Acetic Acid → (9-(2-Fluoro-3-(1-hydroxy-2-methylpropan-2-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone

HRID 471218Notes

Reaction equation

HRID 471218 reaction equation
C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[CH:22]([C:25]1[S:26][CH:27]=[C:28]([C:30]([N:32]2[CH2:37][C:36]3([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[O:35][CH2:34][CH2:33]2)=[O:31])[N:29]=1)([CH3:24])[CH3:23].[Si]([O:50][CH2:51][C:52]([C:55]1[C:56]([F:63])=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH:58]=O)([CH3:54])[CH3:53])(C(C)(C)C)(C)C.C(O)(=O)C>CN1C(=O)CCC1>[F:63][C:56]1[C:55]([C:52]([CH3:54])([CH3:53])[CH2:51][OH:50])=[CH:62][CH:61]=[CH:60][C:57]=1[CH2:58][N:40]1[CH2:39][CH2:38][C:36]2([O:35][CH2:34][CH2:33][N:32]([C:30]([C:28]3[N:29]=[C:25]([CH:22]([CH3:24])[CH3:23])[S:26][CH:27]=3)=[O:31])[CH2:37]2)[CH2:42][CH2:41]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 579890123-(1-(tert-Butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluorobenzaldehydeHCID 66964182(2-Isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate

Product 1

HCID 57989311(9-(2-Fluoro-3-(1-hydroxy-2-methylpropan-2-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
20 °C

Procedure

Sodium triacetoxyborohydride (0.502 g) was added to a stirred solution at 0° C. of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.668 g) and 3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluorobenzaldehyde (example 90, step f) (0.49 g) and acetic acid (0.090 mL) in NMP (20 mL). The reaction mixture was then stirred at 20° C. for 18 hours. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The resultant gum was dissolved in THF (20 mL) and treated with tetrabutylammonium fluoride (1M in THF, 3.16 mL). The solution was allowed to stand at 20° C. for 8 hours. The solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 0 to 1% methanol in dichloromethane with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.63 g.

Workup

  1. customThe mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution
  2. washthe organic layer was washed twice with brine
  3. dry with materialdried over sodium sulphate
  4. filtrationfiltered
  5. customthe solvent evaporated under reduced pressure
  6. dissolutionThe resultant gum was dissolved in THF (20 mL)
  7. additiontreated with tetrabutylammonium fluoride (1M in THF, 3.16 mL)
  8. waitto stand at 20° C. for 8 hours
  9. customThe solvent was evaporated under reduced pressure
  10. customthe crude product was purified by flash silica chromatography, elution gradient 0 to 1% methanol in dichloromethane with 1% triethylamine
  11. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-ddddd14a7b254e2fae6cae45ae4b6897
Source dataset
uspto-grants-2014_01
Patent number
US08629271B2

Reaction notes

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