4-Methylmorpholine → HCID 67191213, compound

HRID 2355448Notes

Reaction equation

HRID 2355448 reaction equation
[CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:17][C:16]([F:19])([F:18])[CH2:15]1)[C:10](O)=[O:11])=[O:7].CN1CCOCC1.ClC(OCC(C)C)=O.ClC([O-])=O.[BH4-].[Na+]>C1COCC1.O>[F:19][C:16]1([F:18])[CH2:17][CH:14]([CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][CH2:4][CH2:3][Si:2]([CH3:20])([CH3:1])[CH3:21])[CH2:10][OH:11])[CH2:15]1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 21226386CarbonochloridateHCID 57545038HCID 57545038, compound

Product 1

HCID 67191213HCID 67191213, compoundYield 91.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-10 °C

Procedure

Crude 2-(2-(trimethylsilyl)ethoxycarbonyl)amino-3-(3,3-difluorocyclobutyl)propanoic acid (273 mg, 0.844 mmol) was dissolved in THF (5 mL) and the solution was cooled to −10° C. N-methylmorpholine (95 mg, 0.929 mmol, 1.1 equiv) was added and the mixture stirred for 15 min. After this time isobutyl chloroformate (127 mg, 0.929 mmol, 1.1 equiv) was added. After stirring for 30 min LC-MS showed remaining starting material. The procedure was repeated with an additional 0.55 equiv of the amine and chloroformate. This consumed all of the starting material. The reaction mixture was quickly filtered through a pad of celite into a solution of NaBH4 (128 mmol, 3.4 mmol, 4.0 equiv) in water (4 mL). The filter cake was washed with an additional dry THF (5 mL). LC-MS analysis showed formation of the desired alcohol. The solvent was removed and the residue partitioned between EtOAc and brine. The layers were separated and the aqueous layer extracted with additional EtOAc. The combined organic layers were dried over Na2SO4. The solvent was removed to yield 2-(trimethylsilyl)ethyl 3-(3,3-difluorocyclobutyl)-1-hydroxypropan-2-ylcarbamate (240 mg, 90%) as an orange oil. 1H and 19F NMR were consistent with the desired product.

Workup

  1. stirringAfter stirring for 30 min LC-MS
  2. customThis consumed all of the starting material
  3. washThe filter cake was washed with an additional dry THF (5 mL)
  4. customThe solvent was removed
  5. customthe residue partitioned between EtOAc and brine
  6. customThe layers were separated
  7. extractionthe aqueous layer extracted with additional EtOAc
  8. dry with materialThe combined organic layers were dried over Na2SO4
  9. customThe solvent was removed

Sources & evidence

ORD record
ord-8195de57cbd64ddc888965f7d1fbe4a1
Source dataset
uspto-grants-2010_07
Patent number
US07754737B2

Reaction notes

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