CN102675079B - Recovery method of aliphatic calcium alpha-keto acid - Google Patents
Recovery method of aliphatic calcium alpha-keto acid Download PDFInfo
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- CN102675079B CN102675079B CN201210081124.8A CN201210081124A CN102675079B CN 102675079 B CN102675079 B CN 102675079B CN 201210081124 A CN201210081124 A CN 201210081124A CN 102675079 B CN102675079 B CN 102675079B
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- picrolonate
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Abstract
The invention relates to a recovery method of aliphatic calcium alpha-keto acid. The recovery method of aliphatic calcium alpha-keto acid includes acidifying productive mother liquid of low-level aliphatic calcium alpha-keto acid, and converting the calcium alpha-keto acid into corresponding alpha-keto acid; performing extraction and concentration by organic solvents such as methyl tertiary butyl ether, ethyl acetate or diethyl ether to obtain alpha-keto acid; and finally allowing the alpha-keto acid to react with calcium chloride under partially neutral condition to generate salt to obtain calcium alpha-keto acid. Therefore, the calcium alpha-keto acid in the mother liquor is recovered, product yield is increased, emission of COD (chemical oxygen demand) is reduced effectively, and economic benefit and social benefit are increased.
Description
Technical field
The present invention relates to the synthetic technical field of bulk drug, be specifically related to the recovery method of alpha-calcium picrolonate.
Technical background
Alpha-ketoacid is the organic acid that a class has vital role in vivo, plays a central role in amino acid metabolism with in maintaining the process of redox state.Medically alpha-ketoacid is used for the treatment of emphatically the disease of chronic renal failure, it is patient's utilization by the transamination synth essential amino acid of enzyme in vivo, in not increasing kidney burden, improve patient nutritional status, mitigation symptoms, delay PD, also can reduce renal insufficiency patient and use the number of times of dialysis treatment.
At present, as a kind of important product, on market, alpha-ketoacid mainly exists with the form of its calcium salt.The synthesis technique of commercially producing aliphatic alpha-calcium picrolonate is mainly take glycolylurea as starting raw material, obtains intermediate with corresponding alkanoic or aliphatic ketone condensation, obtains alpha-calcium picrolonate by steps such as hydrolysis, extraction, salifies.Wherein as salify step 1, in the aqueous solution, carry out.For example glycolylurea respectively with isobutyric aldehyde, butanone and acetone generation condensation reaction, more just can obtain respectively alpha-keto-leucine-calcium, α-one Isoleucine calcium and α-one α-amino-isovaleric acid calcium through hydrolysis, salify etc.
Applicant finds that aliphatic alpha-calcium picrolonate has certain dissolving in water.At 20 ℃, solubilized alpha-keto-leucine-calcium 2-3g, dissolving α-one Isoleucine calcium 3-4g, dissolving α-one α-amino-isovaleric acid calcium 5-6g in 100ml water.Although low temperature crystallization can improve yield, have too much impurity and separate out, product related substance is difficult for qualified.So general alpha-calcium picrolonate Tc, at 10-30 ℃, still has considerable product to exist in mother liquor under this temperature condition, if mother liquor discharge causes sewage effluent COD value higher, not only cause waste but also increased environmental protection pressure.
Summary of the invention
The object of the invention is in order to reclaim aliphatic alpha-calcium picrolonate, especially lower aliphatic alpha-calcium picrolonate is produced the alpha-calcium picrolonate product containing in mother liquor, thereby effectively reduces the discharge of COD, improves product yield, increases benefit.Simultaneously additionally do not increase again raw material or varieties of reagent compared with the production technique of alpha-calcium picrolonate, can form with it a systems engineering.The carbonatoms of described lower aliphatic alpha-calcium picrolonate is 4-6.
The invention is characterized in and comprise the following steps:
A. at 0 ℃-60 ℃, with diluted acid by the mother liquor acidifying that contains alpha-calcium picrolonate.Activated carbon decolorizing, filtration.
B. at 0 ℃-50 ℃, filtrate extracts with extraction agent.Concentrating under reduced pressure extraction agent phase, obtains alpha-ketoacid.Dilute with water obtains alpha-ketoacid solution again.
C. at 0 ℃-80 ℃, with alkaline solution adjusting alpha-ketoacid pH 6-8, then react and obtain alpha-calcium picrolonate with calcium chloride solution.
Preferred processing condition are as follows:
A. get the mother liquor that unit volume contains alpha-keto-leucine-calcium or α-one Isoleucine calcium or α-one α-amino-isovaleric acid calcium, in mother liquor, the content of corresponding alpha-calcium picrolonate is at 1%-10%.With sulfuric acid, hydrochloric acid or the glacial acetic acid solution adjusting pH value of 5%-50%, the preferred 20%-50% of concentration of diluted acid.PH value is adjusted to 1-5, preferably 2-4.Control temperature at 0 ℃-60 ℃, preferably 20 ℃-40 ℃.Add proper amount of active carbon decolouring 0.5-1 hour, filter.
B. at 0 ℃-50 ℃, preferably 20 ℃-40 ℃, filtrate is with 0.2-2 times of methyl tertbutyl
Ether, ethyl acetate or ether equal solvent extraction 0.5-1 hour.Phase-splitting, retains organic pressure of subtracting each other concentrated, obtains oily alpha-ketoacid.Obtain alpha-ketoacid solution with being equivalent to alpha-ketoacid weight 1-10 water dilution doubly again, preferably 4-8 doubly.
C. at 0 ℃-80 ℃, preferably 30 ℃-60 ℃, use the sodium hydroxide of 10%-30% or potassium hydroxide solution to regulate alpha-ketoacid pH 6-8.Then within 1-3 hour, add the aqueous solution of calcium chloride or the aqueous solution containing alcohol, wherein in calcium chloride and mother liquor, the mol ratio of contained alpha-calcium picrolonate is 1-1.05: 1.Be down to again 20 ℃ of following 1-2 hour of stirring, filter or centrifugal, washing in right amount, obtain alpha-calcium picrolonate.Wherein, the concentration of preparation calcium chloride solution is 10%-30%, preferably 20%.
Adopt the present invention, corresponding alpha-calcium picrolonate productive rate can increase 10%-20%, and in its mother liquor waste water, the total emission volumn of COD can reduce more than 50%, and can combine closely with the flow process of alpha-calcium picrolonate again on producing, and is convenient to management.So the present invention can reduce discharge protection of the environment, can improve again yield and increase output, there is obvious economic and social benefit.
Unless otherwise indicated, per-cent of the present invention is mass percent.
Below in conjunction with specific examples, the present invention is further elaborated.
Embodiment
The recovery experiment one of embodiment 1 α-one α-amino-isovaleric acid calcium
A. get the mother liquor of 10L α-one α-amino-isovaleric acid calcium, wherein containing 6% of α-one α-amino-isovaleric acid calcium.Control 40 ℃ of left and right of temperature, stir, the dilute sulphuric acid with 30% regulates pH value to 3-4.Add 30g gac, decolour 30 minutes, filter.
B. filtrate is cooled to 30 ℃ of left and right, adds 3L methyl tertiary butyl ether, fully stirs 30 minutes, leaves standstill phase-splitting.Retain organic phase, control vacuum concentrating under reduced pressure under-0.09MPa condition, to without cut out till.Stirring adds 1.2L water, obtains α-one α-amino-isovaleric acid solution.
C. above-mentioned solution regulates pH value 7-8 with 20% sodium hydroxide solution, controls temperature 60 C left and right, and the calcium chloride water of agitation and dropping 1250kg 20%, adds for 2 hours.There are a large amount of white solids to separate out, are then cooled to 20 ℃ and continue reaction 1 hour.Filter, with washing in right amount, vacuum-drying obtains the about 440g of α-one α-amino-isovaleric acid calcium.
The recovery experiment two of embodiment 2 α-one α-amino-isovaleric acid calcium
Difference from Example 1 is to adopt in step a 20% dilute hydrochloric acid; In step b, extract 2 times with equivalent methyl tertiary butyl ether, remerged organic phase concentrated.Finally obtain the about 460g of α-one α-amino-isovaleric acid calcium.
The recovery experiment one of embodiment 3 alpha-keto-leucine-calciums
A. get the mother liquor of 10L alpha-keto-leucine-calcium, wherein containing 3% of alpha-keto-leucine-calcium.Control 40 ℃ of left and right of temperature, stir, the dilute sulphuric acid with 30% regulates pH value to 3-4.Add 30g gac, decolour 30 minutes, filter.
B. filtrate is cooled to 30 ℃ of left and right, adds 5L methyl tertiary butyl ether, fully stirs 30 minutes, leaves standstill phase-splitting.Retain organic phase, control vacuum concentrating under reduced pressure under-0.09MPa condition, to without cut out till.Stirring adds 1.5L water, obtains alpha-keto-leucine solution.
C. above-mentioned solution regulates pH value 7-8 with 20% sodium hydroxide solution.The calcium chloride water of preparation 560g20%, sneaks into 40g methyl alcohol therein.Control temperature 60 C left and right, in 2 hours, drip calcium chloride solution, have a large amount of white solids to separate out.Then be cooled to 20 ℃ and continue reaction 1 hour.Filter, with washing in right amount, vacuum-drying obtains the about 220g of alpha-keto-leucine-calcium.
The recovery experiment two of embodiment 4 alpha-keto-leucine-calciums
Difference from Example 3 is that in step a, pH value is adjusted to 2-3; In step b, extraction agent is selected ethyl acetate; In step c, adopt 20% potassium hydroxide solution.Finally obtain the about 240g of alpha-keto-leucine-calcium.
The recovery experiment one of embodiment 5 α-one Isoleucine calcium
A. get the mother liquor of 10L α-one Isoleucine calcium, wherein containing 4% of α-one Isoleucine calcium.Control 40 ℃ of left and right of temperature, stir, the dilute sulphuric acid with 30% regulates pH value to 2-3.Add 30g gac, decolour 30 minutes, filter.
B. filtrate is cooled to 30 ℃ of left and right, adds 5L methyl tertiary butyl ether, fully stirs 30 minutes, leaves standstill phase-splitting.Retain organic phase, control vacuum concentrating under reduced pressure under-0.09MPa condition, to without cut out till.Stirring adds 1.5L water, obtains α-one Isoleucine solution.
C. above-mentioned solution regulates pH value 7-8 with 20% sodium hydroxide solution.Control temperature 60 C left and right, the calcium chloride water of agitation and dropping 750g 20%, added in 2 hours, had a large amount of white solids to separate out.Then be cooled to 20 ℃ and continue reaction 1 hour.Filter, with washing in right amount, vacuum-drying obtains the about 310g of α-one Isoleucine calcium.
The recovery experiment two of embodiment 6 α-one Isoleucine calcium
With embodiment 5 relatively differences be to adopt in step a 20% Glacial acetic acid; In step b, adopt ether to make extraction agent, temperature of reaction is 20 ℃; In step c, pH value is adjusted to 6-7.Finally obtain the about 285g of α-one Isoleucine calcium.
Claims (8)
1. a recovery method for aliphatic alpha-calcium picrolonate, is characterized in that comprising the following steps:
A. at 0 ℃-60 ℃, with diluted acid by the mother liquor acidifying that contains aliphatic alpha-calcium picrolonate, activated carbon decolorizing, filtration;
B. at 0 ℃-50 ℃, filtrate extracts with extraction agent, and concentrating under reduced pressure extraction agent phase, obtains aliphatics alpha-ketoacid, then dilute with water obtains aliphatic alpha-one acid solution;
C. at 0 ℃-80 ℃, with alkaline solution adjusting alpha-ketoacid pH 6-8, then react and obtain aliphatic alpha-calcium picrolonate with calcium chloride solution.
2. the recovery method of aliphatic alpha-calcium picrolonate according to claim 1, the mother liquor that it is characterized in that the aliphatic alpha-calcium picrolonate of indication in step a is the aqueous solution of alpha-keto-leucine-calcium, α-one Isoleucine calcium or α-one α-amino-isovaleric acid calcium, and in solution, the content of corresponding aliphatic alpha-calcium picrolonate is between 1%-10%.
3. the recovery method of aliphatic alpha-calcium picrolonate according to claim 1, is characterized in that diluted acid used in step a is the aqueous solution of sulfuric acid, hydrochloric acid or Glacial acetic acid.
4. the recovery method of aliphatic alpha-calcium picrolonate according to claim 1, is characterized in that in step a, aliphatic alpha-calcium picrolonate mother liquor need be acidified to pH value 1-5.
5. the recovery method of aliphatic alpha-calcium picrolonate according to claim 1, is characterized in that extraction agent used in step b is methyl tertiary butyl ether, ethyl acetate or ether; The amount of extraction agent used is 0.2-2 times of mother liquor volume.
6. the recovery method of aliphatic alpha-calcium picrolonate according to claim 1, is characterized in that in step b, and the water yield of dilution aliphatics alpha-ketoacid is 1-10 times of aliphatics alpha-ketoacid weight.
7. the recovery method of aliphatic alpha-calcium picrolonate according to claim 1, is characterized in that in step c, alkaline solution used is the aqueous solution of sodium hydroxide or potassium hydroxide.
8. the recovery method of aliphatic alpha-calcium picrolonate according to claim 1, is characterized in that in step c, the aqueous solution that calcium chloride solution used is calcium chloride or the aqueous solution containing alcohol.
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| US11484579B2 (en) | 2017-11-29 | 2022-11-01 | Edgar L Hull | Vitamins and alpha keto acid compositions for use in a treatment program for chronic kidney disease patients |
| EP3716966A4 (en) | 2017-11-29 | 2021-08-18 | Hull, Edgar, L., Jr. | Alpha keto acid compositions for treating hypo-albuminemia |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4076745A (en) * | 1976-07-08 | 1978-02-28 | Syntex (U.S.A.) Inc. | Process for calcium salts α-ketocarboxylic acids |
| CN101607888A (en) * | 2009-07-23 | 2009-12-23 | 河北九派制药有限公司 | The preparation method of alpha-keto-leucine-calcium |
| CN101759553A (en) * | 2008-11-21 | 2010-06-30 | 扬子江药业集团北京海燕药业有限公司 | Method for preparing alpha-calcium picrolonate |
-
2012
- 2012-03-26 CN CN201210081124.8A patent/CN102675079B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4076745A (en) * | 1976-07-08 | 1978-02-28 | Syntex (U.S.A.) Inc. | Process for calcium salts α-ketocarboxylic acids |
| CN101759553A (en) * | 2008-11-21 | 2010-06-30 | 扬子江药业集团北京海燕药业有限公司 | Method for preparing alpha-calcium picrolonate |
| CN101607888A (en) * | 2009-07-23 | 2009-12-23 | 河北九派制药有限公司 | The preparation method of alpha-keto-leucine-calcium |
Non-Patent Citations (2)
| Title |
|---|
| 丁威.海因法合成几种α-酮酸及α-酮酸盐.《中国硕士学位论文全文数据库》.2007, |
| 海因法合成几种α-酮酸及α-酮酸盐;丁威;《中国硕士学位论文全文数据库》;20070415;第7、11页 * |
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