Pyridine → 3-[5-(Azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(4-methyl1,3-thiazol-2-yl)benzamide

HRID 600510Notes

Reaction equation

HRID 600510 reaction equation
ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH3:39][C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:45][C:42]3[S:43][CH:44]=[C:40]([CH3:39])[N:41]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1

Participants

6

Reactant 4

HCID 1049PyridineHCID 741432-Amino-4-methylthiazoleHCID 6407921-Chloro-N,N-2-trimethylpropenylamine2×HCID 597611423-[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid2×

Product 1

HCID 249519413-[5-(Azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(4-methyl1,3-thiazol-2-yl)benzamideYield 58%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.10 mL, 0.75 mmol) was added to a solution of the 3-[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 6) (265 mg, 0.62 mmol) in DCM (5 mL) and stirred at ambient temperature for 30 minutes, a further aliquot of 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.10 mL) was added and stirring continued for a further 30 minutes. 4-Methyl-1,3-thiazol-2-amine (142 mg, 1.2 mmol) and pyridine (0.10 mL, 1.2 mmol) were added and the reaction stirred for 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and DCM (15 mL), washed with water (2×10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated under reduced pressure to give the crude product which was purified by flash chromatography on silica, eluting with a gradient of 0-5% methanol in DCM, to afford the product (181 mg, 58%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.26 (m, 4H), 2.38 (quintet, 2H), 2.50-2.63 (m, 1H), 2.93 (s, 3H), 3.33-3.56 (m, 2H), 4.26 (t, 2H), 4.69 (t, 2H), 4.84 (t, 1H), 6.54 (s, 1H), 7.15 (s, 1H), 7.36 (s, 1H), 7.53 (s, 1H), 8.32 (s, 1H), 8.82 (s, 1H), 10.43 (s, 1H); m/z 509 (M+H)+

Workup

  1. stirringstirring
  2. waitcontinued for a further 30 minutes
  3. stirringthe reaction stirred for 16 hours
  4. customThe solvent was evaporated under reduced pressure
  5. dissolutionThe residue was dissolved in ethyl acetate (15 mL)
  6. washDCM (15 mL), washed with water (2×10 mL) and brine (10 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. customevaporated under reduced pressure
  10. customto give the crude product which
  11. customwas purified by flash chromatography on silica
  12. washeluting with a gradient of 0-5% methanol in DCM

Sources & evidence

ORD record
ord-a5705b5135a14035a004d9f8aba98d06
Source dataset
uspto-grants-2011_03
Patent number
US07902200B2

Reaction notes

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