Structure of Cycloguanil Hydrochloride by Neutron Diffraction

Diamino- 1- (p-chlorophenyl)- hydro-2,2-dimethyl-s-triazine hydrochloride, C~HIs- C1N+.C1 -, M r= 288.20, monoclinic, P2Je, a = 8.783 (2), b= 10.267 (2), c= 17.234 (3) A, /3= 115.72 (1) °, U= 1400.1 (5)/~3, Z = 4, O x = 1.337 Mg m -s, 2 = 1. 15882 (7) A for unit-cell deter- mination and 1-04702 (7)/~, for collection of intensity data, /1=0.191ram -~, T= 15.0(5) K, final R(F'-) =0.050 and wR(F2)=O.063 for 3099 independent reflections. Five atoms of the triazine ring are nearly coplanar. The sixth, the quaternary C(2), is displaced from this plane (P1) so that the bond to one of its methyl substituents is nearly perpendicular to P I while the other methyl substituent lies almost in the plane. The chlorophenyl-ring plane is nearly perpendicular to P1. The heterocycles form cyclic dimers via hydrogen bonds from the 6-amino group to ring atom N(5) of an adjacent molecule. All other N-H units are hydrogen bonded to the CI- counter ion. The ring is protonated at position N(3). Introduction. A variety of 2,4-diamino-l,3-diazine heterocyclic systems inhibit the important enzyme dihydrofolate reductase (DHFR). Of the various classes of heterocycles, the pyrimidine antifolates have been most extensively investigated by diffraction methods (Schwalbe & Cody, 1983) including one neutron diffraction study, of 2,4-diamino-5-(3,4,5-tri- methoxybenzyl)pyrimidine (trimethoprim (Koetzle & Williams, 1976)). Fewer s-triazine antifolate structures have been analyzed; these include the anti-cancer drugs 4,6-diamino- 1-(3-chloro-4-(m-dinlethylcarbamoyl- benzyloxy)phenyl)- 1,2-dihydro-2,2-dimethyl-s-triazine ethanesulfonate (I) and 4,6-diamino-l-(4-(4'-fluorosul- fonyl-3'-methylanilinocarbonylethyl)phenyl 1-1,2-di- *This research was carried out at Brookhaven National Laboratory under contract DE-AC02-76CH00016 with the US