Triethylamine → HCID 67055039, compound

HRID 1772810Notes

Reaction equation

HRID 1772810 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.[CH3:45][C@@H:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1[CH2:52][CH:53]([N:57]1[CH:61]=[C:60]([C:62]2[C:63]3[CH:70]=[CH:69][N:68](COCC[Si](C)(C)C)[C:64]=3[N:65]=[CH:66][N:67]=2)[CH:59]=[N:58]1)[CH2:54][C:55]#[N:56]>C1COCC1>[C:55]([CH2:54][CH:53]([N:57]1[CH:61]=[C:60]([C:62]2[C:63]3[CH:70]=[CH:69][NH:68][C:64]=3[N:65]=[CH:66][N:67]=2)[CH:59]=[N:58]1)[CH2:52][N:47]1[CH2:48][CH2:49][N:50]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:12])=[O:9])[CH2:51][C@H:46]1[CH3:45])#[N:56]

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 67054921HCID 67054921, compound

Product 1

HCID 67055039HCID 67055039, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-cyano-2-fluorobenzoic acid (50.4 mg, 0.305 mmol, Alfa Aesar), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (107 mg, 0.282 mmol) and triethylamine (196 uL, 1.41 mmol) in THF (2.8 mL) was stirred for 15 minutes, followed by the addition of the diastereomeric 4-[(2R)-2-methylpiperazin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride salt (130 mg, 0.23 mmol). After stirring for 2 hours, the reaction was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. To separate diastereomers, preparative HPLC-MS was used: Waters mass directed fractionation system, Waters SunFire C18 column, 5 μm particle size, 30×100 mm, mobile phase system: Aq(0.1% TFA)/AcN; flow rate 60 mL/min; separating gradient: 30.4-48.4% B in 12 minutes. Peak 1 (first to elute), and Peak 2 (second to elute) were subjected to the deprotection step separately: stirred for 1 hour in a 1:1 mixture of DCM/TFA, concentrated, then stirred for 30 minutes in a solution of ethylenediamine (0.2 mL) in methanol (1.5 mL). Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product (peak 1: 19 mg, peak 2: 23 mg, total 36% of theoretical). Peak 1: 1H NMR (400 MHz, d6-dmso) (rotamers): δ 12.11 (br s, 1H), 8.81 (d, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.99-7.93 (m, 1H), 7.79-7.68 (m, 1H), 7.62-7.54 (m, 2H), 6.97 (dd, 1H), 4.93-4.83 (m, 1H), 3.85-3.66 (m, 1H), 3.36-2.08 (m, 10H), 0.90 and 0.71 ((each as d) together=3H); LCMS (M+H)+: 498.1. Peak 2: 1H NMR (400 MHz, d6-dmso) (rotamers): δ □12.08 (br s, 1H), 8.82 (d, 1H), 8.68 (d, 1H), 8.37 (d, 1H), 8.01-7.93 (m, 1H), 7.80-7.71 (m, 1H), 7.63-7.54 (m, 2H), 6.98 (t, 1H), 4.94-4.81 (m, 1H), 3.87-2.26 (m, 11H), 1.05 and 0.87 ((each as d) together=3H); LCMS (M+H)+: 498.1.

Workup

  1. stirringAfter stirring for 2 hours
  2. customthe reaction was partitioned between ethyl acetate and water
  3. washThe organic layer was washed successively with water, 0.1 N NaOH and brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. customTo separate diastereomers, preparative HPLC-MS
  7. customseparating gradient
  8. wait30.4-48.4% B in 12 minutes
  9. washPeak 1 (first to elute), and Peak 2 (second to elute)
  10. stirringstirred for 1 hour in a 1:1 mixture of DCM/TFA
  11. concentrationconcentrated
  12. stirringstirred for 30 minutes in a solution of ethylenediamine (0.2 mL) in methanol (1.5 mL)
  13. customPurification via preparative HPLC-MS
  14. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product (peak 1: 19 mg, peak 2: 23 mg, total 36% of theoretical)

Sources & evidence

ORD record
ord-bcfe30681b884754b6cab7c0892730ed
Source dataset
uspto-grants-2016_02
Patent number
US09249145B2

Reaction notes

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