Triethylamine → 4-(4-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

HRID 1772800노트

반응식

HRID 1772800 반응식
[F:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.Cl.[N:23]1([CH2:29][CH:30]([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][N:45](COCC[Si](C)(C)C)[C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[C:3]([C:12]([N:26]2[CH2:25][CH2:24][N:23]([CH2:29][CH:30]([N:34]3[CH:38]=[C:37]([C:39]4[C:40]5[CH:47]=[CH:46][NH:45][C:41]=5[N:42]=[CH:43][N:44]=4)[CH:36]=[N:35]3)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27]2)=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1

참가 물질

5

반응물 3

HCID 8471TriethylamineHCID 130018353-Fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acidHCID 670549114-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride

생성물 1

HCID 509960024-(4-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

실험 절차

N,N,N′,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16.2 mg, 0.0000426 mol) was added to a solution of 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (11 mg, 0.053 mmol) and triethylamine (30 microL, 0.21 mmol) in THF (0.4 mL). After stirring for 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (21 mg, 0.035 mmol; from Example 12, Step 2) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. The residue was dissolved and stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (9 mg, 48%). 1H NMR (300 MHz, d6-dmso): δ □8.88 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.48 (dd, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.99 (tt, 1H), 3.67-3.56 (m, 2H), 3.25-3.12 (m, 4H), 2.92-2.79 (m, 2H), 2.66-2.55 (m, 1H), 2.55-2.38 (m 2H), 2.38-2.25 (m, 1H); LCMS (M+H)+: 528.3.

후처리

  1. stirringthe reaction was stirred for two hours
  2. customThe reaction mixture was partitioned between ethyl acetate and water
  3. washThe organic layer was washed successively with water, 0.1N NaOH and brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved
  7. stirringstirred in a 1:1 mixture of DCM
  8. waitTFA for 1 hour
  9. concentrationconcentrated
  10. stirringstirred in methanol (1 mL)
  11. additioncontaining ethylenediamine (0.2 mL) for one hour
  12. washPreparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH
  13. customto purify the product (9 mg, 48%)

출처 및 근거

ORD 기록
ord-26a6efd50df04cc2bf77e07c2e819726
출처 데이터셋
uspto-grants-2016_02
특허 번호
US09249145B2

반응 노트

불러오는 중…