Synthesis of Urea Derivatives of 9-Aminomethylcytisine
- PDF / 155,399 Bytes
- 3 Pages / 594 x 792 pts Page_size
- 114 Downloads / 281 Views
SYNTHESIS OF UREA DERIVATIVES OF 9-AMINOMETHYLCYTISINE
A. V. Koval′skaya, A. N. Lobov, and I. P. Tsypysheva*
Substituted ureas possess broad spectra of biological activity [1] while the urea pharmacophore itself appears in many approved drugs [2]. Compounds with potential antidiabetic [3], antitumor [4–6], antimicrobial [7], antiviral [8], and neuropharmacological properties [9] have been discovered among new biologically active compounds (BACs) with this structural motif. Compounds with high mnestic [10, 11] and anti-influenza activity [12] were prepared by introducing a urea moiety into natural compounds, e.g., the quinolizidine alkaloid cytisine. The library of methylcytisine (1) derivatives with a substituted urea in the 9-position of the 2-pyridione core of the starting molecule was expanded by us by transforming 9-aminomethylcytisine (2) in situ using the published method [10] directly into ureas 4–8 without isolating intermediate isocyanate 3 (Scheme 1). 11
3
1 11a
N 12
9
N 7
5
N
a N
H2N
1
N
OCN
2
R1
5'
9'
N R2
3
3'
1'
N H
N H
N H
N O 4-8
4: R1 = cyclohexyl; R2 = H 5: R1 = Ph, R2 = H 6: R1 = Bn, R2 = H 7: R1 = -CH2CH2C5H4N, R2 = H 8: R1 = R2 = cyclohexyl
O 7'
N
O
O
O
O
c
b
N O
6
a. [14]; b. triphosgene, Et3N, CH2Cl2, 20 °C; b. amine, NH4Cl, 20 °C
Scheme 1 The reaction was performed in CH2Cl2 at room temperature by treating amine 2 sequentially with triphosgene and Et3N as before [13] to produce a solution of 9-isocyanate 3 that was treated with a two-fold molar excess (relative to 2) of primary or secondary amines (Scheme 1). Substituted ureas 4–8 were produced from amine 2 in 63–95% yields from cyclohexyl-, benzyl-, and picolylamine; aniline; and dicyclohexylamine using this approach. The structures of the synthesized compounds were established using PMR, 13C NMR, and 15N NMR spectroscopy. 13C and 15N NMR spectra of 4–8 had characteristic resonances for the C atom of NC(O)N in the range δ 154–156 ppm, C which was also confirmed by cross-peaks in the corresponding {1H, 13C} HMBC correlation spectra. The alkaloid methylcytisine (1) was isolated from the aerial part of Thermopsis schischkinii (Fabaceae) collected during flowering in the middle of May 2014 with typical weather conditions in Sibay District, Republic of Bashkortostan. The species was identified by Dr. N. I. Fedorov (UIB, UFRC, RAS). Bis(trichloromethyl)carbonate (triphosgene) was commercially available (CAS 32315-10-9). The course of reactions was monitored by TLC on Alugram® plates. Column chromatography (CC) used silica gel (0.05–0.1 mm; Macherey-Nagel, Germany). Optical rotation angles were measured on a PerkinElmer 341 LC polarimeter. Chemical ionization at atmospheric pressure (APCI) mass spectra were taken in an LCMS-2010EV quadrupole liquid chromatograph-mass spectrometer (Shimadzu). IR spectra were recorded on an IR-Fourier Prestige-21 spectrometer (Shimadzu). PMR and 13C NMR spectra were recorded on equipment at the Khimiya CUC, UfIC, UFRC, RAS [Bruker Avance III pulsed spectrometer at operating fre
Data Loading...
