Lithium Hexamethyldisilazide → N-(1-methylpiperidin-3-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-amine

HRID 1520085노트

반응식

HRID 1520085 반응식
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]2[C:21]1[N:22]=[N:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])=[CH:28][CH:27]=2)[CH:25]=1.Cl.Cl.[NH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][N:45]([CH3:49])[CH2:44]1.C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1COCC1.CN(C=O)C.C(Cl)Cl>[CH3:49][N:45]1[CH2:46][CH2:47][CH2:48][CH:43]([NH:42][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[N:22]=[N:23][N:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)[CH:25]=2)[CH2:44]1

참가 물질

8

반응물 4

HCID 2733832Lithium Hexamethyldisilazide2회HCID 177503421-Methylpiperidin-3-amine dihydrochloride2회HCID 25112535Brettphos2회HCID 574046585-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

생성물 1

HCID 57405170N-(1-methylpiperidin-3-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-amine수율 5%

시약·촉매·용매 3

HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 8028Tetrahydrofuran용매2회

반응 조건

온도
70 °C

실험 절차

LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) was added to a degassed suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (200 mg; 0.44 mmol; 1.0 eq.), 3-Amino-1-methylpiperidine dihydrochloride, 98% (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), (7.0 mg; 0.01 mmol; 0.02 eq.) and dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) in DMF (500 μl). The reaction mixture was then heated at 70° C. O/N. As the reaction was not completed, further 3-Amino-1-methylpiperidine dihydrochloride (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (7.0 mg; 0.01 mmol; 0.02 eq.), dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) and LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) were added and the reaction mixture was heated again at 70° C. for 12 h. It was diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a brown solid (10 mg; 5%). 1H NMR (300 MHz, DMSO-d6-d6): 12.96 (brs, 1H), 9.26 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.36-7.33 (m, 1H), 6.96-6.92 (m, 2H), 5.36 (m, 1H), 3.64-3.55 (m, 1H), 3.00 (m, 1H), 2.73 (m, 1H), 2.23 (m, 3H), 1.99-1.59 (m, 3H), 1.30 (m, 1H). HPLC (max plot) 94.3%; Rt % 1.99 min. UPLC/MS: (MS+) 487.3, (MS−) 485.3.

후처리

  1. addition4.5 eq.) were added
  2. temperaturethe reaction mixture was heated again at 70° C. for 12 h
  3. washwashed with water
  4. dry with materialThe organic phase was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by preparative HPLC

출처 및 근거

ORD 기록
ord-6329a50216db48818b3a6e6978e863fa
출처 데이터셋
uspto-grants-2015_07
특허 번호
US09073892B2

반응 노트

불러오는 중…