Hydrochloric Acid → N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({4-[2-(1-piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

HRID 2046284ノート

反応式

HRID 2046284 の反応式
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([N:41]4[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]4)[CH:36]=3)=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]

参加物

8

反応物 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 162179482-(1-Piperaziny) pyridine-4-boronic acid pinacol esterHCID 54739228N-{[2-[(4-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

生成物 1

HCID 54739207N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({4-[2-(1-piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycine収率 67.1%

試薬・触媒・溶媒 3

HCID 178418397HCID 178418397、化合物触媒HCID 962Water溶媒2 回HCID 312751,4-Dioxane溶媒

実験手順

To a 5 mL microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 31 mg, 0.073 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (21.13 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (10 ml) and acidified with 1N HCl. The mixture was then extracted with ethyl acetate (2×50 mL) and the organic layers combined, dried over magnesium sulfate, filtered, and solvents removed by rotary evaporation. The mixture of products, by tlc, was purified by HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA)). However, the product was not there but found in the aqueous extract, 100% clean, which was evaporated to afford the title compound N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({4-[2-(1-piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (26 mg, 0.049 mmol, 66.7% yield) as a tfa salt. 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 10.18 (t, J=5.81 Hz, 1H), 8.80 (br. s., 2H), 8.21 (d, J=5.56 Hz, 1H), 7.78 (d, J=8.34 Hz, 2H), 7.43 (d, J=8.34 Hz, 2H), 7.23 (s, 1H), 7.09 (dd, J=5.31, 1.01 Hz, 1H), 5.32 (s, 2H), 4.11 (d, J=5.81 Hz, 2H), 3.76-3.87 (m, 4H), 3.13-3.29 (m, 5H), 1.22 (d, J=7.07 Hz, 6H). MS (ES+) m/e 507 [M+H]+.

後処理

  1. customThe mixture was irradiated at 100° C. for 20 minutes
  2. extractionThe mixture was then extracted with ethyl acetate (2×50 mL)
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. customsolvents removed by rotary evaporation
  6. additionThe mixture of products
  7. customby tlc, was purified by HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA))
  8. customwhich was evaporated

出典と根拠

ORDレコード
ord-47f9573933594bea90ee50c5f9abea60
出典データセット
uspto-grants-2013_11
特許番号
USRE044613E1

反応ノート

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