Cesium carbonate → [2-Isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

HRID 2054333Notes

Reaction equation

HRID 2054333 reaction equation
Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH2:10][CH:11]([CH3:13])[CH3:12])[N:7]=1.Cl.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:10]([O:9][CH2:8][C:6]1[N:7]=[C:2]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][N:31]=2)[C:3]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][C:4]=2[N:5]=1)[CH:11]([CH3:13])[CH3:12]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 596557614-Chloro-2-isobutoxymethyl-7-(3-trifluoromethyl pyridin-2-yl)-pyrido[2,3-d]pyrimidineHCID 671919732-Amino-5-trifluoromethylpyridine hydrochloride

Product 1

HCID 59655757[2-Isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

Heat a mixture of 4-chloro-2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine (79.2 mg, 0.2 mmol), 2-amino-5-trifluoromethylpyridine hydrochloride (39.6 mg, 0.2 mmol), xantphos (11.6 mg, 0.1 mmol), Pd2(dba)3 (18.3 mg, 0.1 mmol) and Cs2CO3 (130 mg, 0.4 mmol) in dioxane (2.0 mL) at 100° C. for 20 hours. Cool the mixture, concentrate under vacuum, dilute with water (5.0 mL), extract with EtOAc (3×3 mL) and dry with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify by flash column chromatography to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) d 0.88 (6H, d, J=1.7), 1.89 (1H, m), 3.37 (2H, d, J=1.6), 4.67 (2H, s), 7.79 (1H, m), 7.96(1H, d, J=2.1), 8.19 (1H, d, J=1.7), 8.42 (1H, d, J=2.0), 8.82(2H, m), 8.98(1H, d, J=1.1), 9.34 (1H, d, J=2.1). MS=523.2 (M+H). IC50 in standard assay of capsaicin receptor activity is less than 10 nanomolar.

Workup

  1. temperatureHeat
  2. temperatureCool the mixture
  3. concentrationconcentrate under vacuum
  4. additiondilute with water (5.0 mL)
  5. extractionextract with EtOAc (3×3 mL)
  6. dry with materialdry with MgSO4
  7. filtrationFilter the dried
  8. extractionextract
  9. concentrationconcentrate under vacuum
  10. customto afford crude product
  11. customPurify by flash column chromatography

Sources & evidence

ORD record
ord-94fb1533b3bd4fc0bb62725e043eaba4
Source dataset
uspto-grants-2008_02
Patent number
US07329664B2

Reaction notes

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