Formaldehyde → HCID 53312154, compound

HRID 924356Notes

Reaction equation

HRID 924356 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]2[N:22]([CH2:23]C3C=CC(OC)=CC=3)[C:21](=O)[CH2:20][CH2:19]2)=[CH:13][CH:12]=1.[CH3:39][C:40]([CH3:45])(C)[C:41](Cl)=O.C=O.[C:48]([O-:51])([O-])=O.[K+].[K+].O1C[CH2:57][CH2:56][CH2:55]1>[Cl-].[NH4+].[Cl-].[Na+].O>[C:11]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][C:14]([CH2:17][C@H:18]2[N:22](/[CH:23]=[CH:39]/[C:40]3[CH:45]=[CH:57][CH:56]=[CH:55][CH:41]=3)[C:48](=[O:51])[C:20](=[CH2:21])[CH2:19]2)=[CH:15][CH:16]=1

Participants

9

Reactant 6

HCID 712FormaldehydeHCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 62493Pivaloyl chlorideHCID 2733832Lithium HexamethyldisilazideHCID 53311905HCID 53311905, compound

Product 1

HCID 53312154HCID 53312154, compound

Reagents, catalysts & solvents 2

HCID 25517Ammonium ChlorideSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
-10 °C

Procedure

Under N2, LHMDS (12.5 mL, 1.0 M in tetrahydrofuran, 12.5 mmol) is added to the mixture of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1=t-butoxycarbonyl) (1.76 g, 5 mmol) in 15 mL dry tetrahydrofuran is added to the reaction mixture at −10° C., the resulting mixture is then stirred for 30 min at −10° C. 2,2-Dimethyl-propionyl chloride (0.72 g, 6 mmol) is added to the reaction mixture at −10° C., after about 1 hour at −10° C., the reaction mixture is diluted with 10 mL saturated aqueous ammonium chloride solution and stirred for 15 min, stop stirring, and remove the lower aqueous layer. Formaldehyde (37% in water, 1.2 g, 15 mmol), K2CO3 aqueous solution (1.4 g in 5 mL water, 0.01 mol) and tetrabutyl-ammonium-hydroxide solution (40% in water, 0.06 g, 0.25 mmol) are added to the remaining organic phase, and heated to 50° C., and stirred for 2 hours. Then the reaction mixture is diluted with 10 mL brine and stirred for 15 min, stop stirring, and remove the lower aqueous layer. the organic phase is then concentrated in vacuo. ethyl acetate 20 mL is added, filtered and the filtrate concentrated to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1a, R1=t-butoxycarbonyl). Crude (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1a, R1=t-butoxycarbonyl) can be purified by column chromatography eluting with 3:1 heptane/ethyl acetate. The ratio of intermediate (3S,5S-4, R1=t-butoxycarbonyl, R4=t-butyl) to (3R,5S-4, R1=t-butoxycarbonyl, R4=t-butyl) is 80:20 as determined by HPLC. Spectroscopic data as Example 28, Method 1.

Workup

  1. additionis added to the reaction mixture at −10° C.
  2. stirringstirred for 15 min
  3. stirringstop stirring
  4. customremove the lower aqueous layer
  5. temperatureheated to 50° C.
  6. stirringstirred for 2 hours
  7. stirringstirred for 15 min
  8. stirringstop stirring
  9. customremove the lower aqueous layer
  10. concentrationthe organic phase is then concentrated in vacuo
  11. additionethyl acetate 20 mL is added
  12. filtrationfiltered
  13. concentrationthe filtrate concentrated

Sources & evidence

ORD record
ord-e8edbe300d6e454c8451da5354ad59dc
Source dataset
uspto-grants-2016_03
Patent number
US09278908B2

Reaction notes

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