Diisopropylethylamine → 6-((tert-butyldimethylsilyloxy)methyl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide

HRID 572639Notes

Reaction equation

HRID 572639 reaction equation
[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([O:19]C)=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][C:32]=1[O:39][CH3:40]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[C:32]([O:39][CH3:40])[CH:33]=2)=[O:19])[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 442031244-Fluoro-3-methoxybenzylamineHCID 70978757Methyl 6-((tert-butyldimethylsilyloxy)methyl)-2-methylpyrimidine-4-carboxylate

Product 1

HCID 709788136-((tert-butyldimethylsilyloxy)methyl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamideYield 81.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
70 °C

Procedure

To a stirred solution of methyl 6-((tert-butyldimethylsilyloxy)methyl)-2-methylpyrimidine-4-carboxylate (4.70 g, 15.86 mmol, Preparation #6) in MeOH (50 mL) were added DIEA (8.3 mL, 47.59 mmol Spectrochem) and 4-fluoro-3-methoxybenzylamine (3.8 g, 24.58 mmol, WO 2008/083056). The reaction mixture was heated to about 70° C. for about 15 h. The solvents were removed in vacuo and the crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL). The layers were separated and the aqueous layer extracted with EtOAc (1×150 mL). The combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by silica gel (60-120 mesh) chromatography eluting with 25 to 35% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 6-((tert-butyldimethylsilyloxy)methyl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 5.4 g (81%); 1H NMR (400 MHz, DMSO): δ 9.431-9.400 (t, J=6.0 Hz, 1H), 7.884 (s, 1H), 7.173-7.112 (m, 2H), 6.897-6.860 (m, 1H), 4.794 (s, 2H), 4.468-4.452 (d, J=6.4 Hz, 2H), 3.814 (s, 3H), 2.68 (s, 3H), 0.934 (s, 9H), 0.118 (s, 6H), MS m/z: 420 (M+H).

Workup

  1. customThe solvents were removed in vacuo
  2. customthe crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer extracted with EtOAc (1×150 mL)
  5. washThe combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL)
  6. dry with materialdried over sodium sulphate
  7. customevaporated to dryness
  8. customThe residue obtained
  9. customwas purified by silica gel (60-120 mesh) chromatography
  10. washeluting with 25 to 35% of EtOAc in hexane
  11. additionRelevant fractions containing the target compound
  12. customevaporated to dryness under reduced pressure

Sources & evidence

ORD record
ord-9c08fae67b52493f84877923a16ba1a4
Source dataset
uspto-grants-2015_05
Patent number
US09029409B2

Reaction notes

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