MXPA96005090A - Process for the preparation of derivatives of 5,6-dihidroxi-2-amino-1,2,3,4-tetrahidronaftal - Google Patents

Abstract

The present invention relates to: a process, and variations thereof, for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivatives of formula (I), wherein R 1, R2, R3 can independently be hydrogen or lower alkyl

Description

PROCESS FOR THE PREPARATION OF DERIVATIVES OF 5, 6-DIHIDROXI-2-AMINO-1, 2,3, 4-TETRAHIDRONAFTALENO DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of derivatives of 5,6-dihydroxy- 2-amino-1,2,3,4-tetrahydronaphthalene (or arainotetralin) (5,6-ADTN) of formula (I): wherein R,, R ~ and R "Which are the same or different, are hydrogen or a straight or branched chain lower alkyl group. TECHNICAL BACKGROUND Aminotetralins are compounds that have a remarkable sympathomimetic activity. Thanks to their properties, they can be used in different therapeutic fields, as active drugs in the bronchial, cardiovascular, renal and central nervous system levels. A number of methods for the preparation of 5,6-ADTN are described in the literature or in patents, starting with REF: 23341 l of the late sixties. Some syntheses require the preparation of 5,6-dimethoxy-1 -tetralone, which is then transformed into 5,6-ADTN by means of various procedures: by rearrangement of 5 Neber of O-tosyl oxime 5 »6-dimethoxy-l-tetralone (WK Sprenger et al., J. Med. Chera., 12, 487, 1969, modified by JC Kim et al., J. Kor. Chem. Soc., 21 (3), 187, 1977), by alpha-bromination and subsequent bromine substitution (JC Kim et al., J. Kor. Chem. Soc., 20, 91, 1976; 0 Y. Oka et al., Chem. Pharm. Bull., 25 (4), 632, 1977), by • alpha-nitrosation and subsequent reduction (Y. Oka et al., Chem. Pharm. Bull., 25 (4), 632, 1977). Some syntheses require the preparation of 5,6-dimethoxy-2-tetralone, which is then transformed into 2-amino The corresponding derivative by reductive amination (JD McDermed et al., J. Med. Chem., 18 (4), 362, 1975; JG Cannon et al., J. Med. Chem., 20 (9), 1111. , 1977, US Patent No. 646300, 1976 (Iowa Univ.), Or by transformation into the corresponding 0-methyloxime and subsequent reduction (JG Cannon et al., J. Med. Chem., 17 (5). ), 565, 1974) Some syntheses are based on the preparation of 5-hydroxy-6-methoxy-1,2,3,4-tetrahydro-2-naphthoic acid, and the subsequent transformation into 5,6-ADTN by rearrangement from Curtius (K. Mitsuhashi et al., Chem. Pharm. Bull., 20 (6), 1321, 1972).

The only enantiospecific synthesis of 5,6-ADTN is based on the use of 2,2-diraethyl-3-methoxycarbonyloxazolidin-4-aldehyde (A. D. Baxter et al., Tetrahedron Letters, 33 (17), 2331, 1992). All these methods suffer from severe restrictions for industrial use. Recently, a method for the preparation of industrially applicable 2-amino-5,6-dimethoxytetralin has been claimed in EP-A-0 534 536, filed on September 17, 1991, in the name of Zambon. According to the last reference, 5,6-diraethoxy-2-aminotetralin is obtained through the key intermediate, that is to say, the corresponding 1-tetralone, already widely described in the literature cited above. The tetralone is obtained by initiating the condensation of 2,3-dimethoxybenzaldehyde with pyruvic acid (stage A), the transformation of the keto group into an amino group, and the reduction of the unsaturated amino acid (stage B), and the intramolecular cyclization to give the desired 5,6-dimethoxy-2-amino (protected) -1-tetralone. The condensation reaction (A) has already been described by Hudson et al., J. Chem. Soc., 715-722 (1941); and by Pavel et al., Acta Univ. Palacki Olomuc. Fac. Rerum Natur. , 401-404 (1971). On the subject, EP 0 534 536 underlines that such a reaction was carried out in the presence of an inorganic base, such as sodium hydroxide (Hudson) or potassium carbonate.

(Pavel), with very low yields (40 and 6% respectively), and therefore showed no industrial interest. In EP 0 534 536 cited above, the problem of low yield is overcome by carrying out the condensation in the presence of an "organic base, such as triethylamine, piperidine., piperazine and morpholine. The condensation product is obtained in yields of up to about 80%. The condensation described therein requires particular reaction conditions, such as an anhydrous organic solvent (dimethylformamide is cited), an inert atmosphere, low temperatures during the addition phase of the reactants. Recovery of the product requires an extraction procedure to remove the organic solvent. From the industrial point of view, the condensation described above has additional costs in terms of reagents, anhydrous solvents and plant requirements. Now, it has been found that the condensation reaction of 2,3-dialkoxybenzaldehyde and pyruvic acid makes it possible to obtain 4- (2,3-dialkoxyphenyl) -2-ketobutenoic acid in high yields, when carried out in the presence of an inorganic base, in an aqueous / alcoholic solvent. The reaction is carried out at room temperature. BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention a process for the preparation of compounds of formula (I) comprising: a) the condensation of 2, 3-dialcox ibenzaldehyde with pyruvic acid in an aqueous / alcoholic system, and in the presence of an inorganic base, to obtain 2-keto-4- (2, 3-dialkoxyphenyl) -butenoic acid; b) the transformation of the keto group of the acid into an amino or alkylamino group, with simultaneous reduction of the double bond, to give respectively 2-amino or 2-alkylamino-4- (2,3-dialkoxyphenyl) butyric acids; c) transformation of 2-amino or 2-alkylamino-4- (2,3-dialkoxyphenyl) butyric acid into 4- (2- (2,3-dialkoxyphenyl) -ethyl) -N-alkyl-2,5-oxazolidinedione; d) the cyclization of the N-carboxyanhydride by the intramolecular acylation of Friedel-Crafts in the presence of a Lewis acid, to directly give the unprotected 5,6-dialkoxy-2-alkylamino-1-tetralone; e) the catalytic reduction of the ketone, to give 5,6-dialkoxy-2-alkylaminotetralin and, if desired, f) the O-dealkylation of 5,6-dialkoxy-2-alkylaminotetraline, to give 5,6-dihydroxy-2-alkylaminotetralin. The process can be shortened using a halohydric acid or a Lewis acid under suitable conditions, to directly obtain the unprotected 5,6-dihydroxy-2-alkylamino-l-tetra-tarpaulin of the N-carboxyanhydride. In another aspect, the process of the present invention comprises steps a) and b) described above, and then: c) cyclization of 2-alkylamino-4- (2,3-dialkoxy-phenyl) butyric acid with simultaneous dealkylation on the oxygen, to give 2-alkylamino-5,6-dihydroxy-l-tetra- lane directly in a single step; d) the catalytic reduction of the ketone, to give the hydrochloride of 5,6-dihydroxy-2-alkylaminotetralin. The final compound is usually obtained in the form of a salt, but the process according to the present invention also provides for the transformation of the derivative into the free base, or the conversion thereof into another acid addition salt. Examples of the lower alkyl group are alkyl groups of 1 to 4 carbon atoms, straight or branched chain. In a preferred embodiment, the present invention provides a process for the preparation of compounds of formula (I) wherein R is methyl and R ~ and R3 are H.

DETAILED DESCRIPTION OF THE INVENTION According to a first embodiment of the present invention, the compounds of formula (I) are prepared according to the following Scheme 1: Scheme 1 NHF, In the following, the individual stages are described in detail: the stage - The condensation reaction of 2,3-dimethoxy-benzaldehyde with pyruvic acid is already known from the literature, as mentioned above. According to the present invention, the reaction can be carried out in 80% yields, operating in an aqueous / alcoholic medium, preferably water / ethanol, and using an inorganic base, preferably commercial potassium hydroxide. Other inorganic bases which can be used according to the present invention are, for example, sodium hydroxide. 2nd stage - Consists in the transformation of the ketone into an alkylamino group by reductive amination. The transformation is carried out in a single step with conventional procedures, using a suitable alkylamine, for example aqueous methylamine, and a suitable reducing system, for example by catalytic hydrogenation (Pd catalyst) in methanol. The reaction takes place with the simultaneous reduction of the double bond, in a single stage, in yields of about 60%. The reaction is carried out using methylamine or other alkylamines, thus making it possible to directly obtain 2-aminotetralin derivatives already substituted on the amino group with alkyl groups, which in turn are optionally substituted. The medium is an alcoholic or hydroalcoholic solution, under moderate and low cost conditions. The amino acid can be obtained both in the form of the hydrochloride and the neutral amino acid (amphoteric ion). The method can be carried out using ammonia instead of alkylamine, to also obtain unsubstituted 2-amino-tetralin derivatives on the amino. 3rd step - The transformation of the amino acid into the corresponding cyclic N-carboxyanhydride takes place in a single step using phosgene, according to conventional methods (compare A. R. Katritzky, C. Rees; Comprehensive Heterocyclic Chemistry, part 4B, page 231, 1984, Pergamon Press; J. P. Greenstein, M. Winitz; Chemistry of the Amino Acids, Vol. 2, pages 867-868, 1961, and cited references). For practical purposes, it is preferred to subdivide the reaction in two steps: transformation of the araino group from 2-alkylamino-4- (2,3-dialkoxyphenyl) butyric acid into carbamate, using a suitable chloroformate, for example benzyl chloroformate or chloroformate of ethyl, in a quantitative yield; cyclisation of 4- (2,3-dialkoxyphenyl) -2- (N-alkyl-N-alkyloxycarbonylamino) butyric acid to the cyclic N-carboxyanhydride, with simultaneous removal of alkyl halide, for example by means of thionyl chloride, in the absence or in the presence of an organic solvent. The yields are almost quantitative. The resulting product is solid, stable and easy to handle without specific operational attentions. To our knowledge, the use of this particular anhydride in the preparation of compounds with an aminotetralin structure has never been described in the literature. This method allows 2-alkyl-amino-5,6-dialkoxy-l-tetralone to be obtained directly in the subsequent stage, avoiding the protection / deprotection procedure of the amino group, which is otherwise required in EPO 0 534 536 Stage 4 - This stage consists of an intramolecular Friedel-Crafts acylation of 4- (2- (2,3-dialkoxyphenyl) ethyl) -N-alkyl-2, 5-oxazolidinedione, to give the 5,6-dialkoxy -2-alkylamino-1-tetralone, carried out with conventional procedures, using for example aluminum trichloride or other suitable Lewis acids (such as B3r ~, BC1", SnCl,, TiCl,) in an anhydrous aprotic solvent, preferably chlorinated 5th step - The reduction of 5,6-dialkoxy-2-alkylamino-no-1-tetralone to tetralin is carried out in an aqueous or hydroalcoholic medium, acid by means of hydrochloric acid, using Pd on carbon as a catalyst. The yields are almost quantitative. 6th stage - The possible O-dealkylation reaction of - Il ¬5,6-dialkoxy-2-alkylaminotetralin, to give 5,6-dihydroxy-2-alkylaminotetralin is carried out with conventional procedures, for example using a suitable concentrated hydrohalic acid (such as aqueous HBr), or a suitable Lewis acid in an apolar aprotic solvent (for example aluminum trichloride in anhydrous toluene), in quasi-quantitative yields. In a second embodiment of the present invention, the compounds of formula (I) are prepared according to the following Scheme 2: Scheme 2 The individual stages are described in detail in the following: Process 2 the stage and 2nd stage - They are carried out according to the procedure described for steps 1 and 2 of Process 1. 3rd stage '- This stage consists of cyclization by acylation intramolecular amino acid, with simultaneous deprotection of hydroxyl catechol. The reaction takes place using a suitable aqueous concentrated hydrohalic acid, for example 48% hydrobromic acid under reflux, 37% hydrochloric acid at a temperature from 100 to 140 ° C under pressure, or 57% hydroiodic acid. The reaction can also be carried out using a suitable Lewis acid in an aprotic solvent (for example BBr "in methylene chloride). This stage is particularly important. In fact, that the Applicant knows, no method described in the literature performs in a single stage the intramolecular cyclization with the simultaneous deprotection of the hydroxyls, avoiding the steps of protection and deprotection of the amino or alkylamino group. In fact, the described methods usually involve a) the protection of the amino group and the cyclization according to Friedel-Craf so in a single step, with trifluoroacetic anhydride in trifluoroacetic acid (see EP 0 534 536) or in more stages (see literature cited in EPO 0 534 536 and in AD Baxter et al., Tetrahedron Letters, 33 (17), 2331, 1992); b) the deprotection of the amino group; c) deprotection of the hydroxyls, usually by treatment with hydrobromic acid; d) the possible N-alkylation of 2-amino-tetralin. On the other hand, the present method is particularly interesting industrially, due to the high yields (close to 90%) and the low costs of the reagents. When an acid other than hydrochloric acid is used, the product is transformed into the hydrochloride simply by treatment with concentrated hydrochloric acid, to obtain the desired salification quantitatively. The process can also be used starting from an amino acid in the optically active form, to obtain the corresponding enantiomer of 2- (alkyl) amino-5,6-dihydroxy-l-tetralone. 4th step - This step consists in the reduction of 2-alkylamino-5,6-dihydroxy-1-tetralone, to give 2-alkyl-amino-5,6-dihydroxytetraline by catalytic hydrogenation. The reaction is carried out in an aqueous or hydroalcoholic medium, acid by means of hydrochloric acid, using Pd on carbon as the catalyst. The yields are almost quantitative. According to the process of the present invention, which includes the modification of the same described above, derivatives of 5,6-dihydroxy-2-aminotetralin substituted in the amino with an alkyl group are obtained directly, and the group in turn it can optionally be replaced. In a first embodiment, the process provides the use of the N-carboxy-anhydride, which has the double function of protecting the amino and activating the carboxyl, and from which 5,6-dimethoxy- or 5,6-dihydroxy is obtained. -2-methylamino-l-tetralone by subsequent cyclization, avoiding the step of deprotection of the amine. The second embodiment of the process of the present invention is even more advantageous, since it makes it possible to obtain 5,6-dihydroxy-2-alkylaminotetralin starting from 2-alkylamino-4- (2,3-dialkoxyphenyl) butyric acid in only two stages, of which one is the cyclization and simultaneous dealkylation of the catechol group, and the other is reduction. To our knowledge, this is the simplest and most direct method for obtaining 5,6-dihydroxy-2- (alkyl) aminotetranoline, and in particular 5,6-dihydroxy-2-methylaminotetra-line. According to a third embodiment of the invention, the compounds of formula (I) are prepared according to the following Scheme 3: That nema 3 In which Rj is methyl Such a process comprises: a) the condensation of 4- (2,3-dialkoxyphenyl) -2-keto-butenoic acid with a lower alkyl carbamate, to give 5- (2,3-dialkoxyphenyl) -3-a coxycarbonylamino- 2,5-dihydrofuran-2-one; b) the reduction of the condensation product to give 4- (2,3-dialkoxyphenyl) -2-alkoxycarbonylaminobutyric acid; c) intramolecular cyclization, to give 5,6-dialkoxy-2-alkoxycarbonylamino-1-tetral; d) the reduction of the keto group, to give 5,6-dialkoxy-2-alkoxycarbonylaminotetralin; e) the reduction of the carbamate, to give 5,6-dialkoxy-2-methylarainotetralin. The individual steps are described in detail in the following: the step - The step consists of the condensation of 4- (2,3-dialkoxyphenyl) -2-oxo-3-butenoic acid with a suitable alkyl carbamate, for example carbamate methyl, carried out in an anhydrous organic solvent, in the presence of a catalyst, for example p-toluenesulfonic acid, thus introducing the substituted amino group in a single step. The reaction takes place in almost quantitative yields. Stage 2 - The stage consists in the catalytic hydrogenation of 3-alkyloxycarbonylamino-5- (2,3-dialkoxyphenyl) -2,5-dihydrofuran-2-one, using as catalyst for example palladium on carbon in an alcoholic medium, thus obtaining 2-alkyloxycarbonylamino-4- (2,3-dialkoxyphenyl) butriric acid. The reaction takes place in quasi-quantitative yields. A further advantage can be derived from the fact that the reduction reaction of the dehydroamino acid 3-alkyloxycarbonylamino-5- (2,3-dialkoxyphenyl) -2,5-dihydrofuran-2-one can be carried out under enantioselectivity conditions, for obtaining 2-alkyloxycarbonylamino-4- (2,3-dial-coxyphenyl) butyric acid in an optically active form. For example, by asymmetric hydrogenation, particularly using suitable transition metal complexes with optically active ligands as catalyst, as described by RM Williams in Synthesis of Optically Active alpha-Amino Acids, pages 230-256, Pergamon Press, and cited references . 3rd stage - The step consists in the cyclization of 2-alkyloxycarbonylamino-4- (2,3-dialkoxyphenyl) butyric acid, to give 2-alkyloxycarbonylamino-5,6-dialkoxy-1-tetralone. The intramolecular acylation reaction is carried out with conventional procedures, for example using polyphosphoric acid without solvent, heating, still as an example, PC ,, - and tin tetrachloride, or other Friedel-Crafts catalysts in a suitable solvent , for example methylene chloride, at room temperature (this second procedure is preferred in case of cyclization of an optically active product, to obtain the corresponding enantiomer of tetralone). This stage also takes place in quasi-quantitative yields. 4th stage - The reduction is carried out with conventional methods, also on the optically active compound, for example by catalytic hydrogenation (see also the methods above). The yields are almost quantitative. 5th step - Consists in the reduction of the alkyl carbamate group, in particular of the methoxycarbonylamino group, to the methylamino group, using a suitable reducing agent, in particular lithium aluminum hydride in a suitable solvent (for example tetrahydrofuran), in stoichiometric amounts. cas This process produces good yields (60-70%), and can also be applied to the optically active compound, to obtain the corresponding enantiomer of 5,6-dial-coxy-2-alkylaminotetralin. 6th stage - Consists of the deprotection of the cate-col group with conventional (and enantiospecific) methods, for example with concentrated hydrobromic acid and heating, to obtain 5,6-dihydroxy-2-methylaminotetralin in quasi-quantitative yields.

The procedure is less manageable and longer than the preceding ones, but it gives very high total yields, and it can also be applied to obtain optically active compounds. A fourth procedure is carried out in four stages, starting with 4- (2,3-dimethoxyphenyl) -2-oxo-3-bute-noic acid, and is applicable to obtain 5,6-dihydroxy-2 -amino-tetralin. This fourth process was subdivided into two parallel routes (A and B), which are almost equivalent. According to route A, the compounds of formula (I). are prepared according to the following Scheme 4: Scheme 4 The steps are as follows: a) the condensation of 4- (2,3-dialkoxyphenyl) -2-oxo-3-butenoic acid with benzyl carbamate, to give the 3-benzyloxycarbonylamino-5- (2,3- dialkoxyphenyl) -2,5-dihydrofuran-2-one; b) the catalytic reduction and simultaneous deprotection of 3-benzyloxycarbonylamino-5- (2,3-dialkoxyphenyl) -2,5-dihydrofuran-2-one, to give the acid 2-amino-4- (2, 3 -di- alkoxyphenyl) butyric; c) simultaneous cyclization and deprotection with HBr, to give 5,6-dihydroxy-2-amino-1-tetralone; d) the reduction of 2-amino-5,6-dihydroxy-l-tetralone, to give 2-amino-5,6-dihydroxytetraline. The individual steps are described in detail in the following: the step - The step consists of the condensation of 4- (2,3-dimethoxyphenyl) -2-oxo-3-butenoic acid with benzyl carbamate. The reaction is carried out in an anhydrous organic solvent, in the presence of a catalyst, for example p-toluenesulfonic acid, thus introducing the protected amino group in a single step. The reaction takes place in quasi-quantitative yields. 2nd stage - The stage consists in the catalytic hydrogenation of 3-benzyloxycarbonylamino-5- (2,3-dimethoxyphenyl) -2,5-dihydrofucan-2-one, for example with palladium on carbon as a catalyst in an alcoholic medium, obtaining thus directly in a single step the 2-amino-4- (2,3-dime-toxiphenyl) butyric acid deprotected. The reaction takes place in quasi-quantitative yields. The reaction, as already discussed in the above process, can be carried out under enantioselectivity conditions, to obtain 2-amino-4- (2,3-dimethoxyphenyl) butyric acid in an optically active form. 3rd step - The step consists in the cyclization, by intramolecular acylation of the amino acid, with simultaneous deprotection of the hydroxyl of the catechol, to give the 5,6-dihydroxy-2-amino-1-tetralone. The reaction takes place, for example, using a suitable hydrohalic acid, for example 48% hydrobromic acid with heating. The yields are high (close to 80%). 4th stage - Consists in the reduction of 2-amino-5,6-dihydroxy-1-tetralone, to give 2-amino-5,6-dihydroxytetraline by catalytic hydrogenation, for example using palladium on carbon as a catalyst, in an alcoholic or hydroalcoholic medium. The yields are almost quantitative. Alternatively, according to route B, in the step, 4- (2,3-dimethoxyphenyl) -2-oxo-3-butenoic acid is condensed with an alkyl carbamate, for example methyl carbamate, under them terms. The 2nd stage consists of the catalytic hydrogenation of 3-alkyloxycarbonylamino-5- (2,3-dimethoxyphenyl) -2,5-dihydro-drofuran-2-one, under the conditions described for the 2nd stage of Process 3. The 3rd This step consists of cyclization by intramolecular acylation of the amino acid, with simultaneous deprotection of both the hydroxyl of the catechol and the amino group, to give the 5,6-dihydroxy-2-amino-1-tetrone. The 4th stage is carried out as described for Scheme 4 above. This process, although limited to the achievement of 2-amino-5,6-dihydrotetralin, is particularly interesting industrially because of the high yields, the simple operations and the low costs of the reagents. It should be evidenced that, as is known in the literature, the catechol group is particularly unstable, especially in basic medium, thus requiring the use of protective groups, or salification. This involves difficult problems to solve, for example when organic salts of the product are desired.

The following examples further illustrate the invention. EXAMPLE 1 2-Keto-4- (2,3-dimethoxyphenyl) -3-butenoic acid 300 ml of deionized water and 50 g of potassium hydroxide are placed in a 3-liter flask. The mixture is stirred until dissolved , then 150 ml of ethanol and 100 g of 2,3-dimethoxybenzaldehyde are added. After this, 60.0 g of pyruvic acid are added thereto (in about 30 minutes), and the mixture is stirred for about 15 minutes at a temperature of 35 to 40 ° C, then it rises to 6500 ml. of water, and it is brought to a markedly acidic pH with about 140 ml of concentrated HCl. The mixture is cooled with stirring for about 30 minutes, then filtered, washed with water, and dried under vacuum at 60 ° C, to obtain an orange solid. Yield: 115 g, 81% (moles), 115% (weight); TLC: methylene chloride / methanol / acetic acid 80/20/2; Rf = 0.5; P.F. : 136-138 ° C. EXAMPLE 2 2-Methylamino-4- (2,3-dimethoxyphenyl) -butyric acid hydrochloride 70.0 g of 2-keto-4- (2,3-dimethoxyphenyl) acid are placed in a hydrogenator. 3-butenoic acid (0.30 mol) dissolved in 700 ml of ethanol, then 43.0 g of a solution of "methylamine 8.03 M (0.34 mol) and glacial acetic acid under nitrogen atmosphere, at a pH of 8 to 9, maintaining the temperature below 25 ° C. Stirring is continued for about 15 minutes, then 14.0 g are added from Pd / C to 5% (near 50% humidity), under pressure of 2 hydrogen (2. * 812 kg / cm, 40 psi, room temperature) 6 hours. The reaction mixture is then adjusted to a markedly acid pH with concentrated HCl, filtered, and the solution evaporated to dryness. The resulting solid is taken and triturated with heating (50 ° C) with 300 ml of acetone, then allowed to cool while stirring, filtered and dried under vacuum at 40 ° C. Yield: 51 g, 60 % (moles), 73% (weight); TLC: methylene chloride / methanol / acetic acid 75/20/10; Rf = 0.5; Developer: ninhydrina. P.F. = 165-166 ° C. EXAMPLE 3 4- (2,3-Dimethoxyphenyl) -2- (N-methyl-N-benzyloxycarbonylamino) butyric acid. 250 ml 14.0 g of hydrochloride are placed in a 250 ml flask. 2-Methylamino-4- (2,3-dimethoxyphenyl) butyric acid (0.048 mol) and 24 ml of 4 N NaOH, the resulting solution is cooled to about 0 ° C, then 9.1 g of chloroformate are added thereto. benzyl (0.053 moles) and 13.5 ml of 4 N NaOH, at the same time but separately, to maintain the environment always slightly basic, cooling to a T l less than 20 ° C, and then maintaining an ambient temperature for about 2 hours. The reaction mixture is diluted with ethanolic HCl, washed with 100 ml of ethyl ether (2 x 50 ml), then acidified markedly with about 30 ml of 2N HCl, and extracted with 150 ml of ethyl acetate ( 3 x 50 mi). The organic phase is dried over sodium sulfate, filtered and evaporated to dryness (40 ° C), to obtain a thick, light yellow oil, which is used directly for the subsequent stage. Yield: 18.5 g, close to 100% (moles), about 132.% (weight); TLC: methylene chloride / methanol / 90/10; Rf = 0.88. The protection of the amino group was also obtained with ethyl chloroformate, with the same procedure and analogous results. EXAMPLE 4 4- [2- (2,3-Dimethoxyphenyl) -ethyl] -N-methyl-2,5-oxazolidinadione They are placed in a 250 ml round bottom flask 18.5 g of 4- (2, 3-) acid. dimethoxyphenyl) -2- (N-methyl-N-benzyloxycarbonylamino) butyric acid (0.048 mol) and 28.7 g of thio-0 nyl chloride, refluxing for 2 hours, and then stripping off thionyl chloride by vacuum distillation , until obtaining a thick oil. The oil is taken in 100 ml of hexane, stirred until solidification, then it is decanted and triturated with 100 ml more of hexane, filtered and dried under vacuum at 30 ° C, to obtain a fine crystalline powder. Yield: 12.5 g, 93% (moles), 68% (weight). EXAMPLE 5 5,6-Dimethoxy-2-methylamino-1-tetralone hydrochloride 12.5 g of anhydrous aluminum chloride (0.094 mol /) are placed in a 3 1 round bottom flask under a nitrogen atmosphere in 200 g of Methylene chloride, cooling to 0 ° C, then 12.5 g of 4- [2- (2,3-dimethoxyphenyl) -ethyl] -N-methyl-2,5- or azolidinedione dissolved in 200 mg are added in about 10 minutes. methylene chloride, keeping the T below 10 ° C. The mixture is stirred for 30 minutes at a T lower than 10 ° C, then for 1 hour at room temperature. The mixture is again cooled to 0 ° C, and 200 ml of water are added thereto, keeping the T below 20 ° C, then the mixture is stirred at room temperature for about 1 hour, and the organic phase it is separated and extracted with water (3 x 400 ml). The combined aqueous phases are slowly alkaline with 400 ml of a 20% KHCO-solution, and extracted with 3 x 400 ml of chloroform. The organic phase is then dried over sodium sulfate, filtered, markedly acidified with methanolic HCl (1 M) and evaporated to dryness to obtain a waxy compound, which is taken in 150 ml of acetone at 50 ° C. C, is stirred for one hour under heating and left to stand overnight, then filtered and dried under vacuum at room temperature. Yield: 8.2 g, 67% (moles); 1 TLC: methylene chloride / methanol, 90/10; Rf = 0.35; P.F. - 208-209 ° C. Example 6 5,6-Dimethoxy-2-methylaminotetralin Hydrochloride 5 14.0 g of 5,6-dimethoxy-2-methylaminole hydrochloride are placed in an autoclave (with 50% humidity). -tetralone 9 0.051 moles), 400 ml of absolute ethanol, 10 ml of 1 M methanolic HCl and 4.0 g of 5% Pd / C, then the mixture was hydrogenated (at P of about 7,231 kg / cm [7 atra], T = 80 ° C) with J.) Agitation for 24 hours. The mixture is filtered, the filter cake is completely washed with hot methanol, then the alcohol solution is evaporated to dryness. The resulting solid is taken up in 150 ml of acetone, then the precipitate is filtered and dried under vacuum at 60 ° C. Yield: 10.8 g, 82% (moles), 77% (weight); P.F. - 219-220 ° C. EXAMPLE 7 5,6-Dihydroxy-2-methylaminotetralin. Hcl Place in a 4-neck round bottom flask, with stirring, under a gentle stream of dry nitrogen, 41.4 g of dry A1C13 (310.4 moles), 230 ml of toluene and 20.0 g of 5,6-dimethoxy-2-methylaminotetralin HCl (77.6 moles). The temperature is brought to 80 ° C, to obtain a brown mixture that can be stirred, left at 80 ° C for 4 hours, then cooled to room temperature and poured into water ice (about 1000 mi in total). The aqueous phase is separated and evaporated under vacuum (T of about 80 ° C). The off-white solid is triturated at room temperature in 750 ml of absolute ethanol, then dried at 60 ° C. Yield: 16.1 g, 90% (mol), 80% (weight); P.F. 280 ° C. EXAMPLE 8 5,6-Dihydroxy-2-methylamino-1-tetralone Bromhydrate A mixture of 15.0 g of 2-methyl-amino-4- (2,3-dimethoxyphenyl) butyric acid hydrochloride (52 mmol) and 100.0 ml of 48% aqueous HBr (900 mmol) is refluxed, with stirring, for 3 hours, then cooled to 0 ° C, and the resulting precipitate is recovered by filtration, washed with acetone (50 ml) and dried under vacuum at 60 ° C. Yield: 13.5 g; TLC: CH2C12 / CH30H / CH3C00H 70/20/10 (FeCl3 / K3Fe (CN) 6); MP: 240-243 ° C. EXAMPLE 9 5,6-Dihydroxy-2-methylaminotetraline Hydrochloride A mixture of 10.0 g of 5,6-dihydroxy-2-methylamino-1-tetralone hydrobromide, 2.0 g of Pd / C at 5%, 90 ml of water and 10 ml of 37% HCl are hydrogenated in an autoclave (Haste-lloy) (20.66 kg / cm [20 atrm], 80 ° C) for 8-9 hours, then filtered and wash with hot water. The aqueous solution is concentrated under vacuum, and the resulting solid is triturated hot with 100 ml of 37% hydrochloric acid, then cooled to 0 ° C and filtered. The resulting solid is recrystallized from acetone, and dried under vacuum at 60 ° C. Yield: 7.4 g. EXAMPLE 10 3-Methoxycarbonylamino-5- (2,3-dimethoxyphenyl) -2,5-dihydrofu-ran-2-one 300 g of 2-keto-4- (2,3-dimethoxyphenyl) -3-butenoic acid, 2680 ml of toluene, 13.4 g of p-toluenesulfonic acid and 133.8 g of methyl carbamate are placed in a 6-neck round bottom flask, in an oil bath, the. The mixture is heated at 105 ° C for 4 hours with stirring, and the water present is azeotropically removed, the mixture is filtered and the solution is evaporated to dryness under vacuum, then the residue is crushed for about 2 hours with 1260 ml of Et. 0 is filtered, washed with petroleum ether (40-70 ° C), and dried under vacuum at 60 ° C. 313.00 g are obtained. ( Performance 94%). EXAMPLE 11 2-Methoxycarbonylamino-4- (2,3-dimethoxyphenyl) butyric acid 150 g of 3-methoxycarbonylamino-5- (2,3-dimethoxyphenyl) -2,5-dihydrofuran-2-one and 1190 ml of CH-0H they are placed in a 2000 ml flask of a Parr hydrogenator, then heated to full dissolution with agitation (T of about 64 ° C); 30 g of Pd / C are added to 5 Z, and 2 hydrogenation is started at 2.46 kg / cm (35 psi) until no more H "is absorbed (about 60 minutes). The disappearance of the starting compound is checked by TLC, then the mixture is filtered through Celite, and the filtrate is evaporated to dryness, the resulting oil is precipitated with agitation by adding ethyl ether and petroleum ether, stirring is continued for about 30 minutes, then the mixture is filtered and dried under vacuum at 60 ° C. 141.6 g (Yield 93%) are obtained. EXAMPLE 12 2-Methoxycarbonylamino-5,6-dimethoxy-1-tetralone In a 5000 ml reactor, 610 g of po-lifosphoric acid are placed, heating to 60 ° C, then 61 g of 2-methoxycarbonylamino-4 acid are added. -(2, 3-dimethoxyphenyl) butyric, with strong mechanical agitation. After about 20 minutes of stirring the mixture is diluted with water (2000 ml), then stirring is continued for 60 minutes at room temperature. The resulting mixture is filtered, and the solid is dissolved in 3000 ml of chloroform. The resulting solution is washed with water, at neutral pH of the washings. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The light brown solid residue is triturated for about 2 hours in 300 ml of ethyl ether and 50 ml of petroleum ether, then filtered and dried at 60 ° C under vacuum, to obtain a powdery yellow-brown solid. Yield 51.2 g, 89.5% (moles), 84.0% (pe-so); TLC: Methylene chloride 95 - Methanol 5; Rf - 0.95.

EXAMPLE 13 2-Methoxycarbonylamino-5,6-dimethoxy-1,2,4,4-tetrahydronaphthalene 50 g of 2-methoxycarbonylamino-5,6-dimethoxy-1 -tetralone in 500 ml of methanol are dissolved in a 1000 ml flask, with stirring, 20 g of 5% Pd / C are added, then everything is placed in an autoclave (Hastelloy) under an atmosphere of 2 hydrogen at 80 ° C and at a pressure of 1.76 kg / cm (25 atm) for about 6 hours with stirring, after which the mixture is allowed to cool to about 30 ° C in the autoclave. The mixture is filtered through Celite, and the filtrate is evaporated to dryness under vacuum.The resulting white solid is triturated in 400 ml of n-hexane at 60 ° C, then allowed to cool to about 30 ° C with stirring. , filtered and dried under vacuum at 60 ° C, to obtain an off-white solid Yield: 40.6 g, 85.5% (moles), 81.2% (weight); TLC: Methylene chloride 95 - Methanol 5; Rf = 0.76; PF = 108.7-111.4 ° C. EXAMPLE 14 5,6-Dimethoxy-2-methylamino-l, 2, 3, 4-tetrahydro-naphthalene hydrochloride 13.5 g of lithium aluminum hydride and 250 ral of anhydrous tetrahydrofuran are placed in a 1000 ml round bottom flask, stirring for 15 minutes, then 80 g of 2-methoxycarbonylamino-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene, dissolved in 350 ml of tetrahydrofuran, are added slowly. Anhydrous, to maintain the temperature at about 60 ° C. Stirring is continued for about 30 minutes, and the mixture is filtered.The filtrate is cooled to about 0 ° C, Grease water (1000 ml) with stirring, keeping the temperature at about 30 ° C. The reaction mixture is filtered and extracted with chloroform, the organic phase is dried over sodium sulfate, filtered and acidified with HCl. methanolic The solution is stirred for about 30 minutes, then evaporated to dryness. The resulting residue is triturated at 60 ° C in 350 ml of acetonitrile, cooled to about 4 ° C with stirring, then filtered and dried under vacuum at 50 ° C, to obtain a white solid. Yield 40.7 g, 52.4% (moles), 50.9% (weight). EXAMPLE 15 5,6-Dihydroxy-2-methylamino-1,2,3,4-tetrahydro-naphthalene hydrochloride A suspension of 2-methylamino-5,6-dihydroxytetraline hydrochloride (5 g) in water (45 ml) ) is added to a solution of potassium carbonate (2.5 g) in water (25 ml) saturated with sodium sulfate. The mixture is stirred for a few minutes, the solid formed is filtered, washed with some water and acetone, then dried under vacuum at room temperature, to obtain 3.8 g of a product. RMH of! H (DMS0-d O,): 1.40 ppra (ra, 1 H, H., a?), 1.95 (m, 1 H, H-), 2.40 (s, 3 H, N-Me), Jeq 2.3-3.0 (m, 5 H, H4, H2, Hl), 5.0- 6.0 (sa, 2 H, 0r-H), 6.45 (d, 1 H, H7), 6.56 (d, 1 H, H8) . IE / MS (70 ev): m / z and 193 (M +). EXAMPLE 16 a) (-) -2-Methoxycarbonylamino-4- (2,3-dimethoxyphenyl) butadiene acid A solution of 3-methoxycarbonylamino-5- (2,3-dimethoxy-phenyl) -2,5-dihydrofuran -2-one (500 mg, 1.7 mmol) in oxygen-free meta-nol (0.25 M) is placed in a hydrogenator.

Parr, the catalyst (SS) -EtDiPhos (COD) OTs (1.5 jLiraols) is added, and the mixture is stirred for 1.5 hours at room temperature under hydrogen pressure (2.11 kg / cm [30 psi]) The mixture is filtered, and the filtrate is evaporated under vacuum, to obtain about 500 mg of the product (% e.e. (NMR) = 95). The product is subsequently purified by crystallization. NMR analysis (300 MHz, CDCl-) "in the presence of R- (+) - alpha-raetoxy-alpha-trifluoromethylphenylacetic acid, the signals were analyzed at 3.842 ppm (enantiomer (-)) and at 3838 ppm (enantiomer (+ )). b) Acid (=) - 2-methoxycarbonylamino-4- (2,3-dimethoxyphenyl) butadiene A solution of 3-methoxycarbonylamino-5- (2,3-dimethoxy-phenyl) -2,5-dihydrofuran- 2-one (500 mg, 1.7 mmol) in oxygen-free methanol (0.25 M) is placed in a Parr hydrogenator, the catalyst (RR) -EtDiPhos (C0D) 0Ts (1.5 limole) is added, and the mixture is stirred by 1.5 hours at room temperature 2, under hydrogen pressure (2.11 kg / cm [30 psi]). The mixture is filtered, and the filtrate is evaporated under vacuum, to obtain about 500 mg of the product (% e.e. (NMR) = 92). The product is subsequently purified by crystallization. NMR analysis (300 MHz, CDCl.,), In the presence of R - (+) - alpha-methoxy-alpha-trifluoromethylphenylacetic acid, the signals were analyzed at 3,842 ppm (enantiomer (-)) and at 3,838 ppm (enantiomer ( +)). EXAMPLE 17 (+) - 2-Araino-4- (2,3-dimethoxyphenyl) butyric acid A solution of 3-benzyloxyonylamino-5- (2,3-dimethoxyphenyl) -2,5-dihydrofuran-2-one ( 500 mg, 1.35 mmole) in oxygen-free methanol (0.25 M) is placed in a Parr hydrogener, the catalyst (RR) -EtDiPhos (C0D) 0Ts (1.3 limole) is added, and the mixture is stirred for 3 hours at ambient temperature under hydrogen pressure (2.11 kg / cm 2 [30 psi]).

The mixture is filtered, and the filtrate is evaporated under vacuum, to obtain 320 mg of the product (% e.e. (NMR) = 75).

The product is subsequently purified by crystallization. NMR analysis: the signals were analyzed at 3.34 ppm (enantiomer (-) and at 3.22 ppm (enantiomer (+)).

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.

Having described the invention as above, property is claimed as contained in the following:

Claims (12)

1. CLAIMS 1. A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3-tetrahydronaphthalene derivatives of formula (I) wherein: R ,, R2 and R ~, which are the same or different, are hydrogen or a lower alkyl group, and the acid addition salts thereof, the process is characterized in that it comprises the following steps: a) condensation of 2, 3-dialkoxybenzaldehyde with pyruvic acid in an aqueous / alcoholic system, in the presence of an inorganic base, to obtain 2-keto-4- (2,3-dialkoxyphenyl) butenoic acid; b) transformation of the ketone which is in the 2-position to an amino or alkylamino group, with simultaneous reduction of the double bond, to give respectively 2-amino- or 2-alkylamino-4- (2,3-dialkoxyphenyl) butyric acid; c) transformation of 2-amino- or 2-alkylamino-4- (2, 3-dialkoxyphenyl) butyric acid into 4- [2- (2,3-dialkoxyphenyl) ethyl] -N-alkyl-2,5-oxazolidinedione; d) intramolecular cyclization of the N-carboxyanhydride, to give the 5,6-dialkoxy-2-amino- or 2-alkylamino-1-tetralone; e) reduction of the ketone to give 5,6-dialkoxy-2-amino- or 2-alkylamino-1,2,3,4-tetrahydronaphthalene salified, and, if desired, f) O-dealkylation to give the , 6-dihydroxy-2-amino- or 2-alkylamino-1, 2, 3, 4-tetrahydronaphthalene salified, and, if desired, g) transformation of the resulting salt into the free base, or in another acid addition salt .
2. 2. A process according to claim 1, characterized in that in step a) a water / ethanol system is used, and the inorganic base in potassium hydroxide.
3. 3. A process in accordance with the claims 1 or 2, characterized in that in step c) 4- (2, 3-dialkoxyphenyl) -2-alkylaminobutyric acid is first reacted with a chloroformate, to give the 2-N-alkyl-N-alkoxy-carbonylamino derivative corresponding to e, which is subsequently cyclized to the corresponding cyclic N-carboxyanhydride.
4. 4. A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivatives of formula (I) wherein: R., R "and R", which are the same or different, are hydrogen or a lower alkyl, the process is characterized in that it comprises the following steps: a) cyclization of 2-alkylamino-4- (2, 3-dialkoxyphenyl) -butyric, with simultaneous dealkylation on oxygen, to give directly in a single step, 2-alkylamino-5,6-dihydroxy-1-tetralone salified; b) reduction of the ketone to give salted 5,6-dihydroxy-2-alkyl-amino-1,2,3-tetrahydronaphthalene, and, if desired, c) transformation of the resulting salt into the free base, or another salt of acid addition.
5. 5. A process according to claim 4, characterized in that step a) is carried out with an aqueous concentrated hydrochloric acid.
6. 6. A process according to claims 4-5, characterized in that the 2-alkylamino-4- (2,3-di-alkoxyphenyl) butyric acid is optically active.
7. 7. A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3-tetrahydronaphthalene derivatives of formula (I) wherein: R ,, R2 and Ro, which are the same or different, are hydrogen, or a lower alkyl group, the process is characterized in that it comprises the following steps: a) condensation of 2-keto-4- (2, 3-dialkoxyphenyl) butenic with a lower alkyl carbamate, to give 5- (2,3-dialkoxyphenyl) -3-alkoxycarbonylamino-2,5-dihydro-furan-2-one; b) reduction of the condensation product, to give 4- (2,3-dialkoxyphenyl) -2-alkoxycarbonylaminobutyric acid; c) intramolecular cyclization, to give 5,6-dialkoxy-2-alkoxycarbonylamino-1 -tetralone; d) reduction of the keto group, to give 5,6-dialkoxy-2-alkoxycarbonylamino-l, 2,3,4-tetrahydronaphthalene; e) reduction of the carbamate, to give 5,6-dialkoxy-2-alkyl-amino-1,2,3,4-tetrahydronaphthalene, and, if desired, f) transformation of the resulting salt into the free base, or another salt of acid addition.
8. 8. A process according to claim 7, characterized in that step b) is carried out by symmetric hydrogenation, to give optically active 2-alkoxycarbonylamino-4- (2,3-dialkoxyphenyl) butyric acid.
9. 9. A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3-tetrahydronaphthalene, the process is characterized in that it comprises the following steps: a) condensation of 4- (2,3-dialkoxyphenyl) acid -2-oxo-3-butenoic with benzyl carbamate, to give 3-benzyloxycarbon'-bonylamino-5- (2,3-dialkoxyphenyl) -2,5-dihydrofuran-2-one; b) simultaneous reduction and deprotection of the nitrogen, to give 2-amino-4- (2,3-dialkoxyphenyl) butyric acid; c) cyclization and simultaneous deprotection of the hydroxyl of the catechol, to give 5,6-dihydroxy-2-amino-1-tetralone; d) reduction of the ketone, to give 5,6-dihydroxy-2-amino-1, 2,3,4-tetrahydronaphthalene.
10. 10. A process according to claim 9, characterized in that step c) is carried out with a hydrohalic acid.
11. 11. A process according to claim 9, characterized in that step b) is carried out by asymmetric hydroge-natalp, to give optically active 2-amino-4- (2,3-dialkoxyphenyl) butyric acid.
12. 12. A process according to claims 8, characterized in that R is methyl