Water → 2-[4-pyrrolidin-1-yl-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-2-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide TFA salt

HRID 2039719Notes

Reaction equation

HRID 2039719 reaction equation
Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH:10]([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])[N:3]=1.[CH:20]([N:23]([CH:26]([CH3:28])C)CC)([CH3:22])C.CC1(C)C(C)(C)OB([C:37]2[C:45]3[CH:44]=[N:43][CH:42]=[N:41][C:40]=3[N:39](S(C3C=CC(C)=CC=3)(=O)=O)[CH:38]=2)[O:31]1.[F-:57].[Cs+].[OH2:59]>COCCOC>[OH:59][C:14]([C:15]([F:18])([F:16])[F:57])=[O:31].[N:23]1([C:2]2[CH:7]=[C:6]([C:37]3[C:45]4[CH:44]=[N:43][CH:42]=[N:41][C:40]=4[NH:39][CH:38]=3)[N:5]=[C:4]([NH:9][CH:10]([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])[N:3]=2)[CH2:20][CH2:22][CH2:28][CH2:26]1

Participants

7

Reactant 5

HCID 962WaterHCID 25953Cesium fluorideHCID 81531DiisopropylethylamineHCID 693263825-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7h-pyrrolo[2,3-d]pyrimidine2×HCID 866148292-(4,6-dichloro-pyrimidin-2-ylamino)-N-(2,2,2-trifluoro-ethyl)-propionamide

Product 1

HCID 866148282-[4-pyrrolidin-1-yl-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-2-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide TFA salt

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
160 °C

Procedure

As shown in FIG. 4—step v, to a solution of compound 1019 (31.7 mg, 0.100 mmol) in DME (0.50 mL) was added a nucleophilic amine (pyrrolidine, 10 μL, 0.11 mmol) and diisopropylethylamine (25.8 mg, 34.8 μL, 0.200 mmol). The mixture was heated at 160° C. with microwave for 5 min, followed by the addition of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (compound 1005, 39.9 mg, 0.100 mmol) and a solution of CsF (30 mg, 0.20 mmol) in water (0.25 mL). The mixture was heated at 160° C. with microwave for 5 min. The reaction mixture was filtered through a short pad of silica gel using EtOAc/hexanes as eluent to provide, after concentration in vacuo, the crude intermediate tosylate. This intermediate was dissolved in 1 mL of dry methanol and 200 uL of 25% sodium methoxide in methanol was added. The reaction mixture was stirred at 60° C. for 1 hour and quenched with trifluoroacetic acid. Purification by reversed-phase HPLC gave 35.0 mg of 2-[4-pyrrolidin-1-yl-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-2-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide TFA salt (a compound of formula IX where R10 is 1-pyrrolidine).

Workup

  1. temperatureThe mixture was heated at 160° C. with microwave for 5 min
  2. filtrationThe reaction mixture was filtered through a short pad of silica gel
  3. customto provide
  4. concentrationafter concentration in vacuo
  5. dissolutionThis intermediate was dissolved in 1 mL of dry methanol
  6. addition200 uL of 25% sodium methoxide in methanol was added
  7. customquenched with trifluoroacetic acid
  8. customPurification by reversed-phase HPLC

Sources & evidence

ORD record
ord-c6e2677445384ac9a118d1d695826835
Source dataset
uspto-grants-2013_11
Patent number
US08580802B2

Reaction notes

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