Benzeneethanamine, alpha-methyl-, phosphate (1:1) → Methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate

HRID 634306Notes

Reaction equation

HRID 634306 reaction equation
[Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.CC(N)[CH2:15][C:16]1[CH:21]=CC=CC=1.OP(O)(O)=O.[Br-].C1([Zn+])CC1>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH:21]2[CH2:16][CH2:15]2)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 62885Benzeneethanamine, alpha-methyl-, phosphate (1:1)HCID 23156323Methyl 2,4-dichloropyrimidine-5-carboxylateHCID 178419765HCID 178419765, compound

Product 1

HCID 83835308Methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylateYield 31.5%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A 20 mL glass microwave tube was charged with methyl 2,4-dichloropyrimidine-5-carboxylate (Aldrich, St. Louis, Mo., 831 mg, 4.01 mmol and Amphos (Aldrich, St. Louis, Mo., 71.1 mg, 0.100 mmol) were treated with cyclopropylzinc(II) bromide (Rieke Metals, Lincoln, Nebr., 0.5 M in THF, 16.1 mL, 8.03 mmol) via syringe under an atmosphere of argon. The solution was then heated in the microwave at 80° C. for 20 min. The reaction mixture was treated with EtOAc and then with 1 N NaOH resulting in a white suspension as the zinc hydroxide salts precipitated. It was extracted with EtOAc (50 mL) a second time and washed with brine and dried over anhydrous Na2SO4, filtered and concentrated. Purification of the crude residue on the ISCO Combiflash Rf (40 g Redisep column, using 100% DCM) afforded two readily separable peaks. The first eluting peak was found to be methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (269 mg, 1.26 mmol, 31.5% yield) as a white amorphous solid upon concentration. MS (ESI, pos. ion) m/z: 213.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (1H, s), 3.97 (3H, s), 3.12-3.20 (1H, m), 1.34-1.40 (2H, m), 1.20-1.27 (2H, m).

Workup

  1. customwith 1 N NaOH resulting in a white suspension as the zinc hydroxide salts precipitated
  2. extractionIt was extracted with EtOAc (50 mL) a second time
  3. washwashed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification of the crude residue on the ISCO Combiflash Rf (40 g Redisep column, using 100% DCM)
  8. customafforded two readily separable peaks

Sources & evidence

ORD record
ord-4b17d76062a840728fba5cbaac200a06
Source dataset
uspto-grants-2016_04
Patent number
US09321756B2

Reaction notes

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