Formaldehyde → HCID 53312154, compound

HRID 924352Notes

Reaction equation

HRID 924352 reaction equation
C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]2[N:24]([CH2:25]C3C=CC(OC)=CC=3)[C:23](=O)[CH2:22][CH2:21]2)=[CH:15][CH:14]=1.[C:41](Cl)(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C=O.[C:52]([O-:55])([O-])=O.[K+].[K+]>O1CCCC1.[Cl-].[NH4+].[Cl-].[Na+].O>[C:13]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:14]=[CH:15][C:16]([CH2:19][C@H:20]2[N:24](/[CH:25]=[CH:41]/[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:52](=[O:55])[C:22](=[CH2:23])[CH2:21]2)=[CH:17][CH:18]=1

Participants

10

Reactant 6

HCID 712FormaldehydeHCID 7412Benzoyl chlorideHCID 7912DiisopropylamineHCID 11430Potassium CarbonateHCID 53311905HCID 53311905, compoundHCID 178418339Butyllithium2×

Product 1

HCID 53312154HCID 53312154, compound

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
-10 °C

Procedure

Under N2, n-butyllithium (56 mL, 2.5 M in hexane, 0.14 mol) is added to the mixture of Diisopropylamine (14.2 g, 0.15 mol) in 300 mL dry tetrahydrofuran at −10° C., the resulting mixture is then stirred for 30 min at −10° C. a mixture of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1=t-butoxycarbonyl) (35.1 g, 0.1 mol) in 50 mL dry tetrahydrofuran is added to the reaction mixture at −10° C., after about 30 min, n-butyllithium (40 mL, 2.5 M in hexane, 0.1 mol) is added to the reaction mixture at −10° C., the resulting mixture is then stirred for 30 min at −10° C. benzoyl chloride (15.5 g, 0.11 mol) is added to the reaction mixture at −10° C., after about 1 hour at −10° C., the reaction mixture is diluted with 100 mL saturated aqueous ammonium chloride solution and stirred for 15 min, stop stirring, and remove the lower aqueous layer. Formaldehyde (37% in water, 24.3 g, 0.3 mol), K2CO3 aqueous solution (27.6 g in 100 mL water, 0.2 mol) and tetrabutyl-ammonium-hydroxide solution (40% in water, 1.3 g, 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 100 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 200 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=phenyl) 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., after about 30 min
  2. additionis added to the reaction mixture at −10° C., after about 1 hour at −10° C.
  3. stirringstirred for 15 min
  4. stirringstop stirring
  5. customremove the lower aqueous layer
  6. temperatureheated to 50° C.
  7. stirringstirred for 2 hours
  8. stirringstirred for 15 min
  9. stirringstop stirring
  10. customremove the lower aqueous layer
  11. concentrationthe organic phase is then concentrated in vacuo
  12. additionethyl acetate 200 mL is added
  13. filtrationfiltered
  14. concentrationthe filtrate concentrated

Sources & evidence

ORD record
ord-f5a2f0a27ec34a2da97727375bdf47f8
Source dataset
uspto-grants-2016_03
Patent number
US09278908B2

Reaction notes

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