Dimethylformamide → (S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic Acid Methyl Ester

HRID 1365084Notes

Reaction equation

HRID 1365084 reaction equation
CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH3:11][O:12][C:13]([N:15]1[CH:20]=[CH:19][CH2:18][C:17]([CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])=[CH:16]1)=[O:14].CC([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:11][O:12][C:13]([N:15]1[CH:16]=[C:17]([C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH2:18][C:19]([CH:4]=[O:5])=[CH:20]1)=[O:14]

Participants

8

Reactant 5

HCID 6228DimethylformamideHCID 24813Phosphorus oxychlorideHCID 516892Sodium BicarbonateHCID 517045Sodium AcetateHCID 235967383-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester

Product 1

HCID 11615761(S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic Acid Methyl EsterYield 54%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of DMF (0.04 mL, 0.54 mmol) in 4 mL of CH2Cl2 cooled at 0° C. was slowly added POCl3 (0.025 mL, 0.27 mmol). The ice bath was removed and the mixture was stirred at RT for 30 min. It was then transferred via a double tipped needle to a solution of 3-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester II (0.0404 g, 0.18 mmol) in 4 mL of CH2Cl2 cooled at 0° C. The reaction mixture was stirred at RT for 1 day. A solution of NaOAc (0.024 g, 0.29 mmol) in 0.5 mL of water was added and the reaction mixture was stirred at RT for 20 min. A saturated aqueous solution of NaHCO3 was slowly added until pH was basic (about 10 mL). The aqueous layer was extracted with CH2Cl2 (4 times), and the combined organic layers were dried over MgSO4. After evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (15% EtOAc/hexanes) to afford 0.0241 g (54%) of (S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester III as white crystals, mp 78-80° C. IR (thin film, neat, NaCl): 2955, 2767, 1731, 1667, 1620, 1437, 1394, 1203, 991 cm−1; 1H NMR (CDCl3, 300 MHz) δ 9.45 (s, 1H), 7.65 (m, 1H), 6.81 (s, 1H), 3.91 (s, 3H), 3.12-3.07 (m, 1H), 2.93 (s, 2H), 2.59 (m, 1H), 2.20-2.12 (m, 3H), 1.81-1.62 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 191.13, 141.44, 122.61, 120.52, 118.42, 69.75, 56.98, 54.47, 40.61, 29.45, 22.91, 19.86. HRMS Calcd for C13H18N2O3: 251.1396 [M+H]+. Found: 251.1390 [M+H]+. [α]25D −51.7 (c=0.8, CH2Cl2).

Workup

  1. customThe ice bath was removed
  2. temperaturecooled at 0° C
  3. stirringThe reaction mixture was stirred at RT for 1 day
  4. stirringthe reaction mixture was stirred at RT for 20 min
  5. extractionThe aqueous layer was extracted with CH2Cl2 (4 times)
  6. dry with materialthe combined organic layers were dried over MgSO4
  7. customAfter evaporation of the solvent under reduced pressure
  8. customthe crude material was purified by RPLC (15% EtOAc/hexanes)

Sources & evidence

ORD record
ord-bb490b44f84a438daa3b6851986f6b1e
Source dataset
uspto-grants-2011_02
Patent number
US07888512B2

Reaction notes

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