Trifluoroacetic acid → HCID 86719387, compound

HRID 2175651Notes

Reaction equation

HRID 2175651 reaction equation
[CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8]([OH:10])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Cl:18][C:19]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][CH3:43])[CH:37]=2)[C:22]2[N:23]=[CH:24][N:25]=[C:26]([NH:27]C(=O)OC(C)(C)C)[C:21]=2[C:20]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1.C(O)(C(F)(F)F)=O>CC#N.CN(C=O)C>[NH2:27][C:26]1[C:21]2[C:20]([C:44]3[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=3)=[C:19]([Cl:18])[N:35]([C:36]3[CH:37]=[C:38]([N:42]([CH3:43])[C:8](=[O:10])/[CH:7]=[CH:6]/[CH2:5][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:11])[CH:39]=[CH:40][CH:41]=3)[C:22]=2[N:23]=[CH:24][N:25]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 65578Oxalyl chlorideHCID 62344125HCID 62344125, compoundHCID 86719386HCID 86719386, compound

Product 1

HCID 86719387HCID 86719387, compoundYield 39%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

A suspension of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (110 mg, 0.34 mmol) in dry MeCN (5.0 mL) was cooled to 0° C. Oxalyl chloride (0.5 mL, 0.69 mmol) and one drop of DMF were added, respectively. The resulting mixture was stirred at 0° C. for 2 hrs. After the suspension was gradually turned into a clear solution, the solvents were removed under reduced pressure (below 35° C.). Dry DCM (5.0 mL) was added and evaporated to remove excess oxalyl chloride. The freshly generated acid chloride was dissolved in dry DCM (5.0 mL) was added dropwise to a solution of tert-butyl 6-chloro-5-(4-chlorophenyl)-7-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbamate (22) (81 mg, 0.18 mmol). After the resulting mixture was stirred at r.t. for 1 hr, TFA (2.0 mL) was introduced. Stirring was continued for 30 min before it was finally quenched with MeOH (1.0 mL). The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3H2O)) to afford (E)-N-(3-(4-amino-6-chloro-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide (23) (34 mg, 39% yield) as a white solid. LC-MS (ESI): m/z (M/M+2) 521.2/523.1. 1H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.53-7.43 (m, 5H), 6.75-6.63 (m, 1H), 6.24 (br, 1H), 6.09-5.96 (m, 1H), 3.29 (s, 3H), 3.11 (d, J=6.2 Hz, 2H), 2.10 (s, 3H), 1.63-1.54 (m, 1H), 0.38-0.26 (m, 2H), 0.25-0.15 (m, 2H).

Workup

  1. customthe solvents were removed under reduced pressure (below 35° C.)
  2. additionDry DCM (5.0 mL) was added
  3. customevaporated
  4. customto remove excess oxalyl chloride
  5. dissolutionThe freshly generated acid chloride was dissolved in dry DCM (5.0 mL)
  6. stirringAfter the resulting mixture was stirred at r.t. for 1 hr
  7. stirringStirring
  8. waitwas continued for 30 min before it
  9. customwas finally quenched with MeOH (1.0 mL)
  10. concentrationThe reaction mixture was concentrated under reduced pressure
  11. customThe residue was purified by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3H2O))

Sources & evidence

ORD record
ord-8464e72565b242caa19246999b3653c9
Source dataset
uspto-grants-2015_06
Patent number
US09062058B2

Reaction notes

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