Pyridine → N,N-dimethyl-5-[3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-[(3-methyl-1,2,4-thiadiazol-5-yl)carbamoyl]phenoxy]pyrazine-2-carboxamide

HRID 600527Notes

Reaction equation

HRID 600527 reaction equation
ClC(N(C)C)=C(C)C.[CH3:9][N:10]([CH3:37])[C:11]([C:13]1[N:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)[C:23](O)=[O:24])=[N:17][CH:18]=1)=[O:12].[CH3:38][C:39]1[N:43]=[C:42]([NH2:44])[S:41][N:40]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:37][N:10]([CH3:9])[C:11]([C:13]1[CH:18]=[N:17][C:16]([O:19][C:20]2[CH:21]=[C:22]([C:23](=[O:24])[NH:44][C:42]3[S:41][N:40]=[C:39]([CH3:38])[N:43]=3)[CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)=[CH:15][N:14]=1)=[O:12]

Participants

6

Reactant 4

HCID 1049PyridineHCID 3506395-Amino-3-methyl-1,2,4-thiadiazoleHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 59761148HCID 59761148, compound2×

Product 1

HCID 24951580N,N-dimethyl-5-[3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-[(3-methyl-1,2,4-thiadiazol-5-yl)carbamoyl]phenoxy]pyrazine-2-carboxamideYield 72%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.142 mL, 1.07 mmol) was added to a solution of 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 45) (358 mg, 0.9 mmol) in DCM (7 mL) and stirred at ambient temperature for 30 minutes. 3-Methyl-1,2,4-thiadiazol-5-amine (CAS no. 17467-35-5) (206 mg, 1.8 mmol) and pyridine (0.147 mL, 1.8 mmol) were added and the reaction stirred for 20 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and DCM (15 mL), washed with water (10 mL) and filtered to give a solid which was washed with water and dried. The filtrate was washed with citric acid (1N, 10 mL), water (10 mL), saturated sodium bicarbonate solution (10 mL), brine (10 mL), dried (MgSO4) and evaporated. The residue was combined with the solid isolated from the filtration and purified by flash chromatography on silica eluting with a gradient of 0-3% methanol in DCM to afford the product (322 mg, 72%). 1H NMR δ (300 MHz, CDCl3) 1.93-2.06 (m, 1H), 2.45 (s, 3H), 2.55-2.66 (m, 1H), 2.80 (s, 3H), 3.03 (s, 6H), 3.19-3.53 (m, 2H), 5.14 (t, 1H), 7.30 (s, 1H), 7.63 (s, 1H), 7.72 (s, 1H), 8.43 (s, 1H), 8.58 (s, 1H), 11.9-12.8 (br s, 1H); m/z 498 (M+H+).

Workup

  1. stirringthe reaction stirred for 20 hours
  2. customThe solvent was removed under reduced pressure
  3. dissolutionThe residue was dissolved in ethyl acetate (15 mL)
  4. washDCM (15 mL), washed with water (10 mL)
  5. filtrationfiltered
  6. customto give a solid which
  7. washwas washed with water
  8. customdried
  9. washThe filtrate was washed with citric acid (1N, 10 mL), water (10 mL), saturated sodium bicarbonate solution (10 mL), brine (10 mL)
  10. dry with materialdried (MgSO4)
  11. customevaporated
  12. customisolated from the filtration
  13. custompurified by flash chromatography on silica eluting with a gradient of 0-3% methanol in DCM

Sources & evidence

ORD record
ord-feb3b12a7da847cc9b05a1f68d26c251
Source dataset
uspto-grants-2011_03
Patent number
US07902200B2

Reaction notes

Loading…