Sodium Carbonate → 3-chloro-N-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)propyl]-2-fluoro-benzamide

HRID 1517350Notes

Reaction equation

HRID 1517350 reaction equation
[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35](=[O:67])[N:36]([NH:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:37]([C@H:41]([NH:45][CH2:46][CH2:47][CH2:48][N:49]3[C:57](=[O:58])[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[CH2:42][C:43]#[CH:44])=[N:38]2)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:45]([C@@H:41]([C:37]1[N:36]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:35](=[O:67])[C:34]2[C:39](=[CH:40][C:31]([Cl:30])=[CH:32][CH:33]=2)[N:38]=1)[CH2:42][C:43]#[CH:44])[CH2:46][CH2:47][CH2:48][N:49]1[C:50](=[O:59])[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:57]1=[O:58])=[O:7]

Participants

7

Reactant 5

HCID 10340Sodium CarbonateHCID 81531Diisopropylethylamine2×HCID 3029313-Chloro-2-fluorobenzoic acidHCID 111266512-chloro-1,3-dimethyl-1H-imidazol-3-ium chlorideHCID 57695432(R)-2-{3-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione

Product 1

HCID 576954593-chloro-N-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)propyl]-2-fluoro-benzamideYield 96%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

To a solution of 3-chloro-2-fluoro-benzoic acid (3.2 g, 18.3 mmol) of in acetonitrile (30 ml) was added 2-chloro-1,3-dimethylimidazolium chloride (DMC) (3.3 g, 19.5 mmol), followed by diisopropylethyl amine (6.8 ml, 39 mmol). The resulted solution was stirred at room temperature for 10 min, then transferred into flask containing (R)-2-{3-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (6.1 g) in a 2.5M solution of diisopropylethyl amine in acetonitrile (30 ml). The reaction mixture was stirred at room temperature and the reaction progress was monitored by HPLC/MS. Upon completion, a saturated solution of sodium carbonate (100 ml) was added. The organic layers were collected and the aqueous layer was washed with EtOAc (2×50 ml). The combined organic layers were washed with brine (100 ml) and dried over sodium sulfate. The solvent was removed and residue was separated on silica gel column to afford 3-chloro-N-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)propyl]-2-fluoro-benzamide as off-white solid (7.6 g, 96%). M.p. 130-132° C. LCMS: m/e 682 [M+H]. 1H NMR (CDCl3): δ 8.09 (m, 1H), 7.71 (m, 3H), 7.46 (m, 1H), 7.35 (m, 2H), 7.29 (m, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 7.03 (m, 1H), 6.90 (m, 1H), 6.82 (m, 1H), 6.68 (m, 1H), 6.50 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.51 (m, 1H), 3.38 (m, 1H), 3.26 (m, 1H), 3.06 (m, 1H), 2.88 (m, 1H), 2.01 (s, 1H), 1.80 (m, 1H), 1.54 (m, 1H).

Workup

  1. customtransferred into flask
  2. stirringThe reaction mixture was stirred at room temperature
  3. customThe organic layers were collected
  4. washthe aqueous layer was washed with EtOAc (2×50 ml)
  5. washThe combined organic layers were washed with brine (100 ml)
  6. dry with materialdried over sodium sulfate
  7. customThe solvent was removed
  8. customresidue was separated on silica gel column

Sources & evidence

ORD record
ord-9f67d1fcb3fb4bec92c0e84130366c1c
Source dataset
uspto-grants-2012_07
Patent number
US08232285B2

Reaction notes

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