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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
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1047017
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
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Komponenten

7

Edukt 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

Produkt 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
Ausbeute 56,4 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)KatalysatorHCID 8857Ethyl AcetateLösungsmittelHCID 21962138N,N-Dimethylformamide--water (1/1)Lösungsmittel

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), 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].

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. 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

Quellen und Nachweise

ORD-Eintrag
ord-53628a55b2b04ed4b49f5b9b97273a3c
Quelldatensatz
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08569331B2

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