Deutsche Gold- Und Silber-scheideanstalt Vormals Roessler

Friedrich Asinger

Heribert Offermanns

Gerd Schreyer

Paul Scherberich

Karl-Heinz Gluzek

Wolf-Dieter Pfeifer

Miklos Ghyczy

Walter VONBebenburg

Karl-Heinz Gulzek

Wolf Dieter Pfeifer

Penicillamine or a homolog thereof is obtained by reacting a 2-disubstituted-5,5-alkyl-thiazolidine nitrile, alkyl having 1 to 6 carbon atoms, with a mineral acid in a two-stage proceeding wherein in the first stage relatively low temperatures and a relatively high concentration of the mineral acid are employed while in the second stage the concentration of the acid is relatively low and the temperatures are relatively high, the term 'relatively' referring to the relationship of said two stages of the reaction with mineral acid.

Process of making penicillamine

Penicillamine and its hydrochloride are made by reacting i-butyraldehyde with elemental sulfur or a sulfur-containing compound and with gaseous ammonia so as to form 2-isopropyl-5.5-dimethyl-thiazoline-.DELTA..sup.3, then reacting the latter compound with substantially anhydrous hydrogen cyanide so as to form the corresponding thiazolidine 4-carbonitrile, thereupon treating the latter compound with an excess of concentrated hydrochloric acid at an elevated temperature and separating the components of the mixture formed and recovering the penicillamine hydrochloride which may then be converted to the free D,L-penicillamine.

Penicillamine or a homolog thereof is made by reacting an aldehyde branched at the .alpha.-carbon atom, sulfur and ammonia to form a thiazoline- .DELTA..sup.3 ; converting the latter compound by reaction with anhydrous hydrogen cyanide into the corresponding thiazolidine-4-carbonitrile; hydrolyzing the nitrile with an aqueous concentrated hydrochloric acid containing at least 30% by weight of hydrogen chloride at a temperature between 40.degree. and 70.degree. C to form the hydrochloric salt of the thiazolidine-4-acid amide and then, at a higher temperature continuing the hydrolysis to form the salt of the thiazolidine-4-carboxylic acid together with the ammonium salt. The ammonium salt is then separated from the mixture and the carboxylic acid hydrochloride is hydrolytically decomposed whereby the penicillamine is obtained.

Process of preparing penicillamine

Improvements in the process of preparing penicillamine or a homolog thereof by reacting an .alpha.-carbon atom branched aldehyde, sulfur and ammonia to form a thiazoline-.DELTA..sup.3, reacting the thiazoline-.DELTA..sup.3 with anhydrous hydrogen cyanide to form a thiazolidine-4-carbonitrile, hydrolyzing the nitrile to form a mixture of the salt of the thiazolidine-4-carboxylic acid and ammonium salts, separating off the ammonium salts and hydrolytically decomposing the thiazolidine-4-carboxylic acid, wherein under the action of a mineral acid the thiazolidine-4-carbonitrile is in the first stage converted at low temperatures into the salt of the thiazolidine-4-carbonamide and then at higher temperatures converted into the salt of the thiazolidine-4-carboxylic acid.

The D-form of an optically active protected penicillamine is prepared by treating a solution of D,L protected penicillamine of the formula: ##EQU1## wherein Ac is formyl, and R.sub.1 and R.sub.2 are both methyl or are joined together to form the pentamethylene group.

Resolution of D,L-protected-penicillamine

The d,1-phenylpropanolamine(norephedrine) racemate is split with optically active thiazolidine-4-carboxylic acids of the formula: ##EQU1## where R.sub.1 and R.sub.2 are both methyl or are joined together to form the pentamethylene group.

Process for the splitting of the racemate of d-1-phenylpropanolamine

Penicillamine and its hydrochloride are made by reacting isobutyraldehyde with elemental sulfur or a sulfur-containing compound and with gaseous ammonia so as to form 2-isopropyl-5.5-dimethyl-thiazoline-.DELTA..sup.3, then reacting the latter compound with substantially anhydrous hydrogen cyanide so as to form the corresponding thiazolidine 4-carbonitrile, thereupon treating the latter compound with an excess of concentrated hydrochloric acid at an elevated temperature and separating the components of the mixture formed and recovering the penicillamine hydrochloride which may then be converted to the free D,L-penicillamine.

The d,l-phenylpropanolamine racemate is split with optically active thiazolidine-4-carboxylic acids of the formula: ##EQU1## where R.sub.1 R.sub.2 are hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, aryl or alkylene of at least 2 carbon atoms or R.sub.1 and R.sub.2 together form a ring of alkyl or alkylene with 4 to 12 carbon atoms and AC is acyl, especially benzoyl, tosyl, nitrophenylsulfenyl, acetyl or preferably formyl.

Salts of phenylpropanolamine with thiazolidine carboxylic acids

2 AND 5 SUBSTITUTED THIAZOLINE-(3) COMPOUNDS OF THE FORMULA: ##EQU1## in which R.sub.1, R.sub.2, and R.sub.3 and R.sub.4 are the same or different, R.sub.1 and R.sub.2 are straight or branched chain lower alkyl, alkenyl or aralkyl groups or together are a straight or branched chain alkylene or ethylenically unsaturated divalent aliphatic hydrocarbon group which joins with the adjacent carbon atom to form a ring and R.sub.3 and R.sub.4 are similarly defined except R.sub.3 can also be hydrogen by reaching a 2,2' dioxodisulfide of the formula ##EQU2## with an oxo compound of the formula ##EQU3## and with ammonia and hydrogen sulfide in the presence of an amine and an ammonium salt.

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Aachen, Germany

Friedrich Asinger