MXPA97008995A - New derivatives of 2-azabiciclo [2.2.1] heptano, its preparation and its application - Google Patents

Abstract

New derivatives of 2-azabicyclo [2.2.1] heptane IR or IS of general formula (I) or (I '), their preparation and their application in which the general formula (1) and (I'), R represents a hydrogen atom or respectively a radical of formula (II) or (II ') in which R 1 represents an alkyl radical containing from 1 to 4 carbon atoms and Ar represents a phenyl or alpha-o-naphthalene radical optionally substituted. The new products of general formula (I) are particularly useful for preparing adenosine antagonists

Description

NEW DERIVATIVES OF 2-AZABICICLO [2.2.1] HEPTANO, ITS PREPARATION AND ITS APPLICATION The present invention relates to new derivatives of 2-azabicyclo [2.2.1] eptane IR or 2S of the general formula: its preparation and its application.

In the general formulas (I) and (I '), R represents a radical of a hydrogen atom or a radical of the general formula: REP: 25881 wherein Ri represents an alkyl radical containing 1 to 4 carbon atoms and Ar represents a phenyl or α- or β-naphthyl radical optionally substituted by one or more identical or different atoms or radicals chosen from the halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms or nitro.

Preferably, Ri represents a methyl or ethyl radical and Ar represents a phenyl radical optionally substituted by one or more methyl or methoxy radicals. More particularly still, Ri represents a methyl radical and Ar represents a phenyl radical.

According to the invention, the products of the general formula (I) or (I '.) In which R represents respectively a radical of the general formula (II) or (II') can be obtained by bis-hydroxylation of a product of general formula 0: in which Rx and Ar are defined as above.

Generally, bis-hydroxylation is effected by operating under the conditions described by V. VanRheenen et al., Tetrahedron Letters, 23, 1973-1976 (1976). More particularly, the oxidation may be carried out in the medium of potassium permanganate or osmium tetraoxide operating in the presence of N-methyl morpholine-oxide or of triethylamino-oxide or potassium ferricyanide (K3FeCN6). Generally, it is operated in a hydro-organic medium such as a water-tert-butanol or water-acetone mixture.

In a general manner, the oxidation must be chosen in such a way that only the 5,6-dihydroxy derivative is formed in exo form.

The product of general formula (III) or (III ') can be obtained by reaction of Diels-Alder between a homochiral amine of the general formula: wherein Ri and Ar are defined as above, in salt form, preferably with a mineral acid such as hydrochloric acid, formaldehyde and cyclopentadiene in operation under the conditions described by S.D. Larsen et P.A. Grieco, J. Amer. Chem. Soc, 107, 1768-1769 (1985).

The start-up of the process leads, starting from a homochiral amine of form R or S, a mixture of 2 diastereoisomers that react in the same way as in the subsequent stage of bis-hydroxylation, they should not necessarily be separated.

According to the invention, the product of the general formula (I) or (I ') in which R represents a hydrogen atom which can be obtained by hydrogenolysis of a product of the general formula (I) or (I') in the which R represents a radical of general formula (II) or (II ') in hydrogen medium in the presence of a catalyst such as palladium on carbon in operation in an organic solvent such as an alcohol such as methanol.

The Ri isomer of the general formula (I) in which R represents a radical of the general formula (II) can be isolated from a mixture of the products of the general formulas (I) and (I ') by diastereoselective crystallization with an organic acid optically active in an appropriate organic solvent. This is particularly advantageous for using L-dimethoxysuccinic acid in an aliphatic alcohol such as isopropanol.

The new products of the general formula (I) are particularly useful for the preparation of the products that were the subject of the American patent US 5,364,862 and which are the active agents in the treatment of cardiovascular diseases such as hypertension and myocardial ischemia. .

Of particular interest is [1-S- [la, 2ß, 3ß, 4 alpha (S *)]] - 4 - [[7 - [[2- (3-chloro-2-thionyl) - 1-ethylethyl] amino] -3H-imidazol [4, 5-b] pyridin-3-yl] -N-ethyl-2,3-dihydroxycyclopentanecarboxamide of the formula: The products of the general formula (I) are particularly useful for the preparation of carbo-sugar of the general formula: wherein R 2 represents a carboxy radical, alkoxycarbonyl wherein the alkylation contains from 1 to 4 carbon atoms, N-alkylaminocarbonyl wherein the alkylation contains from 1 to 4 carbon atoms or hydroxy ethyl or alkoxymethyl, and R 'and R' ', identical or different, represent a hydrogen atom or a residue of the aliphatic organic acid containing 2 to 4 atoms, such as an acetyl or propionyl radical or of the aromatic acid such as a benzoyl radical or R' and R ' 'together form a methylene radical where the carbon atom is optionally substituted by one or more radicals, identical or different chosen from the alkyl radicals containing from 1 to 4 carbon atoms can together form an aliphatic radical containing 5 or 6 carbon atoms. carbon, or the phenyl radicals, and Gi represents a hydrogen atom or a G2 protecting group of the amino function. More particularly, R 2 represents an ethylaminocarbonyl or hydroxymethyl radical and R 'and R "form an isopropylidene radical.

The sugar cane of general formula (V) constitutes one of the elements of the structure of the products claimed in the American patent US 5,364,862.

The preparation of carbo-sugar of general formula (V) from the product of general formula (I) which can be carried out in the following manner.

The hydroxy functions of the product of the general formula (I) in which R represents a hydrogen atom or a radical of the general formula (II) can be protected in the form of an ester or an acetal to give a product of the general formula: wherein R represents a hydrogen atom or a radical of general formula (II) and R'i and R "', identical or different, represent a residue of organic acid aliphatic containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical or an aromatic acid such as a benzoyl radical or R'i and R "? together they form a methylene radical where the carbon atom is optionally substituted by one or more radicals, identical or different chosen among the alkyl radicals containing from 1 to 4 carbon atoms can together form an alicyclic radical containing 5 or 6 carbon atoms. carbon, or phenyls radicals.

Generally, the protection of the hydroxy radicals is carried out under the usual conditions of esterification or acetalization, for example by the action of acetic or propionic acid in the presence of the acid, p-toluene sulfonic acid in an organic solvent such as an aromatic hydrocarbon such as benzene or the toluene separating the water little by little and as measured from its formation or by the action of an aldehyde or of a ketone optionally or 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 such as benzene or toluene, a a temperature comprising between 50C and the reflux temperature of the reaction mixture. The product of general formula (VI) in which R represents a radical of general formula (II) can be transformed into a product of general formula (VI) in which R represents a hydrogen atom by hydrogenolysis.

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

The product of the general formula (VI), which is a new product, which constitutes a further objective of the present invention.

The product of the general formula (VI) in which R represents a hydrogen atom that can be transformed into a product of the general formula: in which R'i and R "'i are defined as above and G2 represents a protecting group of the amino function by the action of a convenient reagent which allows the selective introduction of a protecting group.

The protective groups are chosen among celui which can be subsequently selectively eliminated. Among the protecting groups which may conveniently be particularly well-formed are chloroacetyl, methoxymethyl, trichloro-2,2,2-ethoxycarbonyl, t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, alkyloxycarbonyl, benzyloxycarbonyl, wherein the phenyl nucleus is optionally substituted by a halogen atom or by an alkyl radical containing 1 to 4 carbon atoms or alkyloxy containing 1 to 4 carbon atoms, or t-butoxycarbonyl. Among the other protective groups that conveniently particularly can well be cited those core described by T. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis ", Chapitre 7, 2eme edition, John Wiley &Sons (1991).

Of a more particular interest is the t-butoxycarbonyl group. The product of general formula (VII) in which G2 represents a t-butoxycarbonyl radical which can be obtained directly from a product of general formula (VI) in which R represents a radical of general formula (II) by hydrogenolysis and simultaneous tert-butoxycarbonylation.

Generally, the reaction is put into operation by simultaneously reacting the hydrogen in the presence of a catalyst such as palladium on carbon and di-t-butyl bicarbonate in a product of general formula (VI) in operation in an organic solvent such as an alcohol such as methanol, ethanol, or isopropanol at a temperature between 0 and 50C.

The product of the general formula (VII) is a new product that constitutes a further objective of the present invention.

The product of the general formula (VII) is then oxidized into a product of the general formula: in which R'i, R ''? and G2 is defined as above.

Generally, the oxidation is carried out in the ruthenium oxide medium (Ru04) eventually generated in situ from a precursor such as Ru02 or RuCl3 in the presence of an oxidant chosen from periodates such as sodium periodate, hypochlorite or hypobromite. of sodium or a bromate such as sodium bromate or an organic tertiary amine oxide such as N-methyl-morpholino-oxide or triethylamine-oxide in operation in water or in a homogeneous or heterogeneous hydro-organic medium such as a mixture of water-ethyl acetate.

The oxidation may also be carried out in the medium of sodium hypochlorite alone (soda water) or in the medium of potassium permanganate or in the medium of sodium tungstate in the presence of an oxidant such as sodium hypochlorite, hydrogen peroxide or a hydroperoxide. of alkyl.

The product of general formula (VIII) can also be obtained by oxidation of a product of general formula (VI) in which R represents a hydrogen atom under the conditions described below, followed by the protection of the lactam nitrogen atom obtained of the general formula: in which R'i and R ''? is defined as above, by a protecting group as defined above.

The product of general formula (VIII) is a new product that constitutes a further objective of the present invention.

The product of general formula (VIII) can be transformed into a product of general formula (V) under conditions appropriate to the nature of a substituent R2 which can be introduced.

The product of general formula (V) in which R2 represents a carboxy radical can be obtained by the action of a mineral base such as soda in the product of general formula (VIII), followed by replacement of the protective group G2 with a hydrogen and eventually the radicals R'i and R "? by the hydrogen atoms. The product of the general formula (V) in which R2 represents a carboxy radical can be obtained by replacing the protective group G2 of the product of the general formula (VIII) with a hydrogen atom followed by the action of a mineral base such as the soda, and optionally of replacement of the radicals R '? and R "? by the hydrogen atoms.

The product of general formula (V) in which R 2 represents an alkoxycarbonyl radical where the alkylation part contains from 1 to 4 carbon atoms which can be obtained by the action of a metal alcohol in the product of general formula (VIII), followed of the replacement of the protecting group G2 by a hydrogen atom and, optionally, of the radicals R'l and R''1 for the hydrogen atoms.

The product of general formula (V) in which R 2 represents an alkoxycarbonyl radical where the alkylation part contains from 1 to 4 carbon atoms can be obtained by replacement of the protecting group G 2 of the product of general formula (VIII) with a hydrogen atom followed by the action of an alkali metal alkylate, and optionally the replacement of the radicals R'i and R "? by the hydrogen atoms. The product of general formula (V) in which R2 represents an N-alkylaminocarbonyl radical where the alkylation part contains from 1 to 4 carbon atoms which can they be obtained by the action of an alkylamino in the product of the general formula (VIII), followed by the replacement of the protective group G2 by a hydrogen atom, and optionally the replacement of the radicals R'i and R "? by the hydrogen atoms.

The product of general formula (V) in which R 2 represents an N-alkylaminocarbonyl radical wherein the alkylation part contains from 1 to 4 carbon atoms which can be obtained by replacing the protecting group G 2 of the product of general formula (VIII) with a hydrogen atom, followed by the action of an alkylamino, and optionally replacement of the radicals R'i and R "? by the hydrogen atoms.

The product of general formula (V) in which R 2 represents a hydroxymethyl radical which can be obtained by the action of a reducing agent such as a borohydride such as sodium or potassium borohydride in the product of general formula (VIII), followed by replacement of the protecting group G2 by a hydrogen atom and optionally the radicals R'i and R "? by the hydrogen atoms.

The product of general formula (V) in which R 2 represents a hydroxymethyl radical which can be obtained by replacing the protective group G 2 of the product of general formula (VIII) with a hydrogen atom followed by the action of an agent such as borohydride such as sodium or potassium borohydride, and the eventual replacement of radicals R'i and R "? by the hydrogen atoms.

The product of general formula (V) can be used in the conditions described in US Pat. No. 5,364,862 to obtain the therapeutically active products.

Suitable examples illustrating the present invention.

EXAMPLE 1 In a 250 cm3 ball flask equipped with a coolant and a stirring system, a solution of 20 g of a-S- is introduced under an argon atmosphere. methylbenzylamine (165 mol) in 60 cm3 of water where the pH is adjusted to 6.10 by the addition of 17 cm3 of hydrochloric acid to 36% (w / v). After cooling to 5 C, 20 cm3 of an aqueous formaldehyde solution at 37% (w / v) are added. It is stirred for 5 minutes at 5 ° C, then 21.8 g of cyclopentadiene (330 mol) are added. It is stirred for 16 hours between -5 and OC. The aqueous phase is separated by decantation, then washed with 50 cm.sup.3 of pentane. It is neutralized to pH = 8.0 by the addition of concentrated sodium hydroxide. It is then extracted twice from 70 cm.sup.3 of ethyl acetate. The aqueous phase is maintained at pH = 11 by the addition of concentrated sodium hydroxide, then extracted twice with 70 cm 3 of ethyl acetate. The organic phases are combined, then washed twice with 50 cm.sup.3 of driest water in sodium sulfate. After filtering and concentrating it is dried under reduced pressure, 33.10 g of 2- (a-S-methylbenzyl) -2-azabicyclo [2.2, 1] hept-5-ene are obtained in the form of a slightly yellow oil.

In a 500 cm3 ball flask fitted with a coolant and a stirring system, containing a solution of 20 g of 2- (a-S-methylbenzyl) -2- azabicyclo [2, 2, l] hept-5-ene (75.34 mol) in 220 cm3 of tert-butanol, is added at a temperature similar to 25C, 12 g of N-methylmorpholine-oxide in 32 cm3 of water more, slowly , 6.3 cm3 of a 2.5% (w / v) solution of sodium tetraoxide (0s04) in the tert-butanol. It is stirred for 2 hours at a temperature similar to 20C more, for 3 hours at 65C. After evaporation of tert-butanol under reduced pressure, the residue is recovered by 350 cm 3 of isopropanol. After concentrating to dryness under reduced pressure, 24 g of cis-5,6-dihydroxy-2- (a-S-methylbenzyl) -2-azabicyclo [2.2.1] eptane are obtained in the form of an oil. 14 g of 5R, 6S-dihydroxy-2- (a-S-methylbenzyl) -2-azabicyclo [2, 2, 1] heptane is obtained, where the isomeric purity is greater than 95%.

The R.M.N. spectrum is determined in the deuterium chloroform, shows the appropriate chemical shifts (&): 1.21 (3H, d); 1.38 (1H, d); 1.59 (1H, d); 2.22 (2H, m); 2.45 (1H, dd); 2.95 (1H, s); 3.39 (1H, q); 3. 78 (1H, d); 3.90 (1H, d); 7.28 (5H, m).

EXAMPLE 2 In a 500 cm3 ball flask, fitted with a coolant and a stirring system, containing a solution of 18.4 g of 5R, 6S-dihydroxy-2- (aS-methylbenzyl) -2-azabicyclo [2, 2, 1] heptane (76 mol) in 130 cm 3 of toluene, stir 31.7 g of 2,2-dimethoxypropane (304 mol) plus, slowly, 13 g of trifluoroacetic acid (114 mol). It is distilled for 4 hours 10 minutes at 65C. After cooling to 30 C and concentrating on the rotary evaporator to remove toluene, the excess of 2,2-dimethoxypropane and particularly trifluoroacetic acid, the reaction mixture is recovered with dichloromethane is neutralized by the addition of 100 cm 3 of sodium hydroxide. 2N. After decanting, the organic phase is dried over sodium sulphate, filtered, treated with a decolorizing black color (30 g) for 30 minutes under reflux of dichloromethane, filtered off and concentrated to dryness under reduced pressure, 18.8 g of 5R, 6S-isopropylidenedioxy-2- (aS-methylbenzyl) -2-azabicyclo [2, 2, 1] heptane where the structure is confirmed by the spectrum of R.M.N. of proton, which determines the deutero chloroform, shows the appropriate chemical shifts (&): 1.22 (3H, d); 1.23 (6H, s); 1.31 (1H, d); 1.57 (1H, d); 2.08 (1H, d); 2.34 (1H, s long); 2.45 (1H, dd); 3.06 (1H, s); 3.40 (1H, q); 4.09 (1H, d); 4.19 (1H, d); 7.26 (5H, m).

In a 250 cm3 ball flask equipped with a stirring system, 0.5 g of 5% by weight palladium on carbon, 5 g of 5R, 6S-isopropylidenedioxy-2- (aS-methylbenzyl) -2-azabicyclo [0.5 g] are introduced. 2, 2, 1] heptane, 3.98 g of di-tert-butyl bicarbonate and 36 cm 3 of methanol. The apparatus is purged in argon plus hydrogen, below a hydrogen atmosphere at 25C. The reaction is continued for 5 hours a hydrogen purge is performed every quarter of an hour in order to eliminate the carbon gas formed.

After filtering off in clear and concentrating to dryness under reduced pressure, 4.84 g of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane is obtained where the structure is confirmed by the NMR spectrum that determines the dimethylsulfoxide-d6, shows the appropriate chemical shifts (&): l, 16 (s, 3H); 1.28 (s, 3H (, 1.32 (3, 1H), 1.34 (s, 3H), 1.65 (d, 1H), 2.3d (m, 1H), 2.65 (d, 1H), 2.99 (m, 1H); 3.84 (m, 1H), 3.94 (d, 1H), 4.16 (d, 1H).

In a 30 cm3 tube, 270 mg of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2, 2, 1] heptane (1 mole) and 40 mg of Ru02, H2O (0.3) are introduced. equivalent). 10 cm3 of ethyl acetate and 720 of water (40 equivalent) are added. 2.14 g of sodium periodate (10 equivalent) are then added and the tube sealed. It is stirred for 16 hours at 50C. The reaction mixture is filtered over clear and extracted twice more than 20 cm3 of ethyl acetate. The organic phases are dried in sodium sulphate. After filtering and concentrating to dryness under reduced pressure, 245 mg of a solid containing 68% of 5R, 6S-iso-pyrrolidinedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] are obtained. hepyano-3-one and 32% of an output product. The structure of the product is obtained, it is confirmed by the spectrum of R.M.N. which determines dimethisulfoxide d6, shows the appropriate chemical shifts (&): 1.38 (9H, s); 1.23 (3H, s); 1.33 (3H, s); 1.85 (1H, d); 1.93 (1H, d); 2.69 (1H, s); 4.24 (1H, s); 4.4M1H, d); 4.5K1H, d).

EXAMPLE 3 Into a 25 cm3 autoclave, provided with magnetic stirring, 1.47 g of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane-3-one is introduced into a solution in 10 cm3 of anhydrous toluene, plus 0.7 cm3 of ethylamino. Firm the autoclave of the distillation at a temperature between 90 and 100C for 21 hours. After cooling, the toluene is evaporated and taken up by 10 cm 3 of dichloromethane and 10 cm 3 of water. After decanting, the organic phase is washed with 10 cm 3 of water. The combined aqueous layers are washed with 10 cm 3 of dichloromethane. The combined organic phases are washed with 10 cm.sup.3 of a saturated solution of sodium chloride, dried over sodium sulfate. After filtering and concentrating to dryness under reduced pressure, 1.58 g of a product containing 95% of 2R, 3S-isopropylidinodioxy-4-R-tert-butoxycarbonylamino-1-S-ethylaminocarbonylcyclopentane is obtained where the structure is confirmed by the NMR spectrum which determines dimethylsulfoxide d6, shows the appropriate chemical shifts: 0.95 (t, 3H); 1.14 (s, 3H), 1.31 (s, 12H); 1.55 (m, 1H) 2.11 (m, 1H); 2.64 (m, 1H); 3. 00 (qi, 2H); 3.77 (m, 1H); 4.23 (m, 1H); 4.54 (m, 1H); 7.07 (d, 1H); 8.12 (t, 1H).

Into a 25 cm3 ball flask, 1.22 g of 2R, 3S-isopropylidenedioxy-4R-tert-butoxycarbonylamino-lS-ethylaminocarbonylcyclopentane and 10 cm3 of dichloromethane are introduced. At a similar temperature of 25 C, 0.85 g of trifluoroacetic acid is added with magnetic stirring. After stirring for 6 hours and concentrating to dryness, 1.16 g of 2R, 3S-isopropylidenedioxa-4R-amino-1S-ethylaminocarbonylcyclopentane trifluoroacetate are obtained, where the structure is confirmed by the R.M.N. which determines the dimethisulfoxide d6, shows the appropriate chemical shifts: 0.79 (t, 3H); 1.03 (s, 3H); 1.19 (s, 3H); 1.42 (m, 1H); 2.05 (m, 1H); 2.52 (m, 1H); 2.89 (qi, 2H); 3.04 (m, 1H); 4.16 (m, 1H).

EXAMPLE 4 A solution of 0.5 mol of a mixture (78/22 mol) of 5R, 6S-dihydroxy-2- (aS-methylbenzyl) -2-azabicyclo [2.2.1] heptane and of 5S, 6R-dihydroxy-2 - (αS-methylbenzyl) -2-azabicyclo [2.2.1] heptane and 0.5 mol of L-dimethoxysuccinic acid in 1 cm3 of isopropanol is stirred for 24 hours at a temperature similar to 25C at 5C. The crystals obtained are separated by filtration and dried. 110 mg of 5R, 6S-dihydroxy-2- (a-S-methylbenzyl) -2-azabicyclo [2, 2, 1] heptane are thus obtained with an enantiomer excess of 97%.

The mixture (78/22 mole) of 5R, 6S-dihydroxy-2- (aS-methylbenzyl) -2-azabicyclo [2, 2, 1] heptane and of 5S, 6R-dihydroxy-2- (aS-methylbenzyl) -2-azabicyclo [2, 2, 1] heptane can be obtained in the following manner: In a 250 cm3 ball flask, fitted with a coolant and a stirring system, containing a solution of 7 g of 2- (aS-methylbenzyl) -2-azabicyclo [2, 2, 1] hept-5- ene (35 moles) in 70 cm3 of tert-butanol, are added at a similar temperature of 25C, 4. 12 g of N-methylmorpholine-oxide in 11 cm3 of water plus, slowly, 360 ml of a 25% (w / v) solution of sodium tetraoxide (Os0) in the tert-butanol. Stir for 1 hour at a similar temperature of 20 ° C for 4 hours at 65 ° C. After evaporation of tert-butanol under reduced pressure, the residue is recovered by 150 cm3 of isopropanol. After concentrating to dryness under reduced pressure, 8.27 g of a product are obtained where the spectrum of R.M.N. of proton showing that it is composed of a mixture of (78/22 mol) of 5R, 6S-dihydroxy-2- (a-S-methylbenzyl) -2-azabicyclo [2, 2, 1] heptane. EXAMPLE 5 In a Berghoff tube, 568 mg of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-a? Abicyclo [2, 2, 1] heptane-3-one and 10 cm3 of an aqueous solution of ethylamino are introduced. to 70% (by weight). It is distilled for 4 hours at 60C under stirring. After cooling, excess triethylamine and water are removed at reduced pressure. After drying under reduced pressure, 650 mg of 2R, 3S-isopropylidenedioxy-4-R-tert-butoxycarbonyl-amino-1-S- is obtained in a yield of 98%. ethylaminocarbonylcyclopentane where the structure is confirmed by the spectrum of R.M.N. of proton and where the rotary power is [alpha [D 20 = 15.0 (C = 1; methanol)].

To a solution of 200 mg of 2R, 3S-isopropylidenedioxy-4-R-tert-butoxycarbonylamino-1-S-ethylaminocarbonylcyclopentane in 1.6 cm 3 of anhydrous dichloromethane is added 275 μl of trifluoroacetic acid. It is stirred overnight at a similar temperature of -5C. The reaction mixture is poured into 4 cm 3 of 2.5N aqueous sodium hydroxide. The organic layer is concentrated under reduced pressure at a temperature below 25C. Thus, 125 mg of a product that dissolves in 0.5 cm3 of tetrahydrofuran is obtained. To this solution, 70 mg of the benzoic acid are added. After the solution obtained is cooled to a similar temperature of 0 C, the crystals obtained are separated by filtration and washed with pentane. 138 mg of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane benzoate are thus obtained.

EXAMPLE 6 To a solution of 167 mg of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane-3-one in 1 cm3 of dichloromethane, is cooled to CO, 90 is added my trifluoroacetic acid. The temperature is spaced back to 23C in 40 minutes plus it is stirred for 22 hours at this temperature. A new 90 ml of trifluoroacetic acid is added, further stirred for 1 hour at a temperature of 23 ° C. After evaporation under reduced pressure, 123 mg of 5R, 6S-isopropylidenedioxy-2-azabicyclo [2, 2, 1] heptane-3-one are obtained, where the purity is determined by liquid chromatography at a similar time of 92% and where the structure is confirmed by the NMR spectrum of proton.

A solution of 10 g of 5R, 6S-isopropylidenedioxy-2-azabicyclo [2, 2, 1] heptane-3-one in 100 cm3 of an aqueous solution of 70% triethylamine (by weight) is distilled at 110C for 20 hours under autogenous pressure. After cooling, the excess triethylamine is removed under reduced pressure plus, washed in dichloromethane to eliminate the output product interested in the reaction step. The aqueous layer is then concentrated and dried. 10.54 g of 2R, 3S-isopropylidenedioxy-4R-amino-1S-5-ethylaminocarbonylcyclopentane are thus obtained.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. or_. Having described the invention as above, property is claimed as contained in the following: fifteen twenty

Claims (18)

1. I. New derivatives of 2-azabicyclo [2.2.1] heptane IR or 2S of the general formula: wherein R represents a hydrogen atom or a radical of the formula: R. Ar (II) or Ar (ID wherein Ri represents an alkyl radical containing from 1 to 4 carbon atoms and Ar represents a phenyl or α- or β-naphthyl radical optionally substituted by one or several identical or different atoms or radicals selected from halogen atoms and alkyl radicals containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms or nitro.
2. 2. New derivatives of 2-azabicyclo [2, 2, 1] heptane according to claim 1 characterized in that Ri represents a methyl or ethyl radical and Ar represents a phenyl radical optionally substituted by one or more methyl or methoxy radicals.
3. 3. New derivatives of 2-azabicyclo [2, 2, 1] heptane according to claim 1 characterized in that Ri represents a methyl radical and Ar represents a phenyl radical.
4. 4. Process for the preparation of a product according to claim 1, 2 or 3, wherein R represents a radical of the general formula (II) or (II '), characterized in that a bis-hydroxylation is carried out in a product of the general formula: wherein Ri and Ar are defined as in one of claims 1, 2 or 3.
5. 5. Process according to claim 4, characterized in that the bis-hydroxylation is carried out in the presence of potassium permanganate or sodium tetroxide in operation, in the presence of N-methylmorpholine-oxide or of triethylamino-oxide or potassium ferricyanide (K3FeCN6) .
6. 6. Process for preparing a product according to claim 1 whereby R represents a hydrogen atom, characterized in that a product according to one of claims 1, 2 or 3 is treated by the hydrogen in the presence of a catalyst such as palladium in operation in an organic solvent chosen from aliphatic alcohols containing 1 to 3 carbon atoms.
7. 7. Process for the preparation of a product according to claim 1 of the general formula (I) whereby R represents a radical of general formula (II) from a mixture of a product of general formula (I) and a product of general formula (I ') by which the symbols R represent respectively a radical of general formula (II) or (II ') characterized in that the diastereoselective crystallization of a product of general formula (I) is carried out by which R represents a radical of general formula (II) with an optically active acid, such as L-dimethoxysuccinic acid operating in an organic solvent chosen from aliphatic alcohols containing from 1 to 3 carbon atoms.
8. 8. Process of preparation of a product of general formula: wherein R'i and R "', identical or different, represent a residue of the organic aliphatic acid containing from 2 to 4 carbon atoms, such as the acetyl or propionyl radical or the aromatic acid such as a benzoyl radical or R'i and R "? together form a methylene radical wherein the carbon atom is optionally substituted by one or more radicals, identical or different chosen from the alkyl radicals containing from 1 to 4 carbon atoms which can together form an alicyclic radical containing from 5 to 6 atoms of carbon or the phenyl radicals and G2 represents a protecting group of an amino radical, characterized in that: a) the hydroxy functions of a product according to one of claims 1, 2 or 3 are protected to obtain a product of the general formula: R " in which R'i and R ''? is as defined above and R is defined as in one of claims 1, 2 or 3 under the usual conditions of esterification or acetalization, b) the product of the general formula (VI) is transformed into a product of the general formula: in which R'i and R ''? is as defined above and G2 represents a protecting group of the nitrogen atom, by, or i) hydrogenolysis of a product of general formula (VI) in which R represents a radical of general formula (II) and the action of a reagent that allows the introduction of a protective group of the nitrogen atom, the hydrogenolysis and the protection of the nitrogen atom that can be carried out simultaneously, or ii) The action of a reagent that allows the introduction of a protective group of the nitrogen atom in a product of general formula (VI) in which R represents a hydrogen atom, more the oxide of the product of general formula (VII) in a product of general formula (VIII).
9. 9. Process according to claim 8, characterized in that it protects the hydroxy functions of a product according to one of claims 1, 2 or 3 is carried out in the middle of an aliphatic acid containing from 2 to 4 carbon atoms or from an aldehyde or a ketone optionally in the form of an acetal in the presence of an acid in an inert organic solvent at a temperature between 50C and the reflux temperature of the reaction mixture.
10. . Process according to claim 8, characterized in that the hydrogenolysis is carried out in the medium of a hydrogen in the presence of a catalyst such as palladium on carbon and the protection of the nitrogen atom, is carried out under the usual conditions of protection as a function of the nature of the protective group.
11. . Process according to claim 8, characterized in that G represents a tert-butoxycarbonyl radical, hydrogenolysis and simultaneous protection is carried out in order to simultaneously record the hydrogen in the presence of a catalyst such as palladium on carbon and di-ter dicarbonate. -butyl in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature between 0 and 50C.
12. . Process according to claim 8, characterized in that the oxidation of the product of the general formula (VII) is carried out in the middle of a ruthenium oxide (Ru04), eventually generating a site in the presence of an oxidant.
13. 13. Process of preparation of a product of general formula: in which R'i and R ''? and G2 is as defined in claim 8, characterized in that in the oxide of a product of general formula. in which R '? and R "? is as defined in claim 8 and R represents a hydrogen atom under the conditions of claim 11 more protected the Lactam nitrogen atom obtained in the conditions of claim 10.
14. 14. A product of general formula: wherein R'i and R ", identical or different, represent a residue of the aliphatic organic acid containing from 2 to 4 carbon atoms, such as an acetyl or propionyl radical or of an aromatic acid such as a residue of benzoyl or R'i and R "? together they form a methylene radical wherein the carbon atom is optionally substituted by one or more radicals, identical or different chosen from the alkyl radicals containing from 1 to 4 carbon atoms which together can form an alicyclic radical containing 5 or 6 carbon atoms. carbon, or the phenyl radicals and G2 represents a protective group of an amino radical.
15. 15. A product of general formula: wherein R represents a hydrogen atom or a radical of general formula (II) as defined in claims 1, 2 or 3 and R'i and R ", identical or different, representing a residue of the acid organic aliphatic containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical or an aromatic acid such as the benzoyl radical or R'i and R "? together they form a methylene radical where the carbon atom is optionally substituted by one or several radicals, identical or different chosen from the alkyl radicals containing from 1 to 4 carbon atoms. carbon which can together form an alicyclic radical containing 5,66 carbon atoms, or the phenyl radicals.
16. 16. A product of general formula: wherein R'x and R '' ?, identical or different, represent a residue of the aliphatic organic acid containing from 2 to 4 carbon atoms, such as an acetyl or propionyl radical or an aromatic acid such as a benzoyl radical or R'i and R "? together form a methylene radical where the carbon atom is optionally substituted by one or more radicals, identical or different chosen from the alkyl radicals containing from 1 to 4 carbon atoms can together form an alicyclic radical containing 5 or 6 carbon atoms , or the phenyl radicals and G2 represents a protective group of the amino function.
17. 17. Process of preparation of a product of general formula: wherein R 2 represents a carboxy radical, alkoxycarbonyl wherein the alkylation portion contains from 1 to 4 carbon atoms, N-alkylaminocarbonyl where the alkylation contains from 1 to 4 carbon atoms or hydroxymethyl or alkoxymethyl, and R 'and R " , identical or different, represent a hydrogen atom or a residue of the aliphatic organic acid containing from 2 to 4 carbon atoms, such as an acetyl or propionyl radical or of an aromatic acid such as a benzoyl or R 'radical and R "together form a methylene radical wherein the carbon atom is optionally substituted by one or more radicals, identical or different chosen from the alkyl radicals containing from 1 to 4 carbon atoms. carbon which can together form an alicyclic radical containing 5 or 6 carbon atoms, or the phenyl radicals, and Gl represents a hydrogen atom or a protective group G2 of the amino function, characterized by a carbon atom which is to be reacted according to the nature of the a radical R2 obtained, a mineral base, an alkali metal alcoholate, an alkali metal or an alkali metal borohydride in a product of the general formula: in which R'i, R ''? and G2 is as defined above, the radicals R'i and R "? and the protecting group G2 are eventually replaced by two hydrogen atoms.
18. 18. Process of preparation of a product of general formula: R, NH "C (V) R" -0 0 -R ' wherein R 2 represents a carboxy radical, alkoxycarbonyl wherein the alkylation portion contains from 1 to 4 carbon atoms, N-alkylaminocarbonyl where the alkylation contains from 1 to 4 carbon atoms or hydroxymethyl or alkoxymethyl, and R 'and R " , identical or different, represent a hydrogen atom or a residue of the aliphatic organic acid containing from 2 to 4 carbon atoms, such as an acetyl or propionyl radical or of an aromatic acid such as a benzoyl or R 'radical and R "together form a methylene radical wherein the carbon atom is optionally substituted by one or more radicals, identical or different chosen from the alkyl radicals containing from 1 to 4 carbon atoms which can together form an alicyclic radical containing 5 to 6 carbon atoms. 6 carbon atoms, or phenyl radicals, and Gi represents a hydrogen atom or a group G2 protector of the amino function, characterized in that the protective group G2 of a product of the general formula is replaced: wherein R'i, R "? and G2 is as defined above by a hydrogen atom, then a mineral base, an alkali metal alcohol, a reactant is reacted according to the nature of the R2 radical that is desired to be obtained; alkylamino or an alkali metal borohydride in the product obtained, the radicals R'i and R "are optionally replaced? by the hydrogen atoms.