Triethylamine → HCID 67055048, compound

HRID 1772842Notes

Reaction equation

HRID 1772842 reaction equation
[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[F:45][CH:46]([F:80])[CH:47]1[CH2:52][NH:51][CH2:50][CH2:49][N:48]1[CH2:53][CH:54]([N:58]1[CH:62]=[C:61]([C:63]2[C:64]3[CH:71]=[CH:70][N:69]([CH2:72][O:73][CH2:74][CH2:75][Si:76]([CH3:79])([CH3:78])[CH3:77])[C:65]=3[N:66]=[CH:67][N:68]=2)[CH:60]=[N:59]1)[CH2:55][C:56]#[N:57]>C1COCC1>[C:56]([CH2:55][CH:54]([N:58]1[CH:62]=[C:61]([C:63]2[C:64]3[CH:71]=[CH:70][N:69]([CH2:72][O:73][CH2:74][CH2:75][Si:76]([CH3:77])([CH3:79])[CH3:78])[C:65]=3[N:66]=[CH:67][N:68]=2)[CH:60]=[N:59]1)[CH2:53][N:48]1[CH2:49][CH2:50][N:51]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:12])=[O:9])[CH2:52][CH:47]1[CH:46]([F:45])[F:80])#[N:57]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 5906594-Cyano-2-fluorobenzoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67273345HCID 67273345, compound

Product 1

HCID 67055048HCID 67055048, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-cyano-2-fluorobenzoic acid (47.0 mg, 0.285 mmol, Alfa Aesar), N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (101 mg, 0.264 mmol) and triethylamine (0.170 mL, 1.22 mmol) in THF (2.5 mL) was stirred at RT for 15 min, and then 4-[2-(difluoromethyl)piperazin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloric acid salt (0.12 g, 0.20 mmol; a mixture of diastereomers from Step 7) was added. The mixture was stirred at RT for 1 h. The reaction was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with water, 0.1N NaOH, and brine; dried over sodium sulfate, decanted and concentrated. Flash chromatography on a 12 g silica gel cartridge, eluting with 0-80% solvent mixture [A] in hexanes ([A]=10% IPA: 50% EtOAc: 40% Hexanes); afforded desired product as a mixture of diastereomers (110 mg, 81%). The isomers were separated by chiral HPLC (Chiral Technologies Chiralcel OD-H, 20×250 mm, eluting with 30% EtOH/Hexanes at a flow rate of 10 mL/min and a loading of 20 mg/injection). Three peaks were obtained: Peak 1 retention time: 26.30 min, 19 mg; Peak 2 retention time: 33.82 min, 49 mg, mixture of 2 isomers; Peak 3 retention time 44.26 min, 29 mg. Peak 1: 1H NMR (300 MHz, CDCl3, rotamers): δ 8.84 (s, 0.4H), 8.83 (s, 0.6H), 8.32 (s, 1H), 8.31 (s, 0.4H), 8.30 (s, 0.6H), 7.79-7.32 (m, 4H), 6.79-6.76 (2d, 1H), 5.96 (td, 0.6H), 5.84 (br t, 0.4H), 5.67 (s, 2H), 4.68-4.55 (m, 1H), 4.51-4.21 (m, 1H), 3.61-0.75 (m, 14H), −0.07 (s, 9H); LCMS (M+H)+: 663.8. Peak 2 (mixture of two isomers and rotamers observed): 1H NMR (300 MHz, CDCl3): δ 8.84 (s, 0.814), 8.83 (s, 1.2H), 8.33 (s, 0.8H), 8.32 (s, 1.2H), 8.30 (s, 2H), 7.54-7.35 (m, 8H), 6.78 (d, 2H), 5.97 (td, 1.2H), 5.91 (td, 0.8H), 5.68 (s, 4H), 4.65-4.51 (m, 2H), 4.24-4.08 (m, 2H), 3.56 (dd, 4H), 3.47-0.80 (m, 24H), −0.07 (s, 18H); LCMS (M+H)+: 663.8. Peak 3: 1H NMR (300 MHz, CDCl3, rotamers): δ 8.84 (s, 0.4H), 8.83 (s, 0.6H), 8.32 (s, 1H), 8.31 (s, 0.4H), 8.30 (s, 0.6H), 7.79-7.32 (m, 4H), 6.79-6.76 (2d, 1H), 5.96 (td, 0.6H), 5.84 (br t, 0.4H), 5.67 (s, 2H), 4.68-4.55 (m, 1H), 4.51-4.21 (m, 1H), 3.61-0.75 (m, 14H), −0.07 (s, 9H); LCMS (M+H)+: 663.8.

Workup

  1. additiona mixture of diastereomers from Step 7)
  2. additionwas added
  3. stirringThe mixture was stirred at RT for 1 h
  4. customThe reaction was partitioned between ethyl acetate and water
  5. customThe layers were separated
  6. washthe organic layer was washed with water, 0.1N NaOH, and brine
  7. dry with materialdried over sodium sulfate
  8. customdecanted
  9. concentrationconcentrated
  10. washFlash chromatography on a 12 g silica gel cartridge, eluting with 0-80% solvent mixture [A] in hexanes ([A]=10% IPA

Sources & evidence

ORD record
ord-edea2698d0b34f8483d09011743a8457
Source dataset
uspto-grants-2016_02
Patent number
US09249145B2

Reaction notes

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