1334513-02-8

Basic information

• Product Name: N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl ester
• Synonyms: 1. (S)-isopropyl2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl);N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl ester (SIDE CHAIN);L-Alanine, N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-, 1-methylethyl ester;propan-2-yl (2S)-2-{[(S)-pentafluorophenoxy(phenoxy)phosphoryl]amino}propanoate;Sofosbuvir Intermediate 5;Sofosbuvir side chain N-1;isopropyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate;N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl ester
• CAS NO: 1334513-02-8
• Molecular Formula: C₁₈H₁₇F₅NO₅P
• Molecular Weight: 453.297057
• EINECS: 1592732-453-0
• Product Categories: Sofosbuvir intermediate;Pharmaceuticalintermediates
• Mol File: 1334513-02-8.mol

Chemical Properties

• Boiling Point: 442.6±55.0 °C(Predicted)
• Appearance: /
• Density: 1.405
• Vapor Pressure: 0Pa at 25℃
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: -3.81±0.70(Predicted)
• CAS DataBase Reference: N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl ester(1334513-02-8)
• EPA Substance Registry System: N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl ester(1334513-02-8)

Safety Data

• Hazardous Substances Data: 1334513-02-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl ester is used as a reactant for the synthesis of phosphoramidate imidazo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs. These prodrugs are designed to enhance the anti-HCV (hepatitis C virus) activity, providing a potential therapeutic approach for treating hepatitis C infections.

InChI:InChI=1S/C18H17F5NO5P/c1-9(2)27-18(25)10(3)24-30(26,28-11-7-5-4-6-8-11)29-17-15(22)13(20)12(19)14(21)16(17)23/h4-10H,1-3H3,(H,24,26)/t10-,30?/m0/s1

Synthetic route

2,3,4,5,6-pentafluorophenol (771-61-9) + O-phenyl phosphorodichloridate (770-12-7) + alanine isopropyl ester hydrochloride (39613-92-8, 62062-56-0, 62062-65-1) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
Stage #1: 2,3,4,5,6-pentafluorophenol; O-phenyl phosphorodichloridate With triethylamine In chloroform at 0℃; under 11251.1 Torr; Stage #2: alanine isopropyl ester hydrochloride In chloroform Temperature;	88%
Stage #1: alanine isopropyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at -68℃; for 0.5h; Stage #2: O-phenyl phosphorodichloridate In dichloromethane at -10℃; for 0.5h; Stage #3: 2,3,4,5,6-pentafluorophenol With N-ethyl-N,N-diisopropylamine In dichloromethane	78%
Stage #1: O-phenyl phosphorodichloridate; alanine isopropyl ester hydrochloride With triethylamine In dichloromethane at -78 - 20℃; for 2h; Stage #2: 2,3,4,5,6-pentafluorophenol With triethylamine In dichloromethane at -78 - 20℃; for 3h;	61.6%

phenyl(isopropoxy-L-alaninyl) phosphorochloridate (261909-49-3) + sodium pentafluorophenolate (2263-53-8) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
Stage #1: phenyl(isopropoxy-L-alaninyl) phosphorochloridate; sodium pentafluorophenolate In tetrahydrofuran at -10℃; Stage #2: With triethylamine In n-heptane; tert-butyl methyl ether pH=8;	66.81%

phenyl(isopropoxy-L-alaninyl) phosphorochloridate (261909-49-3) + 2,3,4,5,6-pentafluorophenol (771-61-9) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
With triethylamine In dichloromethane at 0℃; for 4h;	45.1%
With triethylamine In dichloromethane at 0℃; for 4h; Inert atmosphere;	45.1%

2,3,4,5,6-pentafluorophenyl dichlorophosphate (17788-07-7) + alanine isopropyl ester hydrochloride (39613-92-8, 62062-56-0, 62062-65-1) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (1337529-56-2)

Conditions	Yield
Stage #1: 2,3,4,5,6-pentafluorophenyl dichlorophosphate With triethylamine; phenol In dichloromethane at 20℃; for 0.5h; Stage #2: alanine isopropyl ester hydrochloride With triethylamine In dichloromethane at 0℃; for 1h;

phenyl(isopropoxy-L-alaninyl) phosphorochloridate (261909-49-3) + 2,3,4,5,6-pentafluorophenol (771-61-9) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (1337529-56-2)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
With triethylamine In dichloromethane at -10 - 0℃; for 1.5h;	A n/a B n/a
With triethylamine In dichloromethane at -15 - 5℃; for 1h; Inert atmosphere;	A n/a B n/a

alanine isopropyl ester hydrochloride (39613-92-8, 62062-56-0, 62062-65-1) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (1337529-56-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 0.5 h / -10 °C / Inert atmosphere 2: triethylamine / dichloromethane / 1.5 h / -10 - 0 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tert-butyl methyl ether / 2 h / -65 - -50 °C / Inert atmosphere; Cooling with acetone-dry ice 2: triethylamine / dichloromethane / 1 h / -15 - 5 °C / Inert atmosphere View Scheme

O-phenyl phosphorodichloridate (770-12-7) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (1337529-56-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 0.5 h / -10 °C / Inert atmosphere 2: triethylamine / dichloromethane / 1.5 h / -10 - 0 °C View Scheme

2,3,4,5,6-pentafluorophenol (771-61-9) + O-phenyl phosphorodichloridate (770-12-7) + alanine isopropyl ester hydrochloride (39613-92-8, 62062-56-0, 62062-65-1) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + C18H17F5NO4P

Conditions	Yield
Stage #1: alanine isopropyl ester hydrochloride With triethylamine In dichloromethane at -70℃; for 0.75h; Stage #2: O-phenyl phosphorodichloridate In dichloromethane at -70 - 0℃; for 8h; Stage #3: 2,3,4,5,6-pentafluorophenol With triethylamine In dichloromethane at 0 - 20℃;

O-phenyl phosphorodichloridate (770-12-7) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / ethyl acetate / 1 h / -10 °C / Enzymatic reaction 1.2: 2.5 h / -5 - 25 °C 2.1: triethylamine / ethyl acetate; n-heptane / 4 - 8 h / Resolution of racemate View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 1.5 h / -60 - 25 °C / Inert atmosphere 2.1: tetrahydrofuran / -10 °C 2.2: pH 8 View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 20 h / -70 - 20 °C 2: triethylamine / dichloromethane / 20 h / -5 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / -78 - 20 °C 2: triethylamine / dichloromethane / 4 h / 0 °C View Scheme

isopropyl L-alanine (39825-33-7) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / ethyl acetate / 1 h / -10 °C / Enzymatic reaction 1.2: 2.5 h / -5 - 25 °C 2.1: triethylamine / ethyl acetate; n-heptane / 4 - 8 h / Resolution of racemate View Scheme

2,3,4,5,6-pentafluorophenol (771-61-9) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / ethyl acetate / 1 h / -10 °C / Enzymatic reaction 1.2: 2.5 h / -5 - 25 °C 2.1: triethylamine / ethyl acetate; n-heptane / 4 - 8 h / Resolution of racemate View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 25 - 30 °C 2.1: tetrahydrofuran / -10 °C 2.2: pH 8 View Scheme

(S)-2-[(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino]propionic acid isopropyl ester (1256490-52-4) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
With triethylamine In n-heptane; ethyl acetate for 4 - 8h; Resolution of racemate;	350 g

2,3,4,5,6-pentafluorophenol (771-61-9) + N-dichlorophosphoryl-L-alanine isopropyl ester + phenol (108-95-2) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
Stage #1: N-dichlorophosphoryl-L-alanine isopropyl ester; phenol With triethylamine In dichloromethane at 0 - 20℃; for 1h; Stage #2: 2,3,4,5,6-pentafluorophenol With triethylamine In dichloromethane at 20℃; for 5h; Reagent/catalyst; Cooling with ice;	10.8 g

2,3,4,5,6-pentafluorophenol (771-61-9) + O-phenyl phosphorodichloridate (770-12-7) + alanine isopropyl ester hydrochloride (39613-92-8, 62062-56-0, 62062-65-1) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (1337529-56-2)

Conditions	Yield
Stage #1: O-phenyl phosphorodichloridate; alanine isopropyl ester hydrochloride With triethylamine In dichloromethane at -60℃; Inert atmosphere; Green chemistry; Stage #2: 2,3,4,5,6-pentafluorophenol In dichloromethane at 20℃; for 3h; Inert atmosphere; Green chemistry;
Stage #1: O-phenyl phosphorodichloridate; alanine isopropyl ester hydrochloride In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at -60℃; Inert atmosphere; Stage #3: 2,3,4,5,6-pentafluorophenol In dichloromethane at 0 - 5℃; for 4h; Inert atmosphere;

2,3,4,5,6-pentafluorophenol (771-61-9) + C12H17ClNO4P → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
With triethylamine In dichloromethane at -5 - 20℃; for 20h;

phenol (108-95-2) → (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: trichlorophosphate; triethylamine / diethyl ether / -78 - 20 °C / Inert atmosphere 2: triethylamine / dichloromethane / 1 h / -78 - 20 °C 3: triethylamine / dichloromethane / 4 h / 0 °C View Scheme

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (2R,3S,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-azido-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (1403249-88-6) → isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-azido-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 20h; Inert atmosphere; diastereoselective reaction;	99%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) → sofosbuvir (1190307-88-0)

Conditions	Yield
With pyridine; aluminum (III) chloride In dichloromethane at 20℃; Reagent/catalyst; Temperature;	97.5%
With 2,6-dimethylpyridine; dimethylaluminum chloride In tetrahydrofuran; hexane at 0 - 45℃; for 20h;	86%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With 3,3-diphenyl-2-propenal; tert-butylmagnesium chloride In tetrahydrofuran at -5 - 5℃; for 19h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran Reagent/catalyst;	86.2%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 2',3'-isopropylidene adenosine (362-75-4) → (S)-isopropyl 2-(((S)-(((3aR,4R,6R,6aR)-6-(6-amino-0H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propionoate (1334513-09-5)

Conditions	Yield
Stage #1: 2',3'-isopropylidene adenosine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 0.55h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 20℃; for 18.05h;	96%
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 6h; Inert atmosphere; diastereoselective reaction;	94%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (2R,3R,4R,5R) 5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (1199809-30-7) → isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 24h; Inert atmosphere; diastereoselective reaction;	96%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) → (S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}propionic acid isopropyl ester (1190308-01-0)

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With isopropyl magnesium chloride lithium chloride complex In tetrahydrofuran at -60℃; for 1h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at -50℃; for 1h; Temperature; Reagent/catalyst;	95%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 1.16667h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 5 - 20℃; for 10h; Inert atmosphere;	76%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + C11H15FN2O4 → (S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}propionic acid isopropyl ester (1190308-01-0)

Conditions	Yield
With dmap; N,N-dimethyl-aniline In tetrahydrofuran at 5 - 20℃; for 5h; Reagent/catalyst; Inert atmosphere; Large scale;	93%

5-chloropyridin-3-ol (74115-12-1) + (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + lithium phenolate (555-24-8) → C17H20ClN2O5P

Conditions	Yield
With lithium tert-butoxide In tetrahydrofuran at 0 - 10℃; for 2h; Reagent/catalyst; Temperature; Large scale;	92%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + Deoxydifluorouridine (114248-23-6) → isopropyl ((S)-(((2R,3R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 20h; Inert atmosphere; diastereoselective reaction;	87%
Stage #1: Deoxydifluorouridine With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0 - 20℃; for 1.5h;

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (+)-2-((2S,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-3-methyltetrahydrofuran-3-yl)acetonitrile → (+)-isopropyl ((S)-(((2S,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3-(cyanomethyl)-4-fluoro-3-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
Stage #1: (+)-2-((2S,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-3-methyltetrahydrofuran-3-yl)acetonitrile With tert-butylmagnesium bromide In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran for 16h; Inert atmosphere;	87%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + C15H19N3O6 → C27H35N4O10P

Conditions	Yield
With 2,6-dimethylpyridine; aluminum tri-tert-butoxide In tetrahydrofuran at 20℃; for 15h;	86%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 1-(2'-C-methyl-β-D-arabinofuranosyl)uracil (114262-49-6) → (S)-isopropyl 2-(((S)-(((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-di-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 50℃; for 25h; Inert atmosphere; diastereoselective reaction;	86%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + gemcitabine (95058-81-4) → isopropyl ((S)-(((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 22h; Inert atmosphere; diastereoselective reaction;	83%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 1‐((2R,3R,4R,5R)‐3‐fluoro‐4‐hydroxy‐5‐(hydroxy‐[D2]methyl)‐3‐methyltetrahydrofuran‐2‐yl)pyrimidine‐2,4(1H,3H)‐dione → isopropyl ((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐yl) [D2]methoxy)(phenoxy)phosphoryl)‐L‐alaninate

Conditions	Yield
Stage #1: 1‐((2R,3R,4R,5R)‐3‐fluoro‐4‐hydroxy‐5‐(hydroxy‐[D2]methyl)‐3‐methyltetrahydrofuran‐2‐yl)pyrimidine‐2,4(1H,3H)‐dione With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0 - 20℃; for 16h;	82%
Stage #1: 1‐((2R,3R,4R,5R)‐3‐fluoro‐4‐hydroxy‐5‐(hydroxy‐[D2]methyl)‐3‐methyltetrahydrofuran‐2‐yl)pyrimidine‐2,4(1H,3H)‐dione With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 20℃; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 5℃;	40%
With tert-butylmagnesium chloride In tetrahydrofuran

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + [(1SR,2SR,4RS)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-(methoxymethoxy)cyclopentyl]methanol → propan-2-yl N-[(S)-{[(1RS,2RS,4SR)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-(methoxymethoxy)cyclopentyl]methoxy}(phenoxy)phosphoryl]-L-alaninate

Conditions	Yield
Stage #1: [(1SR,2SR,4RS)-4-(2-amino-6-ethoxy-9H-purin-9-yl)-1-ethynyl-2-(methoxymethoxy)cyclopentyl]methanol With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere;	82%

(2R,3R,4R,5R) 5-(2-amino-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (1199809-27-2) + (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) → (S)-2-{(S)-[(1R,4R,5R)-5-(2-amino-6-methoxy-purin-9-yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-ylmethoxy]phenoxy-phosphorylamino}propionic acid isopropyl ester (1231747-08-2)

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 16h; Inert atmosphere; diastereoselective reaction;	81%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 1-((2R,3R,4R,5R)-3-bromo-3-chloro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4( 1H,3H)-dione → (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-4-bromo-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Conditions	Yield
Stage #1: 1-((2R,3R,4R,5R)-3-bromo-3-chloro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4( 1H,3H)-dione With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0 - 20℃; for 1.5h;	81%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (+)-2-((2S,3R,4S,5R)-5-(2-chloro-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-3-methyltetrahydrofuran-3-yl)acetonitrile → (+)-isopropyl ((S)-(((2S,3R,4S,5R)-5-(2-chloro-6-methoxy-9H-purin-9-yl)-3-(cyanomethyl)-4-fluoro-3-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
Stage #1: (+)-2-((2S,3R,4S,5R)-5-(2-chloro-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-3-methyltetrahydrofuran-3-yl)acetonitrile With tert-butylmagnesium bromide In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran for 16h; Inert atmosphere;	80%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 2'-C-methyluridine (31448-54-1) → isopropyl ((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 50℃; for 25h; Inert atmosphere; diastereoselective reaction;	79%
Stage #1: 2'-C-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 20℃;	56%
Stage #1: 2'-C-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 20℃; for 1.5h; Inert atmosphere; Schlenk technique; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 20℃; for 17h; Inert atmosphere;	24%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + stavudin (3056-17-5) → isopropyl ((S)-(((2S,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 20℃; for 20h; Inert atmosphere; diastereoselective reaction;	78%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (+)-2-((2S,3R,4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-3-methyltetrahydrofuran-3-yl)acetonitrile → (+)-isopropyl ((S)-(((2S,3R,4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-3-(cyanomethyl)-4-fluoro-3-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions	Yield
Stage #1: (+)-2-((2S,3R,4S,5R)-5-(6-(benzylamino)-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-3-methyltetrahydrofuran-3-yl)acetonitrile With tert-butylmagnesium bromide In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran for 16h; Inert atmosphere;	76%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 2',3'-isopropylideneguanosine (362-76-5) → (S)-isopropyl 2-(((S)-(((3aR,4R,6R,6aR)-6-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1334513-11-9)

Conditions	Yield
Stage #1: 2',3'-isopropylideneguanosine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 0.55h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 20℃; for 18.05h;	75%

(2'R)-2'-deoxy-2'-fluoro-2'-methylcytidine (817204-33-4) + (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) → (S)-isopropyl 2-(((R)-(((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1334513-10-8)

Conditions	Yield
With pyridine; dimethylaluminum chloride In hexane at 0 - 4℃; for 24h; Inert atmosphere; diastereoselective reaction;	71%
Stage #1: (2'R)-2'-deoxy-2'-fluoro-2'-methylcytidine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 0.55h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 20℃; for 18.05h;	53%
Stage #1: (2'R)-2'-deoxy-2'-fluoro-2'-methylcytidine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0℃; for 1h;	30%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 1-((2R,3S,4R,5R)-3-chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione → (S)-2-(((S)-(((2R,3R,4S,5R)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoic acid isopropyl ester

Conditions	Yield
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; tert-butylmagnesium chloride In tetrahydrofuran at -10 - -8℃; for 1.81667h; Temperature; Solvent; Reagent/catalyst; Large scale;	70%
Stage #1: 1-((2R,3S,4R,5R)-3-chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione With tert-butylmagnesium chloride In tetrahydrofuran; water at -10℃; for 0.666667h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran; water at -10℃; for 22h;	874 mg
Stage #1: 1-((2R,3S,4R,5R)-3-chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0 - 20℃; for 1.5h;

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + C18H27FN6O5 → C30H43FN7O9P

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at -10 - 20℃; for 1h;	68.5%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 1-((2R,3S,4R,5R)-3-bromo-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4( 1H,3H)-dione → (S)-isopropyl 2-(((S)-(((2R,3R,4S,5R)-4-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Conditions	Yield
Stage #1: 1-((2R,3S,4R,5R)-3-bromo-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4( 1H,3H)-dione With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 25℃; for 0.5h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0 - 4℃; for 16h; Inert atmosphere;	68%
Stage #1: 1-((2R,3S,4R,5R)-3-bromo-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4( 1H,3H)-dione With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0 - 20℃; for 1.5h;	62.6%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + C17H15(2)H2ClN2O6 → C22H27(2)H2ClN3O9P

Conditions	Yield
Stage #1: C17H15(2)H2ClN2O6 With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 5℃; for 0.5h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 0 - 5℃;	67%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + 1-((3aR,4R,6aR)-6-((R)-1-hydroxyethyl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (1418141-24-8) → isopropyl ((S)-((R)-1-((3aR,4S,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethoxy)(phenoxy)phosphoryl)-L-alaninate

Conditions

Yield

Stage #1: 1-((3aR,4R,6aR)-6-((R)-1-hydroxyethyl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione With tert-butylmagnesium chloride In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at -5 - 20℃; for 1.5h; Inert atmosphere; Schlenk technique; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 20℃; for 17h; Inert atmosphere;

67%

(S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) + (2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol → C25H35FN7O7P

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 20℃; for 2h; Inert atmosphere;	65%

Upstream product

• 17788-07-7 2,3,4,5,6-pentafluorophenyl dichlorophosphate 
• 39613-92-8 alanine isopropyl ester hydrochloride 
• 771-61-9 2,3,4,5,6-pentafluorophenol 
• 770-12-7 O-phenyl phosphorodichloridate 
• 261909-49-3 phenyl(isopropoxy-L-alaninyl) phosphorochloridate 
• 39825-33-7 isopropyl L-alanine 
• 1256490-52-4 (S)-2-[(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino]propionic acid isopropyl ester 
• 2263-53-8 sodium pentafluorophenolate 
• 108-95-2 phenol 

Downstream Products

• 1190307-88-0 sofosbuvir 
• 1334513-10-8 (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 
• 1334513-09-5 (S)-isopropyl 2-(((S)-(((3aR,4R,6R,6aR)-6-(6-amino-0H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propionoate 
• 1334513-11-9 (S)-isopropyl 2-(((S)-(((3aR,4R,6R,6aR)-6-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 
• 1567898-19-4 (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 

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