CN102070620B - Preparation method of antibacterial ester - Google Patents
Preparation method of antibacterial ester Download PDFInfo
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- CN102070620B CN102070620B CN 201110026992 CN201110026992A CN102070620B CN 102070620 B CN102070620 B CN 102070620B CN 201110026992 CN201110026992 CN 201110026992 CN 201110026992 A CN201110026992 A CN 201110026992A CN 102070620 B CN102070620 B CN 102070620B
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Abstract
The invention discloses a preparation method of an antibacterial ester, namely (+/-)cis-4-[4-[[2-(2,4-dichlorophenyl)-2-(1-H-imidazolylmethyl)-1,3-dioxolan-4-yl] methoxy]phenyl]-1-piperazinecarboxylate. The preparation method is that active lipid and N-(4-cresyl)piperazine are used as raw materials to synthetize the hydrolyzate of 1-acetyl-4-[4-[2-(2,4-dichlorophenyl)-2(1H-imidazolyl-1-methyl)-1,3-dioxolan-4-methoxy]phenyl]-piperazine through direct condensation and the hydrolyzate is esterified to obtain the target antibacterial ester. The method disclosed by the invention has reasonable technological process, mild reaction conditions, shorter production cycle of antibacterial ester, lower production cost and higer product quality and yield.
Description
Technical field
The present invention relates to a kind of compound method of imidazoles antifungal drug compounds; Especially be particularly related to a kind of antibacterial ester (±) cis-4-[4-[[2-(2; The 4-dichlorophenyl)-and 2-(1-H-imidazoles methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-preparation method of 1-piperazinecarboxylic acid ethyl ester.
Background technology
(±) cis-4-[4-[[2-(2; The 4-dichlorophenyl)-2-(1-H-imidazoles methyl)-1; 3-dioxolane-4-yl] methoxyl group] phenyl]-1-piperazinecarboxylic acid ethyl ester; Be the antimycotic esters medicine compound of a kind of imidazoles, the present invention abbreviates antibacterial ester as, mainly is used in to be used for control oil in the makeup.
U.S. Pat 5849279 disclosed a kind of (±) cis-4-[4-[[2-(2; The 4-dichlorophenyl)-2-(1-H-imidazoles methyl)-1; 3-dioxolane-4-yl] methoxyl group] phenyl]-preparation method of 1-piperazinecarboxylic acid ethyl ester; This method is a starting raw material with another kind imidazoles antifungal compound KETOKONAZOL (1-ethanoyl-4 [4-[2-(2,4 dichloro benzene base)-2 (1H-imidazoles-1-methyl)-1,3 dioxolane-4-methoxyl group] phenyl]-piperazine) commonly used; Through hydrolysis, esterification; Obtain antibacterial ester (±) cis-4-[4-[[2-(2,4 dichloro benzene base)-2-(1-H-imidazoles methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-1-piperazinecarboxylic acid ethyl ester.KETOKONAZOL usually by active fat (suitable-[2-(2; The 4-dichlorophenyl)-and 2-(1H-imidazoles-1-ylmethyl)-1,3-dioxolane-4-yl] methyl alcohol p-toluenesulfonic esters or methanesulfonates) obtain through condensation with the side chain (1-ethanoyl-4-(4-hydroxy phenyl) piperazine) of KETOKONAZOL.And be that starting raw material prepares in the side chain process with the piperazine; Be to obtain the ethanoyl in the object through acetylization reaction; Such as a kind of preparation method commonly used is with Uricida elder generation and p-Nitrophenyl chloride condensation; Generate 1-(4-nitrophenyl) piperazine, get 1-ethanoyl-4-(4-nitrophenyl) piperazine with acetic anhydride then, the latter is made this article after nitroreduction, diazotization, hydrolysis; Perhaps make through acetylization reaction with N-(4-phenylor) piperazine (hydrolyzate of side chain is the product behind the removal ethanoyl).
Above-mentioned technology be equivalent to active fat (suitable-[2-(2; The 4-dichlorophenyl)-2-(1H-imidazoles-1-ylmethyl)-1; 3-dioxolane-4-yl] methyl alcohol p-toluenesulfonic esters or methanesulfonates) with the side chain (1-ethanoyl-4-(4-hydroxy phenyl) piperazine) of KETOKONAZOL through condensation; Synthetic earlier a kind of and unwanted compound 1-ethanoyl-4 [4-[2-(2,4 dichloro benzene base)-2 (1H-imidazoles-1-methyl)-1,3 dioxolane-4-methoxyl group] phenyl]-piperazine in addition; After the 1-ethanoyl on the KETOKONAZOL is removed in hydrolysis again, esterification and make antibacterial ester.Owe on the aforesaid method technology rationally, cause that antibacterial ester production cost is high, the cycle is long.
Summary of the invention
The object of the invention be to provide a kind of antibacterial ester (±) cis-4-[4-[[2-(2; The 4-dichlorophenyl)-2-(1-H-imidazoles methyl)-1; 3-dioxolane-4-yl] methoxyl group] phenyl]-preparation method of 1-piperazinecarboxylic acid ethyl ester; Above-mentioned technology is improved, and is the synthetic 1-ethanoyl-4 [4-[2-(2,4 dichloro benzene base)-2 (1H-imidazoles-1-methyl)-1 of the direct condensation of raw material with active fat and N-(4-phenylor) piperazine (producing the raw material of side chain); 3 dioxolane-4-methoxyl group] phenyl]-hydrolysate of piperazine, promptly get the antibacterial ester of target compound through esterification again.
The technical scheme that the present invention adopts is following:
A kind of preparation method of antibacterial ester may further comprise the steps:
1) condensation reaction
Active fat, N-(4-phenylor) piperazine and alkali are dissolved in the solvent, 25～30 ℃ of condensation reactions 20～30 hours, add water for cooling to 0～5 ℃ after reaction finishes, stir insulation 1～3h down, suction filtration gets antibacterial ester condensates;
2) esterification
The resulting antibacterial ester condensates of step 1) is added alkali be dissolved in the solvent, slowly add Vinyl chloroformate, after adding finishes; Controlled temperature is at 20～30 ℃, and insulation reaction 1～2 hour adds water and continues to stir 2h after reaction finishes; Organic layer is washed with water to PH to 7, and the pressure reducing and steaming solvent adds hexone behind the evaporate to dryness; 0～5 ℃ keeps 2～4h down, and suction filtration gets antibacterial ester.
Described active fat is meant suitable-[2-(2,4 dichloro benzene base)-2-(1H-imidazoles-1-ylmethyl)-1,3-dioxolane-4-yl] methyl alcohol p-toluenesulfonic esters or methanesulfonates can adopt commercial goods or synthetic by known method.
In the combined reaction, the mol ratio of described active fat and N-(4-phenylor) piperazine is 1:0.9～1.1.
The condensation reaction solvent comprises methylene dichloride, trichloromethane, DMSO 99.8MIN. or N, dinethylformamide, preferred DMSO 99.8MIN..
The antibacterial ester condensates that combined reaction obtains is the hydrolysate of KETOKONAZOL, can get the antibacterial ester of object through esterification.
The esterification solvent comprises ETHYLE ACETATE, methylene dichloride, trichloromethane or acetone, preferred methylene dichloride.
Described alkali is Pottasium Hydroxide, sodium hydroxide, salt of wormwood or yellow soda ash, preferred Pottasium Hydroxide.
The mol ratio of antibacterial ester condensates and Vinyl chloroformate is 1:0.9～1.1 in the esterification.
But the antibacterial ester purifying that obtains through aforesaid method obtains content greater than 97% pure article, and antibacterial ester heating is dissolved in the acetone, adds gac; Insulation refluxes, and filters, and adds water for cooling to 0～5 ℃ after filtrating concentrates; Stir insulation 1～3h down, suction filtration gets the pure article of antibacterial ester.
The preparation method of antibacterial ester of the present invention is the synthetic 1-ethanoyl-4 [4-[2-(2,4 dichloro benzene base)-2 (1H-imidazoles-1-methyl)-1 of the direct condensation of raw material with active fat and N-(4-phenylor) piperazine; 3 dioxolane-4-methoxyl group] phenyl]-hydrolysate of piperazine, promptly get target compound through esterification again, saved unnecessary acetylize and hydrolysing step; Technological process is reasonable; Reaction conditions is gentle, can shorten the production cycle and its production cost of reduction, more existing compound method of antibacterial ester; The quality and the yield of product all increase, and the antibacterial ester content in refining back is greater than 97%.
Describe the present invention below in conjunction with specific embodiment.Protection scope of the present invention is not exceeded with embodiment, but is limited claim.
Embodiment
Embodiment 1
Antibacterial ester prepared according to the methods of the invention (±) cis-4-[4-[[2-(2,4 dichloro benzene base)-2-(1-H-imidazoles methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-1-piperazinecarboxylic acid ethyl ester may further comprise the steps:
1, condensation reaction
In exsiccant 500ml there-necked flask, add the 473g DMSO 99.8MIN., the active fat of 130g, 50g N-(4-phenylor) piperazine, 21g Pottasium Hydroxide; Controlled temperature was 30 ℃ of insulation reaction 24 hours, and reaction is finished, and added purified water 520g; After finishing, adding is cooled to 5 ℃; Stir insulation 2h, suction filtration gets antibacterial ester condensates, condensation yield about 85%.
2, esterification
In there-necked flask, add the 322g methylene dichloride, the antibacterial ester condensates of 50g behind the 52g salt of wormwood, slowly adds the 11.9g Vinyl chloroformate, after adding finishes; Controlled temperature is at 25 ℃, and insulation reaction 4 hours is reacted and finished, and slowly adds the 108g purified water; After adding finishes, continue to stir 2h, organic layer is washed to PH to 7 for three times with purifying moisture, reduces pressure and steam methylene dichloride in the washing back; Add the 60ml hexone behind the evaporate to dryness, 0～5 ℃ keeps 2～4h down, and suction filtration gets antibacterial ester, esterification yield about 80%.
Antibacterial ester heating is dissolved in the acetone of 8 times of amounts, adds the gac of 0.5 times of amount, insulation 0.5h refluxes; Be cooled to and do not reflux; Suction filtration is removed gac, and filtrating is concentrated into 5 times of amounts of antibacterial ester weight, concentrates to add water for cooling to 0～5 ℃ after finishing; Stir insulation 1～3h down, suction filtration gets the off-white color crystalline powder.Through analyzing, antibacterial ester content is greater than 97%.
Embodiment 2
Antibacterial ester prepared according to the methods of the invention (±) cis-4-[4-[[2-(2,4 dichloro benzene base)-2-(1-H-imidazoles methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-1-piperazinecarboxylic acid ethyl ester may further comprise the steps:
1, condensation reaction
In exsiccant 500ml there-necked flask, add the 473g DMSO 99.8MIN., the active fat of 130g, 50g N-(4-phenylor) piperazine, 21g Pottasium Hydroxide; Controlled temperature was 25 ℃ of insulation reaction 24 hours; Reaction is finished, and adds purified water 520g, is cooled to 0 ℃ after adding finishes; Stir insulation 2h, suction filtration gets antibacterial ester condensates.
2, esterification
In there-necked flask, add 184g ETHYLE ACETATE, the antibacterial ester condensates of 50g behind the 52g salt of wormwood, slowly adds the 11.9g Vinyl chloroformate; After adding finished, controlled temperature was at 20 ℃, and insulation reaction 4 hours is reacted and finished; Slowly add the 108g purified water, after adding finishes, continue to stir 2h, organic layer is washed to PH to 7 for three times with purifying moisture; ETHYLE ACETATE is steamed in the decompression of washing back, and being concentrated to volume is 150ml, and 0～5 ℃ keeps 2～4h down, and suction filtration gets antibacterial ester carboxylate.
Antibacterial ester heating is dissolved in the acetone of 8 times of amounts, adds the gac of 0.5 times of amount, insulation 0.5h refluxes; Be cooled to and do not reflux, suction filtration is removed gac, and filtrating is concentrated into 5 times of amounts of antibacterial ester weight; Add water for cooling to 0～5 ℃ after concentrate finishing, stir insulation 1～3h down, suction filtration gets antibacterial ester.
Embodiment 3
Antibacterial ester prepared according to the methods of the invention (±) cis-4-[4-[[2-(2,4 dichloro benzene base)-2-(1-H-imidazoles methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-1-piperazinecarboxylic acid ethyl ester may further comprise the steps:
1, condensation reaction
In exsiccant 500ml there-necked flask, add the 473g DMSO 99.8MIN., the active fat of 130g, 50g N-(4-phenylor) piperazine, 21g Pottasium Hydroxide; Controlled temperature was 25～30 ℃ of insulation reaction 24 hours; Reaction is finished, and adds purified water 520g, is cooled to 0～5 ℃ after adding finishes; Stir insulation 2h, suction filtration gets antibacterial ester condensates.
2, esterification
In there-necked flask, add the 322g methylene dichloride, the antibacterial ester condensates of 50g behind the 52g salt of wormwood, slowly adds the 11.9g Vinyl chloroformate; After adding finished, controlled temperature was at 30 ℃, and insulation reaction 4 hours is reacted and finished; Slowly add the 108g purified water, after adding finishes, continue to stir 2h, organic layer is washed to PH to 7 for three times with purifying moisture; ETHYLE ACETATE is steamed in the decompression of washing back, and being concentrated to volume is 150ml, and 0～5 ℃ keeps 2～4h down, and suction filtration gets antibacterial ester carboxylate.
Antibacterial ester heating is dissolved in the acetone of 8 times of amounts, adds the gac of 0.5 times of amount, insulation 0.5h refluxes; Be cooled to and do not reflux, suction filtration is removed gac, and filtrating is concentrated into 5 times of amounts of antibacterial ester weight; Add water for cooling to 0～5 ℃ after concentrate finishing, stir insulation 1～3h down, suction filtration gets antibacterial ester.
Claims (7)
1. the preparation method of an antibacterial ester may further comprise the steps:
1) condensation reaction
Active fat, N-(4-phenylor) piperazine and alkali are dissolved in the solvent; 25～30 ℃ of condensation reactions 20～30 hours, after finishing, reaction adds water for cooling to 0～5 ℃, stir insulation 1～3h down; Suction filtration gets antibacterial ester condensates; Described active fat is meant suitable-[2-(2,4 dichloro benzene base)-2-(1H-imidazoles-1-ylmethyl)-1,3-dioxolane-4-yl] methyl alcohol p-toluenesulfonic esters or methanesulfonates;
2) esterification
The resulting antibacterial ester condensates of step 1) is added alkali be dissolved in the solvent, slowly add Vinyl chloroformate, after adding finishes; Controlled temperature is at 20～30 ℃, and insulation reaction 1～2 hour adds water and continues to stir 2h after reaction finishes; Organic layer is washed with water to PH to 7, and the pressure reducing and steaming solvent adds hexone behind the evaporate to dryness; 0～5 ℃ keeps 2～4h down, and suction filtration gets antibacterial ester.
2. the preparation method of antibacterial ester according to claim 1, it is characterized in that: in the described condensation reaction, the mol ratio of active fat and N-(4-phenylor) piperazine is 1:0.9～1.1.
3. the preparation method of antibacterial ester according to claim 1, it is characterized in that: the condensation reaction solvent is methylene dichloride, trichloromethane, DMSO 99.8MIN. or N, dinethylformamide.
4. the preparation method of antibacterial ester according to claim 1, it is characterized in that: the esterification solvent is ETHYLE ACETATE, methylene dichloride, trichloromethane or acetone.
5. the preparation method of antibacterial ester according to claim 1, it is characterized in that: in the described esterification, the mol ratio of antibacterial ester condensates and Vinyl chloroformate is 1:0.9～1.1.
6. the preparation method of antibacterial ester according to claim 1, it is characterized in that: described alkali is Pottasium Hydroxide, sodium hydroxide, salt of wormwood or yellow soda ash.
7. the preparation method of antibacterial ester according to claim 1; It is characterized in that described method is further comprising the steps of: with step 2) resulting antibacterial ester heating is dissolved in the acetone, adds gac, and insulation refluxes; Filter; Add water for cooling to 0～5 ℃ after filtrating concentrates, stir insulation 1～3h down, suction filtration gets the pure article of antibacterial ester.
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| CN 201110026992 CN102070620B (en) | 2011-01-25 | 2011-01-25 | Preparation method of antibacterial ester |
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| CN 201110026992 CN102070620B (en) | 2011-01-25 | 2011-01-25 | Preparation method of antibacterial ester |
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| CN102070620B true CN102070620B (en) | 2012-12-12 |
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| CN102627633A (en) * | 2012-03-21 | 2012-08-08 | 浙江丽晶化学有限公司 | New method for purifying elubiol |
| CN111689948A (en) * | 2020-06-29 | 2020-09-22 | 南京白敬宇制药有限责任公司 | Ketoconazole refining process |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4335125A (en) * | 1977-01-31 | 1982-06-15 | Janssen Pharmaceutica, N.V. | 1-(1,3-Dioxolan-2-ylmethyl)-1H-imidazoles |
| US5849279A (en) * | 1992-03-20 | 1998-12-15 | Janssen Pharmaceutica, Nv | Agent for regulating the greasiness of the skin |
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2011
- 2011-01-25 CN CN 201110026992 patent/CN102070620B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4335125A (en) * | 1977-01-31 | 1982-06-15 | Janssen Pharmaceutica, N.V. | 1-(1,3-Dioxolan-2-ylmethyl)-1H-imidazoles |
| US5849279A (en) * | 1992-03-20 | 1998-12-15 | Janssen Pharmaceutica, Nv | Agent for regulating the greasiness of the skin |
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