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Method for the production of ketoacids and their derivatives

A technology of derivatives and ketoacids, applied in the field of preparation of α-ketoacids, which can solve problems such as difficult separation and instability

Inactive Publication Date: 2010-03-31
EVONIK DEGUSSA GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another disadvantage of the process described in WO 06-727211 is that none of the existing plants can be used for the production of methionine or MHA, so new production plants have to be built for each of the individual processes described
The synthetic route described in WO 06-72711 always leads to free α-ketomethionine, which is unstable and difficult to isolate

Method used

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  • Method for the production of ketoacids and their derivatives
  • Method for the production of ketoacids and their derivatives
  • Method for the production of ketoacids and their derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Preparation of 1,1,3-tris(methylthio)propane (2) from 3-(methylthio)propanal (1)

[0080]

[0081] Me = methyl

[0082] 3-(Methylthio)propanal (1) (1.44 mol, 150 g) was saturated with HCl (g) at 0°C, then added directly to MeSH (6.25 mol, 300 g) dropwise over 30 minutes at 0°C )middle. The reaction mixture was heated to 20 °C and stirred at 20 °C for 24 h. After removal of excess MeSH under reduced pressure, GC analysis showed the following product distribution: 91% thioacetal (2) and 8% 3-(methylthio)propanal (1). For further purification, the mixture was dissolved in ether and treated with 30% sodium metabisulfite (Na 2 S 2 o 5 ) aqueous solution washing. After phase separation, MgSO 4 The organic phase is dried. After removal of the solvent, the thioacetal (2) was obtained as a pale yellow oil (168 g, yield = 64%, GC purity = 98%).

[0083] 1,1,3-tris(methylthio)propane (2) 1 H NMR (500MHz, CDCl 3 ): δ=2.01-2.05 (m, 2H, CH 2 ), 2.11(s, 9H, 3×SCH 3 ), ...

example 2

[0086] Preparation of 1,1,3-tris(methylthio)propane (2) from acrolein (3)

[0087]

[0088] Acrolein (3) (89 mmol, 5.0 g) was added dropwise to MeSH (358 mmol, 17.2 g) which had been saturated with HCl gas at 0 °C over 15 minutes under stirring at -78 °C. This mixture was heated slowly to 20°C and then stirred at 20°C for a further 24h. After removal of excess MeSH under reduced pressure, the mixture was dissolved in ether and washed with 30% aqueous sodium metabisulfite. After phase separation, MgSO 4 The organic phase is dried. After distillation (88° C. at 1.2 mbar), pure thioacetal (2) was obtained as a pale yellow oil (11.4 g, yield=70%, GC purity=98%). NMR characterization gave the same data as in Example 1.

Embodiment 3

[0090] Through 1,1,3-tris(methylthio)propane (2) and dry ice (CO 2 ) to prepare 2,2,4-tri(methylthio)butanoic acid (4).

[0091]

[0092] In a three-neck flask under a protective gas atmosphere, 1,1,3-tris(methylthio)propane (2) (3.65 g, 20 mmol) was dissolved in 50 ml of anhydrous THF. Subsequently, a solution of butyllithium in n-hexane (14ml, 1.6M) was slowly added dropwise under stirring at -20°C. During this time, the solution turned bright yellow. After continuing to stir at this temperature for 2 h, anhydrous dry ice (CO 2 , 10g). The reaction solution was slowly thawed to 20° C., and 10% aqueous KOH (80 ml) was added. After phase separation, the organic phase was washed with 10% aqueous KOH (2 x 50 ml). The combined KOH phases were washed with diethyl ether (3 x 30 ml) and carefully adjusted to pH=1 with concentrated HCl while cooling. The product was extracted with ether (3 x 50ml). followed by Na 2 SO 4 The combined ether phases were dried, filtered and c...

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Abstract

A method for the production of a-ketoacids, in particular of a-ketomethionine, and their derivatives is described, as also is the use of thiols for reversing the polarity of aliphatic or aromatic aldehydes. In this method, a) an aldehyde is reacted with thiols to give the corresponding dithioacetal, and b) the resultant dithioacetal then reacts with an electrophile in the presence of a base and after hydrolysis to give an a,a-(dithio)carboxylic acid and c) the a,a-(dithio)carboxylic acid is then reacted via acid-catalysed solvolysis to give the a-ketoacid or its derivatives, with liberation of thiol.

Description

technical field [0001] The present invention relates to a new method for preparing α-ketoacids, especially α-ketomethionine and its derivatives. Background technique [0002] Alpha-keto acids are important products and can be used in particular for the supplementation of amino acids in the treatment of chronic renal failure (Jungers et al., Blood Purification 1988, 6, 299-314 and Clasen et al., Med.Klin.1978 , 73, 1403-1408). [0003] Various methods for the synthesis of α-ketoacids have been described in the literature, involving the reaction of Grignard reagents with dialkyl oxalates and subsequent hydrolysis of the resulting esters to form the free acids (Rambaud et al., Synthesis 1988, 564 and Macritchie et al., Tetrahedron: Asymmetry 1997, 8, 3895). Acid-catalyzed hydrolysis of acylcyanides can also generate α-keto acids (Nozaki et al., Tetrahedron: Asymmetry 1993, 4, 2179). Billek reported the preparation of a series of α-keto acids. In this preparation, alkylene h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/15C07C323/52C07C59/185
CPCC07B41/06C07D317/32C07C323/52C07C319/14C07D493/08C07C67/313C07C51/373C07C319/20C07B41/08C07C62/18C07C69/716C07C321/14
Inventor C·科布勒M·哈特利P·罗特B·耶格尔C·韦克贝克K·胡特马赫尔
Owner EVONIK DEGUSSA GMBH
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