4-Methylmorpholine → 2-(((2S,3R)-1-(2-Fluoro-6-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione

HRID 61199

Reaction equation

HRID 61199 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][NH:38][C@@H:37]1[CH2:42][N:43]1[C:51](=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]1=[O:53]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[C:4]([N:38]1[CH2:39][CH2:40][CH2:41][C@@H:36]([CH3:35])[C@H:37]1[CH2:42][N:43]1[C:51](=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]1=[O:53])=[O:6]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 184502-Chloro-4,6-dimethoxy-1,3,5-triazineHCID 670866032-Fluoro-6-(2-pyrimidinyl)benzoic acidHCID 1177276302-(((2S,3R)-3-Methylpiperidin-2-yl)methyl)isoindoline-1,3-dione

Product 1

HCID 1177278022-(((2S,3R)-1-(2-Fluoro-6-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dioneYield 15.5%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
80 °C

Procedure

A solution of 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (366 mg, 1.67 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (292 mg, 1.67 mmol), and N-methylmorpholine (421 mg, 4.18 mmol) in anhydrous 1,4-dioxane (10 mL) was stirred at rt under nitrogen for 1.5 h. A solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (359 mg, 1.39 mmol) in anhydrous 1,4-dioxane (3 mL) was added at rt. After the addition was completed, the reaction was heated to 80° C. under nitrogen for 5 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), subsequently washed with 0.1 N HCl (100 mL), 0.1 N NaOH (100 mL), and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) to afford the title compound as a white foam (99 mg, 15%). ESI MS (M+H) 459.

Workup

  1. additionAfter the addition
  2. temperatureThe reaction mixture was cooled to rt
  3. washsubsequently washed with 0.1 N HCl (100 mL), 0.1 N NaOH (100 mL), and brine (100 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-459f3c8d67f74102a9567f7f3da642cd
Source dataset
uspto-grants-2016_09
Patent number
US09440982B2

Linked notes

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