FI88723C - / 2,5-Dihydro-2-oxo-5-phenyl-3-furanyl / amines and their use in the preparation of ACE inhibitors - Google Patents

Description

The present invention relates to a new process for the preparation of ACE inhibitors using cheaper starting materials and less toxic reagents. and and compared to conventional synthesis, diastereomeric separation is simple, efficient and inexpensive. The invention further relates to novel [2,5-dihydro-2-oxo-5-phenyl-3-furanyl] amine intermediates which make it possible to carry out the new process.

Hitherto, angiotensin-modifying enzyme inhibitors (ACE inhibitors) of the formula (I) S \ '\ ϊ <s> I II (Si - k — CU — CHi — CKt - f> (I) 1, in which R1 represents carboxy and R2 represents carboxy or lower alkoxycarbonyl, has been prepared according to an expensive, time-consuming preparation process in several steps, which requires numerous purification steps: and finally Borsch reduction and extremely difficult diastereomeric separation. can be seen in U.S. Patents 4,410,520 and 4,473,575, the specific synthesis of which is further disclosed in the literature in Drugs of the Future, Vol. 9, No. 5, 1984.

The present invention relates to a synthetic process for the preparation of angiotensin-modifying enzyme inhibitors (ACEIs) of formula (I) or their salts, which is simpler and cheaper than the known process.

The invention further relates to a synthetic process for the preparation of ACEIs which allows the rapid separation of diastereomeric products.

The invention further relates to a process for the synthesis of ACEI which avoids the use of the numerous, highly toxic reagents which are essential in the known synthesis.

These and other important objects are achieved by the present invention, according to which the corresponding ACE inhibitors are prepared starting from 2-oxo-4-phenyl-trans-3-butenoic acid by condensing it with a suitable amine of formula R-NH 2. In this way a new intermediate R-N- [2,5-dihydro-2-oxo-5-phenyl-3-furanyl] amine is obtained. This compound is then hydrogenated, whereby the furanyl ring is saturated and opened. The hydroxy function in the benzyl moiety is hydrogenated to form a diastereomeric, racemic mixture which can be separated into a relatively pure (S, S) diastereomer by recrystallization or slurry of the product from acetonitrile.

The definitions used above and below have the following meanings: R is the residue [1] -benzazepin-2-one- (3S) -3-yl, which in the 1-position, i.e. R1-CH2- is substituted on the ring nitrogen atom.

Except for compounds of formula (I) wherein R 1 is exclusively carboxy, R 1 and R 2 are independently carboxy or lower alkoxycarbonyl.

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The term "lower" defines groups containing up to 7 carbon atoms, preferably up to 4 carbon atoms, and especially preferably one or two carbon atoms.

Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl, such as tert-butoxycarbonyl.

Salts of the compounds of formula (I) may be formed with acids or bases and are preferably pharmaceutically acceptable salts such as those formed with hydrohalic acids, e.g. hydrochloric acid, or the acids and bases disclosed in U.S. Patent 4,410,520. The corresponding portion of this U.S. patent publication is hereby incorporated by reference into this specification.

In particular, the process comprises the reaction of an amine of formula (II) with trans-2-oxo-4-phenyl-3-butenoic acid in an alcohol, preferably a lower alkanol, especially ethanol 4 -. In the presence of B 7 V 5 to give a new intermediate of formula (III).

/ v ~ \ i I II (S) 'ft— · == ·. · -.

\ / \ / i 1— / \ 1'N, x- = y (III) 'tämän These intermediates in which R1 represents carboxy or lower alkoxycarbonyl are also the subject of the present invention. A process in which aniline is used instead of the capped compound of formula (II) is described in J. Org.Chem. 33 3991-3993 (1968).

The intermediate of formula (III) is then catalytically hydrogenated, with the addition of an alcohol, preferably a lower alkanol, and in particular ethanol, to give the compound of formula (IV).

! (S> R) R-N CH-CH2-CH2-^ (IV).

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The hydrogenation reaction satisfies the double bond in the 2,5-dihydrofuran ring and a lactone bond is formed, which opens the ring. Since this leads to the formation of a benzylic hydroxy function, the hydrogenation is continued to give the product of formula (IV). Although in principle most hydrogenation catalysts are possible, a palladium / carbon catalyst is particularly preferred.

A surprising and important aspect of the invention is that the separation of the S, SR racemic mixture into the desired S, s compounds of formula (I) can be carried out simply and rapidly by recrystallizing or slurrying the mixture from acetonitrile. The S, S-dia stereoisomer is usually obtained in a purity of more than 98%.

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When R * in the desired compound of formula (I) represents carboxy and R1 in the starting material already means carboxy, the process is completed after recrystallization or slurrying with acetonitrile. When the desired product is to contain lower alkoxycarbonyl as a substituent R 2, the product of the crystallization or slurrying step is reacted with the desired lower alkanol, especially ethanol, in the presence of thionyl chloride. Further treatment of this product with e.g. about 4 N hydrochloric acid or about 1 N alkali metal hydroxide such as sodium or potassium hydroxide at about 50 ° C for about at least 1 hour selectively releases the R 1 '- carboxy group without affecting its R 2 ester. Further treatment with an acid or base also releases the R2 carboxy group. Also suitable as acids or bases are hydrochloric acid or alkali metal hydroxides, such as sodium or potassium hydroxide.

In any case, when it is desired to obtain a compound of formula (I) in which R 2 represents a free carboxy group, all alcohols which do not react at the second point with the rest of the molecule and can be easily removed again in a known manner are suitable as temporary esterification groups. When it is desired to obtain a free R 1 'carboxy group in a compound of formula (I), any esterifying group is suitable as the R 1' carboxy group in the starting material, provided that it can be readily removed again, even when such groups are not mentioned in detail herein.

. Q fi 7 O 7 O * v- · / o

The following are a few examples to better understand the invention, which are intended to be illustrative only and not to limit the scope of the invention. Temperatures are given in degrees Celsius.

Example 1 a) Ethyl 3 - [(2,5-dihydro-2-oxo-5-phenyl-5S-3-furanyl) amino] -2,3,4,5-tetrahydro-2- of formula (III) oxo- (3S) - [1) -benzazepine-1-acetate

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

b) Preparation of a compound of formula (I) wherein R - * - represents COOKt and COOH

The unsaturated aminolactone of formula (III) (25 g, 0.06 mol) is suspended in ethanol (1500 ml). To this

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a 4 A molecular sieve (50 g) and 5 g of 5% palladium / carbon catalyst are adjusted. The mixture is hydrogenated at room temperature for about 20 hours until the theoretical amount of hydrogen has been consumed. The reaction mixture is filtered to remove the catalyst and molecular sieve and the filter cake is washed with fresh ethanol (about 1000 ml). Combined filtrates CO "'" 7

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filtered again with Celite and evaporated to give 25 g of a white solid (crude product). The crude product is recrystallized from acetonitrile (ca. 200 ml, 80 ° C) and cooled to give 8.3 g (first portion) of the S, S-diastereomer of formula (I) wherein COOEt and R 2 COOH have a melting point. 185-186 ° C, rotation [α] 25 = -156.87 ° (1% ethanol-. D

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c) Preparation of a compound of formula (I) wherein R 1 and R 2 are each COOEt

To a suspension of the compound described in b) [8 g (0.0188 mol) in ethanol (ca. 80 L), cooled to 6 °] is added dropwise thionyl chloride (3.2 mL, 4.88 g, 0.41 mol). This gives a clear solution. The mixture is heated to reflux for about 40 hours. The mixture is then chromatographed on thin layer, eluting with toluene / ethyl acetate (1: 1) and, for ethyl acetate, methanol, ammonium hydroxide solution (17: 3: 3). The reaction takes place more than 90%. The eluate is evaporated to dryness. A crude product is obtained which, according to HPLC analysis, contains more than 90% of the pure, S, S-diastereomer of formula (I), in which R1 and R2 are each COOEt.

d) Preparation of a compound of formula (I) wherein R 2 represents C00H and R 2 COOEt (alkaline conditions)

To a solution of the diester (1 g, 0.002 mol) described in c) in ethanol (10 ml) is added a solution of sodium carbonate (212 mg, 0.002 mol) in 8 ml of water, followed by a 1 molar solution of sodium hydroxide (1.8 ml, 0 ml). 0018 moles). The mixture is stirred at room temperature and monitored by HPLC (C18 column water -> methanol gradient for 20 minutes) when the reaction is complete, "\ r-> - -> 8 * Ο / ό completely, after which the ethanol is removed in vacuo and the aqueous the residue is extracted twice with diethyl ether (to remove unreacted starting material), then the aqueous phase is adjusted to pH 4.3 with 12 N hydrochloric acid, the aqueous phase is extracted accurately with dichloromethane, the extracts are combined, dried over sodium sulfate and concentrated to give about 400 mg (about 46%). a compound of formula (I) wherein carboxy and R 2 are ethoxycarbonyl and which is 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1Η- [1 ] benzazepin-2-one.

e) Preparation of a compound of formula (I) wherein R * is COOH and R 2 is COOE (acidic conditions)

A suspension of the diester described in c) (0.5 g, 0.01 mol) in 10 ml of 4N hydrochloric acid is heated at 50 ° for about 4 hours. The mixture is then homogenized and checked by HPLC (water / methanol, 25:75). This gives more than 88.5% of the desired monoester of formula (I). The mixture is cooled and the product crystallizes. The crystals are filtered off and dried. There is thus obtained as a crude product a compound of formula (I) in which R1 is carboxy and R2 is ethoxycarbonyl and which is 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro -1H- [1] -benzazepin-2-one which, according to HPLC, is more than 95% pure (about 1% diacid and 2% diester as impurities).

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

To a suspension of the compound described in d) (1 g, 0.002 mol) in ethanol (about 10 ml) is added 4 ml of a 1.9 N solution of potassium hydroxide. The mixture is stirred at room temperature 9 'fir.7? 3

In the patient for 1 hour, heat to 50 ° within 10 minutes, then cool. The ethanol is removed in vacuo and the pH of the remaining aqueous solution is adjusted to 1 with 12 N hydrochloric acid. The desired product precipitates out of solution. The product is filtered, washed with acetone and dried. There is thus obtained 600 mg of the hydrochloride of the compound of formula (I) in which R1 and represents carboxy. Mp 278-280 °.

Examples 2-4: Example 1 is repeated with the difference that R 1 in the compound of formula (II) means methoxycarbonyl, tert-butoxycarbonyl or carboxy. In the case where R 1 represents carboxy, hydrogenation and recrystallization of the compound of formula dll) from acetonitrile leads directly to the formation of the diacid.

Claims (6)

10 ί'ρ 7 2 3 A process for the preparation of a compound of formula (I) A / \ 5 <s) s ~ \ m ί N (ST - A — CH — CH2 — CH, - (·· (I) \ an '/ L • a R1 wherein R1 represents carboxy and R2 represents carboxy or lower alkoxycarbonyl, or a salt thereof, characterized in that a) a compound of formula (II) in (s} -nh2 (in \ A. / * f wherein R1 is carboxy or lower alkoxycarbonyl, is reacted with trans-2-oxo-4-phenyl-3-butenoic acid in the presence of an alcohol to give the compound of formula (III) N / i (s) -V '/ s an), 1 „Λ σ b) this compound of formula (III) is hydrogenated from the catalytic in the presence of an alcohol. fc R 7 7 X 11" '' c 0 c) the hydrogenation product obtained is recrystallized from acetonitrile or slurried in acetonitrile to give the compound of formula (I). ) wherein R 2 represents carboxy, d) if desired a compound of formula (I) wherein R 1 represents carboxy and R 2 represents lower alkoxycarbonyl, or c) the product is further reacted with a lower alkanol in the presence of thionyl chloride and the product thus obtained is reacted with 4 N hydrochloric acid or 1 N sodium hydroxide or potassium hydroxide, whereby the lower alkoxycarbonyl group R1 is selectively saponified. Process for the preparation of a compound of formula (I) according to claim 1, wherein R 1 represents carboxy and R 2 represents lower alkoxycarbonyl, characterized in that steps a), b) and c) of claim 1 are carried out, wherein in these steps R 1 represents lower alkoxycarbonyl, product of step c) is further reacted in the next step with a lower alkanol in the presence of thionyl chloride to convert the group R from carboxy to lower alkoxycarbonyl, and the product thus obtained is reacted with 4 N hydrochloric acid or 1 N sodium hydroxide or potassium hydroxide to give a lower alkoxycarbonyl group. A process according to claim 2 for the preparation of 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one. A compound of formula (III) 12 k 3 7 2 3 • «- · H ^ \ / \ T i s is-V - * - · - 'VK r 0 wherein R1 represents carboxy or lower alkoxycarbonyl. 13 S 8 7 2 '6