Dimethylformamide → 2-methyl-2-propanyl (2S,4R)-2-(5-{4-[(methoxycarbonyl)amino]phenyl}-1H-imidazol-2-yl)-4-[1-(methylsulfonyl)-4-piperidinyl]-1-pyrrolidinecarboxylate

HRID 1053833Notes

Reaction equation

HRID 1053833 reaction equation
[CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[CH2:10][C@H:9]1C(OC)=O)=[O:7])([CH3:4])[CH3:3].Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:41])[O:39][CH3:40])=[CH:33][CH:32]=1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(=O)C.[NH4+:52].C[N:54]([CH3:57])C=O>C1(C)C(C)=CC=CC=1>[CH3:40][O:39][C:38]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[NH:54][C:57]([C@@H:9]3[CH2:10][C@H:11]([CH:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:15][CH2:14]4)[CH2:12][N:8]3[C:6]([O:5][C:2]([CH3:3])([CH3:4])[CH3:1])=[O:7])=[N:52][CH:28]=2)=[CH:32][CH:33]=1)=[O:41]

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 517165Ammonium AcetateHCID 57976391Methyl 4-(2-bromoacetyl)phenylcarbamateHCID 122584918methyl (2S,4R)-1-{[(2-methyl-2-propanyl)oxy]carbonyl}-4-[1-(methylsulfonyl)-4-piperidinyl]-2-pyrrolidinecarboxylate

Product 1

HCID 1317363052-methyl-2-propanyl (2S,4R)-2-(5-{4-[(methoxycarbonyl)amino]phenyl}-1H-imidazol-2-yl)-4-[1-(methylsulfonyl)-4-piperidinyl]-1-pyrrolidinecarboxylateYield 71%

Reagents, catalysts & solvents 1

HCID 7237O-XyleneSolvent

Procedure

To a solution of the compound prepared in Example 62 (2.35 g, 6.2 mmol) in N,N-dimethylformamide (50 mL) at 0° C. was added methyl 4-(2-bromoacetyl)phenylcarbamate (2.04 g, 7.49 mmol) followed by cesium carbonate (4.47 g, 13.7 mmol). The reaction was warmed to room temperature and stirred for 1.5 h whereupon the mixture was filtered through diatomaceous earth and the filter cake washed with dichloromethane. The filtrate was concentrated to afford crude product as a yellow solid. To a suspension of crude material in xylene (45 mL) in a glass pressure bottle was added ammonium acetate (2.88 g, 37.4 mmol). The reaction vessel was filled with nitrogen, sealed and heated at 140° C. for 1 h whereupon the mixture was cooled to room temperature, concentrated and partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried and concentrated. Purification by flash chromatography (silica gel, 120 g, 40-60% ethyl acetate/dichloromethane then 3-5% methanol/dichloromethane) afforded the title compound (2.42 g, 71% for two steps) as a pale yellow solid.

Workup

  1. filtrationwas filtered through diatomaceous earth
  2. washthe filter cake washed with dichloromethane
  3. concentrationThe filtrate was concentrated
  4. customto afford crude product as a yellow solid
  5. additionThe reaction vessel was filled with nitrogen
  6. customsealed
  7. temperatureheated at 140° C. for 1 h whereupon the mixture
  8. temperaturewas cooled to room temperature
  9. concentrationconcentrated
  10. custompartitioned between ethyl acetate (200 mL) and water (50 mL)
  11. washThe organic layer was washed with aqueous sodium bicarbonate solution and brine
  12. customdried
  13. concentrationconcentrated
  14. customPurification by flash chromatography (silica gel, 120 g, 40-60% ethyl acetate/dichloromethane

Sources & evidence

ORD record
ord-720f2264fff74d2a9c0b6c75ea49356b
Source dataset
uspto-grants-2016_07
Patent number
US09394250B2

Reaction notes

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