WO2013057196A1 - Procédé de préparation de nafate de céfamandole - Google Patents

Procédé de préparation de nafate de céfamandole Download PDF

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Publication number
WO2013057196A1
WO2013057196A1 PCT/EP2012/070664 EP2012070664W WO2013057196A1 WO 2013057196 A1 WO2013057196 A1 WO 2013057196A1 EP 2012070664 W EP2012070664 W EP 2012070664W WO 2013057196 A1 WO2013057196 A1 WO 2013057196A1
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Prior art keywords
cefamandole
acetate
formula
formic
formate
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PCT/EP2012/070664
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English (en)
Inventor
Harold Monro Moody
Peter Johannes Dominicus Maas
Thomas SCHMITGES
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Dsm Sinochem Pharmaceuticals Netherlands B.V.
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Publication of WO2013057196A1 publication Critical patent/WO2013057196A1/fr

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    • 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
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a process for the preparation of cefamandole nafate from O-formyl cefamandole.
  • Cefamandole ((1 ); CAS 34444-01 -4; (6R,7R)-7-[[(2R)-hydroxyphenyl- acetyl]amino]-3-[[(1 -methyl-1 /-/-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 - azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is a second generation broad-spectrum semi-synthetic cephalosporin antibiotic, the preparation of which was first disclosed in US 3,641 ,021 .
  • Cefamandole nafate ((3); CAS 42540-40-9) is the sodium salt of the formate ester of cefamandole and is the clinically used form of cefamandole.
  • the compound can be prepared by chemical N-acylation of the appropriate ⁇ -lactam nucleus, 7-amino-3-(1 -methyl-1 H-tetrazol-5-ylthiomethyl)-3- cephem-4-carboxylic acid (7-TMCA) as for instance described in Kaiser et al. (J. Infect. Dis. (1978) 137, 1 0-16).
  • 7-TMCA 7-amino-3-(1 -methyl-1 H-tetrazol-5-ylthiomethyl)-3- cephem-4-carboxylic acid
  • an enzymatically catalyzed kinetically controlled acylation of 7-TMCA has been proposed in more recent literature by, amongst others, Nierstrasz et al.
  • cefamandole nafate (3) The current most promising approach for the preparation of cefamandole nafate (3) is kinetically controlled acylation of 7-TMCA with an ester of mandelic acid, such as methyl mandelate, to give cefamandole (1 ) followed by conversion into O- formyl cefamandole (2) and subsequently into cefamandole nafate (3).
  • step (b) contacting the mixture obtained in step (a) with a sodium source in an organic solvent,
  • step (a) characterized in that said impurity is present in an amount of from 0.5% to 25% by weight relative to the amount of O-formyl cefamandole or a salt thereof formed in step (a).
  • the compounds present in step (b) are O-formyl cefamandole (2) or a salt thereof and an impurity chosen from the list consisting of mandelic acid, methyl mandelate, O-acetyl mandelic acid and O-formyl mandelic acid or salts thereof.
  • the method remarkably enables production of highly pure cefamandole nafate (3) and is characterized in that any of the impurities mentioned above are removed to completion or near completion even when present in high amounts in the starting material, such as from 1 % to 10%, from 2% to 20% or from 3% to 30%, all by weight relative to amount of said O-formyl cefamandole (2) or a salt thereof.
  • Suitable organic solvents are esters such as acetates, formats and propionates and ketones.
  • Preferred organic solvent are acetone, butyl acetate, butyl formate, ethyl acetate, ethyl formate, isobutyl acetate, isobutyl formate, isopropyl acetate, isopropyl formate but also mixtures of two or more of these and/or other solvents may be employed.
  • suitable sodium sources are sodium halides or sodium salts of organic acids such as sodium acetate, sodium ethyl hexanoate or sodium formate or mixtures thereof.
  • mandelic acid is formed as a side product (usually in significant amounts) during the enzymatic synthesis of cefamandole (1 ) from 7-TMCA and an ester of mandelic acid. Like cefamandole (1 ), this mandelic acid is also formylated to give O-formyl mandelic acid.
  • O-formyl cefamandole (2) or a salt thereof is prepared by reacting cefamandole or a salt thereof with a formylating agent.
  • formylation of alcohols is well studied, as for instance in a review by G.A. Olah et al. (Chem. Rev. (1987) 87, 671 -686) and can be carried out using a variety of reagents such as formic acid (M. Chakrabarty et al., Synth. Commun. (2000) 30:2, 187-200), formic anhydrides, formic esters, formic halides or N-formyl derivatives. Examples are N-formylbenzotriazole (A.R.
  • the formylating agent is formic acid, a formic anhydride, a formic ester, a formic halide or an N-formyl derivative.
  • the formylating agent is a mixed anhydride such as acetic formic anhydride of formula CH 3 C(0)OC(0)H, a compound that can conveniently be prepared from acetic anhydride and formic acid.
  • a sterically hindered derivative of acetic formic anhydride may be used, such as butyric formic anhydride of formula CH 3 CH2CHC(0)OC(0)H or 2-ethylbutyric formic anhydride of formula (C2H 5 )2CHC(0)OC(0)H or isobutyric formic anhydride of formula (CH 3 )2CHC(0)OC(0)H or 2-methyl butyric formic an hyd ride of form u la CH 3 CH 2 CH(CH 3 )C(0)OC(0)H or propionic formic anhydride of formula CH 3 CH 2 C(0)OC(0)l-l or mixtures thereof.
  • acetic formic anhydride have the additional advantage of reduced formation of unwanted acylated products.
  • the presence of acetylated contaminations may lead to liberation of traces of acetate upon parenteral administration.
  • Acetate is known (A. Amore et al., J. Amer. Soc. Nephrol. (1997), 1431 ) for its negative effects in man leading to acetate intolerance, a condition associated with arterial hypertension, nausea, vomiting and headaches.
  • acetic formic anhydride formic acid is preferably present in amounts of from 0.05 to 100 mol% based on the amount of acetic formic anhydride, more preferably of from 0.1 to 50 mol%, most preferably of from 0.2 to 10 mol%.
  • the formation of unwanted acetylated products can be avoided by isolating the acetic formic anhydride by means of distillation prior to reaction with cefamandole (1 ). Distillation may be carried out at normal pressure or reduced pressure.
  • acetic formic anhydride is prepared shortly prior to use as the compound is labile (degradation to form carbon monoxide).
  • the acetic formic anhydride within 24h after its preparation, preferably within 12h after its preparation, more preferably within 6h after its preparation and most preferably within 3h of its preparation.
  • this formylating agent is preferably added in excess compared to the amount of cefamandole (1 ).
  • the molar ratio acetic formic anhydride/cefamandole (1 ) is between 100/1 and 100/99, more preferably between 50/1 and 100/95, most preferably between 10/1 and 10/9.
  • the formylation is carried out in the presence of a base. It has been found that improved conversions are obtainable, in particular when the formylation is carried out at lower temperatures such as from -78°C to 30°C when the base in question has a dissociation constant pK a (at 25°C) of from 3.0 to 1 1 .0, preferably of from 6.0 to 9.0, more preferably of from 6.5 to 8.0. Examples are
  • 2- ethylbenzimidazole N-ethylaniline, 1 -ethylpiperidine, 2-ethylpyridine, heptylamine, hexadecylamine, hexylamine, imidazole, isoquinoline, melamine, methoxypyridine, methylamine, p-methylaniline, 1 -methylimidazole, N-methylmorpholine, 1 -methylpiperidine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, N-methylpyrrolidine, 2-methylquinoline, morfoline, pentylamine, p-phenetidine, phenethylamine, propylamine, pyridine, 2-pyridinamine, 2,5-pyridinediamine, theobromine, 2-thiazolamine, triethylamine, trimethylamine, 2,4,6-trimethylpyridine.
  • bases to be used in the method of the present invention are imidazole and derivatives thereof such as 1 -methylimidazole, morpholine and derivatives thereof such as N-methylmorpholine, pyridine and derivatives thereof such as the mono-, di- and tri-methyl pyridines and triethylamine.
  • dissociation constant pK a is defined as the negative logarithm of the acid dissociation constant K a .
  • cefamandole nafate (3) may be isolated following known procedures. Hence the crystalline product may be separated from the mother liquor by centrifugation, decantation, filtration, sedimentation and the like. The solid particles so obtained may be dried, either at atmospheric pressure or under reduced pressure, at temperatures ranging from 0°C to 100°C, preferably ranging from 10°C to 80°C, more preferably ranging from 15°C to 60°C.
  • the cefamandole nafate (3) thus obtained may be re-crystallized.
  • the mother liquor remaining after the isolation procedure as described above may be used for recovering traces cefamandole nafate (3) or starting materials.
  • the cefamandole nafate obtained by the processes of the first aspect is used for the manufacture of a medicament with antibacterial properties for the treatment of a bacterial disease.
  • the medicament thus obtained has the advantage of being produced in high purity and with low environmental burden as compared to prior art approaches.
  • the cefamandole nafate obtained by the process of the first aspect is particularly suitable for use in the manufacture of a medicament for treatment of a bacterial disease in persons having acetate intolerance.
  • mutant penicillin G acylases may be carried out as described in WO 1996/005318 and WO 2003/055998.
  • genes encoding mutant penicillin G acylases may be obtained by gene synthesis.
  • Production of the mutant penicillin G acylase was achieved by cloning the genes encoding mutant penicillin G acylases into an appropriate expression vector, transforming a suitable host such as Escherichia coii with said vector and culturing the transformed host under conditions suitable for the production of the mutant penicillin G acylases and recovery and purification of the mutants was carried out as described in WO 2010/072765.
  • Penicillin G acylase AA (the Escherichia coii wild type penicillin G acylase with mutations B:F24A and B:V148L) and penicillin G acylase mutant 1 (the Escherichia coii wild type penicillin G acylase with mutations V1 1A, A:S3L, A:V192E, B:F24A, B:V148L and B:F460L) as disclosed in Example 1 of WO 2010/072765 were immobilized according to the method disclosed in EP 839192 and EP 222462.
  • the measurement is performed using 718 STAT Titrino from Metrohm.
  • the pH electrode is from Metrohm, series number 6.0234.1 10. It contains 3M KCI.
  • the pH meter calibration is performed at 20°C at pH 4 and pH 7 using standard solutions from Merck, using the calibration program present in the instrument.
  • the enzymatic reaction was carried out with R-methyl mandelate (20.9 g; 294 mmol), 7-TMCA (58.4 g; 165 mmol) and water (671 g) at 2°C and pH 8.5.
  • the reaction was started by adding immobilized penicillin G acylase mutant 1 (82.4 g, see Materials and Methods). At a conversion of 87% the reaction was stopped by removing the enzyme by filtration.
  • the mother liquor of the enzymatic reaction was extracted at room temperature twice with isopropyl acetate (850 g each time) to remove the remaining methyl mandelate.
  • the organic layer was evaporated under vacuum resulting in methyl mandelate oil. Remaining solvents were removed from the aqueous layer by evaporation.
  • Acetic anhydride (10.0 mL; 105.8 mmol) and formic acid (4 ml_; 106.0 mmol) were mixed and stirred at 55°C for 2h.
  • the mixed anhydride solution was added to a cefamandole mixture from an enzymatic reaction comprising cefamandole (5.290 g), methyl mandelate (0.124 g), mandelic acid (0.166 g) and isopropyl acetate (16.92 g).
  • imidazole was added as solution in mixed anhydride (10.3 mg imidazole in 500 ⁇ - mixed anhydride). Samples were taken over time and analyzed by means of HPLC. After 20h, 95 mg imidazole was added. Isopropyl acetate (56 g) and water (50 g) were added, the pH of the aqueous phase was adjusted to 1 .5 using 25% H 2 S0 4 and the phases were separated. The organic phase was washed with aqueous HCI (pH 1 .8, 2 x 20 mL). Approximately 2.2 mol% of cefamandole remained in the combined aqueous phases.
  • Example 2 The organic phase obtained in Example 2 was evaporated to dryness at 37°C using a rotavap. Isopropanol (15 mL) and acetone (15 mL) were added and the resulting mixture was titrated at room temperature to pH 5.6 wi t h a 1 0 % s od i u m 2-ethylhexanoate solution in acetone (718 STAT Titrino by Methrohm filled with 25% NH 3 ). The resulting crystals were isolated by filtration in a yield of 82.6%. Apart from the title product, HPLC analysis indicated the presence of cefamandole and acetyl cefamandole but not of any mandelic acid derivatives.
  • Example 3 The organic phase obtained in Example 3 was evaporated to 23.4 g at 38°C using a rotavap. Acetone (21 g) was added and the resulting mixture was titrated at room temperature to pH 5.66 with a 10% sodium 2-ethylhexanoate solution in acetone (55 mL). The resulting crystals were isolated by filtration to give, after drying overnight under vacuum at 30°C, 2.36 g of white solid.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Cette invention concerne un procédé de préparation de nafate de céfamandole à partir de céfamandole et son utilisation dans la fabrication d'un médicament destiné à traiter une maladie bactérienne.
PCT/EP2012/070664 2011-10-20 2012-10-18 Procédé de préparation de nafate de céfamandole WO2013057196A1 (fr)

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EP11185954.2 2011-10-20
EP11185954 2011-10-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104193767A (zh) * 2014-08-07 2014-12-10 杭州长典医药科技有限公司 一种头孢孟多酯钠超细粉体制剂及其制备方法
CN112694488A (zh) * 2020-12-28 2021-04-23 苏州盛达药业有限公司 一种l型头孢孟多酯钠的合成方法

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3641021A (en) 1969-04-18 1972-02-08 Lilly Co Eli 3 7-(ring-substituted) cephalosporin compounds
US3928592A (en) * 1974-02-22 1975-12-23 Lilly Co Eli Antibiotic pharmaceutical compositions
DE2614669A1 (de) * 1975-04-11 1976-10-21 Lilly Co Eli Gamma-kristalline wasserfreie form von 7-(d-alpha-formyloxy-alpha-phenylacetamido)-3-(1-methyl-1h-tetrazol-5- ylthiomehtyl)-3-cephem-4-natriumcarboxylat und verfahren zu ihrer herstellung
DE2730579A1 (de) * 1976-07-10 1978-01-12 Pierrel Spa Verfahren zur herstellung von cephalosporin-antibiotika
EP0156771A2 (fr) * 1984-03-29 1985-10-02 Biochemie Gesellschaft M.B.H. Céphalosporines
EP0222462A1 (fr) 1985-11-15 1987-05-20 Gist-Brocades N.V. Biocatalyseurs immobilisés, leur préparation et utilisation
US4877783A (en) 1981-07-25 1989-10-31 Beecham Group P.L.C. β-lactam antibacterial agents
WO1996005318A1 (fr) 1994-08-12 1996-02-22 Gist-Brocades B.V. Genes mutants d'acylases de la penicilline g
EP0839192A1 (fr) 1995-07-18 1998-05-06 Gist-Brocades B.V. Penicilline g acylase immobilisee amelioree
WO2003055998A2 (fr) 2001-12-27 2003-07-10 Dsm Ip Assets B.V. PROCEDE DE PREPARATION D'UNE ss-LACTAMINE
WO2010072765A2 (fr) 2008-12-23 2010-07-01 Dsm Ip Assets B.V. Acylases de pénicilline g mutantes
CN101880290A (zh) * 2010-06-28 2010-11-10 海南新中正制药有限公司 头孢孟多酯钠的制备方法
CN102276629A (zh) * 2011-08-22 2011-12-14 苏州二叶制药有限公司 一种头孢孟多酯钠的合成路线

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3641021A (en) 1969-04-18 1972-02-08 Lilly Co Eli 3 7-(ring-substituted) cephalosporin compounds
US3928592A (en) * 1974-02-22 1975-12-23 Lilly Co Eli Antibiotic pharmaceutical compositions
DE2614669A1 (de) * 1975-04-11 1976-10-21 Lilly Co Eli Gamma-kristalline wasserfreie form von 7-(d-alpha-formyloxy-alpha-phenylacetamido)-3-(1-methyl-1h-tetrazol-5- ylthiomehtyl)-3-cephem-4-natriumcarboxylat und verfahren zu ihrer herstellung
DE2730579A1 (de) * 1976-07-10 1978-01-12 Pierrel Spa Verfahren zur herstellung von cephalosporin-antibiotika
US4877783A (en) 1981-07-25 1989-10-31 Beecham Group P.L.C. β-lactam antibacterial agents
EP0156771A2 (fr) * 1984-03-29 1985-10-02 Biochemie Gesellschaft M.B.H. Céphalosporines
EP0222462A1 (fr) 1985-11-15 1987-05-20 Gist-Brocades N.V. Biocatalyseurs immobilisés, leur préparation et utilisation
WO1996005318A1 (fr) 1994-08-12 1996-02-22 Gist-Brocades B.V. Genes mutants d'acylases de la penicilline g
EP0839192A1 (fr) 1995-07-18 1998-05-06 Gist-Brocades B.V. Penicilline g acylase immobilisee amelioree
WO2003055998A2 (fr) 2001-12-27 2003-07-10 Dsm Ip Assets B.V. PROCEDE DE PREPARATION D'UNE ss-LACTAMINE
WO2010072765A2 (fr) 2008-12-23 2010-07-01 Dsm Ip Assets B.V. Acylases de pénicilline g mutantes
CN101880290A (zh) * 2010-06-28 2010-11-10 海南新中正制药有限公司 头孢孟多酯钠的制备方法
CN102276629A (zh) * 2011-08-22 2011-12-14 苏州二叶制药有限公司 一种头孢孟多酯钠的合成路线

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
A. AMORE ET AL., J. AMER. SOC. NEPHROL., 1997, pages 1431
A.R. KATRITZKY ET AL., SYNTHESIS, 1995, pages 503 - 505
D.R. HILL ET AL., ORG. LETT., 2002, pages 111 - 113
FUGANTI ET AL., BIOTECHNOL. LETT., vol. 14, 1992, pages 543 - 546
G.A. OLAH ET AL., CHEM. REV., vol. 87, 1987, pages 671 - 686
KAISER ET AL., J. INFECT. DIS., vol. 137, 1978, pages 10 - 16
M. CHAKRABARTY ET AL., SYNTH. COMMUN., vol. 30, no. 2, 2000, pages 187 - 200
M.H. HABIBI ET AL., TETRAHEDRON, vol. 57, 2001, pages 8333 - 8337
NIERSTRASZ ET AL., BIOCATALYSIS AND BIOTRANSFORMATION, vol. 17, 1999, pages 209 - 223
SERRA ET AL., EUR. J. ORG. CHEM., 2009, pages 1384 - 1389
TERRENI ET AL., APPL. MICROBIOL. BIOTECHNOL., vol. 77, 2007, pages 579 - 587
V. MIRKHANI ET AL., MONATSHEFTE FUR CHEMIE, vol. 135, 2004, pages 1257 - 1263

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104193767A (zh) * 2014-08-07 2014-12-10 杭州长典医药科技有限公司 一种头孢孟多酯钠超细粉体制剂及其制备方法
CN112694488A (zh) * 2020-12-28 2021-04-23 苏州盛达药业有限公司 一种l型头孢孟多酯钠的合成方法
CN112694488B (zh) * 2020-12-28 2022-04-22 苏州盛达药业有限公司 一种l型头孢孟多酯钠的合成方法

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