Subscribe to RSS
DOI: 10.1055/s-2007-1000858
Reaction of α-(n-Alkylcarbonyloxy)alkyl (ACOA) Halides with 4-Hydroxyacetanilide and 2,2,5,7,8-Pentamethyl-6-chromanol: The Effect of Steric Hindrance on Reaction Path
Publication History
Publication Date:
18 December 2007 (online)
Abstract
A convenient synthesis of α-(n-alkylcarbonyloxy)alkyl (ACOA) iodides has been developed and a homologous series of n-alkylcarbonyloxymethyl (ACOM) iodides have been used to alkylate 4-hydroxyacetanilide (acetaminophen, APAP), a sterically unhindered phenol, and a sterically hindered phenol (2,2,5,7,8-pentamethyl-6-chromanol). Steric hindrance was not a significant factor in the ratio of acylated (Path b) to alkylated (Path a) for these reactions. Given the reported toxicity associated with sterically hindered ACOM prodrugs, n-alkyl ACOM and ACOA promoieties present themselves as viable alternatives to the more commonly used pivalate-based derivatives.
Key words
acylation - alkyl halides - alkylation - phenols - steric hindrance
- 1
Bodor N, andSloan KB. inventors; US Patent 4061753. Chem. Abstr. 1977, 87, 152278 - 2
Sloan KB.Wasdo S. Med. Res. Rev. 2003, 23: 763 - 3
Mollgaard B.Hoelgaard A.Bundgaard H. Int. J. Pharm. 1982, 12: 153 - 4
Roberts W.Sloan KB. J. Pharm. Sci. 2003, 92: 1028 - 5
Rautio J.Nevalainen T.Taipale H.Vepsalainen J.Gynther J.Laine K.Jarvinen T. J. Med. Chem. 2000, 43: 1489 - 6
Stinchcomb AL.Swaan P.Ekabo O.Harris K.Browe J.Hammell D.Cooperman T.Pearsall M. J. Pharm. Sci. 2002, 91: 2571 - 7
Abbas A.Fadel P.Wang Z.Arbique D.Jialal I.Vongpatanasin W. Arterioscler. Thromb. Vasc. Biol. 2004, 24: e164 - 8
Thomas JD.Sloan KB. Int. J. Pharm. 2007, 346: 80 - 9
Brass E. Pharmacol. Rev. 2002, 54: 589 - 10
Tabbache S.Loubinoux B. Synthesis 1982, 665 - 11
Sloan KB.Koch S. J. Org. Chem. 1983, 48: 3777 - 12
Ouyang H.Borchardt R.Siahaan T. Tetrahedron Lett. 2002, 43: 577 - 13
Thomas J.Sloan KB. Tetrahedron Lett. 2006, 47: 8785 - 14
Iyer R.Yu D.Ho N.Agrawal S. Synth. Commun. 1995, 25: 2739 - 15
Binderup E.Hansen ET. Synth. Commun. 1984, 14: 857 - 16
Thomas JD. Ph.D. Thesis University of Florida; USA: 2006. - 18
Bundgaard H.Klixbull U.Falch E. Int. J. Pharm. 1986, 30: 111 - 19
Bensel N.Reymond M.Reymond J. Chem. Eur. J. 2001, 7: 4604 - 20
Charton M. J. Am. Chem. Soc. 1975, 97: 1552 - 21
Ramesh C.Mahender G.Ravindranath N.Das B. Tetrahedron 2003, 59: 1049 - 22
Blay G.Cardona M.Garcia M.Pedro J. Synthesis 1989, 438 - 23
Kunesch N.Miet C.Poisson J. Tetrahedron Lett. 1987, 28: 3569 - 24
Bell K. Tetrahedron Lett. 1986, 27: 2263 - 25
Chakraborti A.Sharma L.Sharma U. Tetrahedron 2001, 57: 9343 - 26
Datta A.Hepperle M.Georg G. J. Org. Chem. 1995, 60: 761 - 27
Roberts W.Sloan KB. J. Heterocycl. Chem. 2002, 39: 905 - 28
Fairbrother J. In Analytical Profiles of Drug Substances Vol. 3:Florey K. Academic Press; New York: 1974. p.1-110 - 29
McClelland R.Kanagasabapathy VM.Mathivanan N. Can. J. Chem. 1991, 69: 2084 - 30 Nagase and co-workers have used a similar procedure for deprotecting 1-benzyloxycarbonyloxymethyl-5-fluoro-uracil:
Nasage T.Seike K.Shiraishi K.Yamada Y.Ozaki S. Chem. Lett. 1988, 1381 - 31
Smith M.March J. In March’s Advanced Organic Chemistry: Reactions, Mechanisms, and StructureSmith M.March J. Wiley; New York: 2001. 5th ed.. p.389-675 - 32
Sloan KB.Koch S. J. Org. Chem. 1983, 48: 635 - 33
Charton M. J. Org. Chem. 1978, 43: 3995 - 34
Beaumont K.Webster R.Gardner I.Dack K. Curr. Drug Metab. 2003, 4: 461 - 35
Bauguess CT.Sadik F.Fincher JH.Hartman CW. J. Pharm. Sci. 1975, 64: 117
References
Yields of 1 shown were obtained using the most effective batches of commercial NaI. Yields obtained using less effective NaI and AlCl3/I2 were generally 20% lower than those shown.