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 1047022ノート

反応式

HRID 1047022 の反応式
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

参加物

7

反応物 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

生成物 1

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

試薬・触媒・溶媒 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)触媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
160 °C

実験手順

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].

後処理

  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

出典と根拠

ORDレコード
ord-cdc90b5a48184c7685bd920fb6bab400
出典データセット
uspto-grants-2013_10
特許番号
US08569331B2

反応ノート

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