Methods for the total chemical synthesis of enantiomerically-pure 7-(2′-trimethylsilyl)ethyl camptothecin
Inventors
Chen, Xinghai • Hausheer, Frederick H. • Malakhov, Andrey • Kochat, Harry
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-8722886-B1
Publication Date
2014-05-13
Expiration Date
Abstract
The present invention discloses and claims five (5) novel, highly efficient synthetic routes for the total synthesis of enantiomerically-pure (i.e., 99%) 7-(2′-trimethylsilyl)ethyl camptothecin (BNP1350; Karenitecin; Cositecan). These aforementioned synthetic schemes are the first to disclose the total syntheses of 7-(2′-trimethylsilyl)ethyl camptothecin using a highly novel direct, non-linear and convergent synthetic strategy which involves annealing the key C7-(trimethylsilyl)ethyl side chain-bearing A ring key synthons to an enantiomerically-pure tricyclic pyridone; rather than through the conventional methodology which incorporates the C7-(trimethylsilyl)ethyl side chain as the final synthetic step on a totally synthesized camptothecin parent compound. The current novel synthetic approaches reported herein since utilize desirably functionalized A-ring with preinstalled trimethyl silyl ethyl side chain, the aforementioned synthetic methodologies have a wider scope of making wide range of pharmaceutically relevant A-ring substituted BNP1350 analogs by substituting desirably functionalized nitro or protected amino phenyl carboxy A-ring as the starting material.
Core Innovation
The invention describes total chemical synthesis routes to enantiomerically pure (99% ee) 7-(2′-trimethylsilyl)ethyl camptothecin (BNP1350/Karenitecin/Cositecan). The disclosed strategy uses a direct, non-linear convergent approach in which a prefunctionalized C7-(trimethylsilyl)ethyl side-chain A-ring key synthone is annealed to an enantiomerically pure tricyclic pyridone (CDE ring). This construction forms the camptothecin framework without installing the side chain as the final step on a fully assembled camptothecin parent.
The background problem addressed includes camptothecin/lactone stability, poor solubility, and side effects associated with sodium-hydroxide formulations. The invention also relates to the mechanism of action of camptothecin via Topoisomerase I inhibition and the presence of cleavable complex as part of the biological effect. These issues provide motivation for an efficient synthesis of a specific enantiomerically pure camptothecin derivative.
The disclosed synthetic concept is supported by multiple synthesis schemes, including Scheme 1 through Scheme 5. Each scheme specifies formation of an A-ring key synthone followed by an organic acid catalyzed Friedlander condensation with a commercially-available chiral CDE ring intermediate compound to give enantiomerically pure 7-(2′-trimethylsilyl)ethyl camptothecin. Chirality verification is stated using chiral HPLC, and cytotoxicity comparisons are stated using SRB assay results and IC50-based potency and resistance factor comparisons.
Claims Coverage
The partial claim set provides five independent claims, each tied to a different synthesis scheme (Synthesis Scheme 1 to Synthesis Scheme 5). Across all independent claims, the main inventive features follow the same overall pattern: preparation of a key A-ring synthone leading to an organic acid catalyzed Friedlander condensation with a commercially-available chiral CDE ring intermediate to produce enantiomerically pure 7-(2′-trimethylsilyl)ethyl camptothecin.
Scheme 1 convergent A-ring synthone formation and Friedlander condensation
A method for the total chemical synthesis set forth in Synthesis Scheme 1, including addition of 2-(trimethylsilyl)vinylmagnesium bromide to 2-nitrobenzaldehyde followed by oxidation to produce a vinyl trimethylsilyl aryl ketone, Pd/C hydrogenation to produce the key A-ring synthone 1-(2-amino-phenyl)-3-trimethylsilanyl-propan-1-one, and organic acid catalyzed Friedlander condensation of this A-ring synthone with a commercially-available chiral CDE ring intermediate to give enantiomerically pure 7-(2′-trimethylsilyl)ethyl camptothecin.
Scheme 2 trimethylsilylpropionylated N-Boc-aniline formation and Friedlander condensation
A method for the total chemical synthesis set forth in Synthesis Scheme 2, including treatment of N-Boc-aniline with tert-butyl lithium followed by addition to methoxymethyl(3-trimethylsilyl)propionamide to generate 2-(3′-trimethylsilylpropionyl)-N-Boc-aniline, and organic acid catalyzed Friedlander condensation of this compound with the commercially-available chiral CDE ring intermediate to give enantiomerically pure 7-(2′-trimethylsilyl)ethyl camptothecin.
Scheme 3 carbon monoxide Suzuki coupling to trimethylsilylpropionyl N-Boc-aniline and Friedlander condensation
A method for the total chemical synthesis set forth in Synthesis Scheme 3, including Suzuki-type coupling of N-Boc-2-iodoaniline with ethynyltrimethylsilane in presence of carbon monoxide to produce a 2-(3′-trimethylsilylacetylenic ketone)-N-Boc-aniline intermediate, followed by hydrogenation in presence of Pd/C to generate 2-(3′-trimethylsilylpropionyl)-N-Boc-aniline, and organic acid catalyzed Friedlander condensation of this compound with the commercially-available chiral CDE ring intermediate to give enantiomerically pure 7-(2′-trimethylsilyl)ethyl camptothecin.
Scheme 4 cryogenic n-butyllithiated trimethylsilane route to A-ring synthone and Friedlander condensation
A method for the total chemical synthesis set forth in Synthesis Scheme 4, including synthesis of 1-(2-nitrophenyl)-3-trimethylsilanyl-2-propyn-1-ol by addition of THF solution of n-butyllithiated trimethylsilane to o-nitrobenzaldehyde, oxidation of propyn-1-ol with manganese dioxide to form 2-(3′-trimethylsilylpropiolyl)-nitrobenzene followed by conversion to the key A-ring synthone 1-(2-amino-phenyl)-3-trimethylsilanyl-propan-1-one by hydrogenation in presence of Pd/C, and organic acid catalyzed Friedlander condensation of the A-ring synthone with the commercially-available chiral CDE ring intermediate to give enantiomerically pure 7-(2′-trimethylsilyl)ethyl camptothecin.
Scheme 5 2-nitrobenzoyl chloride to A-ring synthone and Friedlander condensation
A method for the total chemical synthesis set forth in Synthesis Scheme 5, including conversion of 2-nitrobenzoic acid to 2-nitrobenzoyl chloride, Friedel-Craft alkynylation of the crude 2-nitrobenzoyl chloride with bis(trimethylsilyl)acetylene to generate 1-nitrophenyl-3-trimethylsilyl-propynone, hydrogenation in presence of Pd/C to produce the key A-ring synthone 1-(2-amino-phenyl)-3-trimethylsilanyl-propan-1-one followed by obtaining the hydrochloride salt, and organic acid catalyzed Friedlander condensation of the hydrochloride salt with the commercially-available chiral CDE ring intermediate to give enantiomerically pure 7-(2′-trimethylsilyl)ethyl camptothecin.
Across all five independent claims, the coverage centers on constructing enantiomerically pure 7-(2′-trimethylsilyl)ethyl camptothecin via a scheme-specific preparation of a key A-ring synthone, followed by an organic acid catalyzed Friedlander condensation with a commercially-available chiral CDE ring intermediate.
Stated Advantages
Efficient total chemical synthesis routes to enantiomerically pure (99% ee) 7-(2′-trimethylsilyl)ethyl camptothecin (BNP1350/Karenitecin/Cositecan).
Chirality verification is stated using chiral HPLC.
Cytotoxicity comparison indicates similar potency (nanomolar IC50) between BNP1350 from natural camptothecin and from total synthesis, with a low resistance factor.
Documented Applications
SRB assay cytotoxicity evaluation comparing BNP1350 derived from natural camptothecin versus BNP1350 from total synthesis, including IC50 and resistance factor assessments.
Interested in licensing this patent?