1-[5-Methoxy-2-nitro-4-[3-(1-pyrrolidinyl)propoxy]phenyl]cyclobutanecarbonitrile → 5'-Methoxy-6'-[3-(1-pyrrolidinyl)propoxy]spiro[cyclobutane-1,3'-[3H]indol]-2'-amine

HRID 925124Notes

Reaction equation

[CH3:1][O:2][C:3]1[C:4]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:5][C:6]([N+:15]([O-])=O)=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:8]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[N:15]=[C:13]([NH2:14])[C:9]12[CH2:12][CH2:11][CH2:10]1

Participants

Conditions

Temperature: 80 °C

Procedure

A solution of 1-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)cyclobutanecarbonitrile (0.063 g, 1.742 mmol), from Step 4, in acetic acid (10 mL), was treated with 10% Pd/C (0.56 g, 0.523 mmol). The mixture was stirred under an atmosphere of hydrogen at 80° C. for 5 hours. The catalyst was filtered off and washed with EtOH. The filtrate was concentrated and resulting crude product was purification by flash chromatography (silica gel, 15-25% 3N methanolic ammonia/dichloromethane) to afford 0.161 g (28%) of 5′-methoxy-6′-(3-(pyrrolidin-1-yl)propoxy)spiro[cyclobutane-1,3′-indol]-2′-amine 1H NMR (400 MHz, METHANOL-D4) δ 7.28 (s, 1H), 6.71 (s, 1H), 4.11 (t, J=5.7 Hz, 2H), 3.88 (s, 3H), 3.27-3.19 (m, 6H), 2.63 (t, J=9.9 Hz, 2H), 2.52-2.42 (m, 1H), 2.38 (dd, J=13.0, 10.4 Hz, 2H), 2.31-2.22 (m, 1H), 2.17 (dt, J=12.8, 6.2 Hz, 2H), 2.04 (t, J=6.8 Hz, 6H). MS (ESI) m/z 330 (M+H)+.

Workup

filtrationThe catalyst was filtered off
washwashed with EtOH
concentrationThe filtrate was concentrated
customresulting crude product
custompurification by flash chromatography (silica gel, 15-25% 3N methanolic ammonia/dichloromethane)

Sources & evidence

ORD record: ord-aac15b8a99014e83bdab2fb34d7697a5
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09284272B2

Reaction notes

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