Formaldehyde → HCID 53312154, compound

HRID 924353Notes

Reaction equation

HRID 924353 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.[C:39](Cl)(=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C=O.[C:50]([O-:53])([O-])=O.[K+].[K+]>O1CCCC1.[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:44][CH:43]=[CH:42][CH:41]=3)[C:50](=[O:53])[C:20](=[CH2:21])[CH2:19]2)=[CH:15][CH:16]=1

Participants

9

Reactant 5

HCID 712FormaldehydeHCID 7412Benzoyl chlorideHCID 11430Potassium CarbonateHCID 2733832Lithium HexamethyldisilazideHCID 53311905HCID 53311905, compound

Product 1

HCID 53312154HCID 53312154, compound

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 25517Ammonium ChlorideSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
50 °C

Procedure

Under N2, LHMDS (25 mL, 1.0 M in tetrahydrofuran, 25 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) (3.51 g, 10 mmol) in 20 mL dry tetrahydrofuran is added to the reaction mixture at −10° C., the resulting mixture is then stirred for 30 min at −10° C. benzoyl chloride (1.55 g, 11 mmol) is added to the reaction mixture at −10° C., after about 1 hour at −10° C., the reaction mixture is diluted with 15 mL saturated aqueous ammonium chloride solution and stirred for 15 min, stop stirring, and remove the lower aqueous layer. Formaldehyde (37% in water, 2.43 g, 0.03 mol), K2CO3 aqueous solution (2.76 g in 10 mL water, 0.02 mol) and tetrabutyl-ammonium-hydroxide solution (40% in water, 0.13 g, 0.5 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 15 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-4a, R1=t-butoxycarbonyl, R4=benzyl) to (3R,5S-4, R1=t-butoxycarbonyl, R4=phenyl) is 70:30 as determined by HPLC. Spectroscopic data as Example 28, Method 1.

Workup

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

Sources & evidence

ORD record
ord-4d78ed271fbb49fca33cccaf72e5db5c
Source dataset
uspto-grants-2016_03
Patent number
US09278908B2

Reaction notes

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