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 527742Notes

Reaction equation

HRID 527742 reaction equation
[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]

Participants

6

Reactant 4

HCID 6371PhosgeneHCID 81531Diisopropylethylamine2×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×

Product 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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
-30 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-4e7c97bf7c764b8ea395005e9bfec3ff
Source dataset
uspto-grants-2016_05
Patent number
US09345740B2

Reaction notes

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