Triacetoxyborohydride → Methyl 7-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate

HRID 1506392Notes

Reaction equation

HRID 1506392 reaction equation
[CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=O.C(O)(=O)C.[NH:24]1[CH2:27][CH:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CO.ClCCCl.C(O)(=O)C>[C:31]([O:30][C:28]([CH:26]1[CH2:25][N:24]([CH2:1][C:3]2[CH:4]=[C:5]3[C:13](=[CH:14][CH:15]=2)[C:12]2[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=2[CH2:7][CH2:6]3)[CH2:27]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]

Participants

8

Reactant 4

HCID 2724942TriacetoxyborohydrideHCID 5049666Sodium triacetoxyborohydride3×HCID 66677484tert-Butyl azetidine-3-carboxylate acetateHCID 86669891Methyl 7-formyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate

Product 1

HCID 67168670Methyl 7-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylateYield 85.2%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 176Acetic AcidSolventHCID 887MethanolSolvent

Procedure

To a solution of methyl 7-formyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (Preparation 45C, 72 mg, 0.280 mmol) in methanol (5 mL) and 1,2-dichloroethane (1 mL) was added acetic acid (0.1 mL) and tert-butyl azetidine-3-carboxylate acetic acid salt (73.0 mg, 0.336 mmol). The contents were allowed to stir at room temperature for 40 min. and then sodium triacetoxyborohydride (178 mg, 0.840 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. Additional sodium triacetoxyborohydride (2 eq) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. Additional sodium triacetoxyborohydride (4 eq) was added and the reaction mixture was allowed to stir at room temperature for 3 days. Additional amine (0.5 eq.), followed by additional triacetoxyborohydride (3 eq.) was added and the reaction mixtures was stirred at room temperature for 6 more hours to drive the reaction to about 90% conversion. The solvents were evaporated and the residue was re-dissolved into 80 ml ethyl acetate, washed twice with sat. sodium bicarbonate, dried over sodium sulfate, and concentrated to give 95 mg of product. The compound had an HPLC ret. time=0.75/2.0 min. (condition E); MS:(M+H)=399.3.

Workup

  1. stirringto stir at room temperature overnight
  2. stirringto stir at room temperature for 2 hours
  3. stirringto stir at room temperature for 3 days
  4. additionwas added
  5. customthe reaction mixtures
  6. stirringwas stirred at room temperature for 6 more hours
  7. customthe reaction to about 90% conversion
  8. customThe solvents were evaporated
  9. dissolutionthe residue was re-dissolved into 80 ml ethyl acetate
  10. washwashed twice with sat. sodium bicarbonate
  11. dry with materialdried over sodium sulfate
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-22814e92177040b597ba38fa3c43b8be
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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