Potassium Phosphate, Tribasic → methyl (4-{3-[4-(1-aminocyclobutyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl}phenyl)acetate

HRID 1047022Notes

Reaction equation

HRID 1047022 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.OB(O)[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47]([OH:49])=[O:48])=[CH:42][CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:59]N(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>[NH2:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:40]3[CH:45]=[CH:44][C:43]([CH2:46][C:47]([O:49][CH3:59])=[O:48])=[CH:42][CH:41]=3)=[CH:25][CH:24]=2)[CH2:27][CH2:28][CH2:29]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 218789612-(4-Boronophenyl)acetic acidHCID 21962138N,N-Dimethylformamide--water (1/1)HCID 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 69087718methyl (4-{3-[4-(1-aminocyclobutyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl}phenyl)acetateYield 41%

Reagents, catalysts & solvents 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 8857Ethyl AcetateSolvent

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), [4-(dihydroxyboryl)phenyl]acetic acid (32 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. To the fraction, conc. HCl (3 ml) and methanol (3 ml) were added and the residue was evaporated after 24 h. The residue was purified by HPLC to give the titled compound as a white solid (23 mg, 41%). 1HNMR (DMSO-d6) 400 MHz δ: 8.55 (s, 1H), 8.25 (s, 1H), 8.07 (dd, J=4.6, 1.7 Hz, 1H), 7.95 (dd, J=7.7, 1.4 Hz, 1H), 7.48 (d, J=10.0 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.35 (td, J=7.7, 1.7 Hz, 1H), 7.28 (dd, J=8.0, 1.1 Hz, 1H), 7.19 (dd, J=8.3, 6.0 Hz, 4H), 7.11 (t, J=7.4 Hz, 1H), 6.88 (dd, J=8.0, 1.7 Hz, 1H), 6.73 (dd, J=7.7, 4.9 Hz, 1H), 3.66 (s, 2H), 3.61 (s, 3H), 2.44-2.37 (m, 2H), 2.17-2.14 (m, 2H), 2.08-1.99 (m, 1H), 1.74-1.66 (m, 1H); LCMS: 514 [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. additionTo the fraction, conc. HCl (3 ml) and methanol (3 ml) were added
  7. customthe residue was evaporated after 24 h
  8. customThe residue was purified by HPLC

Sources & evidence

ORD record
ord-cdc90b5a48184c7685bd920fb6bab400
Source dataset
uspto-grants-2013_10
Patent number
US08569331B2

Reaction notes

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