Method of producing cis,endo-2-azabicyclo-(3,3,0)-octane-3-carboxylic acids or acid-additive salts t

专利摘要:

公开号:SU1327787A3
申请号:SU823513217
申请日:1982-11-03
公开日:1987-07-30
发明作者:Теетц Фолькер；Гайгер Рольф；Урбах Хансйорг；Беккер Райнхард；Шелькенс Бернвард
申请人:Хехст Аг (Фирма)；
IPC主号:

专利说明:

1.27 (t, 2H), 4.17 (g, 3N), 5.13 (S, 2H), 7.18 (S, 5H), 7.32 (S, 5H) CDCHj,
Calculated,%: N 5.53.
C, 71.1; H 7.56;
C3H34N, Oj
11327787
This invention relates to the preparation of new derivatives of cis, endo-2-azabicyclic- (3,3,0) -octane-3-carboxylic acids of the general formula
Y
Found, -%: C 70.8; H7.85 N 5.7.
b) (1-8-carbethoxy-3-fensh1-propyl) -5-alanyl cisR-2-2-azabi-10 cyclo- (3,3,0) -octane-3-5 carboxylic acid,
8.0 g of Eb-benzyl ether is dissolved in 100 ml of ethanol and adding 0.5 g of 10% palladium on activated carbon to a benzyl group under normal pressure by hydrogeolysis. This reaction can also be carried out under pressure while simultaneously reducing the reaction time. After
X-C-CHo-CH-NH-CH-CO-- -.-,
I I I ill
Z C02R2 HI R, - lower alkyl, - (CH) W,
- CH2 - (Q-OH or CH - O rotten
alkyl
Rg is H, C. is alkyl or benzyl;
Y N or HE;
Z - H or Y and Z - together form
oxygen; X is phenyl.
or their acid addition salts, absorbing the calculated amount
have a long, intense blood pressure reducing effect. The purpose of the invention is the development of a method based on known methods
The target compound is a thermally stable complex zinc salt (decomposition above 1bO C).
Calculated,%: C, 66.3; H 7.7;
N.6,73.
CajHggN Gs
new compounds with 25 so pl. 110-112 ° C (decomposed) with valuable pharmacological properties. Acid chloride (decomposed below
The invention is illustrated as follows: 120 ° C) can be obtained with the addition of examples. an equimolar amount of hydrochloric acid; Example 1 "(1-S-Kap6lot) or by adding ethoxy-3-phenyl-propyl) -8-alanyl-ZO of an aqueous solution of zinc salt to concentrate, endo-2-azabicyclo- (3.3,0) -octane methanol solution of 3-5-carboxylic acid
a) Benzyl ester of (1-S-carb-ethoxy-3-phenyl-propyl) -S-alanyl-cis, endo-2-azabicyclo- (3,3,0) -octane-3-5-carboxylic acid.
14 g of benzyl chloride
cis, endo-2-azabicyclo- (3.3.0) ester - Found%: C 66.1; H 7.8; N6,6. octane-3-carboxylic acid with 6.7-g NMR and mass spectra of 13.8 g of CO- (1-5-carbethoxyp-3-phenyl-40) obtained are treated with the indicated structure (D) propyl) - S-alanine and 10.2 g dicyclo-D + 15.6 ° b (, methanol).
PRI me R 2.
a) Tert-butyl ether (1-8-carbazyloxy-3-oxo-3-phenyl-propyl) -8-: The dicyclohex-45 alanine which is sucked off is sucked off.
Silvouralis, evaporated, introduced into 1 liter of 12.0 g of acetophenone, 17 g of benzyl ethyl acetate and shaken with 3x500 ml of hyloxylic acid ester and 5% NaHCOj solution. Organic 31.7 g of alanine-tert-butyl toluenesulfonate ester is heated in 200 ml of ethyl acetate to 45-50 ° C for 24- 48 hours. The reaction is monitored by thin-layer chromatography and interrupted when the optimum time is reached. - The stock mixture is evaporated in vacuo, alkalized with sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is evaporated as completely as possible and the crystallhexylcarbodiimide in 200 ml of dimethylformamide is reacted. After 3 hours of stirring at room temperature, the evaporation is evaporated and the mixture is chromatographed with ethyl acetate: petroleum ether in a ratio of 2: 1 through a column with 1 kg of silica gel. The isomer eluted at the beginning is a 8,5,8-compound. Subsequently, the eluate after evaporation gives S, 3, E-compound.
Suitably 8.0 g of product are obtained in the form of an oil.
Data PMR: 5,3,5-connection (characteristic signals) of 1.20 (g, 3H),
50
1.27 (t, 2H), 4.17 (g, 3N), 5.13 (S, 2H), 7.18 (S, 5H), 7.32 (S, 5H) CDCHj,
Calculated,%: N 5.53.
C, 71.1; H 7.56;
C3H34N, Oj
Found -%:
hydrogen mixture is filtered from the catalyst and evaporated in vacuo. The amphoteric ion crystallizes with almost quantitative yield from the ether:
35
The target compound is a thermally stable complex zinc salt (decomposition above 1bO C).
Calculated,%: C, 66.3; H 7.7;
N.6,73.
CajHggN Gs
 lots or as a result of adding ZOR of an aqueous solution of zinc salt to the concentrated methanol solution
 Found%: C 66.1; H 7.8; N6,6. The resulting PMR and mass spectra are consistent with the indicated structure (D) D + 15.6 ° b (, methanol).
31327787
the 8.5 isomer from the cyclohexane petroleum ether K mixture is prepared, the 8-compound remains in solution. For seed preparation, chromatography with a mixture on silica gel in a cyclohexane-ethyl acetate 2; 1 system is recommended, to which 0.1% triethylamine is added.
The S, S compound is eluted as diastereomers and precipitated in large amounts. Get 9g.
C, 70.0; H 6.9;
N
Calculated,%: 3.5.
C ,, N05
Found,%: C 70.1; H 7.1; N 3.4.
b) N- (l-S-carbobenzyloxy-3-oxo-3-phenyl-propyl) -S-alanine trifluoroacetate
8 g of the Mannich condensation product, as in 2a, is dissolved in 25 ml of anhydrous trifluoroacetic acid and left for 1 hour at room temperature. It is then evaporated in vacuo, mixed with diisopropyl ether and precipitated with petroleum ether. 7.2 g of amorphous substance are obtained.
Calculated,%: C 56.3; H 4.7; 3.0.
N
C ,, H ,,,
N 3.1
Found,%: C 56.0; H 4.8;
Molecular weight 469.
c) (1-5-Carbobenzyloxy-3-oco-3-phenyl) -S-alanyl-J-cis, endo-2-azabicyclo- (3,3,0) - octane-3-carboxylic acid tert-butyl ester.
35.5 g of N-substituted alanine, as in 26, are dissolved in 21.1 g of tert-butyl azabicyclo-octanecarboxylic ester of Example 1a. after chromatography over silica gel, 20.3 g of the title compound.
Calculated,%: C, 70.04; H 7.35; N 5.10. ,
Found,%: C 69.6; H 7.4; N 5.3.
d) 2-N- (1-S-carbobenzyloxy-3-oxo 3-phenyl-propyl) -3-alanyl-2-cis, endo-azabicyclo- (3.3.0) -octane-3-carboxylic acid.
20 g of the tert-butyl ester obtained as Example 2c are dissolved in 100 ml of trifluoroacetic acid, and allowed to stand for 1 hour at room temperature. The mixture is evaporated in vacuo, the remaining resin is taken up in ethyl acetate and neutralized with an aqueous solution of bicarbonate. From the ethyl acetate phase, 14 g of the title compound are obtained.
N
Calculated,%: C 68.27; H 6.55; 5.69.
0
five
0
five
0
CjsHjsN O,
Found,%: C 68.1; H 6.4; N 5.7.
d) (1-S-Kap6oKCH-3-R, S-hydroxy-3-phenyl-propyl) -S-alanyl-cis, endo-2-azabicyclo- (3,3,0) -octane-3- carbonic acid.
1 g of (1-5-carbobenzyloxy-3-oxo-3-phenyl-propyl) -S-alanyl-cis, endo-2-azabicyclo (3.3.0) -octane-3-carboxylic acid is dissolved in 50 ml of ethanol, mixed with 150 g of palladium
on BaSO. and under normal pressure
- /
hydrated. After absorption of the calculated amount of hydrogen, it is filtered, evaporated and chromatographed over silica gel with solvent 0 CHCl 4 (CH 2 OH) CH 2 COOH 50: 20: 5. Output 0.6 g
e) 2- H- (1-5-carbobenzyloxy-3-K, 5-hydroxy-3-phenyl-propyl) -5-alanyl-cis, endo-2-azabicyclo- (3.3.0) -octane 5 3 - carboxylic acid.
1 g of 2-m-ST-B-carbobenzyloxy-3-oxo-3-phenyl-propyl) -S-alanyl-cis, endo-2-azabicyclo- (3.3.0) -octane-3-carboxylic acid solution 50 ml of a mixture of acetonitrile and water are reduced and 150 mg of NaBH are reduced. After 12 hours, the mixture is evaporated to dryness, the reaction solution is neutralized by the addition of dilute hydrochloric acid, and the target compound is extracted with ethyl acetate. To remove boric acid and other impurities, it is chromatographed over silica gel with a solvent: -CHjCOOH in a ratio of 50: 10: 5.
Calculated,%: C, 67.99; H 6.93;
CHCl j -CH., ONN 5.66.

C, 67.7; H 6.6; N 5.3. 3. General method: esterification to obtain a compound
general formula with cd - n.
10 g of the corresponding ethyl or benzyl ester of the general formula is dissolved in 200 ml of dimethoxyethane. One drop of the diluted indicator solution, for example bromothymolblau, is added and with intensive
while stirring for 5 minutes, an equivalent amount of 4% KOH (aqueous solution) is added, after completion of the reaction pH 9-10. The pH is then adjusted to 4 by addition of hydrochloric acid, evaporated to dryness in vacuo, taken up in 250 ml of ethyl acetate and filtered.
The evaporation of ethyl acetate precipitates dicarc boic acids in the form of solid, crystalline or amorphous compounds. The yield is 80-95%.
a) (1-8-carboxy-3-phenyl-pro-sawed) -S-alanyl-cis, endo -2-ae abicyclo- (3,3,0) -octane-3-8-carboxylic acid.
1 g of H- (1-8-carboxy-3-phenyl-propyl) -8-alanyl-2-azabicyclo- (3,3,0) - octane-3-3-carboxylic acid, as in Jo example 16 Wash for 1 hour as described in Example 3 and process. Yield 0.85 g. Mol. Weight (m / s) 388.
EXAMPLE 4: Benzyl ether
coal (10%) at room temperature and normal pressure. . After absorption of the mole equivalent: the hydrogen band is stopped by hydrogenation. The catalyst is filtered off with suction and the solution is evaporated. Output 600 mg of oil.
 H-NMR (dimethyl sulfoxide-dg): 1.0-3.0 (t, 15H), 3.3-5.0 (t, yu), 7.2-8.1 (t, 5H).
Example 8. 2-n- (1-y-carbethoxy-3-phenyl-propyl) -8-lysyl-cis, endo-2-azabicyclo- (3,3,0) - octane 3-8-carboxylic acid dichlorohydride.
a) H () 6- (1-8-carbethoxy-3-oxo-3N- (1-S-carbethoxy-3-oxo-3-phenyl-pro f5 phenyl-propyl) -N-benzyl-oxycarbonylsyl ) -5-carboxylic acid. 8-lysinbenzyl ester.
67.5 g of ethyl 3-phenyl-3-oxo-1-propy-1-carboxylic acid (benzoyl acrylic acid ethyl ester) was dissolved in 225 ml of ethanol and 1 ml of triethylamine was added to this solution. A solution of 70 g of 8-alanine benzyl ether in 90 ml of ethanol is quickly added dropwise to this mixture at room temperature. Seine 25 vacuum. The oily residue is dissolved for 2 hours at room temperature in a mixture of isopropanol and diisopropyl ether. 13 g of Ng- (1-8-carbethoxy-3-oxo-3-phenyl-propyl) -N, are crystallized. -benzyloxycarboxy-1-8-30-zinbenzyl ether.
4 ° 3.5 ° (,). H-NMR (COCl3) ;: 1.0-1.4 (tr, 3H), 1.0-2.0 (m, 9H), 2.0-2.6 (wide 8, 1H), 2, 9-3.9 (t, 6P), 3.9-4.4 (quad.
0.1 g of palladium on activated j 2H), 4.6-4.9 (wide 8, 1H), 5.0-5.2 coal (10%) -, and at room temperature (doubled, 8, 4P), 7.1-8.1 (w, 15H).
b) Ni (, - (1-8-carbethoxy-3-fensh-1-properate and then the solution is cooled. 8.8-isomer crystallizes. Yield 94.3 g. Mp. 83-74 ° C, L ;. + 17.8 ° (, CHjOH) ..
Example 5. N- (1-8-carbethoxy-3-oxo-3-phenyl-propyl) -8-alanine.
0.5 g of the compound, as in Example 4, is dissolved in 40 ml of ethanol and added to the mixture and normal pressure is hydrogenated. Yield: 300 mg m.p. 210-220 ° C.
 H-NMR (dimethyl sulphoxide-dg): 1.0-1.4 (t, 6H), 3.2-5.0 (t, 8H), 7.2-8.2 (t, 5H).
Example 6. Benzyl ester of (lS-carbethoxy-3-hydroxy-3-phenylpropyl) -8-alanyl} -cis, endo-2-azabicycly- (3,3,0) -octane-3-8- carboxylic acid.
Compound from cis, endo-2-azabicyclo- (3,3,0) -octane-3-8-carboxylic acid benzyl ester chloride and N- (1-8-carbethoxy-3-oxo-3-phenylpropyl ) -8-alanine, as in example 5,
drank) Ir-benzyloxycarbonyl-8-lysine. 4.0 g of the lysinbenzyl 0 ester derivative prepared in Example 8a is dissolved in 50 ml of glacial acetic acid, 0.6 g of palladium on activated carbon (10%) and 0.6 g are added to it. concentrated chamois
15 acid. The mixture is hydrogenated for 6 hours at room temperature and at normal pressure. After that, the catalyst is filtered off, the ethanol solution is mixed with 1.4 g of solid
50 sodium bicarbonate. The solution is stirred and the residue is dissolved in water. The aqueous phase is extracted with ethyl sodium bicarbonate. Rast stir and the rest is a solution of water. The aqueous phase of the extract
get analogously to example 1a.
Example 7. (1-8-Kap63TOK-acetate and methylene chloride, Ci-3-oco-3-phenyl-propyl) -S-alailj-cis, endo-2-azabicyclo- (3,3,0) -octane- 55 3 -8-carboxylic acid.
1 g of benzyl ether, as in Example 6, is dissolved in 30 ml of ethanol, and hydrogenated from 100 g of palladium to the organic phase, the separated phase is evaporated into vacuum. The residue is stirred from a methanol evaporated residue, which is left
coal (10%) at room temperature and normal pressure. . After absorption of the mole equivalent: the hydrogen band is stopped by hydrogenation. The catalyst is filtered off with suction and the solution is evaporated. Output 600 mg of oil.
 H-NMR (dimethyl sulfoxide-dg): 1.0-3.0 (t, 15H), 3.3-5.0 (t, yu), 7.2-8.1 (t, 5H).
Example 8. 2-n- (1-y-carbethoxy-3-phenyl-propyl) -8-lysyl-cis, endo-2-azabicyclo- (3,3,0) - octane 3-8-carboxylic acid dichlorohydride.
a) H () 6- (1-8-carbethoxy-3-oxo-310 g of ethyl 3-phenyl-3-oxo-1-propane-T-carboxylic acid) is dissolved in 100 ml of ethanol. To this 20 solution is added 1.9.1 g of K-benzyl-hydroxycarbonyl-8-lysinbenzyl ether and 0.2 g of triethyl-amine, the solution is stirred for 3 hours at room temperature, after which it is evaporated in
drank) Ir-benzyloxycarbonyl-8-lysine. 4.0 g of the lysine benzyl 0 ester derivative prepared in Example 8a is dissolved in 50 ml of glacial acetic acid, 0.6 g of palladium on activated carbon (10%) and 0.6 g of concentrated sulfuric
15 acid. The mixture is hydrogenated for 6 hours at room temperature and at normal pressure. After that, the catalyst is filtered off, the ethanol solution is mixed with 1.4 g of solid
50 sodium bicarbonate. The solution is stirred and the residue is dissolved in water. The aqueous phase is extracted with ethyl acetate and methylene chloride.
The organic phase is separated and the aqueous phase is evaporated under vacuum to dryness. The residue is stirred with methanolysis. After evaporation of the methanol, an oily residue remains, which during processing
diisopropyl ether becomes solid.
Yield (1-S-carboxylic-3-phenyl-propyl S-lysine 2.0 g
 H-NMR (DjO): 1.0-1.4 (tr, 3N), 1.0-2.5 (m, 9H), 2.5-4.4 (m, 9H), 3.9- 4.4 (q, 2H), 4.5-5.0 (m, 1H), 7.1-7.6 (m, 5H). Mol. 336.
3.4 g of (1-5-carbethoxy-3-phenylpropyl) -8-lysine is dissolved in 30 mp of methylene chloride and cooled to 0 s. Under cooling with ice, 2.1 g of triethylamine and nepo
35
after that, dropwise to g of the carboxylic acid, then add 1.9 g of benzyl chloroformate, then stir for 1 hour at 0 ° C and bring to room temperature. The methylene chloride solution is shaken in succession with water, sodium carbonate solution and water. After drying, evaporate and the oily residue is chromatographed over silica gel with methylene chloride-methanol. 2.0 g of (1-S-Kap6-ethoxy-3-phenyl-propyl) -N-benzyl-xycarboxy-1-8-lysine are obtained.
V N-PMR (DgO): 1.0-t, 4 (tr, ЗН), 1.0-2.5 (m, 5H), 2.5-4.4 (m, 9H), 3.9 -4.4 (g, 2H), 4.5-5.0. (M, 1H), 5.1 (S, 2H), 7.1-7.5 (m, 1, OH).
c) Benzyl ester ,, (, - (1-S-carbethoxy-3-phenyl-propyl) -N-benzyl-X-carbonyl-B-lysyl-cyc, endo-2-azabicyclo- (3,3,0) octane-3-Z-carboxylic acid.
c1) 560 mg of benzoyl 2-azabicyclo-3,3,0-3-carboxylic acid benzoate, prepared according to an example, is reacted with 940 mg of N (- (1-S-carboxy-3 -phenyl-propyl) -b-benzyloxycarbon.yl-8-lysine obtained in Example 86. After the treatment, 1.5 g of oil are obtained, which is a mixture of two diastereomeric compounds.
The mixture of diastereomers is separated by chromatography over silica gel with a mixture of cyclohexane-ethyl acetate (2: 1) as an elution liquid. Initially, the eluted isomer is the title compound. 0.6 g of oil is obtained.
 H-PMR (CDCl1): 1.0-2.6 (m, 20H), 2.6-4.5 (m, 8H), 4.6-5.0 (m, 2H), after replacement of H (D): 5.1-5.3 (dual S, 4H), 7.1-7.6 (t, 15H), D 2.
 mg of benzyl 8-carbethoxy-3-fensh zyloxycarbonyl-8-l azabicyclo- (3,3,0) acid is taken from 20 ml of ethanol 0.1 g of 10% palatable carbon at normal debenzylate at d 25 roliz . At the end of the type of catalyst, the foliar solution is mixed with chlorine to pH 1, followed by 30 in vacuum. The residue with propyl ether, n hardens. Get 2
N-PMR betaine, n (DcDjO, CClj): 1.02, 6-4.4 (m, 8H), 4.4-7.2 (8, 5H).
Example 9. D N, - (1-8-carbethoxy-8-lysylj-cis, endo-20) -octane-3-K-carbono
0.3 mg of the corresponding ester from the example of the interaction is lepol and processed. By carboxylic acid to hydride.
 N-PMR betaine (C H (DcDjO): 1.04, 4 (w, 8H), 4.1-5.1 5H).
Example 10. (1-8-carboxy-Zlizil-cis, endo-2-az octane-3-8-carboxylic
0.5 g ethoxy-3-fenSh1-propy endo-2-azabicyclo-3 dichlorohydrin (3 carboxylic acid, suspended in 20 m
40
45
50

77878
c2) The next eluate gives 0.4 g of benzyl ester (l-S-carb-ethoxy-3-phenyl-propyl) -Cr-benzyloxy-. carbrnil-8-lysyl | -cis, endo-2-azabicyclic- (3,3,0) -octane-Z-E-carboxylic acid.
 H-PMR (CDClI): after replacing H (DC D.0): 1.0-2.6 (m, 20H), 2.6-4.4 10 (m, 8H), 4.5-5, 0 (m, 2H), 5.1-5.3
(double S, 4H), 7.1-7.5 (m, 15H). .
d) Dichlorohydride (1-5-carbethoxy-3-phenylpropyl) -5 lysyl-cis, endo-2-azabicyclo (3.3.0) -octane-3-S0
five
g carboxylic acid,
 mg of benzyl ester (1- 8-carbethoxy-3-fensh1-propyl) -N -benzyloxycarbonyl-8-lysyl-cis, endo-2-azabicyclo- (3.3.0) octane-3-8-carbono- The acid from Example 8B1 is dissolved in 20 ml of ethanol and, when 0.1 g of 10% palladium on activated carbon is added, is de-benzylated under normal pressure during destructive hydrolysis. At the end of the hydrogen uptake, the catalyst is filtered off, the ethanol solution is mixed with an ethanol solution of hydrogen chloride to pH 1, after which the ethanol is evaporated 0 in vacuo. The residue is mixed with diisopropyl ether, while the product hardens. Get 200 mg.
N-PMR betaine, after replacing H (DcDjO, CClj): 1.02.5 (m, .20H), 2.6-4.4 (m, 8H), 4.4-5.1 (m, 2H ), 7.2 (8, 5H).
Example 9. 2-N, - (1-8-carbethoxy-3-phenyl-propyl) -8-lysyl j-cis, endo-2 azabicyclo- (3,3, 0) -octane-3-K-carboxylic acid dichloride.
0.3 mg of the corresponding benzyl ester from example 8b2 is reacted analogously to example 8g and processed. 110 mg of carboxylic acid are obtained in the form of the dichlorohydride.
 N-PMR betaine (CDClj), after replacing H (DcDjO): 1.02.6 (tn, 20H), 2.6- 4.4 (w, 8H), 4.1-5.1 (ha, 2H ), 7.2 (8., 5H).
Example 10. Chloride 2- (1-8-carboxy-4-phenyl-propyl) - lysyl-cis, endo-2-azabicyclo (3.3.0) - octane-3-8-carboxylic acid.
0.5 g of (1-S-Kap6-ethoxy-3-fen-S1-propyl) -8-lysyl-cis dichlorohydride. endo-2-azabicyclo- (3 | 3.0) -octane-3-S-carboxylic acid, as in Example 8g, is suspended in 20 ml of dimethoxy;
five
0
U1
on. Aqueous 4% KOH solution is added and the pH is adjusted to 9-10. Stir for half an hour. Thereafter, the acid is acidified with hydrochloric acid to pH 4, evaporated to dryness in vacuo, the residue is taken up in ethyl acetate and filtered. The ethyl acetate solution is evaporated, the residue is triturated with diisopropyl ether, and it becomes solid. Output 0.35 g
PPMR (DjO): 1.2-2.5 (m, 17H), 2.5-4.5 (m, 6H), 4.5-5.0 (m, 2H), 7.2 (S, .5H).
Example 11. 2-N j (, - (1 -S-carboxy-3-phenyl-propyl) -S-lysyl-cis, endo-2-azabicyclo- (3.3.0 6 octane-2-K-carboxylic acid chloride) .
500 mg of disloranhydride (1-8-carbethoxy-3-phenyl-propyl) -B-lysyl-cis, endo-2-azabicyclo (3.3.0) -octane-3-K-carboxylic acid, as in Example 9 , is washed as in Example 10 and processed. Output 0.32 g
 N-PMR (VZO): 1.2-2.5 (w, 17H), 2.5-4.5 (t, .6H), 4.5-5.0 (t, 2H), 7.2 (S, 5H),
Example 12. (1-3-carbethoxy-3-phenylpropyl) -0-ethyl-5-tyrosyl-cis, endo-2-azabicyclo (3.3.0) - octane-3-Z-carboxylic acid.
a) N- (1-R, S-Carbethoxy-3-phenylpropyl) -0-3 ethyl-3-tyrosine benzyl ether.
Analogously to Example 4, 24 g of benzyl acrylic acid ethyl ester is reacted with 30 g of 0-ethyl-3-tyrosine benzyl ester in 100 ml of ethanol in the presence of 0.5 ml of triethylamine and obtained after concentrating the solution and digesting the residue with ethyl ether of petroleum ether ( 1: 1) and vacuum drying 42 g K, 3,5-compounds
b) N- (R, 3-carbethoxy-3-phenylpropyl) -0-ethyl-3-tyrosine.
40 g of this compound in 300 m of acetic acid are hydrogenated with 4 g of Pd / C (10%) at 100 bar (100-10 N / m2) and at room temperature. A biolonent chromatographic field on silica gel with ethyl acetate-cyclohexane (1: 3) and drying the residue after evaporation gives 25 g according to chromatography in a thin layer approximately identical to the title compound. M.p. 205-213 C,
Calculated,%: C 69.15; H 7.31; N, 3.50.


0
five
0
787
ten
CssHjsNOj (399,5).
Found,%: C 69.5; H 7.4; N 3.3.
c) (l-S-carbethoxy-3-phenyl-propyl) -O-ethyl-3-tyrosyl-cis-endo-2-azabicyclo (3.3.0) -octane-3-3-carboxylic acid,
5 g of cis benzyl ester, endo-2-azabicyclo- (3, 3.0) -octane-3-3-carboxylic acid, obtained from cis benzyl ester hydrochloride, endo-2-azabicyclo- (3.3.0 ) -Octane-3-carboxylic acid of Example 1a, by shaking the alkaline solution with diethyl ether, is reacted with 2.7 g of hydroxybenzotriazole, 8 g of N- (1-R-3-carbethoxy-3-phenylpropyl ) - 0-ethyl-3-tyrosine and 4,4 dicyclohexylcarbodiimide in 90 ml of dimethylformamide. After 3 hours stirring at. At room temperature, the precipitated dicyclohexyl urea is sucked off, evaporated, the residue is dissolved in 400 ml of ethyl acetate and shaken 3 times with 5% 5% NaHCOj solution, taken in 200 ml portions. The organic phases are evaporated and the chromatographic column is filtered through a silica gel (0.5 kg) mixture of ethyl acetate / petroleum ether in a 2: 1 ratio. The first eluted isomer is S, 3.8-compound, the later eluate, after evaporation, gives compound 3.3, the I-compound. Thus, 2.9 g of oily benzyl ester is obtained as an intermediate product.
1H mass spectra are consistent with the proposed compound structure.
The benzyl ester is catalytically hydrated in 50 ml of ethanol at normal pressure on Pd (C). After filtering off the catalyst and distilling off the solvent, a solid residue remains, which is extracted with a mixture of diethyl .J. ether - petroleum ether and dried. Yield 2.2 g.
1H-PMR (CDClj): 1.2-3.0 (m, 1.5H), 1.27 (t, 3N), 1.4 (t, 3N), 3.0-4.3 (m, 4H), 3.8-4.2 (m, 4H), 6.5-7.1 (2d, 4H), 7.3 (3, 5H).
0
five
0
55
Example 13. (1-S-Kap6-ethoxy-3-phenylpropyl) -0-methyl-5-tyrosyl-cis, endo-2-az abicyclo- (3.3, 0) -octane-3-8-carboxylic acid .
In example 12, using benzyl ester of O-methyl-8-tyrosine, get mentioned in the title compound
eleven
The effectiveness of compounds of General formula 1 - confirm the following pharmacological data.
Intravenous administration of anesthetized rats, 50% inhibition of the pressure reaction caused by 310 Ig of angiotensin 1 30 minutes after administration at a dose of EDj (mg / kg):
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12

-CH2-CH2-CH () - NH-CH (CHj) -CO) - proline 709.
Thus, the proposed compounds are more active than known compounds.

权利要求:
Claims (1)
[1]
Invention Formula

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公开号 | 公开日 | 专利标题

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SU820659A3|1981-04-07|Method of preparing 4-amino-5-alkylsulfonyl-o-anisamide derivatives,their salts,oxides,left-and right-rotational isomers |

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US4281180A|1981-07-28|Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them

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SU1327787A3|1987-07-30|Method of producing cis,endo-2-azabicyclo-|-octane-3-carboxylic acids or acid-additive salts thereof

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JPH0694443B2|1994-11-24|Amino acid derivative

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SU1320207A1|1987-06-30|Dextrorotatory enanthiomer or |-alpha-ethyl-2-oxo-1-pyrrolidineacetamide possessing mnesic activity

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EP0109020A2|1984-05-23|Derivatives from tricyclic amino acids, process for their preparation, compounds containing them and their use, as well as bicyclic amino acids as intermediates and process for their preparation

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US3032585A|1962-05-01|Process for the production of p-bis-|-aminophenylalanine

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CA1106838A|1981-08-11|6-| acetamido penicillin derivatives

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Herz et al.1948|Alkylation of Substituted Malonic and Cyanoacetic Esters with 2-Diamethylaminomethylpyrrole. A Proposed Synthesis of β-2-Pyrrolealanine1

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US5451606A|1995-09-19|Anthraquinone compounds useful to treat osteoarticular conditions, pharmaceutical compositions and method of treatment

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US4490386A|1984-12-25|Phosphate salts of 1-[2-[|-amino]-1-oxoalkyl]octahydro-1H-indole-2-carboxylic acids, preparation of, and medical compositions thereof

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FR2505330A1|1982-11-12|NOVEL CARCINOSTATIC SUBSTANCE BASED ON N- | AMINOBUTYL) -2 - | -7-GUANIDINO-3-HYDROXYHAPTANAMIDO) -2-HYDROXYETHANAMIDE DERIVATIVE AND PROCESS FOR PREPARING THE SAME

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DE2809036A1|1978-09-07|EPOXY AMBER ACID DERIVATIVES

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US5795891A|1998-08-18|Acylphenylglycine derivative and preventive and remedy for diseases caused by increased collagenase activity containing said compound as active ingredient

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DK151957B|1988-01-18|METHOD OF ANALOGUE FOR THE PREPARATION OF 3-SUBSTITUTED 2-OXO-1-BENZIMIDAZOLINICANIC ACIDES OR ESTERS OR AMIDES THEREOF OR SALTS THEREOF WITH BASES

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US4503236A|1985-03-05|Antiallergic 4Hfuro[3,2-b]indoles

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US3470233A|1969-09-30|Process for the manufacture of l-|-beta-|-alpha-methylalanine

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Pande et al.1970|Synthesis and application in peptide chemistry of amino acids possessing an optically active selenohomocysteine skeleton

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US3639382A|1972-02-01|O-ethyl threonine derivatives

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HU201042B|1990-09-28|Process for production of derivatives of 4-amin-6-fluor-cromane-4-carbonic qcid and 2 |-methil

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US4238507A|1980-12-09|Pharmacological compound with immunopotentiating activity and production and uses thereof

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US2478788A|1949-08-09|Process for preparing amino acids

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SU1757471A3|1992-08-23|Method for preparation of l-alanyl-l-prolyn derivatives or their pharmaceutically acceptable salts

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US2813876A|1957-11-19|Resolution of tryptophane derivatives

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US4923888A|1990-05-08|Butenoic acid amides, their salts, and pharmaceutical compositions containing them

同族专利:

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公开号 | 公开日

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ZA828085B|1983-09-28|

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MX9217A|1993-07-01|

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JPH0559105B2|1993-08-30|

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JPS6251A|1987-01-06|

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JPS58103364A|1983-06-20|

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JPH047741B2|1992-02-12|

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JPH0531544B2|1993-05-12|

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JPS61293967A|1986-12-24|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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DE3177311D1|1980-08-30|1994-06-09|Hoechst Ag|Amino acid derivatives, processes for their preparation, compositions containing them and their use.|

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FR2503155B2|1980-10-02|1983-07-01|Science Union & Cie|

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ZA817261B|1980-10-23|1982-09-29|Schering Corp|Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them|

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JPH074338B2|1987-02-27|1995-01-25|オリンパス光学工業株式会社|Endoscope|DE3324263A1|1983-07-06|1985-01-17|Hoechst Ag, 6230 Frankfurt|DERIVATIVES OF 2-AZABICYCLOHEXAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF, AND 2-AZABICYCLOHEXANE DERIVATIVES AS INTERMEDIATE PRODUCTS AND PROCESS PRODUCTS|

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DE3333455A1|1983-09-16|1985-04-11|Hoechst Ag, 6230 Frankfurt|METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS|

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DE3413710A1|1984-04-12|1985-10-24|Hoechst Ag, 6230 Frankfurt|METHOD FOR TREATING HEART INSUFFICIENCY|

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US4925969A|1985-02-04|1990-05-15|Kanegafuchi Kagaku Kogyo Kabushiki Kaisha|Process for preparing ethyl-alpha-amino-gamma-oxo-gamma-phenybutyrate derivatives|

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DE3536687A1|1985-10-15|1987-04-16|Hoechst Ag|METHOD FOR TREATING ATHEROSCLEROSIS, THROMBOSIS AND PERIPHERAL VESSEL DISEASE|

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JP2754010B2|1988-05-23|1998-05-20|株式会社リコー|Cleaning method of image carrier in image forming apparatus|

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US4947750A|1988-08-19|1990-08-14|Presstek, Inc.|Printing member for a press with dampening|

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JP3316639B2|1993-03-05|2002-08-19|コニカ株式会社|Silver halide photographic material with high sensitivity and excellent stability|

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JP3792777B2|1996-05-10|2006-07-05|株式会社カネカ|Method for producing 1-alkoxycarbonyl-3-phenylpropyl derivative|

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AR033048A1|2001-03-19|2003-12-03|Kaneka Corp|METHOD FOR PURIFICATION OF THE N--ETOXICARBONIL-3-PHENYLPROPIL) -L-ALANINA|

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CA2554199C|2004-01-19|2013-07-02|Lupin Limited|Process for crystallization of ramipril and preparation of a hydrated form thereof|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE3143946|1981-11-05|LV930305A| LV5255A3|1981-11-05|1993-05-07|Contribution to cis endo-2-aza-bicyclo--octan-3-carbohydrates and their additive suffixes|

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LTRP654A| LT2582B|1981-11-05|1993-06-12|ENDO-2-AZABICICLO--OCTAN-3-CARBONIAN RUGSCIU AND JU SALT BUDGET|