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With ammonium formate In methanol at 35℃; for 2 h;
A mixture of 4-nitro-2,3-dihydro-lH-isoindol-l-one (2Og), ammonium formate (35g) and 7.5percent Pd/C( 0.6g) in methanol (60ml) was stirred for 2 hours by heating up to 35°C . Pd/C was filtered and the filtrate concentrated under reduced pressure. The residue was recrystallized from water to give 15.3g of light yellow solid, yield: 92percent. mp: 195.6-197°C .1H-NMR: (300MHz, DMSO-dβ) δ: 4.3 l(s, 2H), 6.76(d, IH), 7.14(t, IH), 6.86(d, IH), 5.30(s, 2H), 8.26(s, IH)1H-NMR: (300MHz, DMSO-dβ/ D2O) δ: 4.14(s, 2H), 6.79(d, IH), 6.93(d, IH), 7.16(t, IH)FAB(M+1): 149 Element analysis: theoretical data: C 64.85percent, H 5.44percent, N 18.91percent measured data: C 64.96percent, H 5.61percent, N 19.02percent Test condition of HPLC: type and specification of column: phenomenex Luna 5u Cl 8250mmχ4.6mm; velocity: l .Oml/min; λ=230nm mobile phase: acetonitrile/0.1percentphosphate = 15/85 or acetonitrile/O.OIMammonium acetate = 10/90 appearance time of tar get yield: 3.580minutes ; 4.790minutes purity of target yield: 99.66percent
83%
With ammonium formate In N,N-dimethyl-formamide
d Synthesis of 4-amino-2,3-dihydro-1H-isoindol-1-one (4): To a solution of 4-nitro-2,3-dihydro-1H-isoindol-1-one (compound 3, 3.2 gm, 0.018 mmol.) in DMF (10 ml), was added ammonium formate (5.750 gm), and Pd-C (100 mg), and the reaction mixture was stirred at 100° C. for 30 min. The mixture was then filtered through a pad of celite, and the celite was washed with DMF (10 ml) and water (10 ml). The filtrate was concentrated under vacuum to give compound 4 (2.2 gm, 83percent). 1NMR (DMSO-D6): 4.20 (s, 2H, CH2), 5.20 (bs, NH2), 6.82 (dd,1H, Ar-H), 7.02 (dd,1H, Ar-H), 7.16 (t,1H, Ar-H), 8.20 (bs,1H).
A mixture of methyl 2-bromomethyl-3-nitrobenzoate (2Og) and methanol (200ml) was stirred under ammonia gas for 30 min at room temperature, and was kept in heat preservation for 2 hours. Crystal grew in an ice bath for 2 hours, and then filtered, and dried to give 11.7g of light yellow crystal, yield: 90percent. mp: 235.4~236.7°C .1H-NMR: (300MHz, DMSO-dβ) δ: 4.78(s, 2H), 7.79(t, IH), 8.10(d, IH), 8.41(d, IH), 8.90(S, IH).1H-NMR: (300MHz, DMSO-dβ/EhO) δ: 4.76(s, 2H), 7.77(t, IH), 8.08(d, IH), 8.39(d, IH). FAB(M+1): 179 Element analysis: theoretical data: C 53.94percent, H 3.39percent, N 15.72percent measured data: C 54.08percent, H 3.49percent, N 15.81percent Test condition of HPLC: type and specification of column: phenomenex Luna 5u Cl 8250mmχ4.6mm; velocity: l .Oml/min; λ=230nm mobile phase: acetonitrile /0.1percent phosphate = 30/70 appearance time of target yield : 5.810 minutes purity of target yield: 99.59percent
Reference：
[1] Patent: WO2010/139266, 2010, A1, . Location in patent: Page/Page column 37-38
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 81 - 85
[3] Angewandte Chemie - International Edition, 2017, vol. 56, # 1, p. 248 - 253[4] Angew. Chem., 2017, vol. 129, # 1, p. 254 - 259,6
[5] Patent: WO2006/12374, 2006, A1, . Location in patent: Page/Page column 209
[6] Patent: US2002/95044, 2002, A1,
[7] Patent: US2003/225106, 2003, A1, . Location in patent: Page 93
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 814 - 819
3
[ 59382-59-1 ]
[ 366452-97-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 81 - 85
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 814 - 819
[3] Angewandte Chemie - International Edition, 2017, vol. 56, # 1, p. 248 - 253[4] Angew. Chem., 2017, vol. 129, # 1, p. 254 - 259,6
Stage #1: 4-nitro-2,3-dihydro-1H-isoindol-1-one With caesium carbonate; triethylamine at 0 - 20℃; Inert atmosphere;
Stage #2: Glutamic acid With triethylamine In tetrahydrofuran at 0℃; Reflux;
18
A mixture of 4-nitro-2,3-dihydro-lH-isoindol-l-one (8Og) and cesium carbonate (219g) in triethylamine (100ml) was stirred for over half an hour. Under nitrogen ethyl chloroformate (68ml) was added by droplet below 0°C and reacted by stirring at room temperature for 3 ~ 5 hours. The resulting mixture was added in ice water (100OmL) and then light yellow solid was precipitated. After filter, the cake was washed by iced water. The aqueous phase was extracted with dichloromethane twice and the combined extracts were dried with anhydrous sodium sulphate. After filtered, the filtrate was concentrated to dry under reduced pressure. The concentrated was diluted with n-hexane (120ml) and stirred to precipitate crystal. Filter and drying under reduced pressure gave light yellow solid.A mixture of D,L-glutamic acid (66.7 g) in tetrahydrofuran (330ml) was stirred with the intermediate prepared above in batches at subzero temperature. Triethylamine (6.5ml) was added in the mixture to react for 20min and then for 16 ~ 24 hours under reflux. The reaction mixture was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane (60ml) and extracted with saturated sodium bicarbonate solution. When pH of the resulting mixture was adjusted to 2 by 2N hydrochloric acid, a number of light yellow solid was precipitated, subsequently extracted with dichloromethane, and washed with distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, finally cystal grew by standing, filtered and dried to give 94.2 g of title product as light yellow solid, yield79%. purity95.81%. FAB(M+1): 309.Element analysis: theoretical data: C 50.65%, H 3.92%, N 9.09%measured data: C 50.54%, H 4.01%, N 9.04%
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