1809249-37-3

Basic information

• Product Name: Remdesivir
• Synonyms: GS5734;Remdesivir;Remdesivir(GS-5734);L-Alanine,N-[(S)-hydroxyphenoxyphosphinyl]-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-anhydro-D-altrononitrile;2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• CAS NO: 1809249-37-3
• Molecular Formula: C₂₇H₃₅N₆O₈P
• Molecular Weight: 602.575961
• Mol File: 1809249-37-3.mol
• Article Data: 21

Chemical Properties

• Density: 1.47±0.1 g/cm3(Predicted)
• CAS DataBase Reference: Remdesivir(CAS DataBase Reference)
• NIST Chemistry Reference: Remdesivir(1809249-37-3)
• EPA Substance Registry System: Remdesivir(1809249-37-3)

Safety Data

• Hazardous Substances Data: 1809249-37-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Remdesivir is used as an antiviral agent for the treatment of viral infections, particularly COVID-19. It is employed to inhibit the viral RNA polymerase, thereby reducing the severity and duration of symptoms in infected patients.
Used in Clinical Research:
In the field of clinical research, Remdesivir is utilized as a subject of investigation for its potential efficacy and safety in treating various viral infections. Ongoing studies aim to explore its full therapeutic potential and to establish optimal treatment protocols for patients.
Used in Emergency Response:
During public health emergencies, such as the COVID-19 pandemic, Remdesivir is used as a critical component of the medical response to manage the disease's impact and improve patient outcomes. Its emergency use authorization underscores its importance in addressing urgent health crises.

Product Description:

Novel inhibitor of the replication of several taxonomically diverse RNA viruses such as Middle East respiratory syndrome virus, Ebola virus, Lassa fever virus, Junin virus and respiratory syncytial virus, while having low cytotoxicity in a wide-range of cell lines

Remdesivir Properties

Background Information

Remdesivir is a nucleoside analogue, with effective antiviral activity, with EC50s of 74 nM for ARS-CoV and MERS-CoV in HAE cells, and 30 nM for murine hepatitis virus in delayed brain tumor cells. 
Remdesivir, also known as GS-5734, is an antiviral drug, a novel nucleotide analog prodrug. It was developed by Gilead Sciences as a treatment for filovirus infections such as Ebola virus disease and Marburg virus, though it has subsequently also been found to show reasonable antiviral activity against more distantly related viruses such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-coronavirus. GS-5734 was rapidly pushed through clinical trials due to the 2013–2016 West African Ebola virus epidemic crisis, eventually being used in at least one human patient despite its early development stage at the time. Preliminary results have been promising, and further clinical trials are planned.
GS-5734 (Remdesivir) is a monophosphoramidate prodrug of adenosine analogue that exhibits antiviral activity against multiple variants of EBOV (EC50=70-140 nM) and other filoviruses (EC50=0.019-1.48 uM) in cell-based assays; suppresses EBOV replication and protects 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers.

Synthetic route

2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With hydrogenchloride In water; acetone at 20℃; for 3h; pH=3 - 4; Reagent/catalyst;	91%
With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 8h;	73%
With hydrogenchloride In tetrahydrofuran; water at 20℃; Inert atmosphere;	69%

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) + C21H26N3O9P → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Stage #1: (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile With titanium(IV) isopropylate; tert-butylmagnesium chloride In tetrahydrofuran at -10 - 0℃; for 0.5h; Stage #2: C21H26N3O9P In tetrahydrofuran at -10 - 20℃; Solvent; Reagent/catalyst;	86.2%

2-ethylbutyl (2S)-2-{[(S)-{[(3aR,4R,6R,6aR)-6-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-6-cyano-2-phenyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methoxy}(phenoxy)phosphoryl]amino}propanoate → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
at 60℃;	84%

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) + C19H27N2O7P → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With diisopropylamine; zinc dibromide In tetrahydrofuran at 20℃; for 4h; Reagent/catalyst; Solvent; Inert atmosphere; Molecular sieve;	81%

2-ethylbutyl (2S)-2-{[chloro(phenoxy)phosphoryl]amino}propanoate (1355049-92-1) + (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (1191237-80-5) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; C17H21N3O2 In dichloromethane at -20 - 20℃; for 0.333333h; Inert atmosphere; Molecular sieve; Stage #2: 2-ethylbutyl (2S)-2-{[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at -20 - 20℃; for 24h; Inert atmosphere; Molecular sieve; Stage #3: With toluene-4-sulfonic acid In methanol at 20℃; for 24h; Inert atmosphere;	73%
Multi-step reaction with 2 steps 1.1: C17H21N3O2; 2,6-dimethylpyridine / dichloromethane / 0.33 h / -40 - 20 °C / Inert atmosphere; Molecular sieve 1.2: 24 h / 4 - 20 °C / Inert atmosphere; Molecular sieve 2.1: hydrogenchloride / tetrahydrofuran; water / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: C17H21N3O2; 2,6-dimethylpyridine / dichloromethane / 0.33 h / -40 - 20 °C / Inert atmosphere; Molecular sieve 1.2: 24 h / 4 - 20 °C / Inert atmosphere; Molecular sieve 2.1: hydrogenchloride / tetrahydrofuran; water / 20 °C / Inert atmosphere View Scheme
Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With tert-butylmagnesium chloride In tetrahydrofuran at -40 - 30℃; Stage #2: 2-ethylbutyl (2S)-2-{[chloro(phenoxy)phosphoryl]amino}propanoate In tetrahydrofuran at -40 - 10℃;	100 mg

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) + C20H26ClN2O5P → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With triethylamine; zinc(II) chloride In tetrahydrofuran at 65℃; for 25h; Inert atmosphere;	44%

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) + C20H26ClN2O5P → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; magnesium chloride In 1,4-dioxane at 55℃; for 25h; Inert atmosphere;	42%

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) + C20H26BrN2O5P → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With potassium carbonate; zinc dibromide In tert-butyl methyl ether at 75℃; for 25h; Inert atmosphere;	40.5%

(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile + (2S)-2-ethylbutyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: tert-butylmagnesium chloride / tetrahydrofuran / 16 h / -10 - 5 °C 2: hydrogenchloride; water / 72 h / 0 - 20 °C View Scheme

(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile + 2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 21 h / 50 °C 2: hydrogenchloride; water / 72 h / 0 - 20 °C View Scheme

(S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis((tertbutyldimethylsilyl)oxy)-5-cyanotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With hydrogenchloride; water at 0 - 20℃; for 72h;

(3R,4R,5R)-2-(4-aminopyrrole-[2,1-f][1,2,4]-triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol (1355049-94-3) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 1.2: 1 h / -78 °C / Inert atmosphere 2.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 3.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 1.2: 1 h / -78 °C / Inert atmosphere 2.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 3.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 1.2: 1 h / -78 °C / Inert atmosphere 2.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 3.1: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere View Scheme

(3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy) methyl)tetrahydrofuran-2-carbonitrile (1191237-68-9) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 2: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 2: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme
Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 2: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere View Scheme

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / acetone / 0.5 h / 45 °C 2: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 20 °C 3: hydrogenchloride; water / tetrahydrofuran / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: acetone / 0.5 h / 20 °C 2: potassium carbonate / water; ethyl acetate 3: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 20 °C 4: hydrogenchloride; water / tetrahydrofuran / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid / acetone / 0.5 h / 45 °C 2.1: magnesium chloride / acetonitrile / 0.25 h / 20 °C 2.2: 4 h 3.1: water; hydrogenchloride / tetrahydrofuran / 0 - 20 °C View Scheme

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) + (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (1439900-56-7) → (2S)-2-ethylbutyl 2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate + (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;
Multi-step reaction with 2 steps 1: tert-butylmagnesium chloride / N,N-dimethyl-formamide; tetrahydrofuran / 2.17 h / 20 °C / Inert atmosphere 2: Lux Cellulose-2 / acetonitrile; methanol / Resolution of racemate View Scheme

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) + (2S)-2-ethylbutyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; magnesium chloride In N,N-dimethyl acetamide at 30℃; for 5h;

(2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1191237-69-0) + 2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; magnesium chloride In N,N-dimethyl acetamide at 30℃; for 6h;

4-amino-7-iodopyrrolo[2,1-f ][1,2,4]triazine (1770840-43-1) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme

(2R,3R,4R,5R)‐2‐{4‐aminopyrrolo[2,1‐f][1,2,4]triazin‐7‐yl}‐3,4‐bis(benzyloxy)‐5‐[(benzyloxy)methyl]tetrahydrofuran‐2‐carbonitrile (1355357-49-1) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 2: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 2: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme
Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 2: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere View Scheme

O-phenyl phosphorodichloridate (770-12-7) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / Isopropyl acetate / 1 h / -20 °C 1.2: 1.5 h 2.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 1.5 h / -15 °C / Inert atmosphere 1.2: 2 h 2.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / Isopropyl acetate / 1 h / -20 °C 1.2: 1.5 h 2.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 21 h / 50 °C 3.1: hydrogenchloride; water / 72 h / 0 - 20 °C View Scheme

4-aminopyrrolo[2,1-f][1,2,4]triazine (159326-68-8) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 0 °C 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.58 h / 0 - 5 °C 3.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 4.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 5.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 0 °C 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.58 h / 0 - 5 °C 3.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 4.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 5.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 0 °C 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.58 h / 0 - 5 °C 3.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 °C / Inert atmosphere 4.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 5.1: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere View Scheme

2-ethylbutyl (S)-2-aminopropanoate hydrochloride (946511-97-3) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / Isopropyl acetate / 1 h / -20 °C 1.2: 1.5 h 2.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 1.5 h / -15 °C / Inert atmosphere 1.2: 2 h 2.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / Isopropyl acetate / 1 h / -20 °C 1.2: 1.5 h 2.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 21 h / 50 °C 3.1: hydrogenchloride; water / 72 h / 0 - 20 °C View Scheme

(3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one (14233-64-8, 134307-32-7, 55094-52-5) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.17 h / -78 °C / Inert atmosphere 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.17 h / -78 °C / Inert atmosphere 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.17 h / -78 °C / Inert atmosphere 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme

2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 20 °C 2: hydrogenchloride; water / tetrahydrofuran / 0 - 20 °C View Scheme

(3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (1191237-80-5) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 20 °C 2: hydrogenchloride; water / tetrahydrofuran / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium chloride / acetonitrile / 0.25 h / 20 °C 1.2: 4 h 2.1: hydrogenchloride / tetrahydrofuran; water / 0 - 20 °C View Scheme

(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile p-tolylsulfonic acid salt → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / water; ethyl acetate 2: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 20 °C 3: hydrogenchloride; water / tetrahydrofuran / 0 - 20 °C View Scheme

2,3,5-tri-O-benzyl-D-ribofuranose (16838-89-4) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 2.2: 0.17 h / -78 °C / Inert atmosphere 3.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 °C / Inert atmosphere 4.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 5.1: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 2.2: 0.17 h / -78 °C / Inert atmosphere 3.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 °C / Inert atmosphere 4.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 5.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 5 h / 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 2.2: 0.17 h / -78 °C / Inert atmosphere 3.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 °C / Inert atmosphere 4.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 5.1: magnesium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 6 h / 30 °C View Scheme

2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate + (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (1191237-80-5) → (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 50 °C 2: hydrogenchloride / tetrahydrofuran; water / 0 °C View Scheme
With N-ethyl-N,N-diisopropylamine; magnesium chloride In tetrahydrofuran at 20℃; for 3h; Temperature;
Multi-step reaction with 2 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 50 °C / Inert atmosphere 2: hydrogenchloride / tetrahydrofuran; water / 20 °C / Inert atmosphere View Scheme

4-amino-7-iodopyrrolo[2,1-f ][1,2,4]triazine (1770840-43-1) → (2S)-2-ethylbutyl 2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate + (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane; phenylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 5 °C / Inert atmosphere 1.2: 0.17 h / -15 - -12 °C 1.3: 1 h / -20 °C 2.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 2.2: 1 h / 0 °C 3.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 4.1: 1-methyl-1H-imidazole / tetrahydrofuran / 0 °C / Inert atmosphere 5.1: Lux Cellulose-2 chiral column / acetonitrile; methanol / Resolution of racemate View Scheme
Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane; phenylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 5 °C / Inert atmosphere 1.2: 0.17 h / -15 - -12 °C 1.3: 1 h / -20 °C 2.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 2.2: 1 h / 0 °C 3.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 4.1: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / 20 °C 5.1: Lux Cellulose-2 chiral column / acetonitrile; methanol / Resolution of racemate View Scheme
Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane; phenylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 5 °C / Inert atmosphere 1.2: 0.17 h / -15 - -12 °C 1.3: 1 h / -20 °C 2.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 2.2: 1 h / 0 °C 3.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 4.1: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 2.17 h / Inert atmosphere 5.1: Lux Cellulose-2 chiral column / acetonitrile; methanol / Resolution of racemate View Scheme

O-phenyl phosphorodichloridate (770-12-7) → (2S)-2-ethylbutyl 2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate + (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 4 h / -78 °C / Inert atmosphere 1.2: 4 h / 0 - 20 °C 2.1: tert-butylmagnesium chloride / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / 20 °C 3.1: Lux Cellulose-2 chiral column / acetonitrile; methanol / Resolution of racemate View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 4 h / -78 - 20 °C 1.2: 4 h / 0 - 20 °C 2.1: tert-butylmagnesium chloride / N,N-dimethyl-formamide; tetrahydrofuran / 1 h 3.1: Lux Cellulose-2 / acetonitrile; methanol / Resolution of racemate View Scheme

(2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (1809249-37-3) → ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)oxidophosphoryl)alanine bis-sodium salt

Conditions	Yield
With sodium hydroxide In water; acetonitrile for 2h;

Upstream product

• 1191237-80-5 (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile 
• 1355050-11-1 (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 
• 1439900-56-7 (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate 
• 159326-68-8 pyrrolo[2,1-f][1,2,4]triazin-4-amine 
• 1911578-98-7 (2S)-2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoic acid 2-ethylbutyl ester 
• 1355049-92-1 2-ethylbutyl (2S)-2-{[chloro(phenoxy)phosphoryl]amino}propanoate 
• 1191237-69-0 (2R,3R,4S,5R)?2?(4?aminopyrrolo[1,2?f][1,2,4]triazin?7?yl)?3,4?dihydroxy?5?(hydroxymethyl)tetrahydrofuran?2?carbonitrile 
• 946511-97-3 2-ethylbutyl (S)-2-aminopropanoate hydrochloride 
• 97-95-0 2-ethyl-1-butanol 
• 888720-29-4 4-chloropyrrolo[1,2-f][1,2,4]triazine 
• 946565-74-8 (S)-2-aminopropanoic acid 2-ethylbutyl ester 
• 1770840-43-1 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine 
• 937046-98-5 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine 

Downstream Products

• 1911579-04-8 GS-704277 

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