Synthesis of the Selective D2 Receptor Agonist PNU-95666E from D-Phenylalanine Using a Sequential Oxidative Cyclization Strategy

Journal of Organic Chemistry

Volumn 62, Issue 19, 1997, Pages 6582-6587

  Romero, Arthur G ^a   Darlington, William H ^a   McMillan, Moses W ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0000618755     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo970526a     Document Type: Article

References (23)

1. Seeman, P.; Niznik, H. B. Dopamine receptors and transporters in Parkinson's disease and schizophrenia. FASEB J. 1990, 2737-2744.
2. Coleman, R. J. Current drug therapy for Parkinson's disease. A review. Drugs and Aging 1992, 2, 112-1124. Collier, D. S.; Berg, M. J.; Fincham, R. W. Parkinsonism treatment: Part III-Update. Ann. Pharmacother. 1992, 26, 227-233.
3. Coleman, R. J. Current drug therapy for Parkinson's disease. A review. Drugs and Aging 1992, 2, 112-1124. Collier, D. S.; Berg, M. J.; Fincham, R. W. Parkinsonism treatment: Part III-Update. Ann. Pharmacother. 1992, 26, 227-233.
4. 2 and cholinergic receptors is greater than 1100 nM. Heier, R. F.; Dolak, L. A.: Duncan, J. N.; Hyslop, D. K.; Lipton, M. F.; Martin, I. J.; Mauragis, M. A.; Piercey, M. F.; Nichols, N. F.; Schreur, P. J. K. D.; Smith, M. W.; and Moon, M. W. Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites. J. Med. Chem. 1997, 40, 639-646.
5. The original synthesis was 12 steps, including a tartaric acid resolution to obtain optically pure 1 (see ref 3). Also, the use of potentially hazardous reagents such as p-toluenesulfonyl azide made it not amenable to large scale use.
6. Kawase, M.; Kitamura, T.; Kikugawa, Y. Electrophilic aromatic substitution with N-methoxy-N-acylnitrenium ions generated from N-chloro-N-methoxyamides: synthesis of nitrogen heterocyclic compounds bearing a N-methoxyamide group. J. Org. Chem. 1989, 54, 3394-3403.
7. Kikugawa, Y.; Kawase, M. An electrophilic aromatic substitution by N-methoxyamides via hypervalent iodine intermediates, Chem. Lett. 1990, 581-582.
8. Enantiomeric purity was determined by converting 1 to the BOC-amine and analyzing this with a chiral HPLC column, where the two enantiomers cleanly resolved, as determined by examination of racemic 1. See Experimental Section for details. We thank Malcolm W. Moon for providing us with this procedure.
9. (a) Louden, M. G.; Radhakrishna, A. S.; Almond, M. R.; Blodgett, J. K.; Boutin, R. H. Conversion of aliphatic amides into amines with [I,I-bis(trifluoroacetoxy)iodo]benzene. 1. Scope of the reaction. J. Org. Chem. 1984, 49, 4272-4276.
10. (b) Using bis(acetoxy)iodobenzene: Moriarty, R. M.; Chany, C. J., II; Vaid, R. K; Prakash, O.; Tuladhar, S. M. Preparation of methyl carbamates from primary alkyl- and arylcarboxamides using hypervalent iodine. J. Org. Chem. 1993, 58, 2478-2482.
11. The coupling reagent EDC is a water soluble form of dicyclohexylcarbodimide (DCC): Sheehan, J. C.; Preston, J.; Cruickshank, P. A. A rapid synthesis of oligopeptide derivatives without isolation of intermediates. J. Am. Chem. Soc. 1965, 87, 2492-2493.
12. The ethyl carbamate version of 9 was not crystalline and required silica gel chromatography for purification.
13. For another example of in situ generation of the more reactive bis(trifluoroacetoxy)iodobenzene reagent, see ref 6 in the following: Radhakrishna, A. S.; Parham, M. E.; Riggs, R. M.; Louden, G. M. New method for direct conversion of amides to amines. J. Org. Chem. 1979, 44, 1746-1747.
14. Not surprisingly, selective protection with the more reactive trifluoroacetic anhydride totally failed, giving a statistical mixture of products.
15. This selectivity, the relative stability of this crystalline reagent to storage, and its non-lachrymator properties also made it more desirable than CBZ-Cl for the multikilo-scale reaction.
16. Cooley, J. H.; and Jacobs, P. T. Oxidative ring closure of 1-benzyloxy-3-arylureas to 1-benzyloxybenzimidazolones. J. Org. Chem. 1975, 40, 552-557.
17. Perronnet, J.; and Demoute, J.-P. Approach to the 1-methoxy-2-benzimidazolinones. Gazz. Chim. Ital. 1982, 112, 507-511.
18. The N-chlorination/sodium hydride procedure requires a substrate containing a hydrogen on the aryl-substituted nitrogen; an attempt to perform the cyclization without such substitution failed, demonstrating the need to enhance the reactivity of the aryl ring by converting the aryl nitrogen into its anionic form. See ref 15.
19. The absence of a substituent on the aryl-substituted nitrogen of the N-methoxyurea apparently open up other avenues for bis(trifluoroacetoxy)iodobenzene oxidation, leading to decomposition. This does not appear to be a problem when this nitrogen is substituted. For further discussion, see: Romero, A. G.; Darlington, W. H.; Jacobsen, E. J.; Mickelson, J. W. Oxidative cyclization of acyclic ureas with bis(triflyoroacetoxy)iodobenzene to generate N-substituted 2-benzimidazolinones. Tetrahedron Lett. 1996, 37, 2361-2364.
20. For example, treatment of the N-methoxyurea obtained from N-benzyl-N-methylamine with bis(trifluoroacetoxy)iodobenzene led to decomposition. We postulate that this is due to the enhanced sensitivity of the benzylic methylene group to oxidation.
21. Phosgene was replaced with triphosgene, affording a similar yield when the reaction was scaled-up. While also effective, substitution of carbonyldiimidazole (CDI) was less satisfactory.
22. This synthesis was presented at the Technical Achievement Symposium at the 210th National Meeting of the American Chemical Society, Chicago, IL, August 20-24, 1995.
23. For a preparation of bis(trifluoroacetoxy)iodobenzene, see ref 8a.