CN102976927A - Preparation method of calcium alpha-ketoglutarate - Google Patents
Preparation method of calcium alpha-ketoglutarate Download PDFInfo
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- CN102976927A CN102976927A CN2012105716979A CN201210571697A CN102976927A CN 102976927 A CN102976927 A CN 102976927A CN 2012105716979 A CN2012105716979 A CN 2012105716979A CN 201210571697 A CN201210571697 A CN 201210571697A CN 102976927 A CN102976927 A CN 102976927A
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- methyl
- ketoglutarate
- preparation
- ketoglutaric acid
- acid calcium
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Abstract
The invention provides a preparation method of calcium alpha-ketoglutarate, which comprises the following steps: a) adding sodium methoxide into methyl dichloroacetate, and dropwisely adding methyl acrylate to carry out reaction; b) washing the mixed solution in the step a) with water, separating the water phase from the organic phase, and carrying out vacuum distillation on the organic phase to obtain dimethyl 2,2-dichloroglutarate; c) adding NaOH into the dimethyl 2,2-dichloroglutarate, and reacting at 60 DEG C to generate sodium alpha-ketoglutarate; and d) adding calcium chloride into the product in the step c), and stirring to obtain the calcium alpha-ketoglutarate. By changing the addition mode of the catalyst, the catalyst is uniformly distributed in the reaction system; and as the other product is added gradually, the concentration of the catalyst becomes lower, thereby effectively controlling the reaction process between the methyl dichloroacetate and methyl acrylate and enhancing the product yield. The intermediate product can be prepared into the sodium alpha-ketoglutarate by hydrolysis once, thereby shortening the procedure and enhancing the yield.
Description
Technical field
The invention belongs to the preparation method of alpha-ketoglutarate, be specially a kind of preparation method of α-ketoglutaric acid calcium.
Background technology
α-ketoglutaric acid calcium is white powder, is slightly soluble in water, and chemical formula is C
5H
4O
5Ca, structural formula is:
The preparation method of α-ketoglutaric acid calcium is in the prior art: with methyl dichloroacetate with after methyl acrylate mixes, drip again the catalyzer sodium methylate and prepare the ketoisocaproic dimethyl ester, the ketoisocaproic dimethyl ester that obtains is hydrolyzed under acidic conditions first, through the alkaline condition hydrolysis, last and calcium chloride reaction makes calcium ketoglutarate again.
Yet along with splashing into gradually of sodium methylate, the concentration of sodium methylate constantly increases in methyl dichloroacetate and the methyl acrylate reaction system, so that the reaction between methyl dichloroacetate and the methyl acrylate is more and more violent, is difficult to control the process of reaction.
Simultaneously, in this reaction, the molar percentage that catalyzer occupies with respect to reactant is less, in the real reaction process, may exist local sodium methylate concentration larger, certainly do not get rid of the less possibility of local sodium methylate, both of these case all is fatal defective for this reaction, finally can have influence on yield and the purity of ketoisocaproic dimethyl ester.
Summary of the invention
For solving the problems of the technologies described above, the invention provides a kind of preparation method of α-ketoglutaric acid calcium.
Technical scheme of the present invention is: a kind of preparation method of α-ketoglutaric acid calcium may further comprise the steps:
A) sodium methylate is joined in the methyl dichloroacetate, stir, system temperature is controlled at 40 ℃～50 ℃, and the dropping methyl acrylate reacts;
B) a) add water washing in the mixed solution after finishing to step, water phase separated and organic phase obtain 2,2-dichloro Methyl glutarate with the organic phase underpressure distillation;
C) in 2,2-dichloro Methyl glutarate, add NaOH, 60 ℃ of lower reactions, generate sodium alpha-ketoglutarate;
D) in the product of step c), add calcium chloride, stir, obtain α-ketoglutaric acid calcium.
Described step a) in the ratio of methyl dichloroacetate and the amount of substance of methyl acrylate be 1:1.1.
The described step a) usage quantity of middle sodium methylate is 1% ~ 2% of methyl dichloroacetate and methyl acrylate quality sum.
Described step c) in 2,2-dichloro Methyl glutarate is 1:0.7 with the ratio of the amount of substance of NaOH.
The preparation method of α-ketoglutaric acid calcium of the present invention is by changing the adding mode of catalyzer, catalyzer is evenly distributed in reaction system, and the gradually adding along with another product, catalyst concn is more and more less, not only effectively control the process of methyl dichloroacetate and methyl acrylate reaction, also improved the yield of product.Intermediate product 2,2-dichloro Methyl glutarate only just obtain sodium alpha-ketoglutarate through once being hydrolyzed, and have shortened operation, have improved yield.
Embodiment
Below, the preparation method to α-ketoglutaric acid calcium of the present invention is described further in conjunction with chemical equation and specific embodiment:
The related chemical reaction of the preparation method of α-ketoglutaric acid calcium of the present invention is:
A) be the 30%(mass percent with concentration) sodium methoxide solution join in the methyl dichloroacetate, stir, system temperature is controlled at 40 ℃～50 ℃, be incubated 30 minutes, rear dropping methyl acrylate reacts, and reacts after 4 hours, stop to stir, kept temperature of reaction 10 minutes; Wherein, the methyl dichloroacetate of adding is 1:1.1 with the ratio of the amount of substance of methyl acrylate, and the usage quantity of sodium methylate is 1% ~ 2% of two kinds of reactant quality sums;
B) a) add water washing in the mixed solution after finishing to step, leave standstill, water and organic phase layering, aqueous phase discarded keeps organic phase, 3 times repeatedly, then the organic phase underpressure distillation is obtained 2,2-dichloro Methyl glutarate;
C) adding concentration in 2, the 2-dichloro Methyl glutarate is the 30%(mass percent) NaOH solution, 60 ℃ of lower reactions 4 hours, 2,2-dichloro Methyl glutarate was 1:0.7 with the ratio of the amount of substance of NaOH; Wherein 2, two Cl on the 2-dichloro Methyl glutarate are replaced by two OH, and two hydroxyls that are connected on the same carbon are unstable, and dehydration forms carbonyl, and the ester at two ends be hydrolyzed under alkaline condition becomes carboxyl, the generation sodium alpha-ketoglutarate;
D) add calcium chloride in the product of step c), sodium alpha-ketoglutarate is 1:0.5～1.2 with the ratio of the amount of substance of calcium chloride, stirs 4 hours, obtains α-ketoglutaric acid calcium.
The preparation method of α-ketoglutaric acid calcium of the present invention is by changing the adding mode of catalyzer, catalyzer is evenly distributed in reaction system, and the gradually adding along with another product, catalyst concn is more and more less, not only effectively control the process of methyl dichloroacetate and methyl acrylate reaction, also improved the yield of product.Intermediate product 2,2-dichloro Methyl glutarate only just obtain sodium alpha-ketoglutarate through once being hydrolyzed, and have shortened operation, have improved yield.Two improved combinations are so that the yield of the α-ketoglutaric acid calcium that method provided by the present invention makes is 80%, and purity is 99%, and the yield of prior art institute supplying method only is 70%.
Claims (4)
1. the preparation method of a α-ketoglutaric acid calcium is characterized in that, may further comprise the steps:
A) sodium methylate is joined in the methyl dichloroacetate, stir, system temperature is controlled at 40 ℃～50 ℃, and the dropping methyl acrylate reacts;
B) a) add water washing in the mixed solution after finishing to step, water phase separated and organic phase obtain 2,2-dichloro Methyl glutarate with the organic phase underpressure distillation;
C) in 2,2-dichloro Methyl glutarate, add NaOH, 60 ℃ of lower reactions, generate sodium alpha-ketoglutarate;
D) in the product of step c), add calcium chloride, stir, obtain α-ketoglutaric acid calcium.
2. the preparation method of α-ketoglutaric acid calcium according to claim 1 is characterized in that: described step a) in the ratio of methyl dichloroacetate and the amount of substance of methyl acrylate be 1:1.1.
3. the preparation method of α-ketoglutaric acid calcium according to claim 1 is characterized in that: described step a) in the usage quantity of sodium methylate be 1% ~ 2% of methyl dichloroacetate and methyl acrylate quality sum.
4. the preparation method of α-ketoglutaric acid calcium according to claim 1 is characterized in that: described step c) 2,2-dichloro Methyl glutarate is 1:0.7 with the ratio of the amount of substance of NaOH.
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| CN2012105716979A CN102976927A (en) | 2012-12-26 | 2012-12-26 | Preparation method of calcium alpha-ketoglutarate |
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| CN2012105716979A CN102976927A (en) | 2012-12-26 | 2012-12-26 | Preparation method of calcium alpha-ketoglutarate |
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| CN102976927A true CN102976927A (en) | 2013-03-20 |
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| CN2012105716979A Pending CN102976927A (en) | 2012-12-26 | 2012-12-26 | Preparation method of calcium alpha-ketoglutarate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020068705A1 (en) * | 2018-09-25 | 2020-04-02 | Ponce De Leon Health Designated Activity Company | Process of making calcium alpha-ketoglutarate |
| CN112941116A (en) * | 2021-01-04 | 2021-06-11 | 上海朴颐化学科技有限公司 | Method for preparing alpha-ketoglutarate calcium by enzyme method |
| CN116813466A (en) * | 2023-08-28 | 2023-09-29 | 江苏惠利生物科技有限公司 | Preparation process of alpha-ketoglutaric acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531968A (en) * | 2010-10-13 | 2012-07-04 | 张国基 | Process for preparation of l-arginine alpha-ketoglutarate 1:1 and 2:1 |
| CN102584568A (en) * | 2010-10-13 | 2012-07-18 | 张国基 | Process for preparation of alpha-ketoglutaric acid |
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2012
- 2012-12-26 CN CN2012105716979A patent/CN102976927A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531968A (en) * | 2010-10-13 | 2012-07-04 | 张国基 | Process for preparation of l-arginine alpha-ketoglutarate 1:1 and 2:1 |
| CN102584568A (en) * | 2010-10-13 | 2012-07-18 | 张国基 | Process for preparation of alpha-ketoglutaric acid |
Non-Patent Citations (2)
| Title |
|---|
| 李燕芸等: "3-(3, 5-二叔丁基-4-羟基苯基)丙酸甲酯的合成", 《精细石油化工》, no. 3, 31 May 2000 (2000-05-31), pages 1 - 3 * |
| 阎峰等: "5-甲基-3 ,5-二乙酯基-环戊-2-烯-2-羟基-1-酮的合成", 《沈阳化工学院学报》, vol. 18, no. 2, 30 June 2004 (2004-06-30), pages 81 - 84 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020068705A1 (en) * | 2018-09-25 | 2020-04-02 | Ponce De Leon Health Designated Activity Company | Process of making calcium alpha-ketoglutarate |
| US20210371368A1 (en) * | 2018-09-25 | 2021-12-02 | David Eugene Pereira | Process of making calcium alpha-ketoglutarate |
| EP3856166A4 (en) * | 2018-09-25 | 2022-06-22 | Ponce de Leon Health Designated Activity Company | Process of making calcium alpha-ketoglutarate |
| US11802103B2 (en) * | 2018-09-25 | 2023-10-31 | Ponce De Leon Health Designated Activity Company | Process of making calcium alpha-ketoglutarate |
| CN112941116A (en) * | 2021-01-04 | 2021-06-11 | 上海朴颐化学科技有限公司 | Method for preparing alpha-ketoglutarate calcium by enzyme method |
| CN116813466A (en) * | 2023-08-28 | 2023-09-29 | 江苏惠利生物科技有限公司 | Preparation process of alpha-ketoglutaric acid |
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Application publication date: 20130320 |