Dichloromethane → tert-butyl 5-(5-amino-6-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate

HRID 596088Notes

Reaction equation

HRID 596088 reaction equation
[NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:34]2[CH2:35][CH2:36][CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:39]=2)O1.C(Cl)Cl>COCCOC.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]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:36]2[CH2:35][CH2:34][CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:37]=2)=[N:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 59327225tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylateHCID 118046172Methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate

Product 1

HCID 118045639tert-butyl 5-(5-amino-6-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylateYield 60.2%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
110 °C

Procedure

To a mixture of methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (240 mg, 0.70 mmol) in DME (6 mL) and 2 M sodium carbonate (1.0 mL, 2.0 mmol) was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate(180 mg, 0.582 mmol) followed by PdCl2(dppf).CH2Cl2 adduct (14.4 mg, 17.5 μmol). The reaction mixture was heated in microwave at 110° C. for 20 min. The reaction mixture was partitioned between ethylacetate and water. The organic layer was separated, and washed with water and brine. The organic was dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography eluting with 0-50-80% EtOAc in heptane to yield the desired product as a yellow solid (150 mg, 60%). LCMS (m/z): 429.2 (MH+), 1.03 min.

Workup

  1. customThe reaction mixture was partitioned between ethylacetate and water
  2. customThe organic layer was separated
  3. washwashed with water and brine
  4. dry with materialThe organic was dried over sodium sulfate
  5. filtrationfiltered
  6. customevaporated
  7. customThe residue was purified by flash chromatography
  8. washeluting with 0-50-80% EtOAc in heptane

Sources & evidence

ORD record
ord-df4fe5bd386f401abde46e619fe1e56c
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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