Potassium Phosphate, Tribasic → N-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxamide

HRID 634312노트

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HRID 634312 반응식
[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:81]1[N:86]=[C:85]([C:87]([NH:89][CH:90]2[CH2:92][CH2:91]2)=[O:88])[CH:84]=[CH:83][N:82]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:90]1([NH:89][C:87]([C:85]2[CH:84]=[CH:83][N:82]=[C:81]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:9][N:8]=5)[CH:11]=4)[N:15]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:14]=3)[N:86]=2)=[O:88])[CH2:92][CH2:91]1

참가 물질

6

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 68328163HCID 68328163, 화합물HCID 86725119HCID 86725119, 화합물

생성물 1

HCID 68328372N-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxamide수율 89%

시약·촉매·용매 1

HCID 9811564Bis(dibenzylideneacetone)palladium촉매

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온도
130 °C

실험 절차

N-Isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.300 g, 0.574 mmol), Xphos (Strem Chemicals, Newburyport, Mass., 16 mg, 0.034 mmol), Pd2(dba)3 (Strem Chemicals, Newburyport, Mass., 16 mg, 0.017 mmol), potassium phosphate (0.366 g, 1.723 mmol) and 2-chloro-N-cyclopropylpyrimidine-4-carboxamide (0.136 g, 0.689 mmol) were weighed into a 5 mL glass microwave tube. The tube was purged with argon, the solids were treated with dioxane (3 mL) and water (0.30 mL) and the tube was heated at 130° C. for 20 min in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden). The reaction mixture was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography using an ISCO Combiflash Rf(25 g Thomson Single Step silica gel column; 0-10% MeOH in DCM) to give N-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxamide (284 mg, 0.509 μmol, 89% yield) as a light brown tar. MS (ESI, pos. ion) m/z: 558.0 (M+H)+. N-Cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxamide (284 mg, 0.509 mmol) was weighed into a 20 mL glass microwave tube, and was treated with dioxane (5.0 mL) and 1 N NaOH (1.5 mL). The solution was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 10 min. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL). The organic layer was concentrated in vacuo. The crude residue was dissolved in DMSO (4.0 mL) and purified using a Gilson automated platform (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 20-95% 0.1% TFA/CH3CN in 0.1% TFA/water by volume over 10 min), then dried in a Genevac Series II Evaporator affording the title compound (31.5 mg, 0.061 mmol, 11.95% yield) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 404.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12-12.22 (m, 1H), 9.04 (d, J=5.1 Hz, 1H), 8.98 (s, 1H), 8.93 (d, J=4.5 Hz, 1H), 8.84 (d, J=2.9 Hz, 1H), 7.83 (d, J=7.0 Hz, 1H), 7.71 (dd, J=8.5, 1.7 Hz, 1H), 7.67 (d, J=4.9 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 3.76 (dq, J=13.2, 6.4 Hz, 1H), 2.87-3.00 (m, 1H), 1.24 (d, J=6.5 Hz, 6H), 0.73-0.84 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.84 (s, 3F).

후처리

  1. customThe tube was purged with argon
  2. additionthe solids were treated with dioxane (3 mL) and water (0.30 mL)
  3. additionThe reaction mixture was treated with water
  4. extractionextracted with EtOAc
  5. washThe organic layer was washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude material was purified by flash chromatography

출처 및 근거

ORD 기록
ord-c4cf7a72b9ca497ab24134b389e186f0
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09321756B2

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