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Diisopropylamine → HCID 86658257, 화합물

HRID 1040179
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HRID 1040179 반응식
C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[C:16]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:17]=[C:18]([C:20]2[S:24][CH:23]=[N:22][CH:21]=2)[CH:19]=1.[Li+].CC([N-]C(C)C)C.[CH3:44][C:45]1([CH3:56])[CH2:50][C:49](=O)[CH2:48][CH2:47][CH:46]1[C:52]([O:54]C)=[O:53].[Li]>C1COCC1>[CH3:56][C:45]1([CH3:44])[CH2:50][C@:49]2([C:23]3[S:24][C:20]([C:18]4[CH:17]=[C:16]([NH:25][C:26]5[N:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][N:27]=5)[CH:15]=[C:14]([CH3:13])[CH:19]=4)=[CH:21][N:22]=3)[CH2:48][CH2:47][C@H:46]1[C:52](=[O:53])[O:54]2
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참가 물질

8

반응물 6

HCID 7912DiisopropylamineHCID 2724682Lithium diisopropylamideHCID 3028194LithiumHCID 58456348Cyclohexanecarboxylic acid, 2,2-diMethyl-4-oxo-, Methyl esterHCID 58456403N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine2회HCID 178418339Butyllithium

생성물 1

HCID 86658257
HCID 86658257, 화합물
수율 4.9%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매3회

반응 조건

온도
-65 °C

실험 절차

A solution of N,N-Diisopropylamine (13.98 mL, 98 mmol) in THF (55 mL) was cooled to −78° C. n-butyllithium (1.6M in hexanes, 61.3 mL, 98 mmol) was added portionwise via syringe, maintaining an internal temperature lower than −65° C. The reaction mixture warmed to −60° C. and aged for 45 min. and then cooled back to −78° C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 4, 2.113 g, 6.28 mmol) in THF (55 mL) was transferred via cannula (using positive pressure) to the freshly made LDA over the course of 30 min, maintaining the internal temperature below −70° C. The reaction mixture was aged at −78° C. for 35 min, warmed to −50° C. and aged for another 15 min., then cooled to −70° C. A solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (9.04 g, 49.1 mmol) in THF (50 mL) was transferred via cannula (using positive pressure) to the flask containing the lithium salt, over the course of 45 min, maintaining the internal temperature below −65° C. The reaction was aged at −65° C. for 20 min. The cold bath was removed and the reaction allowed to warm to rt. The solution was cooled to 0° C. and quenched using ethanol (1 mL) and water (1 mL). The mixture was diluted with EtOAc (1 L) and washed with saturated ammonium chloride (3 times, total volume of wash 1.5 L). The organic layer was concentrated under reduced pressure and purified by column chromatography on silica (0-30% EtOAc:Hexanes) to afford the title compound (149 mg, 0.8%) as a yellow solid. MS ESI: [M+H]+ m/z 489. 1H NMR (600 MHz, CDCl3) δ 8.66 (d, J=4.8, 1H), 7.89 (d, J=7.0, 2H), 7.39 (s, 1H), 7.29-7.22 (m, 1H), 7.11-7.01 (m, 2H), 2.40 (m, 1H) 2.39 (s, 3H), 2.29 (m, 2H), 2.15 (m, 2H), 2.05-1.90 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H). rhSYK activity=++

후처리

  1. additionwas added portionwise via syringe
  2. temperatureThe reaction mixture warmed to −60° C. and aged for 45 min.
  3. temperaturecooled back to −78° C
  4. temperaturemaintaining the internal temperature below −70° C
  5. temperaturewarmed to −50° C.
  6. waitaged for another 15 min.
  7. temperaturecooled to −70° C
  8. temperatureover the course of 45 min, maintaining the internal temperature below −65° C
  9. waitThe reaction was aged at −65° C. for 20 min
  10. customThe cold bath was removed
  11. temperatureto warm to rt
  12. temperatureThe solution was cooled to 0° C.
  13. customquenched
  14. additionThe mixture was diluted with EtOAc (1 L)
  15. washwashed with saturated ammonium chloride (3 times, total volume of wash 1.5 L)
  16. concentrationThe organic layer was concentrated under reduced pressure
  17. custompurified by column chromatography on silica (0-30% EtOAc:Hexanes)

출처 및 근거

ORD 기록
ord-77a296d6ccf24a27b95f91836489eb20
출처 데이터셋
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08551984B2

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