Ethanol → HCID 67054931, compound

HRID 1772837Notes

Reaction equation

HRID 1772837 reaction equation
[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23]O)#[N:2].COCCN(CCOC)S(F)(F)[F:53].C(O)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23][F:53])#[N:2]

Participants

6

Reactant 4

HCID 702EthanolHCID 6422Trifluoroacetic acidHCID 2734690(Bis(2-methoxyethyl)amino)sulfur trifluorideHCID 67272963HCID 67272963, compound

Product 1

HCID 67054931HCID 67054931, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (13 mg, 0.020 mmol; Peak 1 from Example 156, Step 5) in methylene chloride (0.87 mL, 14 mmol) was cooled to 0° C., then 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (11 μL, 0.060 mmol, Aldrich) was added, followed by ethanol (0.24 μL, 0.0040 mmol). The mixture was stirred at 0° C. for 70 min, then at RT for 20 min, and quenched by the addition of 5% sodium bicarbonate. The mixture was then extracted with EtOAc. The extract was washed with water (2×), brine, dried over sodium sulfate, decanted and concentrated. The yellow solid obtained was then dissolved and stirred for 1 h in a 1:1 mixture of TFA:DCM (1.74 mL). Solvent was removed in vacuo and the residue was stirred in a solution of methanol (0.43 mL) containing aqueous ammonium hydroxide (0.13 mL). After reaction was complete as determined by LCMS, solvent was removed in vacuo. Purification via preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded two regioisomeric products, the second peak to elute was the desired piperazine product (2 mg, 19%). 1H NMR (500 MHz, CD3OD, rotamers): δ 8.66 (s, 0.45H), 8.65 (s, 0.55H), 8.62 (s, 0.45H), 8.60 (s, 0.55H), 8.37 (s, 0.45H), 8.37 (s, 0.55H), 7.68-7.58 (m, 2H), 7.55-7.48 (m, 2H), 6.94 (d, 0.45H), 6.93 (d, 0.55H), 4.90-4.43 (m, 3H), 3.81-3.60 (m, 2H), 3.33-3.05 (m, 6H), 2.90-2.50 (m, 3H); 19F NMR (400 MHz, CD3OD): −230.21 (t, 1F), −115.45 (br s, 1F); LCMS (M+H)+: 516.3.

Workup

  1. waitat RT for 20 min
  2. customquenched by the addition of 5% sodium bicarbonate
  3. extractionThe mixture was then extracted with EtOAc
  4. washThe extract was washed with water (2×), brine
  5. dry with materialdried over sodium sulfate
  6. customdecanted
  7. concentrationconcentrated
  8. customThe yellow solid obtained
  9. dissolutionwas then dissolved
  10. customSolvent was removed in vacuo
  11. stirringthe residue was stirred in a solution of methanol (0.43 mL)
  12. additioncontaining aqueous ammonium hydroxide (0.13 mL)
  13. customAfter reaction
  14. customwas removed in vacuo
  15. customPurification via preparative HPLC-MS (C18
  16. washeluting with a gradient of H2O/MeCN containing 0.15% NH4OH)
  17. customafforded two regioisomeric products
  18. washthe second peak to elute

Sources & evidence

ORD record
ord-ffb1011eff4444ff940188c6a0dc9750
Source dataset
uspto-grants-2016_02
Patent number
US09249145B2

Reaction notes

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