CN107573288A - Process for refining, examination criteria and its application of fenticonazole nitrate - Google Patents
Process for refining, examination criteria and its application of fenticonazole nitrate Download PDFInfo
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Abstract
The invention belongs to chemosynthesis technical field, discloses the process for refining of fenticonazole nitrate, it comprises the following steps：Step 1）Intermediate compound I：The synthesis of 4 benzene sulfydryl benzaldehydes；Step 2）Intermediate II:The synthesis of 4 benzene sulfydryl phenmethylols；Step 3）Intermediate III:The synthesis of 4 benzene sulfydryl benzyl chlorides；Step 4）The synthesis of fenticonazole nitrate crude product；Step 5）Fenticonazole nitrate refines.The invention also discloses the detection method of in-between product and its in medical usage.
Description
Technical field
The invention belongs to chemosynthesis technical field, and in particular to the process for refining of fenticonazole nitrate, examination criteria and
It is applied.
Background technology
Fenticonazole nitrate, English name: Fenticonazole Nitrate；English language Chemical name: 1-[2-(2,4-
dichlorophenyl)-2-[[4-(phenylthio)phenyl] methoxy] ethyl- 1H-imidazole
mononitrate；Chinese chemical name:1- [2- (2,4 dichloro benzene base) -2- [[4- (benzene is thio) phenyl] methoxyl group] ethyl -
1H- imidazole nitrate；Molecular formula: C24H20Cl2N2OS·HNO3, molecular weight: 518.4；Physicochemical property:This product for white or
Off-white color crystallizes or crystalline powder；It is odorless；This product is readily soluble in methanol and DMF, slightly molten in ethanol,
It is almost insoluble in water；The fusing point of this product is 134~137 DEG C；This product specific rotation is -0.10 °~+0.10 °.
Fenticonazole nitrate possesses extensive purposes in field of medicaments, and its preparation general route is similar, respectively with difference
Initiation material passes through multistep synthetic intermediate：4- benzene sulfydryl benzyl chlorides and intermediate：1- (2,4- dichlorophenyl) -2- imidazolyl ethanols,
At different conditions by being condensed to yield Fenticonazole, finally with nitric acid into salt.
Method 1. reacts generation 4- benzene sulfydryl benzyl chlorides as raw material using diphenyl sulfide and formaldehyde under the conditions of HCl；With a dichloro
Benzene and chloracetyl chloride are condensed to yield the chloro- 1- of 2-（2,4- dichlorophenyls）Ethyl ketone, then after sodium borohydride reduction, with 1H- imidazoles
It is condensed to yield intermediate 1- (2,4 dichloro benzene base) -2- imidazolyl ethanols.4- benzene sulfydryl benzyl chlorides and 1- (2,4 dichloro benzene base) -2- miaows
Azoles ethanol under anhydrous, anaerobic conditions, using sodium hydride as condensing agent, reacts in HMPA or dimethyl sulfoxide (DMSO)
To Fenticonazole.
Method 2. obtains benzenethiol using benzene sulfonyl chloride as raw material, with zinc powder reduction, cuprous oxide effect under with parachlorobenzoic-acid
4- benzene mercaptobenzoic acids are condensed to yield, then obtain 4- benzene sulfydryl phenmethylols through sodium borohydride reduction, chlorination of hydrochloric acid obtains 4- benzene
Sulfydryl benzyl chloride；With the chloro- 1- of 2-（2,4- dichlorophenyls）Ethyl ketone be raw material after sodium borohydride reduction with 1H- imidazoles is condensed to yield
1- (2,4 dichloro benzene base) -2- imidazolyl ethanols；Under anhydrous, anaerobic conditions, using sodium hydride as condensing agent, in dimethyl sulfoxide (DMSO)
Obtain Fenticonazole.
Method 3. improves the condensation condition of 1- (2,4- dichlorophenyl) -2- imidazolyl ethanols and 4- benzene sulfydryl benzyl chlorides, uses
Phase transfer catalyst tetrabutylammonium chloride, under the conditions of existing for sodium hydroxide reaction obtain fenticonazole nitrate.
According to market survey situation, commercially available 1- (2,4- dichlorophenyl) -2- imidazolyl ethanol steady qualities are inexpensive, can
Meet requirement of the industrialized production as raw material, thus need to solve the problems, such as be 4- benzene sulfydryl benzyl chlorides synthesis and last two
The condensation of individual intermediate.It is summarized as follows：
Compare the above method：
（1）The synthesis of 4- benzene sulfydryl benzyl chlorides
The cost of material of method 1 it is high and during use formaldehyde, and formaldehyde has volatility, has stronger penetrating odor and has
Toxicity and corrosivity, are unfavorable for labour protection, big to equipment corrosion, and environmental protection condition and labour protection require high.
Method 2 is compared with method 1, and the raw materials used benzene sulfonyl chloride of this method or wherein mesosome benzenethiol are easily bought, but the method
Reactions steps are more, the cycle is long, cumbersome, therefore it is contemplated that using bibliography general principle modified technique route：With benzene
Thiophenol and p-bromobenzaldehyde are that initiation material is condensed to yield 4- benzene sulfydryl benzaldehydes, are obtained by sodium borohydride reduction, halogenation
4- benzene sulfydryl benzyl chlorides.
（2）The condensation of 1- (2,4 dichloro benzene base) -2- imidazolyl ethanols and 4- benzene sulfydryl benzyl chlorides
Method 1 and method 2 are all under anhydrous, anaerobic conditions, to react to obtain Fenticonazole using sodium hydride as condensing agent, distinguish
In the solvent difference used, respectively HMPA and dimethyl sulfoxide (DMSO), although having with yield during dimethyl sulfoxide (DMSO) bright
It is aobvious to improve, but these solvents are expensive, the chemical reactivity of reactant sodium hydride is very high, can be certainly in humid air
Combustion, it is heated or is contacted with moisture, acid and release heat and hydrogen, and cause burning and blast, meets moisture and moisture is given birth to
Hydrate, corrosivity is strong, therefore required solvent needs absolute, and to be reacted under inert gas shielding, uncomfortable
In industrialized production.
The content of the invention
The present invention is improved the preparation method of known fenticonazole nitrate, there is provided the essence of fenticonazole nitrate
Technique, examination criteria and its application processed.
The present invention is achieved by the following technical solution：
The process for refining of fenticonazole nitrate, it comprises the following steps：Step 1）Intermediate compound I：The synthesis of 4- benzene sulfydryl benzaldehydes；
Step 2）Intermediate II:The synthesis of 4- benzene sulfydryl phenmethylols；Step 3）Intermediate III:The synthesis of 4- benzene sulfydryl benzyl chlorides；Step
4）The synthesis of fenticonazole nitrate crude product；Step 5）Fenticonazole nitrate refines.
Further, the step 1）Intermediate compound I：The synthesis of 4- benzene sulfydryl benzaldehydes, comprises the following steps：Room temperature（25
℃）Under, by p-bromobenzaldehyde 592g, benzenethiol 360g, that potassium carbonate 480g, CuI16g and DMF 2000ml put into 5000mL is anti-
Answer in bottle, stirring is warming up to 124~128 DEG C, reacts about 6 hours, thin layer detection（N-hexane：Ethyl acetate=10：1）To reaction
Terminal, 90 DEG C of filterings are down to, depressurized（Pressure 1720Pa, 85 DEG C of temperature）It is concentrated to dryness, reclaims DMF, obtain thick residue, add
Entering dichloromethane 2400ml, three times, anhydrous magnesium sulfate is dried for washing, and filtering, filtrate decompression is concentrated to dryness, and reclaims dichloromethane,
Residue mixed solution（Hexane：Ethyl acetate=1：1）240ml dissolves, and freezes crystallization, filters, and is done at 25 DEG C of filter cake normal pressure
It is dry, obtain white crystalline powder.
Further, the intermediate II:The synthesis of 4- benzene sulfydryl phenmethylols, comprises the following steps：
Room temperature（25℃）It is lower to put into 4- benzene sulfydryl benzaldehydes 527g, methanol 2965ml in 5000mL reaction bulbs, add in three batches
Enter sodium borohydride 29.65g, stirring is warming up to 48 DEG C, reacts about 1 hour, thin layer detection（N-hexane：Ethyl acetate=10：1）Extremely
Reaction end, hydrochloric acid regulation pH=6, decompression is added dropwise（Pressure 1330Pa, temperature 45 C）It is concentrated to dryness, reclaims methanol.Obtain sticky
Shape residue, dichloromethane 2200ml is added, be washed to neutrality, anhydrous magnesium sulfate is dried, filtering, filtrate decompression（Pressure
1720Pa, 25 DEG C of temperature）It is concentrated to dryness, reclaims dichloromethane, obtain light yellow crystalline powder.
Further, the intermediate III:The synthesis of 4- benzene sulfydryl benzyl chlorides, comprises the following steps：
Room temperature（25℃）It is lower by 4- benzene sulfydryl phenmethylols 518.0g, pyridine 147ml and dichloromethane 2444ml, put into 5000mL
In reaction bulb, 20~24 DEG C of dropwise addition thionyl chlorides of frozen water cooling temperature control, room temperature（25℃）Stirring 2 hours, thin layer detection（Just oneself
Alkane：Ethyl acetate=10：1）To reaction end.Neutrality is washed to, anhydrous magnesium sulfate is dried, filtering, filtrate decompression（Pressure
1720Pa, 25 DEG C of temperature）It is concentrated to dryness, reclaims dichloromethane, obtain brownish red grease.
Further, the synthesis of the fenticonazole nitrate crude product, comprises the following steps：
Room temperature（25℃）Under, by sodium hydroxide 710g, 1- (2,4- dichlorophenyl) -2- imidazolyl ethanols 511.2g, water 1136ml, first
Benzene 5680ml and TBAB 56.8g, puts into 10L reaction bulbs, and stirring is warming up to 58 DEG C, and 4- benzene sulfydryl benzyl chlorides are added dropwise
Toluene solution（554.1g→1130ml）, it is added dropwise within 1.5 hours.Reacted 12 hours at 60 DEG C, be layered, discard water layer, have
Machine layer is washed 3 times with saturated sodium-chloride water solution（250ml × 1+200ml × 2）, wash 2 times（200ml×2）, anhydrous magnesium sulfate
Dry, filtering, filtrate decompression（Pressure 1330Pa, 55 DEG C of temperature）It is concentrated to dryness, reclaims toluene, obtain grease 1250.5g, adds
Mixed solution（Ethyl acetate：Toluene=1：1）5680ml, 20% nitroacetyl ethyl ester solution 1136ml is added, is stirred at 25 DEG C
Mix 3 hours, filter, washing, collect filter cake, dried at 40 DEG C of normal pressure, obtain faint yellow solid.
Further, the fenticonazole nitrate is refined, comprises the following steps：
Absolute ethyl alcohol 2800ml, water 340ml and fenticonazole nitrate crude product 738g are put into 5000ml reaction bulbs, is warming up to 60
DEG C making complete molten, naturally cool to 25 DEG C of crystallizations 12 hours, filtering, filter cake washs with a little ethyl acetate, drying at 45 DEG C of normal pressure,
Obtain white solid.
Purposes of the product prepared according to above-mentioned technique in fungal infection is treated is also claimed in the present invention.
Figure of description
Fig. 1：The synthetic schemes of fenticonazole nitrate.
Embodiment
In order that those skilled in the art more fully understand the technical scheme in the application, have below in conjunction with the application
Body embodiment, the present invention is more clearly and completely described, it is clear that described embodiment is only the application one
Divide embodiment, rather than whole embodiments.Based on the embodiment in the application, those of ordinary skill in the art are not making
The every other embodiment obtained under the premise of creative work, should all belong to the scope of protection of the invention.
Embodiment 1
The process for refining of fenticonazole nitrate, agents useful for same is cheap and easy to get, and synthesis cost substantially reduces, easy to operate, to equipment
Without particular/special requirement, it is more suitable for large-scale production, specific synthetic route is shown in Fig. 1；Synthesis flow is as follows：
Embodiment 2
Intermediate compound I：The synthesis of 4- benzene sulfydryl benzaldehydes
Room temperature（25℃）Under, p-bromobenzaldehyde 592g, benzenethiol 360g, potassium carbonate 480g, CuI16g and DMF 2000ml are thrown
Enter into 5000mL reaction bulbs, stirring is warming up to 124~128 DEG C, reacts about 6 hours, thin layer detection（N-hexane：Ethyl acetate
=10：1）To reaction end, 90 DEG C of filterings are down to, are depressurized（Pressure 1720Pa, 85 DEG C of temperature）It is concentrated to dryness, reclaims DMF, obtain viscous
Thick shape residue, dichloromethane 2400ml being added, three times, anhydrous magnesium sulfate is dried for washing, and filtering, filtrate decompression is concentrated to dryness,
Reclaim dichloromethane, residue mixed solution（Hexane：Ethyl acetate=1：1）240ml dissolves, and freezes crystallization, filtering, filter cake
Dried at 25 DEG C of normal pressure, obtain white crystalline powder 536g, yield 78.3%.HPLC purity:99.2%.
Embodiment 3
Intermediate II:The synthesis of 4- benzene sulfydryl phenmethylols
Room temperature（25℃）It is lower to put into 4- benzene sulfydryl benzaldehydes 527g, methanol 2965ml in 5000mL reaction bulbs, add in three batches
Enter sodium borohydride 29.65g, stirring is warming up to 48 DEG C, reacts about 1 hour, thin layer detection（N-hexane：Ethyl acetate=10：1）Extremely
Reaction end, hydrochloric acid regulation pH=6, decompression is added dropwise（Pressure 1330Pa, temperature 45 C）It is concentrated to dryness, reclaims methanol.Obtain sticky
Shape residue, dichloromethane 2200ml is added, be washed to neutrality, anhydrous magnesium sulfate is dried, filtering, filtrate decompression（Pressure
1720Pa, 25 DEG C of temperature）It is concentrated to dryness, reclaims dichloromethane, obtain light yellow crystalline powder 518.7g, yield 97.3%, HPLC
Purity: 99.56%.
Embodiment 4
Intermediate III:The synthesis of 4- benzene sulfydryl benzyl chlorides
Room temperature（25℃）It is lower by 4- benzene sulfydryl phenmethylols 518.0g, pyridine 147ml and dichloromethane 2444ml, put into 5000mL
In reaction bulb, 20~24 DEG C of dropwise addition thionyl chlorides of frozen water cooling temperature control, room temperature（25℃）Stirring 2 hours, thin layer detection（Just oneself
Alkane：Ethyl acetate=10：1）To reaction end.Neutrality is washed to, anhydrous magnesium sulfate is dried, filtering, filtrate decompression（Pressure
1720Pa, 25 DEG C of temperature）It is concentrated to dryness, reclaims dichloromethane, obtain brownish red grease 548.0g, yield 97.7%, HPLC is pure
Degree: 99.66%.（Be chilled to -10 DEG C or so it is curable）.
Embodiment 5
The synthesis of fenticonazole nitrate crude product：
Room temperature（25℃）Under, by sodium hydroxide 710g, 1- (2,4- dichlorophenyl) -2- imidazolyl ethanols 511.2g, water 1136ml, first
Benzene 5680ml and TBAB 56.8g, puts into 10L reaction bulbs, and stirring is warming up to 58 DEG C, and 4- benzene sulfydryl benzyl chlorides are added dropwise
Toluene solution（554.1g→1130ml）, it is added dropwise within 1.5 hours.Reacted 12 hours at 60 DEG C, be layered, discard water layer, have
Machine layer is washed 3 times with saturated sodium-chloride water solution（250ml × 1+200ml × 2）, wash 2 times（200ml×2）, anhydrous magnesium sulfate
Dry, filtering, filtrate decompression（Pressure 1330Pa, 55 DEG C of temperature）It is concentrated to dryness, reclaims toluene, obtain grease 1250.5g, adds
Mixed solution（Ethyl acetate：Toluene=1：1）5680ml, 20% nitroacetyl ethyl ester solution 1136ml is added, is stirred at 25 DEG C
Mix 3 hours, filter, washing, collect filter cake, dried at 40 DEG C of normal pressure, obtain faint yellow solid 738g.Yield 71.4%, HPLC is pure
Degree:99.84%.
Embodiment 6
Fenticonazole nitrate refines：
Absolute ethyl alcohol 2800ml, water 340ml and fenticonazole nitrate crude product 738g are put into 5000ml reaction bulbs, is warming up to 60
DEG C making complete molten, naturally cool to 25 DEG C of crystallizations 12 hours, filtering, filter cake washs with a little ethyl acetate, drying at 45 DEG C of normal pressure,
Obtain white solid 628g.Yield：85.1%, purity HPLC：99.97%.
Embodiment 7
Fed intake according to embodiment 1-6 steps and product situation is shown in Table 1.
Table 1
Conclusion：Upper table illustrates the preparation technology feasible route that we use, and process stabilizing, can carry out the amplification of workshop scale
Experiment.
Embodiment 8
Raw material and intermediate inner quality standard of the present invention
To ensure the stabilization of preparation technology, ensure that the quality of product has formulated predominant starting material corresponding inner quality standard, such as
Under：
P-bromobenzaldehyde
C7H5BrO2 185.02
【Character】This product is white or slightly yellow crystalline powder.
【Assay】According to high effective liquid chromatography for measuring.
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With water-acetonitrile（40：60）
For mobile phase；Detection wavelength is 260nm.The separating degree at p-bromobenzaldehyde peak and adjacent chromatographic peak should meet the requirements.
This product is taken, adds mobile phase that the solution containing 0.2mg in every 1ml is made, as need testing solution, 20 μ l is taken, injects liquid
Chromatography, record chromatogram are calculated to 3 times of principal component peak retention time by area normalization method, should be not less than 99.0%.
【Storage】It is sealed.
【The term of validity】36 months.
Benzenethiol
C6H6S 110.18
【Character】This product is colourless transparent liquid, irritant foul odour.
【Assay】Determined according to gas chromatography.
Chromatographic condition uses SE-54 chromatographic columns with system suitability（30m × 0.25mm, 0.33 μm of thickness of liquid film）, in post
120 DEG C of temperature, 180 DEG C of injection port, 180 DEG C of measure of detector, using flame ionization ditector, number of theoretical plate is based on benzenethiol
Calculation should be greater than 700.
The μ l of this product 0.2 are taken, are rapidly injected gas chromatograph, chromatogram is recorded, calculates, should cannot be less than by areas of peak normalization method
98.5%。
【Storage】Sealing, preserved at shady and cool drying.
【The term of validity】36 months.
1- (2,4 dichloro benzene base) -2- imidazolyl ethanols
C11H10OCl2N2 257.11
【Character】White crystalline powder.
【Assay】According to high effective liquid chromatography for measuring.
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With water-acetonitrile（60：40）
For mobile phase；Detection wavelength is 229nm.Number of theoretical plate is calculated by 1- (2,4 dichloro benzene base) -2- imidazolyl ethanols peak to be not less than
2000.The separating degree at 1- (2,4 dichloro benzene base) -2- imidazolyl ethanols peaks and adjacent chromatographic peak should meet the requirements.
This product is taken, adds mobile phase that the solution containing 1mg in every 1ml is made, as need testing solution.20 μ l are taken, inject liquid phase
Chromatograph, record chromatogram are calculated to 2 times of principal component peak retention time by area normalization method, should be not less than 98.0%.
【Storage】It is sealed.
【The term of validity】36 months.
To ensure the stabilization of preparation technology, technical process is monitored in time, ensures the quality of product, in main
Mesosome 4- benzene sulfydryls benzaldehyde, 4- benzene sulfydryl phenmethylols and 4- benzene sulfydryl benzyl chlorides have formulated corresponding inner quality standard.It is as follows：
4- benzene sulfydryl benzaldehydes
C13H10OS 214.28
【Character】This product is white or slightly yellow crystalline powder.
【Assay】According to high effective liquid chromatography for measuring.
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With methanol-water（90：10）
For mobile phase；Detection wavelength is 310nm.Number of theoretical plate is calculated by 4- benzene sulfydryl benzaldehydes peak is not less than 2000.4- benzene sulfydryl benzene
The separating degree at formaldehyde peak and adjacent chromatographic peak should meet the requirements.
This product is taken, adds mobile phase that the solution containing 0.2mg in every 1ml is made, as need testing solution, 20 μ l is taken, injects liquid
Chromatography, record chromatogram are calculated to 3 times of principal component peak retention time by area normalization method, should be not less than 96.0%.
【Purposes】Fenticonazole nitrate intermediate I
【Storage】It is sealed.
【The term of validity】24 months.
4- benzene sulfydryl phenmethylols
C13H12OS 216.30
【Character】This product is white or slightly yellow crystalline powder.
【Assay】According to high effective liquid chromatography for measuring.
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With methanol-water（80：20）
For mobile phase；Detection wavelength is 250nm.Number of theoretical plate is calculated by 4- benzene sulfydryl phenmethylols peak is not less than 2000.4- benzene sulfydryl benzene
The separating degree at formaldehyde peak and adjacent chromatographic peak should meet the requirements.
This product is taken, adds mobile phase that the solution containing 0.2mg in every 1ml is made, as need testing solution, 20 μ l is taken, injects liquid
Chromatography, record chromatogram are calculated to 3 times of principal component peak retention time by area normalization method, should be not less than 96.0%.
【Purposes】Fenticonazole nitrate intermediate II
【Storage】It is sealed.
【The term of validity】24 months.
4- benzene sulfydryl benzyl chlorides
C13H11ClS 234.74
【Character】This product is thick liquid.
【Assay】According to high effective liquid chromatography for measuring.
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With methanol-water（90：10）
For mobile phase；Detection wavelength is 254nm.Number of theoretical plate is calculated by 4- benzene sulfydryl benzyl chlorides peak is not less than 2000.4- benzene sulfydryl benzyl chlorides
The separating degree at peak and adjacent chromatographic peak should meet the requirements.
This product is taken, adds mobile phase that the solution containing 0.2mg in every 1ml is made, as need testing solution, 20 μ l is taken, injects liquid
Chromatography, record chromatogram are calculated by area normalization method, should be not less than to 3.5 times of principal component peak retention time
98.0%。
【Purposes】Fenticonazole nitrate intermediate III
【Storage】It is sealed.
【The term of validity】24 months.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specific example " or
The description of " some examples " etc. means that combining specific features, structure, material or feature that the embodiment or example describe includes
In at least one embodiment or example of the present invention.In this manual, to the schematic representation of above-mentioned term necessarily pin
To be identical embodiment or example.Although embodiments of the invention have been shown and described above, it is to be understood that
Above-described embodiment is exemplary, it is impossible to is interpreted as limitation of the present invention, one of ordinary skill in the art is the present invention's
In the range of above-described embodiment can be changed, change, replace and modification.
Claims (7)
1. the process for refining of fenticonazole nitrate, it comprises the following steps：Step 1）Intermediate compound I：The conjunction of 4- benzene sulfydryl benzaldehydes
Into；Step 2）Intermediate II:The synthesis of 4- benzene sulfydryl phenmethylols；Step 3）Intermediate III:The synthesis of 4- benzene sulfydryl benzyl chlorides；Step
Rapid 4）The synthesis of fenticonazole nitrate crude product；Step 5）Fenticonazole nitrate refines.
2. process for refining according to claim 1, it is characterised in that the step 1）Intermediate compound I：4- benzene sulfydryl benzaldehydes
Synthesis, comprise the following steps：At room temperature, by p-bromobenzaldehyde 592g, benzenethiol 360g, potassium carbonate 480g, CuI16g and DMF
2000ml is put into 5000mL reaction bulbs, and stirring is warming up to 124~128 DEG C, is reacted about 6 hours, thin layer detection（N-hexane：
Ethyl acetate=10：1, volume ratio）To reaction end, be down to 90 DEG C of filterings, be concentrated under reduced pressure into it is dry, reclaim DMF, obtain thick residual
Thing is stayed, adds dichloromethane 2400ml, three times, anhydrous magnesium sulfate is dried for washing, and filtering, filtrate decompression is concentrated to dryness, recovery two
Chloromethanes, residue mixed solution（Hexane：Ethyl acetate=1：1, volume ratio）240ml dissolves, and freezes crystallization, filters, filter
Dried at 25 DEG C of cake normal pressure, obtain white crystalline powder.
3. process for refining according to claim 2, it is characterised in that the intermediate II:The conjunction of 4- benzene sulfydryl phenmethylols
Into comprising the following steps：
At room temperature, 4- benzene sulfydryl benzaldehydes 527g, methanol 2965ml are put into 5000mL reaction bulbs, adds boron hydrogen in three batches
Change sodium 29.65g, stirring is warming up to 48 DEG C, reacts about 1 hour, thin layer detection（N-hexane：Ethyl acetate=10：1）To reaction eventually
Point, hydrochloric acid regulation pH=6 is added dropwise, is concentrated under reduced pressure into dry, reclaim methanol, obtain thick residue, add dichloromethane 2200ml,
Neutrality is washed to, anhydrous magnesium sulfate is dried, and filtering, filtrate decompression is concentrated to dryness, and is reclaimed dichloromethane, is obtained pale yellow crystals powder
End.
4. process for refining according to claim 3, it is characterised in that the intermediate III:The conjunction of 4- benzene sulfydryl benzyl chlorides
Into comprising the following steps：
At room temperature by 4- benzene sulfydryl phenmethylols 518.0g, pyridine 147ml and dichloromethane 2444ml, 5000mL reaction bulbs are put into
In, 20~24 DEG C of dropwise addition thionyl chlorides of frozen water cooling temperature control, it is stirred at room temperature 2 hours, thin layer detection（N-hexane：Ethyl acetate=
10：1, volume ratio）To reaction end；Neutrality is washed to, anhydrous magnesium sulfate is dried, filtering, filtrate decompression（Pressure 1720Pa, temperature
Degree）It is concentrated to dryness, reclaims dichloromethane, obtain brownish red grease.
5. process for refining according to claim 4, it is characterised in that the synthesis of the fenticonazole nitrate crude product, including
Following steps：
At room temperature, by sodium hydroxide 710g, 1- (2,4- dichlorophenyl) -2- imidazolyl ethanols 511.2g, water 1136ml, toluene
5680ml and TBAB 56.8g, puts into 10L reaction bulbs, and stirring is warming up to 58 DEG C, and 4- benzene sulfydryl benzyl chlorides are added dropwise
Toluene solution, it is added dropwise within 1.5 hours；Reacted 12 hours at 60 DEG C, be layered, discard water layer, organic layer saturated sodium-chloride water
Solution is washed 3 times, is washed 2 times, and anhydrous magnesium sulfate is dried, and filtering, filtrate decompression is concentrated to dryness, and is reclaimed toluene, is obtained grease
1250.5g, add mixed solution（Ethyl acetate：Toluene=1：1, volume ratio）5680ml, add 20% nitroacetyl ethyl ester
Solution 1136ml, stir 3 hours at 25 DEG C, filter, washing, collect filter cake, dried at 40 DEG C of normal pressure, obtain faint yellow solid.
6. process for refining according to claim 5, it is characterised in that the fenticonazole nitrate refines, including as follows
Step：
Absolute ethyl alcohol 2800ml, water 340ml and fenticonazole nitrate crude product 738g are put into 5000ml reaction bulbs, is warming up to 60
DEG C making complete molten, naturally cool to 25 DEG C of crystallizations 12 hours, filtering, filter cake washs with a little ethyl acetate, drying at 45 DEG C of normal pressure,
Obtain white solid.
7. purposes of the product prepared according to claim 6 in fungal infection is treated.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101955462A (en) * | 2009-07-16 | 2011-01-26 | 邹巧根 | Fenticonazole nitrate, preparation of levorotatory form and dextrorotatory form and application of levorotatory form in preparing antifungal medicaments |
| CN103349755A (en) * | 2013-07-08 | 2013-10-16 | 林凡友 | Fenticonazole nitrate and synthesis process thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101955462A (en) * | 2009-07-16 | 2011-01-26 | 邹巧根 | Fenticonazole nitrate, preparation of levorotatory form and dextrorotatory form and application of levorotatory form in preparing antifungal medicaments |
| CN103349755A (en) * | 2013-07-08 | 2013-10-16 | 林凡友 | Fenticonazole nitrate and synthesis process thereof |
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