Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1988-11-25
1989-12-19
Lone, Werren B.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 9, 560 22, 560 37, 560170, C07C 6708
Patent
active
048884405
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the preparation of aspartic acid 4-(phenylmethyl) ester from aspartic acid and benzyl alcohol.
Such processes have been known previously (Houben-Weyl: "Methoden der organischen Chemie" [Methods of Organic Chemistry], Georg Thieme Publishers, D-Stuttgart, vol. XV/1, "Syntheses of Peptides, Part 1", 1974, pp. 645 et seq.). The most advantageous procedure for the partial esterification of aspartic acid with benzyl alcohol is deemed to be the condensation of the components, catalyzed by sulfuric acid. According to this process, it is assertedly possible to prepare the desired product of the process in a yield of 40-45% of theory (Can. J. Chem., 40: 571, 1962); however, it was found under practical conditions that the yields of the product of the process obtained according to this method are substantially lower. Furthermore, this conventional process has the drawback that the process per se and also the purification of the primarily obtained crude products, as well as the recovery of unreacted starting materials are rather expensive.
The present invention is based on the object of developing a process which is less expensive than the prior-art processes and which makes it possible to prepare the aspartic acid 4-(phenylmethyl) ester in a higher yield.
This object has been attained by making a process available which is characterized by using a reaction mixture containing, per mole of aspartic acid, 10-40 moles of benzyl alcohol and 1-5 moles of acetyl chloride; by performing the reaction at a temperature of -10.degree. C. to 50.degree. C.; and by separating the product of the process, after reaction has taken place, by neutralization with organic bases.
The process of this invention is suitable for the controlled esterification of the .beta.-positioned carboxy groups of L-aspartic acid, of D-aspartic acid, and of D,L-aspartic acid.
In order to conduct the process of this invention, a reaction mixture is employed containing, per mole of aspartic acid, 10-40 (preferably 15-30 and especially 20-30) moles of benzyl alcohol and 1-5 (preferably 1-4 and especially 1.5-3.0) moles of acetyl chloride.
In accordance with the invention, the reaction is performed at -10.degree. C. to +50.degree. C. It proved to be expedient to conduct the reaction at a temperature of -10.degree. C. to +20.degree. C. (preferably -10.degree. C. to +15.degree. C. and especially at -5.degree. C. to +10.degree. C.), as long as the reaction still proceeds exothermally. In order to avoid overheating of the reaction mixture during this phase, the aspartic acid is suitably introduced in incremental portions under agitation into the provided benzyl alcohol - acetyl chloride mixture. The time required for this purpose is normally 1-4 hours. After termination of the exothermal reaction phase, the further reaction is suitably performed at a temperature of 10.degree. C. to 50.degree. C., preferably at 15.degree.-30.degree. C., and especially at room temperature. The required reaction period is, of course, dependent on the choice of the reaction temperature; this period can be readily determined by means of the customary analytical methods (e.g. by thin-layer chromatography). When performing the reaction after the exothermal phase at room temperature, the reaction time is normally 2-4 days.
After reaction has taken place, the reaction product will be precipitated by neutralization of the reaction mixture with organic bases (such as triethylamine, N-methylmorpholine and, in particular, pyridine). For this purpose, 1 mole of organic base is needed per mole of acetyl chloride utilized. The use of an excess of organic base is uncritical so that it is advantageous to employ 1 to 1.25 moles of organic base per mole of acetyl chloride utilized. Neutralization is usually performed at a temperature of 10.degree.-40.degree. C.--preferably at room temperature. For obtaining a complete precipitation of the product of the process (as the crude product), the neutralized mixture is suitably allowed to stand an additional 6-20 hours,
REFERENCES:
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patent: 4394308 (1983-07-01), Sampathkumar et al.
patent: 4622413 (1986-11-01), Krogh
patent: 4709086 (1987-11-01), Schlingmann et al.
patent: 4761495 (1988-08-01), Wirth et al.
Clarke Vera C.
Diamalt AG
Lone Werren B.
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