MXPA99005931A - Process for the preparation of heteroaryl-phenylalanines - Google Patents

Abstract

Se describe un proceso para la preparación de heteroaril-fenilalaninas de la fórmula (II) en el que R es unátomo de hidrógeno, grupos alquilo C1-C4 lineales o ramificados o un grupo bencilo;R1 es un grupo heterocíclico aromático de 5ó6 miembros sustituidos opcionalmente con uno o dos heteroátomos seleccionados entre nitrógeno, oxígeno y azufre;que comprende una reacción de acoplamiento cruzado entre derivados de haluro de heteroaril-zinc de fenilalanina. Los compuestos de la fórmula (II) son intermediariosútiles en la preparación de compuestos dotados con actividad farmacológica.

Description

PROCESS FOR THE PREPARATION OF HETEROARIL-FENILALA INAS FIELD OF THE INVENTION The present invention relates to a process for the preparation of heteroaryl-phenylalanines and more particularly, relates to a cross-coupling process for the preparation of phenylalanine derivatives having the phenyl group substituted by a heteroaryl group. Heteroaryl-phenylalanines are known compounds, well described in the literature. For example, heteroaryl-phenylalanines endowed with pharmacological activity as anti-hypertensive agents have been described in British Patent No. 1554667 (Merck &Co., Inc.). In addition, heteroaryl-phenylalanines can be used as synthetic intermediates for the preparation of compounds endowed with pharmacological activity. In the International patent application No. WO 97/24342 in the name of the same applicant, heteroaryl-phenylalanines are used for the preparation of N-mercaptoacyl phenylalanine derivatives of the formula: Ra Rj-CHj-CH-CONH- (i) P1367 / 99MX wherein R is a hydrogen atom, a linear or branched Cx-C4 alkyl group or a benzyl group; R x is a 5-6 membered aromatic heterocyclic group, optionally substituted, having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur; R2 is a linear or branched C2-C4 alkyl group or an aryl or arylalkyl group having between 1 and 6 carbon atoms in the alkyl moiety in which the aryl group is phenyl or a 5- or 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with one or more substituents, the same or different, selected from halogen atoms, hydroxyl groups, alkoxy, alkyl, alkylthio, alkylsulfonyl or alkoxycarbonyl groups having between 1 and 6 atoms of carbon in the alkyl fraction, C1-C3 alkyl groups including one or more fluorine atoms, carboxy groups, nitro groups, amino or amidocarbonyl groups, acylamino groups, aminosulfonyl groups, mono- or di-alkylamino or mono- or di- -alkylaminocarbonyl having between 1 and 6 carbon atoms in the alkyl fraction; R3 is a mercapto group or a R4C0S group convertible into P1367 / 99MX the organism in a mercapto group in which R4 is a linear or branched C ^ C alkyl group or a phenyl group. These compounds are endowed with inhibitory activity of metallopeptidases and are useful in therapy for the treatment of cardiovascular diseases. Many processes for the preparation of heteroaryl-phenylalanines are described in the literature. Within this field, processes that include cross coupling reactions from heterocyclic compounds and phenylalanine derivatives are particularly interesting. For example, 4- (2-furanyl) -phenylalanine is prepared following a cross-coupling process comprising the reaction between the N- (tert-butoxycarbonyl) -tyrosine triflate methyl ester and 2-furanboronic acid in the presence of palladium ( O) tetrakis (triphenylphosphine) as described by WC Shieh in J. Org. Chem. 1992, 57, 379-381. However, as reported by the same author, for the preparation of a compound of this type with good performance, catalyst quantities equal to 30% by mole compared to 2-furanboronic acid, significantly higher than those required for the conversion of other arylboronic substrates, for example, phenylboronic. An alternate route from the previous process for the P13S7 / 99MX thienyl-phenylalanine preparation, which basically comprises a cross-coupling reaction between thienylboronic acids and bromo-phenylalaniha in the presence of palladium acetate and tri (o-tolyl) phosphine, has been described by M.J. Burk et al. in J. Am. Chem. Soc. 1994, 116, 10847-10848. The arylboronic derivatives used as synthetic intermediates in the above process are in turn prepared from the corresponding aryl magnesium or aryl lithium derivatives, by reaction with trialkylborates. However, to avoid the formation of di- or tri-arylboron derivatives as by-products, the preparation of the arylboronic acids, for example 2- and 3-furanboronic acids, requires particularly low reaction temperatures equal to -70 ° C (J. Org. Chem. 1984, 49, 5237-5243). According to an alternative synthetic process, heteroaryl-phenylalanines can be prepared by cross-coupling between halogenated heterocyclic derivatives and stanyl-phenylalanine derivatives (Bioconjugate Chem., 1993, 4, 574-580); however, the alkyltannanes used for the preparation of stanyl-phenylalanines are very toxic compounds. Therefore, the high toxicity and the prolonged and difficult preparation of some intermediaries make inadequate the processes of P13S7 / 99MX cross coupling for synthesis of heteroaryl-phenylalanine, described in the literature, for industrial application. We have now found a process for the preparation of heteroaryl-phenylalanines by the cross-coupling reaction using organo-zinc compounds, easily realizable and indicated in particular for an industrial application. Therefore, the object of the present invention is a process for the preparation of heteroaryl-phenylalanines of the formula wherein R is a hydrogen atom, linear or branched Cx-C4 alkyl groups or a benzyl group; Rj_ is a 5- or 6-membered aromatic heterocyclic group optionally substituted with one or two heteroatoms selected from nitrogen, oxygen and sulfur; which comprises the reaction between a compound of the formula P1367 / 99MX in which R1 has the meanings reported in the above and Y is a chlorine, bromine or iodine atom; and a compound of the formula R'- in which R has the meanings reported in the above; R1 is an optionally protected amino group; X is an iodine or bromine atom or a methanesulfonyloxy, fluoromethanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy group; in the presence of a catalyst based on a transition metal (O); and, when R 'is a protected amino group, the deprotection reaction of the amino group. The object of the process of the present invention is easily realizable and makes it possible to obtain the heteroaryl-phenylalanines of the formula II with high yields, equal to or greater than 80% with respect to the starting compound of the formula IV. The cross-coupling reaction, according to the object of the process of the present invention, is carried out by the reaction between an organo-P1367 / 99MX zinc compound of the formula III and a compound of the formula IV. Preferably, compound III and compound IV are used in a molar ratio III: IV between 1: 1 and 3: 1. Even more preferably, the molar ratio of compounds III: IV is between 1: 1 and 2: 1. In the object of the process of the present invention preferably the compounds of the formula IV are used in which X is an iodine atom. The cross-coupling reaction is carried out in the presence of a catalyst based on a transition metal (O). The amount of catalyst is preferably between 0.05% and 5% by mole with respect to the organo-zinc compound of formula III. Preferred examples of the transition metal (O) -based catalysts are palladium or nickel optionally supported, in the presence of ligands such as, for example, triphenylphosphine. The transition metal (O) -based catalysts can optionally be prepared in if you starting from the corresponding salts such as, for example, nickel chloride, cobalt chloride, nickel acetylacetonate, ferric chloride, palladium chloride, tetrachlorocuprate lithium, palladium acetate and palladium acetylacetonate. Exclusively for practical reasons, P13S7 / 99MX prefer palladium tetrakis (triphenylphosphine), nickel tetrakis (triphenylphosphine) or palladium carbon in the presence of triphenylphosphine, optionally prepared in itself as described, for example, in Org. Synth., 66, 67-74, 1988. The cross-coupling reaction is carried out in the presence of an organic solvent. Suitable organic solvents are, for example, C6-C12 aliphatic hydrocarbons, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dioxane, toluene, xylene or mixtures thereof. Preferably, tetrahydrofuran, toluene or mixtures thereof are used. Commonly the reaction temperature is between 20 ° C and the reflux temperature of the reaction mixture. Preferably, a temperature between 40 ° C and 60 ° C is used. From the practical point of view, for the preparation of the compounds of the formula II, the use of a compound of the formula IV in which R 'is a protected amino group is preferred. Examples of suitable protecting groups are acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, formyl, benzyl, ethoxycarbonyl and phthaloyl. Preferably, the protective group is ter- P1367 / 99MX butoxycarbonyl or formyl. The starting compounds of the formula IV in which R 'is a protected amino group are known compounds or are prepared easily according to the known methods from the corresponding derivatives of the formula IV in which R' is an amino group (H2N -) (Bioconjugate Chem. 1993, 4, 574-580). When R 'is a protected amino group, the compounds of formula II according to the present process are prepared by cross-coupling reaction and subsequent deprotection of the amino group. Deprotection is carried out according to standard procedures. As a general reference in the use of protective groups in organic chemistry see Theodora W. Greene and Peter G.M. Wuts "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., II Ed., 1991. Commonly, the cross coupling reaction is carried out by starting from a compound of the formula IV in which R is other than hydrogen, thereby obtaining the corresponding compounds of the formula II (R other than hydrogen). From these, working according to conventional procedures, the corresponding compounds of the formula II can be obtained in which R = H. The starting compounds of formula III P1367 / 99MX are known compounds or are prepared easily according to known methods. For example, the compounds of formula III can be prepared by reacting the corresponding heteroaryl lithium or heteroaryl magnesium derivatives with an anhydrous zinc halide, for example, zinc chloride, in the same manner as reported in Heterocycles, Vol. 31, No. 12, 1990, 2181-2186. Examples of compounds of the formula II, which can be prepared according to the object of the process of the present invention, are the compounds in which the Rx group is an aromatic heterocyclic group as for example, thiazole, isoxazole, oxazole, isothiazole, pyrazole, imidazole, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, pyridazine and furan. Specific examples of compounds of formula II are: ~~ 4- (2-thiazolyl) -phenylalanine; 4- (2-pyridyl) -phenylalanine; 4- (3-pyridyl) -phenylalanine; 4- (2-furyl) -phenylalanine; 4- (3-furyl) -phenylalanine; 4- (5-pyrimidinyl) -phenylalanine; 4- (2-pyrazinyl) -phenylalanine; 4- (2-thienyl) -phenylalanine; 4- (3-thienyl) -phenylalanine; and the corresponding methyl and ethyl esters.

P1367 / 99MX According to a particularly advantageous aspect of the object of the process of the present invention, the starting compounds of the formula III are prepared in itself from the corresponding heteroaryl lithium or heteroaryl magnesium derivatives and are therefore used directly in the cross coupling reaction. More particularly, the heteroaryl lithium or heteroaryl magnesium derivatives are reacted with an anhydrous zinc halide, in the presence of the same solvent used in the cross coupling reaction, to obtain the corresponding heteroaryl zinc derivatives of the formula III. Therefore, the thus-prepared compounds of formula III thereof are reacted with the compounds of formula IV, according to the object of the process of the present invention. The preparation of compounds of the formula III is carried out using an anhydrous zinc chloride: heteroaryl lithium or heteroaryl magnesium derivative ratio between 1: 1 and 3: 1. Preferably, the heteroaryl-zinc derivatives of the formula III are prepared with "anhydrous zinc chloride." The heteroaryl lithium or heteroaryl-magnesium derivatives are known compounds or are prepared easily according to known methods, such as P1367 / 99MX describes for example, in J. Am. Chem. Soc. 1952, 74, 6260-6262 or in the aforementioned Heterocycles, Vol. 31, No. 12, 1990, 2181-2186. In a preferred embodiment of the subject of the process of the present invention, the compounds of the formula II are prepared from the corresponding heteroaryl magnesium derivatives, by their anhydrous zinc halide reaction and subsequent cross-coupling reaction of the resulting compounds. Formula III, in the same medium, as previously described. The compounds of the formula II can be used as synthetic intermediates for the preparation of compounds endowed with pharmacological activity, such as, for example, the N-mercaptoacyl phenylalanine derivatives of the formula I, as set out in the aforementioned International patent application No. WO 97/24342. In a particularly preferred embodiment, the subject of the process of the present invention is used for the preparation of the compounds endowed with pharmacological action described in the aforementioned International patent application. In a preferred embodiment of the process object of the present invention, a suitable amount of heteroaryl magnesium halide is treated with anhydrous zinc halide in a molar ratio equal to 1: 2.

P1367 / 99 X respectively, at room temperature and in the presence of a suitable solvent. Therefore, the compound of the formula IV, suitably protected, is added to the reaction mixture containing the compound prepared in itself of the formula III. The cross-coupling reaction is carried out in the presence of catalytic amounts, for example equal to 1% by mole, of a palladium-based catalyst prepared in itself. The compounds of the formula II, in the protected form, are thus obtained, with high yields, by heating the reaction mixture. The subsequent deprotection reaction, which is carried out according to standard procedures, leads to the compounds of the formula II. The resulting compounds of the formula II can be used, for example, as synthetic intermediates in the preparation of pharmacologically active compounds. The object of the process of the present invention is easily realizable and makes it possible to obtain the heteroaryl-phenylalanines of the formula II in high yields and under moderate reaction conditions. In addition, from a compound of the formula IV as stereoisomer alone, the object of the process of the present invention allows to obtain the compounds of P13S7 / 99MX formula II with high optical purity, without any racemization. Finally, the use of particularly stable intermediates, which can easily be obtained and used in itself for the subsequent reactions without any additional purification step, makes the object of the process of the present invention particularly suitable for industrial application. With the intention of illustrating the present invention, the following examples are now given.

EXAMPLE 1 PREPARATION OF METHYL ESTER OF N- (TER-BUTOXICARBONYL) - 4- (2-TIAZOLYL) -L-PHENYLALANIN A solution of 2-thiazolyl magnesium bromide, prepared from 2-bromo thiazole (0.528) Kg; 3.22 moles) and magnesium chips (0.093 Kg, 3.82 moles) in a 1: 1 mixture of tetrahydrofuran: toluene (1.8 1), was slowly added during 2 hours to a suspension, prepared by the slow addition of anhydrous zinc chloride (0.853 Kg, 6.27 mole) to tetrahydrofuran (1.92 1), with stirring and in an inert atmosphere at a temperature of 30 ° C. The mixture was heated to 50 ° C and N- (tert-butoxycarbonyl) -4-iodo-L-phenylalanine methyl ester (1.0 Kg, 2.34 moles) was added gradually.

P1367 / 99MX To the resulting mixture was added a pre-prepared mixture of palladium acetate (8 g, 0.036 mol) and triphenylphosphine (19.2 g, 0.072 mol). The mixture maintained under stirring at a temperature of 50 ° C for 2 hours to complete the reaction (TLC hexane: ethyl acetate = 7: 3), then cooled to room temperature and emptied into an ice water bath (3 Kg) containing toluene (11). At that time glacial acetic acid (130 g) was added and the phases were separated. The aqueous phase was extracted with toluene (0.5 1) and the combined organic phases were washed twice with water (2.2 1) and evaporated to dryness under vacuum to yield the N- (tert-butoxycarbonyl) -4- (2-methyl ester). -thiazolyl) -L-phenylalanine (1.19 Kg) used as it is in the subsequent reaction. EXAMPLE 2 PREPARATION OF METHYL ESTER OF N- (TER-BUTOXICARBONYL) - 4- (2-TIAZOLYL) -D, L-PHENYLALANIN A solution of 2-thiazolyl magnesium bromide prepared by 2-bromo thiazole (1.8 g, 11 mmol) and magnesium shavings (320 mg, 13.1 mmol) in a 1: 1 mixture of tetrahydrofurane: toluene (6.6 ml) was gradually added over 0.5 hours to a suspension, prepared by gradually adding anhydrous zinc chloride (3 g; mmoles) to tetrahydrofuran (6.6 ml), kept under stirring and under an inert atmosphere at 30 ° C.

P1367 / 99MX The mixture was then heated to 50 ° C and N- (tert-butoxycarbonyl) -4-bromo-D, L-phenylalanine methyl ester (1.6 g, 4.5 mmol) was added. Palladium acetate (33.6 mg, 0.15 mmol) and triphenylphosphine (118 mg) were added to the resulting mixture.; 0.45 mmoles). The mixture, kept under stirring at 50 ° C for 15 hours, was then cooled to room temperature and emptied into an ice-water bath (10 ml) containing toluene (10 ml). Then glacial acetic acid (approximately 1 g) was added and the phases were separated. The organic phase was evaporated to dryness. The residue consisted of about 70% N- (tert-butoxycarbonyl) -4- (2-thiazolyl) -D, L-phenylalanine methyl ester and about 15% of the starting compound (eluent TLC hexane: ethyl acetate = 6: 4).

EXAMPLE 3 PREPARATION OF METHYL ESTER OF N-FORMIL-4- (2-TIAZOLYL) -L-PHENYLALANIN Working in a manner similar to that described in example 1 but starting from the methyl ester of N-formyl-4- iodine-L-phenylalanine was obtained the methyl ester of N-formyl-4- (2-thiazolyl) -L-phenylalanine (yield> 90%) as crude to be used as it is without any further purification.

P1367 / 99MX EXAMPLE 4 PREPARATION OF METHYL ESTER DICHLORHYDRATE 4- (2-TIAZOLYL) -L-PHENYLALANIN Thionyl chloride (0.48) was added dropwise Kg; 4.03 moles) for 1.5 hours to a solution of N- (tert-butoxycarbonyl) -4- (2-thiazolyl) -L-phenylalanine methyl ester (1,208 Kg, 2.06 moles), prepared as described in example 1, in methanol (1.6 1), kept under stirring, under an inert atmosphere at a temperature of 15 ° C. At the end of the addition, the suspension was allowed to cool to 25 ° C and was kept under stirring for 1 hour. After adding methyl ethyl ketone (3.4 1) to the resulting mixture and heating to reflux, the solvent mixture (1.9 1) was distilled. The resulting suspension was cooled to 20 ° C and the precipitate that formed was filtered and washed with methyl ethyl ketone (3x0.3 1) providing, after drying under vacuum, the methyl ester dihydrochloride of 4- (2-thiazolyl) - L-phenylalanine [820 g ~; 91.5% yield calculated on N- (tert-butoxycarbonyl) -4-iodo-L-phenylalanine methyl ester described in Example 1; HPLC title 87%].

P1367 / 99MX

Claims (11)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. A process for the preparation of heteroaryl-phenylalanines of the formula H2N-CH-COOR (ID wherein R is a hydrogen atom, a linear or branched Cx-C4 alkyl group or a benzyl group; R x is a 5- or 6-membered aromatic heterocyclic group optionally substituted with one or two heteroatoms selected from nitrogen, oxygen or sulfur; which comprises the reaction between a compound of the formula Rx-Zn-Y (lili in which Rx has the meanings reported in the above and Y is a chlorine, bromine or iodine atom; and a compound P1367 / 99MX of the formula in which R has the meanings reported in the above; R1 is an optionally protected amino group; X is an iodine or bromine atom or a methanesulfonyloxy, fluoromethanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy group; in the presence of a catalyst based on a transition metal (O); and when R "is a protected amino group, the deprotection reaction of the amino group 2. A process according to claim 1, wherein compounds III and IV are used in a molar ratio between 1: 1 and 3: 1. 3. A process according to claim 2, wherein the molar ratio is between 1: 1 and 2: 1. 4. A process according to claim 1, wherein the compound of the formula IV is used wherein X is a iodine atom 5. A process according to claim 1, wherein the amount of catalyst is between 0.05% and 5% in moles with respect to the organo-zinc compound of formula III. P1367 / 99 X 6. A process according to claim 1, wherein the catalyst is a palladium or nickel-based catalyst optionally supported, in the presence of ligands. A process according to claim 6, wherein the catalyst is selected from palladium tetrakis (triphenylphosphine), nickel tetrakis (triphenylphosphine) or palladium in carbon in the presence of triphenylphosphine. 8. A process according to claim 1, wherein a compound of the formula IV is used in which R 'is a tert-butoxycarbonylamino group or a formyl amino group. 9. A process according to claim 1, wherein the compounds of the formula III are prepared in themselves from the corresponding heteroaryl lithium or heteroaryl magnesium derivatives by reaction with anhydrous zinc halide. 10. A process according to claim 1, for the preparation of a compound of formula II wherein Rx is a heterocyclic group selected from thiazolyl and thienyl. 11. A process for the preparation of N-mercaptoacyl phenylalanine derivatives of the formula P13S7 / 99MX R2 I wherein R and Rx have the meanings reported in claim 1; R2 is a linear or branched C2-C4 alkyl group or an aryl or arylalkyl group having 1 to 6 carbon atoms in the alkyl moiety in which the aryl group is a phenyl or a 5- or 6-membered aromatic heterocyclic group with 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with one or more substituents, the same or different, selected from halogen atoms, hydroxy groups, alkoxy, alkyl, alkylthio, alkylsulfonyl or alkoxycarbonyl groups having between 1 and carbon in the alkyl fraction, Cx-C3 alkyl groups having one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulfonyl groups, mono- or dialkylaminocarbonyl groups having between 1 and 6 carbon atoms carbon in the alkyl fraction; R3 is a mercapto group or a R4COS group convertible into the organism in a mercapto group in which R4 is a linear or branched alkyl group Cx-C4 or a group P1-367 / 99MX phenyl; which comprises the reaction of a compound of the formula Rx-Zn-Y (III) with a compound of the formula R'- wherein R, R ', X and Y have the meanings reported in claim 1; in the presence of a catalyst based on transition metal (O); and, when R 'is a protected amino group, the deprotection reaction of the amino group to provide the compound of the formula where R and Rx have the meanings reported in the above. P1367 / 99MX