CN103319454A - Preparation method of high-purity tetraethyl ranelate and intermediate thereof - Google Patents
Preparation method of high-purity tetraethyl ranelate and intermediate thereof Download PDFInfo
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Abstract
The invention relates to a preparation method of 5-amino-4-cyano-3-(2-ethyoxyl-2-carboxymethyl)-thiophene-2-ethyl formate. The preparation method comprises the following steps of: (a) reacting acetonedicarboxylic acid diethyl ester with malononitrile in the presence of an acid-binding agent and ethanol to generate an active intermediate; and (b) after ammonium sulfide is added as a cosolvent, carrying out cyclization reaction on the active intermediate and sulphur under the reflux of the ethanol, cooling, separating out a crystal, filtering and collecting a filter cake to obtain the 5-amino-4-cyano-3-(2-ethyoxyl-2-carboxymethyl)-thiophene-2-ethyl formate. The 5-amino-4-cyano-3-(2-ethyoxyl-2-carboxymethyl)-thiophene-2-ethyl formate prepared by the invention is high in purity, high in yield and low in cost, and three-waste emission is low.
Description
Technical field:
The invention belongs to the technical field of medicine synthesis in the pharmacy field, be specifically related to a kind of thunder Buddhist nun acid tetra-ethyl ester and intermediates preparation thereof.
Background technology:
Strontium in the Strontium Ranelate is the important component part of skeleton, can promote the growth of bone and the formation of osteoid, and has the effect of regulating calcium metabolism.The Strontium Ranelate clinical data shows: this medicine is specially adapted to treat and prevents osteoporosis behind the postmenopausal women, significantly reduces the danger that vertebral fracture and hip fracture take place, and has clinical effectiveness preferably.
The method that prepare at present Strontium Ranelate all adopt 5-[two (2-oxyethyl group-2-carboxymethyl) amino-]-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-2-thiophene ethyl formate (being called for short thunder Buddhist nun acid tetra-ethyl ester) is intermediate, a kind of method is, the hydrolysis in sodium hydroxide or potassium hydroxide solution of thunder Buddhist nun acid tetra-ethyl ester is changeed salt with the strontium chloride reaction again and is generated Strontium Ranelate; Another kind method is directly hydrolysis salify generation Strontium Ranelate in strontium hydroxide solution of thunder Buddhist nun acid tetra-ethyl ester.
Thunder Buddhist nun acid tetra-ethyl ester is the key intermediate compound of preparation Strontium Ranelate.Strontium Ranelate is water-soluble hardly, and is also almost insoluble in most of organic solvents such as acetone, methyl alcohol, ethanol, tetrahydrofuran (THF), methyl-sulphoxide, slightly molten in the hydrochloric acid soln of 0.1mol/L and boiling water, is difficult to purify by recrystallization.Therefore, the thunder Buddhist nun of prior art for preparing acid tetra-ethyl ester need just can be used for preparing Strontium Ranelate after making with extra care under the boiling water condition, and refining effect is often not good enough, makes strontium ranelate raw material medicine complicated process of preparation, the cost costliness.
The common method that bibliographical information prepares thunder Buddhist nun acid tetra-ethyl ester is that Bing Tongersuosuan diethyl ester, the third two eyeballs, ethanol, sulphur reacts acquisition 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl under acid binding agent)-the 2-thiophene ethyl formate, it is intermediate compound I, intermediate compound I makes solvent with acetone again and hydrocarbonylation reagent is done reaction acquisition under the acid binding agent at salt of wormwood, and its synthetic route is:
Document Chem Ber, 1966,99:94-99 are acid binding agent with the morpholine, and more than the reaction 3h, the reaction yield of intermediate I only has 42.0%, and because morpholine toxicity is big, and a large amount of uses are caused danger easily and environment is also being constituted potential threat in the production.Document Journal of Chemical Technology and Biotechnology, 1990,47:39-46 uses diethylamine to replace morpholine, though the reaction yield of intermediate I can reach 80.0%, but need to consume a large amount of washing diethylamine to neutral, produce a large amount of alkaline waste waters.Chinese patent CN102321068 also adopts diethylamine to make acid binding agent, make the water instead of ethanol make solvent, though a large amount of sodium sulphite (consumption be sulphur quality 28.1%) can increase the solubleness of sulphur in water, reaction is accelerated, but because the organism in the reaction is poorly soluble in water, make to be reflected in water-organic two-phase and carry out that reaction is uneven, cause overall reaction rate to reduce; In addition, because the intermediate compound I poorly water-soluble, crystallization immediately after reaction generates wraps up a large amount of inorganic salt easily, and massive laundering is washed and also is difficult to remove fully during filtration, has reduced the quality of product, and the meeting of water washing simultaneously produces a large amount of waste water.Therefore, all there is long reaction time (more than the 3h) in the method for preparing intermediate compound I, the big shortcoming of waste liquid environmental stress of generation.
Document Bull.Soc.Chim.France, 1975:1786-1792 discloses employing salt of wormwood and has made acid binding agent, ethyl bromoacetate is hydrocarbonylation reagent, under refluxad react the method for preparing thunder Buddhist nun acid tetra-ethyl ester more than the 48h with intermediate compound I, but this method yield only has 65.0%, need to consume a large amount of water dilution organic solvents after reaction finishes and separate thunder Buddhist nun acid tetra-ethyl ester, produce a large amount of alkaline waste waters.Chinese patent CN1496986, CN100391955, CN102180864 and CN101665483 have improved the preparation method by adding catalyzer, have reported the method for making Preparation of Catalyst thunder Buddhist nun acid tetra-ethyl ester with C8-C10 type quaternary ammonium salt (as Adogen 464R and Aliquat 336R), crown ether or KF/Al2O3, polyoxyethylene glycol and ionic liquid respectively.The use of above-mentioned catalyzer can be accelerated speed of reaction, and the reaction times is foreshortened in the 15h, but the purity of gained thunder Buddhist nun acid tetra-ethyl ester all≤98.0%, single impurity 〉=0.5%; Thunder Buddhist nun acid tetra-ethyl ester with this purity is that the Strontium Ranelate that intermediate preparation obtains also is difficult to make quality product meet medicinal requirements through repeatedly refining.In addition, the alkyl chain of C8-C10 type quaternary ammonium salt is longer, sterically hindered big, cause catalytic efficiency low, C8-C10 type quaternary ammonium salt has satisfactory stability and strong sterilization idiocratic simultaneously, can influence the metabolism of all kinds of materials in the environment to the production by biological toxigenicity in the environment, have very important environmental risk; And adopt polyoxyethylene glycol to make catalyzer, and then aftertreatment need use ethyl acetate extraction, 80.0% ethanol to boil making beating, a large amount of boiling water washing leaching cake, can produce a large amount of waste liquids, and environmental stress is big; Adopt crown ether or KF/Al2O3, ionic liquid to make catalyzer and all have expensive shortcoming, thereby limited its industrial applications.
Summary of the invention
The objective of the invention is to overcome the above-mentioned weak point of prior art, a kind of preparation method of new high purity thunder Buddhist nun acid tetra-ethyl ester is provided.The contriver is carrying out a large amount of explorations aspect the preparation technology of thunder Buddhist nun acid tetra-ethyl ester, against expectation finds: by adding ammonium sulfide as solubility promoter, can significantly improve speed of reaction, and improve reaction yield and the quality product of intermediate I.Based on above-mentioned discovery, thereby finish the present invention.
Purpose of the present invention will further embody and illustrate by following detailed.
Among the present invention, intermediate I refers to 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-the 2-thiophene ethyl formate.
An aspect the invention provides a kind of 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-preparation method of 2-thiophene ethyl formate, may further comprise the steps:
A) Bing Tongersuosuan diethyl ester and propane dinitrile react in the presence of acid binding agent and ethanol and generate active intermediate;
B) add ammonium sulfide as solubility promoter after, described active intermediate under alcohol reflux with sulphur generation cyclization, the cooling crystallization filters and collects filter cake, obtains 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-the 2-thiophene ethyl formate.
In the cyclization that generates intermediate I, the contriver has utilized ammonium sulfide to be dissolved in the character of ethanol dexterously, find to add a spot of ammonium sulfide and can increase the solubleness of sulphur in ethanol as solubility promoter, make to be reflected in the homogeneous phase and carry out, being conducive to reaction carries out to positive dirction, make the reaction times foreshorten to 1.0h by 3 ~ 5h of prior art, thereby significantly improved speed of reaction, and improved the reaction yield of intermediate I.In addition, because ammonium sulfide is dissolved in ethanol, therefore, can ammonium sulfide be removed by filtering after the reaction that generates intermediate I finishes, thereby improve the quality product of intermediate I, the intermediate I purity height of acquisition can be directly used in preparation thunder Buddhist nun acid tetra-ethyl ester.
The consumption of described ammonium sulfide is the 2.0-7.5% of described sulphur quality, is preferably 4.0%-5.5%, more preferably 5% of described sulphur quality.
Described acid binding agent is diethylamine.
On the other hand, the invention provides a kind of preparation method of high purity thunder Buddhist nun acid tetra-ethyl ester, may further comprise the steps:
A) Bing Tongersuosuan diethyl ester and propane dinitrile react in the presence of acid binding agent and ethanol and generate active intermediate;
B) add ammonium sulfide as solubility promoter after, described active intermediate under alcohol reflux with sulphur generation cyclization, the cooling crystallization filters and collects filter cake, obtains 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-the 2-thiophene ethyl formate;
C) described 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-the 2-thiophene ethyl formate is in the presence of salt of wormwood and catalyzer, under organic solvent refluxes with hydrocarbonylation reagent generation substitution reaction, cooled and filtered, filtrate decompression concentrates removes organic solvent, it is refining to add recrystallization solvent, filter and collect filter cake, be drying to obtain thunder Buddhist nun acid tetra-ethyl ester.
The present invention realizes by following technological line:
Described catalyzer adopts potassiumiodide or sodium iodide.Consumption is little, can shorten the reaction times more significantly, has reduced the generation of side reaction, purity 〉=99.6% of prepared thunder Buddhist nun acid tetra-ethyl ester, and single impurity≤0.1%, and have cheap advantage.Potassiumiodide or sodium iodide, are removed along with filtrate during filtration through the recrystallization of 95% alcoholic solution as catalyzer.
Described catalyst levels is the 1-5% of described Bing Tongersuosuan diethyl ester quality, is preferably 2-3.5%, more preferably 2.5%.Use cheap catalyst potassiumiodide or sodium iodide in the substitution reaction of generation thunder Buddhist nun acid tetra-ethyl ester, can make the reaction times foreshorten to 1.5～2.0h, visible potassiumiodide or sodium iodide have katalysis preferably to substitution reaction.Iodide ion is strong nucleophilic group, is again strong leavings group, and iodide ion and hydrocarbonylation reagent react generate the iodacetyl ethyl acetate in the reaction process, are conducive to the attack of the N atom pairs C-I key of primary amine, and accelerated reaction improves degree of purity of production.
Described acid binding agent is diethylamine.Described organic solvent is selected from acetone or acetonitrile.Described hydrocarbonylation reagent is selected from ethyl chloroacetate or ethyl bromoacetate.Described recrystallization solvent is methyl alcohol, ethanol or the Virahol of 95% volume percent.
The contriver found through experiments, and the quality of thunder Buddhist nun acid tetra-ethyl ester has great effect to the quality of Strontium Ranelate, as long as obtain highly purified thunder Buddhist nun acid tetra-ethyl ester, the content that particularly reduces single impurity just can improve purity and the yield of Strontium Ranelate greatly.
Compared with prior art, the invention has the beneficial effects as follows: by adding ammonium sulfide as solubility promoter, make the reaction times foreshorten to 1.0h by 3 ~ 5h of prior art, significantly improved speed of reaction, and improved reaction yield and the quality product of intermediate I, the purity of intermediate I 〉=99.6%, single impurity≤0.1% can be directly used in preparation thunder Buddhist nun acid tetra-ethyl ester, greatly reduces the use of organic solvent and the generation of waste water, reduced production cost, environmental benefit is good.In addition, adopt potassiumiodide or sodium iodide as catalyzer, consumption is little, can shorten the reaction times significantly, purity 〉=99.6% of prepared thunder Buddhist nun acid tetra-ethyl ester, and single impurity≤0.1%, and have cheap advantage.
Preparation method provided by the invention is simple, quick, the reaction conditions gentleness, avoided the process of repeatedly making with extra care, reduced production cost, environmental benefit is good, the thunder Buddhist nun acid tetra-ethyl ester purity height that makes is fit to industrial amplification production, is that the Strontium Ranelate quality that intermediate preparation obtains meets medicinal requirements with the sour tetra-ethyl ester of the thunder Buddhist nun of this purity.
In the present invention, if not refer in particular to, all equipment and starting material etc. all can be buied from market or the industry is commonly used.
Description of drawings
Fig. 1 is the HPLC figure of intermediate compound I related substance.
Fig. 2 is the HPLC figure of thunder Buddhist nun acid tetra-ethyl ester related substance.
Embodiment
Be described in further detail below in conjunction with accompanying drawing and the present invention of embodiment, these specific embodiments only are used for further narration the present invention, do not limit the claim protection domain of the present patent application.
The preparation of embodiment 1 intermediate I
In the 100L enamel reaction still, add 20.0kg Bing Tongersuosuan diethyl ester, 6.6kg propane dinitrile, 3.2kg sulphur, 40.0kg ethanol, the ammonium sulfide that adds 0.16kg again, the water-bath cooling down, slowly stream adds the 10.0kg diethylamine, stream adds and material in reactor is warming up to the reaction 1.0h down that refluxes after finishing, reaction finishes, and (employing TLC detects to judge whether reaction reaches home in the back, developping agent: ethyl acetate is mixed with the volume ratio of 1:4 with chloroform), be down to room temperature, ice-water bath growing the grain 1.0h, filter and collect filter cake, the ethanol that adds 95% volume percent is refining, filters, and drying obtains intermediate I 22.9kg, purity is 99.86%, and yield is 82.1%.
The HPLC figure of the intermediate compound I that present embodiment makes as shown in Figure 1.
The preparation of embodiment 2 thunder Buddhist nuns acid tetra-ethyl ester
In the 100L enamel reaction still, add 22.9kg intermediate compound I, 30.0kg acetone, 28.8kg ethyl bromoacetate, 19.8kg Anhydrous potassium carbonate and the 0.5kg potassiumiodide fine powder for preparing by method among the embodiment 1 successively, after the stirring at room, heat up, maintain the temperature at 60 ℃ of following backflow 1.5h, the reaction solution color gradually becomes red by golden yellow.Reaction finishes, and (employing TLC detects to judge whether reaction reaches home in the back, developping agent: ethyl acetate is mixed with the volume ratio of 1:4 with chloroform), be cooled to room temperature, remove by filter salt of wormwood, filtrate is evaporated to dried under 45 ℃, get brown oil, the ethanol stirring and dissolving that adds 180.0kg 95% volume percent, behind the heat filtering, the crystallization of lowering the temperature naturally, room temperature growing the grain 2h, filter and collect filter cake, drying obtains thunder Buddhist nun acid tetra-ethyl ester 32.1kg, and purity is 99.94%, single impurity＜0.1%, the total recovery of thunder Buddhist nun acid tetra-ethyl ester is that 71.3%(is in the Bing Tongersuosuan diethyl ester).
The HPLC figure of the thunder Buddhist nun acid tetra-ethyl ester that present embodiment makes as shown in Figure 2.
The preparation of intermediate I
In the 100L enamel reaction still, add 20.0kg Bing Tongersuosuan diethyl ester, 6.6kg propane dinitrile, 3.2kg sulphur, 40.0kg ethanol, the ammonium sulfide that adds 0.096kg again, the water-bath cooling down, slowly stream adds the 10.0kg diethylamine, stream adds and material in reactor is warming up to the reaction 1.0h down that refluxes after finishing, reaction finishes, and (employing TLC detects to judge whether reaction reaches home in the back, developping agent: ethyl acetate is mixed with the volume ratio of 1:4 with chloroform), be down to room temperature, ice-water bath growing the grain 1.0h, filter and collect filter cake, the ethanol that adds 95% volume percent is refining, filters, and drying obtains intermediate I 22.9kg, purity is 99.69%, and yield is 81.9%.
The preparation of embodiment 4 thunder Buddhist nuns acid tetra-ethyl ester
In the 100L enamel reaction still, add 22.9kg intermediate compound I, 30.0kg acetone, 28.8kg ethyl bromoacetate, 19.8kg Anhydrous potassium carbonate and the 0.4kg potassiumiodide fine powder for preparing by method among the embodiment 3 successively, after the stirring at room, heat up, maintain the temperature at 60 ℃ of following backflow 1.5h, the reaction solution color gradually becomes red by golden yellow.Reaction finishes, and (employing TLC detects to judge whether reaction reaches home in the back, developping agent: ethyl acetate is mixed with the volume ratio of 1:4 with chloroform), be cooled to room temperature, remove by filter salt of wormwood, filtrate is evaporated to dried under 45 ℃, get brown oil, the ethanol stirring and dissolving that adds 180.0kg 95% volume percent, behind the heat filtering, the crystallization of lowering the temperature naturally, room temperature growing the grain 2 hours, filter and collect filter cake, drying obtains thunder Buddhist nun acid tetra-ethyl ester 32.1kg, and purity is 99.68%, single impurity＜0.1%, the total recovery of thunder Buddhist nun acid tetra-ethyl ester is that 71.1%(is in the Bing Tongersuosuan diethyl ester).
The preparation of intermediate I
In the 100L enamel reaction still, add 20.0kg Bing Tongersuosuan diethyl ester, 6.6kg propane dinitrile, 3.2kg sulphur, 40.0kg ethanol, the ammonium sulfide that adds 0.176kg again, the water-bath cooling down, slowly stream adds the 10.0kg diethylamine, stream adds and material in reactor is warming up to the reaction 1.0h down that refluxes after finishing, reaction finishes, and (employing TLC detects to judge whether reaction reaches home in the back, developping agent: ethyl acetate is mixed with the volume ratio of 1:4 with chloroform), be down to room temperature, ice-water bath growing the grain 1.0h, filter and collect filter cake, the ethanol that adds 95% volume percent is refining, filters, and drying obtains intermediate I 22.9kg, purity is 99.73%, and yield is 82.0%.
The preparation of embodiment 6 thunder Buddhist nuns acid tetra-ethyl ester
In the 100L enamel reaction still, add 22.9kg intermediate compound I, 30.0kg acetone, 28.8kg ethyl bromoacetate, 19.8kg Anhydrous potassium carbonate and the 0.7kg sodium iodide fine powder for preparing by method among the embodiment 5 successively, after the stirring at room, heat up, maintain the temperature at 60 ℃ of following backflow 2h, the reaction solution color gradually becomes red by golden yellow.Reaction finishes, and (employing TLC detects to judge whether reaction reaches home in the back, developping agent: ethyl acetate is mixed with the volume ratio of 1:4 with chloroform), be cooled to room temperature, remove by filter salt of wormwood, filtrate is evaporated to dried under 45 ℃, get brown oil, the ethanol stirring and dissolving that adds 180.0kg 95% volume percent, behind the heat filtering, the crystallization of lowering the temperature naturally, room temperature growing the grain 2.5 hours, filter and collect filter cake, drying obtains thunder Buddhist nun acid tetra-ethyl ester 32.1kg, and purity is 99.78%, single impurity＜0.1%, the total recovery of thunder Buddhist nun acid tetra-ethyl ester is that 71.2%(is in the Bing Tongersuosuan diethyl ester).
Comparative Examples 1:
The preparation of intermediate I
In the 100L enamel reaction still, add 20.0kg Bing Tongersuosuan diethyl ester, 6.6kg propane dinitrile, 3.2kg sulphur, 40.0kg ethanol, the water-bath cooling down, slowly stream adds the 10.0kg diethylamine, stream adds and material in reactor is warming up to the reaction 1.0h down that refluxes after finishing, reaction finishes, and (employing TLC detects to judge whether reaction reaches home in the back, developping agent: ethyl acetate is mixed with the volume ratio of 1:4 with chloroform), be down to room temperature, ice-water bath growing the grain 1.0h filters and collects filter cake, and the ethanol that adds 95% volume percent is refining, filter, drying obtains intermediate I 22.9kg, and purity is 97%, and yield is 75.0%.
Comparative Examples 1 is not add ammonium sulfide as solubility promoter with the difference of embodiment 1,3,5, and as can be seen, its purity and yield all have obvious reduction.
The preparation of Comparative Examples 2 thunder Buddhist nuns acid tetra-ethyl ester
In the 100L enamel reaction still, add 22.9kg intermediate compound I, 30.0kg acetone, 28.8kg ethyl bromoacetate, 19.8kg Anhydrous potassium carbonate and the 0.5kg Adogen 464 for preparing by method among the embodiment 1 successively
R, after the stirring at room, heat up, maintain the temperature at 60 ℃ of following backflow 5h, the reaction solution color gradually becomes red by golden yellow.Reaction finishes, and (employing TLC detects to judge whether reaction reaches home in the back, developping agent: ethyl acetate is mixed with the volume ratio of 1:4 with chloroform), be cooled to room temperature, remove by filter salt of wormwood, filtrate is evaporated to dried under 45 ℃, get brown oil, the ethanol stirring and dissolving that adds 180.0kg 95% volume percent, behind the heat filtering, the crystallization of lowering the temperature naturally, room temperature growing the grain 3.5 hours, filter and collect filter cake, drying obtains thunder Buddhist nun acid tetra-ethyl ester 32.1kg, and purity is 96.05%, and the total recovery of thunder Buddhist nun acid tetra-ethyl ester is that 65%(is in the Bing Tongersuosuan diethyl ester).
Comparative Examples 2 is to adopt Adogen 464 with the difference of embodiment 2,4,6
RAs catalyzer, as can be seen, its purity and total recovery all have obvious reduction, and the reaction times significantly increases.
The contriver carries out the effect experiment with the catalyzer of reporting in the prior art, and the result is as shown in table 2.As known from Table 2, the used catalyzer (potassiumiodide or sodium iodide) of the present invention can shorten the reaction times more significantly, and the purity of prepared thunder Buddhist nun acid tetra-ethyl ester is higher.
Table 2 different catalysts is to the preparation time of thunder Buddhist nun acid tetra-ethyl ester and the influence of purity
| Catalyzer | Preparation time | Thunder Buddhist nun acid tetra-ethyl ester purity |
| Adogen?464 R | 5h | 96.05% |
| Aliquat?336 R | 4h | 95.32% |
| Crown ether or KF/Al 2O 3 | 10h | 95.00%～98.00% |
| Polyoxyethylene glycol | 6～8h | 96.00%～98.00% |
| Ionic liquid | 10～14h | 96.00%～98.00% |
| Potassiumiodide | 1.5h | >99.6% |
| Sodium iodide | 2h | >99.6% |
Above content be in conjunction with concrete preferred implementation to further describing that the present invention does, can not assert that concrete enforcement of the present invention is confined to these explanations.For the general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, can also make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
Claims (11)
1. 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-and the preparation method of 2-thiophene ethyl formate, it is characterized in that: may further comprise the steps:
A) Bing Tongersuosuan diethyl ester and propane dinitrile react in the presence of acid binding agent and ethanol and generate active intermediate;
B) add ammonium sulfide as solubility promoter after, described active intermediate under alcohol reflux with sulphur generation cyclization, the cooling crystallization filters and collects filter cake, obtains 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-the 2-thiophene ethyl formate.
2. 5-amino according to claim 1-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-and the preparation method of 2-thiophene ethyl formate, it is characterized in that: the consumption of described ammonium sulfide is the 2.0-7.5% of described sulphur quality.
3. 5-amino according to claim 1 and 2-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-and the preparation method of 2-thiophene ethyl formate, it is characterized in that: the consumption of described ammonium sulfide is the 4.0-5.5% of described sulphur quality.
4. 5-amino according to claim 1 and 2-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-and the preparation method of 2-thiophene ethyl formate, it is characterized in that: described acid binding agent is diethylamine.
5. the preparation method of high purity thunder Buddhist nun acid tetra-ethyl ester is characterized in that: may further comprise the steps:
A) Bing Tongersuosuan diethyl ester and propane dinitrile react in the presence of acid binding agent and ethanol and generate active intermediate;
B) add ammonium sulfide as solubility promoter after, described active intermediate under alcohol reflux with sulphur generation cyclization, the cooling crystallization filters and collects filter cake, obtains 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-the 2-thiophene ethyl formate;
C) described 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-the 2-thiophene ethyl formate is in the presence of salt of wormwood and catalyzer, under organic solvent refluxes with hydrocarbonylation reagent generation substitution reaction, cooled and filtered, filtrate decompression concentrates removes organic solvent, it is refining to add recrystallization solvent, filter and collect filter cake, be drying to obtain thunder Buddhist nun acid tetra-ethyl ester.
6. the preparation method of high purity thunder Buddhist nun according to claim 5 acid tetra-ethyl ester, it is characterized in that: the consumption of described ammonium sulfide is 2.0-7.5% of described sulphur quality.
7. the preparation method of high purity thunder Buddhist nun according to claim 5 acid tetra-ethyl ester, it is characterized in that: the consumption of described ammonium sulfide is the 4.0-5.5% of described sulphur quality.
8. according to the preparation method of each described high purity thunder Buddhist nun acid tetra-ethyl ester in the claim 5 to 7, it is characterized in that: described catalyzer adopts potassiumiodide or sodium iodide.
9. according to the preparation method of each described high purity thunder Buddhist nun acid tetra-ethyl ester in the claim 5 to 8, it is characterized in that: described catalyst consumption is the 1-5% of described Bing Tongersuosuan diethyl ester quality.
10. according to the preparation method of each described high purity thunder Buddhist nun acid tetra-ethyl ester in the claim 5 to 8, it is characterized in that: described catalyst consumption is the 2-3.5% of described Bing Tongersuosuan diethyl ester quality.
11. according to the preparation method of each described high purity thunder Buddhist nun acid tetra-ethyl ester in the claim 5 to 8, it is characterized in that: described acid binding agent is diethylamine; Described organic solvent is selected from acetone or acetonitrile; Described hydrocarbonylation reagent is selected from ethyl chloroacetate or ethyl bromoacetate; Described recrystallization solvent is selected from methyl alcohol, ethanol or the Virahol of 95% volume percent.
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| CN109962292A (en) * | 2019-01-31 | 2019-07-02 | 合肥工业大学 | A kind of lithium-ion battery electrolytes and the lithium ion battery comprising it |
| CN110105622A (en) * | 2019-04-29 | 2019-08-09 | 广州湘环新材料有限公司 | A kind of high-performance composite thermal stabilizer |
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| CN1500783A (en) * | 2002-09-24 | 2004-06-02 | ɪά��ʵ���� | New process for the industrial synthesis of the tetraesters of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylicacid, and application to the synthesis ofbivalent salts of ranel |
| CN101665483A (en) * | 2008-09-01 | 2010-03-10 | 河北医科大学 | Environmentally-friendly synthesis method for strontium ranelate intermediate compound II |
| WO2011124992A1 (en) * | 2010-03-24 | 2011-10-13 | Actavis Group Ptc Ehf | Substantially pure strontium ranelate |
| CN102180864A (en) * | 2011-03-28 | 2011-09-14 | 中国药科大学 | Preparation method of strontium ranelate |
| CN102321068A (en) * | 2011-08-01 | 2012-01-18 | 山东铂源化学有限公司 | Method for preparing strontium ranelate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109962292A (en) * | 2019-01-31 | 2019-07-02 | 合肥工业大学 | A kind of lithium-ion battery electrolytes and the lithium ion battery comprising it |
| CN109962292B (en) * | 2019-01-31 | 2021-03-12 | 合肥工业大学 | Lithium ion battery electrolyte and lithium ion battery comprising same |
| CN110105622A (en) * | 2019-04-29 | 2019-08-09 | 广州湘环新材料有限公司 | A kind of high-performance composite thermal stabilizer |
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| CN103319454B (en) | 2014-06-18 |
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