5-Fluorocytosine CAS 2022-85-7
Introduction：Basic information about 5-Fluorocytosine CAS 2022-85-7, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
5-Fluorocytosine Basic informationOverview Mechanism of action and resistance Pharmacokinetic and dosage Toxicity and side effects References
| Product Name: | 5-Fluorocytosine |
| Synonyms: | 4-amino-5-fluoro-2(1h)-pyrimidinon;4-Amino-5-fluoro-2(1H)-pyrmidinone;5-fluorocystosine;5-fluorocytosin;5-fluoro-cytosin;fluocytosine;4-Amino-5-Fluoro-2(1H)-pyrimidine, Flucytosine, 5-FC;5-Fluorocytosine98% |
| CAS: | 2022-85-7 |
| MF: | C4H4FN3O |
| MW: | 129.09 |
| EINECS: | 217-968-7 |
| Product Categories: | Nucleotides and Nucleosides;Antifungals for Research and Experimental Use;Biochemistry;Chemical Reagents for Pharmacology Research;Nucleobases and their analogs;Nucleosides, Nucleotides & Related Reagents;Nucleic acids;Bases & Related Reagents;Nucleotides;Phenylacetic acid;ketone;Amines;Heterocycles;Pyrimidine series;API;PYRIMIDINE;Pyridines, Pyrimidines, Purines and Pteredines;Anticancer;amine |ketone| alkyl Fluorine;GLUCOTROL;2022-85-7 |
| Mol File: | 2022-85-7.mol |
5-Fluorocytosine Chemical Properties
| Melting point | 298-300 °C (dec.) (lit.) |
| density | 1.3990 (estimate) |
| vapor pressure | 0Pa at 25℃ |
| storage temp. | 2-8°C |
| solubility | Sparingly soluble in water, slightly soluble in ethanol (96 per cent) |
| form | Crystalline Powder |
| pka | 3.26(at 25℃) |
| color | White to almost white |
| Water Solubility | 1.5g/100mL (25 ºC) |
| Sensitive | Light Sensitive |
| Merck | 14,4125 |
| BRN | 127285 |
| BCS Class | 1 |
| Stability: | Light Sensitive |
| InChI | 1S/C4H4FN3O/c5-2-1-7-4(9)8-3(2)6/h1H,(H3,6,7,8,9) |
| InChIKey | XRECTZIEBJDKEO-UHFFFAOYSA-N |
| SMILES | NC1=NC(=O)NC=C1F |
| LogP | -1.36 at 22.1℃ and pH6.4-6.9 |
| Dissociation constant | 2.74-10.71 at 21.4℃ |
| CAS DataBase Reference | 2022-85-7(CAS DataBase Reference) |
Safety Information
| Hazard Codes | Xn,T,Xi |
| Risk Statements | 40-36/37/38-63 |
| Safety Statements | 22-24/25-45-36/37-36/37/39-27-26 |
| WGK Germany | 2 |
| RTECS | HA6040000 |
| F | 10-23 |
| Hazard Note | Toxic/Light Sensitive |
| HazardClass | IRRITANT, LIGHT SENSITIVE |
| HS Code | 29335990 |
| Storage Class | 11 - Combustible Solids |
| Hazard Classifications | Repr. 2 |
| Hazardous Substances Data | 2022-85-7(Hazardous Substances Data) |
| Toxicity | LD50 in mice (mg/kg): >2000 orally and s.c.; 1190 i.p.; 500 i.v. (Grunberg, 1963) |
| Overview | A fluorinated pyrimidine, 5-flucytosine (fluorocytosine; 5-FC, Fig. 1), was initially developed as a potential anti-cancer agent but it was not sufficiently effective in the field of cancer chemotherapy[1]. Later, 5-FC proved to be active in experimental candidiasis and cryptococcosis in mice[2] and was used to treat human infections[3]. In addition to its activity against Candida and Cryptococcus, 5-FC also has an inhibitory activity against fungi causing chromoblastomycosis[4]; however, it is ineffective against infections caused by filamentous fungi. 5-FC has a high prevalence of primary resistance in many fungal species. Due to this primary resistance, 5-FC is used mainly in combination with other antifungals (primarily amphotericin B, AmB) and more recently it has been investigated in combination with other agents including fluconazole (FLU), ketoconazole (KTZ), itraconazole (ITRA), voriconazole (VORI) and echinocandins (e.g., micafungin, MICA and caspofungin, CAS). It is used only rarely as a single agent. Flucytosine (5-FC) is a synthetic antimycotic compound, first synthesized in 1957. It has no intrinsic antifungal capacity, but after it has been taken up by susceptible fungal cells, it is converted into 5-fluorouracil (5-FU), which is further converted to metabolites that inhibit fungal RNA and DNA synthesis. Monotherapy with 5-FC is limited because of the frequent development of resistance. In combination with amphotericin B, 5-FC can be used to treat severe systemic mycoses, such as cryptococcosis, candidosis, chromoblastomycosis and aspergillosis. Figure 1 the chemical structure of Fluorocytosine |
| Mechanism of action and resistance | 5-FC is most active against yeasts, including Candida, Torulopsis and Cryptococcus spp., and against the dematiaceous fungi causing chromomycosis (Phialophora and Cladosporium spp.) and Aspergillus spp.[5] The MICs of 5-FC vary from 0.1 to 0.25 mg/L for these fungal species. In Emmonsia crescens, Emmonsia parva, Madurella mycetomatis, Madurella grisea, Pyrenochaeta romeroi, Cephalosporium spp., Sporothrix schenckii and Blastomyces dermatitidis, MICs vary from 100 to 1000 mg/L.14 5-FC is also active against some protozoa, including Acanthamoeba culbertsoni both in vitro and in vivo and Leishmania spp. in patients.[5] Antimycotic activity of 5-FC results from its rapid conversion into 5-fluorouracil (5-FU) by the enzyme cytosine deaminase, within susceptible fungal cells. There are two mechanisms involved by which 5-fluorouracil exerts its antifungal activity. The first mechanism includes the conversion of 5-fluorouracil through 5-fluorouridine monophosphate (FUMP) and 5-fluorouridine diphosphate (FUDP) into 5-fluorouridine triphosphate (FUTP)[6]. FUTP is further incorporated into fungal RNA in place of uridylic acid; this alters the aminoacylation of tRNA, disturbs the amino acid pool and inhibits protein synthesis[6]. The second mechanism is the metabolism of 5-FU into 5-fluorodeoxyuridine monophosphate (FdUMP) by uridine monophosphate pyrophosphorylase[6]. FdUMP is a potent inhibitor of thymidylate synthase, which is a key enzyme involved in DNA synthesis and nuclear division[7]. Thus, 5-FC acts by interfering with pyrimidine metabolism and protein synthesis in the fungal cell. These activity results in cell lysis and death. The occurrence of resistance with the use of 5-FC has been widely described and precludes use of 5-FC as a single agent[8, 10] Two basic mechanisms of resistance can be distinguished: (i) certain mutations can result in a deficiency in the enzymes necessary for cellular transport and uptake of 5-FC or for its metabolism (i.e. cytosine permease, uridine monophosphate pyrophosphorylase or cytosine deaminase);[9,11] (ii) resistance may result from increased synthesis of pyrimidines, which compete with the fluorinated antimetabolites of 5-FC and thus diminish its antimycotic activity.[9] It has been shown that defective uridine monophosphate pyrophosphorylase is the most frequently occurring type of acquired 5-FC resistance in fungal cells.[12] Normark & Schönebeck have reported that two different phenotypes of 5-FC-resistant strains can be recognized:[10] strains of resistance phenotype class 1 are not affected by 5-FC at high concentrations (these are the totally (intrinsically) resistant strains), while those of class 2 are susceptible to 5-FC at low concentrations but, after long exposure to 5-FC (even at high concentrations) resistance develops (these are said to be partially resistant or to have acquired resistance). Development of resistance in the latter strains probably results from selection of non-susceptible mutants, leading to a secondary resistant population.[9] The incidence of resistance to 5-FC varies between species.20 Up to 7–8% of intrinsically resistant strains are found among pretreatment isolates of C. albicans, unspeciated candida and Torulopsis glabrata. In C. neoformans the incidence of resistance is lower (1–2%), but in Candida spp. other than C. albicans it is 22%, because of the prevalence of generally less sensitive species such as Candida tropicalis and Candida krusei[13]. The exact incidence of primary 5-FC resistance is not clear. Different investigators report rates ranging between 8% and 44% for Candida spp[14]. Possible factors contributing to this wide range include the susceptibility methods used, local factors involving use of antifungal agents and differences in the prevalence of various Candida spp[14]. |
| Pharmacokinetic and dosage | 5-FC is absorbed very rapidly and almost completely: 76–89% is bioavailable after oral administration.[16] In patients with normal renal function, peak concentrations are attained in serum and other body fluids within 1–2 h.[15, 16]. 5-FC penetrates well into most body sites, including cerebrospinal, vitreous and peritoneal fluids, and into inflamed joints, because it is small and highly water-soluble and is not bound by serum proteins to a great extent[15-17]. 5-FC is principally eliminated by the kidneys and the plasma clearance of the drug is closely related to creatinine clearance[15, 17]. 5-FC is only minimally metabolized in the liver. Renal elimination is via glomerular filtration; no tubular resorption or secretion takes place. The half-life of 5-FC is c.3–4 h in patients with normal renal function, but can be extended up to 85 h in patients with severe renal insufficiency.[12, 16, 18] Renal insufficiency alters 5-FC pharmacokinetics since it slows absorption, prolongs serum half-life and decreases clearance[15]. The apparent volume of distribution of 5-FC approaches that of total body water and is not altered by renal failure. Dosage must be adjusted in patients with renal impairment. Various recommendations have been made[15-18]. Daneshmend & Warnock have suggested the following guidelines for the administration of 5-FC to patients with renal insufficiency.[15]. In patients with a creatinine clearance of >40 mL/min, a standard dose of 37.5 mg/kg every 6 h should be used. If the creatinine clearance is between 20 and 40 mL/min, the recommended dose is 37.5 mg/kg every 12 h. In patients with a creatinine clearance of <20 mL/ minute, the dose of 5-FC should be 37.5 mg/kg once daily. Finally, if the creatinine clearance is <10 mL/min, frequent determinations of 5-FC concentration should be used as guidance for the frequency of dosing. |
| Toxicity and side effects | 5-FC is known to have some relatively minor side effects, such as nausea, vomiting and diarrhoea, it also has more severe side effects, including hepatotoxicity and bonemarrow depression. Gastrointestinal side effects, the most common and least harmful side effects associated with 5-FC treatment, include nausea, diarrhoea and, occasionally, vomiting and diffuse abdominal pain. They occur in approximately 6% of patients treated with 5-FC[18]. Although these side effects are usually not severe; two cases of ulcerative colitis and bowel perforation have been reported[19]. Hepatotoxicity can occur during 5-FC treatment. In most cases it involves increases in serum concentrations of transaminases and alkaline phosphatase[20]. The incidence of hepatotoxicity is between 0 and 25%[20]. The most severe toxicity associated with 5-FC treatment are bone-marrow depression. There have been several reports of serious or life-threatening leucocytopenia, thrombocytopenia and/or pancytopenia[21-23]. The mechanism of toxicity of 5-FC is still not fully understood. It is likely that some of the side effects caused by 5-FC, for example hepatotoxicity and bone-marrow depression, are dose-dependent, although not all reports support this theory. Furthermore, it has been postulated that conversion of 5-FC to certain metabolites, especially 5-FU, could be one of the mechanisms of development of 5-FC-associated toxicity. |
| References |
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| Description | 5- |
| Chemical Properties | White Crystalline Solid |
| Originator | Ancobon,Roche,US,1972 |
| Uses | 5-Fluorocytosine acts as an antidiabetic, antifungal and antimicrobial agent. It is useful for the treatment of serious infections arises due to susceptible strains of Candida or Cryptococcus neoformans and chromomycosis. Further, it is employed in studies on TMP biosynthesis. |
| Uses | 5-FC is a toxic antifungal/antimicrobial agent |
| Indications | Flucytosine (Ancobon) is a synthetic, fluorinated pyrimidine that is structurallyrelated to fluorouracil (FU) and floxuridine. It can be fungistatic andfungicidal. Although it is used more frequently in the treatment of systemicinfections caused by Candida and Cryptococcus, dermatologic indicationsmay include infections due to chromomycosis, sporotrichosis, Cladosporium,and Sporothrix species. It is generally ineffective against Aspergillus species. |
| Definition | ChEBI: Flucytosine is an organofluorine compound that is cytosine that is substituted at position 5 by a fluorine. A prodrug for the antifungal 5-fluorouracil, it is used for the treatment of systemic fungal infections. It has a role as a prodrug. It is an organofluorine compound, a pyrimidone, an aminopyrimidine, a nucleoside analogue and a pyrimidine antifungal drug. It is functionally related to a cytosine. |
| Manufacturing Process | The preparation of 5-fluorouracil is given under "Fluorouracil." As described inUS Patent 3,040,026, 5-fluorouracil is then subjected to the following steps togive flucytosine. Step 1: 2,4-Dichloro-5-Fluoropyrimidine - A mixture of 104 grams (0.8 mol)of 5-fluorouracil, 1,472 grams (9.6 mols) of phosphorus oxychloride and 166grams (1.37 mols) of dimethylaniline was stirred under reflux for 2 hours.After cooling to room temperature, phosphorus oxychloride was removed bydistillation at 18 to 22 mm and 22° to 37°C. The residue was then poured intoa vigorously stirred mixture of 500 ml of ether and 500 gram of ice. Afterseparating the ether layer, the aqueous layer was extracted with 500 ml, then200 ml of ether. The combined ether fractions were dried over sodium sulfate,filtered, and the ether removed by vacuum distillation at 10° to 22°C. Theresidue, a yellow solid melting at 37° to 38°C, weighed 120 gramscorresponding to a 90% yield. Vacuum distillation of 115 grams of thismaterial at 74° to 80°C (16 mm) gave 108 grams of white solid melting at38° to 39°C corresponding to an 84.5% yield. Step 2: 2-Chloro-4-Amino-5-Fluoropyrimidine - To a solution of 10.0 grams(0.06 mol) of 2,4-dichloro-5-fluoropyrimidine in 100 ml of ethanol, 25 ml ofconcentrated aqueous ammonia were slowly added. A slightly opalescentsolution resulted. The temperature gradually rose to 35°C. The solution wasthen cooled in ice to 18°C and thereafter remained below 30°C. After threehours, a Volhard titration showed that 0.0545 mol of chlorine was present inionic form. Storage in a refrigerator overnight resulted in some crystallizationof ammonium chloride. A white sludge, resulting from the evaporation of thereaction mixture at 40°C, was slurried with 75 ml of water, filtered andwashed free of chloride. After drying in vacuo, the product melted at 196.5°to 197.5°C, yield 6.44 grams. Evaporation of the mother liquors yielded asecond crop of 0.38 gram, raising the total yield to 6.82 grams (79.3%). Step 3: 5-Fluorocytosine - A slurry of 34.0 grams (0.231 mol) of 2-chloro-4-amino-5-fluoropyrimidine in 231 ml of concentrated hydrochloric acid washeated in a water bath at 93° to 95°C for 125 minutes. The reaction wasfollowed by means of ultraviolet spectrophotometry using the absorption at245, 285, and 300 mμ as a guide. The absorption at 300 mμ rose to amaximum after 120 minutes and then dropped slightly. The clear solution wascooled to 25°C in an ice bath, then evaporated to dryness under vacuum at40°C. After slurrying with water three times and reevaporating, the residuewas dissolved in 100 milliliters of water. To this solution, cooled in ice, 29 mlof concentrated ammonia were added dropwise. The resulting precipitate wasfiltered, washed free of chloride with water, then with alcohol and ether. Afterdrying in vacuo at 65°C, the product weighed 22.3 grams. An additional 6.35grams was obtained by evaporation of the mother liquor, thus yielding a totalof 28.65 grams (96.0%). |
| Brand name | Ancobon (Valeant). |
| Therapeutic Function | Antifungal |
| Antimicrobial activity | The spectrum of activity is restricted to Candida spp., Cryptococcusspp. and some fungi causing chromoblastomycosis. |
| Acquired resistance | About 2–3 of Candida spp. isolates (more in some centers) areresistant before treatment starts, and resistance may developduring treatment. The most common cause of resistanceappears to be loss of the enzyme uridine monophosphatepyrophosphorylase. |
| Pharmaceutical Applications | A synthetic fluorinated pyrimidine available for intravenousinfusion or oral administration. |
| Biochem/physiol Actions | Nucleoside analog that has antifungal activities. 5-FC is deaminated by cytosine deaminase to product 5-fluorouracil, resulting in RNA miscoding. 5-Fluorocytosine inhibits DNA and RNA synthesis and interferes with ribosomal protein synthesis. |
| Mechanism of action | Flucytosine (5-flucytosine, 5-FC; Ancoban) is a fluorinated pyrimidine analogue of cytosine that was originally synthesized for possible use as an antineoplastic agent. It is indicated only for the treatment of serious systemic infections caused by susceptible strains of Candida and Cryptococcus spp.The mechanism of action of 5-fluorocytosine (5-FC)has been studied in detail.The drug enters the fungal cell by active transport onATPases that normally transport pyrimidines. Once insidethe cell, 5-fluorocytosine is deaminated in a reaction catalyzedby cytosine deaminase to yield 5-fluorouracil(5-FU). 5-Fluorouracil is the active metabolite of the drug.5-Fluorouracil enters into pathways of both ribonucleotideand deoxyribonucleotide synthesis. The fluororibonucleotidetriphosphates are incorporated into RNA, causingfaulty RNA synthesis. This pathway causes cell death. Inthe deoxyribonucleotide series, 5-fluorodeoxyuridinemonophosphate (F-dUMP) binds to 5,10-methylenetetrahydrofolicacid, interrupting the one-carbon pool substratethat feeds thymidylate synthesis. Hence, DNA synthesisis blocked. |
| Pharmacology | 5-FC is well absorbed orally, with greater than 90%bioavailability. The serum half-life is 3 to 5 hours, withserum levels peaking 4 to 6 hours after a single dose.Thedrug is widely distributed in body fluids, with cerebrospinalfluid levels 60 to 80% of serum levels.The drugalso penetrates well into urine, aqueous humor, andbronchial secretions.Minimal serum protein binding allowsmore than 90% of each dose to be excreted in theurine; significant dosage reductions are required in thepresence of renal impairment. 5-FC can be removed byboth hemodialysis and peritoneal dialysis. 5-FC conversionto toxic metabolites may occur in mammalian cellsto a limited extent, which accounts for 5-FC toxicity. |
| Pharmacokinetics | Oral absorption: Complete Cmax 25 mg/kg 6-hourly oral: 70–80 mg/L after 1–2 h Plasma half-life: 3–6 h Volume of distribution: 0.7–1 L/kg Plasma protein binding c. 12% Absorption is slower in persons with impaired renal function,but peak concentrations are higher. Levels in the CSFare around 75% of the simultaneous serum concentration.More than 90% of a dose of flucytosine is excreted in theurine in unchanged form. The serum half-life is much longerin renal failure, necessitating modification of the dosage regimen:for patients with a creatinine clearance below 40 mL/min the dosage interval should be doubled to 12 h; in severerenal failure the dosage interval should be further increased toonce daily or less, based on frequent serum drug concentrationmeasurements. |
| Clinical Use | Flucytosine has significant antifungal activity againstC. albicans, other Candida spp., C. neoformans, and thefungal organisms responsible for chromomycosis. Notconsidered the drug of choice for these fungal infections,5-FC does remain useful as part of combinationtherapy for systemic candidiasis and cryptococcalmeningitis and as an alternative drug for chromomycosis.When it is used as monotherapy, resistance andclinical failure are common. Potential mechanisms fordrug resistance include decreased fungal cell membranepermeability and reduced levels of fungalcytosine deaminase. Combination therapy with amphotericinB and flucytosine in the treatment ofcryptococcal meningitis and deep-seated Candida infections,such as septic arthritis and meningitis, permitsreduced dosing of amphotericin B and prevents theemergence of 5-FC resistance. When higher doses ofamphotericin B are used, combination therapy with5-FC confers no additional clinical benefit except inthe treatment of Candida endophthalmitis, where tissuepenetration remains problematic. |
| Clinical Use | Candidosis (in combination with amphotericin B or fluconazole) Cryptococcosis (in combination with amphotericin B or fluconazole) Monitoring of flucytosine concentrations is desirable in allpatients, and mandatory in those with renal impairment. |
| Side effects | Nausea, vomiting, abdominal pain and diarrhea are common.Serious side effects include myelosuppression and hepatictoxicity; they occur more frequently when serum concentrationsexceed 100 mg/L. The nephrotoxic effects of amphotericin B can result inelevated blood concentrations of flucytosine, and levels of thelatter drug should be monitored when these compounds areadministered together. When 5-FC is prescribed alone to patients with normal renal function, skin rash, epigastric distress, diarrhea, and liver enzyme elevations can occur. |
| Synthesis | Flucytosine, 5-fluorocytosine (35.4.4), is synthesized from fluorouracil (30.1.3.3). Fluorouracil is reacted with phosphorous oxychloride in dimethylaniline to make 2,4-dichloro-5-fluoropyrimidine (35.4.2), which is reacted with ammonia to make a product substituted with chlorine at the fourth position of the pyrimidine ring—4-amino- 2-chloro-5-fluoropyrimidine (35.4.3). Hydrolysis of the chlorovinyl fragment of this compound in a solution of hydrochloric acid gives the desired flucytosine. An alternative way of synthesis consists of making flucytosine from a precursor of fluorouracil—5-fluoro-2-methylthiouracil (30.1.3.2) using a somewhat analogous scheme. Treating 5-fluoro-2-methylthiouracil (30.1.3.2) with phosphorous pentachloride gives 4-chloro-5-fluoro-2-methylthiopyrimidine (35.4.5), which upon being reacted with ammonium is transformed into 4-amino-5-fluoro-2-methylthiopyrimidine (35.4.6). Hydrolysis of the methylthiovinyl fragment using concentrated hydrobromic acid gives the desired flucytosine. |
| Drug interactions | Potentially hazardous interactions with other drugs Cytarabine: concentration of flucytosine possibly reduced. |
| Metabolism | Flucytosine itself is not cytotoxic but, rather, is a pro-drug that is taken up by fungi and metabolized to 5-fluorouracil (5-FU) by fungal cytidine deaminase. Then, 5-FU is converted to 5-fluorodeoxyuridine, which as a thymidylate synthase inhibitor interferes with both protein and RNA biosynthesis. 5-Fluorouracil is cytotoxic and is employed in cancer chemotherapy. Human cells do not contain cytosine deaminase and, therefore, do not convert flucytosine to 5-FU. Some intestinal flora, however, do convert the drug to 5-FU, so human toxicity does result from this metabolism. |
| References | [1] Patent: CN104326990, 2016, B. Location in patent: Paragraph 0042-0043 [2] Patent: CN106432099, 2017, A. Location in patent: Paragraph 0028-0031; 0047-0051 [3] Patent: WO2016/30662, 2016, A1. Location in patent: Paragraph 00251 [4] Patent: CN107089952, 2017, A. Location in patent: Paragraph 0036; 0037; 0038; 0039; 0040; 0041; 0042; 0043 |
5-Fluorocytosine Preparation Products And Raw materials
| Raw materials | Phosphorus oxitrichloride-->N-Methylaniline-->5-Fluorouracil-->4-Amino-2-chloro-5-fluoropyrimidine-->2,4-Dichloro-5-fluoropyrimidine-->5-FLUORO-4-HYDROXY-2-METHOXYPYRIMIDINE-->Phosphorus oxychloride-->2-Methoxy-5-fluoro-4-aminopyrimidine-->2,5-difluoro-4-chloro-pyrimidine-->Cytosine |
| Preparation Products | 2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine |
