4-Methylmorpholine → bis(2-methyl-2-propanyl){[4-({(2S,4R)-2-(5-{4-[(methoxycarbonyl)amino]phenyl}-1H-imidazol-2-yl)-4-[1-(methylsulfonyl)-4-piperidinyl]-1-pyrrolidinyl}carbonyl)-1-piperidinyl]methylylidene}biscarbamate

HRID 1053836Notes

Reaction equation

HRID 1053836 reaction equation
Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]3[NH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.[CH3:62][C:63]([O:66][C:67]([NH:69][C:70]([N:79]1[CH2:84][CH2:83][CH:82]([C:85](O)=[O:86])[CH2:81][CH2:80]1)=[N:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])=[O:68])([CH3:65])[CH3:64]>ClCCl.CN(C)C=O>[CH3:78][C:75]([O:74][C:72](=[O:73])[NH:71][C:70]([N:79]1[CH2:80][CH2:81][CH:82]([C:85]([N:15]2[CH2:16][C@@H:12]([CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH2:13][C@H:14]2[C:17]2[NH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([O:30][CH3:31])=[O:32])=[CH:26][CH:27]=3)=[CH:20][N:21]=2)=[O:86])[CH2:83][CH2:84]1)=[N:69][C:67](=[O:68])[O:66][C:63]([CH3:62])([CH3:64])[CH3:65])([CH3:76])[CH3:77]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 1317362991-(N,N'-Bis(tert-butoxycarbonyl)carbamimidoyl)piperidine-4-carboxylic acidHCID 131736307methyl [4-(2-{(2S,4R)-4-[1-(methylsulfonyl)-4-piperidinyl]-2-pyrrolidinyl}-1H-imidazol-5-yl)phenyl]carbamate hydrochloride

Product 1

HCID 131736309bis(2-methyl-2-propanyl){[4-({(2S,4R)-2-(5-{4-[(methoxycarbonyl)amino]phenyl}-1H-imidazol-2-yl)-4-[1-(methylsulfonyl)-4-piperidinyl]-1-pyrrolidinyl}carbonyl)-1-piperidinyl]methylylidene}biscarbamateYield 38%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of the compound prepared in Example 66 (0.11 g, 0.25 mmol) in dichloromethane (5.0 mL) and N,N-dimethylformamide (2.0 mL) was added 1-hydroxy-7-azabenzotriazole (0.034 g, 0.25 mmol), followed by N-methyl morpholine (0.075 g, 0.74 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.095 g, 0.50 mmol) and the compound prepared in Example 7 (0.10 g, 0.27 mmol). The reaction was stirred at room temperature under nitrogen overnight whereupon it was concentrated under reduced pressure. The resultant residue was diluted with dichloromethane (20 mL), washed with brine (10 mL), dried and concentrated. Purification by flash chromatography (silica gel, 12 g, 0-5% methanol/dichloromethane) and trituration from methanol and methyl tert-butyl ether afforded the title compound (0.067 g, 38%) as a yellow solid.

Workup

  1. concentrationwas concentrated under reduced pressure
  2. additionThe resultant residue was diluted with dichloromethane (20 mL)
  3. washwashed with brine (10 mL)
  4. customdried
  5. concentrationconcentrated
  6. customPurification by flash chromatography (silica gel, 12 g, 0-5% methanol/dichloromethane) and trituration from methanol and methyl tert-butyl ether

Sources & evidence

ORD record
ord-0057ee8e3e634e92b037c1445cc1dce8
Source dataset
uspto-grants-2016_07
Patent number
US09394250B2

Reaction notes

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