FI80442B - Cis,endo-2-azabiscyclo[3,3,0]octane-3-carboxylic acids and their esters, together with a process for their preparation - Google Patents

Description

1 80442

Cis, endo-2-azabicyclo [3.3.3] octane-3-carboxylic acids and their esters, and a process for their preparation

Divided by application 823757 5

The invention relates to cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid and its ester of formula IIIa or IIIb

10 h H

HN-f-1 HN--. ; pp W02C H WO „C *

15 2 H

Ala IIIb wherein W represents hydrogen, alkyl having 1 to 6 carbon atoms or aralkyl having 7 or 8 carbon atoms, and its salts with acids and (in the case of W = hydrogen) bases.

EP-A-37 231 discloses octahydroindole-2-carboxylic acid derivatives and octahydroindole-2-carboxylic acids used as intermediates in their preparation. This invention instead relates to novel cis, endo-2-azabicyclo [3.3.07] octane-3-carboxylic acids and their esters of the formulas lila or mb as defined above.

The invention further relates to a process for the preparation of these compounds.

The chiral center located at the C atom of the 3-position of the bicyclic group may have the R or S configuration.

The process according to the invention for the preparation of the novel cis, endo-2-azabicyclo [3.3.7] octane-3-carboxylic acids and their esters and salts according to formula IIIa and IIIb is characterized in that the cyclopentanone 2 80442

an enamine of formula VI

X1 __s'

^ VI

5 wherein represents a dialkylamino having 2 to 10 carbon atoms or a group of formula VII

(CV.V

10 „* VI1

wherein m and o represent an integer from 1 to 3, (m + o)> 3, and A is CH 2, NH, O or S, is reacted with N-acylated N-halo-O-aminocarboxylic acid esters of formula VIII

X1

CH

20 | VIII

CH

1 / \ 2

Y -HN COOR

wherein X represents a nucleophilic group, preferably chlorine or bromine, Y represents an alkanoyl having 1 to 5 carbon atoms, an aroyl having 7 to 9 carbon atoms or other acid-cleavable protecting groups 2 common in peptide chemistry, and R represents 1 to 5 carbon atoms. alkyl or aralkyl having 7 to 9 carbon atoms,

30 or with acrylic acid esters of formula IX

COOR 1,

ch2 = c ^^ IX

35 ΝΗ-γ1 3 80442 1 2 wherein Y and R have the same meaning as above, to compounds of formula X COOR2 NH-Y 1 10 2 1 where R and Y have the same meaning as above, these are cyclized with strong acids, whereby acyl the amide and ester are cleaved to give compounds of formula Xla or Xlb, (Xla)

N COOH

FM

I COOH

II

these are converted by catalytic hydrogenation in the presence of transition metal catalysts or by reduction with boranamine complexes or complex boron compounds in lower alcohols to compounds of formula IIIa or IIIb, wherein W represents hydrogen and optionally esterified to compounds of formula IIIa or IIIb, C-alkyl or aralkyl having 7 to 8 C-atoms.

The bicyclic amino acids of formulas lila and IIIb have a cis endoconfiguration, i. The -CO 2 W group faces the cyclopentane ring.

4 80442

Preferred enamines are, for example, pyrrolidino-cyclopentene and morpholino-cyclopentene. The alkylation products of formula X are preferably cyclized with aqueous hydrochloric acid. Compounds of formula III (where W = H) can be esterified by methods conventional for amino acids. e.g. Houben-Weyl, Methoden der organischen Chemie, Volume VIII (1952), e.g. thionyl chloride / benzyl alcohol or isobutylene / sulfuric acid.

After corresponding further treatment, they lead to the compounds of the formula III in the form of free bases or salts.

For example, the compounds of formulas IIIa and IIIb can be used as intermediates in the preparation of pharmaceutically useful cis-endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid derivatives, as disclosed in FI-15 patent application 823757.

The invention is further illustrated by the following examples.

Example I: N- (1S-Ethoxycarbonyl-3-phenylpropyl) -5-alanyl-2-20 cis, endo-azabicyclo / 3.3.07 octane-3-S-carboxylic acid (1) 2-acetylamino-3- (2- oxocyclopentyl) propionic acid methyl ester 269 g of 3-chloro-2-acetylaminopropionic acid methyl ester and 257 g of cyclopentenopyrrolidine are kept in 1.5 l of 25 dimethylformamide for 24 hours at room temperature. Evaporate in vacuo, take up the residue in a small amount of water, adjust the pH to 2 with concentrated hydrochloric acid and extract twice with 4 l of ethyl acetate. Evaporation of the organic phase leaves a pale yellow oil.

Yield: 290 g.

NMR: 2.02 (s, 3H); 3.74 (s. 3H); 4.4-4.8 (m, 1H) (CDCl 3)

Analysis: C N

calculated 58.1 7.54 6.16 found 58.5 7.2 6.5 35 (2) Cis, endo-2-azabicyclo / 3.3.07 octane-3-carboxylic acid hydrochloride_ 270 g of the acetylamino derivative prepared in (1) are boiled reflux with cooling in 1.5 l of 2N hydrochloric acid for 45 minutes. Evaporate in vacuo,

II

The residue is taken up in glacial acetic acid, 5 g of Pt / C (10% Pt) are added and hydrogenated at a pressure of 5 bar. After filtration, the residue is evaporated and the residue is crystallized from chloroform / diisopropyl ether.

Melting point: 205-209 ° C, yield 150 g of (3) Cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester hydrochloride 40 g of the carboxylic acid prepared in (2) are added to an ice-cold mixture of form 390 g of benzyl alcohol and 65 g of thionyl chloride and are kept at room temperature for 24 hours. After evaporation in vacuo, 47 g of benzyl ester crystallize from chloroform / isopropanol. Melting point: 175 ° C (hydrochloride) 15 (4) N- (2-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-cis, endo-2-azabicyclo [3.3.30] octane-3-S-carboxylic acid benzyl ester 14 g of the benzyl ester prepared in (3), 6.7 g of HOBt, 13.8 g of N- (1S-ethoxycarbonyl-3-phenylpropyl-20-yl) -5-alanine and 10.2 g of dicyclohexylcarbodiimide are reacted with 200 ml of: in dimethylformamide. After stirring for 3 hours at room temperature, the precipitated dicyclohexyl urea is removed by suction filtration, evaporated, taken up in 1 l of ethyl acetate and shaken with 3 x 500 ml of 5% NaHCO3 solution. The organic phase is evaporated and chromatographed on ethyl acetate / Petro-ether (2: 1) through a column of 1 kg of silica gel. The first eluting isomer is the S, S, S compound, the subsequent eluate is obtained by evaporation of the S, S, R compound. 30 8.0 g of product are obtained in each case as an oil.

NMR: for S, S, S: characteristic signals: 1.20 (d, 311), 1.27 (t, 2H), 4.17 (q, 3H), 5.13 (s, 2H), δ , 18 (s, 5H), 7.32 (s, 5H) (CDCl 3)

Analysis: C H N

35 C30H38N2O5 calculated 71.1 7.56 5.53 found 0.8 7.8 5.7 6 80442 (5) N- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-cis, endo 2-Azabicyclo [3.3.0] octane-3-S-carboxylic acid 8.0 g of the L, L, L-benzyl ester 5 obtained in (4) are dissolved in 100 ml of ethanol and the benzyl group is removed by hydrogenolytic addition of 0.5 g of 10%: ista Pd / C at normal pressure. This reaction can also be carried out under elevated pressure, thereby shortening the reaction time. After the calculated amount of hydrogen has passed, the solution is separated from the catalyst by suction filtration and evaporated to dryness in vacuo. My zwitterion crystallizes in almost quantitative yields from ether:

Melting point: 110-112 ° C (decomposes)

Addition of an equivalent amount of hydrochloric acid can give the hydrochloride (decomposition from 120 ° C) or adding aqueous zinc salts to a concentrated methanol solution of the title compound can give a thermally very stable zinc complex salt (decomposes above 160 ° C). Analysis: C H N

20 * “23 ^ 32Ν2®5 calculated 66.3 7.7 6.73 found 66.1 7.8 6.6

The NMR and mass spectra obtained are consistent with the given structure.

= + 15.6 ° (c = 1, methanol).

25

Example II

(1) Cis, endo-2-azabicyclo [3.3.0 octane-3-carboxylic acid tert-butyl ester] 25 g of the azabicyclo 30 / 3.3.07 octane carboxylic acid hydrochloride obtained in Example I (2) are reacted in 250 ml of dioxane with 250 ml. with isobutylene and with 25 ml of concentrated sulfuric acid. After 14 hours at room temperature, the mixture is made alkaline with sodium hydroxide, evaporated in vacuo, 35 ml of water are added and the ester is taken up in ether. After evaporation of the ether, 15 g of a colorless oil are obtained.

il 7 80442

Analysis: C H N

C12H21NO2 calculated 68.2 10.2 6.63 expected 7.9 10.1 6.3 (2) N- (1S-benzyloxycarbonyl-3-oxo-3-phenyl-5-propyl) -S-alanine tert-butyl ester_12 .0 g of acetophenone, 17 g of benzyl ester of glyoxylic acid and 31.7 g of alanine tert-butyl ester toluenesulfonate are heated in 200 ml of glacial acetic acid at 45-50 ° C for 48 hours. The progress of the reaction is monitored by thin layer chromatography and the reaction is stopped at the optimum point. Evaporate to dryness in vacuo, basify with aqueous bicarbonate and extract with ethyl acetate. The organic phase is evaporated to dryness as closely as possible and the S, S-isomer is crystallized from cyclohexane / petroleum ether. R, S-compound 15 remains mainly in solution. To obtain seed crystals, it is suitable to chromatograph the crude mixture on silica gel in a solvent system of cyclohexane / ethyl acetate 2: 1 to which 0.1% of triethylamine is added. The S, S compound elutes from the latter two diastereomers and there are more. Yield 9 g.

20 Analysis: C H N

C24H29NO5 calculated 70.1 7.1 3.4 found 70.0 6.9 3.5 (3) N1S-benzyloxycarbonyl-3-oxo-3-phenyl-propyl) -S-alanine trifluoroacetate 8 g in (2) the obtained Mannich condensation product is dissolved in 25 ml of anhydrous trifluoroacetic acid and left for one hour at room temperature. Evaporate to dryness in vacuo, add diisopropyl ether and precipitate with petroleum ether. 7.2 g of an amorphous substance are obtained.

; Analysis: C H M

^ 22 ^ 22 ^ 7 ^ 3 cascaded 56.3 4.7 3.0 found 56.0 4.8 3.1

Molecular Weight: 469 80442 8 (4) N- (1S-Benzyloxycarbonyl-3-oxo-3-phenyl-propyl) -S-alanyl-2-cis, endo-azabicyclo [3.3.07] octane-3-carboxylic acid tert-butyl ester _______ 5 35.5 g of the N-substituted alanine obtained in (3) are reacted with 21.1 g of the azabicyclooctanecarboxylic acid tert-butyl ester obtained in Example II (1) in analogy to Example I (4). Chromatography on silica gel gives 20.3 g of the title compound.

10 Analysis: C H N

CttH N n calculated 70.04 7.35 5.10 32 40 2 6 found 69.6 7.4 5.3 (5) N- (1S-benzyloxycarbonyl-3-oxo-3-phenylprop-15-yl) - S-Alanyl-2-cis, endo-azabicyclo / 3.3-7 octanecarboxylic acid 20 g of the tert-butyl ester obtained in (4) are dissolved in 100 ml of TFA and left at room temperature for one hour. Evaporate in vacuo, take up the remaining resin in ethyl acetate and neutralize with aqueous bicarbonate.

14 g of the title compound are obtained from the ethyl acetate phase.

Analysis: C H N

C_OH N-O, calculated 68.27 6.55 5.69 28 32 2 6 found 68.1 6.4 5.7 25 (6) N- (1S-carboxy-3, R, S-hydroxy-3- phenylpropyl) -5-alanyl-cis, endo-2-azabicyclo [3.3.10] octane-3-carboxylic acid 1 g of N- (1-S-benzyloxycarbonyl-3-oxo-3-phenylprop-30-yl) -5-alanyl-cis , endo-2-azabicyclo [3.3.07] octane-3-carboxylic acid is dissolved in 50 ml of ethanol, 150 mg of Pd / BaSO4 are added and the mixture is hydrogenated under normal pressure. After uptake of hydrogen, filter, evaporate and chromatograph on silica gel with a solvent system of CHCl 3 / CH 3 OH / CH 3 COOH (50: 20: 5).

Yield: 0.6 g

II

9 80442 (7) N- (1S-Benzyloxycarbonyl-3-R, S-hydroxy-3-phenylpropyl) -S-alanyl-cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid 1 g N- (1-S-Benzyloxycarbonyl-3-oxo-3-phenyl-propyl) -5-alanyl-2-cis, endo-azabicyclo [3.3.0] octane-3-carboxylic acid is dissolved in 50 ml of a mixture of acetonitrile and water and reduced to 150 ml. mg: 11a NaBH4. After 12 hours, evaporate to dryness. Neutralize with dilute hydrochloric acid and extract the title compound with ethyl acetate. To remove boric acid and other impurities, chromatograph through silica gel with a solvent system of CHCl 3 -CH 3 OH-CH 3 COOH (50: 10: 5).

Analysis: C H N

] _5 ^ "28 ^ 34 ^ 2 ^ 6 calculated 67.99 6.93 5.66 found 67.7 6.6 5.3

Example III

General procedure: Ester hydrolysis for the preparation of compounds of formula I disclosed in FI patent application V 823757, where R = H.

10 g of the corresponding ethyl or benzyl ester of the formula I are dissolved in 200 ml of dimethoxyethane. A drop of dilute indicator solution, e.g. bromothymol blue, is added and an equivalent amount of 4-n KOH (aq) is added over 5 minutes with vigorous stirring so that the indicator shows a pH of 9-10 at the end of the reaction. The pH is then adjusted to 4 with hydrochloric acid, evaporated to dryness in vacuo, taken up in 250 ml of ethyl acetate and filtered. Evaporation of the ethyl ester precipitates dicarboxylic acids as solid, crystalline or amorphous compounds. Yields are 80-95%.

Example IIIa N- (1S-carboxy-3-phenylpropyl) -S-alanyl-cis, endo-2-azabicyclo [3.3.3] octane-3-S-carboxylic acid 35 g of the N- (1S) 1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid is hydrolyzed (1 hour) and worked up as described in Example III.

Yield: 0.85 g m / e: 388

Example IV

5 N- (1S-Ethoxycarbonyl-3-oxo-3-phenyl-propyl) -5-alanine benzyl ester ____ 65.7 g of 3-phenyl-3-oxo-1-propene-1-carboxylic acid ethyl ester (benzoylacrylic acid ethyl ester) are 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 ml of ethanol are added rapidly 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

Λ max 20 = 17.8 ° (c = 1, CH-.OH)

D

Example V

N- (1S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -S-20 alanine_ 0.5 g of the compound obtained in Example IV are dissolved in 40 ml of 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); 7.2 - 8.2 (m. 5H)

Example VI

N- (1-S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -5-alanyl-cis, endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid benzyl ester__

The compound is prepared from cis, endo-2-azabicyclo / 3.3-7 octane-3-S-carboxylic acid benzyl ester hydrochloride and N- (1S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -S-alanine obtained in Example V in analogy to the method is described in Example I (4).

Il 11 80442

Example VII

N- (1S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -S-alananyl-cis, endo-2-azabicyclo [3.3.07] octane-3-S-carboxylic acid_ 5 g of the benzyl ester obtained in Example Vi are dissolved. To 30 ml of ethanol / hydrogenate with 100 mg of Pd / C (10%) at room temperature and normal pressure. When an equivalent molar amount of hydrogen has been consumed, the hydrogenation is stopped. The solution is separated from the catalyst by suction filtration 10 and evaporated.

Yield: 600 mg of oil.

1 H-NMR (DMSO-d 6): 1.0-3.0 (m, 15H); 3.3-5.0 (m. 10H); 7.2-8.1 (m. 5H)

Example VIII

15 N- (1-S-ethoxycarbonyl-3-phenylpropyl) -5-lysyl-cis, endo-2-azabicyclo [3.3. O-Octane-3-S-carboxylic acid dihydrochloride (1) N, N- (1S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -N, N-benzyloxycarbonyl-S-lysine benzyl ester 10 g 3- Phenyl 3-oxo-1-propene-1-carboxylic acid ethyl ester is dissolved in 100 ml of ethanol. To the solution are added 19.1 g of N-benzyloxycarbonyl-S-lysine benzyl ester and 0.2 g of triethylamine. The solution is stirred for 3 · 25 hours at room temperature then evaporated in vacuo. The oily residue (31 g) is dissolved in isopropanol / diisopropyl ether and cooled. 13 g of N-N- (1-S-ethoxycarbonyl-3-oxo-3-phenylpropyl) -N-benzyloxycarbonyl-S-lysine benzyl ester crystallize.

30 DEG = 3.5 DEG (C = 1'CH3OH) 1 H-NMR (CDCl3): 1.0-1.4 (tr, 311); 1.0-2.0 (m. 9H); 2.0-2.6 (broad s, 1H); 2.9 - 3.9 (m, 6H); 3.9-4.4 (q, 211); 4.6-4.9 (broad s, 1H); 5.0-5.2 (double s, 4H); 7.1-8.1 (m. 15H).

35 12 80442 (2) N - ((1S-ethoxycarbonyl-3-phenylpropyl) -N-benzyloxycarbonyl-5-lysine_ 4.0 g of the benzyl benzyl ester derivative of lysine prepared in Example VIII (1) are dissolved in 50 ml of glacial acetic acid and 5 0.6 g of Pd / C (10%) and 0.6 g of concentrated sulfuric acid are added, lysed 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 stirred together 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 N- (α-S-ethoxycarbonyl-3-phenylpropyl) -5-lysine: 2.0 g.

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); Δ 4.5-5.0 (m, 1 H); 7.1-7.6 (m, 5H) m / e: 336 3.4 g of N, - (1-S-ethoxycarbonyl-3-phenylpropyl) -S-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 drying, the mixture is evaporated and the oily residue is chromatographed on silica gel using methylene chloride / methanol as solvent. 2.0 g of N, N - (1-S-ethoxycarbonyl-3-phenylpropyl) -N, N-benzyloxycarbonyl-5-lysine are obtained.

Il 13 80442 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, 211); 7.1-7.5 (m, 10H) δ (3) N- (1-ethoxycarbonyl-3-enylpropyl) -N, N-benzyloxycarbonyl-5-lysyl-cis, endo-2-azabicyclo / 3.3.07 octane 3-S-carboxylic acid benzyl ester (a) 560 mg of 2-azabicyclo [3.3.07] octane-3-carboxylic acid benzyl ester hydrochloride prepared according to Example I (3) and 940 mg of - (1S-ethoxycarbonyl-3-phenylpropyl) -N- benzyloxycarbonyl-S-lysine, prepared according to Example VIII (2), is reacted analogously with Example I (4). After further treatment, 1.5 g of an oil are obtained, which is a mixture of two di-astereomeric compounds.

The diastereomeric mixture is separated by column chromatography on silica gel with the eluting solvent cyclohexane / ethyl ester (2: 1) as its individual components. First, the eluting isomer is the above-mentioned compound. 0.6 g of oil is obtained.

1 H-NMR (CDCl 2): 1.0-2.6 (m, 20H); 2.6-4.5 (m. 8H); (H / D exchange residue 4.6-5.0 (m, 2H): 5.1-5.3 (doublet of k, DgO5) - 4H); 7.1-7.6 (m. 15H).

b) The latter eluate gives 0.4 g of Nas- (1-S-ethoxy-carbonyl-3-phenylpropyl) -N 1 -benzyloxycarbonyl-S-: lysyl-cis, endo-2-azabicyclo [3.3.0] octane-3- Benzyl ester of R-carboxylic acid.

1 H-NMR δ (CDCl 3): 1.0-2.6 (m, 20H); 2.6-4.4 (m, 8H), - (H / D exchange residue 4.5-5.0 (m, 2H); 5.1-5.3 (double s, 30 k D 2 : 11a) 4H); 7.1-7.5 (m, 15H) (4) N, 1- (1-S-ethoxycarbonyl-3-phenylpropyl) -5-lysyl-cis, cyclo-2-azabicyclo [3.3.07] octane-3-; S-carboxylic acid dihydrochloride 500 mg of ΝΛ- (1-S-ethoxy-carbonyl-3-phenylpropyl) -N-benzyloxycarbonyl-S-lysyl-cis, endo-2-azabicyclo / 3.3.07 octane obtained in Example VIII (3a) The benzyl ester of 3-S-carboxy-1480442 is dissolved in 20 ml of ethanol and debenzylated by the addition of 0.1 g of 10% Pd / C under normal pressure. When the consumption of hydrogen has ceased, the catalyst is removed by filtration, the pH of the ethanolic solution is adjusted to 1 with ethanolic hydrogen chloride solution, and the ethanol is evaporated off under vacuum. Diisopropyl ether is added to the residue, whereupon the product solidifies. 200 mg are obtained.

1 HNMR of betaine (CDCl 3, 10 after H / D exchange with D 2 O); 1.0-2.5 (m. 20H); 2.6-4.4 (m. 8H); 4.4-5.1 (m. 2H); 7.2 (s. 5H)

Example IX

N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-lysyl-15 cis, endo-2-azabicyclo [3.3.07] octane-3-R-carboxylic acid dihydrochloride____ 0.3 mg of the corresponding benzo obtained in Example VIII (3b). the silyl ester is reacted and worked up analogously to Example VIII (4). 110 mg of carboxylic acid are obtained in the form of the dihydrochloride.

1 H-NMR of betaine (CDCl 3, after H / D-exchange 020): 1.0-2.6 (m, 20H); 2.6-4.4 (m. 8H); 4.1-5.1 (m. 2H); 7.2 (s. 5H)

Example X

25 N- (1S-carboxy-3-phenylpropyl) -S-lysyl-cis, endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid hydrochloride 0.5 g (1S-ethoxycarbonyl-3-phenylpropyl ) -S-lysyl-cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid dihydrochloride from Example VIII (4) is suspended in 20 ml of dimethoxyethane. Add 4 N aqueous KHH until pH 9-10 is reached. The mixture is stirred for half an hour. The pH is then adjusted to 4 with hydrochloric acid, evaporated to dryness in vacuo, the residue taken up in ethyl acetate and filtered. The ethyl acetate solution is evaporated and the residue is triturated with diisopropyl ether to solidify.

il is 80442

Yield: 0.35 g 1 H-NMR (D 2 O): 1.2-2.5 (in, 17H); 2.5-4.5 (m. 6H); 4.5-5.0 (m. 2H); 7.2 (s. 5H)

Example XI

5 NO> (1-S-carboxy-3-phenylpropyl) -5-lysyl-cis-endo-2-azabicyclo [3.3.7] octane-3-R-carboxylic acid hydrochloride - 500 mg N & - (1-S (ethoxycarbonyl-3-phenylpropyl) -5-lysyl-cis, endo-2-azabicyclo [3.3.0] octane-3-R-carboxylic acid dihydrochloride from Example IX is hydrolyzed and worked up analogously to Example X. Yield: 0.32 g.

1 H-NMR (D 2 O): 1.2-2.5 (m, 17H); 2.5-4.5 (m. 6H); 4.5-5.0 (m. 2H); 7.2 (s. 5H)

15 Example XII

N- (1S-carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl-cis, endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid (1) N- (1-R, S-carbethoxy -3-Phenylpropyl-O-ethyl-S-tyrosine benzyl ester ____ 20 24 g of benzoacrylic 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 IV, whereupon 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-S-tyrosine 40 g of the compound obtained in (1) are hydrogenated in 800 ml of 30 acetic acid over a 10% Pd / C catalyst ( 4 g) in the presence of room temperature at a pressure of 100 bar. Chromatography on silica gel, eluting with ethyl acetate / cyclohexane (1: 3), evaporating to dryness and drying the residue, gives 25 g of thin-layer chromatography of 35 almost uniform title compound, m.p. 205-213 ° C.

16 80442

Analysis; C H N

C23H29NO5 (399'5) calculated: 69.15 7.31 3.50 found 9.5 7.4 3.3 5 (3) N- (1S-carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl -cis, endo-2-azabicyclo / 3.3.07 octane-3-S-carboxylic acid_

The free benzyl ether (5 g) extracted from an alkaline solution in diethyl ether prepared in Example I (3) is reacted with the compound (8 g) obtained in (2) and dicyclohexylcarbodiimide (4.4 g) and 1-hydroxybenzotriazole (2, 7 g) in the presence of that described in Example I (4), the oily benzyl ester intermediate (2.9 g) is obtained by chromatography as described in Example I (4).

The 1 H-NMR and mass spectra of the compound correspond to the expected structure.

The benzyl ester obtained is catalytically hydrogenated in 50 ml of ethanol in the presence of a Pd / C catalyst at normal pressure. The catalyst is filtered off and the solvent is evaporated. The resulting solid residue is triturated with diethyl ether / petroleum ether, filtered and dried to give 2.2 g.

1 H-NMR (CDCl 3): 1.2-3.0 (m, 15H), 1.27 (t, 3H), 1.4 (t, 3H), 3.0-4.3 (m, 4H) ), 3.8-4.2 (m, 4H), 6.5-7.1 (2d, 4H), 7.3 (s, 5H).

Example XIII

N- (1S-carbethoxy-3-phenylpropyl) -O-methyl-S-tyrosyl-cis, endo-2-azabicyclo [3.3.3] octane-3-S-carboxylic acid The preparation is carried out as in Example XII, wherein however, in the analogous step (1), O-methyl-S-tyrosine benzyl ester is used. The 1 H NMR spectrum of the title compound corresponds to the expected structure.

Il

Claims (3)

17 80442 Cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid or an ester thereof of formula IIIa or IIIb 5 H HN - ^ - purple 10 wo IIIb W ° 2C 'wherein W represents hydrogen, alkyl-20 containing 1 to 6 carbon atoms or aralkyl having 7 or 8 carbon atoms, and its! salts of acids and (in the case of W = hydrogen) base; with them. Compound according to Claim 1, characterized in that in the formulas IIIa and IIIb W is hydrogen, tert-butyl, benzyl or nitrobenzyl. Process for the preparation of compounds of the formula IIIa or IIIb according to Claim 1, characterized in that the compounds of the formula X 3 -CHOR 2 ·: I-1-CH 9 -CH X 1 in which 1-5 alkanoyl, benzyl or other acid-cleavable protecting groups conventional in peptide chemistry and R is alkyl or benzyl having 1 to 5 18 80442 C atoms, is cyclized with strong acids, and the resulting compounds are converted by catalytic hydrogenation in the presence of transition metal catalysts or in the presence of transition metal catalysts or complex borohydrides in lower alcohols to compounds of formula IIIa or IIIb where W is hydrogen and optionally esterified to compounds of formula IIIa or IIIb where W is alkyl of 1 to 6 carbon atoms or aralkyl of 10 to 7 carbon atoms . Il i9 80442