CN101863834B - Preparation method of S-carboxymethyl-5,5-diphenyl-2-thiohydantoin - Google Patents
Preparation method of S-carboxymethyl-5,5-diphenyl-2-thiohydantoin Download PDFInfo
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- CN101863834B CN101863834B CN 201010211519 CN201010211519A CN101863834B CN 101863834 B CN101863834 B CN 101863834B CN 201010211519 CN201010211519 CN 201010211519 CN 201010211519 A CN201010211519 A CN 201010211519A CN 101863834 B CN101863834 B CN 101863834B
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- thiohydantoin
- phenylbenzene
- alkali lye
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- acid
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Abstract
The invention belongs to the field of preparation methods of heterocyclic compounds, in particular to a method for synthesizing S-carboxymethyl-5,5-diphenyl-2-thiohydantoin by using 5,5-diphenyl-2-thiohydantoin as starting raw materials. The method sequentially comprises the following steps of:1, reacting chloroacetic acid or bromoacetic acid with alkali liquor under the condition of room temperature stirring to obtain a solution for later use; 2, mixing the 5,5-diphenyl-2-thiohydantoin with the alkali liquor, heating until refluxing under the condition of stirring; and 3, dropping the solution obtained in the step 1 in the step 2, ending the dropping, continuously refluxing for a period of time, stopping heating, and carrying out cooling, diluting, acidizing, separating, drying and alcohol recrystallizing on reaction liquid to obtain a target product. The purity of the pure product is more than 98 percent. The invention has simple and convenient operation, environmental-friendly process, easy obtaining of the raw materials, low cost and high yield, is beneficial to large-scale production, and can meet requirements for high yield and high purity in the fields of chemical industry and medicine.
Description
Technical field
The invention belongs to heterogeneous ring compound preparation method field, relate in particular to a kind ofly with 5,5-phenylbenzene-2-thiohydantoin is a starting raw material, synthetic S-ethyloic-5, the method for 5-phenylbenzene-2-thiohydantoin.
Background technology
Hydantoin-based compound and verivate thereof have pharmacological action widely, mainly show the generation of antibiotic, anti-inflammatory, lowering blood glucose, inhibition uremic toxins, as sodium ion channel blocker etc.Such material also is a kind of excellent prevention and treatment chronic disease and the suitable medicine of taking for a long time; Aspect treatment mellitus, ephrosis and even immunological disease and the hemopathy good application prospects is being arranged all; And as a kind of disinfection sanitizer of wide spectrum, the market outlook of hydantoin-based compound and verivate thereof are boundless.Up to the present, domestic synthetic and clinical application report to glycolylurea and verivate thereof is less, mainly is some external reports.
The present invention relates to prepare S-ethyloic-5, the method for 5-phenylbenzene-2-thiohydantoin.S-ethyloic-5,5-phenylbenzene-2-thiohydantoin are 2-(4,5-dihydro-5-oxygen-4,4-phenylbenzene-1H-imidazoles-2-sulfo-)-acetate again, and molecular formula is C
17H
14N
2O
3S, molecular weight are 326.37, have reported 285 ℃ of fusing points, and structural formula is:
In the compound method of having reported, S-ethyloic-5,5-phenylbenzene-2-thiohydantoin synthetic; With 5,5-phenylbenzene-2-thiohydantoin is a starting raw material, one-step synthesis title product (Phosphorus in ethanol-water solution; Sulfur; And silicon and the related elements, 2007, vol182:529-536).Yield is merely 70% behind the crude product recrystallization, owing to contain other impurity, it is yellow causing product, is difficult to reach the production requirement of medical chemistry article.
Summary of the invention
The present invention is intended to overcome the weak point of prior art and a kind of S-ethyloic-5 is provided, the compound method of 5-phenylbenzene-2-thiohydantoin, and this method operating process is easy, the technology environmental protection, raw material is easy to get, and cost is low, and product purity is high, and productive rate is high.
For achieving the above object, the present invention is achieved in that
A kind of preparation S-ethyloic-5, the method for 5-phenylbenzene-2-thiohydantoin, can carry out successively as follows:
(1) Mono Chloro Acetic Acid or bromoacetic acid and alkali lye are reacted the gained solution for later use under the stirring at room condition;
(2) with 5,5-phenylbenzene-2-thiohydantoin and alkali lye are mixed, under agitation condition, are heated to backflow;
(3) with step (1) gained solution, be added drop-wise in (2), dropwise, continue back flow reaction, stop heating; Reaction solution promptly gets title product through cooling, dilution, acidifying, separation, drying, ethyl alcohol recrystallization.
As a kind of preferred version, in step according to the invention (1) or the step (2), the alkali in the alkali lye is a kind of or its mixture in oxyhydroxide and the carbonate; Solvent in the alkali lye is a kind of or its mixed solvent in water, ethanol, methyl alcohol, n-propyl alcohol, Virahol, the propyl carbinol.
As another kind of preferred version, in the step according to the invention (3), reflux time is 1h～5h.
Further, in the step according to the invention (3), the solvent that dilution step adopts is a water.
Further, in the step according to the invention (3), it is that 1%～35% hydrochloric acid or mass concentration are 1%～35% sulfuric acid that acidification step adopts mass concentration.
In addition, in the step according to the invention (3), the pH value of solution is controlled in 1～3 scope after the acidifying.
Secondly, in the step according to the invention (3), it is that 1%～10% aqueous sodium carbonate or mass concentration are that 1%～10% sodium bicarbonate aqueous solution washing leaching cake is to neutral that water or mass concentration are adopted in sepn process.
Once more, in step according to the invention (1) or the step (2), the volumetric molar concentration of alkali lye is 0.1mol/L～5mol/L.
In the step according to the invention (1), the mol ratio of the alkali in Mono Chloro Acetic Acid or bromoacetic acid and the alkali lye is 1: 0.3～2; In the said step (2), 5, the mol ratio of the alkali in 5-phenylbenzene-2-thiohydantoin and the alkali lye is 1: 0.5～2; In the said step (2) 5, the Mono Chloro Acetic Acid in 5-phenylbenzene-2-thiohydantoin and the said step (1) or the mol ratio of bromoacetic acid are 1: 1～2.
The present invention has following remarkable advantage with compared with techniques in the past:
(1) the disclosed technology of the present invention, reaction process can not with an organic solvent be carried out at aqueous phase, more meets green, environmental protection requirement.
(2) the S-ethyloic-5 that obtains of the present invention, 5-phenylbenzene-2-thiohydantoin is a kind of white crystal, and the straight product yield is more than 80%, and purity is greater than 98%.Can satisfy chemical industry, the high yield of medicine and other fields, requirement of high purity.
Embodiment
Through embodiment the present invention is further described below.Protection scope of the present invention not only is confined to the statement of following content.
Embodiment 1:
With 60mmol Mono Chloro Acetic Acid and 60mL concentration is the aqueous sodium hydroxide solution reaction of 1mol/L, makes sodium chloroacetate solution, subsequent use.In the 500mL reaction flask, add 50mmol 5,5-phenylbenzene-2-thiohydantoin and 50mL concentration are the aqueous sodium hydroxide solution of 1mol/L, are heated to backflow under the agitation condition; In 30min, slowly add subsequent use sodium chloroacetate solution then, after adding finishes, continue back flow reaction 2h.In the process of cooling, add 50mL water, after the question response system was reduced to room temperature, dripping mass concentration and be 5% hcl acidifying to pH value was 3.The separate solid product, washing, dry, ethyl alcohol recrystallization get white crystal S-ethyloic-5,5-phenylbenzene-2-thiohydantoin.The straight product yield is 88%, m.p.:279～282 ℃.Through liquid chromatogram measuring, product purity is 98.5%.Product is through IR,
1H NMR,
13C NMR, mass spectrum characterizes.Analytical results is following:
IR (KBr pressed disc method): 3467,3013,2915,1716,1670,1588,1560,1495,1450,1290,1190,1089,754cm
-1
1H?NMR(DMSO-d
6，500MHz)δ
H：11.12(s，1H，COOH)，9.32(s，1H，NH)，7.44-7.29(m，10H，ArH)，4.07(s，2H，CH
2)ppm。
13C?NMR(DMSO-d
6，500MHz)δ
C：186.8，181.8，159.0，140.4，128.4，127.4，126.6，70.1，26.0ppm。
MS(ESI)：m/z?327(M+H)
+。
Embodiment 2:
With 55mmol bromoacetic acid and 60mL concentration is the potassium hydroxide methanol solution reaction of 1mol/L, makes the bromoacetic acid potassium solution, subsequent use.In the 500mL reaction flask, add 50mmol 5,5-phenylbenzene-2-thiohydantoin and 50mL concentration are the potassium hydroxide methanol solution of 1mol/L, are heated to backflow under the agitation condition; In 30min, slowly add subsequent use bromoacetic acid potassium solution then, after adding finishes, continue back flow reaction 1.5h.In the process of cooling, add 50mL water, after the question response system was reduced to room temperature, dripping mass concentration and be 5% sulfuric acid acidation to pH value was 3.The separate solid product, washing, dry, ethyl alcohol recrystallization get white crystal S-ethyloic-5,5-phenylbenzene-2-thiohydantoin.The straight product yield is 85%, m.p.:280～282 ℃.Through liquid chromatogram measuring, product purity is 98.5%.Product is through IR,
1H NMR,
13C NMR, mass spectrum characterizes, and characterization result is consistent with embodiment 1.
Embodiment 3:
With 65mmol Mono Chloro Acetic Acid and 60mL concentration is salt of wormwood alcohol-water (volume ratio 1: the 1) solution reaction of 0.5mol/L, makes potassium chloroacetate solution, subsequent use.In the 500mL reaction flask, add 50mmol5,5-phenylbenzene-2-thiohydantoin and 50mL concentration are salt of wormwood alcohol-water (volume ratio 1: the 1) solution of 0.5mol/L, are heated to backflow under the agitation condition; In 30min, slowly add subsequent use potassium chloroacetate solution then, after adding finishes, continue back flow reaction 2h.In the process of cooling, add 50mL water, after the question response system was reduced to room temperature, dripping mass concentration and be 10% hcl acidifying to pH value was 3.The separate solid product, washing, dry, ethyl alcohol recrystallization get white crystal S-ethyloic-5,5-phenylbenzene-2-thiohydantoin.The straight product yield is 81%, m.p.:281～283 ℃.Through liquid chromatogram measuring, product purity is 98.5%.Product is through IR,
1H NMR,
13C NMR, mass spectrum characterizes, and characterization result is consistent with embodiment 1.
Be with being appreciated that; More than about specific descriptions of the present invention; Only be used to the present invention is described and be not to be subject to the described technical scheme of the embodiment of the invention; Those of ordinary skill in the art should be appreciated that still and can make amendment or be equal to replacement the present invention, to reach identical technique effect; As long as satisfy the use needs, all within protection scope of the present invention.
Claims (1)
1. one kind prepares S-ethyloic-5, and the method for 5-phenylbenzene-2-thiohydantoin is characterized in that, carries out successively as follows:
(1) Mono Chloro Acetic Acid or bromoacetic acid and alkali lye are reacted the gained solution for later use under the stirring at room condition;
(2) with 5,5-phenylbenzene-2-thiohydantoin and alkali lye are mixed, under agitation condition, are heated to backflow;
(3) with step (1) gained solution, be added drop-wise in the step (2), dropwise, continue back flow reaction, stop heating; Reaction solution promptly gets title product through cooling, dilution, acidifying, separation, drying, ethyl alcohol recrystallization; Reflux time is 1h～5h; The solvent that dilution step adopts is a water; It is that 1%～10% aqueous sodium carbonate or mass concentration are that 1%～10% sodium bicarbonate aqueous solution washing leaching cake is to neutral that water or mass concentration are adopted in sepn process;
In said step (1) or the step (2), the alkali in the alkali lye is a kind of or its mixture in oxyhydroxide and the carbonate; Solvent in the alkali lye is a water; To adopt mass concentration be that 1%～35% hydrochloric acid or mass concentration are 1%～35% sulfuric acid to acidification step in the said step (3); The volumetric molar concentration of alkali lye is 0.1mol/L～5mol/L;
In the said step (1), the mol ratio of the alkali in Mono Chloro Acetic Acid or bromoacetic acid and the alkali lye is 1: 0.3～2; In the said step (2), 5, the mol ratio of the alkali in 5-phenylbenzene-2-thiohydantoin and the alkali lye is 1: 0.5～2; In the said step (2) 5, the Mono Chloro Acetic Acid in 5-phenylbenzene-2-thiohydantoin and the said step (1) or the mol ratio of bromoacetic acid are 1: 1～2.
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| CN 201010211519 CN101863834B (en) | 2010-06-29 | 2010-06-29 | Preparation method of S-carboxymethyl-5,5-diphenyl-2-thiohydantoin |
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| CN 201010211519 CN101863834B (en) | 2010-06-29 | 2010-06-29 | Preparation method of S-carboxymethyl-5,5-diphenyl-2-thiohydantoin |
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| CN101863834A CN101863834A (en) | 2010-10-20 |
| CN101863834B true CN101863834B (en) | 2012-10-10 |
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Non-Patent Citations (1)
| Title |
|---|
| Asmaa A. Magd El-Din, et.al..A Novel Synthesis of Some New Imidazothiazole and Glycocyamidine Derivatives and Studies on Their Antimicrobial Activities.《Phosphorus, Sulfur, and Silicon》.2007,第182卷第529-536页. * |
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