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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 2110678
Notes
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Reaction equation

HRID 2110678 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]
ParticipantsProcedureWorkupSources & evidenceReaction notes

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-fad9936b81704f4588152e170c6e1064
Source dataset
uspto-grants-2009_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07517889B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes