Potassium Carbonate → 3-Chloro-5-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-pyridine

HRID 617296Notes

Reaction equation

[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.C(O)=O.C=O.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1

Participants

Reactant 3

HCID 11430Potassium Carbonate

HCID 18761834Formaldehyde formic acid

HCID 542993835-chloro-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine

Product 1

HCID 443189813-Chloro-5-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-pyridineYield 63%

Procedure

To 5-chloro-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine (0.600 g, 1.92 mmol), from Example 15b, was added a solution of formic acid/formaldehyde (1:2, 3 mL). The mixture was heated at reflux for 3 hours, then basified with sat. K2CO3. The aqueous phase was extracted with CH2Cl2 (3×) then the organic layer was dried (MgSO4) and concentrated. The crude product was purified by chromatography over silica gel eluted with CHCl3/MeOH to afford 0.274 g (63%) of the title compound as a pale yellow oil. TLC Rf =0.23 (10%MeOH/CHCl3). MS (DCI/NH3) m/e: 227 (M+H)+ with 35Cl and 229 (M+H)+ with 37Cl. 1H NMR (CDCl3, 300 MHz) δ: 8.22 (d, J=2.6 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.22 (t, J=2 Hz, 1H), 4.00 (dd, J=9, 5.50 Hz, 1H), 3.92 (dd, J=9, 5.20 Hz, 1H), 3.14-3.08 (m, 1H), 2.69-2.64 (m, 1H), 2.47 (s, 3H), 2.36-2.27 (m, 1H), 2.07-1.97 (m, 1H), 1.88-1.69 (m, 3H).

Workup

temperatureThe mixture was heated
temperatureat reflux for 3 hours
extractionThe aqueous phase was extracted with CH2Cl2 (3×)
dry with materialthe organic layer was dried (MgSO4)
concentrationconcentrated
customThe crude product was purified by chromatography over silica gel
washeluted with CHCl3/MeOH

Sources & evidence

ORD record: ord-52cb57b4256d4950abcd48679de34328
Source dataset: uspto-grants-1999_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US05948793

Reaction notes

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