CN101440012A - Method for purifying alpha-oxo-carboxyl acid - Google Patents
Method for purifying alpha-oxo-carboxyl acid Download PDFInfo
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- CN101440012A CN101440012A CNA2007103068716A CN200710306871A CN101440012A CN 101440012 A CN101440012 A CN 101440012A CN A2007103068716 A CNA2007103068716 A CN A2007103068716A CN 200710306871 A CN200710306871 A CN 200710306871A CN 101440012 A CN101440012 A CN 101440012A
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Abstract
The invention relates to a method for purifying alpha-oxo-carboxylic acid of a formula (I) and a formula (II) respectively.
Description
Technical field
The present invention relates to the method for the alpha-oxo-carboxyl acid of difference purifying formula (I) and formula (II).
Background technology
Alpha-oxo-carboxyl acid is the multi-usage intermediate in the organic synthesis, when being used for chronic renal failure as the medicine of the additive of infusion solution or parenteral nutrition and play important effect (Walser et al., ClinicalNephrology 1975,3,178f.; Macia et al., Clinical Nephrology 1997,48,181f.).
The generation of instant acid be those skilled in the art known (Beyer, Walter, Lehrbuch derorganischen Chemie, S.Hirzel Verlag Stuttgart, 22.Auflag, s.293; US4948920).Advantageously, α, β-unsaturated glycolylurea can be split by acid or basic hydrolysis, thereby forms thick alpha-ketoacid (JP59199652; JP54103824).α, β-unsaturated glycolylurea itself can obtain (DE3527477) by glycolylurea and ketone or the reaction of aldehyde under alkalescence or acidic catalyst.
Yet alpha-hydroxy carboxylic acid compounds can obtain (also can referring to GB1080667) by so-called cyanalcohol route by the reduction alpha-ketoacid or according to DE19548538.
The third method can be by adding ketone or aldehyde in barkite under strong alkaline condition, and carry out acidity or alkaline hydrolysis subsequently and realize (referring to JP54088217).
Yet,, therefore must carry out high-caliber purifying to it because prepared product will be used in nutrition or the formula of medicine.Described carboxylic acid enters into prescription with the form of its salt.Therefore, if purifying can with form needed salt simultaneously then be favourable.
US4076745 proposes the acid of being envisioned is dissolved in the organic solvent with amine in this regard, and calcium salt crystallization that subsequently should acid.
DE10212322 has instructed the crystallization by an alkali metal salt of instant each calcium salt of acid to come purifying.The hydrochlorate that is produced is enough pure, can spraying drying and directly sneak in the formula of medicine.
But still need purification process, particularly those are adopted by industrialization easily, are used to produce the method that is enough to be directly used in the high product of the purity of producing formula of medicine.
Therefore, the novel method that the purpose of this invention is to provide purifying alpha-oxo-carboxyl acid.Especially method of the present invention can advantageously be used in technical scale, and does not need to install complicated technology equipment.This method can obtain qualified product (in-spec-product), its stable and control easily, and more be better than those methods well known in the prior art, particularly from economical and ecological aspect.
Description of drawings
Fig. 1: solvent cycle schema
Summary of the invention
These purposes are achieved by implementing the described method of claim.
By implementing the method for purifying formula (I) or alpha-oxo-carboxyl acid (II), unexpectedly realized described purpose, promptly obtain high-quality material with simple and strict method, described in addition method can also be used in industrial-scale production easily.This method has produced reliable purified product, and it can directly be used for being incorporated in the formula of medicine subsequently, and does not need further purification step.In addition, the method for the present invention method for protrusion (prominent process) that will produce alpha-oxo-carboxyl acid is attached in a kind of purification process.Therefore, highly beneficial ground, various types of formulas (I) or alpha-oxo-carboxyl acid (II) can carry out purifying with the identical operations method.Do not need to change batching or equipment when changing the substrate of wanting purifying, this point all is very favorable from actually operating and logic aspect.These superior aspects can not be inferred from the purification process of prior art and draw, and therefore, are non-obvious to those skilled in the art.
Wherein
α-the group of R ' expression natural amino acid,
It comprises the steps:
A) will be adjusted to pH4-0.1 from the crude product (I) of basic hydrolysis step or the pH value of aqueous reaction mixture (II);
B) use the organic solvent of logP value＜4 with described mixture extraction at least once under related reaction conditions, to cause to be separated;
C) separate organic layer, and the organic layer that will choose merging wantonly is incorporated in the aqueous solution of Ca salt;
D1) by separation remove organic layer or
D2) under vacuum, remove organic solvent, and
E) the Ca salt of crystallization and separate type (I) or acid (II),
In preferred embodiments, the α-group of formula (I) or alpha-oxo-carboxyl acid (II) is identical with the group of the natural a-amino acid that is selected from L-Ala, arginine, l-asparagine, l-asparagine acid, halfcystine, glutaminase, glutamy propylhomoserin (glutamineacid), glycine, Histidine, Isoleucine, leucine, methionine(Met), phenylalanine, Serine, Threonine, tryptophane, tyrosine and Xie Ansuan.Particularly preferably be group as L-Ala, glutaminase, glycine, Isoleucine, leucine, methionine(Met), phenylalanine and Xie Ansuan.Most preferably as the group in L-Ala, glycine and the leucine.
In the step a) of present method, the acid of purifying can directly take from following alkaline saponification process.The preferred crude product mixture of using, it is that knowledge according to those skilled in the art (is used mineral acid for example HCl, H
3PO
4Deng) acidifying.
The pH value that will reach in the acidization of reaction mixture can be selected according to common practise.Have been found that pH is that 0.1-4 is feasible, this depends on the acid of the purifying of wanting.Though the pH value of 0.1-1 is preferred, more preferably use the pH value of 1-3.Best be range regulation with pH to 1.5-2.5, do not produce by product thereby do not take place to decompose, particularly when use comparatively high temps in acidifying yet.
Reaction mixture can be handled with charcoal and flocculating aids (as diatomite), thereby makes the solution decolouring.
Temperature in the step a) during reaction mixture acidifying can be regulated to 100 ℃ at 0 ℃ by those skilled in the art.Described temperature should be high as much as possible, thereby stop product or salt to precipitate from aqueous mixture or separate, and should be enough low and do not form by product.The temperature that is lower than 60 ℃ is feasible, but preferably described temperature is remained on 60 ℃ to 80 ℃ scope, most preferably about 70 ℃, more preferably～75 ℃.
In second step b), with the aqueous reaction mixture of organic solvent extraction from step a).This solvent can be selected by those skilled in the art.He trends towards using those solvents that form two-phase mixture under related extraction conditions with water.He can select the most advantageously acid product to be extracted into the solvent in the organic layer on the other hand.Therefore, described solvent should have enough polarity, thereby related acid is had good solubility.Polarity of solvent can be by measuring (the definition: the logP value of compound, i.e. the logarithm log (c of partition ratio between n-Octanol and the water of so-called logP value
Octanol/ c
Water), be compound wetting ability module used for a long time.Low wetting ability and the high logP value of therefore bringing cause bad absorption and infiltration) represent.This numerical value should＜4, more preferably＜2.5, most preferably between 0.5 to 2.0.
Preferably, described organic solvent is selected from ketone, ether, pure and mild halogenated aliphatic or aromatic hydrocarbons.More preferably use solvent as chloroform, methylene dichloride, MiBK, acetonitrile, diethyl ether, Virahol and chlorobenzene.Most preferably, described solvent is selected from Virahol, propyl carbinol, diethyl ether, MiBK or chloroform, methylene dichloride or their mixing.
Temperature in the extraction process step b) preferably between 0 ℃ to one higher limit, certainly, depends on the boiling point under the employed organic solvent normal pressure.Because acidifying is preferably carried out about 70 ℃, described extraction also can be carried out under this temperature, and acid is dispensed in the organic phase more quickly.But extraction also can be carried out under lower temperature, as about room temperature or lower slightly 0 ℃-20 ℃.Most preferably, extraction is carried out at 30 ℃-60 ℃, and the most preferred (utmost preferably) is at 50 ℃-60 ℃.
Organic extraction can be carried out several.Usually need carry out repeatedly, so that abundant product dissolves in the organic layer.This need be determined from the angle of economy by those skilled in the art.From aqueous reaction mixture, separate organic layer and collection subsequently respectively.
The organic layer that merges can with use the salt water washing before the Ca salt brine solution contact, thereby the saltiness of reduction organic phase, and reextraction is from the water-soluble impurity of reaction process.
At next procedure c) in, with the aqueous solution merging of organic layer and Ca salt (as calcium chloride or lime acetate).Other appropriate C a salt can be selected from: lime carbonate, citrate of lime, calcium chloride, calglucon, nitrocalcite, calcium propionate, lime acetate, calcium formiate, calcium saccharate, secondary calcium phosphate, calcium lactate, calcium ascorbate, calcium tartrate, calcium acetylacetonate, calcium ammonium nitrate, Calcium glutamate, caoxalate, calcium stearate, calcium thiocyanide.
Should stir described two-phase, thereby make the acid product of organic phase change into its Ca salt.In making that the form of salt of product mainly is soluble in the aqueous phase.Step c) can be carried out under the temperature that those skilled in the art select.Preferably, the temperature of mentioning extraction step b) also can be used in this step.
Step subsequently can be carried out in two ways.Organic layer separated from the aqueous product mixture or organic layer steamed under vacuum and remove.Method selected often depends on employed alpha-oxo-carboxyl acid.By the test of routine, those skilled in the art can select the best way for the acid that will prepare.
In steps d 1) in, being separated under 40 ℃-60 ℃ the temperature of organic layer carried out, and this is the normal temps of mixture after the extraction step.The organic solvent that is deposited in aqueous phase can steam under vacuum and remove.
Alternatively, under vacuum, distill, preferably, distilling more than 70 ℃, thereby keep of short duration distillation time (steps d 2).
In any case people can both obtain the Ca salt brine solution of formula (I) or alpha-oxo-carboxyl acid product (II) in above-mentioned two kinds of methods.Subsequently this solution is carried out crystallization, and come precipitation separation by known method (for example filtration or centrifugal).
Crystallization is preferably carried out being lower than under 20 ℃ the temperature, thereby obtains to be suitable for filtering precipitation with high yield.In order to increase crystallization, aqueous product mixture and organic solvent (for example acetone, ethanol, methyl alcohol, dioxane, THF) that can be miscible with water can be mixed.
Employed organic solvent can reclaim and reuse.Mother liquor can reclaim, and is used as the solvent and the solvent change step (Fig. 1) of Ca salt.
Formula (I) or α-ketone (II)-or Alpha-hydroxy-acid can be preferably synthetic by three kinds of dissimilar methods respectively.Glycolylurea (Hydantoine) method can advantageously be applied to the ketone acid that those ketone group ortho positions have methylene radical.Alpha-position at ketone group has under the situation of other group, uses the method for oxalic acid diethyl ester can obtain good result.For alcohol acid, can use commercially available dimeric cracking (as ABCR, Aldrich etc.).
Dimeric cracking
The glycolylurea method
The oxalic acid diethyl ester method
Specific embodiments
The preparation of glycolylurea precursor:
In the presence of basic catalyst, aldehyde is joined in the protic solvent (preferably water) of glycolylurea.This can be amine, amino alcohol or amino acid.Reaction mixture forms foam easily.Need to add defoamer in this case.The temperature that adds must be lower than 100 ℃.If the use fatty aldehyde preferably add temperature and be lower than 30 ℃, and for aromatic aldehyde, the temperature of adding should be lower than 85 ℃.Described adding can begin under lower temperature, and can be increased to maximum value by the adding of aldehyde.After adding was finished, the afterreaction between 1 to 6 hour must be finished between 85 ℃ at 80 ℃.Under the situation of aromatic aldehyde, need be between 4.5 with pH regulator to 4.0.Solution can be cooled to crystallization below 30 ℃, and product can separate by centrifugal or filtration.Mother liquor can be reused, preferably by the distillation concentrated mother liquor.
The glycolylurea method
Glycolylurea or dimer (for example according to above-mentioned prepared in reaction) is water-soluble and be heated to 80 ℃ to 105 ℃.Add NaOH solution.Adding NaOH solution carries out under 80 ℃.Finish after the adding of NaOH, solution was further stirred 1.5 hours to 5.0 hours between 80 ℃ to 105 ℃.Can add defoamer (it can be from BYK Chemie, and Germany buys) if take place to bubble.
Dimeric cracking
The water of 150ml and the alcohol acid dimer of 250ml are mixed together and are heated to 60 ℃.Adding 100ml caustic solution also stirred 2 hours under 60 ℃., and solution is cooled to below 30 ℃ pH regulator to 2 with hydrochloric acid.In the presence of 5g gac (Norrit B supra) and 5g are diatomaceous, with solution stirring 1 hour.Charcoal and flocculating aids are filtered out, and use this solution according to the operation steps of other two kinds of methods.
The oxalic acid diethyl ester method
Between 0 ℃ to 20 ℃, oxalic acid second diester is joined in the methanol solution of sodium methylate.Under this temperature, add aldehyde.Between 20 ℃ to 40 ℃, slowly add NaOH solution then.Adding is finished to steam under vacuum afterwards and is desolventized, and adds entry at 50 ℃ between 70 ℃.
With thus obtained formula (I) or α-ketone (II)-or the alkaline aqueous solution of Alpha-hydroxy-acid carry out purification process according to the present invention who describes in detail above.
Present method can produce enough pure product, and it can be directly used in the medicinal application.It can be at the form administration that is with or without under the situation of other additive with solution or pill.Even in scale operation, this method also is very easy to install and control, and can similarly be applied to every kind of alpha-oxo-carboxyl acid.Therefore, when changing the substrate of wanting purifying, do not need to consider to replace processing units and operation batching.This is with respect to the very important advantage of means known in the art, and its knowledge according to those skilled in the art can not be expected, also is non-obvious.
The glycolylurea operating process:
The ethylidene glycolylurea (ethyliden hydantoine) of water and the 0.4mol of 180ml is mixed in reaction vessel.Elevated temperature to 90 ℃, and add the NaOH solution of 14ml.Elevated temperature arrives near 100 ℃ once more, and adds the NaOH solution of 100ml.Adding is stirred reaction mixture 2 hours under this temperature after finishing.Reaction mixture is cooled to below 30 ℃, with hydrochloric acid with below the pH regulator to 2.With twice of the chloroform extraction aqueous solution.The 58.4g caoxalate is dissolved in the 1600ml water.Organic solution is joined in the Ca salts solution under 60 ℃.Each layer separated, and the organic solvent of remnants is removed from water layer by vacuum distilling.Solution is cooled to below 20 ℃, and separated product is also dry.(41g＝85％)
Oxalate diester operation (work-up) process:
Sodium methoxide solution (190ml) is cooled to 5 ℃, and adds the 109.3g oxalic acid diethyl ester.Add the 91g propionic aldehyde.Temperature must be lower than 20 ℃.After stirring 1 hour under 20 ℃, add the NaOH solution of 177g 17.5%.The water that adds 100ml subsequently.Steam the solvent that removes 400ml under the vacuum.At 62 ℃ of water that add 230ml down.Reaction mixture is cooled to below 30 ℃, and with hydrochloric acid with below the pH regulator to 2.With twice of the chloroform extraction aqueous solution.The 63.3g caoxalate is dissolved in the 1850ml water.Organic solution is joined in the Ca salts solution under 60 ℃.Each layer separated, and the organic solvent of remnants is removed from water layer by vacuum distilling.Solution is cooled to below 20 ℃, and separated product is also dry.(78.7g＝87％)
The extraction step of being mentioned can be carried out in a continuous manner, such as, in mixing sedimenting system (Mixer Settler-system).
Claims (9)
1, the method for purifying formula (I) or alpha-oxo-carboxyl acid (II),
Wherein
α-the group of R ' expression natural amino acid,
It may further comprise the steps:
A) will be adjusted to pH4-0.1 from the crude product (I) of basic hydrolysis step or the pH value of aqueous reaction mixture (II);
B) use the organic solvent of logP value＜4 with described mixture extraction at least once under related reaction conditions, to cause to be separated;
C) separate organic layer, and the organic layer that will choose merging wantonly is incorporated in the aqueous solution of Ca salt;
D1) by separation remove organic layer or
D2) under vacuum, remove organic solvent, and
E) the Ca salt of crystallization and separate type (I) or acid (II).
2, the process of claim 1 wherein:
Described α-group is identical with the α-group of the natural a-amino acid that is selected from L-Ala, arginine, l-asparagine, l-asparagine acid, halfcystine, glutaminase, glutamy propylhomoserin, glycine, Histidine, Isoleucine, leucine, methionine(Met), phenylalanine, Serine, Threonine, tryptophane, tyrosine and Xie Ansuan.
3, the process of claim 1 wherein:
In step a), the pH value is adjusted to 1-3.
4, the method for claim 3, wherein:
Temperature with mixture in step a) remains between 0 ℃ to 100 ℃.
5, the process of claim 1 wherein:
Organic solvent in the step b) is selected from ketone, ether, pure and mild halogenated aliphatic or aromatic hydrocarbons.
6, the process of claim 1 wherein:
With the optional organic layer that merges with use the salt water washing before the Ca salt brine solution contacts.
7, the process of claim 1 wherein:
In steps d 1) in being separated under 40 ℃-60 ℃ the temperature of organic layer carry out.
8, the process of claim 1 wherein:
Steps d 2) distillation is carried out being higher than under 70 ℃ the vacuum.
9, the process of claim 1 wherein:
Described crystallization is carried out being lower than under 20 ℃ the temperature.
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Citations (6)
| 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 |
| GB1550993A (en) * | 1976-10-07 | 1979-08-22 | Grace W R & Co | Preparation of aliphatic and heteocyclic alphaketo carboxylic acids |
| US4948920A (en) * | 1989-03-24 | 1990-08-14 | The Nutrasweet Company | Process for the preparation of phenylpyruvic acid from benzyl chloride |
| JPH1036312A (en) * | 1996-07-25 | 1998-02-10 | Toray Ind Inc | Ph adjustment of pyruvic acid-containing liquid |
| DE10018098A1 (en) * | 2000-04-12 | 2001-11-08 | Rudolf Erich Klemke | Treatment of cancer by apoptosis induction comprises administration of amino acid and saturated fatty acid derivatives |
| CN1592730A (en) * | 2000-09-15 | 2005-03-09 | 普拉克生化公司 | Method for the purification of an alpha-hydroxy acid on an industrial scale |
-
2007
- 2007-11-23 CN CNA2007103068716A patent/CN101440012A/en active Pending
Patent Citations (6)
| 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 |
| GB1550993A (en) * | 1976-10-07 | 1979-08-22 | Grace W R & Co | Preparation of aliphatic and heteocyclic alphaketo carboxylic acids |
| US4948920A (en) * | 1989-03-24 | 1990-08-14 | The Nutrasweet Company | Process for the preparation of phenylpyruvic acid from benzyl chloride |
| JPH1036312A (en) * | 1996-07-25 | 1998-02-10 | Toray Ind Inc | Ph adjustment of pyruvic acid-containing liquid |
| DE10018098A1 (en) * | 2000-04-12 | 2001-11-08 | Rudolf Erich Klemke | Treatment of cancer by apoptosis induction comprises administration of amino acid and saturated fatty acid derivatives |
| CN1592730A (en) * | 2000-09-15 | 2005-03-09 | 普拉克生化公司 | Method for the purification of an alpha-hydroxy acid on an industrial scale |
Non-Patent Citations (2)
| Title |
|---|
| 丁威: "海因法合成几种α-酮酸及α-酮酸盐", 《工程科技I辑》 * |
| 祝馨怡等: "α-酮酸、α-酮酸酯及α-酮酰胺的合成进展", 《合成化学》 * |
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Application publication date: 20090527 |