Lithium Chloride → Tert-butyl 2-(3-(3-chloro-4-(2-hydroxyethyl)phenyl)ureido)cyclohexylcarbamate

HRID 1023860Notes

Reaction equation

HRID 1023860 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16](=[O:31])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=[O:26])=[C:20]([Cl:30])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Li+].[Cl-]>C1COCC1.CCO>[Cl:30][C:20]1[CH:19]=[C:18]([NH:17][C:16](=[O:31])[NH:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:23]=[CH:22][C:21]=1[CH2:24][CH2:25][OH:26]

Participants

5

Reactant 3

HCID 433294Lithium ChlorideHCID 4311764Sodium borohydrideHCID 67204990Ethyl 2-(4-(3-(2-(tert-butoxycarbonylamino)cyclohexyl)ureido)-2-chlorophenyl)acetate

Product 1

HCID 67206716Tert-butyl 2-(3-(3-chloro-4-(2-hydroxyethyl)phenyl)ureido)cyclohexylcarbamate

Reagents, catalysts & solvents 1

HCID 21873804Tetrahydrofuran ethanolSolvent

Procedure

To a solution of ethyl 2-(4-(3-(2-(tert-butoxycarbonylamino)cyclohexyl)ureido)-2-chlorophenyl)acetate (452 mg, 0.996 mmol) in a mixture of THF:EtOH (1:2, 12 mL) at room temperature, was added NaBH4 (124 mg, 3.29 mmol) and LiCl (139 mg, 3.29 mmol). The reaction mixture was stirred overnite. The solvents were distilled off and the crude was diluted with saturated aqueous NH4Cl (20 mL), the product was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent distilled off under reduced pressure. The crude product was purified by flash column chromatography to separate cis 964 mg, 0.155 mmol) and trans (83 mg, 0.201 mmol) diastereomers. These alcohols were converted into tosylates using general procedure for the preparation of tosylates. 1H NMR (cis): 1.23-1.26 (m, 3H), 1.36 (s, 9H), 1.70-1.74 (m, 2H), 1.99-2.06 (m, 2H), 2.41-2.43 (m, 1H), 2.92 (t, 2H, J=6.4 Hz), 3.25-3.29 (m, 1H), 3.51-3.54 (m, 1H), 3.83-3.86 (m, 2H), 5.03 (d, 1H, J=8.8 Hz), 5.62 (d, 1H, J=8.4 Hz), 7.04 (d, 1H, J=8.4 Hz), 7.09 (d, 1H, J=8 Hz), 7.32 (s, 2H). 1H NMR (trans): 1.26-1.29 (m, 1H), 1.37-1.42 (m, 12H), 1.69-1.72 (m, 2H), 1.97 (s, 1H), 2.53-2.55 (m, 1H), 2.85 (t, 2H, J=6.4 Hz), 3.75-3.77 (m, 3H), 3.97-3.99 (m, 1H), 5.15 (br s, 1H), 5.86 (br s, 1H), 6.98-7.05 (m, 2H), 7.30 (s, 1H), 7.41 (s, 2H).

Workup

  1. distillationThe solvents were distilled off
  2. additionthe crude was diluted with saturated aqueous NH4Cl (20 mL)
  3. extractionthe product was extracted with ethyl acetate (2×20 mL)
  4. dry with materialThe combined organic extracts were dried over Na2SO4
  5. distillationthe solvent distilled off under reduced pressure
  6. customThe crude product was purified by flash column chromatography
  7. customto separate cis 964 mg, 0.155 mmol) and trans (83 mg, 0.201 mmol) diastereomers
  8. customThese alcohols were converted into tosylates using general procedure for the preparation of tosylates

Sources & evidence

ORD record
ord-2cf8acc454574a6f8fa4b384e0ae93bf
Source dataset
uspto-grants-2014_05
Patent number
US08722720B2

Reaction notes

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