Isopropanol → HCID 67004723, compound

HRID 1513953Notes

Reaction equation

HRID 1513953 reaction equation
F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:24][CH:23]=1)=[O:21].C([BH-](CC)CC)C.[Li+].C(O)(C)C.C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:55].C(O)(C)C>O1CCOCC1>[ClH:55].[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:21][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:27]=1)[C:10]1[C:9]2=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([OH:19])=[CH:15]2

Participants

7

Reactant 5

HCID 3776IsopropanolHCID 516892Sodium BicarbonateHCID 21906603Chloroform isopropyl alcoholHCID 23664628LithiumtriethylborohydrideHCID 67004412HCID 67004412, compound

Product 1

HCID 67004723HCID 67004723, compoundYield 35%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
45 °C

Procedure

Charge a flask with R-methyl CBS reagent (50 m, 0.18 mmol) dissolved in 100 mL dioxane and warm to 45° C. Dissolve [2-(2,3-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (400 mg, 0.82 mmol) in 100 mL of dioxane and add dropwise to the reaction mixture over a two hour period. Continue heating at 45° C. under nitrogen overnight and add lithium triethylborohydride (15 mL of 1.0 M solution in THF, 15 mmol) and heat reaction to 100° C. for 24 hours. Cool the reaction mixture and add 25 mL of isopropanol to quench the reaction. Evaporate the reaction to an oil and add saturated sodium bicarbonate and a 3/1 mixture of chloroform/isopropanol. Extract in a separatory funnel and remove the organic layer. Dry the organic layer over 3 Å molecular sieves, evaporate to a paste and purify on a silica column eluting with 0-10% methanol/methylene chloride. Convert the isolated product to the HCl salt using HCl in ether to give 145 mg (35%) of the title compound. The two enantiomers are separated using chiral chromatography (Conditions D). The preferred isomer eluted second with a retention time of 16.5 minutes (98 mgs).

Workup

  1. additionCharge a flask with R-methyl CBS reagent (50 m, 0.18 mmol)
  2. temperatureContinue heating at 45° C. under nitrogen overnight
  3. temperatureheat
  4. customreaction to 100° C. for 24 hours
  5. temperatureCool the reaction mixture
  6. customto quench
  7. customthe reaction
  8. customEvaporate
  9. customthe reaction to an oil
  10. extractionExtract in a separatory funnel
  11. customremove the organic layer
  12. customDry the organic layer over 3 Å molecular sieves
  13. customevaporate to a paste
  14. custompurify on a silica column
  15. washeluting with 0-10% methanol/methylene chloride

Sources & evidence

ORD record
ord-e1f3298d195f4835a1ada59921079f5f
Source dataset
uspto-grants-2012_07
Patent number
US08217032B2

Reaction notes

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