Phosgene → (R)-1-((S)-3-(4-(3-((3S,5S)-1-((S)-3,3-Dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)ureido)phenyl)-2-((S)-2-(methylamino)propanamido)propanoyl)-3,3-dimethyl-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide

HRID 527742ノート

反応式

HRID 527742 の反応式
[C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:36][C:37](=[O:49])[C@@H:38]([N:40]([CH3:48])C(=O)OC(C)(C)C)[CH3:39])[C:14]([N:16]2[C@H:20]([C:21](=[O:33])[NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[CH2:19][Si:18]([CH3:35])([CH3:34])[CH2:17]2)=[O:15])=[CH:8][CH:7]=1.C[CH2:51][N:52](C(C)C)C(C)C.[NH2:59][C@@H:60]1[CH2:64][N:63]([C:65](=[O:85])[C@@H:66]([NH:71][C:72](=[O:84])[C@@H:73](N(C)C(=O)OC(C)(C)C)[CH3:74])[C:67]([CH3:70])([CH3:69])[CH3:68])[C@H:62]([C:86](=[O:98])[NH:87][C@H:88]2[C:97]3[C:92](=[CH:93][CH:94]=[CH:95][CH:96]=3)[CH2:91][CH2:90][CH2:89]2)[CH2:61]1>C(Cl)Cl>[CH3:69][C:67]([CH3:68])([CH3:70])[C@H:66]([NH:71][C:72](=[O:84])[C@@H:73]([NH:52][CH3:51])[CH3:74])[C:65]([N:63]1[C@H:62]([C:86](=[O:98])[NH:87][C@H:88]2[C:97]3[C:92](=[CH:93][CH:94]=[CH:95][CH:96]=3)[CH2:91][CH2:90][CH2:89]2)[CH2:61][C@H:60]([NH:59][C:1](=[O:2])[NH:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:36][C:37](=[O:49])[C@@H:38]([NH:40][CH3:48])[CH3:39])[C:14]([N:16]3[C@H:20]([C:21]([NH:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25][CH2:24]4)=[O:33])[CH2:19][Si:18]([CH3:35])([CH3:34])[CH2:17]3)=[O:15])=[CH:10][CH:11]=2)[CH2:64]1)=[O:85]

参加物

6

反応物 4

HCID 6371PhosgeneHCID 81531Diisopropylethylamine2 回HCID 57806830Tert-butyl (s)-1-((s)-1-((2s,4s)-4-amino-2-((r)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamateHCID 89930786tert-butyl ((S)-1-(((S)-3-(4-aminophenyl)-1-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate2 回

生成物 1

HCID 89930825(R)-1-((S)-3-(4-(3-((3S,5S)-1-((S)-3,3-Dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)ureido)phenyl)-2-((S)-2-(methylamino)propanamido)propanoyl)-3,3-dimethyl-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒3 回

反応条件

温度
-30 °C

実験手順

To a solution of phosgene (120 μL of 20% in toluene by weight) in CH2Cl2 (1.5 mL) at −78° C. was added a solution of tert-butyl ((S)-1-(((S)-3-(4-aminophenyl)-1-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (Compound G of Example 1, 54 mg, 0.09 mmol) and DIEA (50 μL) in CH2Cl2 (2 mL) with stirring under N2 atm. After 30 minutes at −78° C., the mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (2 mL), cooled to −30° C. and treated with a solution of tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-amino-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (47 mg, 0.09 mmol) and DIEA (50 μL) in CH2Cl2 (2 mL). After 10 minutes, the reaction mixture was warmed to rt, stirred for 1 h, concentrated in vacuo and the residue was purified by preparative HPLC to provide the urea product as a white solid.

後処理

  1. concentrationthe mixture was concentrated in vacuo
  2. dissolutionthe residue was dissolved in CH2Cl2 (2 mL)
  3. waitAfter 10 minutes
  4. temperaturethe reaction mixture was warmed to rt
  5. stirringstirred for 1 h
  6. concentrationconcentrated in vacuo
  7. customthe residue was purified by preparative HPLC

出典と根拠

ORDレコード
ord-4e7c97bf7c764b8ea395005e9bfec3ff
出典データセット
uspto-grants-2016_05
特許番号
US09345740B2

反応ノート

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