Methylamine → (3S*,4R*)-3-{[Cyclopropyl-(2-methyl-2-methylcarbamoyl-propoxycarbonyl)-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1158412Notes

Reaction equation

HRID 1158412 reaction equation
[CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][N:38]([CH:55]([CH3:57])[CH3:56])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=2)[C@H:34]([CH2:58][N:59]([C:63]([O:65][CH2:66][C:67]([C:70]([OH:72])=O)([CH3:69])[CH3:68])=[O:64])[CH:60]2[CH2:62][CH2:61]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN.C(N(CC)CC)C>CC#N>[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][N:38]([CH:55]([CH3:57])[CH3:56])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=2)[C@H:34]([CH2:58][N:59]([CH:60]2[CH2:61][CH2:62]2)[C:63]([O:65][CH2:66][C:67]([CH3:69])([C:70](=[O:72])[NH:2][CH3:1])[CH3:68])=[O:64])[CH2:33]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]

Participants

6

Reactant 4

HCID 6329Methylamine2×HCID 8471Triethylamine2×HCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 68617188(3S*,4R*)-3-{[(2-carboxy-2-methyl-propoxycarbonyl)-cyclopropyl-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 59512274(3S*,4R*)-3-{[Cyclopropyl-(2-methyl-2-methylcarbamoyl-propoxycarbonyl)-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

HBTU (161 mg, 0.43 mmol) is added to a solution of (3S*,4R*)-3-{[(2-carboxy-2-methyl-propoxycarbonyl)-cyclopropyl-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (240 mg, 0.35 mmol) in CH3CN (10 mL) at 0° C. After 5 min a solution of methylamine (44 μL, 0.35 mmol, 8M in EtOH) and triethylamine (493 μL, 3.54 mmol) in CH3CN (10 mL) is added at 0° C. and the reaction solution is stirred at RT for 5 h. Another portion of methylamine (0.22 mL, 1.75 mmol) is added and stirring is continued for another 16 h. Then, triethylamine (247 μL, 1.77 mmol) and HBTU (268 mg, 1.02 mmol) are added and the reaction mixture is stirred at 50° C. for another 16 h. The solvent is evaporated and the crude product purified by HPLC (Interchrom C18 ODB 10 μm, 28×250 mm, eluent: CH3CN/H2O 5%/2.5 min, CH3CN/H2O 5-100%/23 min, 100% CH3CN/4.5 min, flow 40 mL/min) to give the title compound. MS (LC-MS): 691.4 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.38 min.

Workup

  1. stirringstirring
  2. waitis continued for another 16 h
  3. stirringthe reaction mixture is stirred at 50° C. for another 16 h
  4. customThe solvent is evaporated
  5. customthe crude product purified by HPLC (Interchrom C18 ODB 10 μm, 28×250 mm, eluent: CH3CN/H2O 5%/2.5 min, CH3CN/H2O 5-100%/23 min, 100% CH3CN/4.5 min, flow 40 mL/min)

Sources & evidence

ORD record
ord-84b72ce1f6ba488d995022473eceb8f6
Source dataset
uspto-grants-2010_10
Patent number
US07807709B2

Reaction notes

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