Compositions and methods of making a photoactive agent
View Patent ↗An improved two stage reaction process for production of mono-L-aspartyl chlorin e 6 . In a first stage, the activation reaction between chlorin e 6 and a carbodiimide produces a previously unknown anhydride in an activation reaction product (Formula I). This reaction product is purified to remove a significant proportion of the precursors of di-L-aspartyl chlorin e 6 . The purified activation reaction product contains a higher concentration of the previously unknown anhydride. This purified reaction product is used in a second stage: a coupling reaction of the purified activation reaction product with aspartate. The coupling reaction produces a coupling reaction product that has significantly reduced di-L-aspartyl chlorin e6 concentration. This reduced di-L-aspartyl chlorin e6 concentration facilitates purification of mono-L-aspartyl chlorin e6 from the coupling reaction mixture.
1. A process for preparing mono-L-aspartyl chlorin e 6 , or a pharmaceutically acceptable salt thereof, comprising:
combining chlorin e 6 with a carboxyl activating agent to obtain a mixture comprising a Formula I intermediate
or a salt thereof;
isolating the Formula I intermediate, or salt thereof; and
combining the isolated Formula I intermediate, or salt thereof, with an amine-containing reagent, to form talaporfin sodium, or a pharmaceutically acceptable salt thereof.
2. The process of claim 1 , wherein combining the chlorin e 6 with the carboxyl activating agent comprises reacting the chlorin e 6 with a carbodiimide.
3. The process of claim 2 wherein the carbodiimide is N,N′-dicyclohexyl-carbodiimide, N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride, or mixtures thereof.
4. The process of claim 1 , wherein combining the chlorin e 6 with the carboxyl activating agent comprises reacting the chlorin e 6 with a carbodiimide in the presence of dimethyl sulfoxide or dimethyl formamide.
5. The process of claim 1 wherein reacting the chlorin e 6 with the carboxyl activating agent comprises reacting the chlorin e 6 with N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride or N,N′-dicyclohexyl-carbodiimide.
6. The process of claim 1 wherein isolating the Formula I intermediate, or salt thereof, comprises separating the Formula I intermediate, or salt thereof, from the mixture by using activated silica to yield a substantially pure Formula I intermediate, or salt thereof.
7. The process of claim 1 wherein combining the isolated Formula I intermediate, or salt thereof, with an amine-containing reagent, comprises reacting the isolated Formula I intermediate, or salt thereof, with sodium aspartate to form talaporfin sodium.
8. The process of claim 1 wherein combining the isolated Formula I intermediate, or salt thereof, with an amine-containing reagent, comprises combining the isolated Formula I intermediate, or salt thereof, in the presence of dimethyl sulfoxide, with L-aspartic acid or ester thereof to form talaporfin sodium.
9. The process of claim 1 wherein combining the isolated Formula I intermediate, or salt thereof, with an amine-containing reagent, comprises coupling the isolated Formula I intermediate with L-aspartic acid or ester thereof in an aqueous alkaline solution to form a tetra-sodium salt of mono-L-aspartyl chlorin e 6 .