Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-07-25
1999-12-07
Shaver, Paul F.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540331, C07D50100, C07D49948
Patent
active
059986107
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the production of silylated 7-amino-desacetoxy-cephalosporanic acid or 6-aminopenicillanic acid by silylation of a 7-amino-desacetoxy-cephalosporanic acid or 6-aminopenicillanic acid and use of the silylated intermediates in the production of a 7-alpha-aminoacyl-desacetoxy-cephalosporin or a 6-alpha-aminoacyl-penicillin.
In EP 439 096 which is incorporated herein by reference, a mixed anhydride process for the production of i.a. ampicillin, amoxicillin, epicillin, cephradine, cephalexin, cefadroxil is described, starting from 6-aminopenicillanic acid (6-APA), or 7-amino-desacetoxy-cephalosporanic acid (7-ADCA).
According to this publication water-immiscible, halogen-free solvents are used in the production of the mixed anhydride resulting in good yields and purities of the products. It is stated that the penicillanic or cephalosporanic acid used as starting material therein may also be silylated, but a process for the silylation of the starting material is not specifically exemplified.
It has now surprisingly been found that silylated starting material used in the process of EP 439 096 for the preparation of products mentioned above results in extremely high yields and purities of the products obtained, if the silylation of the starting material 7-ADCA or 6-APA is carried out in certain carboxylic acid ester solvents.
The invention therefore provides in one aspect a process for the production of a silylated 7-amino-desacetoxy-cephalosporanic acid by silylation of a 7-amino-desacetoxy-cephalosporanic acid in a carboxylic acid ester of formula
In another aspect the present invention provides a process for the production of a silylated 6-aminopenicillanic acid by silylation of 6-aminopenicillanic acid in a carboxylic acid ester of formula presence of a silylation agent other than N,N-bistrimethylsilyl acetamide, N,N'-bistrimethylsilylmalonic acid amide and N,N'-bistrimethylsilyl urea.
Alkyl includes, for example, straight chain or branched (C.sub.1-8)alkyl or (C.sub.5-6)cycloalkyl, in particular straight chain or branched alkyl. Examples include alkyl acetates wherein Y has at least 3 carbon atoms, e.g. 3 to 8 C-atoms and X denotes C.sub.1-8, preferably C.sub.1-6, more preferably C.sub.1-4 alkyl. X may, for example, denote methyl and Y alkyl of at least 3 carbon atoms.
Preferred solvents include propyl acetates or butyl acetates, for example n-butyl acetate or isopropyl acetate.
In a further aspect the present invention provides a process for the production of a silylated 7-amino-desacetoxy-cephalosporanic acid or a silylated 6-aminopenicillanic acid by silylation of 7-amino-desacetoxy-cephalosporanic acid, or 6-aminopenicillanic acid in iso-propylacetate or n-butylacetate.
A compound of formula (I) is used at least as part of the solvent system. The solvent system used may contain more than one compound of formula (I).
The silylation process may be carried out as follows: in a solvent of formula I as defined above.
If desired a small amount of a co-solvent may be present, for example those known in the art, including organic amides, e.g. formamide or an acetamide, or their N-mono or N,N-dimethyl derivatives, e.g. dimethyl formamide, or N-methylacetamide, N,N-dimethylacetamide, or N-methylpyrrolidine or tetramethylurea. Conveniently the co-solvent comprises about 10 to 50 percent by weight of the solvent system. In particular, however, a co-solvent is not necessarily used.
Silylation agents which are common for the silylation of 7-ADCA or 6-APA may be used; including silanes, such as trichlorosilane or alkylsilanes, such as trialkylmonochlorsilane, e.g. trimethylchlorosilane, dialkyldichlorosilanes; silylated amides, such as bissilylacetamide, e.g. N,O-bis(trimethylsilyl)acetamide, N,N'-bis-trimethylsilylmalonic acid amide, N,N'-bis-trimethylsilylsuccinic acid amide, N-methyl-N-trimethylsilyltrifluoroacatamide; N,N'-bistrimethylsilylmalonic acid diamide, N,N'-bistrimethylsilylsuccinic acid diamide; silylated ureas such as bissilylurea, e.g. N,N-bis(trimethylsilyl)urea,
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Centellas Victor
Diago Jose
Ludescher Johannes
Biochemie Gesellschaft m.b.H.
Dohmann George R.
Kalinchak Stephen G.
Shaver Paul F.
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