CS219409B1 - Method of making the new optical active and racemic derivatives of the alpha-amino-beta-aminooxypropion acid - Google Patents

Description

The present invention relates to a process for the preparation of novel optically active and racemic α-amino-, 8-aminooxypropionic acid derivatives of the general formula I:

Ri \

C = N.O.CH2.CH.COOR3 [I] / I

R2 NH2 in which

R1 is hydrogen of (1-5C) alkyl, aryl or aralkyl,

R2 represents hydrogen, alkyl of 1-5 carbon atoms, aryl, aralkyl or heterocyclic radical, wherein the radicals R1 and R2 may be joined to form an aliphatic ring and

R 3 denotes hydrogen or alkyl of 1-4 carbon atoms.

These novel substances are important both for their pharmacological activity and for the fact that they can be further processed either to serine or to cycloserine.

As stated by Ρ. H. Hidy sp. (J. Am. Chem. Soc. 77, 2345, 1955), it is possible to cleave D, L-cycloserin and its optical antipodes in an alcoholic hydrochloric acid environment at the lactam moiety to form hydrochlorides of D-, L- and DL- However, further reactions are also carried out using aqueous hydrochloric acid, and the cleavage takes place up to the serine.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel optically active and racemic α-amino-6-aminooxypropionic acid derivatives of formula (I) which comprises treating D-, L- or D, L-cycloserine in an aqueous or alcoholic solution with an aqueous solution. or an alcoholic solution of hydrogen chloride in the presence of compounds of formula II:

Rt

CO (II)

OF

Rz t

in which

R1 and R2 are the same as in formula I, whereupon the hydrochloride of the compound of formula I obtained is optionally converted by alkalization in the free base.

The mother liquors may advantageously be used as starting materials after cleavage of D, L-cycloserine to optical antipodes containing L- or

D-cycloserine in the form of D- or L-tartrate; it is also possible to start from a crude mixture of D- and L219409

-cycloserin, isolated from the mother liquors after cleavage of D, L-cycloserin to tannins in the form of tannins.

According to the invention, a number of novel substances with interesting efficacy can be obtained by simple technical means and, in addition, the mother liquors remaining during the cleavage of D, L-cycloserine can be economically processed into optically active components.

Examples

Example 1

D-cycloserinic acid methyl ester hydrochloride of D-α-amino- [3-isopropylideneaminooxypropionic acid (m.p. 152 ° C) was poured over a mixture of 5 ml of acetone and 50 ml of a 20% methanolic hydrogen chloride solution. Stir at room temperature until dissolution and allow to stand for 24 hours. After filtration, the solution is concentrated in vacuo, the crystalline residue is dissolved in 20 ml of methanol and ether is added until the solution is cloudy. After standing overnight in the refrigerator, 8.8 g of product is recovered, i.

85.4%. Recrystallization gave colorless needles of mp 162-164 ° C. Esterhydrochloride is a substance soluble in water, methanol and ethanol, insoluble in ether. [α] D ²⁰ = - - - 17.3 °, (c = 1.36 ethanol).

Example 2

D-L, -α-amino-6-isopropylideneaminooxypropionic acid methyl ester hydrochloride

Analogous to the previous case, using D, L-cycloserine and other components in the same amount, the ester hydrochloride was obtained in 79% yield, mp 155-158 ^° C. By hot hydrochloric acid, the substance decomposes into acetone and D, N-amino-3-aminooxypropionic acid hydrochloride.

Example 3

D, L-.alpha.-amino-.beta.-benzylideneaminooxypropionic acid D is dissolved in 50 ml of water, acidified with 20 ml of hydrochloric acid and 5 ml of benzaldehyde is added dropwise with stirring. Stir for 48 hours. A small amount of racemic 2,5-bis- (benzylideneaminooxymethyl) -3,6-diketopiperazine precipitated is filtered off and the filtrate is evaporated to dryness at 40 ° C under vacuum. The crude crystalline D, L -? - amino- [3-benzylideneaminooxypropionic acid hydrochloride is dissolved in 50 ml of water and, after neutralization with ammonia to pH 7, the free acid is filtered off with suction. Yield 6.5 g, mp 204-205 ° C. Analogously, the acid in D- or L-form can be obtained from D- or L-cycloserine.

D-acid [α] _η ² θ = -73.0 ° (dil. HCl),

L-acid [α] ο ^2θ = + 73.15 ⁰ (dil. HCl). Example 4

D, La-amino + - (c + phenylethylidene} -aminooxyproplonic acid D) was dissolved in 40 ml of water and 20 ml of conc. HCl and 7 ml of acetophenone was added with stirring. Crystalline D, La-amino + - (α-phenylethylidene) -aminooxypropionic acid hydrochloride precipitates, which melts at 198-200 ° C after recrystallization from water, the mother liquors are concentrated in vacuo, the residue is dissolved in 50 ml of water and neutralized. ammonia to pH

7. The precipitated acid is aspirated and dried. The total yield is 80%.

The D- and L-form of the acid is prepared analogously from D- and L-cycloserine.

The D-form has [α] ο ^2θ = -56 ° (dilute HCl). Example 5

L-α-amino-β- (e + phenylethylidene) -aminooxypropionic acid

The racemic cycloserine digestion liquor, containing about 20 g of L-cycloserine as D-tartrate and a small amount of D-tartrate D-tartrate, was acidified with 80 ml of 20% HCl and 25 ml of acetophenone was added to the reaction mixture. The mixture is stirred for 4 hours, concentrated in vacuo to about 1/3 of the original volume and the residue is neutralized with ammonia to pH 7. The crystalline acid is filtered off with suction, washed with water and dried. Yield 27.7 g. After recrystallization from acetic acid, the substance melts at 178-180 ° C and has a [.alpha.] D @ 20 = -56.3 DEG (dil. HCl).

Example 6

L-α-amino-4-isopropylideneaminooxypropionic acid methyl ester hydrochloride

100 ml of the mother liquor after cleavage of D, Lycycloserin, containing about 10 g of L-cycloserin in the form of D-tartrate, are made alkaline with NaOH solution, concentrated and after removal of sodium D-tartrate, 1.5 g, mp 1) 48 ° C, [α] _D ²⁰ = -1013 °. The crude product was worked up as in the example

L-6-Amino-4-isopropylideneaminooxypropionic acid methyl ester hydrochloride is obtained in a yield of 75%, m.p. 158-162 ° C.

[α] D ²⁰ = + 10.7, ethanol.

Claims (3)

Subject 1. A process for the preparation of novel optically active and racemic derivatives of .epsilon.-amino-.beta.-aminooxypropionic acid of the formula I: Ri \ C = N.O.CH2.CH.COOR3 (I) / I R2 NH2 in which R1 is hydrogen, alkyl of 1-5 carbon atoms, aryl or aralkyl, R 2 is hydrogen, C 1-5 alkyl, aryl, aralkyl, or a heterocyclic radical, wherein R 1 and R 2 together may be taken together to form an alicyclic ring and R5 is hydrogen or (1-4C) alkyl, characterized in that D-, L- or D, L-cycloserine is treated in aqueous or alcoholic solution with aqueous or alcoholic hydrogen chloride solution in the presence of compounds of formula II: OF THE INVENTION Ri CO (II) z R2 in which R 1 and R 2 are the same as in formula Γ, whereupon the hydrochloride of the compound of formula I obtained is optionally converted by alkalization in the free base. 2. Process according to claim 1, characterized in that the mother liquors used are the mother liquors after cleavage of D, L-cycloserine into optical antipodes containing L- or D-cycloserine in the form of D- or L-tartrate. 3. Process according to claim 1, characterized in that the raw materials used are crude mixtures of D- and L-cycloserine isolated from the mother liquors after cleavage of D, L-cycloserine into tartrate optical antipodes.