4-(2-ethoxy-6-iodo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine → 7-{2-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]ethynyl}-5H,6H,7H-cyclopent a[b]pyridin-7-ol

HRID 1398644Notes

Reaction equation

HRID 1398644 reaction equation
[CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[C:7]2[CH:16]=[C:17](I)[CH:18]=[CH:19][C:6]=2[N:5]=1)[CH3:2].[C:21]([C:23]1([OH:32])[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25][CH2:24]1)#[CH:22]>N1CCCCC1.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.[Cu]I>[NH2:15][C:11]1[N:10]=[C:9]([N:8]2[C:7]3[CH:16]=[C:17]([C:22]#[C:21][C:23]4([OH:32])[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH2:25][CH2:24]4)[CH:18]=[CH:19][C:6]=3[N:5]=[C:4]2[O:3][CH2:1][CH3:2])[CH:14]=[CH:13][N:12]=1

Participants

6

Reactant 2

HCID 681820714-(2-ethoxy-6-iodo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amineHCID 866695787-ethynyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

Product 1

HCID 681818217-{2-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]ethynyl}-5H,6H,7H-cyclopent a[b]pyridin-7-ol

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8082PiperidineSolvent

Procedure

A mixture of 4-(2-ethoxy-6-iodo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (150 mg, 0.394 mmol) and 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol (118 mg, 0.59 mmol) was dissolved in piperidine (1 mL). The solution was de-gassed with nitrogen for 2 mins. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) and copper(I) iodide (6 mg, 0.031 mmol) were added and the resultant solution heated to 30° C. for 2 hr. The mixture was concentrated in vacuo, DCM (10 mL) added and re-concentrated in vacuo (twice). The residue was purified by column chromatography (Biotage, 0-10% MeOH gradient in DCM), followed by reverse phase preparative HPLC purification to give the title compound; 1H NMR (500 MHz, DMSO) delta 1.44 (3H, t, J=7.1 Hz), 2.36-2.42 (1H, m), 2.52-2.62 (1H, m), 2.83-2.95 (1H, m), 2.94-3.08 (1H, m), 4.63 (2H, q, J=7.0 Hz), 6.96 (1H, d, J=5.5 Hz), 7.08 (2H, s), 7.19-7.32 (2H, m), 7.44 (1H, d, J=8.2 Hz), 7.72 (1H, d, J=7.6 Hz), 8.13 (1H, s), 8.38 (1H, d, J=5.5 Hz), 8.44 (1H, d, J=4.8 Hz), 8.51 (1H, s); LC-MS: m/z=+413.05 (M+H)+.

Workup

  1. customThe solution was de-gassed with nitrogen for 2 mins
  2. concentrationThe mixture was concentrated in vacuo, DCM (10 mL)
  3. additionadded
  4. concentrationre-concentrated in vacuo (twice)
  5. customThe residue was purified by column chromatography (Biotage, 0-10% MeOH gradient in DCM)
  6. customfollowed by reverse phase preparative HPLC purification

Sources & evidence

ORD record
ord-e83d59f9e0494d1f8df29b27e6abc4c6
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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