Potassium Carbonate → (+)-2-(4-Ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-fluoroquinolin-7-yl)phenyl)acetamide

HRID 1525940노트

반응식

HRID 1525940 반응식
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[C:56]([F:61])[CH:57]=[N:58]2)=[CH:53][CH:52]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:51]4[CH:60]=[C:59]5[C:54]([CH:55]=[C:56]([F:61])[CH:57]=[N:58]5)=[CH:53][CH:52]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]

참가 물질

8

반응물 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 690851037-Bromo-3-fluoroquinolineHCID 712709392-(4-Bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

생성물 1

HCID 71270827(+)-2-(4-Ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-fluoroquinolin-7-yl)phenyl)acetamide

시약·촉매·용매 2

HCID 178418807HCID 178418807, 화합물촉매2회HCID 312751,4-Dioxane용매

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온도
110 °C

실험 절차

A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (266 mg, 0.47 mmol) in dry 1,4-dioxane (3 mL) was treated with bis(pinacolato)diboron (142 mg, 0.56 mmol), potassium acetate (49 mg, 0.5 mmol) and PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol). The reaction mixture was degassed with nitrogen for ˜3 min and the vessel was purged with nitrogen, sealed, and heated to 110° C. for 3 h. Analysis of a reaction mixture aliquot indicated complete conversion of the starting material to the boronate intermediate. To the cooled reaction mixture was added 7-bromo-3-fluoroquinoline (105 mg, 0.47 mmol), PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol) and 2M aq K2CO3 (0.7 mL, 1.4 mmol). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by reverse phase HPLC (5-75% acetonitrile:water with 0.1% NH4OH) afforded the racemic title product, which was resolved by chiral HPLC (Lux Cell 4, methanol) to afford the title product in 95% ee (29 mg, 12% yield). αD=+26 deg (c=0.14, methanol); MS(ES)+ m/e 495 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.06-1.18 (m, 3 H) 1.63-1.84 (m, 2 H) 1.90-1.97 (m, 2 H) 2.27-2.39 (m, 1 H) 2.53-2.73 (m, 2 H) 2.80 (d, J=11.37 Hz, 1 H) 3.18 (s, 2 H) 3.41 (q, J=7.07 Hz, 2 H) 3.95-4.08 (m, 2 H) 4.53 (s, 1 H) 6.28 (br. s., 1 H) 7.29 (br. s., 1 H) 7.47 (t, J=7.71 Hz, 1 H) 7.55 (dd, J=11.24, 1.89 Hz, 1 H) 7.62 (dd, J=7.96, 1.89 Hz, 1 H) 7.83-7.93 (m, 2 H) 7.93-8.00 (m, 1 H) 8.37 (d, J=1.77 Hz, 1 H) 8.88 (d, J=2.53 Hz, 1 H).

후처리

  1. customThe reaction mixture was degassed with nitrogen for ˜3 min
  2. customthe vessel was purged with nitrogen
  3. customsealed
  4. customTo the cooled reaction mixture
  5. customThe reaction mixture was purged with nitrogen
  6. customsealed
  7. temperatureheated at 120° C. for 1 h
  8. additionThe reaction mixture was diluted with water (50 mL)
  9. extractionextracted with dichloromethane (3×100 mL)
  10. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customPurification of the residue by reverse phase HPLC (5-75% acetonitrile:water with 0.1% NH4OH)

출처 및 근거

ORD 기록
ord-d0f3053f72ae4d62a5321c9167eea091
출처 데이터셋
uspto-grants-2015_07
특허 번호
US09084794B2

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