Tetrahydrofuran → HCID 67055040, compound

HRID 1772835Notes

Reaction equation

HRID 1772835 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.C1COCC1.Cl.[CH3:50][O:51][CH2:52][CH:53]1[CH2:58][NH:57][CH2:56][CH2:55][N:54]1[CH2:59][CH:60]([N:64]1[CH:68]=[C:67]([C:69]2[C:70]3[CH:77]=[CH:76][N:75]([CH2:78][O:79][CH2:80][CH2:81][Si:82]([CH3:85])([CH3:84])[CH3:83])[C:71]=3[N:72]=[CH:73][N:74]=2)[CH:66]=[N:65]1)[CH2:61][C:62]#[N:63]>>[C:62]([CH2:61][CH:60]([N:64]1[CH:68]=[C:67]([C:69]2[C:70]3[CH:77]=[CH:76][N:75]([CH2:78][O:79][CH2:80][CH2:81][Si:82]([CH3:84])([CH3:83])[CH3:85])[C:71]=3[N:72]=[CH:73][N:74]=2)[CH:66]=[N:65]1)[CH2:59][N:54]1[CH2:55][CH2:56][N:57]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:12])=[O:9])[CH2:58][CH:53]1[CH2:52][O:51][CH3:50])#[N:63]

Participants

6

Reactant 5

HCID 8028TetrahydrofuranHCID 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 67055049HCID 67055049, compound

Product 1

HCID 67055040HCID 67055040, compound

Procedure

4-cyano-2-fluorobenzoic acid (24.2 mg, 0.146 mmol, Alfa Aesar), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (51.7 mg, 0.136 mmol) and triethylamine (87.4 μL, 0.627 mmol) in THF (1.3 mL, 16 mmol) was stirred at RT for 15 min. Following this, 4-[2-(methoxymethyl)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 (0.061 g, 0.10 mmol, as a mixture of diastereomers from Step 4) was added. After 1 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 0.1N NaOH and brine, dried over sodium sulfate, decanted and concentrated. The product was purified by preparative HPLC-MS, (C18 eluting with a gradient of H2O/MeCN/0.1% TFA. After removing solvent in vacuo, the residue was dissolved in saturated sodium bicarbonate and DCM. The aqueous phase was extracted with a further portion of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated under high vacuum to afford product as a mixture of diastereomers (55 mg, 80%). The diastereomers were partially separated using chiral HPLC (Phenomenex Lux Cellulose-1, 20×250 mm, 5 micron particle size, 30% ethanol in hexane, 20 mL/min, 8 mg/injection). Retention time of Peak 1: 32.84 min, retention time of peak 2: 37.30 min, retention time of peak 3: 45.74 min (contains two isomers).

Workup

  1. additionas a mixture of diastereomers from Step 4)
  2. additionwas added
  3. customthe reaction mixture was partitioned between ethyl acetate and water
  4. washThe organic layer was washed with water, 0.1N NaOH and brine
  5. dry with materialdried over sodium sulfate
  6. customdecanted
  7. concentrationconcentrated
  8. customThe product was purified by preparative HPLC-MS
  9. wash(C18 eluting with a gradient of H2O/MeCN/0.1% TFA
  10. customAfter removing solvent in vacuo
  11. dissolutionthe residue was dissolved in saturated sodium bicarbonate
  12. extractionThe aqueous phase was extracted with a further portion of DCM
  13. dry with materialThe combined extracts were dried over sodium sulfate
  14. customdecanted
  15. concentrationconcentrated under high vacuum
  16. customto afford product
  17. additionas a mixture of diastereomers (55 mg, 80%)
  18. customThe diastereomers were partially separated
  19. custom32.84 min, retention time of peak 2
  20. custom37.30 min, retention time of peak 3
  21. custom45.74 min (contains two isomers)

Sources & evidence

ORD record
ord-1dfebe8fb329494fbafe15dd7cae1d93
Source dataset
uspto-grants-2016_02
Patent number
US09249145B2

Reaction notes

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