O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate → (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((S)-2,6-bis((tert-butoxycarbonyl)amino)hexanamido)-3-methylbutanoate

HRID 921956Notes

Reaction equation

HRID 921956 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:49][C@@H:50]([CH:89]([CH3:91])[CH3:90])[C:51]([O:53][C@H:54]1[C@H:59]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH2:58][CH2:57][N:56]([C:65]2[CH:70]=[C:69]([C:71]#[N:72])[CH:68]=[C:67]([NH:73][C:74]3[N:79]=[C:78]([NH:80][CH2:81][CH3:82])[C:77]4=[N:83][CH:84]=[C:85]([C:86]#[N:87])[N:76]4[N:75]=3)[C:66]=2[Cl:88])[CH2:55]1)=[O:52]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:49][C@@H:50]([CH:89]([CH3:90])[CH3:91])[C:51]([O:53][C@H:54]1[C@H:59]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH2:58][CH2:57][N:56]([C:65]2[CH:70]=[C:69]([C:71]#[N:72])[CH:68]=[C:67]([NH:73][C:74]3[N:79]=[C:78]([NH:80][CH2:81][CH3:82])[C:77]4=[N:83][CH:84]=[C:85]([C:86]#[N:87])[N:76]4[N:75]=3)[C:66]=2[Cl:88])[CH2:55]1)=[O:52])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

5

Reactant 3

HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 7349648(2S)-2,6-bis((((tert-butoxy)carbonyl)amino))hexanoic acidHCID 89923202(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-amino-3-methylbutanoate dihydrochloride

Product 1

HCID 118253524(S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((S)-2,6-bis((tert-butoxycarbonyl)amino)hexanamido)-3-methylbutanoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To an ice cooled solution of (S)-2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid (30 mg, 0.087 mmol) in dry DCM (1 mL) was added TBTU (27.5 mg, 0.086 mmol) and TEA (0.030 mL, 0.214 mmol) under N2 atmosphere. The reaction mixture was stirred 0.5 h at the same temperature and (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-amino-3-methylbutanoate dihydrochloride (36.5 mg, 0.053 mmol) was added. The reaction stirred 1 h at room temperature; the LCMS showed complete conversion. The reaction mixture was diluted with DCM, washed with water, and dried over Na2SO4. The solvent was removed and the reaction mixture was taken-up in DCM and purified on a silica gel column: eluting with 10-80% acetone-hexane to afford (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((S)-2,6-bis((tert-butoxycarbonyl)amino)hexanamido)-3-methylbutanoate.

Workup

  1. additionwas added
  2. washwashed with water
  3. dry with materialdried over Na2SO4
  4. customThe solvent was removed
  5. custompurified on a silica gel column
  6. washeluting with 10-80% acetone-hexane

Sources & evidence

ORD record
ord-edad01b0baef464e8504889e1334105e
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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