CN1303073C - Substituted triazolone benzyl amine triazole antifungal compounds and method for preparing same - Google Patents

Substituted triazolone benzyl amine triazole antifungal compounds and method for preparing same Download PDF

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CN1303073C
CN1303073C CNB2005100263313A CN200510026331A CN1303073C CN 1303073 C CN1303073 C CN 1303073C CN B2005100263313 A CNB2005100263313 A CN B2005100263313A CN 200510026331 A CN200510026331 A CN 200510026331A CN 1303073 C CN1303073 C CN 1303073C
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methyl
tertbutyloxycarbonyl
triazole
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CN1699351A (en
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张万年
盛春泉
姚建忠
张珉
缪震元
徐辉
张晶
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Second Military Medical University SMMU
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Second Military Medical University SMMU
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Abstract

The present invention provides a novel triazole alcohol antifungal compound, namely a 1-(1H-1, 2, 4-triazole-1-base)-2-(2, 4-difluorophenyl)-3-[N-methyl-N-(2-substitution-2H-1, 2, 4-triazole-3-ketone-4-base) benzylamino]-2-propyl alcohol compound, salt and a preparation method thereof, which relates to the technical field of medicine. The compound has strong antifungal effect on various fungi on superficial parts and deep parts. Compared with the existing antifungal medicines for clinical application, the compound has the advantages of high efficiency, low toxicity and wide antifungal spectrum, and is capable of being used for preparing novel antifungal medicines.

Description

Substituted triazolone benzyl amine triazole antifungal compounds and preparation method thereof
Technical field
The present invention relates to medical technical field, be a kind of novel trinitrogenazole alcohol antifungal compound---1-(1H-1,2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-[N-methyl-N-(2-replacement-2H-1,2,4-triazole-3-ketone-4-yl) benzamido group]-2-propanol compound and its esters and preparation method.
Background technology
In recent years, extensive application along with broad-spectrum antibiotics, antitumour drug, immunosuppressor, extensively carrying out of radiotherapy and organ transplantation, generally carrying out of conduit and intubate, and especially AIDS patient's increase rapidly of immune deficiency patient, cause fungi infestation particularly deep fungal infection rise significantly, deep fungal infection has now become major disease main causes of death such as acquired immune deficiency syndrome (AIDS) and tumour.But with regard to the antifungal drug of present clinical application, have that side effect is big, narrow antimicrobial spectrum, easily produce problem such as resistance, effectively the particularly anti-deep fungal medicine of antifungal drug extremely lacks, and far can not satisfy the treatment needs.Existing antifungal drug is mainly the propylamine that acts on the squalene cyclooxygenase, acts on the nitrogen azole of lanosterol 14 α demethylases and act on lipopeptid class of cell walls β-(1,3)-glucan synthase etc.But yet there are no 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[N-methyl-N-(2-replacement-2H-1,2,4-triazole-3-ketone-4-yl) benzamido group so far]-report of 2-propanol compound and anti-mycotic activity thereof.
Summary of the invention
The invention provides-kind efficient, the novel diazo alcoholic antifungal compound of low toxicity, wide spectrum, comprise 1-(1H-1,2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-[N-methyl-N-(2-replacement-2H-1,2,4-triazole-3-ketone-4-yl) benzamido group]-hydrochloride, nitrate, hydrobromate and the methane sulfonates of 2-propanol compound (comprise its raceme, and R type or S type isomer) and this compounds.
The general structure of The compounds of this invention is as follows:
Wherein: X group representation hydroxy or ester group
The ester group here refers to the straight or branched ester group of 1～4 carbon atom and has the ester group of easy leavings group, as formic acid ester group, acetate groups, propionic acid ester group, isopropyl acid ester group, tertiary butyl formic acid ester group, phenylformic acid ester group, toluylic acid ester group, N, N-diethylamide ethylamino benzonitrile perester radical etc.Special preferred tertiary butyl formic acid ester group and N, N-diethylamide ethylamino benzonitrile perester radical.
Y group is represented the various substituting groups on the aromatic ring, the position of substitution can be positioned at the neighbour,, contraposition.Can be single replacement, also can be polysubstituted.Substituting group refers to:
(1) halogen, preferred especially 2 as F, Cl, Br, I, 4-difluoro or 2, the 4-dichloro replaces;
(2) aliphatic chain, as methyl, ethyl, trifluoromethyl, the tertiary butyl etc., preferred trifluoromethyl replaces.
The M group is represented hydrogen or methyl, special preferable methyl.
The representative of R group
(1) benzyl or substituted benzyl
On the substituted benzyl phenyl ring substituting group can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group refers to:
A. halogen, preferred especially 2 as F, Cl, Br, I, the 4-difluoro replaces and the replacement of 4-iodine;
B.1～5 the straight or branched alkyl of a carbon atom, as methyl, ethyl, the tertiary butyl etc., special preferred tertiary butyl;
C. trifluoromethyl, trifluoromethoxy, cyano group, nitro, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido, preferred especially trifluoromethyl and trifluoromethoxy;
The straight or branched alkyl of (2) 1～5 carbon atoms, as methyl, ethyl, trifluoromethyl, the tertiary butyl, tert-pentyl etc., preferred especially 2-amyl group replaces and the 3-amyl group replaces;
(3) 2-oxo styroyl or replacement 2-oxo styroyl
Replace on the 2-oxo styroyl phenyl ring substituting group can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group refers to:
A. halogen, preferred especially 2 as F, Cl, Br, I, the 4-difluoro replaces and the replacement of 4-iodine;
B.1～5 the straight or branched alkyl of a carbon atom, as methyl, ethyl, the tertiary butyl etc., special preferred tertiary butyl;
C. trifluoromethyl, trifluoromethoxy, cyano group, nitro, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido, preferred especially trifluoromethyl and trifluoromethoxy;
(4) phenyl or substituted-phenyl
Substituting group on the substituted-phenyl phenyl ring can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group is meant:
A. halogen, as F, Cl, Br, I, preferred especially iodine atom;
B.1～5 the straight or branched alkyl of a carbon atom, as methyl, ethyl, the tertiary butyl etc., special preferred tertiary butyl;
C. trifluoromethyl, trifluoromethoxy, cyano group, nitro, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido, preferred especially trifluoromethyl and trifluoromethoxy.
The The compounds of this invention salt comprises: hydrochloride, nitrate, hydrobromate and methane sulfonates.
Above-mentioned substituted triazolone benzyl amine triazole compound can be its raceme, also can be its R type or S type isomer.Through the test anti-mycotic efficiency preferably compound be the respectively following compound of combination of X, Y, M and R group:
(1) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 4-trifluoro-methoxybenzyl.
(2) the X group is an acetate groups, and Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is the 4-trifluoromethyl benzyl.
(3) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is the 4-luorobenzyl.
(4) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is a 4-benzyl chloride base.
(5) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is a 4-iodine benzyl.
(6) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is a 4-cyano group benzyl.
(7) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is the 4-methoxy-benzyl.
(8) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is 2, the 4-difluorobenzyl.
(9) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-trifluoromethoxy 2-oxo styroyl.
(10) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-trifluoromethyl 2-oxo styroyl.
(11) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-fluorine 2-oxo styroyl.
(12) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-chlorine 2-oxo styroyl.
(13) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-iodine 2-oxo styroyl.
(14) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is 2,4-difluoro 2-oxo styroyl.
(15) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-cyano group 2-oxo styroyl.
(16) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 4-Trifluoromethoxyphen-l.
(17) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 4-trifluoromethyl.
(18) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 4-nitrophenyl.
(19) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 2-amyl group.
(20) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 3-amyl group.
The building-up reactions flow process of The compounds of this invention is as follows:
Figure C20051002633100131
The synthetic of The compounds of this invention salt is on the basis of above-mentioned reaction, further does following reaction:
Figure C20051002633100132
Wherein HX represents hydrochloride, nitrate, hydrobromate or methane sulfonates.
Concrete steps are:
(1) preparation N-methyl is to nitro-benzylamine (II)
4-nitro bromobenzyl and methylamine alcohol solution reaction generate N-methyl-4-nitro-benzylamine (II);
(2) preparation N-methyl-N-tertbutyloxycarbonyl-4-nitro-benzylamine (III)
N-methyl-to nitro-benzylamine (II) is at CH 2Cl 2Down, through (BOC) 2O protect N-methyl-N-tertbutyloxycarbonyl-4-nitro-benzylamine (III);
(3) preparation N-methyl-N-tertbutyloxycarbonyl-4-amido benzylamine (IV)
N-methyl-N-tertbutyloxycarbonyl-4-nitro-benzylamine (III) through nickel/hydrazine hydrate reduction reaction 10h, generates N-methyl-N-tertbutyloxycarbonyl-4-amido benzylamine (IV) in ethanol;
(4) preparation N-methyl-N-tertbutyloxycarbonyl-(4-carbobenzoxy amino) benzylamine (V)
N-methyl-N-tertbutyloxycarbonyl-4-amido benzylamine (IV) is an alkali with the pyridine in ethyl acetate, with phenyl chloroformate reaction 3h, generates N-methyl-N-tertbutyloxycarbonyl-(4-carbobenzoxy amino) benzylamine (V);
(5) preparation 4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) anilino urea (VI)
N-methyl-N-tertbutyloxycarbonyl-(4-carbobenzoxy amino) benzylamine (V) in glycol dimethyl ether with 85% hydrazine hydrate room temperature reaction 24h, hydrazinolysis product 4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) anilino urea (VI);
(6) preparation 4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl-2H-1,2,4-triazole-3-ketone (VII)
4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) anilino urea (VI) generates 4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl-2H-1,2,4-triazole-3-ketone (VII) with carbonamidine acetate generation ring-closure reaction under the acetic acid existence condition in DMF;
(7) preparation 2-replacement-4-[4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (VIII)
4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl-2H-1,2,4-triazole-3-ketone (VII) is in DMF, with K 2CO 3Be alkali, react 8～12h with various halides, generate 2-replacement-4-[4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl at 80 ℃]-2H-1,2,4-triazole-3-ketone (VIII);
(8) preparation 2-replacement-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (IX)
2-replacement-4-[4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (VIII) and 10% hydrochloric acid reaction 24h are sloughed the BOC protecting group and are generated 2-replacement-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (IX);
(9) preparation 2-chloro-2 ', 4 '-difluoro acetophenone (XI)
M-difluorobenzene (X) and chloroacetyl chloride are at anhydrous AlCl 3The middle Friedel-Crafts reaction that takes place generates 2-chloro-2 ', 4 '-difluoro acetophenone (XI);
(10) preparation 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (XII)
2-chloro-2 ', 4 '-difluoro acetophenone (XI) and triazole, 3-ethyl benzyl ammonium chloride (TEBA) and K 2CO 3At CH 2Cl 2In 0～5 ℃ of reaction 5 hours, then, generate 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (XII) room temperature reaction 24 hours;
(11) preparation 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (XIII)
2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (XII) and iodate trimethylammonium oxygen sulphur, trimethylammonium hexadecyl brometo de amonio, reaction generates 1-[2-(2,4 difluorobenzene base)-2 in toluene and sodium hydroxide, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (XIII);
(12) preparation target compound (XIV)
2-replacement-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (IX) and 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (XIII) is in ethanol, with the triethylamine is alkali, and 80 ℃ of back flow reaction 6～9h generate target compound (XIV);
(13) preparation target compound (XV)
Target compound (XIV) at room temperature reacted 2～3 hours with excessive acid, generated target compound (XV).
The present invention's chemical structure, productive rate, fusing point and molecular formula of synthetic part preferred compound sees Table 1.
Chemical structure, productive rate, fusing point and the molecular formula of table 1 part preferred compound
Figure C20051002633100151
Compound number The X group The M group The R group Productive rate (%) Fusing point (℃) Molecular formula
1 2 3 4 OH OH OH OH H H H H p-CH 3-benzyl p-NO 2-benzyl p-F-benzyl p-C(CH 3) 3-benzyl 74.1 68.9 76.2 84.6 80～82 86～88 102～104 70～73 C 29H 29F 2N 7O 2 C 28H 26F 2N 8O 4 C 28H 26F 3N 7O 2 C 32H 35F 2N 7O 2
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H o-F-benzyl o-Cl-benzyl m-Cl-benzyl p-CH 2CH 3-benzyl 2，4-2Cl-benzyl p-Cl-benzyl benzyl p-I-benzyl m-I-benzyl p-Br-benzyl m-CH 3-benzyl 2-F-4-Br-benzyl 2-Br-4-F-benzyl 2-Br-5-F-benzyl 4-CF 3-benzyl 3-CF 3-benzyl 4-OCF 3-benzyl 2，4-2Cl-PhCH 2CO- 4-C(CH 3) 3-PhCH 2CO- 4-CH 3-PhCH 2CO- 2，4-2CH 3-PhCH 2CO- 4-CH 2CH 3-PhCH 2CO- 4-Cl-PhCH 2CO- 4-F-PhCH 2CO- 4-Br-PhCH 2CO- 4-OCH 3-PhCH 2CO- 4-CH(CH 3) 2-PhCH 2CO- PhCH 2CO- 2-Cl-4-CH 3-PhCH 2CO- 2，4-2F-PhCH 2CO- 2-pentyl 65.1 75.1 81.6 69.4 76.4 71.3 81.6 75.4 76.8 78.1 68.9 70.5 71.9 76.5 72.8 82.6 74.6 78.5 71.4 69.6 85.1 63.5 68.9 75.1 76.4 77.1 63.9 81.6 79.8 77.8 86.6 88～90 69～72 82～84 73～75 68～70 78～80 108～110 110～112 102～104 88～89 99～102 108～112 128～131 138～141 50～51 70～73 oil 77～78 181～183 175～177 63～64 180～183 172～173 72～73 188～190 57～60 190～193 144～147 64～66 60～63 73～75 C 28H 26F 3N 7O 2 C 28H 26ClF 2N 7O 2 C 28H 26ClF 2N 7O 2 C 30H 31F 2N 7O 2 C 28H 25Cl 2F 2N 7O 2 C 28H 26ClF 2N 7O 2 C 28H 27F 2N 7O 2 C 28H 26F 2IN 7O 2 C 28H 26F 2IN 7O 2 C 28H 26BrF 2N 7O 2 C 29H 29F 2N 7O 2 C 28H 25BrF 3N 7O 2 C 28H 25BrF 3N 7O 2 C 28H 25BrF 3N 7O 2 C 29H 26F 5N 7O 2 C 29H 26F 5N 7O 2 C 29H 26F 5N 7O 3 C 29H 25Cl 2F 2N 7O 2 C 33H 35F 2N 7O 2 C 30H 29F 2N 7O 2 C 31H 31F 2N 7O 2 C 31H 31F 2N 7O 2 C 29H 26ClF 2N 7O 2 C 29H 26F 3N 7O 2 C 29H 26BrF 2N 7O 2 C 30H 29F 2N 7O 3 C 32H 33F 2N 7O 2 C 29H 27F 2N 7O 2 C 30H 28ClF 2N 7O 2 C 29H 25F 4N 7O 2 C 26H 31F 2N 7O 2
36 37 38 39 40 41 OH OH OH OH OH OH H H H H H H 3-pentyl 4-CF 3-phenyl 4-CF 3O-phenyl 4-CN-phenyl 4-F-phenyl 2，4-2F-phenyl 79.9 74.4 74.1 81.7 88.2 76.8 110～113 78～79 135～136 104～105 165～166 125～106 C 26H 31F 2N 7O 2 C 28H 24F 5N 7O 2 C 28H 24F 5N 7O 3 C 28H 24F 2N 8O 2 C 27H 24F 3N 7O 2 C 27H 23F 4N 7O 2
Annotate: the measured value and the calculated value of C, H, three kinds of ultimate analyses of N differ less than 0.3%.
Embodiment:
Embodiment 1:N-methyl is to the preparation of nitro-benzylamine (II)
In the 1000ml round-bottomed flask, add the saturated methylamine alcohol solution of 700ml and to nitro benzyl chloride 24g (0.14mol), 60 ℃ of following back flow reaction 5h, reaction solution becomes red-brown by green, reaction finishes the back solvent evaporated, resistates disperses in dilute hydrochloric acid liquid 300ml and 100ml anhydrous diethyl ether, and water layer transfers to alkalescence with NaOH, and anhydrous diethyl ether extracts (200ml * 3), united extraction liquid, anhydrous Na 2SO 4Drying is filtered, and the filtrate evaporate to dryness gets solid 21.9g, productive rate 92.86%.
The preparation of embodiment 2:N-methyl-N-tertbutyloxycarbonyl-4-nitro-benzylamine (III)
In the 500ml round-bottomed flask, adding N-methyl-to nitro-benzylamine (II) 16.7g (0.1mol) and 250mlCH 2Cl 2, (ice bath) slowly drips (BOC) under 0 ℃～5 ℃ 2O 22g (0.1mol) is dissolved in CH 2Cl 2The solution of 50ml.After dropwising, promptly there are most of products to generate.Continue room temperature reaction 10h, reaction almost completely.Add chloroform 300ml dilution, washing (200ml * 3), saturated common salt washing (200ml * 3), anhydrous Na 2SO 4Drying is filtered, and evaporate to dryness filtrate gets brown liquid 25g, yield 93.4%.
The preparation of embodiment 3:N-methyl-N-tertbutyloxycarbonyl-4-amido benzylamine (IV)
Get compound (III) 24g (0.09mol), 85% hydrazine hydrate 96ml and dehydrated alcohol 300ml and place the 500ml round-bottomed flask, carefully add the active nickel of catalytic amount.75 ℃ of back flow reaction 10h after reaction finishes, filter (handling remaining nickel with dilute hydrochloric acid), and the filtrate evaporate to dryness promptly gets yellow solid 21.3g, yield 100%.Fusing point: 105～107 ℃. need not promptly can be used for next step reaction by purifying.
1HNMR：6.04～7.03(4H，m，Ar-H)，4.29(2H，s，-CH2-Ph)，3.63(2H，br，-NH 2)，2.78(3H，s，N-CH 3)，1.48(9H，s，-C(CH 3) 3)
The preparation of embodiment 4:N-methyl-N-tertbutyloxycarbonyl-(4-carbobenzoxy amino) benzylamine (V)
Get compound (IV) 23.6g (0.1mol), pyridine 8.5g (0.11mol) and ethyl acetate 200ml place the 500ml round-bottomed flask, 0 ℃ drips phenyl chloroformate 17.2g (0.11mol) down, notice that rate of addition is slow, dropwise back room temperature reaction 3h, the TLC monitoring, reaction is carried out almost completely, small amount of solid is arranged in the reaction solution, and reaction solution washes (200ml * 3), anhydrous Na with water 2SO 4Drying is filtered, and the filtrate evaporate to dryness gets yellow liquid, becomes solid 34.8g after the placement, yield 97.75%.Fusing point: 109～110 ℃.
1HNMR：7.18～7.42(9H，m，Ar-H)，7.00(1H，br，-NH)，4.39(2H，s，-CH 2-Ph)，2.82(3H，s，N-CH 3)，1.48(9H，s，-C(CH 3) 3)
The preparation of embodiment 5:4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) anilino urea (VI)
In the 500ml round-bottomed flask, add compound (V) 35.6g (0.1mol), 85% hydrazine hydrate 10ml and glycol dimethyl ether 150ml, stirring at room 24h.After reaction finishes the solvent evaporate to dryness is got faint yellow solid, with ethyl acetate wash white solid 25g, yield 85%.
1HNMR：8.21(1H，s，-NHCONH-)，7.16～7.42(4H，m，Ar-H)，6.76(1H，br，-NHCONH-)，4.36(2H，s，-CH 2-Ph)，3.84(2H，br，-NH 2)，2.81(3H，s，N-CH 3)，1.48(9H，s，-C(CH 3) 3)
Embodiment 6:4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl-2H-1,2, the preparation of 4-triazole-3-ketone (VII)
Get compound (VI) 15g (0.05mol), carbonamidine acetate 22g (0.2mol) is dissolved in DMF250ml, and stirring at room reaction 30min adds acetic acid 14.3ml, is warming up to 80 ℃ then, continues stirring reaction 6h.After reaction finishes, the pressure reducing and steaming solvent, resistates is handled with frozen water, spends the night, and filters, and gets faint yellow solid 12.5g, yield 82.24%.
1HNMR：11.80(1H，br，NH)，8.31(1H，s，Triazolone，C 5-H)，7.33～7.67(4H，m，Ar-H)，4.40(2H，s，benzyl)，2.74(3H，s，N-CH 3)，1.42(9H，s，-C(CH 3) 3)
Embodiment 7:2-replacement-4-[4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl]-2H-1,2, the preparation of 4-triazole-3-ketone (VIII)
In the 50ml round-bottomed flask, add compound (VII) 1.5g (0.005mol), to trifluoromethyl benzyl chloride 2.9g (0.015mol), K 2CO 31.4g with DMF 15ml, in 80 ℃ of stirring reaction 12h.Reaction adds water 50ml, ethyl acetate extraction (50ml * 3), anhydrous Na after finishing 2SO 4Drying is filtered, the filtrate evaporate to dryness, and resistates column chromatography purification (linear gradient elution method, developping agent: ethyl acetate: sherwood oil=1: 4,1: 2,1: 1) gets colorless solid 1.8g, yield 78.26%.
1HNMR：8.48(1H，s，Triazolone，C 5-H)，7.35～7.74(8H，m，Ar-H)，5.07(2H，s，benzyl)，4.41(2H，s，-CH 2-Ph)，2.78(3H，s，N-CH 3)，1.42(9H，s，-C(CH 3) 3)
Other VIII compounds is a raw material with different replacement bromobenzyls, halogeno-benzene, 1-chloro-2-oxo substituted benzene ethyl or haloalkyl, with compound (VII) substitution reaction takes place, and the step that repeats among the embodiment 7 makes.
Embodiment 8:2-(4-trifluoromethyl benzyl)-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2, the preparation of 4-triazole-3-ketone (IX)
Get compound (VIII) 1.8g (0.0039mol) and be dissolved in ethyl acetate 25ml, add 10% hydrochloric acid 20ml, stirring at room reaction 24h.After reaction finished, solvent evaporated added water 50ml, K 2CO 3Transfer PH to 8, filter, get white solid 1.1g, yield 78.57%.
1HNMR：8.55(Triazolone，C 5-H)，7.53～7.80(8H，m，Ar-H)，5.08(2H，s，benzyl)，4.10(2H，s，-CH 2-Ph)，2.50(3H，s，N-CH 3)
Other IX compounds makes with the step that corresponding compounds VIII repeats among the embodiment 8.
The preparation of embodiment 9:2-chloro-2 ', 4 '-difluoro acetophenone (XI)
Aluminum trichloride (anhydrous) 100g (0.747mol) and m-difluorobenzene 75.33g (0.667mol) place the 500ml three-necked bottle, stir under the room temperature, slowly drip chloroacetyl chloride 75.33g (0.667mol), continue at after dropwising under the room temperature and stirred 30 minutes, slowly be warming up to 50 ℃, under this temperature, continue to stir 5 hours, reaction solution is poured in the frozen water, separate out crystallization, filter solid, filtrate is extracted at twice with methylene dichloride 400ml, and the combined dichloromethane extracting solution is washed to neutrality, anhydrous sodium sulfate drying, filter, reclaim solvent and get solid, merge gained solid recrystallizing methanol twice, get 2-chloro-2 ', 4 '-difluoro acetophenone 107.38g, yield 87.2%, fusing point: 46～47 ℃.
Embodiment 10:2-(1H-1,2,4-triazol-1-yl)-2 ', the preparation of 4 '-difluoro acetophenone (XII)
With triazole 27.2g (0.4mol), TEBA0.4g, anhydrous K 2CO 341.56g (0.3mol) add the CH of 180ml 2Cl 2In suspension; 2-chloro-2 ', 4 '-difluoro acetophenone (XI) 38.2g (0.2mol) is dissolved in 60mlCH 2Cl 2In, under condition of ice bath, it is added dropwise in the above-mentioned 180ml suspension, dripped off in about 1.5 hours, drip and finish the back in 0～5 ℃ of reaction 5 hours, normal-temperature reaction 24 hours.Filter filter cake CH then 2Cl 2Wash for several times, collect filtrate, filtrate water is washed 3 times, each 100ml, anhydrous Na 2SO 4Drying is filtered, and steams CH 2Cl 2, residue is dissolved in the 100ml anhydrous ethyl acetate agitation and dropping concentrated nitric acid, till no longer separating out to yellow solid, filter, filter cake is washed for several times with amount of ethyl acetate, drying is dissolved in 100ml water with it, and it is 9 that the NaOH solution (w/w) with 30% is transferred pH value, separate out solid, filter, the dry crude product that gets, use normal hexane: ethyl acetate (v/v)=1: 1 recrystallization, get compound (XII) 37.98g, yield 85.2%, fusing point: 104～105 ℃.
Embodiment 11:1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2, the preparation of 4-triazole mesylate (XIII)
Get 2-(1H-1,2, the 4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (XII) 29.8g (0.115mol), trimethylammonium oxygen sulfuration iodine 25.3g (0.115mol), trimethylammonium hexadecyl brometo de amonio 1.6g puts into the 500ml three-necked bottle, add toluene 180ml and 20% sodium hydroxide solution (w/w) 225ml, 60 ℃ were heated 3 hours, and reaction is isolated toluene layer after finishing, water layer extracts (100ml * 2) with toluene, the combining methylbenzene layer is washed to neutrality, reclaim most toluene after, debris adds the dilution of 120ml ethyl acetate, 0 ℃ drips the ethyl acetate 2ml that is dissolved with the 8.3g methylsulfonic acid down, separates out faint yellow solid, filters, use recrystallizing methanol, get compounds X III 21.71g, productive rate 56.7%, fusing point: 128～129 ℃.
Embodiment 12:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-{N-methyl-N-[2-(4-methyl-benzyl)-2H-1,2,4-triazole-3-ketone-4-yl] benzamido group }-preparation of 2-propyl alcohol (compound 1 in the table)
Get epoxide XIII 1.1g (0.0033mol), Compound I X 1.0g (0.0033mol), triethylamine 2m] be dissolved in dehydrated alcohol 25ml, be warming up to 80 ℃, backflow stirring reaction 9h is after reaction finishes, solvent evaporated, resistates is dissolved in ethyl acetate, washes (50ml * 3) and saturated common salt washing (50ml * 3) successively with water, anhydrous Na 2SO 4Drying is filtered filtrate evaporate to dryness, resistates column chromatography purification (developping agent: CH 2Cl 2: CH 3OH=98: 2), get colorless solid 1.33g, yield 74.10%.
1HNMR(CDCl 3，TMS)δ：8.06(1H，Triazolone-C5-H)，6.80～7.76(13H，m，Ar-H)，5.00(2H，d，triazolone-CH 2)，4.47(2H，d-d，J1＝14.2Hz，J2＝33.7Hz，C1-H)，3.72(2H，d-d，Jl＝7.0Hz，J2＝14.0Hz，N-benzyl)，2.40(2H，d，C3-H)，2.03(3H，s，N-CH 3)，1.24(3H，s，ph-CH 3))
IR(cm -1，KBr)：3413，3126，3054，1710，1615，1554，1500
Embodiment 13:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-{N-methyl-N-[2-(4-luorobenzyl)-2H-1,2,4-triazole-3-ketone-4-yl] benzamido group }-preparation of 2-propyl alcohol (compound 3 in the table)
Get epoxide XIII 1.1g (0.0033mol), Compound I X 1.0g (0.0033mol), triethylamine 2ml is dissolved in dehydrated alcohol 25ml, be warming up to 80 ℃, backflow stirring reaction 9h is after reaction finishes, solvent evaporated, resistates is dissolved in ethyl acetate, washes (50ml * 3) and saturated common salt washing (50ml * 3) successively with water, anhydrous Na 2SO 4Drying is filtered filtrate evaporate to dryness, resistates column chromatography purification (developping agent: CH 2C 2: CH 3OH=98: 2), get colorless solid 1.38g, yield 76.20%.
1HNMR(CDCl 3，TMS)δ：8.05(1H，Triazolone-C5-H)，6.81～7.76(13H，m，Ar-H)，4.99(2H，s，triazolone-CH 2)，4.44(2H，d-d，J1＝14.3Hz，J2＝35.3Hz，C1-H)，3.45(2H，d-d，J1＝13.1Hz，J2＝36.4Hz，N-benzyl)，3.08(1H，d，J＝13.4Hz，C3-Ha)，2.77(1H，d，J＝13.4Hz，C3-Hb)2.04(3H，s，N-CH 3)IR(cm -1，KBr)：3475，3124，3055，1709，1617，1562，1152
Embodiment 14:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-{N-methyl-N-[2-(4-trifluoromethyl benzyl)-2H-1,2,4-triazole-3-ketone-4-yl] benzamido group }-preparation of 2-propyl alcohol (compound 19 in the table)
Get epoxide XIII 1.1g (0.0033mol), Compound I X 1.03g (0.0033mol), triethylamine 2ml is dissolved in dehydrated alcohol 20ml, be warming up to 80 ℃, backflow stirring reaction 7h is after reaction finishes, solvent evaporated, resistates is dissolved in ethyl acetate, washes (50ml * 3) and saturated common salt washing (50ml * 3) successively with water, anhydrous Na 2SO 4Drying is filtered filtrate evaporate to dryness, resistates column chromatography purification (developping agent: CH 2Cl 2: CH 3OH=98: 2), get colorless solid 1.4g, yield 71.90%.
1HNMR(CDCl 3，TMS)δ：8.46(1H，Triazolone-C 5-H)，6.93～8.37(13H，m，Ar-H)，5.01(2H，s，triazolone-CH 2)，4.56～4.59(2H，m，C 1-H)，3.57(1H，d，J＝13.6Hz，N-benzyl-Ha)，3.44(1H，d，J＝13.6Hz，N-benzyl-Hb)，3.06(1H，d，J＝13.6Hz，C 3-Ha)，2.78(1H，d，J＝13.6Hz，C 3-Hb)，2.08(3H，s，N-CH 3)
IR(cm -1，KBr)：3391，3128，3075，2950，1710，1617，1555，1500，1423，1399，1367，1325，1272，1209，1165，1137，1066，1018，966，851，817
Embodiment 15:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-{N-methyl-N-[2-(4-fluoro-2-oxo styroyl)-2H-1,2,4-triazole-3-ketone-4-yl] benzamido group }-preparation of 2-propyl alcohol (compound 28 in the table)
Get epoxide XIII 1.1g (0.0033mol), compound 2-(4-fluorine 2-oxo styroyl)-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone 1.1g (0.0033mol), triethylamine 2ml is dissolved in dehydrated alcohol 20ml, be warming up to 80 ℃, backflow stirring reaction 9h is after reaction finishes, solvent evaporated, resistates is dissolved in ethyl acetate, washes (50ml * 3) and saturated common salt washing (50ml * 3) successively with water, anhydrous Na 2SO 4Drying is filtered filtrate evaporate to dryness, resistates column chromatography purification (developping agent: CH 2Cl 2: CH 3OH=98: 2), get colorless solid 1.43g, yield 75.10%.
1HNMR(CDCl 3，TMS)δ：8.50(1H，s，Triazolone-C 5-H)，6.94～8.27(13H，m，Ar-H)，5.67(1H，s，-OH)，5.42(2H，s，triazolone-CH 2)，4.54～4.55(2H，m，C 1-H)，3.61(1H，d，J＝13.6Hz，N-benzyl-Ha)，3.45(1H，d，J＝13.6Hz，N-benzyl-Hb)，3.06(1H，d，J＝14.4Hz，C 3-Ha)，2.79(1H，d，J＝14.4Hz，C 3-Hb)，2.09(3H，s，N-CH 3)；IR(cm -1，KBr)：3428，3130，3074，1699，1615，1598，1566
Embodiment 16:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-{N-methyl-N-[2-(3-amyl group)-2H-1,2,4-triazole-3-ketone-4-yl] benzamido group }-preparation of 2-propyl alcohol (compound 36 in the table)
Get epoxide XIII 1.1g (0.0033mol), compound 2-(3-amyl group)-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone 0.9g (0.0033mol), triethylamine 2ml is dissolved in dehydrated alcohol 20ml, be warming up to 80 ℃, backflow stirring reaction 9h is after reaction finishes, solvent evaporated, resistates is dissolved in ethyl acetate, washes (50ml * 3) and saturated common salt washing (50ml * 3) successively with water, anhydrous Na 2SO 4Drying is filtered filtrate evaporate to dryness, resistates column chromatography purification (developping agent: CH 2Cl 2: CH 3OH=98: 2), get colorless solid 1.35g, yield 79.90%.
1HNMR(CDCl 3，TMS)δ：8.41(1H，s，Triazolone-C 5H)，6.94～8.28(9H，m，Ar-H)，4.56(2H，d-d，J 1＝14.4Hz，J 2＝27.6Hz，C 1-H)，3.90(1H，p，-CH(CH 2) 2(CH3) 2)3.60(1H，d，J＝13.2Hz，N-benzyl-Ha)，3.44(1H，d，J＝13.2Hz，N-benzyl-Hb)，3.06(1H，d，J＝13.6Hz，C 3-Ha)，2.78(1H，d，J＝13.6Hz，C 3-Hb)，2.08(3H，s，N-CH 3)，1.70(4H，h，-CH(CH 2) 2(CH3) 2)，0.79(6H，t，-CH(CH 2) 2(CH 3) 2)；IR(cm -1，KBr)：3128，3066，1690，1614，1554，1508.
All the other target compounds are synthesis material with different substituted triazole ketone benzylamines, and are listed as table 1, repeat the step among the embodiment 12,13,14,15 and 16, just can synthesize required alpha substituted benzylamine trinitrogenazole alcohol antifungal compound or its esters.Agents useful for same is commercially available analytical pure among the embodiment.
Embodiment 17: synthetic 1-of the present invention (1H-1,2,4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-[N-methyl-N-(2-replacement-2H-1,2,4-triazole-3-ketone-4-yl) benzamido group]-the 2-propanol compound has antifungic action, and its The pharmacological results is as follows:
(1) experimental technique: (see for details: Antimicrob AgentsChemother 1995,39 (5): 1169) to adopt conventional external bacteriostatic experiment method
1. materials and methods
(1) experimental strain
This experiment has selected for use following 8 kinds of common human body cause illness's standard fungal bacterial strains as the screening object, and fungal bacterial strain is provided by Long March hospital Mycology Lab.
1) Candida albicans (Candida albicans, type strain ATCC64550);
2) Candida parapsilosis (Candida parapsilosis, type strain ATCC18062);
3) Oidium tropicale (Candida tropicalis type strain ATCC12034);
4) Cryptococcus neoformans (Cryptococcus neoformans type strain ATCC32609);
5) aspergillus fumigatus (Aspergillus fumigatus clinical strain 0109196);
6) fonsecaea pedrosoi (Fonsecaea pedrosoi clinical strain 0208007);
7) trichophyton (Trichophyton rubrum clinical strain 0310404);
8) sporotrichum schenckii (Sporothrix schenckii clinical strain 9503060).
(2) test method
The bacteria suspension preparation: above-mentioned fungi was cultivated 16 hours for 35 ℃ through the YEPD liquid nutrient medium, and twice activation with the blood cell counting plate counting, adjusted bacteria concentration to 1 * 10 with the RPM1640 liquid nutrient medium 4～1 * 10 5Individual/ml.
Soup preparation: get testing compound of the present invention and be dissolved in methyl-sulphoxide, be made into the medicine storage liquid of 8.0mg/ml, be diluted to 640 μ g/ml with RPM1640 before the experiment.
Inoculation: No. 1 hole of 96 orifice plates adds RPM1640 100 μ l and makes blank, the 3-12 hole respectively adds bacteria suspension 100 μ l, No. 2 the hole adds bacteria suspension 180 μ l and soup 20 μ l, the drug level in 2-11 hole is made 10 grades of doubling dilutions, and each hole drug level is respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/ml.No. 12 the hole does not add soup, makes positive control.The medicine contrast is fluconazole and KETOKONAZOL.
Cultivate and detect: establishing positive control hole optical density value (OD value) is 100%, and being lower than 80% lowest concentration of drug with optical density value than positive control hole is minimal inhibitory concentration value (MIC).
(2) experimental result
External bacteriostatic experiment the results are shown in Table 2
The external antimycotic minimal inhibitory concentration value of table 2 part selected objective target compound (MIC, μ g/ml)
Compound number Bai Nian Near flat Yearning New latent The cigarette song Pei Shi Red hair Spore
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 0.002 0.0625 0.004 0.031 0.031 0.004 0.016 0.008 0.002 0.002 0.031 0.031 0.002 0.002 0.004 0.002 0.004 0.002 0.001 0.002 0.002 0.031 0.125 0.25 4 4 2 0.06 4 0.008 0.008 0.008 0.016 0.031 0.008 0.008 0.008 0.008 0.008 0.008 0.008 0.008 0.008 1 0.5 0.0625 1 1 0.0625 0.125 0.5 0.25 0.0625 0.0625 1 1 0.0625 0.0625 0.125 0.0625 0.125 0.25 0.0625 0.0625 0.0312 5 0.125 1 16 4 2 1 1 0.5 0.5 0.008 0.5 64 0.25 0.25 0.008 1 0.125 0.125 0.5 0.25 0.125 0.016 16 32 64 64 8 32 32 8 8 2 4 64 2 2 8 16 4 16 32 8 16 8 64 0.25 4 1 0.25 0.0625 0.5 0.125 0.25 0.125 0.125 0.5 0.0625 0.0625 0.0625 1.25 0.125 0.25 0.25 0.0625 0.125 0.125 4 1 16 8 0.5 1 4 0.5 0.5 0.25 0.5 16 0.25 0.25 0.25 0.5 0.5 1 2 0.5 0.5 0.25 32 64 64 32 32 64 32 32 64 4 64 64 64 64 64 64 64 64 16 16 64 32 64
23 24 25 26 27 28 29 30 31 32 33 34 35 36 0.0625 0.002 0.002 0.25 0.004 0.004 0.002 0.016 0.004 0.016 0.125 0.008 0.002 0.008 2 0.008 0.125 2 0.03 0.06 1 0.03 0.06 0.008 0.5 0.016 0.5 0.031 0.5 0.0312 5 0.0625 0.5 0.0625 0.0625 0.0625 0.125 0.125 0.0625 0.0625 0.0625 0.0625 0.0625 32 0.125 0.5 16 2 1 0.25 8 1 8 64 8 0.5 4 64 16 8 64 64 64 16 32 32 64 32 64 2 32 2 0.125 0.0625 8 0.25 0.0625 0.0625 1 0.125 1 1 2 0.0625 0.25 64 1 0.5 32 4 2 0.25 4 1 8 64 4 0.5 4 64 64 64 64 64 64 64 64 64 64 64 64 64 64
Flu Ket Ter 0.25 0.0625 16 0.5 0.031 16 0.5 0.0625 32 16 0.031 4 32 1 0.25 64 0.0625 ≤0.125 8 0.0625 ≤0.125 ＞64 0.5 2
Flu：Fluconazole；Ket：Ketoconazole；Ter：Terbinafine。
Above-mentioned experimental result shows that compound of the present invention and its esters have anti-mycotic activity preferably, most vitro inhibition activity to selected fungi all are better than fluconazole, with KETOKONAZOL quite or more excellent, illustrate that this compound and its esters can be used for preparing the medicine for the treatment of anti-fungal infection.
Advantage of the present invention and good effect
Compound of the present invention has very strong anti-mycotic efficiency to various superficial parts and deep fungal, compares with the antifungal drug of existing clinical practice, have efficient, toxicity is low, the advantage of antimycotic spectrum width, can be used for preparing new antifungal drug.

Claims (7)

1. trinitrogenazole alcohol compounds is characterized in that such structural general formula is:
Figure C2005100263310002C1
Wherein: X group representation hydroxy or ester group;
The ester group here refers to have the straight or branched ester group of 1～4 carbon atom, formic acid ester group, acetate groups, propionic acid ester group, isopropyl acid ester group;
Y group is represented the various substituting groups on the aromatic ring, the position of substitution can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group refers to:
(1) halogen, F, Cl, Br, I;
(2) methyl, ethyl, trifluoromethyl, the tertiary butyl;
The M group is represented hydrogen or methyl;
The representative of R group
(1) benzyl or substituted benzyl
On the substituted benzyl phenyl ring substituting group can be positioned at phenyl ring the neighbour, or contraposition, can be single replacement, also can be polysubstituted, substituting group is meant;
a.F、Cl、Br、I；
B.1～5 the straight or branched alkyl of a carbon atom;
C. trifluoromethyl, trifluoromethoxy, cyano group, nitro, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido;
(2) 2-oxo styroyl or replacement 2-oxo styroyl
Replace each neighbour that substituting group on the 2-oxo styroyl phenyl ring can be positioned at phenyl ring, or contraposition, can be single replacement, also can be polysubstituted, substituting group is meant:
a.F、Cl、Br、I；
B.1～5 the straight or branched alkyl of a carbon atom;
C. trifluoromethyl, trifluoromethoxy, cyano group, nitro, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido;
(3) phenyl or substituted-phenyl;
On the substituted-phenyl phenyl ring substituting group can be positioned at phenyl ring the neighbour, or contraposition, can be single replacement, also can be polysubstituted, substituting group is meant;
a.F、Cl、Br、I；
B.1～5 the straight or branched alkyl of a carbon atom;
C. trifluoromethyl, trifluoromethoxy, cyano group, nitro, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido;
The straight or branched alkyl of (4) 1～5 carbon atoms;
The straight or branched alkyl nail base of said 1～5 carbon atom, ethyl, the tertiary butyl, tert-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl.
2. by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that said compound is the following respectively compound of combination of X, Y, M and R group:
(1) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 4-trifluoro-methoxybenzyl,
(2) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is 2, the 4-difluorobenzyl,
(3) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-fluorine 2-oxo styroyl,
(4) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-chlorine 2-oxo styroyl,
(5) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is 2,4-difluoro 2-oxo styroyl,
(6) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 4-Trifluoromethoxyphen-l,
(7) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 4-trifluoromethyl,
(8) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 2-amyl group
(9) the X group is a hydroxyl, and Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is the 3-amyl group.
3. claim 1 or 2 described trinitrogenazole alcohol compounds is characterized in that its esters is hydrochloride, nitrate, hydrobromate or methane sulfonates.
4. claim 1 or the 2 described trinitrogenazole alcohol compounds application in the preparation antifungal drug.
5. the application of the salt of the described trinitrogenazole alcohol compounds of claim 3 in the preparation antifungal drug.
6. the preparation method of the described trinitrogenazole alcohol compounds of claim 1, synthetic route is as follows, and wherein the R group is according to claim 1:
Concrete steps are:
(1) preparation N-methyl is to nitro-benzylamine (II)
4-nitro bromobenzyl and methylamine alcohol solution reaction generate N-methyl-4-nitro-benzylamine (II);
(2) preparation N-methyl-N-tertbutyloxycarbonyl-4-nitro-benzylamine (III)
N-methyl-to nitro-benzylamine (II) is at CH 2Cl 2Down, through (BOC) 2O protect N-methyl-N-tertbutyloxycarbonyl-4-nitro-benzylamine (III);
(3) preparation N-methyl-N-tertbutyloxycarbonyl-4-amido benzylamine (IV)
N-methyl-N-tertbutyloxycarbonyl-4-nitro-benzylamine (III) through nickel/hydrazine hydrate reduction reaction 10h, generates N-methyl-N-tertbutyloxycarbonyl-4-amido benzylamine (IV) in ethanol;
(4) preparation N-methyl-N-tertbutyloxycarbonyl-(4-carbobenzoxy amino) benzylamine (V)
N-methyl-N-tertbutyloxycarbonyl-4-amido benzylamine (IV) is an alkali with the pyridine in ethyl acetate, with phenyl chloroformate reaction 3h, generates N-methyl-N-tertbutyloxycarbonyl-(4-carbobenzoxy amino) benzylamine (V);
(5) preparation 4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) anilino urea (VI)
N-methyl-N-tertbutyloxycarbonyl-(4-carbobenzoxy amino) benzylamine (V) in glycol dimethyl ether with 85% hydrazine hydrate room temperature reaction 24h, hydrazinolysis product 4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) anilino urea (VI);
(6) preparation 4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl-2H-1,2,4-triazole-3-ketone (VII)
4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) anilino urea (VI) generates 4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl-2H-1,2,4-triazole-3-ketone (VII) with carbonamidine acetate generation ring-closure reaction under the acetic acid existence condition in DMF;
(7) preparation 2-replacement-4-[4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (VIII)
4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl-2H-1,2,4-triazole-3-ketone (VII) is in DMF, with K 2CO 3Be alkali, react 8～12h with various halides, generate 2-replacement-4-[4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl at 80 ℃]-2H-1,2,4-triazole-3-ketone (VIII);
(8) preparation 2-replacement-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (IX)
2-replacement-4-[4-(N-methyl-N-tertbutyloxycarbonyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (VIII) and 10% hydrochloric acid reaction 24h are sloughed the BOC protecting group and are generated 2-replacement-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (IX);
(9) preparation 2-chloro-2 ', 4 '-difluoro acetophenone (XI)
M-difluorobenzene (X) and chloroacetyl chloride are at anhydrous AlCl 3The middle Friedel-Crafts reaction that takes place generates 2-chloro-2 ', 4 '-difluoro acetophenone (XI);
(10) preparation 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (XII)
2-chloro-2 ', 4 '-difluoro acetophenone (XI) and triazole, 3-ethyl benzyl ammonium chloride (TEBA) and K 2CO 3At CH 2Cl 2In 0～5 ℃ of reaction 5 hours, then, generate 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (XII) room temperature reaction 24 hours;
(11) preparation 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (XIII)
2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (XII) and iodate trimethylammonium oxygen sulphur, trimethylammonium hexadecyl brometo de amonio, reaction generates 1-[2-(2,4 difluorobenzene base)-2 in toluene and sodium hydroxide, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (XIII);
(12) preparation target compound (XIV)
2-replacement-4-[4-(N-methyl-amine methyl) phenyl]-2H-1,2,4-triazole-3-ketone (IX) and 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (XIII) is in ethanol, with the triethylamine is alkali, and 80 ℃ of back flow reaction 6～9h generate target compound (XIV).
7. the preparation method of the described trinitrogenazole alcohol compounds of claim 3 salt, further do following reaction under the said triadimenol compounds of claim 6 synthetic route:
Figure C2005100263310007C1
Wherein HX represents hydrochloride, nitrate, hydrobromate or methane sulfonates respectively,
Concrete steps are:
1-(1H-1,2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-{N-methyl-N-[(2-replacement-2H-1,2,4-triazole-3-ketone-4-yl) benzamido group] }-2-propyl alcohol (XIV) at room temperature reacted 2～3 hours with excessive hydrochloric acid, nitric acid, Hydrogen bromide or methanesulfonic, generated the salt (XV) of target compound (XIV).
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CN101723933B (en) * 2009-12-08 2013-08-21 中国人民解放军第二军医大学 Piperidine-4-ketone-O-substituted oxime triadimenol-type antifungal compound and preparation method thereof
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