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Publication numberUS2553737 A
Publication typeGrant
Publication dateMay 22, 1951
Filing dateMar 26, 1949
Priority dateJun 16, 1945
Publication numberUS 2553737 A, US 2553737A, US-A-2553737, US2553737 A, US2553737A
InventorsNoel F Albertson, Archer Sydney
Original AssigneeWinthrop Stearns Inc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Lower alkyl (beta-cyanoalkyl)-(lower acyl) aminomalonates
US 2553737 A
Abstract  available in
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Description  (OCR text may contain errors)

Patented May 22, 1951 STATES TNT OFFICE LOWER ALKYL (BETA- CYANOALKYL) (LOWER ACYL) AMINOMALONATES No Drawing. ()riginal application June 16, 1945,

Serial No. 599,970. Divided and this application March 26, 1949, Serial No. 83,758

3 Claims. 1

This invention relates to a process for the preparation of certain diaminocarboxylic acids and to the intermediates utilized in said process.

The principal object of this invention is the provision of a method for obtaining ornithine and substitution products thereof on a large scale and in high yield.

Although several methods for synthesizing ornithine are available in the literature, none of these gives a good yield of the desired amino acid and most of them require numerous steps. We have now discovered that ornithine and related amino acids can be readily synthesized in high yield by a three-step process which is adaptable to large-scale manipulation.

In general, our process comprises: condensing an acrylonitrile with a lower alkyl (lower acylamino) -malonate; catalytically hydrogenating the condensation product, whereby a piperidone is obtained; and hydrolyzing and decarboxylatingthe piperidone to yield ornithine or substitution product thereof.

We have found that acrylonitriles can be reacted in the manner of the Michael condensation [J. Org. Chem, 3, 5'70 (1939)] with lower alkyl (lower acylamino)-malonates, -cyanoacetates and -acetoacetates in accordance with the equation:

wherein X is cyano, acetyl, or carbalkoxyl. It is to be understood that in this illustrative equation, and in those which follow, the unattached valences are satisfied by groups unreactive under conditions of the Michael reaction. The con densation is effected by a catalytic base, and for this purpose we have found that approximately from 1 to 20 mole per cent, preferably about 4 mole per cent, of alkali metal alkoxide, such as sodium ethoxide, is most suitable. Under ordinary conditions, secondary amines such as piperidine and diethylamine have been found to be too weak to be efiective.

The use of as much as 100 mole per cent, 1. e. an equivalent portion, of alkali metal alkoxide leads to the formation of undesired products and thus is to be avoided. Provided that mild condensation conditions are employed, alkali metals or alkali metal amides or other like strong bases catalytic base acyl) amino-3-carbalkoxy-2 piperidones.

2 can be employed in place of the alkali metal alkoxide. While We have found it to be convenient to use a lower anhydrous alcohol such as anhydrous ethyl alcohol, inert diluents such as benzene or ether can be employed; alternatively the diluent may be omitted entirely.

We have found that certain of the condensation products obtained in the above fashion, viz. wherein X is carbalkoxyl, are useful as intermediates adapted to a new synthesis of ornithine and related amino acids. These condensation products chemically can be designated as lower alkyl (beta-cyanoalkyl) -(lower acy1)aminomalonates. Since the unsaturated nitrile component employed in the Michael condensation can be any having no other groupings reactive under the conditions of the condensation, it will be appreciated that acrylonitriles substituted by groups such as methyl, ethyl, phenyl, anisyl, and so on fall within the purview of the invention, and accordingly, the term (beta-cyano-alkyl) is to be understood to include alkyl groups substituted in corresponding fashion. These condensation products, when hydrogenated in the presence of a metal catalyst, for example Raney nickel, platinum, for palladium, are converted to piperidone derivatives according to the equation:

O O O(lowcr alkyl) These piperidones are hydrolyzed and decarboxylated by aqueous mineral acid to diaminocarboxylic acids as shown by the following equation.

The product is obtained in the form of a salt 3 with the acid used in the hydrolysis. The hydrolysis and decomposition step can conveniently be efiected by boiling with moderately strong aqueous mineral acid, such as concentrated hydrochloric acid or approximately 20% sulfuric acid.

Hydrolysis of the piperidones with concentrated alkali solution produces alkali metal salts of (gamma aminopropyl) (lower acyl) aminomalonic acids. These acids lose carbon dioxide when heated, thus forming 3-acylamino-2-piperidones. The (gamma-aminopropyl) (lower acyDaminomalonic acids can be condensed with cyanamide, dicyandiamide, an isothiuronium salt, or a guanidine salt to yield delta-guanido derivatives which can be hydrolyzed to arginine or substitution products thereof.

The terms lower alkyl and lower acyl as used in the above discussion and in the subjoined claims refer to those aliphatic groups of lower molecular weight having about five carbon atoms or less, so that the respective hydroxyl derivatives, alcohols or acids respectively, are wholly or in substantial degree water-soluble. This requirement is of practical significance because the by-products of the reactions are then readily removed.

Our invention is illustrated by the following example, but is not limited thereto.

Example 1 g. of sodium is dissolved in 500 ml. of anhydrous ethyl alcohol and to this solution is added 217 g. of ethyl acetamidomalonate. This slurry is stirred and cooled in a water bath, and during a period of twenty minutes 60 g. of acrylonitrile is added dropwise. During this addition all of the ethyl acetamidomalonate goes into solution. The reaction mixture is allowed to stand for one hour at room temperature and is then cooled and filtered. The filtrate is concentrated in vacuo and the residual liquid is poured into cold water. The white solid which precipitates is collected on a filter. This product, which is ethyl (beta cyanoethyl)acetamidomalonate, weighs 253-257 g. and melts at 92-94 C.

127 g. of ethyl (beta-cyanoethyl)acetamidomalonate is dissolved in 400 ml. of ethyl alcohol and is treated at 68 C. with hydrogen under a pressure of 600 lbs. per sq. in. The reduction is complete after one and one-half hours. The catalyst is removed from the reaction mixture by filtration and the filtrate is concentrated in vacuo to remove most of the ethyl alcohol. The residue is cooled and the solid is collected on a filter and is washed successively with very small portions of cold ethyl alcohol and ethyl ether. The white, crystalline product, which is 3 acetamido 3 carbetoxy 2 piperidone,

weighs 96 g. and melts at 136-1385 C.

ml. of concentrated hydrochloric acid and the reaction mixture is then evaporated to dryness. The residue is dissolved in 60 ml. of ethyl alcohol and about 14 ml. of concentrated ammonium hydroxide is added to neutralize the solution, which is cooled in ice for one hour. The solid is collected on a filter and washed with ethyl alcohol. To free it of ammonium chloride, the residue is suspended in 150 ml. of boiling ethyl alcohol and the suspension is filtered. The residue, which is dl-ornithine hydrochloride, weighs 16.4 g. and melts at 225 C. with decomposition. If the free amino acid, ornithine, is desired it can readily be obtained from the above hydrochloride by known means.

If in the above example methacrylorn'trile is substituted for the acrylonitrile, the condensation with ethyl acetamidomalonate produces ethyl (beta cyanopropyl)acetamidomalonate, which on hydrogenation yields 3-acetamido-3- carbethoxy-Ex-methyl-2-piperidone, and the latter on hydrolysis and decomposition yields the hydrochloride of alpha, delta-diamino-gammamethylvaleric acid.

This application is a division of our copending application Ser. No. 599,970 (now U. S. Patent 2,496,326), filed June 16, 1945.

We claim:

1. A lower alkyl (beta cyanoalkyl) (lower acyl) aminomalonate.

2. A compound having the formula C O 0- (lower alkyl) NCCH2CH2ONH- (lower acyl) O O-(lower alkyl) 3. Ethyl (beta-cyanoethyl) acetamidomalonate, having the formula and being characterized by melting at approximately 92-94 C.


REFERENCES CITED The following references are of record in the file of this patent:

Dunn et al.: J. Biol. Chem., vol. 94, pp. 599-609 (1931).

Redemann et al.: J. Biol. Chem., vol. 130, pp. 341-343 (1939).

Moureu et al.: Beilstein (Handbuch, 4th ed, 2nd suppl.), vol. 2, p. 231 (1942).

Dakin: J. Biol. Chem., vol. 154, pp. 549-555 (1944).

Block: Chem. Reviews, vol. 38, pp. 543-545 (1946).

Non-Patent Citations
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4271088 *May 18, 1979Jun 2, 1981Suntech, Inc.High selectivity cyanoalkylation process
U.S. Classification558/442, 546/243, 562/561
International ClassificationC07C255/24, C07D211/78
Cooperative ClassificationC07C255/00
European ClassificationC07C255/00