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

HRID 471079Notes

Reaction equation

HRID 471079 reaction equation
[F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.FC(F)(F)C(O)=O.[CH:21]([C:24]1[S:25][CH:26]=[C:27]([C:29]([N:31]2[CH2:36][C:35]3([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[O:34][CH2:33][CH2:32]2)=[O:30])[N:28]=1)([CH3:23])[CH3:22].C(O)(=O)C>CN1CCCC1=O>[F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[CH2:4][N:39]1[CH2:40][CH2:41][C:35]2([O:34][CH2:33][CH2:32][N:31]([C:29]([C:27]3[N:28]=[C:24]([CH:21]([CH3:22])[CH3:23])[S:25][CH:26]=3)=[O:30])[CH2:36]2)[CH2:37][CH2:38]1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 579889022,4-Difluoro-3-(2-hydroxyethyl)benzaldehydeHCID 66964182(2-Isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate

Product 1

HCID 57988951(9-(2,4-Difluoro-3-(2-hydroxyethyl)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

Procedure

2,4-Difluoro-3-(2-hydroxyethyl)benzaldehyde (example 45, step b) (0.35 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.67 g) and acetic acid (0.09 mL) in N-methyl-2-pyrrolidinone (1 mL). The resulting mixture was stirred for 1 h then quenched by portionwise addition of sodium triacetoxyborohydride (0.335 g) over 5 min. The resulting mixture was stirred overnight, diluted with acetonitrile (20 mL) and applied to a SCX cartridge (10 g Varian, pre-wetted with acetonitrile, (50 mL)). The cartridge was washed with acetonitrile (50 mL) and eluted with 10% ‘880’ aqueous ammonia in acetonitrile solution (50 mL). The eluent was evaporated, azeotroped with toluene and purified by silica gel chromatography eluting with 77.5:17.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient to give the subtitled compound as a yellow gum. Yield 0.74 g.

Workup

  1. customthen quenched by portionwise addition of sodium triacetoxyborohydride (0.335 g) over 5 min
  2. stirringThe resulting mixture was stirred overnight
  3. additiondiluted with acetonitrile (20 mL)
  4. washThe cartridge was washed with acetonitrile (50 mL)
  5. washeluted with 10% ‘880’ aqueous ammonia in acetonitrile solution (50 mL)
  6. customThe eluent was evaporated
  7. customazeotroped with toluene
  8. custompurified by silica gel chromatography
  9. washeluting with 77.5:17.5:5 isohexane

Sources & evidence

ORD record
ord-25c0d80debc842d299b2a0e49d0b3acd
Source dataset
uspto-grants-2014_01
Patent number
US08629271B2

Reaction notes

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