Isopropyl Acetate → Imidazo[1,2-a]pyrimidine-5-carboxylic acid (adamantan-1-ylmethyl)-amide

HRID 1971257Notes

Reaction equation

HRID 1971257 reaction equation
Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.Cl.[C:12]12(NC)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[Cl-].Cl[C:26]1N(C)CC[N+:27]=1[CH3:32].[OH-].[Na+].C([O:38]C(C)=O)(C)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].C(#N)C.O.CN(C=O)C>[C:12]12([CH2:32][NH:27][C:26]([C:2]3[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[N:5]=[CH:4][CH:3]=3)=[O:38])[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2

Participants

12

Reactant 5

HCID 7915Isopropyl AcetateHCID 14798Sodium HydroxideHCID 19477N-methyladamantan-1-amine hydrochlorideHCID 101763062-Chloro-1,3-dimethylimidazolinium chlorideHCID 469120805-Chloroimidazo[1,2-a]pyrimidine

Product 1

HCID 59451925Imidazo[1,2-a]pyrimidine-5-carboxylic acid (adamantan-1-ylmethyl)-amide

Reagents, catalysts & solvents 6

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
120 °C

Procedure

In a ½ dram vial, 5-chloro-imidazo[1,2-a]pyrimidine (20.2 mg, 0.13 mmol), Zn(CN)2 (9.3 mg, 0.079 mmol), Pd2(dba)3 (3.0 mg, 0.003 mmol) and DPPF (3.6 mg, 0.006 mmol) are treated with DMF (300 μL) and H2O (3 μl). The vial is flushed and then sealed under argon and heated to 120° C. overnight. At RT, the vial is treated with NaOH (1M, 0.5 mL) and i-PrOAc (0.5 mL), and the upper organic layer is purified via strong cation exchange chromatography. The base-eluted solution is concentrated to dryness and treated with HCl (conc., 0.1 mL) and shaken at RT for 1 h and then at 100° C. for an additional 1 h. The reaction is concentrated to dryness under a stream of nitrogen and treated with adamantan-1-yl-methylamine hydrochloride (8.1 mg, 0.040 mmol), TEA (10% (v/v) ACN, 200 μL), and 2-chloro-1,3-dimethyl-4,5-dihydro-3H-imidazolium chloride (0.2 M ACN, 200 μL, 0.040 mmol). The reaction is sealed under nitrogen and shaken at RT for 1 h. NaOH (1M, 0.5 mL) and i-PrOAc (0.5 mL) are added, and the upper organic layer is removed and concentrated to dryness. The residue is purified via silica gel chromatography using EtOAc followed by TEA/MeOH/EtOAc (2.5:2.5:95% v/v/v) to afford the title compound. NMR (400 MHz, CDCl3) δ 1.59 (m, 6H), 1.64 (m, 3H), 1.72 (m, 3H), 1.99 (m, 3H), 3.18 (d, J=6.4, 2H), 7.68 (d, J=1.2, 1H), 7.83 (d, J=6.8, 1H), 7.99 (d, J=1.6, 1H), 8.12 (bs, 1H), 8.58 (d, J=6.8, 1H).

Workup

  1. customThe vial is flushed
  2. customsealed under argon
  3. additionAt RT, the vial is treated with NaOH (1M, 0.5 mL) and i-PrOAc (0.5 mL)
  4. customthe upper organic layer is purified via strong cation exchange chromatography
  5. concentrationThe base-eluted solution is concentrated to dryness
  6. additiontreated with HCl (conc., 0.1 mL)
  7. waitat 100° C. for an additional 1 h
  8. concentrationThe reaction is concentrated to dryness under a stream of nitrogen
  9. customThe reaction is sealed under nitrogen
  10. stirringshaken at RT for 1 h
  11. customthe upper organic layer is removed
  12. concentrationconcentrated to dryness
  13. customThe residue is purified via silica gel chromatography

Sources & evidence

ORD record
ord-7347959fe1b54d0dbd44bd91dc69f56b
Source dataset
uspto-grants-2013_04
Patent number
US08431593B2

Reaction notes

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