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Bromomethylcyclopropane → 5-(3'-Amino-6-cyclopropylmethoxy-2-ethoxy-biphenyl-4-ylmethyl)-pirimidine-2,4-diamine

HRID 2416310
Notes
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Reaction equation

HRID 2416310 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:26][CH2:34][CH:35]3[CH2:37][CH2:36]3)=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 81503BromomethylcyclopropaneHCID 226369793'-Amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-olHCID 23665647Potassium tert-butoxide

Product 1

HCID 98225635-(3'-Amino-6-cyclopropylmethoxy-2-ethoxy-biphenyl-4-ylmethyl)-pirimidine-2,4-diamine

Reagents, catalysts & solvents 2

HCID 6228Dimethylformamide
Solvent
HCID 22728543Water ethylacetateSolvent

Procedure

3′-Amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (351 mg; 1 mmol) is dissolved in dimethylformamide (22.5 ml; dried over a molecular sieve), while gassing with argon, and potassium tert-butylate (172 mg; 1.5 mmol) is added at room temperature. After the mixture has been stirred for one hour, bromomethyl-cyclopropane (0.124 ml; 1.3 mmol) is added and stirring is continued for 1 hour at a bath temperature of 60° C. The reaction mixture is then cooled to room temperature and concentrateds The residue is taken up in water/ethyl acetate and the mixture is poured into a separating funnel and extracted by shaking. The aqueous phase is separated off and re-extracted once with ethyl acetate. The combined organic phases are washed with an aqueous saturated sodium chloride solution, dried over magnesium sulphate, filtered with suction and concentrated. The residue is chromatographed over silica gel (21 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05). The pure fractions are concentrated and the residue is stirred with diethyl ether (10 ml) for 1 hour, filtered off with suction, rinsed with diethyl ether and dried under a high vacuum.

Workup

  1. customdried over a molecular sieve),
  2. additionis added at room temperature
  3. stirringstirring
  4. waitis continued for 1 hour at a bath
  5. customtemperature of 60° C
  6. additionthe mixture is poured into a separating funnel
  7. extractionextracted
  8. stirringby shaking
  9. customThe aqueous phase is separated off
  10. extractionre-extracted once with ethyl acetate
  11. washThe combined organic phases are washed with an aqueous saturated sodium chloride solution
  12. dry with materialdried over magnesium sulphate
  13. filtrationfiltered with suction
  14. concentrationconcentrated
  15. customThe residue is chromatographed over silica gel (21 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05)
  16. concentrationThe pure fractions are concentrated
  17. stirringthe residue is stirred with diethyl ether (10 ml) for 1 hour
  18. filtrationfiltered off with suction
  19. washrinsed with diethyl ether
  20. customdried under a high vacuum

Sources & evidence

ORD record
ord-43b96883703f448ba807ceeb62a227f3
Source dataset
uspto-grants-2004_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06821980B1

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes