Trifluoroacetic acid → HCID 59013754, compound

HRID 907552Notes

Reaction equation

HRID 907552 reaction equation
C(O)(C(F)(F)F)=O.C([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([F:35])[CH:30]=3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C(N(CC)CC)C.[N:43]([C:46]1[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[C:48]([C:56]([F:59])([F:58])[F:57])[CH:47]=1)=C=O>ClCCl.CCOC(C)=O>[F:53][C:52]([F:54])([F:55])[C:50]1[CH:51]=[C:46]([NH:43][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([F:35])[CH:30]=4)=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:12])[CH:47]=[C:48]([C:56]([F:57])([F:59])[F:58])[CH:49]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 27333143,5-Bis(trifluoromethyl)phenyl isocyanateHCID 59013845HCID 59013845, compound

Product 1

HCID 59013754HCID 59013754, compoundYield 32%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 20% solution of TFA in dichloromethane was added to 3′-(2-fluoro-pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (113 mg, 0.290 mmol). The solution was stirred at room temperature for 1 h until complete de-protection was evident by LCMS, then concentrated in vacuo. The resulting solid was diluted with dichloromethane (3 mL). Triethylamine (193 mg, 1.91 mmol) was added and assured bacisity with pH paper. The solution was cooled to −5° C. and 1-isocyanato-3,5-bis-trifluoromethyl-benzene (88.6 mg, 0.347 mmol) was added dropwise. After the addition was complete, the solution was stirred at −5° C. for 5 min, then allowed to warm up to room temperature and stirred for an additional 3 h. The solution was then diluted with EtOAc (20 mL), washed with satd. NaHCO3(aq) and brine, dried over MgSO4 and concentrated in vacuo. The crude solids were dissolved in MeOH and purified by preparative HPLC (50 mM NH4OAc(aq), acetonitrile solvent system). The product was isolated by lyophilization of pure fractions yielding N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-fluoropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide (50.5 mg, 32.0% yield). 1H NMR (CDCl3) 8.24 (d, 1H), 7.91 (s, 2H), 7.82 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.22 (d, 1H), 6.98 (s, 1H), 6.73 (d, 1H), 5.51 (s, 2H), 3.70-3.65 (m, 8H) ppm.

Workup

  1. concentrationconcentrated in vacuo
  2. additionThe resulting solid was diluted with dichloromethane (3 mL)
  3. temperatureThe solution was cooled to −5° C.
  4. additionAfter the addition
  5. stirringthe solution was stirred at −5° C. for 5 min
  6. temperatureto warm up to room temperature
  7. stirringstirred for an additional 3 h
  8. washwashed with satd
  9. dry with materialNaHCO3(aq) and brine, dried over MgSO4
  10. concentrationconcentrated in vacuo
  11. dissolutionThe crude solids were dissolved in MeOH
  12. custompurified by preparative HPLC (50 mM NH4OAc(aq), acetonitrile solvent system)
  13. customThe product was isolated by lyophilization of pure fractions

Sources & evidence

ORD record
ord-2f17b0842379449ab97817c2534b4c29
Source dataset
uspto-grants-2011_09
Patent number
US08013156B2

Reaction notes

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