Sodium cyanoborohydride → Indoline

Temperature

70 °C

To a suspension of thiophene-2-sulfonic acid ((E)-3-1H-indol-7-yl-acryloyl)-amide I-4 (120 mg, 0.39 mmol) in acetic acid (glacial, 10 mL) was added sodium cyanoborohydride (95%, 150 mg, 2.5 mmol) portion wise at rt. The mixture which resulted was allowed to heat and stir at 70° C. for 4 h. The reaction mixture was cooled to 0° C. and the reaction was quenched with the addition of water (10 mL) at 0° C. The mixture was acidified with addition of aq HCl (10%) until PH=1, which was followed by extraction of CH2Cl2/MeOH (20:1, 3×30 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, EtOAc/hexane,=1:5-1:1) to afford desired indoline I-18 (80 mg, 65%) as a white solid. MS(ESI−)m/z=335.2. To a stirring solution of the indoline I-18 (37 mg, 0.11 mmol) in CH2Cl2 (7 mL) was added triethylamine (21 mg, 0.22 mmol) and then 2-naphthalenesulfonyl chloride (25 mg, 0.1 mmol) at 0° C. The mixture which resulted was allowed to warm to rt and stir at rt for 24 h. The reaction mixture was cooled to 0° C. then acidified with addition of aq HCl (10%) until PH=1, which was followed by extraction of CH2Cl2/MeOH (10:1, 3×20 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, EtOAc/hexane,=1:5-1:1) to afford desired product P045 (12 mg, 21%) as a light yellow solid. MS(ESI−)m/z=523.5, 100%), LCMS(ESI−)>70%. 1H NMR (500 MHz, CD3OD) 2.11 (t, J=8.0 Hz, 2H), 4.08 (t, J=8.0 Hz, 2H), 6.62 (d, J=16.0 Hz, 1H), 7.01 (dd, J=7.5, 1.0 Hz, 1H) 7.11 (dd, J=5.0, 4.0 Hz, 1H), 7.19 (dd, J=7.5, 7.5 Hz, 1H), 7.36 (dd, J=8.5, 2.0 Hz, 1H), 7.60 (m, 1H), 7.67 (m, 2H), 7.73 (dd, J=5.5, 1.5 Hz, 1H), 7.79 (dd, J=3.5, 0.5 Hz, 1H), 7.87 (m, 2H), 7.93 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 8.19 (d, J=16.0 Hz, 1H).

1. customThe mixture which resulted
2. temperatureto heat
3. temperatureThe reaction mixture was cooled to 0° C.
4. customthe reaction was quenched with the addition of water (10 mL) at 0° C
5. additionThe mixture was acidified with addition of aq HCl (10%) until PH=1, which
6. extractionwas followed by extraction of CH2Cl2/MeOH (20:1, 3×30 mL)
7. dry with materialThe combined organic layers were dried (Na2SO4)
8. customthe solvent was removed under reduced pressure
9. customto provide the crude product which
10. customwas purified by flash chromatography (silica gel, EtOAc/hexane,=1:5-1:1)

ORD record

ord-e1a4d5b2bbd74420a8332c9ae158f73f

Source dataset

uspto-grants-2009_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07598397B2