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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/057196 Al 25 April 2013 (25.04.2013) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 501/36 (2006.01) A61P 31/04 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/546 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP2012/070664 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 18 October 2012 (18.10.2012) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 11185954.2 20 October 201 1 (20. 10.201 1) EP (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: DSM SINOCHEM PHARMACEUTICALS GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, NETHERLANDS B.V. [NL/NL]; P.O.Box 245, Alexan UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, der Fleminglaan 1, NL-2613 AX Delft (NL). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors: MOODY, Harold, Monro; P.O.Box 4, NL- MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 6100 AA Echt (NL). MAAS, Peter, Johannes, Domini- TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, cus; P.O. Box 4, NL-6100 AA Echt (NL). SCHMITGES, ML, MR, NE, SN, TD, TG). Thomas; P.O. Box 4, NL-6100 AA Echt (NL). Published: (74) Agent: VROOM, DE, Erik; DSM Intellectual Property, P.O. Box 130, NL-6100 AC Echt (NL). — with international search report (Art. 21(3)) © o (54) Title: PROCESS FOR THE PREPARATION OF CEFAMANDOLE NAFATE (57) Abstract: The present invention relates to a process for the preparation of cefamandole nafate from cefamandole and to the use thereof in the manufacture of a medicament for treatment of a bacterial disease. PROCESS FOR THE PREPARATION OF CEFAMANDOLE NAFATE Field of the invention The present invention relates to a process for the preparation of cefamandole nafate from O-formyl cefamandole. Background of the invention 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. Various approaches towards the preparation of cefamandole nafate have been reported. In a first approach, the compound can be prepared by chemical N-acylation of the appropriate β-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, 10-16). In a second and environmentally more benign approach, an enzymatically catalyzed kinetically controlled acylation of 7-TMCA has been proposed in more recent literature by, amongst others, Nierstrasz et al. (Biocatalysis and Biotransformation (1999) 17, 209-223), Terreni et al. (Appl. Microbiol. Biotechnol. (2007) 77, 579-587) and Serra et al. (Eur. J. Org. Chem. (2009), 1384-1389). Although direct kinetically controlled acylation of 7-TMCA with D,L-0-formyl methyl mandelate towards O-formyl cefamandole (2) has been suggested by Fuganti et al. (Biotechnol. Lett. (1992) 14, 543-546) using the enzyme penicillin G acylase from Escherichia coii immobilized on Eupergit C, the general opinion is that the active site of penicillin G acylase is only moderately suited to accommodate the D,L-0-formyl mandelate side chain. Unfortunately, an efficient approach leading from cefamandole (1) or O-formyl cefamandole (2) to cefamandole nafate (3), has not been reported yet. Detailed description of the invention 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). It is an object of the present invention to provide a method for the preparation of cefamandole nafate (3) from O-formyl cefamandole (2). In a first aspect of the invention there is provided a method for the preparation of cefamandole nafate (3) comprising the steps of: (a) reacting cefamandole or a salt thereof and an impurity chosen from the list consisting of mandelic acid, methyl mandelate and O-acetyl mandelic acid or salts thereof with a formylating agent; (b) contacting the mixture obtained in step (a) with a sodium source in an organic solvent, 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). As a result of the formylation reaction 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. In one embodiment, 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. It is well known that 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. Surprisingly it is found that upon conversion of O-formyl cefamandole (2) to the sodium salt cefamandole nafate (3), only the latter crystallizes and can be isolated in high purity whereas the sodium salt of O-formyl mandelic acid remains dissolved in the mother liquor. This unexpected phenomenon results in a highly efficient purification step. In another embodiment, O-formyl cefamandole (2) or a salt thereof is prepared by reacting cefamandole or a salt thereof with a formylating agent. In general, 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. Katritzky et al., Synthesis (1995), 503-505), ethyl formate (M.H. Habibi et al., Tetrahedron (2001 ) 57, 8333-8337), 2,2,2-trifluoroethyl formate (D.R. Hill et al., Org. Lett. (2002), 111-1 13), acetic acid with ethyl formate (V. Mirkhani et al., Monatshefte fur Chemie (2004) 135, 1257-1263). However not much is known of formylation of the class of sensitive β-lactams. In US 4,877,783 formylation of a β-lactam is reported using acetic formic anhydride, however the formylation concerns the carbon adjacent to the carbonyl of the β-lactam ring and the carboxyl group of the β-lactam is protected. If not for anything else this example stresses the ease of formation of unwanted side products in β-lactam formylation reactions. In one embodiment, the formylating agent is formic acid, a formic anhydride, a formic ester, a formic halide or an N-formyl derivative. Preferably, the formylating agent is a mixed anhydride such as acetic formic anhydride of formula CH3C(0)OC(0)H, a compound that can conveniently be prepared from acetic anhydride and formic acid. Alternatively, a sterically hindered derivative of acetic formic anhydride may be used, such as butyric formic anhydride of formula CH3CH2CHC(0)OC(0)H or 2-ethylbutyric formic anhydride of formula (C2H 5)2CH C(0)OC(0)H or isobutyric formic anhydride of formula (CH 3)2CHC(0)OC(0)H or 2-methylbutyric formic anhydride of formula C H3C H2CH(CH 3)C(0)OC(0)H or propionic formic anhydride of formula CH3CH2C(0)OC(0)l-l or mixtures thereof.
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  • Revised Group Additivity Values for Enthalpies of Formation (At 298 K) of Carbon– Hydrogen and Carbon–Hydrogen–Oxygen Compounds

    Revised Group Additivity Values for Enthalpies of Formation (At 298 K) of Carbon– Hydrogen and Carbon–Hydrogen–Oxygen Compounds

    Revised Group Additivity Values for Enthalpies of Formation (at 298 K) of Carbon– Hydrogen and Carbon–Hydrogen–Oxygen Compounds Cite as: Journal of Physical and Chemical Reference Data 25, 1411 (1996); https://doi.org/10.1063/1.555988 Submitted: 17 January 1996 . Published Online: 15 October 2009 N. Cohen ARTICLES YOU MAY BE INTERESTED IN Additivity Rules for the Estimation of Molecular Properties. Thermodynamic Properties The Journal of Chemical Physics 29, 546 (1958); https://doi.org/10.1063/1.1744539 Critical Evaluation of Thermochemical Properties of C1–C4 Species: Updated Group- Contributions to Estimate Thermochemical Properties Journal of Physical and Chemical Reference Data 44, 013101 (2015); https:// doi.org/10.1063/1.4902535 Estimation of the Thermodynamic Properties of Hydrocarbons at 298.15 K Journal of Physical and Chemical Reference Data 17, 1637 (1988); https:// doi.org/10.1063/1.555814 Journal of Physical and Chemical Reference Data 25, 1411 (1996); https://doi.org/10.1063/1.555988 25, 1411 © 1996 American Institute of Physics for the National Institute of Standards and Technology. Revised Group Additivity Values for Enthalpies of Formation (at 298 K) of Carbon-Hydrogen and Carbon-Hydrogen-Oxygen Compounds N. Cohen Thermochemical Kinetics Research, 6507 SE 31st Avenue, Portland, Oregon 97202-8627 Received January 17, 1996; revised manuscript received September 4, 1996 A program has been undertaken for the evaluation and revision of group additivity values (GAVs) necessary for predicting, by means of Benson's group additivity method, thermochemical properties of organic molecules. This review reports on the portion of that program dealing with GAVs for enthalpies of formation at 298.15 K (hereinafter abbreviated as 298 K) for carbon-hydrogen and carbon-hydrogen-oxygen compounds.
  • (Hexamine) Formaldehyde (Formalin) Pentaerythritol Sodium Formate

    (Hexamine) Formaldehyde (Formalin) Pentaerythritol Sodium Formate

    Hexamethylenetetramine (Hexamine) ▶Hexamethylenetetramine (Hexamine) White crystalline or powder compound that easily dissolves in water. It releases heat when dissolving in Characteristics water, with solubility decreasing as the temperature increases. This product has a larger crystalline piece size compared to other companies made possible by setting the granularity distribution during manufacturing. Key Used phenol-formaldehyde resin hardeners, RDX, fuel, gas absorbent and rubber vulcanizing agents, etc. applications Formaldehyde (Formalin) ▶Formaldehyde (Formalin) Aldehyde substance in a simple structure stored and sold in an aqueous solution state (37~42%) since it Characteristics exists as gas at room temperature. It has the property of becoming polymerized at a low temperature, so methanol has been added as an additive (content in the range of 2 ~ 12%). Key Used in insecticides, disinfectants, germicides, medical drugs, raw ingredient of synthetic resins and applications raw organic synthetic materials, etc. Pentaerythritol ▶Pentaerythritol Odorless white crystalline compound without hygroscopicity and non-volatile, making it a safe substance in Characteristics the air. Although there is a risk of explosion with the fine powder, the minimum explosion powder concentration in air is 30mg/㎥, with the minimum ignition temperature being 450℃. Key Used in alkyd resin, raw material for polyurethane, rosin ester, synthetic drying oil, reagent, applications PVC plasticizer and surfactant, etc. Sodium Formate ▶Sodium Formate Product generated as a byproduct in the pentaerythritol manufacturing process. This is a colorless crystal or Characteristics white crystalline powder that can be dissolved in water easily due to its hygroscopicity, but it does not dissolve easily in ethyl alcohol. Used in analysis of precipitants for precious metals, as an astringent, in textile dyes and printing, formic acid, Key electroplating agent, acidifier for leather manufacturing, reductant, organic chemical substance, analytic applications reagent, etc..