DE827945C - Process for the preparation of derivatives of beta-oxy-alpha-aminoacrylic acid - Google Patents

Description

(WiGBL p. 175)

ISSUED JANUARY 14, 1952

GERMAN PATENT OFFICE PATENT LETTERING

CLASS 12 O GROUP

p 1765 IVc1120 B

have been named as inventors

Schering A. G., Berlin

The / J-oxy-a-aminoacrylic acid is the parent substance of penaldic acids

O = CH-CH <or HO-CH = C ^

^ COOH ^ COOH

which as hypothetical breakdown products of the penicillins and as possible building blocks for the synthetic one Build up of penicillins are of interest. Looking for suitable methods to Representation of penaldic acids and their derivatives had to be due to the fact that neither the /? - oxy-aaminoacrylic acid even their O-derivatives are still described in the literature as a disturbing one Loophole can be felt, because it was to be suspected that it was precisely this missing connection a very useful starting material for the preparation of penaldic acids and their derivatives could be.

One could expect that especially the enol ethers of ^ -oxy-a-aminoacrylic acid by acylation on nitrogen, e.g. B. according to the method of Schotten-Baumann, without any difficulty Enol ethers of the corresponding penaldic acids with freely chosen R, d. H. so the group through which the native penicillins alone would provide.

It has now been found that one

aminoacrylic acid or its hydrohalic acid salts obtained in a surprisingly smooth reaction, when using 4-alkoxymethyleneoxazolone- (5) of the general formula

= C - R

RO-CH = C <f I

^ CO-O

the R and R 'mean aliphatic or aromatic radicals, some of which by condensation of Orthoformic acid esters with acylglycollens are readily available, using a mild treatment subjected to anhydrous alcoholic hydrohalic acid. (Obtained as a further reaction product one here the ester R.COOR '). This course of the reaction is so surprising because Oxazolone of the type

N = C-R R "-CH = C /

\ co — ο

and also the corresponding acylaminoacrylic acids of the type

R "-CH = C-

NH-CO -R

-COOH

it is known that when exposed to aqueous or aqueous alcoholic mineral acids (under Elimination of the amino nitrogen as acid amide) in a-keto acids.

"- fH = f /

N = C-R

NH-CO-R

^ CO-O

ν R "-CH = C

> - R "-CH ₂ -CO

COOH

• COOH

(R "means any hydrocarbon radical); see Journal of biological Chem. Volume 129, i939> page 359; Journal Chemical Society 1935,

_a5 page 532; 1931, page 2885 and reports German chem. ües. Volume 62, 1921, page 321.

Since the / J-alkoxy-a-aminoacrylic acids available as stated above As expected, they can be substituted on the nitrogen with any acid radicals by customary methods, they form valuable starting material for the preparation of enol ethers of penaldic acids and for others Modification products of the same.

example 1

a. 16.24 g (= 8/100 mol) of 2-phenyl "4-methoxymethyleneoxazolon- (5) are suspended in 200 ecm of absolutely anhydrous methanol and placed in a double-tubed round-bottomed flask, which is placed in an ice-saline mixture and on Dry HCl gas is then introduced into the solution, cooled to -10 °, through one tube by means of an inlet tube until the azlactone has dissolved. The other tube is closed with a CaCl ₂ tube The azlactone has dissolved in about 3 hours with a pale yellow color and absorption of 58.08 g of HCl. The solution becomes

₅ "then distilled to dryness on a water bath at 30 ⁰ under reduced pressure (10 mm Hg). A yellow crystalline mass remains as a residue, which is then extracted three times with dry benzene (distilled over KOH) and then three times with anhydrous ether in order to remove the methyl benzoate that is also formed. Remains unsolved as bone dry yellow crystalline yS-methoxy-a-aminoacrylic back, which, recrystallized from methanol, is obtained = 97 to 98 ⁰ in fine white needles, mp; Yield: 9.65 g = 70.65% of theory.

b. 5.16 g (= 3/100 mol) /? - methoxy-α-aminoacrylic acid hydrochloride be in little water

clearly dissolved and against phenolphthalein with 60 ecm g ^ n-NaOH neutralized.

According to Schotten-Baum's method on η, benzoylation is carried out in a strongly alkaline medium, for which 5.60 g of benzoyl chloride and 50 ecm of n-NaOH are required. _go

The benzoylated alkaline solution is shaken out immediately with 1 liter of ether for cleaning Separated ether and washed neutral with a little water. The alkaline solution and the washing water are then combined and treated with concentrated HCl (D. = 1.19) with ice cooling until Blueing of Congo paper acidified. A thick, white precipitate separates out and is filtered off with suction and is shaken out again for cleaning with ether. There is partial solution of the same.

The ether-insoluble part, the methoxymethylene hippuric acid, is recrystallized from hot water with the addition of a little charcoal and thus obtained in white crystals with a melting point of 203 to 204 ^° (decomposition); Yield: 2.47 g = 37.4% of theory.

Example 2

2.51 g / J-methoxy-α-aminoacrylic acid hydrochloride are clearly dissolved in a little water and neutralized against phenolphthalein with 30 ecm n-NaOH.

According to the Schotten-Baumann method, phenacetylation is carried out in a strongly alkaline medium, including 3, iogPhenacetylchlorid and 25ccmn-NaOH are needed.

The phenacetylated alkaline solution is shaken out immediately with 1 liter of ether for cleaning Separated ether, washed neutral with a little water and distilled off.

The alkaline solution and the wash water are combined and washed with concentrated HCl (D. = 1.19) acidified with ice cooling until the Congo paper turns blue. Here a thick one falls white precipitate, which is sucked off and shaken out corn for cleaning with ether.

The ether-insoluble part, the methoxymethylene phenaceturic acid, is recrystallized from hot water with the addition of a little charcoal and obtained in white crystals from F. = 193 to 194 ⁰ (decomposition); Yield: 2.35 g = 68.5% of theory.

Example 3

4.60 g of a-methoxy-yS-aminoacrylic acid hydrochloride are neutralized with 56 cm of n-NaOH and with 7.3 g of chlorophenacetyl chloride and 60.0 cm of n-NaOH implemented according to the Schotten-Baumann method. Further processing takes place as in Example 3 is given.

Methoxymethylene-chlorophenaceturic acid is obtained as an ether-insoluble acidic component in white crystals, which, recrystallized from methanol, shows the F. = 210 to 215 ^° (decomposition); Yield: 4.60 g = 64.1% of theory.

Claims (1)

Claim: Process for the preparation of derivatives of yS-oxy-a-aminoacrylic acid, characterized in that that one 4-alkoxymethyleneoxazolone- (5) of the general formula C-R R'_O-CH = C CO-O in which R and R 'denote aliphatic or aromatic radicals, treated under mild conditions with anhydrous alcoholic hydrogen halide and the salts of β- alkoxy-α-aminoacrylic acid formed, optionally acylated by methods known per se. 3779 1.52