CN115536643A - Preparation method of key intermediate of isavuconazole medicine - Google Patents
Preparation method of key intermediate of isavuconazole medicine Download PDFInfo
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- CN115536643A CN115536643A CN202211545335.2A CN202211545335A CN115536643A CN 115536643 A CN115536643 A CN 115536643A CN 202211545335 A CN202211545335 A CN 202211545335A CN 115536643 A CN115536643 A CN 115536643A
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- isavuconazole
- triazole
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 title claims abstract description 24
- 229960000788 isavuconazole Drugs 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 19
- 239000000543 intermediate Substances 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 14
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 11
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 8
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 4
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- -1 S1A compound Chemical class 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- PEUPUKDBCPLDIH-UHFFFAOYSA-N 1,2,4-triazole Chemical group C1=NC=N[N]1 PEUPUKDBCPLDIH-UHFFFAOYSA-N 0.000 claims description 9
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 7
- 239000007818 Grignard reagent Substances 0.000 claims description 7
- 150000004795 grignard reagents Chemical class 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- UONUQRSSRHLRNT-BFHBGLAWSA-N (3r)-3-(oxan-2-yloxy)-1-(1,2,4-triazol-1-yl)butan-2-one Chemical compound O([C@H](C)C(=O)CN1N=CN=C1)C1CCCCO1 UONUQRSSRHLRNT-BFHBGLAWSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229960003116 amyl nitrite Drugs 0.000 claims description 2
- SKRDXYBATCVEMS-UHFFFAOYSA-N isopropyl nitrite Chemical compound CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 238000006386 neutralization reaction Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 150000003852 triazoles Chemical class 0.000 abstract description 5
- FMCUPJKTGNBGEC-UHFFFAOYSA-N 1,2,4-triazol-4-amine Chemical compound NN1C=NN=C1 FMCUPJKTGNBGEC-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 2
- GLXBESPTJANBLW-UHFFFAOYSA-N 1-chloro-3-(oxan-2-yloxy)butan-2-one Chemical compound ClCC(=O)C(C)OC1CCCCO1 GLXBESPTJANBLW-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000006227 byproduct Substances 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
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000006680 Reformatsky reaction Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JKOSHCYVZPCHSJ-UHFFFAOYSA-N benzene;toluene Chemical compound C1=CC=CC=C1.C1=CC=CC=C1.CC1=CC=CC=C1 JKOSHCYVZPCHSJ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to the technical field of drug synthesis, in particular to a preparation method of key intermediates of isavuconazole drugs; the preparation method comprises the following steps: s1, carrying out diazotization reaction on a compound shown as a formula V to prepare a compound shown as a formula VI; s2, carrying out Grignard reaction and deprotection of levo-camphorsulfonic acid on the compound shown in the formula VI to obtain a compound shown in the formula VII; s3, preparing an isavuconazole key intermediate I from a compound shown in a formula VII through an epoxidation step; according to the invention, 4-amino-1,2,4-triazole is used as a raw material in the preparation of the key intermediate I, so that the 4-position participation of triazole in a reaction can be effectively avoided in the preparation process, the occurrence of single impurities is avoided, and the quality and yield of the key intermediate I are improved.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of key intermediates of isavuconazole drugs.
Background
Isavuconazole was developed by ansitant, japan, and the FDA approved antifungal drug was approved 3/6/2015, and the main process routes of isavuconazole at the present stage include the following:
route one: a pilot synthesis route for the ionic portion of the compound and salts and the metabolite isaconazole intermediate is disclosed by CN 00815329.9: the active amine reacts with the Grignard reagent to form ketone, the ketone is further subjected to ring oxidation, the triazole is subjected to ring opening, deprotection and resolution, epoxidation is carried out again, cyano is introduced through ring opening, the cyano forms thioamide, and finally, the thiazole is formed through ring closing.
And a second route: provided by patent US20040176432, the key raw material is 3-alkynyl-R-2-butanol;
and a third route: using 2'5' -difluoro-2- [1- (1H-1,2,4-triazolyl) ] acetophenone as starting material,
the patent US20110087030A1 has the following process:
and a fourth route: the route derived from raviconazole patent EP1231210 is roughly as follows:
route five: by reformatsky reaction, VT001 raw material is used as initial experimental material, and reference is made to
The design of US20040176432 and patent CN104507917 is as follows:
the preparation methods have advantages and disadvantages, but no matter which synthesis method, the byproduct of triazole 4-position reaction is easily generated when the 1,2,4-triazole ring is connected. Affecting the purity and yield of the intermediate and the product.
Disclosure of Invention
The purpose of the invention is: overcomes the defects in the prior art, and provides a preparation method of key intermediate of isavudine drugs, which can avoid the byproduct of triazole 4-position reaction when the 1,2,4-triazole ring is connected, thereby improving the purity and yield of the product.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of key intermediates of isavuconazole medicaments comprises the following steps:
S1A compound 4-amino-1- ((3R) -2-oxo-3- ((tetrahydro-2H-pyran-2-yl) oxy) butyl) -4H-1,2,4-triazole-1-chloroonium salt shown in a formula V is subjected to diazotization reaction to prepare a compound (3R) -3- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (1H-1,2,4-triazole-1-yl) butan-2-one shown in a formula VI:
S2A compound (3R) -3- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (1H-1,2,4-triazole-1-yl) butyl-2-ketone shown in a formula VI is subjected to Grignard reaction and levo-camphorsulfonic acid deprotection to prepare a compound (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazole-1-yl) butyl-2,3-diol levo-camphorsulfonate shown in a formula VII:
s3, preparing an isavuconazole key intermediate I from a compound (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazole-1-yl) butyl-2,3-diol levocamphorsulfonate shown as a formula VII through an epoxidation step:
further, the specific steps of step S1 are: in the presence of a solvent, uniformly mixing the compound shown in the formula V with glacial acetic acid, and dropwise adding a diazotization reagent to perform diazotization reaction.
Further, in the step S1, a diazotizing reagent used in the diazotization reaction is one of sodium nitrite, isopropyl nitrite, isoamyl nitrite, amyl nitrite and butyl nitrite; preferably isoamyl nitrite;
the reaction solvent in the step S1 is one of isopropanol, ethanol, tetrahydrofuran and dichloromethane; preferably dichloromethane.
Further, the temperature of the diazotization reagent dropwise added in the step S1 is 0-30 ℃, preferably 0-10 ℃, the reaction temperature is controlled to be 0-10 ℃ after the dropwise addition, and the dropwise addition and heat preservation reaction time is 1-10 hours; preferably 2-6 hours.
Further, in the step S1, the molar ratio of 4-amino-1- ((3R) -2-oxo-3- ((tetrahydro-2H-pyran-2-yl) oxy) butyl) -4H-1,2,4-triazole-1-chloroonium salt to isoamyl nitrite is 1.0 (0.9-1.3); preferably 1.0 (0.9-1.1).
Further, the specific steps in step S2 are: in the presence of a solvent, dropwise adding a Grignard reagent, and salifying the product obtained after the reaction with levocamphorsulfonic acid to obtain the compound shown in the formula VII.
Further, the reaction temperature in the step S2 is 10 ℃ to 50 ℃; preferably 20 ℃ to 30 ℃;
the reaction time in the step S2 is 2-10 hours; preferably 3 to 5 hours;
the reaction solvent in the step S2 is one of tetrahydrofuran, methyltetrahydrofuran and ethylene glycol dimethyl ether; methyl tetrahydrofuran is preferred.
Further, in the step S2, the molar ratio of (3R) -3- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (1H-1,2,4-triazole-1-yl) butyl-2-ketone (formula VI) to the Grignard reagent is 1.0 (0.8-1.2); preferably 1.0 (1.0-1.1).
Further, in the step S3, the base selected for neutralizing and dissociating the (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butyl-2,3-diol levo-camphorsulfonate (formula VII) is one of triethylamine and tri-n-butylamine; triethylamine is preferred.
Further, the epoxidation reaction time in the step S3 is 8-20 hours; preferably 10-15 hours;
the epoxidation reaction temperature in the step S3 is 0 ℃ to 20 ℃; preferably 0 ℃ to 10 ℃;
the epoxidation reaction solvent in the step S3 is one of toluene, xylene and benzene; toluene is preferred.
The technical scheme adopted by the invention has the following beneficial effects:
1. according to the invention, 4-amino-1,2,4-triazole is used as a raw material in the preparation of the key intermediate I, so that the 4-position participation of triazole in a reaction can be effectively avoided in the preparation process, the occurrence of single impurities is avoided, and the quality and yield of the key intermediate I are improved. As follows:
2. the key intermediate I of the isavuconazole medicine prepared by the invention has high quality, ideal yield and little environmental pollution, and is suitable for industrial mass production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Compound V in this application is self-made, as follows:
example A: preparation of 4-amino-1- ((3R) -2-oxo-3- ((tetrahydro-2H-pyran-2-yl) oxy) butyl) -4H-1,2,4-triazole-1-chloronium salt (formula V):
750ml of isopropanol, 103.4g (0.500 mol) of 1-chloro-3- ((tetrahydro-2H-pyran-2-yl) oxy) butan-2-one (formula IV) and 46.2g (0.550 mol) of 4-amino-4H-1,2,4-triazole are added into a reaction bottle, stirring is started, a return pipe is installed, the temperature is raised to about 70 ℃, the reaction is kept for 5 hours, the TLC is controlled (a developing agent is dichloromethane: methanol = 5:1), and the raw material IV basically disappears. Cooling to 0-5 ℃, slowly stirring for 2-3 hours, separating out a large amount of light yellow solid, carrying out suction filtration, leaching a filter cake with a small amount of isopropanol at about 0 ℃, and drying under reduced pressure at 50 ℃ to obtain 136.4g of light yellow solid, wherein the molar yield is 93.8%, and the HPLC purity is 98.12%. Taking a small amount of the intermediate V, recrystallizing the intermediate V with isopropanol once to obtain a small amount of white-like solid with HPLC purity of 99.36%, and performing detection for nuclear magnetism and liquid chromatography-mass spectrometry, wherein the detection result is as follows:
the nuclear magnetic hydrogen spectrum and carbon spectrum data of the intermediate V are as follows: 1H NMR (400MHz, DMSO): δ =7.95 (s, 1H), 4.65 (m, 1H), 4.30 (m, 1H), 3.70 (m, 2H), 3.43 (s, 2H), 2.45 (s, 2H), 1.52-1.79 (m, 6H), 1.23 (d, 3H); 13C NMR (75MHz, DMSO): δ =206.8, 146.8, 128.8, 111.5, 75.3, 62.9, 58.0, 30.7, 25.1, 20.2, 15.8ppm;
intermediate V mass spectral data were as follows: C11H19ClN4O3, molecular weight: 290.75, [ M + H ] + measured: 291.6.
example B: preparation of 4-amino-1- ((3R) -2-oxo-3- ((tetrahydro-2H-pyran-2-yl) oxy) butyl) -4H-1,2,4-triazole-1-chloronium salt (formula V):
750ml of tert-butyl alcohol, 103.4g (0.500 mol) of 1-chloro-3- ((tetrahydro-2H-pyran-2-yl) oxy) butan-2-one (formula IV) and 46.2g (0.550 mol) of 4-amino-4H-1,2,4-triazole are added into a reaction bottle, stirring is started, a return pipe is installed, the temperature is raised to about 60 ℃, the reaction is kept for 5 hours, the TLC is controlled (a developing agent dichloromethane: methanol = 5:1), and the raw material IV basically disappears. Cooling to 0-5 ℃, slowly stirring for 2-3 hours, separating out a large amount of light yellow solid, carrying out suction filtration, leaching a filter cake with a small amount of tert-butyl alcohol at about 0 ℃, and drying under reduced pressure at 50 ℃ to obtain 131.8g of light yellow solid, wherein the molar yield is 90.7%, and the HPLC purity is 97.53%.
The compound V is adopted to prepare the key intermediate I of isavuconazole, and the preparation method specifically comprises the following steps:
example 1: preparation of (3R) -3- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (1H-1,2,4-triazol-1-yl) butan-2-one (formula VI):
adding 600ml of dichloromethane, 100.0g (0.344 mol) of the intermediate V prepared in the example A and 24.8g (0.413 mol) of glacial acetic acid into a reaction bottle, uniformly stirring, cooling to about 0 ℃, slowly dropwise adding 40.3g (0.344 mol) of isoamyl nitrite for diazotization, wherein the dropwise adding time is controlled to be 1-2 hours, and the temperature is controlled to be 0-10 ℃; after the addition was completed, the incubation was continued at 0-10 ℃ for 2 hours and the disappearance of the starting intermediate V was controlled in TLC (developer dichloromethane: methanol = 5:1). 200ml of water is added into a reaction bottle for washing, standing and layering are carried out, 10g of anhydrous magnesium sulfate is added into a dichloromethane layer for drying for 2 hours, suction filtration is carried out, and 76.3g of light yellow oily matter is obtained after the filtrate is decompressed and desolventized, the yield is 92.7 percent, and the HPLC purity is 98.92 percent.
Example 2: preparation of (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butyl-2,3-diol levocamphorsulfonate (formula VII):
350ml of methyltetrahydrofuran and 75.0g (0.313 mol) of the intermediate VI prepared in example 1 are added into a reaction bottle, stirring is started to dissolve the solution, the temperature is controlled to be 20-30 ℃, 68.0g (0.313 mol) of Grignard reagent (formula III) is added dropwise, the 20-30 ℃ reaction is kept for 3 hours after the dropwise addition is finished, and the intermediate VI basically disappears under the control of TLC (a developing agent dichloromethane: methanol = 3:1). Adding 150ml of saturated ammonium chloride, stirring, extracting for 15 minutes, standing for layering, adding 10g of anhydrous sodium sulfate into a methyltetrahydrofuran layer, drying, performing suction filtration, slowly adding levo-camphorsulfonic acid (CSA) into the filtrate in batches while stirring, closely paying attention to the pH value of the system, stopping adding the levo-camphorsulfonic acid (CSA) when the pH value is less than 3, stirring for 1 hour at the temperature of 20-30 ℃, fully salifying, cooling to 0-5 ℃, stirring for 1 hour, performing suction filtration, and performing reduced pressure drying to obtain 76.3g of gray solid, wherein the yield is 90.5%, and the HPLC purity is 99.23%.
Example 3: preparation of key isavuconazole intermediate I:
75.0g (0.150 mol) of (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butyl-2,3-diol levo camphor sulfonate (formula VII) prepared in example 2 and 300ml of toluene are added into a reaction bottle and stirred uniformly, when the temperature is controlled to be between-5 ℃ and 0 ℃, 45.5g (0.450 mol) of triethylamine is added dropwise, after the system is slowly dissolved, 25.8g (0.225 mol) of methanesulfonyl chloride is added dropwise, and the reaction is kept for 1 hour at the temperature of between-5 ℃ and 0 ℃. Then, a prepared 16% aqueous solution of sodium hydroxide (25.2 g (0.630 mol)) was added dropwise thereto, and the mixture was reacted at 0 to 5 ℃ for 10 hours, followed by TLC (developer dichloromethane: methanol = 3:1) in which formula VII disappeared, standing for layering, the toluene layer was washed three times (100ml. Times.3 times) with saturated sodium chloride, and the organic phase was removed by pressure to obtain 37.0g of a brown oily substance with a yield of 98.2% and a HPLC purity of 97.35%.
Example 4: preparation of (3R) -3- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (1H-1,2,4-triazol-1-yl) butan-2-one (formula VI):
adding 600ml of dichloromethane, 100.0g (0.344 mol) of the intermediate V prepared in the example B and 24.8g (0.413 mol) of glacial acetic acid into a reaction bottle, uniformly stirring, cooling to about 10 ℃, slowly dropwise adding 44.3g (0.378 mol) of isoamyl nitrite for diazotization, wherein the dropwise adding time is controlled to be 1-2 hours, and the temperature is controlled to be 0-10 ℃; after the dropwise addition was continued at 0-10 ℃ for 4 hours, the starting intermediate V disappeared in TLC (developer dichloromethane: methanol = 5:1). The reaction bottle is added with 200ml of water for washing, and is kept stand for layering, 10g of anhydrous magnesium sulfate is added into a dichloromethane layer for drying for 2 hours, and is filtered, and 77.8g of light yellow oily matter is obtained after the filtrate is decompressed and desolventized, the yield is 94.5%, and the HPLC purity is 98.77%.
Example 5: preparation of (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butyl-2,3-diol levocamphorsulfonate (formula VII):
350ml of methyltetrahydrofuran and 75.0g (0.313 mol) of the intermediate VI prepared in example 4 are added into a reaction bottle, stirring is started to dissolve the solution, the temperature is controlled to be 20-30 ℃, 74.8g (0.344 mol) of Grignard reagent (formula III) is added dropwise, the 20-30 ℃ reaction is kept for 4 hours after the dropwise addition is finished, and the intermediate VI basically disappears by TLC (developing agent dichloromethane: methanol = 3:1). Adding 150ml of saturated ammonium chloride, stirring, extracting for 15 minutes, standing for layering, adding 10g of anhydrous sodium sulfate into a methyltetrahydrofuran layer, drying, performing suction filtration, slowly adding levo-camphorsulfonic acid (CSA) into the filtrate in batches while stirring, closely paying attention to the pH value of the system, stopping adding the levo-camphorsulfonic acid (CSA) when the pH value is less than 3, stirring for 1 hour at the temperature of 20-30 ℃, fully salifying, cooling to 0-5 ℃, stirring for 1 hour, performing suction filtration, and performing reduced pressure drying to obtain 77.1g of gray solid, wherein the yield is 91.5%, and the HPLC purity is 99.17%.
Example 6: preparation of key isavuconazole intermediate I:
75.0g (0.150 mol) of (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butyl-2,3-diol levo camphor sulfonate (formula VII) prepared in example 5 and 300ml of toluene are added into a reaction bottle and stirred uniformly, when the temperature is controlled to be between-5 ℃ and 0 ℃, 45.5g (0.450 mol) of triethylamine is added dropwise, after the system is slowly dissolved, 25.8g (0.225 mol) of methanesulfonyl chloride is added dropwise, and the reaction is kept for 1 hour at the temperature of between-5 ℃ and 0 ℃. Then, a prepared 16% aqueous solution of sodium hydroxide (25.2 g (0.630 mol)) was added dropwise thereto, and the mixture was reacted at 5 to 10 ℃ for 15 hours, followed by TLC (developer dichloromethane: methanol = 3:1) in which formula VII disappeared, standing for layering, the toluene layer was washed three times (100ml. Times.3 times) with saturated sodium chloride, and the organic phase was removed by pressure to obtain 37.3g of a brown oily substance with a yield of 99.0% and a HPLC purity of 97.11%.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.
Claims (10)
1. A preparation method of key intermediates of isavuconazole medicaments is characterized by comprising the following steps: the preparation method comprises the following steps:
S1A compound 4-amino-1- ((3R) -2-oxo-3- ((tetrahydro-2H-pyran-2-yl) oxy) butyl) -4H-1,2,4-triazole-1-chloroonium salt shown in a formula V is subjected to diazotization reaction to prepare a compound (3R) -3- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (1H-1,2,4-triazole-1-yl) butan-2-one shown in a formula VI:
S2A compound (3R) -3- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (1H-1,2,4-triazole-1-yl) butyl-2-ketone shown in a formula VI is subjected to Grignard reaction and levo-camphorsulfonic acid deprotection to prepare a compound (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazole-1-yl) butyl-2,3-diol levo-camphorsulfonate shown in a formula VII:
s3, preparing an isavuconazole key intermediate I from a compound (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazole-1-yl) butyl-2,3-diol levocamphorsulfonate shown as a formula VII through an epoxidation step:
2. the preparation method of the key intermediate of isavuconazole medicaments according to claim 1, which is characterized in that: the specific steps of the step S1 are as follows: in the presence of a solvent, uniformly mixing the compound shown in the formula V with glacial acetic acid, and dropwise adding a diazotization reagent to perform diazotization reaction.
3. The preparation method of the key intermediate of isavuconazole medicaments according to claim 2, which is characterized in that: in the step S1, a diazotization reagent used in the diazotization reaction is one of sodium nitrite, isopropyl nitrite, isoamyl nitrite, amyl nitrite and butyl nitrite;
the reaction solvent in the step S1 is one of isopropanol, ethanol, tetrahydrofuran and dichloromethane.
4. The preparation method of the key intermediate of isavuconazole medicaments according to claim 2, which is characterized by comprising the following steps: in the step S1, the dropping temperature of the diazotization reagent is 0-30 ℃, the reaction temperature is controlled to be 0-10 ℃ after the dropping is finished, and the dropping and reaction time is 1-10 hours.
5. The preparation method of the key intermediate of isavuconazole medicaments according to claim 1, which is characterized in that: in the step S1, the molar ratio of 4-amino-1- ((3R) -2-oxo-3- ((tetrahydro-2H-pyran-2-yl) oxy) butyl) -4H-1,2,4-triazole-1-chloroonium salt to isoamyl nitrite is 1.0 (0.9-1.3).
6. The preparation method of the key intermediate of isavuconazole medicaments according to claim 1, which is characterized in that: the specific steps in the step S2 are as follows: in the presence of a solvent, dropwise adding a Grignard reagent, and reacting the product obtained completely with levocamphorsulfonic acid to form a salt to obtain the compound shown in the formula VII.
7. The preparation method of the key intermediate of isavuconazole medicaments according to claim 6, which is characterized in that: the reaction temperature in the step S2 is 10-50 ℃, the reaction time is 2-10 hours, and the solvent is one of tetrahydrofuran, methyltetrahydrofuran and ethylene glycol dimethyl ether.
8. The preparation method of the key intermediate of isavuconazole medicaments according to claim 6, which is characterized in that: in the step S2, the molar ratio of (3R) -3- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (1H-1,2,4-triazole-1-yl) butyl-2-ketone (formula VI) to the Grignard reagent is 1.0 (0.8-1.2).
9. The preparation method of the key intermediate of isavuconazole medicaments according to claim 1, which is characterized in that: in the step S3, bases selected for neutralization and free of (2S, 3R) -2- (2,5-difluorophenyl) -1- (1H-1,2,4-triazole-1-yl) butyl-2,3-diol levocamphorsulfonate (formula VII) are triethylamine and tri-n-butylamine.
10. The preparation method of the key intermediate of isavuconazole medicaments according to claim 1, which is characterized in that: the epoxidation reaction time in the step S3 is 8-20 hours, the reaction temperature is 0-20 ℃, and the solvent is one of toluene, xylene and benzene.
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