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 527742노트

반응식

HRID 527742 반응식
[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]

참가 물질

6

반응물 4

HCID 6371PhosgeneHCID 81531Diisopropylethylamine2회HCID 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)carbamate2회

생성물 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

시약·촉매·용매 1

HCID 6344Dichloromethane용매3회

반응 조건

온도
-30 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-4e7c97bf7c764b8ea395005e9bfec3ff
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09345740B2

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