Cesium fluoride → 5-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-thiophene-2-carboxylic acid

HRID 216247Notes

Reaction equation

HRID 216247 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.CC1(C)COB([C:28]2[S:32][C:31]([C:33]([OH:35])=[O:34])=[CH:30][CH:29]=2)OC1.[F-].[Cs+]>O.COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=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[S:32][C:31]([C:33]([OH:35])=[O:34])=[CH:30][CH:29]=2)[CH:3]=1

Participants

7

Reactant 3

HCID 25953Cesium fluorideHCID 576360046-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]-2-methoxy-4-pyrimidinamine2×HCID 689325775-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-thiophene-2-carboxylic acid

Product 1

HCID 576359995-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-thiophene-2-carboxylic acidYield 53.7%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [277 mg, 0.83 mmol, Intermediate (44)], 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-thiophene-2-carboxylic acid (300 mg, 1.25 mmol), cesium fluoride (378 mg, 2.5 mmol) and tetrakis(triphenylphosphine) palladium (77 mg, 0.07 mmol) in water (2 mL) and ethylene glycol dimethyl ether (8 mL) is degassed with bubbling nitrogen for 5 minutes and is heated at 85° C. for 16 hours. The reaction mixture is cooled, diluted with water (150 mL) and brine (50 mL), and extracted three times with EtOAc (150 mL) and the extracts are concentrated in vacuo. The residue is subjected to flash column chromatography on silica (10 g) eluting with 0 to 15% MeOH in ethyl acetate. The product is triturated twice with heptanes (5 mL) and twice with ether (5 mL) and dried to afford 5-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-thiophene-2-carboxylic acid (189 mg, Example 87) as a solid. MS: 424 (M+H); 1H NMR [300 MHz, (CD3)2SO]: δ 13.2 (1H, s); 7.7 (3H, m); 7.6 (1H, s); 7.35 (2H, s); 6.6 (1H, s); 4.85 (3H, s); 3.6 (2H, m); 3 (2H, t). IC50=0.16 nM

Workup

  1. customis degassed with bubbling nitrogen for 5 minutes
  2. temperatureThe reaction mixture is cooled
  3. additiondiluted with water (150 mL) and brine (50 mL)
  4. extractionextracted three times with EtOAc (150 mL)
  5. concentrationthe extracts are concentrated in vacuo
  6. washeluting with 0 to 15% MeOH in ethyl acetate
  7. customThe product is triturated twice with heptanes (5 mL) and twice with ether (5 mL)
  8. customdried

Sources & evidence

ORD record
ord-4e70a43400f94479baf642b8c5ee736f
Source dataset
uspto-grants-2012_06
Patent number
US08193183B2

Reaction notes

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