Hydrochloric Acid → 4-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(3(methylsulphonyl)propoxy)quinazoline hydrochloride

HRID 547185Notes

Reaction equation

HRID 547185 reaction equation
[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[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]([O:43][CH3:44])[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])=[C:40]([O:43][CH3:44])[CH:41]=3)[N:36]=[CH:35][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 184747804-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(3(methylsulphonyl)propoxy)quinazoline hydrochlorideYield 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 (1.36g). 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 freer 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 recrystalilsed from methanol/methylene chloride/hexane to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3(methylsulphonyl)propoxy)quinazoline hydrochloride (640 mg, 29%).

Workup

  1. custom(prepared
  2. filtrationthe resulting precipitate was collected by filtration
  3. customdried
  4. customto give crude product (1.36g)
  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 freer crude product (0.23 g)
  14. filtrationThe precipitated product was collected by filtration

Sources & evidence

ORD record
ord-0f19f19a506242849895b3b30f6cd14a
Source dataset
uspto-grants-2011_05
Patent number
USRE042353E1

Reaction notes

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