Formaldehyde → Benzyl 3-((3S)-3,4-dimethylpiperazin-1-yl)azetidine-1-carboxylate

HRID 707513Notes

Reaction equation

HRID 707513 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[C@@H:17]([CH3:28])[CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C1COCC1.ClCCl>[CH3:28][C@@H:17]1[N:18]([CH3:21])[CH2:19][CH2:20][N:15]([CH:13]2[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:14]2)[CH2:16]1

Participants

9

Reactant 5

HCID 712Formaldehyde2×HCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 118162427Tert-Butyl(2S)-4-(1-((benzyloxy)carbonyl)azetidin-3-yl)-2-methylpiperazine-1-carboxylate

Product 1

HCID 118162400Benzyl 3-((3S)-3,4-dimethylpiperazin-1-yl)azetidine-1-carboxylateYield 100.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a mixed solution of tert-butyl(2S)-4-(1-((benzyloxy)carbonyl)azetidin-3-yl)-2-methylpiperazine-1-carboxylate (36.7 g, 94.2 mmol) described in Production Example 4-1 and dichloromethane (20 mL) was added TFA (30 mL) at room temperature. The resultant mixture was stirred at room temperature for 35 minutes. The reaction mixture was concentrated under a reduced pressure. An aqueous formaldehyde solution (70.1 mL, 942 mmol) was added to a mixed solution of the resultant residue and THF (100 mL) at room temperature and then stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (29.9 g, 141 mmol) was added to the reaction mixture at 0° C., and the resultant mixture was stirred at room temperature for 12 hours and 45 minutes. An aqueous formaldehyde solution (10.0 mL) and sodium triacetoxyborohydride (17.5 g, 82.6 mmol) were further added to the reaction mixture at room temperature, and the resultant mixture was stirred at room temperature for 45 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture at 0° C., and the resultant solution was extracted with ethyl acetate and then with dichloromethane. A combined organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (ethyl acetate:methanol=3:1) and then further purified by NH silica gel column chromatography (ethyl acetate) to give the title compound (28.6 g, yield: quantitative).

Workup

  1. concentrationThe reaction mixture was concentrated under a reduced pressure
  2. extractionthe resultant solution was extracted with ethyl acetate
  3. dry with materialA combined organic layer was dried over anhydrous magnesium sulfate
  4. filtrationfiltrated
  5. customThe solvent was evaporated under a reduced pressure
  6. customthe resultant residue was purified by silica gel column chromatography (ethyl acetate:methanol=3:1)
  7. customfurther purified by NH silica gel column chromatography (ethyl acetate)

Sources & evidence

ORD record
ord-45b637810a754f2d9cc517b3ac8786d7
Source dataset
uspto-grants-2015_11
Patent number
US09174998B2

Reaction notes

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