Tributylphosphine → 4-(4-Chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline

HRID 1791528Notes

Reaction equation

HRID 1791528 reaction equation
[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(P(CCCC)CCCC)CCC.[O:36]=[S:37]1(=[O:47])[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:45][CH2:44][CH2:43][N:40]4[CH2:39][CH2:38][S:37](=[O:47])(=[O:36])[CH2:42][CH2:41]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1

Participants

7

Reactant 4

HCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 114354734-(3-Hydroxypropyl)thiomorpholine 1,1-DioxideHCID 1356162044-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 219359994-(4-Chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazolineYield 70%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Procedure

4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (5.0 g, 15.6 mmol) was suspended in dichloromethane (150 ml) and tributylphosphine (11.1 ml, 44.6 mmol) was added followed by stirring at ambient temperature for 30 minutes. To this mixture was added 3-(1,1-dioxothiomorpholino)-1-propanol (4.2 g, 21.8 mmol) followed by the addition of 1,1′-(azodicarbonyl)dipiperidine (11.7 g, 46.4 mmol) in portions. The mixture was stirred at ambient temperature overnight then diluted with ether (300 ml) and the precipitate was removed by filtration. The residue was chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give a solid which was triturated with ethyl acetate filtered and dried to give 4-(4-chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (5.4 g, 70%). This was used without further purification in the next step.

Workup

  1. stirringThe mixture was stirred at ambient temperature overnight
  2. customthe precipitate was removed by filtration
  3. customThe residue was chromatographed on silica eluting with dichloromethane and methanol (95/5)
  4. customevaporated
  5. customto give a solid which
  6. customwas triturated with ethyl acetate
  7. filtrationfiltered
  8. customdried

Sources & evidence

ORD record
ord-d77ca0f9e0534ccab0157a4494ac4df6
Source dataset
uspto-grants-2006_07
Patent number
US07074800B1

Reaction notes

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