Purification of caspofungin intermediates
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Publication Number
US-8951958-B2
Publication Date
2015-02-10
Expiration Date
Abstract
The present invention relates to a method for the purification of cyclopeptides of general formula (3) by means of a silicate.
Core Innovation
The invention concerns a method for the purification of a compound of general formula (3) wherein R1 is C(O)R3 with R3 being C9-C21 alkyl, C9-C21 alkenyl, C1-C10 alkoxyphenyl, C1-C10 alkoxynaphthyl, or C1-C10 alkoxyterphenyl, wherein R2 is benzimidazol-2-yl, benzothiazol-2-yl, 1-methylimidazol-2-yl, 4-methoxyphenyl, or phenyl, and wherein X is O or H,H. The purification comprises dissolving the compound in a first solvent, contacting the solution with silica gel, and eluting the compound with a second solvent to reach a purity of 98.3% or greater.
The background problem addressed is the purification of cyclopeptide intermediates associated with pneumocandin/caspofungin, including removal of a C0 impurity, including a difficult impurity A when X=H,H. The disclosed approach uses adsorption on silica gel to separate the pneumocandin/caspofungin-related cores from the C0 impurity(ies), including thiol- or thio- and amide/amine-substituted intermediate variants (X=O or X=H,H).
In the described purification strategy, a silica gel/silicate step enables successful separation by elution with a second solvent system. The partial content further describes that improved separation can be obtained by applying the silica mixture to a silicate column prior to elution, including successful purification outcomes for thiophenyl-substituted intermediate variants (X=O) and thio/amine variants (X=H,H).
Claims Coverage
The document includes one independent claim covering a silica gel-based purification method for compounds of general formula (3), with the key inventive requirements being contact with silica gel and elution to achieve a specified purity level. Dependent claims further refine solvent composition/components and optionally include downstream conversion to caspofungin.
Silica gel contact and elution to achieve high purity
A method for purification of a compound of general formula (3) comprising dissolving the compound in a first solvent; contacting the solution with silica gel; and eluting the compound with a second solvent to obtain a purity of 98.3% or greater.
Across the claims, purification hinges on contacting a general formula (3) compound with silica gel followed by eluting to reach 98.3% or greater purity, with dependent claims specifying refinements to the first and second solvent selections and optionally converting the purified intermediate into caspofungin.
Stated Advantages
Eluting the compound to achieve a purity of 98.3% or greater.
Improved separation of C0 impurity(ies) from pneumocandin/caspofungin-related cores, including a difficult impurity A for X=H,H.
Documented Applications
Purification of cyclopeptide intermediates of general formula (3) associated with pneumocandin B0 and caspofungin, including separation of C0 impurity(ies).
Conversion of a purified compound of general formula (3) into caspofungin or a pharmaceutically acceptable salt thereof.
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