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Potassium Phosphate, Tribasic → [1-(6-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 72041
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인쇄 미리보기

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HRID 72041 반응식
[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH3:54][O:55][C:56](=[O:87])[NH:57][CH:58]([C:62]([N:64]1[CH:70]([C:71]2[NH:72][C:73]([C:76]3[CH:85]=[CH:84][C:83]4[C:78](=[CH:79][CH:80]=[C:81](Br)[CH:82]=4)[CH:77]=3)=[CH:74][N:75]=2)[CH2:69][C:66]2([CH2:68][CH2:67]2)[CH2:65]1)=[O:63])[CH:59]([CH3:61])[CH3:60].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:54][O:55][C:56](=[O:87])[NH:57][CH:58]([C:62]([N:64]1[CH:70]([C:71]2[NH:72][C:73]([C:76]3[CH:85]=[CH:84][C:83]4[C:78](=[CH:79][CH:80]=[C:81]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:30])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:82]=4)[CH:77]=3)=[CH:74][N:75]=2)[CH2:69][C:66]2([CH2:68][CH2:67]2)[CH2:65]1)=[O:63])[CH:59]([CH3:61])[CH3:60]
참가 물질반응 조건실험 절차후처리출처 및 근거반응 노트

참가 물질

7

반응물 5

HCID 62657Potassium Phosphate, TribasicHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 66620752(1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 66620764(1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

생성물 1

HCID 66620650[1-(6-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester수율 24%

시약·촉매·용매 1

HCID 312751,4-Dioxane용매

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온도
85 °C

실험 절차

(1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.10 g, 0.24 mmol), bis(pinacolato)diboron (0.073 g, 0.29 mmol), Palladium dichloride(dppf) (0.018 g, 0.024 mmol), and potassium acetate (0.071 g, 0.72 mmol) were suspended in 1,4-dioxane (1.2 mL) and degassed with argon for 30 minutes. The suspension was heated at 85° C. for 2 hours. The mixture was cooled, (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.182 g, 0.346 mmol) and aqueous potassium phosphate (2M, 0.84 mL, 0.84 mmol) was added. The mixture was returned to heat for 16 hours at which time, Palladium(tetrakis)triphenylphosphine (0.014 g, 0.012 mmol) was added. The reaction was heated for an additional 4 hours. Upon completion, the crude reaction mixture was concentrated in vacuo and filtered through a Pd scavenging cartridge (Polymer Labs, PL-Guanidine MP SPE). The resulting slurry was diluted in DMF and purified by reverse phase HPLC (15-40% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving [1-(6-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.048 g, 24%) as a white solid.

후처리

  1. customdegassed with argon for 30 minutes
  2. temperatureThe mixture was cooled
  3. additionwas added
  4. temperatureThe reaction was heated for an additional 4 hours
  5. customUpon completion, the crude reaction mixture
  6. concentrationwas concentrated in vacuo
  7. filtrationfiltered through a Pd scavenging cartridge (Polymer Labs, PL-Guanidine MP SPE)
  8. additionThe resulting slurry was diluted in DMF
  9. custompurified by reverse phase HPLC (15-40% acetonitrile:water; 0.1% formic acid modifier)

출처 및 근거

ORD 기록
ord-d04df39c63b344a29726e81fc3f564a2
출처 데이터셋
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08822430B2

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