Dichloromethane → 3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionic acid tert-butyl ester

HRID 713973Notes

Reaction equation

HRID 713973 reaction equation
[C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[C:36]([C:41](=O)[C:42]([F:45])([F:44])[F:43])[CH:35]=[CH:34]3)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21].C(Cl)Cl.C([BH3-])#N.[Na+]>CO.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:10])[CH2:7][CH2:8][NH:9][CH:41]([C:36]1[CH:35]=[CH:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([O:30][CH:27]3[CH2:28][CH2:29][CH:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:25][CH2:26]3)[CH:32]=2)[CH:37]=1)[C:42]([F:43])([F:44])[F:45])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 5

HCID 6344Dichloromethane2×HCID 81531DiisopropylethylamineHCID 4192171tert-Butyl 3-aminopropanoateHCID 5003444Sodium cyanoborohydrideHCID 681727961-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethanone

Product 1

HCID 669267293-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 24193Titanium TetrachlorideCatalystHCID 887MethanolSolvent

Procedure

3-Amino-propionic acid tert-butyl ester (106 mg, 0.727 mmol) was combined with N,N-Diisopropylethylamine (575 uL, 3.30 mmol) and 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethanone (250 mg, 0.66 mmol) in Methylene chloride (4 mL, 60 mmol). 1 M (of Titanium(IV) chloride in Methylene chloride (727 uL, 0.727 mmol) was added and the mixture was stirred at RT for 5 hours. TLC (20% EtOAC/Hex) shows only traces of SM with new lower Rf spot. The reaction was cooled to 0° C. and Sodium cyanoborohydride (208 mg, 3.30 mmol) in methanol (5 mL) was added carefully in two portions (lots of bubbling so remove cap.) The reaction was then diluted with 10 mL DCM and the solids were removed via filtration. pH was adjust to 10 with 1 M NaOH and the reaction was extracted three times with methylene chloride. Organics were combined and dried over MgSO4. Solids were removed via filtration and the crude reaction was absorbed onto silica (1 g) and purified via column chromatography on 12 g SiO2 using a gradient of 0-15% Ethylacetate/hexane to give material that was impure by NMR and LCMS (compound eluted around 1% EtOAc.) Material was repurified on 24 g ISCO gold column using a long gradient of 0-10% EtOAc/Hex over 30 minutes (desired compound was 2nd major peak) to give the title compound as a colorless solid.

Workup

  1. temperatureThe reaction was cooled to 0° C.
  2. customof bubbling so
  3. customremove
  4. customcap
  5. addition) The reaction was then diluted with 10 mL DCM
  6. customthe solids were removed via filtration
  7. extractionthe reaction was extracted three times with methylene chloride
  8. dry with materialdried over MgSO4
  9. customSolids were removed via filtration
  10. customthe crude reaction
  11. customwas absorbed onto silica (1 g)
  12. custompurified via column chromatography on 12 g SiO2 using a gradient of 0-15% Ethylacetate/hexane
  13. customto give material that
  14. washwas impure by NMR and LCMS (compound eluted around 1% EtOAc.) Material
  15. customwas repurified on 24 g ISCO gold column
  16. customHex over 30 minutes

Sources & evidence

ORD record
ord-1cb75939c33b4b458d616ba540678055
Source dataset
uspto-grants-2015_11
Patent number
US09186367B2

Reaction notes

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