Diisopropylamine → pyridin-3-ylmethyl 3-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}azetidine-1-carboxylate

HRID 1253493Notes

Reaction equation

HRID 1253493 reaction equation
[C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:4]1)#[CH:2].I[C:18]1[CH:19]=[N:20][N:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:24]=[C:23]([O:33][CH3:34])[C:22]=12.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(NC(C)C)(C)C>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].[Cu]I.C(#N)C>[CH3:34][O:33][C:23]1[C:22]2[N:21]([N:20]=[CH:19][C:18]=2[C:2]#[C:1][CH:3]2[CH2:4][N:5]([C:7]([O:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[CH2:6]2)[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[CH:24]=1

Participants

8

Reactant 4

HCID 7912DiisopropylamineHCID 521585Tris(furan-2-yl)phosphaneHCID 44816768HCID 44816768, compoundHCID 77231360HCID 77231360, compound

Product 1

HCID 58404697pyridin-3-ylmethyl 3-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}azetidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
45 °C

Procedure

Pyridin-3-ylmethyl 3-ethynylazetidine-1-carboxylate (50 mg, 0.23 mmol), 3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (40 mg, 0.11 mmol), allylpalladium chloride dimer (12 mg, 0.03 mmol), tri(2-furyl)phosphine (16 mg, 0.07 mmol) and copper (I) iodide (2.1 mg, 0.011 mmol) were combined into one vial fitted with a Teflon septum. The vial was flushed with nitrogen and acetonitrile (1.6 ml) and diisopropylamine (0.048 mL, 0.34 mmol) were added. After sparging with nitrogen for 5 minutes, the reaction was heated to 45° C. for two hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate two times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give pyridin-3-ylmethyl 3-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}azetidine-1-carboxylate. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.58 (s, 1H), 8.50-8.54 (m, 1H), 8.29 (s, 1H), 8.02 (s, 2H), 7.74-7.82 (m, 1H), 7.35-7.43 (m, 1H), 6.94 (s, 1H), 5.09 (s, 2H), 4.12-4.38 (br, 2H), 3.80-3.98 (m, 8H), 3.67-3.76 (m, 1H). LRMS (ESI) calculated for C24H23N6O3 [M+H]+, 443.2; found 443.2.

Workup

  1. additionwere added
  2. customAfter sparging with nitrogen for 5 minutes
  3. temperatureThe mixture was cooled to ambient temperature
  4. additiondiluted with ethyl acetate
  5. washwashed with saturated aqueous sodium bicarbonate
  6. customThe organic layer was separated
  7. extractionthe aqueous layer was back extracted with ethyl acetate two times
  8. dry with materialThe combined organic layers were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by preparative HPLC reverse phase (C-18)
  12. washeluting with acetonitrile/water+0.05% TFA
  13. additionThe fractions containing product
  14. additiondiluted in ethyl acetate
  15. washwashed with aqueous sodium bicarbonate
  16. dry with materialdried over sodium sulfate
  17. filtrationThe solution was filtered
  18. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-aebdf5a983a146278deda0516bf5d86f
Source dataset
uspto-grants-2013_06
Patent number
US08455477B2

Reaction notes

Loading…