Hydrochloric Acid → (S)-Benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate

HRID 604592Notes

Reaction equation

HRID 604592 reaction equation
[C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl>C1COCC1>[CH3:21][O:20][N:19]([CH3:18])[C:14](=[O:16])[C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:13]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 736104N-carbobenzyloxyalanineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 10515879(S)-Benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
5 °C

Procedure

CBZ-L-Alanine (6.5 kg, 28.5 mol), HOBT-hydrate (4.8 kg, 34.8 mol), N,O-dimethylhydroxylamine hydrochloride (3.4 kg, 36.2 mol) and THF (32 L) are charged to a clean flask under nitrogen. The mixture is cooled to 0-10° C. and then DIPEA (12.4 L) is slowly added at a temperature less than 20° C. EDC-HCl (7 Kg, 36.2 mol) is then added slowly with slight cooling at 15-25° C. The slurry is aged overnight at 20-25° C. The mixture is then cooled to 0-10° C. and 3 N HCl (13 L) is added slowly. Then IPAC (45.5 L) is added and the layers are separated. The organic layer is washed once with HCl (13 L) and twice with 8% NaHCO3 (13 L). The organic layer is then concentrated under vacuum to <20 L at 50° C. The clear solution is cooled slowly to room temperature, allowing the product to crystallize. Heptane (˜70 L) is then added slowly. The slurry is filtered, washed with heptane (18 L), and dried at room temperature on the filter pot. Product is obtained with >99.9% ee measured by chiral HPLC.

Workup

  1. temperaturewith slight cooling at 15-25° C
  2. temperatureThe mixture is then cooled to 0-10° C.
  3. additionThen IPAC (45.5 L) is added
  4. customthe layers are separated
  5. washThe organic layer is washed once with HCl (13 L) and twice with 8% NaHCO3 (13 L)
  6. concentrationThe organic layer is then concentrated under vacuum to <20 L at 50° C
  7. temperatureThe clear solution is cooled slowly to room temperature
  8. customto crystallize
  9. additionHeptane (˜70 L) is then added slowly
  10. filtrationThe slurry is filtered
  11. washwashed with heptane (18 L)
  12. customdried at room temperature on the filter pot
  13. customProduct is obtained with >99.9% ee

Sources & evidence

ORD record
ord-dc6871c9f5b843619d1f390949df1926
Source dataset
uspto-grants-2011_03
Patent number
US07910592B2

Reaction notes

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