Triphenylphosphine → 1-tert-butyl 2-methyl (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1,2-dicarboxylate

HRID 1027914Notes

Reaction equation

HRID 1027914 reaction equation
[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C@@H:46]1[CH2:51][C@H:50](O)[CH2:49][CH2:48][N:47]1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:45]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][C@H:50]4[CH2:49][CH2:48][N:47]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[C@H:46]([C:44]([O:43][CH3:42])=[O:45])[CH2:51]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 11776TriphenylphosphineHCID 11299919Methyl (2S,4R)-4-hydroxypiperidine-2-carboxylate, N-BOC protectedHCID 574768684-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol

Product 1

HCID 583186481-tert-butyl 2-methyl (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1,2-dicarboxylateYield 69%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

DTAD (13.3 g, 57.9 mmol) dissolved in 50 ml of DCM was added over a period of 10 minutes to a stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-ol (1) (4.94 g, 15.5 mmol, prepared as described in WO 03/082831, Reference Example 2 therein), triphenylphosphine (18.3 g, 69.5 mmol) and (2S,4R)—N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid methyl ester (ex ACROS, 6 g, 23.2 mmol) in DCM (150 ml) at −15° C. (acetone/ice). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, concentrated to approximately 50 ml and purified directly by flash chromatography (silica gel, eluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50) to give 1-tert-butyl 2-methyl (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1,2-dicarboxylate (2) (6 g, 69%) as a white foam; 1H NMR Spectrum: (DMSO d6) 1.47-1.53 (m, 11H), 1.86-1.91 (m, 1H), 2.25-2.36 (m, 1H), 2.95-3.13 (m, 1H), 3.70 (s, 3H), 3.95 (s, 3H), 3.98-4.04 (m, 1H), 4.45 (m, 1H), 4.86-4.94 (m, 1H), 7.31 (t, 1H), 7.51-7.64 (m, 3H), 7.80 (s, 1H), 8.39 (s, 1H), 9.54 (s, 1H); Mass Spectrum: (M+H)+ 561.1.

Workup

  1. customprepared
  2. customat −15° C.
  3. concentrationconcentrated to approximately 50 ml
  4. custompurified directly by flash chromatography (silica gel
  5. washeluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50)

Sources & evidence

ORD record
ord-e13eea648afb491681091cf6c248a9dc
Source dataset
uspto-grants-2014_05
Patent number
US08735410B2

Reaction notes

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