CN103319454B - 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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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- UJPLQWOIPCSWCI-UHFFFAOYSA-N ethyl 5-[bis(2-ethoxy-2-oxoethyl)amino]-4-cyano-3-(2-ethoxy-2-oxoethyl)thiophene-2-carboxylate Chemical compound CCOC(=O)CN(CC(=O)OCC)C=1SC(C(=O)OCC)=C(CC(=O)OCC)C=1C#N UJPLQWOIPCSWCI-UHFFFAOYSA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 56
- UYJXRRSPUVSSMN-UHFFFAOYSA-P ammonium sulfide Chemical compound [NH4+].[NH4+].[S-2] UYJXRRSPUVSSMN-UHFFFAOYSA-P 0.000 claims abstract description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000005864 Sulphur Substances 0.000 claims abstract description 16
- ZSANYRMTSBBUCA-UHFFFAOYSA-N diethyl 3-oxopentanedioate Chemical compound CCOC(=O)CC(=O)CC(=O)OCC ZSANYRMTSBBUCA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000010992 reflux Methods 0.000 claims abstract description 15
- 239000012065 filter cake Substances 0.000 claims abstract description 14
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 58
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 30
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 235000007715 potassium iodide Nutrition 0.000 claims description 10
- 229960004839 potassium iodide Drugs 0.000 claims description 10
- 238000007670 refining Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 9
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 235000009518 sodium iodide Nutrition 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 235000015320 potassium carbonate Nutrition 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical group CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 abstract description 8
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000006184 cosolvent Substances 0.000 abstract 1
- 239000013078 crystal Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000000034 method Methods 0.000 description 14
- XXUZFRDUEGQHOV-UHFFFAOYSA-J strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 description 13
- 229940079488 strontium ranelate Drugs 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- 230000035484 reaction time Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 210000003298 dental enamel Anatomy 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 4
- JJNZXLAFIPKXIG-UHFFFAOYSA-N 2-Chlorobenzylidenemalononitrile Chemical compound ClC1=CC=CC=C1C=C(C#N)C#N JJNZXLAFIPKXIG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000003983 crown ethers Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 239000002608 ionic liquid Substances 0.000 description 3
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 3
- -1 polyoxyethylene Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052593 corundum Inorganic materials 0.000 description 2
- 230000006353 environmental stress Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 2
- 229940006461 iodide ion Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229910001845 yogo sapphire Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010020100 Hip fracture Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000004900 laundering Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 206010041569 spinal fracture Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 229910001631 strontium chloride Inorganic materials 0.000 description 1
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 description 1
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 description 1
- 229910001866 strontium hydroxide Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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 pharmacy field, be specifically related to the preparation method of a kind of thunder Buddhist nun acid tetra-ethyl ester and intermediate thereof.
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.
The method of 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 is hydrolyzed 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.
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 thunder Buddhist nun acid tetra-ethyl ester is provided.Contriver, having carried 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 complete the present invention.
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.
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, 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;
B) after adding ammonium sulfide as solubility promoter, described active intermediate under alcohol reflux with sulphur generation cyclization, cooling crystallization, filter collect filter cake, obtain 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-2-thiophene ethyl formate.
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 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 generating the reaction of intermediate I and finishing, can ammonium sulfide be removed by filtering, thereby improve the quality product of intermediate I, the intermediate I purity of acquisition is high, can be directly used in and prepare 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, 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;
B) after adding ammonium sulfide as solubility promoter, described active intermediate under alcohol reflux with sulphur generation cyclization, cooling crystallization, filter collect filter cake, obtain 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-2-thiophene ethyl formate;
C) described 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-2-thiophene ethyl formate is under salt of wormwood and catalyzer exist, organic solvent reflux under 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.
The present invention realizes by following technological line:
Described catalyzer adopts potassiumiodide or sodium iodide.Consumption is little, and Reaction time shorten has more significantly 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, as catalyzer, through the recrystallization of 95% alcoholic solution, are removed along with filtrate when filtration.
Described catalyst levels is the 1-5% of described β-ketoglutaric acid diethyl ester quality, is preferably 2-3.5%, more preferably 2.5%.In the substitution reaction of generation thunder Buddhist nun acid tetra-ethyl ester, use cheap catalyst potassiumiodide or sodium iodide, can make the reaction times foreshorten to 1.5～2.0h, visible potassiumiodide or sodium iodide have good katalysis to substitution reaction.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.
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.
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.
Preparation method provided by the invention is simple, quick, reaction conditions gentleness, avoid repeatedly refining process, reduce production cost, environmental benefit is good, the thunder Buddhist nun acid tetra-ethyl ester purity making is high, is applicable to industrial amplification production, meets medicinal requirements take the thunder Buddhist nun acid tetra-ethyl ester of this purity as the Strontium Ranelate quality that intermediate prepares.
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.
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.
Embodiment 3
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% |
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 thunder Buddhist nun acid tetra-ethyl ester, 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;
B) after adding ammonium sulfide as solubility promoter, described active intermediate under alcohol reflux with sulphur generation cyclization, cooling crystallization, filter collect filter cake, obtain 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-2-thiophene ethyl formate;
C) described 5-amino-4-cyano group-3-(2-oxyethyl group-2-carboxymethyl)-2-thiophene ethyl formate is under salt of wormwood and catalyzer exist; organic solvent reflux under 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 adopts potassiumiodide or sodium iodide.
2. the preparation method of high purity thunder Buddhist nun acid tetra-ethyl ester according to claim 1, is characterized in that: the consumption of described ammonium sulfide is 2.0-7.5% of described sulphur quality.
3. the preparation method of high purity thunder Buddhist nun acid tetra-ethyl ester according to claim 1, is characterized in that: the consumption of described ammonium sulfide is the 4.0-5.5% of described sulphur quality.
4. according to the preparation method of the high purity thunder Buddhist nun acid tetra-ethyl ester described in any one in claims 1 to 3, it is characterized in that: the consumption of described catalyzer is the 1-5% of described β-ketoglutaric acid diethyl ester quality.
5. according to the preparation method of the high purity thunder Buddhist nun acid tetra-ethyl ester described in any one in claims 1 to 3, it is characterized in that: the consumption of described catalyzer is the 2-3.5% of described β-ketoglutaric acid diethyl ester quality.
6. according to the preparation method of the high purity thunder Buddhist nun acid tetra-ethyl ester described in any one in claims 1 to 3, 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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| CN102180864A (en) * | 2011-03-28 | 2011-09-14 | 中国药科大学 | Preparation method of strontium ranelate |
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