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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- 0 C[C@@]([C@](C[n]1ncnc1)(c(c(F)c1)ccc1F)OCCCC(*)=O)c(ncnc1)c1F Chemical compound C[C@@]([C@](C[n]1ncnc1)(c(c(F)c1)ccc1F)OCCCC(*)=O)c(ncnc1)c1F 0.000 description 2
- LXVZHKSFOXNFPW-IVZQSRNASA-N CCOC(CCCO[C@](C[n]1ncnc1)([C@H](C)c(ncnc1)c1F)c(ccc(F)c1)c1F)=O Chemical compound CCOC(CCCO[C@](C[n]1ncnc1)([C@H](C)c(ncnc1)c1F)c(ccc(F)c1)c1F)=O LXVZHKSFOXNFPW-IVZQSRNASA-N 0.000 description 1
- FGKZXIDPWRHSJN-WIXGBYQCSA-N C[C@@H]([C@](C[n]1ncnc1)(c1ccc(C)cc1F)OCC(O)OC)c(ncnc1)c1F Chemical compound C[C@@H]([C@](C[n]1ncnc1)(c1ccc(C)cc1F)OCC(O)OC)c(ncnc1)c1F FGKZXIDPWRHSJN-WIXGBYQCSA-N 0.000 description 1
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 pharmaceutical chemistry field, be specifically related to the preparation method of a kind of water soluble triazole compound and this compound.
Background technology
Antifungal drug in triazole class is the especially medicine of deep mycosis of the most widely used present treatment mycosis.It is that a carbon atom in the imidazole ring is replaced the five-membered ring obtain by nitrogen, have lower toxicity than imidazoles and appear at widely in multiclass medicine, the agricultural chemicals as the pharmacophore triazole, and existing so far numerous triazole type medicine is used for clinical and agriculture.As the important function base, triazole has stronger complexation of metal ions and enjoys favor with the ability that forms hydrogen bond at chemical field.Its mechanism of action be on the triazole ring N-4 through with fungal cell's pigment P-450 in the iron atom coordination at iron porphyrin center; Suppress the substrate demethylation reaction; Cause the important substance ergosterol that forms cytolemma to lack; Lanosterol is accumulated, and causes fungal cell's film rupture, reaches antibacterial and germ-resistant effect.
Mycosis is deep mycosis especially, and on traditional treatment, amphotericin B is a standard drug, but this poisonous side effect of medicine is bigger, for this reason, has developed liposome administration system.The exploitation of antifungal drug in triazole class listing is that to amphotericin B replenishes.Early be used for the Triaconazole (Terconazole) that clinical triazole antifungal agent is the nineteen eighty-three listing.Started the triazole compounds antifungal therapy beginning, caused very big interest the triazole class compounds research and development.Afterwards, itraconazole (Itraconazole) and fluconazole (Fluconazole) sequential use are in clinical.Triazole antifungal agent, like fluconazole, Vorionazole long half time, efficient, low toxicity, but not only taking orally but also intravenously administrable clinically are used to treat deep fungal infection, and good effect, untoward reaction are little.But because the water miscible problem of such medicine, or make jumbo infusion solutions, or add solubility promoter and make the suitable clinical preparation of using, but also bring the risk of security simultaneously.
To this problem, Many researchers is carried out structural modification to antifungal drug in triazole class,, reduction toxicity water-soluble to increase; The one, form the SULPHOSUCCINIC ACID ESTER prodrug, like the phosphorus fluconazole (Fosfluconazole) of listing in 2003, be the SULPHOSUCCINIC ACID ESTER of fluconazole; Compare water-soluble increase with fluconazole; Anti-mycotic activity is strong, and security is good, mainly acts on Candida and genera cryptococcus fungi.The 2nd, utilize that nitrogen-atoms becomes quaternary ammonium salt on the triazole ring, can increase that it is water-soluble.The 3rd, utilize natural glucose to contain the characteristics of poly-hydroxy, good water solubility, form the new type water-solubility glycosyl compound.
We are in the long-term exploratory development process to the antifungal triazole compounds of hydroxyl, and discovery can utilize the functional group of hydroxyl to change increases the water-soluble of this compounds, and has obtained great successes.In we the previous CN200810025585.7 that delivers, be to utilize with di-carboxylic acid that can be medicinal to carry out behind the single-esterification again and pharmaceutically useful alkaline metal ions and amino acid salify.Expand for the further excavation to this field, we study other analog derivative that has prepared such medicine, and this analog derivative all has better water-solubility, and lower toxicity has strengthened medicinal security.
Summary of the invention
The purpose of this invention is to provide the new type water-solubility triazole derivative, introduce new functional group on the basis of efficient, the broad-spectrum antifungal compound of in clinical application at present and new drug development process, finding, it is water-soluble thereby increase, and reduces toxicity.Be the verivate of antifungal drug in triazole class, it is wide to have an anti-fungus spectra, characteristics such as anti-mycotic activity is strong, and security is good.
Another object of the present invention provides the preparation method of above-mentioned new type water-solubility triazole derivative.
A further object of the invention provides the purposes of above-mentioned new type water-solubility triazole derivative aspect preparation treatment fungi infestation medicine.
The object of the invention can reach through following measure:
A kind of water soluble triazole compound, its structural formula is following:
Formula Ia
Or
Formula Ib
Or
Formula Ic
Or
Formula Id
Wherein, R
1It is formula II group
Formula II
Say that further water soluble triazole compound of the present invention has following structure:
Formula Ia formula Ib
Formula Ic formula Id
Among the present invention,
X is 0～6 integer, is preferably 0～4 integer, as 0,1,2,3 or 4; So x is 0 o'clock in the formula Ia structure, compound is a formate; X is 1 o'clock, and compound is an acetate; X is 2 o'clock, the compound propionic salt; X is 3 o'clock, and compound is a butyrates.
Y is 1～6 integer, is preferably 1～3 integer, as 1,2 or 3; So y is 1 o'clock in the Ib structure, compound is a methoxyl group phosphoric acid salt; Y is 2 o'clock, compound oxyethyl group phosphoric acid salt; Y is 3 o'clock, and compound is a propoxy-phosphoric acid salt.
M, M '
N+Or M "
N+Be respectively metals ion, be preferably sodium ion, potassium ion, calcium ion or mg ion, concrete like Na
+, K
+, Mg
2+, Ca
2+Deng;
R
2Or R
3Be respectively H or
X ' is 0～6 integer, and x ' is preferably 0～4 integer;
R
4Be H, C
1-4Alkyl or halogen, be preferably H or C
1-4Alkyl.
R in the Ic structure
2, R
3, R
4During for H, compound is 1, the 2-dihydroxypropyl; R
2Be hydroxyl, R
4Be H, R
3For
The time, compound is the 2-hydroxycarboxylate; R
3Be hydroxyl, R
4Be H, R
2For
The time, compound is 3-hydroxyl-2-carboxylate salt; R
4Be H, R
2, R
3For
The time, compound is a 2-hydroxydicarboxylic acid salt.
Formula II unit structure comprises cis-structure and transconfiguration; R ' is for to have the 5-member heterocyclic ring containing nitrogen of substituting group or unsubstituted, hexa-atomic nitrogen heterocyclic ring, phenyl or hydrogen, and wherein said substituting group is selected from halogen, C
1-4Alkyl, cyanic acid or cyano-phenyl in one or more.R ' is H, have replace or do not have substituted triazolyl, have replace or do not have substituted pyrimidyl, have replace or when not having substituted thiazolyl the anti-microbial activity of compound better, wherein said substituting group is selected from one or more in halogen, cyanic acid or the cyano-phenyl.R ' most preferably is H, 1,2,4-triazole-1-base, 5-fluorine pyrimidine-4-base or 4-(4-cyano-phenyl)-2-thiazolyl.
R " is H or C
1-4Alkyl, be preferably H or methyl.
Water soluble triazole compound of the present invention comprises the optically active isomer of this water soluble triazole compound.
R of the present invention
1Group most preferably adopts following structure:
2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy-of 3-,
(2R, 3S)-2-(2,4 difluorobenzene base)-3-(5-fluorine pyrimidine-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butoxy, perhaps
(2R, 3S)-2-(2,4 difluorobenzene base)-3-[4-4-(nitrile phenyl)-2-thiazolyl]-1-(1H-1,2,4-triazol-1-yl)-2-butoxy.
The working method of formula Ia of the present invention, formula Ib, formula Ic and Id perhaps further is transformed into its pharmaceutical salts with the product that obtains for reacting with the compound and the following formula III compound that contain formula II group
Formula III
Wherein X is halogen or other blocking groups.
The preparation method of formula Ia of the present invention, formula Ib, formula Ic or formula Id compound is specific as follows:
Formula Ia compound:
Wherein X is a halogen;
The solvent of reaction can be non-proton organic solvents such as N, dinethylformamide, DMAC N,N, methyl-sulphoxide, acetone, acetonitrile.Preferred N, dinethylformamide, methyl-sulphoxide.Temperature of reaction can be reacted between 0 ℃ to 80 ℃.Preferred 50-70 ℃.Reaction times the best is 2-4 hour.
Formula Ib compound:
The solvent of reaction can be acetone, ETHYLE ACETATE, N, and dinethylformamide, DMAC N,N, methyl-sulphoxide, THF, dioxane, acetonitrile etc. do not contain the organic solvent of reactive hydrogen.Preferred acetone, ETHYLE ACETATE, THF, acetonitrile.Temperature of reaction can be reacted between 0 ℃ to 100 ℃.Reaction times the best is 3-6 hour.
Formula Ic compound:
The solvent of reaction can be acetone, ETHYLE ACETATE, N, and dinethylformamide, DMAC N,N, methyl-sulphoxide, THF, dioxane etc. do not contain the organic solvent of reactive hydrogen.Preferred acetone, ETHYLE ACETATE, THF, dioxane.Temperature of reaction can be reacted between-10 ℃ to 100 ℃.Preferred 50-70 ℃.Reaction times the best is 3-6 hour.
In this reaction formula, like R
2And R
3Be H, then can only carry out the first step reaction.
Formula Id compound:
Forming phosphatase reaction can react in inorganic phosphorous compounds such as phosphorus trichloride, POCl3, five phosphorus oxide, phosphorus pentachloride, preferred POCl3.The solvent of salt-forming reaction can be organic solvents such as acetone, ETHYLE ACETATE, N, dinethylformamide, DMAC N,N, methyl-sulphoxide, THF, dioxane.Preferred acetone, ETHYLE ACETATE, THF, dioxane.Temperature of reaction can be reacted between-10 ℃ to 100 ℃.Preferred 50-70 ℃.Reaction times the best is 3-6 hour.
R in above-mentioned each reaction equation
1-H does
In each reaction equation, x, y, M, M '
N+, M "
N+, R
2, R
3, R
4, R ' or R " definition as stated.
Compound of the present invention belongs to the prodrug of antifungal drug in triazole class, and it can be hydrolyzed enzyme in vivo or other enzymic hydrolysiss are antifungal drug in triazole class:
This medicine and then bring into play antimycotic effect in vivo.
Pharmaceutical active compounds of the present invention can use or be mixed with pharmaceutical composition separately and use, and said pharmaceutical composition also contains medicine acceptable carrier, auxiliary agent or thinner except that containing active triazole composition.Can in several ways this compound be carried out administration, for example oral administration, topical or parenteral administration (intravenous injection or intramuscular injection).This pharmaceutical composition can be a solid-state form, like capsule, tablet, powder etc., or liquid form, like solution, suspensoid or emulsion.Composition for injection can prepare in Chengan County's bottle or multi-dose container in unit dosage, and can contain additive such as suspension agent, stablizer and dispersion agent.Said composition can be the i.e. form of usefulness, or when sending, carries out reconstituted powder type with the carrier such as the sterilized water that are fit to.
Another is selected, and compound of the present invention can carry out administration with the form of suppository or vagina agent, and perhaps they can washing lotion, the form of solution or emulsifiable paste carries out topical application.In addition, can they be incorporated into (with up to 10% concentration) by Chinese wax or soft, white paraffin alkali in the ointment that required stablizer and/or sanitas are formed.
Compound of the present invention is useful, because they are animal, particularly comprise in Mammals (the most human) body having pharmacological activity.Specifically; Compound of the present invention can be used for treatment or the prevention local fungal infects; Comprise those infection that cause by mycocandida, trichophyton, little robe Pseudomonas or Epidermophyton. in addition, they can be used for treatment by the caused mucosal infections of white candiyeast.They can also be used for treating by following fungus-caused whole body fungi infestation: for example white candiyeast, novel Cryptococcus, flavus, Aspergillus fumigatus, ball robe Pseudomonas, secondary ball robe Pseudomonas, Histoplasma or Blastomyces.
Therefore, according to another aspect of the present invention, a kind of method of treating fungi infestation is provided, this method comprise with the treatment significant quantity compound to acceptor, particularly mammalian receptors, the most particularly human patients carry out administration.Also provide the purposes of compound of the present invention, and treated the purposes of the medicine of fungi infestation with compound manufacturing of the present invention as medicine.
The dosage of administration depends on concrete compsn, the route of administration of used particular compound, preparation, the attribute and the situation of acceptor to a great extent, and the concrete position and the organism of treatment.Then; Yet judge concrete preferred dosage and the selection of using the path by doctor or animal doctor.; Usually this compound being carried out parenteral administration or oral administration with the amount of about 5mg/ days～1.0g/ days to mammalian receptors. these dosage are demonstrations of average case; Possibly in the discrete situation, use higher or lower dosage, this type dosage is within scope of the present invention.And, can be disposable or be divided into many parts compound of the present invention carried out administration.
Through measuring minimum inhibitory concentration (MIC) anti-mycotic activity by the compound of the inventive method preparation is carried out in-vitro evaluation.MIC is the concentration of test compound ability inhibition test microorganism growth.In practice, fungal bacterial strain is implanted in the agar plate of a series of test compounds that added certain concentration, then each plate was cultivated 48 hours down at 37 ℃.To check these plates, see whether there is fungal growth, the concentration that record is relevant. the mikrobe that can be used for this test comprises Candida albicans, Aspergillus fumigatus, trichophyton, little robe Pseudomonas, acrothesium floccosum, thick ball robe bacterium and torulopsis glabrata.Should admit that compounds more of the present invention do not have activity as prodrug in vitro tests.
Compound through with the present invention's preparation carries out peritoneal injection or intravenous injection or oral administration by a series of dosage levels to the mouse of having implanted fungi (for example Candida albicans) bacterial strain, comes the compound of the present invention's preparation is carried out interior evaluating.After death measure activity in untreated mouse group through the survival rate that the mouse of relatively having used the various dose level to treat is organized.Dosage level when the record test compound can provide 50% protection to the lethal effect that infects.
Beneficial effect of the present invention: The compounds of this invention is the wide spectrum of in clinical application at present and new drug development process, finding; Introduce new group on the architecture basics of efficient antifungal compound; Thereby it is water-soluble greatly to have increased it; Reduce toxicity, compare with existing compound and have more excellent performance.The prodrug of this antifungal drug in triazole class, it is wide to have an anti-fungus spectra, characteristics such as anti-mycotic activity is strong, and security is good.
On the basis of foregoing, according to the ordinary skill knowledge and the customary means of this area, under the prerequisite that does not break away from the above-mentioned basic fundamental thought of the present invention, can also make the modification of various ways, replacement or change.
Embodiment
Through the specific embodiments of following examples form, foregoing of the present invention further is elaborated.
Embodiment 1
(1) 4-[2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy-of 3-]-ethyl n-butyrate is synthetic
The 2-(2,4 difluorobenzene base)-1 that adds 30.6g (0.1mol) in the there-necked flask, two (1H-1,2,4-the triazol-1-yl)-2-propyl alcohol (fluconazole) of 3-, the 4-bromo-butyric acid ethyl ester of 27.2g (1.3mol), n-Bu4Br 2.5g, triethylamine 5mL, ethanol 100ml.Be warming up to back flow reaction 5 hours under stirring, cooling adds entry 100mL and stirs in the reaction mixture, ETHYLE ACETATE 150ml * 2 extractions.Be evaporated to dried, column chromatography for separation.Get yellow oil 17.6g, yield: 42.0%.
(2) 4-[2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy-of 3-]-Sodium propanecarboxylate is synthetic
Add with above-mentioned oily matter 17.6g (0.042mol) sodium hydroxide 1.8g (0.045mol), water 75ml, ethanol 50ml in the there-necked flask.Stirring reaction is 4 hours under the normal temperature, the yellow solid of concentrating under reduced pressure.With gained solid water 10ml, ethanol 35ml recrystallization obtains 15.5g faint yellow solid 89.0% [M+1]
+: 414.14, H-NMR (DOCH
3) δ ppm: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).
Embodiment 2
(1) 2-[2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy-of 3-]-ETHYLE ACETATE is synthetic
The 2-(2,4 difluorobenzene base)-1 that adds 30.6g (0.1mol) in the there-necked flask, two (1H-1,2,4-the triazol-1-yl)-2-propyl alcohol (fluconazole) of 3-, the 4-ethyl chloroacetate of 15.9g (1.3mol), n-Bu4Br 2.2g, triethylamine 5mL, ethanol 100ml.Be warming up to back flow reaction 5 hours under stirring, cooling adds entry 100mL and stirs in the reaction mixture, ETHYLE ACETATE 150ml * 2 extractions.Be evaporated to dried, column chromatography for separation.Get yellow oil 19.6g, yield: 50.1%.
(2) 4-[2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy-of 3-]-sodium acetate is synthetic
Add with above-mentioned oily matter 19.6g (0.05mol) sodium hydroxide 2.1g (0.053mol), water 80ml, ethanol 55ml in the there-necked flask.Stirring reaction is 4 hours under the normal temperature, the yellow solid of concentrating under reduced pressure.With gained solid water 12ml, ethanol 40ml recrystallization obtains 15.5g faint yellow solid 89.0% [M+1]
+: 414.14, H NMR (DOCH
3) δ ppm: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).
Embodiment 3
(1) 4-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy]-ethyl n-butyrate synthetic
Add in the there-necked flask 43.7g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butanols, the 4-bromo-butyric acid ethyl ester of 23.3g (0.12mol), n-Bu
4Br 2.2g, triethylamine 5mL, ethanol 120ml.Be warming up to back flow reaction 3 hours under stirring, cooling adds entry 100mL and stirs in the reaction mixture, ETHYLE ACETATE 150ml * 2 extractions.Be evaporated to dried, column chromatography for separation.Get yellow oil 23.7g, yield: 43.1%.
(2) 4-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy]-Sodium propanecarboxylate synthetic
Get step product 23.7g (0.043mol) sodium hydroxide 2.0g (0.05mol), water 100ml, ethanol 70ml.Stirring reaction is 4 hours under the normal temperature, the yellow solid of concentrating under reduced pressure.With gained solid water 15ml, ethanol 60ml recrystallization obtains 21.4g faint yellow solid 91.0%.[M+1]
+：545.5，H-NMR(DOCH
3)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).
Embodiment 4
(1) 2-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy]-ETHYLE ACETATE synthetic
Add in the there-necked flask 43.7g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butanols, the 4-METHYL BROMOACETATE of 19.9g (0.12mol), n-Bu
4Br 2.2g, triethylamine 5mL, ethanol 100ml.Be warming up to back flow reaction 5 hours under stirring, cooling adds entry 100mL and stirs in the reaction mixture, ETHYLE ACETATE 150ml * 2 extractions.Be evaporated to dried, column chromatography for separation.Get yellow oil 25.7g, yield: 49.0%.
(2) 2-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy]-sodium acetate synthetic
Get step product 25.7g (0.049mol) sodium hydroxide 2.0g (0.05mol), water 100ml, ethanol 70ml.Stirring reaction is 4 hours under the normal temperature, the yellow solid of concentrating under reduced pressure.With gained solid water 12ml, ethanol 55ml recrystallization obtains 22.3g faint yellow solid 88.0%.[M+1]
+：517.1，H-NMR(DOCH
3)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).
Embodiment 5
(1) 4-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy]-ethyl n-butyrate synthetic
Add in the there-necked flask 34.9g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butanols, the 4-bromo-butyric acid ethyl ester of 23.3g (0.12mol), n-Bu
4Br 2.2g, triethylamine 5mL, ethanol 120ml.Be warming up to back flow reaction 4 hours under stirring, cooling adds entry 100mL and stirs in the reaction mixture, ETHYLE ACETATE 150ml * 2 extractions.Be evaporated to dried, column chromatography for separation.Get yellow oil 19.96g, yield: 43.1%.
(2) 4-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy]-Sodium propanecarboxylate synthetic
Get step product 19.96g (0.043mol) sodium hydroxide 2.0g (0.05mol), water 100ml, ethanol 70ml.Stirring reaction is 4 hours under the normal temperature, the yellow solid of concentrating under reduced pressure.With gained solid water 12ml, ethanol 55ml recrystallization obtains faint yellow solid 17.9g 91.0%.[M+1]
+：545.5，H?NMR(DOCH
3)：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)。
Embodiment 6
(1) 2-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy]-ETHYLE ACETATE synthetic
Add in the there-necked flask 34.9g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butanols, the 4-METHYL BROMOACETATE of 19.9g g (0.12mol), n-Bu
4Br 2.2g, triethylamine 5mL, ethanol 120ml.Be warming up to back flow reaction 4 hours under stirring, cooling adds entry 100mL and stirs in the reaction mixture, ETHYLE ACETATE 150ml * 2 extractions.Concentrating under reduced pressure is as for, column chromatography for separation.Get yellow oil 23.49g, yield: 54.0%.
(2) 2-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy]-Sodium propanecarboxylate synthetic
Get step product 23.4g (0.054mol) sodium hydroxide 2.4g (0.06mol), water 120ml, ethanol 80ml.Stirring reaction is 4 hours under the normal temperature, the yellow solid of concentrating under reduced pressure.With gained solid water 12ml, ethanol 55ml recrystallization obtains faint yellow solid 20.4g, yield 87.0%.[M+1]
+：429.1，H?NMR(DOCH
3)：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)。
Embodiment 7
(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-methyl acid phosphate calcium synthetic
(1) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-methyl acid phosphate diethyl ester synthetic
Add in the there-necked flask 34.9g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butanols, DMF (98ml) be at N
2Protection down in-5 ℃ of stirrings add down 80%NaH (7g, 0.23mol).Stir and drip tosic acid diethoxy phosphonium mesitoyl base methyl esters (50.4g, DMF 0.16mol) (18ml) solution, equality of temperature stirring 4h down; HPLC shows that (remaining 4 the are no more than 3%) back that reacts completely drips glacial acetic acid (13.4ml), stirs lh, and reaction solution is evaporated to dried; Add methylene dichloride (60ml), filter, filter cake is used washed with dichloromethane; Filtrating and washing lotion merge, water 10ml * 3 washings, and water layer is used dichloromethane extraction 10ml * 3 again; The combined dichloromethane phase removes solvent under reduced pressure, freeze overnight behind the adding toluene in the residuum.Filter, filter cake gets white powder solid 27.9g, yield 56.0% in 50 ℃ of drying under reduced pressure.
(2) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-methyl acid phosphate synthetic
Add in the there-necked flask (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2; The 4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-methyl acid phosphate diethyl ester 27.9g (0.056mol), bromotrimethylsilane 74.2ml and acetonitrile 40ml be in stirring at room 3h, is warming up to back flow reaction 7h, is chilled to be evaporated to after the room temperature driedly, adds entry 80ml in the residuum; The adularescent deposition generates, and reactant is warming up to 55 ℃ and stirs 1h, is cooled to room temperature, adds saturated sodium hydroxide solution and transfers to pH 3.2; Stirring heating backflow 3h postcooling is to room temperature, and reactant refrigerator hold over night is filtered; Add entry 100ml in the filter cake, be heated to 75 ℃ and stir 1h, stop to heat suction filtration behind the restir 1h; Filter cake is water and ether washing successively, gets white solid 22.6g, yield 91.0%.
(3) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-methyl acid phosphate calcium synthetic
Add (2R in the there-necked flask; 3S)-2-(2; The 4-difluorophenyl)-1-(1H-1; 2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-methyl acid phosphate 22.6g (0.051mol) and ethanol 200ml under 50 ℃ of stirrings, slowly add hydration lime acetate 12g (0.076mol) contain the 20ml aqueous solution.Synthermal down stirring reaction half a hour, cold filtration, filter cake is with 70% aqueous solution recrystallization.Filtering white solid, 45 ℃ of vacuum-dryings get 23.9g, yield 97.5%.[M+1]
+：481.1，HNMR(DOCH
3)：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)。
Embodiment 8
2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy--methyl acid phosphate calcium of 3-synthetic
(1) 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy--methyl acid phosphate diethyl esters of 3-synthetic
The 2-(2,4 difluorobenzene base)-1 that adds 30.6g (0.1mol) in the there-necked flask, two (1H-1,2,4-the triazol-1-yl)-2-propyl alcohol of 3-, DMF (90ml) are at N
2Protection down in-5 ℃ of stirrings add down 80%NaH (7g, 0.23mol).Stir and drip tosic acid diethoxy phosphonium mesitoyl base methyl esters (50.4g, DMF 0.16mol) (15ml) solution, equality of temperature stirring 4h down; HPLC shows that (remaining 4 the are no more than 4%) back that reacts completely drips glacial acetic acid (13ml), stirs lh, and reaction solution is evaporated to dried; Add methylene dichloride (60ml), filter, filter cake is used washed with dichloromethane; Filtrating and washing lotion merge, water 10ml * 3 washings, and water layer is used dichloromethane extraction 10ml * 3 again; The combined dichloromethane phase removes solvent under reduced pressure, freeze overnight behind the adding toluene in the residuum.Filter, filter cake gets white powder solid 27.3g, yield 60.0% in 50 ℃ of drying under reduced pressure.
(2) 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy--methyl acid phosphates of 3-synthetic
Add 2-(2,4 difluorobenzene base)-1 in the there-necked flask, 3-two (1H-1,2; The 4-triazol-1-yl)-2-propoxy--methyl acid phosphate diethyl ester 27.3g (0.06mol), bromotrimethylsilane 74.2ml and acetonitrile 40ml be in stirring at room 3h, is warming up to back flow reaction 7h, is chilled to be evaporated to after the room temperature driedly, adds entry 80ml in the residuum; The adularescent deposition generates, and reactant is warming up to 55 ℃ and stirs 1h, is cooled to room temperature, adds saturated sodium hydroxide solution and transfers to pH 3.2; Stirring heating backflow 3h postcooling is to room temperature, and reactant refrigerator hold over night is filtered; Add entry 100ml in the filter cake, be heated to 75 ℃ and stir 1h, stop to heat suction filtration behind the restir 1h; Filter cake is water and ether washing successively, gets white solid 21.4g, yield 89.0%.
(3) 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propoxy--methyl acid phosphate calcium of 3-synthetic
Add 2-(2,4 difluorobenzene base)-1 in the there-necked flask, what two (1H-1,2,4-the triazol-1-yl)-2-propoxy-of 3--methyl acid phosphate 21.4g (0.053mol) and ethanol 200ml slowly added hydration lime acetate 12g (0.076mol) under 50 ℃ of stirrings contains the 20ml aqueous solution.Synthermal down stirring reaction half a hour, cold filtration, filter cake is with 70% aqueous solution recrystallization.Filtering white solid, 45 ℃ of vacuum-dryings get 20.8g, yield 98%.[M+1]
+：438.14，H?NMR(DOCH
3)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)。
Embodiment 9
(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy-methyl acid phosphate calcium synthetic
(1) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy-methyl acid phosphate diethyl ester synthetic
Add in the there-necked flask 43.6g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butanols, DMF (90ml) is at N
2Protection down in-5 ℃ of stirrings add down 80%NaH (7g, 0.23mol).Stir and drip tosic acid diethoxy phosphonium mesitoyl base methyl esters (50.4g, DMF 0.16mol) (15ml) solution, equality of temperature stirring 4h down; HPLC shows that (remaining 4 the are no more than 4%) back that reacts completely drips glacial acetic acid (13ml), stirs lh, and reaction solution is evaporated to dried; Add methylene dichloride (60ml), filter, filter cake is used washed with dichloromethane; Filtrating and washing lotion merge, water 10ml * 3 washings, and water layer is used dichloromethane extraction 10ml * 3 again; The combined dichloromethane phase removes solvent under reduced pressure, freeze overnight behind the adding toluene in the residuum.Filter, filter cake gets white powder solid 30.5g, yield 55.0% in 50 ℃ of drying under reduced pressure.
(2) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy-methyl acid phosphate synthetic
Add in the there-necked flask (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2; The 4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy-methyl acid phosphate diethyl ester 30.5g (0.055mol), bromotrimethylsilane 74.2ml and acetonitrile 40ml be in stirring at room 3h, is warming up to back flow reaction 7h, is chilled to be evaporated to after the room temperature driedly, adds entry 80ml in the residuum; The adularescent deposition generates, and reactant is warming up to 55 ℃ and stirs 1h, is cooled to room temperature, adds saturated sodium hydroxide solution and transfers to pH3.2; Stirring heating backflow 3h postcooling is to room temperature, and reactant refrigerator hold over night is filtered; Add entry 100ml in the filter cake, be heated to 75 ℃ and stir 1h, stop to heat suction filtration behind the restir 1h; Filter cake is water and ether washing successively, gets white solid 25.7g, yield 94%.
(3) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy-methyl acid phosphate calcium synthetic
Add (2R in the there-necked flask; 3S)-2-(2; The 4-difluorophenyl)-1-(1H-1; 2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy-methyl acid phosphate 25.7g (0.052mol) and ethanol 200ml under 50 ℃ of stirrings, slowly add hydration lime acetate 12g (0.076mol) contain the 20ml aqueous solution.Synthermal down stirring reaction half a hour, cold filtration, filter cake is with 70% aqueous solution recrystallization.Filtering white solid, 45 ℃ of vacuum-dryings get 26.9g, yield 91%.[M+1]
+：569.1，H?NMR(DOCH
3)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).
Embodiment 10
3-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy]-1,2-Ucar 35 synthetic
Add in the there-necked flask 34.9g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butanols, DMF (98ml) be at N
2Protection down in-5 ℃ of stirrings add down 80%NaH (7g, 0.23mol).(equality of temperature stirs 4h for 8.8g, DMF 0.12mol) (20ml) solution, drips glacial acetic acid (12ml), stirs 1h, and it is dried that reaction solution is evaporated to, and adds 100ml absolute ethyl alcohol recrystallization to R-GLYCIDOL to stir dropping down.Get white solid 33.0g, yield 78.0%.[M+1]
+：423.2，H?NMR(DOCH
3)：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)。
Embodiment 11
3-[2-(2,4 difluorobenzene base)-1,3-two (1H-1,2,4-triazol-1-yl)-2-propoxy-]-1,2-Ucar 35 synthetic
Add in the there-necked flask 30.6g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butanols, DMF (98ml) be at N
2Protection down in-5 ℃ of stirrings add down 80%NaH (7g, 0.23mol).(equality of temperature stirs 4h for 8.8g, DMF 0.12mol) (20ml) solution, drips glacial acetic acid (12ml), stirs 1h, and it is dried that reaction solution is evaporated to, and adds 100ml absolute ethyl alcohol recrystallization to R-GLYCIDOL to stir dropping down.Get white solid 30.8g, yield 81.0%.[M+1]
+：380.1，H?NMR(DOCH
3)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)。
Embodiment 12
3-[(2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butoxy]-1,2-Ucar 35 synthetic
Add in the there-necked flask 43.7g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butanols, DMF (98ml) be at N
2Protection down in-5 ℃ of stirrings add down 80%NaH (7g, 0.23mol).(equality of temperature stirs 4h for 8.8g, DMF 0.12mol) (20ml) solution, drips glacial acetic acid (12ml), stirs 1h, and it is dried that reaction solution is evaporated to, and adds 100ml absolute ethyl alcohol recrystallization to R-GLYCIDOL to stir dropping down.Get white solid 37.8g, yield 74.0%.[M+1]
+：511.2，HNMR(DOCH
3)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).
Embodiment 13
(1) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-phosphoric acid synthetic
Add in the there-necked flask 34.9g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butanols, 50 ℃ of left and right sides heating for dissolving of pyridine (500ml).Be cooled to 5 ℃, at N
2Protection adds PCl down in stirring down
3(153.0g, 1.0mol).Dropwise, slowly be warming up to room temperature, continue stirring reaction 4h.Be cooled to 5 ℃, add water 2L, extract 500ml * 2 with MIBK.Merge organic layer.The hydrochloric acid 1L that adds 2mol/L is in 50 ℃ of stirring reaction 2h.Reduce to room temperature, static layering is obtained organic layer, and with saturated aqueous common salt 600ml washing, anhydrous sodium sulfate drying filters, and filtrate steaming removal solvent obtains yellow oil 51.2g, does not need purifying, directly is used for step reaction down.
(2) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-calcium phosphate synthetic
Add above-mentioned oily matter 51.2g, ethanol 300ml in the there-necked flask, stirring and dissolving slowly splashes into the aqueous solution 150ml of hydration lime acetate 19.4g (0.12mol) under 50 ℃ of stirrings.The synthermal 30min of reaction down.Reduce to room temperature, suction filtration.Filter cake washs with 50% ethanol 20ml.In 45 ℃ of following drying under reduced pressure.Get needle-like crystal 34.8g, yield 74.5%.[M+1]
+：467.4，H?NMR(DOCH
3)：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)。
Embodiment 14
(1) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-ethyl formate synthetic
Add in the there-necked flask 34.9g (0.1mol) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butanols, toluene (500ml), pyridine 5ml, triethylamine 40ml, 50 ℃ of left and right sides heating for dissolving.Be cooled to about 0 ℃, at N
2Protection down in stir add down the chloroformyl ethyl ester (12.96g, 0.12mol).Dropwise, slowly be warming up to room temperature, continue stirring reaction 4h.Reaction solution is poured in the frozen water into stirring and crystallizing.Need not after the filtration to handle and directly be used for step reaction down.
(2) (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butoxy-sodium formiate synthetic
Add above-mentioned solid, sodium hydroxide 4.8g (0.12mol), water 200ml, ethanol 80ml in the there-necked flask.Stirring reaction is 4 hours under the normal temperature, the yellow solid of concentrating under reduced pressure.With gained solid water 10ml, ethanol 60ml recrystallization obtains faint yellow solid 31.9g, yield 77.0%.[M+1]
+：429.1，H?NMR(DOCH
3)：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)。
Embodiment 15
To 12 corresponding compounds of the foregoing description 1 to example, carry out solubility test in the water 25 ℃ of room temperatures by ordinary method, and compare with the parent compound that does not carry out functional group's conversion.
Wherein, parent compound 1 is: 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-the triazol-1-yl)-2-propyl alcohol of 3-
Parent compound 2 is: (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-[4-(4-cyano-phenyl)-3-thiazolyl]-2-butanols
Parent compound 3 is: (2R, 3S)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl)-3-(5-fluoro-4-pyrimidyl)-2-butanols
Its result sees table 1, table 2 and table 3.
Table 1:
Table 2:
Table 3:
Claims (9)
1. water soluble triazole compound, its structural formula is following:
Wherein, R
1It is formula II group
Wherein,
X is 0～6 integer, and M is a metals ion,
R
2Or R
3Be respectively H or
X ' is 0～6 integer,
R
4Be H, C
1-4Alkyl or halogen,
R ' is for to have the 5-member heterocyclic ring containing nitrogen of substituting group or unsubstituted, hexa-atomic nitrogen heterocyclic ring, phenyl or hydrogen, and wherein said substituting group is selected from halogen, C
1-4Alkyl, cyanic acid or cyano-phenyl in one or more,
R " is H or C
1-4Alkyl.
2. water soluble triazole compound according to claim 1; It is characterized in that R ' for H, have and replace or do not have substituted triazolyl, have and replace or do not have substituted pyrimidyl, have and replace or do not have substituted thiazolyl, wherein said substituting group is selected from one or more in halogen, cyanic acid or the cyano-phenyl.
3. water soluble triazole compound according to claim 2 is characterized in that R ' is H, 1,2,4-triazole-1-base, 5-fluorine pyrimidine-4-base or 4-(4-cyano-phenyl)-2-thiazolyl.
4. water soluble triazole compound according to claim 1 is characterized in that R " is H or methyl.
5. water soluble triazole compound according to claim 2 is characterized in that R
1For
6. water soluble triazole compound according to claim 1 is characterized in that x is 0～4 integer.
7. water soluble triazole compound according to claim 1 is characterized in that M is sodium ion or potassium ion; R
2Or R
3Be respectively H or
X ' is 0～4 integer.
8. the compound method of the described water soluble triazole compound of claim 1 is characterized in that the preparation method of formula Ic compound is following:
Formula Ic compound:
R wherein
1-H does
Said R
1, R
2, R
3, R
4, R ' or R " definition with claim 1.
9. the purposes of the described water soluble triazole compound of claim 1 aspect preparation treatment fungi infestation medicine.
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| JP2020506950A (en) | 2017-02-08 | 2020-03-05 | バイエル アクチェンゲゼルシャフトＢａｙｅｒ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Triazolethione derivative |
| WO2019091898A1 (en) | 2017-11-09 | 2019-05-16 | Bayer Aktiengesellschaft | Process for the preparation of 5-substituted imidazole derivatives and manganese compounds useful therefor |
| EP3710432A1 (en) | 2017-11-13 | 2020-09-23 | Bayer Aktiengesellschaft | Tetrazolylpropyl derivatives and their use as fungicides |
| WO2019162228A1 (en) | 2018-02-21 | 2019-08-29 | Bayer Aktiengesellschaft | 1-(5-substituted imidazol-1-yl)but-3-en derivatives and their use as fungicides |
| CN108676031A (en) * | 2018-05-29 | 2018-10-19 | 重庆威鹏药业有限公司 | Water-soluble triazole antifungal phosphinic acid compounds and its preparation method and application |
-
2010
- 2010-05-13 CN CN2010101711214A patent/CN101824002B/en active Active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2813499A1 (en) * | 2013-06-12 | 2014-12-17 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds |
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| CN101824002A (en) | 2010-09-08 |
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