Hydrochloric Acid → HCID 18753470, compound

HRID 1838549Notes

Reaction equation

HRID 1838549 reaction equation
[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].N(C(N1CCCCC1)=O)=N[C:11](N1CCCCC1)=[O:12].[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][C:39](O)=[C:40](OC)[CH:41]=3)[N:36]=[CH:35][N:34]=2)=[C:30]([F:48])[CH:29]=1.C(P(CCCC)CCCC)CCC.Cl>C(Cl)Cl.CC(C)=O.CO.C(Cl)Cl>[ClH:27].[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:40][CH:41]=3)[N:36]=[C:35]([O:12][CH3:11])[N:34]=2)=[C:30]([F:48])[CH:29]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 2004243-(Methylsulfonyl)-1-propanolHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 18753470HCID 18753470, compoundYield 57.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21584259acetone MeOH DCMSolvent

Procedure

3-(Methylsulphonyl)propan-1-ol (0.6 g, 4.3 mmol) followed by 1,1′-(azodicarbonyl)dipiperidine (4.2 g, 16 mmol) in portions were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.5 g, 4.7 mmol), (prepared as described for the starting material in Example 2), and tributylphosphine (4.0 ml, 16 mmol) in methylene chloride (50 ml) under nitrogen. The mixture was stirred for 18 hours, the resulting precipitate was collected by filtration and dried to give crude product (1.36 g). The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (a gradient from 100/0 to 90/10). The semi-purified product was triturated with acetone and the solid product collected by filtration and dried to give further crude product (0.53 g). The filtrate from the trituration was repurified by column chromatography as before to give further crude product (0.23 g). The crude products were combined and dissolved in acetone/methanol/methylene chloride and ethereal hydrogen chloride (6 ml of a 1M solution) added. The precipitated product was collected by filtration and recrystallised from methanol/methylene chloride/hexane to give 4-(4-chloro-2-fluoroanilino)-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline hydrochloride (640 mg, 29%). m.p. >250° C.

Workup

  1. custom(prepared
  2. filtrationthe resulting precipitate was collected by filtration
  3. customdried
  4. customto give crude product (1.36 g)
  5. customThe solvent was removed from the filtrate by evaporation
  6. customthe residue was purified by column chromatography
  7. washeluting with methylene chloride/methanol (a gradient from 100/0 to 90/10)
  8. customThe semi-purified product was triturated with acetone
  9. filtrationthe solid product collected by filtration
  10. customdried
  11. customto give further crude product (0.53 g)
  12. customThe filtrate from the trituration was repurified by column chromatography as before
  13. customto give further crude product (0.23 g)
  14. filtrationThe precipitated product was collected by filtration
  15. customrecrystallised from methanol/methylene chloride/hexane

Sources & evidence

ORD record
ord-fae2d3de297844bbac14f7664d6ef2f4
Source dataset
uspto-grants-2004_01
Patent number
US06673803B2

Reaction notes

Loading…