Potassium Carbonate → 3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid

HRID 2243646ノート

反応式

HRID 2243646 の反応式
Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][C:24]=3[CH3:23])[C:28]([OH:30])=[O:29])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]

参加物

7

反応物 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 160860864-Methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acidHCID 575305005-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

生成物 1

HCID 119506223-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid収率 62.4%

試薬・触媒・溶媒 2

HCID 178418397HCID 178418397、化合物触媒HCID 962Water溶媒

反応条件

温度
150 °C

実験手順

To a stirring solution of 3-iodo-4-methylbenzoic acid (60 g, 0.22 mol, 1 eq) in degassed DMF (1400 mL, 23.3 vol.) was charged 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (81.4 g, 0.32 mol, 1.4 eq) followed by potassium acetate (112 g, 1.14 mole, 5 eq) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18.7 g, 0.02 mole, 01.eq). The resulting mixture was placed under a nitrogen atmosphere and was heated to 80° C. with the exclusion of light overnight. The mixture was then concentrated under high vacuum and the residue partitioned between EtOAc and 2M HCl. The mixture was then filtered and the layers separated. The aqueous phase was re-extracted with EtOAc. The combined organics were then washed with brine, dried and evaporated to yield a brown solid that was applied to a silica plug then eluted with 2:1 cyclohexane:ethyl acetate. Fractions were then combined and evaporated to yield a brown foam that was triturated with cyclohexane, collected by filtration then dried in vacuo to yield 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. (CDCl3) 8.50-8.49 (1H, d), 8.04-8.02 (1H, dd), 7.27-7.25 (1H, d), 2.61 (3H, s), 1.36 (12H, s) 5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, 0.58 mmol) was mixed with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.23 g), K2CO3 (0.485 g), dioxane (18 mL) and H2O (6 mL). The resultant mixture was passed through by a stream of argon for 10 min, mixed with Pd(PPh3)4 (34 mg) and heated at 150° C. for 1 h. It was filtered through celite, mixed with 1 mL acetic acid and washed with brine. The organic layers were collected, dried over MgSO4, filtered and concentrated and the residue was purified by flash column chromatography to provide the title compound (160 mg). LC-MS m/z 443.2 (M+H)+, 1.98 min (ret. time).

後処理

  1. filtrationIt was filtered through celite
  2. additionmixed with 1 mL acetic acid
  3. washwashed with brine
  4. customThe organic layers were collected
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customthe residue was purified by flash column chromatography

出典と根拠

ORDレコード
ord-ec012bcaca7c456f97f2249039be9cf0
出典データセット
uspto-grants-2010_03
特許番号
US07674789B2

反応ノート

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