Triethylamine → {1-(1-{[6-[(dimethylamino)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 1617403ノート

反応式

HRID 1617403 の反応式
[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]([OH:17])=O)[CH:6]=1)[CH3:3].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:49]1[CH2:54][CH2:53][CH:52]([N:55]2[CH2:58][C:57]([CH2:81][C:82]#[N:83])([N:59]3[CH:63]=[C:62]([C:64]4[C:65]5[CH:72]=[CH:71][N:70](COCC[Si](C)(C)C)[C:66]=5[N:67]=[CH:68][N:69]=4)[CH:61]=[N:60]3)[CH2:56]2)[CH2:51][CH2:50]1>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:8]=[C:7]([C:15]([N:49]2[CH2:50][CH2:51][CH:52]([N:55]3[CH2:56][C:57]([CH2:81][C:82]#[N:83])([N:59]4[CH:63]=[C:62]([C:64]5[C:65]6[CH:72]=[CH:71][NH:70][C:66]=6[N:67]=[CH:68][N:69]=5)[CH:61]=[N:60]4)[CH2:58]3)[CH2:53][CH2:54]2)=[O:17])[CH:6]=1)[CH3:1]

参加物

6

反応物 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 584314096-[(Dimethylamino)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

生成物 1

HCID 53380543{1-(1-{[6-[(dimethylamino)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

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

実験手順

6-[(Dimethylamino)methyl]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (22.8 mg, 0.0913 mmol, from Step B) was dissolved in tetrahydrofuran (0.67 mL), and triethylamine (33.9 μL, 0.244 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (32.4 mg, 0.0852 mmol) were added. The mixture was stirred for 15 minutes, followed by the addition of {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 (30.0 mg, 0.0609 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base). After two hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) until the deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH), afforded the desired compound as a white powder. Yield: 0.014 g (39%); LC-MS: 594.4 (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), 7.90 (s, 1H), 7.61 (dd, 1H), 7.07 (dd, 1H), 4.07 (ddd, 1H), 3.77-3.72 (m, 2H), 3.70 (s, 2H), 3.63-3.48 (m, 5H), 3.31-3.22 (m, 1H), 3.16-3.07 (m, 1H), 2.60-2.53 (m, 1H), 2.25 (s, 6H), 1.85-1.73 (m, 1H), 1.71-1.59 (m, 1H), 1.37-1.18 (m, 2H). 19F NMR (400 MHz, DMSO-d6): δ −69.45 (s, 3F).

後処理

  1. customprepared
  2. customto provide the free base)
  3. waitAfter two hours
  4. customthe reaction mixture was partitioned between ethyl acetate and water
  5. washThe organic layer was washed with water, 0.1N NaOH and sat. NaCl
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. stirringThe residue was stirred in a 1:1 mixture of DCM
  9. waitTFA for 1 hour
  10. concentrationconcentrated
  11. stirringstirred in methanol (1 mL)
  12. additioncontaining ethylenediamine (0.2 mL) until the deprotection
  13. customPurification via preparative HPLC-MS (C18
  14. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH),

出典と根拠

ORDレコード
ord-59971589d92e41b78b3cc1fc70cb1633
出典データセット
uspto-grants-2014_07
特許番号
US08765734B2

反応ノート

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