Urea derivatives are important structural platforms in medicinal chemistry that are used to develop antitumor, antibacterial, anticonvulsive, anti-HIV, and antidiabetic agents and other drugs [1].

The traditional methods for synthesizing urea derivatives include reactions of amines with phosgene, carbon monoxide, or isocyanates.

figure a

Lappaconitine can be used as starting material to prepare new derivatives although its structure contains two N-containing groups, i.e., an aromatic N-acetylamine and a tertiary N atom in a heterocycle. While transformations of the aromatic amine are often used to produce new lappaconitine derivatives [2,3,4,5,6,7,8], modifications involving the heterocyclic N atom are rare [9, 10].

Two lappaconitine derivatives, N-deacetyllappaconitine (1) and N-20-norlappaconitine (2) [11, 12], have been used as platforms to introduce a carbamide motif.

The reactions of 1 and 2 with potassium isocyanate in an AcOH–H2O mixture produced the corresponding carbamide derivatives 3 and 4 in yields of 54 and 50%, respectively.

The reaction of 1 with phenylisocyanate in DMF was unsuccessful while 2 (DMF, room temp., 24 h) gave 5 in 66% yield.

The presence of the carboxamide on the amine on the aromatic ring of 3 was confirmed by a shift of the resonance in the 15N NMR spectrum for the Ar-NH group from δN 63.5 ppm for N-deacetyllappaconitine (1) to δN 102.9 ppm. Its presence on the heterocyclic N atom in 4 and 5 was confirmed by a weak-field shift of the H-17 resonance in the 1H NMR spectra from δ 3.06 ppm for N-20-norlappaconitine (2) to δ 4.28 and 4.34 ppm (for 4 and 5, respectively) and a shift of the N-20 resonance in the 15N NMR spectra of 4 and 5 to δN 94.1 and 93.6 ppm, respectively, as compared to the starting resonance of 2 at δN 38.0 ppm.

Derivatives 6–15 (78–94% yields) were prepared using triphosgene followed by treatment with amines to produce the carbamide derivatives on the aromatic amine of 1; derivatives 16–21 (46–81%), by using 2 as starting material.

Resonances of C atoms and the protons corresponding to them in 1H and 13C NMR spectra were completely assigned based on 2D NMR experiments for all products 3–21 (Tables 1–4). In all instances, additional resonances as compared to 1 and 2 appeared for the carbamide moiety in the range δ 152.8–165.9 ppm in the 13C NMR spectra.

TABLE 1. 1H and 13C NMR Spectral Data for Products 3 and 6–9 (CDCl3, δ, ppm)*
Full size table
TABLE 2. 1H and 13C NMR Spectral Data for Products 10–14 (CDCl3, δ, ppm)*
Full size table
TABLE 3. 1H and 13C NMR Spectral Data of Products 4, 5, and 15–17 (CDCl3, δ, ppm)*
Full size table
TABLE 4. 1H and 13C NMR Spectral Data of Products 18–21 (CDCl3, δ, ppm)*
Full size table

Experimental

Mass spectra using chemical ionization at atmospheric pressure (APCI) were measured in an LCMS-2010 EV quadrupole LC-MS (Shimadzu). 1H, 13C NMR, and 15N NMR spectra were recorded in CDCl3 on a Bruker Avance III-500 pulsed spectrometer [500.13 MHz (1H), 125.76 MHz (13C)] with TMS internal standard and at 50.67 MHz (15N) with liquid ammonia external digital standard. Methods for recording NMR spectra embedded in the spectrometer operating system (COSY, HSQC, HMBC, NOESY, 13C-dept 135, dept 90) with full suppression of protons were used for accurate assignment of resonances in 1H and 13C NMR spectra. Chemical shifts (CSs) of protons were determined from 2D HSQC spectra; CSs of N atoms, from 1H–15N HMBC spectra. TLC monitoring used C6H6–MeOH (80:20 vol%). The spectral part of the research utilized equipment at the Khimiya CCU, UfIC, UFRC, RAS, and the Agidel′ RCCU, UFRC, RAS.

General Method for Preparing Carbamide Derivatives 3 and 4. A solution of N-deacetyllappaconitine (1) or N-20-norlappaconitine (2) (0.001 mol) in a mixture of AcOH (0.4 mL) and H2O (4 mL) was treated slowly dropwise with a solution of KNCO (0.004 mol) in H2O (8 mL). The mixture was stirred for 3 h at room temperature, made basic with saturated Na2CO3 solution to pH 9, and extracted with CHCl3 (4 × 20 mL). The solvent was distilled off. The product was purified by column chromatography (CC) over SiO2 using C6H6–MeOH (1–3 vol%).

N-Deacetyllappaconitine-N-carboxamide (3). Elution by C6H6–MeOH (1%) isolated starting 1 (0.093 g, 83% conversion); by C6H6–MeOH (2%), product 3 (0.262 g), yield 54% considering conversion; mp 152–153°C. Mass spectrum (APCI), m/z 586 [M + H]+ (calcd for C31H44N3O8, 586.312). 15N NMR (δ, ppm): 42.4 (N-20), 77.1 (Ar-NHC(O)NH2), 102.9 (Ar-NH).

N-20-Norlappaconitine-N-20-carboxamide (4). Elution by C6H6–MeOH (2%) isolated product 4 (0.108 g), 50% yield; mp 140–141°C. Mass spectrum (APCI), m/z 600 [H + M]+ (calcd for C31H42N3O9, 600.291). 15N NMR (δ, ppm): 73.1 (C(O)NH2), 94.1 (N-20), 128.4 (Ar-NH).

N-20-Norlappaconitine-N-20-phenylcarboxamide (5). A mixture of N-20-norlappaconitine (2, 0.222 g, 0.4 mmol) and phenylisocyanate (0.13 mL, 1.2 mmol) was dissolved in DMF (3 mL) and stirred for 24 h at room temperature. The solvent was distilled off. The product was purified by column chromatography (CC) over SiO2 using C6H6–MeOH (1–3 vol%). Elution by C6H6–MeOH (2%) isolated product 5 (0.178 g), 66% yield; mp 126–127°C. Mass spectrum (APCI), m/z 676 [Ì + Í]+ (calcd for C37H46N3O9, 676.323). 15N NMR (δ, ppm): 93.6 (N-20), 104.6 (C(O)NH), 128.4 (Ar-NH).

General Method for Preparing Carbamide Derivatives 6–21 [13]. A solution of triphosgene (0.37 mmol) in anhydrous CH2Cl2 (2.5 mL) was added slowly dropwise with stirring to a solution of 1 or 2 (1 mmol) and DIPEA (1.1 mmol) in CH2Cl2 (3.5 mL), held for 15 min after the addition, and treated with a solution of the appropriate amine (1 mmol) (aniline, diethylamine, isopropylamine, N-methylpiperazine, 4-benzylpiperidine, morpholine, pyrrolidine, benzylamine, trimetazidine, cytisine) and DIPEA (1.1 mmol) in CH2Cl2 (2 mL). The mixture was stirred for 2–3 h (TLC monitoring), treated with CH2Cl2 (10 mL), rinsed with Na2CO3 solution, dried over Na2SO4, and evaporated. The product was purified by CC over SiO2 using C6H6–MeOH (1–3 vol%).

N-Phenyl-N-deacetyllappaconitinecarboxamide (6). Elution by C6H6–MeOH (2%) isolated product 6 (0.595 g), 90% yield; mp 136–137°C. Mass spectrum (APCI), m/z 662 [M + H]+ (calcd for C37H48N3O8, 662.343). 15N NMR (δ, ppm): 41.9 (N-20), 105.6 (OC(O)-Ar-NH), 109.7 (NH-Ar).

N′,N′-Diethyl-N-deacetyllappaconitinecarboxamide (7). Elution by C6H6–MeOH (2%) isolated product 7 (0.497 g), 78% yield; mp 102–103°C. Mass spectrum (APCI), m/z 642 [M + H]+ (calcd for C35H52N3O8, 642.375). 15N NMR (δ, ppm): 41.8 (N-20), 100.8 (Ar-NH), 100.2 (N(Et)2).

N′-iso-Propyl-N-deacetyllappaconitinecarboxamide (8). Elution by C6H6–MeOH (2%) isolated product 8 (0.593 g), 94% yield; mp 138–139°C. Mass spectrum (APCI), m/z 628 [H + M]+ (calcd for C34H50N3O8, 628.359). 15N NMR (δ, ppm): 41.9 (N-20), 102.9 (Ar-NH), 106.8 (NH-i-Pr).

Lappaconine-4-[2-(4-methylpiperazine-1-carboxamido)]benzoate (9). Elution by C6H6–MeOH (2%) isolated product 9 (0.580 g), 87% yield; mp 114–115°C. Mass spectrum (APCI), m/z 669 [M + H]+ (calcd for C36H53N4O8, 669.386). 15N NMR (δ, ppm): 37.8 (N(C2H4)2N-CH3), 41.2 (N-20), 86.7 (N(C2H4)2N-CH3), 100.9 (Ar-NH).

Lappaconine-4-[2-(4-benzylpiperidine-1-carboxamido)]benzoate (10). Elution by C6H6–MeOH (1%) isolated product 10 (0.688 g), 93% yield; mp 104–105°C. Mass spectrum (APCI), m/z 744 [M + H]+ (calcd for C43H58N3O8, 744.422). 15N NMR (δ, ppm): 42.6 (N-20), 101.7 (Ar-NH), 93.5 (N(C2H4)2CH-Bn).

Lappaconine-4-[2-(morpholine-4-carboxamido)]benzoate (11). Elution by C6H6–MeOH (1.5%) isolated product 11 (0.603 g), 92% yield; mp 110–111°C. Mass spectrum (APCI), m/z 656 [M + H]+ (calcd for C35H50N3O9, 656.354). 15N NMR (δ, ppm): 41.8 (N-20), 86.4 (N(C2H4)2O), 101.2 (Ar-NH).

Lappaconine-4-[2-(pyrrolidine-1-carboxamido)]benzoate (12). Elution by C6H6–MeOH (2%) isolated product 12 (0.575 g), 90% yield; mp 131–132°C. Mass spectrum (APCI), m/z 640 [M + H]+ (calcd for C35H50N3O8, 640.359). 15N NMR (δ, ppm): 41.7 (N-20), 104.2 (Ar-NH), 93.0 (N(C2H4)2).

N′-Benzyl-N-deacetyllappaconitinecarboxamide (13). Elution by C6H6–MeOH (1.5%) isolated product 13 (0.562 g), 83% yield; mp 112–113°C. Mass spectrum (APCI), m/z 676 [M + H]+ (calcd for C38H50N3O8, 676.359). 15N NMR (δ, ppm): 42.2 (N-20), 91.2 (NH-Bn), 102.8 (Ar-NH).

Lappaconine-4-[2-(trimetazidine-1-carboxamido)]benzoate (14). Elution by C6H6–MeOH (1.5%) isolated product 14 (0.784 g), 94% yield; mp 101–102°C. Mass spectrum (APCI), m/z 835 [M + H]+ (calcd for C45H63N4O11, 835.449). 15N NMR (δ, ppm): 41.7 (N-20), 101.7 (Ar-NH), 89.4 (C(O)N(C2H4)2N), 49.0 (C(O)N(C2H4)2N).

Lappaconine-4-[2-(cytisine-12-carboxamido)]benzoate (15). Elution by C6H6–MeOH (2%) isolated product 15 (0.697 g), 92% yield; mp 148–149°C. Mass spectrum (APCI), m/z 759 [M + H]+ (calcd for C42H55N4O9, 759.396). 15N NMR (δ, ppm): 41.9 (N-20), 101.5 (Ar-NH), 82.1 (N-12′′), 173.9 (N-1′′).

Diethylcarbamoyl-N-20-norlappaconitine (16). Elution by C6H6–MeOH (1%) isolated product 16 (0.452 g), 69% yield; mp 195–196°C. Mass spectrum (APCI), m/z 656 [M + H]+ (calcd for C35H50N3O9, 656.354). 15N NMR (δ, ppm): 90.6 (N-20), 91.1 (N(Et)2), 128.9 (Ar-NÍ).

Isopropylcarbamoyl-N-20-norlappaconitine (17). Elution by C6H6–MeOH (2%) isolated product 17 (0.487 g), 76% yield; mp 115–116°C. Mass spectrum (APCI), m/z 642 [M + H]+ (calcd for C34H48N3O9, 642.338). 15N NMR (δ, ppm): 89.5 (N-20), 102.1 (NH-i-Pr), 128.9 (Ar-NÍ).

N-20-Norlappaconitin-20-yl(4-methylpiperazin-1-yl)methanone (18). Elution by C6H6–MeOH (3%) isolated product 18 (0.550 g), 81% yield; mp 132–133°C. Mass spectrum (APCI), m/z 683 [M + H]+ (calcd for C36H51N4O9, 683.365). 15N NMR (δ, ppm): 38.4 (N(C2H4)2N-CH3), 79.9 (N(C2H4)2N-CH3), 91.3 (N-20), 128.9 (Ar-NH).

N-20-Norlappaconitin-20-yl(4-morpholin-4-yl)methanone (19). Elution by C6H6–MeOH (2%) isolated product 19 (0.534 g), 80% yield; mp 142–143°C. Mass spectrum (APCI), m/z 670 [M + H]+ (calcd for C35H48N3O10, 670.333). 15N NMR (δ, ppm): 79.2 (N(C2H4)2O), 91.8 (N-20), 128.9 (Ar-NH).

N-20-Norlappaconitin-20-yl(trimetazidin-1-yl)methanone (20). Elution by C6H6–MeOH (1.5%) isolated product 20 (0.622 g), 73% yield; mp 95–96°C. Mass spectrum (APCI), m/z 849 [M + H]+ (calcd for C45H61N4O12, 849.428). 15N NMR (δ, ppm): 49.3 (C(O)N(C2H4)2N), 81.8 (C(O)N(C2H4)2N), 91.0 (N-20), 128.8 (Ar-NH).

N-20-Norlappaconitin-20-yl(cytisin-12-yl)methanone (21). Elution by C6H6–MeOH (2%) isolated product 21 (0.358 g), 46% yield; mp 178–179°C. Mass spectrum (APCI), m/z 773 [M + H]+ (calcd for C42H53N4O10, 773.376). 15N NMR (δ, ppm): 90.0 (N-20), 129.2 (Ar-NH), 137.1 (N-12'’), 175.8 (N-1'’).