CN103030561A - Synthesis method for 5-bromo-ethyl levulinate - Google Patents
Synthesis method for 5-bromo-ethyl levulinate Download PDFInfo
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- CN103030561A CN103030561A CN2013100083989A CN201310008398A CN103030561A CN 103030561 A CN103030561 A CN 103030561A CN 2013100083989 A CN2013100083989 A CN 2013100083989A CN 201310008398 A CN201310008398 A CN 201310008398A CN 103030561 A CN103030561 A CN 103030561A
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- acetobrom
- ethyl propionate
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- ethyl levulinate
- ether
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Abstract
A synthesis method for 5-bromo-ethyl levulinate relates to a 5-aminolevulinic acid. Ethyl levulinate and liquid bromine are used as raw materials. The provided synthesis method for the 5-bromo-ethyl levulinate has the advantages of simplicity, wide raw material source, cheap raw materials, high yield and easiness in industrial production. The synthesis method comprises the following steps of: adding the ethyl levulinate raw material and a solvent into a reactor and reacting, and in the reaction process, adding the liquid bromine into the reactor to carry out bromination reaction; after the reaction is over, recycling the solvent in reaction liquid by a reduced pressure distillation method; dissolving distillation residues by water, adding diethyl ether for extraction, and obtaining a diethyl ether layer; washing the diethyl ether layer by a saturated sodium carbonate solution until the pH (Potential of Hydrogen) of the diethyl ether layer is neutral; drying and filtering by anhydrous magnesium sulfate, and recycling the diethyl ether through distillation so as to obtain a 5-bromo-ethyl levulinate crude product; and dissolving the 5-bromo-ethyl levulinate crude product in a mixed solvent of the diethyl ether and cyclohexane, and carrying out cooling crystallization in a cold trap to obtain the 5-bromo-ethyl levulinate.
Description
Technical field
The present invention relates to a kind of 5-ALA, especially relate to a kind of synthetic method of pharmaceutical intermediate 5-acetobrom ethyl propionate.
Background technology
5-ALA and lipid derivant thereof are having this great using value as New Generation Optical kinetics medicine aspect the diagnosis of the diseases such as brain tumor, skin carcinoma and the treatment.5-acetobrom ethyl propionate is important intermediate in the synthetic 5-ALA ethyl ester take ethyl levulinate as raw material, obtains high yield, highly purified 5-acetobrom ethyl propionate is very important to the acquisition of 5-ALA ethyl ester.At present, few about the relevant report of this intermediate study on the synthesis both at home and abroad.
The production method of 5-ALA can be divided into microbe fermentation method and chemical synthesis.Microbe fermentation method has that raw material is cheap to be easy to get, the advantage that Environmental compatibility is good, but yield is very low at present, and the difficult regulation and control of biological respinse condition are difficult to carry out large-scale industrial production at short notice.Traditional chemical synthesis is mainly with urobenzoic acid, monomester succinate acyl chlorides, chaff amine, hydroxymethylfurfural, oxopentanoic acid methyl esters and the succinyl oxide method as raw material.But these method Financial cost are higher, productive rate is low and by product is many, are difficult for extensively promoting suitability for industrialized production.
Ethyl levulinate can obtain from the hydrolysis of renewable biomass resource, take ethyl levulinate as raw material, through the synthetic 5-ALA ethyl ester of 5-acetobrom ethyl propionate, wide material sources, price is low, and transformation efficiency is high, reaction conditions is gentle, and is nonflammable explosive, and good industrial prospect is arranged.
Summary of the invention
The object of the present invention is to provide take ethyl levulinate, bromine as raw material, simple synthetic method, raw material sources are extensively cheap, and productive rate is high, easily the synthetic method of a kind of 5-acetobrom ethyl propionate of suitability for industrialized production.
The present invention includes following steps:
1) raw material methyl aceto acetate and solvent are joined in the reactor react, concentration is 0.5 ~ 2mol/L, in the reaction process, adds bromine in the reactor and carries out bromination reaction, and the mol ratio of described ethyl levulinate and bromine can be 0.8～1.2;
2) after reaction finishes, utilize vacuum distillation method to reclaim the solvent in the reaction solution;
3) will distill the residuum water dissolution, and add ether and extract, obtain ether layer, and with the saturated sodium carbonate solution washing, until ether layer pH layer is neutral, the anhydrous magnesium sulfate drying filtration, the Distillation recovery ether obtains 5-acetobrom ethyl propionate crude product;
4) 5-acetobrom ethyl propionate crude product is dissolved in the mixed solvent of ether and hexanaphthene, decrease temperature crystalline in cold-trap obtains 5-acetobrom ethyl propionate, and gained 5-acetobrom ethyl propionate is white crystalline material.
In step 1), described solvent can be selected from ethanol etc.; The temperature of described reaction can be 5 ~ 45 ℃, and the time of reaction can be 2 ~ 8h, begins calculating reacting time from adding bromine; The speed of described adding bromine can be 0 ~ 5ml/h.
In step 2) in, the temperature of described underpressure distillation is lower than 60 ℃.
In step 3), the volume ratio of described ether and water can be (3 ~ 6): 1.
In step 4), the volume ratio of described ether and hexanaphthene can be 1: 1.
The present invention in ethanol medium, through bromination, obtains 5-acetobrom ethyl propionate take methyl aceto acetate as raw material behind the separation purifying such as distillation, extraction.
Synthetic method of the present invention is simple, the raw material ethyl levulinate is easy to get, can be by reproducible biomass alcoholysis preparation, and transformation efficiency is high, reaction conditions is gentle, and good application prospect is arranged.
Description of drawings
Fig. 1 is the GC figure of reaction product, and the residence time 10.969 is 5-acetobrom ethyl propionate.
Fig. 2 is 5-acetobrom ethyl propionate MS figure.
Embodiment
The present invention will be further described below in conjunction with embodiment, need to prove, embodiment not office consists of restriction to the claimed scope of the present invention.
Embodiment 1
Producing of 5-ALA ethyl ester intermediate product 5-acetobrom ethyl propionate.
Get ethyl levulinate (14.4g) and mix with the 100ml dehydrated alcohol, and 2h drips bromine 16g in the medium, under agitation condition, in 35 ℃ of reaction 4h, obtain little yellow transparent liquid.Get the 1ml reaction solution, with the content of gas chromatographic detection 5-acetobrom ethyl propionate.The selectivity of 5-acetobrom ethyl propionate can reach 60%.
Get the 200g reaction solution behind 45 ℃ of lower underpressure distillation ethanol, add respectively 200ml anhydrous diethyl ether and 10ml water, standing separation goes out water, with a large amount of saturated Na
2CO
3Solution flushing organic phase, then anhydrous MgSO
4Drying is steamed except behind the ether and is obtained the bromination mixture, dissolves afterwards decrease temperature crystalline with the mixed solvent (volume ratio is 1: 1) of ether and hexanaphthene and then obtains the high purity sample of 5-acetobrom ethyl propionate through recrystallization repeatedly.
Embodiment 2
Producing of 5-ALA ethyl ester intermediate product 5-acetobrom ethyl propionate.
Get ethyl levulinate (14.4g) and mix with the 50ml dehydrated alcohol, and 2h drips bromine 16g in the medium, under agitation condition, in 35 ℃ of reaction 8h, obtain little yellow transparent liquid.Get the 1ml reaction solution, with the content of gas chromatographic detection 5-acetobrom ethyl propionate.The selectivity of 5-acetobrom ethyl propionate reaches 47.4%.
Get the 300g reaction solution behind 45 ℃ of lower underpressure distillation ethanol, add respectively 300ml anhydrous diethyl ether and 30ml water, standing separation goes out water, with a large amount of saturated Na
2CO
3Solution flushing organic phase, then anhydrous MgSO
4Drying is steamed except behind the ether and is obtained the bromination mixture, dissolves afterwards decrease temperature crystalline with the mixed solvent (volume ratio is 1: 1) of ether and hexanaphthene and then obtains the high purity sample of 5-acetobrom ethyl propionate through recrystallization repeatedly.
Embodiment 3
Producing of 5-ALA ethyl ester intermediate product 5-acetobrom ethyl propionate.
Get ethyl levulinate (14.4g) and mix with the 50ml dehydrated alcohol, and 2h drips bromine 16g in the medium, under agitation condition, in 5 ℃ of reaction 2h, obtain little yellow transparent liquid.Get the 1ml reaction solution, with the content of gas chromatographic detection 5-acetobrom ethyl propionate.The selectivity of 5-acetobrom ethyl propionate reaches 30.1%.
Get the 200g reaction solution behind 45 ℃ of lower underpressure distillation ethanol, add respectively 200ml anhydrous diethyl ether and 10ml water, standing separation goes out water, with a large amount of saturated Na
2CO
3Solution flushing organic phase, then anhydrous MgSO
4Drying is steamed except behind the ether and is obtained the bromination mixture, dissolves afterwards decrease temperature crystalline with the mixed solvent (volume ratio is 1: 1) of ether and hexanaphthene and then obtains the high purity sample of 5-acetobrom ethyl propionate through recrystallization repeatedly.
Embodiment 4
Producing of 5-ALA ethyl ester intermediate product 5-acetobrom ethyl propionate.
Get ethyl levulinate (14.4g) and 100ml1, the 2-ethylene dichloride mixes, and 2h drips bromine 16g in the medium, in 35 ℃ of reaction 4h, obtains little yellow transparent liquid under agitation condition.Get the 1ml reaction solution, with the content of gas chromatographic detection 5-acetobrom ethyl propionate.The selectivity of 5-acetobrom ethyl propionate reaches 20.3%.
Get the 200g reaction solution behind 45 ℃ of lower underpressure distillation ethanol, add respectively 200ml anhydrous diethyl ether and 10ml water, standing separation goes out water, with a large amount of saturated Na
2CO
3Solution flushing organic phase, then anhydrous MgSO
4Drying is steamed except behind the ether and is obtained the bromination mixture, dissolves afterwards decrease temperature crystalline with the mixed solvent (volume ratio is 1: 1) of ether and hexanaphthene and then obtains the high purity sample of 5-acetobrom ethyl propionate through recrystallization repeatedly.
The GC figure of reaction product is referring to Fig. 1, and in Fig. 1, the residence time 10.969 is 5-acetobrom ethyl propionate, and 5-acetobrom ethyl propionate MS figure is referring to Fig. 2.
Claims (7)
1. the synthetic method of a 5-acetobrom ethyl propionate is characterized in that may further comprise the steps:
1) raw material methyl aceto acetate and solvent are joined in the reactor react, concentration is 0.5 ~ 2mol/L, in the reaction process, adds bromine in the reactor and carries out bromination reaction, and the mol ratio of described ethyl levulinate and bromine is 0.8～1.2;
2) after reaction finishes, utilize vacuum distillation method to reclaim the solvent in the reaction solution;
3) will distill the residuum water dissolution, and add ether and extract, obtain ether layer, and with the saturated sodium carbonate solution washing, until ether layer pH layer is neutral, the anhydrous magnesium sulfate drying filtration, the Distillation recovery ether obtains 5-acetobrom ethyl propionate crude product;
4) 5-acetobrom ethyl propionate crude product is dissolved in the mixed solvent of ether and hexanaphthene, decrease temperature crystalline in cold-trap obtains 5-acetobrom ethyl propionate.
2. a kind of synthetic method of 5-acetobrom ethyl propionate as claimed in claim 1 is characterized in that in step 1), and described solvent is selected from ethanol.
3. a kind of synthetic method of 5-acetobrom ethyl propionate as claimed in claim 1 is characterized in that in step 1), and the temperature of described reaction is 5 ~ 45 ℃, and the time of reaction is 2 ~ 8h, begins calculating reacting time from adding bromine.
4. a kind of synthetic method of 5-acetobrom ethyl propionate as claimed in claim 1 is characterized in that in step 1), and the speed of described adding bromine is 0 ~ 5ml/h.
5. a kind of synthetic method of 5-acetobrom ethyl propionate as claimed in claim 1 is characterized in that in step 2) in, the temperature of described underpressure distillation is lower than 60 ℃.
6. a kind of synthetic method of 5-acetobrom ethyl propionate as claimed in claim 1 is characterized in that in step 3), and the volume ratio of described ether and water is (3 ~ 6): 1.
7. a kind of synthetic method of 5-acetobrom ethyl propionate as claimed in claim 1 is characterized in that in step 4), and the volume ratio of described ether and hexanaphthene is 1: 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113416142A (en) * | 2021-06-22 | 2021-09-21 | 邯郸市赵都精细化工有限公司 | Preparation method of 5-ALA intermediate 5-bromolevulinate |
-
2013
- 2013-01-10 CN CN2013100083989A patent/CN103030561A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| HYUN-JOON HA ET AL.: "Selective Bromination of Ketones. A Convenient Synthesis of 5-Aminolevulinic Acid", 《SYNTHETIC COMMUNICATIONS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113416142A (en) * | 2021-06-22 | 2021-09-21 | 邯郸市赵都精细化工有限公司 | Preparation method of 5-ALA intermediate 5-bromolevulinate |
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Application publication date: 20130410 |