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Hydrochloric Acid → 2'-{[5-{[(carboxymethyl)amino]carbonyl}-4-hydroxy-3-(1-methylethyl)-6-oxo-1(6H)-pyridazinyl]methyl}-4-biphenylcarboxylic acid

HRID 2046290
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HRID 2046290 반응식
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[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]1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([OH:29])=[O:28].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>[C:20]([CH2:19][NH:18][C:16]([C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:33]2[CH:34]=[CH:35][C:30]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[N:10]=[C:11]([CH:24]([CH3:26])[CH3:25])[C:12]=1[OH:23])=[O:17])([OH:22])=[O:21]
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참가 물질

8

반응물 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 3121834-Carboxyphenylboronic AcidHCID 54739212N-{[2-[(2-Bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine

생성물 1

HCID 547391982'-{[5-{[(carboxymethyl)amino]carbonyl}-4-hydroxy-3-(1-methylethyl)-6-oxo-1(6H)-pyridazinyl]methyl}-4-biphenylcarboxylic acid
수율 36.2%

시약·촉매·용매 3

HCID 178418397HCID 178418397, 화합물촉매HCID 962Water용매2회HCID 312751,4-Dioxane용매

실험 절차

To a 5 ml microwave tube was added N-{[2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 78(b), 75 mg, 0.177 mmol), 4-carboxybenzeneboronic acid (29.3 mg, 0.177 mmol), potassium carbonate (73.3 mg, 0.530 mmol), and tetrakis(triphenylphosphine)palladium (0) (6.13 mg, 5.30 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 (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound 2′-{[5-{[(carboxymethyl)amino]carbonyl}-4-hydroxy-3-(1-methylethyl)-6-oxo-1(6H)-pyridazinyl]methyl}-4-biphenylcarboxylic acid (non-preferred name) (30 mg, 0.064 mmol, 36.1% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.82 (s, 1H), 12.99 (br. s., 2 H), 10.06 (t, J=5.68 Hz, 1H), 7.99 (d, J=8.34 Hz, 2H), 7.52 (d, J=8.34 Hz, 2 H), 7.38 (dt, J=4.36, 2.24 Hz, 2H), 7.25-7.32 (m, 1H), 7.17-7.24 (m, 1H), 5.26 (s, 2H), 4.06 (d, J=5.56 Hz, 2H), 3.11 (sept, J=6.82 Hz, 1H), 1.10 (d, J=6.82 Hz, 6H). MS (ES+) m/e 466 [M+H]+.

후처리

  1. customThe mixture was irradiated at 100° C. for 20 minutes
  2. extractionextracted with ethyl acetate (20 ml)
  3. dry with materialThe organic phase was dried over MgSO4
  4. filtrationfiltered
  5. customsolvents removed under reduced pressure
  6. customThe crude residue was purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA))

출처 및 근거

ORD 기록
ord-fbc0386263b74a9f8adc35a9b947b016
출처 데이터셋
uspto-grants-2013_11
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
USRE044613E1

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