CN105198818B - A kind of method of industrialized production Butoconazole Nitrate - Google Patents
A kind of method of industrialized production Butoconazole Nitrate Download PDFInfo
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- CN105198818B CN105198818B CN201510648064.7A CN201510648064A CN105198818B CN 105198818 B CN105198818 B CN 105198818B CN 201510648064 A CN201510648064 A CN 201510648064A CN 105198818 B CN105198818 B CN 105198818B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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Abstract
The present invention relates to a kind of method for producing Butoconazole Nitrate.It the described method comprises the following steps：(1) it is heated to reflux in acetone for raw material with 1 (2 chlorine 4 (4 chlorphenyl) butyl) 1 hydrogen imidazoles, 2,6 thiophenol dichlorobenzenes, Anhydrous potassium carbonate, fully after reaction, cooling, filtering, filtering, after filtrate is concentrated, concentrate is obtained；(2) concentrate obtained by step (1) is taken, adds extract, it is 2~3 that weight ratio is included in the extract：1~2 ether and water；Fully after extraction, aqueous phase is abandoned, organic phase is standby；(3) concentrated nitric acid is added dropwise in organic phase obtained by step (2), is filtered to after stopping generation precipitation；Filtrate is abandoned, after Washing of Filter Cake, drying, obtains Butoconazole Nitrate.Method provided by the invention is comprehensively preferred to the condition during synthesis and parameter progress, and the impurity that may be introduced in production process is control effectively, production efficiency and the purity and yield of product is improved, is more suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the synthesis technique of compound, and in particular to a kind of method of industrialized production Butoconazole Nitrate.
Background technology
Butoconazole Nitrate (Butoconazole nitrate) is a kind of medicine for being clinically used to treat outer vaginal candida
Thing, have the characteristics that evident in efficacy, recurrence rate is low, better tolerance, adverse reaction rate are low.
Butoconazole Nitrate chemical constitution is as follows：
Keith A.M.Walker, Allen C.Braemer are equal to the article " 1- [4- (4- delivered for 1978
Chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]-1H-imidaz ole nitrate,a new
In potent antifungal agent ", the synthetic method of Butoconazole Nitrate is disclosed；In recent years, the scholar such as Zhang Haibo for
The synthetic method of the medicine has also been reported.
The main body synthetic route of Butoconazole Nitrate is as follows：
However, the research of the multipair medicine of prior art focuses mostly in laboratory level, the large-scale production for medicine
For, the Butoconazole Nitrate production technology that prior art provides lacks effective control to impurity, causes the post processing step such as purifying
Rapid complexity, cost are higher, and product yield and purity can not meet the needs of industrialized production.
The content of the invention
The purpose of the present invention is the defects of overcoming prior art, by being carried out comprehensively to the condition during synthesis and parameter
Adjustment, in production process may introduce impurity control effectively, there is provided one kind meets pharmaceutical factory large-scale industry metaplasia
Produce the Butoconazole Nitrate synthetic method needed.
For preparing 1- as raw material using 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles and 2,6- thiophenol dichlorobenzenes
For the reaction of (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyl) is thio) butyl) -1 hydrogen-imidazoles, due to raw material 1-, (2- is chloro-
4- (4- chlorphenyls) butyl) 2 sites that can be reacted with 2,6- thiophenol dichlorobenzenes in -1 hydrogen-imidazoles be present, except target is produced
Beyond the region of objective existence, additionally it is possible to impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1 hydrogen-imidazoles is generated, it is described
Impurity structure is as follows：
Due to the impurity and target product 1- (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyls) is thio) butyl) -1 hydrogen -
The physical property difference of imidazoles is little, it is difficult to by routine extraction, purification process remove, and the impurity easily it is follow-up into
In reactant salt with nitric acid act on, further formed 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1 hydrogen -
Imidazole nitrate, have a strong impact on technological process and the product quality of industrialized production Butoconazole Nitrate.
The present invention to extraction procedure, reagent and the parameter of correlation by optimizing, there is provided one kind production nitric acid cloth health
The method of azoles, reduce impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1 hydrogen-imidazoles, improve
The yield and purity of Butoconazole Nitrate.
Specifically, the invention provides a kind of method for producing Butoconazole Nitrate, the described method comprises the following steps：
(1) using 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles, 2,6- thiophenol dichlorobenzenes, Anhydrous potassium carbonate as original
Material, is heated to reflux in acetone, fully after reaction, cooling, filtering, filtering, after filtrate is concentrated, obtains concentrate；
(2) concentrate obtained by step (1) is taken, adds extract, it is 2~3 that weight ratio is included in the extract：1~2
Ether and water；Fully after extraction, aqueous phase is abandoned, organic phase is standby；
(3) concentrated nitric acid is added dropwise in organic phase obtained by step (2), is filtered to after stopping generation precipitation；Filtrate is abandoned, by filter cake
Washing, after drying, obtain Butoconazole Nitrate.
The present invention further carries out preferred to step (2).Specifically：
The addition of step (2) the of the present invention extract is 6~10 times of the concentrate weight, preferably described dense
8 times of contracting thing weight.
The weight ratio of step (2) ether and water is preferably 2~3：1.5.
In order to pointedly improve impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyls) is thio) phenyl) butyl) -1 hydrogen -
The removal efficiency of imidazoles, acetone can also be included in step (2) described extract.Preferably, weight is included in the extract
Than for 2~3：1~3：1~2 ether, acetone and water.It is highly preferred that the extract by ether, acetone and water with weight ratio 2
~3：2~3：1.5 composition.As most preferably scheme, step (2) extract is by ether, acetone and water with weight ratio 2.5：
2：1.5 composition.
Step (2) it is described extraction be specially：After stirring 5~15min under conditions of not higher than 20 DEG C, stand.It is described to stir
It is preferably 10min to mix the time.
The present invention on the basis of step (2) is carried out preferably, to step (1) and the scheme of (3) preferably, made
The preferred scheme of standby Butoconazole Nitrate.
The step (1) is preferably：By 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles and 2,6- dichloro-benzenes sulphur
Phenol, Anhydrous potassium carbonate and acetone are with weight ratio 4~6：4~6：1~4：30~50 mixing, the back flow reaction 4.5 at 55~65 DEG C
~5.5 hours, it was 0.5~1 to add with the 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles weight ratio：4~6 nothing
Aqueous carbonate potassium, back flow reaction 6.5~7.5 hours at 55~65 DEG C, with 0~4 DEG C of recirculated water Slow cooling, 2800~
10~30min is centrifuged under the conditions of 2900r/min, abandons solid, retains liquid, as filtrate；Filtrate is concentrated at 55~65 DEG C
To being steamed without acetone, concentrate is obtained.
The step (3) is preferably：Under ice bath, 1~2 revolutions per second of stirring condition, in organic phase obtained by step (2)
Concentration is added dropwise as 65~70% nitric acid using 1~3ml/s speed, in 2800~2900r/ of rotating speed after being precipitated to stopping generation
20~40min is centrifuged under conditions of min, abandons filtrate, retains solid；Filled after the filter cake is mixed with the ether of 3~4 times of weight
Divide stirring, 20~40min is centrifuged under conditions of 2800~2900r/min of rotating speed, abandon liquid, retain solid；Ether is washed
The solid retained afterwards is sufficiently stirred after being mixed with the acetone of 6~8 weight, is centrifuged under conditions of 2800~2900r/min of rotating speed
20~40min, liquid is abandoned, retain solid, dried 3~7 hours under the conditions of 45~55 DEG C, -0.5~0.5Mpa, obtain nitric acid cloth
Health azoles.
One of preferred scheme as the present invention, the described method comprises the following steps：
(1) by 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles and 2,6- thiophenol dichlorobenzenes, Anhydrous potassium carbonate and
Acetone is with weight than 4~6：4~6：1~4：30~50 mixing, back flow reaction 4.5~5.5 hours at 55~65 DEG C, add with
1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles weight ratio is 0.5~1：4~6 Anhydrous potassium carbonate, 55~
Back flow reaction 6.5~7.5 hours at 65 DEG C, with 0~4 DEG C of recirculated water Slow cooling, under the conditions of 2800~2900r/min from
10~30min of the heart, solid is abandoned, retain liquid, as filtrate；No acetone is concentrated the filtrate at 55~65 DEG C to steam, and is obtained dense
Contracting thing；
(2) added in the concentrate and account for the extract of 6~10 times of its weight, be comprising weight ratio in the extract
2~3：1~3：1~2 ether, acetone and water；After stirring 5~15min under conditions of not higher than 20 DEG C, stand, abandon aqueous phase,
Retain organic phase；
(3) under ice bath, 1~2 revolutions per second of stirring condition, with 1~3ml/s speed in organic phase obtained by step (2)
The nitric acid that concentration is 65~70% is added dropwise, 20 are centrifuged under conditions of 2800~2900r/min of rotating speed to after stopping generation precipitation
~40min, filtrate is abandoned, retain solid；It is sufficiently stirred after the filter cake is mixed with the ether of 3~4 times of weight, in rotating speed 2800
20~40min is centrifuged under conditions of~2900r/min, abandons liquid, retains solid；The solid retained after ether is washed and 6~8
It is sufficiently stirred after the acetone mixing of weight, 20~40min is centrifuged under conditions of 2800~2900r/min of rotating speed, abandons liquid, is protected
Solid is stayed, is dried 3~7 hours under the conditions of 45~55 DEG C, -0.5~0.5Mpa, obtains Butoconazole Nitrate.
In order to meet the needs of large-scale industrial production, the raw material 1- of the present invention for being used to produce Butoconazole Nitrate
(the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles preferably uses chemical synthesis process to produce to obtain, and the 1- that will synthesize gained
(the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is directly used in the synthesis of follow-up Butoconazole Nitrate as intermediate product.So
And for preparing 1- (the chloro- 4- of 2- (4- chlorphenyls) fourths by raw material of 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles
Base) -1 hydrogen-imidazoles reaction for, industrialization mass produce in, because raw material and target product structure are closely similar, not
Anti- complete 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles can have a strong impact on follow-up nitric acid synthesis butoconazole process
The yield and purity of product.
The present invention is in order to improve the yield of finished product Butoconazole Nitrate and purity, to intermediate product 1- (2- chloro- 4- (4- chlorine
Phenyl) butyl) preparation process of -1 hydrogen-imidazoles is optimized.By the optimization to above-mentioned course of reaction and relevant parameter, one
Aspect ensures the abundant progress of reaction, improves the purity of product, is on the other hand fully carried by the control to other reaction conditions
The yield of high product, so that it is guaranteed that continuing to synthesize as raw material using intermediate 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles
The purity and yield of Butoconazole Nitrate.
Specifically, 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles can be by comprising the following steps method system
It is standby to form：
By 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles with weight than 2~5：20~40 are dissolved in dichloromethane
Alkane, it is 2~5 to be slowly added dropwise at 15~25 DEG C with the 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles weight ratio：2
~5 thionyl chloride, fully reacted after being to slowly warm up to 25~45 DEG C, cool down, obtain reaction solution；Delay successively in the reaction solution
It is slow to add cold water and natrium carbonicum calcinatum, filter, abandon solid, by liquid concentration, drying, obtain intermediate product 1- (2- chloro- 4- (4- chlorine
Phenyl) butyl) -1 hydrogen-imidazoles.
Preferably, 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is prepared by the method comprised the following steps
Form：
By 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles with weight than 2~5：25~35 are dissolved in dichloromethane
Alkane, it is added dropwise and the 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles with 1~2ml/s speed at 15~25 DEG C
Weight ratio is 2~5：2~5 thionyl chloride, is to slowly warm up to 30~35 DEG C, insulation reaction 0.5~1.5 hour, then 55~
65 DEG C of back flow reactions 0.5~1.5 hour, slowly cool to less than 20 DEG C, obtain reaction solution；In the reaction solution while stirring with
0.1~1ml/s speed adds the water that temperature is not higher than 20 DEG C, and the volume ratio of the reaction solution and water is 0.004~0.006：
1, then natrium carbonicum calcinatum is added with 1.0~1.5kg/L, filter, abandon solid, filtrate is concentrated into no dichloromethane at 50~60 DEG C
Untill alkane steams, dry, obtain 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles.
It is of the present invention to be used to produce 1- (the chloro- 4- of 2- (4- chlorphenyls) in order to meet the needs of large-scale industrial production
Butyl) -1 hydrogen-imidazoles raw material 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles preferably use chemical synthesis process give birth to
Production is obtained, and 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles for synthesizing gained is directly used in as intermediate product
The synthesis of follow-up Butoconazole Nitrate.
However, in industrialization mass produces, 1- (2- hydroxyls are produced by raw material of the chloro- 4- of 1- (4- chlorphenyls) -2- butanol
Base -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles course of reaction in easily introduce a large amount of impurity, including 1- (1- chloro- 4- (4- chlorine
Phenyl) butane -2- bases) -1 hydrogen-imidazoles, 4- (4- (1 hydrogen-imidazoles -1- bases) phenyl) chloro- 2- butanol of -1- etc., influence nitric acid synthesis
The subsequent process of butoconazole.The structure of the impurity is as shown in table 1.
Table 1：Major impurity in 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles synthesis
The present invention is in order to improve the yield of finished product Butoconazole Nitrate and purity, to intermediate product 1- (2- hydroxyl -4- (4-
Chlorphenyl) butyl) preparation process of -1 hydrogen-imidazoles is optimized.By the optimization to above-mentioned course of reaction and relevant parameter,
The generation of the impurity can be substantially reduced, to improve the intermediate 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-miaow
The purity and yield of azoles, so as to improve the quality of Butoconazole Nitrate finished product.
Specifically, 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles can be by comprising the following steps method
It is prepared：
Take the sodium hydride DMF solution of concentration 10~30%, under condition of ice bath, the imidazoles of concentration 10~30% is slowly added dropwise
DMF solution, heating stirring reaction, after cooling, 1- chloro- 4- (4- chlorphenyls) -2- butanol obtained by step (1) is slowly added to, it is described
The weight ratio of sodium hydride DMF solution, imidazoles DMF solution and the chloro- 4- of 1- (4- chlorphenyls) -2- butanol is 5~9：5~9：3~7；
Heating stirring is reacted, and after cooling, obtains reaction solution；N-hexane and frozen water are sequentially added in the reaction solution, is sufficiently stirred, to stopping
Filtered after only separating out precipitation, wash filter cake, centrifugal drying, recrystallized with ethyl acetate and activated carbon, obtain intermediate product 1- (2- hydroxyls
Base -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles.
Preferably, the method that 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles can be by comprising the following steps
It is prepared：
Take the sodium hydride DMF solution of concentration 10~30%, under condition of ice bath, dripped while stirring with 1~3ml/s speed
Add the imidazoles DMF solution of concentration 10~30%, 55~65min of stirring reaction at 58~62 DEG C, after being cooled down with ice salt bath method, delay
It is slow to add 1- chloro- 4- (4- chlorphenyls) -2- butanol, the sodium hydride DMF solution, imidazoles DMF solution and 1- chloro- 4- (4- chlorobenzenes
Base) -2- butanol weight ratio be 5~9：5~9：3~7；115~125min of stirring reaction at 58~62 DEG C, with ice salt bath method
After cooling, reaction solution is obtained；Added in the reaction solution and account for the n-hexane of the reaction solution weight 20~25%, with 1~5 turn/
After the speed of second stirs 10~20min, the frozen water for accounting for the reaction solution weight 300~400% is added, with 1~5 revolutions per second
Speed is stirred to stopping filtering after separating out precipitation, with the water washing filter cake 1~2 time for accounting for 1/3~1/2 times of filter cake weight, with rotating speed
2500~3000r/min pelleted by centrifugation dries 50~70min, with account for respectively 2~3 times of the centrifugal drying products therefrom weight and
0.04~0.06 times of ethyl acetate and activated carbon, stand 10~16 hours at -7~-3 DEG C and recrystallized, at 45~55 DEG C
Under to recrystallization products therefrom be dried, obtain 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles.
It is of the present invention to be used to produce 1- (2- hydroxyls -4- (4- chlorobenzenes in order to meet the needs of large-scale industrial production
Base) butyl) the chloro- 4- of raw material 1- (4- chlorphenyls) -2- butanol of -1 hydrogen-imidazoles preferably uses chemical synthesis process to produce to obtain, and
The synthesis of follow-up Butoconazole Nitrate is directly used in using the chloro- 4- of 1- (4- the chlorphenyls) -2- butanol for synthesizing gained as intermediate product.
However, in industrialization mass produces, it is easily introduced in the building-up process of the chloro- 4- of 1- (4- chlorphenyls) -2- butanol
A large amount of impurity, including parachlorotoluene, chloromethylbenzene, 1,2- (4- chlorphenyls) ethane, the chloro- 4- of 1- (4- (chlorine) benzyl) benzene, 3- are chloro-
2- (4- chlorobenzyls) -1- propyl alcohol, 1,2- (4- chlorphenyls) epoxy butane etc. are, it is necessary to pass through the extraction of complexity, purification process ability
It is enough efficiently to remove, influence the subsequent process of nitric acid synthesis butoconazole.The structure of the impurity is as shown in table 2.
Table 2：Major impurity in the synthesis of the chloro- 4- of 1- (4- chlorphenyls) -2- butanol
The present invention is in order to improve the yield of finished product Butoconazole Nitrate and purity, 4- (4- chlorobenzenes chloro- to intermediate product 1-
Base) preparation process of -2- butanol is optimized.By the optimization to above-mentioned course of reaction and relevant parameter, can significantly subtract
The generation of few impurity, simplifies purge process, to improve the pure of the chloro- 4- of intermediate 1- (4- the chlorphenyls) -2- butanol
Degree and yield, so as to improve the quality of Butoconazole Nitrate finished product.
Specifically, the chloro- 4- of 1- (4- the chlorphenyls) -2- butanol can be prepared by the method comprised the following steps：
Take the iodine of 1.5~2.5 parts of magnesium powders, initiation ether and catalytic amount, be slowly added dropwise 35~45 parts of concentration for 0.2~
0.4g/ml p-chlorobenzylchloride diethyl ether solution, back flow reaction after finishing is dripped, obtains p-chlorobenzylchloride RMgBr；15~25 are slowly added dropwise again
The epoxychloropropane diethyl ether solution that part concentration is 0.25~0.45g/ml, drips back flow reaction after finishing, obtains reaction solution；In condition of ice bath
It is lower be slowly added dropwise into the reaction solution concentration be 20~30% sulfuric acid, to without solid residue when stop be added dropwise；Stratification,
Aqueous phase is abandoned, organic phase is concentrated, rectifying, obtains the chloro- 4- of intermediate product 1- (4- chlorphenyls) -2- butanol.
Preferably, the chloro- 4- of the 1- (4- chlorphenyls) -2- butanol can be prepared by the method comprised the following steps：
Take 1.5~2.5 parts of magnesium powders, the ether of initiating amount and the iodine of catalytic amount, the magnesium powder and the quality of initiation ether
Volume ratio is 1.5~2.5kg/50ml；At 30~40 DEG C using 2~4ml/s speed be added dropwise 35~45 parts of concentration as 0.25~
0.3g/ml p-chlorobenzylchloride diethyl ether solution, drop are reacted 0.5~1.5 hour after finishing at 35~40 DEG C, obtain the examination of p-chlorobenzylchloride grignard
Agent；The epoxychloropropane diethyl ether solution that 15~25 parts of concentration are 0.33~0.37g/ml is slowly added dropwise again, 35~40 after drop is complete
Reacted 1~2 hour at DEG C, obtain reaction solution；With 1~3ml/s speed to the reaction under 0~10 DEG C, at the uniform velocity stirring condition
In liquid be added dropwise concentration be 24~26% sulfuric acid, to without solid residue when stop be added dropwise；At the uniform velocity stir 5~15min after stand 8~
12min makes liquid layered；Abandon aqueous phase, take organic phase be concentrated under the conditions of -0.05~0MPa, 50~60 DEG C no ether steam for
Only, 160~180 DEG C/10mmHg cut is collected in rectifying, obtains the chloro- 4- of 1- (4- chlorphenyls) -2- butanol.
As the present invention most preferably scheme, methods described include following S1~S4 described in the step of being carried out continuously：
S1：Take 1.5~2.5 parts of magnesium powders, the ether of initiating amount and the iodine of catalytic amount, the magnesium powder and the matter of initiation ether
Amount volume ratio is 1.5~2.5kg/50ml；35~45 parts of concentration are added dropwise as 0.25 using 2~4ml/s speed at 30~40 DEG C
~0.3g/ml p-chlorobenzylchloride diethyl ether solution, drop are reacted 0.5~1.5 hour after finishing at 35~40 DEG C, obtain p-chlorobenzylchloride grignard
Reagent；Be slowly added dropwise the epoxychloropropane diethyl ether solution that 15~25 parts of concentration are 0.33~0.37g/ml again, drop finish after 35~
Reacted 1~2 hour at 40 DEG C, obtain reaction solution；With 1~3ml/s speed to described anti-under 0~10 DEG C, at the uniform velocity stirring condition
Answer in liquid be added dropwise concentration be 24~26% sulfuric acid, to without solid residue when stop be added dropwise；8 are stood after at the uniform velocity stirring 5~15min
~12min makes liquid layered；Aqueous phase is abandoned, takes organic phase to be concentrated into no ether under the conditions of -0.05~0MPa, 50~60 DEG C and steams
Untill, 160~180 DEG C/10mmHg cut is collected in rectifying, obtains the chloro- 4- of intermediate product 1- (4- chlorphenyls) -2- butanol；
S2：The sodium hydride DMF solution of concentration 10~30% is taken, under condition of ice bath, is stirred with 1~3ml/s speed side
The imidazoles DMF solution of concentration 10~30% is added dropwise in side, 55~65min of stirring reaction at 58~62 DEG C, is cooled down with ice salt bath method
Afterwards, be slowly added to 1- chloro- 4- (4- chlorphenyls) -2- butanol obtained by step S1, the sodium hydride DMF solution, imidazoles DMF solution with
The weight ratio of the chloro- 4- of 1- (4- chlorphenyls) -2- butanol is 5~9：5~9：3~7；At 58~62 DEG C stirring reaction 115~
125min, after being cooled down with ice salt bath method, obtain reaction solution；Added in the reaction solution and account for the reaction solution weight 20~25%
N-hexane, after stirring 10~20min with 1~5 revolutions per second of speed, add the ice for accounting for the reaction solution weight 300~400%
Water, stirred to stopping filtering after separating out precipitation with 1~5 revolutions per second of speed, filtered with the water washing for accounting for 1/3~1/2 times of filter cake weight
Cake 1~2 time, 50~70min is dried with 2500~3000r/min of rotating speed pelleted by centrifugation, with accounting for respectively obtained by the centrifugal drying
The ethyl acetate and activated carbon that 2~3 times and 0.04~0.06 times of products weight, stand 10~16 hours at -7~-3 DEG C and carry out weight
Crystallization, recrystallization products therefrom is dried at 45~55 DEG C, obtains intermediate product 1- (2- hydroxyls -4- (4- chlorphenyls) fourths
Base) -1 hydrogen-imidazoles；
S3：By the 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles with weight than 2~5：25~35 dissolvings
In dichloromethane, at 15~25 DEG C with 1~2ml/s speed be added dropwise with the 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -
1 hydrogen-imidazoles weight ratio is 2~5：2~5 thionyl chloride, is to slowly warm up to 30~35 DEG C, insulation reaction 0.5~1.5 hour,
Again in 55~65 DEG C of back flow reactions 0.5~1.5 hour, less than 20 DEG C are slowly cooled to, obtains reaction solution；The side in the reaction solution
Stir side and water of the temperature not higher than 20 DEG C is added with 0.1~1ml/s speed, the volume ratio of the reaction solution and water is 0.004
~0.006：1, then natrium carbonicum calcinatum is added with 1.0~1.5kg/L, filter, abandon solid, filtrate is concentrated at 50~60 DEG C
Untill being steamed without dichloromethane, dry, obtain intermediate product 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles；
S4：By the 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles and 2,6- thiophenol dichlorobenzenes, Carbon Dioxide
Potassium and acetone are with weight ratio 4~6：4~6：1~4：30~50 mixing, back flow reaction 4.5~5.5 hours at 55~65 DEG C, are mended
It is 0.5~1 to add with the 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles weight ratio：4~6 Anhydrous potassium carbonate,
Back flow reaction 6.5~7.5 hours at 55~65 DEG C, with 0~4 DEG C of recirculated water Slow cooling, in 2800~2900r/min conditions
10~30min of lower centrifugation, solid is abandoned, retain liquid, as filtrate；No acetone is concentrated the filtrate at 55~65 DEG C to steam,
Obtain concentrate；The extract for accounting for 6~10 times of its weight is added in the concentrate, it is 2 that weight ratio is included in the extract
~3：1~3：1~2 ether, acetone and water；After stirring 5~15min under conditions of not higher than 20 DEG C, stand, abandon aqueous phase,
Retain organic phase；It is dense with 1~3ml/s speed dropwise addition in the organic phase under ice bath, 1~2 revolutions per second of stirring condition
Spend the nitric acid for 65~70%, to stop generation precipitation after under conditions of 2800~2900r/min of rotating speed centrifugation 20~
40min, filtrate is abandoned, retain solid；Be sufficiently stirred after the filter cake is mixed with the ether of 3~4 times of weight, rotating speed 2800~
20~40min is centrifuged under conditions of 2900r/min, abandons liquid, retains solid；The solid retained after ether is washed and 6~8 times
It is sufficiently stirred after the acetone mixing of weight, 20~40min is centrifuged under conditions of 2800~2900r/min of rotating speed, abandons liquid, is protected
Solid is stayed, is dried 3~7 hours under the conditions of 45~55 DEG C, -0.5~0.5Mpa, produces Butoconazole Nitrate.
Method provided by the invention is easy to operate, and raw material and dosage are reasonable, and impurity contains in gained Butoconazole Nitrate product
Measure it is low, suitable for large-scale industrial production.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1
Butoconazole Nitrate is produced according to following steps：
(1) take 6kg 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles, 6kg 2,6- thiophenol dichlorobenzenes, 4kg without
Aqueous carbonate potassium and 50kg acetone, back flow reaction 5.5 hours, adds 1kg Anhydrous potassium carbonates, the back flow reaction at 65 DEG C at 65 DEG C
7.5 hours, with 0~4 DEG C of recirculated water Slow cooling, 30min is centrifuged under 2825r/min speed conditions, abandons solid, retains liquid
Body, as filtrate；No acetone is concentrated the filtrate at 65 DEG C to steam, and obtains concentrate；
(2) concentrate obtained by taking step (1), adds the extract of 8 times of the concentrate weight, the extract is by weight
Than for 2.5：2：1.5 ether, acetone and water composition；After stirring 10min at 15 DEG C, stand, abandon aqueous phase, organic phase is standby；
(3) under ice bath, stirring condition, concentrated nitric acid is added dropwise in organic phase obtained by step (2), to after stopping generation precipitation
Filtering；Filtrate is abandoned, washs filter cake using ether and acetone successively, after drying, obtains Butoconazole Nitrate.
After testing, the yield of the present embodiment product is 95.3%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, target product 1- (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyl) is thio) butyl) -1 hydrogen-miaow
The content of azoles single nitric acid salt is 92.25%, impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1
The content of hydrogen-imidazoles single nitric acid salt is 0.94%.
Embodiment 2
Butoconazole Nitrate is produced according to following steps：
(1) with embodiment 1；
(2) concentrate obtained by taking step (1), adds the extract of 6 times of the concentrate weight, the extract is by weight
Than for 2：1：1 ether, acetone and water composition；After stirring 5min at 10 DEG C, stand, abandon aqueous phase, organic phase is standby；
(3) with embodiment 1.
After testing, the yield of the present embodiment product is 91.36%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, target product 1- (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyl) is thio) butyl) -1 hydrogen-miaow
The content of azoles single nitric acid salt is 90.17%, impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1
The content of hydrogen-imidazoles single nitric acid salt is 1.25%.
Embodiment 3
Butoconazole Nitrate is produced according to following steps：
(1) with embodiment 1；
(2) concentrate obtained by taking step (1), the extract of 10 times of the concentrate weight is added, the extract is by weight
Amount is than being 3：3：2 ether, acetone and water composition；After stirring 15min at 20 DEG C, stand, abandon aqueous phase, organic phase is standby；
(3) with embodiment 1.
After testing, the yield of the present embodiment product is 92.17%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, target product 1- (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyl) is thio) butyl) -1 hydrogen-miaow
The content of azoles single nitric acid salt is 91.36%, impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1
The content of hydrogen-imidazoles single nitric acid salt is 1.08%.
Embodiment 4
Butoconazole Nitrate is produced according to following steps：
(1) with embodiment 1；
(2) concentrate obtained by taking step (1), adds the extract of 3 times of the concentrate weight, the extract is by weight
Than for 2：1.5 ether and water composition；After stirring 15min at 20 DEG C, stand, abandon aqueous phase, organic phase is standby；
(3) with embodiment 1.
After testing, the yield of the present embodiment product is 88.65%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, target product 1- (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyl) is thio) butyl) -1 hydrogen-miaow
The content of azoles single nitric acid salt is 78.36%, impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1
The content of hydrogen-imidazoles single nitric acid salt is 4.58%.
Embodiment 5
Butoconazole Nitrate is produced according to following steps：
(1) with embodiment 1；
(2) concentrate obtained by taking step (1), the extract of 15 times of the concentrate weight is added, the extract is by weight
Amount is than being 2:1 ether and water composition；After stirring 5min at 20 DEG C, stand, abandon aqueous phase, organic phase is standby；
(3) with embodiment 1.
After testing, the yield of the present embodiment product is 89.33%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, target product 1- (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyl) is thio) butyl) -1 hydrogen-miaow
The content of azoles single nitric acid salt is 79.31%, impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1
The content of hydrogen-imidazoles single nitric acid salt is 4.36%.
Embodiment 6
Butoconazole Nitrate is produced according to following steps：
(1) with embodiment 1；
(2) concentrate obtained by taking step (1), adds the extract of 8 times of the concentrate weight, the extract is by weight
Than for 4：1 ether and water composition；After stirring 15min at 20 DEG C, stand, abandon aqueous phase, organic phase is standby；
(3) with embodiment 1.
After testing, the yield of the present embodiment product is 86.37%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, target product 1- (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyl) is thio) butyl) -1 hydrogen-miaow
The content of azoles single nitric acid salt is 77.15%, impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1
The content of hydrogen-imidazoles single nitric acid salt is 3.78%.
Embodiment 7
Butoconazole Nitrate is produced according to following steps：
(1) with embodiment 1；
(2) concentrate obtained by taking step (1), adds the extract of 8 times of the concentrate weight, the extract is by weight
Than for 2：1 acetone and water composition；After stirring 15min at 20 DEG C, stand, abandon aqueous phase, organic phase is standby；
(3) with embodiment 1.
After testing, the yield of the present embodiment product is 61.21%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, target product 1- (4- (4- chlorphenyls) -2- ((2,6- dichlorophenyl) is thio) butyl) -1 hydrogen-miaow
The content of azoles single nitric acid salt is 89.33%, impurity 1- (the chloro- 4- of 2- (4- ((2,6- dichlorophenyl) is thio) phenyl) butyl) -1
The content of hydrogen-imidazoles single nitric acid salt is 1.78%.
Embodiment 8
1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is prepared using following methods：
5kg1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is taken, 35kg dichloromethane is completely dissolved in, 20
5kg thionyl chlorides are added dropwise with 1.5ml/s speed at DEG C, are to slowly warm up to 32 DEG C, insulation reaction 1 hour, then in 60 DEG C of backflows
Reaction 1 hour, slowly cools to 15 DEG C, obtains reaction solution；10 are added in the reaction solution while stirring with 0.5ml/s speed
DEG C water, the volume ratio of the reaction solution and water is 0.005：1, then natrium carbonicum calcinatum is added with 1.0~1.5kg/L, filter, abandon
Solid, liquid is concentrated at 55 DEG C untill no dichloromethane steams, dries, produce 1- (the chloro- 4- of 2- (4- chlorphenyls) fourths
Base) -1 hydrogen-imidazoles, purity 99.17%.
The 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is used for embodiment 1~7 as raw material.
Embodiment 9
1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is prepared using following methods：
The sodium hydride DMF solution for taking 7kg concentration to be 20%, under condition of ice bath, is added dropwise while stirring with 2ml/s speed
7kg concentration is 20% imidazoles DMF solution, the stirring reaction 60min at 60 DEG C；After being cooled down with ice salt bath method, it is slowly added to
The chloro- 4- of 5kg1- (4- chlorphenyls) -2- butanol, the stirring reaction 120min at 60 DEG C, after being cooled down with ice salt bath method, obtain reaction solution；
The n-hexane for accounting for its weight 25% is added in the reaction solution, after 3 revolutions per seconds of speed stirring 15min, is added described in accounting for
The frozen water of reaction solution weight 350%, stirred with 3 revolutions per seconds of speed to stopping filtering after separating out precipitation, with accounting for filter cake weight 1/3
Times water washing filter cake 1 time, 60min is dried with rotating speed 2825r/min pelleted by centrifugation, with accounting for respectively obtained by the centrifugal drying
The ethyl acetate and activated carbon that 2.5 times and 0.05 times of products weight, stand 13 hours at -5 DEG C and recrystallized, it is right at 50 DEG C
Recrystallization products therefrom is dried, and produces 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles, purity is
99.31%.
The 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is used for embodiment 8 as raw material.
Embodiment 10
1- chloro- 4- (4- chlorphenyls) -2- butanol is prepared using following methods：
Take the iodine of 2.5kg magnesium powders, 50ml ether and catalytic amount, at 35 DEG C using 3ml/s speed be added dropwise 40kg concentration as
0.28g/ml p-chlorobenzylchloride diethyl ether solution, drop are reacted 1 hour after finishing at 38 DEG C, obtain p-chlorobenzylchloride RMgBr；It is slow again
The epoxychloropropane diethyl ether solution that 20kg concentration is 0.35g/ml is added dropwise, drop is reacted 1.5 hours at 38 DEG C after finishing, must reacted
Liquid；Concentration is added dropwise as 25% sulfuric acid into the reaction solution using 2ml/s speed under 4 DEG C, at the uniform velocity stirring condition, to without solid
Stop being added dropwise when body remains；Standing 10min makes liquid layered after at the uniform velocity stirring 10min；Abandon aqueous phase, take organic phase-
0.01MPa, it is concentrated under the conditions of 55 DEG C untill no ether steams, 160~180 DEG C/10mmHg cut is collected in rectifying, is dried
Afterwards, the chloro- 4- of 1- (4- chlorphenyls) -2- butanol, purity 95.51% are obtained.
It is used for embodiment 9 using the chloro- 4- of the 1- (4- chlorphenyls) -2- butanol as raw material.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed
Scope.
Claims (8)
- A kind of 1. method for producing Butoconazole Nitrate, it is characterised in that comprise the following steps：(1) by 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles and 2,6- thiophenol dichlorobenzenes, Anhydrous potassium carbonate and acetone With weight than 4~6：4~6：1~4：30~50 mixing, back flow reaction 4.5~5.5 hours at 55~65 DEG C, add with it is described 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles weight ratio is 0.5~1：4~6 Anhydrous potassium carbonate, at 55~65 DEG C Lower back flow reaction 6.5~7.5 hours, with 0~4 DEG C of recirculated water Slow cooling, 10 are centrifuged under the conditions of 2800~2900r/min ~30min, solid is abandoned, retain upper liquid；Upper liquid is concentrated into no acetone at 55~65 DEG C to steam, obtains concentrate；(2) take concentrate obtained by step (1), add extract, the addition of the extract for the concentrate weight 6~ 10 times, the extract is 2~3 by weight ratio：1~3：1~2 ether, acetone and water composition；The extraction is specially： After stirring 5~15min under conditions of not higher than 20 DEG C, stand；Aqueous phase is abandoned, organic phase is standby；(3) under ice bath, 1~2 revolutions per second of stirring condition, it is added dropwise in organic phase obtained by step (2) with 1~3ml/s speed Concentration be 65~70% nitric acid, to stop generation precipitation after under conditions of 2800~2900r/min of rotating speed centrifugation 20~ 40min, filtrate is abandoned, retain solid；Be sufficiently stirred after the filter cake is mixed with the ether of 3~4 times of weight, rotating speed 2800~ 20~40min is centrifuged under conditions of 2900r/min, abandons liquid, retains solid；The solid and 6~8 weights retained after ether is washed It is sufficiently stirred after the acetone mixing of amount, 20~40min is centrifuged under conditions of 2800~2900r/min of rotating speed, abandons liquid, is retained Solid, dried 3~7 hours under the conditions of 45~55 DEG C, -0.5~0.5Mpa, obtain Butoconazole Nitrate.
- 2. according to the method for claim 1, it is characterised in that the addition of the extract is the concentrate weight 8 times.
- 3. method according to claim 1 or 2, it is characterised in that step (2) described extract is by weight than 2~3：2~ 3：1.5 ether, acetone and water composition.
- 4. according to the method for claim 3, it is characterised in that the extract is by ether, acetone and water with weight ratio 2.5：2：1.5 composition.
- 5. according to the method for claim 3, it is characterised in that step (2) it is described extraction be specially：In 10~15 DEG C of bar After stirring 10min under part, stand.
- 6. method according to claim 1 or 2,1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles by including The method of following steps is prepared：By 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles with weight than 2~5：20~40 are dissolved in dichloromethane, It is 2~5 to be slowly added dropwise at 15~25 DEG C with the 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles weight ratio：2~5 Thionyl chloride, fully reacted after being to slowly warm up to 25~45 DEG C, cool down, obtain reaction solution；It is slow successively in the reaction solution Add cold water and natrium carbonicum calcinatum, filter, abandon solid, by liquid concentration, drying, obtain 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl)- 1 hydrogen-imidazoles.
- 7. according to the method for claim 6, it is characterised in that -1 hydrogen of the 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) - Imidazoles is prepared by the method comprised the following steps：The sodium hydride DMF solution of concentration 10~30% is taken, under condition of ice bath, the imidazoles DMF of concentration 10~30% is slowly added dropwise Solution, heating stirring reaction, after cooling, is slowly added to the chloro- 4- of 1- (4- chlorphenyls) -2- butanol, the sodium hydride DMF solution, The weight ratio of imidazoles DMF solution and the chloro- 4- of 1- (4- chlorphenyls) -2- butanol is 5~9：5~9：3~7；Heating stirring is reacted, cold But after, reaction solution is obtained；N-hexane and frozen water are sequentially added in the reaction solution, is sufficiently stirred, mistake after separating out precipitation to stopping Filter, filter cake is washed, centrifugal drying, is recrystallized with ethyl acetate and activated carbon, obtains 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 Hydrogen-imidazoles.
- 8. according to the method for claim 7, it is characterised in that the chloro- 4- of 1- (4- the chlorphenyls) -2- butanol by including with The method of lower step is prepared：The iodine of 1.5~2.5 parts of magnesium powders, initiation ether and catalytic amount is taken, it is 0.2~0.4g/ that 35~45 parts of concentration, which are slowly added dropwise, Ml p-chlorobenzylchloride diethyl ether solution, back flow reaction after finishing is dripped, obtains p-chlorobenzylchloride RMgBr；15~25 parts of concentration are slowly added dropwise again For 0.25~0.45g/ml epoxychloropropane diethyl ether solution, back flow reaction after finishing is dripped, obtains reaction solution；To institute under condition of ice bath State be slowly added dropwise in reaction solution concentration be 20~30% sulfuric acid, to without solid residue when stop be added dropwise；Stratification, abandon water Phase, organic phase is concentrated, rectifying, obtain the chloro- 4- of 1- (4- chlorphenyls) -2- butanol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1077493A (en) * | 1975-07-28 | 1980-05-13 | Syntex (U.S.A.) Llc. | Derivatives of substituted n-alkyl imidazoles |
| CN102649796A (en) * | 2011-02-24 | 2012-08-29 | 四川滇虹医药开发有限公司 | Preparation method for important intermediates of butoconazole nitrate |
| CN103880596A (en) * | 2012-12-21 | 2014-06-25 | 凌沛学 | Preparation method of butoconazole nitrate intermediate suitable for industrial production |
-
2015
- 2015-10-09 CN CN201510648064.7A patent/CN105198818B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1077493A (en) * | 1975-07-28 | 1980-05-13 | Syntex (U.S.A.) Llc. | Derivatives of substituted n-alkyl imidazoles |
| CN102649796A (en) * | 2011-02-24 | 2012-08-29 | 四川滇虹医药开发有限公司 | Preparation method for important intermediates of butoconazole nitrate |
| CN103880596A (en) * | 2012-12-21 | 2014-06-25 | 凌沛学 | Preparation method of butoconazole nitrate intermediate suitable for industrial production |
Non-Patent Citations (2)
| Title |
|---|
| 1-[4-(4-Chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]-1H-imidazole Nitrate, a New Potent Antifungal Agent;Keith A. M. Walker，等;《 Journal of Medicinal Chemistry》;19781231;第21卷(第8期);第840-843页 * |
| Heme oxygenase inhibition by 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes: Effect of halogen substitution in the phenyl ring;Gheorghe Roman，等;《Bioorganic & Medicinal Chemistry》;20070222;第15卷;第3225-3234页 * |
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