Potassium Phosphate, Tribasic → Tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-cyano-pyrazol-1-yl]piperidine-1-carboxylate

HRID 908471노트

반응식

HRID 908471 반응식
[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[C:42]([C:59]#[N:60])=[N:43][N:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH:45]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:41]2[C:42]([C:59]#[N:60])=[N:43][N:44]([CH:46]3[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:50][CH2:51]3)[CH:45]=2)[CH:13]=[N:12][C:11]=1[N:25]([C:26]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:32])[C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34]

참가 물질

8

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 67388208Tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamateHCID 67388412Tert-butyl 4-(4-bromo-3-cyanopyrazol-1-yl)piperidine-1-carboxylate

생성물 1

HCID 67387978Tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-cyano-pyrazol-1-yl]piperidine-1-carboxylate수율 86.7%

시약·촉매·용매 3

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 312751,4-Dioxane용매

반응 조건

온도
120 °C

실험 절차

Compound [1] was prepared using the following procedure: A mixture of tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (291 mg), tert-butyl 4-(4-bromo-3-cyanopyrazol-1-yl)piperidine-1-carboxylate (150 mg), tris(dibenzylideneacetone)dipalladium (19.33 mg), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine (17.34 mg) and potassium phosphate (0.084 g) in a mixture of dioxane (5 ml) and water (150 μl) was degassed. The resulting suspension was stirred and heated to 120° C. for 3 hours under argon. After the mixture was cooled to room temperature the solvent was concentrated, ethyl acetate (80 ml) and water (20 ml) were added. The organic layer was washed with brine, dried over Magnesium sulphate, filtered and evaporated under reduce pressure. The crude product was purified by flash chromatography on silica gel eluting with 20 to 75% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-cyano-pyrazol-1-yl]piperidine-1-carboxylate (251 mg) as pale pink foam. The N-tert-butoxycarbonyl groups on the resultant product were removed using the procedure described for example 61. The product gave the following characterizing data: NMR Spectrum: (DMSOd6) 1.82 (dd, 1H), 1.87 (dd, 1H), 2.01-2.09 (m, 2H), 2.58-2.67 (m, 2H), 3.04-3.12 (m, 2H), 4.34-4.42 (m, 1H), 7.43-7.52 (m, 2H), 7.81 (dd, 1H), 7.87 (dd, 1H), 7.92 (bs, 2H), 8.58 (s, 2H), 8.51 (s, 1H); Mass spectrum: M+H+ 386.

후처리

  1. customwas degassed
  2. temperatureAfter the mixture was cooled to room temperature the solvent
  3. concentrationwas concentrated
  4. additionethyl acetate (80 ml) and water (20 ml) were added
  5. washThe organic layer was washed with brine
  6. dry with materialdried over Magnesium sulphate
  7. filtrationfiltered
  8. customevaporated
  9. customThe crude product was purified by flash chromatography on silica gel eluting with 20 to 75% ethyl acetate in petroleum ether
  10. customThe solvent was evaporated to dryness

출처 및 근거

ORD 기록
ord-0b2b92438cde43feab3bd355ee0baed5
출처 데이터셋
uspto-grants-2011_09
특허 번호
US08017611B2

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