Water → 4-[4-(6-Amino-5-naphthalen-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1926450

反応式

HRID 1926450 の反応式
[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30]([C:32]3[CH:33]=[N:34][C:35]([NH2:39])=[C:36](Br)[CH:37]=3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OC(N1CCC(N2C=C(C3C(N)=NC=C(Br)C=3)C=N2)CC1)=O)(C)(C)C.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O.C(OC(N1CCC(N2C=C(C3C(N)=NC=C(C4C=CC5C(=CC=CC=5)C=4)C=3)C=N2)CC1)=O)(C)(C)C>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30]([C:32]3[CH:33]=[N:34][C:35]([NH2:39])=[C:36]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH:37]=3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]

参加物

10

反応物 7

HCID 962WaterHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 2734375(Naphthalen-2-yl)boronic acid3 回HCID 67366272tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateHCID 675205204-[4-(2-Amino-5-bromopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl esterHCID 675216094-[4-(2-Amino-5-naphthalen-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

生成物 1

HCID 675207484-[4-(6-Amino-5-naphthalen-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

試薬・触媒・溶媒 2

HCID 178418397HCID 178418397、化合物触媒3 回HCID 8857Ethyl Acetate溶媒

反応条件

温度
105 °C

実験手順

A solution of 2-naphthylboronic acid (43 mg, 0.25 mmol), Pd(PPh3)4 (23 mg, 0.020 mmol), and a mixture of 4-[4-(6-amino-5-bromopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester and 4-[4-(2-amino-5-bromopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (together 92.2 mg, 0.138 mmol) in 1,4-dioxane (3.5 mL, 45 mmol) in a sealable microwave tube was charged with a solution of Cs2CO3 (140 mg, 0.44 mmol) in H2O (0.90 mL, 50 mmol), flushed with nitrogen, sealed and irradiated in the microwave reactor at 105° C. for 60 min. More 2-naphthylboronic acid (11 mg, 0.064 mmol) and Pd(PPh3)4 (5.6 mg, 0.0048 mmol) were added, and the solution was heated in the microwave reactor at 105° C. for 30 min. Further 2-naphthylboronic acid (12 mg, 0.070 mmol) and Pd(PPh3)4 (4.5 mg, 0.0039 mmol) were added to the solution, which was then heated in the microwave reactor to 105° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with aq. NaHCO3 solution, water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]. One obtained a mixture of the title compound and its regioisomer, 4-[4-(2-amino-5-naphthalen-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester, as yellow-brown solid. This mixture of regioisomers was separated using the MDPS. 1H NMR (400 MHz, CDCl3): δ=8.26 (d, J=2.4 Hz, 1H), 7.99-7.45 (m, 10H), 4.60 (s, 2H), 4.39-4.21 (m, 3H), 2.98-2.85 (brm, 2H), 2.19 (brt, J=13.0 Hz, 2H), 2.05-1.89 (mc, 2H), 1.48 (s, 9H). MS(ES+): m/z=470.19 (100) [MH+]. HPLC: tR=2.85 min (polar—5 min, ZQ3).

後処理

  1. customflushed with nitrogen
  2. customsealed
  3. customirradiated in the microwave reactor at 105° C. for 60 min
  4. temperaturewas then heated in the microwave reactor to 105° C. for 30 min
  5. washwashed with aq. NaHCO3 solution, water, and brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]
  10. customOne obtained

出典と根拠

ORDレコード
ord-1e824f00859e4ef082604b00736016f7
出典データセット
uspto-grants-2012_05
特許番号
US08178668B2

関連ノート

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