PNU-95666E (sumanirole) was reported to be a highly selective D2 receptor full agonist. It was originally developed for the treatment of Parkinson’s disease. An eight steps synthesis was developed for the scale up of enantiomerically pure (R)-sumanirole with an overall yield of 26%. Two critical steps were involved 1) the synthesis of a tetrahydroquinoline ring system (compound 10, yield 85%) and 2) in situ reduction and deprotection of the lactam intermediate 10 to the diamine 11 (yield 65%)
Comments on experimental reproducibility:
- In step 1, protection of D-phenylalanine with methyl chloroformate is exothermic in the beginning and forms a thick viscous reaction mixture later. Hence, the rate of addition of methyl chloroformate and vigorous stirring are critical for optimal yields.
- In step 2, synthesis of the amide (9) can be carried out using Schotten-Baumann reaction conditions in oxalyl chloride, which is significantly less expensive than EDC as a coupling reagent.
- In step 4, during the workup of compound 11, the pH should be >10 during the neutralization step and THF must be added as a co-solvent along with ether during the extraction in workup, as the compound has low solubility in ether alone.
- During the synthesis of compound 12, a minor product with CBZ protection at both N-methyl and tetrahydroisoquinoline nitrogen also formed (~12% yield) as an impurity.
- Compound 18 can be purified by crystallization with hot EtOH to provide a white crystalline material instead of column chromatography on a large scale.
- For complete conversion of compound 18 to sumanirole, the amount of Pd(OH)2 needs to be doubled as compared to that described in the published procedure.
- A manuscript in which this synthesis and the synthesis of several novel sumanirole analogues are described is in preparation.