MXPA97004641A - Production of cefotaxima and new social salts - Google Patents
Production of cefotaxima and new social saltsInfo
- Publication number
- MXPA97004641A MXPA97004641A MXPA/A/1997/004641A MX9704641A MXPA97004641A MX PA97004641 A MXPA97004641 A MX PA97004641A MX 9704641 A MX9704641 A MX 9704641A MX PA97004641 A MXPA97004641 A MX PA97004641A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- compound
- cefotaxime
- acetone
- sodium salt
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 31
- GPRBEKHLDVQUJE-QSWIMTSFSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-QSWIMTSFSA-N 0.000 title description 9
- 150000003839 salts Chemical class 0.000 title description 4
- 239000011780 sodium chloride Substances 0.000 title description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 114
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 25
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 claims description 75
- 150000001875 compounds Chemical class 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 18
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7-ACA Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims description 11
- 229910001415 sodium ion Inorganic materials 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- 229960004261 Cefotaxime Drugs 0.000 abstract description 73
- GPRBEKHLDVQUJE-VINNURBNSA-N Cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 abstract 2
- 239000002253 acid Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 9
- 230000005712 crystallization Effects 0.000 description 9
- -1 2-aminothiazolyl function Chemical group 0.000 description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 229940088530 Claforan Drugs 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 229940087562 Sodium Acetate Trihydrate Drugs 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- AYRVGWHSXIMRAB-UHFFFAOYSA-M sodium acetate trihydrate Chemical compound O.O.O.[Na+].CC([O-])=O AYRVGWHSXIMRAB-UHFFFAOYSA-M 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229960002727 Cefotaxime Sodium Drugs 0.000 description 2
- DAZXVJBJRMWXJP-UHFFFAOYSA-N N,N-Dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- TZYRSLHNPKPEFV-UHFFFAOYSA-N 2-Ethyl-1-butanol Chemical compound CCC(CC)CO TZYRSLHNPKPEFV-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-Methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The present invention relates to a process for the production of cefotaxime in acetone / water and its use in the production of a sodium salt of cefotaxime in the form of rounded agglomerates and in the form of a needle.
Description
PRODUCTION OF CEFOTAXIMA AND NEW SODIUM SALTS
The present invention relates to a process for the production of a cephalosporin, that is to say a cefotaxime of formula
COOH
Cefotaxime is a third generation cephalosporin, broad spectrum, and one of the most important antibiotics applied parenterally.
It is usually administered in the form of its sodium salt. According to known processes in the production of cefotaxime a corresponding side chain in which the amine group can be in the protected or unprotected form can be introduced into a 7-ACA of formula
COOH
REP: 24872 Cefotaxime in the free acid form can be converted into the corresponding sodium salt in an additional step, using a source of sodium ions. A highly effective method for the introduction of the side chain in 7-ACA is the reaction of the same with a reactive thioester of formula
that is, the MAEM. According to the described reaction route it is not necessary to protect the amino group from the 2-aminothiazolyl function, and the acylation reaction results in high yields without notable side reactions. This technology of active esters was described for the first time in EP-0037380. According to examples 1 and 2 of EP-0037380, the production of cefotaxime in the free acid form is carried out by a) the silylation of 7-ACA of formula II with acetamine of N, O-bistrimethylsilyl b ) acylation of silylated 7-ACA, with MAEM of formula III, in dichloromethane c) extraction with water / potassium acid carbonate
d) the reextraction of cefotaxime in the form of the free acid in a mixture of ethyl acetate / butanol e) the drying and evaporation of the organic phase containing the cefotaxime, and the washing with diethyl ether. This process is economically feasible, however, for ecological reasons it is difficult to use dichloromethane on an industrial scale, especially in the production of medicines and diethyl ether should be avoided for reasons of technological safety.
The preparation of the reaction mixture according to EP-0037380 is complicated. Cefotaxime in the free acid form has a high tendency to fix solvents and to form solvates, as described for example in the
US 5,336,776 or US 4,224,371. The production of a sodium salt of cefotaxime, from a solvate of cefotaxime, carries with it the solvent corresponding to the solvate within the step of forming the sodium salt. This results in unwanted contamination of the sodium salt with solvents used in the acylation step and problems of recovery of the solvents used in the salt formation step. Surprisingly, a simplified, ecologically harmless, and economical process has now been found for the production of cefotaxime, which overcomes the disadvantages of the processes of the prior art and which provides cefotaxime and the sodium salt thereof, with excellent purity, stability and high yields. In one aspect the present invention provides a process for the production of a compound of the formula
COOH by reacting a compound of formula
COOH
with a compound of formula
in acetone. The process of the invention can be carried out as follows: A compound of formula II is acylated with a compound of formula III using acetone as a solvent. Water may be present. Preferably a mixture of acetone / water is used. The concentration of the reactants in the acylation reaction mixture generally has no influence on the reaction per se. However, it was surprisingly found that the yields may be dependent on the concentration of the reactants in the water and the acetone used, although it is known that cefotaxime is almost insoluble in water and / or acetone. The yields can decrease with the dilution of the reaction mixture. Thus, the reaction can be carried out at a high concentration. Optimal yields can be obtained if per gram of 7-ACA approximately 3 to 6 ml are used, for example from 3 to 5, for example from 3.1 to 4.5 ml, of acetone, and approximately from 0.1 to 0.3, for example from 0.1 to 0.25, for example from 0.13 to 0.18 ml of water. The ratio of water to acetone can be such that a solution is obtained in the presence of a base, for example from about 8: 1 to about 45: 1, for example from 10: 1 to about 35: 1. The acylation can be carried out as usual. In one embodiment of the invention the 7-ACA of formula II can be suspended in a mixture of acetone and water, in the presence of MAEM of formula III and in the presence of a base. Suitable bases include teralkylamines of 1 to 8 carbon atoms, for example triethylamine, N-ethyl-dimethylamine, a picoline, an N-substituted morpholine.; or an inorganic base such as sodium hydroxide, sodium bicarbonate or sodium carbonate, or their potassium analogs. The ratio of the base and a compound of the formula 2 can be from about 1: 1 to 1: 2; for example 1: 1; 1: 1.2; 1: 1.5. The ratio of a compound of formula II and a compound of formula III can be as described in EP-0 037 380. The temperature is not critical and can be, for example, between 0 and 50 ° C, for example between 10 and 50 ° C. and 20 ° C. After completion of the reaction, which can be determined as usual, for example by chromatography, an acid is added. Suitable acids include an inorganic acid, such as hydrochloric acid, or an organic acid such as methanesulfonic acid or benzenesulfonic acid or toluenesulfonic acid. The crystalline cefotaxime is obtained in the form of the free acid of formula I. If desired, for example, for greater ease of agitation, more acetone or acetone / water mixture can be added to the crystal suspension, before of the isolation of cefotaxime. In another aspect the invention provides the use of a process according to claim 1 in the production of the sodium salt of a compound of formula I as defined in claim 1, for example a process for the production of the salt of sodium of a compound of formula I as defined in claim 1, which comprises 1) reacting a compound of formula II with a compound of formula III in acetone ii) converting a compound of formula I obtained in step i) into the presence of a source of sodium ions in acetone. The compound of formula I obtained in step i) can be isolated. In a further aspect the invention provides a process for the production of sodium cefotaxime of formula
COONa
reacting the 7-ACA of formula II with a compound of formula III in a mixture of solvents, of acetone and water, in the presence of a base and converting the compound of formula I as defined in claim 1, into a compound of formula la, in a mixture of acetone solvents and water, in the presence of a source of sodium ions.
The conversion can be carried out in a conventional manner. In one embodiment of the invention, the conversion is carried out in a solvent as used in the production of the compound of formula I, ie the cefotaxime in the free acid form can be suspended in acetone, for example, in a mixture of acetone and water, in the presence of a source of sodium ions. The acetone / water ratio is not critical for the formation of the salt per se. A source of sodium ions includes, for example, a sodium salt of a carboxylic acid, such as sodium acetate, a sodium salt of diethylacetic acid or sodium 2-ethylhexanoate, or inorganic sources of sodium such as sodium hydroxide. , sodium bicarbonate or sodium carbonate. The sodium ions can be added in an amount equivalent to the carboxyl group of the cefotaxime or in an excess, for example in a ratio of 1: 1 to 1: 2, for example 1: 1 or 1: 1.5, or 1: 1.2 . Seed crystals can be added after optional filtration of the reaction mixture. More acetone can be added to complete the crystallization. The temperature of the reaction is not critical. The crystallization can be carried out, for example at temperatures between 0 and 50 ° C. To complete the crystallization, the suspension of the crystals can be further cooled before the isolation of the product. The isolation of a sodium salt from cefotaxime can be carried out in a conventional manner. The advantages of this process compared to that of EP-0037380 are: -The production of cefotaxime and the production of a sodium salt of cefotaxime can be carried out in the same solvent -The traces of acetone in a sodium salt of the Cefotaxime are physiologically acceptable - Silylation can be avoided - Extraction is omitted. The process according to the invention is therefore a simple process for the production of a sodium salt of cefotaxime of formula I, without protective group technology and without extraction, that is, the crystallization of cefotaxime can be carried out directly in the reaction vessel. Only a single organic solvent, acetone, is required, which is easy to recover. In addition, cefotaxime and a sodium salt of cefotaxime produced according to the process of the invention are of excellent quality. The process according to the invention is therefore the most suitable for use on an industrial scale. It was found, surprisingly, that the sodium salt of cefotaxime that can be obtained according to the process of the invention, can be crystallized in the form of different crystals (macroscopic). The primary crystals appear in the form. of needles similar to tin. The sodium salt of cefotaxime, after completion of crystallization, can be found in the form of (i) rounded agglomerates (ii) needles formed on a regular basis (iii) a mixture of rounded needles and agglomerates. The shape of the crystals can be dependent on the crystallization conditions, such as the time of addition of the acetone in the crystallization step (a shortened time of addition can result in rounded agglomerates), the ratio of acetone / water (reducing the amount of water can result in rounded agglomerates), the amount of seed crystals (reducing the amount of seed crystals can result in a mixture of small needles and small rounded agglomerates), the shape of the crystals of sowing (the use of needles as seed crystals may unexpectedly result in the sodium salt of cefotaxime in the form of rounded agglomerates); the use of crystals of the prior art, such as by MR example Claforan crystals as seed crystals, may unexpectedly result in the sodium salt of cefotaxime in the form of needles). Under the conditions, for example, of example 7, the sodium salt of cefotaxime is obtained substantially in the form of rounded agglomerates, and under the conditions, for example, of example 8, the sodium salt of cefotaxime is obtained substantially in the Needle shape. The crystals of the sodium salt of cefotaxime, as previously known, for example as they were introduced to the market through the product
MR Claforan, seem to be a mixture of primary crystals (mainly in the form of fragments), which are different from tin-like needles, and agglomerates that have sharp edges. The shape of the crystal is determined by optical microscope photography.
A sodium salt of cefotaxime in the form of rounded agglomerates, or in the form of needles, or in the form of a mixture of rounded agglomerates and needles, is new and advantageous. the present invention therefore provides, in another aspect, the sodium salt of cefotaxime, ie a sodium salt of a compound of formula I as defined in claim 1, in the form of rounded agglomerates and in a further aspect the sodium salt of cefotaxime, that is, a sodium salt of a compound of formula I as defined in claim 1, in the form of needles. The apparent density of the rounded agglomerates that can be obtained according to the present invention (determined according to the European Pharmacopoeia) can vary, for example from 0.23 to 0.5 g / ml (Claforan ™: 0.46 g / ml). Its compacted density is preferably more than 0.2 g / ml and less than 0.65 g / ml; more particularly less than 0.6 g / ml, especially less than 0.55 g / ml. The compacted density of the crystals of the prior art, for example Claforan ™, is 0.68 g / ml. The density compacted is determined according to the method that is provided in the European Pharmacopoeia, after 2,500 taps, in a sample for example of 10 g. The density rises but becomes constant after approximately 2,500 knocks. the present invention provides in another aspect the sodium salt of cefotaxime, ie a sodium salt of a compound of formula I as defined in claim 1, in the form of rounded agglomerates having a compacted density of 0.2 g / ml at 0.6 g / ml. The sodium salt of cefotaxime obtainable in accordance with the present invention can be used in the same manner and can be administered in the same doses and in the same manner as the sodium salt of cefotaxime which is in accordance with the prior art. The sodium salt of cefotaxime in the form of rounded agglomerates and in the form of needles has better flow characteristics than the crystals which are in accordance with the prior art, for example that the crystals of
Claforan MR. The prior art crystals, R for example the Claforan crystals, are generally adhered to the wall of a glass container, and the rounded agglomerates and needles obtainable according to the present invention do not. In the following examples, which should illustrate the invention more completely without limiting its scope, all temperatures are given in degrees Celcius.
Abbreviations:
7 -. 7 -ACÁ:
The compound of formula II
MAEM:
The compound of formula III
Cefotaxime
(Z) - (6R, 7R) -3- (Acetoxymethyl) -7- [2- (2-amino-1,3-thiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo-5-tia acid -l-azabicyclo [4, 2, 0] oct-2-en-2-carboxylic acid (compound of formula I) Sodium salt of cefotaxime:
Sodium salt of (Z) - (6R, 7R) -3- (Acetoxymethyl) -7- [2- (2-amino-1, 3-thiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo- 5-thia-l-azabici-clo [4,2,0] oct-2-en-2-carboxyl
The content of cefotaxime or a sodium salt of cefotaxime is determined by High Performance Liquid Chromatography (HPLC).
Example 1 Production of cefotaxime
54.4 g of 7-ACA are suspended in a mixture of 20 ml of water and 60 ml of acetone. 30.7 ml of triethylamine are added at room temperature in a time of about 10 minutes. A solution is obtained in approximately 30 minutes. Add 72.7 g of MAEM and 120 ml of additional acetone. After 1.5 hours, no initial material is detected. A total of 18.3 ml of concentrated aqueous hydrochloric acid is added in a time of about 10 minutes. After about 5 minutes, cefotaxime crystallizes in the free acid form. The crystal suspension is stirred for 30 minutes at room temperature and the pH value is adjusted to a pH of 3.5 using more hydrochloric acid. They are added, drop by drop, 400 ml of acetone, in a time of 30 minutes, and the mixture is stirred for 1 hour. The crystalline cefotaxime, in the free acid form, is separated by filtration and dried overnight in a vacuum drying chamber. Yield: 71.6 g Cefotaxime content: 93.5% Residual solvents: 6.2% acetone, 0.6% water
Example 2 Production of the sodium salt of cefotaxime
40 g of cefotaxime are suspended in the free acid form, in a mixture of 40 ml of water and 60 ml of acetone. 12 g of sodium acetate trihydrate are added. A solution is obtained and filtered. The filtered bed is washed with a mixture of 3 ml of water and 15 ml of acetone in two portions. 0.4 g of seed crystals are added to the combined filtrates at 25 °. The mixture is stirred for one hour. The sodium salt of cefotaxime crystallizes slowly. 600 ml of acetone are added dropwise over a period of 3 hours, and the suspension is stirred for an additional 30 minutes at the temperature indicated above. The sodium salt of cefotaxime, crystalline, is separated by filtration, washed with acetone and dried overnight in a vacuum drying chamber at 40 °. Yield: 36.6 g Content of the sodium salt of cefotaxime: 95.9% Water content: 3.8%.
Example 3 Production of cefotaxime
228.3 g of 7-ACA are suspended in 720 ml of acetone. The suspension is mixed with 30 ml of water, and cooled to a temperature of 0 to 2 °. 112.4 ml of N-ethyldimethylamine are added in a time of about 2 minutes. The mixture is stirred at this temperature until a clear solution is obtained (approximately 30 minutes). 296.5 g of MAEM are added, the reaction mixture is heated to 15 ° and stirred at this temperature. A solution is obtained after approximately 30 minutes. After 2.5 hours no additional initial material is detected. A solution of 207.7 g of p-toluenesulfonic acid monohydrate in 300 ml of acetone is added dropwise over a period of 5 minutes. The reaction mixture is seeded with 1 g of seed crystals and heated to 20 °. The resulting crystal suspension is stirred for another three hours at this temperature. The crystalline cefotaxime, in the free acid form, is separated by filtration, washed with acetone and dried in a vacuum drying chamber at 40 °. Yield: 301.0 g Cefotaxime content: 91.7% Residual solvent: 7.8% acetone
Example 4 Production of cefotaxime
228.3 g of 7-ACA are suspended in 720 ml of acetone. The suspension is mixed with 30 ml of water, and cooled to a temperature of 0 to 2 °. 134 ml of triethylamine are added in an approximate time of 2 minutes. The mixture is stirred at this temperature, until a clear solution is obtained (approximately 30 minutes). 296.5 g of MAEM are added. The reaction mixture is heated to 15 ° and stirred at this temperature. A solution is obtained after approximately 30 minutes. After 4 hours no additional initial material is detected. 191.7 g of solid p-toluenesulfonic acid monohydrate are added in portions in a range of about 5 minutes. The internal temperature is brought up to 20 ° and the mixture is stirred additionally. In a range of about 10 minutes, the total amount of p-toluenesulfonic acid goes into solution. 2 g of seed crystals are added to the solution, and stirring is carried out for 2 hours at this temperature. The crystal suspension is cooled to 10 ° and stirred overnight at this temperature. The product is separated by filtration, washed with acetone and dried in a vacuum drying chamber at 40 °. Yield: 341.4 g Content of cefotaxime: 94.1% Residual solvents: acetone 6.6%, water 0.5%
Example 5 Production of cefotaxime
The reaction is carried out analogously to that of Example 4 but using 177.2 g of benzenesulfonic acid instead of 191.7 g of p-toluenesulfonic acid monohydrate. Yield: 308.8 g Cefotaxime content: 93.6% Residual solvents: 7.2% acetone
Example 6 Production of cefotaxime
The reaction is carried out analogously to that of Example 4 but using 92.3 g of methanesulfonic acid in place of 191.7 g of p-toluenesulfonic acid monohydrate. Yield: 323.9 g Content of cefotaxime: 93.7% Residual solvents: acetone 7.7%, water 0.6% Example 7 Production of. the sodium salt of cefotaxime
Dissolve 12 g of sodium acetate trihydrate in 30 ml of water. To the stirred solution are added 150 ml of acetone and 40 g of cefotaxime in the free acid form. A solution is obtained after about 10 minutes. The solution is filtered through a filter bed and subsequently through a sterile filter. The filters are washed with a mixture of a total of 6 ml of water and 30 ml of acetone. The filtrate is brought to a temperature of 20 °, sown with 0.4 g of seed crystals and stirred for 30 minutes. The sodium salt of cefotaxime partially crystallizes. To complete the crystallization, 550 ml of acetone are added dropwise over a period of 3 hours, and stirring is carried out for an additional 30 minutes at 20 °. The sodium salt of cefotaxime is separated by filtration, washed with acetone and dried overnight in a vacuum drying chamber at 40 °. Cefotaxime sodium, crystalline, substantially in the form of rounded agglomerates is obtained in a flowing form and having a compacted density below 0.68 g / ml. Yield: 38.8 g Content of the sodium salt of cefotaxime: 95.9%
Residual solvents: 0.4% acetone, 4.0% water
Example 8 Production of the sodium salt of cefotaxime
Dissolve 6 g of sodium acetate trihydrate in 20 ml of water. 40 ml of acetone and 20 g of cefotaxime in the free acid form are added to the stirred solution. The mixture is cooled to 0 °. A solution is obtained in a range of 2 to 5 minutes. The solution is filtered through a filter bed and subsequently through a sterile filter. The filters are washed with a mixture, suddenly cooled, of 3 ml of water and 15 ml of acetone. The filtrate is seeded with 0.2 g of MR seed crystals (Claforan) and heated to 20 °. The mixture is stirred for 60 minutes. The sodium salt of cefotaxime partially crystallizes. To complete the crystallization, 300 ml of acetone are added dropwise over a period of 3 hours, and stirring is carried out for an additional 30 minutes at 20 °. The sodium salt of cefotaxime is filtered off, washed with acetone and dried overnight and dried in a vacuum drying chamber, at 40 °, and for 1.5 hours in a stream of dry nitrogen gas, at 70 ° C. °. Cefotaxime sodium, crystalline, is obtained substantially in the form of needles. Yield: 18.7 g Content of the sodium salt of cefotaxime: 97.9% Residual solvents: acetone 0.36%, water 1.4%.
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, the content of the following is claimed as property:
Claims (11)
1. A process, characterized in that it is for the production of a compound of the formula COOH by reacting a compound of the formula COOH with a compound of the formula in acetone
2. A process according to claim 1, characterized in that water is present.
3. A process according to claim 1 or claim 2, characterized in that a base is present.
4. The use of a process according to claim 1, in the production of a sodium salt of a compound of the formula I as defined in claim 1.
5. A process for the production of the sodium salt of a compound of formula I, as defined in claim 1, characterized in that it comprises: i) reacting a compound of formula II with a compound of formula III in acetone ii) converting a compound of the formula I, obtained in step i) in the presence of a source of sodium ions, in acetone.
6. A process according to claim 5, characterized in that water is present.
7. A process, characterized in that it is for the production of a sodium cefotaxime of formula COONa by reacting the 7-ACA of formula COOH with a compound of formula in a mixture of acetone solvents and water, in the presence of a base and converting the compound of formula I as defined in claim 1, into a compound of formula as defined above, in a mixture of acetone solvents and water, in the presence of a source of sodium.
8. A process for the production of the sodium salt of a compound of the formula I as defined in claim 1, characterized in that it comprises the steps of: a) reacting a compound of the formula II with a compound of the formula III in the the presence of an inorganic base or a teralkylamine of 1 to 8 carbon atoms, in a mixture of acetone / water b) isolating the compound of formula I c) reacting a compound of formula I in the presence of a source of sodium ions in a mixture of acetone / water, and d) isolating the sodium salt of a compound of formula I.
9. A sodium salt of a compound of formula I, as defined in claim 1, characterized in that it is in the form of rounded agglomerates.
10. A sodium salt of a compound of formula I, as defined in claim 1, characterized in that it is in the form of rounded agglomerates having a compacted density of 0.2 g / ml to 0.6 g / ml.
11. A sodium salt of a compound of formula I, as defined in claim 1, characterized in that it is in the form of needles.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ATA2397/94 | 1994-12-23 | ||
AT0239794A AT402928B (en) | 1994-12-23 | 1994-12-23 | NEW METHOD FOR PRODUCING CEFOTAXIM |
PCT/EP1995/005088 WO1996020198A1 (en) | 1994-12-23 | 1995-12-22 | Production of cefotaxime and new sodium salts |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9704641A MX9704641A (en) | 1997-09-30 |
MXPA97004641A true MXPA97004641A (en) | 1998-07-03 |
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