CN103319455B - Preparation method of high-purity strontium ranelate - Google Patents
Preparation method of high-purity strontium ranelate Download PDFInfo
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Abstract
The invention relates to a preparation method of high-purity strontium ranelate. 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 after a cosolvent is added, carrying out cyclization reaction on the active intermediate and sulphur under the reflux of ethanol to prepare 5-amino-4-cyano-3-(2-ethyoxyl-2-carboxymethyl)-thiophene-2-ethyl formate, i.e., an intermediate I; (b) reacting the intermediate I with a hydrocarbonylation reagent in the presence of potassium carbonate and a catalyst to prepare tetraethyl ranelate; and (c) hydrolyzing the tetraethyl ranelate in an alkali metal hydroxide solution to generate salt, adding an insoluble organic solvent to wash impurities, decoloring by using active carbon, filtering, forming strontium salt, and adjusting the pH value of the solution to obtain the strontium ranelate. The strontium ranelate prepared by the invention is high in purity, good in stability and capable of meeting the requirement of bulk drugs for purity, content and strontium content; the preparation process is low in three-waste emission and low in cost.
Description
Technical field
The invention belongs to the technical field of medicine synthesis in pharmacy field, be specifically related to a kind of preparation method of high purity Strontium Ranelate.
Background technology
Strontium in Strontium Ranelate is the important component part of skeleton, can promote the growth of bone and the formation of osteoid, and has the effect that regulates calcium metabolism.Strontium Ranelate clinical data shows: this medicine is specially adapted to the osteoporosis after treatment and prevention postmenopausal women, significantly reduces the danger that vertebral fracture and hip fracture occur, and has good clinical effectiveness.
Two kinds of methods preparing at present Strontium Ranelate all adopt 5-[bis-(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, one method is, thunder Buddhist nun acid tetra-ethyl ester hydrolysis salifying in sodium hydroxide or potassium hydroxide solution, then react with strontium chloride and turn salt generation Strontium Ranelate; Another kind method is directly hydrolysis salifying 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 preparing Strontium Ranelate.Strontium Ranelate is water-soluble hardly, 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, thunder Buddhist nun acid tetra-ethyl ester prepared by prior art just can be used for preparing Strontium Ranelate after need to refining under boiling water condition, and refining effect is often not good enough, makes strontium ranelate raw material medicine complicated process of preparation, cost costliness.
The common method that bibliographical information is prepared thunder Buddhist nun acid tetra-ethyl ester is that β-ketoglutaric acid 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)-2-thiophene ethyl formate, it is intermediate compound I, intermediate compound I is made solvent with acetone again and under salt of wormwood is made acid binding agent, is reacted acquisition with hydrocarbonylation reagent, and its synthetic route is:
Document Chem Ber, 1966,99:94-99 is take morpholine as acid binding agent, and more than reaction 3h, the reaction yield of intermediate I only has 42.0%, and because morpholine toxicity is large, in production, a large amount of uses are easily caused danger and environment is also being formed to potential threat.
Document Journal of Chemical Technology and Biotechnology, 1990,47:39-46 uses diethylamine to replace morpholine, although 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 water instead of ethanol make solvent, although a large amount of sodium sulphite (consumption be sulphur quality 28.1%) can increase the solubleness of sulphur in water, make to a certain extent reaction accelerate, but because the organism in reaction is poorly soluble in water, reaction is carried out in water-organic biphasic, and reaction is uneven, causes overall reaction rate to reduce; In addition, due to intermediate compound I poorly water-soluble, crystallization immediately after reaction generates, easily wraps up a large amount of inorganic salt, and when filtration, massive laundering is washed and is also difficult to remove completely, has reduced the quality of product, and the meeting of water washing simultaneously produces a large amount of waste water.Therefore, aforesaid method is prepared intermediate compound I and is all had long reaction time (more than 3h), the large 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 reflux conditions react with intermediate compound I the method that 48h prepares thunder Buddhist nun acid tetra-ethyl ester above, but this method yield only has 65.0%, need after completion of the reaction to consume a large amount of water dilution organic solvents and separate thunder Buddhist nun acid tetra-ethyl ester, produce a large amount of alkaline waste waters.
Chinese patent CN1496986, CN100391955, CN102180864 and CN101665483, by adding catalyzer to improve preparation method, have reported respectively the method for preparing 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 as catalyzer.The use of above-mentioned catalyzer, can accelerate speed of reaction, and the reaction times is foreshortened in 15h, but the purity of gained thunder Buddhist nun acid tetra-ethyl ester all≤98.0%, single impurity >=0.5%; Also be difficult to make quality product meet medicinal requirements through repeatedly refining take the thunder Buddhist nun acid tetra-ethyl ester of this purity as the Strontium Ranelate that intermediate prepares.In addition, the alkyl chain of C8-C10 type quaternary ammonium salt is longer, sterically hindered large, cause catalytic efficiency low, C8-C10 type quaternary ammonium salt has satisfactory stability and strong sterilization idiocratic simultaneously, can, to the production by biological toxigenicity in environment, affect the metabolism of all kinds of materials in environment, there is very important environmental risk; And adopt polyoxyethylene glycol to make catalyzer, and aftertreatment need make to be extracted with ethyl acetate, 80.0% ethanol boils making beating, a large amount of boiling water washing leaching cake, can produce a large amount of waste liquids, and environmental stress is large; Adopt crown ether or KF/Al2O3, ionic liquid to make catalyzer and all have expensive shortcoming, thereby limited its industrial applications.
Bibliographical information is with purity≤99.0%, the low-purity thunder Buddhist nun acid tetra-ethyl ester of single impurity >=0.5% is raw material, employing method one is prepared Strontium Ranelate, the step that increases concentrated organic solvent after sodium salt need be hydrolyzed into, can improve to a certain extent the yield of Strontium Ranelate, but concentration of lye raises along with the minimizing of solvent, be conducive to the generation of side reaction, thermally labile dopant species is increased.In the time of intensification concentrated solvent, concentration of lye increases, if temperature >=40 ℃, 5-decarboxylation impurity (be two (carboxymethyl) amino of 2-[]-3-cyano group-4-thiophene acetic acid sodium salt) obviously increase of amount, cause technique to be amplified to product purity≤99.0% after pilot scale, single impurity >=0.5%, cannot meet the requirement of medicinal chemicals to purity, adopt method two to prepare Strontium Ranelate, need refine or washing leaching cake with boiling water or the organic solvent-water mixture boiling, on the one hand because the solubleness of strontium hydroxide in boiling water is also less, in the product of gained, can comprise strontium hydroxide solid, cause product content of strontium higher than Strontium Ranelate theoretical value, product content≤98.0%, cannot meet the requirement of medicinal chemicals to content, excess Temperature is also conducive to the generation of 5-decarboxylation impurity (be two (carboxymethyl) amino of 2-[]-3-cyano group-4-thiophene acetic acid strontium salt) on the other hand, can produce a large amount of waste liquids simultaneously, bring environmental risk.
Summary of the invention
The object of the invention is to overcome the above-mentioned weak point of prior art, a kind of preparation method of new high purity Strontium Ranelate is provided.The method, by adding ammonium sulfide as solubility promoter, can significantly improve speed of reaction, and improves reaction yield and the quality product of intermediate I; By adding potassiumiodide or sodium iodide as catalyzer, Reaction time shorten more significantly, has reduced the generation of side reaction, and improves reaction yield and the quality product of thunder Buddhist nun acid tetra-ethyl ester; By adding the organic impurity in water-insoluble organic solvents washing thunder Buddhist nun acid sodium-salt solution, can avoid heating up concentrates the process of organic solvent, has improved reaction yield and the quality product of Strontium Ranelate.
Object of the present invention will be further described in detail below reflect and description.
In the present invention, intermediate I refers to 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-2-thiophene ethyl formate.
The preparation method who the invention provides a kind of high purity Strontium Ranelate, comprises the following steps:
A) reaction under acid binding agent and ethanol existence of β-ketoglutaric acid diethyl ester and propane dinitrile generates active intermediate, after adding ammonium sulfide as solubility promoter, described active intermediate generates 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl with sulphur generation cyclization under alcohol reflux)-2-thiophene ethyl formate, cooling crystallization, filter and collect filter cake, obtain intermediate compound I;
B) described intermediate compound I is under salt of wormwood and catalyzer exist, under organic solvent refluxes with hydrocarbonylation reagent generation substitution reaction, cooled and filtered, the concentrated organic solvent of removing of filtrate decompression, add recrystallization solvent refining, filter and collect filter cake, be drying to obtain thunder Buddhist nun acid tetra-ethyl ester;
C) described thunder Buddhist nun acid tetra-ethyl ester hydrolysis salifying in alkali hydroxide soln, adds water-insoluble organic solvents washing impurity, the phase of fetching water after layering, add activated carbon decolorizing, filter, in filtrate, add strontium chloride to become strontium salt, adjust pH, filter and obtain Strontium Ranelate.
The present invention realizes by following technological line:
In the cyclization of generation intermediate I, contriver has utilized ammonium sulfide to be dissolved in the character of ethanol dexterously, discovery adds a small amount of ammonium sulfide can increase the solubleness of sulphur in ethanol as solubility promoter, reaction is carried out in homogeneous phase, being conducive to reaction carries out to positive dirction, make the reaction times foreshorten to 1.0h by the 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, after finishing, the reaction of generation intermediate I can ammonium sulfide be removed by filtering, thereby improved the quality product of intermediate I, the intermediate I purity of acquisition is high, can be directly used in step and prepares thunder Buddhist nun acid tetra-ethyl ester in b).
The consumption of described ammonium sulfide is the 2-7.5% of described sulphur quality, is preferably 4.0%-5.5%, most preferably is 5%.
Described in the substitution reaction of generation thunder Buddhist nun acid tetra-ethyl ester, catalyzer is potassiumiodide or sodium iodide, its consumption is the 1-5% of described β-ketoglutaric acid diethyl ester quality, be that every 1g β-ketoglutaric acid diethyl ester reactant needs 10-50mg catalyzer, more preferably 2-3.5%, most preferably is 2.5%.Use catalyzer iodate potassium or sodium iodide, substitution reaction is had to good katalysis.Iodide ion is strong nucleophilic group, is again strong leavings group, and in reaction process, iodide ion and hydrocarbonylation reagent react generate iodacetyl ethyl acetate, are conducive to the attack of the N atom pairs C-I key of primary amine, accelerated reaction, the purity of raising product.Reaction time shorten to 1.5～2.0h 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 there is cheap advantage.Potassiumiodide or sodium iodide can, through the recrystallization of 95% alcoholic solution, be removed along with filtrate when filtration simultaneously.
Described water-insoluble organic solvents adopts methylene dichloride.Contriver studies discovery by experiment: add water-insoluble organic solvents, organic impurity in solubilized thunder Buddhist nun acid sodium-salt solution, the aqueous solution layering that easy and thunder Buddhist nun acid tetra-ethyl ester contains ethanol after being hydrolyzed again, thereby avoid the generation of " emulsification ", can remove organic impurity by separatory, effectively having avoided heats up concentrates the process of organic solvent, has improved reaction yield and the quality product of thunder Buddhist nun acid sodium-salt, and then has improved reaction yield and the quality product of Strontium Ranelate.
Contriver investigates ethyl acetate, butylacetate, methylene dichloride, toluene, these several conventional organic solvents of hexone, result is as shown in table 1: washing effect the best of methylene dichloride, in the time being in batches amplified to 100g/ and criticizing, not there is not " emulsification ", very easily layering, the purity of target product is high, and mass yield is high; When industrial scale is amplified to 25.0kg/ and criticizes, use methylene dichloride to wash, also there will not be " emulsification " phenomenon of extremely difficult layering, when having improved target product purity and yield, greatly reduce the generation of waste liquid, environmental benefit is good, and industrial applications prospect is good.
Table 1 different solvents washs the impact on Strontium Ranelate quality
Described acid binding agent is diethylamine; Described step a) the middle collection filter cake that filters also can comprise the step that adds recrystallization solvent refining; Described recrystallization solvent is methyl alcohol, ethanol or the Virahol of 95% volume percent.
Described organic solvent is selected from acetone or acetonitrile; Described hydrocarbonylation reagent is selected from ethyl chloroacetate or ethyl bromoacetate.
Described step c) in, hydrolysis temperature is 35～40 ℃, is preferably 36～38 ℃; Becoming strontium salt temperature is 15～25 ℃, is preferably 17～20 ℃; Adjust pH to 7.5～8.0.
Contriver experimental studies have found that the temperature of reaction that is hydrolyzed into sodium salt: temperature is during lower than 35 ℃, and thunder Buddhist nun acid tetra-ethyl ester hydrolysis rate is slower, and impurity level increases; Temperature of reaction is during higher than 40 ℃, and thunder Buddhist nun acid tetra-ethyl ester hydrolysis rate is fast, and the reaction times foreshortens in 1h, but is difficult to carry out intermediate process control, and impurity level increases, and particularly 5-decarboxylation impurity obviously increases; Temperature is hydrolyzed into sodium salt while being 35～40 ℃, in taking into account the reaction times, can effectively reduce the generation (especially 5-decarboxylation impurity) to thermally labile impurity, has improved the purity of thunder Buddhist nun acid sodium-salt, and then has improved the purity of Strontium Ranelate.
Contriver experimental studies have found that the temperature of reaction that becomes strontium salt: temperature of reaction is during lower than 15 ℃, becomes the sad filter of solidliquid mixture after strontium salt, and filter cake water-content is high, is unfavorable for the dry of product; Temperature of reaction is during higher than 25 ℃, and side reaction increases, and causes impurity level to increase; 15～25 ℃ time, turn strontium reactant salt and can effectively avoid the generation of 5-decarboxylation impurity, improved the purity of Strontium Ranelate.
Described alkali metal hydroxide is selected from sodium hydroxide or potassium hydroxide.
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, purity >=99.6% of intermediate I, single impurity≤0.1%, can be directly used in and prepare 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, Reaction time shorten significantly, and purity >=99.6% of prepared thunder Buddhist nun acid tetra-ethyl ester, single impurity≤0.1%, and there is cheap advantage.By adding the organic impurity in water-insoluble organic solvents washing thunder Buddhist nun acid sodium-salt solution, can avoid heating up concentrates the process of organic solvent, has improved reaction yield and the quality product of Strontium Ranelate.
Preparation method provided by the invention is simple, fast, reaction conditions gentleness, has avoided repeatedly refining process, reduced production cost, environmental benefit is good, Strontium Ranelate purity >=99.6% making, single impurity≤0.05%, mass yield is stabilized between 100.0%～110.0%.
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 conventional.
Accompanying drawing explanation
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.
Fig. 3 is the HPLC figure of Strontium Ranelate related substance.
Embodiment
Below in conjunction with accompanying drawing and embodiment, the present invention is described in further detail, these specific embodiments, only 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 100L enamel reaction still, add 20.0kg β-ketoglutaric acid diethyl ester, 6.6kg propane dinitrile, 3.2kg sulphur, 40.0kg ethanol, add again the ammonium sulfide of 0.16kg, under water-bath is cooling, slowly stream adds 10.0kg diethylamine, after stream adds, material in reactor is warming up to the lower reaction 1.0h that refluxes, (adopt TLC to detect to judge whether reaction reaches home after completion of the reaction, 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, add the ethanol of 95% volume percent refining, filter, the dry intermediate I 22.9kg that obtains, purity is 99.86%, yield is 82.1%.
The HPLC of the intermediate compound I that the present embodiment makes schemes as shown in Figure 1.
The preparation of embodiment 2 thunder Buddhist nun acid tetra-ethyl esters
In 100L enamel reaction still, add successively the 22.9kg intermediate compound I, 30.0kg acetone, 28.8kg ethyl bromoacetate, 19.8kg Anhydrous potassium carbonate and the 0.5kg potassiumiodide fine powder that prepare by method in embodiment 1, after stirring at room temperature, heat up, maintain the temperature at the 1.5h that refluxes at 60 ℃, reaction solution color gradually becomes red by golden yellow.(adopt TLC to detect to judge whether reaction reaches home after completion of the reaction, 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 dry at 45 ℃, obtain brown oil, add the ethanol stirring and dissolving of 180.0kg 95% volume percent, after heat filtering, naturally cooling crystallization, room temperature growing the grain 2h, filter and collect filter cake, the dry thunder Buddhist nun acid tetra-ethyl ester 32.1kg that obtains, 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 β-ketoglutaric acid diethyl ester).
The HPLC of the thunder Buddhist nun acid tetra-ethyl ester that the present embodiment makes schemes as shown in Figure 2.
The preparation of intermediate I
In 100L enamel reaction still, add 20.0kg β-ketoglutaric acid diethyl ester, 6.6kg propane dinitrile, 3.2kg sulphur, 40.0kg ethanol, add again the ammonium sulfide of 0.096kg, under water-bath is cooling, slowly stream adds 10.0kg diethylamine, after stream adds, material in reactor is warming up to the lower reaction 1.0h that refluxes, (adopt TLC to detect to judge whether reaction reaches home after completion of the reaction, 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, add the ethanol of 95% volume percent refining, filter, the dry intermediate I 22.9kg that obtains, purity is 99.69%, yield is 81.9%.
The preparation of embodiment 4 thunder Buddhist nun acid tetra-ethyl esters
In 100L enamel reaction still, add successively the 22.9kg intermediate compound I, 30.0kg acetone, 28.8kg ethyl bromoacetate, 19.8kg Anhydrous potassium carbonate and the 0.4kg potassiumiodide fine powder that prepare by method in embodiment 3, after stirring at room temperature, heat up, maintain the temperature at the 1.5h that refluxes at 60 ℃, reaction solution color gradually becomes red by golden yellow.(adopt TLC to detect to judge whether reaction reaches home after completion of the reaction, 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 dry at 45 ℃, obtain brown oil, add the ethanol stirring and dissolving of 180.0kg 95% volume percent, after heat filtering, naturally cooling crystallization, room temperature growing the grain 2 hours, filter and collect filter cake, the dry thunder Buddhist nun acid tetra-ethyl ester 32.1kg that obtains, 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 β-ketoglutaric acid diethyl ester).
The preparation of intermediate I
In 100L enamel reaction still, add 20.0kg β-ketoglutaric acid diethyl ester, 6.6kg propane dinitrile, 3.2kg sulphur, 40.0kg ethanol, add again the ammonium sulfide of 0.176kg, under water-bath is cooling, slowly stream adds 10.0kg diethylamine, after stream adds, material in reactor is warming up to the lower reaction 1.0h that refluxes, (adopt TLC to detect to judge whether reaction reaches home after completion of the reaction, 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, add the ethanol of 95% volume percent refining, filter, the dry intermediate I 22.9kg that obtains, purity is 99.73%, yield is 82.0%.
The preparation of embodiment 6 thunder Buddhist nun acid tetra-ethyl esters
In 100L enamel reaction still, add successively the 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 that prepare by method in embodiment 5, after stirring at room temperature, heat up, maintain the temperature at the 2h that refluxes at 60 ℃, reaction solution color gradually becomes red by golden yellow.(adopt TLC to detect to judge whether reaction reaches home after completion of the reaction, 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 dry at 45 ℃, obtain brown oil, add the ethanol stirring and dissolving of 180.0kg 95% volume percent, after heat filtering, naturally cooling crystallization, room temperature growing the grain 2.5 hours, filter and collect filter cake, the dry thunder Buddhist nun acid tetra-ethyl ester 32.1kg that obtains, 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 β-ketoglutaric acid diethyl ester).
Comparative example 1:
The preparation of intermediate I
In 100L enamel reaction still, add 20.0kg β-ketoglutaric acid diethyl ester, 6.6kg propane dinitrile, 3.2kg sulphur, 40.0kg ethanol, under water-bath is cooling, slowly stream adds 10.0kg diethylamine, after stream adds, material in reactor is warming up to the lower reaction 1.0h that refluxes, (adopt TLC to detect to judge whether reaction reaches home after completion of the reaction, 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, add the ethanol of 95% volume percent refining, filter, the dry intermediate I 22.9kg that obtains, purity is 97%, yield is 75.0%.
Comparative example 1 is not add ammonium sulfide as solubility promoter with the difference of embodiment 1,3,5, can find out, its purity and yield all have obvious reduction.
The preparation of comparative example 2 thunder Buddhist nun acid tetra-ethyl esters
In 100L enamel reaction still, add successively the 22.9kg intermediate compound I, 30.0kg acetone, 28.8kg ethyl bromoacetate, 19.8kg Anhydrous potassium carbonate and the 0.5kg Adogen 464 that prepare by method in embodiment 1
r, after stirring at room temperature, heat up, maintain the temperature at the 5h that refluxes at 60 ℃, reaction solution color gradually becomes red by golden yellow.(adopt TLC to detect to judge whether reaction reaches home after completion of the reaction, 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 dry at 45 ℃, obtain brown oil, add the ethanol stirring and dissolving of 180.0kg 95% volume percent, after heat filtering, naturally cooling crystallization, room temperature growing the grain 3.5 hours, filter and collect filter cake, the dry thunder Buddhist nun acid tetra-ethyl ester 32.1kg that obtains, purity is 96.05%, the total recovery of thunder Buddhist nun acid tetra-ethyl ester is that 65%(is in β-ketoglutaric acid diethyl ester).
Comparative example 2 is to adopt Adogen 464 with the difference of embodiment 2,4,6
ras catalyzer, can find out, its purity and total recovery all have obvious reduction, and the reaction times significantly increases.
The catalyzer of reporting in prior art is carried out effect experiment by contriver, and result is as shown in table 2.As known from Table 2, catalyzer (potassiumiodide or the sodium iodide) Reaction time shorten more significantly that the present invention is used, the purity of prepared thunder Buddhist nun acid tetra-ethyl ester is higher.
Table 2 different catalysts is on the thunder Buddhist nun acid preparation time of tetra-ethyl ester and the impact 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% |
The preparation of embodiment 7 Strontium Ranelates
Getting thunder Buddhist nun acid tetra-ethyl ester, the 60mL water that 100.0g prepares by method in embodiment 2 puts in three mouthfuls of reaction flasks, stream hydro-oxidation sodium water solution (8.8g sodium hydroxide and the preparation of 400mL water), control 38 ℃ of reaction 1.5h of temperature, add 100mL washed with dichloromethane, stratification, water intaking phase; In water, add 2.5g activated carbon decolorizing 0.5h, accurate filter filters, and filtrate becomes strontium salt in 18 ℃ of water-soluble 200mL aqueous solution that obtain of the dirty 117.2g of adding strontium chloride, and 1mol/L dilute hydrochloric acid regulates reaction solution pH=7.5～8.0, growing the grain 2h, filter, filter cake, in 30 ℃ of vacuum-drying 12h, obtains 108.0g Strontium Ranelate, mass yield 108.0%, purity 99.74%, single impurity≤0.05%, content 99.91%.
The HPLC of the Strontium Ranelate that the present embodiment makes schemes as shown in Figure 3.
The preparation of embodiment 8 Strontium Ranelates
Getting thunder Buddhist nun acid tetra-ethyl ester, the 60mL water that 100.0g prepares by method in embodiment 2 puts in three mouthfuls of reaction flasks, stream hydro-oxidation sodium water solution (8.8g sodium hydroxide and the preparation of 400mL water), control 35 ℃ of reaction 1.5h of temperature, add 100mL washed with dichloromethane, stratification, water intaking phase; In water, add 2.5g activated carbon decolorizing 0.5h, accurate filter filters, and filtrate becomes strontium salt in 20 ℃ of water-soluble 200mL aqueous solution that obtain of the dirty 117.2g of adding strontium chloride, and 1mol/L dilute hydrochloric acid regulates reaction solution pH=7.5～8.0, growing the grain 2h, filter, filter cake, in 30 ℃ of vacuum-drying 12h, obtains 105.0g Strontium Ranelate, mass yield 105.0%, purity 99.66%, single impurity≤0.05%, content 99.73%.
The preparation of embodiment 9 Strontium Ranelates
Getting thunder Buddhist nun acid tetra-ethyl ester, the 60mL water that 100.0g prepares by method in embodiment 6 puts in three mouthfuls of reaction flasks, stream hydro-oxidation sodium water solution (8.8g sodium hydroxide and the preparation of 400mL water), control 40 ℃ of reaction 1.5h of temperature, add 100mL washed with dichloromethane, stratification, water intaking phase; In water, add 2.5g activated carbon decolorizing 0.5h, accurate filter filters, and filtrate becomes strontium salt in 17 ℃ of dirty water-soluble 200mL aqueous solution that obtain of 117.2 strontium chlorides that add, and 1mol/L dilute hydrochloric acid regulates reaction solution pH=7.5～8.0, growing the grain 2h, filter, filter cake, in 30 ℃ of vacuum-drying 12h, obtains 110.0g Strontium Ranelate, mass yield 110.0%, purity 99.71%, single impurity≤0.05%, content 101.24%.
Above content is in conjunction with concrete preferred implementation further description made for the present invention, can not assert that specific embodiment of the invention is confined to these explanations.For 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 (1)
1. a preparation method for high purity Strontium Ranelate, is characterized in that: comprise the following steps:
A) reaction under acid binding agent and ethanol existence of β-ketoglutaric acid diethyl ester and propane dinitrile generates active intermediate, after adding ammonium sulfide as solubility promoter, described active intermediate generates 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl with sulphur generation cyclization under alcohol reflux)-2-thiophene ethyl formate, cooling crystallization, filter and collect filter cake, obtain intermediate compound I;
B) described intermediate compound I is under salt of wormwood and catalyzer exist, under organic solvent refluxes with hydrocarbonylation reagent generation substitution reaction, cooled and filtered, the concentrated organic solvent of removing of filtrate decompression, add recrystallization solvent refining, filter and collect filter cake, be drying to obtain thunder Buddhist nun acid tetra-ethyl ester; Described catalyzer is potassiumiodide or sodium iodide;
C) described thunder Buddhist nun acid tetra-ethyl ester hydrolysis salifying in alkali hydroxide soln, adds water-insoluble organic solvents washing impurity, the phase of fetching water after stratification, add activated carbon decolorizing, filter, in filtrate, add strontium chloride to become strontium salt, adjust pH, filter and obtain Strontium Ranelate.
2. the preparation method of high purity Strontium Ranelate according to claim 1, is characterized in that: the described step a) consumption of middle ammonium sulfide is 2.0-7.5% of described sulphur quality.
3. the preparation method of high purity Strontium Ranelate according to claim 2, is characterized in that: the consumption of described ammonium sulfide is 4.0-5.5% of described sulphur quality.
4. the preparation method of high purity Strontium Ranelate according to claim 1, is characterized in that: the consumption of described catalyzer is the 1-5% of described β-ketoglutaric acid diethyl ester quality.
5. the preparation method of high purity Strontium Ranelate according to claim 4, is characterized in that: the consumption of described catalyzer is the 2-3.5% of described β-ketoglutaric acid diethyl ester quality.
6. the preparation method of high purity Strontium Ranelate according to claim 1, is characterized in that: described water-insoluble organic solvents is methylene dichloride.
7. according to the preparation method of the high purity Strontium Ranelate described in any one in claim 1 to 6, it is characterized in that: described step a) the middle collection filter cake that filters also comprises the step that adds recrystallization solvent refining; Described acid binding agent is diethylamine.
8. according to the preparation method of the high purity Strontium Ranelate described in any one in claim 1 to 6, it is characterized in that: described step b) middle 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.
9. according to the preparation method of the high purity Strontium Ranelate described in any one in claim 1 to 6, it is characterized in that: described step c) in, hydrolysis temperature is 35～40 ℃; Becoming strontium salt temperature is 15～25 ℃; Adjust pH to 7.5～8.0; Described alkali metal hydroxide is selected from sodium hydroxide or potassium hydroxide.
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