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Sodium Carbonate → (S)-methyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate

HRID 1752405
Notes
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Reaction equation

HRID 1752405 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:12][C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[N:3]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:12][C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[N:3]=3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 666684382-[4-(4-Fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 89422478(S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate

Product 1

HCID 71283656(S)-methyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylateYield 2%

Reagents, catalysts & solvents 2

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst
HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of the (S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate (4.826 g, 17.63 mmol) in dioxane (100 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.651 g, 21.17 mmol), 2M aqueous Na2CO3 (17.6 mL, 35.2 mmol) and PdCl2(dppf) (0.727 g, 0.89 mmol). The flask was flushed with argon, sealed, and heated on a 100° C. oil bath for 30 minutes. The flask ruptured. As much of the reaction mixture as possible was partitioned between methanol and hexanes. The hexanes were removed and the methanol layer was washed a second time. The methanol fraction was evaporated in vacuo and chromatographed over silica gel with 20-60% EtOAc in hexanes. The product fractions were isolated and evaporated in vacuo and chromatographed a second time over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo and the resulting solid triturated with 2 mL MeOH, filtered, rinsed once with 1 mL MeOH, and dried under vacuum at 40° C. to give (S)-methyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a yellow powder (0.140 g, 0.329 mmol, 2% yield). 1H NMR (400 MHz, DMSO-d6): 8.34-8.25 (3H, m), 7.31-7.24 (2H, m), 7.19-7.14 (2H, m), 7.10 (1H, s), 7.06 (2H, d, J=8.8 Hz), 4.60-4.52 (1H, m), 3.89 (3H, s), 3.64 (3H, s), 1.45 (3H, d, J=7.2 Hz). LC/MS: m/z=426.1 [M+H]+.

Workup

  1. customThe flask was flushed with argon
  2. customsealed
  3. customAs much of the reaction mixture as possible was partitioned between methanol and hexanes
  4. customThe hexanes were removed
  5. washthe methanol layer was washed a second time
  6. customThe methanol fraction was evaporated in vacuo
  7. customchromatographed over silica gel with 20-60% EtOAc in hexanes
  8. customThe product fractions were isolated
  9. customevaporated in vacuo
  10. customchromatographed a second time over silica gel with 10-50% EtOAc in hexanes
  11. customThe product fractions were evaporated in vacuo
  12. customthe resulting solid triturated with 2 mL MeOH
  13. filtrationfiltered
  14. washrinsed once with 1 mL MeOH
  15. customdried under vacuum at 40° C.

Sources & evidence

ORD record
ord-c4313b55411748fba55fd91b73d92a91
Source dataset
uspto-grants-2015_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09163008B2

Reaction notes

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