Potassium Carbonate → tert-butyl 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

HRID 1913452Notes

Reaction equation

HRID 1913452 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20](Br)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[K+].Cl[C:33]1[N:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][N:34]=1.C([O-])([O-])=O.[K+].[K+]>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].O1CCOCC1>[CH2:39]([C:36]1[CH:35]=[N:34][C:33]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[C@H:15]([N:13]2[CH2:14][C:11]4([CH2:25][CH2:26][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[CH2:12]2)[CH2:16][CH2:17]3)=[N:38][CH:37]=1)[CH3:40]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 35727632-Chloro-5-ethylpyrimidineHCID 53392276tert-Butyl (R)-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Product 1

HCID 58438491tert-butyl 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylateYield 92%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To an oven-dried round-bottomed flask was added (R)-tert-butyl-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 600 mg, 1.42 mmol), bispinacolatodiboron (398 mg, 1.71 mmol), 559 mg potassium acetate (559 mg, 5.70 mmol) and anhydrous dioxane (20 mL). The resulting mixture was purged with nitrogen (3×). Pd(dppf)Cl2 (58.0 mg, 0.07 mmol) was added and the reaction mixture was purged with nitrogen (3×). The reaction was heated under nitrogen at 110° C. for 4 hours at which time LCMS showed conversion to the desired boronate intermediate. Pd(dppf)Cl2 catalyst (58.0 mg, 0.07 mmol), 2-chloro-5-ethylpyrimidine (224 mg, 1.57 mmol) and aqueous K2CO3 solution (de-oxygenated with nitrogen for 15 minutes prior to addition, 2M, 5.0 mL) were added to the reaction mixture. The reaction was purged with nitrogen (3×) and heated for 6 hours at 110° C. The reaction was cooled to room temperature and the dioxane solvent was removed under reduced pressure. The residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1N NaOH solution. The organic layer was washed with 100 mL of brine, dried (Na2SO4) and concentrated to afford thecrude product as a dark brown oil. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column, eluted with 0-10% MeOH in CH2Cl2 over 20 minutes to afford 583 mg (92%) of the desired product (3-1b) as a brown foam. MS (ES+) 449.5 (M+H)+. 1H NMR (CDCl3) δ 1.23 (t, 3H), 1.40 (s, 9H), 1.56-1.67 (m, 4H), 1.83-1.91 (m, 1H), 2.07-2.16 (m, 1H), 2.59 (q, 2H), 2.76-2.85 (m, 1H), 2.99-3.13 (m, 5H), 3.24-3.31 (m, 4H), 3.91 (dd, 1H), 7.27-7.34 (m, 1H), 8.17-8.23 (m, 2H), 8.56 (s, 2H).

Workup

  1. customThe resulting mixture was purged with nitrogen (3×)
  2. customthe reaction mixture was purged with nitrogen (3×)
  3. additionto addition, 2M, 5.0 mL)
  4. additionwere added to the reaction mixture
  5. customThe reaction was purged with nitrogen (3×)
  6. temperatureheated for 6 hours at 110° C
  7. temperatureThe reaction was cooled to room temperature
  8. customthe dioxane solvent was removed under reduced pressure
  9. customThe residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1N NaOH solution
  10. washThe organic layer was washed with 100 mL of brine
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated
  13. customto afford thecrude product as a dark brown oil
  14. customThe crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column
  15. washeluted with 0-10% MeOH in CH2Cl2 over 20 minutes

Sources & evidence

ORD record
ord-94ac2c02f2a74ee88fd5803622f05234
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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