Dimethylformamide → HCID 11997172, compound

HRID 641984Notes

Reaction equation

HRID 641984 reaction equation
[CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:23](O)=[O:24])[C:13]3=[O:30])[CH2:5]1)([CH3:3])[CH3:2].CN(C=O)C.S(Cl)(Cl)=O.[NH2:40][C:41]1[CH:45]=[CH:44][O:43][N:42]=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:23]([NH:40][C:41]2[CH:45]=[CH:44][O:43][N:42]=2)=[O:24])[C:13]3=[O:30])[CH2:5]1)([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 24386Thionyl ChlorideHCID 18102163-IsoxazolamineHCID 68603382HCID 68603382, compound

Product 1

HCID 11997172HCID 11997172, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred slurry of 3-[6-{[(3S)-1-isopropylpyrrolidin-3-yl]oxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.29 g) and DMF (0.05 ml) in methylene chloride (15 ml) at 0° C. was added thionyl chloride (0.15 ml). The resultant solution was stirred at room temperature for 21 hour. To this mixture was added 3-aminoisoxazole (0.316 ml) and the resultant solution was stirred for 18 hours. The reaction mixture was evaporated and the residue was dissolved in methanol and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution. The fraction containing the product was further purified by column chromatography on an ion exchange column (isolute NH2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) eluting with MeOH. After evaporation and the residue was dissolved in ethyl acetate and triturated with ether, the resultant solid was removed by filtration and iso-hexane was added to the filtrate and the resulting solid was filtered and dried to give 3-[6-{[(3S)-1-isopropylpyrrolidin-3-yl]oxy}-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide as light tan solid (114 mg); NMR Spectrum: (DMSOd6) 1.02 (m, 6H), 1.76 (m, 1H), 2.18 (s, 3H), 2.27 (m, 1H), 2.40 (m, 2H), 2.85 (m, 3H), 5.01 (m, 1H), 7.04 (m, 1H), 7.49 (m, 2H), 7.60 (d, 1H), 7.72 (d, 1H), 8.07 (m, 2H), 8.21 (s, 1H), 11.45 (s, 1H); Mass Spectrum: M+H+ 474.

Workup

  1. customThe reaction mixture was evaporated
  2. dissolutionthe residue was dissolved in methanol
  3. custompurified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK)
  4. additiona 99:1 mixture of methanol and aqueous ammonia solution
  5. additionThe fraction containing the product
  6. customwas further purified by column chromatography on an ion exchange column (isolute NH2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK)
  7. washeluting with MeOH
  8. customAfter evaporation
  9. dissolutionthe residue was dissolved in ethyl acetate
  10. customtriturated with ether
  11. customthe resultant solid was removed by filtration and iso-hexane
  12. additionwas added to the filtrate
  13. filtrationthe resulting solid was filtered
  14. customdried

Sources & evidence

ORD record
ord-c2d505dd079646a1b2abceeb4e19f2dd
Source dataset
uspto-grants-2010_04
Patent number
US07696215B2

Reaction notes

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