Preparation of guanine PDE inhibitors: Development of the common synthetic route strategy. A case study

Organic Process Research and Development

Volumn 8, Issue 3, 2004, Pages 396-400

  Gala, D ^a   DiBenedetto, D ^a   Gloor, G ^a   Jenkins, J ^a   Kugelman, M ^a   Maloney, D ^a   Miller, A ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GUANINE PHOSPHODIESTERASE INHIBITOR; PHOSPHODIESTERASE INHIBITOR; UNCLASSIFIED DRUG;

CHIRALITY; CONFERENCE PAPER; CYCLIZATION; ENANTIOMER; SCALE UP; SYNTHESIS;

EID: 3042637407     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op030212r     Document Type: Conference Paper

References (19)

1. Gala, D.; DiBenedetto, D. J.; Kugleman, M.; Puar, M. S. Tetrahedron Lett. 2003, 44, 2717.
2. Gala, D.; DiBenedetto, D. J.; Kugelman, M.; Mitchell, M. B. Tetrahedron Lett. 2003, 44, 2721.
3. 2-Chloropurine is the key intermediate pathway approach.
4. Gala, D.; DiBenedetto, D.; Günter, F.; Kugelman, M.; Maloney, D.; Cordero, M.; Mergelsberg, I. Org. Process Res. Dev. 1997, 1, 85.
5. (a) Barr, A.; Frencel, I.; Robinson, J. B. Can. J. Chem. 1977, 55, 4180.
6. (b) Overman, L. E.; Sugai, S. J. Org. Chem. 1985, 50, 4154.
7. 4Cl gave the best results. Since the latter is inexpensive, appeared to improve solubility/stirability of the reaction mixtures, and did not interfere with the workup, it was used in excess (3-5 mol).
8. The use of a mild base was desirable in view of the instability of these PDE inhibitors to strong base such as aqueous NaOH. See Gala, D.; Puar, M. S.; Czarniecki, M.; Das, P. R.; Kugelman, M.; Kaminiski, J. Tetrahedron Lett. 2000, 41, 5025.
9. Such favorable faster amidation compared to the hydrolysis of this acid chloride under such basic conditions was unexpected. This procedure was applicable to several aliphatic as well as aromatic acid chlorides (unpublished results).
10. 1 4-chloropyrimidine derivative of 17 and or 18 can also be the sources of the minor compounds. (Equation Presented)
11. Kugelman, M.; Gala, D.; Jaret, R. S.; Nyce, P. L.; McPhail, A. T. Synlett 1990, 431. (Equation Presented)
12. Trans-substituted chlorosulfonylamines are suitable intermediates to form aziridines, but the latter were not detected in these reactions. In other reactions we have noticed that tautomerism in imidazole ring led to the reactions at either of the nitrogen atoms. In this series tautomers of 15 and 20 (i.e. 39 and 40, respectively), if present, did not lead to 41 and 42. This may be due to the fact that 39 and 40 would lead to seven-membered strained ring products which are far less favorable than the desired five-membered products, 1 and 2.
13. Enantiopure cis isomer was prepared by using the literature procedure for the conversion of trans-α-amino alcohols to cis-α-amino alcohols: Barnard, R. A. B.; Parkkari, J. H. Can. J. Chem. 1970, 48, 1377.
14. 13C NMR, HPLC, and MS studies of the isolated compounds.
15. Incidentally, this observation can be used for the next generation of inexpensive amino alcohol where the chirality at only the amino carbon would be important, and chirality at the alcohol carbon would be less important.
16. Gala, D.; Stamford, A.; Jenkins, J.; Kugelman, M. Org. Process Res. Dev. 1997, 1, 163.
17. Subsequently we discovered that treating 16 with the requisite quantity (necessary to consume water as determined by the Karl Fischer method) of either bis-trimethylsilylacetamide (BSA) or mono-silylmethylacetamide (MSA) prior to addition of acid chloride of 33 allowed for a successful preparation of 34 without the use of EDCI.
18. Ahn, H.-S.; Bercovici, A.; Boykow, G.; Bronnenkant, A.; Chackalamannil, S.; Chow, J.; Cleven, R.; Cook, J.; Czarniecki, M.; Domalski, C.; Fawzi, A.; Green, M.; Gundes, A.; Ho, G.; Laudicina, M.; Lindo, N.; Ma, K.; Manna, M.; McKittrick, B.; Mirzai, B.; Nechuta, T.; Neustadt, B.; Puchalski, C.; Pula, K.; Silverman, L.; Smith, E.; Stamford, A.; Tedesco, R. P.; Tsai, H.; Tulshian, D.; Vaccaro, H.; Watkins, R. W.; Weng, X.; Witkowski, J. T.; Xia, Y.; Zhang, H. J. Med. Chem. 1997, 40, 2196.
19. Vemulapalli, S.; Watkins, R. W.; Chintala, M.; Davis, H.; Ahn, H.-S.; Fawi, A.; Tulshian, D.; Chiu, P.; Chatterjeee, M.; Lin, C.-C.; Sybertz, E. J. J. Cardiovasc. Pharmacol. 1996, 28, 862.