CN101148447A - Method for preparing Sertaconazole Nitrate by using polyglycol-400 as catalyst - Google Patents
Method for preparing Sertaconazole Nitrate by using polyglycol-400 as catalyst Download PDFInfo
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- CN101148447A CN101148447A CNA2007101500851A CN200710150085A CN101148447A CN 101148447 A CN101148447 A CN 101148447A CN A2007101500851 A CNA2007101500851 A CN A2007101500851A CN 200710150085 A CN200710150085 A CN 200710150085A CN 101148447 A CN101148447 A CN 101148447A
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- sertaconazole
- preparation
- polyoxyethylene glycol
- catalysis
- thiophene
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Abstract
The present invention discloses polyglycol-400 phase transfer catalyzed sertaconazole nitrate preparing process with lowered toxicity and reduced preparation cost. The present invention features that sertaconazole nitrate is prepared with 1-(2, 4-dichloro benzene)-2-(1-imidazolyl) ethanol and 3-bromomethyl-7chlorobenzo[b] thiophene as materials, tetrahdrofuran and water as solvent, and polyglycol-400 as catalyst, and through phase transfer catalyzed reaction with sodium hydroxide. The present invention has simple operation, lowered solvent toxicity, reduced preparation cost and stable yield, and is suitable for industrial production.
Description
[technical field]
The present invention relates to technical field of organic synthesis, particularly a kind of preparation method who adopts polyoxyethylene glycol-400 catalysis sertaconazole.
[background technology]
Desenex's sertaconazole (Sertaconazole Nitrate), molecular formula: C
20H
15Cl
3N
2OSHNO
3, develop by Spain Ferrer company, and went on the market in Spain first in 1992, now, have characteristics such as curative effect height, recurrence rate is low, toxicity is little in multinational list marketings such as China, the U.S., Germany, Argentina, Peru.In prior art; following patent relates to the preparation method of sertaconazole; as EP 0151477; ES 529608; ED 535656; JP60/181186; US 5135943 etc.; above-mentioned patented technology is correlated with, its synthetic route adopt with 1-(2,4 dichloro benzene)-2-(1-imidazoles) ethanol and 3-brooethyl-7-chlorobenzene also [b] thiophene be raw material; under protection of inert gas; with the HMPA is solvent, and sodium hydride participates in reaction and makes Sertaconazole, prepares nitrate with nitric acid reaction again.The weak point of this synthetic method is:
Reaction needed is finished under protection of inert gas; Used sodium hydride is inflammable, explosive chemicals, and is dangerous big, uses dangerously, must operate under anhydrous, oxygen free condition so react; Used HMPA is a noxious solvent, and carcinogenesis is arranged, and costs an arm and a leg, and reclaims difficulty; At first prepare Sertaconazole, and will use the silicagel column separation and purification, prepare sertaconazole with nitric acid reaction again, complex operation, difficulty are unsuitable for large-scale production.
In addition, Chinese patent ZL 01 127506.5 relates to a kind of new preparation method of sertaconazole, with 1-(2, the 4-dichlorobenzene)-2-(1-imidazoles) ethanol and 3-brooethyl-7-chlorobenzene also [b] thiophene be raw material, with toluene, water is solvent, tetrabutylammonium chloride is a catalyzer, under participating in, sodium hydroxide carries out phase-transfer-catalyzed reactions, without separating Sertaconazole, directly be carried out to reactant salt and prepare sertaconazole, do not need anhydrous, oxygen free operation, with the foreign literature method bigger improvement is arranged relatively, but also have weak point: phase-transfer-catalyzed reactions needs the higher tetrabutylammonium chloride of price to make catalyzer, and toluene toxicity is big, for the bulk drug preparation limits the use of solvent, because reaction needed (80 ℃) under relative comparatively high temps is carried out, products therefrom is sorrel, product decolouring difficulty, and be difficult for purifying, loss is big, and complex operation has improved synthetic cost.
[summary of the invention]
Purpose of the present invention is intended to for overcoming the deficiencies in the prior art, and a kind of preparation method of new sertaconazole is provided, this method reaction conditions gentleness, and easy and simple to handle, cost is lower.
The present invention addresses the above problem the preparation method that the scheme that is adopted is a kind of sertaconazole of design.It is characterized in that with 1-(2, the 4-dichlorobenzene)-2-(1-imidazoles) ethanol and 3-brooethyl-7-chlorobenzene also [b] thiophene be raw material, add organic solvent and water, under alkaline condition, carry out phase-transfer-catalyzed reactions with catalyst polyethylene glycol-400, without separating Sertaconazole, directly be carried out to reactant salt and prepare sertaconazole.
The invention has the beneficial effects as follows: preparation method of the present invention compares with other preparation methods; the catalyst system therefor cost is lower; with tetrahydrofuran (THF) or hexanaphthene is solvent; overcome the toxicity that solvent brought; the reaction conditions gentleness, easier the carrying out of product decolouring, easy and simple to handle; reduced synthetic cost, made its technology be more suitable for large-scale production.
[embodiment]
Also [b] thiophene, alkali, catalyst polyethylene glycol-400 and organic solvent water are mixed with 1-(2,4 dichloro benzene)-2-(1-imidazoles) ethanol, 3-brooethyl-7-chlorobenzene in the present invention, slowly are warming up to 80 ℃, constant temperature stirred 3～5 hours, cooling, washing, the extracted with diethyl ether several, collected organic layer is used anhydrous sodium sulfate drying, filter, add the concentrated nitric acid of 65-68% under the stirring at room, filter drying, recrystallization gets sertaconazole.
1-(2,4 dichloro benzene)-2-(1-imidazoles) ethanol of said every 1mol (closing 256.0g) and 3-brooethyl-7-chlorobenzene of 1mol (closing 260.0g) also [b] thiophene water are: 400～500ml, organic solvent are 1200～1500ml.Said organic solvent is a kind of in tetrahydrofuran (THF), the hexanaphthene.Said alkali is a kind of in sodium hydroxide or the potassium hydroxide.
The embodiment of the invention:
With 25.6g (0.1mol) 1-(2,4 dichloro benzene)-2-(1-imidazoles) ethanol, also [b] thiophene, 6g sodium hydroxide, 1.2g polyoxyethylene glycol-400 are dissolved in 120ml tetrahydrofuran (THF) and the 40ml water 26.0g (0.1mol) 3-brooethyl-7-chlorobenzene.Slowly be warming up to 80 ℃, constant temperature stirred 4 hours, was chilled to room temperature, washing (3 * 20ml), and extracted with diethyl ether (3 * 40ml), merge organic layer, anhydrous sodium sulfate drying filters, and splashes into the concentrated nitric acid of 4ml 65-68% under the stirring at room, separate out solid, filter drying, 95% ethyl alcohol recrystallization, get sertaconazole finished product 29.7g, yield 59.3%, fusing point 163-164 ℃.Its synthetic route is as follows:
Claims (5)
1. the preparation method of polyoxyethylene glycol-400 catalysis sertaconazole, it is characterized in that with 1-(2, the 4-dichlorobenzene)-2-(1-imidazoles) ethanol and 3-brooethyl-7-chlorobenzene also [b] thiophene be raw material, add organic solvent and water, under alkaline condition, carry out phase-transfer-catalyzed reactions with catalyst polyethylene glycol-400, without separating Sertaconazole, directly be carried out to reactant salt and prepare sertaconazole.
2. the preparation method of polyoxyethylene glycol-400 catalysis sertaconazole according to claim 1, it is characterized in that 1-(2,4 dichloro benzene)-2-(1-imidazoles) ethanol and 3-brooethyl-7-chlorobenzene also two kinds of raw material molar ratios of [b] thiophene be 1: 1; It is 12～15g that every mole of raw material adds polyoxyethylene glycol-400, and organic solvent is 1200～1500ml, and water is 400～500ml.
3. the preparation method of polyoxyethylene glycol-400 catalysis sertaconazole according to claim 1 is characterized in that said alkali is a kind of in sodium hydroxide or the potassium hydroxide.
4. the preparation method of polyoxyethylene glycol-400 catalysis sertaconazole according to claim 1 and 2 is characterized in that said organic solvent is a kind of of tetrahydrofuran (THF) or hexanaphthene.
5. the preparation method of polyoxyethylene glycol-400 catalysis sertaconazole according to claim 1 is characterized in that said temperature of reaction is 80 ℃, and the reaction times is 3～5 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101500851A CN101148447A (en) | 2007-11-06 | 2007-11-06 | Method for preparing Sertaconazole Nitrate by using polyglycol-400 as catalyst |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101500851A CN101148447A (en) | 2007-11-06 | 2007-11-06 | Method for preparing Sertaconazole Nitrate by using polyglycol-400 as catalyst |
Publications (1)
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|---|---|
| CN101148447A true CN101148447A (en) | 2008-03-26 |
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| CNA2007101500851A Pending CN101148447A (en) | 2007-11-06 | 2007-11-06 | Method for preparing Sertaconazole Nitrate by using polyglycol-400 as catalyst |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860933A (en) * | 2015-05-22 | 2015-08-26 | 池州中瑞化工有限公司 | Synthesis method of Sertaconazole nitrate |
| CN113735843A (en) * | 2021-09-07 | 2021-12-03 | 海南海神同洲制药有限公司 | Preparation method of low-melting-point sertaconazole nitrate |
-
2007
- 2007-11-06 CN CNA2007101500851A patent/CN101148447A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860933A (en) * | 2015-05-22 | 2015-08-26 | 池州中瑞化工有限公司 | Synthesis method of Sertaconazole nitrate |
| CN113735843A (en) * | 2021-09-07 | 2021-12-03 | 海南海神同洲制药有限公司 | Preparation method of low-melting-point sertaconazole nitrate |
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Open date: 20080326 |