MXPA99004322A - Process for the preparation of salts and esters of clavulanic acid - Google Patents
Process for the preparation of salts and esters of clavulanic acidInfo
- Publication number
- MXPA99004322A MXPA99004322A MXPA/A/1999/004322A MX9904322A MXPA99004322A MX PA99004322 A MXPA99004322 A MX PA99004322A MX 9904322 A MX9904322 A MX 9904322A MX PA99004322 A MXPA99004322 A MX PA99004322A
- Authority
- MX
- Mexico
- Prior art keywords
- clavulanic acid
- clavulanate
- amine
- water
- addition
- Prior art date
Links
- HZZVJAQRINQKSD-PBFISZAISA-N Clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 title claims abstract description 81
- 229960003324 Clavulanic Acid Drugs 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 23
- 239000011780 sodium chloride Substances 0.000 title claims abstract description 17
- 150000002148 esters Chemical class 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000003839 salts Chemical class 0.000 title claims description 12
- 150000001412 amines Chemical class 0.000 claims abstract description 26
- -1 alkali metal salts Chemical class 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 238000007792 addition Methods 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- GTEXIOINCJRBIO-UHFFFAOYSA-N 2-[2-(dimethylamino)ethoxy]-N,N-dimethylethanamine Chemical compound CN(C)CCOCCN(C)C GTEXIOINCJRBIO-UHFFFAOYSA-N 0.000 claims description 14
- 229940090805 Clavulanate Drugs 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000005712 crystallization Effects 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 9
- 238000000855 fermentation Methods 0.000 claims description 9
- 230000004151 fermentation Effects 0.000 claims description 9
- 239000002002 slurry Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- YBRBMKDOPFTVDT-UHFFFAOYSA-N Tert-Butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- JGVZJRHAZOBPMW-UHFFFAOYSA-N 1,3-bis(dimethylamino)propan-2-ol Chemical compound CN(C)CC(O)CN(C)C JGVZJRHAZOBPMW-UHFFFAOYSA-N 0.000 claims description 3
- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical compound CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 claims description 3
- 241000187433 Streptomyces clavuligerus Species 0.000 claims description 3
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 claims description 3
- 244000005700 microbiome Species 0.000 claims description 3
- 229960004920 Amoxicillin Trihydrate Drugs 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N Tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- MQXQVCLAUDMCEF-CWLIKTDRSA-N amoxicillin trihydrate Chemical compound O.O.O.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 MQXQVCLAUDMCEF-CWLIKTDRSA-N 0.000 claims description 2
- 230000000875 corresponding Effects 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000003763 carbonization Methods 0.000 claims 2
- SLFUXNFVAANERW-UHFFFAOYSA-N ethyl hexanoate;potassium Chemical compound [K].CCCCCC(=O)OCC SLFUXNFVAANERW-UHFFFAOYSA-N 0.000 claims 2
- 238000002955 isolation Methods 0.000 claims 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-Butylamine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 23
- 235000012970 cakes Nutrition 0.000 description 12
- 239000012467 final product Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000003610 charcoal Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- MELCWEWUZODSIS-UHFFFAOYSA-N 2-[2-(diethylamino)ethoxy]-N,N-diethylethanamine Chemical compound CCN(CC)CCOCCN(CC)CC MELCWEWUZODSIS-UHFFFAOYSA-N 0.000 description 2
- ZUFQCVZBBNZMKD-UHFFFAOYSA-M Potassium 2-ethylhexanoate Chemical compound [K+].CCCCC(CC)C([O-])=O ZUFQCVZBBNZMKD-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N 2-Pentanone Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- SBOJXQVPLKSXOG-UHFFFAOYSA-N O-amino-Hydroxylamine Chemical class NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 description 1
- 102100010976 SLC39A2 Human genes 0.000 description 1
- 101710017106 SLC39A2 Proteins 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 102000006635 beta-Lactamases Human genes 0.000 description 1
- 108020004256 beta-Lactamases Proteins 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
Abstract
An improved process for the preparation of pharmaceutically acceptable alkali metal salts or esters of clavulanic acid has been provided for. Furthermore, also potassium clavulanate with an extremely low amine content and pharmaceutical compositions comprising the same have been provided for.
Description
PROCESS FOR THE PREPARATION OF SALTS AND ESTERS OF THE CLAVULAN ACID
DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of pharmaceutically acceptable alkali metal salts and esters of clavulanic acid, especially potassium clavulanate. Clavulanic acid and its alkali metal salts and esters are inhibitors of β-lactamase, capable of improving the effectiveness of penicillins and cephalosporins. Clavulanic acid is usually prepared by the fermentation of a microorganism that produces clavulanic acid such as for example strains of Streptomyces such as Streptomyces clavuligerus. The resulting aqueous broth is usually subjected to conventional purification and concentration processes, such as those described in GB-1508977. EP-A-26044 describes the use of the tertiary butylamine salt of clavulanic acid as a useful intermediate in the preparation of clavulanic acid. Other amine salts of clavulic acid are described in for example WO 93/25557,
REF. : 30276 WO 94/22873, EP-A-0387178, EP-A-562583, WO 96/26944 and WO 96/20199. In the present application also the diaminoethers described in the last application are considered as amines. All of these cited references are incorporated in the present application by reference. The object of this invention is to prepare clavulanic acid and its pharmaceutically acceptable salts such as the potassium salt, wherein the desired substance is obtained in high yield and high purity. A lot of process improvements were surprisingly found. First of all, the extraction of the complete broth seems to be an advantageous alternative to remove solids from the fermentation broth. A further improvement is related to the application of an amine, which forms, with clavulanic acid, an amine clavulanate, which adheres to the walls in the normally applied ethyl acetate / acetone solution. The addition of an organic solvent miscible with water as an alcohol, preferably absolute alcohol, avoids the tendency to adhere to the walls of the diamine crystals of the crystallization vessel, which results in a loss of performance. In addition, it seems to be possible to influence the morphology of the crystals of the final product by regulating the amount of water added during the crystallization stage. According to the present invention there has been provided a process for the preparation of a pharmaceutically acceptable salt or ester of clavulanic acid, comprising one or more of the following steps: fermentation of a microorganism that produces clavulanic acid; - acidify the broth containing the clavulanic acid; - optional addition of a small amount of a water-miscible solvent; extraction of the broth containing acidified clavulanic acid with an organic solvent immiscible in water; concentration of the immiscible organic solution in water containing clavulanic acid by evaporation; - purification of the concentrated solution of clavulanic acid by adsorption; filtration of the clavulanic acid solution; - optional addition of one or more organic solvents miscible in water;
adding an amine, optionally together with a water-miscible solvent, to prepare a clavulanate salt of the amine; optional recrystallization of the clavulanate salt of the formed amine; conversion to purified clavulanic acid by acidification or in a pharmaceutically acceptable salt or ester of clavulanate by adding a source of the corresponding salt or ester; separation of the pharmaceutically acceptable salt or clavulanate ester from the solution. This applies, for example, to the application of amines, especially of N, N, N ', N' -tetramethyl-ethylenediamine, 1,3-bis (di-methylamino) -2-propanol, t-butylamine, t-octylamine, benzhydrylamine and bis (2- (dimethylamino) ethyl) ether. In almost all processes of the prior art it is emphasized that it must be necessary to remove all suspended solids before solvent extraction. Although filtration or ultrafiltration give favorable results, it turns out that the extraction of the complete broth gives a final result comparable in terms of yield and purity of the final product. An important advantage of eliminating the filtration step is of course a greater efficiency of the process eliminating a stage of the process. The possible difficulties of the broth instability and the formation of an emulsion can be overcome by adding a small amount (up to about 25% of the total volume of the fermentation broth) of solvent such as a ketone or water miscible alcohol and / or adjustment of the pH to denature the proteins in the broth and / or addition of a suitable demulsifier and thus improve the efficiency of the extraction of the complete broth. During the step of crystallizing the amine clavulanate it has been found advantageous to add a small amount of an alcohol such as absolute ethanol to the mixture comprising clavulanic acid and the extraction solvent, preferably ethyl acetate and the crystallization solvent, of acetone preference. In a preferred embodiment, the alcohol is added before or simultaneously with the amine. The application of this mixture of three solvent components decreases the display of the crystals that adhere to the walls, resulting in a loss of performance and also surprisingly results in an improvement of the purity and general quality characteristics. All the ways of adding the amine to the mixture comprising clavulanic acid then result in favorable crystallization results, for example in addition to the addition of the amine to the mixture comprising clavulanic acid, both the simultaneous addition of the amine and the mixture of clavulanic acid to a reaction vessel and the addition of the clavulanic acid mixture to the amine. In addition, recrystallization may optionally be applied by treating the aqueous solution of amine clavulanate, either without solvent or partially diluted with solvent, with charcoal and then filtering the resulting solution sterile prior to sterile crystallization. During the formation of potassium clavulanate it has been found to be advantageous to form the same by making a slurry of the amine salt in solvent, preferably a ketone or water-irascible alcohol and then adding a potassium source, preferably ethenohexanoate. potassium in a solvent, also preferably a ketone or water miscible alcohol. The use of a slurry system significantly reduces the amount of solvent required, which reduces costs and increases the yield of the final product.
In addition, it has been found that it is advantageous to add a small amount of water to the solvent (slurry). Surprisingly it has been found that by doing this it is possible to influence the crystalline morphology of the final product. Thus, it is possible to obtain crystals that can be washed more easily, and that have improved filtration and drying characteristics. In this way it is possible to form crystals in the form of rosettes or needles, preferably a cluster of needle-shaped crystals. Furthermore, especially in the case where bis (2- (di-methylamino) ethyl) ether is applied as an amine, the residual amine in the final product is extremely low, less than 0.05% w / w, preferably less than 0.02% p. / p seems to be possible, ie ten times less than the tertiary butylamine concentration allowed by the British Pharmacopoeia. A low amine content in the amine clavulanate intermediate is desirable, since it results in a more stable end product. Therefore, it is actually advantageous to apply potassium clavulanate, prepared in this way, in a pharmaceutical composition comprising potassium clavulanate and amoxicillin trihydrate.
The following examples are given for illustration purposes only.
Examples
EXAMPLE 1 Extraction of the whole broth from a broth containing clavulanic acid The broth that resulted from a formation with Streptomyces clavuligerus (3.5 1, containing 13.3 g of clavulanic acid) was cooled to 2 ° C. This broth was added to 10.5 1 of ethyl acetate at 1-3 ° C while stirring. After addition of the broth, the pH of the mixture was adjusted to pH = 1.6 with the help of 3 M sulfuric acid. The mixture was allowed to settle for 5 minutes, and the layers were separated. 9.25 1 was collected from the ethyl acetate layer, which contained 7.5 g of clavulanic acid.
EXAMPLE 2 Evaporation of the ethyl acetate solution containing the clavulanic acid The ethyl acetate solution (9: 1) of the previous example was evaporated in vacuo at 30-35 ° C, using a natural circulation evaporator. A concentrated solution (0.88 1) was obtained, which contained 7.5 g of clavulanic acid. This solution was concentrated using a rotary thin film evaporator (vacuum, 30-35 ° C). A concentrate (0.11 1) was obtained, which contained 7.4 g of clavulanic acid.
EXAMPLE 3 Preparation of crystalline bis (2- (dimethylamino) ethyl) ether diclavulanate A ethanol (50 ml) was placed in a one-liter three-necked round bottom flask fitted with a thermometer, two addition funnels and a stirrer. The temperature was brought to 10 ° C and under stirring an impure solution of clavulanic acid (400 ml, 32.9 g of clavulanic acid co / liter) in ethyl acetate and a solution of bis (2- (di-ethylamino) ethyl) ether ( 13.5 g) in ethanol (230 ml) were added simultaneously. The temperature during the addition was maintained between 10-15 ° C. After the addition (15-20 minutes), the mixture was stirred for one hour at 5 ° C. The crystals were filtered, washed twice with ethyl acetate (40 ml) and dried under vacuum at room temperature. 16 g of bis (2- (dimethylamino) ethyl) ether diclavulanate were obtained.
Example 4 Purification of the clavulanic acid solution by treatment with carbon The concentrated ethyl acetate solution of example 2 (7.4 g of clavulanic acid in 110 ml) was subjected to a charcoal treatment. The solution was cooled to 5 ° C, and charcoal (16.5 g, Norit SX Ultra) was added. The mixture was stirred for two hours at 5-10 ° C. Filtration aid (Dicalite, 5 g) was added, and the mixture was filtered. The solid cake was washed with ethyl acetate until the volume of the collected filtrate was 185 ml.
Example 5 Crystallization of bis (2- (dimethylamino) ethyl) ether diclavulanate from a concentrated solution of clavulanis acid in ethyl acetate The following experiment was carried out under a nitrogen atmosphere. Absolute ethanol (450 ml) was added to a solution of clavulanic acid in ethyl acetate (900 ml, concentration of 40 g of clavulanic acid / liter). The solution was stirred, cooled to 10 ° C, and bis (2- (dimethylamino) ethyl) ether (35.1 ml, 0.18 mol) was added. The mixture was cooled to 3 ° C, and stirred for one hour.
The crystalline suspension was filtered, and the cake was washed with 200 ml of acetone, and again with 200 ml of acetone. The wet cake was dried in vacuum at room temperature. 45 g of bis (2- (dimethylamino) ethyl) ether diclavulanate were obtained.
Example 6 Crystallization of potassium clavulanate starting from bis (2- (dimethylamino) ethyl) ether diclavulanate The following experiment was carried out under a nitrogen atmosphere. The diclavulanate of bis (2- (dimethylamino) ethyl) ether (10 g) was suspended in a mixture of acetone (300 ml) and water (6 ml). The mixture was stirred, cooled to 12 ° C, and a solution of potassium 2-ethylhexanoate in acetone (125 ml of a 0.34 M solution) was added over the course of 10 minutes. The mixture was cooled to 5 ° C, and stirred for one hour. The crystalline suspension was filtered and the cake was washed with three volumes of acetone cake. The wet cake was dried in vacuum at 20 ° C. 8.22 g of potassium clavulanate were obtained.
* Example 7 Purification of bis (2- (dimethylamino) ethyl) ether diclavulanate by recrystallization The following experiment was carried out under a nitrogen atmosphere. Bis (2- (dimethylamino) ethyl) ether diclavulanate (10 g) was dissolved in a mixture of absolute ethanol (45 ml) and water (5 ml) at 20 ° C. The clear solution was added to acetone (250 ml) over the course of 20 minutes, while stirring the mixture at 20 ° C. The mixture was cooled to 5 ° C, and stirred for 30 minutes. The crystalline suspension was filtered, and the cake was washed with two volumes of acetone cake. The crystals were dried in vacuo at 20 ° C. They were obtained
9. 44 g of bis (2- (dimethylamino) ethyl) ether diclavulanate.
Example 8 Crystallization of potassium clavulanate starting from bis (2- (di-ethylamino) ethyl) ether diclavulanate with an intermediate treatment with carbon The following experiment was carried out under a nitrogen atmosphere. Bis (2- (dimethylamino) eti 1) ether diclavulanate (10 g) was dissolved in a mixture of absolute ethanol (45 ml) and water (5 ml) at 20 ° C. The pH of the mixture was adjusted to pH = 6.5 with the aid of 2-ethylhexanoic acid. Charcoal (1 g) was added, and the mixture was stirred for 30 minutes. Filtration aid (Dicalite, 0.3 g) was added, and the mixture was filtered.
The cake was washed with absolute ethanol (5 ml), and acetone (10 ml). The combined filtrates were added to acetone (250 ml) at 10 ° C. A crystalline suspension was obtained. A solution of potassium 2-ethylhexanoate in acetone (125 ml of a 0.34 M solution) was added over the course of 10 minutes. The mixture was cooled to 5 ° C, and stirred for one hour. The crystalline suspension was filtered and the cake was washed with three volumes of acetone cake. The wet cake was dried under vacuum at 20 ° C. Obtained 7.56 g of potassium clavulanate needle clusters.
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.
Claims (14)
1. A process for the preparation of a pharmaceutically acceptable salt or ester of clavulanic acid or for the isolation of clavulanic acid, consisting essentially of the following steps: fermentation of a microorganism that produces clavulanic acid; acidifying the broth containing the clavulanic acid; - optional addition of a small amount of a water-miscible solvent; - extraction of the broth containing acidified clavulanic acid with an organic solvent immiscible in water; - concentration of the immiscible organic solvent in water containing clavulanic acid by evaporation; purification of the concentrated solution of clavulanic acid by treatment with carbon; - filtration of the clavulanic acid solution; optional addition of one or more organic solvents miscible in water; - addition of an amine, optionally together with a water-miscible solvent, to prepare a clavulanate salt of the amine; - optional recrystallization of the clavulanate salt of the amine formed; - conversion to purified clavulanic acid by acidification or in a pharmaceutically acceptable salt or ester of clavulanate by adding a source of the corresponding salt or ester; - separation of the clavulanic acid or pharmaceutically acceptable salt or ester of clavulanate from the solution. Characterized in that the conversion of the clavulanate salt of the amine into a clavulanate of a pharmaceutically acceptable salt or ester or clavulanic acid is carried out in a slurry system by making a watery slurry of amine clavulanate in a solvent to make the gaseous paste if necessary, and contacting it with a compound that forms the pharmaceutically acceptable salt or ester or with an acid.
2. A process according to claim 1, characterized in that a small amount of water is added to the solvent that forms the slurry.
3. A process according to claim 1 or 2, characterized in that any of the amines N, N, N ', N'-tetramethylethylenediamine, 1,3-bis (dimethylamino) -2-propanol, t-butylamine, is applied as amine. t-octylamine, benzhydrylamine and bis (2- (dimethylamino) ethyl) ether.
4. A process according to any of claims 1-3, characterized in that the solids are removed from the fermentation broth containing clavulanic acid prior to extraction.
5. A process according to any of claims 1-4, characterized by the addition of a ketone and / or water miscible alcohol to the fermentation broth.
6. A process according to any of claims 1-5, characterized by extracting the broth containing acidified clavulanic acid with ethyl acetate.
7. A process according to any of claims 1-6, characterized by the addition of the water-miscible solvent acetone to the clavulanic acid solution after the purification and filtration steps.
8. A process according to any of claims 1-7, characterized by the addition of the water-miscible solvent ethanol to the solution comprising clavulanic acid, before or simultaneously with the addition of the amine to prepare a clavulanate salt of the amine.
9. A process according to claim 8, characterized by the simultaneous addition of the amine and the solution comprising clavulanic acid to a reaction vessel.
10. A process according to claim 8, characterized by the addition of the solution comprising clavulanic acid to the amine.
11. A process according to any of claims 1-10, characterized by recrystallization of the amine clavulanate in a mixture of ethanol and water, optional treatment with carbon and crystallization by the addition of acetone.
12. A process for the preparation of potassium clavulanate, consisting essentially of the following stages: fermentation of Streptomyces clavuligerus to produce clavulanic acid; acidify the broth containing clavulanic acid at a pH between 1 and 3 by the addition of a concentrated acid solution; - optional removal of solids from the fermentation broth; - optional addition of a small amount of a ketone or water-miscible alcohol; extraction of the broth containing acidified clavulanic acid with ethyl acetate; concentration of ethyl acetate solution containing clavulanic acid by evaporation; purification of the solution by treatment with carbon; filtration of the resulting solution of clavulanic acid; optional addition of acetone; addition of ethanol and any of the amines N, N, N ', N' -tetramethi leti lendiamine, 1,3-bis (di-methylamino) -2-propanol, t-15 butylamine, t-octylamine, benzhydrylamine and bis ( 2- (dimethylamino) ethyl) ether; optional recrystallization of the amine clavulanate formed by dissolving it in a mixture of ethanol and water, optional treatment with carbon, and crystallization from acetone; conversion to potassium clavulanate by adding potassium ethylhexanoate; - isolation of potassium clavulanate 25 from the watery paste, characterized in that conversion of the amine clavulanate salt to potassium clavulanate is carried out in a slurry system and contacting it with potassium ethylhexanoate in a ketone. or miscible alcohol in water.
13. A process according to claim 12, characterized in that a small amount of water is added to the solvent that forms the slurry.
14. Pharmaceutical composition characterized in that it comprises potassium clavulanate prepared according to any of claims 1-13, and amoxicillin trihydrate.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96203117.5 | 1996-11-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99004322A true MXPA99004322A (en) | 2000-02-02 |
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