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 79910Notes

Reaction equation

HRID 79910 reaction equation
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]

Participants

10

Reactant 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

Product 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

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

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]+.

Workup

  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

Sources & evidence

ORD record
ord-7a2490fe919f4ba7bdda19a22f22beb1
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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