FI83633B - FOERFARANDE FOER FRAMSTAELLNING AV AMINOSYRADERIVAT OCH I FOERFARANDET ANVAEND MELLANPRODUKT. - Google Patents

Description

1 83633

Process for the preparation of amino acid derivatives and intermediate used in the process 5 Separated from application 823757

The invention relates to a process for the preparation of compounds of formula II

10 Y R 1 -v I * 1 (! 7-C - CH, - CH - NH - CH - COOH (II) 15 WI | H COOR 2 wherein 20 R 1 is methyl p-ethoxybenzyl or a group (CH 2) 4 NHR where R is hydrogen or benzyloxycarbonyl and R 2 is lower alkyl or benzyl and Y is hydrogen or hydroxy and an intermediate used in the process.

Chiral centers located on the C atoms of the chain marked with an asterisk (*) may have the R or S configuration. However, compounds in which these centers have the S configuration are preferred.

The process according to the invention for the preparation of compounds of the formula II is characterized in that the ketoacrylic acid esters © -CO-CH = CH-CO 2 R 2 are converted by reaction with α-amino acid esters H 2 N-CH (R 1) -CO 2 W ', where W is lower alkyl with R 2 being benzyl. or benzyl R 2 is lower alkyl, to compounds of formula 35 IV.

In formula IV, W is primarily benzyl 2 83633 or tert-butyl.

Compounds of formula IV can be obtained in maximum yields by Michael addition of the corresponding ketoacrylic acid esters with α-amino acid esters.

5 0 R1

<- C - CH - CH - CO2R2 + NH2 - CH - CO2W '- * · IV

Diastereomers having the preferred S, S configuration are formed using an excess of L-alanine esters and can be recovered by crystallization or chromatographic separation of the esters from compound II on silica gel.

The invention therefore further relates to compounds of formula IV

CO2R2 R1

/ —Λ I I

// V) - CO - CH2 - CH - NH - CH - CO2W '(IV) 20 wherein

R 1 is methyl, p-ethoxybenzyl or a group - (CH 2) 4 -NHR, where R is hydrogen or benzyloxycarbonyl and one of R 2 and W is lower alkyl while the other is benzyl. The compounds are useful as intermediates of formula II

in the manufacture of compounds according to

The compounds of formula II can be used as intermediates in the preparation of therapeutically useful cis-endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid derivatives as described in FI application 823757.

The invention is further illustrated by the following examples.

Example I

35 Benzyl ester of N- (1-S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -S-3,836.53 alanine 65.7 g of ethyl 3-phenyl-3-oxo-1-propene-1-carboxylic acid ( benzoylacrylic acid ethyl ester) is dissolved in 225 ml of ethanol and 1 ml of triethylamine is added to the solution. To this solution, 70 g of S-alanine benzyl ester dissolved in 90 g of ethanol are rapidly added dropwise at room temperature. Stir for 2 hours at room temperature and then cool the solution.

The S, S isomer crystallizes.

Yield: 94.3 g M.p .: 83-74 ° C

[α] D = 17.8 ° (c = 1, CH 3 OH)

Example II

N- (1-S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -S-alanine_ 0.5 g of the compound obtained in Example IV are dissolved

40 ethanol and 0.1 g of 10% Pd / C is added and hydrogenated at room temperature and normal pressure. Yield: 300 mg M.p .: 210-220 ° C

1 H-NMR (DMSO-d 6): 1.0-1.4 (t, 6H); 3.2-5.0 (m. 8H); Δ 7.2-8.2 (m. 5H)

Example III

(1) Na- (1S-Ethoxycarbonyl-3-oxo-3-phenyl-propyl) -Nc-benzyloxycarbonyl-S-lysine-1-benzyl ester_.25 10 g of 3-phenyl-3-oxo-1-propylene-1-carboxylic acid ethyl ester are dissolved. To 100 ml of ethanol. To the solution are added 19.1 g of Na-benzyloxycarbonyl-S-lysine benzyl ester and 0.2 g of triethylamine. The solution is stirred for 3 hours at room temperature and then evaporated in vacuo, the oily residue (31 g) is dissolved in isopropanol / diisopropyl ether and cooled. 13 g of benzyl ester of Na- (1-S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -N e benzyloxycarbonyl-S-lysine crystallize.

35 4 83633 α d ° = 3.5 ° (C = 1, CH 3 OH): 1 H-NMR (CDCl 3): 1.0-1.4 (tr, 3H); 1.0-2.0 (m. 9H); 2.0-2.6 (broad s, 1H); 2.9 - 3.9 (m, 6H); 3.9-4.4 (q. 2H); 4.6-4.9 (broad s, 1H); Δ 5.0-5.2 (double-s, 4H); 7.1-8.1 (m. 15H).

(2) Na- (1S-ethoxycarbonyl-3-phenylpropyl) -Nε benzyloxycarbonyl-5-lysyl] 4.0 g of the benzyl ester derivative of lysine prepared in Example III (1) are dissolved in 50 ml of glacial acetic acid and 0.6 g of Pd is added. / C (10%) and 0.6 g of concentrated sulfuric acid. Hydrogenate for 6 hours at room temperature and normal pressure. The solution is then separated from the catalyst by suction filtration and the ethanolic solution is mixed with 1.4 g of solid sodium bicarbonate. The solution is evaporated on a rotary evaporator and the residue is dissolved in water. The aqueous phase is extracted with ethyl acetate and methylene chloride. The organic phases are discarded and the aqueous phase is evaporated to dryness in vacuo. The residue is triturated with methanol. After evaporation of the methanol, an oily residue remains which solidifies on treatment with diisopropyl ether. Yield of Na- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-lysine: 2.0 g.

1 H-NMR (D 2 O): 1.0-1.4 (tr, 3H); 1.0-2.5 (m, 9 H), 2.5-4.4 (m, 9 H); 3.9-4.4 (q. 2H); 4.5-5.0 (m. 1H); 7.1-7.6 (m, 5H) m / e: 336 3.4 g of gα- (1S-ethoxycarbonyl-3-phenylpropyl) -5-lysine are dissolved in 30 ml of methylene chloride and cooled to 0 ° C. C. 2.1 g of triethylamine are added thereto under ice-cooling, followed by dropwise addition of 1.9 g of benzyl ester of chloroformic acid. Stir for 1 hour at 0 ° C and then bring to room temperature. The methylene chloride solution is shaken successively with water, sodium carbonate solution and water. After evaporation, 83633 is evaporated and the oily residue is chromatographed on silica gel using methylene chloride / methanol as solvent. 2.0 g of Na- (1-S-ethoxycarbonyl-3-phenylpropyl) -N ε-benzyloxycarbonyl-S-lysine are obtained. 1 H-NMR (D 2 O): 1.0-1.4 (tr, 3H); 1.0-2.5 (m. 9H); 2.5-4.4 (m. 9H); 3.9-4.4 (q. 2H); 4.5 - 5.0 (m, 1 H); 5.1 (s. 2H); 7.1-7.5 (m. 10H)

Example IV

10 (1) N- (1-R, S-Carbethoxy-3-oxo-3-phenylpropyl-O-ethyl-S-tyrosine benzyl ester) 24 g of benzoylacrylic acid ethyl ester in 100 ml of ethanol are reacted with O-ethyl-S-tyrosine benzyl ester (30 g). ) in the presence of triethylamine (0.5 ml) in analogy to Example I, after evaporation of the solution and trituration of the residue (diethyl ether / petroleum ether, 1: 1) and drying of the product in vacuo, 42 g of RS, S are obtained.

(2) N- (R, S-Carbethoxy-3-phenylpropyl) -O-ethyl-20-S-tyrosline 40 g of the compound obtained in (1) are hydrogenated in 800 ml of acetic acid under 10% Pd / C catalyst (4 g) in the presence of room temperature at a pressure of 100 bar. Chromatography on silica gel, eluting with an ethyl acetate / cyclohexane mixture (1: 3), evaporating to dryness and drying the residue, gives 25 g of a thin-layer chromatographically almost uniform title compound, m.p. 205-213 ° C.

Analysis: C H N

30 C23H29NO5 (399.5) calculated: 69.15 7.31 3.50 found 69.5 7.4 3.3

Claims (2)

A process for the preparation of compounds of formula II, Y 1 - R - C - CH 2 - CH - NH - CH - COOH (II) H COOR 2 wherein R 1 is methyl, p-ethoxybenzyl or a group - (CH 2) 4 NHR wherein R is hydrogen or benzyloxycarbonyl, R 2 is lower alkyl or benzyl and Y is hydrogen or hydroxy, characterized in that ketoacrylic acid esters ® -CO-CH = CH-CO 2 R 2 are reacted with α-amino acid esters H2N-CHiRM-CO 2 of formula IV, CO 2 R 2 R 1 - CO - CH 2 - CH - NH - CH - CO 2 W - (IV) where W, R 1 and R 2 hydrogenation. Compounds of Formula IV, CO 2 R 2 R 1 O 1 - CO - CH 2 - CH - NH - CH - CO 2 W - (IV) wherein R 1 is methyl, p-ethoxybenzyl or a group - (CH 2) 4 where R is hydrogen or benzyloxycarbonyl and one of the groups R2 and W is lower alkyl while the other is benzyl.