Lithium Hydroxide → 2-[6-phenyl-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-4-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide

HRID 2039718Notes

Reaction equation

HRID 2039718 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:18])[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[C:41]3[CH:40]=[N:39][CH:38]=[N:37][C:36]=3[N:35](S(C3C=CC(C)=CC=3)(=O)=O)[CH:34]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Li+]>O1CCOCC1.O>[C:19]1([C:4]2[N:3]=[C:2]([C:33]3[C:41]4[CH:40]=[N:39][CH:38]=[N:37][C:36]=4[NH:35][CH:34]=3)[N:7]=[C:6]([NH:8][CH:9]([CH3:18])[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 693263825-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7h-pyrrolo[2,3-d]pyrimidine2×HCID 86614827HCID 86614827, compound

Product 1

HCID 693026602-[6-phenyl-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-4-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

As shown in FIG. 3—step i, a mixture of phenylboronic acid (1.22 g), 2,4,6-trichloropyrimidine (compound 1011), tetrakis(triphenylphosphine) palladium(0) and 2N sodium carbonate (15 mL) in DME (25 mL) was heated at 80° C. overnight. After cooling to rt, addition of water (30 mL), extraction with dichloromethane (3×20 mL), drying and evaporation, purification by column chromatography (SiO2, 10-20% ethyl acetate in hexane) afforded the desired product, 6-phenyl-2,4-dichloropyrimidine (compound 1012) (0.544 g). As shown in FIG. 3—step ii, compound 1012 (0.34 g) was mixed with (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (0.3 g) and diisopropylethylamine (0.63 mL) in isopropanol (5 mL) and the reaction mixture heated at 80° C. overnight. Evaporation gave a residue, which after aqueous workup and purification (SiO2, 20% ethyl acetate/hexane) produced 2-(2-chloro-6-phenyl-pyrimidin-4-ylamino)-N-(2,2,2-trifluoro-ethyl)propionamide (compound 1013) (0.165 g). As shown in FIG. 3—step iii, compound 1013 (29 mg), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 1005), PdCl2dppf2 (7 mg), and potassium phosphate (32 mg) were heated in 1,4-dioxane (2 mL) at 80° C. overnight. To the reaction was added aqueous lithium hydroxide solution (2 mL). After heating at 60° C. for 1 h, water (20 mL) was added. Extraction with dichloromethane (3×), drying, evaporation and purification (SiO2, 50-100% ethyl acetate/hexane) gave 3.7 mg of 2-[6-phenyl-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-4-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide (compound 18).

Workup

  1. extractionExtraction with dichloromethane (3×)
  2. customdrying
  3. customevaporation and purification (SiO2, 50-100% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-1b1e7a045dbc43feae076d6b68cacc33
Source dataset
uspto-grants-2013_11
Patent number
US08580802B2

Reaction notes

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