N-Alkylation of 17-azasteroids Jacek W. Morzycki and Zenon Lotowski Institute of Chemistry, University of Warsaw, Bialystok Branch, Bialystok, Poland N-Alkylation of 17-azasteroid lactams (16-oxo-17-azaandrost-5-en-3fl-ol acetate 3 and its D-homo analo# 4) was studied. It has been found that both lactams are readily alkylated with iodomethane or iodoethane. In contrast to this there was no reaction with 2-iodo-6-methylheptane due to the steric hindrance. 1,4-Addition of lactam to the conjugated systems was also studied The addition to acrylonitrile proved to be easy compared to crotononitrile. However the efficient addition to the latter compound was also attained by using potassium t-butoxide as a base in t-butanol. Keywords: 17-azasteroids; N-alkylation; 3fl-hydroxy-24-nor-17-azachol-5-enonitrile; 17-azacholesterol. Introduction The replacement of one or more carbon atoms of a steroid molecule with nitrogen often results in useful alteration of its biological properties. 1'2 Hundreds of azasteroids have been prepared by total or partial synthesis. Many interesting examples of such biologically active compounds have been described in the litera- ture. 3-5 Several azasteroids were tested for their hypocholesterolemic activity and some analogs of cholesterol with nitrogen atom in the side chain were found to be inhibitors of cholesterol biosynthesis. 6 The aim of this work was to elaborate the conditions for N-alkylation of 17-azasteroids having in mind the future synthesis of 17-azacholesterol (1). The synthesis of this compound is of interest since the 17-position of steroid hormones is particularly important in both receptor recognition and as the site of key biosynthetic transformations. There are a number of efficient routes to 17-aza -7 or 17~-aza-D-homo-steroids s'9 belonging to androstane or estrane series. Recently a convenient new method for preparation of 17-azasteroids with a normal five-membered D-ring has been elaborated. 1° However 17-azasteroids bearing the cholesterol side chain (2-isooctyl) are not known to date either in the case of normal D-ring system or in D-homo series. It is likely that the lack of reports of the synthesis of 17- azacholesterol or its D-homo analog is mainly due to a steric hindrance that makes alkylation at nitrogen in 17-azasteroids quite difficult. Address reprint requests to Professor Jacek W. Morzycki, Institute of Chemistry, University of Warsaw, Bialystok Branch, AI. Pilsudskiego 11/4, 15-443 Bialystok, Poland. Received March 27, 1993; accepted June 23, 1993. Scheme 1 R X 1 ! R1 = H; R 2 = CH(CHa)CHzCHzCH2CH(CH3)2; X~--m-H2; n = 1 2 R 1 = R 2 = H; X=H2; n = 1 _3 R I = A c ; R 2=H;X=O;n= 1 4 R I=Ac;R 2=H;X=O;n=2 5 R I=Ac;R z=CH3;X=O;n= 1 6 R t = Ac; R 2 = CH3; X=O; n = 2 7 R1 = Ac; R 2 = CH2CH3; X=O; n = 1 8 R~ = Ac; R 2 = CH2CH3; X=O; n = 2 9 R t = Ac; R 2 = CH2CH=CH2; X=O; n = 1 10 R 1 = Ac; R 2 = CH2CH2CN; X=O; n = 1 11 R 1 = H; R 2 = CH(CH3)CH2CN; X=O; n = 1 12 R~ = Ac; R e = CH(CH3)CH2CN; X=O; n = 1 13 R]=Ac;R e=CI;X=O;n= 1 Experimental Melting points were determined on K6ffler apparatus of Boetius type and were uncorrected. NMR spectra were taken with Bruker AC 200F Spectrometer (Bruker-Spectrospin, Switzerland) using CDCI3 solutions with tetramethylsilane (TMS) as an internal standard. Infrared spectra were recorded on a Specord 75 IR spectrophotometer (Carl Zeiss Jena, Germany) as CCI4 or CHC1 a solutions unless otherwise stated. Mass spectra were obtained at 70eV with AMD-604 30 Steroids, 1994, vol. 59, January © 1994 Butterworth-Heinemann