Potassium Carbonate → (S)-1-((S)-6-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl-carbamic acid methyl ester

HRID 79910ノート

反応式

HRID 79910 の反応式
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][N:14]3[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[CH:63]=[C:62]([C:67]1[NH:71][C:70]([C@@H:72]3[CH2:78][C:75]4([CH2:77][CH2:76]4)[CH2:74][N:73]3[C:79](=[O:89])[C@@H:80]([NH:84][C:85](=[O:88])[O:86][CH3:87])[CH:81]([CH3:83])[CH3:82])=[N:69][CH:68]=1)[CH:61]=[CH:60]2.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.CS(C)=O.O1CCOCC1>[CH3:87][O:86][C:85](=[O:88])[NH:84][C@@H:80]([CH:81]([CH3:82])[CH3:83])[C:79]([N:73]1[C@H:72]([C:70]2[NH:71][C:67]([C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:2]5[CH:7]=[CH:6][C:5]([C:8]6[NH:12][C:11]([C@@H:13]7[CH2:21][C:16]8([O:17][CH2:18][CH2:19][O:20]8)[CH2:15][N:14]7[C:22](=[O:32])[C@@H:23]([NH:27][C:28]([O:29][CH3:30])=[O:31])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=6)=[CH:4][CH:3]=5)[CH:58]=4)[CH:63]=3)=[CH:68][N:69]=2)[CH2:78][C:75]2([CH2:76][CH2:77]2)[CH2:74]1)=[O:89]

参加物

10

反応物 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 59610362((S)-1-{(S)-8-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-1,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 59610490methyl(S)-1-((S)-6-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate

生成物 1

HCID 59610451(S)-1-((S)-6-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl-carbamic acid methyl ester

試薬・触媒・溶媒 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 178418397HCID 178418397、化合物触媒HCID 679Dimethyl Sulfoxide溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
90 °C

実験手順

Methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (200 mg, 0.39 mmol), bis(pinacolato)diboron (130 mg, 0.51 mmol), potassium acetate (116 mg, 1.18 mmol), and Pd(dppf)Cl2 (29 mg, 0.039 mmol) were all weighed out in a glass pressure vessel and anhydrous 1,4-Dioxane (2 mL) was added. The mixture was bubbled with nitrogen gas for about 5 min. The vessel was then capped and sealed and heated in an oil bath at 90° C. overnight with continuous stirring. The reaction vessel was cooled down to room temperature and methyl (S)-1-((S)-6-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate (215 mg, 0.41 mmol), 2M K2CO3, and Pd(PPh3)4 (46 mg, 0.04 mmol) were all added along with 2 mL of DMSO and the mixture was bubbled with nitrogen gas for 5 minutes. The vessel, again, was capped, sealed and placed in an oil bath at 100° C. for 4 hours. The resulting crude mixture was diluted with ethyl acetate and washed, respectively, with brine, 10% Na2CO3, 10% citric acid, saturated solution of NH4Cl, and brine. The organic layer was then dried over Na2SO4 and the volatiles were removed on rotovap. The residue was first purified on normal phase chromatography and then on prep HPLC. Yield=205 mg (60%). 1H-NMR: 400 MHz, (CDCl3) δ 8.18-7.97 (m, 1H), 7.83-7.6 (m, 8H), 7.82-7.22 (m, 3H), 5.47-5.34 (m, 4H),4.33-4.26 (m, 1H), 4.08-4.03 (m, 4H), 3.94-3.89 (m, 1H), 3.78-3.69 (m, 8H), 3.22 (brs, 1H), 2.96-2.94 (m, 1H), 2.49-2.46 (m, 1H), 2.22-2.17 (m, 1H), 1.99 (brs, 1H), 1.08-1.04 (m, 2H), 0.94-0.79 (m, 12H), 0.71 (m, 4H). MS (ESI) m/z 873.79 [M+H]+.

後処理

  1. customall weighed out in a glass pressure vessel
  2. customThe mixture was bubbled with nitrogen gas for about 5 min
  3. customThe vessel was then capped
  4. customsealed
  5. temperatureThe reaction vessel was cooled down to room temperature
  6. customthe mixture was bubbled with nitrogen gas for 5 minutes
  7. customThe vessel, again, was capped
  8. customsealed
  9. additionThe resulting crude mixture was diluted with ethyl acetate
  10. washwashed
  11. dry with materialThe organic layer was then dried over Na2SO4
  12. customthe volatiles were removed on rotovap
  13. customThe residue was first purified on normal phase chromatography

出典と根拠

ORDレコード
ord-7a2490fe919f4ba7bdda19a22f22beb1
出典データセット
uspto-grants-2014_09
特許番号
US08841278B2

反応ノート

読み込み中…