Processes for the preparation of substituted tetrahydro beta-carbolines

A process for preparing a compound of Formula (IIa):

• comprising the steps of:
• i) preparing a mixture by adding 2% water to absolute ethanol then adding N-acetyl-(L) phenylalanine;
• ii) heating the mixture to reflux;
• iii) cooling the refluxed mixture from step ii) to a temperature between about 58° C. and 52° C.;
• iv) preparing a solution by adding 2% water to absolute ethanol then adding a compound of Formula (IVa):
• v) heating the solution to reflux;
• vi) cooling the refluxed solution from step v) to a temperature between about 58° C. and 52° C.;
• vii) preparing a reaction mixture by adding 0.1 equivalents of N-acetyl-(L) phenylalanine from the mixture from step iii) to one equivalent of Formula (IVa) from the solution from step vi) while maintaining a temperature between about 58° C. and 52° C.;
• viii) seeding the reaction mixture by adding (S)-piperindinoindole Form B, wherein (S)-piperindinoindole Form B is a crystalline form of the compound of Formula (IIa), and stirring for about 5 minutes;
• ix) forming a suspension by adding an additional 0.4 equivalents of N-acetyl-(L)-phenylalinine from the mixture from step iii) to the reaction mixture from step viii) while maintaining a temperature of between about 58° C. and 52° C.;
• x) cooling the suspension from step ix) to a temperature of between about 17° C. and 13° C. at a linear rate over a period of about 2 hours;
• xi) stirring the cooled suspension from step x) while maintaining the temperature between about 17° C. and 13° C. for about 1 hour;
• and
• xii) filtering the stirred suspension of step xi) and washing with a mixture of absolute ethanol and 2% water.