Piperidine → HCID 58529476, compound

HRID 1972780Notes

Reaction equation

HRID 1972780 reaction equation
[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:17]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[N:6]3[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)[CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1

Participants

7

Reactant 5

HCID 8082PiperidineHCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 58529551HCID 58529551, compound

Product 1

HCID 58529476HCID 58529476, compoundYield 5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a cooled (0° C.) solution of 4-{4-amino-5-[3-(benzyloxy)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}butan-1-ol (80 mg, 0.21 mmol) in dichloromethane (1 mL) was added triethylamine (32 μL, 0.23 mmol) and methanesulfonyl chloride (17 μL, 0.22 mmol). The reaction was stirred (0° C.) for 4 h and then warmed to rt. The mixture was quenched with the addition of ice water (1 mL). The layers were separated and the organic layer was dried (Na2SO4) and evaporated. The residue was dissolved in DMF (1 mL) and potassium carbonate (85 mg, 0.62 mmol) and piperidine (18 μL, 0.22 mol) were added to the mixture. The reaction was stirred (60° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (15 mL) and water (15 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (2×10 mL). The combined organics were dried (Na2SO4) and evaporated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water to obtain 4 mg (5%) of the desired product. 1H NMR (300 MHz, CD3CN) δ 7.86 (s, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.32 (m, 4 H), 7.12-7.09 (m, 1 H), 7.09-7.06 (m, 1 H), 7.04-7.00 (s, 1 H), 6.56 (s, 1 H), 5.17 (s, 2 H), 2.96 (t, 2 H), 2.47-2.27 (m, 6 H), 1.83-1.73 (m, 2 H), 1.63-1.1.51 (m, 6 H), 1.48-1.40 (m, 2 H); ES-MS m/z 456.3 [M+H]+, HPLC RT (min) 2.29.

Workup

  1. temperaturewarmed to rt
  2. customThe mixture was quenched with the addition of ice water (1 mL)
  3. customThe layers were separated
  4. dry with materialthe organic layer was dried (Na2SO4)
  5. customevaporated
  6. dissolutionThe residue was dissolved in DMF (1 mL)
  7. stirringThe reaction was stirred (60° C.) for 17 h
  8. temperaturecooled to rt
  9. customThe mixture was partitioned between ethyl acetate (15 mL) and water (15 mL)
  10. customThe layers were separated
  11. extractionthe aqueous was further extracted with ethyl acetate (2×10 mL)
  12. dry with materialThe combined organics were dried (Na2SO4)
  13. customevaporated
  14. customThe residue was purified by preparative HPLC
  15. washa gradient elution from 15% to 45% acetonitrile in water

Sources & evidence

ORD record
ord-22717608a2674fe8a3a0fcf3c11270b6
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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