1038924-97-8

Basic information

• Product Name: Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate
• Synonyms: Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate;Sacubitril Impurity 22;LCZ700;(2R,4S)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoate;LCZ-696 Impurity 4
• CAS NO: 1038924-97-8
• Molecular Formula: C₂₄H₂₇NO₄
• Molecular Weight: 393.47548
• Product Categories: LCZ696
• Mol File: 1038924-97-8.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 581.3±50.0 °C(Predicted)
• Appearance: /
• Density: 1.166±0.06 g/cm3(Predicted)
• PKA: -1.52±0.20(Predicted)
• CAS DataBase Reference: Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate(1038924-97-8)
• EPA Substance Registry System: Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate(1038924-97-8)

Safety Data

• Hazardous Substances Data: 1038924-97-8(Hazardous Substances Data)

Usage

Description

Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate is a complex organic compound with a specific stereochemistry, characterized by its chiral centers and functional groups. It is derived from the combination of ethyl, biphenyl, and pyrrolidine moieties, which contribute to its unique structural and chemical properties.

Uses

Used in Pharmaceutical Industry:
Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate is used as an impurity in the synthesis of antihypertensive drugs, specifically Sacubitril (S080895). It plays a crucial role in the development and quality control of Sacubitril, ensuring the safety and efficacy of the final drug product when used in combination with valsartan for the treatment of hypertension.
As an impurity, it is essential to monitor and control the levels of Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoate in the manufacturing process to maintain the desired therapeutic effects and minimize potential side effects. Its presence in the pharmaceutical industry highlights the importance of understanding and managing impurities in drug development and production.

Synthetic route

ethanol (64-17-5) + C22H23NO4 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
With thionyl chloride at 20℃; for 7h;	91%
With thionyl chloride at 20℃; for 7h;	91%
With thionyl chloride at 50 - 60℃;

(2R,4S)-5-biphenyl-4-yl-4-[3-(2-bromoethoxycarbonyl)propionylamino]-2-methylpentanoic acid → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 2h;

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / 8 h / 0 - 50 °C 2: acetic acid / 12 h / 110 °C View Scheme

succinic acid anhydride (108-30-5) + (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (752174-62-2) → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
With acetic acid at 110℃; for 12h; Concentration; Temperature;	0.3 g

C18H16O2 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions

Yield

Multi-step reaction with 7 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 16 h / 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / Reflux 3: dmap; triethylamine / dichloromethane / 12 h / 20 °C / Cooling with ice 4: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C 6: ruthenium(III) trichloride hydrate; sodium periodate / acetonitrile; tetrachloromethane; water / 5 h / 20 °C / Cooling with ice 7: thionyl chloride / 7 h / 20 °C View Scheme

C18H18O2 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions

Yield

Multi-step reaction with 6 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / Reflux 2: dmap; triethylamine / dichloromethane / 12 h / 20 °C / Cooling with ice 3: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C 4: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C 5: ruthenium(III) trichloride hydrate; sodium periodate / acetonitrile; tetrachloromethane; water / 5 h / 20 °C / Cooling with ice 6: thionyl chloride / 7 h / 20 °C View Scheme

C18H22O2 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions

Yield

Multi-step reaction with 5 steps 1: dmap; triethylamine / dichloromethane / 12 h / 20 °C / Cooling with ice 2: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C 4: ruthenium(III) trichloride hydrate; sodium periodate / acetonitrile; tetrachloromethane; water / 5 h / 20 °C / Cooling with ice 5: thionyl chloride / 7 h / 20 °C View Scheme

(2R,4R)-1-([1,1'-biphenyl]-4-yl)-5-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-ol → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C 3: ruthenium(III) trichloride hydrate; sodium periodate / acetonitrile; tetrachloromethane; water / 5 h / 20 °C / Cooling with ice 4: thionyl chloride / 7 h / 20 °C View Scheme

C28H39NO3Si → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C 2: ruthenium(III) trichloride hydrate; sodium periodate / acetonitrile; tetrachloromethane; water / 5 h / 20 °C / Cooling with ice 3: thionyl chloride / 7 h / 20 °C View Scheme

C22H25NO3 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: ruthenium(III) trichloride hydrate; sodium periodate / acetonitrile; tetrachloromethane; water / 5 h / 20 °C / Cooling with ice 2: thionyl chloride / 7 h / 20 °C View Scheme

C20H22O3 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions

Yield

Multi-step reaction with 8 steps 1: trifluoroacetic acid / dichloromethane / 4 h / 20 °C 2: palladium 10% on activated carbon; hydrogen / ethanol / 16 h / 20 °C 3: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / Reflux 4: dmap; triethylamine / dichloromethane / 12 h / 20 °C / Cooling with ice 5: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C 6: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C 7: ruthenium(III) trichloride hydrate; sodium periodate / acetonitrile; tetrachloromethane; water / 5 h / 20 °C / Cooling with ice 8: thionyl chloride / 7 h / 20 °C View Scheme

C19H18INO2 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1.33 h / -30 °C 1.2: 0.5 h 2.1: lithium hydroxide; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 3.1: thionyl chloride / 50 - 60 °C View Scheme

C28H32N2O5 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium hydroxide; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 2: thionyl chloride / 50 - 60 °C View Scheme

(S)-1-([1,1’-biphenyl]-4-yl)-3-chloropropan-2-ol (1573000-28-8) → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 0 - 30 °C 2.1: sodium hexamethyldisilazane / tetrahydrofuran / 1.33 h / -70 °C 2.2: 0.5 h 3.1: lithium hydroxide; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 4.1: thionyl chloride / 50 - 60 °C View Scheme
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 2 h / 0 °C 2.1: titanium tetrachloride / dichloromethane / 0.5 h / 0 °C 2.2: 10 h / 20 - 25 °C 3.1: dihydrogen peroxide / 0.5 h / 0 °C 3.2: 3 h / 20 - 25 °C 4.1: thionyl chloride / 7 h / 20 °C View Scheme

(1-([1,1‘-biphenyl]-4-yl)-3-chloropropan-2-yl)pyrrolidine-2,5-dione (1573000-36-8) → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 1.33 h / -70 °C 1.2: 0.5 h 2.1: lithium hydroxide; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 3.1: thionyl chloride / 50 - 60 °C View Scheme

C15H15IO → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / dichloromethane / 0 - 30 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 1.33 h / -30 °C 2.2: 0.5 h 3.1: lithium hydroxide; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 4.1: thionyl chloride / 50 - 60 °C View Scheme

C19H18ClNO2 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: titanium tetrachloride / dichloromethane / 0.5 h / 0 °C 1.2: 10 h / 20 - 25 °C 2.1: dihydrogen peroxide / 0.5 h / 0 °C 2.2: 3 h / 20 - 25 °C 3.1: thionyl chloride / 7 h / 20 °C View Scheme

C32H32N2O5 → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dihydrogen peroxide / 0.5 h / 0 °C 1.2: 3 h / 20 - 25 °C 2.1: thionyl chloride / 7 h / 20 °C View Scheme

4-bromo-1,1'-biphenyl (92-66-0) → (2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: magnesium; iodine / tetrahydrofuran / 2 h / 40 - 50 °C 1.2: 2 h / -15 - 5 °C 2.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 2 h / 0 °C 3.1: titanium tetrachloride / dichloromethane / 0.5 h / 0 °C 3.2: 10 h / 20 - 25 °C 4.1: dihydrogen peroxide / 0.5 h / 0 °C 4.2: 3 h / 20 - 25 °C 5.1: thionyl chloride / 7 h / 20 °C View Scheme

(2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8) → α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate (149709-62-6)

Conditions	Yield
In tetrahydrofuran; water for 1.5h;	85%
With lithium hydroxide In tetrahydrofuran; water at 20℃; for 1.5h;	70%
With ethanol; potassium carbonate at 50 - 60℃;	44.6 g

(2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8) → C22H23NO4

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; water at 70℃; for 5h; Solvent; Temperature;	66.7%

(2R,4S)-5-biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (1038924-97-8) → α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate monosodium salt (149690-05-1)

Conditions	Yield
With sodium hydroxide; water In tetrahydrofuran; ethanol for 16h;

Upstream product

• 92-66-0 4-bromo-1,1'-biphenyl 
• 1573000-36-8 (1-([1,1‘-biphenyl]-4-yl)-3-chloropropan-2-yl)pyrrolidine-2,5-dione 
• 1573000-28-8 (S)-1-([1,1’-biphenyl]-4-yl)-3-chloropropan-2-ol 
• 64-17-5 ethanol 
• 1639970-62-9 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrol-1-yl)-2-methylpentanoic acid 
• 108-30-5 succinic acid anhydride 
• 752174-62-2 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester 
• 1012341-50-2 (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid 

Downstream Products

• 149690-05-1 α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate monosodium salt 
• 1639970-62-9 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrol-1-yl)-2-methylpentanoic acid 
• 149709-62-6 α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate 

Relevant articles and documents

Preparation method of

The preparation method comprises the following steps 1-11: Wherein. ROH (Formula X) is a chiral alcohol and the like, PG is a hydroxy protecting group, a compound of Formula VI and a compound of Formula V are the chiral auxiliary of the present invention. To the invention, the chiral auxiliary base ROH compound and the chiral alcohol X (Formula VI) are used for preparing the chiral auxiliary base-type compound of formula V IV and the compound of Formula XI, and the compound of formula IV can be prepared through three-step simple operation steps of chiral auxiliary base. Be applicable to industrial production.

Sacubitril intermediate and preparation method and application thereof

The invention discloses a sacubitril intermediate and a preparation method and application thereof. The sacubitril intermediate has the chemical structure as shown in the formula III and/or formula IV, wherein R is phenyl, benzyl and isopropyl. The application of the intermediate for synthesis of sacubitril has advantages as follows: the preparation process is simple; the reaction condition is mild; and the environment is protected. The invention has great significance and use value for low-cost, large-sale and high-efficiency preparation of high-purity sacubitril.

A LCZ696 preparation method of drug impurity (by machine translation)

The present invention provides a LCZ696 preparation method of drug impurities, including: the (2 R, 4 S) - 5 - (biphenyl - 4 - yl) - 4 - [(uncle butoxy carbonyl) amino] - 2 - methyl valeric acid in chloro- medicinal preparation in the reaction with the organic alcohol, in order to get the product and succinic anhydride as a raw material, preparation (2 R, 4 S) - 5 - biphenyl - 4 - yl - 4 - (2, 5 - dicarbonyl - pyrrolidine - 1 - yl) - 2 - methyl pentanoate; make (2 R, 4 S) - 5 - biphenyl - 4 - yl - 4 - (2, 5 - dicarbonyl - pyrrolidine - 1 - yl) - 2 - methyl pentanoate hydrolyzed under acidic conditions, make (2 R, 4 S) - 5 - biphenyl - 4 - yl - 4 - (2, 5 - dicarbonyl - pyrrolidine - 1 - yl) - 2 - methyl valeric acid. The method of the invention the operation is simple, low cost, and is capable of LCZ696 pharmaceutical quality control to provide qualified reference substance. (by machine translation)