DE1178858B - Process for the preparation of ª-alkyl-ª-(3,4-dihydroxyphenyl)-alanines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Boarding school Class: C 07 c

GERMAN

PATENT OFFICE

EDITORIAL

German KL: 12 q - 34

Number: 1178 858

File number: M 48943IV b / 12 q

Filing date: May 5, 1961

Opening day: October 1, 1964

The invention relates to a process for the preparation of α-alkyl- / S- (3,4-dihydroxyphenyl) -alanines the general formula

HO
HO

R CH ₂ -C-COOH

NH ₂

in which R is a straight-chain, low-molecular-weight alkyl radical. These connections are commercial useful for the treatment of hypertension.

One of these compounds, namely a-methyl - /? - (3,4-dihydroxyphenyl) -alanine, has already been described in the literature.

This compound is made by adding 5-methyl-5- (3 ', 4'-dimethoxybenzyl) hydantoin with Barium hydroxide to a barium salt of α-methylß- (3,4-dimethoxyphenyl) -alanine converts, the barium ions are removed by precipitation with sulfuric acid, by neutralizing the filtrate with a base Produces the free amino acid, the free amino acid by boiling with 48% hydrobromic acid under reflux in α-methyl - /? - (3,4-dihydroxyphenyl) alanine hydrobromide and this compound is converted into the free amino acid by neutralization.

It has now been found that hydantoin compounds of the general formula

CH ₃ O
CH ₃ O

R CH ₂ -C-

HN

C = O

NH

in which R has the above meaning, can be hydrolyzed directly with 35 to 55% aqueous hydrobromic acid to give the hydrobromide of α-alkyl-jS- (3,4-dihydroxyphenyl) alanine. This hydrolysis is carried out at a temperature in the range of about 9O ⁰ C to the reflux temperature. Preferably, the hydrolysis with 48 ° / cent hydrobromic acid is carried out at about 126 ⁰ C. The amino acid hydrobromide obtained in this way is with a base or another proton acceptor, such as sodium hydroxide, diethyl process for the production of
α-alkyl- _/ S- (3,4-dihydroxyphenyl) -alanines

Applicant:

Merck & Co., Inc., Rahway, N. J. (V. St. A.)

Representative:

Dr. W. Kühl, patent attorney,

Hamburg 36, Esplanade 36 a

Named as inventor:

George Gal, Summit, N. J. (V. St. A.)

Claimed priority:

V. St. v. America May 13, 1960 (28 863)

amine, a basic ion exchange resin or ethylene oxide, neutralized to the free amino acid. Eliminating the hydrolysis stage with barium hydroxide leads to higher overall yields in converting the hydantoin into the desired amino acid while simplifying the process by increasing the number of Process steps are reduced and the previously required removal of barium ions is no longer necessary will.

example 1
α-methyl- / H3,4-dihydroxyphenyl) alanine

17 g of 5-methyl-5- (3 ', 4'-dimethoxybenzyl) hydantoin and 90 ecm of 48% aqueous hydrobromic acid are refluxed for 18 hours. In this case, solution occurs after 5 minutes. The excess hydrobromic acid is then removed by heating in vacuo (20 torr) on the water bath. The heating continues until most of the water has been driven off. In this case, crystals are obtained which are dissolved in a mixture of 50 cc of methanol and 5 cc of water at 30 ⁰ C. This solution is cooled to 5 ° C. and adjusted to a pH of 6 with 12 normal aqueous ammonia. The solution is diluted with 300 ecm of acetone, ^{cooled to 0} ° C. and kept at this temperature for 3 hours. The crude α-methyl- / 9- (3,4-dihydroxyphenyl) -alanine which precipitates out is filtered off and washed three times with 10 ecm acetone each time. Yield 13.2 g = 97%; F. = 275 to 280 ⁰ C.

409 689/330

The crude α-methyl- / H3,4-dihydroxyphenyl) alanine is added to a solution of 150 mg sodium bisulfite in 140 ecm water at 90 to 95.degree. After it has gone into solution, 500 mg of activated charcoal and 150 mg of tartaric acid are added. The mixture is heated to 90 to 95 ° C. under nitrogen for 10 minutes and filtered. The filtrate is ^{cooled to 0} ° C. and left to stand at ⁰ ° C. for 12 hours. The purified compound is filtered off and washed three times with 10 ecm acetone each time. Yield 7.1 g = 52.5%; F. = 316 to 317 ⁰ C (with decomposition). Concentrating the mother liquor to 15 ecm gives a further 2.45 g; F. = 280 to 282 ⁰ C.

Example 2

<z-EthyI- / H3,4-dihydroxyphenyl) -alamn

A mixture of 5 g (0.018 mol) of 5-ethyl-5- (3 ', 4'-dimethoxybenzyl) hydantoin and 30 cm of 48% aqueous hydrobromic acid is refluxed for 46 1/2 hours. Then the solution is evaporated in vacuo. The residue is dissolved in tert-butanol and the solvent is then evaporated off in vacuo. This procedure is repeated. The residue is dissolved in water and the solution is filtered. The pH is adjusted to 6 by adding concentrated aqueous ammonia. The solution is decolorized by heating with 250 mg activated charcoal and filtered. A small amount of sulfur dioxide is introduced into the filtrate for further decolorization. The solution is concentrated in vacuo until crystals form, then cooled and kept at about 5 to 10 ^° C. for 16 hours. The crystals of a-ethyl- / S- (3,4-dihydroxyphenyl) -alanine are filtered off, washed successively with cold water and with ether and dried at about 75 to 80 ° C in a vacuum. Yield 1.87 g = 46%; F. = 308 to 309 ^° C; l _max 282 πΐμ (145), 222 ιτίμ (282) in methanol.

Claims (1)

Claim: Process for the preparation of α-AIkyI- / 3- {3,4-dihydroxyphenyl) alanines the general formula HO
HO CH ₂ -C- COOH
NH ₂ in which R denotes a straight-chain low molecular weight alkyl radical, characterized in that that one is a compound of the general formula CH ₃ O
CH ₃ O CH ₂ -C- HN C = O NH wherein R has the above meaning, is hydrolysed in a 35 to 55% aqueous solution of hydrobromic acid at a temperature of about 9O ⁰ C to the reflux temperature and then neutralized. «9« M / 330 9.M © Receipt printer B «B»