tert-butyl N-(2-(methoxy(methyl)carbamoyl)ethyl)carbamate → 3-Amino-1-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}-1-propanone

HRID 565371Notes

Reaction equation

HRID 565371 reaction equation
[C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(OC([NH:41][CH2:42][CH2:43][C:44](N(OC)C)=[O:45])=O)(C)(C)C>C1COCC1>[NH2:41][CH2:42][CH2:43][C:44]([C:21]1[N:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)[CH2:19][CH2:18]2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)=[O:45]

Participants

5

Reactant 3

HCID 10823469tert-butyl N-(2-(methoxy(methyl)carbamoyl)ethyl)carbamateHCID 225621971-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazoleHCID 178418339Butyllithium

Product 1

HCID 212681083-Amino-1-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}-1-propanoneYield 74%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole (Example 12, 66.3 mg, 0.178 mmol) in THF(4 ml) was added n-butyllithium (1.54M solution in hexane, 0.923 ml, 1.42 mmol) at −78° C. After 1 h stirring at −78° C., a solution of 3-t-butoxycarbonylamino-N-methoxy-N-methylpropionamide (140 mg, 0.604 mmol, this was prepared according to the reported procedure: G. Bitan et al, J. Chem. Soc., Perkin Trans. 1, 1997, 1501-1510) in THF (1.5 ml) was added to the reaction mixture at −78° C. After 0.5 h stirring at −78° C. and 15 h stirring at ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (1 mm plate×3, n-hexane/acetone: 5/1, 6 times developed) to give 71.7 mg (74%) of pale brown amorphous solid. This solid (70 mg, 0.131 mmol) was dissolved in HCl solution in MeOH (10 ml). After evaporation of the solvent, the residue was dried in vacuo at 45° C. for 18 h to afford 60 mg (89%) of pale brown amorphous solid.

Workup

  1. stirringAfter 0.5 h stirring at −78° C. and 15 h
  2. stirringstirring at ambient temperature
  3. customthe reaction mixture was quenched with water
  4. extractionextracted with ethyl acetate
  5. washThe extracts combined were washed with brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by preparative TLC (1 mm plate×3, n-hexane/acetone: 5/1, 6 times developed)

Sources & evidence

ORD record
ord-f6df9f2d26bc4cd08afcc80d5ff3a75d
Source dataset
uspto-grants-2001_01
Patent number
US06172067B2

Reaction notes

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