Ethyl Acetate → tert-butyl 3-(9-isopropyl-6((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 928170Notes

Reaction equation

HRID 928170 reaction equation
Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][CH2:31][CH:30]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH3:3].[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:31]1[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:29][CH:30]=1)=[N:3][C:4]=2[NH:14][C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1)([CH3:13])[CH3:12]

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 62657Potassium Phosphate, TribasicHCID 49835909Tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 118073689HCID 118073689, compound

Product 2

HCID 222AmmoniaHCID 118073695tert-butyl 3-(9-isopropyl-6((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylateYield 205.5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-chloro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (600 mg, 2 mmol), as prepared in step 1 of Example 2, tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 2.3 mmol, 1.1 mol eq), tripotassium phosphate (1.11 g, 5.1 mmol, 2.5 mol eq), PdCl2(dppf) (75 mg, 0.1 mmol, 0.05 mol eq) in dioxane (10 mL) and water (5 mL) was degassed, stirred and heated at 80° C. (using microwave at normal absorption level) for 30 min. The reaction was then diluted with ethyl acetate (120 mL), washed with brine (20 mL), dried over Na2SO4 and evaporated to give a residue that was purified via flash chromatography with gradients from 50% ethyl acetate-50% heptane to 100% ethyl acetate and then to 10% ammonia (7 N in methanol)-90% ethyl acetate to give the title product as a red solid (901 mg, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.89 (s, 1 H) 8.29 (s, 1 H) 8.00 (br. s., 1 H) 7.79 (br. s., 1 H) 7.22 (br. s., 1 H) 4.77 (dt, J=13.39, 6.76 Hz, 1 H) 4.45 (br. s., 2 H) 3.84 (s, 3 H) 3.50 (t, J=5.38 Hz, 2 H) 2.36 (d, J=3.18 Hz, 2 H) 1.57 (d, J=6.72 Hz, 6 H) 1.44 (s, 9 H). m/z (APCI+) for C22H30N8O2 439.3 (M+H)+.

Workup

  1. customwas degassed
  2. additionThe reaction was then diluted with ethyl acetate (120 mL)
  3. washwashed with brine (20 mL)
  4. dry with materialdried over Na2SO4
  5. customevaporated
  6. customto give a residue that
  7. customwas purified via flash chromatography with gradients from 50% ethyl acetate-50% heptane to 100% ethyl acetate

Sources & evidence

ORD record
ord-71ebbbf7f0974db696dfcbc783da0c2d
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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