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

Uses

Sacubitril Impurity 2 is an impurity of Sacubitril (S080895) which is an antihypertensive drug used in combination with valsartan.

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

• 64-17-5 ethanol 
• 1639970-62-9 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrol-1-yl)-2-methylpentanoic acid 
• 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 
• 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 
• 92-66-0 4-bromo-1,1'-biphenyl 

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)