Isopropanolate → 5-(2,4-dimethyl-1,3-thiazol-5-yl)-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione

HRID 1925067Notes

Reaction equation

HRID 1925067 reaction equation
[F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.CC(C)[O-].[CH3:21][C:22]1[S:23][C:24]([C:28]2[C:29](=[O:39])[NH:30][C:31](=[O:38])[N:32]([CH2:34][CH2:35][CH:36]=O)[CH:33]=2)=[C:25]([CH3:27])[N:26]=1>C(#N)C>[CH3:21][C:22]1[S:23][C:24]([C:28]2[C:29](=[O:39])[NH:30][C:31](=[O:38])[N:32]([CH2:34][CH2:35][CH2:36][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[CH:33]=2)=[C:25]([CH3:27])[N:26]=1

Participants

5

Reactant 3

HCID 3260420IsopropanolateHCID 59337591(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexaneHCID 594483663-[5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]propanal

Product 1

HCID 252534435-(2,4-dimethyl-1,3-thiazol-5-yl)-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedioneYield 41.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (269 mg, 1.186 mmol) in acetonitrile (4 mL), Titanuim (IV) isopropoxide (0.434 mL, 1.482 mmol) and a solution of 3-[5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]propanal (Prep36, 276 mg, 0.988 mmol) in acetonitrile (6 mL) were added and the mixture was stirred at rt for 20 minutes. Afterwards, it was cooled to 0° C. and Sodiumtriacetoxyboronhydride (314 mg, 1.482 mmol) was added. The mixture was stirred at rt for 1.5 h, then quenched with water. Acetonitrile was eliminated under reduced pressure and the aqueous residue was extracted with DCM. Organic phase was washed with NaHCO3 saturated solution, dried and concentrated under vacuum. Crude product was purified by flash chromatography (eluent: DCM/MeOH/NH3 97:3:0.1) affording the title compound (E37, 200 mg, 0.408 mmol) as a white solid.

Workup

  1. temperatureAfterwards, it was cooled to 0° C.
  2. additionSodiumtriacetoxyboronhydride (314 mg, 1.482 mmol) was added
  3. stirringThe mixture was stirred at rt for 1.5 h
  4. customquenched with water
  5. extractionthe aqueous residue was extracted with DCM
  6. washOrganic phase was washed with NaHCO3 saturated solution
  7. customdried
  8. concentrationconcentrated under vacuum
  9. customCrude product was purified by flash chromatography (eluent: DCM/MeOH/NH3 97:3:0.1)

Sources & evidence

ORD record
ord-b48b83ccf3804b0496f4d112bc0c415f
Source dataset
uspto-grants-2012_05
Patent number
US08178549B2

Reaction notes

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