1012341-50-2

Basic information

• Product Name: (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpentanoic acid
• Synonyms: (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpentanoic acid;LCZ696 inter.;(2R,4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl)aMino]-2-Methylpentanoic acid;(2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpentanoic;(2R,4S)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pentanoic acid;LCA696 inter;[1,1'-Biphenyl]-4-pentanoic acid, γ-[[(1,1-dimethylethoxy)carbonyl]amino]-α-methyl-, (αR,γS);sacubitril intermediate
• CAS NO: 1012341-50-2
• Molecular Formula: C₂₃H₂₉NO₄
• Molecular Weight: 383.48066
• EINECS: 1592732-453-0
• Product Categories: LCZ696;intermediate;intermediates;1
• Mol File: 1012341-50-2.mol

Chemical Properties

• Boiling Point: 582.6±50.0 °C(Predicted)
• Appearance: /
• Density: 1.115±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly, Sonicated)
• PKA: 4?+-.0.23(Predicted)
• CAS DataBase Reference: (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpentanoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpentanoic acid(1012341-50-2)
• EPA Substance Registry System: (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)aMino)-2-Methylpentanoic acid(1012341-50-2)

Safety Data

• Hazardous Substances Data: 1012341-50-2(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Synthesis:
(2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid is used as a building block for the synthesis of various pharmaceuticals. Its unique structure and functional groups make it a valuable component in the development of new drugs.
2. Used in Antimicrobial Applications:
In the medical industry, (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid is used as an active ingredient for treating bacterial infectious diseases. Its specific structure allows it to target and combat bacterial pathogens effectively.
3. Used in Drug Delivery Systems:
Similar to gallotannin, (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid can also be incorporated into drug delivery systems to enhance its bioavailability and therapeutic outcomes. This application can lead to the development of more efficient and targeted treatments for various diseases, including bacterial infections.

Synthetic route

C33H38N2O5 → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Stage #1: C33H38N2O5 With dihydrogen peroxide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With lithium hydroxide at 25 - 30℃; for 3h;	95%

(2E,4R)-5-{[1,1'-biphenyl]-4-yl}-4-{[(tert-butoxy)carbonyl]amino}-2-methylpent-2-enoic acid (1012341-48-8) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
With ammonium formate; nickel(II) acetate tetrahydrate; (R,R)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine In ethanol at 55℃; for 8h; Temperature;	91.9%
With hydrogen under 15001.5 - 18751.9 Torr;	90%
With hydrogen; diiodo(p-cymene)ruthenium(II) dimer; (SP,S′P)-1,1′-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2′-bis[(R)-α-(dimethylamino)benzyl]ferrocene In ethanol at 40℃; under 15001.5 Torr; for 6h; Product distribution / selectivity;	86.9%

C33H38N2O5 → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Stage #1: C33H38N2O5 With dihydrogen peroxide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With lithium hydroxide In tetrahydrofuran; water at 20 - 25℃; for 3h;	90%

(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1038924-76-3) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
With sodium hydroxide at 60℃; Reagent/catalyst;	86%
Stage #1: (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester With lithium hydroxide In tetrahydrofuran; water at 20℃; for 1h; Stage #2: With phosphoric acid In tetrahydrofuran; water Product distribution / selectivity;

di-tert-butyl dicarbonate (24424-99-5) + (R)-2-methyl-4-hydroxyimino-5-(4-biphenyl)pentanoic acid → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Stage #1: (R)-2-methyl-4-hydroxyimino-5-(4-biphenyl)pentanoic acid With ((+)-(1R)-[1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine-κP])chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]ruthenium(1+) chloride; hydrogen In methanol at 40℃; under 30003 Torr; Autoclave; Stage #2: di-tert-butyl dicarbonate With lithium hydroxide Reflux; diastereoselective reaction;	80%

(R)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (149709-68-2) + cyclohexylamine (108-91-8) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + (2S,4S)-5-biphenyl-4-yl-(4-tert-butoxycarbonylamino)-2-methylpentanoic acid cyclohexylamine salt

Conditions	Yield
Stage #1: (R)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid With palladium 10% on activated carbon; hydrogen In ethanol; water at 40℃; under 3750.38 Torr; for 3h; Stage #2: cyclohexylamine In Isopropyl acetate at 70℃;	A 58% B 10%

(2R/S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
With (S)-1-(1-Naphthyl)ethylamine In methanol at 60℃; for 1h; Temperature;	37%
With (S)-1-phenyl-ethylamine In ethanol at 20℃; for 2h;

(2E,4R)-5-{[1,1'-biphenyl]-4-yl}-4-{[(tert-butoxy)carbonyl]amino}-2-methylpent-2-enoic acid (1012341-48-8) → (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid + (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
With diiodo(p-cymene)ruthenium(II) dimer; (SP,S′P)-1,1′-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2′-bis[(R)-α-(dimethylamino)benzyl]ferrocene; hydrogen In ethanol at 75℃; under 22502.3 Torr;	A 5.3% B 93.66 %Chromat.
With diiodo(p-cymene)ruthenium(II) dimer; (SP,S′P)-1,1′-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2′-bis[(R)-α-(dimethylamino)benzyl]ferrocene; hydrogen In dichloromethane; water at 60℃; under 45004.5 Torr; for 16h; Autoclave; Ionic liquid; Inert atmosphere;	A n/a B n/a

(2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid hydrochloride (1038924-71-8) + di-tert-butyl dicarbonate (24424-99-5) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Stage #1: (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid hydrochloride; di-tert-butyl dicarbonate With potassium carbonate In water; isopropyl alcohol at 20℃; for 1h; Stage #2: With phosphoric acid In water; isopropyl alcohol Product distribution / selectivity;

(3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1038924-76-3) → (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid + (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydride; potassium hexamethylsilazane / toluene / 1 h / -15 °C 1.2: 0.5 h / -15 °C 1.3: 1 h / 20 °C 2.1: water; lithium hydroxide / tetrahydrofuran / 20 h / 20 °C 3.1: triethylamine; hydrogen / 5% rhodium-on-charcoal / Isopropyl acetate / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydride; potassium hexamethylsilazane / toluene; mineral oil / 1 h / -15 °C 1.2: 0.5 h / -15 °C 1.3: 1 h / 20 °C 2.1: lithium hydroxide; water / tetrahydrofuran / 20 h / 20 °C 3.1: hydrogen; triethylamine; 10% Pt/activated carbon / Isopropyl acetate / 20 °C / 760.05 Torr View Scheme

(R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1174130-72-3) → (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid + (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0); triphenylphosphine / xylene / Reflux 2: water; lithium hydroxide / tetrahydrofuran / 20 h / 20 °C 3: triethylamine; hydrogen / 5% rhodium-on-charcoal / Isopropyl acetate / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; sodium hydrogencarbonate / 5,5-dimethyl-1,3-cyclohexadiene / Reflux 2: lithium hydroxide; water / tetrahydrofuran / 20 h / 20 °C 3: hydrogen; triethylamine; 10% Pt/activated carbon / Isopropyl acetate / 20 °C / 760.05 Torr View Scheme

(Z)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (1361408-16-3) → (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid + (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
With hydrogen; triethylamine; 5% rhodium-on-charcoal In Isopropyl acetate at 20℃; under 760.051 Torr; Product distribution / selectivity;
With hydrogen; triethylamine; palladium 10% on activated carbon In Isopropyl acetate at 20℃; under 760.051 Torr; Product distribution / selectivity;
With palladium 10% on activated carbon; hydrogen; triethylamine In Isopropyl acetate at 20℃; under 760.051 Torr; Reagent/catalyst;
With 10% Pt/activated carbon; hydrogen; triethylamine In Isopropyl acetate at 20℃; under 760.051 Torr; Reagent/catalyst;

(R)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (1361408-15-2) → (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid + (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: water; lithium hydroxide / tetrahydrofuran / 20 h / 20 °C 2: triethylamine; hydrogen / 5% rhodium-on-charcoal / Isopropyl acetate / 20 °C / 760.05 Torr View Scheme

C19H27NO5 → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: bis(dicyclopentadiene)rhodium tetrafluoroborate; C52H44N2O2P2; hydrogen / methanol / 50 °C / Autoclave 2: pyridine / dichloromethane / 0.17 h / -17 - -15 °C 3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / toluene / 80 °C / Inert atmosphere 4: lithium hydroxide; water / ethanol / 70 °C View Scheme

ethyl(2S,4S)-4-((tert-butoxycarbonyl)amino)-5-(4-hydroxyphenyl)-2-methylpentanoate → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 0.17 h / -17 - -15 °C 2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / toluene / 80 °C / Inert atmosphere 3: lithium hydroxide; water / ethanol / 70 °C View Scheme

(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (149709-61-5) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
With water; lithium hydroxide In ethanol at 70℃;

N-(tert-butoxycarbonyl)-D-tyrosine (70642-86-3) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions

Yield

Multi-step reaction with 7 steps 1: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / 37.5 - 75.01 Torr 2: lithium aluminium tetrahydride / diethyl ether / 0 °C 3: dichloromethane / 20 - 25 °C 4: bis(dicyclopentadiene)rhodium tetrafluoroborate; C52H44N2O2P2; hydrogen / methanol / 50 °C / Autoclave 5: pyridine / dichloromethane / 0.17 h / -17 - -15 °C 6: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / toluene / 80 °C / Inert atmosphere 7: lithium hydroxide; water / ethanol / 70 °C View Scheme

tert-butyl (R)-3-(4-hydroxyphenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-ylcarbamate (929872-80-0) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: lithium aluminium tetrahydride / diethyl ether / 0 °C 2: dichloromethane / 20 - 25 °C 3: bis(dicyclopentadiene)rhodium tetrafluoroborate; C52H44N2O2P2; hydrogen / methanol / 50 °C / Autoclave 4: pyridine / dichloromethane / 0.17 h / -17 - -15 °C 5: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / toluene / 80 °C / Inert atmosphere 6: lithium hydroxide; water / ethanol / 70 °C View Scheme

C14H19NO4 → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: dichloromethane / 20 - 25 °C 2: bis(dicyclopentadiene)rhodium tetrafluoroborate; C52H44N2O2P2; hydrogen / methanol / 50 °C / Autoclave 3: pyridine / dichloromethane / 0.17 h / -17 - -15 °C 4: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / toluene / 80 °C / Inert atmosphere 5: lithium hydroxide; water / ethanol / 70 °C View Scheme

(2R,4S)-5-(4-bromophenyl)-4-(tert-butoxycarbonyl) amino-2-methylpentanoic acid + phenylboronic acid (98-80-6) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
With dipotassium hydrogenphosphate; formic acid; palladium diacetate In water at 25 - 45℃; for 6h; Inert atmosphere;	8 g

(2R)-3-(4-bromophenyl)-2-[[(tert-butoxy)carbonyl]amino]propanoic acid → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: sodium tetrahydroborate / ethanol / 4 h / 25 - 35 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide; sodium hypochlorite solution / ethyl acetate; water / 2 h 3: ethyl acetate / 2 h / 25 - 35 °C 4: lithium hydroxide / ethanol; water / 3 h / 50 - 85 °C 5: diiodo(p-cymene)ruthenium(II) dimer; (α,α)2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis-[di(3,5-dimethyl-4-methoxyphenyl)-phosphino]ferrocene; hydrogen / methanol / 7 h / 55 - 65 °C / 11251.1 - 15001.5 Torr / Autoclave; Inert atmosphere 6: formic acid; dipotassium hydrogenphosphate; palladium diacetate / water / 6 h / 25 - 45 °C / Inert atmosphere View Scheme

tert-butyl [(2R)-1-(4-bromophenyl)-3-hydroxypropan-2-yl] carbamate → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions

Yield

Multi-step reaction with 5 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide; sodium hypochlorite solution / ethyl acetate; water / 2 h 2: ethyl acetate / 2 h / 25 - 35 °C 3: lithium hydroxide / ethanol; water / 3 h / 50 - 85 °C 4: diiodo(p-cymene)ruthenium(II) dimer; (α,α)2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis-[di(3,5-dimethyl-4-methoxyphenyl)-phosphino]ferrocene; hydrogen / methanol / 7 h / 55 - 65 °C / 11251.1 - 15001.5 Torr / Autoclave; Inert atmosphere 5: formic acid; dipotassium hydrogenphosphate; palladium diacetate / water / 6 h / 25 - 45 °C / Inert atmosphere View Scheme

(2R)-2-amino-3-(4-bromophenyl)propanoic acid (62561-74-4) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: thiophosgene / methanol / 4 h / 60 - 65 °C 1.2: 6 h / 25 - 35 °C 2.1: sodium tetrahydroborate / ethanol / 4 h / 25 - 35 °C 3.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide; sodium hypochlorite solution / ethyl acetate; water / 2 h 4.1: ethyl acetate / 2 h / 25 - 35 °C 5.1: lithium hydroxide / ethanol; water / 3 h / 50 - 85 °C 6.1: diiodo(p-cymene)ruthenium(II) dimer; (α,α)2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis-[di(3,5-dimethyl-4-methoxyphenyl)-phosphino]ferrocene; hydrogen / methanol / 7 h / 55 - 65 °C / 11251.1 - 15001.5 Torr / Autoclave; Inert atmosphere 7.1: formic acid; dipotassium hydrogenphosphate; palladium diacetate / water / 6 h / 25 - 45 °C / Inert atmosphere View Scheme

di-tert-butyl dicarbonate (24424-99-5) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: thiophosgene / methanol / 4 h / 60 - 65 °C 1.2: 6 h / 25 - 35 °C 2.1: sodium tetrahydroborate / ethanol / 4 h / 25 - 35 °C 3.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide; sodium hypochlorite solution / ethyl acetate; water / 2 h 4.1: ethyl acetate / 2 h / 25 - 35 °C 5.1: lithium hydroxide / ethanol; water / 3 h / 50 - 85 °C 6.1: diiodo(p-cymene)ruthenium(II) dimer; (α,α)2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis-[di(3,5-dimethyl-4-methoxyphenyl)-phosphino]ferrocene; hydrogen / methanol / 7 h / 55 - 65 °C / 11251.1 - 15001.5 Torr / Autoclave; Inert atmosphere 7.1: formic acid; dipotassium hydrogenphosphate; palladium diacetate / water / 6 h / 25 - 45 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: dmap / 20 °C 2: sodium hydroxide / 60 °C View Scheme

tert-butyl [(2R)-1-(4-bromophenyl)-3-oxypropan-2-yl] carbamate (1246363-08-5) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions

Yield

Multi-step reaction with 4 steps 1: ethyl acetate / 2 h / 25 - 35 °C 2: lithium hydroxide / ethanol; water / 3 h / 50 - 85 °C 3: diiodo(p-cymene)ruthenium(II) dimer; (α,α)2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis-[di(3,5-dimethyl-4-methoxyphenyl)-phosphino]ferrocene; hydrogen / methanol / 7 h / 55 - 65 °C / 11251.1 - 15001.5 Torr / Autoclave; Inert atmosphere 4: formic acid; dipotassium hydrogenphosphate; palladium diacetate / water / 6 h / 25 - 45 °C / Inert atmosphere View Scheme

ethyl (2E, 4R)-5-(4-bromophenyl)-4-[(tert-butoxycarbonyl) amino]-2-methylpent-enoate (1257266-88-8) → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions

Yield

Multi-step reaction with 3 steps 1: lithium hydroxide / ethanol; water / 3 h / 50 - 85 °C 2: diiodo(p-cymene)ruthenium(II) dimer; (α,α)2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis-[di(3,5-dimethyl-4-methoxyphenyl)-phosphino]ferrocene; hydrogen / methanol / 7 h / 55 - 65 °C / 11251.1 - 15001.5 Torr / Autoclave; Inert atmosphere 3: formic acid; dipotassium hydrogenphosphate; palladium diacetate / water / 6 h / 25 - 45 °C / Inert atmosphere View Scheme

(2E,4R)-5-(4-bromophenyl)-4-[(tert-butoxycarbonyl) amino-2-methylpent-2-enoic acid] → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions

Yield

Multi-step reaction with 2 steps 1: diiodo(p-cymene)ruthenium(II) dimer; (α,α)2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis-[di(3,5-dimethyl-4-methoxyphenyl)-phosphino]ferrocene; hydrogen / methanol / 7 h / 55 - 65 °C / 11251.1 - 15001.5 Torr / Autoclave; Inert atmosphere 2: formic acid; dipotassium hydrogenphosphate; palladium diacetate / water / 6 h / 25 - 45 °C / Inert atmosphere View Scheme

(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-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: dmap / 20 °C 2: sodium hydroxide / 60 °C View Scheme

(3R,5S)-5-(hydroxymethyl)-3-methyl-2-pyrrolidone → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 4 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 3.1: dmap / 20 °C 4.1: sodium hydroxide / 60 °C View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 20 °C 2.1: magnesium; iodine / tetrahydrofuran / 0 - 60 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere 3.1: dmap / 20 °C 4.1: sodium hydroxide / 60 °C View Scheme

(3R,5S)-5-(bromomethyl)-3-methyl-2-pyrrolidone → (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: magnesium; iodine / tetrahydrofuran / 0 - 60 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: dmap / 20 °C 3.1: sodium hydroxide / 60 °C View Scheme

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + 2,2,2,-trichloroethoxycarbonyl azide → tert-butyl (2,2,2-trichloroethyl) ((2R,4R)-1-([1,1'-biphenyl]-4-yl)pentane-2,4-diyl)dicarbamate

Conditions	Yield
With dmap; copper diacetate In acetonitrile at 80℃; Schlenk technique; Sealed tube;	99%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + ethanol (64-17-5) → (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (149690-12-0)

Conditions	Yield
With thionyl chloride	98%
With thionyl chloride at 20 - 50℃;	96%
With thionyl chloride at 60℃;	96%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) → (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (149690-12-0)

Conditions	Yield
With thionyl chloride In ethanol at 60℃; for 1h;	96.5%
With thiophosgene In ethanol at 70 - 75℃; for 3h;
With thionyl chloride In ethanol; tert-butyl methyl ether at 60 - 70℃; for 3h;

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + 6-(N,N-dimethylamino)-1-hexanol (1862-07-3) → C26H38N2O2*2ClH

Conditions	Yield
With thionyl chloride In dichloromethane for 1h; Reflux;	89.7%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + benzyl bromide (100-39-0) → (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester (1257266-74-2)

Conditions	Yield
With potassium carbonate In acetonitrile at 60℃; for 0.5h;	88.7%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;

2-(N,N-dimethylamino)ethanol (108-01-0) + (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) → C22H30N2O2*2ClH

Conditions	Yield
With thionyl chloride In dichloromethane for 1h; Reflux;	88.7%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + ethanol (64-17-5) → (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (752174-62-2)

Conditions	Yield
With thionyl chloride at 78℃; Temperature;	88%
With thionyl chloride at 40℃; for 4h;	87.8%
With thionyl chloride at 0 - 50℃; for 8h; Reagent/catalyst; Temperature;	0.7 g

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + 2-(Diethylamino)ethanol (100-37-8) → C24H34N2O2*2ClH

Conditions	Yield
With thionyl chloride In dichloromethane for 1h; Reflux;	87.2%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + N-(2-Hydroxyethyl)phthalimide (3891-07-4) → C33H36N2O6

Conditions	Yield
Stage #1: (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane for 0.5h; Stage #2: N-(2-Hydroxyethyl)phthalimide In dichloromethane for 4h; Reflux;	85.7%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + ethanol (64-17-5) → ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoate (149709-60-4)

Conditions	Yield
With thionyl chloride for 10h; Reflux;	85%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + N-benzyl-2-(ethylamino)ethanol (91339-47-8) → C29H36N2O2*2ClH

Conditions	Yield
With thionyl chloride In dichloromethane for 11h; Reflux;	83.2%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + isopropyl alcohol (67-63-0) → (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid isopropyl ester

Conditions	Yield
With thionyl chloride at 85℃; for 9h;	80%
With thionyl chloride at 0 - 80℃; for 8h;	0.75 g

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + D-lysine + N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine (137862-53-4) → C24H28N5O3(1-)*Ca(2+)*C6H14N2O2*C22H23NO5(2-)

Conditions	Yield
Stage #1: (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid; D-lysine; N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine With water; sodium hydroxide In acetone at 20℃; for 1h; Stage #2: With calcium chloride In acetone for 3h;	75.5%

methanol (67-56-1) + (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) → (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid methyl ester

Conditions	Yield
With thionyl chloride at 40℃; for 4h; Temperature; Concentration;	75%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + C28H38N6O3 + triethylamine (121-44-8) → C49H59N7O8(1-)*2C6H16N(1+)

Conditions	Yield
In tetrahydrofuran for 6h;	64.5%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + C30H42N6O3 + triethylamine (121-44-8) → C51H63N7O8(1-)*2C6H16N(1+)

Conditions	Yield
In tetrahydrofuran for 6h;	61.5%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + methanesulfonamide (3144-09-0) → ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (1257266-71-9)

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	55%

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + ethanol (64-17-5) → (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrobromide (1038924-98-9)

Conditions	Yield
With dibromo sulfoxide at 65℃; for 1.5h;

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + ethanol (64-17-5) → (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrogen sulphate

Conditions	Yield
With sulfuric acid at 65℃;

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + ethanol (64-17-5) → (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid hydrochloride (1038924-71-8)

Conditions	Yield
With hydrogenchloride; water In ethyl acetate at 130℃; for 1.75h; Product distribution / selectivity;

(2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (1012341-50-2) + ethyl iodide (75-03-6) → ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoate (149709-60-4)

Conditions	Yield
Stage #1: (2R,4S)-5-[(1,1‘-biphenyl)-4-yl]-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid With caesium carbonate In N,N-dimethyl-formamide Stage #2: ethyl iodide In N,N-dimethyl-formamide at 20℃; Product distribution / selectivity;
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;

Upstream product

• 149709-68-2 (R)-5-(biphenyl-4-yl)-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid 
• 149709-59-1 ethyl 5-(4-<1,1'-biphenyl>yl)-4-<<(1,1-dimethylethoxy)carbonyl>amino>-2-methyl-2-pentenoate 
• 149709-58-0 (R)-α-<<(1,1-dimethylethoxy)carbonyl>amino><1,1'-biphenyl>-4-propanal 
• 1213855-60-7 methyl (R)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate 
• 24424-99-5 di-tert-butyl dicarbonate 
• 108-91-8 cyclohexylamine 
• 1426129-50-1 N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid tert-butyl ester 
• 149818-98-4 methyl (R)-α-<<(1,1-dimethylethoxy)carbonyl>amino><1,1'-biphenyl>-4-propanoate 
• 1012341-54-6 (2R/S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid 
• 1038924-70-7 (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one 
• 1012341-48-8 (2E,4R)-5-{[1,1'-biphenyl]-4-yl}-4-{[(tert-butoxy)carbonyl]amino}-2-methylpent-2-enoic acid 
• 1257266-88-8 ethyl (2E, 4R)-5-(4-bromophenyl)-4-[(tert-butoxycarbonyl) amino]-2-methylpent-enoate 
• 1246363-08-5 tert-butyl [(2R)-1-(4-bromophenyl)-3-oxypropan-2-yl] carbamate 

Downstream Products

• 1038924-71-8 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid hydrochloride 
• 149690-12-0 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride 
• 149709-60-4 ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoate 
• 1038924-70-7 (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one 
• 752174-62-2 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester 
• 1639970-62-9 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrol-1-yl)-2-methylpentanoic acid 
• 1038924-97-8 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrol-1-yl)-2-methyl pentanoate 
• 149690-05-1 α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate monosodium salt 
• 149709-62-6 α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate 

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