake in vacuum to obtain 8.5g of voriconazole, wherein the yield is 88.7%, and the liquid phase purity is 100.0%.
Claims (10)
1. The preparation method of the voriconazole intermediate II or the acid addition salt thereof is characterized in that the compound shown in the formula III and the compound shown in the formula IV are used as raw materials, an aprotic organic solvent is used as a solvent, and the voriconazole intermediate II or the acid addition salt thereof is prepared under the action of zinc powder, trimethylhalosilane and 1, 2-dibromoethane; the trimethyl halosilane is used for removing water from the aprotic organic solvent and activating the zinc powder; the structural formula of the voriconazole intermediate II is shown in a formula II;
2. the method according to claim 1, characterized in that it comprises in particular the following steps:
(1) Mixing the zinc powder, the trimethyl halosilane and the aprotic organic solvent to obtain a suspension, and heating to reflux;
(2) Dripping the 1, 2-dibromoethane into the suspension prepared in the step (1) to perform reflux reaction to obtain a reaction solution;
(3) Mixing the compound shown in the formula III with the aprotic organic solvent, adding the mixture into the reaction liquid obtained in the step (2), and stirring at a high speed to form a complex;
(4) And (3) mixing the compound shown in the formula IV with the aprotic organic solvent, and then adding the mixture into the complex obtained in the step (3) to react to obtain the voriconazole intermediate II or the acid addition salt thereof.
3. The method of claim 1, wherein the trimethylhalosilane comprises any one or more of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane.
4. The method according to claim 1, wherein the aprotic organic solvent comprises C 2 -C 10 Any one or more of a substituted or unsubstituted ether solvent, an alkane solvent, and an aromatic hydrocarbon solvent.
5. The method according to claim 4, wherein the aprotic organic solvent is tetrahydrofuran.
6. The method according to claim 1, wherein the weight ratio of trimethylhalosilane to the compound of formula iii is from 0.02 to 0.1:1, a step of; the molar ratio of the zinc powder to the 1, 2-dibromoethane to the compound shown in the formula III is 2.5-5.5:0.4-2.4:1.
7. the method according to claim 2, wherein in step (4), the reaction temperature is-20 ℃ to 50 ℃; the reaction time is 0.4h-1h.
8. The preparation method of the compound shown in the formula V is characterized by comprising the following steps:
(1) Preparing voriconazole intermediate ii or an acid addition salt thereof by the method of claim 1;
(2) The voriconazole intermediate II or acid addition salt thereof is subjected to hydrogenation dechlorination to prepare a compound shown in a formula V;
9. the preparation method of voriconazole is characterized by comprising the following steps:
(1) Preparing a compound of formula v by the process of claim 9;
(2) Resolving the compound shown in the formula V by adopting L-camphorsulfonic acid to obtain a compound shown in the formula VI; the compound shown in the formula VI is subjected to alkali regulation and free recrystallization to prepare the voriconazole;
10. use of the trimethylhalosilane of claim 1 as a water scavenger and/or zinc powder activator in the preparation of voriconazole and intermediates thereof.
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