Sodium Carbonate → HCID 22115344, compound

HRID 1276369Notes

Reaction equation

HRID 1276369 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(OC([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:26](=[O:36])[CH2:27][O:28][C:29]2[N:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)[CH2:20]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:26](=[O:36])[CH2:27][O:28][C:29]2[N:30]=[CH:31][C:32]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:33][N:34]=2)[CH2:20]1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 11776TriphenylphosphineHCID 201262(4-Methoxyphenyl)boronic acidHCID 22115316HCID 22115316, compound

Product 1

HCID 22115344HCID 22115344, compound

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 10311-PropanolSolvent

Procedure

4-Methoxyphenylboronic acid (1.0 g, 6.8 mmol, 1.05 equiv.) was added to a solution of N-(1-tert-butoxycarbonylpyrrolidin-3-(RS)-ylmethyl)-2-(5-bromopyrimidin-2-yloxy)acetamide (2.7 g, 6.5 mmol) in 1-propanol (30 mL). The suspension was stirred until all ingredients had dissolved (~10 min). The resulting solution was treated with palladium acetate (29 mg, 0.13 mmol, 0.02 equiv.), triphenylphosphine (103 mg, 0.39 mmol, 0.06 equiv.), 2 M aqueous sodium carbonate (3.9 mL, 7.8 mmol, 1.2 equiv.) and deionized water (9 mL). The reaction mixture was heated at reflux under N2 for 1 h. Water (20 mL) was added and the N2 inlet was removed. After stirring at room temperature overnight, the reaction mixture was thoroughly extracted with ethyl acetate. The combined organic phase was washed with saturated sodium bicarbonate solution and brine. The organic phase was stirred with activated charcoal for 15 min, dried over sodium sulfate and concentrated. Recrystallization of the residue from ethyl acetate in hexane afforded clean N-(1-tert-butoxycarbonylpyrrolidin-3-(RS)-ylmethyl)-2-(5-(4-methoxyphenyl)pyrimidin-2-yloxy)acetamide (2.1 g). The solid was dissolved into methylene chloride (30 mL) and neat trifluoroacetic acid (5 mL) added dropwise. After about 1 h, the solution was concentrated to an oil on a Teflon dryvac, then under high vacuum to give N-(pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-yloxy]acetamide.

Workup

  1. dissolutionhad dissolved (~10 min)
  2. temperatureThe reaction mixture was heated
  3. temperatureat reflux under N2 for 1 h
  4. customthe N2 inlet was removed
  5. stirringAfter stirring at room temperature overnight
  6. extractionthe reaction mixture was thoroughly extracted with ethyl acetate
  7. washThe combined organic phase was washed with saturated sodium bicarbonate solution and brine
  8. stirringThe organic phase was stirred with activated charcoal for 15 min
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated
  11. customRecrystallization of the residue from ethyl acetate in hexane afforded clean N-(1-tert-butoxycarbonylpyrrolidin-3-(RS)-ylmethyl)-2-(5-(4-methoxyphenyl)pyrimidin-2-yloxy)acetamide (2.1 g)
  12. dissolutionThe solid was dissolved into methylene chloride (30 mL) and neat trifluoroacetic acid (5 mL)
  13. additionadded dropwise
  14. concentrationthe solution was concentrated to an oil on a Teflon dryvac

Sources & evidence

ORD record
ord-f9ad73c486234371a70eb7a722c5ded5
Source dataset
uspto-grants-2000_12
Patent number
US06166015

Reaction notes

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