1,2-Dichloroethane → N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxamide

HRID 1616810노트

반응식

HRID 1616810 반응식
[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]=2[C:11]([OH:13])=O)[C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].Cl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>CS(C)=O>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:11]([C:9]1[CH:8]=[C:7]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[C:4]2[CH:20]([CH3:21])[CH3:22])=[O:13]

참가 물질

8

반응물 6

HCID 111,2-DichloroethaneHCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 181649HOAtHCID 70638443-(Aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-oneHCID 678144821-Methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxylic acid

생성물 1

HCID 67817283N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxamide수율 26.1%

시약·촉매·용매 1

HCID 679Dimethyl Sulfoxide용매

실험 절차

1-Methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxylic acid (62.5 mg, 0.21 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl (58.5 mg, 0.31 mmol) and 1-hydroxy-7-azabenzotriazole (47.8 mg, 0.35 mmol) were stirred in 2 mL of DMSO for 10 min under nitrogen. N-methylmorpholine (0.095 mL, 0.87 mmol) was added along with EDC (67.4 mg, 0.35 mmol) and the mixture was stirred at rt overnight under nitrogen. Ice-water was added but no solid crashed out. The reaction mixture was concentrated until only DMSO was left and purified using a reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes). Fractions containing the desired product were evaporated until a minimum of water remained and saturated solution of NaHCO3 was added. The light orange solids that crashed out were filtered off and dissolved in DMF. Water was added and the solids that crashed out were filtered, air-dried for 15 min and dried in vacuum-oven overnight to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxamide (24 mg, 26.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (s, 1H) 8.33 (t, J=4.93 Hz, 1H) 7.04 (d, J=2.27 Hz, 1H) 6.96 (s, 1H) 6.80 (d, J=2.27 Hz, 1H) 5.87 (s, 1H) 4.33 (s, 1H) 4.31 (s, 1H) 3.72-3.78 (m, 4H) 3.60 (s, 3H) 3.06-3.12 (m, 1H) 3.00-3.06 (m, 4H) 2.22 (s, 3H) 2.11 (s, 3H) 1.26 (d, J=6.8 Hz, 6H). MS (ES) [M+H]+ 437.0.

후처리

  1. concentrationThe reaction mixture was concentrated until only DMSO
  2. waitwas left
  3. custompurified
  4. customa reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes)
  5. additionFractions containing the desired product
  6. customwere evaporated until a minimum of water
  7. additionsaturated solution of NaHCO3 was added
  8. filtrationThe light orange solids that crashed out were filtered off
  9. dissolutiondissolved in DMF
  10. additionWater was added
  11. filtrationthe solids that crashed out were filtered
  12. customair-dried for 15 min
  13. customdried in vacuum-oven overnight

출처 및 근거

ORD 기록
ord-c621835ab5a24805936d37a26c319d29
출처 데이터셋
uspto-grants-2014_07
특허 번호
US08765792B2

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