tert-butyl N-(4-oxocyclohexyl)carbamate → HCID 178498037, compound

HRID 1050459Notes

Reaction equation

HRID 1050459 reaction equation
[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]([O:18][C:19]([NH:21][CH:22]1[CH2:28][CH2:27][C:25](=O)[CH2:24][CH2:23]1)=[O:20])([CH3:17])[CH3:16].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:15]([O:18][C:19]([NH:21][C@@H:22]1[CH2:28][CH2:27][C@H:25]([NH:1][C:2]2[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:24][CH2:23]1)=[O:20])([CH3:17])([CH3:14])[CH3:16]

Participants

6

Reactant 3

HCID 1512535tert-butyl N-(4-oxocyclohexyl)carbamateHCID 5003444Sodium cyanoborohydrideHCID 68295455Methyl 3-amino-5-chloro-2-methylbenzoate

Product 1

HCID 178498037HCID 178498037, compoundYield 29.1%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent

Procedure

To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (500 mg, 2.505 mmol) and 4-N-Boc-aminocyclohexanone (2.0 g, 9.38 mmol) in methanol (20 mL) was added zinc chloride (1.0 g, 7.34 mmol). The reaction was stirred for 2 h at room temperature, then sodium cyanoborohydride (700 mg, 11.14 mmol) was added portionwise over 2 h. The reaction was then heated to 40° C. and stirred for 24 h. LCMS showed that the reaction was mostly complete (11% starting amine remained with two product peaks 40% and 49% corresponding to the trans and cis products). The reaction was evaporated to dryness, taken up in EtOAc, washed with aq. NH4Cl, 1 N Na2CO3, brine, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, SF25-80 g, 10 to 30% EtOAc in hexanes). The cis-diastereomer was contaminated with 27% of the methyl 3-amino-5-chloro-2-methylbenzoate starting material. Trituration and filtration from a small volume of 10% EtOAc in hexanes gave the pure cis-diastereomer methyl 3-(((cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (305 mg, 0.730 mmol, 29.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=6.85 (d, J=2.3 Hz, 1 H), 6.74 (d, J=2.0 Hz, 1 H), 6.62 (d, J=7.1Hz, 1 H), 4.66 (d, J=6.8 Hz, 1 H), 3.81 (s, 3 H), 3.47 (br. s., 2 H), 2.19 (s, 3 H), 1.75-1.51 (m, 8 H), 1.39 (s, 9 H). MS(ES) [M+H]+ 397.2.

Workup

  1. temperatureThe reaction was then heated to 40° C.
  2. stirringstirred for 24 h
  3. customThe reaction was evaporated to dryness
  4. washwashed with aq. NH4Cl, 1 N Na2CO3, brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified by silica gel chromatography (Analogix
  9. filtrationTrituration and filtration from a small volume of 10% EtOAc in hexanes

Sources & evidence

ORD record
ord-316c2af0f3d74ec3baedc040cff604d8
Source dataset
uspto-grants-2016_07
Patent number
US09382234B2

Reaction notes

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