DK167018B1 - 3-FURYLAMINO-1-BENZAZEPINES AND PROCEDURES FOR PREPARING THEREOF - Google Patents

Description

in DK 167018 B1

The invention relates to novel 3-furylamino-1-benzazepines which can be used as intermediates in the preparation of ACE inhibitors. The invention also relates to a process for the preparation of the 3-furylamino-1-benzazepines of the invention.

The 3-furylamino-1-benzazepines according to the invention are peculiar in that they have the formula / \ / \ f for 5 (s) · —N— · = ♦.

V \ _ / J i_ / s t \ </ V (III), CH,

R 10a wherein R 1a is carboxy or lower alkoxycarbonyl.

It is known to prepare the angiotensin-converting enzyme inhibitors (ACE inhibitors) of the formula S \ S \ B (s) / '~ * \ in il (MN-CH-CH2-CH2 () · (I) v <r <1 wherein r 1 means carboxy and R 1 carboxy or lower alkoxy-carbonyl, using a costly and time-consuming, multi-step process from 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H - [1] benzazepine-2, i.e. a compound of the formula (II) hereinafter, which is reacted with ethyl 2-bromo-4-phenylbutyr 20 in the presence of triethylamine under protective gas and heated to 70 ° C for 18 hours in dimethyl formamide After working up the resulting 1-ethoxycarbonyl-3S- (1-ethoxy-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepine 2-one is separated by column chromatography in the pure (S, S) and (S, R) enantiomers. The (S, S) diastereomer is hydrolyzed to 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3 -phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepi n-5 2-on, which is worked up. The details of this process are disclosed in U.S. Patent No. 4,410,520, Examples 24 and 25. A specific synthetic route is described in Drugs of the Future, Vol. 9, No. 5, 1984.

The object of the invention is to provide novel intermediates which enable the preparation of angiotensin-converting enzyme inhibitors (ACEI) of formula I or their salts without the use of highly toxic reagents in a simpler and less expensive manner than in the known process.

This is achieved by using the subject 3-furylamino-1-benzazepines of formula III as intermediates in the preparation of the ACE inhibitors of formula I, hydrogenating the compounds of formula III, thereby saturating and opening the furanyl ring. The hydroxy function thus formed on the benzyl group is hydrogenated to form a diastereomeric racemic mixture which can be separated into the nearly pure (S, S) diastereomer, the product being recrystallized from acetonitrile or slurried therein. In preparing the compounds of formula I 25 using the compounds of formula III, which will be described in greater detail hereinafter, the compounds of formula I are obtained in a yield of the enantiomerically pure compound which is substantially greater than the yield of the above known process.

In the foregoing and in the following, the definitions used have the following meaning: R is the group [1] -benzazepin-2-one- (3S) -3-yl, as in the 1-position, ie. on the ring nitrogenator, is substituted with

RLA-CH2-.

DK 167018 B1 3

With the exception of the compounds of formula I wherein R 1a is a carboxy exclusively, R 1a and R 2 are independently carboxy or lower alkoxycarbonyl.

The term "low" is defined as groups having at most 7 carbon atoms, preferably at most 4 carbon atoms, and most preferably with 1 or 2 carbon atoms.

Low alkoxycarbonyl is e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl such as tert-butoxycarbonyl.

The process of the invention for the preparation of the 3-furylamino-1-benzazepines of formula III is characterized by reacting a compound of the formula: - - / - / vii * (sy-nh2 (id ^ / \. / • Λ) - 15 LN> li a in which R1a means carboxy or lower alkoxycarbonyl, with trans-2-oxo-4-phenyl-3-butenoic acid in the presence of an alcohol.

In the process of the invention, preferably a lower alkanol, especially ethanol, is used.

For the preparation of compounds of formula I

the intermediate of formula III is catalytically hydrogenated in the presence of an alcohol, preferably a lower alkanol, preferably ethanol, to a compound of formula H (S, R) R-N-CH-CH 2 -CH 2 - CH 2 (IV).

C00H

DK 167018 B1 4

The hydrogenation reaction saturates the double bond in the 2,5-dihydro-uranium ring and breaks the lactone bond, thereby opening the ring. As this leads to a benzyl hydroxy function, the hydrogenation proceeds to form the product of formula IV. Although most hydrogenation catalysts can in principle be used, a paladium carbon catalyst is particularly preferred.

Surprisingly, it has been found that the separation of the S, SR 10 racemic mixture into the desired S, S compounds of formula I can be accomplished simply and quickly, with the mixture being recrystallized from acetonitrile or slurried therein.

The S, S diastereomer is usually obtained in a purity of more than 98%.

When r 2 means carboxy in the desired compound of formula I and R 2a already in the starting material has the meaning carboxy, the process is completed after the recrystallization from acetonitrile or the slurry therein. On the other hand, when R 2a originally meant 20 lower alkoxycarbonyl, the reaction with hydrogen chloride gives the desired product. When r 2 in the desired product is meant to mean lower alkoxycarbonyl, the product of the crystallization or slurry step can be reacted with the desired lower alkanol, especially with ethanol, in the presence of thionyl chloride. Further treatment of this product with e.g. ca. 4 N hydrochloric acid or with a ca. 1 N

alkali metal hydroxide solution such as sodium or potassium hydroxide solution at approx. 50 ° C for approx. at least 1 hour selectively releases the Rla carboxy group without affecting the R 1 ester 30. Further treatment with acids or bases then also releases the R 2 carboxy group. Hydrochloric acid or alkali metal hydroxides such as sodium or potassium hydroxide can also be used as acids or bases. In any case, when a compound of formula I, 35 wherein r 2 is the free carboxy group, is desired, then all the alcohols are suitable as temporary ester group for r 2 which does not react elsewhere with the rest of the molecule, and which in a known way can easily be removed again. Since the free 5 R 1 carboxy group is desired in the compound of formula I, any esterification group for the R 11 carboxy group in the starting material is suitable, provided that it can be readily removed again, although such groups are not discussed further herein.

The invention and preparation of compounds of formula I are explained in more detail by the following examples.

Example 1 a) Preparation of ethyl 3-f (2,5-dihydro-2-oxo-5-phenyl-5S-3-furanyl) amino 1-2,3,4,5-tetrahydro-2-oxo (3S) -T 11-benz-

azepine-1-acetate of formula III

To a solution of 0.935 g (0.0055 mol) of 2-oxo-4-phenyl-trans-3-butenoic acid in 8-10 ml of cold ethanol is added dropwise at 0 ° C with an ethanolic solution of 1.3 g of 20 ( 0.005 mol) ethyl 3-amino-2,3,4,5-tetrahydro-2-oxo- (3S) - [1] benzazepine-1-acetate. After the addition is complete, the mixture is stirred for 1 hour at 20 ° C, then allowed to warm to room temperature. After 20-48 hours, the product precipitates, which can then be filtered off. Thus, between 60 and 90% of the desired product is obtained, depending on reaction time and temperature. The product has a melting point of 144-146 ° C (crude) or 146-148 ° C after recrystallization.

b) Preparation of the compound corresponding to Formula I, wherein R 1 is COOC 3 Hr; and r 2 is COOH.

25 g (0.06 mol) of the unsaturated aminolactone of formula III is suspended in 1500 ml of ethanol. Then 50 g of DK 167018 B1 6 4 Å molecular sieve and 5 g of 5% palladium-on-charcoal are added. The mixture is hydrogenated at room temperature for approx. 20 hours until the theoretical amount of hydrogen is consumed. The reaction mixture is filtered to remove the catalyst and the molecule, and the filter cake is washed with ca. 1000 ml of fresh ethanol. The mixed filtrates are again filtered over Celite® and evaporated to give 25 g of a white solid (crude product). The crude product is recrystallized from acetonitrile (about 200 mL, 80 ° C) and cooled to give 8.3 g (first product) of the S, S diastereomer of formula I wherein R 1 is COOC 2 H 5 and R 2 is COOH.

25

Melting point 185-186 ° C, specific rotation [or] D = -156.87 ° (1% in ethanol).

C) Preparation of the compound corresponding to Formula I wherein R 1 and R 2 are COOC-aHg

To a suspension of 8.0 g (0.0188 mol) of the compound prepared above under b) for approx. 80 ml of ethanol, cooled to 6 ° C, is added dropwise with 3.2 ml (4.88 g, 0.41 mol) of thionyl chloride. A clear solution is thus formed. The mixture is heated for approx. 40 hours at reflux. Next, the thin-layer chromatographic mixture is examined with toluene / ethyl acetate (1: 1) and ethyl acetate, methanol, ammonium hydroxide solution (17: 3: 3). Turnover turns out to be more than 90%. The mixture is evaporated to dryness. A crude product is obtained which, by HPLC analysis, contains more than 91% pure S, S-diastereomer of formula I wherein R 1 and R 2 are COOC 2 H 5.

d) Preparation of the compound of formula I wherein R 2 is C 30 H and R 2 is COOC 7 H 5 (basic conditions)

To a solution of 1 g (0.002 mol) of the diester prepared in c) in 10 ml of ethanol is added a solution of 212 mg (0.002 mol) of sodium carbonate in 8 ml of water and then a 1-molar solution of 1, 8 ml (0.0018 mol) of sodium hydroxide. The mixture is stirred at room temperature and checked by HPLC (Cg column using a water-methanol gradient over 20 minutes).

When the reaction is complete, the ethanol is removed in vacuo and the aqueous residue is extracted twice with diethyl ether (to remove unreacted starting material) and the aqueous phase is then adjusted with 12N hydrochloric acid 10 to pH 4.3. The aqueous phase is extracted intensively with dichloromethane. The extracts are mixed, dried with sodium sulfate and concentrated. This way you get approx.

400 mg (about 46%) of the compound of formula I wherein R 1 is carboxy and R 2 is ethoxycarbonyl, i.

1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] -benzazepin-2-one.

e) Preparation of the compound of formula I wherein R 1 is C00H and R 2 is C00C? Hc; (acidic conditions)

A suspension of 0.5 g (0.01 mol) of the diester prepared above in c) 20 in 10 ml of 4N hydrochloric acid is heated for approx. 4 hours to 50 ° C. Then the mixture becomes homogeneous and the reaction is followed by HPLC (water / methanol 25:75). There is thus obtained more than 88.5% of the desired monoester of formula I. The mixture is cooled and the product 25 crystallizes. The crystals are filtered off and dried.

Thus, as the crude product, the compound of formula I is obtained, wherein R 1 is carboxy and R 2 is ethoxycarbonyl, i. 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which, by HPLC, is more than 96% pure (impurities are about 1% diacetic and 2% diester).

f) Preparation of the compound of formula I wherein R 1 and R 2 represent COOH as hydrochloride salt.

To a suspension of 1 g (0.002 mol) of the compound prepared above under DK 167018 B1 8 d) for approx. 10 ml of ethanol are added to 4 ml of a 1.9 N solution of potassium hydroxide. The mixture is stirred at room temperature for 1 hour, heated for 10 minutes to 50 ° C and then cooled. The ethanol is removed under vacuum and the pH of the residual aqueous solution is adjusted with 12N hydrochloric acid to 1. The desired product is precipitated from the solution. The product is filtered off, washed with acetone and dried. There is thus obtained 600 mg of hydrochloride 10 of the compound of formula I wherein R 1 and R 2 are carboxy, m.p. 278-280 ° C.

Examples 2-4

Example 1 is repeated except that R 1a means methoxycarbonyl, tert-butoxycarbonyl or carboxy of the compound of formula II. In the case where R 2a is carboxy, the hydrogenation of the compound of formula III and the recrystallization from acetonitrile leads directly to the diacid.

Claims (1)

Process for the preparation of 3-furylamino-1-benzazepines according to claim 1, characterized in that a compound of the formula é · - - - · γ · / i (Si · -NH2 (II) 1) is reacted a 10 wherein R1a is carboxy or lower alkoxycarbonyl, with trans-2-oxo-4-phenyl-3-butenoic acid in the presence of an alcohol.