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
• Article Data: 25

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

(2R,4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic Acid is a useful building block in the synthesis of various pharmaceuticals. Could be useful for treating bacterial infectious disease.

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

• 1038924-70-7 (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one 
• 24424-99-5 di-tert-butyl dicarbonate 
• 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 
• 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 
• 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 
• 1257265-30-7 6-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethylbutylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid 
• 1257265-29-4 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxybutylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid 
• 1257266-14-0 (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methylpentanoic acid benzyl ester 
• 1257265-46-5 1-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethylbutylcarbamoyl)-1H-pyrazole-3-carboxylic acid 
• 1257265-45-4 1-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxybutylcarbamoyl)-1H-pyrazole-3-carboxylic acid 
• 1038924-97-8 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrol-1-yl)-2-methyl pentanoate 
• 1639970-62-9 (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(2,5-dioxopyrrol-1-yl)-2-methylpentanoic acid 
• 752174-62-2 (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester 
• 1038924-70-7 (3R,5S)-5-({[1,1'-biphenyl]-4-yl}methyl)-3-methylpyrrolidin-2-one 

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