CA1046524A - Process for the preparation of beta-hydroxy-aminoacids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The present invention relates to a process for the preparation of d1-serine starting from alkali-labile precursors of glycolaldehyde through the Strecker reaction and variations thereof characterized in that said precursors are selected from the following compounds: - monochloroethyleneoxide, vinylacetateepoxide, monoacetoxiacetaldehyde, 2,2-diacetoxy-ethanole, monochloroethylenecarbonate, monoacetoxyethylenecarbonate, vinylencarbonate, 2,5-dichlorodioxane and 2,5-diacetoxydioxane.

Description

iSZ4 The present invention relates to a process for the preparation of dl-serine starting from alkali-labile precursors of glycolaldehyde through the Strecker reaction and variations thereof.
It is known that serine is an important aminoacid employable in the pharmaceutical industry as intermediate for the preparation of O-phospho-d, l-serine and cycloserine.
An economical synthesis of serine, moreover, could allow this amino-acid to be used as intermediate in the enzymatic production of l-tryptophan which is a fundamental aminoacid employed in the human and animal nourishment.
The object of the present invention is constituted by a process for the preparation of dl-serine starting from alkali-labile precursors of glycolaldehyde, characterized in that such precursors can be obtained from low cost products and reagents, anyhow lower than the one of the intermediates -~
till now employed in the synthesis of serine.
As abovesaid the formation of dl-serine occurs through ~ `
the Strecker reaction, preferably according to the modified run of Zelinsky - Stadnikoff, and may be carried out directly on the alkali-labile precursors of glycolaldehyde without any preliminar hydrolisis step, since the hydrolisis of these derivatives can `~ `
occur in situ in the alkaline conditions of the Strecker reaction ;
itself.
According to a possible alternative way, the hydrolisis can be firstly performed and then, without isolating the product thereof, the Strecker reaction can be carried out in the same reaction : every man skilled in the art will be able to choice the best conditions for obtaining good yields of the final product.
The alkali-labile precursors of glycolaldehyde, object of the present invention may be obtained according to cheap and easily realizable processes, for instance according to what said -- 1 -- ~

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in some co-pending applica-tions in the name of the same applicant.
They can be selected from the following compounds:
- monochloroethyleneoxide, vinylacetateepoxide, monoacetoxiacetaldehyde, 2,2-diacetoxyethanole, monochloroethy-lenecarbonate, monoacetoxyethylenecarbonate, vinylencarbonate,

2,5-dichlorodioxane and 2,5-diacetoxydioxane.
The working conditions will be, anyhow, more clear from reading the following examples which, however, purpose only to illustra-te the invention, without being limitative thereof.

General method for the preparation of dl-serine through the Zelinsky - Stadnikoff reaction on glycolaldehyde and precursors thereof:
20 mmoles of substrate (10 mmoles in the case of 2,5-dichloro- and 2,5-diacetoxy-dioxane) dissolved in 15 ml of methyl alcohol (15 ml of water when use was made of water-soluble substrates) were added to a solution formed by 1.30 g :-, (20 mmoles) of potassium cyanide and 1.18 g (22 mmoles) of ammonium chloride in 10 ml of concentrated ammonia (about 30%~
the addition being carried out under stirring and cooling so that the temperature did not go beyond 20-25 C.
The mix-ture was kept under stirring at a temperature of 30-35C over 18-20 hours, was acidified with 11 ml of concentrated hydrochloric acid and dried at 60C under vacuum.
The residual was added with 11 ml of concentrated hydrochloric acid and 11 ml of water and was refluxed over 3-5 hours, then dried under vacuum and treated with 10 ml of anhydrous ethyl alcohol while the insoluble salts were filtered.

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~ he alcoholic solution was brought to a pH of 6 with triethylamine (or ammonia~ and, after cooling, precipitated dl-serine was collected and, if necessary, again crystallized from ethyl alcohol-water.
Examp~es of yields to obtained serine are reported in the following table:
Substrate - Yield as dl-serine ~:
Glycolaldehyde 70% :.
Vinylacetateepoxicle 70 2 9 5-diacetoxydioxane 70%
2,5-dichlorodioxane ~5% -~
Monoacetoxyethylenecarbonate 55%
Monochlorethylenecarbonate 35 Vinylencarbonate 45 EXAMP~E 2 Preparation of dl-serine from monochloroethyleneoxide via glycolaldeh~de~
1057 g (20 mmoles) of monochloroethyleneoxide were ~; .-added, drop by drop under stirring and cooling, to 15 ~l of water by keeping the temperature below 5C. The whole was kept ~:
under stirring over two hours at room temperature. Now the hydrolisis to glyco.laldehyde was over (disappearance of mono~
chloroethyleneoxide) and a yield of 65~ was calculated from a titrimetric dosage of hydrochloric acid developed, carried out .
on a sample of the reaction mixture by means of an excess of :
sodium hydroxide. ~.
~he mixture at the hydrolisis end was added, under ~-.
stirring and cooling so that the temperature did not go~ :
beyond 20-25C, with a solution formed by 1.30 g (20 mmoles) 30 of potassium cyanide in 15 ml of concentrated ammonia (30%);

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it was again stirred for 18-20 hours at 30-35C and the acid treatment and the following procedure of example 1 were carried out. The yield aS serine from monochloroethyleneoxide was about ~5%. (~hi~ datum confirm a hydrolisis yield to glycol-aldehyde of 65~o~ s~nce it is known that -the yield, from this substrate, ~or the Zelinsky-Stadnikoff is 70%, see the foreg~ing table).
EXAMP~E 3 Preparation of dl-serine from monochloroethylene-carbonate via ~lycolaldehydeO
2,45 g (20 mmole~) of monochloroethylenecarbonatewere slowly added, under a strong stirring, with the stoichio-metric amount (with respect to developing hydrochloric acid) of a base (for instance sodium or potassium carbonate or bicar-bonate, sodium or potassium hydroxide) dissolved in 15 ~l of water (when use was made of water-low soluble bases, the inso-luble portion into 15 ml was then added in the solid state).
~ he addition rate was regulated so that the mixture temperature did not overcome 25C (preferably 5C ln the case of strong bases as sodium and potassium hydroxides) and pH
remained at alkaline values, which preferably had not to over-come the value of 8-9, for the most possible short time.
~he addition time necessary for this purpose was about 30-60 minutes. At the addition end, the stirring was still pro- -secuted over 3 hours at room temperature, during which one only phase had being formed, At the end, carbon dioxide did no more develop and the hydrolisis to glycolaldehyde was over pH was about 4 and wa~ again brought to 7 by adding the base~
~he yield was seen to be quanti-tative through a titrimetric dosage carried out on a sample of the react~on mixture by mean~ of hydroxilamine chlorohydrate method (see . Hauser i~ "Methoden der Organ. Chemie" (Houben-Weyl), D~ --f ~ ~
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Georg-~hiema-Verlag, Stuttgart, 1953, p. 458), A solution constituted by 1.30 g (20 mmoles) of potassium cyanide and 1.18 g (22 mmoles) of ammonium chloride in 10 ml of concentrated ammonia (about 30 %) was added to the hydrolisis - end mixture under stirring and cooling so that the temperature did not go beyond 20-25C, the s-tirring was pro-secuted over 18-20 hours at 30-35C and the acid treatment and the following procedure of example 1 were performed, ~ he yield as serine from monochloroethylene carbonate .
was 70~o.

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Claims (2)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for the preparation of d1-serine starting from alkali-labile precursors of glycolaldehyde through the Strecker reaction and variations thereof characterized in that said precursors are selected from the following compounds:
- monochloroethyleneoxide, vinylacetateepoxide, monoacetoxiacetaldehyde, 2,2-diacetoxyethanole, monochloro-ethylenecarbonate, monoacetoxyethylenecarbonate, vinylencarbonate,

2,5-dichlorodioxane and 2,5-diacetoxydioxane.