Hydrochloric Acid → methyl {(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

HRID 2038828ノート

反応式

HRID 2038828 の反応式
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[C:17]1[NH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]3[C:54]4[C:30](=[C:31]5[C:51](=[CH:52][CH:53]=4)[C:35]4[N:36]=[C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6C(OC(C)(C)C)=O)[NH:38][C:34]=4[CH:33]=[CH:32]5)[O:29][CH2:28][C:26]=3[CH:27]=2)=[CH:20][N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@H:61]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:62]([OH:64])=O)=[O:59].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C.C(O)C>[CH3:56][O:57][C:58]([NH:60][C@H:61]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:62]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:38][C:34]2[CH:33]=[CH:32][C:31]3[C:51](=[CH:52][CH:53]=[C:54]4[C:25]5[CH:24]=[CH:23][C:22]([C:19]6[NH:18][C:17]([C@H:13]7[CH2:14][CH2:15][CH2:16][N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])=[N:21][CH:20]=6)=[CH:27][C:26]=5[CH2:28][O:29][C:30]4=3)[C:35]=2[N:36]=1)=[O:64])=[O:59]

参加物

11

反応物 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphateHCID 86688818tert-butyl (2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

生成物 1

HCID 86688820methyl {(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate収率 51%

試薬・触媒・溶媒 5

HCID 14798Sodium Hydroxide触媒HCID 702Ethanol溶媒HCID 887Methanol溶媒HCID 6342Acetonitrile溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
60 °C

実験手順

A mixture of tert-butyl (2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (270 mg, 0.37 mmol), concentrated HCl (1.5 mL) and ethanol (8 mL) was heated to 60° C. for 1 hour. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off two more times. The crude material was dissolved in 5:1 dichloromethane/dimethylformamide (3.8 mL). To this solution was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (96 mg, 0.46 mmol), COMU (190 mg, 0.44 mmol) and diisopropylethylamine (0.20 mL, 1.1 mmol). The reaction was stirred at 0° C. for 30 minutes then warmed to room temperature. Upon completion, the reaction was diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. The crude material was purified by reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA) to yield methyl {(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (155 mg, 51% yield over 2 steps). LCMS-ESI+: calculated for C46H48N807: 824.92; observed [M+1]+: 825.67.

後処理

  1. concentrationThe reaction was concentrated
  2. dissolutionredissolved in a minimal amount of methanol
  3. additionAn equal volume of dichloromethane was added
  4. concentrationthe solution was again concentrated
  5. additionDichloromethane was added to the resulting residue
  6. concentrationconcentrated off two more times
  7. dissolutionThe crude material was dissolved in 5:1 dichloromethane/dimethylformamide (3.8 mL)
  8. temperaturethen warmed to room temperature
  9. stirringstirring
  10. waitwas continued for 30 minutes
  11. washthe organic layer was washed with water and brine
  12. extractionThe combined aqueous washings were extracted three times with ethyl acetate
  13. dry with materialthe combined organic layers were dried (MgSO4)
  14. concentrationconcentrated
  15. customThe crude material was purified by reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA)

出典と根拠

ORDレコード
ord-24520975fa0d41ae815545d63ace08b9
出典データセット
uspto-grants-2013_11
特許番号
US08575135B2

反応ノート

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