Potassium Phosphate, Tribasic → 1-{4-[2-(1H-pyrrolo[3,2-b]pyridin-6-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutanamine

HRID 1047001Notes

Reaction equation

HRID 1047001 reaction equation
Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[C:48]3[NH:54][CH:53]=[CH:52][C:49]3=[N:50][CH:51]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH:54]1[C:48]2[C:49](=[N:50][CH:51]=[C:46]([C:2]3[N:3]=[C:4]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]5[N:15]=[CH:16][CH:17]=[CH:18][C:6]=5[N:5]4[C:19]=3[C:20]3[CH:21]=[CH:22][C:23]([C:26]4([NH2:30])[CH2:29][CH2:28][CH2:27]4)=[CH:24][CH:25]=3)[CH:47]=2)[CH:52]=[CH:53]1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 242292706-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo(3,2-b)pyridineHCID 136331865tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate

Product 1

HCID 569685261-{4-[2-(1H-pyrrolo[3,2-b]pyridin-6-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutanamineYield 71.7%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 8857Ethyl AcetateSolventHCID 21962138N,N-Dimethylformamide--water (1/1)Solvent

Conditions

Temperature
160 °C

Procedure

A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine (44 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. The fraction was evaporated to dryness. Step 2: The residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL) was added. After overnight reaction, the mixture was evaporated and the residue was purified by HPLC to give the titled compound as a white solid (32 mg, 60%). 1HNMR (DMSO-d6) 400 MHz δ: 11.39 (s, 1H), 8.58 (s, 1H), 8.38 (d, J=1.7 Hz, 1H), 8.25 (s, 1H), 8.09 (dd, J=4.6, 1.7 Hz, 1H), 7.99 (dd, J=8.0, 1.7 Hz, 1H), 7.89 (d, J=1.1 Hz, 1H), 7.63 (t, J=3.2 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.36 (td, J=7.4, 1.7 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.13 (t, J=7.4 Hz, 1H), 6.90 (dd, J=7.7, 1.4 Hz, 1H), 6.75 (dd, J=8.0, 4.6 Hz, 1H), 6.51-6.49 (m, 1H), 2.48-2.41 (m, 2H), 2.26-2.19 (m, 2H), 2.11-2.02 (m, 1H), 1.77-1.68 (m, 1H); LCMS: 496 [M+H].

Workup

  1. temperatureAfter cooling to room temperature
  2. washwashed with water (×3)
  3. dry with materialThe organic layer was dried over anhydrous Na2SO4
  4. concentrationconcentrated
  5. customThe residue was purified by HPLC
  6. customThe fraction was evaporated to dryness
  7. dissolutionStep 2: The residue was dissolved in methanol (10 mL)
  8. addition4M HCl in dioxane (10 mL) was added
  9. customAfter overnight reaction
  10. customthe mixture was evaporated
  11. customthe residue was purified by HPLC

Sources & evidence

ORD record
ord-344eab8f0cc742b19afabfeed54cea44
Source dataset
uspto-grants-2013_10
Patent number
US08569331B2

Reaction notes

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