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 1047022노트

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HRID 1047022 반응식
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

참가 물질

7

반응물 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

생성물 1

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

시약·촉매·용매 2

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

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온도
160 °C

실험 절차

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].

후처리

  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

출처 및 근거

ORD 기록
ord-cdc90b5a48184c7685bd920fb6bab400
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08569331B2

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