(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione—Synthesis and Crystallographic Studies

Synthesis of the (S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione (4)

(S)-piperazine-2-carboxylic acid dihydrochloride (5, 700 mg, 3.45 mmol, 1 equiv.) was dispersed in 50 mL of 1:1 water:dioxane mixture and treated with sodium hydroxide (276 mg, 6.89 mmol, 2 equiv.). After dissolution of the starting material, 4-chlorobenzoyl chloride (6, 0.49 mL, 3.79 mmol, 1.1 equiv.) was added and reaction mixture was stirred in room temperature for 18 h. The next day, the disappearance of starting material and formation of (S)-4-(4-chlorobenzoyl)piperazine-2-carboxylic acid (7) was confirmed by LRMS-ESI spectra. Then, isatoic anhydride (8, 1.69 g, 10.34 mmol, 3 equiv.) was added, followed by addition of sodium carbonate (1.10 g, 10.34 mmol, 3 equiv.); the reaction mixture was heated in 60 °C for 18 h. The following day, formation of the (S)-1-(2-aminobenzoyl)-4-(4-chlorobenzoyl)piperazine-2-carboxylic acid 9 was confirmed by LRMS-ESI spectra. The volatiles were evaporated under reduced pressure, then the residue was co-evaporated with toluene (3 × 50 mL) and dissolved in dry DMF. For cyclization of 9, HATU (3.93 g, 10.34 mmol, 3 equiv.) and DIPEA (1.80 mL, 10.34 mmol, 3 equiv.) were added, and reaction mixture was stirred in room temperature for 18 h. The day after, the volatiles were evaporated under reduced pressure and residue was dissolved in water:ethyl acetate biphasic system. The organic phase was washed with water (2 × 50 mL), 0.5 M HCl (3 × 50 mL), saturated sodium bicarbonate (1 × 50 mL), and dried over magnesium sulphate. The crude product dissolved in ethyl acetate was evaporated with silica gel (2 g) and purified by column chromatography using hexane:ethyl acetate 2:8 v/v mixture, followed by pure ethyl acetate. Yield: 711 mg (56%). 1H-NMR (500 MHz, DMSO-d6): 10.55, 10.45 (2 × s, 2 × NH); 7.80–7.70 (m, 1H, HAr); 7.70–7.40 (m, 5H, HAr); 7.30–7.20 (m, 1H, HAr); 7.20–7.00 (m, 1H, HAr); 4.45–3.30 (m, 7H, 3 × CH2, 1 × CH); 13C-NMR (125 MHz, DMSO-d6): 170.5, 169.5, 166.6, 136.6, 135.0, 134.2, 132.3, 130.9, 129.3, 129.0, 128.5, 128.3, 125.6, 124.0, 120.9, 51.7, 42.7, 42.2, 38.2; HRMS (ESI): m/z [M + H]+ calcd. for C19H17ClN3O3: 370.09530, 372.09235, found: 370.09517, 372.09206; m.p. 248–250 °C. [α]20D$$ = +290 (c 1.0, DMSO). IR (KBr): cm−1 3465, 3369, 3229, 3160, 3109, 3068, 2909, 2866, 1694, 1657, 1620, 1521, 1477, 1431, 1407, 1339, 1303, 1262, 1219, 1181, 1162, 1092, 1035, 1010.

Molbank 2017, 2017(4), M964; doi: 10.3390/M964

Communication

(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione—Synthesis and Crystallographic Studies

Adam Mieczkowski 1,*, Damian Trzybiński 2, Marcin Wilczek 3, Mateusz Psurski 4, Maciej Bagiński 1,3, Bartosz Bieszczad 1,3, Magdalena Mroczkowska 1,3 and Krzysztof Woźniak 2

1

Institute of Biochemistry and Biophysics Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland

2

Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland

3

Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland

4

Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 R. Weigl, 53-114 Wroclaw, Poland

*

Correspondence: Tel.: +48-22-592-35-06; Fax: +48-22-592-21-90

Received: 12 October 2017 / Accepted: 25 October 2017 / Published: 27 October 2017

Abstract

: 

(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione was obtained in a three-step, one-pot synthesis, starting from optically pure (S)-2-piperazine carboxylic acid dihydrochloride. Selective acylation of the β-nitrogen atom followed by condensation with isatoic anhydride and cyclization with HATU/DIPEA to a seven-member benzodiazepine ring, led to the tricyclic benzodiazepine derivative. Crystallographic studies and initial biological screening were performed for the title compound.

Keywords:

 (S)-2-piperazinecarboxylic acid; tricyclic benzodiazepines; isatoic anhydride; cytotoxicity

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