Dimethylformamide → tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate

HRID 1663307Notes

Reaction equation

HRID 1663307 reaction equation
Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:4][C:5]([N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH3:24][C:25]1([CH3:41])[O:30][C@@H:29]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C@@H:27]([CH:39]=[CH2:40])[O:26]1.C1(CNCC2CCCCC2)CCCCC1.CN(C)C=O>C(OCC)(=O)C.O.C(O)(=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:3]2[C:2](/[CH:40]=[CH:39]/[C@H:27]3[O:26][C:25]([CH3:24])([CH3:41])[O:30][C@@H:29]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]3)=[C:7]([CH:8]([CH3:10])[CH3:9])[N:6]=[C:5]([N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=2)=[CH:18][CH:19]=1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 4594378Bis(cyclohexylmethyl)amineHCID 11495059N-(5-Bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamideHCID 67371871tert-butyl 2-((4R,6S)-2,2-dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate

Product 1

HCID 9916218tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
50 °C

Procedure

A mixture of N-(5-bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (1.00 g, 2.50 mmol), bis-tri-tert-butylphosphine palladium (0) (131 mg, 0.250 mmol), tert-butyl 2-((4R,6S)-2,2-dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate (640 mg, 2.50 mmol), water (5 mL), N,N-dicyclohexylmethylamine (0.530 mL, 2.50 mmol), and N,N-dimethylformamide (5 mL) was heated and stirred at 50° C. under nitrogen for four days. The mixture was then diluted with ethyl acetate (11 mL), water (10 mL), and acetic acid (0.2 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 mL). The combined organic phases were washed with water (10 mL), then brine (10 mL), and concentrated in vacuo to give a yellow oil containing some solids. This material was adsorbed onto silica gel through dissolution in ethyl acetate, then purified by flash chromatography (5% ethyl acetate in isohexane gradually increasing to 20% ethyl acetate in hexane, silica column 25 mm in diameter and 250 mm in height) to yield tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethanesulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of the formula

Workup

  1. temperaturewas heated
  2. customThe organic phase was separated
  3. extractionthe aqueous phase was extracted with ethyl acetate (5 mL)
  4. washThe combined organic phases were washed with water (10 mL)
  5. concentrationbrine (10 mL), and concentrated in vacuo
  6. customto give a yellow oil
  7. additioncontaining some solids
  8. custompurified by flash chromatography (5% ethyl acetate in isohexane
  9. temperaturegradually increasing to 20% ethyl acetate in hexane, silica column 25 mm in diameter and 250 mm in height)

Sources & evidence

ORD record
ord-b4ef65ee28e84db0a8587c4fe9643027
Source dataset
uspto-grants-2011_10
Patent number
US08034932B2

Reaction notes

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