Dimethylformamide dimethyl acetal → tert-Butyl 4-{5-[2-(methylamino)pyrimidin-4-yl]-4-phenyl-1H-imidazol-1-yl}piperidine-1-carboxylate

HRID 1896662Notes

Reaction equation

HRID 1896662 reaction equation
[C:1]([C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=[N:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)[CH3:2].C(C1[N:35]([CH:36]2CN(C(OC(C)(C)C)=O)C2)[CH:34]=[N:33][C:32]=1C1C=CC(F)=CC=1)(=O)C.[NH2:54]C1CCN(C(OC(C)(C)C)=O)CC1.[N+](C(C1C=CC=CC=1)S(C1C=CC(C)=CC=1)(=O)=O)#[C-].FC1C=CC(C([N+]#[C-])S(C2C=CC(C)=CC=2)(=O)=O)=CC=1.COC(OC)N(C)C.[Na].Cl.CNC(N)=N.C[O-].[Na+]>O.CO>[CH3:36][NH:35][C:34]1[N:54]=[C:1]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]3)[CH:7]=[N:6][C:5]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:32][N:33]=1

Participants

12

Reactant 9

HCID 78373Dimethylformamide dimethyl acetalHCID 12682914-Amino-1-Boc-piperidineHCID 5360545SodiumHCID 10827289a-Tosyl-(4-fluorobenzyl) isocyanideHCID 10942334Sodium MethoxideHCID 10967613a-Tosylbenzyl isocyanideHCID 57461730tert-Butyl 3-[5-acetyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]azetidine-1-carboxylateHCID 58235101tert-butyl 4-(5-acetyl-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylateHCID 178485118HCID 178485118, compound

Product 1

HCID 58235109tert-Butyl 4-{5-[2-(methylamino)pyrimidin-4-yl]-4-phenyl-1H-imidazol-1-yl}piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of tert-butyl 4-(5-acetyl-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate [C24, prepared according to the general procedure for the synthesis of tert-butyl 3-[5-acetyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]azetidine-1-carboxylate (C3) in Example 1, except that tert-butyl 4-aminopiperidine-1-carboxylate was used in place of tert-butyl 3-aminoazetidine-1-carboxylate, and 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (C21) was employed rather than 1-fluoro-4-{isocyano[(4-methylphenyl)sulfonyl]methyl}benzene (C2)] (414 mg, 1.12 mmol) and N,N-dimethylformamide dimethyl acetal (4 mL) was heated to 100° C. for 18 hours, then cooled and concentrated in vacuo. The residue was dissolved in anhydrous methanol (2 ml) and added to a solution of N-methylguanidine in methanol [prepared by reacting sodium metal (70 mg, 3 mmol) with anhydrous methanol (2 mL), then adding N-methylguanidine hydrochloride (413 mg, 3.77 mmol) to the resulting sodium methoxide solution]. The reaction mixture was heated at 50° C. for 21 hours, then cooled to room temperature and treated with water (1 mL). The solids were collected by filtration, rinsed with saturated aqueous sodium bicarbonate solution and water and dried to provide the product as a light tan solid. Yield: 230 mg, 0.53 mmol, 47%. APCI m/z 435.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 1.82-1.93 (m, 2H), 2.19 (br d, J=12 Hz, 2H), 2.73-2.82 (m, 2H), 3.06 (d, J=5.1 Hz, 3H), 4.26-4.35 (m, 2H), 4.81-4.90 (m, 1H), 5.16-5.21 (m, 1H), 6.45 (d, J=5.1 Hz, 1H), 7.28-7.34 (m, 3H), 7.48-7.51 (m, 2H), 7.75 (s, 1H), 8.15 (br d, J=4.9 Hz, 1H).

Workup

  1. customprepared
  2. temperaturecooled
  3. concentrationconcentrated in vacuo
  4. dissolutionThe residue was dissolved in anhydrous methanol (2 ml)
  5. additionadded to a solution of N-methylguanidine in methanol [
  6. customprepared
  7. temperatureThe reaction mixture was heated at 50° C. for 21 hours
  8. temperaturecooled to room temperature
  9. filtrationThe solids were collected by filtration
  10. washrinsed with saturated aqueous sodium bicarbonate solution and water
  11. customdried

Sources & evidence

ORD record
ord-d3982063a6af4309867da9f29a576f42
Source dataset
uspto-grants-2013_08
Patent number
US08518944B2

Reaction notes

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