MXPA06003215A - New process for the preparation of a diphenyl ether compound - Google Patents

Abstract

The present invention is concerned with an improved process for the preparation of the selective serotonin reuptake inhibitor 3-[(Dimethylamino) methyl]-4-[4- (methylsulfanyl) phenoxy]benzenesulfonamide (L) or (D) tartrate (I) and with intermediate products therein.

Description

New procedure for the preparation of a biphenyl ether compound The present invention relates to an improved method for the preparation of the selective serotonin reuptake inhibitor (L) or (D) tartrate of 3 - [(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide and with intermediate products in it.

WO 01/72687 describes the preparation of (L) tartrate of 3 - [(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide (I) in which the compound is prepared by (i) making reacting 4- (methylmercapto) phenol (III) with 2-fluorobenzaldehyde (II) in the presence of potassium carbonate in a suitable solvent such as DF; (ii) carrying out a reductive amination of 2- [4- (methylsulfanyl) phenoxy] benzaldehyde (IV) with sodium triacetoxyborohydride and dimethylamine hydrochloride and then optionally forming the HCl salt of the product; (iii) reacting? /, / V-dimethyl -? / -. { 2- [4- (Methylsulfanyl) phenoxy] benzyl} amine (V) with chlorosulfonic acid in dichloromethane; and (iv) treating 3 - [(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonyl (VI) chloride with aqueous ammonia or ammonia in ethanol to give (VII). Steps (iii) and (iv) can be combined. The corresponding salt tartrate can be obtained by dissolving (Vil) in an organic solvent, adding the appropriate tartaric acid, optionally cooling the solution and collecting the resulting crystals of (I). The complete sequence can be represented as follows: .HO2CCH (OH) CH (0H) C02H There are a number of problems with this route: (a) Stage (i) of the procedure is carried out under dilute reaction conditions, the result of which is that you must dispose of a large amount of waste solvent at the end of the reaction. Additionally, when the reaction is carried out on a large scale the reaction times are slow. In addition, the product of the reaction, compound (IV), is difficult to isolate. It has a low melting point (37-399C), and therefore the compound is not flexible to be dried in a vacuum oven, which makes it difficult to remove the solvent from the product at the end of the reaction. Isolation by crystallization is also hindered by this property. (b) The reductive amination of the compound (IV), step of the process (ii), proceeds slowly, in particular on a large scale where the reactions can take up to a week to reach its completion, this has significant economic disadvantages. In addition, the yields are modest and impurities are generated. The generation of by-products, such as the primary alcohol derivative of the compound (IV), further reduces the yield. (c) In the process step (iii), the chlorosulfonylation of the compound (V) is carried out using a large excess of 97% of the chlorosulfonic acid (10 molar equivalents) in the solvent dichloromethane. The hazardous nature of the reagent and the solvent makes it difficult to handle them safely, particularly on a large scale. In addition, the excess reagent can be neutralized at the end of the reaction generating a large amount of waste. The elimination of large amounts of dichloromethane is also expensive and harmful to the environment. Additionally, various impurities are generated as by-products in this stage of the process. These impurities have to be carried to the next stage of the sequence due to the highly reactive nature of the compound (VI) and its physical form (a sticky solid), which makes it difficult to effectively isolate and purify. (d) Due to the moderate purification of the compound (VI), the stage (iv) of the process is of low yield. Additionally, the sulfonic acid derivative (IX) is generated as a by-product. The compound (IX) is difficult to separate from the desired product, the compound (VII), as are the impurities charged from the stage (iii) of the process. In summary, although this reaction sequence provides an adequate route for the production of compounds of formula (I) on a laboratory scale, there is a clear requirement for a solid procedure that would be more applicable for the generation of these compounds on an industrial scale. As a result an improved synthetic process has been developed for the (L) or (D) tartrate of 3 - [(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide (I) which overcomes the problems described above . The complete sequence can be represented as follows: .HO2CCH. { 0H) CH (0H) C02H In one embodiment of the invention the compounds of formula (IV) may be prepared by reacting compounds of formula (II) and (lll) under the conditions of process step (i) nucleophilic aromatic substitution in the presence of a base in a suitable solvent. Suitable bases include carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate; butoxide bases such as potassium t-butoxide, lithium t-butoxide, sodium t-butoxide; hydroxide bases such as sodium hydroxide; and organic bases such as pyridine and morpholine. Suitable solvents include aprotic polar solvents such as N.N-dimethylformamide, tetrahydrofuran, dimetiisulfóxido, dioxane, acetonitrile and ethers. The preferred base for the reaction is potassium carbonate and the preferred solvent is N, N-dimethylformamide. More preferably, the potassium carbonate is of small particle size (Dgn <1000 microns). The resulting compounds of formula (VIII) may be prepared by step (iv) of the method, a reductive amination reaction by reacting the compounds of formula (IV) with a source of dimethylamine and a suitable reducing agent; wherein M is a suitable counterion such as chloride, bromide, toluenesulfonate, benzenesulfonate, methanesulfonate, hydrogen sulfate, acetate or trifluoroacetate. Suitable sources of dimethylamine include dimethylamine, dimethylamine salts in the presence of a base (a suitable salt will include hydrochloride, a suitable base will include triethylamine); and N, N-dimethylformamide in the presence of an acid or base (a suitable acid will include formic acid, a suitable base will include triethylamine). Suitable reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen gas in the presence of a catalyst, formic acid and formic acid salts such as potassium formate and sodium formate.

In some cases the addition of a Lewis acid such as titanium tetra-isopropoxide may be beneficial. Suitable solvents for the reaction include dichloromethane, tetrahydrofuran, fer-butyl methyl ether, ethanol, ethyl acetate, N, N-dimethylformamide. The preferred source of the reducing agent is formic acid in which the required dimethylamine is generated by the acid-mediated degradation of N, N-dimethylformamide. N, N-dimethylformamide is the preferred solvent of the reaction. The reaction is preferably carried out at elevated temperature. The tertiary amine intermediate can then be isolated as a crystalline salt by reacting the amine with a suitable acid in the presence of a suitable solvent. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid and trifluoroacetic acid. Preferred acids are hydrochloric acid, sulfuric acid and methanesulfonic acid. Suitable solvents include ferric butyl methyl ether and methyl ethyl ketone, either alone or in combination or in the presence of some water. Sulfuric acid salts are particularly preferred. Preferred conditions for its preparation are treatment with methyl ethyl ketone and sulfuric acid. The steps of process 1 and 2 can be combined, that is to say that the compounds of formula (IV) are not isolated or purified. This is particularly advantageous since the low melting point of the compound (IV) makes it particularly difficult to isolate. According to an embodiment of the invention, the compounds of formula (Vll1) can be prepared by reacting compounds of formulas (II) and (III) under the conditions of step (i) of the process, before treating the crude reaction mixture under the conditions of step (vi) of the process. In this embodiment, the preferred conditions for process step (i) are N, N-dimethylformamide as the solvent and potassium carbonate as a base. More preferably, the potassium carbonate is of small particle size (Dgo <1000 microns). In this embodiment, the preferred conditions for process step (vi) are N, N-dimethylformamide as solvent and formic acid as a reducing agent, at elevated temperature. According to another embodiment of the invention, the compounds of formula (IX) can be prepared by step (vii) of the process, a sulfonylation reaction by reacting the compounds of formula (Vlll) in the presence of a sulfonylating reagent in the presence of a suitable solvent. Suitable sulfonylating reagents include chlorosulfonic acid, sulfuric acid and fuming sulfuric acid. The preferred sulfonylating agent is chlorosulfonic acid (99%). Suitable solvents include dichloromethane, chlorosulfonic acid, trifluoroacetic acid, methanesulfonic acid and sulfuric acid. Preferred solvents are trifluoroacetic acid and methanesulfonic acid. The most preferred conditions are chlorosulfonic acid (99%) and methanesulfonic acid or chlorosulfonic acid (99%) and trifluoroacetic acid. The preferred reaction temperature is between 0 and 5eC, when the trifluoroacetic acid is the solvent. The preferred reaction temperature is 09C at room temperature, when the methanesulfonic acid is the solvent. According to still another embodiment of the invention, the compounds of the formula (VII) can be prepared by the process step (viii), formation of a sulfonamide by reacting compounds of the formula (IX) with a chlorinating agent in a suitable solvent , before inactivating the sulfonyl chloride intermediate with ammonia. Suitable chlorinating agents include PCI5, POCI3, SOCI2 and (COCI) 2. Suitable solvents include acetonitrile, propionitrile, toluene and ethyl acetate. Suitable ammonia sources include ammonia gas and a solution of ammonia gas either in an organic solvent or in water. Preferred conditions include phosphorus oxychloride in acetonitrile followed by treatment with aqueous ammonia. Most preferred conditions encompass the addition of aqueous ammonia to a solution of the sulfonyl chloride intermediate (VI), followed by treatment with water. In a further embodiment of the invention, the resulting compound of formula (VII) can be treated with absorbers to increase its purity. Suitable absorbers include activated carbon, resins and Fuller's Earth. According to another embodiment of the invention, the compounds of formula (I) can be prepared by process step (ix), by reacting the compounds of formula (VII) with tartaric acid D or L in a solvent system. Suitable solvent systems include isopropyl alcohol, isopropyl alcohol / water, ethanol, ethanol / water, methyl ethyl ketone, methyl ethyl ketone / water, methyl isobutyl ketone, methyl isobutyl ketone / water, acetone, acetone / water. The most preferred conditions are aqueous (L) -tartaric acid with methyl ethyl ketone as the solvent. The formation of the tartrate salt using the solvent system set forth above gives salts of increased purity in increased yield in a process suitable for an industrial scale. The advantages of this novel process can be summarized as follows: i) The use of potassium carbonate of particle size D90 < 1000 microns, reduces the reaction time required for the process step (i) to reach its term when carried out on a large scale. The use of this reagent facilitates the completion of multi-kilo reactions in less than 24 hours; This has significant economic advantages. ii) The use of N, N-dimethylformamide both as solvent and source of dimethylamine in step (vi) of the process allows the combination of the steps of the processes (i) and (vi) to be possible. The combination of the steps of the processes (i) and (vi) avoids the isolation of the intermediate compound (IV) of low melting point and also significantly reduces the volume of solvent required for these two transformations. The reaction efficiency thus increases as more product is generated from a lower reaction volume. iii) The use of formic acid as a reducing agent in step (vi) of the process is particularly advantageous for two reasons. Firstly, since it is a liquid, it can be added in a controlled manner to the reaction mixture at the end of step (i) of the process. Therefore, the gas evolution accompanying the pH change between process steps (i) and (vi) can be safely controlled. Second, the oxidation of formic acid does not generate any chemical residue; CO2 is the only by-product. iv) The purity of the compound (Vlll) is increased by the formation of its preferred sulfate salt during step (vi) of the process. This salt form is easily isolated from the reaction mixture at the end of the reaction. v) In step (vii) of the process, the use of 99% chlorosulfonic acid (instead of the 97% chlorosulfonic acid used in step (iii) of the process) reduces the amount of by-products generated by more than 50%. Additionally, even less sulfonylating reagent is required compared to the process step (iii), therefore there is less chemical waste to be removed at the end of the reaction. In addition, the solvent dichloromethane can be replaced by the more benign methanesulfonic acid with the environment, or trifluoroacetic acid. vi) The compound (IX) is formed as a precipitate from the process step (vii). The ability to isolate this product provides a valuable opportunity to purify this intermediate, if necessary, at the midpoint of the reaction sequence. This allows more control to be exercised with respect to purity during the procedure. vii) The isolation of the intermediate reactive compound (VI) is avoided by the process step (viii) where it is generated in situ. The reaction conditions used in this step are milder than those of the reaction stage (iii) and therefore less impurities are generated, improving the purity of the intermediate. viii) The subsequent inactivation of this intermediate is carried out in a novel way by the addition of aqueous ammonia to the reaction mixture, followed by the addition of water and brought to reflux in situ. The industrial-scale practice accepted in the art would be to add the reaction mixture to an excess of aqueous ammonia. This new inverse addition mode has the following advantages: (a) The byproduct derived from sulfonic acid (IX) is soluble in the reaction mixture which facilitates its elimination from the product. (b) It is not necessary to transfer the suspension of the intermediate (VI) to another reaction vessel, thus avoiding handling problems associated with its physical form, (c) Reflux increases the solubility of the inorganic impurities in the mixture of reaction, and therefore facilitates its separation from the product. In addition, the organic impurities are purified. The above-stated advantages result in a higher yield of the compound (VII). ix) This new process is suitable for producing quantities of compound (I) on an industrial scale.

In a further embodiment of the present invention there are provided compounds of formula (Vll1) and (IX) in which M is a suitable counterion as described above.

These compounds are particularly useful in the synthesis of the compounds of formula (I) by the process of the present invention.

Experimental.

The following abbreviations and definitions are used: MEK methyl ethyl ketone DMF? /, / V-dimethylformamide TBME tert-butyl methyl ether DMSO dimethylsulfoxide POCI3 phosphorus oxychloride DCM dichloromethane DMSO dimethisulfoxide m / z peak HPLC mass spectrum high pressure liquid chromatography MS mass spectrum NMR nuclear magnetic resonance c cuartete s singlet t triplet to width TFA trifluoroacetic acid MSA methanesulfonic acid Kg kilograms 1 liter ml ml g grams CDCI3 chloroform marked with deuterium.

Powder X-ray diffraction patterns (PXRD) were determined using a Siemens D5000 powder X-ray diffractometer equipped with a teta-theta goniometer, automatic beam divergence slots, a secondary monochromator and a scintillation counter. The sample was rotated while it was irradiated with K-alpha1 copper X-rays (wavelength = 1.5046 angstroms) filtered with a graphite monochromator (? = 0.15405 nm) with the X-ray tube operating at 40 ° C. kv / 40 mA. The main peaks (in degrees 2T) of the PXRD patterns for the various solid forms are illustrated. The melting points were determined using either a Perkin equipment Elmer DSC7 at a heating rate of 209C / minute or a Buchi B-545 melting point apparatus. The NMR spectra were obtained using a Varian Inova spectrometer at 300 mHz by dissolving the sample in a suitable solvent. The mass spectra were obtained using an LC / MS system consisting of a Hewlett Packard 1100 series LC set in combination with a Micromass ZMD mass spectrometer.

Sulfate of? /, / V-dimethyl-2-r4- (methylthio) phenoxy-benzylamine hydrocarbane HO 2-Fluorobenzaldehyde (38.0 kg), 4- (methyl mercapto) phenol (43.8 kg), potassium carbonate (46.6 kg, with one size) were charged to a suitable reactor and heated at 110 g for 24 hours. of particle Dg0 <1000 microns) and DMF (171 I). When all 2-fluorobenzaldehyde was consumed (< 3% as evidenced by HPLC) the reaction mixture was cooled to room temperature, and treated with formic acid (169.1 kg) for 30 minutes. The mixture was heated to 130 ° C for an additional 24 hours and then allowed to cool to room temperature. Water (9.5 L) was added followed by aqueous concentrated ammonia (152 L) to adjust the pH to more than 8.5. The mixture was extracted with TBME (114 I) and the phases allowed to separate, the lower aqueous phase was then discarded. To prepare the sulfate salt the TBME extract was diluted with MEK (114 I). The solution was cooled to 159 ° C and concentrated sulfuric acid (30.6 kg) was added maintaining the temperature below 25 ° C. The mixture was then allowed to cool to 20 ° C. and stirred overnight, finally the mixture was cooled to 0-5BC for 1 hour and the product was collected by filtration under reduced pressure. The filter cake was washed with MEK (76 I). The product was then dried at 50 ° C under vacuum overnight. Yield = 81%, dH (DMSO-d6, 300 MHz) 2.48 (6H, s), 2.81 (3H, s), 4.39 (2H, s), 6.82 (1H, d), 7.05 (2H, d), 7.22 (1H, t), 7.39 (2H, d), 7.43 (1H, t), 7.61 (1H, d), 9.46 (1H , sa); MS m / z (TS +) 274 (MH +), melting point = 139-1419C. 3-I (dimethylamino) metill-4-y4- (methylthio) phenoxybenzenesulfonic acid The title compound can be prepared either using methanesulfonic acid (method A) or trifluoroacetic acid (method B) as the solvent.

Procedure A Methanesulfonic acid (17.66 I) was added to a suitable beaker followed by? /,? / - dimethyl-2- [4- (methylthio) phenoxy] benzylamine hydrogen sulphate (7.85 kg), the mixture was stirred at room temperature until a solution was achieved. The reaction mixture was cooled to 09C and treated with chlorosulfonic acid (11.36 kg), keeping the temperature below 59C, for 1 hour. The reaction was followed by HPLC and the reaction was completed after 5 hours by detecting < 2% of the starting material. In a separate vessel, water (70.65 kg) was cooled to 59C. The cooled reaction mixture is then quenched in the cooled water keeping the temperature below 35 ° C. A thick white precipitate formed during inactivation.

Finally, the reaction mixture remaining in the deactivation was washed with methanesulfonic acid (2.91 kg), then with water (7.85 kg). The resulting suspension was stirred overnight at room temperature before cooling to (PC for 1 hour.) The product was filtered under reduced pressure and the cake was washed with water (15.7 I). water (78.5 I) at room temperature for 1 hour The product was filtered under reduced pressure and the cake was washed with water (15.7 I) The material was then dried at 50 ° C under vacuum overnight. = 62%.

Procedure B To a suitable vessel was added trifluoroacetic acid (138 ml) followed by? /,? - dimethyl-2- [4- (methylthio) phenoxy] benzylamine hydrogen sulfate (50 g), the mixture was stirred at -39 C until got a dissolution. The reaction mixture was maintained at -39 C and treated with chlorosulfonic acid (36 ml) while maintaining the temperature below 69 C, for 0.25 hours. Using 99% quality chlorosulfonic acid minimizes the generation of impurities in the reaction (as compared to lower grades of reagent) and the resulting solid is thus isolated with increased purity. The reaction was followed by HPLC and the reaction was completed after 24 hours detecting <2% of the starting material. In a separate vessel, water (500 ml) was cooled to 2 ° C. The reaction mixture is then quenched in the cooled water (for 2.5 minutes) keeping the temperature below 27 ° C. Rapid addition is necessary to keep the product in solution until the end of the addition, at which time the product begins to precipitate slowly, and the largest crystal size is observed. The reaction mixture was washed in the inactivated mixture with trifluoroacetic acid (12 ml) and the suspension was stirred at 20 ° C for 2.5 hours, and then at 09 ° C overnight. The product was filtered under reduced pressure. Several options are available to increase the quality of the material before drying. Option 1. The solid product was stirred in water (250 ml) at room temperature for 0.5 hour and then filtered under reduced pressure. The solid was stirred in a 1: 1 mixture of acetonitrile / water (250 ml) for 2 hours at 40 ° C. The suspension was cooled to room temperature and after 1 hour, filtered under reduced pressure. The 1: 1 acetonitrile / water resuspension (250 ml) at 40 ° C was repeated once more in the wet product and then dried at 50 ° C under vacuum overnight. Yield = 54%. Option 2. The solid product was washed with water (2 x 50 ml). The solid was then stirred in a 1: 1 mixture of acetonitrile / water (250 ml) at 60 ° C for 1 hour. The suspension was cooled to room temperature and stirred at this temperature for 4 hours. The product was filtered under reduced pressure and then dried at 50 ° C under vacuum overnight. Performance = 55%.

Option 3. The solid was then stirred in a 1: 1 mixture of acetonitrile / water (250 ml) at 60 ° C for 1 hour. The suspension was cooled to room temperature and stirred at this temperature for 4 hours. The product was filtered under reduced pressure and then dried at dC C in vacuo overnight. Yield = 58%. To further increase the purity of this key intermediate, an additional resuspension or recrystallization may be carried out if necessary. Recrystallization increases purity to a greater degree than resuspension and the procedure is outlined below. Acetonitrile (24.9 l), water (20.75 l) and 3- [(dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonic acid (4.15 kg) were added to a vessel and they were heated at reflux for 1 hour. The resulting solution was then cooled to room temperature for 3 hours and the suspension was stirred overnight at that temperature. The solid was recollected by filtration under reduced pressure and the cake was washed with a 1: 1 mixture of acetonitrile and water (4.15 I of each). The material was then dried at 50 ° C under vacuum overnight. Yield = 72%, dH (DMSO-d6, 300 MHz) 2.52 (3H, s), 2.80 (6H, s), 4.40 (2H, d), 6.78 (1H, d), 7.04 (2H, d), 7.18 (2H, d), 7.62 (1H, d), 7.93 (1H, s), 9.55 (1H, sa); MS m / z (TS) 352 (MH). 3-r (dimethylamino) methyl-1-4-r4- (methylthio) phenoxflbenzenesulfonamide Acetonitrile (60 ml) was added to a beaker and 3 - [(dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonic acid (10.0 g) was added followed by POC (2.9 ml) . The reaction mixture was heated to reflux (approximately 819C) for 2 hours. The reaction was followed by HPLC and was considered to be complete when the starting material was reduced to < 2%. The reaction mixture was then cooled to -10 ° C and treated with concentrated aqueous ammonia (60 ml) keeping the temperature below 20 ° C. The reaction mixture was then treated with additional water (60 ml) at 40 ° C. Here, an optional heating cycle at reflux can be used for 1 hour before cooling to room temperature. The optional heating cycle provides a higher level of purification of the impurities related to the process. The reaction mixture was stirred overnight at room temperature. The resulting solid was filtered under reduced pressure and the filter cake was washed with water (20 ml) before being dried at 50 ° C under vacuum overnight. Performance = 88%. dH (CDCl 3, 300 MHz) 2.35 (6H, s), 2.49 (3H, s), 3.66 (2H, s), 5.20 (2H, a), 6.81 (1H, d) ), 6.92 (2H, d), 7.27 (2H, d), 7.72 (1H, dd), 8.14 (1H, d); MS m / z (JS *) 353 (MH +). (fl.?) - 3-r (dimethylammono) metip-4-f4- (methylthio) phenoxylbenzenesulfonamide tartrate There are two options for preparing (fl, 7) -3- [(dimethylamino) methyl] -4 - [(4-methylthio) phenoxy] benzenesulfonamide depending on whether the activated carbon is used in a loose or fixed form to a solid. Option 1. 3 - [(Dimethylamino) methyl] -4 [-4- (methylthio) phenoxy] benzenesulfonamide (10 g) was mixed with MEK (80 ml) at room temperature. The stirred mixture was heated to reflux (about 80 ° C) for 15 minutes and then cooled to room temperature. The mixture was treated with activated carbon (20% w / w, 2 g of Cuno "Pfizer type A"). The suspension was stirred at room temperature for 15 minutes and then filtered by washing the carbon with an additional amount of MEK (20 ml). The MEK solution was treated with a solution of (-) - tartaric acid (4.26 g) dissolved in water (13 ml) and MEK (13 ml) at room temperature for 10 minutes and the resulting suspension was stirred at room temperature for 1 hour. hour. The solid product was then collected by filtration under reduced pressure and the filter cake was washed with MEK (20 ml). The salt was dried at 50 ° C under vacuum. Performance = 82%.

Option 2. 3 - [(Dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonamide (31.65 kg) was mixed with MEK (253.2 I) at room temperature. The stirred mixture was heated to reflux (about 80 ° C) for 1 hour and then cooled to room temperature. The mixture was clarified by filtration under reduced pressure. The solution was passed through an activated carbon cartridge supported by solid at 10-12 I / minute (0.5 g / cm2 carbon surface area, from Cuno "R50Sp Pfizer Type A"). MEK (95 I) was used to wash the filter cake followed by the solid-supported carbon cartridge. The MEK solution was treated with a solution of () -tartaric acid (13.5 kg) dissolved in water (41.0 I) and MEK (41.1 I) at room temperature for 20 minutes, washing with an additional amount of water (16 I) and the resulting suspension was stirred at room temperature for 3 hours. The solid product was then collected by filtration under reduced pressure and the filter cake was washed with MEK (63.3 I). The salt was then dried at dC ^ C in vacuo. Performance = 87%. The main peaks (in 2T degrees) of the PXRD pattern are as follows:

Claims (14)

Claims

1. A process for the preparation of a compound of formula (I): • H02CCH (OH) CH (OH) C02H comprising the reaction of a compound of formula (VII) with tartaric acid in a suitable solvent.

2. A process according to claim 1 wherein the solvent is methyl ethyl ketone and the (L) form of tartaric acid is used.

3. A process according to claim 1 which further comprises the preparation of a compound of formula (VII) by reaction of a compound of formula (IX) with a suitable chlorinating agent, in a suitable solvent, to generate a sulfonyl chloride in situ; and then inactivating this sulfonyl chloride by adding a suitable ammonia source to the reaction mixture.

4. A process according to claim 3 which further comprises the preparation of a compound of formula (IX) by the reaction of a compound of formula (Vlll) wherein M is a suitable counterion, with a suitable sulfonylating agent in a suitable solvent.

5. A process according to claim 4 wherein the solvent is methanesulfonic acid or trifluoroacetic acid and M is the chloride ion, hydrogen sulfate, or methanesulfonate.

6. A process according to claim 4 which further comprises the preparation of a compound of formula (Vlll) by the reaction of a compound of formula (IV) with a suitable dimethylamine source in the presence of a suitable reducing agent, in a suitable solvent and then treating the resulting amine with a suitable acid.

7. A process according to claim 6 wherein the reducing agent is formic acid and the solvent is N, N-dimethylformamide.

8. A process according to claim 6 which further comprises the preparation of a compound of formula (IV) by the reaction of a compound of formula (II) with a compound of formula (III) in the presence of a suitable base, in a suitable solvent.

9. A process, according to claim 8, for the preparation of a compound of formula (Vlll) wherein: (i) the reaction of compounds (II) and (III) is carried out in N, N-dimethylformamide in the presence of a base; (ii) the resulting crude reaction mixture containing compound (IV) is treated with formic acid and then allowed to react at elevated temperature; (iii) the salt of the resulting amine product is formed by treatment with an appropriate acid.

10. A process for the preparation of a compound of formula (VII): comprising the reaction of a compound of formula (XI) with a suitable chlorinating agent, in a suitable solvent, to generate a sulfonyl chloride in situ; and then inactivating this sulfonyl chloride by adding a suitable ammonia source to the reaction mixture.

11. A process for the preparation of a compound of formula (XI): comprising the reaction of a compound of formula (Vlll) wherein M is the chloride ion, hydrogen sulfate, or methanesulfonate, with a suitable sulfonylating agent in a methanesulfonic acid or trifluoroacetic acid as the solvent.

12. A process for the preparation of a compound of formula (Vlll): wherein M is an adequate counterion; comprising the reaction of a compound of formula (IV) with a suitable dimethylamine source in the presence of a suitable reducing agent, in an appropriate solvent and then treat the resulting amine with a suitable acid.

13. A compound of formula (IX):

14. A compound of formula (Vlll): (Vttt) wherein M is the hydrogen sulfate or methanesulfonate ion.