1038924-70-7

Basic information

• Product Name: 2-Pyrrolidinone, 5-([1,1'-biphenyl]-4-ylMethyl)-3-Methyl-, (3R,5S)-
• Synonyms: 2-Pyrrolidinone, 5-([1,1'-biphenyl]-4-ylMethyl)-3-Methyl-, (3R,5S)-;(3R,5S)-5-biphenyl-4-ylMethyl-3-Methylpyrrolidin-2-one;(3R,5S)-;Sacubitril Impurity 18;LCZ699;(3R,5S)-5-([1,1'-biphenyl]-4-ylmethyl)-3-methylpyrrolidin-2-one;LCZ-696 Impurity 5;AHU09-B
• CAS NO: 1038924-70-7
• Molecular Formula: C₁₈H₁₉NO
• Molecular Weight: 265.34956
• Mol File: 1038924-70-7.mol
• Article Data: 16

Chemical Properties

• Boiling Point: 474.0±24.0 °C(Predicted)
• Appearance: /
• Density: 1.083±0.06 g/cm3(Predicted)
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 16.35±0.60(Predicted)
• CAS DataBase Reference: 2-Pyrrolidinone, 5-([1,1'-biphenyl]-4-ylMethyl)-3-Methyl-, (3R,5S)-(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Pyrrolidinone, 5-([1,1'-biphenyl]-4-ylMethyl)-3-Methyl-, (3R,5S)-(1038924-70-7)
• EPA Substance Registry System: 2-Pyrrolidinone, 5-([1,1'-biphenyl]-4-ylMethyl)-3-Methyl-, (3R,5S)-(1038924-70-7)

Safety Data

• Hazardous Substances Data: 1038924-70-7(Hazardous Substances Data)

Usage

Uses

Sacubitril Impurity 1 is an impurity of Sacubitril (S080895) which is an antihypertensive drug used in combination with valsartan.

Synthetic route

(2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (149690-12-0) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; methanol	95%
With lithium hydroxide In ethanol Reflux;

(3R,5S)-5-([1,1'-biphenyl]-4-ylchloromethyl)-3-methylpyrrolidin-2-one → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With palladium on activated charcoal In methanol at 20℃; for 5h;	95%

(3R,5S)-5-([1,1'-biphenyl]-4-carbonyl)-3-methylpyrrolidin-2-one → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; acetic acid In ethanol at 50℃; under 7600.51 Torr; for 6h; Temperature;	92.3%
With sulfuric acid; palladium 10% on activated carbon; hydrogen at 40℃; for 30h;	80.6%

ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-azido-2-methylpentanoate → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 18h;	92%

(3R,5S)-5-([1,1'-biphenyl]-4-yl-methyl)-1-((R)-2-hydroxy-1-phenylethyl)-3-methyl-2-pyrrolidone → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 80℃; under 30003 Torr; for 24h;	89%

(1S,3R,5S)-1-[[3-methyl-5-(1,1'-biphenyl-4-ylmethyl)-2-pyrrolidone]benzyl]-2-naphthol → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; Reagent/catalyst; Solvent;	88%

4-bromo-1,1'-biphenyl (92-66-0) + (3R,5S)-5-(iodomethyl)-3-methyl-2-pyrrolidinone → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Stage #1: (3R,5S)-5-(iodomethyl)-3-methyl-2-pyrrolidinone With chloro-trimethyl-silane; ethylene dibromide; zinc In N,N-dimethyl acetamide at 0 - 5℃; for 1h; Inert atmosphere; Stage #2: 4-bromo-1,1'-biphenyl With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl acetamide at 5℃; for 24h; Negishi Coupling;	87.8%

4-biphenylylmagnesium bromide (3315-91-1) + (3R,5S)-5-(tosyloxymethyl)-3-methyl-2-pyrrolidone → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With copper(l) cyanide In tetrahydrofuran at -30 - 20℃; Inert atmosphere;	82.3%

4-bromo-1,1'-biphenyl (92-66-0) + (3R,5S)-5-(bromomethyl)-3-methyl-2-pyrrolidone → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Stage #1: 4-bromo-1,1'-biphenyl With iodine; magnesium In tetrahydrofuran at 0 - 60℃; Inert atmosphere; Stage #2: (3R,5S)-5-(bromomethyl)-3-methyl-2-pyrrolidone With iron(III)-acetylacetonate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	82%

C7H13NO4S (1447173-69-4) + 4-biphenylboronic acid (5122-94-1) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In water; dimethyl sulfoxide at 80℃; for 10h; Reagent/catalyst; Solvent; Inert atmosphere;	82%

4-bromo-1,1'-biphenyl (92-66-0) + (3R,5S)-5-(tosyloxymethyl)-3-methyl-2-pyrrolidone → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Stage #1: 4-bromo-1,1'-biphenyl With iodine; magnesium In tetrahydrofuran at 0 - 60℃; Inert atmosphere; Stage #2: (3R,5S)-5-(tosyloxymethyl)-3-methyl-2-pyrrolidone With iron(III)-acetylacetonate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	74%

(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (752174-62-2) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In ethyl acetate at 40℃; Reagent/catalyst;	72%
With methanol; potassium hydroxide at 60 - 65℃; for 4h;	49.3%

ethyl 5-ambo-(2R,4S)-5-([1,1 '-biphenyl]-4-yl)-4-{[(tertbutoxy)carbonyl]amino}-5-hydroxy-2-ethypentanoate + methyl chloroformate (79-22-1) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Stage #1: ethyl 5-ambo-(2R,4S)-5-([1,1 '-biphenyl]-4-yl)-4-{[(tertbutoxy)carbonyl]amino}-5-hydroxy-2-ethypentanoate; methyl chloroformate In Isopropyl acetate at 0 - 20℃; for 0.0833333h; Stage #2: With 2-methylbutan-2-ol (lithium salt) In n-heptane; Isopropyl acetate at 0 - 2℃; for 3h;	66%

(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1038924-61-6) + methyl iodide (74-88-4) → (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (1038925-00-6) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Stage #1: (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one With n-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 0.5h; Heating / reflux; Stage #2: methyl iodide In tetrahydrofuran; cyclohexane at -78℃; for 2h; Product distribution / selectivity;

ethyl (2S,4S)-4-amino-5-[(1,1'-biphenyl)-4-yl]-2-methylpentanoate hydrochloride (149690-13-1) + (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (149690-12-0) → (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (1038925-00-6) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Stage #1: ethyl (2S,4S)-4-amino-5-[(1,1'-biphenyl)-4-yl]-2-methylpentanoate hydrochloride; (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride With triethylamine In Isopropyl acetate at 55℃; for 1h; Stage #2: In Isopropyl acetate for 24h; Product distribution / selectivity; Heating / reflux;

(3R,5R)-5-(biphenyl-4-yl)methyl-3-methyl-2-oxopyrrolidine-3-carboxylic acid (1038925-08-4) + (3S,5R)-5-biphenyl-4-ylmethyl-3-methyl-2-oxopyrrolidine-3-carboxylic acid (1038925-09-5) → (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (1038925-00-6) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
In toluene for 16h; Product distribution / selectivity; Heating / reflux;

(3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (1038924-66-1) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 1h; Product distribution / selectivity; Heating / reflux;

(3R/S,5S)-5-biphenyl-4-ylmethyl-3-iodomethyl-pyrrolidin-2-one (1174131-32-8) → (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (1038925-00-6) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With hydrogen; triethylamine; palladium on activated charcoal In ethanol at 20℃; under 750.075 Torr;	A n/a B n/a

(3R,5S)-5-(bromomethyl)-3-methyl-2-pyrrolidone + 4-biphenylylmagnesium bromide (3315-91-1) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Stage #1: 4-biphenylylmagnesium bromide With zinc(II) chloride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (3R,5S)-5-(bromomethyl)-3-methyl-2-pyrrolidone With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 0 - 20℃; Negishi Coupling;	0.32 g

(3R,5S)-5-(iodomethyl)-3-methyl-2-pyrrolidinone + 4-biphenylylmagnesium bromide (3315-91-1) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
With copper(II) sulfate In tetrahydrofuran at -5 - 20℃; for 48h; Inert atmosphere;	1.82 g

(3R,5S)-5-(hydroxymethyl)-3-methyl-2-pyrrolidone → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: dmap; triethylamine / dichloromethane / 5 - 20 °C 2: copper(l) cyanide / tetrahydrofuran / -30 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: dmap; triethylamine / dichloromethane / 5 - 20 °C 2.1: sodium iodide / acetone / 24 h / Reflux 3.1: ethylene dibromide; zinc; chloro-trimethyl-silane / N,N-dimethyl acetamide / 1 h / 0 - 5 °C / Inert atmosphere 3.2: 24 h / 5 °C View Scheme
Multi-step reaction with 3 steps 1: dmap; triethylamine / dichloromethane / 5 - 20 °C 2: sodium iodide / acetone / 24 h / Reflux 3: copper(II) sulfate / tetrahydrofuran / 48 h / -5 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: triphenylphosphine; bromine / dichloromethane / 0 - 20 °C 2.1: magnesium; iodine / tetrahydrofuran / 0 - 60 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 20 °C 2.1: magnesium; iodine / tetrahydrofuran / 0 - 60 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere View Scheme

(3R,5S)-5-(tosyloxymethyl)-3-methyl-2-pyrrolidone → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium iodide / acetone / 24 h / Reflux 2.1: ethylene dibromide; zinc; chloro-trimethyl-silane / N,N-dimethyl acetamide / 1 h / 0 - 5 °C / Inert atmosphere 2.2: 24 h / 5 °C View Scheme
Multi-step reaction with 2 steps 1: sodium iodide / acetone / 24 h / Reflux 2: copper(II) sulfate / tetrahydrofuran / 48 h / -5 - 20 °C / Inert atmosphere View Scheme

C25H38O4SSi → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 6 h / 60 °C / Inert atmosphere 2: Jones reagent / acetone / 4 h / 0 °C / Inert atmosphere 3: thionyl chloride / 7 h / 20 °C / Inert atmosphere 4: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C View Scheme

(2R,4R)-5-((tert-butyldimethylsilyl)oxy)-4-methylpentane-1,2-diol (1006724-46-4) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; Nonafluorobutanesulfonyl fluoride / dichloromethane / 3 h / 0 °C / Inert atmosphere 2.1: magnesium; iodine / tetrahydrofuran / Heating; Inert atmosphere 2.2: 0.5 h / 0 °C 2.3: 0 - 20 °C 3.1: dmap; triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere 4.1: sodium azide / N,N-dimethyl-formamide / 6 h / 60 °C / Inert atmosphere 5.1: Jones reagent / acetone / 4 h / 0 °C / Inert atmosphere 6.1: thionyl chloride / 7 h / 20 °C / Inert atmosphere 7.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C View Scheme

C18H19N3O2 → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / 7 h / 20 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C View Scheme

tert-butyl dimethyl ((R)-2-methyl-3-((R)-oxiran-2-yl)propoxy)silane → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: magnesium; iodine / tetrahydrofuran / Heating; Inert atmosphere 1.2: 0.5 h / 0 °C 1.3: 0 - 20 °C 2.1: dmap; triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere 3.1: sodium azide / N,N-dimethyl-formamide / 6 h / 60 °C / Inert atmosphere 4.1: Jones reagent / acetone / 4 h / 0 °C / Inert atmosphere 5.1: thionyl chloride / 7 h / 20 °C / Inert atmosphere 6.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C View Scheme

(2R,4R)-1-([1,1'-biphenyl]-4-yl)-5-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-ol → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: dmap; triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 6 h / 60 °C / Inert atmosphere 3: Jones reagent / acetone / 4 h / 0 °C / Inert atmosphere 4: thionyl chloride / 7 h / 20 °C / Inert atmosphere 5: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C View Scheme

(((2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-azido-2-methylpentyl)oxy)(tert-butyl)dimethylsilane → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: Jones reagent / acetone / 4 h / 0 °C / Inert atmosphere 2: thionyl chloride / 7 h / 20 °C / Inert atmosphere 3: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C View Scheme

(2R)-2-methyl-4-oxobutanoic acid → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene / 36 h / 40 - 50 °C 2.1: ethyl bromide; magnesium / tetrahydrofuran / 20 °C / Inert atmosphere 2.2: -78 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 20 °C View Scheme

(4S,1'R)-4,5-dihydro-2-(1-methyl-3-butenyl)-4-(1-methylethyl)oxazole (88362-53-2) → (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: water; hydrogenchloride / 3 h / 0 - 5 °C / Inert atmosphere 2.1: ozone / dichloromethane / 0.25 h / -78 - 20 °C 3.1: toluene / 36 h / 40 - 50 °C 4.1: ethyl bromide; magnesium / tetrahydrofuran / 20 °C / Inert atmosphere 4.2: -78 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 20 °C View Scheme

ethanol (64-17-5) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) → (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester sulfuric acid salt (1038924-74-1)

Conditions	Yield
With sulfuric acid at 75 - 85℃; for 16h; Reagent/catalyst;	88.2%
With sulfuric acid at 80 - 120℃; for 24h; Product distribution / selectivity;

(3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) → (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (149690-12-0)

Conditions	Yield
With hydrogenchloride In ethanol for 16h; Time; Reflux;	85.6%
With hydrogenchloride In methanol at 70 - 85℃; for 24h;	82%

(3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) → (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid hydrochloride (1038924-71-8)

Conditions	Yield
With hydrogenchloride; acetic acid for 20h; Reflux;	80%
With hydrogenchloride; acetic acid In water for 20h; Heating / reflux;

(3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) + C7H11ClO4 → C25H29NO4

Conditions	Yield
With sodium hydride In 1,4-dioxane; N,N-dimethyl-formamide at -15 - 0℃; Inert atmosphere;	68%

pyrrolidine (123-75-1) + formaldehyd (50-00-0) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) → (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one (1038924-80-9)

Conditions	Yield
In ethanol; water for 3h; Product distribution / selectivity; Heating / reflux;

(3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (1038925-00-6) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) + pivaloyl chloride (3282-30-2) → (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (1038924-66-1) + (3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (1038924-67-2)

Conditions	Yield
Stage #1: (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one; (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: pivaloyl chloride at -78 - 20℃; for 4h; Product distribution / selectivity;

(3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) + pivaloyl chloride (3282-30-2) → (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (1038924-66-1)

Conditions	Yield
Stage #1: (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: pivaloyl chloride In tetrahydrofuran; hexane at -78 - 20℃; for 0.5h; Product distribution / selectivity;

ethanol (64-17-5) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) → (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (149690-12-0)

Conditions	Yield
With hydrogenchloride In water at 80 - 120℃; for 24h; Product distribution / selectivity;

ethanol (64-17-5) + (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) → (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (p-toluenesulphonate salt) (1039357-84-0)

Conditions	Yield
With toluene-4-sulfonic acid at 80 - 120℃; for 24h; Product distribution / selectivity;

(3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one (1038924-70-7) + di-tert-butyl dicarbonate (24424-99-5) → (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1038924-76-3)

Conditions	Yield
With dmap; triethylamine In ethyl acetate at 50℃; for 1h; Product distribution / selectivity;
Stage #1: (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one With dmap at 20℃; Stage #2: di-tert-butyl dicarbonate With triethylamine

Upstream product

• 3315-91-1 4-biphenylylmagnesium bromide 
• 92-66-0 4-bromo-1,1'-biphenyl 
• 1006724-46-4 (2R,4R)-5-((tert-butyldimethylsilyl)oxy)-4-methylpentane-1,2-diol 
• 1012341-50-2 (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid 
• 752174-62-2 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester 
• 3218-36-8 4-Phenylbenzaldehyde 
• 113538-22-0 3-([1,1'-biphenyl]-4-yl)acrylaldehyde 
• 1147334-63-1 3-biphenyl-4-yl-prop-2-en-1-ol 

Downstream Products

• 1038924-80-9 (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one 
• 1038924-66-1 (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one 
• 1038924-67-2 (3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one 
• 149690-12-0 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride 
• 1039357-84-0 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (p-toluenesulphonate salt) 
• 1038924-76-3 (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester 
• 1038924-71-8 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid hydrochloride 
• 1012341-50-2 (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid 
• 149709-62-6 α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate 
• 149709-60-4 ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoate 

Relevant articles and documents

Radiosynthesis of the 11C-methyl derivative of LBQ657 for PET investigation of the neprilysin inhibitor sacubitril

Neprilysin, also known as neutral endopeptidase, is a cell surface membrane metalo-endopeptidase that cleaves various peptides. Altered neprilysin expression has been correlated with various cancers and cardiovascular diseases. In this work, we present the radiosynthesis of the novel O-11C-methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [11C]methyl ester ([11C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a 11C-methyl instead of an ethyl. [11C]MeOLBQ was produced in a one-pot two-step synthesis. The O-11C-methylation of the pentanoic acid part was done with [11C]methyl triflate followed by the deprotection of the tert-butyl ester precursor in acidic conditions. [11C]MeOLBQ ([11C]7) was produced in 9.5 ± 2.5% RCY (25 ± 6% decay-corrected from [11C]CO2, n = 3) high molar activity 348 ± 100 GBq/μmol (9425 ± 2720 mCi/μmol) at EOS, in high chemical (>95%) and radiochemical (>99%) purities. The total synthesis time including HPLC purification and reformulation was 29 minutes. To our knowledge, this is the first PET-labeled analog of the clinically used NEP inhibitor sacubitril.

Highly Regio- A nd Enantioselective Hydrogenation of Conjugated α-Substituted Dienoic Acids

Highly regio- A nd enantioselective hydrogenation of conjugated α-substituted dienoic acids was realized for the first time using Trifer-Rh complex, providing a straightforward method for the synthesis of chiral α-substituted ?,?′-unsaturated acids. DFT calculations revealed N+H-O hydrogen bonding interaction is formed to stabilize the transition state and the coordination of 4,5-double bond to Rh(III) center would facilitate the reductive elimination process. This hydrogenation provided a gram-scale synthesis of the precursor of sacubitril.

A biphenyl methyl lactam compound preparation method

A biphenyl methyl lactam compound preparation method, relates to the field of compound preparation techniques, the method comprising the following steps: (1) compound a in the alcohol organic solvent and in the presence of strongly alkaline inorganic alkali reaction, to the reaction solution, the reaction liquid filter, for adjusting the pH value of the filtrate acetic acid to weak acid, concentrated, to obtain white solid, adding water stirring beating, and fighting slurry, obtain white solid biphenyl methyl lactam compound crude product; (2) in a certain amount of 2nd organic solvent is added in the benzyl group of the connection lactam compound crude product, heated and dissolved and across the membrane, slow cooling crystallization, to obtain purified diphenyl methyl lactam compounds. The method of having high yield, purity of the product and the like.