MXPA00003334A - Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates - Google Patents

Abstract

The invention concerns (R)-sulphonyloxyacetic ester derivatives of general formula (I) in which R1 represents a benzyl group, C1-C4 alkyl optionally substituted by one or several halogen atoms, or phenyl optionally substituted by one or several halogen atoms or by one or several linear or branched C1-C4 alkyl groups or by a nitro group. Said compounds are intermediates in the synthesis of clopidogrel.

Description

DERIVATIVES OF HYDROXYACETIC ESTER, PREPARATION, METHOD AND USE AS INTERMEDIARIES OF SYNTHESIS The present invention relates, in general, to new derivatives of hydroxyacetic esters, and their use as synthesis intermediates. More specifically, the object of the invention is the sulfonyloxyacetic esters with the general formula: wherein R ^ represents a benzyl group, a C1-C4 alkyl, which can be substituted by one or more halogen atoms, such as chlorine or bromine, or a phenyl group, which can be substituted by one or more carbon atoms. halogen or by one or more branched or linear C 1 -C 4 alkyl groups or by a nitro group. In particular, the invention relates to compounds of the formula I in which R ^ represents a methyl, ethyl, propyl, trifluoromethyl, benzyl, phenyl, chlorophenyl, tolyl, trimethylphenyl, triisopropylphenyl, dichlorophenyl group, in particular 2, 5-dichlorophenyl or nitrophenyl, in particular p-nitrophenyl. The compounds of Formula I have shown themselves to be particularly useful as intermediates, notably start the synthesis of (S) -2 (2-chlorophenyl) -2 (4,5,6,7-tetrahydrothieno [3,2-c] -5-pyridyl) methyl or clopidrogel. This enantiomer, which has the following structural formula: It is known for its therapeutic value, notably for its inhibition of aggregation of platelet and antithrombotic properties. In patent EP 0465358, a process is described for the preparation of the (R) and (S) acetate enantiomers of 2- (halogenophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] ] -5-pyridyl) of an alkyl of 0 ^ 04, using 2-arylacetic esters with a labile group in the 2-position. According to this process: a) racemic a 2- (halogenophenyl) -2-halogeno C-alkyl ? -C or a C 1 -C 4 alkylsulfonyloxy, or alkyl (aryisulfonyloxy) acetate C6-C? O is coupled with 4,5,6,7-tetrahydrothieno [3,2-c] pyridine in the form of a base or salt to obtain a racemic compound. b) the racemate thus formed is resolved by optically recrystallizing salts of active acid to obtain the desired (R) or (S) enantiomers.

However, the only example given of this process started from Racemic methyl 2 (2-chlorophenyl) -2-chloroacetate for the final preparation of clopidogrel and no precise indication or example was given for To polish the preparation of a 2- (halophenyl) -2- (bromine or alkylsulfonyloxy or arylsulfonyloxy) -acetic acid of C? -C4. According to this example, clopidogrel is obtained by carrying out the following 5 steps, starting from a 2-hydroxyacetic ester: a) and b) reaction of racemic 2 (2-chlorophenyl) -2-hydroacetic acid with phosphorus pentachloride and esterification with methanol to form racemic methyl 2- (2-chlorophenyl) -2-chloroacetate in 45% yield, c) coupling of methyl 2- (2-chlorophenyl) -2-chloroacetate formed in this manner, with 4,5,6,7-tetrahydrothieno [3,2-c] pyridine in the presence of potassium carbonate, which produces 2- (4,5,6,7-tetrahydrothieno [3,2-c] -5-pyridyl) ) -2- (2-chlorophenyl) - racemic methyl acetate, with an average yield of 80%, d) resolution of the racemate obtained by salification with camphorsulfonic acid (yield: 88% in terms of the desired salt) e) regeneration of clopidogrel in basic form treating the alconforsulfonic salt in question with sodium bicarbonate. Using this process, clopidogrel is obtained with a chemical yield of more than 30% 2 (2-chlorophenyl) -2-hydroxyacetic acid.

During the preliminary tests carried out in the context of the present invention, an attempt was made to prepare clopidogrel or its (R) -enantiomer by means of a reaction analogous to that described in the aforementioned patent, but starting from the enantiomers (R ) and (S) of methyl 2 (2-chlorophenyl) -2-chloroacetate. However, all tests performed on methanol, acetonitrile or ethyl acetate as a solvent at a temperature between room temperature and 65 ° C, with 1 or 2 equivalents of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine, either in the form of the base or in the hydrochloride form, with or without sodium bicarbonate, leads to the yield of 72 to 88% racemic methyl 2 (2-chlorophenyl) -2 (4,5,6,7-tetrahydrothieno [3,2-c] -5-pyridyl) acetate. Other tests carried out with heating at 80 ° C and using (S) -2 (2-chlorophenyl) -2-chloroacetate methyl and 4,5,6,7-tetrahydrothieno [3,2-c] pyridine in the presence of sodium carbonate and in a methylisobutyl ketone / water solvent, produced (R) -1 (4,5,6,7-tetrahydrothieno [3,2-c] -5-pyridyl) -2- (chlorophenyl) methyl acetate with an enantiomeric excess of only 20%. Consequently, the development of a process for the preparation of clopidogrel 4,5,6,7-tetrahydrothieno [3,2-c] pyridine using a stereo-selective method, which involves as few steps as possible, giving a performance appreciable of the desired compound, remains of incomparable importance. It has surprisingly been discovered, according to the invention, that clopidogrel can be obtained in only 3 steps of the (R) -2 (2-chlorophenyl) -2-hydroxyacetic acid with an overall yield of the order of 80% replacing methyl (R) -2 (2-chlorophenyl) -2-halogenoacetate, by (R) -2 ( 2-chlorophenyl) -acetate methyl, which has a sulfonyloxy group in the 2-position, ie, a compound with the above formula I. This process is the most surprising of all, because: A) it is known that the 2-methanesulfonyloxy groups and 2-toluenesulfonyloxy groups of carboxyl esters are subjected to racemization when they are involved in a nucleophilic substitution by an amine function (Angew, Chem. Int. Ed. Eng. 22 (1983), No. 1). pp. 65-66).

These claims have been confirmed in Tetrahedron, Vol. 47, no. 7, p. 1109-1135 (1991), where it is reported that the 2-methanesulfonyloxy and 2-p-toluenesulfonyloxy esters of carboxylic acids are suitable substrates for a stereoselective nucleophilic substitution reaction at position 2. Similar observations have been published in Leibigs. . Ann. Chem. 1986, p. 314-433, where it is reported that yields of < 30% during the substitution of 2-p-toluenesulfonyloxy methyl or 2-methanesulfonyloxy-methyl propionate with benzylamine. B) the (R) and (S) enantiomers of 2-sulfonyloxyacetic esters, which include an additional 2-phenyl group, are known to produce compounds with considerably reduced stereoselectivity after nucleophilic substitution in the 2-position.

For example, Tetrahedron, Vol. 44, no. 17, pgs. 5583-5595 (1988) reports the substitution of derivatives of (S) or (R) 2-trifliloxy-2-X-methyl acetate by O-benzylhydroxylamine in dichloromethane as a solvent and a temperature between 0 ° C and room temperature with in order to form the acetic esters of (R) and (S) of 2-O-benzylhydroxylamino-2-X, respectively. As is known, the triflyl group designates the trifluoromethylsulfonyl radical. This reaction is highly selective in the case of esters in which X represents an alkyl group, which can be substituted, such as methyl or benzyl (enantiomeric excess ee> 95%), but has much lower selectivity when X represents the group phenyl as the enantiomeric excess of the corresponding (R) -2-O-benzylhydroxylamino-2-phenyl ester is not greater than 50%. Very similar results have been reported after other experiments carried out using 2-sulfonyloxy derivatives of 2-phenylacetic esters. Therefore: a) Tetrahedron Letters, Vol. 31, no. 21, pgs. 2953 - 2956 (1990) describes the substitution reaction of esters of (S) -2-trifliloxy-2-X-methyl acetate with t-butyloxycarbonylhydrazine or BOC-hydrazine, in dichloromethane and at 0 ° C, to form esters (R) -2 -BOC-hydrazinyl-2-X-acetic acid. It has also been shown that the selectivity of this reaction is quite considerable when X represents an alkyl group, which can be substituted, such as methyl, isobutyl benzyl (ee> 95%), but in contrast, it is very limited when X represents phenyl (ee: 28%). b) Tetrahedron, Vol. 48, no. 15, pgs. 3007-3020 (1992) reports the substitution of (S) -2-nosyloxy-2-X-methyl acetate derivative with azido groups, the reaction taking place in dichloromethane and at room temperature, in order to form esters of (R ) -2-azido-2-X acetic. Once again, the substitution of the 2-sulphonyloxy group, in this case the nosyloxy group, takes place in a highly selective form when X represents an alkyl group, which can be substituted, such as methyl, isopropyl, sec-butyl or benzyl ( ee > 92%), but disappointed when X represents the phenyl group (ee: 35%). These recent discoveries currently lead the authors of the publication in question to conclude that the "phenyl group is well known for reducing stereoselectivity when the esters of 2-nosyloxy and 2-triflyloxy esters are replaced by different classes of nucleophilic agents". As is known, the nosyl group designates the p-nitrophenylsulfonyl radical. The sulfonyloxy derivatives of the acetic esters of the formula I which have shown themselves to be particularly interesting synthesis intermediates, notably for the preparation of clopidogrel are: (R) -2-benzenesulfonyloxy-2 (2-chlorophenyl) acetate methyl (R) -2 (2-chlorophenyl) -2 (p-toluenesulfonyloxy) methyl acetate (R) -2 (2-chlorophenyl) -2-methanesulfonyloxy methyl acetate (R) -2- (4-chlorobenzenesulfonyloxy) -2- (2-chlorophenyl) methyl acetate (R) -2- (2-chlorophenyl) -2- (2,4,6-trimethylbenzenesulfonyloxy) methyl acetate (R) -2- (2-chlorophenyl) -2- (2,4,6-triisopropylbenzenesulfonyloxy) methyl acetate ( R) -2- (2-chlorophenyl) -2- (4-nitrobenzenesulfonyloxy) methyl acetate (R) -2- (2-chlorophenyl) -2- (2,5-dichlorobenzenesulfonyloxy) methyl acetate In particular, the following are preferred: (R) -2-benzenesulfonyloxy-2- (2-chlorophenyl) methyl acetate (R ) -2 (2-chlorophenyl) -2- (2,4,6-trimethylbenzenesulfonyloxy) methyl acetate (R) -2- (2-chlorophenyl) -2- (2,4,6-triisopropylbenzenesulfonyloxy) methyl acetate (R) -2 (2-chlorophenyl) -2- (2,4,6-nitrobenzenesulfonyloxy) methyl acetate (R) -2- (4-chlorobenzenesulfonyloxy) -2 (2-chlorophenyl) methyl acetate (R) -2 (2-chlorophenyl) -2 (2,5-dichlorobenzenesulfonyloxy) methyl acetate The sulfonyloxy derivatives of the invention can be obtained by reacting the (R) -2 (2-chlorophenyl-2-hydroxy) acetic ester. with the formula: II with an anhydride or sulfonyl halide, with the general formula wherein R2 represents a group OSO2-R? or, preferably, a halogen atom such as chlorine or bromine, and R1 has the same importance as before, in the presence of a lithium salt and an aromatic amine which acts as a catalyst and as an acid acceptor such as pyridine or 4-dimethylaminopyridine, which produces the desired compound. The reaction in question is generally carried out in an aprotic solvent, such as a C 1 -C aliphatic hydrocarbon, preferably halogenated, for example dichloromethane, dichloroethane, chloroform, carbon tetrachloride or tetrachloroethane, and at a temperature between 0 ° C and room temperature. In addition, the aromatic mine, preferably C6-C2O, is used in stoichiometric amount or preferably a slight excess which can be 1.2 mol equivalent in terms of the compound of the formula III The coupling reaction of the compounds of the formula -11 and formula-III in which R2 represents a halogen atom, can give rise to a side reaction which results in the formation of a halogenated derivative, that is, an acetate derivative 2 (2-chlorophenyl) -2-methyl halogen. However, it was fortuitously noted that the presence of a lithium salt in the reaction mixture makes it possible to reduce this side reaction considerably and consequently obtain high proportions of the compound of Formula I.

By way of example, the reaction between methyl (R) -2 (2-chlorophenyl) -2-hydroxyacetate with p-nitrobenzenesulfonyl chloride or p-toluenesulfonyl chloride in dichloromethane at 20 ° C in the presence of pyridine and lithium perchlorate yields a yield of 92% (R) -2 (2-chlorophenyl) -2 (p-nitrobenzenesulfonyloxy) methyl acetate with a yield of 85% of (R) (2-chlorophenyl) -2 acetate (p. toluene sulfonyloxy), respectively, after 5 hours, whereby the same reaction, conducted in the absence of lithium perchlorate, gives yields of only 28% and 30% of the final product, respectively. The lithium salt, which may be, for example, lithium perchlorate (LiCIO4) or lithium tetrafluoroborate (LiBF4), is used in a stoichiometric amount. However, it is preferable to take a slight excess of this lithium salt, which is above 1.2 molar equivalent in terms of the compound of the formula-III. As for the ester of formula-ll, it can be obtained using a non-racemization reaction by esterifying (R) -2 (2-chlorophenyl) -2-hydroxyacetic acid or (R) -2-chloro-mandelico acid, which is commercial product, with methanol and in the presence of a strong acid, such as sulfuric acid. According to a variant of the above process, the sulfonyloxy derivatives of the formula I can also be prepared by reacting the ester of the formula -11 with a halogenide of the formula-III in the presence of 4-dimethylaminopyridine as a catalyst and another acid acceptor, such as an aliphatic amine, for example triethylamine to produce the desired compound. The reaction is generally conducted at a temperature of -10 ° C to + 10 ° C, preferably at 0 ° C, and in an aprotic solvent, such as one of those already mentioned, notably dichloromethane. The process described above makes it possible to obtain sulfonyloxy derivatives of the formula I in particular with good yields, usually of the order of 90 to 98% and with much notorious enantiomeric excess of > 99% As previously indicated, the sulfonyloxy derivatives of the invention can be used remarkably for the preparation of clopidogrel. Accordingly, another object of the invention relates to the preparation of clopidogrel by a process in which 4,5,6,7-tetrahydrothieno [3,2-c] pyridine in the form of a base or salt with a derivative of disulfonyloxy of the formula I in the presence of a basic agent used alone or in aqueous solution, produces the desired compound. The reaction medium used is usually a polar solvent, such as aliphatic C2-C5 ester, for example ethyl acetate or isopropyl, an aliphatic C1-C4 alcohol, N, N-dimethylformamide, a cyclic C4-Cβ ester or an aliphatic C 2 -C β ester such as tetrahydrofuran or isopropyl ether, an aliphatic C 2 -C 8 ketone, for example methyl isobutyl ketone or, preferably, a non-polar solvent, such as a halogenated aliphatic hydrocarbon of C 1 -C 4, for example dichloromethane, dichloroethane, chloroform, carbon tetrachloride or tetrachloroethane or a C 6 -C 0 aromatic hydrocarbon, for example benzene, toluene or a xylene in such a way that a two-phase system is formed if water is present in the reaction medium . In the latter case, if necessary, a phase transfer catalyst, such as a quaternary ammonium, a phosphonium salt or a co-terminating ether may be used. Similarly, the basic agent can be an alkali metal carbonate, such as sodium or potassium carbonate, or an alkali metal bicarbonate, for example sodium or potassium bicarbonate, and the reaction can be conducted at a temperature that is from room temperature to the reflux temperature of the medium used. As for the pyridine of 4,5,6,7-tetrahydrothieno [3,2-c], a known compound is used in the stoichiometric but usual amount and preferably in an excess which can be as much as 2.5 molar equivalent in terms of of the sulfonyloxy derivative of the formula-1. Conducting this last reaction in toluene, methyl isobutyl ketone or isopropyl acetate at a temperature of 80 ° C in about 4 hours, it is possible to obtain clopidogrel with a chemical yield in excess of 95% and with an enantiomeric excess of between 80 and 88%. Using dichloromethane as the solvent and at a temperature of 40 ° C: a) the percentage converted to clopidogrel can reach 94 to 95% in 5 hours with an enantiomeric excess of 96%. b) starting from (R) -2 (4-chlorobenzenesulfonyloxy) -2 (2-chlorophenyl) methyl acetate, the conversion to clopidogrel reaches 100% after 10 hours and the enantiomeric excess is 96%. c) starting from (R) -2 (2-chlorophenyl) -2- (4-nitrobenzenesulfonyloxy) methyl acetate, the conversion to clopidogrel reaches 100% after 30 minutes the enantiomeric excess is > 98%. Using an alternative route, clopidogrel can also be prepared from the sulfonyloxy derivatives of the invention and 2 (thien-2-yl) eti lamina. Accordingly, the invention also applies to the preparation of clopidogrel according to a process in which: a) 2 (thien-2-yl) ethylamine in the form of the base or salt is reacted with a sulfonyloxy derivative of the formula-l in the presence of basic agent used alone or in aqueous solution, to form (+) - (S) -a (thien-2-yl) - - (2-chlorophenyl) methyl acetate, which has the formula: IV b) the thienylethylamine derivative thus formed is reacted with a formylating agent and cyclized in the presence of an acid, which produces the desired compound. The formylating agent used in the above process may be: any formic aldehyde or any generally known compound for releasing it in a reactive form, such as for example its hydrate or its polymerization derivatives. These formylating agents can be considered preferred in the context of the invention; or compounds with the general formula: wherein R 3 represents a halogen atom, a C 1 -C alkyloxy group, a C 1 -C 4 alkylthio group or an amino group and R 4 represents a C 1 -C 4 alkoxy group, a C 1 -C 4 alkylthio group, a C2-C5 alkoxycarbonyl or phenoxycarbonyl group or heterocyclic compounds with the general formula: wherein Z represents O, NH, or S such as s-trioxane. The step involving the use of 2 (thien-2-yl) ethylamine, a known compound, can be conducted under the same operating conditions as previously described to use 4,5,6,7-tetrahydrothieno [3,2-a] ] pyridine The step of formylation and cyclization may give rise to intermediates, such as a hydroxymethyleneamine or a heterocycle of the trimethylenetriamine type, as reported in EP 466 569. Consequently, reactions with the formylating and cyclizing agent can be carried out successfully, possibly isolating the intermediary compounds in question, or conversely, can take place simultaneously. When the reactions occur successfully, the step involving the formylating agent can optionally be carried out in the presence of an ether, a hydrocarbon solvent, such as benzene, toluene, xylene or petroleum ether or a halogenated solvent, such as sodium chloride. methylene or dichloroethane.

The cyclization is then carried out in a polar solvent, such as water, an alcohol dimethylformamide or a mixture of these solvents. As the formylating agent, the formic aldehyde is generally preferred and this can be added to the reaction medium in the form of an aqueous solution. The acid can be an organic and inorganic acid, in general a strong acid, such as sulfuric acid, or a hydrazide, such as hydrochloric acid, or a sulfonic acid, such as methanesulfonic acid. When the reactions are carried out simultaneously, the reaction medium consists of a polar solvent, such as water or a alcohol, and the acid, which may be inorganic or organic, is added to the medium, preferably in a stoichiometric amount in terms of the compound employed of formula IV. In this case, this acid is a strong acid, which can be simply added to the medium in the form of its salt with the compound of the formula IV. An acid solvent, such as formic acid or acetic acid, can also be used, the former combined with paraformaldehyde which is particularly preferred. The clopidogrel is obtained according to the invention, which is using the different methods described above, subsequently it can be purified, if necessary, by a conventional method using a recrystallization process or by chromatographic methods. The following non-exhaustive examples illustrate the invention. PREPARATION (R) -2-hydroxy-2 (2-chlorophenyl) methyl acetate A 1000 ml reactor adapted with a double jacket and a valve in the lower part, a mechanical stirrer, a thermometer and a condenser, was charged with 120 g (0.643 mol) of (R) -2-hydroxy-2 (2-chlorophenyl) acetic acid, 480 ml of methanol and 4.8 g of 95% sulfuric acid. The solution obtained was then heated under reflux for 2 hours and the excess methanol was then removed under reduced pressure. The oily residue was then brought to 650 ml of dichloromethane and 240 g of a 10% aqueous potassium carbonate solution.

After decanting, the chlorinated phase was washed with 200 ml of water and then concentrated under reduced pressure. In this way, 124.4 g of methyl (R) -2-hydroxy-2 (2-chlorophenyl) acetate were obtained in the form of a colorless oil. Yield: 94% Optical purity by liquid chromatography of the chiral phase: > 99% NMR (CDC | 3): 7.4-7.2 ppm (4 aromatic multiplet protons) 5.57 ppm (singlet, 1 CH proton) 3.76 ppm (singlet, 3 protons of OCH3) 3.59 ppm (wide syllable, 1 OH proton) EXAMPLES 1 to 7 (R) -2-benzenesulfonyloxy-2 (2-chlorophenyl) methyl acetate (Example 1) In a three-port round bottom flask, of 100 ml, dry, coupled with a magnetic stirrer, a condenser and a thermometer and operating under a nitrogen atmosphere, 3.81 g (36 mmoles) of lithium perchlorate, 30 mmoles of benzenesulfonyl chloride and 45 ml of dichloroethane were taken. . To the obtained solution, 2.9 ml (36 mmoles) of pyridine were added. The non-uniform white reaction medium was then stirred 15 minutes before adding 6.0 g of methyl (R) -2-hydroxy-2 (2-chlorophenyl) acetate dissolved in 15 ml of dichloroethane. The obtained milky reaction mixture was stirred for 5 hours and then immersed in a stirred mixture of 120 ml of N-hydrochloric acid and 240 ml of dichloromethane. After decanting, the chlorinated phase was washed with 120 ml of water of a colorless viscous liquid. Purification on a silicon column produced an analytically pure sample. In this form, (R) -2-benzenesulfonyloxy-2 (2-chlorophenyl) methyl acetate was obtained. Yield: 90% Optical purity: > 99% [] 25589: -53 ° (2%, methanol) NMR (CDCI3) 7.88 ppm (doublets or triplets, 2- aromatic protons) 7.63 to 7.55 ppm (multiplet, 1 aromatic proton) 7.50 to 7.38 ppm (multiplet, 3 aromatic protons) 7.33 to 7.17 ppm (multiplet, 3 aromatic protons) 6.30 ppm (singlet, 1 proton of (CH)) 3.70 ppm (singlet, 1 proton of (OCH3)) Following the same process as previously described, the following compounds: (R) -2 (2-chlorophenyl) -2 (4-p-toluenesulfonyloxy) acetate (Example 2) Yield: 85% Optical purity: > 99% [a] 25589: -58.3 ° (2%, methanol) NMR (CDCl3) 7.75 to 7.25 ppm (multiplet, 8 aromatic protons) . 79 ppm (singlet, 1 proton of (CH-O)) 3.67 ppm (singlet, 3 protons of (OCH3)) 2.41 ppm (singlet, 3 protons of (CH3-phenyl)) (R) -2 (2-chlorophenyl) -2-methanesulfonyloxy methyl acetate (Example 3) Yield: 87% Optical purity: > 99% [a] 25589: -75.6 ° (2%, methanol) NMR (CDCI3) 7.49 to 7.28 ppm (multiplet, 4 aromatic protons) 6.40 ppm (singlet, 1 proton of (CH)) 3.79 ppm (singlet, 3 protons of (OCH3)) 3.14 ppm (singlet, 3 protons of (SO2CH3)) (R) -2 (4-chlorobenzenesulfonyloxy) -2 (2-chlorophenyl) methyl acetate (Example 4) Yield: 90% Optical purity: > 99% NMR (CDCI3) 7.8 and 7.43 ppm (2 doublets, 4 aromatic protons) 7.42 to 7.18 ppm (multiplet, 4 aromatic protons) 6.31 ppm (singlet, 1 proton of (CH)) 3.73 ppm (singlet, 3 protons of ( OCH 3)) (R) -2- (2-chlorophenyl) -2- (2,4,6-trimethylbenzenesulfonyloxy) methyl acetate (Example 5) Yield: 93% Optical purity: > 99% NMR (CDCI3) 7.50-7.20 ppm (multiplet, 4 aromatic protons) 6.92 ppm (singlet, 2 aromatic protons) 6.21 ppm (singlet, 1 proton of (CH)) 3.69 ppm (singlet, 3 protons of (OCH3)) 2.62 ppm (singlet, 6 protons of (CH3)) 2.30 ppm (singlet, 3 protons of (CH3)) (R) -2 (2-chlorophenol) -2 (2,4,6-tri-isopropylbenzenesulfonyloxy) Methyl Acetate (Example 6) Yield: 93% Optical Purity: > 99% NMR (CDCI3) 7.50 to 7.20 ppm (multiplet, 4 aromatic protons) 7.14 ppm (singlet, 2 aromatic protons) 6.25 ppm (singlet, 2 aromatic protons) 6.25 ppm (singlet, 1 proton (CH)) 4.09 ppm (septuplete , 2 protons (2CH-isopropyl)) 3.71 ppm (singlet, 3 protons (OCH3)) 2.85 ppm (septuplet, 1 proton (CH isopropyl)) 1.24 ppm (doublet, 6 protons (2 CH3)) 1.22 ppm (doublet, 6 protons (2 CH3)) 1.10 ppm (doublet, 6 protons (2 CH3)) (R) -2 (2-chlorophenyl) 2 (4-nitrobenzenesulfonyloxy) methyl acetate (Example 7) Yield: 92% Optical Purity: > 99% NMR (CDCI3) 8.29 and 8.06 ppm (2 doublets, 4 aromatic protons) 7.40 to 7.15 (multiplet, 4 aromatic protons) 6.37 ppm (singlet, 1 proton (CH)) 3.74 ppm (singlet, 3 protons (OCH3)) EXAMPLE 8 (R) -2-Benzenesulfoniumloxy-2 (2-chlorophenyl) methyl acetate In a dry three-port round bottom flask, fitted with a double jacket, a magnetic stirrer, a condenser and a thermometer and operating under a nitrogen atmosphere, 0.72 g (6 mmoles) of 4-dimethylaminopyridine, 12.0 g (60 mmoles) of methyl (R) -2-hydroxy-2 (2-chlorophenyl) acetate, 6.06 g (60 mmol) were taken. of triethylamine and then 20 ml of dichloromethane. The colorless solution obtained was cooled to 0 ° C and then, operating at this temperature, 60 mmoles of benzenesulfonyl chloride in solution in 30 ml of dichloromethane were added. The reaction mixture was stirred for 3 hours at 0 ° C and then poured into a stirred mixture consisting of 240 ml of 1N hydrochloric acid and 240 ml of dichloromethane. After decanting, the chlorinated phase was washed with 120 ml of water and then concentrated under reduced pressure.

The sulfonate thus formed takes the form of a colorless viscous liquid. An analytically pure sample was obtained after purification on a silica column. In this way, (R) -2-benzenesulfonyloxy-2 (2-chlorophenyl) methyl acetate was obtained; Yield: 97% Optical purity: > 99% [a] 25589 -53 ° (2%, methanol) Following the same procedure as described above, the following compounds were obtained: (R) -2 (2-chlorophenyl) -2- (4-nitrobenzenesulfonyloxy) methyl acetate (Example 9) Yield: 88% Optical Purity: > 99% (R) -2 (2-chlorophenyl) -2 (215-dichlorobenzenesulfonyloxy) methyl acetate (Example 10) Yield: 95% Optical purity: > 99% NMR (CDCI3) 7.98 ppm (doublet, 1 aromatic proton) 7.15 to 7.50 ppm (multiplets, 6 aromatic protons) 6.38 ppm (singlet, 1 proton (CH)) 3.74 ppm (singlet, 3 protons (OCH3)) EXAMPLE 11 (R) -2-Benzenesulfonyloxy-2 (2-chlorophenyl) methyl acetate This compound was obtained using the method described in Example 8, but replacing dichloromethane with toluene. Yield: 95% EXAMPLE 12 (R) -2-Benzenesulfonyloxy-2 (2-chlorophenyl) methyl acetate In a dry three-port round-bottomed flask, adapted as in Example 8, 0.72 g (6 mmol) was taken. 0.1 equivalent) of 4-dimethylaminopyridine, 12.0 g (50 mmol, 1 equivalent) of methyl (R) -2-hydroxy-2 (2-chlorophenyl) acetate and 7.8 g (78 mmol, 1.3 equivalents) of treethylamine and ml of dichloromethane. The colorless solution obtained was cooled to 0 ° C and then, operating at this temperature, 6.06 g (60 mmol, 1 equivalent) of benzenesulfinyl chloride in solution in 30 ml of dichloromethane. The reaction mixture was stirred for 3 hours at 0 ° C and then poured into a stirred mixture consisting of 240 ml of 1N hydrochloric acid and 240 ml of dichloromethane, while stirring this mixture. After decanting, the chlorinated phase was washed with dilute hydrochloric acid and then with water, before being concentrated under reduced pressure. An analytically pure sample was obtained after purification on a silica column. In this way, methyl (R) -2-benzenesulfonyloxy-2 (2-chlorophenyl) acetate was obtained: Yield: 98% Optical purity: 100% (S) (*) undetected enantiomer).

EXAMPLE 13 (S) -2 (2-Chlorophenyl) -2 (4.5.6.7-tetrahydrothieno r3,2-cl-5-pyridyl) methyl acetate In a dry-walled, three-port round bottom flask, 50 ml , adapted with a double jacket, a magnetic stirrer, a condenser and a thermometer, were taken Y mmoles of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine in solution in 7.5 ml of solvent and 2. 85 g of 30% aqueous solution of potassium carbonate. After stirring for 10 minutes, 5 mmoles of the compound of formula I, previously dissolved in 2.5 ml of solvent, were added. The two-phase medium thus obtained was heated under reflux for the indicated time and then cooled to 70 ° C and decanted. In this way, (S) -2 (2-chlorophenyl) -2 (4,5,6,7-tetrahydrothieno [3,2-c] -5-pyridyl) methyl acetate or clopidogrel was obtained. NMR (CDCI3) 7.70 ppm (multiplet, 1 aromatic benzene proton) 7.41 ppm (multiplet, 1 benzene aromatic proton) 7.33 to 7.22 ppm (multiplet, 2 aromatic benzene protons) 7.06 ppm (doublet, 1 thiophene aromatic proton) 6.67 ppm (doublet, 1 aromatic proton of thiophene) 4.93 ppm (singlet, 1 proton of CHCO) 3.73 ppm (singlet, 3 protons of OCH3) 3.76 and 3.64 ppm (2 doublets, 2 protons of CH3) 2.89 ppm (singlet, 4 protons of 2CH2) Depending on the compounds of formula I used, the concentrations of 4,5,6,7-tetrahydrothieno [3,2c] pyridine used, the yields obtained using the above solvents and the reaction times are as follows: Compound Y Solvent Time of Clopidogrel of the Formula (mmoles) Reaction I R1 Performance Purity (%) Optical (%) Phenyl 5 (1.7 g; 1 toluene 4.5 85 90 equivalent) Phenyl 6 (1.2 Dichloromethane 94.5 96.2 equivalents) Phenyl 12.5 (2.5 Dichloromethane 98.5 89 equivalents) Dichloromethane 10 Around 96 chlorophenyl of 100 Dichloromethane 0.5 Around > 98 nitrophenyl of 100 EXAMPLE 14 (S) -2 (2-Chlorophenyl) -2 (4,5,6,7-tetrahydroxy-3,5-c-5-pyridyl) methyl acetate In a 50 ml three-port round-bottom flask, adapted with a double jacket, a magnetic stirrer, a condensate and a thermometer, 1.2 mmoles of 4,5,6,7-tetrahydrothieno [3,2-c] was taken. ] pyridine in solution in 7.5 ml of dichloromethane and 2.85 g of a 30% aqueous solution of potassium carbonate. After stirring for 10 minutes, 5 mmoles of methyl (R) -2- (2-chlorophenyl) -2- (2,5-dichlorobenzenesulfonyloxy) acetate, previously dissolved in 2.5 ml of solvent, was added. The two-phase medium thus obtained was heated under reflux for 3.5 hours, cooled to 70 ° C and then decanted. In this way, (S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] -5-pyridyl) -ethyl acetate was obtained. Yield: 89% Optical purity: 96% EXAMPLE 15 (S) -2 (2-chlorophenyl) -2 (4.5.6,7-tetrahydrothieno r3.2-cl-5-pyridyl) methyl hemisulfate or clopidoqrel hemisulfate a) (+) - (S) -a- (2-thien-2-yl) ethylamino) - - (2-chlorophenyl) methyl acetate In a 250 ml reactor, adapted with a double jacket, a motor-driven stirrer, a capacitor and a thermometer were taken 7.62 g of 2 (thien-2-yl) ethylamine (0.06 moles); 1.2 molar equivalents in terms of the sulfonyloxy derivative) in solution in 67.5 ml of dichloromethane and an aqueous solution of 7.0 g of potassium bicarbonate (0.07 moles; 1.4 equivalents in terms of the derivative of sulfonyloxy) in 30 ml of water. After stirring for 5 minutes, 0.05 mol (1 equivalent) of the compound of formula I, dissolved in 40 ml of dichloromethane, was added. The two-phase medium thus obtained was heated under reflux for the indicated time, cooled and then decanted and the (+) (S) -a- (2-thien-2-yl) ethylamino-a- (2) was recovered. chlorophenyl) methyl acetate (formula IV). Depending on the compounds of the formula I used and with the previous reaction times, the following yields were obtained: b) Clopidogrel Hemisulfate During stirring, 20.5 g of methyl (+) (S) - a- (2-thien-2-yl) ethylamino- a- (2-chlorophenyl) acetate in solution in 200 ml of Methylene was added over 25 minutes to 40 ml of 30% (w / w) of an aqueous solution of formic aldehyde.

After stirring for 3 hours, the organic phase was decanted, washed with water, dried and the solvent was evaporated. The residue was dissolved in 50 ml of methylene chloride and the solution, at a temperature of 60 ° C, was added to 100 ml of anhydrous N, N-dimethylformamide containing 6N hydrochloric acid. After an hour and a half, the solvents were removed by distillation under reduced pressure and the residue was dissolved in 200 ml of methylene chloride and 100 ml of water. Sodium bicarbonate was added to release the base of its hydrochloride, the organic phase was decanted, dried and concentrated under reduced pressure, which gives clopidogrel as the free base. The hemisulfate of this basic compound was formed in 150 ml of acetone by reacting with 4.9 g of concentrated sulfuric acid (96%). In this way, 17 g of clopidogrel hemisulfate were obtained. [a] 20D = 53 ° (C = 1, methanol).

Claims (31)

1. CLAIMS 1. Derivatives of esters (R) -sulfoniloxiacéticos with the general formula: wherein R 1 represents a benzyl group, a C 1 -C 4 alkyl, which can be substituted by one or more halogen atoms or a phenyl group, which can be substituted by one or more halogen atoms or by one or more alkyl groups of C? -C4 linear or branched or by a nitro group.
2. 2. Derivatives of esters (R) -sulfonyloxyacetic acids, according to claim 1, in which R ^ represents a methyl, ethyl, propyl, trifluoromethyl, benzyl, phenyl, chlorophenyl, tolyl, trimethylphenyl, tri-isopropylphenyl or nitrophenyl group. 3. (R) -2-Benzenesulfonyloxy-2 (2-chlorophenyl) methyl acetate 4. (R) -2 (2-chlorophenyl) -2 (2,4,6-trimethylbenzenesulfonyloxy) methyl acetate 5. (R ) -2- (4-chlorobenzenesulfonyloxy) -2- (2-chlorophenyl) methyl acetate 6. (R) -2 (2-chlorophenyl) -2- (4-nitrobenzenesulfonyloxy) methyl acetate 7. (R) -2 (2 -chlorophenyl) -2 (2,4,6-triisopropylbenzenesulfonyloxy) methyl acetate 8. (R) -2 (2-chlorophenyl) -2 (2,5-dichlorobenzenesulfonyloxy) methyl acetate 9. Process for the preparation of (R) -sulfonyloxyacetic esters according to one of claims 1 to 8, characterized by the fact that the (R) -2- (2-chlorophenyl) -2-hydroxy acetic ester used for the reaction has the formula: with an anhydride or sulfonyl halide with the general formula: R? -SO2- R2 III in which R2 represents a group OSO2-R1, or preferably, a halogen atom and Ri has the same importance as in claim 1, the reaction taking place in the presence of a lithium salt and an aromatic amine to form the desired compound. 10. Process according to claim 9, characterized in that the lithium salt used is lithium perchlorate or lithium tetrafluoroborate. 11. Process according to claim 9 or 10, characterized in that the lithium salt is used in an amount of 1 or 1.2 molar equivalents per molar equivalent of the compound of the formula III. 12. Process according to claims 9 to 11, characterized in that the aromatic amine used is pyridine or 4-dimethylaminopyridine. Process according to claim 12, characterized in that the aromatic amine is used in an amount of 1 to 1.2 molar equivalents per molar equivalent of the compound of the formula III. Process according to claims 9 to 13, characterized in that the reaction takes place at a temperature between 0 ° C and room temperature. 15. Process for the preparation of (R) -sulfonyloxyacetic esters according to one of claims 1 to 8, characterized in that the ester (R) -2- (2-chlorophenyl) -2-hydroxyacetic used for the reaction has the formula: II with an anhydride or sulfonyl halide, with the general formula III in which R2 represents a group OSO2-R1 or a halogen atom and Ri has the same importance as in claim 1, the reaction taking place in the presence of 4-dimethylaminopyridine and another acid acceptor, to give the desired compound. 16. Process according to claim 15, characterized in that the acid acceptor is an amine. 17. Process according to claim 15 or 16, characterized in that the reaction takes place at a temperature between -10 ° C and + 10 ° C. 18. Process according to one of claims 9 to 217, characterized in that the reaction takes place in an aprotic solvent. 19. Process according to claim 18, characterized in that the aprotic solvent is a halogenated hydrocarbon. 20. Process for the preparation of clopidogrel, which has the formula. characterized in that 4,5,6,7-tetrahydrothieno [3,2-cj-5-pyridine, in the form of the base or a salt, is reacted with a (R) sulfonyloxy-acetic ester derivative according to one of claims 1 to 8, which may be in the presence of a basic agent used alone in an aqueous solution, which produces the desired compound. 21. Process according to claim 20, characterized in that the basic agent is an alkali metal carbonate or an alkali metal bicarbonate. 22. Process according to claim 20 or 21, characterized in that the reaction takes place at a temperature which would be from room temperature to the reflux temperature. 23. Process according to one of claims 20 to 22, characterized in that the reaction occurs in a polar or non-polar solvent. 24. Process according to claim 23, characterized in that the solvent is an aliphatic ester of C2-C5, an aliphatic alcohol of C1-C4, N, N-dimethylformamide, a cyclic ester of C1-C4, a aliphatic ketone of C2-Ca, a halogenated aliphatic hydrocarbon of C? -C, or a C6 aromatic hydrocarbon 25. Process for the preparation of clopidogrel, which has the formula: characterized by the fact that: a) the 2- (thien-2-yl) ethylamine, in the form of the salt or a salt, is reacted with an ester derivative (R) -sulphonyloxy-acetic acid according to one of claims 1 to 8, in the presence of basic agent, used alone or in aqueous solution, to form methyl (+) - (S) -a (2 (thien-2-yl) ethylamino) - a- (2-chlorophenyl) acetate, having the formula: b) the thienoletyl amine derivative thus formed, is reacted with a formylating agent and the cyclization is carried out in the presence of an acid, which produces the desired compound. 26. Process according to claim 25, characterized in that the formylating agent is chosen from formic aldehyde, its hydrate or its polymerization derivatives, compounds with the general formula: R3-C H2-R in which R3 represents a halogen atom, a C1-C4 alkoxy group, a C1-C4 alkylthio group, a C2-C5 alkoxycarbonyl group or phenoxycarbonyl or heterocyclic compounds with the general formula: wherein Z represents O, NH, or S. 27. Process according to claim 26, characterized in that the formylating agent is chosen from formic aldehyde, its hydrate or its polymerization derivatives. Process according to one of claims 25 to 27, characterized in that the acid is an inorganic or organic acid. 29. Process according to claim 25, characterized in that the reaction with the (R) -sulfonyloxyacetic ester takes place in a polar or non-polar solvent. 30. Process according to claim 25, characterized in that the reaction with the formylating agent and the cyclization takes place simultaneously in a polar solvent. Process according to claim 30, characterized in that the acid is formic acid, which is also used as the solvent.