Trifluoroacetic acid → HCID 118207768, compound

HRID 2205606Notes

Reaction equation

HRID 2205606 reaction equation
C(O)(C(F)(F)F)=O.[NH2:8][C@H:9]([C:11]1[N:16]=[C:15]2[CH:17]=[CH:18][N:19]([CH3:20])[C:14]2=[CH:13][C:12]=1[N:21]1[CH2:25][CH2:24][CH:23]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:22]1)[CH3:10].C([O-])(O)=O.[Na+].[NH2:42][C:43]1[N:48]=[C:47](Cl)[C:46]([C:50]#[N:51])=[C:45]([CH3:52])[N:44]=1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[NH2:42][C:43]1[N:48]=[C:47]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:25][CH2:24][C@H:23]([N:26]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])[CH2:22]2)[CH3:10])[C:46]([C:50]#[N:51])=[C:45]([CH3:52])[N:44]=1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 754124462-Amino-4-chloro-6-methyl-5-pyrimidinecarbonitrileHCID 118207741HCID 118207741, compound

Product 1

HCID 118207768HCID 118207768, compound

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

A TFA salt of 2-(1-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidin-3-yl)isoindoline-1,3-dione (110 mg, 0.218 mmol) was partitioned between saturated NaHCO3 and EtOAc. The aqueous and organic phases were separated and the aqueous layer was extracted with EtOAc (2×). The organic layers were combined, dried over MgSO4, and filtered, and then concentrated in a 50 mL pear flask. To this residue was added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (55.2 mg, 0.328 mmol) in DMSO (1.1 mL) followed by triethylamine (152 μL, 1.09 mmol). The mixture was heated to 85° C. for 3 hours and then partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by preparative HPLC (acid mode, 50-55% ACN/water gradient) to give the title diastereomers. Peak 1 (shorter retention time, 30 mg, 26%): 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (d, J=6.57 Hz, 3H), 2.33-2.40 (m, 3H), 2.40-2.60 (m, 2H), 3.31-3.48 (m, 3H), 3.70 (t, J=8.34 Hz, 1H), 3.76-3.83 (m, 3H), 5.09-5.22 (m, 1H), 5.28 (s, 2H), 5.87-5.96 (m, 1H), 6.66 (dd, J=3.28, 0.76 Hz, 1H), 7.20-7.25 (m, 2H), 7.57 (s, 1H), 7.71-7.79 (m, 2H), 7.84-7.92 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C28H27N9O2, 522. found 522. Peak 2 (longer retention time, 12 mg, 11%): ESI-MS m/z [M+H]+ calc'd for C28H27N9O2, 522. found 522.

Workup

  1. customThe aqueous and organic phases were separated
  2. extractionthe aqueous layer was extracted with EtOAc (2×)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated in a 50 mL pear flask
  6. custompartitioned between saturated NaHCO3 and ethyl acetate
  7. extractionThe aqueous layer was extracted with ethyl acetate
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude product was purified by preparative HPLC (acid mode, 50-55% ACN/water gradient)
  12. customto give the title diastereomers

Sources & evidence

ORD record
ord-97901a251017416185776450c618c32e
Source dataset
uspto-grants-2016_06
Patent number
US09371321B2

Reaction notes

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