4-Methylmorpholine → 1,1-Dimethylethyl N-((1S)-2-(methoxymethylamino)-2-oxo-1-(phenylmethyl)ethyl)carbamate

HRID 61296

Reaction equation

HRID 61296 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[N:37]([O:38][CH3:39])[CH3:36])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 77857L-Phenylalanine, N-[(1,1-dimethylethoxy)carbonyl]-HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)

Product 1

HCID 110559451,1-Dimethylethyl N-((1S)-2-(methoxymethylamino)-2-oxo-1-(phenylmethyl)ethyl)carbamateYield 101.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid (24.85 g, 93.66 mmol) in dichloromethane (150 mL) was added N-methylmorpholine (10.3 mL, 93.66 mmol), followed by addition of isobutyl chloroformate (12.25 mL, 93.66 mmol) at 0° C. The reaction mixture was stirred for 20 min. then N,O-dimethylhydroxylamine hydrochloride (9.14 g, 93.66 mmol) in one portion was added. Subsequently, triethylamine (13 mL, 93.66 mmol) was added dropwise over 15 min. The reaction mixture was stirred for another hour, then it was quenched with 1N HCl (100 mL) and the organic phase was washed with saturated NaHCO3 and brine (500 mL). The organic layers were dried over (MgSO4), filtered, and concentrated in vacua to give the Weinreb amide of Formula VII(a), [(S)-1-(methoxy-methyl-carbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as a clear sticky oil (29.3 g, 100%). 1H NMR (400 MHz, d6-DMSO): δ (ppm) 7.33-7.09 (m, 6H), 4.61-4.47 (m, 1H), 3.70 (s, 3H), 3.08 (s, 3H), 2.89-2.78 (m, 1H), 2.75-2.63 (m, 1H), 1.29 (s, 9H).

Workup

  1. stirringThe reaction mixture was stirred for another hour
  2. customit was quenched with 1N HCl (100 mL)
  3. washthe organic phase was washed with saturated NaHCO3 and brine (500 mL)
  4. dry with materialThe organic layers were dried over (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacua

Sources & evidence

ORD record
ord-cfa14d33b185423a93fed8f10c2a0ec2
Source dataset
uspto-grants-2016_09
Patent number
US09441012B2

Linked notes

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