Sodium Carbonate → (R)-2-{3-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione

HRID 1517349Notes

Reaction equation

HRID 1517349 reaction equation
[NH2:1][C@@H:2]([C:6]1[N:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH2:3][C:4]#[CH:5].C(N(C(C)C)CC)(C)C.[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:45][CH2:46][CH:47]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.ClC(Cl)C>[Cl:24][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:23])[N:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]([C@H:2]([NH:1][CH2:47][CH2:46][CH2:45][N:36]3[C:37](=[O:44])[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]3=[O:34])[CH2:3][C:4]#[CH:5])=[N:7]2)=[CH:12][CH:11]=1

Participants

8

Reactant 5

HCID 10340Sodium CarbonateHCID 75525Phthalimide, N-(2-formylethyl)-HCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 57516539(R)-(1-amino-but-3-ynyl)-7-chloro-3-phenylamino-3H-quinazolin-4-one

Product 1

HCID 57695432(R)-2-{3-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dioneYield 95.8%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 63651,1-DichloroethaneSolvent

Procedure

To a mixture of (R)-(1-amino-but-3-ynyl)-7-chloro-3-phenylamino-3H-quinazolin-4-one (4.60 g, 12.2 mmol) and diisopropylethylamine (DIPEA) (5.5 ml) in dichloromethane (60 ml) was added a solution of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (2.45 g, 12.1 mmol) in dichloroethane (10 ml), followed by a solution of sodium triacetoxy borohydride (NaBH(OAc)3) (0.25M in dichloroethane, 100 ml). The reaction mixture was stirred at room temperature and the reaction progress was monitored by HPLC/MS. Upon completion, a saturated sodium carbonate solution (100 ml) was added. The resulted organic layer was collected and washed with brine solution. The solvent was removed and residue was purified by flash column to afford 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (6.1 g, 95%) as off-white solid. M.p. 78-80° C. LCMS: m/e 526 [M+H]. 1H NMR (DMSO-d6): δ 9.09 (s, br, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.83-7.76 (m, 5H), 7.58 (dd, J=8.8 and 2.0 Hz, 1H), 7.17 (t, J=7.6 Hz, 2H), 6.83 (brm, 1H), 6.65 (m, 2H), 4.1 and 4.0 (s, s, br, 1H, rotomers), 3.6 (t, J=6.8 Hz, 2H), 2.75 (s, br, 1H), 2.67-2.52 (brm, 2H), 2.35 (brm, 2H), 1.67 (brm, 2H).

Workup

  1. customThe resulted organic layer was collected
  2. washwashed with brine solution
  3. customThe solvent was removed
  4. customresidue was purified by flash column

Sources & evidence

ORD record
ord-3c417d261287447cb1d9fc29ebb7fead
Source dataset
uspto-grants-2012_07
Patent number
US08232285B2

Reaction notes

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