Triethylamine → N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamine

HRID 1783611Notes

Reaction equation

HRID 1783611 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=O.P(Cl)(Cl)(Cl)=O.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]=[C:31]4[CH2:32][CH2:33][CH2:34][N:30]4[CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 13387N-methyl-2-pyrrolidone2×HCID 24813Phosphorus oxychlorideHCID 53630477Allitinib metabolite M62×

Product 1

HCID 57590588N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamineYield 8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamine is prepared by reacting N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine and 1-methyl-pyrrolidin-2-one. Phosphorous oxychloride (0.047 g, 0.30 mmol) is added to a stirred solution of 1-methyl-pyrrolidin-2-one (0.63 g, 0.63 mmol) in methylene chloride (3 ml) at −78° C. under N2 (Bullock et al WO0220526). After 10 minutes, the reaction mixture is warmed to room temperature and stirred for 1 hour. N4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine (0.100 g, 0.253 mmol) is added followed by Et3N (0.031 g, 0.30 mmol). After 16 hours, the reaction mixture is quenched with saturated aqueous Na2CO3, the layers separated and the aqueous layer extracted with methylene chloride. The combined organic extracts are dried (Na2SO4), concentrated and purified on a silica gel column (10:2:1 EtOAc:hexanes:MeOH with 0.3% NH4OH solution) to yield 0.010 g (8%) N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamine. MS APCI (+) m/z 476, 478 (M+1, Cl pattern) detected; 1H NMR (400 MHz, MeOH4) δ 8.42 (s, 1 H), 7.89 (s, 2 H), 7.77 (d, 1 H), 7.58 (m, 2 H), 7.33 (m, 3 H), 7.18 (d, 1 H), 7.04 (t, 1 H), 5.20 (s, 2 H), 3.60 (t, 2 H), 2.61 (t, 2 H), 2.03 (m, 2 H).

Workup

  1. customN4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(1-methyl-pyrrolidin-2-ylidene)-quinazoline-4,6-diamine is prepared
  2. waitAfter 16 hours
  3. customthe reaction mixture is quenched with saturated aqueous Na2CO3
  4. customthe layers separated
  5. extractionthe aqueous layer extracted with methylene chloride
  6. dry with materialThe combined organic extracts are dried (Na2SO4)
  7. concentrationconcentrated
  8. custompurified on a silica gel column (10:2:1 EtOAc:hexanes:MeOH with 0.3% NH4OH solution)

Sources & evidence

ORD record
ord-300b23efc5df41b5afa4511337220cd7
Source dataset
uspto-grants-2009_03
Patent number
US07501427B2

Reaction notes

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