DK146414B - PROCEDURE FOR THE PREPARATION OF D-PENICILLAMINE - Google Patents

Description

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The amino acid D-penicillamine is known as an active ingredient in important drugs for the treatment of Wilson's morbus, defect schizophrenia, scleroderma, cystinuria and chronic aggressive hepatitis, and for basic therapy in 5 primary chronic polyarthritis. In addition, D-Penicillamine is used as an antidote for heavy metal intoxications.

Only D-penicillamine can find therapeutic use because the L-isomer is highly toxic.

It is known to recover D-penicillamine by a costly hydrolytic process from penicillin, which in connection with the costly starting material explains the high cost of this amino acid, which prevents the broad medical use of D-penicillamine, especially as a basic therapeutic agent in continuous treatment. of primary chronic polyarthritis. For this reason, providing a total synthesis for D-penicillamine is of particular importance.

However, it is also known to synthesize D, L-20 penicillamine synthetically and thereby extract D-penicillamine by racemate cleavage. As optically active bases, here is used d-pseudoephedrine and 1-ephedrine ("The Chemistry of Penicilline" (1949), Princeton University Press, British Patent No. 585,413, U.S. Pat.

25,450,784 and Belgian Patent No. 738,520).

For racemate cleavage, D, L-penicillamine must be transferred into suitable derivatives, i.e. Protective groups must be introduced into the penicillamine molecule - as is common in amino acid racemate cleavage).

As derivatives suitable for racemate cleavage, e.g. N-acylation products of D, L-penicillamine or of S-benzyl-D, L-penicillamine and acylation products of turnover products between D, L-penicillamine and carbonyl compounds in speech.

35 However, these methods of racemate cleavage of D, L-penicillamine are only slightly satisfactory, since in the reaction between the D, L-penicillamine derivative and the said cleavage bases, a precipitation of the

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2 undesirable salt of the L-penicillamine derivative and the optically active auxiliary base. However, it is known that, in principle, the antipode crystallized from the reaction solution has the greatest purity (H.D. Jakubke and 5 H. Jeschkeit, "Amino Acid, Peptide, Protein").

Akademie-Verlag, Berlin, 1969; as well as L.F. Fieser and M. Fieser, "Lehrbuch der Organischen Chemie", Verlag Chemie, Weinheim, 1957).

In British Patent Specification No. 145780 it is proposed to recover D-penicillamine from D; L-penicillamine using 1-norephedrine (phenylpropanol-amine) 15 H CH-i3

C, H - C - C - H

65 in OH NH 2 20 and accordingly discloses a process for recovering D-penicillamine from D, L-penicillamine, wherein the racemate is converted to a racematic N-acyl-2,2-disubstituted-5.5 dimethyl -thiazolidine-4-carboxylic acid, which is reacted with the optically active base, 1-norephedine, to a salt mixture from which the salt of DN-acyl-2,2-disubstituted-5,5-dimethyl-thiazolidine-4-carboxyl acid is isolated and D-penicillamine is produced therefrom, the racemate cleavage of D, L-penicillamine proceeds by means of this optically active base with very high yields, and D-penicillamine is obtained with high purity when the desired salt of D-penicillamine is obtained. acid and L-base are most soluble and precipitate.

It has now been found that it is particularly advantageous to use 1-norephedrine in the form of salt in place of 1-norephedrine for the extraction of D-penicillamine from D, L-penicillamine as described in Danish Patent Specification No. 145780. .

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In the manufacture of 1-norephedrine, it generally appears in the form of salts. Since these salts, using 1-norephedrine for the extraction of D-penicillamine, are used immediately, the production of 5 of the free norephedrine base is saved. Accordingly, the invention relates to a process for recovering D-penicillamine from D, L-penicillamine, wherein the racemate is converted to a racemic N-acyl-2,2-disubstituted-5,5-dimethyl-thiazolidine-4 carboxylic acid, which is reacted with an optically active base to a salt mixture, from which the salt of DN-acyl-2,2-disubstituted-5,5-dimethyl-thiazolidine-4-carboxylic acid is isolated, whereupon D-penicilamine is prepared therefrom; and the process is characterized in that the base used is 1-norephedrine 15 in the form of a salt thereof.

Preferably, salts of 1-norephedrine are salts with organic acids, especially with sulfonic acids and especially with carboxylic acids. By sulfonic acids is meant e.g.

aliphatic sulfonic acids such as methanesulfonic acid, methane trisulfonic acid and propane-2-sulfonic acid, or aromatic sulfonic acids such as p-toluenesulfonic acid and especially benzenesulfonic acid. The carboxylic acids comprise saturated 2 or unsaturated, optionally with OH, NH 2, NHR, NR, OR, SH, SR or halogen groups substituted aliphatic mono and polycarboxylic acids such as iso-butyric acid, n-valeric acid, isovaleric acid , trimethylacetic acid, lactic acid, oxalic acid, malonic acid, adipic acid, maleic acid, succinic acid, tartaric acid, citric acid, especially those having 1-6 carbon atoms such as formic acid, acetic acid, propionic acid, or araliphatic carboxylic acids such as phenylacetic acid, mandelic acid, especially cinnamic acid. -phenylpropionic acid, or aromatic carboxylic acids such as phthalic acid, terephthalic acid, salicylic acid, especially benzoic acid, or heteroaromatic carboxylic acids such as thiophene-2-carboxylic acid, thiazole-4-carboxylic acid, furan-2-carboxylic acid, picolic acid

D, L-penicillamine is transferred in a known manner to an N-acyl-2,2-disubstituted-5,5-dimethyl-thiazolidine-4

carboxylic acid, preferably one of the general formula COOH

H-C-N-Ac II

Wherein R and R are the same or different and represent a hydrogen atom or an alkyl group of 1-8 carbon atoms or a cycloalkyl or aryl group, and Ac means an acyl group, especially a benzoyl, tosyl, nitrophenylsulphenyl, acetyl or a formyl group.

Among these protected compounds, the compounds obtained by converting D, L-penicillamine into an N-acetyl or preferably N-formyl derivative of a 2,2-dialkyl-5,5-dimethyl-thiazolidine-4-carboxylic acid are further preferred. . Among these, N-formyl-2,2,5,5-tetramethyl-thiazolidine-4-carboxylic acid (N-formyl-isopropylidene-D, L-penicillamine) 20 and N-formyl-2,2-pentamethylene-5 are again distinguished , 5-dimethyl-thiazolidine-4-carboxylic acid. These thiazolidine-4-carboxylic acids can be prepared simply from D, L-penicillamine and appropriate carbonyl compounds (The Chemistry and Penicillin (1949), Princeton University Press). The conversion to N-acyl compounds as well as compounds with protected mercapto group is described in the same literature.

The salts of 1-norphedrine are used in the same manner, under the same conditions and in similar amounts as the free 1-norphedrine base. The use of the salts is particularly advantageous for carrying out the racemate cleavage of D, L ~ penicillamine when present as N-acetyl or preferably as N-formyl derivative, namely as N-formyl-2,2,5,5-tetramethyl -thiazolidine-4-carboxylic acid (N-formyl-isopropylidene-D, L-pencillamine) or N-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid.

As a solvent in the racemate digestion, in addition to water, organic solvents, e.g. alcohols, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, ethers, ketones, esters, aromatic hydrocarbons and others. Preferably, benzene, toluene, isopropanol, dioxane and lower carboxylic acid esters are used.

In carrying out the process according to the invention it is convenient to proceed in such a way that in a known manner, D, L-penicillin is transferred in a racemic N-acyl-2,2-disubstituted-5,5-dimethyl-2 thiazolidine-4-carboxylic acid (protected D, L-penicillamine) and dissolves it in water or preferably in an organic solvent or solvent mixture, and to this mixture, optionally under heating, puts the 1-norephedrine salt, optionally dissolved in an organic solvent, whereby immediately, but possibly only after prolonged standing, optionally at lower temperature and after grafting, the heaviest soluble salt of the D-form of said thiazolidine carboxylic acid 20 and 1-norephedrine is precipitated, while the diastereoisomeric salt, the optically active antipode or the racemic mixture or the racemic mixtures thereof remain in the mother liquor.

However, it is also possible to reverse and add to the solution of the 1-nor-ephedrine salt the above-mentioned racemic thiazolidine carboxylic acid, which is preferably dissolved in an organic solvent.

Advantageously, the process of the invention can be carried out using 0.1 to 3 moles, preferably 0.5 to 1.1 moles of 1-norephedrine salt per liter. mole racemate. In all regions, the heaviest soluble salt of the D form is precipitated by the said thiazolidinedecarboxylic acid and 1-norephedrine. This precipitation is at approx. stoichiometric quantities almost quantitative. When using less than 0.5 mole of 1-norephedrine salt, the mother liquor remains racemate and optical antipode and is used per day. 0.5 to 1 mole of cleavage base, the mother liquor, in addition to optically active antipode, also contains a diastereomeric salt. Do you add per mole of racemate more than 1 mole of active auxiliary base, the mother liquor in addition to diastereomeric salt also contains cleavage base.

The diastereomeric salt of the D-form of thiazolidinedecarboxylic acid and 1-nor-ephedrine obtained by the reaction may, because of the very favorable solubility conditions known per se, e.g. by filtration, evaporation of the mother liquor and purification by recrystallization are recovered in pure form.

The salt can be known per se, e.g. by treatment with dilute mineral acids, is transferred to a mineral acid salt of D-penicillamine, from which D-penicillamine is also known per se, e.g. when treated with bases, is released.

In each case, at the racemate cleavage, the heaviest soluble salt of the D-form of the thiazolidine carboxylic acid and 1-norephedrine is precipitated first, while the second diastereomer remains in solution. This was surprising, because salts of the corresponding L-peni-cillamine derivative and cleavage base are most soluble both using D-pseudoephedrine and 1-ephedrine.

If these latter are used in the form of salts, racemate cleavage does not take place or at least not satisfactorily, and it is therefore also surprising that it takes place satisfactorily in the process according to the invention.

By analogy, L-penicillamine can be recovered from the mother liquor of the racemate digestion. It is particularly advantageous that the L-penicillamine derivative optionally recovered by mineral acid cleavage of a salt thereof with optically active cleavage base can be racemized in a manner known per se, thereby reusing the therapeutically inoperable L penicilla-35 min is possible.

In the following examples, the rotational ability of the substances is indicated as specific rotation [α] β in degree * cm / dm * g. Percentages indicate weight percentages.

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Example 1 21.7 g (0.1 mole) of N-formyl-isopropylidene-D, L-penicillamine (prepared by reaction of 20.0 g of D, L-penicillamine, HCl with 18.7 g of acetone and subsequent formylation with a mixture of formic acid and acetic anhydride and simultaneous neutralization with sodium acetate) were dissolved at 60 to 70 ° C in 80 ml of n-butyl acetate.

The solution was added with stirring 11.7 g (0.06 mol) of 1-norephedrine acetate and then kept for 30 minutes at 80 to 85 ° C. A clear resolution now arose.

10 A few minutes later, the adduct of N-formyl-isopropylidene-D-penicillamine and 1-nor-ephedrine differed. After slow cooling to room temperature was filtered by suction. The recovered adduct was washed with 20 ml of n-butyl acetate and then dried under reduced pressure. It showed a specific rotation of + 34 ° and a melting point of 200 to 203 ° C. The yield was 11.5 g, corresponding to 63%, based on N-formyl-isopropylidene-D, L-pencillamine used.

11 g of the adduct of N-formyl-isopropylidene-D-20 penicillamine and 1-norephedrine were suspended in 40 ml of water. The mixture was adjusted to pH 1. at room temperature with concentrated hydrochloric acid. During the following 15 minutes, N-formyl-isopropylidene-D-penicillamine was separated. It was filtered off with suction, washed with 10 ml of water and dried at reduced pressure. N-Formyl-isopropylidene-D-penicillamine had a specific rotation of + 52 ° and a melting point of 182-183 ° C.

The yield was 5.8 g, corresponding to 90%, based on adduct used.

5 g of the recovered N-formyl-isopropylidene-D-penicillamine was kept in 30 ml of 15% hydrochloric acid at boiling temperature for 2 hours, during which acetone was distilled off. Finally, evaporated to dryness to give 3.6 g of crude D-penicillamine hydrochloride. This was dissolved in 96% ethanol and 2 ml of triethylamine was added to the solution. This precipitated the free D-penicillamine.

This was filtered off with suction, washed with ethanol and dried. The yield of D-penicillamine was 2.6 g, corresponding to 75%, based on the N-for-myl isopropylidene-D-penicillamine used. The D-Penicillamine showed a specific rotation of -53 ° (1% solution in 5 ethanol) and a melting point of 212-214 ° C.

Example 2

As described in Example 1, however, 21.7 g (0.1 mole) of N-formyl isopropylidene-D, L-penicillin min was reacted with 21 g (0.1 mole) of 1-norephedrine acetate in 10 ml of acetic acid ethyl ester. The recovered adduct had a specific rotation of + 32 ° and a melting point of 199-201 ° C. The yield was 15 g, corresponding to 82%.

The adduct was worked up to D-penicillamine in the same manner as in Example 1 and to obtain corresponding yields.

Example 3

Proceed as described in Example 1, however, 43.6 g (0.2 mole) of n-formyl-isopropylidene-D, L-penicillin in 180 ml of toluene were reacted with 24.8 g (0.11 mole) of 1- norephrine propionate. The recovered adduct of N-formyl-isopropylidene-D-penicillamine and 1-norephedrine had a specific rotation of + 30 ° and a melting point of 201-204 ° C. The yield was 24 g, corresponding to 65%.

The adduct was worked up to D-penicillamine in the same manner as in Example 1 and to obtain similar yield.

Example 4

Proceed as indicated in Example 1, however, 21.7 g (0.1 mole) of N-formyl-isopropylidene-D, L-penicillamine 30 was reacted with 11.5 g (0.02 mole) of 1-norephedrine maleate in 80 ml. ml of acetic acid ethyl ester. The recovered adduct of N-formyl-isopropylidene-D-penicillamine and 1-norephedrine had a specific rotation of + 27 ° and a melting point of 199-201 ° C. The yield was 9.4 g, corresponding to 51%. The adduct 35 was worked up to D-penicillamine in the same manner as in Example 1 and to obtain the corresponding yield.

Example 5

Proceed as described in Example 1, however, 43.5 g (0.2 mole) of N-formyl-isopropylidene-D, L-penicillamine 5 was reacted with 20 g (0.11 mole) of 1-norephedrine benzoate. The recovered adduct had a specific rotation of + 30 ° and melting point of 200-203 ° C. The yield was 24 g, which corresponds to 65% work-up for D-penicillamine as in Example 1 to obtain a corresponding yield.

Example 6

Proceed as described in Example 1, however, 21.7 g (0.1 mole) of N-formyl-isopropylidene-D, L-penicillamine was reacted with 10.8 g (0.06 mole) of 1-norephedrine formate. The recovered adduct had a specific rotation of + 32 ° and a melting point of 198-201 ° C. The yield was 11 g, corresponding to 60%. In the same manner as in Example 1 and with similar yield, the adduct for D-penicillin was reprocessed.

Example 7 Proceed as described in Example 1, however, 21.7 g (0.1 mole) of N-formyl-isopropylidene-D, L-penicillamine was reacted with 16.5 g (0.06 mole) of 1-norephedrine-3 -phenyl-propionate. The recovered adduct had a specific rotation of + 32 ° and a melting point of 198-202 ° C. Yield 25 was 11.5 g, corresponding to 62% Work-up of D-penicillamine as in Example 1 and with similar yield.

Example 8

As described in Example 1, 21.7 g (0.1 mole) of N-formyl-isopropylidene-D, L-penicillamine was reacted with 33 g (0.11 mole) of 1-norephedrine benzenesulfonate.

The recovered adduct had a specific rotation of + 31 ° and a melting point of 197-199 ° C. The yield was 14 g, 146414 or 76%. Work-up for D-penicillamine as in Example 1 and with similar yield.

Example 9

As described in Example 1, however, 21.7 g (0.1 mole) of N-formyl-isopropylidene-D, L-penicillamine were reacted with 21.5 g (0.03 mole) of 1-norephedrine citrate. . The recovered adjuvant had a specific rotation of + 30 ° C and a melting point of 198-200 ° C. The yield was 13 g, corresponding to 70%. Work-up for D-penicillamine and its yield as in Example 1.

Example 10

Proceed as described in Example 1, however, 25.7 g (0.1 mole) of D, LN-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid were reacted with 10.8 g 15 (0.06 mol) of 1-norephedrine formate. The recovered adduct of D-N-formyl-2,2-pentamethylene-5,5-dimethyl-thiazoli-din-4-carboxylic acid and 1-norephedrine had a specific rotation of + 25 ° and a melting point of 190-191 ° C. The yield was 16.5 g, corresponding to 81%. The cleavage of the adduct occurred as described in Example 1. The resulting DN-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid thus obtained had a specific rotation of + 62.8 ° and a melting point of 190 -191 ° C. The yield was 9.2 g, corresponding to 90%. The acid was cleaved in the same manner as N-formyl-isopropylidene-D-penicillamine in the foregoing examples and to obtain similar yield of D-penicillamine.

Example 11

As described in Example 1, however, 25.7 g (0.1 mole) of D, LN-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid were reacted with 16.5 g (0.06 mol) of 1-norephedrine benzenesulfonate. The recovered adduct had a specific rotation of + 24 ° and a melting point of 189-191 ° C. The yield was 14.5 g, corresponding to 35 to 71%. The adduct was reprocessed into D-penicillamine on