Monomethyl terephthalate chloride → methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid

HRID 41494

反応式

HRID 41494 の反応式
[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[C:10](CN)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[C:25]([O:36]C)(=O)[C:26]1[CH:34]=[CH:33][C:29]([C:30]([O-:32])=[O:31])=[CH:28][CH:27]=1.[CH:38]([N:41](CC)C(C)C)(C)C.[Cl-].[C:48](OC)(=O)C1C=CC(C([O-])=O)=CC=1>O1CCCC1>[CH3:48][C:28]1[CH:27]=[C:26]([C:25]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=4)[N:11]=[C:10]([NH:41][CH3:38])[N:9]=3)[CH:3]=2)=[O:36])[CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31]

参加物

5

反応物 3

HCID 22493623Monomethyl terephthalate chlorideHCID 25196907[4-(3-Aminophenyl)-6,7-dimethoxyquinazolin-2-yl]methylamineHCID 86617149monomethyl terephthalate chloride N,N-diisopropylethylamine

生成物 1

HCID 66646296methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
0 °C

実験手順

A suspension of 2.000 kg (6.39 mol) of [4-(3-aminophenyl)-6,7-dimethoxyquinazolin-2-yl]methylamine in 71.14 kg of tetrahydrofuran was stirred in a nitrogen atmosphere while being cooled at 0° C. To the suspension was added dropwise 16.70 kg of “monomethyl terephthalate chloride/N,N-diisopropylethylamine” solution (monomethyl terephthalate chloride content: 1.40 kg, 7.03 mol) over 1 hour and 26 minutes, and the container was washed with 1.40 L of 1,2-dimethoxyethane. The mixture was stirred at 0° C. for 13 hours and 4 minutes. Under cooling at 0° C., 36.5 kg of ethyl acetate was added to the reaction mixture and then 80.1 kg of a 5% aqueous solution of sodium hydrogencarbonate was added dropwise, and the mixture was stirred at 20° C. for 1 hour and 10 minutes. Then, 37.3 kg of ethyl acetate was added into the mixture, the mixture was stirred, and the water layer was separated. The organic layer was washed with 40.0 kg of a 5% aqueous solution of sodium chloride, 40.2 kg of water, and 40.1 kg of water in this order. The organic layer was concentrated under reduced pressure at a jacket temperature of 40° C., 23.70 kg of methanol was added to the residue, and stirred for 1 hour and 1 minute while being heated to 60 to 66° C. 23.60 kg of 2-propanol was added dropwise to the suspension over 1 hour while stirring the suspension at a jacket temperature of 50° C. Then, the suspension was cooled at a cooling rate of 10° C./hour and stirred at 20° C. for 12 hours and 23 minutes. The precipitated crystals were filtered, rinsed with a mixed solution of 3.00 L of methanol and 3.00 L of 2-propanol and 6.00 L of 2-propanol in this order to yield 5.52 kg of a crude product (content of the target compound: 2.57 kg, 5.44 mol) as pale yellow crystals (yield: 85.3%).

後処理

  1. wash26 minutes, and the container was washed with 1.40 L of 1,2-dimethoxyethane
  2. stirringThe mixture was stirred at 0° C. for 13 hours and 4 minutes
  3. temperatureUnder cooling at 0° C.
  4. addition36.5 kg of ethyl acetate was added to the reaction mixture
  5. addition80.1 kg of a 5% aqueous solution of sodium hydrogencarbonate was added dropwise
  6. stirringthe mixture was stirred at 20° C. for 1 hour and 10 minutes
  7. additionThen, 37.3 kg of ethyl acetate was added into the mixture
  8. stirringthe mixture was stirred
  9. customthe water layer was separated
  10. washThe organic layer was washed with 40.0 kg of a 5% aqueous solution of sodium chloride, 40.2 kg of water, and 40.1 kg of water in this order
  11. concentrationThe organic layer was concentrated under reduced pressure at a jacket temperature of 40° C., 23.70 kg of methanol
  12. additionwas added to the residue
  13. stirringstirred for 1 hour and 1 minute
  14. temperaturewhile being heated to 60 to 66° C
  15. addition23.60 kg of 2-propanol was added dropwise to the suspension over 1 hour
  16. stirringwhile stirring the suspension at a jacket temperature of 50° C
  17. temperatureThen, the suspension was cooled at a cooling rate of 10° C./hour
  18. stirringstirred at 20° C. for 12 hours and 23 minutes
  19. filtrationThe precipitated crystals were filtered
  20. washrinsed with a mixed solution of 3.00 L of methanol and 3.00 L of 2-propanol and 6.00 L of 2-propanol in this order

出典と根拠

ORDレコード
ord-111941b8e1a14f11967b57b8893aded5
出典データセット
uspto-grants-2013_09
特許番号
US08530654B2

関連ノート

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