key: cord-0781071-4x516l08
authors: Komissarova, N. G.; Dubovitskii, S. N.; Shitikova, O. V.; Orlov, A. V.
title: Synthesis of 2-Aminoethanesulfonamides of Betulinic and Betulonic Acids
date: 2021-07-13
journal: Chem Nat Compd
DOI: 10.1007/s10600-021-03455-2
sha: 943f5da202407d1bffb28cf2eb8d993ef13ab0e7
doc_id: 781071
cord_uid: 4x516l08

New potentially biologically active sulfonamide derivatives of pentacyclic lupane-type triterpenoids, the sulfonamide group of which was bonded to C-17 of the triterpene skeleton through an amidoethane spacer, were synthesized via conjugation of 2-aminoethanesulfonamides to betulinic and betulonic acids in the presence of Mukaiyama reagent (2-bromo-1-methylpyridinium iodide).

2-Aminoethanesulfonamides 3a-c (as the hydrochlorides) were prepared by reacting phthalic anhydride with 2-aminoethanesulfonic acid (taurine) in the presence of NaOAc-AcOH by the literature method [13] followed by treatment of the obtained Na-salt of 2-phthalimidoethanesulfonic acid with PCl 5 and combination of the resulting chloride with amines (NHMe 2 , piperidine, morpholine). The phthalyl protection was removed using NH 2 NH 2 in EtOH to give the corresponding 2-aminoethanesulfonamides [14, 15] .

Mukaiyama reagent (2-bromo-1-methylpyridinium iodide) was prepared by treating 2-bromopyridine with MeI [16, 17] . 2-Amidoethanesulfonamides 4a-c and 5a-c were synthesized via conjugation of 2-aminoethanesulfonamides 3a-c (as the hydrochlorides) with acids 1 and 2, the carboxylic group of which was activated by Mukaiyama reagent [18] . The reaction was carried out in refluxing CH 2 Cl 2 for 1 h in the presence of Et 3 N, Bu 3 N, or i-Pr 2 EtN. Target compounds 4a-c and 5a-c were isolated by chromatography over silica gel in 28-67% yields.

The structures of sulfonamides 4a-c and 5a-c were confirmed by IR, PMR, and 13 C NMR spectroscopy and mass spectrometry. Resonances in PMR and 13 C NMR spectra of sulfonamide 4a were completely assigned using 1D and 2D experiments.

The combination of acids 1 and 2 with taurine in the presence of various condensing agents, conversion of the obtained 2-amidoethanesulfonic acids into the chlorides, and reaction of them with amines could serve as an alternative synthesis of sulfonamides 4a-c and 5a-c. Combination of the carboxylic acids with the amines through the action of diethyl phosphorocyanidate (DEPC) in the presence of Et 3 N was an effective method for preparing the amides [19] . However, compound 6, the mixed anhydride of 1 and diethyl phosphoric acid that did not subsequently react with taurine, was obtained by us in 85% yield upon reaction of 1 with taurine in DMF in the presence of DEPC-Et 3 N. Replacing 1 by sulfonamide 3a under the same conditions led to the formation of anhydride 6 (93%) together with 4a, which was isolated in 5% yield.

The structure of mixed anhydride 6 was confirmed using 1D and 2D PMR, 13 C NMR, and 31 P NMR spectra. The PMR spectrum contained characteristic resonances for the ethyls of the diethyl phosphate group as a triplet at 1.35 ppm (6H, J = 7 Hz, 2OCH 2 CH 3 ) and a multiplet at 4.27 ppm (4H, OCH 2 CH 3 ) that correlated with the 31 P resonance at -7.51 ppm in the 2D 1 H-31 P HMBC spectrum. The 31 P resonance in the 31 P NMR spectrum appeared as a pentet with J H-P = 7.5 Hz.

Thus, a series of 2-amidoethanesulfonamides, new potentially biologically active derivatives of lupane-type triterpenoids, were synthesized from betulinic and betulonic acids.

IR spectra were recorded in Vaseline oil on an IR Prestige-21 spectrophotometer (Shimadzu). PMR, 13 C NMR, and 31 P NMR spectra were taken at 295 K on an AMXIII-300 (Bruker, Germany) at operating frequency 300.13 MHz for 1 H and 75.47 MHz for 13 C or an Avance III-500 spectrometer (Bruker, Germany) at operating frequency 500.13 and 125.47 MHz, respectively, and 202.46 MHz ( 31 P). Chemical shifts in 13 C NMR and PMR spectra were given in ppm vs. CD(H)Cl 3 resonances (δ H 7.27 ppm, δ C 77.1 ppm) or TMS internal standard. Chemical shifts of 31 P resonances were determined vs. phosphoric acid (85%). Mass spectra of positive and negative ions were recorded using APCI or ESI method in an LCMS-2010EV liquid chromatograph (Shimadzu). Rotation angles were measured on a Perkin-Elmer 341C polarimeter. Column chromatography used SiO 2 (L brand, 40/60 μm, Russia); TLC, Sorbfil plates (Imid LLC, Russia). Chromatograms were visualized using anisic detector. Melting points were measured on a Boetius apparatus (Germany).

Preparation of 2-Amidoethanesulfonamides (4a-c, 5a-c). General Method. A suspension of 2-bromo-1methylpyridinium iodide (0.53 mmol) in CH 2 Cl 2 (2 mL) was treated dropwise with acid 1 or 2 (0.44 mmol), the appropriate sulfonamide chloride 3a-c (0.44 mmol), and amine (1.49 mmol) (Et 3 N, for 5a and 5c; Bu 3 N, for 4a, 4b, and 4c; i-Pr 2 EtN, for 5b) in CH 2 Cl 2 (10 mL). The mixture was refluxed for 1 h, cooled, diluted with methyl-tert-butylether (MTBE) (50 mL), and washed with HCl solution (5%, 3 × 10 mL). The organic layer was separated, washed with H 2 O, dried over Na 2 SO 4 , and evaporated. The solid was chromatographed over SiO 2 (C 6 H 6 , C 6 H 6 -MTBE, 8:1). N-[2-(Piperidin-1-ylsulfonyl)ethyl]-3β-hydroxylup-20(29)-en-17β-carboxamide (4b) . Yield 40%, mp 218-220°C; 

0.89, 0.99, 1.04, 1.66 (3H, s, CH 3 -25, 24, 23, 30), 0.95 (6H, s, CH 3 -26, 27), 2.45 (2Í, m, H-2), 3.07 (3H, m, H-19, NCH 2 CH 2 SO 3 ), 3.22 (4Í, m, morpholine: 2Í-2, 6), 3.74 (6H, m, NCH 2 CH 2 SO 3 , morpholine: 2Í-3, 5), 4.57, 4.71 (1H each, s, both H-29), 6.40 (1H, t, J = 5.3, Ñ(Î)NH). 13 C NMR spectrum (75 MHz, CDCl 3 , TMS, δ, ppm): 14.54 (C-27), 15.97 (C-25), 15.97 (C-26), 19.42 (C-30), 19.64 (C-6)

Reaction of Acid 1 with Taurine. A solution of 1 (0.20 g, 0.44 mmol) in DMF (5 mL) at 0°C was treated sequentially with DEPC (0.1 mL, 0.53 mmol), taurine (0.11 g, 0.88 mmol), and Et 3 N (0.73 mL, 5.25 mmol), stirred at 20°C for 10 h, and diluted at 0°C with saturated NaHCO 3 solution (10 mL). The resulting precipitate was filtered off and chromatographed over SiO 2

Mixed Anhydride of Diethyl Phosphoric and Betulinic Acid (6)

17 (d, 2 J C-P = 10.6, C-28). 31 P NMR spectrum (202 MHz, CDCl 3 , TMS, δ, ppm, J/Hz): -7.51 (pentet, 3 J H-P = 7.5). ESI-MS, m/z 563 [M -C 2 H 5 ] -(calcd for C 34 H 57 O 6 P, 592). Reaction of Acid 1 with 3a in the Presence of DEPC

The work was performed on a State Task Topic (Reg. No. AAAA-A20-120012090026-9) with support from RSF Grant No. 14-13-01307. The spectral part of the research used equipment at the Khimiya CCU, UfIC, UFRC, RAS.