Process for the preparation of beta-lactam compounds
Inventors
van der Does, Thomas • Moody, Harold Monro • Van Dooren, Theodorus Johannes Godfried Maria
Assignees
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Publication Number
US-8497088-B2
Publication Date
2013-07-30
Expiration Date
Abstract
The present invention describes a process for the synthesis of a semi-synthetic β-lactam compound from a nucleus and a side chain selected from the group consisting of D-phenylglycine and D-dihydro-phenylglycine in the form of a side chain ester and an enzyme catalyzing the coupling of the side chain ester to the nucleus characterized in that the side chain ester is not isolated as a solid intermediate.
Core Innovation
The invention relates to an improved process for the synthesis of semi-synthetic β-lactam compounds from a nucleus and a side chain selected from D-phenylglycine and D-dihydro-phenylglycine. The side chain is provided in the form of a side chain ester, and the coupling of the side chain ester to the nucleus is catalyzed by an enzyme. The process requires that the side chain ester formed is not isolated as a solid intermediate.
The disclosure states that converting a free side chain with an alcohol to form a mixture comprising the corresponding side chain ester avoids isolating the side chain ester as a solid intermediate. This approach is presented as enabling a higher ester/free-side-chain ratio and improving coupling behavior.
The document further describes preferred conversion of the free side chain to methyl or ethyl esters using an alcohol and a strong acid, followed by optional purification approaches intended to obtain an ester/free-side-chain ratio and enantiomeric excess prior to enzymatic coupling. Recovery and crystallization rationale are presented as being enabled by low free side chain.
Claims Coverage
The partial content includes one independent claim. It sets out a process framework for enzymatic coupling of a side chain ester to a nucleus, with the proviso that the side chain ester is not isolated as a solid intermediate.
Enzymatic coupling of side chain esters to a β-lactam nucleus without solid isolation
A process for the synthesis of a semi-synthetic β-lactam compound comprising converting a free side chain selected from D-phenylglycine and D-dihydro-phenylglycine with an alcohol to form a mixture comprising the corresponding side chain ester, and forming the semi-synthetic β-lactam compound by mixing the mixture obtained in step (a) with a nucleus and the enzyme, with the proviso that the side chain ester formed is not isolated as a solid intermediate.
The central inventive concept is the preparation of a side chain ester as part of a mixture from a free D-phenylglycine or D-dihydro-phenylglycine side chain and alcohol, followed by enzymatic coupling to a selected nucleus, while avoiding isolation of the ester as a solid intermediate.
Stated Advantages
Improved enzymatic coupling behavior associated with avoiding free side chain precipitation and reduced enzymatic coupling yield when solid ester intermediates are not isolated.
Enabling a higher ester/free-side-chain ratio before enzymatic coupling.
Enabling recovery/crystallization rationale enabled by low free side chain.
Supports obtaining enantiomeric excess prior to enzymatic coupling.
Documented Applications
Enzymatic formation and recovery of semi-synthetic β-lactam compounds including cephalexin and cephradine.
Enzymatic formation of amoxicillin and ampicillin-related intermediates as described in the examples.
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