CN101486680A - Method for industrial production of miconazole nitrate - Google Patents
Method for industrial production of miconazole nitrate Download PDFInfo
- Publication number
- CN101486680A CN101486680A CNA2009100961718A CN200910096171A CN101486680A CN 101486680 A CN101486680 A CN 101486680A CN A2009100961718 A CNA2009100961718 A CN A2009100961718A CN 200910096171 A CN200910096171 A CN 200910096171A CN 101486680 A CN101486680 A CN 101486680A
- Authority
- CN
- China
- Prior art keywords
- chloro
- miconazole nitrate
- industrial production
- alpha
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
The invention provides an industrialized production method of miconazole nitrate, pertaining to the technical field of medicine synthesis. The method solves such problems as complex technology, comparatively low yield and purity, and the like in the existing industrialized production method of the miconazole nitrate. The industrialized production method of the miconazole nitrate includes the following steps: a. N-alkylation reaction; b. reducing reaction; c. O-alkylation reaction. The industrialized production method has the advantages of simple technology, no requirement for extracting any intermediate product, high yield and purity, etc.
Description
Technical field
The present invention relates to a kind of method of producing antifungal drug, relate in particular to a kind of method of suitability for industrialized production antifungal drug miconazole nitrate; Belong to technical field of medicine synthesis.
Background technology
The use of miconazole nitrate in present antifungal drug is commonplace, the Monistat IV that what's frequently heard can be repeated in detail at home for example, and in the medicines such as PIKANG SHUANG, its main component is exactly a miconazole nitrate.The antimicrobial spectrum of miconazole and antimicrbial power and clotrimazole are basic identical.To deep fungal and some epidermis fungies such as many clinical pathomycetes such as Candida albicans, aspergillus, cryptococcus neoformans, blastomycete, coccidioides immitis, Pseudosaccharomyceteses, and yeast etc., good anti-microbial effect is all arranged.In addition, also gram positive organisms such as staphylococcus, suis and anthrax bacillus also there is bacteriostatic action.Clinical being used for the treatment of by fungus-caused various tinea diseases, as ringworm of the body, jock itch, tinea pedis etc., result of treatment is good.
Study on the synthesis document about miconazole nitrate is a lot; people such as Ye Baohui are at Chinese medicine company industry magazine; 21 (2); 56; report in 1990 that with 2 4-two chloro-alpha-chloro acetophenones and imidazoles are raw material, through reduction; N alkylation and O alkylation make miconazole nitrate, but the miconazole nitrate yield that this method is produced is very low.Li Jinmei is at the Guangdong chemical industry, the fourth phase, same report also is with 2 in 1990, the reduction of 4-two chloro-alpha-chloro acetophenones, and then make miconazole nitrate by N alkylation and O alkylation, just the reductive agent of reduction selection and alkylating solvent of two steps are different with catalyzer, and it is still lower to make the miconazole nitrate yield by this method.
Chinese patent application (publication number: CN85107116A) a kind of processing method of producing miconazole nitrate with phase transfer reaction, it has been introduced with 2-chloro-1-(2, the 4-dichlorophenyl) ethanol is raw material, avoids reducing this step, makes miconazole nitrate through N alkylation and O alkylation; The synthesis route of this method all is first with 2, and 4-two chloro-alpha-chloro acetophenones are reduced into alcohol, and then carry out next step N alkylation and O alkylated reaction.This technology has 2 deficiencies: at first, the side reaction in this step of reduction reaction is more, influences reaction yield.This is that the ethanol with 95% is solvent because at 25-30 ℃, and with potassium borohydride reduction 4-benzyloxy nitro-alpha-brominated methyl phenyl ketone, reaction mainly obtains 4-benzyloxy nitro oxyethane, is difficult to one step of carbonyl is reduced into hydroxyl.Therefore, want 2,4-two chloro-alpha-chloro acetophenones are reduced into alcohol, and its side reaction is one of important factor that limits this reaction yield.Secondly, 2, the alpha-carbonyl chlorine in the 4-two chloro-alpha-chloro acetophenones itself has very high chemical reactivity, if earlier carbonyl reduction is become alcohol, the chemically reactive of α-chlorine can reduce greatly, is difficult for carrying out the N-alkylated reaction with imidazoles.
Summary of the invention
The present invention is directed to the defective that prior art exists, the method that a kind of technology is simple and easy, do not need to extract the high industrial production of miconazole nitrate of any intermediate product, productive rate and purity is provided.
The objective of the invention is to realize by following technical proposal: a kind of method of industrial production of miconazole nitrate, this method may further comprise the steps:
A, N-alkylated reaction: imidazoles, organic alkali catalyst and organic solvent are put into container, after the stirring heating dissolving, drip 2, the organic solution of 4-two chloro-alpha-chloro acetophenones, it in temperature N-alkylated reaction 0.5～3 hour under 40～100 ℃ the condition, imidazoles and 2 wherein, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 1～2:1;
B, reduction reaction: be solution behind the N-alkylated reaction among 0.5%～2% the dilute hydrochloric acid washing step a with concentration, add phase-transfer catalyst in the dry afterreaction liquid of layering, add POTASSIUM BOROHYDRIDE and lithium salts catalyzer again, it in temperature reduction reaction 1～10 hour under 40～100 ℃ the condition, wherein said POTASSIUM BOROHYDRIDE and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 0.5～1.2:1;
C, O-alkylated reaction: the solution after the reduction reaction among the step b is cooled off, add inorganic base catalyst, drip 2, the 4-dichlorobenzyl chloride is O-alkylated reaction 1～8 hour under 30～120 ℃ the condition in temperature, and question response finishes back water thorough washing, divide and get organic solvent layer, filter, transfer solution pH value 1～2, suction filtration, filter cake is used earlier organic solvent washing, dehydrated alcohol drip washing is used in washing at last then, and dry back is 80%～100% ethyl alcohol recrystallization with concentration, obtain miconazole nitrate after the decolouring oven dry, wherein 2,4-dichlorobenzyl chloride and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 1～1.2:1.
The present invention is earlier with 2,4-two chloro-alpha-chloro acetophenones and imidazoles carry out the N-alkylated reaction under the organic alkali catalyst effect, obtain product α-(1-imidazolyl)-2,4-dichlorophenyl ethyl ketone, and then and POTASSIUM BOROHYDRIDE under phase-transfer catalyst and lithium salts catalyst action, carry out reduction reaction and obtain α-(1-imidazolyl)-2,4-dichlorophenyl alcoholic acid boron complex, this boron complex can not propose, directly in system with 2, the 4-dichlorobenzyl chloride carries out the O-alkylated reaction and obtains the antifungal drug miconazole nitrate under the inorganic base catalyst effect.Above-mentioned production process does not need isolation of intermediate products in reaction process, one kettle way nitric acid synthesis miconazole, and the side reaction of having avoided reduction reaction to produce influences, and has effectively utilized the reactive behavior of raw material, has improved productive rate.The container that adopts among the step a is a there-necked flask, is heated with stirring to 40～100 ℃ raw material is dissolved fully; The volume of dilute hydrochloric acid is about 3 times of reaction solutions behind the step a N-alkylated reaction among the step b, uses the separating funnel branch vibration layer, and dry back imports in the there-necked flask carries out reduction reaction; Solution among the step c after the reduction reaction is cooled to 20～30 ℃, with activated carbon decolorizing, with pH value 1～2 o'clock that nitric acid is transferred solution, has a large amount of white solids to separate out, and the decompression oven dry obtains the white solid miconazole nitrate.
In the method for above-mentioned industrial production of miconazole nitrate, organic alkali catalyst described in the step a is a triethylamine, because of the N-alkylated reaction belongs to the SN2 reaction, help this reaction with triethylamine as the catalyzer of N-alkylated reaction, simultaneously the easy filtered and recycled of catalysate triethylamine hydrochloride does not produce environmental pollution, as preferably, described triethylamine and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 1～1.5:1.
In the method for above-mentioned industrial production of miconazole nitrate, organic solvent described in the step a is a benzene, toluene, sherwood oil, nonpolar or Semi-polarity organic solvent such as acetone, polar organic solvent easily dissolves in the catalysate triethylamine hydrochloride, the aftertreatment difficulty, be unfavorable for the SN2 reaction simultaneously, can carry out in this step reaction with sherwood oil and acetone, but just be difficult for the row of building up in next step reduction, acetone particularly, can be reduced by POTASSIUM BOROHYDRIDE, not change solvent in order to make entire reaction, first-selected solvent is benzene or toluene, as preferably, described organic solvent and organic alkali catalyst volume ratio are 5～10:1.
In the method for above-mentioned industrial production of miconazole nitrate,, adopt the Calcium Chloride Powder Anhydrous solid to carry out drying among the step b as preferably.
In the method for above-mentioned industrial production of miconazole nitrate, phase-transfer catalyst described in the step b is crown ether-like or quaternary ammonium salt-type phase transfer catalyst, described crown ether-like or quaternary ammonium salt-type phase transfer catalyst and 2, the weight ratio of 4-two chloro-alpha-chloro acetophenones is 0.3～2:100.As preferably, crown ether-like phase transfer catalysts described in the step b be PEG400, PEG600, PEG800, PEG1000, in a kind of, described quaternary ammonium salt-type phase transfer catalyst is a kind of in triethyl benzyl ammonia chloride, trimethyl benzyl ammonia chloride, the Tetrabutyl amonium bromide.Crown ether-like phase transfer catalysts is more cheap than quaternary ammonium salt-type phase transfer catalyst from cost.
In the method for above-mentioned industrial production of miconazole nitrate, lithium salts catalyzer described in the step b is a kind of in Quilonum Retard, the Lithium chloride (anhydrous), the lithium salts catalyzer generates lithium borohydride with the POTASSIUM BOROHYDRIDE effect in reaction system, the reducing property of lithium borohydride is stronger than POTASSIUM BOROHYDRIDE, if do not add the lithium salts catalyzer, the reducing activity deficiency of POTASSIUM BOROHYDRIDE is difficult to reduction is carried through to the end.As preferably, described lithium salts catalyzer and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 0.3～1.5:1.
In the method for above-mentioned industrial production of miconazole nitrate, inorganic base catalyst described in the step c is concentrated sodium hydroxide or potassium hydroxide aqueous solution, concentration is generally about 80-90%, sodium hydroxide or potassium hydroxide only work the boron complex effect of decomposing in system, reaction still belongs to SN2 reaction, and sodium hydroxide or potassium hydroxide aqueous solution concentration is too low to be unfavorable for that reaction carries out.As preferably, described inorganic base catalyst and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 0.5～2:1.
In the method for above-mentioned industrial production of miconazole nitrate, as preferably, among the step c during filter cake washing described organic solvent be a kind of in benzene, the toluene.Miconazole nitrate is not soluble in the above-mentioned organic solvent.
The chemical equation of suitability for industrialized production nitro miconazole of the present invention is as follows:
In sum, the present invention has the following advantages:
1, the method improvement of industrial production of miconazole nitrate of the present invention the traditional processing technology route of miconazole nitrate, the side reaction influence of having avoided reduction reaction to produce has effectively utilized the reactive behavior of raw material, has improved productive rate.
2, the method technology of industrial production of miconazole nitrate of the present invention has operational safety, simple, efficient advantages of higher, and entire production process does not need to separate any intermediate product, and one kettle way synthesizes the target product miconazole nitrate.
3, method production miconazole nitrate total recovery of the present invention can reach more than 68%, and purity is the processing method of a very suitable suitability for industrialized production greater than 99%.
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 embodiment.
Embodiment 1
With the 8g imidazoles, the 18mL triethylamine, 150ml benzene places the 500mL there-necked flask, be heated to 70 ℃ and stir 20min, treat that raw material dissolves the back fully and slowly drips 2, the benzole soln of 4-two chloro-alpha-chloro acetophenones (contains 2,4-two chloro-alpha-chloro acetophenone 22.35g), react 1.5h down at 70 ℃.Reaction finishes to filter by filter cloth, remove triethylamine hydrochloride, reaction solution poured into the concentration that is three times in its volume is housed is thorough washing in the 1% salt sour water, fully remove triethylamine hydrochloride and unreacted imidazoles, use the separating funnel branch vibration layer, organic layer adds the Calcium Chloride Powder Anhydrous drying, dried reaction solution adds in three mouthfuls of reaction flasks, add phase-transfer catalyst PEG600 2.1g, POTASSIUM BOROHYDRIDE 3.8g, Quilonum Retard 2.3g.Reduction 5h under 70 ℃.Reaction finishes postcooling to 28 ℃, directly adds 15gNaOH in this reaction solution, and 3ml water drips 2 then, and 4-dichlorobenzyl chloride 16.3g is at 60 ℃ of following stirring reaction 5h.Question response finishes back water thorough washing, divides and gets the benzene layer, filters by filter cloth, use the 3g decolorizing with activated carbon, dropping concentrated nitric acid to the pH value of solution is 1-2 in filtrate, separates out solid, suction filtration, filter cake is washed with benzene and is fallen back, and the washing back added 95% ethanol (10: 1 with draining behind the absolute ethanol washing, W/W) and 2g gac recrystallization once, obtain the white solid miconazole nitrate, productive rate 68.2%, purity is 99.3% after testing.
Embodiment 2
With the 8g imidazoles, the 18mL triethylamine, 150ml benzene places the 500mL there-necked flask, be heated to 40 ℃ and stir 20min, treat that raw material dissolves the back fully and slowly drips 2, the benzole soln of 4-two chloro-alpha-chloro acetophenones (contains 2,4-two chloro-alpha-chloro acetophenone 22.35g), at 40 ℃ of following reaction 3.0h, reaction solution poured into the concentration that is three times in its volume is housed is thorough washing three times in the 1.5% salt sour water, use the separating funnel branch vibration layer, organic layer adds the Calcium Chloride Powder Anhydrous drying, and dried reaction solution adds in three mouthfuls of reaction flasks, adds phase-transfer catalyst PEG400 2.1g, POTASSIUM BOROHYDRIDE 3.8g, lithium chloride 2.0g.Reduction 10h under 40 ℃.Reaction finishes postcooling to 28 ℃, directly adds 15gNaOH in this reaction solution, and 4ml water drips 2 then, and 4-dichlorobenzyl chloride 16.3g is at 30 ℃ of following stirring reaction 8h.Question response finishes back water thorough washing, divides and gets the benzene layer, passes through filter paper filtering, dropping nitric acid to the pH value of solution is 1-2 in filtrate, separates out solid, suction filtration, wash with benzene and to fall back, wash with benzene with draining after the dehydrated alcohol drip washing washing back again, add dehydrated alcohol (10: 1, W/W) and 5g activated carbon recrystallization once, use once with the quadrat method recrystallization, filter, the decompression oven dry obtains the white solid miconazole nitrate, productive rate 65.5%, purity is 99.7% after testing.
Embodiment 3
With the 8g imidazoles, the 18mL triethylamine, 150ml toluene places the 500mL there-necked flask, be heated to 60 ℃ and stir 30min, treat that raw material dissolves the back fully and slowly drips 2, the benzole soln of 4-two chloro-alpha-chloro acetophenones (contains 2,4-two chloro-alpha-chloro acetophenone 22.35g), react 2.0h down at 60 ℃.Reaction finishes to pass through filter paper filtering, reaction solution poured into the concentration that is three times in its volume is housed is thorough washing three times in the 1% salt sour water, use the separating funnel branch vibration layer, organic layer adds the Calcium Chloride Powder Anhydrous drying, dried reaction solution adds in three mouthfuls of reaction flasks, add phase-transfer catalyst triethyl-benzene benzyl ammonium chloride 2.1g, POTASSIUM BOROHYDRIDE 3.8g, Quilonum Retard 2.3g.Reduction 6h under 60 ℃.Reaction finishes postcooling to 28 ℃, directly adds 10gKOH in this reaction solution, drips 2 then, and 4-dichlorobenzyl chloride 16.3g is at 50 ℃ of following stirring reaction 6h.Question response finishes back water thorough washing, divides and gets toluene layer, passes through filter paper filtering, dropping nitric acid to the pH value of solution is 1-2 in filtrate, separates out solid, suction filtration, wash with toluene and to fall back, wash with benzene with draining after the dehydrated alcohol drip washing washing back again, add 95% ethanol (10: 1, W/W) and 5g activated carbon recrystallization once, use once with the quadrat method recrystallization, filter, the decompression oven dry obtains the white solid miconazole nitrate, productive rate 69.5%, purity is 99.1% after testing.
Embodiment 4
With the 8g imidazoles, the 18mL triethylamine, 150ml benzene places the 500mL there-necked flask, be heated to 80 ℃ and stir 20min, treat that raw material dissolves the back fully and slowly drips 2, the benzole soln of 4-two chloro-alpha-chloro acetophenones (contains 2,4-two chloro-alpha-chloro acetophenone 22.35g), react 1h down at 80 ℃.Reaction finishes to filter by filter cloth, reaction solution poured into the concentration that is three times in its volume is housed is thorough washing in the 1% salt sour water, use the separating funnel branch vibration layer, add the Calcium Chloride Powder Anhydrous drying, dried reaction solution adds in three mouthfuls of reaction flasks, add phase-transfer catalyst PEG1000 2.5g, POTASSIUM BOROHYDRIDE 3.8g, Quilonum Retard 2.3g.Reduction 3h under 80 ℃.Reaction finishes postcooling to 28 ℃, directly adds 15gNaOH in this reaction solution, and 4ml water drips 2 then, and 4-dichlorobenzyl chloride 16.3g is at 80 ℃ of following stirring reaction 3h.Question response finishes back water thorough washing, divides and gets the benzene layer, filters by filter cloth, dropping concentrated nitric acid to the pH value of solution is 1 in filtrate, separates out solid, suction filtration, wash with benzene and to fall back, wash with benzene with draining after the dehydrated alcohol drip washing washing back again, added 95% ethanol (10: 1, W/W) and 5g activated carbon recrystallization secondary, draining back decompression oven dry once more, obtaining the white solid miconazole nitrate, productive rate 65.5%, purity is 99.5% after testing.
Embodiment 5
With the 10g imidazoles, the 18mL triethylamine, 150ml benzene places the 500mL there-necked flask, be heated to 70 ℃ and stir 20min, treat that raw material dissolves the back fully and slowly drips 2, the benzole soln of 4-two chloro-alpha-chloro acetophenones (contains 2,4-two chloro-alpha-chloro acetophenone 30.55g), react 1.5h down at 70 ℃.Reaction finishes to filter by filter cloth, reaction solution poured into the concentration that is three times in its volume is housed is thorough washing in the 1% salt sour water, use the separating funnel branch vibration layer, add the Calcium Chloride Powder Anhydrous drying, dried reaction solution adds in three mouthfuls of reaction flasks, add phase-transfer catalyst PEG800 2.1g, POTASSIUM BOROHYDRIDE 3.8g, lithium chloride 2.3g.Reduction 5h under 70 ℃.Reaction finishes postcooling to 28 ℃, directly adds 15gKOH in this reaction solution, and 2ml water drips 2 then, and 4-dichlorobenzyl chloride 16.3g is at 60 ℃ of following stirring reaction 6h.Question response finishes back water thorough washing, divides and gets the benzene layer, filters by filter cloth, dropping nitric acid to the pH value of solution is 1 in filtrate, separates out solid, suction filtration, wash with benzene and to fall back, wash with benzene with draining after the dehydrated alcohol drip washing washing back again, with 95% ethanol (10: 1, W/W) and 5g activated carbon recrystallization secondary, draining back decompression oven dry once more, obtaining the white solid miconazole nitrate, productive rate 67.5%, purity is 99.6% after testing.
Embodiment 6
With the 10g imidazoles, the 18mL triethylamine, 150ml toluene places the 500mL there-necked flask, be heated to 70 ℃ and stir 20min, treat that raw material dissolves the back fully and slowly drips 2, the benzole soln of 4-two chloro-alpha-chloro acetophenones (contains 2,4-two chloro-alpha-chloro acetophenone 22.35g), react 1.5h down at 70 ℃.Reaction finishes to filter by filter cloth, reaction solution is poured into the concentration that is three times in its volume is housed is thorough washing three times in the 1% salt sour water, uses the separating funnel branch vibration layer, man-machine layer adds in three mouthfuls of reaction flasks, add phase-transfer catalyst PEG600 2.1g, POTASSIUM BOROHYDRIDE 3.8g, Quilonum Retard 2.3g.Reduction 5h under 70 ℃.Reaction finishes postcooling to 28 ℃, directly adds 15gNaOH in this reaction solution, drips 2 then, and 4-dichlorobenzyl chloride 20.0g is at 60 ℃ of following stirring reaction 6h.Question response finishes back water thorough washing, divides and gets the benzene layer, filters by filter cloth, dropping concentrated nitric acid to the pH value of solution is 1-2 in filtrate, separates out solid, suction filtration, wash with benzene and to fall back, wash with benzene with draining after the dehydrated alcohol drip washing washing back again, added 95% ethanol (10: 1, W/W) and heavy 5g activated carbon crystallization secondary, draining back decompression oven dry once more, obtaining the white solid miconazole nitrate, productive rate 68.5%, purity is 99.0% after testing.
Specific embodiment described in the present invention only is that the present invention's spirit is illustrated.The technician of the technical field of the invention can make various modifications or replenishes or adopt similar mode to substitute described specific embodiment, but can't depart from spirit of the present invention or surmount the defined scope of appended claims.
Although the present invention has been made detailed explanation and has quoted some specific embodiments as proof, to those skilled in the art, only otherwise leave that the spirit and scope of the present invention can be done various variations or correction is obvious.
Claims (10)
1, a kind of method of industrial production of miconazole nitrate, this method may further comprise the steps:
A, N-alkylated reaction: imidazoles, organic alkali catalyst and organic solvent are put into container, after the stirring heating dissolving, drip 2, the organic solution of 4-two chloro-alpha-chloro acetophenones, it in temperature N-alkylated reaction 0.5～3 hour under 40～100 ℃ the condition, imidazoles and 2 wherein, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 1～2:1;
B, reduction reaction: be solution behind the N-alkylated reaction among 0.5%～2% the dilute hydrochloric acid washing step a with concentration, add phase-transfer catalyst in the dry afterreaction liquid of layering, add POTASSIUM BOROHYDRIDE and lithium salts catalyzer again, it in temperature reduction reaction 1～10 hour under 40～100 ℃ the condition, wherein said POTASSIUM BOROHYDRIDE and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 0.5～1.2:1;
C, O-alkylated reaction: the solution after the reduction reaction among the step b is cooled off, add inorganic base catalyst, drip 2, the 4-dichlorobenzyl chloride is O-alkylated reaction 1～8 hour under 30～120 ℃ the condition in temperature, and question response finishes back water thorough washing, divide and get organic solvent layer, filter, transfer solution pH value 1～2, suction filtration, filter cake is used earlier organic solvent washing, dehydrated alcohol drip washing is used in washing at last then, and dry back is 80%～100% ethyl alcohol recrystallization with concentration, obtain miconazole nitrate after the decolouring oven dry, wherein 2,4-dichlorobenzyl chloride and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 1～1.2:1.
2, the method for industrial production of miconazole nitrate according to claim 1 is characterized in that: the organic alkali catalyst described in the step a is a triethylamine, described triethylamine and 2, and the mol ratio of 4-two chloro-alpha-chloro acetophenones is 1～1.5:1.
3, the method for industrial production of miconazole nitrate according to claim 1 and 2 is characterized in that: the organic solvent described in the step a is nonpolar or the Semi-polarity organic solvent, and described organic solvent and organic alkali catalyst volume ratio are 5～10:1.
4, the method for industrial production of miconazole nitrate according to claim 1 is characterized in that: adopt the Calcium Chloride Powder Anhydrous solid to carry out drying among the step b.
5, according to the method for claim 1 or 4 described industrial production of miconazole nitrate, it is characterized in that: the phase-transfer catalyst described in the step b is crown ether-like or quaternary ammonium salt-type phase transfer catalyst, described crown ether-like or quaternary ammonium salt-type phase transfer catalyst and 2, the weight ratio of 4-two chloro-alpha-chloro acetophenones is 0.3～2:100.
6, the method for industrial production of miconazole nitrate according to claim 5 is characterized in that: the crown ether-like phase transfer catalysts described in the step b is a kind of among PEG400, PEG600, PEG800, the PEG1000.
7, the method for industrial production of miconazole nitrate according to claim 5 is characterized in that: the quaternary ammonium salt-type phase transfer catalyst described in the step b is a kind of in triethyl benzyl ammonia chloride, trimethyl benzyl ammonia chloride, the Tetrabutyl amonium bromide.
8, the method for industrial production of miconazole nitrate according to claim 1, it is characterized in that: the lithium salts catalyzer described in the step b is a kind of in Quilonum Retard, the Lithium chloride (anhydrous), described lithium salts catalyzer and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 0.3～1.5:1.
9, the method for industrial production of miconazole nitrate according to claim 1, it is characterized in that: the inorganic base catalyst described in the step c is aqueous sodium hydroxide solution or potassium hydroxide aqueous solution, described inorganic base catalyst and 2, the mol ratio of 4-two chloro-alpha-chloro acetophenones is 0.5～2:1.
10, according to the method for claim 1 or 9 described industrial production of miconazole nitrate, it is characterized in that: among the step c during filter cake washing described organic solvent be a kind of in benzene, the toluene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100961718A CN101486680B (en) | 2009-02-18 | 2009-02-18 | Method for industrial production of miconazole nitrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100961718A CN101486680B (en) | 2009-02-18 | 2009-02-18 | Method for industrial production of miconazole nitrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101486680A true CN101486680A (en) | 2009-07-22 |
| CN101486680B CN101486680B (en) | 2011-08-31 |
Family
ID=40889761
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100961718A Expired - Fee Related CN101486680B (en) | 2009-02-18 | 2009-02-18 | Method for industrial production of miconazole nitrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101486680B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863832A (en) * | 2010-06-13 | 2010-10-20 | 湖北远成药业有限公司 | Method for producing miconazole nitrate on industrialized basis |
| CN102180835A (en) * | 2011-03-02 | 2011-09-14 | 合肥华方医药科技有限公司 | Synthesis of imidazole aromatic alcohol derivatives and preparations of imidazole aromatic alcohol derivatives |
| CN102399192A (en) * | 2011-12-20 | 2012-04-04 | 扬子江药业集团南京海陵药业有限公司 | Method for preparing isoconazole nitrate |
| CN104230846A (en) * | 2014-09-05 | 2014-12-24 | 杭州华东医药集团新药研究院有限公司 | Method for preparing pramipexole intermediate |
-
2009
- 2009-02-18 CN CN2009100961718A patent/CN101486680B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863832A (en) * | 2010-06-13 | 2010-10-20 | 湖北远成药业有限公司 | Method for producing miconazole nitrate on industrialized basis |
| CN102180835A (en) * | 2011-03-02 | 2011-09-14 | 合肥华方医药科技有限公司 | Synthesis of imidazole aromatic alcohol derivatives and preparations of imidazole aromatic alcohol derivatives |
| CN102180835B (en) * | 2011-03-02 | 2016-04-06 | 合肥华方医药科技有限公司 | The synthesis of imidazole aromatic alcohol analog derivative and preparation thereof |
| CN102399192A (en) * | 2011-12-20 | 2012-04-04 | 扬子江药业集团南京海陵药业有限公司 | Method for preparing isoconazole nitrate |
| CN104230846A (en) * | 2014-09-05 | 2014-12-24 | 杭州华东医药集团新药研究院有限公司 | Method for preparing pramipexole intermediate |
| CN104230846B (en) * | 2014-09-05 | 2016-06-08 | 杭州华东医药集团新药研究院有限公司 | A kind of method preparing pramipexole intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101486680B (en) | 2011-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103193736B (en) | A kind of method of shortening synthesis γ-valerolactone | |
| CN101486680B (en) | Method for industrial production of miconazole nitrate | |
| CN103804242B (en) | A kind of shortening prepares the method for m-sulfanilic acid | |
| CN101823968B (en) | Method for preparing 1,8-diaminonaphthalene by reducing 1,8-dinitronaphthalene with hydrazine hydrate | |
| CN103204801A (en) | Synthesis method for N-Boc-3-piperidone | |
| CN103319487A (en) | Preparation method of sitagliptin and intermediate of sitagliptin | |
| CN101648942B (en) | Method for preparing halofuginone derivative | |
| CN101781264B (en) | Production method of 1-methyl-5-mercapto-1,2,3,4-tetrazole | |
| CN106432038B (en) | A kind of method and its special-purpose catalyst synthesizing N-phenylmaleimide | |
| CN101450921B (en) | Optimization of 1,4-butanedisulfonic acid disodium preparation technology | |
| CN103214534A (en) | Preparation method of 3'-desoxyadenossine | |
| CN101696157A (en) | Method for preparing 1,2,4-butanetriol | |
| CN104356043A (en) | Method for preparing 5-(2-fluorophenyl)-1H-pyrryl-3-formaldehyde | |
| CN101585776A (en) | Method for synthetizing N,N-diisopropylethylamine | |
| CN105481782B (en) | A kind of preparation method of sulfaquinoxaline | |
| CN103664527A (en) | Clean preparation method for 2,4-dichloro-alpha-chloromethyl benzyl alcohol | |
| CN108047276B (en) | Method for synthesizing ruthenium (III) acetylacetonate | |
| CN103193212A (en) | Method for preparing free hydroxylamine | |
| CN102875362A (en) | Preparation method of L-threonic acid or salts thereof | |
| CN112645815A (en) | Preparation method for catalytically synthesizing methyl cinnamate based on eutectic solvent | |
| CN111171022B (en) | Synthesis method of 1-hydroxy-pyrrolo [2,3-c ] piperidine | |
| CN102898419A (en) | Method for preparing voriconazole intermediate I | |
| CN103755578A (en) | Preparation method for erythro-structure methoxamine hydrochloride | |
| CN100500643C (en) | Chemical synthesis of 3,4,5-trioxyaniline | |
| CN103880812B (en) | A kind of preparation method about helional |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110831 Termination date: 20140218 |