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

HRID 1752390Notes

Reaction equation

HRID 1752390 reaction equation
[C:1]([C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][C@@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=1)(=[O:3])[NH2:2].[F:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:21][CH:20]=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]>[C:1]([C:4]1[N:9]=[C:8]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:40][CH:39]=3)=[CH:29][CH:28]=2)[N:7]=[C:6]([NH:11][C@@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=1)(=[O:3])[NH2:2]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 666684382-[4-(4-Fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 89422814(S)-methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate

Product 1

HCID 71283440(S)-methyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoateYield 51%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of (S)-methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (5.133 g, 19.84 mmol) in dioxane (100 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.858 g, 21.83 mmol), 2M aqueous Na2CO3 (19.9 mL, 39.8 mmol) and PdCl2(dppf) (0.809 g, 0.99 mmol). The reaction vessel was flushed with argon, sealed and heated at 100° C. overnight. After cooling, the reaction mixture was diluted with 500 mL EtOAc and washed with brine (3×100 mL). The organic layer was dried over Na2SO4, filtered and chromatographed over silica gel with 20-60% acetone in hexanes. The product fractions were isolated and evaporated in vacuo to give the product (S)-methyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoate as a yellow-orange solid (4.128 g, 10.05 mmol, 51% yield). LC/MS: m/z=411.2 [M+H]+.

Workup

  1. customThe reaction vessel was flushed with argon
  2. customsealed
  3. temperatureAfter cooling
  4. additionthe reaction mixture was diluted with 500 mL EtOAc
  5. washwashed with brine (3×100 mL)
  6. dry with materialThe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. customchromatographed over silica gel with 20-60% acetone in hexanes
  9. customThe product fractions were isolated
  10. customevaporated in vacuo

Sources & evidence

ORD record
ord-df12e73f5ae3430798e6a75b9f445029
Source dataset
uspto-grants-2015_10
Patent number
US09163008B2

Reaction notes

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