• 10.1021/jo970526a
  • The Journal of Organic Chemistry
  • Volume 62
  • September 1997
  • pp 6582-6587

Good synthesis of enantiomerically pure (R)-sumanirole

Details


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%)

Scheme:

Comments on experimental reproducibility:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Compound 18 can be purified by crystallization with hot EtOH to provide a white crystalline material instead of column chromatography on a large scale.
  6. 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.
  7. A manuscript in which this synthesis and the synthesis of several novel sumanirole analogues are described is in preparation.


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