Water → 2-(4-{4-[7-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide

HRID 1262091Notes

Reaction equation

HRID 1262091 reaction equation
Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][S:29]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2B2OC(C)(C)C(C)(C)O2)[CH2:33]1)(=[O:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+].O.O1CCCC1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][S:29]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([CH:18]5[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][CH2:19]5)=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH2:33]1)(=[O:31])=[O:30]

Participants

8

Reactant 5

HCID 962WaterHCID 8028TetrahydrofuranHCID 10340Sodium CarbonateHCID 667107962-{4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-phenyl]-piperidin-1-yl}-acetamideHCID 667112932-Methanesulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindole

Product 1

HCID 573908612-(4-{4-[7-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamideYield 1.9%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6344DichloromethaneSolvent

Procedure

2-{4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-phenyl]-piperidin-1-yl}-acetamide (150 mg, 0.00035 mol), 2-Methanesulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindole (169.4 mg, 0.0005241 mol), 0.9 M of Sodium carbonate in water (0.23 mL, 0.00021 mol), Tetrakis(triphenylphosphine)palladium (O) (0.040 g, 0.000035 mol) and Tetrahydrofuran (2 mL, 0.03 mol) were heated at 80° C. overnight. The reaction was cooled to RT, dissolved partially in DCM and filtered. The filtrate was placed onto a 40 gm column eluting with DCM to 5% MeOH/DCM. Dissolved in DMSO, filtered and placed onto the Gilson. Most pure fractions were free based and worked up to give 2-(4-{4-[7-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide as a yellow solid (3.7 mg, 1.9%). MP 244-247° C. LCMS (E/I+) 546 (M+H). NMR 1H (DMSO-d6)-9.45 (s, 1H), 9.01 (s, 1H), 7.97 (d, 1H, J=7.77 Hz), 7.62 (d, 2H, J=8.60 Hz), 7.56 (t, 1H, J=7.68 Hz), 7.44 (d, 1H, J=7.54 Hz), 7.20 (s, 1H), 7.12 (s, 1H), 7.10 (d, 1H, J=8.51 Hz), 7.06 (d, 1H, J=4.63 Hz), 6.98 (d, 1H, J=4.80 Hz), 4.74 (s, 4H), 2.91-2.92 (m, 4H), 2.86-2.89 (m, 3H), 2.38-2.42 (m, 1H), 2.10-2.20 (m, 2H), 1.65-1.74 (m, 4H).

Workup

  1. filtrationfiltered
  2. washeluting with DCM to 5% MeOH/DCM
  3. dissolutionDissolved in DMSO
  4. filtrationfiltered

Sources & evidence

ORD record
ord-7faf519360e9496695e7d6311db8c9a9
Source dataset
uspto-grants-2013_06
Patent number
US08471005B2

Reaction notes

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