Dichloromethane → HCID 66712288, compound

HRID 1262346Notes

Reaction equation

C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:48])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]4[N:34]=[CH:33][C:32]5=[CH:35][CH:36]=[C:37]([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=6[O:44][CH3:45])[N:31]5[N:30]=4)=[C:24]([O:46][CH3:47])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:47][O:46][C:24]1[CH:23]=[C:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:48])[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[NH:28][C:29]1[N:34]=[CH:33][C:32]2=[CH:35][CH:36]=[C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[N:31]2[N:30]=1

Participants

Reactant 3

HCID 6344Dichloromethane

HCID 6422Trifluoroacetic acid

HCID 66711847HCID 66711847, compound

Product 1

HCID 66712288HCID 66712288, compound

Procedure

Into an 8-dram vial Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (170 mg, 0.46 mmol), 4-{2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester (223 mg, 0.516 mmol), N,N-Diisopropylethylamine (250 uL, 1.4 mmol) and 1-Methoxy-2-propanol (2 mL, 20 mmol). The reaction mixture was heated at 100° C. overnight. After 18 h, the mixture was cooled to RT and the product was purified by flash chromatography (ISCO, 40 g column, EtOAC-MeOH 95:5). The product was obtained as a syrup (156 mg, 52%). MS: 656 (M+H). The product was subjected to the BOC deprotection step. 4-[2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.23 mmol) was treated with trifluoroacetic acid (0.5 mL, 6 mmol) in methylene chloride (10 mL, 200 mmol). The mixture was stirred at RT. After 3 days, solvent was removed and the product, 2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-1-piperazin-1-yl-ethanone, was purified by reverse phase liquid chromatography (Gilson) as a brown solid (61 mg, 48%, —85% pure). LCMS (E/I+) 556 (M+H). NMR 1H (DMSO-d6)-9.6 (br s, 1H), 9.02 (br s, 2H), 8.95 (s, 1H), 7.07 (d, 1H, J=8.27 Hz), 7.82 (d, 1H, J=6.44 Hz), 7.64 (s, 1H), 7.46 (m, 1H), 7.21 (d, 1H, J=8.37 Hz), 7.10 (m, 1H), 6.96 (m, 2H), 6.90 (s, 1H), 6.71 (d, 1H, J=8.34 Hz), 4.35 (m, 2H), 4.2-3.0 (series of m and s along with water peak, 18H), 2.84 (m, 1H), 2.08-1.99 (m, 4H).

Workup

customsolvent was removed
customthe product, 2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-1-piperazin-1-yl-ethanone, was purified by reverse phase liquid chromatography (Gilson) as a brown solid (61 mg, 48%, —85% pure)

Sources & evidence

ORD record: ord-5914c2f3deb04a788aece7606cdb3b74
Source dataset: uspto-grants-2013_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08471005B2

Reaction notes

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