4-Methylmorpholine → HCID 117869999, compound

HRID 525295Notes

Reaction equation

HRID 525295 reaction equation
[C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][CH:17]1[C:25](O)=[O:26])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][CH:17]1[CH2:25][OH:26])=[O:15])[CH:28]([CH3:30])[CH3:29])[CH3:31])[CH3:32])([CH3:3])([CH3:2])[CH3:4]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 117872937HCID 117872937, compound2×

Product 1

HCID 117869999HCID 117869999, compoundYield 73.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

To a stirred solution of 1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionyl amino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 1) (3.8 g, 8.48 mmol) in THF (65 mL) were added N-methylmorpholine (1.11 mL, 10.17 mmol) followed by the addition of isobutyl chloroformate (1.32 mL, 10.17 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 10 min and the white precipitate of N-methylmorpholine hydrochloride salt was removed by filtration. The filtrate was cooled to −20° C., NaBH4 (483 mg, 12.72 mmol) was added followed by cold water (30 mL) at −20° C. After 30 min the reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (80 mL×2). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 28% EtOAc in hexanes) to give {(S)-1-[(S)-1-(2-hydroxymethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (2.7 g), m/z=435 (M+H)

Workup

  1. customthe white precipitate of N-methylmorpholine hydrochloride salt was removed by filtration
  2. temperatureThe filtrate was cooled to −20° C.
  3. extractionextracted with ethyl acetate (80 mL×2)
  4. washThe combined organic layers were washed with water, brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe resulting residue was purified by flash chromatography (silica gel, 28% EtOAc in hexanes)

Sources & evidence

ORD record
ord-436fddd86ad24632811b3c6b3778d463
Source dataset
uspto-grants-2016_05
Patent number
US09340573B2

Reaction notes

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