Propanoic acid, 2-bromo-2-methyl-, ethyl ester → 2-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl ester

HRID 216150Notes

Reaction equation

HRID 216150 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:32]([O:31][C:29](=[O:30])[C:28]([O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:35])[CH3:34])[CH3:33]

Participants

4

Reactant 2

HCID 11745Propanoic acid, 2-bromo-2-methyl-, ethyl esterHCID 114948343-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol

Product 1

HCID 589903752-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl esterYield 37%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A mixture of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol [945 mg, 2.42 mmol, Example 35(i)], PS-TBD (3.38 g, 5 mmol), ethyl 2-bromoisobutyrate (888 mL, 605 mmol) and acetonitrile (20 mL) is heated to reflux and stirred for 2 hours. The heating is turned off and the mixture is stirred overnight at ambient temperature. The reaction mixture is filtered to remove the resin and the resin is washed with MeOH (20 mL) and with acetonitrile (20 mL). The combined filtrate and washings are concentrated by rotary evaporator. The residue is subjected to flash column chromatography on silica (40 g) eluting with 20 to 50% EtOAc in heptane gradient to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl ester [450 mg, 37%, Example 42] as a solid. LCMS: RT=2.9 minutes, MS: 504 (M+H).

Workup

  1. temperatureis heated
  2. temperatureto reflux
  3. stirringthe mixture is stirred overnight at ambient temperature
  4. filtrationThe reaction mixture is filtered
  5. customto remove the resin
  6. washthe resin is washed with MeOH (20 mL) and with acetonitrile (20 mL)
  7. concentrationThe combined filtrate and washings are concentrated by rotary evaporator
  8. washeluting with 20 to 50% EtOAc in heptane gradient

Sources & evidence

ORD record
ord-ecd2f692726d411a98be07d824994587
Source dataset
uspto-grants-2012_06
Patent number
US08193183B2

Reaction notes

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