Sodium Carbonate → (S)-ethyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)oxy)propanoate

HRID 1752425Notes

Reaction equation

HRID 1752425 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[OH:12][C@@H:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[H-].[Na+].[F:22][C:23]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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]>[C:8]([C:6]1[N:7]=[C:2]([C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:44][CH:43]=3)=[CH:33][CH:32]=2)[N:3]=[C:4]([O:12][C@@H:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1)(=[O:9])[NH2:10]

Participants

8

Reactant 5

HCID 10340Sodium CarbonateHCID 24758Sodium hydrideHCID 92831(L)-ethyl lactateHCID 2411282,6-Dichloropyrimidine-4-carboxamideHCID 666684382-[4-(4-Fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Product 1

HCID 71290103(S)-ethyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)oxy)propanoateYield 90%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2,6-dichloropyrimidine-4-carboxamide (0.385 g, 2.01 mmol) in THF (10 mL) was added (S)-ethyl 2-hydroxypropanoate (0.26 mL, 2.3 mmol). The mixture was cooled on a dry-ice acetone bath and 60% NaH in mineral oil (0.094 g, 2.4 mmol) was added. The reaction was allowed to warm up slowly and after 2 h was quenched with 2 mL 10% citric acid solution. The reaction mixture was partitioned between 50 mL EtOAc and 25 mL brine and the organic fraction dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.691 g, 2.20 mmol), 2M aqueous Na2CO3 (2.0 mL, 4.0 mmol), and PdCl2(dppf) (0.091 g, 0.11 mmol) were added. The reaction vessel was flushed with argon, sealed, and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 10-50% acetone in hexanes. The product fractions were evaporated in vacuo to give (S)-ethyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)oxy)propanoate as a pale tan oil (0.762 g, 1.79 mmol, 90% yield). LC/MS: m/z=426.2 [M+H]+.

Workup

  1. temperatureThe mixture was cooled on a dry-ice acetone bath
  2. temperatureto warm up slowly and after 2 h
  3. customwas quenched with 2 mL 10% citric acid solution
  4. customThe reaction mixture was partitioned between 50 mL EtOAc and 25 mL brine
  5. dry with materialthe organic fraction dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue was dissolved in dioxane (10 mL)
  9. customThe reaction vessel was flushed with argon
  10. customsealed
  11. temperatureAfter cooling
  12. customthe reaction mixture was evaporated in vacuo
  13. customthe residue chromatographed over silica gel with 10-50% acetone in hexanes
  14. customThe product fractions were evaporated in vacuo

Sources & evidence

ORD record
ord-460c9aacc3864dfdb302f4a2e5e8efc1
Source dataset
uspto-grants-2015_10
Patent number
US09163008B2

Reaction notes

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