Toluene → HCID 57812728, compound

HRID 911994Notes

Reaction equation

HRID 911994 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3Br)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Zn](C)[CH3:43].C1(C)C=CC=CC=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:39][C:32]1[C:33]([F:38])=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C@H:29]([O:28][C:27]1[C:22]2[O:21][C:20]([CH3:43])=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[C:23]=2[CH:24]=[N:25][C:26]=1[NH2:40])[CH3:30]

Participants

6

Reactant 3

HCID 1140TolueneHCID 57812632HCID 57812632, compoundHCID 178477796HCID 178477796, compound

Product 1

HCID 57812728HCID 57812728, compound

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-(4-{6-amino-2-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.0299 mmol), 2.0 M Me2Zn in PhMe (0.04 mL, 0.08 mmol), and Pd(PPh3)4 (2.9 mg, 0.0025 mmol) in THF (1 mL) was degassed and refilled with argon (3×), then heated at 100° C. for 30 min using a CEM microwave reactor. The solution was passed through a PL-Thiol SPE cartridge to remove metals. The material was then dissolved in dioxane and EtOH, charged with 4M HCl in Dioxane (0.2 mL) and stirred at rt for 4 h. The solution was concentrated in vacuo, redissolved in DMF (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 2.28-2.39 (m, 4H), 2.43 (s, 3H), 3.16-3.26 (m, 2H), 3.55-3.62 (m, 2H), 4.61 (dt, J=10.0, 5.0 Hz, 1H), 6.50 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.1, 4.8 Hz, 1H), 7.79 (s, 1H), 7.89 (s, 1H), 7.99 (s, 1H). MS (ES+): m/z 504.06/506.07 (100/71) [MH+]. HPLC: tR=2.73 min (ZQ3, polar—5 min).

Workup

  1. customwas degassed
  2. additionrefilled with argon (3×)
  3. customto remove metals
  4. dissolutionThe material was then dissolved in dioxane
  5. additionEtOH, charged with 4M HCl in Dioxane (0.2 mL)
  6. concentrationThe solution was concentrated in vacuo
  7. dissolutionredissolved in DMF (0.5 mL)
  8. custompurified via HPLC
  9. additionThe fractions containing the pure product
  10. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-983e7522673d4e50a26da589807bf81e
Source dataset
uspto-grants-2011_09
Patent number
US08022206B2

Reaction notes

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