PREPARATION OF CLAVULANATE SALTS

Abstract: A process for preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, including the steps of: adding an additional solvent to a solution of clavulanic acid in a water immiscible solvent; contacting the solution with an amine; isolating the amine salt of clavulanic acid formed; and converting the amine salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof.

Description: PREPARATION OF CLAVULANATE SALTS This invention relates to a process for preparation of pharmaceutically acceptable salts of clavulanic acid, particularly but not exclusively alkali salts especially potassium clavulanate. Clavulanic acid is the common name for (2R, 5R, Z) -30 (2- hydroxyethylidene) -7-oxo-4-oxa-l-azabicyclo [3.2.0] heptane-2- carboxylic acid. Clavulanic acid and its alkali metal salts and esters are active as inhibitors of beta lactamase produced by some Gram positive as well as Gram negative micro-organisms. In addition to inhibition of beta lactamase, clavulanic acid and alkali metal salts thereof also have a synergistic action with penicillin and cephalosporin antibiotics. Clavulanic acid and its salts are used in pharmaceutical preparations to prevent the deactivation of beta lactam antibiotics. Commercial preparations contain potassium clavulanate in combination with amoxycillin trihydrate. Potassium clavulanate is more stable than the free acid or other salts. Clavulanic acid is prepared by fermentation of a micro¬ organism such as strains of Streptomyces such as S.clavuligerus NRRL 3585, S. jimonjinensis NRRL 5741 and S.katsurahamanus IFO 13716 and Streptomyces sp.P6621 FERM P2804. The aqueous culture obtained after fermentation is purified and concentrated in accordance with conventional processes for example filtration and chromatographic purification as disclosed in GB 1508977, prior to extraction of the aqueous solution with an organic solvent to obtain a solution of impure clavulanic acid in the solvent . GB 1508977 discloses preparation of clavulanate salts by filtration of the fermentation broth by passage through an anionic exchange resin. This process may achieve acceptable yields but sophisticated chromatographic purification methods are required and the use of resin columns involves substantial investment for manufacture on a commercial scale. GB 1543563 discloses a fermentation process wherein the pH value of the medium is maintained in the range 6.3 to 6.7. Pharmaceutically acceptable salts such as potassium clavulanate are prepared by re-salting from lithium clavulanate. EP-A-0026044 discloses use of the tertiary butylamine salt of clavulanic acid as an intermediate for purification of clavulanic acid. This salt was known from BE-862211 or DE 2733230 which disclosed that the salt was even more stable than the sodium or potassium clavulanate salts. Tertiary butylamine is a toxic compound and is also difficult to remove from waste water giving rise to serious pollution concerns. EP-A-0562583 discloses use of salts of clavulanic acid with N,N' -monosubstituted symmetric ethylene diamines such as N,N'- diisopropyethylene diammonium diclavulanate as useful intermediates for isolation and preparation of pure clavulanic acid or alkaline metal clavulanate salts from ethyl acetate extract. W093/25557 discloses use of clavulanate salts with numerous amines as intermediates for preparation of clavulanic acid or pharmaceutically acceptable salts or esters. EP-A-0594099 discloses use of tertiary octylamine with clavulanic acid as an intermediate in preparation of clavulanic acid or pharmaceutically acceptable salts. W094/21647 discloses use of N,N' -substituted diamines such as N,N' -diisopropylethylene diammonium diclavulanate as a useful intermediate for preparation of clavulanic acid and alkali salts. W094/22873 discloses use of novel tertiary diammonium salts of clavulanic acid such as N,N,N' ,N' -tetramethyl-1, 2-diaminoethane clavulanate as a useful intermediate for preparation of clavulanic acid and salts thereof. The aim of this invention is to prepare clavulanic acid and its pharmaceutically acceptable salts, such as potassium clavulanate in a new and simple manner, wherein the desired substance is obtained in a high yield and of high purity, avoiding the use of toxic amines. According to the present invention a process for preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, including the steps of: a. adding an additional solvent to a solution of clavulanic acid in a water immiscible solvent; b. contacting the solution with an amine; c. isolating the amine salt of clavulanic acid formed; and d. converting the amine salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof. The clavulanic acid may be obtained by fermentation of a Streptomyces micro-organism such as Streptomyces sp.P6621 FERM P2804 as disclosed in JP Kokai 80-162993. Alternative Clavulanic acid producing Streptomyces strains such as S.Clavuligerus may be employed. Solids may be removed from the fermentation broth by filtration or preferably by microfiltration. Microfiltration of the broth may be carried out as disclosed in O95/23870. In a preferred process according to this disclosure the aqueous fermentation broth containing crude clavulanic acid, mycelium, proteins and other suspended solid matter is purified by microfiltration at a pH value between 5.8 and 6.2 and a temperature about 20 to 40'C. The purified filtrate may be concentrated by reverse osmosis and then directly extracted in a series of countercurrent centrifugal extractors with a water immiscible solvent, preferably ethyl acetate. The extraction is preferably carried out at a temperature between 15 to 25 * C and a pH between 1 and 3. The extract is then dried to a water content below 0.1 mol.%, further concentrated by evaporation and decolorised with active charcoal to obtain a completely dry organic phase. The concentration of crude clavulanic acid in the dry concentrated extract in the water immiscible solvent such as ethyl acetate may be between 8 g/1 and 40 g/1, preferably between 20 g/1 and 40 g/1. Alternative water immiscible solvents include: methyl acetate, propyl acetate, n-butly acetate, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof. The additional solvent may be selected from: alcohols, nitriles, ketones and mixtures thereof. Preferred additional solvent include C_ to C 6 alcohols, acetonitrile acetone and mixtures thereof. Especially preferred solvents are selected from: methanol, ethanol, isopropanol, n-butanol, isobutanol and acetonitrile. Methanol is the most preferred solvent. The amine may be selected from tertiary butylamine, benzyl tertiary butylamine, tertiary octylamine adamantane amine and sec butylamine. Other amines which have been proposed for purification of clavulanic acid may be employed. In a preferred embodiment of the invention the amine is of formula I (CH,) n —N / wherein the substituents R 1 , R 2 , R 3 , and R 4 are independently: hydrogen; C x to C 8 straight or branched alkyl; C 2 to C hydroxyalkyl or wherein the groups NR^ 2 and NR 3 R 4 jointly denote a heterocyclic group having 3 to 6 methylene groups optionally substituted with oxygen sulphur or an imino group; wherein R 5 denotes hydrogen or methyl; and n is an integer from 1 to 3. Especially preferred amines are symmetrical N,N'- alkylethylene diamines, preferably N,N' -diisopropylethylene diamine, N,N' -diethylethylene diamine, N,N' -dibenzylethylene diamine, N,N,N' ,N' -tetra ethylethylene diamine. N,N'- diisopropylethylene diamine is especially preferred. At least one equivalent of the selected alkaline diamine, preferably a 10% excess up to about 2 molar equivalents may be employed for preparation of the clavulanate ammonium salt . In a preferred embodiment of the invention the reaction of clavulanic acid with N,N' -monosubstituted symmetric diamines can be carried out in a mixture of ethyl acetate and methanol for example having 0 to 80% of methanol, preferably in the ratio 4:1 to 2:1, preferably 3:1. Use of a mixture of ethyl acetate and methanol according to the present invention allows isolation of the diammonium diclavulanate salt free of undesired impurities such as clavam-2- carboxylate . The clavam-2-carboxylic acid is difficult to separate from clavulanic acid (see D Brown et al, JCS, Chem.Com. 1979, 282) . According to the United States Pharmacopoeia US P23, page 385, 1995 no more than 0.01% of potassium clavam-2-carboxylate is permitted. Surprisingly it has been discovered that the yield of the intermediary salts with N,N' -monosubstituted symmetric diamines is substantially higher and is almost quantitative when the transformation is carried out in a mixture of solvents, preferably ethyl acetate and methanol, in comparison to the transformation carried out in a single solvent, for example as disclosed in US 5310898. The ammonium diclavulanate salts prepared in accordance with this invention may be used as intermediate compounds for preparation of completely pure clavulanic acid and its pharmaceutically acceptable salts such as potassium clavulanate. Akali metal clavulanate salts may be prepared using an appropriate source of alkali metal, for example potassium 2-ethyl hexanoate in isopropanol (the solvent containing between 0% and 4% water) . Alternative alkali metal salts include alkali carbonates, bicarbonates, or hydroxides, organic carboxylic acids, alkanoic acid salts such as acetates, propionates, hexanoates of which potassium 2-ethyl hexanoate is especially preferred. Suitable salts in accordance with the present invention are pharmaceutically acceptable alkali salts such as the sodium, potassium, calcium and magnesium salts of which sodium and potassium, especially potassium are preferred. The invention is further described by means of example but in any limitative sense. Reference Example N,N' -diisopropylethylenediammonium diclavulanate A dried concentrated extract of crude clavulanic acid in ethyl acetate was prepared in accordance with known methods, for example as disclosed in WO95/23870. The clavulanic acid content was 32 g/1 and the water content was below 2 g/1. The ethyl acetate extract (500 cm 3 ) was decolorised by treatment with 5 g/1 of activated charcoal. N,N' -diisopropylethylenediamine (10 cm 3 ) was added during 10 min with vigorous stirring. The solution was stirred for a further 15 min and the precipitate was separated. The precipitate was washed with 2 x 50 cm 3 portions of acetone and dried under vacuum (1 hr, 100 mbar, 40"C) . N,N'- diisopropylethylenediammonium diclavulanate (24 g, yield 80%) was obtained. Analysis: Assay of clavulanic acid: 53.0% Transparency of 2% aq. solution of N,N' -diisopropylethylenediammonium diclavulanate: 4.4% Assay of impurities: 4.0 Area % Example 1 N,N' -diisopropylethylenediammonium diclavulanate A dried concentrated extract of crude clavulanic acid in ethyl acetate was prepared in accordance with known methods, for example as disclosed in WO95/23870. The clavulanic acid content was 32 g/1 and the water content below 2 g/1. The ethyl acetate extract (500 cm 3 ) was decolorised by treatment with 5 g/1 of activated charcoal. Methanol (165 cm 3 ) was added followed by N,N' -diisopropylethylenediamine (10 cm 3 ) during 10 min with vigorous stirring. The solution was stirred for a further 15 min and the precipitate was separated. The precipitate was washed with 2 x 50 cm 3 portions of acetone, dried under vacuum (1 hr, 100 mbar, 40 * C) and N,N' -diisopropylethylenediammonium diclavulanate (24 g, yield 96%) was obtained. Analysis : Assay of pure potassium clavulanate: 61.1% Transparency of 2% aq.solution of N,N' -diisopropylethylenediammonium: 81.7% Assay of impurities: 0.3 Area % Example 2 Preparation of pure potassium clavulanate 2 (a) N,N' -diisopropylenediammonium diclavulanate (19.4 g, 0,028 mole) prepared in accordance with Example 1 was dissolved in isopropanol (165 cm 3 ) and water (7 cm 3 ) . The solution was further diluted with isopropanol (320 cm 3 ) and was decolorised with active charcoal (2.5 g) . The solution was filtered and potassium 2-ethyl hexanoate (2 M solution, 25 cm 3 ) was added at room temperature during 15 min. The solution was stirred for an additional 5 min and chilled to 10 * C. The product was filtered, washed with 2 x 5 cm 3 portions of acetone and dried under vacuum at 40 * C. Pure potassium clavulanate (10 g, yield 70%) was obtained as crystalline needles. Analysis: Assay of clavulanic acid: 83.3% Transparency of 2% aq. solution of N,N' -diisopropylethylenediammonium diclavulanate: 91.6% Assay of impurities: 0.0 Area % 2 (b) N,N'Diisopropylethylenediammonium diclavulanate (10.0 g, assay 62%) was added to a mixture of isopropanol (85 cm 3 ) and water (3.5 cm 3 ) . The suspension was warmed to 27 * C to obtain a homogeneous solution. Active charcoal (3.85 g) was added. The solution was stirred for 20 min and the charcoal was removed by filtration and washed with isopropanol (45 cm 3 ) . The filtrate and isopropanol washings were combined and potassium 2-ethyl hexanoate (2 M solution in isopropanol) was added dropwise during 15 min. The mixture was cooled to 0 to 10 * C to stirred for 1 hr. The resultant crystals were filtered, washed once with isopropanol (20 cm 3 ) and washed twice with acetone (20 cm 3 ) . The product was dried under vacuum at 30 to 40 * C to give potassium clavulanate (5.8 g, yield 76%, assay of clavulanic acid 81.6%) . 2 (c) N,N,N' ,N' -Tetramethylethylenediammoniumdiclavulanate (8.0g, assay 71%) was dissolved in water (8 cm 3 ) and diluted with isopropanol (100 cm 3 ) . The resultant mixture was treated with active charcoal (1.2 g) , filtered and a solution of potassium 2- ethyl hexanoate (2 M in isopropanol, 19.0 cm 3 ) was added in small portions. The mixture was stirred for 30 min at room temperature and the precipitate was filtered, dried under vacuum in silica gel at room temperature to give pale yellow crystals of potassium clavulanate (5.26 g, yield 75%, assay 80.9%) . Example 3 A dried concentrated extract of clavulanic acid (20.0 g/1) in ethyl acetate was diluted with methanol (330 cm 3 ) N,N' - diisopropylethylenediamine (DIPEDA) (10.1 cm 3 , 10% excess) was added dropwise with stirring during 10 min. The mixture was cooled to -10"C, further stirred for 30 min and the precipitate filtered, washed with acetone (2 x 50 cm 3 ) and dried at 30 to 40 * C at reduced pressure. Clavulanic acid DIPEDA salt (24.8 g, yield 80%, assay 64.3) was obtained. Example 4 The procedure of Example 3 was repeated with the same amount of other alcohols and the results are shown in Table 1. Table 1: Preparation of N,N' -Diisopropylethylenediamine (DIPEDA) Salt AMINE ADDED YIELD TRANSMIT- ASSAY OF CALCULATED SOLVENT % TANCE (2% CLAV. ASSAY OF sol. , ACID (in THE SALT 420 nm) %) (%) DIPEDA / 62 30 55.4 75.5 DIPEDA n-butanol 50 93 60.9 83.0 DIPEDA isobutanol 73 94 61.0 83.2 DIPEDA isopropanol 84 90 66.0 90 DIPEDA ethanol 69 89 53.5 73.0 DIPEDA methanol 80 96 64.3 87.7 Example 5 A dried concentrated solution of clavulanic acid in ethyl acetate (300 cm 3 , 25.2 g/1) was diluted with methanol (50 cm 3 ) and acetone (50 cm 3 ) . N,N' -diisopropylethylenediamine (4.1 cm 3 , 20% excess) was added in small portions during 5 min. The resulted heterogeneous mixture was stirred at 0 * C for 1 hr and the precipitated product was filtered and treated as described in Example 3 to give clavulanic acid DIPEDA salt (9.61 g, yield 74%, assay 58%) . The results of analogous procedures in which the ethyl acetate extract was diluted with a mixture of different water miscible solvents is shown in Table 2. Table 2: Preparation of N,N' -Diisopropylethylenediamine (DIPEDA) Salt in Three-solvent Mixtures AMINE ADDED ADDED YIELD TRANSMIT- ASSAY OF SOLVENT I SOLVENT II (%) TANCE (2% CLAV. sol. , ACID (%) 420 nm) DIPEDA methanol / 78 99 65 DIPEDA methanol acetone 78 78 61 DIPEDA methanol ethanol 70 93 59 DIPEDA methanol isopropanol 75 94 61 Example 6 A solution of clavulanic acid in ethyl acetate (1 1, 29.8 g/1) was diluted with acetonitrile (330 cm 3 and the procedure was continued as described in Example 3 to give clavulanic acid DIPEDA salt crystals (38.9 g, yield 77%, assay 59%) . Example 7 A solution of clavulanic acid in ethyl acetate (1 1, 22.1 g/1) was diluted with different amounts of methanol, treated with 10% excess of N,N' -diisopropylethylenediamine and the procedure of Example 3 was followed. The results are shown in Table 3. Table 3: Preparation of N,N' -Diisopropylethylenediamine (DIPEDA) Salt using different volumes of methanol AMINE ADDED RATIO YIELD TRANSMIT- ASSAY OF SOLVENT I EtOAc/ (%) TANCE (2% CLAV.ACI methanol sol., 420 D (%) nm) DIPEDA methanol 0% MeOH 77 88 57 DIPEDA methanol 3:1 81 96 61 DIPEDA methanol 2:1 79 96 62 DIPEDA methanol 1:1 73 97 63 Example 8 An ethyl acetate solution of clavulanic acid (1 1, 25.2 g/1) was diluted with ethanol (33 cm 3 ) . N,N' -diethylethylenediamine (10.0 cm 3 , 10% excess) was added dropwise during 15 min with stirring and the mixture was stirred for a further 30 min. After cooling below 0 * C the mixture was filtered to give precipitated product which was washed with acetone and dried at 25 'C under reduced pressure to give 27.1 g (yield 61%, assay 71%) . The results of experiments in which ethanol was omitted or replaced with another alcohol are shown in Table 4. Table 4: Preparation of N,N-Diethylethylenediamine (DEEDA) Salt AMINE ADDED YIELD TRANSMIT- ASSAY OF CALCULATED SOLVENT (%) TANCE (2% CLAV. ACID ASSAY OF sol. , (%) THE SALT 420 nm) (%) DEEDA methanol 0% MeOH 77 88 57 DEEDA methanol 3:1 81 96 61 DEEDA methanol 2:1 79 96 62 DEEDA methanol 1:1 73 96 63 Example 9 An ethyl acetate solution of clavulanic acid (1 1, 24.0 g/1) was diluted with isopropanol (330 cm 3 ) . N,N,N' ,N'- tetramethylethylenediamine (11.0 cm 3 , 10% excess) was added dropwise during a period of 15 min and the solution stirred for 1 hr. After cooling below 0 * C, the mixture was filtered to give a precipitated product which was washed with acetone and dried under reduced pressure at 25"C to give 12.5 g (yield 37%, assay 71%) . The result of experiments in which isopropanol was omitted or replaced with another alcohol are shown in table 5. Table 5: Preparation of N,N,N' ,N' -Tetramethylethylenediamine (TMEDA) Salt Example 10 An ethyl acetate solution of clavulanic acid (1 1, 24.0 g/1) was diluted with ethanol (330 cm 3 ) . N,N-dibenzylethylenediamine (15.7 cm 3 , 10% excess) was added dropwise during 15 min and the mixture was stirred for 1 hr. After cooling below 0 * C the mixture was filtered to give a precipitate which was washed with acetone and dried at 25 * C under reduced pressure to give 22.5 g (yield 54%, assay 57.3%) . The results of experiments in which ethanol was omitted or replaced with other alcohols are shown in Table 6. Table 6 : Preparation of N,N'- -Dibenzylethylenedia ine (DBEDA) Salt AMINE ADDED YIELD TRANSMIT- ASSAY OF CALCULATED SOLVENT (%) TANCE (2% CLAV. ACID ASSAY OF sol. , (%) THE SALT 420 nm) (%) DBEDA / 3 73 DBEDA isopropanol 31 93 58.8 94.4 DBEDA ethanol 54 93 57.3 92.0 DBEDA methanol 0 Example 11 A solution of clavulanic acid in ethyl acetate (1 1, 17.5 g/1) was diluted with isopropanol (330 cm 3 ) . Tert-butylamine (10.1 cm 3 , 10% excess) was added dropwise during 15 min and the mixture stirred for 1 hr. After cooling below 0"C the mixture was filtered to give a precipitated product which was washed with acetone and dried at 25 * C under reduced pressure to give 21.1 g (yield 77%, assay 63.8%) . Results of experiments in which isopropanol was omitted or replaced with another alcohol are shown in Table 7. Table 7 : Preparation of tert -Butylamine (TBA) Salt AMINE ADDED YIELD TRANSMIT- ASSAY OF CALCULATED SOLVENT (%) TANCE (2% CLAV. ACID ASSAY OF sol. , (%) THE SALT 420 nm) (%) TBA / 81 76 67.0 91.7 TBA isopropanol 77 94 63.8 87.3 TBA ethanol 43 96 65.5 89.6 TBA methanol 0 Example 12 A solution of clavulanic acid in ethyl acetate (1 1, 20.9 g/1) was diluted with ethanol (330 cm 3 ) . Benzyl- tert-butylamine (21.9 cm 3 , 10% excess) was added dropwise during 15 min and the mixture was stirred for 1 hr. After cooling below 0 * C the mixture was filtered to give a precipitated product which was washed with acetone and dried at 25 * C in vaccuo to give 27.1 g (yield 68%, assay 52.5%) . The results of experiments in which ethanol was omitted or replaced with another alcohol are shown in Table 8. Table 8: Preparation of Benzyl-tert-butylamine (BTBA) Salt AMINE ADDED YIELD TRANSMIT- ASSAY OF CALCULATED SOLVENT (%) TANCE (2% CLAV. ACID ASSAY OF sol. , (%) THE SALT 420 nm) (%) BTBA / 83 93 53.2 97.0 BTBA isopropanol 67 90 52.1 95.0 BTBA ethanol 68 94 52.5 95.7 BTBA methanol 0 Example 13 A solution of clavulanic acid in ethyl acetate (1 1, 18.4 g/1) was diluted with isopropanol 330 cm 3 . Tert-octylamine (16.4 cm 3 , 10% excess) was added dropwise during 15 min and the mixture was stirred for 1 hr. After cooling below 0 * C the mixture was filtered to give a precipitated product which was washed with acetone and dried at 25 * C under reduced pressure to give 21.6 g (yield 67%, assay 57.2%) . The results of experiments in which isopropanol was omitted or replaced with another alcohol are shown in Table 9. Table 9 : Preparation of tert -Octylamine (TOA) Salt AMINE ADDED YIELD TRANSMIT ASSAY OF CALCULATED SOLVENT (%) -TANCE CLAV. ACID ASSAY OF (2% (%) THE SALT sol. , (%) 420 nm) TOA / 80 75 55.8 92.1 TOA isopropanol 67 90 57.2 94.5 TOA ethanol 35 92 56.8 93.8 TOA methanol 0 Example 14 A solution of clavulanic acid in ethyl acetate (1 1, 28.3 g/1) was diluted with methanol (330 cm 3 ) . 1-adamantanamine (23.7 mg, 10% excess) was added in small portions during 15 min and the mixture was stirred for 1 hr. After cooling below 0"C the mixture was filtered to give a precipitate which was washed with acetone and dried at 25 * C under reduced pressure to give 39.6 g (yield 76%, assay 54.3%) . The results of experiments in which methanol was omitted or replaced by other alcohols are shown in Table 10. Table 10: Preparation of 1-Adamantanamine (AA) Salt AMINE ADDED YIELD TRANSMIT- ASSAY OF CALCULATED SOLVENT (%) TANCE (2% CLAV. ACID ASSAY OF sol. , (%) THE SALT 420 nm) (%) AA / 81 92 55.0 93.3 AA isopropanol 76 89 53.0 89.9 AA ethanol 80 89 54.0 91.6 AA methanol 76 94 54.3 92.1 Example 15 A solution of clavulanic acid in ethyl acetate (1 1, 28.3 g/1) was diluted with ethanol (33 cm 3 ) . Sec-butylamine (15.8 cm 3 , 10% excess) was added dropwise during 15 min and the mixture was stirred for 1 hr. After cooling below 0 * C the mixture was filtered to give a precipitate which was washed with acetone and dried at 25 * C under reduced pressure to give 21.0 g (yield 52.6%, assay 70.8%) . The results of experiments in which ethanol was omitted or replaced with alcohols are shown in Table 11. Table 11: Preparation of sec-Butylamine (SBA) Salt AMINE ADDED YIELD TRANSMIT- ASSAY OF CALCULATED SOLVENT (%) TANCE (2% CLAV. ACID ASSAY OF sol. , (%) THE SALT 420 nm) (%) SBA / 8 65 SBA isopropanol 52 94 70.3 96.2 SBA ethanol 53 96 70.8 96.9 SBA methanol 0

Claims: CLAIMS 1. A process for preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, including the steps of: a. adding an additional solvent to a solution of clavulanic acid in a water immiscible solvent; b. contacting the solution with an amine; c. isolating the amine salt of clavulanic acid formed; and d. converting the amine salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof. 2. A process as claimed in claim 1, wherein the additional solvent is selected from: alcohols, nitriles, ketones and mixtures thereof. 3. A process as claimed in claim 2, wherein the additional solvent is selected from: C_ to C 6 alcohols, acetonitrile, acetone and mixtures thereof. 4. A process as claimed in claim 3, wherein the additional solvent is selected from: methanol, ethanol, isopropanol, n- butanol, isobutanol and acetonitrile. 5. A process as claimed in claim 4, wherein the additional solvent is methanol. 6. A process as claimed in any preceding claim, wherein the amine is of formula I • ■ is N- ( CH 2 ) n — N N • V / wherein the substituents R 1 , R 2 , R 3 , and R 4 are independently: hydrogen; C_ to C 8 straight or branched alkyl ; C 2 to C 4 hydroxyalkyl or wherein the groups NR^ and NR 3 R 4 jointly denote a heterocyclic group having 3 to 6 methylene groups optionally substituted with oxygen sulphur or an imino group; wherein R 5 denotes hydrogen or methyl; and n is an integer from 1 to 3. 7. A process as claimed in claim 6, wherein the amine is a symmetrical N,N' -alkylethylene diamine. 8. A process as claimed in claim 7, wherein the diamine is selected from N,N' -diisopropylethylene diamine, N,N'- diethylethylene diamine, N,N' -dibenzylethylene diamine, N,N,N',N'- tetramethylethylene diamine. 9. A process as claimed in claim 8, wherein the diamine is N,N' -diisopropylethylene diamine. 10. A process as claimed in any of claims 1 to 5, wherein the amine is selected from: tertiary butylamine, benzyl tertiary butylamine, tertiary octylamine, secondary butylamine and adamantine amine. 11. A process as claimed in any of claims 5 to 10 wherein the water immiscible solvent is ethyl acetate, the additional solvent is methanol and the ratio of ethyl acetate to methanol is 4:1 to 2:1. 12. A process as claimed in claim 11 wherein the ratio is 3:1.

Inventors: CAPUDER EGIDIJ, CAPUDER, EGIDIJ
Applicants: CAPUDER EGIDIJ, LEK TOVARNA FARMACEVTSKIH, CAPUDER, EGIDIJ, LEK PHARMACEUTICAL AND CHEMICAL CO. D.D.
Application year: 1996
Main classification: C07D503
IPC codes: A61K31, A61P31, C07D503, C12P17