CS274337B1 - Method of phenylalanine's alkylated derivatives preparation - Google Patents

Abstract

The solution concerns a method of preparation of sterically difficult 2-alkyl or 2,6-dialkylderivates of phenylalanine of formula I, which can influence biological efficiency of peptides, in which they are chemically built. These pharmacologically important peptides with selective, prolonged or antagonistic effect can be used as preparates in human or veterinary medicine. The preparation of the substances of formula I, where R1 and R2 = alkyl or hydrogen is performed by hydrogenolysis of relevant derivates of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid of general formula II, where R1 and R2 have the same meaning as in the formula I, in acetic acid at a temperature of 100 to 120 degrees C during catalysis by palladium black.<IMAGE>

Description

The invention relates to alkylated phenylalanine derivatives. It is the preparation of the non - coded amino acids 2 - alkyl and 2,6 - dialkylphenylalanine.

Non-coding amino acids are often used to prepare analogs of biologically active peptides with determined biological properties, i.e., to obtain a selective, prolonged or antagonistic effect (see, for example, review articles 3, Hlavacka, K. Jošt, M, Lebla and F. Brtnik in Handbook of Neurohypophyseal Hormone Analogs (Jost K, Lebl M., Brtnik F., Eds.), 1987, Vol 1, part 2, ppl 50-3O, 109-188 and Vol.2, part l, pp.17-154, CRC Press , Boca Raton, USA). Such analogs are then more preferred than natural peptides in their eventual use in human or veterinary medicine. Their biological effects are based on the specific contribution of the structure of the non-coding amino acid to the overall conformation of the molecule that affects the interaction of the analog with the biological system and hence its biological activity.

An important group consists of non-coding amino acids with limited side chain flexibility, whose presence in the biologically active peptide analogue molecule often leads, inter alia, to an increase in its resistance to enzymatic cleavage and thus to prolong its biological effect. In particular, the restriction of the amino acid side chain flexibility can be achieved by introducing additional substituents which increase its steric demands. This can be illustrated by the amino acid phenylalanine, a common component of biologically active peptides, where the substitution of the aromatic side chain with an alkyl group at the 3 or 4 position significantly affected the biological properties of the peptides containing the phenylalanine thus modified.

Further development of the structure-biological activity study has led to the need to prepare peptide analogs with phenylalanine, in which the position 2 of the aromatic nucleus is also substituted, and the need to develop a simple and reproducible process for preparing such modified phenylalanine derivatives. The present process for their preparation (Ro.R., Herr et al., J.Amer.Chem.Soc. 79, 4229 (1957)) consists of a multi-step synthesis involving the reaction of alkylated benzyltrimethylammonium halides with ethyl acetamidomalonate. In a further procedure (G.H.Cleland: J. Org. Chem. 34, 744 (1969)), alkylated aryldiazonium halides are reacted with acrylic acid to give the corresponding 2-halo acids which provide the desired amino acids with ammonia. Another preparation is described by P.E. Gagnon: Can.J.Chem. 29.70 (1951), which prepared this type of amino acids from the corresponding substituted concentrates. All of these approaches represent multi-step syntheses with high time demands for the preparation of the phenylalanine derivatives contemplated, burdened by generally low yields.

These disadvantages are overcome by the process for the preparation of the phonylolanine derivatives of the general formula (I)

CS 274 337 Bl

wherein R 1 or R ₂ is alkyl or H which preferably consists in the hydrogenolytic cleavage of 1,2,3,4-tetr 3 -hydroisoquinoline-3-carboxylic acid derivatives (hereinafter Tic), (A.Pictet, T. Premgler: Ber. 44 , 2030 (1911) and K.Wellisch, PLCulian: O.Amer.Chem.Soc., 70, 180 (1948), of formula II

or wherein R ₂ is the same as in Formula I. The hydrogenolysis is carried out in acetic acid at 100-120 ° C under the catalysis of palladium black. In case that _R2 is H, respectively, to only mono-substituted phenylalanine derivatives, alkylated aromatic ring in the 2-position, which can be converted in a further step by cyclization of the above cited works Tic for preparing 5-substituted 1,2,3,4 - tetrahydroisoquinoline - 3-carboxylic acid (Scheme 1), corresponding to the above general formula II.

wherein R 1 is alkyl and R ₂ is alkyl or hydrogen.

Subsequent hydrogenolysis from the above conditions then affords the 2,6 disubstituted phenylalanines represented by Formula I, which are otherwise difficult to access, as shown in the above work.

In the following, the invention is illustrated in more detail by way of examples, without being limited thereto.

CS 274 337 Bl

Example 1

Preparation of 2 - methylphenylalanine

A solution of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (10 g, 56 mmol) in 200 mL of acetic acid is heated to 100 ° C and freshly prepared sponge palladium catalyst (10 to 20% by weight) is added. percent). The reaction mixture, which is maintained at a temperature in the range of 100 to 120 ° C, is introduced with stirring with a slow stream of hydrogen. The progress of the reaction is checked by electrophoresis on Whatman 3MM paper (20 V / cm, 45 min) in 1M acetic acid (pH 2.4) and in pyridine-acetic acid buffer (pH 5.7) and detected with ninhydride. The yellow spot of the secondary amino group of the isoquinoline derivative (see general formula II) gradually becomes a violet spot provided by the ninhydrin with the primary amino group of the resulting 3-substituted phenylalanine (general formula I). The starting material and the product also have different electrophoretic values

0.58 and 8 ^ 4 ° · 3θ. The reaction is complete after 3-4 hours, when the catalyst is filtered off and the solution is evaporated to dryness. The residue was dissolved in hot water, filtered with carboraffin and lyophilized. The prepared 2-methylphenylalanine (9 g, 90% yield) melted at 260 ° C with decomposition. For C ^ qHH ^NO ,, (7979.2) calculated: 67.02% C, 7.31% H, 7.82% N, C ₁₀ H ₁₃ NO ₂ (179.2) calculated: 67.02% C, 7.31% H, 7.82 N, found: 66.78% C, 7.42% H, 7.66% N. The mass spectrum (M ⁺ 180) as measured by FAB on a VG Analytical Limited Manchester, UK) corresponds to the predicted structure of racemic 2-methylphenylalanine, namely: even if the starting material is enantiomerically pure. The mass spectrum of the corresponding N- tert -butyloxycarbonyl derivative (C ₁₅ H ₂ NO ₄ , 279.1) measured by FAB is M ⁺ 280.

Example 2

Preparation of 2,6-dimethylphenylalanine

Hydrogenolysis of 5-methyl, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3 g, 16 mmol) in acetic acid (100 mL) catalysed by palladium as a fungus was prepared under the same conditions as in Example 1 2,6-dimethylphenylalanine (2 g, 65% yield), melting at 235-237 ° C with decomposition. Εθ ¹ ^ 0.56 and 0.34.

For C _u H ₁₆ N0 ₂ (194.3) calculated: 68.02% C 8.30% H 7.21% N Found: 68.25% C, 8.07% H, 07.11% N.

The FAB mass spectrometer as in Example 1 (M ⁺ 195) corresponds to the predicted structure of 2,6-dimethylphenylalanine, which is prepared as a racemic substance. The mass spectrum of its N @ + - tert-butyloxycarbonyl derivative (C11 H23 NO4 293.4) M @ ⁺ 293, was measured by the E1 technique on the same instrument as in Example 1.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of an alkylated phenylalanine derivative of the formula I wherein R R and Rg is alkyl having from one to four carbon atoms nobo hydrogen, characterized in that the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivative of the general formula II is COOH where R 1 and R 8 is the same as in formula (I), porobi hydrogonolyzo in acetic acid at 100 to 120 ° C, under palladium black catalysis.