Hydrochloric Acid → HCID 66877523, compound

HRID 1993875Notes

Reaction equation

HRID 1993875 reaction equation
[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]([CH3:30])([CH3:29])[C:26](O)=O.Cl.[OH-].[NH4+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>O.C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[N:22]=[C:26]2[C:25]([OH:24])([CH3:30])[CH3:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 116712-Hydroxyisobutyric acidHCID 14923Ammonium HydroxideHCID 90495Di-tert-butyl dicarbonateHCID 178453997HCID 178453997, compound

Product 1

HCID 66877523HCID 66877523, compoundYield 40.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
110 °C

Procedure

To a mixture of cis-[4-(2-amino-4-chloro-phenylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.25 g, 3.67 mmol, prepared from 1-chloro-4-fluoro-3-nitrobenzene and tert-butyl cis-4-aminocyclohexanecarbamate) and 2-hydroxyisobutyric acid (2.7 g, 25.9 mmol) in water (5 mL) was added concentrated hydrochloric acid (3.25 mL, 40 mmol). The mixture was stirred and heated at 110° C. for 2 days. The dark colored solution was treated with ammonium hydroxide (15 mL, 225 mmol) and extracted with methylene chloride. The organic layer was washed with brine and dried over sodium sulfate. After the evaporation of solvents, a red colored solid was obtained (1.1 g). This material was dissolved in THF (20 mL) and treated with di-tert-butyl-dicarbonate (950 mg, 4.3 mmol). The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was purified through flash column chromatography using ethyl acetate and hexanes (1:4) to give [4-(5-chloro-2-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl)-cyclohexyl]-carbamic acid tert-butyl ester (600 mg). This compound was dissolved in methylene chloride (4 mL) and trifluoroacetic acid (1 mL) was added. The solution was stirred at room temperature for 1 hr. Solvents were evaporated and the residue was extracted with methylene chloride and sodium hydroxide solution (1N). The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was dissolved in methylene chloride and treated with hydrogen chloride in dioxane (4M). Solvents were evaporated and the residue was triturated with ether. The purple solid was filtered to give a hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol. 1H-NMR (CD3OD) □ 7.96 (d, 1H), 7.57 (s, 1H), 7.21 (d, 1H), 5.34 (m, 1H), 2.61 (m, 2H), 1.72-1.89 (m, 13H).

Workup

  1. extractionextracted with methylene chloride
  2. washThe organic layer was washed with brine
  3. dry with materialdried over sodium sulfate
  4. customAfter the evaporation of solvents
  5. customa red colored solid was obtained (1.1 g)
  6. stirringThe mixture was stirred at room temperature overnight
  7. customSolvents were evaporated
  8. customthe residue was purified through flash column chromatography

Sources & evidence

ORD record
ord-be4a7dcb004945549b1ebe67626feb04
Source dataset
uspto-grants-2010_01
Patent number
US07652053B2

Reaction notes

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