CN105541813A - Imidazole acetonitrile derivative acid salt as well as preparation method and application thereof - Google Patents
Imidazole acetonitrile derivative acid salt as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an imidazole acetonitrile derivative acid salt as well as a preparation method and an application thereof, belongs to the technical field of drug synthesis, and aims to solve the problem about how to improve stability and increase the yield. The method comprises steps as follows: an imidazole acetonitrile derivative is dissolved in a water-insoluble polar organic solvent, then corresponding acid is added for a salt forming reaction, and the acid salt of the product imidazole acetonitrile derivative is gradually separated out, and applied to preparation of Luliconazole. The acid salt itself has better stability and used as an intermediate for preparing Luliconazole at the same time, the problem of mutual inversion of Z-E configuration in the Luliconazole preparation process can be solved, the Z configuration can be inverted into the E configuration, the configuration inversion stability is guaranteed, and the yield is higher. The effects of simple technology and easiness in operation are also realized.
Description
Technical field
The present invention relates to a kind of imidazoles acetonitrile derivative acid salt and its preparation method and application, belong to technical field of medicine synthesis.
Background technology
Luliconazole is the imidazoles antifungal drug that Japanese agricultural chemicals strain formula can be developed, and this medicine gets the Green Light in June, 2005, for tinea disease (ringworm of the foot, ringworm of the body, jock itch), monilial infection (between referring to rotten to the corn disease, intertrigo, purplish or white patches on the skin wind) etc.Compared with antimycotic externally applied agent in the past, it is high that its maximum advantage is that skin stores rate, and the medication cycle is short, good effect and not easily recurring, therefore have larger competitive power.The structural formula of luliconazole is as follows:
Chemistry (E)-(4R)-4-(2,4 dichloro benzene base)-1, the 3-dithiolane-2-Asia by name of luliconazole replaces (1H-imidazoles-1-replaces) acetonitrile.
The research of preparation method about luliconazole and this compound crystal form mostly in existing document.Specifically, different crystal forms for same medicine often causes medicine in physico-chemical property and the significant differences such as drug dissolution, biological effectiveness such as outward appearance, solubleness, fusing point and density, thus affects the performance of the curative effect such as stability, bioavailability of medicine.And in order to the stability that improves luliconazole and bioavailability, as Chinese patent application (publication number: CN103012385A) discloses solvability, bioavailability and the stability and easily process and security that a kind of luliconazole crystal formation I realizes having had in existing document.
And for example Chinese patent application (publication number: CN1091596C) discloses anti-mycotic agent and compound thereof and their preparation method, and the method comprises compound that the glycol derivative with optically active or its equivalent that are represented by formula a and formula b represent and carries out reacting and realize:
X in formula a
1and X
2identical or different, represent mesyloxy, phenylsulfonyloxy, tolysulfonyl oxygen base or halogen atom separately; In formula b, M represents alkali metal atom.The document has been mentioned to and has comprised to needing the human or animal of this prevention or treatment to use the luliconazole of pharmaceutical effective amount or its pharmacologically acceptable salt and pharmaceutically acceptable carrier or thinner, (the R)-enantiomorph being also mentioned to this compound to dermatophytes especially to the anti-mycotic activity of the high sensitive strain racemic mixture high several times than them.But its pharmacologically acceptable salt specifically which kind of salt is not disclosed, the scope of its pharmacologically acceptable salt even unexposed, and it is larger for the impact of the form of its salt formed of the different medicines different physico-chemical property for medicine in art technology, there is too many uncertainty, also there is not yet other report specifically preparing luliconazole salt compounds.Therefore, the present inventor wishes by researching and developing luliconazole salt that is a kind of or a class practicality; On the other hand, mostly there is the problem that isomer impurities content is higher, purity is lower and yield is low in the luliconazole obtained due to existing method, the present inventor also wishes by obtaining corresponding intermediate raw material to the research of medicine and salt preparation process thereof, to realize the effect being easier to purifying and high yield.
Summary of the invention
The present invention is directed to the defect existed in above prior art, imidazoles acetonitrile derivative acid salt and its preparation method and application is proposed, the problem solved realizes a kind of intermediate for the preparation of luliconazole medicine newly, makes realization have the effect of good stability and high yield.
An object of the present invention is achieved by the following technical programs, a kind of imidazoles acetonitrile derivative acid salt, and the structural formula of this imidazoles acetonitrile derivative acid salt is as shown in the formula shown in I:
Described X is acid ion.
Because in the preparation process of existing luliconazole, productive rate is relatively low, main one side reason is because luliconazole is easy to occur the mutual conversion of Z-E configuration in preparation process, and be not easy to control, thus cause the yield of final product luliconazole lower, general yield only can reach about 40% ~ 50%, and impurity increases and makes purity also on the low side accordingly.And the present invention filters out this new imidazoles acetonitrile derivative acid salt structure as corresponding intermediate raw material by research and can solve the problem that Z-E configuration transforms mutually in the process preparing luliconazole well, the Z configuration conversion that makes that can be more stable becomes E, thus realize obtaining highly purified luliconazole, and the effect that yield is relatively high; On the other hand, the configuration requirements of acid salt of the present invention to imidazoles acetonitrile derivative raw material is lower, more be conducive to the selection of raw material, adopt conventional imidazoles acetonitrile derivative raw material, as being the racemic compound raw material of Z configuration, E or (Z, E) configuration, after reaction, all can form the corresponding acid salt of E, and all can abstraction and purification easily, after suitably dissociating, namely can be good at the node configuration being prepared into luliconazole.Meanwhile, imidazoles acetonitrile derivative acid salt of the present invention, due to after forming corresponding salt, makes it have better water-soluble, is conducive to the stripping of medicine and the raising of medicine stability.
In above-mentioned imidazoles acetonitrile derivative acid salt, HX wherein only refers to monoprotic acid, why adopting HX to state is only in order to better description, be not to play restriction, in fact HX can be monoprotic acid, diprotic acid or triprotic acid, can certainly adopt the corresponding acid such as mineral acid or organic acid.As preferably, described HX is selected from hydrogen halide, sulfuric acid, phosphoric acid, fumaric acid, R-SO
3one in H or tartrate; And R-SO
3r group in H is selected from C
1-C
3alkyl, phenyl or substituted-phenyl.If alkyl wherein can be methyl or ethyl etc., substituted-phenyl can be p-methylphenyl, a tolyl, to groups such as ethylbenzenes.Above-mentioned imidazoles acetonitrile derivative acid salt has better stability and bioavailability, and for the preparation of the intermediate raw material of luliconazole medicine, more be conducive to configuration and the yield preparing luliconazole and ensure product, adopt above-mentioned acid salt as intermediate raw material, the molar yield of luliconazole can be made to reach more than 85%.As further preferred, described HX is selected from HBr, HCl, fumaric acid, phosphoric acid, tosic acid, Phenylsulfonic acid, sulfuric acid or tartrate.
In above-mentioned imidazoles acetonitrile derivative acid salt, described imidazoles acetonitrile derivative acid salt can be selected from (E)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile acid salt, (E)-(4R)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile acid salt or (E)-(4S)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replacement (1H-imidazoles-1-replaces) acetonitrile acid salt.The imidazoles acetonitrile derivative acid salt of above-mentioned concrete configuration is adopted more to be conducive to applying as the stable and intermediate of separable purifying, and adopt these raw materials to prepare the yield of luliconazole and purity better, configurational energy is maintained, and purity can reach more than 99%.
Two of object of the present invention is achieved by the following technical programs, a kind of preparation method of imidazoles acetonitrile derivative acid salt, and the method comprises:
Formula II compound imidazole acetonitrile derivative is dissolved in water-insoluble polar organic solvent, and then adds corresponding acid and carry out salt-forming reaction, make the acid salt of separating out corresponding product type I compound imidazoles acetonitrile derivative gradually:
The preparation method of imidazoles acetonitrile derivative acid salt of the present invention, react by making imidazoles acetonitrile derivative and corresponding acid in water-insoluble polar organic solvent, form corresponding acid salt, the configuration of formula II compound imidazole acetonitrile derivative can carry out selecting and adjusting according to actual needs, here the concrete configuration of concrete limitation type II compound imidazole acetonitrile derivative is not had, no matter formula II compound is Z-type or E type, all can obtain the acid salt of E of the present invention expeditiously.It is simple that method of the present invention not only has technological operation, and the corresponding acid alkali formed is above originally E-isomer, and chiral configuration can be maintained, be insoluble to water-insoluble polar organic solvent, more be conducive to being separated, and also there is reaction conditions gentleness, and the effect that raw material is easy to get.
In the preparation method of above-mentioned imidazoles acetonitrile derivative acid salt, as preferably, described water-insoluble polar organic solvent is selected from C
3-C
6ester, C
3-C
6ketone, C
4-C
6ether, toluene, dimethylbenzene, naphthane, methylene dichloride, one or more in 1,2-ethylene dichloride and chloroform.Preferably, described water-insoluble polar organic solvent is selected from one or more in ethyl acetate, ether, toluene and chloroform.Can either reach and effectively make material dissolution, improve reaction efficiency, the effect of the separation of product can be conducive to again.The consumption of solvent can adjust according to actual needs, on reaction not substantial impact itself.
In the preparation method of above-mentioned imidazoles acetonitrile derivative acid salt, as preferably, described acid is selected from hydrogen halide, sulfuric acid, phosphoric acid, fumaric acid, R-SO
3one in H or tartrate; And R-SO
3r group in H is selected from C
1-C
3alkyl, phenyl or substituted-phenyl.Object forms more stable acid salt, more importantly prepares luliconazole in order to more effective, thus the purity of the configuration of guarantee product, yield and product.
In the preparation method of above-mentioned imidazoles acetonitrile derivative acid salt, as preferably, described salt-forming reaction temperature controls more than 40 DEG C or boiling point is less than the reflux temperature of the low boiling point solvent of 40 DEG C.Reaction conditions is gentle, easy handling; Meanwhile, temperature of reaction can be selected to do suitable adjustment according to the solvent in reaction system.As further preferred, the temperature of the anti-salt of described salify is the reflux temperature that 50 DEG C ~ 70 DEG C or boiling point are less than the low boiling point solvent of 40 DEG C.
Three of object of the present invention is achieved by the following technical programs, a kind of application of imidazoles acetonitrile derivative acid salt, and described imidazoles acetonitrile derivative acid salt is for the preparation of luliconazole.Owing to adopting imidazoles acetonitrile derivative acid salt Intermediate Preparation method of the present invention, the imidazoles acetonitrile acid salt obtained based on E type that can be stable, and because can separate out in solid form, purifying is easy; As raw material, in dissociation process, can guarantee that reaction system exists certain acidic conditions, make the maintenance that can be good at realizing configuration in neutralization reaction process.Therefore, no matter adopt the crude material of which kind of configuration, by forming acid salt of the present invention, finally all can be good at the configuration converting luliconazole to, and also there is good yield and stability.
In the application of above-mentioned imidazoles acetonitrile derivative acid salt, as preferably, the described concrete grammar for the preparation of luliconazole is:
Imidazoles acetonitrile derivative acid salt is added to the water dissolving, and then adds alkaline reagents and carry out neutralization reaction and remove acid in reaction system, obtain luliconazole.
Above-mentioned method concrete restriction for temperature of reaction, reacts as long as can realize acid-base neutralisation, thus realizes removing the acid group in reaction system, reaches the effect of dissociating, obtains final product luliconazole.As preferably, the temperature of described neutralization reaction is carried out under normal temperature condition, better can ensure the purity of product.
In the application of above-mentioned imidazoles acetonitrile derivative acid salt, as preferably, described alkaline reagents can be organic or inorganic weakly alkaline reagent or strong basic reagent, and corresponding reagent directly can add in reaction system or first and realizes corresponding effect by being mixed with corresponding alkaline aqueous solution by described alkaline reagents.As further preferred, described alkaline reagents is selected from one or more in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium hydroxide and potassium hydroxide.As more preferably, described alkaline reagents is selected from the weakly alkaline reagent such as triethylamine, sodium carbonate or salt of wormwood.Adopt weakly alkaline reagent to be easier to operation comparatively speaking, the generation of other impurity can be reduced, ensure that the quality index of product is as purity requirement.As long as the consumption of alkaline reagents is inexcessive relative to acid salt.
Imidazoles acetonitrile derivative acid salt of the present invention can also for the preparation of antiseptic-germicide pharmaceutical composition; Preferably, described antiseptic-germicide pharmaceutical composition comprises active medicine imidazoles acetonitrile derivative acid salt and pharmaceutically acceptable carrier, thinner or/and vehicle composition.Described pharmaceutically acceptable vehicle surfactant etc. are as tween 80, polysorbate60; Described vehicle is as sorbitol monostearate, polyoxyl 40 stearate etc.Described thinner adopts the thinner of this area routine, and not concrete restriction, can select according to actual needs in actual fabrication process.
In sum, the present invention compared with prior art, has the following advantages:
Imidazoles acetonitrile derivative acid salt of the present invention, after imidazoles acetonitrile derivative is designed to corresponding acid salt, not only make that itself there is good stability, simultaneously, after it can be used as the intermediate feed preparing luliconazole, the problem that Z-E configuration transforms mutually in the process preparing luliconazole can be solved, the Z configuration conversion that makes that can be more stable becomes E, if and directly adopt the imidazoles acetonitrile derivative of corresponding E as raw material, equally also stably can form the luliconazole product of E, ensure that the relative stability that configuration makes the transition, thus realize making the luliconazole prepared have higher yield.Meanwhile, adopt acid salt of the present invention as intermediate feed to prepare luliconazole, in making and time configuration be maintained, and can ensure that yield reaches the effect of more than 85%; And the preparation method of imidazoles acetonitrile derivative acid salt of the present invention to have technique simple, the effect that easy handling purifying and raw material are easy to get.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail, but the present invention is not limited to these embodiments.
Embodiment 1
A kind of imidazoles acetonitrile derivative hydrobromate, the structural formula of this imidazoles acetonitrile derivative hydrobromate is as shown in the formula shown in (I-1):
The concrete preparation method of the imidazoles acetonitrile derivative hydrobromate (formula (I-1)) in the present embodiment is as follows:
Take formula II compound (Z/E)-(4R)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile 1mol, be dissolved in ethyl acetate solvent, and then add corresponding HBr1.3mol, then, the temperature controlling reaction system carries out reaction 2.5 hours under the condition of 60 DEG C, after reaction terminates, continue to make fully to separate out corresponding solid product under stirring is cooled to normal temperature condition, filter, dry, obtain corresponding solid intermediate product formula I-1 compound (E)-(4R)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile hydrobromate, molar yield is 90%, purity reaches 99.7%.
Fusing point Mp:240.5 ~ 242.1 DEG C.
MS(m/z)：354[M+H]
+。
1H-NMR(400MHz,DMSO-d
6)：4.15～4.27(m,2H),5.90(t,J＝4.0Hz,1H),7.53～7.55(m,1H),7.78～7.80(m,2H),7.90(s,1H),8.07(s,1H),9.53(s,1H)。
Ethyl acetate in the present embodiment also can adopt ethyl propionate or ethyl formate to replace specifically implementing.
Embodiment 2
A kind of imidazoles acetonitrile derivative hydrochloride, the structural formula of this imidazoles acetonitrile derivative hydrochloride is as shown in the formula shown in (I-2):
The concrete preparation method of the imidazoles acetonitrile derivative hydrochloride (formula (I-2)) in the present embodiment is as follows:
Take formula II compound (E)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile 1mol and is dissolved in ethyl acetate solvent, then dry HCl gas is passed into, stop when solid is separated out more, filter, dry, obtain corresponding solid intermediate product formula I-1 compound (E)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrilehydrochlorate, and molar yield is 91%, and purity reaches 99.8%.
Fusing point Mp:214.5 ~ 217.1 DEG C.
MS(m/z)：354[M+H]
+。
1H-NMR(400MHz,DMSO-d
6)：4.13～4.25(m,2H),5.88(t,J＝4.0Hz,1H),7.52～7.55(m,1H),7.77～7.82(m,3H),8.00(s,1H),9.40(s,1H)。
Embodiment 3
A kind of imidazoles acetonitrile derivative fumarate, the structural formula of this imidazoles acetonitrile derivative fumarate is as shown in the formula shown in (I-3):
The concrete preparation method of the imidazoles acetonitrile derivative fumarate (formula (I-3)) in the present embodiment is as follows:
Take formula II compound (E)-(4S)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile 1mol and is dissolved in toluene solvant, and then add corresponding fumaric acid 0.8mol, then, the temperature controlling reaction system carries out reaction 1.5 hours under the condition of 90 DEG C, after reaction terminates, continue to make fully to separate out corresponding solid product under stirring is cooled to normal temperature condition, filter, dry, obtain corresponding solid intermediate product formula I-3 compound (E)-(4S)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile fumarate, molar yield is 88%, purity reaches 99.6%.
Fusing point Mp:172.0 ~ 175.1 DEG C.
MS(m/z)：354[M+H]
+。
1H-NMR(400MHz,DMSO-d
6)：4.02～4.15(m,2H),5.80(t,J＝4.0Hz,1H),6.63(s,1H),7.10(t,J＝4.0Hz,1H),7.41(s,1H),7.52～7.55(m,1H),7.76～7.78(m,2H),7.91(s,1H)。
Toluene in the present embodiment also can adopt dimethylbenzene to replace specifically implementing.
Embodiment 4
A kind of imidazoles acetonitrile derivative phosphoric acid salt, the phosphatic structural formula of this imidazoles acetonitrile derivative is as shown in the formula shown in (I-4):
The concrete preparation method of the imidazoles acetonitrile derivative phosphoric acid salt (formula (I-4)) in the present embodiment is as follows:
Take formula II compound (E)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile 1mol and is dissolved in naphthane solvent, and then add corresponding phosphatase 11 .3mol, then, the temperature controlling reaction system carries out reaction 1 hour under the condition of 50 DEG C, after reaction terminates, continue to make fully to separate out corresponding solid product under stirring is cooled to normal temperature condition, filter, dry, obtain corresponding solid intermediate product formula I-1 compound (E)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile phosphoric acid salt, molar yield is 90%, purity reaches 99.8%.
Fusing point Mp:137.6 ~ 140.9 DEG C.
MS(m/z)：354[M+H]
+。
1H-NMR(400MHz,DMSO-d
6)：4.02～4.16(m,2H),5.80(t,J＝4.0Hz,1H),7.11(s,1H),7.42(s,1H),7.52～7.55(m,1H),7.75～7.80(m,2H),8.19(s,1H)。
Embodiment 5
A kind of imidazoles acetonitrile derivative tosilate, the structural formula of this imidazoles acetonitrile derivative tosilate is as shown in the formula shown in (I-5):
The concrete preparation method of the imidazoles acetonitrile derivative tosilate (formula (I-5)) in the present embodiment is as follows:
Take formula II compound (E)-(4R)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile 1mol and is dissolved in dichloromethane solvent, then, add corresponding tosic acid 1.05mol again, then, control reaction system and under reflux conditions carry out reaction 2.5 hours, after reaction terminates, continue to make fully to separate out corresponding solid product under stirring is cooled to normal temperature condition, filter, dry, obtain corresponding solid intermediate product formula I-5 compound (E)-(4R)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile tosilate, molar yield is 89%, purity reaches 99.7%.
Fusing point Mp:188.1 ~ 192.5 DEG C.
MS(m/z)：354[M+H]
+。
1H-NMR(400MHz,DMSO-d
6)：2.29(s,3H),4.12～4.24(m,2H),5.88(t,J＝4.0Hz,1H),7.11(d,J＝8.0Hz,2H),7.47～7.49(m,2H),7.53～7.55(m,1H),7.75～7.77(m,2H),7.80(s,1H),7.97(s,1H),9.27(s,1H)。
Methylene dichloride in the present embodiment also can adopt chloroform to replace specifically implementing.
Embodiment 6
A kind of imidazoles acetonitrile derivative benzene sulfonate, the structural formula of this imidazoles acetonitrile derivative benzene sulfonate is as shown in the formula shown in (I-6):
The concrete preparation method of the imidazoles acetonitrile derivative benzene sulfonate (formula (I-6)) in the present embodiment is as follows:
Take formula II compound (E)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile 1mol and is dissolved in ether solvent, and then add corresponding Phenylsulfonic acid 1.3mol, then, what control reaction system under reflux conditions carries out reaction 1 hour, after reaction terminates, continue to make fully to separate out corresponding solid product under stirring is cooled to normal temperature condition, filter, dry, obtain corresponding solid intermediate product formula I-1 compound (E)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile benzene sulfonate, molar yield is 91%, purity reaches more than 99.8%.
Fusing point Mp:175.4 ~ 178.5 DEG C.
MS(m/z)：354[M+H]
+。
1H-NMR(400MHz,DMSO-d
6)：4.13～4.25(m,2H),5.88(t,J＝4.0Hz,1H),7.30～7.35(m,3H),7.52～7.55(m,1H),7.59～7.62(m,2H),7.75～7.80(m,2H),7.84(s,1H),8.03(s,1H),9.42(s,1H)。
Embodiment 7
A kind of imidazoles acetonitrile derivative tartrate, the structural formula of this imidazoles acetonitrile derivative tartrate is as shown in the formula shown in (I-7):
The concrete preparation method of the imidazoles acetonitrile derivative tartrate (formula (I-7)) in the present embodiment is as follows:
Take formula II compound (Z/E)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile 1mol and is dissolved in acetone solvent, then, add corresponding tartrate 0.65mol again, then, reaction is carried out 2.5 hours under controlling the temperature of the reaction system condition more than 55 DEG C, after reaction terminates, continue to make fully to separate out corresponding solid product under stirring is cooled to normal temperature condition, filter, dry, obtain corresponding solid intermediate product formula I-7 compound (E)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile tartrate, molar yield is 99.1%, purity reaches 99.7%.
Fusing point Mp:106 ~ 110 DEG C.
MS(m/z)：354[M+H]
+。
1H-NMR(400MHz,DMSO-d
6)：4.02～4.15(m,2H),4.32(s,3H),5.80(t，J＝4.0Hz,1H),7.10(s,1H),7.41(s,1H),7.47～7.54(m,1H),7.70～7.78(m,2H),7.91(s,1H)。
Embodiment 8
A kind of imidazoles acetonitrile derivative vitriol, the structural formula of this imidazoles acetonitrile derivative vitriol is as shown in the formula shown in (I-8):
The concrete preparation method of the imidazoles acetonitrile derivative vitriol (formula (I-8)) in the present embodiment is consistent with embodiment 1, repeats no more here.Finally obtain solid intermediate product formula I-8 compound (E)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile vitriol, and molar yield is 86.2%, and purity reaches 99.0%.
Fusing point Mp:154.4 ~ 157.9 DEG C.
MS(m/z)：354[M+H]
+。
1H-NMR(400MHz,DMSO-d
6)：4.11～4.24(m,2H),5.87(t,J＝4.0Hz,1H),7.53～7.55(m,1H),7.68(s,1H),7.77～7.79(m,2H),7.89(s,1H),9.08(s,1H)。
Embodiment 9
Take (E)-(the 4R)-4-(2 that embodiment 1 obtains, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile hydrobromate 1mol and is added to the water, stirring makes abundant dissolving, then, slowly drip saturated sodium carbonate solution at ambient temperature and carry out neutralization reaction, with the acid in removing system, namely the pH value of system is adjusted to neutral, stir after 20 minutes, system pH is made to remain on neutrality, then, make fully to separate out solid, obtain final product luliconazole, the molar yield of product reaches 90%, purity can reach 99.8%.
Embodiment 10
Take (E)-(the 4S)-4-(2 that embodiment 3 obtains, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile fumarate 1mol and is added to the water, stirring makes abundant dissolving, then, under the condition of control temperature below 40 DEG C, slowly dropping triethylamine or diisopropylethylamine solution carry out neutralization reaction, with the acid in removing system, namely the pH value of system is adjusted to neutral, stir after 20 minutes, system pH is made to remain on neutrality, then, make fully to separate out solid, obtain final product (E)-(4S)-4-(2, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile, the molar yield of product reaches 92%, purity can reach 99.7%.
Embodiment 11
Take (E)-(the 4R)-4-(2 that embodiment 5 obtains, 4-dichlorophenyl)-1, 3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile tosilate 1mol and is added to the water, stirring makes abundant dissolving, then, slowly drip under the condition of control temperature below 40 DEG C mass concentration be 10% sodium hydroxide solution carry out neutralization reaction, with the acid in removing system, namely the pH value of system is adjusted to neutral, stir after 20 minutes, system pH is made to remain on neutrality, then, make fully to separate out solid, obtain final product luliconazole, the molar yield of product reaches 91%, purity can reach 99.6%.
Specific embodiment described in the present invention is only to the explanation for example of the present invention's spirit.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment, but can't depart from spirit of the present invention or surmount the scope that appended claims defines.
Although made a detailed description the present invention and quoted some specific embodiments as proof, to those skilled in the art, only otherwise it is obvious for leaving that the spirit and scope of the present invention can make various changes or revise.
Claims (10)
1. an imidazoles acetonitrile derivative acid salt, is characterized in that, the structural formula of this imidazoles acetonitrile derivative acid salt is as shown in the formula shown in I:
Described X is acid ion.
2. imidazoles acetonitrile derivative acid salt according to claim 1, it is characterized in that, described HX is selected from hydrogen halide, sulfuric acid, phosphoric acid, fumaric acid, R-SO
3one in H or tartrate; And R-SO
3r group in H is selected from C
1-C
3alkyl, phenyl or substituted-phenyl.
3. imidazoles acetonitrile derivative acid salt according to claim 1 or 2, it is characterized in that, the acid salt of described imidazoles acetonitrile derivative is selected from (E)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile acid salt, (E)-(4R)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile acid salt, (E)-(4S)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-Asia replacement (1H-imidazoles-1-replaces) acetonitrile acid salt.
4. a preparation method for imidazoles acetonitrile derivative acid salt, is characterized in that, the method comprises:
Formula II compound imidazole acetonitrile derivative is dissolved in water-insoluble polar organic solvent, and then adds corresponding acid and carry out salt-forming reaction, make the acid salt of separating out corresponding product type I compound imidazoles acetonitrile derivative gradually;
5. the preparation method of the acid salt of imidazoles acetonitrile derivative according to claim 4, it is characterized in that, described water-insoluble polar organic solvent is selected from C
3-C
6ester, C
3-C
6ketone, C
4-C
6ether, toluene, dimethylbenzene, naphthane, methylene dichloride, one or more in 1,2-ethylene dichloride and chloroform; Preferably, described water-insoluble polar organic solvent is selected from one or more in ethyl acetate, ether, toluene and chloroform.
6. the preparation method of the acid salt of imidazoles acetonitrile derivative according to claim 4, it is characterized in that, described acid is selected from hydrogen halide, sulfuric acid, phosphoric acid, fumaric acid, R-SO
3one in H or tartrate; And R-SO
3r group in H is selected from C
1-C
3alkyl, phenyl or substituted-phenyl.
7. the preparation method of imidazoles acetonitrile derivative acid salt according to claim 4-6 any one, is characterized in that, described salt-forming reaction temperature controls more than 40 DEG C or boiling point is less than the reflux temperature of the low boiling point solvent of 40 DEG C.
8. the application of imidazoles acetonitrile derivative acid salt according to claim 1-3 any one, it is characterized in that, described imidazoles acetonitrile derivative acid salt is for the preparation of luliconazole.
9. the application of imidazoles acetonitrile derivative acid salt according to claim 8, it is characterized in that, described imidazoles acetonitrile derivative acid salt for the preparation of the concrete grammar of luliconazole is:
Imidazoles acetonitrile derivative acid salt described in claim 1-3 any one is added to the water, and then adds alkaline reagents and carry out neutralization reaction and remove acid in reaction system, obtain luliconazole.
10. the application of imidazoles acetonitrile derivative acid salt according to claim 8, it is characterized in that, described alkaline reagents is selected from one or more in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium hydroxide and potassium hydroxide.
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| WO2017108972A1 (en) * | 2015-12-21 | 2017-06-29 | Laboratorios Lesvi, S.L. | Compounds of r-(-)-(e)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile-ha (luliconazole-ha) as antifungals |
| CN109721542A (en) * | 2018-12-28 | 2019-05-07 | 上海彩迩文生化科技有限公司 | A kind of preparation method of imidazole radicals cyanide compound |
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| CN104151305A (en) * | 2014-07-18 | 2014-11-19 | 狄庆锋 | Luliconazole configuration converting method |
| CN102387786B (en) * | 2009-04-09 | 2015-09-09 | 宝丽制药股份有限公司 | Antifungal medicine composition |
| CN106170285A (en) * | 2014-04-07 | 2016-11-30 | 日本农药株式会社 | Comprise the pharmaceutical composition of antifungal and steroid |
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| CN102387786B (en) * | 2009-04-09 | 2015-09-09 | 宝丽制药股份有限公司 | Antifungal medicine composition |
| CN103957907A (en) * | 2011-09-26 | 2014-07-30 | 日本农药株式会社 | Anti-fungal agent |
| CN106170285A (en) * | 2014-04-07 | 2016-11-30 | 日本农药株式会社 | Comprise the pharmaceutical composition of antifungal and steroid |
| CN104151305A (en) * | 2014-07-18 | 2014-11-19 | 狄庆锋 | Luliconazole configuration converting method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017108972A1 (en) * | 2015-12-21 | 2017-06-29 | Laboratorios Lesvi, S.L. | Compounds of r-(-)-(e)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile-ha (luliconazole-ha) as antifungals |
| CN109721542A (en) * | 2018-12-28 | 2019-05-07 | 上海彩迩文生化科技有限公司 | A kind of preparation method of imidazole radicals cyanide compound |
| CN109721542B (en) * | 2018-12-28 | 2022-05-03 | 上海彩迩文生化科技有限公司 | Preparation method of imidazolyl acetonitrile compound |
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