SK283809B6 - 2-Azabicyclo[2.2.1]heptane derivatives, preparation and application thereof - Google Patents

Abstract

Novel 1R or 1S 2-azabicyclo[2.2.1]heptane derivatives of general formula (I) or (I'), wherein R is a hydrogen atom or a radical of formula (II) or (II') respectively, where R1 is an alkyl radical containing 1-4 carbon atoms and Ar is an optionally substituted phenyl or 'alpha'- or 'beta'-naphthyl radical, and preparation and application thereof. The novel products of general formula (I) are particularly useful for preparing adenosine agonists.

Description

Technical field

This invention relates to 2-azabicyclo [2.2.1] heptane derivatives having the IR configuration of Formula (I)

(I) and a process for their preparation.

In formula (I), R represents a hydrogen atom or a group of formula (II)

wherein R ¹ is C 1 -C 4 alkyl and Ar is phenyl or α-, or β-naphthyl optionally substituted with one or more of the same or different substituents selected from halogen atoms, C 1 -C 4 alkyl , (C1-C4) alkoxy and nitro.

Preferably R ¹ is methyl or ethyl and Ar is phenyl optionally substituted by one or more methyl or methoxy groups.

More specifically, R ¹ is methyl and Ar is phenyl.

BACKGROUND OF THE INVENTION

2-Azabicycloheptanone derivatives are described in Chem. Pharm. Bull. 39, 1112-1122 (1991) and Tetrahedron Lett. 30, 1645-1648 and 5543-5546 (1989). Described are compounds having a similar structure to the compounds of the invention, and methods for preparing these compounds are also described.

SUMMARY OF THE INVENTION

According to the invention, compounds of formula (1) wherein R is a group of formula (II) may be obtained by bis-hydroxylation of a compound of formula (III)

wherein R 1 and Ar are as defined above.

In general, said bis-hydroxylation is carried out under the conditions described by V. Van Rheenen et al. in Tetrahedron Lett. 23, 1973-1976 (1976). In a specific embodiment, the oxidation can be carried out with potassium permanganate or osmium tetroxide in the presence of N-methylmorpholine oxide, triethylamine oxide or potassium ferricyanide (K ₃ [Fe (CN) _c , J)]. In general, the reaction is carried out in an aqueous-organic medium such as a mixture of water and tert-butanol or a mixture of water and acetone.

Generally, the oxidizing agent should be selected such that only the 5,6-dihydroxy derivative in the exo form is formed.

The compound of formula (III) or (III ') can be obtained by a Diels-Alder reaction between a homochiral amine of formula (IV) or (IV)

R ¹

R ¹

Ar _with NH ₂ Ar _R NH ₂ wherein R ¹ and Ar are as defined above, in the form of a salt, preferably a salt with a mineral acid such as hydrochloric acid, formaldehyde and cyclopentadiene, which is carried out under conditions described by SD Larsen and PA Griec in J Amer. Chem. Soc. 107, 1768-1679 (1985).

A homochiral amine having the R or S configuration yields a mixture of two diastereomers in this way, which, because they react in the next stage of bis-hydroxylation, does not necessarily have to be separated.

According to the invention, a compound of formula (1) in which R is a hydrogen atom can be obtained by hydrogenolysis of a compound of formula (I) in which R is a group of formula (II) which is carried out using hydrogen in the presence of a catalyst such as palladium on coal, and in an environment of an organic solvent such as alcohol, especially methanol.

The R isomer of formula (I) wherein R is a group of formula (II) may be isolated from a mixture of compounds of formulas (I) and (I ').

wherein the symbols R of formula (II) or (II ')

R ¹ represents a group of general (Π ')

by diastereoselective crystallization with an optically active organic acid from an appropriate organic solvent. Especially preferred is the use of L-dimethoxysuccinic acid in an aliphatic alcohol such as isopropanol.

The novel compounds of formula (I) are particularly suitable for the preparation of compounds which are the subject of US patent 5,364,862 and which are effective agents for the treatment of cardiovascular diseases such as hypertension and myocardial ischemia.

Of particular interest is [1S- (1α, 2β, 3β, 4α) -48- <7 - {[2- (3-chloro-2-thienyl) -1-ethylethyl] amino] -3H-imidazo [4, 5-b] pyridin-3-yl> -N-ethyl-2,3-dihydroxycyclopentanecarboxamide

The compounds of formula (I) are particularly suitable for the preparation of compounds of formula (V)

R —O znamenáO OR v wherein R ² represents a carboxyl group, an alkoxycarbonyl group having an alkyl radical having 1 to 4 carbon atoms, an N-alkylaminocarbonyl group having an alkyl radical having 1 to 4 carbon atoms, a hydroxymethyl group or an alkoxymethyl group, and R 1 and R 2, which are the same or different, represent a hydrogen atom or a C 2 -C 4 aliphatic organic acid radical such as acetyl or propionyl, or an aromatic acid radical such as benzoyl, or R ' and R together may form a methylene group, the carbon atom of which is optionally substituted by one or more identical or different substituents selected from the group consisting of alkyl groups containing 1 to 4 carbon atoms, which may together form an alicyclic group containing 5 or 6 carbon atoms, and phenyl groups , and G ¹ represents an atom hydrogen or a protecting group G ^{2 of the} amine function. More specifically, R ² is an ethylaminocarbonyl or hydroxymethyl group and R 1 and R 2 together form an isopropylidene group.

The compound of formula (V) is one of the structural members of the compounds claimed in U.S. Patent No. 5,364,862.

The preparation of a compound of formula (V) from a compound of formula (I) may be carried out as follows.

The hydroxyl functional groups of a compound of formula (I) in which R is a hydrogen atom or a group of formula (II) may be protected in the form of an ester or acetal to form a compound of formula (VI)

wherein R is a hydrogen atom or a group of formula (II) and R ¹ and R ¹ , which are the same or different, are a C 2 -C 4 aliphatic organic acid radical such as an acetyl or propionyl radical or an aromatic radical acids such as benzoyl, or R ¹ and R ¹ may together form a methylene group, the carbon atom of which is optionally substituted by one or more of the same or different substituents selected from the group consisting of C 1-4 alkyl groups which may be taken together to form an alicyclic group containing 5 or 6 carbon atoms, and phenyl groups.

Generally, the protection of hydroxyl functionalities is carried out under the usual esterification or acetalization conditions, for example by treatment with acetic or propionic acid in the presence of p -toluenesulfonic acid in an organic solvent such as an aromatic hydrocarbon, in particular benzene or toluene. or by treatment with an aldehyde or ketone or aldehyde or ketone in the form of an acetal in the presence of an acid such as trifluoroacetic acid in an organic solvent such as an aromatic hydrocarbon, in particular benzene or toluene, at a temperature between 50 ° C and reflux temperature. mixture.

A compound of formula (VI) in which R is a group of formula (II) can be converted to a compound of formula (VI) in which R is a hydrogen atom by hydrogenolysis.

Generally, the hydrogenolysis is carried out using hydrogen, optionally under pressure, in the presence of a catalyst such as palladium on carbon in an organic solvent such as an alcohol, in particular methanol, ethanol or isopropanol, at a temperature between 0 to 50 ° C.

The compound of formula (VI), which is a novel compound, forms a further part of the invention.

A compound of formula (VI) wherein R is hydrogen may be converted to a compound of formula (VII)

wherein R ¹ and R ¹ are as defined above and G ² is an amine functional protecting group, by treatment with a suitable reagent that allows the selective introduction of the protecting group.

Protecting groups are those which can then be removed selectively. Particularly suitable protecting groups include chloroacetyl, methoxymethyl, 2,2,2-trichloroethoxycarbonyl, tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, benzyl, allyloxy a group in which the benzene ring is optionally substituted by a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, or a tert-butoxycarbonyl group. Other suitable protecting groups include those described in T. W. Greenc and P. G. M. Wuts, &quot; Protecting Groups in Organic Synthesis &quot;, 2nd Ed., John Will &amp; Sons, New York 1991, Chap. 7th

Of particular interest in this regard is the tert-butoxycarbonyl group.

A compound of formula (VII) wherein G ² is a tert-butoxycarbonyl group can be obtained directly from a compound of formula (VI) wherein R is a group of formula (II) by simultaneous hydrogenolysis and tert-butoxycarbonylation.

In general, said reaction is carried out by simultaneously treating a compound of formula (VI) with hydrogen in the presence of a catalyst such as palladium on carbon and di-tert-butyl dicarbonate in an organic solvent such as an alcohol, especially methanol, ethanol or isopropanol, at a temperature in the range of 0 to 50 ° C.

The compound of formula (VII), which is a novel compound, is also part of the invention.

The compound of formula (VII) is then oxidized to a compound of formula (VIII).

Wherein R ¹ , R ¹ and G ² are as defined above.

Generally, the oxidation is carried out with ruthenium oxide (RuO ₄ ) optionally formed in situ from a precursor such as ruthenium dioxide (RuO ₂ ) or ruthenium chloride (RuCl ₃ ) in the presence of an oxidizing agent selected from a periodate such as sodium periodate, hypochlorite or bromates such as sodium hypochlorite or sodium bromate, bromates such as sodium bromate, or organic tertiary amine oxides such as N-methylmorpholine oxide or triethylamine oxide in an aqueous or homogeneous or heterogeneous aqueous-organic medium such as a mixture of water and ethyl acetate.

Said oxidation can also be carried out with sodium hypochlorite alone (Javanese lye), with potassium permanganate or with sodium tungstate in the presence of an oxidizing agent such as sodium hypochlorite, hydrogen peroxide or alkyl hydroperoxide.

The compound of formula (VIIa) can also be obtained by oxidizing a compound of formula (VI) in which R is hydrogen, using the conditions described and subsequently protecting the nitrogen atom of the lactam of formula (IX) obtained.

wherein R ¹ and R ¹ are as defined by a protective group.

The compound of formula (VIII), which is a novel compound, is a further object of the invention.

A compound of formula (VIII) can be converted to a compound of formula (V) under conditions adapted to the nature of the group R ² to be introduced.

A compound of formula (V) in which R is a carboxyl group can be obtained by treating a compound of formula (VIII) with a mineral base such as sodium hydroxide and subsequently replacing the protecting group G ² with a hydrogen atom and optionally replacing the groups R1 and R1 with atoms hydrogen.

A compound of formula (V) wherein R 2 is a carboxyl group can be obtained by replacing the protecting group G ^{2 of a} compound of formula (VIII) with a hydrogen atom, followed by treatment with a mineral base such as sodium hydroxide and optionally replacing groups R ¹ and R ¹ hydrogen atoms.

A compound of formula (V) wherein R ² represents an alkoxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, may be obtained by treatment with an alkali metal to a compound of formula (VIII) followed by the replacement of the protecting group ^G2 by hydrogen and optionally replacing the groups R ¹ and R ¹ with hydrogen atoms.

A compound of formula (V) wherein R ² represents an alkoxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, can be obtained by replacing the protective group G ² of the compound of formula (VIII) with hydrogen, followed by treatment with an alkali metal, such as also by optionally replacing the groups R ¹ and R ¹ with hydrogen atoms.

A compound of formula (V), wherein ^R2 is N-alkylaminocarbonyl group in which the alkyl portion contains 1 to 4 carbon atoms, may be obtained by treatment with an alkylamine a compound of formula (VIII) followed by the replacement of the protective group G ² by a hydrogen atom, as well as optionally replacing the groups R ¹ and R ¹ with hydrogen atoms.

A compound of formula (V) wherein R * is an N-alkylaminocarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms can be obtained by replacing the protecting group G ^{2 of a} compound of formula (VIII) with a hydrogen atom and subsequent treatment with an alkylamine such as also by optionally replacing the groups R ¹ and R ¹ with hydrogen atoms.

A compound of formula (V) wherein R ² is hydroxymethyl, may be obtained by treatment with a reducing agent such as borohydride, particularly sodium borohydride, sodium or potassium, into the compound of formula (VIII) followed by the replacement of the protective group G ² by a hydrogen atom, such as also by optionally replacing the groups R ¹ and R ¹ with hydrogen atoms.

A compound of formula (V) wherein ^R2 is hydroxymethyl can be obtained by replacing the protective group G ² of the compound of formula (VIII) with hydrogen, followed by treatment with a reducing agent such as sodium borohydride, in particular sodium borohydride, and potassium, and where appropriate, replacing the groups R ¹ and R ¹ with hydrogen atoms.

The compound of formula (V) may be used under the conditions described in U.S. Patent No. 5,364,862 to obtain therapeutically active compounds.

In the following, the invention will be further elucidated by means of specific examples thereof, the examples being illustrative only and not in any way limiting the scope of the invention, which is clearly defined by the definition of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A 250 ml 3-necked flask equipped with a condenser and stirring system was charged with a solution of 20 g (165 mmol) of S-methylbenzylamine in 60 cm ^{3 of} water under argon and adjusted to pH 6.1 by adding 17 cm ^{3 of} 36% ( % w / v) hydrochloric acid. After cooling to 5 ° C, 20 cm ^{3 of a} 37% (w / v) aqueous formaldehyde solution are added. The mixture was stirred at 5 ° C for 5 minutes and 21.8 g (330 mmol) of cyclopentadiene were added. Stirring at -5 to 0 ° C was continued for 16 hours. The aqueous layer is separated by decantation and washed with 50 cm ^{3 of} pentane. It is then neutralized to pH 8.0 by addition of concentrated sodium hydroxide and extracted twice with 70 cm ^{3 of} ethyl acetate each time. The pH of the aqueous phase is adjusted to 11.0 by addition of an additional amount of concentrated sodium hydroxide and extracted again twice with 70 cm ^{3 of} ethyl acetate. The organic layers are combined, washed twice with 50 cm ^{3 of} water each time and dried over sodium sulfate. After filtration and evaporation to dryness under reduced pressure, 33.10 g of 2- (S-methylbenzyl) -2-azabicyclo [2.2.1] hept-5-ene is obtained as a pale yellow oil.

In a three-necked flask equipped with a condenser and stirring system containing a solution of 20 g (75.34 mmol) of 2- (S-methylbenzyl) -2-azabicyclo [2.2.1] hept-5-ene in 220 cm ^{3 of} tert-butanol at a temperature of about 25 ° C introduced 12 g of N-metylmorfblinoxidu in 32 cm ³ of water and then slowly 6.3 cm ³ of 2.5% (wt.) solution of osmium tetroxide (OsO ₄₎ in tert-butanol. The mixture is stirred at a temperature in the region of 20 DEG C. for 2 hours and at 65 DEG C. for 3 hours. After evaporation of the tert-butanol under reduced pressure, the residue is taken up with 350 cm ^{3 of} isopropanol. Evaporation to dryness under reduced pressure gave 24 g of cis-5,6-dihydroxy-2- (5-methylbenzyl) -2-azabicyclo [2.2.1] heptane as an oil. Recrystallization from cyclohexane yielded 14 g of 5R, 6S-dihydroxy-2- (5-methylbenzyl) -2-azabicyclo [2.2.1] heptane, the isomeric purity of which is greater than 95%.

The 1 H-Nuclear Magnetic Resonance Spectrum determined in deuterated chloroform has the following chemical shifts (δ):

1.21 (3 H, d),

1.59 (1 H, d),

2.45 (1H, dd),

3.39 (1 H, q),

3.90 (1 H, d),

1.38 (1H, d), 2.22 (2H, m), 2.95 (1H, s), 3.78 (1H, d),

7.28 (5 H, m).

Example 2

Three-necked flask containing 500 cm ³ equipped with a condenser and a stirring system, containing a solution of 18.4 g (76 mmol) of 5R, 6S-dihydroxy-2- (Sa-methylbenzyl) -2-azabicyclo [2.2.1] heptane in 130 cm ^{3 of} toluene are introduced

31.7 g of 2,2-dimethoxypropane (304 mmol) and then slowly 13 g (114 mmol) of trifluoroacetic acid. The mixture was then heated at 65 ° C for 5 hours 10 minutes. After cooling to 30 ° C and concentration in a rotary evaporator to remove toluene, excess 2,2-dimethoxypropane and part of the trifluoroacetic acid, the residue is taken up in dichloromethane and neutralized by addition of 100 cm ^{3 of} 2 N sodium hydroxide solution. After decanting the organic layer and drying it over sodium sulfate, filtration, treatment with activated carbon (30 g) for 30 minutes under reflux of dichloromethane, filtration through clarcel filter aid and evaporation to dryness under reduced pressure,

18.8 g of 5R, 6S-isopropylidenedioxy-2- (S-.alpha.-methylbenzyl) -2-azabicyclo [2.2.1] heptane, the structure of which was confirmed by 1 H-NMR spectra as determined in deuterated chloroform. It has the following chemical shifts (δ):

1.22 (3 H, d),

1.31 (1H, d),

2.08 (1H, d),

2.45 (1 H, dd),

3.40 (1H, q),

4.19 (1H, d),

1.23 (6H, s);

1.57 (1H, d),

2.34 (1 H, br s),

3.06 (1 H, s),

4.09 (1H, d),

7.26 (5 H, m).

In a three-necked 250 cm ³ flask equipped with a stirring system is charged 0.5 g of 5% palladium on carbon, 5 g of 5R, 6S-isopropylidenedioxy-2- (5-methylbenzyl) -2-azabicyclo [2.2.1] heptane, 3 g. 98 g of di-tert-butyl dicarbonate and 36 cm ^{3 of} methanol. The apparatus is purged with argon and then with hydrogen, and the introduction of hydrogen is continued for 5 hours at 25 ° C, and the apparatus is purged with hydrogen every 15 minutes to remove the carbon dioxide formed.

After filtration through clarcel filter aid and evaporation to dryness under reduced pressure, 4.84 g of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane is obtained, the chemical structure of which is confirmed by 1 H. - the nuclear magnetic resonance spectrum determined in dimethylsulfoxide-d ₆ .

It has the following chemical shifts (δ):

1.16 (3 H, s),

1.32 (1 H, s),

1.65 (1 H, d),

2.65 (1 H, d),

3.84 (1H, m),

4.16 (1 H, d).

1.28 (3 H, s),

1.34 (3 H, s),

2.38 (1 H, m),

2.99 (1 H, m),

3.94 (1H, d),

A 20 cm ³ reaction tube was charged with 270 mg (1 mmol) of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane and 40 mg (0.3 equivalents) of ruthenium dioxide. in the form of monohydrate (RuO2.H2O). 10 cm ^{3 of} ethyl acetate and 720 mg (40 equivalents) of water are then added. Sodium periodate (2.14 g, 10 equivalents) was added and the tube sealed. The tube contents are then stirred for 16 hours at 50 ° C. After cooling, the reaction mixture is filtered through clarcel filter aid and extracted twice with 20 cm ^{3 of} ethyl acetate each time. The combined extracts were dried over sodium sulfate. Filtration and evaporation to dryness under reduced pressure yielded 245 mg of a solid which contains 68% of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptan-3-one and 32% of the starting material. substances. The chemical structure of the obtained product was confirmed by the 1 H-nuclear magnetic resonance spectrum determined in dimethylsulfoxided6, which has the following chemical shifts (δ):

1.38 (9H, s);

1.33 (3H, s), 1.93 (1H, d), 4.24 (1H, s),

4.51 (1 H, d).

1.23 (3 H, s),

1.85 (1H, d), 2.69 (1H, s), 4.41 (1H, d),

Example 3

A solution of 1.47 g of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptan-3-one in 10 cm ^{3 of} anhydrous toluene is introduced into a 25 cm ³ autoclave equipped with a magnetic stirrer. and about 0.7 cm ^{3 of} ethylamine are added. The autoclave is sealed and heated to 90-100 ° C for 21 hours. After cooling, the toluene is evaporated off under reduced pressure and the residue is diluted with 10 cm ^{3 of} dichloromethane and 10 cm ^{3 of} water. After decantation, the organic layer is washed with 10 cm ^{3 of} water. The aqueous layers are combined and washed with 10 cm ^{3 of} dichloromethane. The combined organic layers are washed with 10 cm ^{3 of} saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation to dryness under reduced pressure, 1.58 g of product is obtained which contains 95% of 2R, 3S-isopropylidenedioxy-4R-tert-butoxycarbonylamino-1S-ethylaminocarbonylcyclopentane, the chemical structure of which is confirmed by @ 1 H-NMR. dimethylsulfoxide-d ₆ . It has the following chemical shifts (δ):

0.95 (311, t),

1.31 (12H, s);

2.11 (1H, m), 3.00 (1H, qi),

4.23 (1H, m), 7.07 (1H, d),

1.14 (3 H, s),

1.55 (1H, m), 2.64 (1H, m), 3.77 (1H, m), 4.54 (1H, m), 8.12 (1H, t).

1.22 g of 2R, 3S-isopropyldioxy-4R-tert-butoxycarbonylamino-1S-ethylaminocarbonylcyclopentane and 10 cm ^{3 of} dichloromethane are introduced into a round-bottomed flask. At a temperature close to 25 ° C, 0.85 g of trifluoroacetic acid is added under magnetic stirring. After 6 hours, the reaction mixture was evaporated to dryness under reduced pressure to give 1.16 g of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane trifluoroacetate, the chemical structure of which was confirmed by 1 H-nuclear magnetic resonance spectra determined in dimethylsulfoxide. d ₆ . It has the following chemical shifts (δ):

0.79 (3 H, t),

1.19 (3 H, s),

2.05 (1H, m)

2.89 (2 H, qi),

4.16 (1H, m).

1.03 (3H, s),

1.42 (1H, m), 2.52 (1H, m), 3.04 (1H, m),

Example 4

A solution of 0.5 mmol of a mixture of 5R, 6S-dihydroxy-2- (5-methylbenzyl) -2-azabicyclo [2.2.1] heptane and 5S, 6R-dihydroxy-2- (5-methylbenzyl) -2-azabicyclo [2.2.1] heptane 2.2.1] Heptane (78: 22 molar ratio) and 0.5 mmol of L-dimethoxysuccinic acid in 1 cm ^{3 of} isopropanol are stirred for 24 hours at 25 ° C, which is gradually reduced to 5 ° C. The separated crystals were collected by filtration and dried. 110 mg of 5R, 6S-dihydroxy-2- (5-methylbenzyl) -2-azabicyclo [2.2. 1 Heptane, whose isomeric purity is 97%.

A mixture of 5R, 6S-dihydroxy-2- (S-a-methylbenzyl) -2-azabicyclo [2.2.1] heptane and 5S, 6R-dihydroxy-2- (S-a-methylbenzyl) -2-azabicyclo [2.2. 1 Heptane (78: 22 molar ratio) can be obtained as follows:

In a three necked flask equipped with a condenser and stirring system containing a solution of 7 g (75.34 mmol) of 2- (S-methylbenzyl) -2-azabicyclo [2.2.1.0 &lt; 2,7 &gt; 1 H -hept-5-ene in 70 cm ^{3 of} tert-butanol at a temperature close to 25 ° C is charged with 4.12 g of N-methylmorpholine oxide in 11 cm ^{3 of} water and then slowly with 360 μΐ 2.5% (w / v) osmium tetroxide solution ( OsO, ₄ ) in tert-butanol. The resulting mixture was stirred for 1 hour at a temperature near 20 ° C and for 4 hours at 65 ° C. After evaporation of the t-butanol under reduced pressure, the residue is diluted with 150 cm ^{3 of} isopropanol and evaporated to dryness under reduced pressure. 8.27 g of product are obtained, the @ 1 H NMR of which shows that it is composed of a mixture of 5R, 6S-dihydroxy-2- (5-methylbenzyl) -2-azabicyclo [2.2. and 5S, 6R-dihydroxy-2- (S-methylbenzyl) -2-azabicyclo [2.2.1] heptane (78: 22 molar ratio).

Example 5

568 mg of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptan-3-one and 10 cm &lt; ^{3 &gt; of a} 70% aqueous solution of ethylamine are introduced into a Berghoff tube. The mixture was heated with stirring at 60 ° C for 4 hours. After cooling, excess triethylamine and water were removed under reduced pressure. After drying under reduced pressure, 650 mg (98%) of 2R, 3S-isopropylidenedioxy-4R-tert-butoxycarbonylamino-1S-ethylaminocarbonylcyclopentane are obtained, the chemical structure of which is confirmed by 1 H-NMR.

Optical rotation of the product obtained [α] D 20 = 15.0 (c = 1, methanol)

To a solution of 200 mg of 2R, 3S-isopropylidenedioxy-4R-tert-butoxycarbonylamino-1S-ethylaminocarbonylcyclopentane in 1.6 cm ^{3 of} anhydrous dichloromethane is added 275 µL of trifluoroacetic acid and the mixture is stirred overnight at a temperature close to -5 ° C. The reaction mixture is then poured into 4 cm @ ^{3 of a} 2.5 N sodium hydroxide solution. The organic layer was separated and evaporated to dryness under reduced pressure and a temperature below 25 ° C. 125 mg of product are obtained, which is dissolved in 0.5 cm @ ^{3 of} tetrahydrofuran and 70 mg of benzoic acid are added. After cooling the solution to a temperature close to 0 ° C, the precipitated crystals were collected by filtration and washed with pentane. 138 mg of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane benzoate are prepared.

Example 6

To a solution of 167 mg of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptan-3-one in 1 cm ^{3 of} dichloromethane cooled to 0 ° C is added 90 μΐ of trifluoroacetic acid. The temperature of the reaction mixture was allowed to rise to 23 ° C over 40 minutes and stirred at this temperature for 22 hours. 90 μΐ of trifluoroacetic acid is added again and the mixture is stirred for 1 hour at 23 ° C. Evaporation under reduced pressure yields 123 mg of 5R, 6S-isopropylidenedioxy-2-azabicyclo [2.2.1] heptan-3-one, which has a purity (determined by high performance liquid chromatography) of near 92% and whose chemical structure is confirmed by 1 H nuclear magnetic resonance spectroscopy.

A solution of 10 g of 5R, 6S-isopropylidenedioxy-2-azabicyclo [2.2.1] heptan-3-one in 100 cm ^{3 of} 70% aqueous triethylamine is heated at 110 ° C for 20 hours at autogenous pressure. After cooling, excess triethylamine was removed under reduced pressure and the residue was washed with dichloromethane to remove unreacted starting material. The aqueous layer was evaporated to dryness and dried under reduced pressure. 10.54 g of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane are obtained.

Claims (15)

PATENT CLAIMS 1. 2-Azabicyclo [2.2.1] heptane derivatives having the IR configuration of formula (I) wherein R represents a hydrogen atom or a group of formula (II) R ¹ wherein R ¹ is C 1-4 alkyl and Ar is phenyl or α- or β-naphthyl optionally substituted with one or more of the same or different substituents selected from halogen atoms, C 1-4 alkyl carbon atoms, C 1 -C 4 alkoxy or nitro. 2-Azabicyclo [2.2.1] heptane derivatives of general formula (I) according to claim 1, in which R ¹ represents a methyl or ethyl group and Ar represents a phenyl group optionally substituted by one or more methyl or methoxy groups. The 2-azabicyclo [2.2.1] heptane derivatives of formula (I) according to claim 1 or 2, wherein R ¹ represents a methyl group and Ar represents a phenyl group. A process for the preparation of 2-azabicyclo [2.2.1] heptane derivatives of formula (I) according to any one of claims 1 to 3, wherein R represents a group of formula (II) characterized in that bis-hydroxylation of a compound of the general formula (III) is carried out in which R ¹ and Ar have the meanings given in any one of claims 1, 2 or 3. The process according to claim 4, characterized in that the bis-hydroxylation is carried out using potassium permanganate or osmium tetroxide in the presence of N-methylmorpholine oxide, triethylamine oxide or potassium ferricyanide. A process for the preparation of 2-azabicyclo [2.2.1] heptane derivatives of the general formula (I) according to claim 1, wherein R represents a hydrogen atom, characterized in that the derivative according to any one of claims 2 or 3, wherein R represents a group of formula (II), is treated with hydrogen in the presence of palladium on a carrier, in an organic solvent selected from the group consisting of aliphatic alcohols containing 1 to 3 carbon atoms. 7. Method for the preparation of 2-azabicyclo [2.2. A compound of formula (I) according to claim 1 wherein R is a group of formula (II) from a mixture of a compound of formula (I) and a compound of formula (I ') wherein R is a group of formula (II) or (II). ') R ^{1 ?} (d ') characterized in that diastereoselective crystallization of a compound of formula (I) in which R is a group of formula (II) with an optically active acid such as L-dimethoxysuccinic acid in an organic solvent selected from the group consisting of aliphatic alcohols containing 1 to 3 carbon atoms. A process for the preparation of a compound of formula (VIII) wherein R ¹ and R ¹ , which are the same or different, represent a radical of an aliphatic organic acid having 2 to 4 carbon atoms or a benzoyl group, or R ¹ and R ¹ together form a methylene group. wherein the carbon atom is optionally substituted by one or more identical or different substituents selected from the group consisting of alkyl groups containing 1 to 4 carbon atoms, which may together form an alicyclic group containing 5 or 6 carbon atoms, and phenyl groups, and G ² represents an amino protecting group a) protecting a hydroxyl function of a compound of formula (I) according to any one of claims 1, 3 or 4 to form a compound of formula (VI) wherein R ¹ and R ¹ are as defined above, and R is as defined in any one of claims 1, 3 or 4, as usual b) then the compound of formula (VI) is converted to a compound of formula (VII) wherein R ¹ and R ¹ are as defined above and G ² is a nitrogen protecting group, either by (i) hydrogenolysis of the compound of formula (VI), wherein R is a group of formula (II) and by treatment with a nitrogen protecting group, wherein hydrogenolysis and nitrogen protection can be carried out simultaneously; or (ii) treatment with a nitrogen protecting group a compound of formula (VI) wherein R is hydrogen, and then c) oxidizing a compound of formula (VII) to a compound of formula (VIII). Process according to claim 8, characterized in that the protection of the hydroxyl functional groups of the compound according to any one of claims 1 to 4 is carried out with an aliphatic acid having 2 to 4 carbon atoms or an aldehyde or a ketone, optionally in the form of acetate. an inert organic solvent at a temperature between 50 ° C and the reflux temperature of the reaction mixture. The process according to claim 8, characterized in that the hydrogenolysis is carried out with hydrogen in the presence of palladium on carbon, and the protection of the nitrogen atom is carried out under usual protective conditions depending on the nature of the protecting group. Process according to Claim 8, characterized in that if G ² represents a tert-butoxycarbonyl group, the simultaneous hydrogenolysis and protection are carried out by simultaneously treating with hydrogen in the presence of palladium on carbon and with di-tert-butyl dicarbonate in an aliphatic environment an alcohol containing 1 to 3 carbon atoms at a temperature between 0 to 50 ° C. Process according to claim 8, characterized in that the oxidation of the compound of the formula (VII) is carried out with ruthenium oxide (RuO ₄ ) or ruthenium oxide formed in situ in the presence of an oxidizing agent. A process for the preparation of a compound of formula (VIII) wherein R ¹ , R ¹ and G ² are as defined in claim 8, characterized in that a compound of formula (VI) wherein R ¹ , R ¹ are as defined above is oxidized. in claim 8, and R is a hydrogen atom, under the conditions set forth in claim 12, and then the nitrogen atom of the obtained lactam is protected under the conditions set forth in claim 11. A compound of formula (VI) (VI) wherein R is a hydrogen atom or a group of formula (II) as defined in any one of claims 1, 2 or 3 and R ¹ and R ¹ which are the same or different , represent an aliphatic organic acid having 2 to 4 carbon atoms or a radical benzoyl, or else R ¹ and R ¹ may together form a methylene group whose carbon atom is optionally substituted by one or more identical or different substituents selected from the group consisting of alkyl having 1-4 carbon atoms which may together form an alicyclic group containing 5 or 6 carbon atoms and phenyl groups. A compound of formula (VII) wherein R ¹ and R ¹ , which are the same or different, represent a radical of an aliphatic organic acid having 2 to 4 carbon atoms or a benzoyl radical, or R ¹ and R ¹ together form a methylene group whose the carbon atom is optionally substituted by one or more of the same or different C 1 -C 4 alkyl groups which may together form an alicyclic group containing 5 or 6 carbon atoms, or phenyl groups, and G ² represents an amine functionality protecting group.