CN101824002B - Water soluble triazole compound and synthesis method thereof - Google Patents
Water soluble triazole compound and synthesis method thereof Download PDFInfo
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- CN101824002B CN101824002B CN2010101711214A CN201010171121A CN101824002B CN 101824002 B CN101824002 B CN 101824002B CN 2010101711214 A CN2010101711214 A CN 2010101711214A CN 201010171121 A CN201010171121 A CN 201010171121A CN 101824002 B CN101824002 B CN 101824002B
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- Prior art keywords
- water
- compound
- triazol
- difluorophenyl
- formula
- Prior art date
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- -1 triazole compound Chemical class 0.000 title claims abstract description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title abstract description 50
- 238000001308 synthesis method Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 239000003814 drug Substances 0.000 claims description 21
- 208000031888 Mycoses Diseases 0.000 claims description 9
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 8
- 206010017533 Fungal infection Diseases 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 3
- 229910021645 metal ion Inorganic materials 0.000 claims description 3
- 229910001415 sodium ion Inorganic materials 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910001414 potassium ion Inorganic materials 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000000843 anti-fungal effect Effects 0.000 abstract description 22
- 150000003852 triazoles Chemical class 0.000 abstract description 20
- 229940121375 antifungal agent Drugs 0.000 abstract description 16
- 231100000419 toxicity Toxicity 0.000 abstract description 6
- 230000001988 toxicity Effects 0.000 abstract description 6
- 238000012362 drug development process Methods 0.000 abstract description 3
- 239000002547 new drug Substances 0.000 abstract description 3
- 238000001228 spectrum Methods 0.000 abstract description 3
- 239000003429 antifungal agent Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 77
- 238000003756 stirring Methods 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000010438 heat treatment Methods 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 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 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
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- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
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- 239000003960 organic solvent Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
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- 230000035484 reaction time Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- GJOWSEBTWQNKPC-UHFFFAOYSA-N 3-methyloxiran-2-ol Chemical compound CC1OC1O GJOWSEBTWQNKPC-UHFFFAOYSA-N 0.000 description 3
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- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
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- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
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- 238000005886 esterification reaction Methods 0.000 description 1
- HVFFICXFJBAZMU-UHFFFAOYSA-N ethoxy dihydrogen phosphate Chemical compound CCOOP(O)(O)=O HVFFICXFJBAZMU-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
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- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a water soluble triazole compound and a synthesis method thereof. The water soluble triazole compound has a structure as shown in Formula Ia, Formula Ib, Formula Ic or Formula Id, wherein R1 is a group in Formula II. The compound of the invention is formed by adding a new group on the structural basis of a broad-spectrum, high-efficiency antifungal compound discovered in the present clinical application and new drug development process to increase the water solubility and reduce the toxicity, is a derivate of the triazole antifungal drug, and has the characteristics of broad antifungal spectrum, high antifungal activity, good safety and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a water-soluble triazole compound and a preparation method of the compound.
Background
Triazole antifungal drugs are the most widely used drugs for treating mycoses, especially deep mycoses at present. The triazole is a five-membered heterocyclic ring obtained by substituting one carbon atom in an imidazole ring by nitrogen, has lower toxicity than imidazole as a pharmacophore and is widely applied to various medicines and pesticides, and a plurality of triazole medicines are used in clinic and agriculture so far. As an important functional group, triazole has strong capability of complexing metal ions and forming hydrogen bonds, and is favored in the chemical field. The action mechanism is that N-4 on the triazole ring is coordinated with an iron atom at the center of ferriporphyrin in fungal cytochrome P-450 to inhibit the demethylation reaction of a substrate, so that ergosterol which is an important substance for forming a cell membrane is deficient, lanosterol is accumulated, the fungal cell membrane is ruptured, and the bacteriostatic and bactericidal effects are achieved.
In the traditional treatment of mycosis, especially deep mycosis, amphotericin B is a standard medicament, but the medicament has large toxic and side effects, and therefore, a liposome delivery system is developed. The development of triazole antifungal drugs is on the market and is a supplement to amphotericin B. An earlier triazole antifungal used clinically was Terconazole (Terconazole) marketed in 1983. The development of antifungal treatment of triazole compounds is pioneered, and great interest in the development of triazole compounds is aroused. Thereafter, Itraconazole (Itraconazole) and Fluconazole (Fluconazole) were sequentially used in the clinic. Triazole antifungal drugs, such as fluconazole and voriconazole, have long half-life, high efficiency and low toxicity, can be orally or intravenously administered, are clinically used for treating deep fungal infection, and have good curative effect and small adverse reaction. However, because of the water solubility problem of the medicines, the medicines are either prepared into large-volume infusion solutions or are prepared into proper clinical preparations by adding cosolvent, but the medicines also bring safety risks.
To solve this problem, many researchers have modified the structure of triazole antifungal drugs to increase water solubility and reduce toxicity, and one of them is to form phosphate prodrugs, such as Fosfluconazole (Fosfluconazole) which is marketed in 2003, which is a phosphate of fluconazole, and has increased water solubility compared to fluconazole, strong antifungal activity and good safety, and mainly acts on candida and cryptococcus fungi. And secondly, the nitrogen atom on the triazole ring is utilized to form quaternary ammonium salt, so that the water solubility of the triazole can be improved. Thirdly, the characteristics of polyhydroxy and good water solubility of the natural glucose are utilized to form the novel water-soluble glycosyl compound.
During the long-term research and research on triazole antifungal compounds containing hydroxyl, the functional group transformation of the hydroxyl can be utilized to increase the water solubility of the compounds, and great results are obtained. In our previously published CN200810025585.7, the salt is formed by mono-esterification reaction of pharmaceutically acceptable dicarboxylic acid and then salt with pharmaceutically acceptable basic metal ion and amino acid. In order to further develop the field, other derivatives of the medicine are researched and prepared, and the derivatives have better water solubility and lower toxicity, and the medicinal safety is enhanced.
Disclosure of Invention
The invention aims to provide a novel water-soluble triazole derivative, which introduces a new functional group on the basis of a high-efficiency and broad-spectrum antifungal compound discovered in the current clinical application and new drug development process, thereby increasing the water solubility and reducing the toxicity. Is a derivative of triazole antifungal drugs, and has the characteristics of wide antifungal spectrum, strong antifungal activity, good safety and the like.
It is another object of the present invention to provide a process for producing the above novel water-soluble triazole derivative.
The invention also aims to provide the application of the novel water-soluble triazole derivative in preparing a medicament for treating fungal infection.
The object of the invention can be achieved by the following measures:
a water-soluble triazole compound has the following structural formula:
formula Ia
Or
Formula Ib
Or
Formula Ic
Or
Formula Id
Wherein R is1Is a radical of the formula II
Formula II
The water-soluble triazole compound has the following structure:
formula Ia formula Ib
Formula Ic formula Id
In the present invention,
x is an integer of 0 to 6, preferably 0 to 4, such as 0, 1, 2, 3 or 4; thus, when x in the structure of formula Ia is 0, the compound is a formate; when x is 1, the compound is acetate; compound propionate when x is 2; when x is 3, the compound is butyrate.
y is an integer of 1 to 6, preferably an integer of 1 to 3, such as 1, 2 or 3; therefore, when y in the structure Ib is 1, the compound is methoxy phosphate; when y is 2, the compound is ethoxy phosphate; when y is 3, the compound is propoxyphosphate.
M、M′n+Or M ″)n+Each is a metal ion, preferably sodium ion, potassium ion, calcium ion or magnesium ion, such as Na+、K+、Mg2+、Ca2+Etc.;
R2or R3Are each H or
x 'is an integer of 0 to 6, and x' is preferably an integer of 0 to 4;
R4is H, C1-4Alkyl or halogen of (1), preferably H or C1-4Alkyl group of (1).
R in Ic Structure2、R3、R4When H, the compound is 1, 2-dihydroxypropyl; r2Is hydroxy, R4Is H, R3Is composed of
When the compound is a 2-hydroxycarboxylic acid salt; r3Is hydroxy, R4Is H, R2Is composed of
When the compound is 3-hydroxy-2-carboxylate; r4Is H, R2、R3Is composed ofWhen the compound is a 2-hydroxydicarboxylate salt.
The structure of the group in the formula II comprises a cis structure and a trans structure; r' is a five-membered nitrogen-containing heterocyclic ring, a six-membered nitrogen-containing heterocyclic ring, phenyl or hydrogen with or without substituent, wherein the substituent is selected from halogen and C1-4One or more of alkyl, cyano or cyanophenyl. The antibacterial activity of the compound is better when R' is H, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrimidyl and substituted or unsubstituted thiazolyl, wherein the substituent is selected from one or more of halogen, cyano or cyanophenyl. R' is most preferably H, 1, 2, 4-triazol-1-yl, 5-fluoropyrimidin-4-yl or 4- (4-cyanophenyl) -2-thiazolyl.
R' is H or C1-4The alkyl group of (1) is preferably H or methyl.
The water-soluble triazole compound comprises an optical active isomer of the water-soluble triazole compound.
R of the invention1Most preferably, the group adopts the following structure:
2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy,
(2R, 3S) -2- (2, 4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1, 2, 4-triazol-1-yl) -2-butoxy, or
(2R, 3S) -2- (2, 4-difluorophenyl) -3- [4-4- (cyanophenyl) -2-thiazolyl ] -1- (1H-1, 2, 4-triazol-1-yl) -2-butoxy.
The formula Ia, Ib, Ic and Id of the invention is produced by reacting a compound containing a group of formula II with a compound of formula III, or by further converting the resulting product into a pharmaceutically acceptable salt thereof
Formula III
Wherein X is halogen or other protecting group.
The preparation method of the compound shown in the formula Ia, Ib, Ic or Id is as follows:
a compound of formula Ia:
wherein X is halogen;
the solvent for the reaction may be an aprotic organic solvent such as N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetone, acetonitrile or the like. N, N-dimethylformamide and dimethylsulfoxide are preferable. The reaction temperature may be between 0 ℃ and 80 ℃. Preferably 50-70 deg.C. The reaction time is preferably 2 to 4 hours.
A compound of formula Ib:
the solvent for reaction can be acetone, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile and other organic solvents without active hydrogen. Acetone, ethyl acetate, tetrahydrofuran, acetonitrile are preferred. The reaction temperature may be between 0 ℃ and 100 ℃. The reaction time is preferably 3 to 6 hours.
A compound of formula Ic:
the solvent for the reaction can be acetone, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and other organic solvents without active hydrogen. Acetone, ethyl acetate, tetrahydrofuran, dioxane are preferred. The reaction temperature may be between-10 ℃ and 100 ℃. Preferably 50-70 deg.C. The reaction time is preferably 3 to 6 hours.
In this reaction, for example, R2And R3All are H, only the first reaction step may be carried out.
A compound of formula Id:
the reaction for forming phosphoric acid may be carried out in an inorganic phosphorus compound such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentoxide or phosphorus pentachloride, and phosphorus oxychloride is preferred. The solvent for salt-forming reaction can be organic solvent such as acetone, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, etc. Acetone, ethyl acetate, tetrahydrofuran, dioxane are preferred. The reaction temperature may be between-10 ℃ and 100 ℃. Preferably 50-70 deg.C. The reaction time is preferably 3 to 6 hours.
R in each of the above reaction equations1-H is
In each reaction equation, x, y, M'n+、M″n+、R2、R3、R4R ', or R' are as defined above.
The compound belongs to a prodrug of the triazole antifungal medicine, and can be hydrolyzed into the triazole antifungal medicine in vivo by hydrolase or other enzymes:
the medicine further has antifungal effect in vivo.
The pharmaceutically active compounds of the present invention may be used alone or formulated in pharmaceutical compositions containing a pharmaceutically acceptable carrier, adjuvant or diluent in addition to the active triazole ingredient. The compounds can be administered in a variety of ways, such as orally, topically, or parenterally (intravenously or intramuscularly). The pharmaceutical composition may be in solid form, such as capsules, tablets, powders, etc., or in liquid form, such as solutions, suspensions or emulsions. Injectable compositions may be prepared in unit dosage form in ampoules or in multi-dose containers, and may contain additives such as suspending, stabilizing and dispersing agents. The composition may be in a ready-to-use form or in a powder form for reconstitution with a suitable carrier, such as sterile water, at the time of delivery.
Alternatively, the compounds of the invention may be administered in the form of suppositories or vaginal formulations, or they may be administered topically in the form of lotions, solutions or creams. In addition, they may be incorporated (at concentrations up to 10%) into ointments consisting of white wax or soft, white paraffin base, together with the required stabilizers and/or preservatives.
The compounds of the present invention are useful because they have pharmacological activity in animals, including particularly mammals (most particularly humans). In particular, the compounds of the present invention are useful for the treatment or prevention of topical fungal infections, including those caused by Candida, Trichophyton, Paidentical or Epidermophyton. They may also be used to treat systemic fungal infections caused by: such as Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Paenibacillus, Cochinosia, Histoplasma or Blastomyces.
Thus, according to another aspect of the present invention there is provided a method of treating a fungal infection, the method comprising administering a therapeutically effective amount of the compound to a subject, particularly a mammalian subject, most particularly a human patient. Also provided is the use of a compound of the invention as a medicament, and the use of a compound of the invention for the manufacture of a medicament for the treatment of fungal infections.
The dosage administered will depend, to a large extent, on the particular compound used, the particular composition formulated, the route of administration, the nature and condition of the recipient, and the particular site and organism being treated. However, the compounds will generally be administered to mammalian recipients parenterally or orally in amounts ranging from about 5 mg/day to 1.0 g/day, these dosages being exemplary of the average case, higher or lower dosages may be employed in individual cases, and such dosages are within the scope of the invention. Furthermore, the compounds of the present invention may be administered at once or in divided portions.
The antifungal activity of the compounds prepared by the method of the present invention was evaluated in vitro by determining the Minimum Inhibitory Concentration (MIC). The MIC is the concentration of test compound that inhibits the growth of the test microorganism. In practice, fungal strains are plated onto a series of agar plates to which a specific concentration of test compound is added, and each plate is then incubated at 37 ℃ for 48 hours. Microorganisms that can be used in this test include Candida albicans, Aspergillus fumigatus, Trichophyton, Microsporum, Epidermophyton floccosum, Coptophytes robusta, and Torulopsis glabrata. It will be recognized that some of the compounds of the present invention are not active as prodrugs in vitro assays.
The compounds prepared according to the present invention were evaluated in vivo by intraperitoneal or intravenous injection or oral administration of the compounds prepared according to the present invention to mice implanted with fungal (e.g., candida albicans) strains at a range of dosage levels. Activity was determined after the group of untreated mice was sacrificed by comparing the survival of groups of mice treated with different dose levels. The level of dose at which the lethal effect of the test compound on infection provides 50% protection was recorded.
The invention has the beneficial effects that: the compound of the invention is a new group introduced on the basis of the structure of a broad-spectrum and high-efficiency antifungal compound discovered in the current clinical application and new drug development process, thereby greatly increasing the water solubility of the compound, reducing the toxicity and having more excellent performance compared with the existing compound. The prodrug of the triazole antifungal drug has the characteristics of wide antifungal spectrum, strong antifungal activity, good safety and the like.
On the basis of the above description, according to the common technical knowledge and the conventional means in the field, various modifications, substitutions or changes can be made without departing from the basic technical idea of the invention.
Detailed Description
The foregoing aspects of the invention are further illustrated by the following examples of specific embodiments.
Example 1
(1) Synthesis of ethyl 4- [2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy ] -butyrate
A three-necked flask was charged with 30.6g (0.1mol) of 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propanol (fluconazole), 27.2g (1.3mol) of ethyl 4-bromobutyrate, n-Bu4Br 2.5.5 g, 5mL of triethylamine, and 100mL of ethanol. Heating to reflux reaction for 5 h under stirring, cooling, adding 100mL of water into the reaction mixture, stirring, and extracting with 150mL of ethyl acetate × 2. Concentrating under reduced pressure to dryness, and separating by column chromatography. 17.6g of yellow oil are obtained, yield: 42.0 percent.
(2) Synthesis of sodium 4- [2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy ] -butyrate
17.6g (0.042mol) of the oily substance, 1.8g (0.045mol) of sodium hydroxide and 75 g of water are added into a three-neck flaskml, 50ml ethanol. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to a yellow solid. The resulting solid was recrystallized from 10ml of water and 35ml of ethanol to give 15.5g of a pale yellow solid (89.0% [ M +1 ]]+：414.14，H-NMR(DOCH3)δppm：8.15(m，2H)，8.11(m，2H)，7.16(d，1H)，6.67(d，1H)，6.56(m，1H)，4.26(s，4H)，3.37(t，2H)，2.30(t，2H)，1.83(m，2H).
Example 2
(1) Synthesis of ethyl 2- [2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy ] -acetate
A three-necked flask was charged with 30.6g (0.1mol) of 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propanol (fluconazole), 15.9g (1.3mol) of ethyl 4-chloroacetate, n-Bu4Br 2.2.2 g, 5mL of triethylamine, and 100mL of ethanol. Heating to reflux reaction for 5 h under stirring, cooling, adding 100mL of water into the reaction mixture, stirring, and extracting with 150mL of ethyl acetate × 2. Concentrating under reduced pressure to dryness, and separating by column chromatography. 19.6g of yellow oil are obtained, yield: 50.1 percent.
(2) Synthesis of 4- [2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy ] -sodium acetate
19.6g (0.05mol) of the oily substance, 2.1g (0.053mol) of sodium hydroxide, 80ml of water and 55ml of ethanol are added into a three-necked flask. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to a yellow solid. The resulting solid was recrystallized from 12ml of water and 40ml of ethanol to give 15.5g of a pale yellow solid (89.0% [ M +1 ]]+：414.14，H NMR(DOCH3)δppm：8.15(m，2H)，8.11(m，2H)，7.16(d，1H)，6.67(d，1H)，6.56(m，1H)，4.26(s，4H)，4.01(s，2H)。
Example 3
(1) Synthesis of ethyl 4- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy ] -butyrate
43.7g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl were added to the three-necked flask]-2-butanol, 23.3g (0.12mol) of ethyl 4-bromobutyrate, n-Bu4Br 2.2g, triethylamine 5mL, ethanol 120 mL. Heating to reflux reaction for 3 hours under stirring, cooling, adding 100mL of water into the reaction mixture, stirring, and extracting with 150mL of ethyl acetate multiplied by 2. Concentrating under reduced pressure to dryness, and separating by column chromatography. 23.7g of yellow oil are obtained, yield: 43.1 percent.
(2) Synthesis of sodium 4- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy ] -butyrate
23.7g (0.043mol) of sodium hydroxide, 2.0g (0.05mol), 100ml of water and 70ml of ethanol are taken. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to a yellow solid. The resulting solid was recrystallized from 15ml of water and 60ml of ethanol to give 21.4g of a pale yellow solid, 91.0%. [ M +1 ]]+：545.5，H-NMR(DOCH3)δppm：8.33(m，1H)，8.21(m，1H)，7.81(m，1H)，7.66(d，2H)，7.57(d，2H)，7.15(d，1H)，6.67(d，1H)，6.61(m，1H)，4.38(dd，2H)，3.71(m，1H)，3.34(t，2H)，2.20(t，2H)，1.72(m，2H)，1.35(d，3H).
Example 4
(1) Synthesis of ethyl 2- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy ] -acetate
43.7g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl were added to the three-necked flask]-2-butanol, 19.9g (0.12mol) of ethyl 4-bromoacetate, n-Bu4Br 2.2g, triethylamine 5mL, ethanol 100 mL. Heating to reflux reaction for 5 h under stirring, cooling, adding 100mL of water into the reaction mixture, stirring, and extracting with 150mL of ethyl acetate × 2. Concentrating under reduced pressure to dryness, and separating by column chromatography. 25.7g of yellow oil are obtained, yield: 49.0 percent.
(2) Synthesis of sodium 2- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy ] -acetate
25.7g (0.049mol) of sodium hydroxide, 2.0g (0.05mol), 100ml of water and 70ml of ethanol are taken. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to a yellow solid. The resulting solid was recrystallized from 12ml of water and 55ml of ethanol to give 22.3g of 88.0% as a pale yellow solid. [ M +1 ]]+：517.1，H-NMR(DOCH3)δppm：8.33(m，1H)，8.21(m，1H)，7.81(m，1H)，7.66(d，2H)，7.57(d，2H)，7.15(d，1H)，6.67(d，1H)，6.61(m，1H)，4.31(dd，2H)，3.84(m，1H)，1.72(d，3H).
Example 5
(1) Synthesis of ethyl 4- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy ] -butyrate
34.9g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butanol, 23.3g (0.12mol) of ethyl 4-bromobutyrate, n-Bu were added to a three-necked flask4Br 2.2g, triethylamine 5mL, ethanol 120 mL. Heating to reflux reaction for 4 hours under stirring, cooling, adding 100mL of water into the reaction mixture, stirring, and extracting with 150mL of ethyl acetate multiplied by 2. Concentrating under reduced pressure to dryness, and separating by column chromatography. 19.96g of yellow oil are obtained, yield: 43.1 percent.
(2) Synthesis of sodium 4- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy ] -butyrate
19.96g (0.043mol) of sodium hydroxide 2.0g (0.05mol), 100ml of water and 70ml of ethanol are taken as the product of the previous step. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to a yellow solid. The resulting solid was recrystallized from 12ml of water and 55ml of ethanol to give 17.9g of a pale yellow solid (91.0%). [ M +1 ]]+：545.5，H NMR(DOCH3)：8.91(m，1H)，8.37(m，1H)，8.17(m，1H)，8.12(m，1H)，7.17(d，1H)，6.69(d，1H)，6.63(m，1H)，4.28(d d，2H)，3.64(m，1H)，3.37(t，2H)2.30(t，2H)，1.73(m，2H)，1.25(d，3H)。
Example 6
(1) Synthesis of ethyl 2- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy ] -acetate
34.9g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butanol, 19.9g g (0.12mol) of ethyl 4-bromoacetate, n-Bu were added to the three-necked flask4Br 2.2g, triethylamine 5mL, ethanol 120 mL. Heating to reflux reaction for 4 hours under stirring, cooling, adding 100mL of water into the reaction mixture, stirring, and extracting with 150mL of ethyl acetate multiplied by 2. Concentrating under reduced pressure, and separating by column chromatography. 23.49g of yellow oil are obtained, yield: 54.0 percent.
(2) Synthesis of sodium 2- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy ] -butyrate
23.4g (0.054mol) of sodium hydroxide 2.4g (0.06mol), 120ml of water and 80ml of ethanol are taken as the product of the previous step. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to a yellow solid. The resulting solid was recrystallized from 12ml of water and 55ml of ethanol to give 20.4g of a pale yellow solid, yield 87.0%. [ M +1 ]]+：429.1，H NMR(DOCH3)：8.91(m，1H)，8.37(m，1H)，8.17(m，1H)，8.12(m，1H)，7.17(d，1H)，6.69(d，1H)，6.63(m，1H)，4.51(s，2H)，4.28(d d，2H)，3.64(m，1H)，1.27(d，3H)。
Example 7
Synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-methyl calcium phosphate
(1) Synthesis of diethyl (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-methylphosphonate
34.9g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butanol, DMF (98ml) in N.N.280% NaH (7g, 0.23mol) was added with stirring at-5 ℃ under protection. A solution of diethoxyphosphonomethyl p-toluenesulfonate (50.4g, 0.16mol) in DMF (18ml) was added dropwise with stirring, the mixture was stirred at the same temperature for 4 hours, after HPLC showed completion of the reaction (residual 4: 3% or less), glacial acetic acid (13.4ml) was added dropwise, the mixture was stirred for lh, the reaction mixture was concentrated to dryness under reduced pressure, methylene chloride (60ml) was added, filtration was carried out, the filter cake was washed with methylene chloride, the filtrate and the washing solution were combined, 10 ml. times.3 of water was used, the aqueous layer was extracted with methylene chloride by 10 ml. times.3, the methylene chloride phases were combined, the solvent was distilled off under reduced. Filtration was carried out, and the filter cake was dried under reduced pressure at 50 ℃ to obtain 27.9g of a white powdery solid with a yield of 56.0%.
(2) Synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-methylphosphonic acid
Adding 27.9g (0.056mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-methyl diethyl phosphate, 74.2ml of trimethyl bromosilane and 40ml of acetonitrile into a three-neck flask, stirring at room temperature for 3H, heating to reflux for 7H, cooling to room temperature, concentrating under reduced pressure to dryness, adding 80ml of water into the residue to generate white precipitate, heating the reaction product to 55 ℃, stirring for 1H, cooling to room temperature, adding saturated sodium hydroxide solution to adjust the pH to 3.2, stirring, heating to reflux for 3H, cooling to room temperature, standing in a refrigerator overnight, filtering, adding 100ml of water into a filter cake, heating to 75 ℃, stirring for 1H, stopping heating, stirring for 1h, filtering, and washing the filter cake with water and ether in sequence to obtain 22.6g of white solid with a yield of 91.0%.
(3) Synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-methyl calcium phosphate
To a three-necked flask were added 22.6g (0.051mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-methylphosphonic acid and 200ml of ethanol, and 12g (0.076mol) of hydrated calcium acetate in 20ml of an aqueous solution was slowly added with stirring at 50 ℃. Stirring at the same temperature for half an hour, cooling, filtering, and recrystallizing the filter cake with 70% aqueous solution. The filtered white solid was dried under vacuum at 45 ℃ to give 23.9g, 97.5% yield. [ M +1 ]]+：481.1，HNMR(DOCH3)：8.91(m，1H)，8.37(m，1H)，8.17(m，1H)，8.12(m，1H)，7.17(d，1H)，6.69(d，1H)，6.63(m，1H)，4.28(d d，2H)，3.64(m，1H)，3.41(d，2H)，1.27(d，3H)。
Example 8
Synthesis of 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy-methyl calcium phosphate
(1) Synthesis of diethyl 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy-methylphosphonate
30.6g (0.1mol) of 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propanol, DMF (90ml) in N280% NaH (7g, 0.23mol) was added with stirring at-5 ℃ under protection. A solution of diethoxyphosphonomethyl p-toluenesulfonate (50.4g, 0.16mol) in DMF (15ml) was added dropwise with stirring, the mixture was stirred at the same temperature for 4 hours, after HPLC showed completion of the reaction (residual 4: 4% or less), glacial acetic acid (13ml) was added dropwise, the reaction mixture was stirred for lh, the reaction mixture was concentrated to dryness under reduced pressure, methylene chloride (60ml) was added, filtration was carried out, the cake was washed with methylene chloride, the filtrate and the washing solution were combined, 10 ml. times.3 of water was used for washing, the aqueous layer was extracted with methylene chloride by 10 ml. times.3 of water, the methylene chloride phases were combined, the solvent was. Filtration was carried out, and the filter cake was dried under reduced pressure at 50 ℃ to obtain 27.3g of a white powdery solid with a yield of 60.0%.
(2) Synthesis of 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy-methylphosphonic acid
Adding 27.3g (0.06mol) of 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy-methyl diethyl phosphate, 74.2ml of trimethyl bromosilane and 40ml of acetonitrile into a three-necked flask, stirring at room temperature for 3H, heating to reflux for reaction for 7H, cooling to room temperature, concentrating under reduced pressure to dryness, adding 80ml of water into the residue to generate a white precipitate, heating the reaction product to 55 ℃, stirring for 1H, cooling to room temperature, adding a saturated sodium hydroxide solution to adjust the pH to 3.2, stirring, heating to reflux for 3H, cooling to room temperature, standing the reaction product in a refrigerator overnight, filtering, adding 100ml of water into a filter cake, heating to 75 ℃, stirring for 1H, stopping heating, stirring again for 1H, filtering, washing the filter cake with water and diethyl ether in sequence to obtain 21.4g of a white solid, the yield thereof was found to be 89.0%.
(3) Synthesis of 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy-methyl calcium phosphate
A three-necked flask was charged with 21.4g (0.053mol) of 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy-methylphosphonic acid and 200ml of ethanol, and then 12g (0.076mol) of hydrated calcium acetate in 20ml of an aqueous solution was slowly added thereto with stirring at 50 ℃. Stirring at the same temperature for half an hour, cooling, filtering, and recrystallizing the filter cake with 70% aqueous solution. The filtered white solid was dried in vacuo at 45 ℃ to give 20.8g, 98% yield. [ M +1 ]]+：438.14，H NMR(DOCH3)δppm：8.15(m，2H)，8.11(m，2H)，7.16(d，1H)，6.67(d，1H)，6.56(m，lH)，4.22(s，2H)，4.01(d，4H)。
Example 9
Synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy-methyl calcium phosphate
(1) Synthesis of diethyl (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy-methylphosphonate
43.6g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl were added to the three-necked flask]-2-Butanol, DMF (90ml) in N280% NaH (7g, 0.23mol) was added with stirring at-5 ℃ under protection. A solution of diethoxyphosphonomethyl p-toluenesulfonate (50.4g, 0.16mol) in DMF (15ml) was added dropwise with stirring, the mixture was stirred at the same temperature for 4 hours, after HPLC showed completion of the reaction (residual 4: 4% or less), glacial acetic acid (13ml) was added dropwise, the reaction mixture was stirred for lh, the reaction mixture was concentrated to dryness under reduced pressure, methylene chloride (60ml) was added, filtration was carried out, the cake was washed with methylene chloride, the filtrate and the washing solution were combined, 10 ml. times.3 of water was used for washing, the aqueous layer was extracted with methylene chloride by 10 ml. times.3 of water, the methylene chloride phases were combined, the solvent was. Filtering, drying the filter cake at 50 ℃ under reduced pressure to obtain 30.5g of white powdery solid with the yield of 55.0%.
(2) Synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy-methylphosphonic acid
Adding 30.5g (0.055mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy-methyl diethyl phosphate, 74.2ml of trimethyl bromosilane and 40ml of acetonitrile into a three-neck flask, stirring at room temperature for 3H, heating to reflux for 7H, cooling to room temperature, concentrating under reduced pressure to dryness, adding 80ml of water into the residue to generate white precipitate, heating the reaction product to 55 ℃, stirring for 1H, cooling to room temperature, adding saturated sodium hydroxide solution to adjust the pH to 3.2, stirring, heating to reflux for 3H, cooling to room temperature, standing in a refrigerator overnight, filtering, adding 100ml of water into the filter cake, heating to 75 ℃, stirring for 1H, stopping heating, stirring for 1h, filtering, and washing the filter cake with water and ether in sequence to obtain 25.7g of white solid with a yield of 94%.
(3) Synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy-methyl calcium phosphate
Adding (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl into a three-mouth bottle]25.7g (0.052mol) of 2-butoxy-methylphosphonic acid and 200ml of ethanol were slowly added to a 20ml aqueous solution of 12g (0.076mol) of hydrated calcium acetate at 50 ℃ with stirring. Stirring at the same temperature for half an hour, cooling, filtering, and recrystallizing the filter cake with 70% aqueous solution. The filtered white solid was dried under vacuum at 45 ℃ to give 26.9g, 91% yield. [ M +1 ]]+：569.1，H NMR(DOCH3)δppm：8.33(m，1H)，8.21(m，1H)，7.81(m，1H)，7.66(d，2H)，7.57(d，2H)，7.15(d，1H)，6.67(d，1H)，6.61(m，1H)，4.27(dd，2H)，3.70(m，1H)，3.38(s，2H)，1.72(d，3H).
Example 10
Synthesis of 3- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy ] -1, 2-propanediol
34.9g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butanol, DMF (98ml) in N.N.280% NaH (7g, 0.23mol) was added with stirring at-5 ℃ under protection. While stirring, a solution of epoxy propanol (8.8g, 0.12mol) in DMF (20ml) was added dropwise, the mixture was stirred at the same temperature for 4 hours, glacial acetic acid (12ml) was added dropwise, the mixture was stirred for 1 hour, the reaction solution was concentrated to dryness under reduced pressure, and 100ml of anhydrous ethanol was added thereto for recrystallization. 33.0g of a white solid was obtained in a yield of 78.0%. [ M +1 ]]+：423.2，H NMR(DOCH3)：8.91(m，1H)，8.37(m，1H)，8.17(m，1H)，8.12(m，1H)，7.17(d，1H)，6.69(d，1H)，6.63(m，1H)，4.30(d d，2H)，3.68(m，1H)，3.61(m，5H)，3.51(d，2H)，1.30(d，3H)。
Example 11
Synthesis of 3- [2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propoxy ] -1, 2-propanediol
30.6g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl were added to the three-necked flask]-2-Butanol, DMF (98ml) in N280% NaH (7g, 0.23mol) was added with stirring at-5 ℃ under protection. While stirring, a solution of epoxy propanol (8.8g, 0.12mol) in DMF (20ml) was added dropwise, the mixture was stirred at the same temperature for 4 hours, glacial acetic acid (12ml) was added dropwise, the mixture was stirred for 1 hour, the reaction solution was concentrated to dryness under reduced pressure, and 100ml of anhydrous ethanol was added thereto for recrystallization. 30.8g of white solid is obtained with a yield of 81.0%. [ M +1 ]]+：380.1，H NMR(DOCH3)δppm：8.15(m，2H)，8.11(m，2H)，7.16(d，1H)，6.67(d，1H)，6.56(m，1H)，4.22(s，2H)，4.01(d，4H)，3.69(m，5H)。
Example 12
Synthesis of 3- [ (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butoxy ] -1, 2-propanediol
43.7g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl were added to the three-necked flask]-2-Butanol, DMF (98ml) in N280% NaH (7g, 0.23mol) was added with stirring at-5 ℃ under protection. Adding dropwise epoxy propanol (8.8g, 0.12mol) solution in DMF (20ml) under stirring, stirring at the same temperature for 4h, adding dropwise glacial acetic acid (12ml), stirring for 1h, concentrating the reaction solution under reduced pressure to dryness, adding 100ml anhydrous ethanolAnd (4) recrystallizing. 37.8g of white solid is obtained, and the yield is 74.0%. [ M +1 ]]+：511.2，HNMR(DOCH3)δppm：8.33(m，1H)，8.21(m，1H)，7.81(m，1H)，7.66(d，2H)，7.57(d，2H)，7.15(d，1H)，6.67(d，1H)，6.61(m，1H)，4.25(dd，2H)，3.80(m，5H)，3.69(m，1H)，3.42(s，2H)，1.31(d，3H).
Example 13
(1) Synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-phosphoric acid
A three-necked flask was charged with 34.9g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butanol and pyridine (500ml) and dissolved by heating at about 50 ℃. Cooling to 5 ℃ under N2Adding PCl under stirring under protection3(153.0g, 1.0 mol). After the dropwise addition, slowly raising the temperature to room temperature, and continuously stirring for reaction for 4 hours. The temperature was reduced to 5 ℃ and 2L of water was added, and 500 ml. times.2 was extracted with methyl isobutyl ketone. The organic layers were combined. 1L of 2mol/L hydrochloric acid is added, and the reaction is stirred at 50 ℃ for 2 h. The reaction mixture was cooled to room temperature, allowed to stand for separation, and the organic layer was separated, washed with 600ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate to obtain 51.2g of a yellow oily substance which was used in the next reaction without purification.
(2) Synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-calcium phosphate
51.2g of the oily substance and 300ml of ethanol were added to a three-necked flask, and the mixture was dissolved by stirring, and 150ml of an aqueous solution of 19.4g (0.12mol) of hydrated calcium acetate was slowly dropped while stirring at 50 ℃. Reacting at the same temperature for 30 min. Cooling to room temperature and filtering. The filter cake was washed with 20ml of 50% ethanol. Drying at 45 deg.C under reduced pressure. 34.8g of needle-like crystals were obtained, and the yield was 74.5%. [ M +1 ]]+：467.4，H NMR(DOCH3)：8.90(m，1H)，8.30(m，1H)，8.15(m，1H)，8.11(m，1H)，7.15(d，1H)，6.64(d，1H)，6.67(m，1H)，4.28(d d，2H)，3.61(m，1H)，1.35(d，3H)。
Example 14
(1) Synthesis of ethyl (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-carboxylate
A three-necked flask was charged with 34.9g (0.1mol) of (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butanol, toluene (500ml), 5ml of pyridine, and 40ml of triethylamine, and the mixture was dissolved by heating at about 50 ℃. Cooling to about 0 ℃ in N2Ethyl chloroformyl chloride (12.96g, 0.12mol) was added with stirring while protecting. After the dropwise addition, slowly raising the temperature to room temperature, and continuously stirring for reaction for 4 hours. Pouring the reaction solution into ice water, and stirring for crystallization. After filtration, the product was used in the next reaction without further treatment.
(2) Synthesis of sodium (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butoxy-carboxylate
The solid, 4.8g (0.12mol) of sodium hydroxide, 200ml of water and 80ml of ethanol are added into a three-necked flask. The reaction was stirred at room temperature for 4 hours and concentrated under reduced pressure to a yellow solid. The resulting solid was recrystallized from 10ml of water and 60ml of ethanol to give 31.9g of a pale yellow solid, yield 77.0%. [ M +1 ]]+：429.1，H NMR(DOCH3)：8.90(m，1H)，8.31(m，1H)，8.12(m，1H)，8.15(m，1H)，7.10(d，1H)，6.61(d，1H)，6.65(m，1H)，4.25(d d，2H)，3.69(m，1H)，1.31(d，3H)。
Example 15
The compounds of examples 1 to 12 were tested for solubility in water at 25 ℃ in the conventional manner and compared with the parent compound without functional group conversion.
Wherein the parent compound 1 is: 2- (2, 4-difluorophenyl) -1, 3-bis (1H-1, 2, 4-triazol-1-yl) -2-propanol
The parent compound 2 is: (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- [4- (4-cyanophenyl) -3-thiazolyl ] -2-butanol
The parent compound 3 is: (2R, 3S) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) -3- (5-fluoro-4-pyrimidinyl) -2-butanol
The results are shown in tables 1, 2 and 3.
Table 1:
table 2:
table 3:
Claims (9)
1. A water-soluble triazole compound, which has the following structural formula:
wherein R is1Is a radical of the formula II
Wherein,
x is an integer of 0 to 6, M is a metal ion,
R2or R3Are each H or
x' is an integer of 0 to 6,
R4is H, C1-4The alkyl group or the halogen of (a),
r' is a five-membered nitrogen-containing heterocyclic ring, a six-membered nitrogen-containing heterocyclic ring, phenyl or hydrogen with or without substituent, wherein the substituent is selected from halogen and C1-4One or more of alkyl, cyano or cyanophenyl,
r' is H or C1-4Alkyl group of (1).
2. The water-soluble triazole compound of claim 1, wherein R' is H, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted thiazolyl, wherein the substituent is selected from one or more of halogen, cyano or cyanophenyl.
3. The water-soluble triazole compound of claim 2, wherein R' is H, 1, 2, 4-triazol-1-yl, 5-fluoropyrimidin-4-yl, or 4- (4-cyanophenyl) -2-thiazolyl.
4. The water-soluble triazole compound of claim 1, wherein R "is H or methyl.
5. The water-soluble triazole compound according to claim 2, wherein R is1Is composed of
6. The water-soluble triazole compound according to claim 1, wherein x is an integer of 0 to 4.
7. The water-soluble triazole compound according to claim 1, wherein M is a sodium ion or a potassium ion; r2Or R3Are each H or
x' is an integer of 0 to 4.
8. The method for synthesizing a water-soluble triazole compound as claimed in claim 1, wherein the compound of formula Ic is prepared as follows:
a compound of formula Ic:
wherein R is1-H is
The R is1、R2、R3、R4R', R "are as defined in claim 1.
9. Use of the water-soluble triazole compound of claim 1 in the preparation of a medicament for treating fungal infection.
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Cited By (1)
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| EP2813499A1 (en) * | 2013-06-12 | 2014-12-17 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds |
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| EP2813499A1 (en) * | 2013-06-12 | 2014-12-17 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds |
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