4-Methylmorpholine → [1-(4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3h-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1h-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl ester

HRID 71977Notes

Reaction equation

HRID 71977 reaction equation
[CH3:1][O:2][C:3]([NH:5][CH:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:27][O:28][C:29](=[O:77])[NH:30][CH:31]([C:35]([N:37]1[CH:43]([C:44]2[NH:45][C:46]([C:49]3[CH:54]=[CH:53][C:52]([C:55]4[CH:64]=[CH:63][C:62]5[C:57](=[CH:58][CH:59]=[C:60]([C:65]6[NH:66][C:67]([CH:70]7[CH2:74][CH:73]([C:75]#[N:76])[CH2:72][NH:71]7)=[N:68][CH:69]=6)[CH:61]=5)[CH:56]=4)=[CH:51][CH:50]=3)=[CH:47][N:48]=2)[CH2:42][C:39]2([CH2:41][CH2:40]2)[CH2:38]1)=[O:36])[CH:32]([CH3:34])[CH3:33].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]([C:7]([N:71]1[CH2:72][CH:73]([C:75]#[N:76])[CH2:74][CH:70]1[C:67]1[NH:66][C:65]([C:60]2[CH:59]=[CH:58][C:57]3[C:62](=[CH:63][CH:64]=[C:55]([C:52]4[CH:51]=[CH:50][C:49]([C:46]5[NH:45][C:44]([CH:43]6[CH2:42][C:39]7([CH2:41][CH2:40]7)[CH2:38][N:37]6[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:77])[CH:32]([CH3:34])[CH3:33])=[N:48][CH:47]=5)=[CH:54][CH:53]=4)[CH:56]=3)[CH:61]=2)=[CH:69][N:68]=1)=[O:9])[C:10]([CH3:13])([CH3:12])[CH3:11]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 103301332-((Methoxycarbonyl)amino)-3,3-dimethylbutanoic acidHCID 66620626(1-(6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride

Product 1

HCID 66621034[1-(4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3h-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1h-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl esterYield 48%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-Methoxycarbonylamino-3,3-dimethyl-butyric acid (37 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5 h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then 1:1 brine/5M NaOH. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (77 mg, 48%). MS (ESI) m/z 855 [M+H]+.

Workup

  1. temperaturethe reaction mixture was cooled to 0° C.
  2. waitAfter 1.5 h
  3. temperaturethe reaction mixture was warmed to RT
  4. washwashed with NaHCO3
  5. dry with materialThe organic phase was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting residue was purified by HPLC

Sources & evidence

ORD record
ord-a6e57e36acbf4e53ac58ba2a1589f9b6
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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