Isopropanol → N-cyano-N'-(3-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-prop-2-ynyl)-morpholine-4-carboxamidine

HRID 415027Notes

Reaction equation

[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH2:28][NH:29][C:30](=[N:38][C:39]#[N:40])OC5C=CC=CC=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.CC(O)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C1COCC1>[C:39]([NH:38][C:30]([N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)=[N:29][CH2:28][C:27]#[C:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:41]=[CH:42][CH:43]=[C:2]([F:1])[CH:3]=1)[N:7]=[CH:8]2)#[N:40]

Participants

Conditions

Temperature: 80 °C

Procedure

Material from step F (9 mg, 0.016 mmol) is placed in a reaction vial and dissolved in 2 ml of a 1:1 THF:i-PrOH mixture. Morpholine (0.08 mmol) is added at r.t, and the sealed vial is heated in an oil bath at 80° C. Reaction progress at 80° C. is followed by LC/MS, and the reaction is stopped after reaching 90% conversion (3 hours). Chromatography of the crude on silica (MeOH/EtOAc) affords pure desired product (1.8 mg, 20%). MS ESI (+) m/z 560 (M+1) detected; 1H NMR (400 MHz, deuterated acetone containing 10% deuterated methanol) δ 8.58 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.84-7.76 (m, 4H), 7.65 (d, 1H), 7.37 (q, 1H), 7.12 (d, 1H), 7.04 (m, 2H).

Workup

customReaction progress at 80° C.
custom90% conversion (3 hours)

Sources & evidence

ORD record: ord-ccc59dfcb9f449f0928978f23dd9346f
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08088766B2

Reaction notes

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