70-00-8

Usage

Uses

Used in Ophthalmic Industry:
Trifluridine is used as an anti-herpesvirus antiviral agent in ophthalmic preparations for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by HSV types 1 and 2. It is effective in inhibiting viral replication and reducing inflammation in the affected eye tissues.
Used in Antiviral Applications:
Trifluridine is used as an antiviral drug, mainly in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis. It has a role as an antiviral drug, an antimetabolite, an EC 2.1.1.45 (thymidylate synthase) inhibitor, and an antineoplastic agent.
Used in Anticancer Applications:
Trifluridine is used as an antitumor antimetabolite agent, possessing antiviral and anticancer activity. After phosphorylation by thymidine kinase, it is incorporated into DNA, where it induces DNA damage and interferes with repair enzymes, enhancing frame shift insertion and deletion in CRISPR genome editing in pluripotent stem cells.
Used in CRISPR Genome Editing:
Trifluridine is used to enhance frame shift insertion and deletion in CRISPR genome editing in pluripotent stem cells, improving the efficiency and accuracy of gene editing processes.

Originator

Trifluorothymidine ,Mann,W. Germany,1975

Indications

Trifluridine (Viroptic) is a fluorinated pyrimidine nucleoside that has in vitro activity against HSV-1 and HSV- 2, vaccinia, and to a lesser extent, some adenoviruses. Activation of trifluridine requires its conversion to the 5 monophosphate form by cellular enzymes.Trifluridine monophosphate inhibits the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by thymidylate synthetase. In addition, it competes with deoxythymidine triphosphate (dTTP) for incorporation by both viral and cellular DNA polymerases. Trifluridine-resistant mutants have been found to have alterations in thymidylate synthetase specificity.

Biochem/physiol Actions

Trifluorothymidine is a thymidine analog and is light sensitive. TFT serves as a thymidine kinase substrate to study enzyme specificity and kinetics. Incorporation of phosphorylated TFT into DNA induces damage, making it useful for DNA repair studies. TFT may also be used in the inhibition of thymidylate synthase and in screening mutant thymidine kinase gene.. It elicits antitumor activity in gastrointestinal (GI) cancers and has therapeutic potential to treat herpetic keratitis.

Mechanism of action

Trifluorothymidine is a fluorinated pyridine nucleoside structurally related to idoxuridine. It has been approved by the U.S. FDA and is a potent, specific inhibitor of replication of HSV-1 in vitro. Its mechanism of action is similar to that of idoxuridine. Like other antiherpes drugs, it is first phos-phorylated by thymidine kinase to mono-, di-, and triphosphate forms, which are then incorporated into viral DNA in place of thymidine to stop the formation of late virus mRNA and subsequent synthesis of the virion proteins.

Pharmacokinetics

Trifluorothymidine is a synthetic halogenated pyrimidine nucleoside, first synthesized as an antitumor agent. It inhibits enzymes of the DNA pathway and is incorporated into both cellular and progeny viral DNA, causing faulty transcription of late messenger RNA and the production of incompetent virion protein. It does not require a viral thymidine kinase for monophosphorylation and is far less selective and more toxic than other analogs. It is active against HSV-1 and HSV-2, vaccinia virus, CMV and possibly adenovirus. Trifluorothymidine, when given IV, shows a plasma half-life of 18 minutes and is excreted in the urine either unchanged or as the inactive metabolite 5-carboxyuracil. When applied as a 1% ophthalmic solution, it rapidly enters the aqueous humor of HSV-infected rabbits’ eyes but is cleared within 60–90 min.

Side effects

The most frequent adverse reactions to trifluridine administration are transient burning or stinging and palpebral edema. Other adverse reactions include superficial punctate keratopathy, epithelial keratopathy, hypersensitivity, stromal edema, irritation, keratitis sicca, hyperemia, and increased intraocular pressure. Trifluridine is mutagenic in vitro and carcinogenic and teratogenic when administered subcutaneously to animals. Topical trifluridine was not teratogenic in animal studies. Because it is applied topically in humans, the likelihood of systemic effects is low.

Synthesis

Trifluridine, 5-trifluoromethyl-1-(2-deoxyribofuranosyl)pyrimidin-2, 4-(1H.3H)-dione (36.1.22), is synthesized from 5-trifluoromethyluracil. This is synthesized by the following scheme. It begins with trifluoroacetone, from which the oxynitrile (36.1.16) is synthesized. Acetylation of this product gives the corresponding trifluoroacetate (36.1.16). Pyrrolysis of Trifluridine gives trifluoromethylacrylonitrile (36.1.17). Adding to this dry hydrogen bromide in methanol solution in a process of which methanolysis of the nitrile group takes place the bromide 36.1.19 is obtained, which upon acidic hydrolysis undergoes heterocyclization to the dihydropyrimidine 36.1.20. Brominating of the obtained dihydropyrimidine with molecular bromine and subsequent dehydrobromination of the resulting product 36.1.21 on heating in dimethylformamide gives 5-trifluoromethyluracil (36.1.22). This is reacted with 2-deoxy-D-ribos-1-phosphate using the nucleoside phosphorylase enzyme, or by treating it with hyxamethyldisylazane and then with trichloromethylsilane to make 2,4- trimethylsilyloxy-5-trifluoromethyl pyrimidine (36.1.23). Hexamethyldisilazane, which itself does not form trimethylsilyl ethers, is used because using a combination of two reagents leads to optimal yield of trimethylsilyl ethers. Reacting the resulting pyrimidine derivative with 3,5-bis-(4-nitrobenzoate)-2-deoxyribofuranosyl chloride in the presence of mercury (II) acetate makes the corresponding ditrimethylsilyloxy nucleoside, which when treated with an aqueous solution of potassium iodide to remove the protecting groups. The resulting product undergoes preliminary purification by chromatography, and then is treated with a methanol solution of diisopropylamine to remove the 4-nitrobenzoyl protection from the furanosyl part, giving the desired trifluridine.

Veterinary Drugs and Treatments

Trifluridine (trifluorothymidine; Viroptic?) is a pyrimidine nucleoside analog. It is structurally related to 2-deoxythymidine, the natural precursor of DNA synthesis. Trifluridine is poorly absorbed by the cornea and is virostatic. Viroptic? interrupts viral replication by substituting “nonsense” pyrimidine analogues. For this reason, a competent surface immunity is necessary to resolve ocular disease, with or without antiviral therapy. A recent in vitro study in which several strains of feline herpes virus were collected from the United States and were used to infect kidney epithelial cells showed that trifluridine was more effective at lower concentrations compared with several other agents. For this reason, trifluridine was the first choice drug employed in the treatment of feline herpes virus ocular disease for many years. Because of the topical toxicity associated with use of trifluridine in cats, its popularity has diminished greatly. In many milder cases, the irritation associated with topical trifluridine is more intense then the inflammation induced by viral infection. Antiviral agents have also been used in the treatment of superficial punctate keratitis in the horse, thought to be associated with equine herpes virus-2 (EHV-2) infection of the cornea.

References

1) Bijnsdorp et al. (2010), Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells; Int. J. Cancer, 126 24572) Temmink et al. (2010), Trifluorothymidine resistance is associated with decreased thymidine kinase and equilibrative nucleoside transporter expression or increased secretory phospholipase A2; Mol. Cancer Ther., 9 10473) Suzuki et al. (2011), Mode of action of trifluorothymidine (TFT) against DNA replication and repair enzymes; Int. J. Oncol., 39 263 4) Yu et al. (2015), Small molecules enhance CRISPR genome editing in pluripotent stem cells; Cell Stem Cell, 16 142

InChI:InChI=1/C10H11F3N2O5/c11-10(12,13)4-2-15(9(19)14-8(4)18)7-1-5(17)6(3-16)20-7/h2,5-7,16-17H,1,3H2,(H,14,18,19)/t5-,6+,7?/m0/s1

Synthetic route

C24H17Cl2F3N2O7 → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With methanol; sodium methylate at 4 - 6℃; for 3.5h;	97%

5-trifluoromethyl-2′-deoxyuridine-3′,5′-diacetate (65499-42-5) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With ammonia In methanol at 20℃;	95%
With ammonia In methanol at 0 - 20℃; for 16h;	84%
With ammonia In methanol at 20℃; for 19h;	76%

2'-deoxyuridine (951-78-0) + Langlois reagent (2926-29-6) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With tert.-butylhydroperoxide In water at -3 - 60℃; for 2h; Temperature; Inert atmosphere;	94.3%
With tert.-butylhydroperoxide In water at -5 - 65℃; for 3h; Inert atmosphere; Large scale;	94.8%
With tert-butyl alcohol In water at 0 - 20℃; for 3h;	59%
With mesoporous graphitic carbon nitride In dimethyl sulfoxide at 25℃; Irradiation;	47%
With acetone In water at 20℃; for 40h; UV-irradiation; Inert atmosphere;	44%

5-(trifluoromethyl)uridine (21618-67-7) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Stage #1: 5-(trifluoromethyl)uridine With sodium hydrogencarbonate; carbonic acid dimethyl ester In N,N-dimethyl-formamide at 120℃; for 8h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 55℃; for 10h; Stage #3: With palladium on activated charcoal; hydrogen; sodium hydroxide In water; N,N-dimethyl-formamide at 15℃; under 4500.45 Torr; for 12h; pH=7 - 8;	86.4%

1-<3,5-bis-O-(p-chlorobenzoyl)-2-deoxy-β-D-erythro-pentofuranosyl>-5-trifluoromethyluracil (129664-47-7) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With sodium methylate In methanol at 20 - 30℃; for 4h;	82.5%
With methanol; sodium methylate for 1h; Ambient temperature;	67%

3',5'-di-O-acetyl-5-(trifluoromethyl)-2'-deoxyuridine (65499-42-5) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With ammonia In methanol for 10h; Ambient temperature;	82%

Togni's reagent II (887144-94-7) + 2'-deoxyuridine (951-78-0) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With copper(l) iodide In N,N-dimethyl-formamide at 80℃; for 23h; Inert atmosphere; Sealed tube; regioselective reaction;	76%

iodotrifluoromethane (2314-97-8) + 2'-deoxyuridine (951-78-0) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With caesium carbonate In dimethyl sulfoxide for 24h; Inert atmosphere; Irradiation;	71%
With caesium carbonate In dimethyl sulfoxide at 20℃; for 24h; Schlenk technique; Inert atmosphere; Irradiation;	68%
With iron(III) sulfate; sulfuric acid; dihydrogen peroxide In water; dimethyl sulfoxide at 40 - 50℃; for 0.333333h;	58%

5-(trifluoromethyl)-3',5'-di-O-trityl-2'-deoxyuridine (76513-99-0) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With formic acid at 0℃; for 0.0166667h;	40%

Hexanoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-2-hexanoyloxymethyl-tetrahydro-furan-3-yl ester (89143-01-1) → 5'-O-hexanoyl-2'-deoxy-5-trifluoromethyluridine (89143-05-5) + 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With phosphate buffer In N,N-dimethyl-formamide at 25℃; for 18h; enzym: Pseudomonas fluorescens;	A 62 % Chromat. B 6 % Chromat.

5-trifluoromethyluracil (54-20-6) + thymidine (50-89-5) → 2'-deoxy-5-trifluoromethyluridine (70-00-8) + thymin (65-71-4)

Conditions	Yield
With thymidine phosphorylase from Escherichia coli In phosphate buffer at 35℃; for 2h; pH=7.0; Title compound not separated from byproducts;	A 47 % Chromat. B n/a

3',5'-di-O-acetyl-2'-deoxyuridine (13030-62-1) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 33 percent / XeF2 / 1 h / Ambient temperature 2: 82 percent / NH3 / methanol / 10 h / Ambient temperature View Scheme

3',5'-di-O-trityl-5-iodo-2'-deoxyuridine (76513-98-9) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) copper powder / 1.) HMPA, 120 deg C, 2.5 h, 2.) 45 deg C, 12 h 2: 40 percent / 98percent formic acid / 0.02 h / 0 °C View Scheme

5-trifluoromethyluracil (54-20-6) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: hexamethyldisilazane / 1,2-dichloro-ethane / 0.75 h / Heating 2: 80 percent / zinc chloride / CHCl3 / 15 h / Ambient temperature 3: 67 percent / sodium methoxide, methanol / 1 h / Ambient temperature View Scheme

5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine (7057-43-4) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / zinc chloride / CHCl3 / 15 h / Ambient temperature 2: 67 percent / sodium methoxide, methanol / 1 h / Ambient temperature View Scheme

5-trifluoromethyluracil (54-20-6) + thymidine (50-89-5) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With thymidine phosphorylase In aq. phosphate buffer at 37℃; for 1h; pH=6.8; Enzymatic reaction;

2'-deoxyuridine (951-78-0) + 5-trifluoromethyluracil (54-20-6) → 2'-deoxy-5-trifluoromethyluridine (70-00-8) + uracil (66-22-8)

Conditions	Yield
With pyrimidine nucleoside phosphorylase from Bacillus subtilis (E.C. 2.4.2.3) immobilized on Sepabeads EC-EP In aq. phosphate buffer at 20℃; for 10h; pH=7.5; Reagent/catalyst; Enzymatic reaction;

2'-deoxyuridine (951-78-0) + 5-trifluoromethyluracil (54-20-6) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With immobilized Bacillus psychrosaccharolyticus CECT 4074 nucleoside 2'-deoxyribosyltransferase In aq. phosphate buffer at 37℃; for 2h; pH=7.5; Concentration; Enzymatic reaction;
With purine nucleoside phosphorylase; uridine phosphorylase In aq. phosphate buffer; dimethyl sulfoxide at 80℃; for 3h; pH=7; Enzymatic reaction;

5-trifluoromethyluracil (54-20-6) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 2 h / 20 - 125 °C 2: copper dichloride / chloroform / 24 h / 20 - 30 °C 3: sodium methylate / methanol / 4 h / 20 - 30 °C View Scheme

5-Iodo-2'-deoxyuridine (54-42-2) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridine / 16 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / -60 °C 2.2: 16 h / 20 °C 3.1: copper(l) iodide; potassium fluoride / N,N-dimethyl-formamide / 16 h / 60 °C 3.2: 16 h / 20 °C 4.1: ammonia / methanol / 16 h / 0 - 20 °C View Scheme

3',5'-O-diacetyl-5-iodo-2'-deoxyuridine (1956-30-5) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / -60 °C 1.2: 16 h / 20 °C 2.1: copper(l) iodide; potassium fluoride / N,N-dimethyl-formamide / 16 h / 60 °C 2.2: 16 h / 20 °C 3.1: ammonia / methanol / 16 h / 0 - 20 °C View Scheme

(N3-para-(methylene)bis(methoxybenzene))-5-iodo-2′-deoxyuridine-3′,5′-diacetate → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: copper(l) iodide; potassium fluoride / N,N-dimethyl-formamide / 16 h / 60 °C 1.2: 16 h / 20 °C 2.1: ammonia / methanol / 16 h / 0 - 20 °C View Scheme

2-deoxy-D-ribose (36792-88-8) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: acetyl chloride / 0.5 h / 5 - 10 °C 1.2: 5 h / 5 - 10 °C 2.1: dmap; triethylamine / toluene / 2 h / 25 - 30 °C 3.1: hydrogenchloride; acetyl chloride; acetic acid / 1,4-dioxane; chloroform / 3.25 h / 10 - 15 °C 4.1: 1,1,1,3,3,3-hexamethyl-disilazane; chloro-trimethyl-silane / 3 h / 120 - 125 °C 4.2: 3 h / 25 - 30 °C 5.1: sodium methylate; methanol / 1.5 h / 10 - 15 °C View Scheme

1-O-methyl-2-deoxy-D-ribofuranoside (51255-17-5, 51255-18-6, 60134-26-1, 89577-26-4, 96038-80-1, 96039-31-5, 144301-84-8, 144301-85-9) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: dmap; triethylamine / toluene / 2 h / 25 - 30 °C 2.1: hydrogenchloride; acetyl chloride; acetic acid / 1,4-dioxane; chloroform / 3.25 h / 10 - 15 °C 3.1: 1,1,1,3,3,3-hexamethyl-disilazane; chloro-trimethyl-silane / 3 h / 120 - 125 °C 3.2: 3 h / 25 - 30 °C 4.1: sodium methylate; methanol / 1.5 h / 10 - 15 °C View Scheme

methyl 3,5-di-O-toluoyl-2-deoxy-D-ribofuranose (4330-34-1) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; acetyl chloride; acetic acid / 1,4-dioxane; chloroform / 3.25 h / 10 - 15 °C 2.1: 1,1,1,3,3,3-hexamethyl-disilazane; chloro-trimethyl-silane / 3 h / 120 - 125 °C 2.2: 3 h / 25 - 30 °C 3.1: sodium methylate; methanol / 1.5 h / 10 - 15 °C View Scheme

2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride (4330-21-6) + 5-trifluoromethyluracil (54-20-6) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane; chloro-trimethyl-silane / 3 h / 120 - 125 °C 1.2: 3 h / 25 - 30 °C 2.1: sodium methylate; methanol / 1.5 h / 10 - 15 °C View Scheme

(2R,3S,5R)-5-(2,4-dioxo-5-(trifluoromethyl)-3,4-dihydropyrimidin-1(2H)-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl-4-methylbenzoate (7057-46-7) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
With methanol; sodium methylate at 10 - 15℃; for 1.5h; Temperature;	39 g

[(2R,3R,4R)-3,4-diacetoxy-5-chlorotetrahydrofuran-2-yl]methyl acetate (40554-98-1) → 2'-deoxy-5-trifluoromethyluridine (70-00-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetonitrile / 3 h / 45 °C 2.1: acetyl chloride; methanol / 10 h / 0 °C 3.1: carbonic acid dimethyl ester; sodium hydrogencarbonate / N,N-dimethyl-formamide / 8 h / 120 °C 3.2: 10 h / 55 °C 3.3: 12 h / 15 °C / 4500.45 Torr / pH 7 - 8 View Scheme

4,4'-dimethoxytrityl chloride (40615-36-9) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 5'-O-(4,4'-dimethoxytrityl)-α,α,α-trifluorothymidine (133128-06-0)

Conditions	Yield
With pyridine; dmap at 0 - 20℃; for 21h;	96%
With pyridine at 20℃; for 41.5h; Inert atmosphere;	72%
With pyridine

chloro-bis-(2-methoxy-phenyl)-phenyl-methane (854751-16-9) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 5-Trifluoromethyl-5'-dimethoxytrityl-2'-deoxyuridine

Conditions	Yield
With dmap In pyridine; dichloromethane	96%

tert-butyldimethylsilyl chloride (18162-48-6) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 5'-O-(tert-butyldimethylsilyl)-2'-deoxy-5-(trifluoromethyl)uridine (127978-84-1)

Conditions	Yield
With 1H-imidazole; dmap In N,N-dimethyl-formamide at 25℃; for 1h;	93%
With pyridine for 12h; Ambient temperature;	88%

acetic anhydride (108-24-7) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 3',5'-di-O-acetyl-5-(trifluoromethyl)-2'-deoxyuridine (65499-42-5)

Conditions	Yield
dmap In acetonitrile	92%

2'-deoxy-5-trifluoromethyluridine (70-00-8) → 5-carboxy-2'-deoxyuridine (14599-46-3)

Conditions	Yield
With sodium hydroxide at 37℃; for 36h; pH=10;	90%

bis(4-methoxyphenyl)phenylmethylium tetrafluoroborate + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 5'-O-(4,4'-dimethoxytrityl)-α,α,α-trifluorothymidine (133128-06-0)

Conditions	Yield
With lithium carbonate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Heating;	87%

2'-deoxy-5-trifluoromethyluridine (70-00-8) + methylamine (74-89-5) → 2'-deoxy-5-(N,N'-dimethylamidinyl)uridine

Conditions	Yield
With water at 60℃; for 24h;	84%

arachidic anhydride (55726-22-2) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → Icosanoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-2-icosanoyloxymethyl-tetrahydro-furan-3-yl ester (89143-03-3)

Conditions	Yield
dmap In acetonitrile	80%

3-fluorobenzoic acid anhydride (56666-54-7) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 3',5'-di-O-(m-fluorobenzoyl)-2'-deoxy-5-trifluoromethyluridine (99502-68-8)

Conditions	Yield
dmap In acetonitrile	72%

2'-deoxy-5-trifluoromethyluridine (70-00-8) + chloromethyl n-heptanoate (76068-79-6) → 3-n-heptanoyloxymethyl-2'-deoxy-5-trifluoromethyluridine (161632-25-3)

Conditions	Yield
With sodium iodide; potassium carbonate	71.3%

1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane (69304-37-6) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 3',5'-O-TPDS-α,α,α-trifluorothymidine (133100-91-1)

Conditions	Yield
With pyridine for 3h; Ambient temperature;	70%

p-methylbenzoic anhydride (13222-85-0) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → (2R,3S,5R)-5-(2,4-dioxo-5-(trifluoromethyl)-3,4-dihydropyrimidin-1(2H)-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl-4-methylbenzoate (7057-46-7)

Conditions	Yield
dmap In acetonitrile	68%

2,3-dihydro-2H-furan (1191-99-7) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 2'-deoxy-3',5'-di-O-(tetrahydro-2-furyl)-5-trifluoromethyluridine (93298-69-2)

Conditions	Yield
With toluene-4-sulfonic acid In 1,4-dioxane for 0.5h; Ambient temperature;	67%

2'-deoxy-5-trifluoromethyluridine (70-00-8) → C10H9F3N2O4 (123822-62-8)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In acetonitrile at -15 - 0℃; for 3.16667h;	67%

4-methyl-benzoyl chloride (874-60-2) + Hexanoyl chloride (142-61-0) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 4-Methyl-benzoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-2-hexanoyloxymethyl-tetrahydro-furan-3-yl ester (110073-57-9)

Conditions	Yield
With pyridine	66%

n-hexanoic anhydride (2051-49-2) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → Hexanoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-2-hexanoyloxymethyl-tetrahydro-furan-3-yl ester (89143-01-1)

Conditions	Yield
dmap In acetonitrile	64%

4-methyl-benzoyl chloride (874-60-2) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 4-Methyl-benzoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-3-hydroxy-tetrahydro-furan-2-ylmethyl ester (99502-67-7)

Conditions	Yield
With pyridine	62%

capric anhydride (2082-76-0) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → Decanoic acid (2R,3S,5R)-2-decanoyloxymethyl-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-3-yl ester (89142-99-4)

Conditions	Yield
dmap In acetonitrile	59%

4-methyl-benzoyl chloride (874-60-2) + Hexanoyl chloride (142-61-0) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → 4-Methyl-benzoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-3-hexanoyloxy-tetrahydro-furan-2-ylmethyl ester (110073-58-0)

Conditions	Yield
With pyridine	57%

benzoyl chloride (98-88-4) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → N3-benzoyl-2'-deoxy-5-(trifluoromethyl)uridine (95969-47-4)

Conditions	Yield
With triethylamine In N,N-dimethyl acetamide for 12h; Ambient temperature;	56%

palmitic anhydride (623-65-4) + 2'-deoxy-5-trifluoromethyluridine (70-00-8) → Hexadecanoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-2-hexadecanoyloxymethyl-tetrahydro-furan-3-yl ester (89143-02-2)

Conditions	Yield
dmap In acetonitrile	53%

2'-deoxy-5-trifluoromethyluridine (70-00-8) + n-hexadecanoyl chloride (112-67-4) → Hexadecanoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-3-hydroxy-tetrahydro-furan-2-ylmethyl ester (89144-54-7)

Conditions	Yield
With pyridine	52%

Upstream product

• 76513-99-0 5-(trifluoromethyl)-3',5'-di-O-trityl-2'-deoxyuridine 
• 65499-42-5 3',5'-di-O-acetyl-5-(trifluoromethyl)-2'-deoxyuridine 
• 54-20-6 5-trifluoromethyluracil 
• 50-89-5 thymidine 
• 7057-43-4 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine 
• 2314-97-8 iodotrifluoromethane 
• 951-78-0 2'-deoxyuridine 
• 2926-29-6 Langlois reagent 
• 36792-88-8 2-deoxy-D-ribose 
• 51255-17-5 1-O-methyl-2-deoxy-D-ribofuranoside 
• 4330-34-1 methyl 3,5-di-O-toluoyl-2-deoxy-D-ribofuranose 
• 4330-21-6 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride 
• 7057-46-7 (2R,3S,5R)-5-(2,4-dioxo-5-(trifluoromethyl)-3,4-dihydropyrimidin-1(2H)-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl-4-methylbenzoate 
• 40554-98-1 [(2R,3R,4R)-3,4-diacetoxy-5-chlorotetrahydrofuran-2-yl]methyl acetate 

Downstream Products

• 65499-42-5 3',5'-di-O-acetyl-5-(trifluoromethyl)-2'-deoxyuridine 
• 116953-93-6 O⁴-benzyl-2'-deoxy-5-(trifluoromethyl)uridine 
• 117069-24-6 N³-benzyl-2'-deoxy-5-(trifluoromethyl)uridine 
• 99502-69-9 3-(4-Fluoro-benzoyl)-1-((2R,4S,5R)-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione 
• 95969-47-4 N³-benzoyl-2'-deoxy-5-(trifluoromethyl)uridine 
• 110073-57-9 4-Methyl-benzoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-2-hexanoyloxymethyl-tetrahydro-furan-3-yl ester 
• 110073-58-0 4-Methyl-benzoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-3-hexanoyloxy-tetrahydro-furan-2-ylmethyl ester 
• 99502-67-7 4-Methyl-benzoic acid (2R,3S,5R)-5-(2,4-dioxo-5-trifluoromethyl-3,4-dihydro-2H-pyrimidin-1-yl)-3-hydroxy-tetrahydro-furan-2-ylmethyl ester 
• 7057-46-7 (2R,3S,5R)-5-(2,4-dioxo-5-(trifluoromethyl)-3,4-dihydropyrimidin-1(2H)-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl-4-methylbenzoate 
• 93298-64-7 1-((2R,4S,5R)-5-Benzyloxymethoxymethyl-4-hydroxy-tetrahydro-furan-2-yl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione 
• 93298-65-8 1-((2R,4S,5R)-4-Benzyloxymethoxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione 
• 93298-66-9 1-((2R,4S,5R)-4-Benzyloxymethoxy-5-benzyloxymethoxymethyl-tetrahydro-furan-2-yl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione 
• 99502-68-8 3',5'-di-O-(m-fluorobenzoyl)-2'-deoxy-5-trifluoromethyluridine 
• 99502-71-3 3-(4-Butyl-benzoyl)-1-((2R,4S,5R)-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione 

Relevant academic research and scientific papers

Enzymatic synthesis of perfluoroalkylated DNA

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METHOD FOR PREPARING TRIFLURIDINE

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Preparation method of perfluoroalkylated aryl compound

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Fluridine crystal form B and preparation method thereof

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SOLID STATE FORMS OF 5-CHLORO-6-[(2-IMINOPYRROLIDIN-1-YL)METHYL]PYRIMIDINE-2,4-(1H,3H)-DIONE HYDROCHLORIDE AND THEIR PROCESSES FOR THE PREPARATION THEREOF

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Synthetic method of 5-trifluoromethyl uracil

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Catalyst-free and visible light promoted trifluoromethylation and perfluoroalkylation of uracils and cytosines

Fluoroalkylated enaminones, such as trifluridine and 5-trifluoromethyluracil, have widespread applications in pharmaceuticals and agrochemicals. Although these kinds of pharmaceutical agent often bear CF3 and perfluoroalkyl motifs in the core structure, access to such analogues typically requires multi-step synthesis. Here, we report a mild, metal-free and operationally simple strategy for the direct perfluoroalkylation of uracils, cytosines and pyridinones through a visible-light induced pathway from perfluoroalkyl iodides. This photochemical transformation features synthetic simplicity, mild reaction conditions without any photoredox catalyst, and high functional group tolerance, providing a facile route for applications in medicinal chemistry.