(R,E)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpent-2-enoate Chemical Properties

Boiling point:

562.7±50.0 °C(Predicted)

Density 

1.081±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

pka

11.14±0.46(Predicted)

Appearance

Off-white to light yellow Solid

optical activity

-31.5534°(C=0.5665g/100ml CHCL3)

(R,E)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpent-2-enoate Usage And Synthesis

Uses

(R)-Ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate is used to prepare dicarboxylic acid dipeptide neutral endopeptidase inhibitors.

Synthesis

Step 5: 23.3 g of the product of Step 4 ((R,E)-ethyl 5-([1,1'-biphenylyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate, 65.6 mmol, 1.0 eq.) was dissolved in 300 mL of dichloromethane (DCM) and cooled under a nitrogen (N2) atmosphere to -70° C. At this temperature, dropwise 109 mL of diisobutylaluminum hydride (DIBAL-H, 1.5 M toluene solution, 164 mmol, 2.5 eq.) was added. After stirring for 15 minutes, thin layer chromatography (TLC) analysis showed that there was still raw material residue. Subsequently, an additional 15 mL of DIBAL-H (1.5 M toluene solution) was added dropwise and stirring was continued for 5 minutes at -70°C. TLC showed that the reaction was complete. The reaction solution was slowly poured into 450 mL of 1 M aqueous hydrochloric acid (HCl), keeping the temperature below 0°C. After stirring for a few minutes, the organic layer was separated and the aqueous phase was extracted with DCM (100 mL × 2). The combined organic layers were washed sequentially with aqueous sodium bicarbonate (NaHCO3) (150 mL) and water (100 mL) and dried over anhydrous sodium sulfate (Na2SO4). After filtration, 19.0 g of ethyl 2-(triphenylphosphoranylidene)propionate was added to the solution, keeping the temperature below 5°C. The resulting solution was stirred at 25°C for 18 h. TLC showed that the reaction was complete. The reaction solution was concentrated, purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) and then crystallized from petroleum ether/ethyl acetate (80 mL/20 mL) to afford 17.0 g of ethyl (4R)-5-[1,1'-biphenyl]-4-yl-4-[[tert-butoxycarbonyl]amino]-2-methyl-2-pentenoate (chemical purity > 99.5%) as a white solid. Total yield in two steps: 89.1%.

References

[1] Patent: WO2015/154673, 2015, A1. Location in patent: Page/Page column 16

(R,E)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpent-2-enoate(149709-59-1)Related Product Information

• (2S,4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid
• (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpent-2-enoic acid
• LCZ Impurity
• (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-aMino-2-Methylpentanoic acid hydrochloride
• AHU-377
• (S)-5-[(Biphenyl-4-yl)carbonyl]pyrrolidin-2-one
• LCZ696 InteMediate
• (2R,4S)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpentanoate
• (2S,4R)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid
• sacubitril
• (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpentanoic acid
• (2R,4S)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-aMino-2-Methylpentanoate
• AHU-377 (heMicalciuM salt)
• Valsartan
• (2R,4R)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid
• Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate
• (2R,4S)-4-([1,1'-Biphenyl]-4-ylmethyl)-4-(4-ethoxy-4-oxobutanamido)-2-methylbutanoic acid
• N-[2’-(1H-tetrazol-5-yl)biphenyl-4-yl methyl]-N-Valeryl-(L)-Valine benzyl ester