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4-Methylmorpholine → [1-(6-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 71980
Notes
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Reaction equation

HRID 71980 reaction equation
[CH:1]1C=C[C:4]2N(O)N=[N:7][C:5]=2[CH:6]=1.Cl.Cl.Cl.[CH3:14][O:15][C:16](=[O:64])[NH:17][CH:18]([C:22]([N:24]1[CH:30]([C:31]2[NH:32][C:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[C:41]([C:46]5[CH:51]=[CH:50][C:49]([C:52]6[NH:53][C:54]([CH:57]7[CH2:61][CH:60]([C:62]#[N:63])[CH2:59][NH:58]7)=[N:55][CH:56]=6)=[CH:48][CH:47]=5)[CH:42]=4)[CH:37]=3)=[CH:34][N:35]=2)[CH2:29][C:26]2([CH2:28][CH2:27]2)[CH2:25]1)=[O:23])[CH:19]([CH3:21])[CH3:20].CN1CC[O:69]CC1.C[CH2:73][O:74][C:75](C)=[O:76]>CN(C=O)C>[CH3:14][O:15][C:16](=[O:64])[NH:17][CH:18]([C:22]([N:24]1[CH:30]([C:31]2[NH:32][C:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[C:41]([C:46]5[CH:51]=[CH:50][C:49]([C:52]6[NH:53][C:54]([CH:57]7[CH2:61][CH:60]([C:62]#[N:63])[CH2:59][N:58]7[C:4](=[O:69])[CH:5]([NH:7][C:75]([O:74][CH3:73])=[O:76])[CH2:6][CH3:1])=[N:55][CH:56]=6)=[CH:48][CH:47]=5)[CH:42]=4)[CH:37]=3)=[CH:34][N:35]=2)[CH2:29][C:26]2([CH2:27][CH2:28]2)[CH2:25]1)=[O:23])[CH:19]([CH3:21])[CH3:20]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 8857Ethyl AcetateHCID 757711-HydroxybenzotriazoleHCID 66620685(1-{6-[5-(6-{4-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl]-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester tris-hydrochloride

Product 1

HCID 66620510
[1-(6-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester
Yield 49%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2-2-Methoxycarbonylamino-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-(6-{4-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-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 brine. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (78 mg, 49%). MS (ESI) m/z 826 [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-f888176c2d4940119a8eda7bc6b91ad7
Source dataset
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08822430B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes