Trifluoroacetic acid → HCID 53373294, compound

HRID 1617418Notes

Reaction equation

HRID 1617418 reaction equation
O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:24][C:23]([CH2:47][C:48]#[N:49])([N:25]4[CH:29]=[C:28]([C:30]5[C:31]6[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=6[N:33]=[CH:34][N:35]=5)[CH:27]=[N:26]4)[CH2:22]3)[CH2:17][CH2:16]2)=[O:14])[CH:4]=1.[CH2:50]([N:52](CC)[CH2:53][CH3:54])[CH3:51].CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N1CCCC1.FC(F)(F)C(O)=O>C(Cl)Cl.C(N(CC)CC)C>[N:52]1([CH2:2][C:3]2[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:24][C:23]([CH2:47][C:48]#[N:49])([N:25]5[CH:29]=[C:28]([C:30]6[C:31]7[CH:38]=[CH:37][NH:36][C:32]=7[N:33]=[CH:34][N:35]=6)[CH:27]=[N:26]5)[CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH:4]=2)[CH2:53][CH2:54][CH2:51][CH2:50]1

Participants

9

Reactant 6

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 31268PyrrolidineHCID 31297Methanesulfonyl chloride2×HCID 85257Methanesulfonate2×HCID 58431331HCID 58431331, compound

Product 1

HCID 53373294HCID 53373294, compound

Reagents, catalysts & solvents 2

HCID 8471TriethylamineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of {1-(1-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}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 (0.030 g, 0.043 mmol, from Step E) and triethylamine (0.015 mL, 0.11 mmol) in methylene chloride (1 mL) at 0° C. was added methanesulfonyl chloride (0.006 mL, 0.08 mmol). The reaction was allowed to warm to room temperature immediately after addition of mesyl chloride (MsCl). When mesylate formation was confirmed to be complete, the solution of mesylate was added to a mixture of pyrrolidine (0.017 mL, 0.20 mmol, Aldrich) and a few drops of triethylamine in DCM (0.2 mL). The displacement reaction was heated to 40° C. for 30 minutes. The reaction was cooled to room temperature and trifluoroacetic acid (1 mL) was added. After stirring for 1 hour, the solvents were removed in vacuo and replaced with methanol (1 mL) and ethylenediamine (0.2 mL). After stirring for 30 minutes, the product was purified by preparative HPLC-MS (Waters SunFire C18, 5 um particle size, 30×100 mm, eluting with a gradient of 5-23% MeCN in H2O containing 0.1% TFA over 12 minutes). Yield: 0.012 g (25%); LC-MS: 620.2 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 9.10 (s, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.01 (s, 1H), 7.83 (d, 1H), 7.29 (d, 1H), 4.95 (d, 2H), 4.85 (s, 2H), 4.77-4.66 (m, 3H), 4.02 (d, 1H), 3.95-3.15 (m, 8H), 3.12-2.99 (m, 1H), 2.31-2.03 (m, 6H), 1.77-1.51 (m, 2H). 19F NMR (300 MHz, CD3OD): δ −72.21 (s, 3F), −77.61 (s, 12F).

Workup

  1. customThe displacement reaction
  2. temperaturewas heated to 40° C. for 30 minutes
  3. temperatureThe reaction was cooled to room temperature
  4. customthe solvents were removed in vacuo
  5. stirringAfter stirring for 30 minutes
  6. customthe product was purified by preparative HPLC-MS (Waters SunFire C18, 5 um particle size, 30×100 mm
  7. washeluting with a gradient of 5-23% MeCN in H2O containing 0.1% TFA over 12 minutes)

Sources & evidence

ORD record
ord-6a9c42c7a0254471bc5d0496582235da
Source dataset
uspto-grants-2014_07
Patent number
US08765734B2

Reaction notes

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