MXPA96004880A - Procedure for the diasteros synthesiselectives of nucleus analogs - Google Patents

Abstract

The present invention relates to a stereoselective process for producing compounds of the formula 8I): wherein W is S, S = O, SO2 or O; X is s, S = O, SO2 or O; R1 is hydrogen or acyl; and R2 is a purine or pyrimidine base or an analogue or derivative thereof, the method comprising the step of reacting the depurine or pyrimidine base or analog thereof with an intermediate of the formula (IVa) or ( IVb) wherein R3 is a substituted carbonyl or carbonyl derivative, and G represents halo, cyano or R9SO2- where R9 represents alkyl optionally substituted by one or more halo, or optionally substituted phenyl, characterized in that the reaction with the base of purine or pyrimidine or analogue thereof, is carried out without the addition of a Lew acid catalyst

Description

PROCEDURE FOR THE DIASTEROSELECTIVE SYNTHESIS OF NUCLEOSIUM ANALOGS FIELD OF THE INVENTION The present invention relates to a diastereoselective process for the preparation of optically active cis-nucleoside analogues and derivatives.

BACKGROUND OF THE INVENTION Nucleosides and their analogs and derivatives are an important class of therapeutic agents. For example, a number of nucleoside analogs have shown antiviral activity against retroviruses such as human immunodeficiency virus (HIV), hepatitis B virus (BHV) and human T lymphotropic virus (HTLV) (PCT publication WO 89). / 05662 and European Patent Publication 0349242 A2). In particular, 4-amino-l- (2R-hydroxymethyl- [1, 3] oxa iolan-5S-yl) -lH-pyrimidin-2-one, which can be represented by the following formula: REF: 23258 MR (also known as 3TC or lamivudine) and its pharmaceutically acceptable derivatives, described in the international application PCT / GB91 / 00706, publication no. W091 / 17159, have been reported to have antiviral activity, in particular against retroviruses such as human immunodeficiency viruses (HIV.'s), AIDS-causing agents (W091 / 17159) and hepatitis B virus ( HBV) (European patent application publication No. 0474119). Most nucleosides and nucleoside analogs and derivatives contain at least two chiral centers (shown as * in formula (A)), and exist in the form of two pairs of optical isomers (i.e., two in the configuration) cis and two in the trans configuration). However, in general, only the cis isomers exhibit useful biological activity. Therefore, a general stereoselective synthesis of the cis nucleoside analogues is an important objective.

HOCH. purine or piriraidine base However, different enantiomeric forms of the same cis-nucleoside analog, may have very different antiviral activities. M M Mansuri et al, "Preparation of The Geometric Isomers of DDC, DDA, D4C and D4T As Potential Anti-HIV Agents", Bioorg. Med. Chem. Lett., 1 (1), pp. 65-68 (1991). Therefore, a general and economically attractive stereoselective synthesis of the enantiomers of the biologically active cis-nucleoside analogs is an important objective. The international patent application, publication No. W092 / 20669 describes a diastereoselective process for producing optically active cis-nucleoside analogs and derivatives of the formula (I). where W is S, S = 0, S02, or 0; X is S, S = 0, S02 or 0; R, is hydrogen or acyl; and R is a desired purine or pyrimidine base or an analog or derivative thereof; the process comprises the step of reacting the desired purine or pyrimidine base, or the like of the same, with an intermediary of the formula (bundle) or (Ilb) wherein R is a substituted carbonyl or carbonyl derivative; and L is a leaving group; using a Lewis acid of the formula (III) in don e Re, Rfi and R7 are independently selected from the group consisting of hydrogen; alkyl of 1 to 20 carbon atoms optionally substituted by fluoro, bromo, chloro, iodo, alkoxy of 1 to 6 carbon atoms or aryl-oxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms optionally substituted by halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; aryl of 6 to 20 carbon atoms optionally substituted by fluoro, bromo, chloro, iodo, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; trialkylsilyl; fluoro; b.jmo; chlorine and iodine; and R_ is selected from the group consisting of fluoro; bromine; chlorine; iodo; sulfonate esters of 1 to 20 carbon atoms, optionally substituted by fluoro, bromo, chloro or iodo; alkyl esters of 1 to 20 carbon atoms optionally substituted by fluoro, bromo, chloro or iodo, polyvalent halides; silyl trisubstituted silyl groups of the general formula (R,) (RA) (R-?) Si (wherein R, -, R, and R-, are as defined above); 6 to 20 carbon atoms saturated or unsaturated selenenilaril; arylsulfenyl of 6 to 20 carbon atoms substituted or unsubstituted; 6 to 20 carbon atoms substituted or unsubstituted alkoxyalkyl; and trial-qylsiloxy. The method of W092 / 20669 allows the stereocontrolled synthesis of a racemic cis-nucleoside analogue from an equimolar mixture of (lia) and (Ilb), and of a given enantiomer of a desired cis-nucleoside analogue at high optical purity, if the initial material is (Ha) or (Hb) optically pure. However, the process of W092 / 20669 depends on the use of a Lewis acid of the formula (III).

There are a number of disadvantages associated with the use of such Lewis acids. In particular, they are hy reactive and unstable compounds and therefore there are dangers associated with their use. In addition, they are expensive and have significant toxic effects. These disadvantages are of particular importance in relation to the large-scale production of nucleoside analogs in industrial processes.

DESCRIPTION OF THE INVENTION It has now been found that, by appropriate selection of the leaving group L in the intermediates (Ha) and (Ilt), the reaction with the purine or pyrimidine base, or analogue thereof, can be carried out successfully without the addition of a Lewis acid catalyst, and in particular, without the addition of a Lewis acid of the formula (III). Accordingly, the present invention provides a stereoselective process for producing cis-nucleoside analogues and derivatives of the formula ( I) where is S, S-0, S02 or 0; X is S, S = 0, S02 Ü 0; R. is hydrogen or acyl; and R "is a purine or pyrimidine base or an analogue thereof; the method comprises the step of glycosylating the purine or pyrimidine base or analogue or derivative thereof, with an intermediate of the formula (IVa) or (IVb) wherein R ~ is a substituted carbonyl or carbonyl derivative; and G represents halo, cyano or R 9SO, - wherein R 9 represents alkyl optionally substituted by one or more halo, or optionally substituted phenyl; characterized in that the glycosylation reaction is carried out without the addition of a Lewis acid catalyst. In a preferred embodiment, the present invention provides a stereoselective process for producing cis-nucleoside analogs and derivatives of the formula (I) as previously described, the method comprises the step of glycosylating the base of u or of pyrimidine or analogue derived therefrom with an intermediate of the formula (IVa) or (IVb) as previously defined, characterized in that the glycosylation reaction is carried out without the addition of a Lewis acid of the formula (III): if -R, (iii) * r wherein R ,, Rfi and R_ are independently selected from the group consisting of hydrogen; alkyl of 1 to 20 carbon atoms optionally substituted by fluorine, bromine, chlorine, iodine, alkoxy of 1 to 6 carbon atoms or aryloxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms optionally substituted by halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; aryl of 6 to 20 carbon atoms optionally substituted by fluoro, bromo, chloro, iodo, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; trialkylsilyl; fluoro; bromine; chlorine and iodine; and R-, is selected from the group consisting of fluoro, bromine; chlorine; iodo; sulfonate esters of 1 to 20 carbon atoms, optionally substituted by fluoro, bromo, chloro or iodo; alkyl esters of 1 to 20 carbon atoms optionally substituted by fluoro, bromo, chloro or iodo, polyvalent halides; silyl-trituted silyl groups of the general formula (R ^) (R,) (R7) Si (wherein R-, R, and R-, are as defined above); selenenilar ilo of 6 to 20 carbon atoms saturated or unsaturated; arylsulfenyl of 6 to 20 carbon atoms substituted or unsubstituted; 6 to 20 carbon atoms substituted or unsubstituted alkoxyalkyl; and trialkylsiloxy. It will be appreciated that, if the glycosylation step is carried out using an equimolar mixture of intermediates (IVa) and (IVb), a racemic mixture of cis-nucleoside analogs will be obtained. However, it is preferred that the glycosylation be carried out using an optically pure compound of the formula (IVa) or (IVb), to thereby produce the desired cis-nucleoside analogue in hoptical purity. A "nucledsido" is defined as any compound consisting of a purine or pyrimidine base linked to a pentose sugar. As used herein, a "nucleoside analog or derivative" is a compound that contains a 1,3-oxatiolane, 1,3-dioxolane or 1,3-dithiolane bonded to a purine or pyrimidine base or an analogue thereof, which can be modified in any of the following, or combinations of the following , mane-ras: base modifications, such as the addition of a substituent (for example 5-fluorocytosine) or the replacement of a group with an isosteric group (for example 7-deazaadenine); sugar modifications, such as the substitution of hydroxyl groups; r any substituent or alteration of the sugar binding site in the base (for example the pyrimidine bases usually attached to the sugar in the Nl position, for example, can be bound at the N-3 or C-6 site and the purines usually joined at site N-9, for example, can be joined at N-7). A purine or pyrimidine base means a purine or pyrimidine base found in naturally occurring nucleosides. An analogue of it, is a base that resembles such bases that occur naturally, in that their structure (the kinds of atoms and their arrangement) is similar to the bases that occur naturally, but can either be In addition, or lack of some of the functional properties of the bases that occur naturally. Such. analogs, include those derived through the replacement of a portion of CH with a hydrogen atom, (for example, 5-azapyrimidines such as 5-azacytosine) or vice versa (for example deacepurines, such as 7-deazaadenine or 7-deazaguanine) or both (for example 7- desaza, 8-azapurinas). By derivatives of such bases or analogs, those bases are meant to be understood wherein the substituents on the ring are either incorporated, removed, modified by conventional substitutes, known in the art, eg, halogen, hydroxyl, amino , alkyl of 1 to 6 carbon atoms *. Such purine or pyrimidine bases, analogs and derivatives are well known to those skilled in the art. As used herein, halo means bromine, chlorine, fluorine or iodine. As used herein, unless stated otherwise, alkyl means saturated, straight, branched or cyclic hydrocarbon groups, or mixtures thereof. Optionally substituted phenyl means unsubstituted phenyl or phenyl substituted by one or more alkyl groups of 1 to 6 carbon atoms, nitro, amino, halo or cyano. Preferably, R2 is a pyrimidine base. More preferably R2 is cytosine or 5-fluoro- cytosine Rg is a carbonyl bonded to hydrogen, hydroxyl, cyhalidyl, trialkylsilyl, alkyl of 1 to 30 carbon atoms, aralkyl of 7 to 30 carbon atoms, alkoxy of 1 to 30 carbon atoms, alkyl amine of 1 to 30 carbon atoms (secondary or tertiary), alkylthio of 1 to 30 carbon atoms; aryl of 6 to 20 carbon atoms; alkenyl of 2 to 20 carbon atoms; alkynyl of 2 to 20 carbon atoms; or R is 1,2-dicarbonyl, such as Oo CH, -c-c- optionally substituted radical with alkyl of 1 to 6 carbon atoms or aryl of 6 to 20 carbon atoms; or R is an anhydride, such as < O O CH3-C-0-C- optionally substituted with alkyl of 1 to 6 carbon atoms or aryl of 6 to 20 carbon atoms; 3 or R is a azomethine bonded in nitrogen to the hydrogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 10 carbon atoms or dialkylamino of 1 to 20 carbon atoms and carbon to hydrogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; or R is a thiocarbonyl (C = S) substituted with hydroxyl, alkoxy of 1 to 20 carbon atoms or thiol of 1 to 20 carbon atoms. Preferably, R represents a group -C (= 0) 0R, where R represents an optionally substituted alkyl group. Preferably, R represents a chiral auxiliary. The term "chiral auxiliary" describes an asymmetric molecule that is used to effect the chemical resolution of a racemic mixture. Such chiral auxiliaries may possess a chiral center such as alpha-methylbenzylamine or several chiral centers such as menthol. The purpose of the chiral auxiliary, once incorporated into the initial material, is to allow simple separation of the resulting diastereomeric mixture. See, for example, J Jacques et al., Enantiomers, Racemates and Resolutions, pp. 251-369, John Wiley & amp;; Sons, New York (1981). Preferably, the chiral auxiliary R, will be selected from (d) -mentlyl, (I) -mentyl, (d) -8-phenylmethyl, (I) -8-phenylmethyl, (+) - norephedrine and (-) - norephedrine. More preferably, R is (I) -mentyl or (d) -mently, more preferably (I) -methyl. Preferably W -.-s. 0. Preferably X is S. Preferably G represents halo such as Cl, Br or I, most preferably Cl. The intermediates of formulas (IVa) and (IVb) are they can isolate or can be generated conveniently in situ. Suitably, the intermediates of the formulas (IVa) and (IVb) are generated from the corresponding trans alcohols of the formulas (Va) and (Vb): wherein R-, W and X are as previously defined, or of the epimeric cis alcohols of the formulas (Vc) and (Vd): by reaction with a reagent, suitable for introducing group G. Suitable reagents for introducing group G will be readily apparent to those skilled in the art and include halogenating agents such as, for example, oxalyl bromide. The preferred halogenating agents are the Vilsmeier type reagents, which can be conveniently generated in situ, by the reaction of a N, N-disulfide amide, such as dimethylformamide (DMF), and a halogenating agent such as an oxalyl halide, for example oxalyl chloride, thionyl halide, for example thionyl chloride, a phosphorus halide, for example phosphorus trichloride or phosphorus oxychloride, an alkyl or phenylsulfonyl halide or anhydride. The halogenation reaction is carried out suitably under conventional conditions. The intermediate of the formula (IVa) or (IVb) is reacted with a base of purine or pyrimidine silylated, conveniently in a suitable organic solvent such as a hydrocarbon, for example toluene, a halogenated hydrocarbon such as dichloromethane, a nitrile, such as acetonitrile, an amide such as dimethylformamide, an ester such as ethyl acetate, an ether such as tetrahydrofuran, or a ketone such acetone, or a mixture thereof, preferably at elevated temperature, such as the reflux temperature of the selected solvent. The silylated purine and pyrimidine bases can be prepared as described in W092 / 20669, the teaching of which is incorporated herein by reference, for example by reacting the purine or pyrimidine base with a silylating agent. such as t-butyldimethylsilyl triflate, 1,1,1,3,3,3-hexamethyldisilazane, t-rimethylsilyl triflate or t-rimethylsilyl chloride, with acid or base catalyst, as appropriate. Appropriate methods are described in detail in the appended examples. The cis-nucleoside analogue obtained from the reaction of the compound of the formula (I) with the purine or pyrimidine base or analogue thereof can then be reduced to give a specific stereoisomer of the formula (1). Suitable reducing agents will be readily apparent to those skilled in the art and include, for example, hydride reducing agents such as aluminum lithium hydride, lithium borohi-drud or sodium borohydride. Stereointegrity has been found to be maintained using sodium borohydride in the presence of a phosphate or borate buffer, eg, dipotassium acid phosphate, as the reducing agent. According to the process of the invention, as well as the process described in W092 / 20669, the final compound is typically taken as a solution in a polar solvent, such as an aqueous solvent. This presents a practical problem in that the compounds of the formula (I) have high solubility in polar media, making it difficult to efficiently isolate such media. It has now been found that the compounds of the formula (I) can be efficiently isolated from the solution in polar solvents, by the formation of a salt having poor aqueous solubility. If desired, the water-insoluble salt can subsequently be converted to the free base, or to a different salt thereof., by conventional methods. It has further been found that the salicylate salt is particularly suitable for this purpose. The present invention thus provides a process as previously described, further comprising the step of isolating the compound of the formula (I) as a water-insoluble salt, especially a salicylate salt. The salicylate salts of the compounds of the formula (I) are within the scope of the pharmaceutically acceptable derivatives, described and claimed in the European patent application publication No. 0382526 and publication No. W091 / 17159, but not specifically described therein. Therefore, such salts are novel and form a further aspect of the present invention. In a further or alternative aspect, the present invention provides salicylate salts of the compounds of the formula (I), or hydrates thereof. In particular, the formation of the salicylate salt of 4-amino-1- (2R-hydroxymethyl- [1,3] oxathiolan-5S-yl) -lH-pyrimidin-2-one (lamivudine) has been found. , 3TC MR) gives considerable advantages for the isolation of this compound with polar solvents. Therefore, in a preferred embodiment, the invention provides the salicylate of 4-amino-1- (2R-hydroxymethyl) - [1,3] oxathiolan-5S-yl) -lH-pyrimidin-2-one, or hydrates of the same. The lamivudine salicylate salt is a pharmaceutically acceptable salt and as such, and its hydrates, can be used as antiviral agents as described in W091 / 17159, which is incorporated herein by reference. Salicylate salt of lamivudine or its Hydrates can be formulated as a pharmaceutical composition as described in W091 / 17159. The salicylate salts of the compounds of the formula (I) can be prepared by treating a solution containing a compound of the formula (I) with salicylic acid. Suitable solvents include, for example, water and polar organic solvents such as ethers, for example tetrahydrofuran or dioxane and alcohols, for example methanol and ethanol, or mixtures of solvents, in particular mixtures containing an organic solvent and water. The salicylate salts are conveniently converted, if desired, to the corresponding free bases by treatment with a base, suitably a tertiary amine such as, for example, triethylamine. Other suitable water-insoluble salts and methods for their preparation and conversion to free bases will be readily appreciated by those skilled in the art. The intermediate alcohols (Va) and (Vb) and the epimeric cis alcohols (Vc) and (Vd) can be prepared by the methods described in W092 / 20669, for example, by reduction of the corresponding carbonyl compounds or by condensation of an aldehyde of the formula R ^ -CHO, or a derivative thereof, with hydroxyacetaldehyde or mercaptoacetaldehyde, or suitable derivatives thereof. Further details of the preparation of such alcohols can be found in the appended examples. The compounds of formulas (Va) and (Vb) are key intermediates for the preparation of enantiomerically pure analogues or cis-nucleoside derivatives, according to the process of the invention. The absolute stereochemistry of the groups R-, W and X in (Va) or (Vb) is maintained in the analogue or cis-nucleoside derivative of the resulting formula (I). The reactions for the preparation of alcohols of the formulas (Va) and (Vb) and their cis (Vc) and (Vd) epimers typically result in the formation of mixtures of isomers. When compounds of the formulas (Va) or (Vb) are isolated by the crystallization of mixtures containing their enantiomers and / or their cis-stereoisomers, the yield can be limited by the proportion of the desired isomer (Va) or (Vb), present in the solution. It has now been found that the crystallization of the trans (Va) and (Vb) isomers is favored over the crystallization of the corresponding cis isomers (Vc) and (Vd). Where R «is an achiral portion, a 1: 1 mixture of the trans isomers (Va) and (Vb) can be crystallized from mixtures of the cis and trans isomers (Va), (Vb), (Vc) and (Vd). Accordingly, the present invention provides, in a further or alternative aspect, a method for increasing the yield of the trans (Va) and (Vb) isomers of a mixture of the trans and cis isomers, the method comprising the treatment of the mixture of trans and cis isomers, at least partially in solution, with an agent capable of effecting the interconversion of the isomers, without complete suppression of the crystallization of the trans isomers. It has further been discovered that, where R is a chiral moiety, a single trans enantiomer of the formula (Va) or (Vb) can be selectively crystallized from a mixture of stereoisomers.

Thus, for example, the compounds of the formula (Va) wherein R ~ represents -C (SI0) R ,, where R, is I-menthyl, can be selectively crystallized from a mixture of stereoisomers, in particular a mixture containing alcohols (Va), (Vb) and cis epimeric alcohols (Vc) and (Vd). Similarly, compounds of the formula (Vb) wherein R3 represents -C (»0) R4, where / is d-menthyl, can be selectively crystallized of a mixture of stereoisomers, in particular a mixture containing alcohols (Va), (Vb) and cis epimeric alcohols (Vc) and (Vd). Therefore, in a preferred aspect, the present invention provides a method for increasing the yield of a single enantiomer of the formula (Va) or (Vb) of a mixture of isomers, the method comprising the treatment of the mixture of isomers, at least partially in solution, with an agent capaof effecting the interconversion of the isomers without complete deletion of the crystallization of the desired individual enantiomer (Va) and (Vb). Agents capaof effecting the interconversion of the isomers without the complete suppression of the crystallization of the trans isomers include, for example, alcohols, such as, for example, methanol, ethanol, n-propanol, i-propanol, n -butanol, i-butanol, t-butanol and organic bases, in particular tertiary amines, per. example pyridine and triethylamine and Hunig's base. A preferred agent is triethylamine. The interconversion of the isomers can be carried out in any suitasolvent or solvent mixtures which do not react in any other way with the alcohols of the formulas (Va) or (Vb) or their cis isomers under conditions of concentration and temperature which allow the crystallization of the desired isomer or isomers and that do not cause significant degradation of the desired isomer or isomers. Suitasolvents may include, for example, aliphatic or aromatic hydrocarbons, ethers, esters and chlorinated hydrocarbons. The interconversion, preferably, will be carried out at a temperature of about -20 ° to 120 ° C, more preferably in the range of about -10 ° to 80 ° C, such as about 0 ° to 50 ° C. It will be appreciated by those skilled in the art, that the selection of the solvent, the temperature, the interconversion agent and, particularly, the amount of the interconversion agent, is conducted better as an integrated exercise, dependent on the nature of the the groups R », X and W present in the isomers. However, when an organic base is used as the interconversion agent, the preferred amount, in general, is less than two mole equivalents based on the total of all isomers of (Va) and (Vb) present. Additional guidance for the preferred reaction conditions can be obtained from the attached examples. The interconversion of the isomers can be conducted separately from the preparation of the isomeric mixture; however, it is conveniently conducted at the same time with that preparation. The interconversion process can also be used to increase the isomeric purity of (Va) or (Vb) isolated. By means of the interconversion process, the desired yield of the desired isomer (Va) or (Vb) can be increased to more than 50% of the theoretical (based on the formation of all stereoisomers), typically to between about 60% and about 90% of the theoretical; but it is not ruled out that one can obtain yields that approach 100% of the theoretical value. A particularly preferred embodiment of the process of the present invention, using I-menthol as a chiral auxiliary, is represented in Scheme 1 and described in detail in the appended examples, which are to be considered as illustrative of the invention and not as limiting thereof.

Esq uema 1 The invention is further illustrated by the following non-limiting examples. All temperatures are in degrees centigrade. DMSO means dimethyl sulfide.

Example 1 4-Amino-l- (2R-hydroxymethyl- [1,3] oxathiolan-5S-yl) -lH-pyrimidin-2-one (a) (2R, 5R) -5-hydroxy- [1,3] oxathiolan-2-carboxylic acid 2S-isopropyl-5R-methyl-1R-cyclohexyl ester A mixture of 1-menthyl glyoxylate hydrate (25 g) and acetic acid (2.5 mL) in toluene (125 mL) was stirred and refluxed. The water was removed by azeotropic distillation via a Dean-Stark trap. The resulting solution of 1-menthyl glyoxylate was concentrated by distillation under reduced pressure, collecting about 70 mL of distillate, and then cooled to 20-25 ° C. The volume was adjusted to 75 mL by adding approximately 15 mL of toluene, dithianediol (8.25 g) was added, and the mixture was heated to reflux for about 1 hour. The mixture was cooled to about 80 °, and clarified. The filtrate was cooled to 0-5 °, and a solution of triethylamine (1.5 mL) in hexane (150 mL) was added for about 1.25 hours at 0-5 ° C. The resulting suspension was stirred at 0-5 ° C for about 6 hours, then the product was isolated by filtration. The product is washed with a mixture of toluene and hexane (1: 3, 2 x 50 mL) and dried in vacuo at 40-45 ° constant weight. (b) 2S-isopropyl-5R-methyl-1R-iclohexyl ester of (2R, 5R) -5- (4-Amino-2-oxo-2H-pyrimidin-1-yl) - [1,3] - oxatiolan-2-carboxylic acid A solution of (2R, 5S) -5-chloro- [1, 3] - * 2S-isopropyl-5R-methyl-1R-cyclohexyl ester was prepared. oxathiolan-2-carboxylic acid as follows: A solution of (2R, 5R) -5-hydroxy- [1,3] oxathiolan-2-carboxylic acid 2S-isopropyl-5R-methyl-1R-cyclohexyl ester (300 g) was treated. ) - in dichloromethane (3000 mL) containing methanesulfonic acid (0.7 mL), * - with dimethylformamide (85 mL), cooled to about 8 ° and thionyl chloride (80 mL) added for about 10 minutes. The resulting solution was stirred at 10-15 ° for about 1.5 hours, then concentrated by distillation under pressure 2 atmospheric (for approximately 1.5 hours), collecting approximately 2.1 L of distillate. The solution was cooled to 20-25 °. A silylcytosine solution was prepared as follows: A suspension of cytosine was heated (115.5 g), methanesulfonic acid (0.7 mL) and hexamethyldisilazane (242 mL) in toluene (290 mL) under reflux until a clear solution was obtained (approximately 1.5 hours). The silylcytosine solution was treated with triethylamine (145 mL), the solution of 2S-isopropyl-5R-methyl-1R-cyclohexylic acid ester (2R, 5S) -5-chloro- [1,3] oxathiolane was added. 2-carboxylic maintaining a mild or moderate reflux, washed with dichloromethane (300 mL). The resulting mixture was heated to reflux for 4 hours and added to a mixture of triethylamine (73 mL) and water (1200 mL) was maintained at 30-35 °, for about 1.5 hours. The resulting suspension was stirred for about 45 minutes, then hexane (1200 mL) was added for about 10 minutes at 30-35 ° C. The suspension was stirred at room temperature overnight, then filtered. The solid was washed with water (2 x 600 mL) and isopropyl acetate (2 x 600 mL), and was dried in vacuo at 40-45 ° constant weight. H NMR (D6 ~ DMS0) R 0.75 (3H, d); 0.89 (d), 0.9 (m), 0.91 (d), 1.0-1.2 (m) (9H); (9H, m); 1.43 1.50 (2H, m); 1.67 (2H, m); 1.9-2.0 (2H, m); 3.14 (1H, dd); 3.55 (1H, dd); 4.69 (1H, dt); 5.70 (1H, s); 5.80 (1H, d), 6.36 (1H, dd), 7.28 (s broad), 7.33 (broad s) (2H); 7.97 (1H, d). (c) 4-Amino-l- (2R-hydroxymethyl- [1, 3] -oxatiolan-5S-yl) -lH-pyrimidin-2-one monosalicylate A solution of dipotassium acid phosphate (137 g) in water (150 mL) was stirred at about 20 °, and 2S-isopropyl-5R-methyl-1R-cyclohexyl acid ester (2R, 5R) -5 was added. - (4-amino-2-oxo-2H-pyrimidin-1-yl) - [1, 3] oxathiolan-2-carboxylic acid (100 g). IMS (750 mL) was added and the suspension was stirred for 10 minutes. A solution of sodium borohydride (20 g) in water (200 mL) containing sodium hydroxide solution was added., 25% w / w (25 mL) for 70 minutes, maintaining the temperature in the range of 15-30 °. The addition funnel was rinsed with water (50 mL), and the mixture was stirred at 15-30 ° until the reaction was fully estimated by CLAP (150 minutes). The mixture was allowed to settle and the lower aqueous layer was discarded. The pH of the remaining organic phase is adjusted to 4-4.5 with concentrated hydrochloric acid (27 mL), while maintaining the temperature in the range of 20-25 °. The addition funnel was rinsed with water (20 mL), then the pH of the solution was adjusted to 6.8-7.2 with 2M sodium hydroxide solution (110 mL). The addition funnel was rinsed with water (20 mL), and the reaction mixture was transferred to a recipient.

Distillation was washed with water (50 mL) and the solution was heated to reflux. The solution was concentrated at approximately 6.45 vol. under atmospheric pressure, then cooled to 20-25 °. Menthol was removed by extraction with toluene (500 mL, 2 x 200 mL), the aqueous phase was diluted with water (255 mL) then treated with salicylic acid (36 g), washing with water (40 mL). The mixture was heated to give a solution (at 71 °), then cooled to 58 °. The solution was started to crystallize with authentic lamivudine salicylate, then cooled to 5-10 ° for about 4 hours. The suspension was stirred for 1 hour at this temperature, then filtered. The product was washed with water (1 x 100 mL, 2 x 200 mL) and dried in vacuo at 45-50 ° to constant weight. H NMR (D ^ -DMSO) SH 3.11 (dd), 3.45 (dd) (2H); 3.77 (2H, m); 5.20 (1H, m); 5.82 (1H, d); 6.22 (1H, m); 6.91 (2H, m); 7.48 (1H, m); 7.62 (2H, broad); 7.80 (1H, dd); 7.92 (1H, d). (d) 4-Ainino-l- (2R-hydroxymethyl- [1,3] oxathiolan-5S-yl) -lH-pyrimidin-2-one The monosalicylate of 4-amino-1- (2R-hydroxymethyl- [1,3] oxathiolan-5S-yl) -lH-pyrimidin-2-one (66.7 g) was stirred with IMS (470 mL), and heated to 70-75 ° for give a solution The solution was clarified in a crystallization vessel, and rinsed with 170 mL of additional IMS. Triethylamine (26 mL) was added and the solution was distilled until 280 mL remained. The solution was cooled to 70 ° for 20 minutes, it was begun to crystallize, then isopropyl acetate maintained at 60 ° (600 mL) was added for 2.25 hours, maintaining the temperature above 55 °. The mixture was cooled to room temperature overnight, then cooled to 8-10 ° and stirred for 1 hour. The product was isolated by filtration (transferred to the filter with 30 mL of isopropyl acetate), washed with isopropyl acetate (2 x 130) and dried in vacuo at 40-45 °, at constant weight. H NMR (Dg-DMSO) δH 3.10 (1H, dd); 3.39 (1H, dd); 3.72 (2H, m); 5.15 (1H, t); 5.29 (1H, t); 5.72 (1H, d); 6.19 (1H, dd); 7.17 (1H, broad s); 7.22 (1H, broad s); 7.80 (1H, d). 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 (24)

1. A stereoselective process for producing compounds of the formula (I) where W is S, S = 0, S02 or 0; X is S, S = 0, S02 or 0; R, is hydrogen or acyl; and R ~ is a purine or pyrimidine base or an analogue or derivative thereof; the process comprises the step of reacting the purine or pyrimidine base or analogue thereof, with an intermediate of the formula (IVa) or (IVb) wherein R ~ is a substituted carbonyl or carbonyl derivative, and G represents halo, cyano or R5S0 ~ where R5 represents alkyl optionally substituted by one or more halo, or optionally substituted phenyl; characterized in that the reaction with the purine or pyrimidine base or analogue thereof is carried out without the addition of a Lewis acid catalyst.

2. A method according to claim 1, characterized in that it further comprises the step of reducing R- to the group R, 0CH23.

A method according to claim 2, characterized in that the reduction is carried out using > sodium orohydride in the presence of a borate or phosphate buffer.

4. A process according to any of claims 1 to 3, characterized in that R2 is a pyrimidine base.

5. A method according to claim 4, characterized in that R2 is cytoxine or 5-f luocytosine.

6. A method according to any of claims 1 to 5, characterized because R ~ represents a group -C (= 0) 0R ,, where R represents an optionally substituted alkyl group.

A method according to claim 6, characterized in that R represents a chiral auxiliary

8. A process according to claim 7, characterized in that R is selected from (d) -mentlyl, (I) -mentlyl, (d) -8-phenylmethyl, (I) -8-phenylmethyl, (+) - norephedrine and (-) - norephedrine.

9. A method according to any of claims 1 to 8, characterized in that W is 0 and X is S.

10. A process according to any of claims 1 to 9, characterized in that G represents Cl, Br or I.

11. A process according to any of claims 1 to 10, characterized in that the compound of the formula (I) is isolated as a salt insoluble in water.

12. A process according to any of claims 11, characterized in that the compound of formula (I) is 4-amino-l- (2R-hydroxymethyl- [1,3] oxat iolan-5S-il) -lH-pyridin-2-one or a salicylate salt thereof.

13. A process according to any of claims 1 to 12, characterized in that the intermediates of the formulas • (IVa) and (IVb) are generated from the corresponding trans alcohols of the formulas (Va) and (Vb) wherein R ~, W and X are as defined in claim 1, or epimeric cis alcohols, by reaction with a reagent, suitable for introducing group G.

14. A method according to claim 13, characterized in that the intermediates of the formulas (IVa) and (IVb) are generated i ^ situ.

15. A method for increasing the yield of the trans (Va) and (Vb) isomers of a mixture of the t rans and cis isomers, the method is characterized in that it comprises the treatment of the mixture of the trans and cis isomers, at least partially in solution, with an agent capable of effecting the interconversion of the isomers without complete suppression of the crystallization of the trans isomers.

16. A method for increasing the yield of a single enantiomer of the formula (Va) or (Vb) of a mixture of isomers, the method is characterized in that it comprises treating the mixture of isomers, at least partially in solution, with a capable agent of effecting the interconversion of the isomers without complete deletion of the crystallization of the desired individual (Va) or (Vb) enantiomer.

17. A method according to claim 16, characterized in that it is for the selective crystallization of compounds of the formula (Va) wherein R represents -C (! S0) 0R ,, where R, is I-menthyl from a mixture of stereoisers containing alcohols (Va), (Vb) and cis epimeric alcohols eos

18. A method according to claim 16, characterized in that it is for the selective crystallization of the compounds of the formula (Vb) wherein R ~ represents -C (= 0) 0R, where R, is d-menthyl, from a mixture of stereoisomers containing alcohols (Va), (Vb) and the epimeric cis alcohols.

19. A method according to claim 17, characterized in that it is for the selective crystallization of 2S-isopropyl-5R-methyl-1R-cyclohexylic acid ester (2R, 5R) -5-hydroxy- [1, 3] oxathiolan-2 -carboxylic.

20. A method according to claim 19, characterized in that the agent capable of effecting the interconversion of the isomers without complete suppression of the crystallization of the desired individual enantiomer is triethylamine.

21. A salicylate salt of a compound of the formula (I), or a hydrate thereof.

22. 4-amino-l- (2R-hydroxymethyl- [1, 3] oxat iolan-5S-yl) -lH-pyrimidin-2-one salicylate and hydrates thereof.

23. A procedure essentially as described in Scheme 1.

24. A process essentially as described herein with reference to Example 1.