Tetrahydrofuran → HCID 86673650, compound

HRID 924325Notes

Reaction equation

HRID 924325 reaction equation
[Li+].[CH3:2][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][C:24]3[CH:29]=[CH:28][C:27](OC)=[CH:26][CH:25]=3)[C:21](=[O:32])[CH2:20][CH2:19]2)=[CH:13][CH:12]=1.[CH3:39][C:40]([CH3:45])(C)[C:41](Cl)=[O:42].O1C[CH2:49][CH2:48][CH2:47]1>[Cl-].[NH4+]>[C:41]([C@@H:20]1[CH2:19][CH:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:12][CH:13]=2)[N:22](/[CH:23]=[CH:24]/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:2]=2)[C:21]1=[O:32])(=[O:42])[C:40]1[CH:45]=[CH:49][CH:48]=[CH:47][CH:39]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 62493Pivaloyl chlorideHCID 2733832Lithium HexamethyldisilazideHCID 53311905HCID 53311905, compound

Product 1

HCID 86673650HCID 86673650, compound

Reagents, catalysts & solvents 1

HCID 25517Ammonium ChlorideSolvent

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. the organic phase is then concentrated in vacuo. Ethyl acetate 20 mL is added, filtered and the filtrate concentrated to give (R/S)-3-(2,2-dimethyl-propionyl)-(S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4a, R1=t-butoxycarbonyl, R4=isopropyl), the ration of (3S,5S) to (3R,5S) is 80:20 as determined by HPLC. 1HNMR (400 MHz, CDCl3): 0.98 (s, 9H, 3CH3), 1.52 (s, 9H, (CH3)3), 2.19 (m, 1H, 3-CHH), 2.42 (m, 1H, 3CHH), 2.67 (m, 1H, 5-CHH), 2.92 (m, 1H, 5-CHH), 3.09 (m, 1H, 2-CH), 4.38 (m, 1H, 4-CH), 7.10˜7.80 (9H, m, aromatic).

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. concentrationthe organic phase is then concentrated in vacuo
  6. additionEthyl acetate 20 mL is added
  7. filtrationfiltered
  8. concentrationthe filtrate concentrated

Sources & evidence

ORD record
ord-9905f340b50e47c19b8f05bb5f660456
Source dataset
uspto-grants-2016_03
Patent number
US09278908B2

Reaction notes

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