CN102391186A - Method for preparing ozagrel intermediate (E)-4-(methyl imidazolyl) methyl cinnamate - Google Patents
Method for preparing ozagrel intermediate (E)-4-(methyl imidazolyl) methyl cinnamate Download PDFInfo
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Abstract
The invention discloses a method for preparing an ozagrel intermediate (E)-4-(methyl imidazolyl) methyl cinnamate, which comprises the following steps of: (1) sodium imidazolide preparation: (1.1) dissolving sodium hydroxides in deionized water, and after the sodium hydroxides is completely dissolved, stirring the obtained product and adding imidazolide to the obtained product; (1.2) putting the solution obtained in the step (1.1) into a reaction kettle and uniformly mixing to obtain a stand-by material; and (1.3) adding toluene to the stand-by material obtained in the step (1.2), then adding acetone to the obtained mixture to obtain an acetone solution; and (2) (E)-4-(imidazolyl-methyl) methyl cinnamate preparation: (2.1) adding methyl 3-(4-bromomethyl) cinnamate to the acetone solution, and after reaction, carrying out depressurized evaporation on the obtained product to remove acetone from the material; and (2.2) adding deionized water to the material subjected to acetone evaporation in the step (2.1), and stirring the obtained mixture to crystallize, thereby obtaining the (E)-4-(imidazolyl-methyl) methyl cinnamate. By using the method disclosed by the invention, the shortages existing in the prior art can be overcome, and the production cost of the intermediate is greatly reduced.
Description
Technical field
The present invention relates to medicine, is the preparation method of (E)-4-(imidazolyl methyl) methyl cinnamate in the middle of a kind of ozagrel.
Background technology
Ozagrel is a kind of antithrombotic, is a kind of powerful thrombus synthetase inhibitors.Because this medicine has prophylactic effect preferably to the cerebral infarction that the obstruction arteria cerebri media causes; Therefore; Be mainly used in the dyspraxia that treatment acute thrombotic cerebral infarction and cerebral infarction are followed, simultaneously, OKY-046 also can be used for bronchial asthma and anginal treatment etc.Because this medicine has broad application prospects, in order to reduce patient's use cost, the pharmacy corporation that China has is also making great efforts to produce this medicine, so that reach quality product height, purpose that production cost is low.Yet the midbody of this medicine (E)-4-(imidazolyl methyl) methyl cinnamate quality good or not in the preparation process directly influences the curative effect of ozagrel medicine, and all there is deficiency in this intermediates preparation of report: for example: adopt imidazoles and the brooethyl methyl cinnamate is reacted the methyl cinnamate through N-alkylation production (E)-4-(imidazolyl methyl); Impurity in this method reaction is generally all at 10-15%; Remove the process relative complex of impurity, be difficult to reach high purity, simultaneously; The productive rate of this method is generally about 75%; Productive rate is lower, and, the difficult control of temperature of reaction; The another kind of employing generates imidazoles bromine father-in-law salt with the reaction of N-acetyl imidazole to the brooethyl methyl cinnamate under nitrogen protection; Imidazoles bromine father-in-law salt obtains (E)-4-(imidazolyl methyl) methyl cinnamate through the yellow soda ash hydrolysis again; This method complicated operation; Reaction times is longer, and yield is lower, and still difficulty reduces production costs.
Summary of the invention
The purpose of this invention is to provide the preparation method of a kind of ozagrel midbody (E)-4-(imidazolyl methyl) methyl cinnamate, make it can solve the deficiency of prior art, this midbody production cost is significantly reduced.
The present invention is for realizing above-mentioned purpose, and realize through following technical scheme: the preparation method of a kind of ozagrel midbody (E)-4-(imidazolyl methyl) methyl cinnamate comprises the steps:
(1) preparation imidazole natrium:
(1.1) sodium hydroxide is dissolved in the deionized water, the dissolving back adds imidazoles under agitation condition, and the weight ratio of sodium hydroxide, deionized water and imidazoles is 1:1:1.62;
(1.2) with the solution in the step (1.1) insert mix in the reaction kettle after, 50-80 ℃ of down reaction 3-5 hour, vacuum decompression steams and removes the wherein moisture of 80%-90%, reduces to room temperature then and obtains subsequent use material;
(1.3) with adding toluene in the subsequent use material in the step (1.2), the weight ratio of toluene and imidazoles is 2.6:1, and reflux water-dividing removes toluene again under reduced pressure then, adds acetone after reducing to room temperature, obtains acetone soln, and the weight ratio of acetone and imidazoles is 4.9:1;
(2) preparation (E)-4-(imidazolyl methyl) methyl cinnamate:
(2.1) getting the brooethyl methyl cinnamate is dropped in the acetone soln, is 3.73:1 to the weight ratio of brooethyl methyl cinnamate and imidazoles, at room temperature reacts 3-4 hour, reacts to remove acetone under reduced pressure after finishing;
(2.2) in step (2.1), steam except that adding the deionized water and stirring crystallization in the material behind the acetone; Deionized water be 1.97:1 to the weight ratio of brooethyl methyl cinnamate; Carry out centrifugal getting rid of after the filter and and dried by the fire material 19-21 hour down, obtain (E)-4-(imidazolyl methyl) methyl cinnamate at 40-50 ℃.
Sodium hydroxide described in the step (1.1) adopts sodium hydrogencarbonate to substitute.
The preparation method of (E)-4-(imidazolyl methyl) methyl cinnamate comprises the steps: in the middle of described a kind of ozagrel
(1) preparation of imidazole natrium:
(1.1) 126 kilograms of sodium hydroxide are dissolved in 126 kilograms the deionized water, the dissolving back is 204 kilograms of imidazoles of adding under agitation condition, obtain mixing solutions;
(1.2) with the mixing solutions in the step (1.1) insert mix in the reaction kettle after, 74 ℃ of down reactions 3.8 hours, vacuum decompression steams and removes wherein 90% moisture, reduces to room temperature then and obtains subsequent use material;
(1.3) with adding 500 kilograms of toluene in the subsequent use material in the step (1.2), reflux water-dividing removes toluene again under reduced pressure then, adds 1000 kilograms of acetone after reducing to room temperature, obtains acetone soln;
(2) preparation (E)-4-(imidazolyl methyl) methyl cinnamate:
(2.1) get in 152.4 kilograms of inputs of brooethyl methyl cinnamate acetone soln, at room temperature reacted 3.5 hours, remove acetone under reduced pressure after reaction finishes;
(2.2) add 1500 kilograms deionized water and stirring crystallization in the material after step (2.1) steam to be removed acetone, carry out centrifugally getting rid of the filter back and, obtaining 135 kilograms of (E)-4-(imidazolyl methyl) methyl cinnamates at 46 ℃ of baking material 20 hours down.
(E)-4-(imidazolyl methyl) methyl cinnamate that adopts ozagrel intermediates preparation of the present invention to obtain has the high characteristics of purity, and purity can reach 99.8%, and yield is up to about 93%; And this method is easy and simple to handle; Reaction times is short, and the solvent that uses in the reaction is single, and reaction is control easily; Production cost is significantly reduced, thereby reduced production cost for the preparation of ozagrel.
Embodiment
The preparation method of a kind of ozagrel midbody of the present invention (E)-4-(imidazolyl methyl) methyl cinnamate comprises the steps:
(1) preparation imidazole natrium:
(1.1) sodium hydroxide is dissolved in the deionized water, the dissolving back adds imidazoles under agitation condition, and the weight ratio of sodium hydroxide, deionized water and imidazoles is 1:1:1.62;
(1.2) with the solution in the step (1.1) insert mix in the reaction kettle after, 50-80 ℃ of down reaction 3-5 hour, vacuum decompression steams and removes the wherein moisture of 80%-90%, reduces to room temperature then and obtains subsequent use material;
(1.3) with adding toluene in the subsequent use material in the step (1.2), the weight ratio of toluene and imidazoles is 2.6:1, and reflux water-dividing removes toluene again under reduced pressure then, adds acetone after reducing to room temperature, obtains acetone soln, and the weight ratio of acetone and imidazoles is 4.9:1;
(2) preparation (E)-4-(imidazolyl methyl) methyl cinnamate:
(2.1) getting the brooethyl methyl cinnamate is dropped in the acetone soln, is 3.73:1 to the weight ratio of brooethyl methyl cinnamate and imidazoles, at room temperature reacts 3-4 hour, reacts to remove acetone under reduced pressure after finishing;
(2.2) in step (2.1), steam except that adding the deionized water and stirring crystallization in the material behind the acetone; Deionized water be 1.97:1 to the weight ratio of brooethyl methyl cinnamate; Carry out centrifugal getting rid of after the filter and and dried by the fire material 19-21 hour down, obtain (E)-4-(imidazolyl methyl) methyl cinnamate at 40-50 ℃.
Sodium hydroxide described in the step (1.1) also can adopt sodium hydrogencarbonate to substitute.
The preparation method of (E)-4-(imidazolyl methyl) methyl cinnamate in the middle of a kind of ozagrel of the present invention, concrete steps are following:
(1) preparation of imidazole natrium:
(1.1) 126 kilograms of sodium hydroxide are dissolved in 126 kilograms the deionized water, the dissolving back is 204 kilograms of imidazoles of adding under agitation condition, obtain mixing solutions;
(1.2) with the mixing solutions in the step (1.1) insert mix in the 3000L reaction kettle after, 72 ℃ of down reactions 3.8 hours, vacuum decompression steams and removes wherein 90% moisture, reduces to room temperature then and obtains subsequent use material;
(1.3) with adding 500 kilograms of toluene in the subsequent use material in the step (1.2), reflux water-dividing removes toluene again under reduced pressure then, adds 1000 kilograms of acetone after reducing to room temperature, obtains acetone soln;
(2) preparation (E)-4-(imidazolyl methyl) methyl cinnamate:
(2.1) get in 152.4 kilograms of inputs of brooethyl methyl cinnamate acetone soln, at room temperature reacted 3.5 hours, remove acetone under reduced pressure after reaction finishes;
(2.2) add 1500 kilograms deionized water and stirring crystallization in the material after step (2.1) steam to be removed acetone, carry out centrifugally getting rid of the filter back and, obtaining 135 kilograms of (E)-4-(imidazolyl methyl) methyl cinnamates at 46 ℃ of baking material 20 hours down.Yield is 93.7%, and purity is 99.8%.
The preparation method of a kind of ozagrel midbody of the present invention (E)-4-(imidazolyl methyl) methyl cinnamate can adopt following method preparation:
Example 1:
(1) preparation imidazole natrium:
(1.1) 25.2 kilograms of sodium hydroxide are dissolved in 25.2 kilograms the deionized water, the dissolving back is 40.8 kilograms of imidazoles of adding under agitation condition, obtain mixing solutions;
(1.2) with the mixing solutions in the step (1.1) insert mix in the 500L reaction kettle after, 80 ℃ of down reactions 3 hours, vacuum decompression steams and removes wherein 90% moisture, reduces to room temperature then and obtains subsequent use material;
(1.3) with adding 100 kilograms of toluene in the subsequent use material in the step (1.2), reflux water-dividing removes toluene again under reduced pressure then, adds 200 kilograms of acetone after reducing to room temperature, obtains acetone soln;
(2) preparation (E)-4-(imidazolyl methyl) methyl cinnamate:
(2.1) get in 152.4 kilograms of inputs of brooethyl methyl cinnamate acetone soln, at room temperature reacted 3 hours, remove acetone under reduced pressure after reaction finishes;
(2.2) steam the deionized water and stirring crystallization that adds 300 kilograms in the material after removing acetone in step (2.1); Carry out centrifugal getting rid of after the filter and and dried by the fire material 21 hours down at 40 ℃; Obtain 135 kilograms of (E)-4-(imidazolyl methyl) methyl cinnamates, yield is 93.2%, and purity is 99.8%.
Example 2:
(1) preparation of imidazole natrium:
(1.1) 126 kilograms of sodium hydroxide are dissolved in 126 kilograms the deionized water, the dissolving back is 204 kilograms of imidazoles of adding under agitation condition, obtain mixing solutions;
(1.2) with the mixing solutions in the step (1.1) insert mix in the 3000L reaction kettle after, 70 ℃ of down reactions 5 hours, vacuum decompression steams and removes wherein 90% moisture, reduces to room temperature then and obtains subsequent use material;
(1.3) with adding 500 kilograms of toluene in the subsequent use material in the step (1.2), reflux water-dividing removes toluene again under reduced pressure then, adds 1000 kilograms of acetone after reducing to room temperature, obtains acetone soln;
(2) preparation (E)-4-(imidazolyl methyl) methyl cinnamate:
(2.1) get in 762 kilograms of inputs of brooethyl methyl cinnamate acetone soln, at room temperature reacted 4 hours, remove acetone under reduced pressure after reaction finishes;
(2.2) steam the deionized water and stirring crystallization that adds 1500 kilograms in the material after removing acetone in step (2.1); Carry out centrifugal getting rid of after the filter and and dried by the fire material 21 hours down at 50 ℃; Obtain 680.2 kilograms of (E)-4-(imidazolyl methyl) methyl cinnamates, yield is 93.7%, and purity is 99.8%.
Preparing method of the present invention, its reaction formula is following:
1, the preparation of imidazole natrium:
2, the preparation of (E)-4-(imidazolyl methyl) methyl cinnamate:
Claims (3)
1. the preparation method of an ozagrel midbody (E)-4-(imidazolyl methyl) methyl cinnamate is characterized in that: comprise the steps:
(1) preparation imidazole natrium:
(1.1) sodium hydroxide is dissolved in the deionized water, the dissolving back adds imidazoles under agitation condition, and the weight ratio of sodium hydroxide, deionized water and imidazoles is 1:1:1.62;
(1.2) with the solution in the step (1.1) insert mix in the reaction kettle after, 50-80 ℃ of down reaction 3-5 hour, vacuum decompression steams and removes the wherein moisture of 80%-90%, reduces to room temperature then and obtains subsequent use material;
(1.3) with adding toluene in the subsequent use material in the step (1.2), the weight ratio of toluene and imidazoles is 2.6:1, and reflux water-dividing removes toluene again under reduced pressure then, adds acetone after reducing to room temperature, obtains acetone soln, and the weight ratio of acetone and imidazoles is 4.9:1;
(2) preparation (E)-4-(imidazolyl methyl) methyl cinnamate:
(2.1) getting the brooethyl methyl cinnamate is dropped in the acetone soln, is 3.73:1 to the weight ratio of brooethyl methyl cinnamate and imidazoles, at room temperature reacts 3-4 hour, reacts to remove acetone under reduced pressure after finishing;
(2.2) in step (2.1), steam except that adding the deionized water and stirring crystallization in the material behind the acetone; Deionized water be 1.97:1 to the weight ratio of brooethyl methyl cinnamate; Carry out centrifugal getting rid of after the filter and and dried by the fire material 19-21 hour down, obtain (E)-4-(imidazolyl methyl) methyl cinnamate at 40-50 ℃.
2. the preparation method of (E)-4-(imidazolyl methyl) methyl cinnamate in the middle of a kind of ozagrel according to claim 1 is characterized in that: the sodium hydroxide described in the step (1.1) adopts sodium hydrogencarbonate to substitute.
3. the preparation method of (E)-4-(imidazolyl methyl) methyl cinnamate is characterized in that: comprise the steps: in the middle of a kind of ozagrel according to claim 1
(1) preparation of imidazole natrium:
(1.1) 126 kilograms of sodium hydroxide are dissolved in 126 kilograms the deionized water, the dissolving back is 204 kilograms of imidazoles of adding under agitation condition, obtain mixing solutions;
(1.2) with the mixing solutions in the step (1.1) insert mix in the reaction kettle after, 74 ℃ of down reactions 3.8 hours, vacuum decompression steams and removes wherein 90% moisture, reduces to room temperature then and obtains subsequent use material;
(1.3) with adding 500 kilograms of toluene in the subsequent use material in the step (1.2), reflux water-dividing removes toluene again under reduced pressure then, adds 1000 kilograms of acetone after reducing to room temperature, obtains acetone soln;
(2) preparation (E)-4-(imidazolyl methyl) methyl cinnamate:
(2.1) get in 152.4 kilograms of inputs of brooethyl methyl cinnamate acetone soln, at room temperature reacted 3.5 hours, remove acetone under reduced pressure after reaction finishes;
(2.2) add 1500 kilograms deionized water and stirring crystallization in the material after step (2.1) steam to be removed acetone, carry out centrifugally getting rid of the filter back and, obtaining 135 kilograms of (E)-4-(imidazolyl methyl) methyl cinnamates at 46 ℃ of baking material 20 hours down.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613546A (en) * | 2013-12-11 | 2014-03-05 | 青岛农业大学 | Chemical synthesizing method of ozagrel |
| CN103787980A (en) * | 2014-01-21 | 2014-05-14 | 济南信和缘科技有限公司 | Preparation method for ozagrel intermediate |
| CN104761500A (en) * | 2014-01-08 | 2015-07-08 | 济南大成医药发展有限公司 | Preparation method of (E)-4-(1-imidazole methyl)methyl cinnamate |
| CN105481771A (en) * | 2015-12-29 | 2016-04-13 | 济南诚汇双达化工有限公司 | Preparation process of ozagrel intermediate methyl (E)-4-(imidazolylmethyl) cinnamate |
| CN108084094A (en) * | 2017-11-09 | 2018-05-29 | 江苏康乐佳材料有限公司 | A kind of technique that imidazole natrium is prepared as raw material using imidazoles |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613546A (en) * | 2013-12-11 | 2014-03-05 | 青岛农业大学 | Chemical synthesizing method of ozagrel |
| CN104761500A (en) * | 2014-01-08 | 2015-07-08 | 济南大成医药发展有限公司 | Preparation method of (E)-4-(1-imidazole methyl)methyl cinnamate |
| CN104761500B (en) * | 2014-01-08 | 2017-11-21 | 济南大成医药发展有限公司 | (E) preparation method of 4 (1 imidazolmethyl) methyl cinnamates |
| CN103787980A (en) * | 2014-01-21 | 2014-05-14 | 济南信和缘科技有限公司 | Preparation method for ozagrel intermediate |
| CN105481771A (en) * | 2015-12-29 | 2016-04-13 | 济南诚汇双达化工有限公司 | Preparation process of ozagrel intermediate methyl (E)-4-(imidazolylmethyl) cinnamate |
| CN108084094A (en) * | 2017-11-09 | 2018-05-29 | 江苏康乐佳材料有限公司 | A kind of technique that imidazole natrium is prepared as raw material using imidazoles |
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