Lithium Hydroxide → HCID 13873825, compound

HRID 847300Notes

Reaction equation

HRID 847300 reaction equation
[CH3:1][C:2]1([CH3:21])[CH2:7][N:6]([CH2:8][C:9]([O:11]CC)=[O:10])[C:5](=[O:14])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1.[Li+].[OH-]>O1CCOCC1>[CH3:1][C:2]1([CH3:21])[CH2:7][N:6]([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:14])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1

Participants

4

Reactant 2

HCID 3939Lithium HydroxideHCID 19882081HCID 19882081, compound

Product 1

HCID 13873825HCID 13873825, compound

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

1,2-Diamino-2-methylpropane (7.4 ml) and methylbenzoyl formate (10 ml) were dissolved in absolute ethanol (250 ml) and heated at reflux for 18 hours. The reaction was concentrated to half volume and hot hexane (225 ml) was added. The solution was filtered and the filtrate was placed in the refrigerator overnight. The resultant crystals were filtered, and dried to give 5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl-2-(2H)-pyrazine. Mass Spec. m/c 203 (M+H)+. Anal Calcd. for C12H14N2O 1/2H2O: C, 69.70; H, 6.82; N, 13.55. Found: C, 70.10; H, 7.04; N, 13.63. 5,6-Dihydro-5,5-dimethyl-2-oxo-3-phenyl (3.5 g) was dissolved in dry THF (35 ml), 1M THF solution of sodium bis-trimethylsilyl amide (17.2 ml) was cannulated into the solution under nitrogen. After the addition was complete, the solution was stirred for an additional 20 minutes. Ethyl bromoacetate (2 ml) in dry THF (2 ml) was added dropwise. Stirring was continued for 48 hours. The solution was then poured into water and extracted twice with ether. The ethereal extracts were washed with saturated brine, dried, and concentrated in vacuo to give ethyl 5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl-1-(2H)-pyrazineacetate as white crystals. This ester was dissolved in dioxane (7 ml) and treated with 1M aqueous solution of LiOH (6.8 ml) at room temperature overnight. The solution was concentrated in vacuo, the residue was treated with 1N HCl (15 ml) and extracted with ethyl acetate. The organic extracts were dried and concentrated in vacuo to give 5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl1-(2H)-pyrazineacetic acid as white crystals; NMR (CDCl3): 7.4-7.8 (m, 5H), 4.3 (s, 2H), 3.5 (s, 2H), 1.4 (s, 6H). Mass spec m/e 261 (M+H)+. Using the same procedure and protocol described in Example 1, 5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl-1-(2H)-pyrazineacetic acid can be coupled to BOC-Ser(OBzl)-Tyr-(O-2-Br-CBZ)-D-Trp-(N-formyl)-Leu-Arg-(Tos)-Pro-O-Resin to give after cleavage from the resin, removal of protecting groups, work up and HPLC purification N-(5,6-dihydro-5,5-dimethyl-2-oxo-3-phenyl-1-(2H)-pyrazineacetyl)-Ser-Tyr-D-Trp-Leu-Arg-ProNHEt.

Workup

  1. concentrationThe solution was concentrated in vacuo
  2. additionthe residue was treated with 1N HCl (15 ml)
  3. extractionextracted with ethyl acetate
  4. customThe organic extracts were dried
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-cb61547dabd544fc8a7529265b3bc0ef
Source dataset
uspto-grants-1992_08
Patent number
US05140009

Reaction notes

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