Tetrahydrofuran → 2-{1-[(7-Chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid

HRID 968887

반응식

HRID 968887 반응식
[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:29])=[N:9]2)=[CH:4][CH:3]=1.C[O:31]CCOC.O1CCCC1.[OH-].[K+]>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:20]([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]([OH:31])=[O:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[N:9]2)=[CH:4][CH:3]=1

참가 물질

6

반응물 4

HCID 8028TetrahydrofuranHCID 80711,2-DimethoxyethaneHCID 14797Potassium HydroxideHCID 131664Pagoclone

생성물 1

HCID 98025152-{1-[(7-Chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid수율 85%

시약·촉매·용매 1

HCID 962Water용매

반응 조건

온도
30 °C

실험 절차

To a reactor was charged racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone (170 kg), 1,2-dimethoxyethane (730 L), tetrahydrofuran (THF, 990 L). The slurry was heated to 30° C. and a solution of potassium hydroxide (140 Kg) in water (1730 L) was added. The slurry was stirred at 34° C. for 34 hours. The solution was cooled to 20° C. and the lower aqueous layer was removed and replaced with water (1000 L). The solution was adjusted to pH 9.0 with 4N hydrochloric acid. The solution was vacuum distilled at 30° C. to remove the THF. Water (550 L) was added and the pH of the reaction was adjusted to 11.5 with 2N potassium hydroxide. The solution was filtered to remove residual racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone. To the liquors was added methylene chloride (1200 L) and the pH was adjusted to 1.4 with 4N HCl. The aqueous layer was removed. The organic layer was washed with water (700 L) and the water was discarded. The organic layer was concentrated under vacuum and replaced with methanol (500 L). The slurry was cooled to 10° C., water was added (500 L), and the mixture was cooled to 0° C. The resulting precipitate was isolated by filtration and dried under vacuum at 50° C. to afford 150 kg (85%) of racemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl]-benzoic acid as a white solid. DCI/MS: M+H+ at 426, 100%. M.P. 173-4° C. UV maxima at 236 nm, 268 nm, and 353 nm.

후처리

  1. temperatureThe solution was cooled to 20° C.
  2. customthe lower aqueous layer was removed
  3. distillationdistilled at 30° C.
  4. customto remove the THF
  5. additionWater (550 L) was added
  6. filtrationThe solution was filtered
  7. customto remove residual racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone
  8. additionTo the liquors was added methylene chloride (1200 L)
  9. customThe aqueous layer was removed
  10. washThe organic layer was washed with water (700 L)
  11. concentrationThe organic layer was concentrated under vacuum
  12. temperatureThe slurry was cooled to 10° C.
  13. additionwater was added (500 L)
  14. temperaturethe mixture was cooled to 0° C
  15. customThe resulting precipitate was isolated by filtration
  16. customdried under vacuum at 50° C.

출처 및 근거

ORD 기록
ord-3f85d83300c940eb8632dfea1fa9e044
출처 데이터셋
uspto-grants-2007_12
특허 번호
US07304158B2

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