CN105646214A - Preparation method of diethyl ethylisopentylmalonate - Google Patents
Preparation method of diethyl ethylisopentylmalonate Download PDFInfo
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- CN105646214A CN105646214A CN201610101361.4A CN201610101361A CN105646214A CN 105646214 A CN105646214 A CN 105646214A CN 201610101361 A CN201610101361 A CN 201610101361A CN 105646214 A CN105646214 A CN 105646214A
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- malonic acid
- acid diethylester
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- ethyl
- ethanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/68—Preparation of metal alcoholates
- C07C29/70—Preparation of metal alcoholates by converting hydroxy groups to O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of diethyl ethylisopentylmalonate. The preparation method comprises following steps: 1), ethanol and sodium react to generate sodium ethoxide; 2), diethyl ethylmalonate is added to sodium ethoxide obtained in the step 1), and diethyl ethylmalonate sodium salt is generated; 3), 1-bromo-3-methylbutane is added to the diethyl ethylmalonate sodium salt obtained in the step 2), and diethyl ethylisopentylmalonate is generated after reaction. Diethyl ethylisopentylmalonate is prepared from ethanol, sodium, diethyl ethylmalonate and 1-bromo-3-methylbutane as the raw materials, and prepared diethyl ethylisopentylmalonate has high yield and high purity and meets the drug quality standard.
Description
Technical field
The present invention relates to ethyl isoamyl-malonic acid diethylester field, the preparation method particularly relating to a kind of ethyl isoamyl-malonic acid diethylester.
Background technology
Ethyl isoamyl-malonic acid diethylester is a kind of important medicine intermediate, and its structural formula is as follows:It is mainly as the intermediate of amobarbital. Generally adopt isoamyl alcohol with bromine hydracid-sulphuric acid bromination at present, generate the bromo-3-methybutane of 1-, then under Sodium ethylate participates in diethyl malonate condensation, obtain ��-isoamyl-malonic acid diethylester, then the latter prepared with bromoethane condensation under Sodium ethylate participates in. But the yield of the ethyl isoamyl-malonic acid diethylester that such scheme prepares and purity are all relatively low, largely effect on the quality of downstream medicine.
Summary of the invention
In view of this, the preparation method that it is an object of the invention to provide a kind of ethyl isoamyl-malonic acid diethylester, solve existing method yield and the low technical problem of purity.
To achieve these goals, the technical scheme is that
The preparation method of a kind of ethyl isoamyl-malonic acid diethylester, comprises the following steps:
1) ethanol and sodium reaction generate Sodium ethylate;
2) to step 1) Sodium ethylate that obtains adds ethyl malonic acid diethylester, generate ethyl malonic acid diethylester sodium salt;
3) to step 2) the ethyl malonic acid diethylester sodium salt that obtains adds bromo isopentane, reaction generates ethyl isoamyl-malonic acid diethylester.
Preferably, step 1) particularly as follows: first pass into N in the reactor fill ethanol2, then sodium is joined in dehydrated alcohol, at 70��73 DEG C, after reaction 12��15h, stop passing into N2; Heating temperatures to 80��120 DEG C is sloughed ethanol simultaneously and obtain Sodium ethylate; The ratio of described sodium and the amount of substance of described ethanol is 1:4��5.
Preferably, step 2) particularly as follows: after passing into cooling water 30��60min in the cooling water jecket of reactor, then pass into N2, it is slowly added dropwise ethyl malonic acid diethylester afterwards, stops after dripping passing into cooling water and N2, obtain ethyl malonic acid diethylester sodium salt.
Preferably, step 3) particularly as follows: to step 2) the ethyl malonic acid diethylester sodium salt that obtains adds bromo isopentane, and at 76��84 DEG C, it is incubated 30��45min, filters, rectification obtains ethyl isoamyl-malonic acid diethylester.
Preferably, the amount of substance of described sodium, described ethyl malonic acid diethylester and described bromo isopentane is than being (3��4): (2.5��3.5): (2��3).
Can be seen that from technique scheme, the preparation method of ethyl isoamyl-malonic acid diethylester provided by the invention, ethyl isoamyl-malonic acid diethylester is prepared for raw material with ethanol, sodium, ethyl malonic acid diethylester and bromo isopentane, the ethyl isoamyl-malonic acid diethylester productivity prepared is high, purity is high, meets medicine quality standard.
Detailed description of the invention
In order to further appreciate that the present invention, below in conjunction with embodiment, the preferred embodiments of the invention are described, but it is to be understood that these describe simply as to further illustrate the features and advantages of the present invention rather than the restriction to patent requirements of the present invention.
The preparation method of a kind of ethyl isoamyl-malonic acid diethylester, comprises the following steps:
1) ethanol and sodium reaction generate Sodium ethylate
2) to step 1) Sodium ethylate that obtains adds ethyl malonic acid diethylester, generate ethyl malonic acid diethylester sodium salt;
3) to step 2) the ethyl malonic acid diethylester sodium salt that obtains adds bromo isopentane, reaction generates ethyl isoamyl-malonic acid diethylester.
The present invention is with ethanol, sodium, ethyl malonic acid diethylester and bromo isopentane for raw material, and the ethyl isoamyl-malonic acid diethylester productivity prepared is high, purity is high, meets medicine quality standard.
Wherein, the reaction equation of the reaction generation Sodium ethylate of ethanol and sodium is as follows:
Na+C2H5OH��C2H5ONa+H2����
In an embodiment of the present invention, being prepared by N of Sodium ethylate2Prepare under atmosphere, it is to avoid the problem that Sodium ethylate easily decomposes, burns. Wherein, the reaction temperature of ethanol and sodium is 70��73 DEG C, and the response time is 12��15h, has reacted and has namely stopped passing into N2; Heating temperatures to 80��120 DEG C is sloughed ethanol simultaneously and obtain Sodium ethylate; The ratio of described sodium and the amount of substance of described ethanol is 1:4��5. Owing to Sodium ethylate existing too much ethanol, affect the reaction of Sodium ethylate and ethyl malonic acid diethylester, it is therefore desirable to sloughed by the ethanol in alcohol sodium solution. In an embodiment of the present invention, adopt the way of distillation to remove ethanol, namely obtain Sodium ethylate.
In the present invention, Sodium ethylate and ethyl malonic acid diethylester react generate ethyl malonic acid diethylester sodium salt reaction equation as follows:
In an embodiment of the present invention, step 1) in adopt the way of distillation to slough ethanol and obtain Sodium ethylate, the temperature in reactor will necessarily be made to raise, and temperature in reactor too high time, the generation of by-product can be caused, it is thus desirable to pass into cooling water in the cooling water jecket of reactor, namely needed first to lead to cold water intaking 30��60min before adding ethyl malonic acid diethylester, make the temperature in reactor lower; Pass into N more simultaneously2, it is slowly added dropwise ethyl malonic acid diethylester, stops after dripping passing into cooling water and N2, thus obtaining ethyl malonic acid diethylester sodium salt.
In the present invention, ethyl malonic acid diethylester sodium salt and bromo isopentane react generate ethyl isoamyl-malonic acid diethylester reaction equation as follows:
In an embodiment of the present invention, adding bromo isopentane, and be incubated 30��45min at 76��84 DEG C in ethyl malonic acid diethylester sodium salt, filtration, rectification obtain ethyl isoamyl-malonic acid diethylester; When wherein temperature is 76��84 DEG C, it is possible to reflux so that ethyl malonic acid diethylester sodium salt and bromo isopentane can fully react.
It should be noted that, in an embodiment of the present invention, filtering the filtrate adopted is water, owing to water and NaBr dissolve each other, insoluble with ethyl isoamyl-malonic acid diethylester, therefore can be layered, and then obtain crude product ethyl isoamyl-malonic acid diethylester, obtain ethyl isoamyl-malonic acid diethylester again through rectification.
By the ethyl isoamyl-malonic acid diethylester adopting technique scheme to prepare, yield is high, and purity is good, meets medicine quality standard;And side-product sodium bromide can be recycled, it is to avoid environmental pollution.
In order to further illustrate the present invention, provide the preparation method of ethyl isoamyl-malonic acid diethylester to be described in detail the present invention below in conjunction with embodiment, but they can not be interpreted as limiting the scope of the present invention.
Raw material used in following example is commercially available.
Embodiment 1
N is passed in the reactor fill 1200g ethanol2, 80g sodium is joined in dehydrated alcohol, at 72 DEG C, after reaction 12h, stops passing into N2; Heating temperatures to 80 DEG C is sloughed ethanol simultaneously and obtain Sodium ethylate; In the cooling water jecket of reactor, pass into cooling water 30min again, then pass into N2, and in Sodium ethylate, drip 600g ethyl malonic acid diethylester lentamente, stop after dripping passing into cooling water and N2, obtain ethyl malonic acid diethylester sodium salt; At dropping 450g bromo isopentane, and being incubated 30min at 76 DEG C, filtration, rectification obtain ethyl isoamyl-malonic acid diethylester.
The productivity of the ethyl isoamyl-malonic acid diethylester that the present embodiment prepares is 83.33%, and purity is 99.52%.
Embodiment 2
N is passed in the reactor fill 1350g ethanol2, 82g sodium is joined in dehydrated alcohol, at 73 DEG C, after reaction 13h, stops passing into N2; Heating temperatures to 80 DEG C is sloughed ethanol simultaneously and obtain Sodium ethylate; In the cooling water jecket of reactor, pass into cooling water 60min again, then pass into N2, and in Sodium ethylate, drip 600g ethyl malonic acid diethylester lentamente, stop after dripping passing into cooling water and N2, obtain ethyl malonic acid diethylester sodium salt; At dropping 460g bromo isopentane, and being incubated 45min at 80 DEG C, filtration, rectification obtain ethyl isoamyl-malonic acid diethylester.
The productivity of the ethyl isoamyl-malonic acid diethylester that the present embodiment prepares is 82.95%, and purity is 99.54%.
Embodiment 3
N is passed in the reactor fill 1250g ethanol2, 83g sodium is joined in dehydrated alcohol, at 72 DEG C, after reaction 14h, stops passing into N2; Heating temperatures to 80 DEG C is sloughed ethanol simultaneously and obtain Sodium ethylate; In the cooling water jecket of reactor, pass into cooling water 45min again, then pass into N2, and in Sodium ethylate, drip 610g ethyl malonic acid diethylester lentamente, stop after dripping passing into cooling water and N2, obtain ethyl malonic acid diethylester sodium salt; At dropping 455g bromo isopentane, and being incubated 60min at 84 DEG C, filtration, rectification obtain ethyl isoamyl-malonic acid diethylester.
The productivity of the ethyl isoamyl-malonic acid diethylester that the present embodiment prepares is 82.74%, and purity is 99.57%.
Embodiment 4
N is passed in the reactor fill 1300g ethanol2, 80g sodium is joined in dehydrated alcohol, at 73 DEG C, after reaction 15h, stops passing into N2; Heating temperatures to 80 DEG C is sloughed ethanol simultaneously and obtain Sodium ethylate; In the cooling water jecket of reactor, pass into cooling water 60min again, then pass into N2, and in Sodium ethylate, drip 610g ethyl malonic acid diethylester lentamente, stop after dripping passing into cooling water and N2, obtain ethyl malonic acid diethylester sodium salt; At dropping 460g bromo isopentane, and being incubated 60min at 82 DEG C, filtration, rectification obtain ethyl isoamyl-malonic acid diethylester.
The productivity of the ethyl isoamyl-malonic acid diethylester that the present embodiment prepares is 83.12%, and purity is 99.54%.
Embodiment 5
N is passed in the reactor fill 1500g ethanol2, 85g sodium is joined in dehydrated alcohol, at 73 DEG C, after reaction 15h, stops passing into N2;Heating temperatures to 80 DEG C is sloughed ethanol simultaneously and obtain Sodium ethylate; In the cooling water jecket of reactor, pass into cooling water 60min again, then pass into N2, and in Sodium ethylate, drip 610g ethyl malonic acid diethylester lentamente, stop after dripping passing into cooling water and N2, obtain ethyl malonic acid diethylester sodium salt; At dropping 460g bromo isopentane, and being incubated 60min at 78 DEG C, filtration, rectification obtain ethyl isoamyl-malonic acid diethylester.
The productivity of the ethyl isoamyl-malonic acid diethylester that the present embodiment prepares is 83.20%, and purity is 99.56%.
Above the preparation method of a kind of ethyl isoamyl-malonic acid diethylester provided by the invention is described in detail; principles of the invention and embodiment are set forth by specific case used herein; the explanation of above example is only intended to help to understand method and the core concept thereof of the present invention; should be understood that; for those skilled in the art; under the premise without departing from the principles of the invention; the present invention can also carry out some improvement and modification, and these improve and modify in the protection domain also falling into the claims in the present invention.
Claims (5)
1. the preparation method of an ethyl isoamyl-malonic acid diethylester, it is characterised in that comprise the following steps:
1) ethanol and sodium reaction generate Sodium ethylate;
2) to step 1) Sodium ethylate that obtains adds ethyl malonic acid diethylester, generate ethyl malonic acid diethylester sodium salt;
3) to step 2) the ethyl malonic acid diethylester sodium salt that obtains adds bromo isopentane, reaction generates ethyl isoamyl-malonic acid diethylester.
2. preparation method as claimed in claim 1, it is characterised in that step 1) particularly as follows: first pass into N in the reactor fill ethanol2, then sodium is joined in dehydrated alcohol, at 70��73 DEG C, after reaction 12��15h, stop passing into N2; Heating temperatures to 80��120 DEG C is sloughed ethanol simultaneously and obtain Sodium ethylate; The ratio of described sodium and the amount of substance of described ethanol is 1:4��5.
3. preparation method as claimed in claim 1, it is characterised in that step 2) particularly as follows: after passing into cooling water 30��60min in the cooling water jecket of reactor, then pass into N2, it is slowly added dropwise ethyl malonic acid diethylester afterwards, stops after dripping passing into cooling water and N2, obtain ethyl malonic acid diethylester sodium salt.
4. preparation method as claimed in claim 1, it is characterized in that, step 3) particularly as follows: to step 2) the ethyl malonic acid diethylester sodium salt that obtains adds bromo isopentane, and at 76��84 DEG C, it is incubated 30��45min, filters, rectification obtains ethyl isoamyl-malonic acid diethylester.
5. the preparation method as described in any one of Claims 1 to 4, it is characterized in that, the amount of substance of described sodium, described ethyl malonic acid diethylester and described bromo isopentane is than being (3��4): (2.5��3.5): (2��3).
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| CN201610101361.4A CN105646214B (en) | 2016-02-24 | 2016-02-24 | The preparation method of ethyl isoamyl-malonic acid diethylester |
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| CN105646214B CN105646214B (en) | 2018-02-13 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO81266B1 (en) * | 1980-12-16 | 1983-02-28 | Ioan Batiu | Process for preparing some derivatives of momo and -disubstituted malonic ester |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO81266B1 (en) * | 1980-12-16 | 1983-02-28 | Ioan Batiu | Process for preparing some derivatives of momo and -disubstituted malonic ester |
Non-Patent Citations (3)
| Title |
|---|
| SUKHANOV, N. N.等: "Phase transfer catalyzed alkylation of malonic ester and monoalkylmalonic ester", 《ZHURNAL ORGANICHESKOI KHIMII》 * |
| 宗茹实等: "用相转移催化法合成催眠药异戊巴比妥", 《上海科技大学学报》 * |
| 张博等: "异戊巴比妥的杂质研究和化学合成", 《山东化工》 * |
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