FI56527C - FOERFARANDE FOER FRAMSTAELLNING AV D-PENISILLAMIN - Google Patents

Description

. —1 r_, KU ULUTUSJULZUU rr C. O n ^ (11) UTLÄGGN I NGSSKRIFT 56527 C Patent «yönni tty il 2 1930 'Patent seddelat' ^ ^ (51) Kv.lk. * / Lnt.CI. 149/243 ENGLISH —FINLAND (21) p * t ,, 'ttlh * kemui - PtMntMiehnlng 1 ^ 03/72 (22) H »k« ml * pälvg - Aniöknlngtdag 17 · 05 · 72 <FI) (23) The beginning of the cloud - Glltlgheudig 17 .05.72 (41) Has become public - Bllvlt offentllg 31 * 01.73

Patent, and Registration Board NihtMIdp · * »j. month »* * m. -

Patent · och reglsterstyrelsen 'An * ök »n utlagd oeh utl.skrlften publlcerad 31.10.79 (32) (33) (31) Pyydetty etuoikeus — Begird prlorltet 30.07-71

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2130122.6 Proof-Styrkt (71) Deutsche Gold- und Silber-Scheideanstalt vormals Roessler, Weissfrauen-Strasse 9 »Frankfurt (Main), Federal Republic of Germany-Förbundsrepubliken Tygkland Aachen, Karl-Heinz Gluzek, Orsoy, Heribert Offermanns, Grossauheim, Walter von Bebenburg, Buchschlag, Federal Republic of Germany Tfyskland (DE) (74) Oy Kolster Ab () Method for producing D-penicillamine - Förfarande för framställ

As an active ingredient, the amino acid D-penicillamine is known to be an important drug in the treatment of Wilson's disease, schizophrenia, sclerosis, cystinurea and chronic hepatitis, and as a basic drug for primary, chronic arthritis. In addition, D-penicillamine is used as an antibody in heavy metal poisoning.

Only D-penicillin has medicinal use, as the L-isomer is significantly more toxic.

D-penicillamine can be prepared from penicillin by a low-yield hydrolysis method. Expensive starting material explains this. the high cost of amino acid, which prevents the widespread medical use of D-penicillamine, especially as a basic drug in the long-term treatment of primary, chronic arthritis. For this reason, the overall synthesis of D-penicillamine is particularly significant.

Indeed, D, L-penicillamine can be prepared synthetically and D-penicillamine is obtained by cleavage of the racemate. In this case, d-pseudoephedrine and 1-ephedrine ("The Chemistry of Penicilline" (1919 * 9) »Princeton University Press, British Patent No. 585 1 * 13, U.S. Patent No. 2 1 * 50 78U, are used as optically active bases. Belgian Patent No. 738,520).

To cleave the racemate, D, L-penicillamine must be converted to the appropriate derivatives, i. as is customary in the cleavage of racemic amino acids 2,56527, protecting groups must be attached to the peniaillamine molecule. Suitable derivatives for the cleavage of the racemate are, for example, the acylation products of D, L-penicillamine or S-benzyl-D, L-penicillamine and the acylation compounds of the reaction products of D, L-penicillamine and carbonyl compounds.

However, this method for cleaving racemic D, L-penicillamine is less satisfactory because the reaction of the D, L-penicillamine derivative and said cleavage bases precipitates an undesired salt of the L-penicillamine derivative and the optically active auxiliary base. However, it is known that the antipode precipitated from the reaction solution is in principle purer (HD Jakubke and H. Jeschkeit, "Aminosäuren, Peptide, Proteine", Akademie-Verlag, Berlin 1969 and LF Fieser and M. Fieser, "Lehrbuch der Organischen Chemie", Verlag Chemie, Weinheim 1957).

It has now been found that in order to obtain D-penicillamine from D, L-penicillamine, it is particularly advantageous to use 1-norephedrine (phenylpropanolamine) H CH_

I »J

C.Hc - C - C - H

o 5 1 1 OH NH2

The invention thus relates to a process for the preparation of D-penicillamine from D, L-penicillamine by converting the racemate to the racemic N-acyl-2,2-disubstituted-5,5-dimethylthiazolidine-U-carboxylic acid, which is reacted with an optically active base to give a salt mixture from which DN- acyl-2,2-disubstituted-5'-dimethylthiazolidine-4-carboxylic acid salt from which D-penicillamine is prepared, characterized in that the base used is 1-norephedrine.

With this optically active base, the cleavage of racemic D, L-penicillamine occurs in the highest yields and D-penicillamine precipitates in very pure form because the desired salt of D-acid and 1-base precipitates more sparingly.

As with current racemate cleavage methods in Method D of this invention, L-penicillamine must first be converted to a derivative particularly well suited for racemate cleavage before the reaction with 1-norephedrine can occur, i. one or both hydrogen atoms of the amino group must first be protected. At the same time, the hydrogen atom of the mercapto group can also be protected. In this case, all known methods described, for example, by J. P. Greenstein and M. Winitz, "Chemistry of the Aminoacids", J. Wiley & Sons Inc., New York 1961 and Houben Weyl, 1958, can be used.

Band 11/2, Georg Thieme Verlag. Such protection is achieved, for example, by modifying the general formula of D, L-penicillamine in a known manner.

COOH

H - C - N - Ac (X)

CH3-C Z

For compounds of formula CH3 sr 3,56527, in which Ac is an acyl group, in particular a benzoyl, tosyl, nitrophenylsulphenyl, acetyl or preferably formyl group, Z is a hydrogen atom, but may also be a diacyl residue, in particular a phthalyl residue, and R is a hydrogen atom or a benzyl residue, and in addition R may be the same as Ac.

Preferably, however, such groups are protected by modifying the general formula of D, L-penicillamine in a known manner.

COOH

H - C - N - Ac c 1 l / 2 (II) C 3 S E 2 1 2 to a thiazolidine-N-carboxylic acid, wherein R and R in the lava are the same or different hydrogen atom or alkyl group containing 1 to δ carbon atoms or cycloalkyl or aryl residue and Ac denote as above.

Of these protected compounds, those obtained by converting the N-aa of D, L-peniflylamine-2,2-dialkyl-5,5-dimethylthiazolidine-4-carboxylic acid to the N-pharmaceutical derivative of ethyl or mlahium are again preferred. The most significant of these is again N-farm; N, N-2,2,5,5-tetramethylthiateolidine-4-carboxylic acid (N * · formylisopropylidene-DL-uenicillamine) A. These thiazolidine-4-carboxylic acids can be easily prepared from D, L penicillamine and related carbonyl compounds ("The Chemistry of Penicilline", 19-9, Princeton University Press). The same literature describes the conversion to N-acyl compounds as well as compounds with a protected mercapto group.

Suitable solvents for the cleavage of the racemate are, in addition to water, in particular organic solvents, e.g. alcohols, aliphatic hydrocarbons, ethers, ketones, esters, aromatic hydrocarbons, etc. Preferably benzene, toluene, isopropanol a, dioxane and lower carbazylic acid esters are used in the process. act by converting D, L-penicillamine into derivatives suitable for cleavage of the racemate by known means (protected D, L-penicillamine) and dissolving the derivatives in water or, preferably, in an organic solvent or solvent mixture, optionally with heating, optionally adding 1-norephedrine dissolved in an organic solvent, the sparingly soluble salt of the penicillamine derivative and 1-norephedrine sometimes precipitates immediately, sometimes only after prolonged standing and possibly after the use and inoculation of low temperature. The mother liquor, diastereoisomeric salt, optical antipode or racemic mixture or mixtures remain in the mother liquor. The sparingly soluble salt can be converted to the mineral acid salts of D-penicillamine by known means, e.g. by treatment with dilute mineral acids. D-penicillamine, free of its mineral acid salts, can be liberated by known means, for example by treatment with bases.

But it is also possible to do the reverse order by adding a derivative of racemic penicillamine, preferably dissolved in an organic solvent, to the 1-norephedrine solution.

The process according to the invention can be advantageously carried out using 0.1 to 3 moles, preferably 0.5 to 1.1 moles of 1-norephedrine per mole of racemate. The sparingly soluble salt of D-penicillamine and 1-norephedrine precipitates at all concentrations. When using almost stoichiometric amounts, the precipitation is almost quantitative. When less than 0.5 moles of 1-norephedrine is used, the racemate and optical antipode remain in the mother liquor, and when 0.5 to 1 moles of cleavage per mole of racemate, the diastereomeric salt remains in the mother liquor. If more than one mole of optically active auxiliary base is used per mole of racemate, the cleavage base remains in the mother liquor in addition to the diastereomeric salt.

The salts precipitated in the reaction of the penicillamine derivative and 1-norephedrine are obtained pure by conventional means due to the very advantageous solubility, e.g. by filtration, evaporation of the mother liquor to dryness and recrystallization.

In all cases, cleavage of the racemate precipitates the sparingly soluble salt of the D-penicillamine derivative and 1-norephedrine, with the second diastereomer remaining in solution first. This was completely surprising, since when both D-pseudoephedrine and 1-ephedrine are used, the salt of the L-penicillamine derivative and the cleavage base is less soluble.

The cleavage of the sparingly soluble salt can also be carried out in a known manner, preferably by treatment with aqueous solutions of mineral acids, e.g. dilute hydrochloric acid, whereby the cleavage base is first recovered as a mineral acid salt to give a D-penicillamine derivative.

The cleavage of the D-penicillamine derivative takes place in a known manner by cleavage of the protecting groups, e.g. by debenzylation or hydrolysis with an acid.

Similarly, L-penicillamine can be isolated from the mother liquor of the racemate cleavage. However, racemization of the L-penicillamine derivative, possibly obtained by cleavage of the salt with a mineral acid and an optically active cleavage base, in a known manner, has proved to be particularly advantageous, making it possible to reuse the medically unusable. L-penicillamine.

Example 1

In a 50 liter glass reaction vessel equipped with a stirrer, reflux condenser, dropping funnel, gas supply line and drain tap, dissolve at 50 ° in 20 liters of ethyl acetate 3 to 26 kg (15 moles) of N-formylisopropylidene-D, L-penicillamine obtained kg (16 moles) of D, L-penicillamine hydrochloride and 2.8 kg (50 moles) of acetone react with each other and then formylated with a mixture of formic acid and acetic anhydride while neutralizing with sodium acetate. 3.28 kg (1.05 x 15 moles) of 1-norephedrine dissolved in 7 liters of ethyl acetate are added to this solution with stirring and heating, whereby the temperature is observed to rise by about 5 ° C. After a few minutes, the adduct (I) of N-foryl-isopropylidene-D-penicillamine and 1-norephedrine precipitates. It is then stirred and heated under reflux for half an hour. After cooling, filter thoroughly, wash the filter residue with about three liters of ethyl acetate and dry in vacuo at about 50 ° C. 2.75 kg = 98% of adduct (I) are obtained, m.p. 200 ° -204 ° C, E 0 * 7 ^ ~ + 33 °.

After evaporation to dryness, a crude adduct (N) of N-formylisopropylidene-L-penicillamine and 1-norephedrine is obtained from the mother liquor, from which a pure adduct is obtained by recrystallization from isopropanol, m.p. ll6 ° C,

At 25 DEG C., 2.75 kg of adduct (i) are added to 10 l of distilled water and 1 l of concentrated hydrochloric acid. After stirring for 1 hour, filter thoroughly, wash the residue with two liters of distilled water and dry at 50 ° C under vacuum. 1.1 * 9 kg = 92% of N-formylisopropylidene-D-penicillamine are obtained, m.p. 183 ° -18 ° C, 601 ° = + 53 °. After evaporation of the mother liquor to dryness and recrystallization from isopropanol, 1.19 kg of 1-norephedrine hydrochloride are obtained, m.p. + 172-17l ° C.

Add 1.9 kg of N-formylisopropylidene-D-penicillamine to 9.0 liters of 15 # hydrochloric acid heated to 70 ° C. Heat for another two hours at the same temperature to remove the liberated acetone. After evaporation to dryness on a 50-liter rotary evaporator, 1.08 kg of crude D-penicillamine hydrochloride are obtained.

Dissolve 1.08 kg of D-penicillamine hydrochloride in 8.7 liters of 96 [mu] l of alcohol and add 0.59 kg (5.82 moles) of triethylamine to precipitate free 6,56527 D-penicillamine. After filtration, washing with 96 # alcohol and drying in vacuo at 50 [deg.] C., 0.78 kg of D-penicillamine are obtained, m.p. 212 ° -214 ° C, δ 7p ° = -62.8 °.

The impure adduct (II) is further treated in the same manner as the adduct (I). 1.3 kg of N-fornyl-isopropylidene-L-penicillamine are obtained, m.p. 182 ° -84 ° C, = -53 °.

Dissolve 1.3 kg of N-formylisopropylidene-L-penicillamine in 4.5 liters of toluene and add 30 ml of acetic anhydride. After cooling to room temperature, pure N-formylisopropylidene-D, L-penicillamine crystallizes.

1.25 kg of N-formylisopropylidene-D, L-penicillamine are obtained, m.p. l4o-l42 ° C, C-0? - ° 0 ·

Example 2

In a 1 liter multi-necked flask equipped with a stirrer, dropping funnel, gas supply line and reflux condenser, dissolve 43.5 g (0.2 mol) of N-formylisopropylidene-D, L-penicillamine in 300 ml of ethyl acetate at 50 ° C. To this solution is added portionwise 16.7 g (0.11 moles) of 1-norephedrine over five minutes and heated under reflux for 30 minutes. After cooling to room temperature, filter thoroughly, wash with 150 ml of ethyl acetate and dry at 50 ° C under vacuum. 33.9 g of 92% of N-formyl-isopropylidene-D-penicillamine-1-norephedrine adduct (I) are obtained, m.p. 202-204 ° C, = + 31 °. The cleavage of the adduct takes place as described in Example 1. 10 g of D-penicillamine are obtained, m.p. 212-214 ° C, -62.7 °.

Example 3

Proceed as in Example 2, but using isopropyl alcohol as the solvent. 33.1 g (90%) of adduct are obtained, from which cleavage gives 9.7 g of D-penicillamine, m.p. 211-213 ° C "62.7 °.

Example 4

Proceed as in Example 2, but using toluene as the solvent. 32 g (87 2) of adduct (I) are obtained, m.p. 201-202 ° C, * "31.8 °.

Example 5

Proceed as in Example 1, but starting from 21.8 g (0.1 mol) of N-formylisopropylidene-D, L-penicillamine and 15.1 g (0.1 mol) of 1-norephedrine and acetone as solvent. 28.5 g of 78% of adduct (I) are obtained, m.p. 200-204 ° C, 1 ° β + 31 ° · 7 56527

Example 6

Proceed as in Example 5, but use dioxoxy as the solvent. 28 g * 75 of adduct (i), b.p. 195-196 ° C, / i7j ° - + 50 * 7 ° ·

Example 7

Proceed as in Example 5, but using benzene as the solvent. 33 g * 90 of adduct (i) are obtained, m.p. 197-201 ° C, -51 °.

Example 8

The procedure is as in Example 5, but carbon tetrachloride is used as the solvent. 34 g * 95 # of adduct (i) are obtained, m.p. 200-201 ° C, Ä7? - + 55 ° *

Example 9

Proceed as in Example 1 except that D, L-3-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid (51-4 g> 0.2 mol) and 1- norephedrine (30.2 g, 0.2 mol). The obtained 2-3-formyl-2,2-pentamethylene-5,5-dimethylthiazolidine-4-carboxylic acid and 1-norephedrine salt have a specific rotation of + 26 °, m.p. 189-191 ° C. Yield 33 g (81 #).

Example 10

Proceed as in Example 1 except that the starting material is E, L-3-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid (51 * 4 g, 0.2 mol) and 1- norephedrine (15 »1 g» 0.1 mol). The resulting salt of D-3-formyl-2,2-pentamethylene-5,5-dimethylthiazolidine-4-carboxylic acid and 1-norephedrine - + 25 ° and m.p. 190-191 ° C. Yield 31 g (76 $ 6). The salt is decomposed as in Example 1. There is thus obtained N, N-formyl-2,2-pentamethylene-5,5-dimethylthiazolidine-4-carboxylic acid, m.p. + 62.2 °, m.p. 191-192 ° C. From this, 9 g of T> -penicillamine are obtained by the method described in Example 1, m.p. 202-205 ° C and -62.5 ° ·