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Synlett 2008(11): 1651-1656  
DOI: 10.1055/s-2008-1078484
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Solid-Phase Synthetic Method for 1,4-Benzodiazepine-2,5-dione Derivatives

Moon-Kook Jeon*, Jeong-Jin Kwon, Myung-Su Kim, Young-Dae Gong
Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Korea
Fax: +82(42)8607694; e-Mail: moteta@krict.re.kr;
Further Information

Publication History

Received 18 March 2008
Publication Date:
11 June 2008 (online)

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Abstract

Utilizing polymer-bound anthranilic acid derivatives 1, we were able to obtain the 1,4-benzodiazepine-2,5-dione derivatives 3 (R3 = H, R4 = H, MeO, Cl) through an unprecedented reaction sequence, reductive alkylation-N-protected amino acid coupling-deprotective cyclization, in 28-71% five-step overall isolated yields and 95-99% purities from Wang resin 4. Applying the novel protocol to the resin 2, the 7-benzamido-1,4-benzodiazepine-2,5-dione derivatives 3 (R1 = Bn, R4 = 7-BzNH) could be obtained in 19-42% seven- or eight-step overall isolated yields and 92-98% purities from AMEBA resin 7.

Key words

combinatorial chemistry - solid-phase synthesis - ­anthranilic acid - benzodiazepine - cyclative cleavage

    References and Notes

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17

Although several other conditions for the resin 5a and
N-Fmoc-protected phenylalanine (R2 = Bn, 3 equiv) were examined varying coupling agent [DCC, DIC, EDC, O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (HBTU), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), BOP, PyBOP, 2-chloro-1,3-dimethylimidazolidium hexafluorophosphate (CIP), 1,1¢-carbonyldiimidazole (CDI), N,N′-disuccinimidyl carbonate (DSC), or diphenylphosphoryl azide (DPPA)], additive [none, N-hydroxybenzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), or N-hydroxysuccinimide (HOSu)], base [none, pyridine, Et3N, diisopropylethylamine (DIEA), or NMM], solvent [CH2Cl2, THF, DMF, or N,N-dimethyl-acetamide (DMA)] at r.t. or elevated temperatures, they did not bring any significant change on the resin 5a when judged on the basis of on-bead ATR-FTIR spectroscopy.

21

Representative Procedures for Preparation of Compounds 3Preparation of ( S )-2-{Benzyl[2-(Fmoc-amino)-3-phenylpropionyl]amino}benzoate Resin (6a; R 4 = H, R ¹ = Bn, R ² = Bn): To a mixture of the resin 5a 2a,b (R4 = H, R1 = Bn, 100 mg, theoretically 0.077 mmol) and Fmoc-phenylalanine (93 mg, 0.23 mmol) in CH2Cl2 (2 mL) at r.t. were added pyridine (37 mg, 0.46 mmol) and phosphorous oxychloride (37 mg, 0.23 mmol). The mixture was stirred at r.t. for 10 h and the resin was filtered, washed several times with CH2Cl2, DMF, MeOH, H2O, and MeOH, and dried in a vacuum oven to give 6a (124 mg). On-bead ATR-FTIR: 3418 (NH), 3028, 2921, 1722 (OC=O, NH-Fmoc, overlapped), 1664 (NC=O), 1601, 1512, 1492, 1451, 1241, 1076, 1028, 824, 757, 738, 697 cm-1.
Preparation of ( S )-1,3-Dibenzyl-1,4-benzodiazepine-2,5-dione (3a; R 4 = H, R ¹ = Bn, R ² = Bn): To the resin 6a (R4 = H, R1 = Bn, R2 = Bn, 124 mg, theoretically 0.074 mmol) was added 20% piperidine-DMF (2 mL) and the mixture was stirred at r.t. for 7.5 h. The mixture was filtered and washed with CH2Cl2. The filtrate was evaporated in vacuo and the residue was purified by a silica gel column chromatography (n-hexane-EtOAc, 1:1) to afford 3a (14 mg, 52%; 99% purity on the basis of LC-UV-MS spectrum). Chiral HPLC analysis of the derivative 3a was performed using CHIRALCEL OD-H (0.46 × 25 cm, DAICEL) column, 10% EtOH in hexane eluent at 0.6 mL/min flow rate, and UV detector at λ = 254 nm and showed a major peak at the t R = 22.40 min and a trace (<1%) at t R = 20.20 min. In the case of the corresponding racemic reference prepared from racemic phenylalanine by the same method, the HPLC spectrum showed two peaks at t R = 21.87 and 23.17 min under the same conditions. 1H NMR (500 MHz, CDCl3): d = 3.08 (dd, J = 7.9, 14.5 Hz, 1 H), 3.48 (dd, J = 6.7, 14.5 Hz, 1 H), 4.14 (m, 1 H), 5.10 (d, J = 15.7 Hz, 1 H), 5.14 (d, J = 15.7 Hz, 1 H), 6.74 (br d, J = 5.4 Hz, 1 H), 7.10 (d, J = 7.2 Hz, 2 H), 7.20-7.30 (m, 10 H), 7.44 (dt, J = 1.5, 8.4 Hz, 1 H), 7.80 (dd, J = 1.5, 7.8 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 34.8, 52.2, 53.8, 122.3, 126.2, 126.8, 127.1, 127.5, 128.8, 129.4, 130.4, 132.6, 136.3, 136.6, 140.1, 168.4, 169.7 (shortage of two aromatic carbon peaks maybe due to peak overlapping). ESI-MS: m/z = 357 [M + H]+.
Preparation of Methyl 5-Benzamido-2-benzylamino-benzoate Resin (8): To a mixture of the resin 2 2b (460 mg, theoretically 0.53 mmol), prepared from AMEBA resin (1.6 mmol/g), and benzaldehyde (169 mg, 1.59 mmol) in DCE (5 mL) at r.t. was added NaBH(OAc)3 (338 mg, 1.59 mmol). The mixture was stirred at r.t. for 5 h and the resin was filtered, washed several times with CH2Cl2, DMF, MeOH, H2O and MeOH, and dried in a vacuum oven to give 8 (482 mg). On-bead ATR-FTIR: 3365 (NH), 3026, 2922, 1681 (OC=O), 1643 (NC=O), 1610, 1587, 1505, 1494, 1451, 1382, 1214, 1196, 1156, 1113, 1029, 819, 756, 697 cm-1.
Preparation of ( S )-Methyl 5-Benzamido-2-{benzyl[2-(Fmoc-amino)-3-phenylpropionyl]amino}benzoate Resin (R ² = Bn): To a mixture of the resin 8 (100 mg, theoretically 0.10 mmol) and Fmoc-phenylalanine (116 mg, 0.300 mmol) in CH2Cl2 (2 mL) at r.t. were added pyridine (47 mg, 0.60 mmol) and phosphorus oxychloride (46 mg, 0.30 mmol). The mixture was stirred at r.t. for 10 h and the resin was filtered, washed several times with CH2Cl2, DMF, MeOH, H2O and MeOH, and dried in a vacuum oven to give the amino acid coupled intermediate resin (R2 = Bn, 125 mg). On-bead ATR-FTIR: 3418 (NH), 3027, 2924, 1724 (OC=O, N-Fmoc, overlapped), 1650 (2 × NC=O, overlapped), 1611, 1504, 1493, 1450, 1264, 1197, 1159, 1030, 822, 757, 735, 698 cm-1.
Preparation of ( S )-7-Benzamido-1,3-dibenzyl-1,4-benzodiazepine-2,5-dione Resin (9; R ² = Bn): To the amino acid coupled intermediate resin (R2 = Bn, 139 mg, theoretically 0.11 mmol) at r.t. was added 20% piperidine-DMF (2 mL). The mixture was stirred at r.t. for 7.5 h and the resin was filtered, washed several times with CH2Cl2, DMF, and MeOH, and dried in a vacuum oven to give 9 (R2 = Bn, 112 mg). On-bead ATR-FTIR: 3418 (NH), 3027, 2923, 1662 (3 × NC=O, overlapped), 1610, 1493, 1450, 1263, 1195, 1158, 1115, 1031, 824, 734, 698 cm-1.
Preparation of ( S )-7-Benzamido-1,3-dibenzyl-1,4-benzodiazepine-2,5-dione (3p; R ¹ = R ² = Bn, R ³ = H, R 4 = 7-BzNH): To the resin 9 (R2 = Bn, 112 mg, theoretically 0.10 mmol) at r.t. was added 50% TFA-CH2Cl2 (2 mL). The mixture was stirred at r.t. for 12 h and the mixture was filtered and washed with CH2Cl2. The filtrate was evaporated in vacuo and the residue, dissolved in CH2Cl2, was passed through a SAX cartridge and washed with CH2Cl2. The filtrate was evaporated in vacuo and the residue was purified by a silica gel column chromatography (n-hexane-EtOAc, 1:1) to afford 3p (19 mg, 40%; 98% purity on the basis of LC-UV-MS spectrum). Chiral HPLC analysis of the derivative 3p was performed using the same protocol as that for the derivative 3a and showed a major peak at t R = 70.42 min and a trace (<1%) at t R = 53.44 min. In the case of the corresponding racemic reference prepared from racemic N-Fmoc-phenylalanine by the same method, the HPLC spectrum showed two peaks at t R = 52.28 and 71.32 min under the same conditions: 1H NMR (500 MHz, CDCl3): d = 3.00 (dd, J = 8.1, 14.4 Hz, 1 H), 3.43 (dd, J = 6.5, 14.4 Hz, 1 H), 4.14 (m, 1 H), 5.02 (d, J = 15.5 Hz, 1 H), 5.17 (d, J = 15.5 Hz, 1 H), 6.31 (br, 1 H), 7.08 (d, J = 6.5 Hz, 2 H), 7.16-7.28 (m, 9 H), 7.43 (t, J = 7.9 Hz, 2 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.78 (d, J = 2.6 Hz, 1 H), 7.86 (d, J = 8.5 Hz, 2 H), 8.32 (dd, J = 2.6, 8.9 Hz, 1 H), 8.84 (br s, 1 H). 13C NMR (125 MHz, CDCl3): d = 34.9, 52.1, 53.8, 121.3, 123.5, 124.8, 127.0, 127.2, 127.3, 127.6, 128.7, 128.8, 128.9, 129.3, 132.2, 134.5, 135.7, 135.9, 136.5, 136.7, 166.1, 168.1, 169.4 (shortage of one aromatic carbon peak maybe due to peak overlapping). ESI-MS: m/z = 476 [M + H]+.