Diisopropylethylamine → (4-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]quinazolin-6-yl}-thiazol-2-ylmethyl)-carbamic acid ter-butyl ester

HRID 415011Notes

Reaction equation

HRID 415011 reaction equation
[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([Sn](C)(C)C)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].Cl.I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][N:25]=[C:24]2[NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]2[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=2)=[C:34]([CH3:46])[CH:33]=1.CCN(C(C)C)C(C)C.CCOC(C)=O.CO>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][N:25]=[C:24]3[NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=3)=[C:34]([CH3:46])[CH:33]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 21584119Ethylacetate methanolHCID 666233074-Quinazolinamine,6-iodo-n-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]phenyl]-,hydrochlorideHCID 66623970(4-Trimethylstannyl-thiazol-2-ylmethyl)-carbamic acid tert-butyl ester

Product 1

HCID 131727277(4-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]quinazolin-6-yl}-thiazol-2-ylmethyl)-carbamic acid ter-butyl esterYield 29.3%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

(4-Trimethylstannyl-thiazol-2-ylmethyl)-carbamic acid tert-butyl ester (191 mg, 0.507 mmol) and [3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride (0.251 g, 0.478 mmol) (from Step C, Example 3) are dissolved in anhydrous DMF under a nitrogen atmosphere. Hunig's base (0.44 ml, 2.53 mmol), and PdCl2(PPh3)2 are added to the reaction mixture at room temperature. The reaction mixture is degassed and heated at 100° C. overnight. After cooling to room temperature the reaction mixture is diluted with water and thoroughly extracted with EtOAc and DCM. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography on silica with EtOAc-MeOH as an eluant affords 81 mg (0.14 mmol, 28%) of clean desired product.

Workup

  1. customThe reaction mixture is degassed
  2. temperatureAfter cooling to room temperature the reaction mixture
  3. additionis diluted with water
  4. extractionthoroughly extracted with EtOAc and DCM
  5. dry with materialThe combined organic extracts are dried (Na2SO4)
  6. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-87c4b374aac646a2b5edb8ee35d45c2b
Source dataset
uspto-grants-2012_01
Patent number
US08088766B2

Reaction notes

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