The claimed manufacturing process is expected to result in a significant reduction in the cost of goods sold, providing a stronger competitive position for the Company.
By reducing the complexity of production and cost of the compound, we will have greater flexibility in potentially ensuring that patients on a worldwide basis have access and can benefit from this therapy.
http://ir.aezsinc.com/press-release/2015/...trengthen-ip-protection-1
Summary of the Invention
It has surprisingly been found, that N-Fmoc-doxorubicin can indeed be used as starting material in enzyme catalyzed acylation reactions with very good yield and high selectivity for C14-OH esterification, despite its low solubility. The present inventions therefore provides a solution to a problem clearly identified in the prior art for esterification of N-Fmoc- doxorubicin, being specifically expressed by the statement "the solubility of N-Fmoc- doxorubicin was ... not synthetically useful" (see Cotterill et al. Biotech and Bioeng. 2008, p 438, left column, 1 st paragraph).
The use of the N-Fmoc protecting group to modify the doxorubicin C3'-NH 2 group is advantageous compared to other commonly used nitrogen modifying groups, because this bulky group shields the doxorubicin C4'-OH group and thus provides due to enhanced selectivity for better yields in shorter reaction times, combined with a better impurity profile.
The lipase catalyzed esterification of N-alloc-doxorubicin or N-trifluoroacetyl-doxorubicin with glutaric acid yielded 51% and 70% of the corresponding products, respectively (see reference experiments 5 and 6). Under the same conditions, N-Fmoc-doxorubicin was converted to N-Fmoc-doxorubicin hemiglutarate in 92% yield (see example la).
Further optimization resulted in yields up to 95%, while reducing the reaction time to 4h (see example Id). This was achieved by organic binary solvent systems, wherein one component provided the possibility to remove water from the reaction vessel in order to drive the reaction to completion, while the other component ensured lipase activity and a sufficient solubility of the starting materials. The need for a solvent to direct regioselective esterification was overcome due to the directing effects of the bulky Fmoc group. Description of the invention
http://www.sumobrain.com/patents/wipo/...turing-n/WO2016116335A1.html
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