Tris(1,1-dimethylethyl)phosphine → N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide

HRID 2046897노트

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HRID 2046897 반응식
Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C@@H:17]2[CH2:22][C@H:21]([CH3:23])[CH2:20][C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:32].[F:33][C:34]1[C:39]([OH:40])=[CH:38][CH:37]=[C:36]([F:41])[C:35]=1B(O)O.[F-].[K+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>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.C1COCC1>[NH2:24][C@H:19]1[CH2:20][C@@H:21]([CH3:23])[CH2:22][C@@H:17]([C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:32])=[C:2]([C:35]3[C:36]([F:41])=[CH:37][CH:38]=[C:39]([OH:40])[C:34]=3[F:33])[N:7]=2)[CH2:18]1

참가 물질

8

반응물 4

HCID 83681Tris(1,1-dimethylethyl)phosphineHCID 522689Potassium FluorideHCID 445581212,6-Difluoro-3-hydroxybenzeneboronic acidHCID 86639735tert-butyl ((1S,3R,5S)-3-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-methylcyclohexyl)carbamate

생성물 1

HCID 46179015N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide

시약·촉매·용매 3

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 8028Tetrahydrofuran용매

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온도
100 °C

실험 절차

To a solution of tert-butyl (1S,3R,5S)-3-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-methylcyclohexylcarbamate (1.0 equiv.) in a microwave vial was added 2,6-difluoro-3-hydroxyphenylboronic acid (5.0 equiv.), KF (5.5 equiv.) and Pd2(dba)3 (0.2 equiv.) followed by THF and water (10:1, 0.03 M). To this mixture was added P(t-Bu)3 (0.4 equiv.) and the reaction was heated in the microwave at 100° C. for 30 min. The organic phase was then separated, the aqueous layer was washed with ethyl acetate, and the organics were combined and concentrated in vacuo. The crude mixture was purified via prep-HPLC, the product fractions were lyophilized and the resulting BOC group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide as the TFA salt. LCMS (m/z): 457.2 (MH+); LC Rt=2.17 min.

후처리

  1. customThe organic phase was then separated
  2. washthe aqueous layer was washed with ethyl acetate
  3. concentrationconcentrated in vacuo
  4. customThe crude mixture was purified via prep-HPLC, the product fractions
  5. customafter RP HPLC purification and lyophilization, N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide as the TFA salt

출처 및 근거

ORD 기록
ord-bf943d8b54d043c5acba2ef56c0f7a3a
출처 데이터셋
uspto-grants-2013_11
특허 번호
US08592455B2

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