Triethylamine → {1-(1-{[6-{[ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

HRID 1617410노트

반응식

HRID 1617410 반응식
[CH2:1]([N:3]([CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([OH:18])=O)[CH:7]=1)[CH3:4])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:59][C:58]([CH2:82][C:83]#[N:84])([N:60]3[CH:64]=[C:63]([C:65]4[C:66]5[CH:73]=[CH:72][N:71](COCC[Si](C)(C)C)[C:67]=5[N:68]=[CH:69][N:70]=4)[CH:62]=[N:61]3)[CH2:57]2)[CH2:52][CH2:51]1>O1CCCC1>[CH2:1]([N:3]([CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[N:9]=[C:8]([C:16]([N:50]2[CH2:51][CH2:52][CH:53]([N:56]3[CH2:57][C:58]([CH2:82][C:83]#[N:84])([N:60]4[CH:64]=[C:63]([C:65]5[C:66]6[CH:73]=[CH:72][NH:71][C:67]=6[N:68]=[CH:69][N:70]=5)[CH:62]=[N:61]4)[CH2:59]3)[CH2:54][CH2:55]2)=[O:18])[CH:7]=1)[CH3:4])[CH3:2]

참가 물질

6

반응물 4

HCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 584312966-{[Ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidine-4-carboxylic acidHCID 67391103{1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

생성물 1

HCID 53380651{1-(1-{[6-{[ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

실험 절차

After prestirring a mixture of 6-{[ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (40.1 mg, 0.152 mmol, from Step A), triethylamine (56.6 μL, 0.406 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (54.0 mg, 0.142 mmol) in tetrahydrofuran (1.1 mL) for 30 minutes, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (50.0 mg, 0.101 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added and the reaction stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The product was deprotected by stirring first in a 1:1 mixture of DCM:TFA for 1 hour, followed by evaporation and stirring with ethylenediamine (0.2 mL) in methanol (1 mL) until deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product. Yield: 0.025 g (41%); LC-MS: 608.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.61 (d, 1H), 7.06 (d, 1H), 4.11-4.02 (m, 1H), 3.78-3.71 (m, 4H), 3.63-3.48 (m, 5H), 3.32-3.21 (m, 1H), 3.17-3.07 (m, 1H), 2.62-2.53 (m, 1H), 2.48 (q, 2H), 2.21 (s, 3H), 1.84-1.74 (m, 1H), 1.70-1.61 (m, 1H), 1.37-1.18 (m, 2H), 1.03 (t, 3H). 19F NMR (400 MHz, DMSO-d6): δ −69.45 (s, 3F).

후처리

  1. customto provide the free base)
  2. additionwas added
  3. stirringthe reaction stirred overnight
  4. customThe reaction mixture was partitioned between ethyl acetate and water
  5. washThe organic layer was successively washed with water, 0.1N NaOH and sat. NaCl
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. stirringby stirring first in a 1:1 mixture of DCM
  10. customfollowed by evaporation
  11. stirringstirring with ethylenediamine (0.2 mL) in methanol (1 mL) until deprotection
  12. customPurification via preparative HPLC-MS (C18
  13. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH)
  14. customafforded product

출처 및 근거

ORD 기록
ord-008a33ffe7d640668b8aa0d0c4014351
출처 데이터셋
uspto-grants-2014_07
특허 번호
US08765734B2

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