Formaldehyde → Methyl 5-chloro-2-methyl-3-((1-methylpiperidin-4-yl)oxy)benzoate

HRID 1050468Notes

Reaction equation

HRID 1050468 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:23])[CH2:17][CH2:16]2)[C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 131736069Methyl 5-chloro-2-methyl-3-(piperidin-4-yloxy)benzoate, hydrochloride

Product 1

HCID 90273068Methyl 5-chloro-2-methyl-3-((1-methylpiperidin-4-yl)oxy)benzoateYield 100%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Procedure

A solution of methyl 5-chloro-2-methyl-3-(piperidin-4-yloxy)benzoate, hydrochloride (140 mg, 0.437 mmol) and formaldehyde (195 μl, 2.62 mmol) in methanol (3580 μl) and acetic acid (597 μl) was added portion wise sodium triacetoxyborohydride (278 mg, 1.312 mmol). The reaction was stirred for 18 h at RT, at which time it was concentrated. The residue was dissolved in water, neutralized with saturated sodium bicarbonate solution, and extracted with EtOAc (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to give methyl 5-chloro-2-methyl-3-((1-methylpiperidin-4-yl)oxy)benzoate (0.130 g, 0.437 mmol, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.61-1.73 (m, 2 H) 1.84-1.94 (m, 2 H) 2.18 (s, 3 H) 2.21-2.27 (m, 2 H) 2.28 (s, 3 H) 3.83 (s, 3 H) 4.54 (dt, J=7.14, 3.63 Hz, 1 H) 7.29 (d, J=2.02 Hz, 1 H) 7.32 (d, J=2.02 Hz, 1 H). MS(ES) [M+H]+ 298.1.

Workup

  1. concentrationwas concentrated
  2. dissolutionThe residue was dissolved in water
  3. extractionextracted with EtOAc (3×25 mL)
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customdried under high vacuum

Sources & evidence

ORD record
ord-0fa04100929247fc877aff2156dbf2a8
Source dataset
uspto-grants-2016_07
Patent number
US09382234B2

Reaction notes

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