Hydrochloric Acid → HCID 11612313, compound

HRID 1027928Notes

Reaction equation

HRID 1027928 reaction equation
Cl.[Cl:2][C:3]1[C:4]([F:40])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:38][CH3:39])=[C:17]([O:20][C@@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@@H:23]([C:34]([NH:36][CH3:37])=[O:35])[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1>O1CCOCC1.C(#N)C>[Cl:2][C:3]1[C:4]([F:40])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:38][CH3:39])=[C:17]([O:20][C@@H:21]4[CH2:26][CH2:25][NH:24][C@@H:23]([C:34]([NH:36][CH3:37])=[O:35])[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1

Participants

5

Reactant 2

HCID 313Hydrochloric Acid2×HCID 67240730HCID 67240730, compound

Product 1

HCID 11612313HCID 11612313, compoundYield 57%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent2×

Procedure

4M Hydrogen chloride (7.5 ml) in dioxane was added to a stirred solution of (1) tert-butyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (4.17 g) in acetonitrile (10 ml) and stirred for 2 hours at room temperature. A second portion of 4M Hydrogen chloride (3.75 ml) in dioxane was added and the mixture stirred a further 1½ hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residues were purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the desired product were combined and evaporated. The resulting solids were triturated with iso-hexane/methylene chloride filtered and dried under high vacuum at 50° C. to give the title product as a white solid (1.94 g, 57%); 1H NMR Spectrum: (DMSO d6) 1.67-1.82 (m, 2H); 1.83-1.94 (m, 1H); 1.98-2.08 (m, 1H); 2.59 (d, 3H); 2.74-2.83 (m, 1H); 2.90-3.01 (m, 1H); 3.48-3.55 (m, 1H); 3.94 (s, 3H); 4.83 (br s, 1H); 7.22 (s, 1H); 7.23-7.30 (m, 1H); 7.43-7.57 (m, 2H); 7.75-7.81 (m, 1H); 7.84 (s, 1H); 8.37 (s, 1H); 9.52 (s, 1H); Mass Spectrum: (M+H)+ 460.

Workup

  1. stirringthe mixture stirred a further 1½ hours
  2. customThe reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution
  3. washThe organics were washed with brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customevaporated
  7. customThe residues were purified by column chromatography
  8. washeluting with methylene chloride/methanol (saturated with ammonia) (96/4)
  9. additionThe fractions containing the desired product
  10. customevaporated
  11. customThe resulting solids were triturated with iso-hexane/methylene chloride
  12. filtrationfiltered
  13. customdried under high vacuum at 50° C.

Sources & evidence

ORD record
ord-e7d25fd33fbc469a8bacb1120b587ab5
Source dataset
uspto-grants-2014_05
Patent number
US08735410B2

Reaction notes

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