Diisopropylethylamine → (S)-methyl 6-((4-amino-6-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidin-5-yl)ethynyl)nicotinate

HRID 1777709Notes

Reaction equation

HRID 1777709 reaction equation
[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]([C:24]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:32](=[O:40])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[Cl:41])[N:25]=1)[CH3:23].[F-].[K+].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=2)=[C:6]([NH:21][C@H:22]([C:24]2[N:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:32](=[O:40])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[Cl:41])[N:25]=2)[CH3:23])[N:5]=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 522689Potassium FluorideHCID 71232632(S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-oneHCID 86723626Methyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate

Product 1

HCID 76286376(S)-methyl 6-((4-amino-6-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidin-5-yl)ethynyl)nicotinate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

To methyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate (50 mg, 0.17 mmol) (prepared according to the procedure in Example 3 above) in NMP (5 mL) was added (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (62 mg 0.21 mmol) (prepared according to the procedure in Example 2A above), KF (33 mg 0.35 mmol), and Hunig's base (0.15 ml, 0.21 mmol). After stirring overnight at 120° C. the reaction was cooled to rt. Water was added. The precipitate was filtered, and then dissolved in DCM. Purification on silica with 0 to 100% EtOAc in hexanes then 0 to 20% MeOH in EtOAc gave material that required further purification. Purification on a reverse phase system run from 0 to 95% ACN in water (0.1% TFA) gave (S)-methyl 6-((4-amino-6-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidin-5-yl)ethynyl)nicotinate.

Workup

  1. customprepared
  2. temperaturewas cooled to rt
  3. filtrationThe precipitate was filtered
  4. dissolutiondissolved in DCM
  5. customPurification on silica with 0 to 100% EtOAc in hexanes
  6. custom0 to 20% MeOH in EtOAc gave material that required
  7. customfurther purification
  8. customPurification on a reverse phase system

Sources & evidence

ORD record
ord-d14dc3fe5e9646e895a9b062e9ec1ac5
Source dataset
uspto-grants-2016_02
Patent number
US09266878B2

Reaction notes

Loading…