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 1047022Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1047022
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

Komponenten

7

Edukt 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

Produkt 1

HCID 69087718methyl (4-{3-[4-(1-aminocyclobutyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl}phenyl)acetateAusbeute 41 %

Reagenzien, Katalysatoren, Lösungsmittel 2

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

Reaktionsbedingungen

Temperatur
160 °C

Versuchsvorschrift

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].

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-cdc90b5a48184c7685bd920fb6bab400
Quelldatensatz
uspto-grants-2013_10
Patentnummer
US08569331B2

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