Dichloromethane → N-(4-chloro-2-fluorophenyl)-6-methoxy-7-{[(3R)-1-methylpiperidin-3-yl]methoxy}quinazolin-4-amine

HRID 2227929Notes

Reaction equation

HRID 2227929 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1.Cl[N:11]([C:19]1[C:28]2[C:23](=[CH:24][C:25](O)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:64]>>[Cl:64][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:9][CH2:8][C@@H:4]4[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:13]([F:18])[CH:14]=1

Participants

6

Reactant 5

HCID 6344Dichloromethane2×HCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 920113(R)-(1-methylpiperidin-3-yl)methanolHCID 1359906824-(Chloro-2-fluoroanilino)7-hydroxy-6-methoxyquinazoline

Product 1

HCID 5329055N-(4-chloro-2-fluorophenyl)-6-methoxy-7-{[(3R)-1-methylpiperidin-3-yl]methoxy}quinazolin-4-amineYield 52%

Procedure

A solution of (R)-(1-methylpiperidin-3-yl)methanol (2.29 g, 18 mmol) in methylene chloride (10 ml) was added to a stirred mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (4.0 g, 12.5 mmol), (prepared as described for the starting material in Example 2), and triphenylphosphine (9.81 g, 37.5 mmol) in methylene chloride (200 ml). Diethyl azodicarboxylate (5.87 ml, 37 mmol) was added dropwise and the reaction mixture was stirred for 18 hours at ambient temperature. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (a gradient from 100/0/0 to 85/15/0.1). The purified product was triturated with ethyl acetate, collected by filtration, washed with ethyl acetate and dried to give (R)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline (2.78 g, 52%).

Workup

  1. custom(prepared
  2. customThe volatiles were removed by evaporation
  3. customthe residue was purified by column chromatography
  4. washeluting with methylene chloride/methanol/aqueous ammonia (a gradient from 100/0/0 to 85/15/0.1)
  5. customThe purified product was triturated with ethyl acetate
  6. filtrationcollected by filtration
  7. washwashed with ethyl acetate
  8. customdried

Sources & evidence

ORD record
ord-8fa460324287420ea06051702c1b06fd
Source dataset
uspto-grants-2002_07
Patent number
US06414148B1

Reaction notes

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