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Potassium Phosphate, Tribasic → 5-{3-[4-(1-aminocyclobutyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl}pyrimidin-2-amine

HRID 1047017
Notes
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Reaction equation

HRID 1047017 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.C(OC([N:45]([C:53]1[N:58]=[CH:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][N:54]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[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>[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:56]3[CH:57]=[N:58][C:53]([NH2:45])=[N:54][CH:55]=3)=[CH:25][CH:24]=2)[CH2:29][CH2:28][CH2:27]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 11977092tert-butyl N-[(tert-butoxy)carbonyl]-N-[5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]carbamateHCID 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 675046355-{3-[4-(1-aminocyclobutyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl}pyrimidin-2-amine
Yield 56.4%

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), di-tert-butyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]imidodicarbonate (75 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 and the residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL). After overnight reaction, the mixture was evaporated and the residue was purified by HPLC to give the titled compound as a white solid (24 mg, 43%). 1HNMR (DMSO-d6) 400 MHz δ: 8.56 (s, 1H), 8.26 (d, J=15.5 Hz, 2H), 8.08 (dd, J=4.6, 1.7 Hz, 1H), 7.93 (dd, J=8.0, 1.7 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.35 (td, J=7.6, 1.5 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.10 (t, J=7.4 Hz, 1H), 6.89 (dd, J=8.0, 1.7 Hz, 1H), 6.75 (dd, J=8.0, 4.6 Hz, 1H), 6.72 (s, 2H), 2.45-2.38 (m, 2H), 2.23-2.16 (m, 2H), 2.10-2.00 (m, 1H), 1.75-1.66 (m, 1H); LCMS: 473 [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
  7. dissolutionthe residue was dissolved in methanol (10 mL)
  8. customAfter overnight reaction
  9. customthe mixture was evaporated
  10. customthe residue was purified by HPLC

Sources & evidence

ORD record
ord-53628a55b2b04ed4b49f5b9b97273a3c
Source dataset
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08569331B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes