WO2011042775A1 - Process for preparation of cefotaxime acid - Google Patents
Process for preparation of cefotaxime acid Download PDFInfo
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- WO2011042775A1 WO2011042775A1 PCT/IB2010/000744 IB2010000744W WO2011042775A1 WO 2011042775 A1 WO2011042775 A1 WO 2011042775A1 IB 2010000744 W IB2010000744 W IB 2010000744W WO 2011042775 A1 WO2011042775 A1 WO 2011042775A1
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- Prior art keywords
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- cefotaxime
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- 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 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims description 35
- 238000002360 preparation method Methods 0.000 title claims description 18
- 239000002904 solvent Substances 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- HSHGZXNAXBPPDL-IOJJLOCKSA-N (6r)-3-(acetyloxymethyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(N)[C@@H]12 HSHGZXNAXBPPDL-IOJJLOCKSA-N 0.000 claims description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- QJNLUNBGDFUULX-UHFFFAOYSA-N 4-n,4-n'-dimethyl-3h-pyridine-4,4-diamine Chemical compound CNC1(NC)CC=NC=C1 QJNLUNBGDFUULX-UHFFFAOYSA-N 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- MTEWAFVECQBILW-UHFFFAOYSA-N n-tert-butylcyclohexanamine Chemical compound CC(C)(C)NC1CCCCC1 MTEWAFVECQBILW-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 12
- 229930186147 Cephalosporin Natural products 0.000 description 8
- 229940124587 cephalosporin Drugs 0.000 description 8
- 150000001780 cephalosporins Chemical class 0.000 description 8
- 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 description 7
- LYFVEJJFORTCPS-YVLHZVERSA-N (2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(2-sulfanylidene-3H-1,3-benzothiazol-4-yl)methoxyimino]acetic acid Chemical compound S1C(N)=NC(C(=N\OCC=2C=3NC(=S)SC=3C=CC=2)\C(O)=O)=C1 LYFVEJJFORTCPS-YVLHZVERSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229960004261 cefotaxime Drugs 0.000 description 4
- -1 methoximino group Chemical group 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 229960002727 cefotaxime sodium Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RJFPBECTFIUTHB-INEUFUBQSA-N (6r,7r)-7-azaniumyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical class S1CC=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 RJFPBECTFIUTHB-INEUFUBQSA-N 0.000 description 2
- JBGVPTVXEXCTEG-UHFFFAOYSA-N 2-amino-2-(1,3-thiazol-2-yl)acetic acid Chemical class OC(=O)C(N)C1=NC=CS1 JBGVPTVXEXCTEG-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 2
- 229960004755 ceftriaxone Drugs 0.000 description 2
- HOKIDJSKDBPKTQ-GLXFQSAKSA-N cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- DOQDWCZUKOXGKY-RNFPGXQISA-N CC(OCC(CS[C@@H]1[C@]2(N)NC(/C(/c3c[s]c(N)n3)=N\OC)=O)=C(C(O)=O)N1C2=O)=O Chemical compound CC(OCC(CS[C@@H]1[C@]2(N)NC(/C(/c3c[s]c(N)n3)=N\OC)=O)=C(C(O)=O)N1C2=O)=O DOQDWCZUKOXGKY-RNFPGXQISA-N 0.000 description 1
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 description 1
- 241001619326 Cephalosporium Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- FUBBGQLTSCSAON-PBFPGSCMSA-N cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 description 1
- 229950004030 cefaloglycin Drugs 0.000 description 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 description 1
- 229960003866 cefaloridine Drugs 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- HJJDBAOLQAWBMH-YCRCPZNHSA-N cefmenoxime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C HJJDBAOLQAWBMH-YCRCPZNHSA-N 0.000 description 1
- 229960003791 cefmenoxime Drugs 0.000 description 1
- 229960001242 cefotiam Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
- 229960001991 ceftizoxime Drugs 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- WRTVTCFELAEIEQ-YVLHZVERSA-N o-(1,3-benzothiazol-2-yl) (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoethanethioate Chemical compound N=1C2=CC=CC=C2SC=1OC(=S)\C(=N/OC)C1=CSC(N)=N1 WRTVTCFELAEIEQ-YVLHZVERSA-N 0.000 description 1
- 125000005646 oximino group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
Definitions
- the present invention is in the field of chemistry and more precisely the present invention relates to the preparation of cefotaxime acid of formula (I) in presence of a base and using in an alcohol as a single solvent in a very safe, simple, economical, user-friendly and in an industrially viable manner.
- Cephalosporin antibiotics inhibit bacteria by interfering with the synthesis of essential structural components of the bacterial cell wall. They are considered as highly effective antibiotics with low toxicity and are used for treating a wide variety of bacterial infections.
- Cephalosporin C was isolated in 1952 from a mold of the genus cephalosporium. A decade later the nucleus (7-aminocephalosporanic acid) was isolated and used as the basis for a series of synthetic derivatives, including cephalothin, cephaloridine and cephaloglycin. Research has produced many cephalosporin derivatives with increased potency and improved stability. For example, derivatives containing a 7-aminothiazolyl group such as cefotiam have been shown to have increased potency.
- Cefotaxime acid of formula (I) is chemically known as (Z)-(6R, 77i)-3- (acetoxymethyl)-7-[2-(2-amino-l ,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5- thia-l -azabicyclo[4,2,0]oct-2-en-2-carboxylic acid and is commercially sold as its sodium salt which is a semisynthetic, broad-spectrum, cephalosporin antibiotic. for parenteral administration.
- 7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) of formula (II) is a well known compound which has been proposed as starting material in various syntheses, in particular in the synthesis of many cephalosporins.
- (III) optionally substituted the 3-acetoxymethyl group of the cephalosporanic ring by a nucleophilic agent.
- the sequencing of these steps may optionally be varied case by case. In ever case the acylation of the 7-amino group of the cephalosporanic ring is carried out with an optionally substituted aminothiazolyl acetic acid whose amino group has been protected, the amino group being then deprotected.
- 4,767,852 discloses a process for the preparation of known 2-oxyiminoacetamido-3-cephem-4-carboxylic acid derivatives, including cefotaxime and ceftriaxone, by acylating 7-amino-3-cephem-4-carboxylic acid derivatives already substituted at the 3-position with 2-mercaptobenzothiazolyl- (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula (III), the latter being often referred to as MAEM, which has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in the 7-acylamido side chain.
- US patent '432 discloses the process for the preparation of cefotaxime sodium of formula (I), which involves treating the cefotaxime acid in aqueous solvent such as methanol, ethanol or acetone in the presence , of base and sodium ions to give cefotaxime sodium.
- US patent '852 discloses a process for the production of cephalosporin derivatives by acylating 7-amino-3-cephem-4- carboxylic acid with 2- mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of the formula (HI), using solvents such as chlorinated hydrocarbon, or esters such as ethyl acetate or in a mixture of such solvent with water.
- solvents such as chlorinated hydrocarbon, or esters such as ethyl acetate or in a mixture of such solvent with water.
- condensation 7-amino-3-acetoxymcthyl-3- cephem-4-carboxylic acid (7-ACA) of formula (II) with 2-mercaptobenzothiazolyl-(Z)- 2- (2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula (III) can be performed using an alcohol as a single solvent at a lower temperature.
- the risk involved by the use of said solvent is remarkably lower than those connected with the use of the solvents cited above.
- said alcohol solvent has remarkably lower toxicity than the solvents reported above such as carbon tetrachloride, ⁇ , ⁇ -dimethylformamide etc.
- the main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is very safe, simple, economical, user- friendly and commercially viable
- Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s) and to avoid hazardous and risky solvents, which makes the present invention more safe and eco-friendly as well.
- the present invention provides a process for the preparation of cefotaxime acid of formula (I); comprising the steps of:
- step (ii) adding water to the reaction mass as obtained from step (i) and filtering the , solution;
- step (iii) adjusting the pH of solution as obtained from step (ii) with an acid
- the said alcoholic solvent in step (i) may be preferably selected from the group consisting of methanol, ethanol, isopropanol and the like or mixture thereof, more preferably methanol.
- the said base in step (i) is an organic base which may be preferably selected from the group consisting of triethylamine, pyridine, N-methylpiperidine, 1 ,8-diazabicycIoundecene, 4,4-dimethylaminopyridine, dicyclo hexylamine, diphenylamine, diisopropylamine, N- tert-butylcyclohexylamine and ⁇ , ⁇ -dibenzylethylenediamine and the like or mixtures thereof, more preferably triethylamine.
- step (i) is preferably performed at a low temperature, more preferably in the range of (-) I 0°C to 10°C.
- step (i) is accomplished relatively in a shorter time, which makes the process more useful against the prior art processes.
- the said condensation of step (i) is proceeding to completion in 1 to 4 hrs.
- step (ii) the by product 2-mercaptobenzothiazole is removed by means of filtration, which is helpful for the better quality of the compound of formula (I).
- the said acid in step (iii) preferably is hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
- step (ii) is in the range of 2 to 4. In another embodiment of the present invention, all the steps except step (i) are preferably performed at a temperature in the range of (-) 10°C to reflux temperature of the solvent used.
- process for preparation of a compound of formula (I) may also be extended further in the making of pharmaceutically acceptable salts of cefotaxime such as cefotaxime sodium by conventional methods.
- Example (1) Preparation of cefotaxime acid 50 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid and 77.3 g of 2-mercapto-benzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-methoxyiminoacetate were added in 250 mL of methanol and stirred at 25°C to 30°C. The reaction mixture was cooled down to 0°C to 5°C. 27.86 g of triethylamine was added to the reaction mixture at the same temperature within 15 mins. The reaction mixture was stirred at 0°C to 5°C until the completion of reaction.
- the process of the present invention uses a solvent which can be recycled and reused and thus makes the process more economical and industrially & commercially viable.
- the process of the present invention is a simple process, which avoids more number of operations, thus resulting in shortening of reaction time and lowering of labor.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Cefotaxime acid of formula (I) is prepared by using a kind of alcohol as the single solvent in presence of a base.
Description
PROCESS FOR PREPARATION OF CEFOTAXIME ACID
Field of the invention
The present invention is in the field of chemistry and more precisely the present invention relates to the preparation of cefotaxime acid of formula (I) in presence of a base and using in an alcohol as a single solvent in a very safe, simple, economical, user-friendly and in an industrially viable manner.
(I)
Background of the invention
Cephalosporin antibiotics inhibit bacteria by interfering with the synthesis of essential structural components of the bacterial cell wall. They are considered as highly effective antibiotics with low toxicity and are used for treating a wide variety of bacterial infections. Cephalosporin C was isolated in 1952 from a mold of the genus cephalosporium. A decade later the nucleus (7-aminocephalosporanic acid) was isolated and used as the basis for a series of synthetic derivatives, including cephalothin, cephaloridine and cephaloglycin. Research has produced many cephalosporin derivatives with increased potency and improved stability. For example, derivatives containing a 7-aminothiazolyl group such as cefotiam have been shown to have increased potency. Resistance to beta- lactamase has been found to be conferred by a methoximino group at the alpha carbon atom in the 7-acyl group. Several cephalosporins have been developed that have combined these structural features to provide highly potent enzyme resistant compounds; e.g. cefotaxime, cefmenoxime, ceftizoxime, and ceftriaxone.
U.S. Patent No. 4,098,888 describes cephem compounds and processes for their preparation. Another U.S. Patent No. 4, 152,432 (henceforth '432) describes 3- acetoxymethyl-7-(iminoacetamido) cephalosporanic acid derivatives, in particular cefotaxime, and processes for preparing the derivatives.
Cefotaxime acid of formula (I) is chemically known as (Z)-(6R, 77i)-3- (acetoxymethyl)-7-[2-(2-amino-l ,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5- thia-l -azabicyclo[4,2,0]oct-2-en-2-carboxylic acid and is commercially sold as its sodium salt which is a semisynthetic, broad-spectrum, cephalosporin antibiotic. for parenteral administration.
(I)
7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) of formula (II) is a well known compound which has been proposed as starting material in various syntheses, in particular in the synthesis of many cephalosporins.
Various important cephalosporins are obtained through the following reaction steps,
(I) effecting an acylation of the 7-amino group of the cephalosporanic ring by an optionally substituted aminothiazolyl acetic acid whose amino group has been protected.
(II) deprotecting the amino protecting group; and
(III) optionally substituted the 3-acetoxymethyl group of the cephalosporanic ring by a nucleophilic agent.
The sequencing of these steps may optionally be varied case by case. In ever case the acylation of the 7-amino group of the cephalosporanic ring is carried out with an optionally substituted aminothiazolyl acetic acid whose amino group has been protected, the amino group being then deprotected. U.S. Patent No. 4,767,852 (henceforth '852) discloses a process for the preparation of known 2-oxyiminoacetamido-3-cephem-4-carboxylic acid derivatives, including cefotaxime and ceftriaxone, by acylating 7-amino-3-cephem-4-carboxylic acid derivatives already substituted at the 3-position with 2-mercaptobenzothiazolyl- (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula (III), the latter being often referred to as MAEM, which has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in the 7-acylamido side chain.
(III)
US patent '432 discloses the process for the preparation of cefotaxime sodium of formula (I), which involves treating the cefotaxime acid in aqueous solvent such as methanol, ethanol or acetone in the presence , of base and sodium ions to give cefotaxime sodium.
US patent '852 discloses a process for the production of cephalosporin derivatives by acylating 7-amino-3-cephem-4- carboxylic acid with 2- mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of the formula (HI), using solvents such as chlorinated hydrocarbon, or esters such as ethyl acetate or in a mixture of such solvent with water.
It has now been found that the condensation 7-amino-3-acetoxymcthyl-3- cephem-4-carboxylic acid (7-ACA) of formula (II) with 2-mercaptobenzothiazolyl-(Z)- 2- (2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula (III) can be performed using an alcohol as a single solvent at a lower temperature. The risk involved by the use
of said solvent is remarkably lower than those connected with the use of the solvents cited above. Furthermore, said alcohol solvent has remarkably lower toxicity than the solvents reported above such as carbon tetrachloride, Ν,Ν-dimethylformamide etc. As discussed above none of the prior art references disclosed or claimed the use of an alcohol as a single solvent at a lower temperature for the preparation of compound of formula (I), hence we focused our research to develop an improved and efficient process for the preparation of a compound of formula (I) along with substantially fair operational safety, satisfactory yield and high chemical purity, which makes the process more distinct and successful at industrial and commercial level.
It should be pointed out that the said condensation, which is extremely aggressive, in solvent such as an alcohol at a lower temperature, has never before been reported in literature. The present invention provides remarkable advantages in the industrial processes for the production of cefotaxime acid of formula (I). In fact, the method of the invention helped the inventors to provide good quality cefotaxime acid in yields quite comparable with those expected with the prior art methods.
Objective of the invention The main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is very safe, simple, economical, user- friendly and commercially viable
Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s) and to avoid hazardous and risky solvents, which makes the present invention more safe and eco-friendly as well.
Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I), in a greater yield with higher chemical purity.
Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the organic solvent used during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.
Summary of the invention
Accordingly, the present invention provides a process for the preparation of cefotaxime acid of formula (I); comprising the steps of:
(I)
(i) condensing 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid of formula (II) with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2- methoxyiminoacetate of formula (III) in the presence of a base in an alcoholic solvent at a lower temperature;
(ii) adding water to the reaction mass as obtained from step (i) and filtering the, solution;
(iii) adjusting the pH of solution as obtained from step (ii) with an acid; and
(iv) isolating cefotaxime acid of formula (I) in pure form.
The above process is illustrated in the following synthetic scheme:
Accordingly in an embodiment of the present invention, the said alcoholic solvent in step (i) may be preferably selected from the group consisting of methanol, ethanol, isopropanol and the like or mixture thereof, more preferably methanol.
In another embodiment of the present invention, the said base in step (i) is an organic base which may be preferably selected from the group consisting of triethylamine, pyridine, N-methylpiperidine, 1 ,8-diazabicycIoundecene, 4,4-dimethylaminopyridine, dicyclo hexylamine, diphenylamine, diisopropylamine, N- tert-butylcyclohexylamine and Ν,Ν-dibenzylethylenediamine and the like or mixtures thereof, more preferably triethylamine.
In another embodiment of the present invention, the condensation of step (i) is preferably performed at a low temperature, more preferably in the range of (-) I 0°C to 10°C.
In another embodiment of the present invention, the condensation of step (i) is accomplished relatively in a shorter time, which makes the process more useful against the prior art processes. The said condensation of step (i) is proceeding to completion in 1 to 4 hrs.
In another embodiment of the present invention in step (ii) the by product 2-mercaptobenzothiazole is removed by means of filtration, which is helpful for the better quality of the compound of formula (I).
In another embodiment of the present invention, the said acid in step (iii) preferably is hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
In another embodiment of the present invention, the pH disclosed in step (ii) is in the range of 2 to 4.
In another embodiment of the present invention, all the steps except step (i) are preferably performed at a temperature in the range of (-) 10°C to reflux temperature of the solvent used.
In yet another embodiment of the present invention, process for preparation of a compound of formula (I) may also be extended further in the making of pharmaceutically acceptable salts of cefotaxime such as cefotaxime sodium by conventional methods.
In the present invention the starting material(s) for the preparation of a compound of formula (I), were prepared according. to the known processes in the prior art.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
Example (1) Preparation of cefotaxime acid 50 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid and 77.3 g of 2-mercapto-benzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-methoxyiminoacetate were added in 250 mL of methanol and stirred at 25°C to 30°C. The reaction mixture was cooled down to 0°C to 5°C. 27.86 g of triethylamine was added to the reaction mixture at the same temperature within 15 mins. The reaction mixture was stirred at 0°C to 5°C until the completion of reaction. 1000 mL of water was added to the reaction mixture and the precipitated 2-mercaptobenzothiazole (by-product) was filtered off. Activated carbon was added to the filtrate and stirred for 30 mins. The carbon was filtered through hyflo bed. 2 g of hydros and 1 g of ethylenediaminetetraacetic acid
(EDTA) were added to the filtrate and stirred for 10 mins at 28°C to 30°C. Dilute hydrochloric acid (1 : 1 ) was added to the reaction mixture to adjust the pH to 2.3 to 2.5 at 0°C to 5°C for precipitation. The resulting precipitated material was stirred at the same temperature for 1.0 hr. The product was filtered and washed with acetone and dried completely to yield 80 g of cefotaxime acid with 99.30% purity by HPLC.
Substantial Advantages and Industrial applicability
(1) The process of the present invention is very safe, simple and yields higher purity and greater yield of a compound of formula ( 1 ).
(2) The process of the present invention avoids excess usages of reagent(s) and organic solvent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting lesser load on environment.
(3) The process of the present invention avoids the use of solvents like carbon tetrachloride, Ν,Ν-dimethylformamide which are harmful for the environment and is very hazardous in nature.
(4) The process of the present invention uses a solvent which can be recycled and reused and thus makes the process more economical and industrially & commercially viable.
(5) The process of the present invention is a simple process, which avoids more number of operations, thus resulting in shortening of reaction time and lowering of labor.
Claims
(1) An improved process for the preparation of cefotaxime acid of formula (I); comprising the steps of:
(I)
(i) condensing 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid of formula (II) with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazoI-4-yl)-2- methoxyiminoacetate of formula (III) in the presence of a base in an alcoholic solvent at a lower temperature;
(II) (III)
(ii) adding water to the reaction mass as obtained from step (i) and filtering the solution;
(iii) adjusting the pH of solution as obtained from step (ii) with an acid; and
(iv) isolating cefotaxime acid of formula (I) in pure form.
(2) A process according to claim 1 , wherein the said alcoholic solvent in step (i) is preferably selected from the group consisting of methanol, ethanol, isopropanol ' and the like or mixture thereof, more preferably methanol.
(3) A process according to claim 1 , wherein the said base in step (i) is an organic base, and is selected from the group consisting of triethylamine, pyridine, N- methylpiperidine, 1 ,8-diazabicycloundecene, 4,4-dimethylaminopyridine, dicyclo hexylamine, diphenylamine, diisopropylamine, N-tert-
butylcyclohexylamine and N,N- dibenzylethylenediamine and the like mixtures thereof, more preferably triethylamine.
A process according to claim 1 , wherein the said pH in step (iii) is preferably the range of 2 to 4.
A process according to claim 1, wherein the said acid in step (iii) hydrochloric acid or sulfuric acid and the like.
(6) A process according to claim 1 , wherein all the steps are preferably performed at a temperature in the range of (-) 10°C to reflux temperature of the solvent used.
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| IN2095DE2009 | 2009-10-09 | ||
| IN2095/DEL/2009 | 2009-10-09 |
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| WO2011042775A1 true WO2011042775A1 (en) | 2011-04-14 |
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| PCT/IB2010/000744 WO2011042775A1 (en) | 2009-10-09 | 2010-04-06 | Process for preparation of cefotaxime acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108117565A (en) * | 2016-11-28 | 2018-06-05 | 上海上药新亚药业有限公司 | A kind of method of synthesis in solid state cefotaxime |
| CN108586490A (en) * | 2018-04-04 | 2018-09-28 | 淄博鑫泉医药技术服务有限公司 | The preparation method of cefotaxime acid |
| CN109988183A (en) * | 2019-04-17 | 2019-07-09 | 广东立国制药有限公司 | A kind of environment-friendly preparation method of the intermediate of cefuroxime acid |
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| EP0231845A2 (en) * | 1986-02-07 | 1987-08-12 | F. Hoffmann-La Roche Ag | Process for the preparation of carboxylic-acid amides |
| WO1996020198A1 (en) * | 1994-12-23 | 1996-07-04 | Biochemie Gesellschaft Mbh | Production of cefotaxime and new sodium salts |
| CN1394863A (en) * | 2002-07-05 | 2003-02-05 | 上海新亚药业有限公司 | Method for synthesizing cefotaxime sodium |
| CN1634932A (en) * | 2004-10-27 | 2005-07-06 | 山东瑞阳制药有限公司 | Process for preparing cefotaxime sodium |
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| EP0231845A2 (en) * | 1986-02-07 | 1987-08-12 | F. Hoffmann-La Roche Ag | Process for the preparation of carboxylic-acid amides |
| WO1996020198A1 (en) * | 1994-12-23 | 1996-07-04 | Biochemie Gesellschaft Mbh | Production of cefotaxime and new sodium salts |
| CN1394863A (en) * | 2002-07-05 | 2003-02-05 | 上海新亚药业有限公司 | Method for synthesizing cefotaxime sodium |
| CN1634932A (en) * | 2004-10-27 | 2005-07-06 | 山东瑞阳制药有限公司 | Process for preparing cefotaxime sodium |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108117565A (en) * | 2016-11-28 | 2018-06-05 | 上海上药新亚药业有限公司 | A kind of method of synthesis in solid state cefotaxime |
| CN108117565B (en) * | 2016-11-28 | 2021-02-26 | 上海上药新亚药业有限公司 | Solid-phase synthesis method of cefotaxime |
| CN108586490A (en) * | 2018-04-04 | 2018-09-28 | 淄博鑫泉医药技术服务有限公司 | The preparation method of cefotaxime acid |
| CN109988183A (en) * | 2019-04-17 | 2019-07-09 | 广东立国制药有限公司 | A kind of environment-friendly preparation method of the intermediate of cefuroxime acid |
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