3-Hydroxypyridine → (S)-1-Methyl-5-((pyridin-3-yloxy)methyl)pyrrolidin-2-one

HRID 59715Notes

Reaction equation

HRID 59715 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][C@H:34]1[N:38]([CH3:39])[C:37](=[O:40])[CH2:36][CH2:35]1.O[C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1>[CH3:39][N:38]1[C@H:34]([CH2:33][O:32][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[CH2:35][CH2:36][C:37]1=[O:40]

Participants

6

Reactant 4

HCID 79713-HydroxypyridineHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 14876039(5S)-5-(Hydroxymethyl)-1-methyl-2-pyrrolidinone

Product 1

HCID 54450751(S)-1-Methyl-5-((pyridin-3-yloxy)methyl)pyrrolidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of 1.57 g (6.0 mmole) triphenylphosphine in 30 ml dry tetrahydrofuran under argon atmosphere at −15° C. 0.95 ml (1.05 g, 6.0 mmole) diethyl azodicarboxylate was added, drop by drop for 5 minutes, then 0.517 g (4.0 mmole) (S)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one in 5 ml dry tetrahydrofuran and 0.40 g (4.2 mmole) 3-hydroxypyridine were added and stirred for 10 minutes, then kept overnight in a refrigerator at −20° C. The solution was evaporated at 35° C. in good vacuum; the residue was dissolved in 15 ml of dichloromethane and washed with 1×7 and 2×2 ml of 1M hydrochloric acid. To the combined acidic solutions 20 ml saturated aqueous sodium bicarbonate solution was carefully added and then further 1 g of solid sodium bicarbonate was added, and this was extracted with 5×10 ml dichloromethane. The combined organic solutions were dried over magnesium sulfate, evaporated on a rotavapor at 35° C. and the residue was purified by column chromatography on 30 g silica gel, and developing with benzene containing 30% of diethylamine; this furnished 0.252 g (31%) of pure product.

Workup

  1. customat −15° C
  2. waitkept overnight in a refrigerator at −20° C
  3. customThe solution was evaporated at 35° C. in good vacuum
  4. dissolutionthe residue was dissolved in 15 ml of dichloromethane
  5. washwashed with 1×7 and 2×2 ml of 1M hydrochloric acid
  6. additionTo the combined acidic solutions 20 ml saturated aqueous sodium bicarbonate solution was carefully added
  7. additionfurther 1 g of solid sodium bicarbonate was added
  8. extractionthis was extracted with 5×10 ml dichloromethane
  9. dry with materialThe combined organic solutions were dried over magnesium sulfate
  10. customevaporated on a rotavapor at 35° C.
  11. customthe residue was purified by column chromatography on 30 g silica gel

Sources & evidence

ORD record
ord-2877c1b8c8924a75a670b459bd472d07
Source dataset
uspto-grants-2016_09
Patent number
US09440948B2

Reaction notes

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