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Hydrochloric Acid → 2-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propionic acid

HRID 216178
Notes
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Reaction equation

HRID 216178 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[C:21]([CH:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)[CH3:25])([OH:23])=[O:22].O.Cl>C(#N)C.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:28]2[CH:27]=[C:26]([CH:24]([CH3:25])[C:21]([OH:23])=[O:22])[CH:31]=[CH:30][CH:29]=2)[CH:3]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 576360046-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]-2-methoxy-4-pyrimidinamine2×HCID 576360703-(1-Carboxy-ethyl)-phenyl boronic acid2×

Product 1

HCID 576360542-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propionic acid

Reagents, catalysts & solvents

3
HCID 178418397HCID 178418397, compoundCatalystHCID 6342AcetonitrileSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
130 °C

Procedure

A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [170 mg, 0.51 mmol, Intermediate (44)] and 3-(1-carboxy-ethyl)-phenyl boronic acid [119 mg, 0.61 mmol, Intermediate (70)] in acetonitrile (2.5 mL) and aqueous Na2CO3 solution (0.4 M, 2.5 mL) is degassed with nitrogen for 5 minutes before addition of tetrakis(triphenylphosphine)palladium (0) (29.5 mg, 5 mol %). The reaction vessel is sealed and heated under microwave to 130° C. for 30 minutes. To the reaction mixture is added 2 mL of water, the pH is adjusted to about 7 using 2 N aqueous hydrochloric acid and this mixture is extracted three times with EtOAc (30 mL). The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The resulting oil is subjected to silica gel chromatography eluting with 0 to 7% MeOH in DCM to give 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propionic acid as a solid, which is treated with 1M hydrogen chloride in ether affording 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propionic acid hydrochloride [122 mg, 50%, Example 49(a)] as a solid. LC/MS: RT=2.47 minutes, MS: 446 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □12.4 (1H, br s), 7.36-7.8 (7H, m), 6.6 (1H, s), 4 (3H, s), 3.78 (1H, q), 3.68 (2H, m), 3.02 (2H, m), 1.42 (3H, d). IC50=1 nM

Workup

  1. customThe reaction vessel is sealed
  2. extractionthis mixture is extracted three times with EtOAc (30 mL)
  3. washThe combined extracts are washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. washeluting with 0 to 7% MeOH in DCM

Sources & evidence

ORD record
ord-fc8fd486d86c4f6a90f01d6f6292a81a
Source dataset
uspto-grants-2012_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08193183B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes