Water → 5-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile

HRID 2222237노트

반응식

HRID 2222237 반응식
[NH2:1][C:2]1[C:3]2[C:4](=[N:13][N:14]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=4)[N:28]=[CH:27][CH:26]=3)[C:15]=2[C:16]2[N:20]([CH3:21])[CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:6](=[O:8])[N:7]=1.[CH2:36]1[CH2:46]CN2C(=NCCC2)C[CH2:37]1.ClCC(=O)C.O>CN(C=O)C.C(OCC)(=O)C>[Cl:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[CH2:24][N:14]1[C:15]([C:16]2[N:20]([CH3:21])[CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)=[C:3]2[C:2]3[N:7]([C:36]([CH3:46])=[CH:37][N:1]=3)[C:6](=[O:8])[N:5]([CH2:9][CH:10]3[CH2:12][CH2:11]3)[C:4]2=[N:13]1

참가 물질

7

반응물 4

HCID 962WaterHCID 6571Chloroacetone2회HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 104354585-[4-amino-2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile

생성물 1

HCID 115554615-[8-[(6-chloroquinolin-4-yl)methyl]-6-(cyclopropylmethyl)-3-methyl-5-oxo-6,8-dihydro-5H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl]-1-methyl-1H-pyrrole-3-carbonitrile수율 25.5%

시약·촉매·용매 2

HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

반응 조건

온도
125 °C

실험 절차

5-[4-amino-2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (75 mg, 0.15 mmol) was dissolved in 1.5 mL anhydrous DMF with 30 mg DBU. Chloroacetone (28 mg, 0.3 mmol, 2.0 eq.) was added and the resulting solution heated in the microwave for 90 minutes at 125° C. Two addition eq. chloroacetone were added, and the reaction returned to the microwave and heated an additional 90 minutes at 125° C. The reaction mixture was diluted with 50 mL. water and 50 mL ethyl acetate. The aqueous layer was washed 3×50 mL with ethyl acetate. The combined organic fractions were washed with 50 mL brine and dried over sodium sulfate. The crude product was purified by chromatography on silica (gradient: dichloromethane to 10% methanol in dichloromethane), followed by reverse phase HPLC using 40% aqueous acetonitrile, yielding 20 mg product. 1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.55 (m, 4H) 1.48 (m, 1H) 2.27 (d, J=0.94 Hz, 3H) 3.42 (s, 3 H) 4.13 (m, 2H) 5.82 (m, 2H) 6.62 (dd, J=4.52, 1.88 Hz, 1H) 6.76 (d, J=4.33 Hz, 1H) 7.36 (d, J=1.51 Hz, 1H) 7.44 (d, J=1.13 Hz, 1H) 7.70 (dd, J=9.04, 2.26 Hz, 1H) 7.90 (d, J=2.26 Hz, 1H) 8.10 (m, 1H) 8.81 (d, J=4.52 Hz, 1H); ES M+H+=524.

후처리

  1. additionwere added
  2. temperatureheated an additional 90 minutes at 125° C
  3. additionThe reaction mixture was diluted with 50 mL
  4. washThe aqueous layer was washed 3×50 mL with ethyl acetate
  5. washThe combined organic fractions were washed with 50 mL brine
  6. dry with materialdried over sodium sulfate
  7. customThe crude product was purified by chromatography on silica (gradient: dichloromethane to 10% methanol in dichloromethane)

출처 및 근거

ORD 기록
ord-d3bbd59f98b044f18f86ba0e19566214
출처 데이터셋
uspto-grants-2008_05
특허 번호
US07371757B2

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