CN104774195A - Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate - Google Patents
Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate Download PDFInfo
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- CN104774195A CN104774195A CN201510104731.5A CN201510104731A CN104774195A CN 104774195 A CN104774195 A CN 104774195A CN 201510104731 A CN201510104731 A CN 201510104731A CN 104774195 A CN104774195 A CN 104774195A
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- 229960004130 itraconazole Drugs 0.000 title claims abstract description 68
- 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 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
- 230000003287 optical effect Effects 0.000 claims abstract description 56
- 150000001875 compounds Chemical class 0.000 claims description 144
- 238000006243 chemical reaction Methods 0.000 claims description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000000126 substance Substances 0.000 claims description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 21
- 230000035484 reaction time Effects 0.000 claims description 19
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 9
- 239000004299 sodium benzoate Substances 0.000 claims description 9
- 235000010234 sodium benzoate Nutrition 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- NCBNOIBUFTWSNX-UHFFFAOYSA-N [O].CC1=C(C(=O)O)C=CC=C1C(=O)O Chemical compound [O].CC1=C(C(=O)O)C=CC=C1C(=O)O NCBNOIBUFTWSNX-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- KYARBIJYVGJZLB-UHFFFAOYSA-N 7-amino-4-hydroxy-2-naphthalenesulfonic acid Chemical compound OC1=CC(S(O)(=O)=O)=CC2=CC(N)=CC=C21 KYARBIJYVGJZLB-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- SSZWWUDQMAHNAQ-VKHMYHEASA-N (R)-3-chloro-1,2-propanediol Chemical compound OC[C@@H](O)CCl SSZWWUDQMAHNAQ-VKHMYHEASA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000005575 aldol reaction Methods 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 19
- 239000012043 crude product Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000007605 air drying Methods 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- -1 hydrogen sodium hydride Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 0 CC*(C)c(ccc(Cl)c1)c1Cl Chemical compound CC*(C)c(ccc(Cl)c1)c1Cl 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229950004288 tosilate Drugs 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 229960004063 propylene glycol Drugs 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 241000233866 Fungi Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000004862 dioxolanes Chemical class 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 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
- C07B53/00—Asymmetric syntheses
-
- 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
- C07D405/14—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 three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention disclsoes an optically pure itraconazole key intermediate and synthetic method thereof, and a method for synthesizing the optically pure itraconazole from the intermediate. The method of the invention uses 1-(2,4-dichlorobenzene)-2-(1-methylene-1,2,4-triazole)-1-ketone for preparing the optically pure itraconazole key intermediate, and the optically pure itraconazole key intermediate is used for the preparation of optically pure itraconazole. The method uses easily available raw materials, not only reduces the production cost, but also obtains the product with high purity; through the control of the optical purity of the key intermediate compound VII, the optical purity of the target product itraconazole can be effectively controlled; therefore, the invention has with industrial value.
Description
Technical field
The present invention relates to the technical field of optical purity itraconazole synthesis, especially relate to a kind of optical purity itraconazole key intermediate and synthetic method and the method by the pure itraconazole of this intermediate synthesizing optical.
Background technology
Itraconazole is a kind of triazole species broad-spectrum antifungal medicine, its English name is Itraconazole, the cis-4-of chinesization formal name used at school [4-[4-[4-[[-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl methyl)-DOX-4-base] methoxyl group] phenyl] piperazine-1-base] phenyl]-2-[(2 ' S)-1-methyl-propyl]-1,2,4-triazole-3-ketone.Itraconazole has 3 chiral carbon atoms, have 8 kinds of optical isomers, antimycotic Clinical practice be the mixture of 4 cis-isomerides on dioxolanes in its structure, correspond to 2S, 4R, 2 ' S-itraconazole, 2S, 4R, 2 ' R-itraconazole, 2R, 4S, 2 ' S-itraconazole and 2R, 4S, 2 ' R-itraconazole.Research finds, there is larger difference in biological activity and the toxic side effect of itraconazole Isomers, selectivity to fungi and endotheliocyte can be improved as CN103263417A discloses itraconazole isomer composition, also be the drug candidate with treatment fungi and relevant diseases of angiogenesis potentiality simultaneously, the optical purity itraconazole of single configuration significantly can also reduce hepatotoxicity, can avoid the side effect that itraconazole causes.Therefore, a kind of method preparing optical purity itraconazole that find economy, that have industrialization potential, tool is of great significance.
The synthetic method of optical purity itraconazole has been reported, document Med.Chem.Lett.2010,1,155 ~ 159 and US20130102614 Al report relatively conventional synthetic route, with chemical compounds I and compound ii for initiator, XianCheng's ring obtains dioxolanes structural unit, by controlling the chirality of compound ii, optically pure compound III can be obtained, then obtain V optical purity itraconazole with optical purity chemicals IV condensation.This route is fairly simple, but this reaction critical materials compound III tosic acid glycerine esterification complicated component, purity and the satisfactory tosic acid glyceryl ester of optical purity often need customization, and production cost is very high, not easily industrialization.
Summary of the invention
The object of the invention is the deficiency existed for prior art, provide a kind of optical purity itraconazole key intermediate, by the pure itraconazole of this intermediate synthesizing optical, production cost is low, the product that optical purity is high can be obtained, be applicable to suitability for industrialized production, reduce drug price.
Present invention also offers the synthetic method of this optical purity itraconazole key intermediate, be easy to realize, be applicable to suitability for industrialized production, for the production cost reducing optical purity itraconazole provides basis.
Present invention also offers by the method for the pure itraconazole of this intermediate synthesizing optical, reduce the production cost of optical purity itraconazole, achieve suitability for industrialized production.
For achieving the above object, the technical solution used in the present invention is:
A kind of optical purity itraconazole key intermediate, chemical name is 2-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-4-chloromethyl-1,3-dioxolanes, sterie configuration is 2S, 4S type (VII-a) or 2R, 4R type (VII-b), structural formula is
Described optical purity itraconazole key intermediate synthetic method, chemical compounds I and compound VI-a or compound VI-b carry out aldol reaction under the effect of organic acid, obtain key intermediate compound VII-a and compound VII-b, the chemical name of chemical compounds I is 1-(2,4 dichloro benzene)-2-(1-methylene radical-1,2,4 triazoles)-1-ketone, compound VI-a and compound VI-b chemical name are respectively S-3-chlorine-1,2-propylene glycol and R-3-chloro-1,2-propylene glycol
The mol ratio of chemical compounds I and compound VI-a or compound VI-b is 1:2 ~ 1:5, described organic acid is tosic acid, methylsulfonic acid or trifluoromethanesulfonic acid, the ratio of chemical compounds I and organic acid is 1:2 ~ 1:8, and described temperature of reaction is 40 DEG C ~ 100 DEG C, and the reaction times is 4 ~ 12h.The preferred trifluoromethanesulfonic acid of organic acid, the preferred 1:4 of ratio of chemical compounds I and organic acid, temperature of reaction preferably 80 DEG C, the reaction times selects 6h.
Described optical purity itraconazole key intermediate is applied to the synthesis of each optical isomer of itraconazole.By controlling the configuration of this key intermediate, the itraconazole optical isomer of different spaces configuration can be obtained.
Method by the described pure itraconazole of optical purity itraconazole key intermediate synthesizing optical:
(1) compound VII-a or compound VII-b and Sodium Benzoate generation substitution reaction obtain optical pure compound VIII-a or compound VIII-b, the chemical name of compound VIII-a is (2S, 4S)-2-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-4-benzoyloxymethy-1,3-dioxolanes, the chemical name of compound VIII-b is (2R, 4R)-2-(2,4 dichloro benzene)-2-(1-methylene radical-1,2,4 triazoles)-4-benzoyloxymethy-1,3-dioxolanes
(2) compound VIII-a or compound VIII-b carries out alkaline hydrolysis and obtains compound Ⅸ-a or compound Ⅸ-b, the chemical name of compound Ⅸ-a is (2S, 4R)-2-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-4-methylol-1,3-dioxolanes, the chemical name of compound Ⅸ-b is (2R, 4S)-2-(2,4 dichloro benzene)-2-(1-methylene radical-1,2,4 triazoles)-4-methylol-1,3-dioxolanes
(3) compound Ⅸ-a or compound Ⅸ-b and Tosyl chloride are obtained by reacting compound III-a or compound III-b, the chemical name of compound III-a is (2S, 4S)-2-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-4-tolysulfonyl oxygen methyl isophthalic acid, 3-dioxolanes, the chemical name of compound III-b is (2R, 4R)-2-(2,4 dichloro benzene)-2-(1-methylene radical-1,2,4 triazoles)-4-tolysulfonyl oxygen methyl isophthalic acid, 3-dioxolanes
(4) compound III-a or compound III-b and compounds Ⅳ-a or compounds Ⅳ-b carries out condensation reaction under the catalysis of highly basic, obtain optical purity itraconazole, the chemical name of compounds Ⅳ-a is S-2-sec-butyl-4-[4-[4-(4-hydroxy phenyl)-piperazine-]-phenyl]-3-carbonyl-1,2,4-triazole, the chemical name of compounds Ⅳ-b is R-2-sec-butyl-4-[4-[4-(4-hydroxy phenyl)-piperazine-]-phenyl]-3-carbonyl-1,2,4-triazole
In described step (1), compound VII-a or compound VII-b is 1:1 ~ 1:8 with the mol ratio of Sodium Benzoate, reaction solvent is N, dinethylformamide, methyl-sulphoxide, N-Methyl pyrrolidone or N, N-N,N-DIMETHYLACETAMIDE, temperature of reaction is 100 DEG C ~ 150 DEG C, and the reaction times is 10 ~ 50h, and Extraction solvent is isopropyl ether, methyl tertiary butyl ether or ethyl acetate.The preferred 1:4 of mol ratio of compound VII-a or compound VII-b and Sodium Benzoate, the preferred DMF of reaction solvent, temperature of reaction preferably 130 DEG C, reaction times preferred 20h, Extraction solvent preferable methyl tertbutyl ether.
In described step (2), described alkali is sodium hydroxide, lithium hydroxide or potassium hydroxide, and the reaction times is 2 ~ 6h, and temperature of reaction is 10 DEG C ~ 35 DEG C.The preferred sodium hydroxide of described alkali, reaction times preferred 4h, temperature of reaction preferably 25 DEG C.
In described step (3), compound Ⅸ-a or compound Ⅸ-b is 1:1 ~ 1:6 with the mol ratio of Tosyl chloride, and temperature of reaction is lower than 25 DEG C, and the reaction times is 5 ~ 20h.Compound Ⅸ-a or compound Ⅸ-b is preferably 1:1.3, reaction times preferred 10h with the mol ratio of Tosyl chloride.
In described step (4), mol ratio 1:1 ~ the 1:3 of compound III-a or compound III-b and compounds Ⅳ-a or compounds Ⅳ-b, described highly basic is sodium hydroxide, potassium hydroxide, lithium hydroxide or sodium hydride, the mol ratio of compound III-a or compound III-b and highly basic is 1:1 ~ 1:3, and the reaction times is 10h ~ 40h.The mol ratio of compound III-a or compound III-b and compounds Ⅳ-a or compounds Ⅳ-b is preferably 1:1.1, the preferred hydrogen sodium hydride of described highly basic, and the preferred 1:1.5 of mol ratio of compound III-a or compound III-b and highly basic, the reaction times is preferably 25h.
The present invention compared with prior art, has the following advantages:
Do not need customization purity and all satisfactory tosic acid glyceryl ester of optical purity can obtain high quality, high optical purity itraconazole; purity is not less than 99.5%, and optical purity higher than 98%, and reduces production cost; be applicable to large-scale industrial to produce, reduce the price of terminal medicine.
Accompanying drawing explanation
Fig. 1 is 2S, 4R, 2 ' S-itraconazole liquid phase chiral analysis collection of illustrative plates.
Fig. 2 is 2S, 4R, 2 ' R-itraconazole liquid phase chiral analysis collection of illustrative plates.
Fig. 3 is 2R, 4S, 2 ' S-itraconazole liquid phase chiral analysis collection of illustrative plates.
Fig. 4 is 2R, 4S, 2 ' R-itraconazole liquid phase chiral analysis collection of illustrative plates.
Embodiment
Below in conjunction with embodiment, illustrate the present invention further, these embodiments should be understood only be not used in for illustration of the present invention and limit the scope of the invention, after having read the present invention, the amendment of those skilled in the art to the various equivalent form of value of the present invention has all fallen within the application's claims limited range.
Embodiment one
The synthesis of compound VII-a
In in 200ml there-necked flask, add chemical compounds I (9.50g, 37mmol, 1.0eq) and S-3-chloro-1, 2-propylene glycol (8.20g, 74mmol, 2.0eq) and toluene 80mL, drip trifluoromethanesulfonic acid (22g while stirring, 5.0mmol, 4.0eq), after dropwising, be heated to 80 DEG C, after stirring reaction 6h, 100ml saturated sodium bicarbonate solution is added in reaction solution, stir 30min, separatory, collect organic phase, concentrating under reduced pressure, obtain 15g optical pure compound VII-a (yellow oil, S, S-configuration), purity 86%, yield 99.7%.
1HNMR(400MHz,CDCl
3,):
8.13(s,1H),7.77(s,1H),7.42～7.44(d,H,J＝8.0),7.35(s,1H),7.14～7.16(d,1H,J＝8.0),4.63～4.75(m,2H,J＝16.0),4.16(m,1H),3.69～3.78(m,2H),2.88～2.93,3.23～3.26(m,2H)
ESI-MS：348.0(M+H
+)。
Embodiment two
The synthesis of compound VII-a
In in 500ml there-necked flask, add chemical compounds I (9.50g, 37mmol, 1.0eq) and S-3-chlorine-1,2-propylene glycol (16g, 148mmol, 4eq) and toluene 90mL, tosic acid (14g, 74mmol is added while stirring, 2eq), after dropwising, be heated to 100 DEG C, after stirring reaction 12h, 150ml saturated sodium bicarbonate solution is added in reaction solution, stir 30min, separatory, collect organic phase, concentrating under reduced pressure, obtain 12g optical pure compound VII (yellow oil, S, S-configuration), purity 84%, yield 78.1%.
Embodiment three
The synthesis of compound VII-b
In in 500ml there-necked flask, add chemical compounds I (9.50g, 37mmol, 1.0eq) and R-3-chlorine-1,2-propylene glycol (20.5g, 185mmol, 5eq) and 90mL toluene, methylsulfonic acid (28g, 296mmol is dripped while stirring, 8eq), after dropwising, be heated to 40 DEG C, after stirring reaction 4h, 200ml saturated sodium bicarbonate solution is added in reaction solution, stir 30min, separatory, collect organic phase, concentrating under reduced pressure, obtain 14g optical pure compound VII (yellow oil, S, S-configuration), purity 83%, yield 90%.
1HNMR(400MHz,CDCl
3,):
7.98(s,1H),7.58(s,1H),7.25～7.28(d,H,J＝12.0),7.17(s,1H),6.97～6.99(d,1H,J＝8.0),4.47～4.63(m,2H,J＝16.0),3.98(m,1H),3.51～3.60(m,2H),2.73～2.78,3.06～3.08(m,2H)
ESI-MS：348.1(M+H
+)。
Embodiment four
2S, 4R, the synthesis of 2 ' S-itraconazole
To in 500mL there-necked flask, add compound VII-a (15g, 84%, 36mmol, 1.0eq), Sodium Benzoate (18g, 144mmol, 4.0eq) and DMF 180mL, be warming up to 130 DEG C, the stirring reaction time is about 20h.Be cooled to 25 DEG C, add 150mL water, stir 30min, extract twice with 120mL isopropyl ether, merge organic phase, use 100mL water washing, organic phase concentrating under reduced pressure obtains compound VIII-a 18g (yellow oil), purity 78%, yield 90%.
To in 500mL there-necked flask, add compound VIII-a (18g, 78%, 32mmol, 1.0eq), 100ml ethanol and 10% sodium hydroxide solution 130g, stirring reaction 5h at 25 DEG C, adds 100mL water, and is cooled to 4 DEG C, there is a large amount of solid to separate out, filter, collect filter cake, in 50 DEG C of forced air drying 24h, obtain 10g compound Ⅸ-a, purity 90%, yield 85%.
10g compound Ⅸ-a (90% is added in 500ml reactor, 27mmol, 1.0eq), 6.8g Tosyl chloride (35mmol, 1.3eq) and 50ml methylene dichloride, be cooled to-20 DEG C, slowly drip 8.2g triethylamine (81mmol, 3eq), keep temperature lower than 25 DEG C in dropping process, after dropwising, 25 DEG C of insulation reaction 10h.In reaction system, add 50ml water, stir 30min, separatory, collect organic phase, concentrating under reduced pressure obtains crude product 15g; Be dissolved in by crude product in 100ml ethyl acetate, at 25 DEG C, drip tosic acid solution (5.6g is dissolved in 50ml ethyl acetate), separate out solid, collect filter cake, 50 DEG C of forced air dryings obtain tosilate crude product.
Crude product is used 240ml recrystallized from acetonitrile, gained highly finished product 50ml methylene dichloride dissolves, then adds 50ml saturated sodium bicarbonate solution, agitator treating, separatory, collects organic phase, is evaporated to dry, obtains 7.6g compound III-a, purity 99%, yield 57.6%.
To in 250ml flask, add 0.6g NaH (24mmol, 1.5eq), add 50ml DMF and 7.5g compounds Ⅳ-a (24mmol, 1.5eq), then add compound III-a (7.6g, 16mmol, DMF (100mL) solution 1eq), is heated to 30-40 DEG C of stirring reaction to terminal, about 25h.Reaction solution is flowed in 50ml water, separate out solid, filter, collect solid.Solid is dissolved in 50ml methylene dichloride, with the salt acid elution three times of 50ml 1%, then add 0.8g gac, decolouring; By destainer evaporate to dryness, then use 80ml ethyl alcohol recrystallization, obtain 2S, 4R, 2 ' S-itraconazole 7g, purity 99.3%, ee 98.5%, yield 61.6%, specific optical rotation [α]
din CH
3-5.0 °.
1HNMR(400MHz,CDCl
3),8.20(s,1H),7.88(s,1H),7.63(s,1H),7.56(d,1H,J＝8.5Hz),7.46(d,3H,J＝2.0Hz),7.42(d,2H,J＝9.0Hz),7.24(dd,1H,J
1＝2.0,J
2＝8.5Hz),7.01(d,2H,J＝9.0Hz,),6.93(d,2H,J＝9.0Hz),6.80(d,2H,J＝9.0Hz,),4.83(d,1H,J＝14.7Hz,),4.75(d,1H,J＝14.7Hz,),4.35(m,1H,J＝5.4Hz),4.28(m,1H,),3.91(t,1H,J＝7.5Hz),3.80(m,2H),3.51(dd,1H,J＝6.3,9.7Hz),3.22～3.35(m,8H),1.90～1.68(m,2H),1.40～1.38(d,3H,J＝6.8Hz),0.92～0.89(t,3H,J1＝7.4Hz,J
2＝7.6)；ESI-MS：705.3(M+H
+)。
Embodiment five
2S, 4R, the synthesis of 2 ' R-itraconazole
To in 500mL there-necked flask, add compound VII-a (15g, 84%, 36mmol, 1.0eq), Sodium Benzoate (36g, 288mmol, 8.0eq) and N,N-dimethylacetamide 180mL, be warming up to 150 DEG C, the stirring reaction time is about 10h.Be cooled to 25 DEG C, add 150mL water, stir 30min, aqueous phase 120mL methyl tertiary butyl ether extracts twice, merges organic phase, uses 100mL water washing, organic phase concentrating under reduced pressure obtains compound VIII-a 19g (yellow oil), purity 74.5%, yield 90.6%.
To in 500mL there-necked flask, add compound VIII-a (19g, 74.5%, 33mmol, 1.0eq), 100ml ethanol and 10% lithium hydroxide solution 130g, stirring reaction 6h at 10 DEG C, adds 100mL water, and is cooled to 4 DEG C, a large amount of solid is had to separate out, filter, collect filter cake, obtain 11g compound Ⅸ-a in 50 DEG C of forced air drying 24h, purity 85%, yield 86%.
11g compound Ⅸ-a (85% is added in 500ml reactor, 28mmol, 1.0eq), 8.6g Tosyl chloride (45mmol, 1.6eq) and 50ml methylene dichloride, be cooled to-20 DEG C, slowly drip 8.5g triethylamine (84mmol, 3eq), keep temperature lower than 25 DEG C in dropping process, after dropwising, 25 DEG C of insulation reaction 5h.In reaction system, add 50ml water, stir 30min, separatory, collect organic phase, concentrating under reduced pressure obtains crude product 16g; Be dissolved in by crude product in 100ml ethyl acetate, at 25 DEG C, drip tosic acid solution (5.7g is dissolved in 50ml ethyl acetate), separate out solid, collect filter cake, 50 DEG C of forced air dryings obtain tosilate crude product.
Crude product is used 240ml recrystallized from acetonitrile, gained highly finished product 50ml methylene dichloride dissolves, then adds 50ml saturated sodium bicarbonate solution, agitator treating, separatory, collects organic phase, is evaporated to dry, obtains 7.5g compound III-a, purity 99%, yield 54.8%.
To in 250ml flask, add 0.7g NaH (30mmol, 2eq), add 50ml DMF and 9.4g compounds Ⅳ-b (30mmol, 2eq), then add compound III-a (7.5g, 15mmol, DMF (100mL) solution 1eq), is heated to 30-40 DEG C of stirring reaction to terminal, about 10h.Reaction solution is flowed in 50ml water, separate out solid, filter, collect solid.Solid is dissolved in 50ml methylene dichloride, with the salt acid elution three times of 50ml 1%, then add 0.8g gac, decolouring; By destainer evaporate to dryness, then use 80ml ethyl alcohol recrystallization, obtain 2S, 4R, 2 ' R-itraconazole 6.2g, purity 99.3%, ee98.5%, yield 58%, specific optical rotation [α]
din CH
3-12.8 °.
1HNMR(400MHz,CDCl3,):8.24(s,1H),7.92(s,1H),7.62(s,1H),7.59(d,1H,J＝8.5Hz),7.48(d,3H,J＝2.0Hz),7.44(d,2H,J＝9.0Hz),7.26(dd,1H,J
1＝2.0,J
2＝8.5Hz),7.04(d,2H,J＝9.0Hz,),6.95(d,2H,J＝9.0Hz),6.81(d,2H,J＝9.0Hz,),4.86(d,1H,J＝14.7Hz,),4.78(d,1H,J＝14.7Hz,),4.39(m,1H,J＝5.4Hz),4.32(m,1H,),3.94(t,1H,J＝7.5Hz),3.84(m,2H),3.50(dd,1H,J＝6.3,9.7Hz),3.22～3.37(m,8H),1.90～1.68(m,2H),1.40～1.38(d,3H,J＝6.8Hz),0.96(t,3H,J1＝7.4Hz,J2＝7.6)；ESI-MS：705.2(M+H
+)。
Embodiment six
2R, 4S, the synthesis of 2 ' S-itraconazole
To in 500mL there-necked flask, add compound VII-b (15g, 86%, 37mmol, 1.0eq), Sodium Benzoate (4.5g, 37mmol, 1.0eq) and methyl-sulphoxide 180mL, be warming up to 100 DEG C, the stirring reaction time is about 50h.Be cooled to 25 DEG C, add 150mL water, stir 30min, extract twice by 120mL ethyl acetate, merge organic phase, use 100mL water washing, organic phase concentrating under reduced pressure obtains compound VIII-b 16g (yellow oil), purity 78%, yield 77.7%.
To in 500mL there-necked flask, add compound VIII-b (16g, 78%, 29mmol, 1.0eq), 100ml ethanol and 10% lithium hydroxide solution 130g, stirring reaction 3h at 25 DEG C, adds 100mL water, and is cooled to 4 DEG C, a large amount of solid is had to separate out, filter, collect filter cake, obtain 9g compound Ⅸ-b in 50 DEG C of forced air drying 24h, purity 91%, yield 86%.
9g compound Ⅸ-b (91% is added in 500ml reactor, 25mmol, 1.0eq), 28.6g Tosyl chloride (150mmol, 6eq) and 70ml methylene dichloride, be cooled to-20 DEG C, slowly drip 15.2g triethylamine (150mmol, 6eq), keep temperature lower than 25 DEG C in dropping process, after dropwising, 25 DEG C of insulation reaction 5h.In reaction system, add 70ml water, stir 30min, separatory, collect organic phase, concentrating under reduced pressure obtains crude product 14g; Be dissolved in by crude product in 100ml ethyl acetate, at 25 DEG C, drip tosic acid solution (5.5g is dissolved in 50ml ethyl acetate), separate out solid, collect filter cake, 50 DEG C of forced air dryings obtain tosilate crude product.
Crude product is used 240ml recrystallized from acetonitrile, gained highly finished product 60ml methylene dichloride dissolves, then adds 50ml saturated sodium bicarbonate solution, agitator treating, separatory, collects organic phase, is evaporated to dry, obtains 7.3g compound III-b, purity 99%, yield 59.7%.
To in 250ml flask, add 0.6g lithium hydroxide (15mmol, 1eq), add 50ml DMF and 7.5g compounds Ⅳ-a (15mmol, 1eq), then add compound III-b (7.3g, 15mmol, DMF (100mL) solution 1eq), is heated to 30-40 DEG C of stirring reaction to terminal, about 40h.Reaction solution is flowed in 50ml water, separate out solid, filter, collect solid.Solid is dissolved in 50ml methylene dichloride, with the salt acid elution three times of 50ml 1%, then add 0.8g gac, decolouring; By destainer evaporate to dryness, then use 80ml ethyl alcohol recrystallization, obtain 2R, 4S, 2 ' S-itraconazole 6.1g, purity 99.7%, ee98.6%, yield 57.5%, specific optical rotation [α]
din CH
3+ 13 °.
1HNMR(400MHz,CDCl
3,):8.21(s,1H),7.89(s,1H),7.62(s,1H),7.57(d,1H,J＝8.5Hz),7.46(d,3H,J＝2.0Hz),7.43(d,2H,J＝9.0Hz),7.27(dd,1H,J
1＝2.0,J
2＝8.5Hz),7.03(d,2H,J＝9.0Hz,),6.94(d,2H,J＝9.0Hz),6.80(d,2H,J＝9.0Hz,),4.85(d,1H,J＝14.7Hz,),4.77(d,1H,J＝14.7Hz,),4.36(m,1H,J＝5.4Hz),4.29(m,1H,),3.93(t,1H,J＝7.5Hz),3.82(m,2H),3.50(dd,1H,J＝6.3,9.7Hz),3.21～3.35(m,8H),1.89～1.67(m,2H),1.39～1.37(d,3H,J＝6.8Hz),0.91～0.86(t,3H,J
1＝7.4Hz,J
2＝7.6)；ESI-MS：705.2(M+H
+)。
Embodiment seven
2R, 4S, the synthesis of 2 ' R-itraconazole
To in 500mL there-necked flask, add compound VII-b (15g, 86%, 37mmol, 1.0eq), Sodium Benzoate (18g, 148mmol, 4.0eq) and N-Methyl pyrrolidone 150mL, be warming up to 120 DEG C, the stirring reaction time is about 10h.Be cooled to 25 DEG C, add 150mL water, stir 30min, extract twice with 120mL methyl tertiary butyl ether, merge organic phase, use 100mL water washing, organic phase concentrating under reduced pressure obtains compound VIII-b 19g (yellow oil), purity 73%, yield 86.3%.
To in 500mL there-necked flask, add compound VIII-b (19g, 73%, 32mmol, 1.0eq), 100ml ethanol and 10% potassium hydroxide solution 130g, stirring reaction 2h at 35 DEG C, adds 100mL water, and is cooled to 4 DEG C, a large amount of solid is had to separate out, filter, collect filter cake, obtain 10g compound Ⅸ-b in 50 DEG C of forced air drying 24h, purity 88%, yield 83%.
10g compound Ⅸ-b (88% is added in 500ml reactor, 27mmol, 1.0eq), 5.1g Tosyl chloride (27mmol, 1eq) and 70ml methylene dichloride, be cooled to-20 DEG C, slowly drip 8.2g triethylamine (81mmol, 3eq), keep temperature lower than 25 DEG C in dropping process, after dropwising, 25 DEG C of insulation reaction 20h.In reaction system, add 60ml water, stir 30min, separatory, collect organic phase, concentrating under reduced pressure obtains crude product 13g; Be dissolved in by crude product in 100ml ethyl acetate, at 25 DEG C, drip tosic acid solution (5.5g is dissolved in 50ml ethyl acetate), separate out solid, collect filter cake, 50 DEG C of forced air dryings obtain tosilate crude product.
Crude product is used 240ml recrystallized from acetonitrile, gained highly finished product 50ml methylene dichloride dissolves, then adds 50ml saturated sodium bicarbonate solution, agitator treating, separatory, collects organic phase, is evaporated to dry, obtains 7.1g compound III-b, purity 99%, yield 53.8%.
To in 250ml flask, add 2.5g potassium hydroxide (45mmol, 3eq), add 50ml DMF and 14.1g compounds Ⅳ-b (45mmol, 3eq), then add compound III-b (7.1g, 15mmol, DMF (100mL) solution 1eq), is heated to 30-40 DEG C of stirring reaction to terminal, about 20h.Reaction solution is flowed in 50ml water, separate out solid, filter, collect solid.Solid is dissolved in 50ml methylene dichloride, with the salt acid elution three times of 50ml 1%, then add 0.8g gac, decolouring; By destainer evaporate to dryness, then use 80ml ethyl alcohol recrystallization, obtain 2R, 4S, 2 ' R-itraconazole 6.2g, purity 99.8%, ee98.2%, yield 58.5%, specific optical rotation [α]
din CH
3+ 6.7 °.
1HNMR(400MHz,CDCl
3,):8.22(s,1H),7.90(s,1H),7.62(s,1H),7.57(d,1H,J＝8.5Hz),7.46(d,3H,J＝2.0Hz),7.43(d,2H,J＝9.0Hz),7.27(dd,1H,J
1＝2.0,J
2＝8.5Hz),7.03(d,2H,J＝9.0Hz,),6.94(d,2H,J＝9.0Hz),6.80(d,2H,J＝9.0Hz,),4.85(d,1H,J＝14.7Hz,),4.77(d,1H,J＝14.7Hz,),4.36(m,1H,J＝5.4Hz),4.29(m,1H,),3.93(t,1H,J＝7.5Hz),3.82(m,2H),3.50(dd,1H,J＝6.3,9.7Hz),3.21～3.36(m,8H),1.89～1.67(m,2H),1.39～1.37(d,3H,J＝6.8Hz),0.91～0.88(t,3H,J
1＝7.4Hz,J
2＝7.6)；ESI-MS：705.2(M+H
+)。
Claims (9)
1. an optical purity itraconazole key intermediate, chemical name is 2-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-4-chloromethyl-1,3-dioxolanes, sterie configuration is 2S, 4S type (VII-a) or 2R, 4R type (VII-b), structural formula is
2. optical purity itraconazole key intermediate synthetic method according to claim 1, it is characterized in that: chemical compounds I and compound VI-a or compound VI-b carry out aldol reaction under the effect of organic acid, obtain key intermediate compound VII-a or VII-b, the chemical name of chemical compounds I is 1-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-1-ketone, compound VI-a and compound VI-b chemical name are respectively S-3-chloro-1,2-propylene glycol and R-3-chloro-1,2-propylene glycol
3. optical purity itraconazole key intermediate synthetic method according to claim 2, it is characterized in that: the mol ratio of chemical compounds I and compound VI-a or compound VI-b is 1:2 ~ 1:5, described organic acid is tosic acid, methylsulfonic acid or trifluoromethanesulfonic acid, the ratio of chemical compounds I and organic acid is 1:2 ~ 1:8, described temperature of reaction is 40 DEG C ~ 100 DEG C, and the reaction times is 4 ~ 12h.
4. optical purity itraconazole key intermediate according to claim 1 is applied to the synthesis of each optical isomer of itraconazole.
5., by the method for the pure itraconazole of optical purity itraconazole key intermediate synthesizing optical according to claim 1, it is characterized in that:
(1) compound VII-a or compound VII-b and Sodium Benzoate generation substitution reaction obtain compound VIII-a or compound VIII-b, the chemical name of compound VIII-a is (2S, 4S)-2-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-4-benzoyloxymethy-1,3-dioxolanes, the chemical name of compound VIII-b is (2R, 4R)-2-(2,4 dichloro benzene)-2-(1-methylene radical-1,2,4 triazoles)-4-benzoyloxymethy-1,3-dioxolanes
(2) compound VIII-a or compound VIII-b carries out alkaline hydrolysis and obtains compound Ⅸ-a or compound Ⅸ-b, the chemical name of compound Ⅸ-a is (2S, 4R)-2-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-4-methylol-1,3-dioxolanes, the chemical name of compound Ⅸ-b is (2R, 4S)-2-(2,4 dichloro benzene)-2-(1-methylene radical-1,2,4 triazoles)-4-methylol-1,3-dioxolanes
(3) compound Ⅸ-a or compound Ⅸ-a and Tosyl chloride are obtained by reacting compound III-a or compound III-b, the chemical name of compound III-a is (2S, 4S)-2-(2,4-dichlorobenzene)-2-(1-methylene radical-1,2,4 triazoles)-4-tolysulfonyl oxygen methyl isophthalic acid, 3-dioxolanes, the chemical name of compound III-b is (2R, 4R)-2-(2,4 dichloro benzene)-2-(1-methylene radical-1,2,4 triazoles)-4-tolysulfonyl oxygen methyl isophthalic acid, 3-dioxolanes
(4) compound III-a or compound III-b and compounds Ⅳ-a or compounds Ⅳ-b carries out condensation reaction under the catalysis of highly basic, obtain optical purity itraconazole, the chemical name of compounds Ⅳ-a is S-2-sec-butyl-4-[4-[4-(4-hydroxy phenyl)-piperazine-]-phenyl]-3-carbonyl-1,2,4-triazole, the chemical name of compounds Ⅳ-b is R-2-sec-butyl-4-[4-[4-(4-hydroxy phenyl)-piperazine-]-phenyl]-3-carbonyl-1,2,4-triazole
6. the method by the pure itraconazole of optical purity itraconazole key intermediate synthesizing optical according to claim 5, it is characterized in that: in described step (1), compound VII-a or compound VII-b is 1:1 ~ 1:8 with the mol ratio of Sodium Benzoate, reaction solvent is N, dinethylformamide, methyl-sulphoxide, N-Methyl pyrrolidone or N, N-N,N-DIMETHYLACETAMIDE, temperature of reaction is 100 DEG C ~ 150 DEG C, reaction times is 10 ~ 50h, and Extraction solvent is isopropyl ether, methyl tertiary butyl ether or ethyl acetate.
7. the method by the pure itraconazole of optical purity itraconazole key intermediate synthesizing optical according to claim 5, it is characterized in that: in described step (2), described alkali is sodium hydroxide, lithium hydroxide or potassium hydroxide, reaction times is 2 ~ 6h, and temperature of reaction is 10 DEG C ~ 35 DEG C.
8. the method by the pure itraconazole of optical purity itraconazole key intermediate synthesizing optical according to claim 5, it is characterized in that: in described step (3), compound Ⅸ-a or compound Ⅸ-b is 1:1 ~ 1:6 with the mol ratio of Tosyl chloride, temperature of reaction is lower than 25 DEG C, and the reaction times is 5 ~ 20h.
9. the method by the pure itraconazole of optical purity itraconazole key intermediate synthesizing optical according to claim 5, it is characterized in that: in described step (4), mol ratio 1:1 ~ the 1:3 of compound III-a or compound III-b and compounds Ⅳ-a or compounds Ⅳ-b, described highly basic is sodium hydroxide, potassium hydroxide, lithium hydroxide or sodium hydride, the mol ratio of compound III-a or compound III-b and highly basic is 1:1 ~ 1:3, and the reaction times is 10h ~ 40h.
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| WO2020166710A1 (en) * | 2019-02-15 | 2020-08-20 | 国立大学法人東北大学 | 1, 3-dioxolan derivative |
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| CN106478615B (en) * | 2016-08-31 | 2019-08-13 | 山东罗欣药业集团股份有限公司 | A kind of Itraconazole crystal-form compound and preparation method thereof |
| WO2020166710A1 (en) * | 2019-02-15 | 2020-08-20 | 国立大学法人東北大学 | 1, 3-dioxolan derivative |
| JPWO2020166710A1 (en) * | 2019-02-15 | 2021-12-16 | 国立大学法人東北大学 | 1,3-Dioxolane derivative |
| US11912688B2 (en) | 2019-02-15 | 2024-02-27 | Tohoku University | 1, 3-dioxolane derivative |
| CN113336715A (en) * | 2021-08-04 | 2021-09-03 | 山东海利尔化工有限公司 | Preparation method of triazole compound containing dioxolane and intermediate thereof |
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