Zalcitabine

Zalcitabine Basic information
Product Name:Zalcitabine
Synonyms:4-AMINO-1-[(2R,5S)-5-(HYDROXYMETHYL)OXOLAN-2-YL]PYRIMIDIN-2-ONE;2',3'-DIDEOXYCYTIDINE;ZALCITABINE;1-(2',3'-DIDEOXY-BETA-RIBOFURANOSYL)CYTOSINE;2',3'-Dideoxy-D-cytidine;2'',3''-DIDEOXYCYTIDINE(ZALCITABINE);Cytidine, 2',3'-dideoxy- (8CI, 9CI);D 2C
CAS:7481-89-2
MF:C9H13N3O3
MW:211.22
EINECS:620-762-3
Product Categories:Antivirals for Research and Experimental Use;Biochemistry;Chemical Reagents for Pharmacology Research;Nucleosides and their analogs;Nucleosides, Nucleotides & Related Reagents;Bases & Related Reagents;Pharmaceutical Raw Materials;Miscellaneous Biochemicals;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Other APIs;Inhibitors
Mol File:7481-89-2.mol
Zalcitabine Structure
Zalcitabine Chemical Properties
Melting point 217-218 °C(lit.)
alpha D25 +81° (c = 0.635 in water)
Boiling point 350.9°C (rough estimate)
density 1.2605 (rough estimate)
refractive index 78 ° (C=0.5, H2O)
storage temp. Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
solubility DMSO (Slightly, Heated), Methanol (Slightly), Water (Slightly, Sonicated)
form powder
pka14.44±0.10(Predicted)
color colorless
Water Solubility 5-10 g/100 mL at 19 ºC
Merck 14,10109
BRN 654956
Stability:Stable. Combustible. Incompatible with strong oxidizing agents.
InChIKeyWREGKURFCTUGRC-POYBYMJQSA-N
CAS DataBase Reference7481-89-2(CAS DataBase Reference)
IARC2B (Vol. 76) 2000
EPA Substance Registry SystemCytidine, 2',3'-dideoxy- (7481-89-2)
Safety Information
Hazard Codes Xn,C
Risk Statements 40-36/37-34
Safety Statements 22-36-45-36/37/39-27-26
WGK Germany 3
RTECS HA3870000
10-23
HS Code 2934990002
Hazardous Substances Data7481-89-2(Hazardous Substances Data)
MSDS Information
ProviderLanguage
DDC English
SigmaAldrich English
ALFA English
Zalcitabine Usage And Synthesis
DescriptionZalcitabine is an orally active dideoxynucleoside andog for combination use with zidovudine in advanced HIV infection and also as monotherapy for AIDS patients who cannot tolerate or have not responded to zidovudine. It has a similar mechanism of action (inhibition of reverse transcriptase) to didanosine. Like didanosine, its side effect profile includes peripheral neuropathy. Unlike zidovudine, zalcitabine does not cause bone marrow suppression.
DescriptionZalcitabine is an analog of pyrimidine derived from deoxycytidine with the replacement of the hydroxyl group in position 3’ with a hydrogen. In cells, it is phosphorylated to the active triphosphate form, ddCTP, which acts as a substrate for HIV reverse transcriptase (Ki = 51 nM). It incorporates into viral DNA where it terminates chain elongation when the missing hydroxyl group is encountered. Zalcitabine was the third antiretroviral approved by the FDA for treatment of HIV infection and AIDS.
Chemical PropertiesWhite to Off-White Cyrstalline Powder
OriginatorNational Cancer Institute (NIH) (U.S.A.)
Usesammonia detoxicant, diagnostic aid
UsesA pyrimidine nucleoside analogue with antiviral activity.
DefinitionChEBI: A pyrimidine 2',3'-dideoxyribonucleoside compound having cytosine as the nucleobase.
IndicationsZalcitabine (ddC, Hivid) is a cytidine analogue active against HIV-1, HIV-2, and hepatitis B virus. It is used for the treatment of HIV infection in adults and asymptomatic children as part of a multidrug regimen. It may be less effective than the other nucleoside inhibitors and is used less frequently.
Manufacturing ProcessBromoacetylation of N-acetylcytidine with 2-acetoxy-2-methylpropanoyl bromide
A 5 L three-nicked, round-bottomed flask equipped with a mechanical stirrer, thermometer, nitrogen inlet tube, and additional funnel was charge with 142.6 g (0.5 mole) of N-acetylcytidine, and 1.25 L of acetonitrile. The suspension was stirred under nitrogen, cooled to 5°C (ice-bath), and treated dropwise (during 20 min) with 225 ml of 2-acetoxy-2-methylpropanoyl bromide (AIBB) during 30 minutes. At the completion of the addition, a homogeneous solution resulted. It was stirred at room temperature overnight (the reaction was complete within 3 hr), cooled to 5°C, and diluted with 1.25 L of ethyl acetate. After recooling to 5°C, 2.0 L of saturated sodium bicarbonate was added. The mixture was stirred for 5 minutes, the organic phase was separated, and the aqueous phase was back-extracted with 500 ml of ethyl acetate. The combined organic extracts were washed with 1 L of saturated brine, dried (MgSO 4 ), and evaporated to give a gum. Final drying at 40°C (1 mm) for 1 hrgave 264.7 g (102%) of a white solid. High pressure liquid chromatographic analysis gave the following results (major peaks only): 40% of [2R- [2α,3β,4α,5α(S*)]]-N-[1-[3-(acetyloxy)-5-[(2-(acetyloxy)-1-oxopropoxy] methyl]-4-bromotetrahydro-2-furanyl]-1,2-dihydro-2-oxo-4-pyrimidinyl] acetamide (a) and 24% of its regioisomer (b).
Preparation of [2R-[2α,3β,4α,5α(S*)]]-N-[1-[3-(acetyloxy)-5-[(2-(acetyloxy)- 1-oxopropoxy]methyl]-4-bromotetrahydro-2-furanyl]-1,2-dihydro-2-oxo-4- pyrimidinyl]acetamide (a) and its regioisomer (b).
A 1-L, three-necked, round-bottomed flask equipped with a mechanical stirrer and argon inlet was charged with 28.52 g of N-acetylcytidine in 250 ml of acetonitrile. The mixture was cooled to 10°C and treated with 48.75 g of (S)- (-)-2-acetoxypropionyl bromide during 15 minutes. It was stirred at room temperature overnight, cooled to 10°C, treated with 400 ml of cold (0°C) saturated sodium bicarbonate, and extracted with 250 ml of ethyl acetate. The extract was washed with 200 ml of saturated brine, dried (MgSO 4 ) and evaporated to give 45.45 g of a white foam. Reversed phase chromatography (C 18 column) with 40% methanol in water gave a pure sample of (a).
Zinc-copper couple was prepared by the next way:
A 12 L three-necked, round-bottomed flask equipped with a mechanical stirrer was charged with 4.50 kg of zinc dust. The zinc dust was washed with 3.75 L of 3% aqueous hydrochloric acid by stirring for 3 to 5 minutes. The hydrochloric acid was decanted from the solid. This cycle was repeated with 3x3.75 L of 3% hydrochloric acid. The reaction was slightly exothermic and the volume of the zinc dust increased to double its original volume. The zinc dust was then washed with 4x3.0 L of deionized water to remove any residual hydrochloric acid. After all the water was decanted, the spongy zinc layer was treated with a solution made by dissolving 240.0 g of cupric sulfate dihydrate in 7.5 L of deionized water. The suspension was stirred rapidly as the solution was added. The aquamarine color of the cupric sulfate solution was removed almost immediately and the zinc suspension changed in color from gray to black. The near colorless aqueous layer was decanted and the solid was washed with 4x3.0 L of deionized water. The suspension of zinc-copper couple was filtered through a piece of Whatman No. 1 filter paper, then washed with 4x30 L ethanol and 3x3.0 L of ether. The solid was carefully dried at 25°C and 140 mm overnight to remove ether, then for 3 hr at 130°-140°C (0.5 mm). The solid was cooled to room temperature under vacuum and was stored under argon in amber bottles. The procedure yielded 3.84 kg of zinc-copper couple.
Preparation of [2R-[2α,5α(S*)]]-N-[1-[5-[[2-(acetyloxy)-1-oxopropoxy] methyl]-2-5-dihydro-2-furanyl]-1,2-dihydro-2-oxo-4-pyrimidinyl]acetamide.
A total of 1.47 g of a mixture of bromoacetates in acetonitril was reduced with 800 mg of zinc-copper couple. The mixture was stirred under argon at room temperature overnight. The mixture was deoxygenated by evacuation followed by filling the reaction vessel with argon (oxygen-free nitrogen may be used); this procedure was repeated three times. It was filtered over Celite, the flask was rinsed out with of acetonitrile, and the rinse was used to wash the Celite. The combined filtrate and washing were evaporated (40°C), and the residue was dissolved in of methylene chloride. This was added to a previously prepared solution of ethylenediaminetetraacetic acid disodium salt dihydrate (Fluka) in deionized water containing of sodium bicarbonate. The mixture was stirred vigorously for 1.5 hr, and filtered over Celite, which was washed with methylene chloride. The organic phase was separated and the aqueous phase was re-extracted with of methylene chloride. The combined organic was washed with of saturated sodium bicarbonate, which was back-extracted with of methylene chloride. The combined organic was dried (MgSO 4 ), filtered, and concentrated. To this was added of acetic anhydride followed by 40 g of poly- 4-vinylpyridine, and the mixture was stirred under nitrogen for 3 hr. It was filtered over Celite, which was washed with methylene chloride. The combined filtrate and washing were evaporated, toluene was added, and the mixture was evaporated again, ether was added with vigorous stirring for 15 minutes. The mixture was filtered (some scraping of the flask was necessary) and washed with ether to give 570 mg of after crystallization from hot tetrahydrofuran, melting point 125°C; [α] D 25 +119.04°(c=0.25, CHCl 3 ).
Preparation of [2R-[2α,5α(S*)]]-N-[1-[5-[[2-(acetyloxy)-1-oxopropoxy] methyl]tetrahydro-2-furanyl]-1,2-dihydro-2-oxo-4-pyrimidinyl]acetamide.
A solution of 720 mg of 2R-[2α,5α(S*)]]-N-[1-[5-[[2-(acetyloxy)-1- oxopropoxy]methyl]-2-5-dihydro-2-furanyl]-1,2-dihydro-2-oxo-4- pyrimidinyl]acetamide set forth in 10 ml L of methanol and 10 ml of tetrahydrofuran was hydrogenated over 200 mg of 10% palladium on charcoal at room temperature and atmospheric pressure until hydrogen uptake ceased (10 ml). The mixture was filtered over Celite and the filtrate was evaporated to give a gum. Chromatography on 10 g of silica (70-230 mesh) with 10% methanol in methylene chloride, gave 290 mg of the product as a foam, [α] D 25 +88.43° (C=0.99, CHCl 3 ).
Preparation of 2',3'-dideoxycytidine.
A solution of 20.7 g of [2R-[2α,5α(S*)]]-N-[1-[5-[[2-(acetyloxy)-1- oxopropoxy]methyl]tetrahydro-2-furanyl]-1,2-dihydro-2-oxo-4-pyrimidinyl] acetamide in 100 ml of ethanol was treated with 10.0 ml of Triton B (N- benzyltrimethyl-ammonium hydroxide), and the mixture was stirred at room temperature overnight. The mixture was concentrated to 20 ml, cooled to 0°C, and the product was collected by filtration. It was washed with 10 ml of cold ethanol to give 4.48 g of 2',3'-dideoxycytidine, melting point 215°-218°C, as an white solid.
Brand nameHivid (Roche).
Therapeutic FunctionAntiviral, Immunosuppressive
General DescriptionZalcitabine, 2',3'-dideoxycytidine or ddCyd, is an analog ofcytosine that demonstrates activity against HIV-1 and HIV-2,including strains resistant to AZT. The potency (in peripheralblood mononuclear cells) is similar to that of AZT, but thedrug is more active in populations of monocytes andmacrophages as well as in resting cells.
The oral bioavailability of zalcitabine is over 80% in adultsand less in children.The major dose-limiting side effect isperipheral neuropathy, characterized by pain, paresthesias,and hypesthesia, beginning in the distal lower extremities.These side effects are typically evident after several months oftherapy with zalcitabine. A potentially fatal pancreatitis is anothertoxic effect of treatment with ddC. The drug has beenapproved for the treatment of HIV infection in adults with advanceddisease who are intolerant to AZT or who have diseaseprogression while receiving AZT. ddC is combined with AZTfor the treatment of advanced HIV infection.
General DescriptionWhite crystalline powder. Odorless.
Air & Water ReactionsWater soluble.
Reactivity ProfileZalcitabine may be sensitive to prolonged exposure to light.
Fire HazardFlash point data for Zalcitabine are not available; however, Zalcitabine is probably combustible.
PharmacokineticsZalcitabine (ddC) is a useful alternate drug to ZDV and is given in combination with ZDV when CD4 cell counts fall to less than 300 cells/mm3 . Monotherapy with ddC is more active than ZDV. Its oral bioavailability is 87%, and its plasma half-life is approximately 1 hour. In low doses (0.005 mg/kg every 4 hours), ddC produces sustained decrease in p24 antigen level and increase in CD4 cell counts. The CSF fluid/plasma ratio of ddC is 0.2. Following oral administration, bioavailability of ddC is less than 80%, which is further reduced when taken with food. The mean maximum plasma concentration of the drug also is reduced from 25.2 to 15.5 ng/mL when the drug was taken with food.
PharmacologyPeripheral neuropathy occurs in up to 50% of patients taking zalcitabine. Stomatitis, esophageal ulceration, hepatotoxicity, rash, and pancreatitis may occur. Zalcitabine should be used with caution in individuals with a history of pancreatitis, liver disease, or alcohol abuse. Dosage adjustment is necessary for individuals with renal impairment. Zalcitabine should not be used in combination with didanosine, lamivudine, or stavudine.
Side effectsIt has side effects, such as stomatitis, rash, fever, malaise, arthritis, and arthralgia.
MetabolismDideoxyuridine is the major metabolite in urine and feces. The drug penetrates the blood-brain barrier. The major toxicity of ddC is peripheral neuropathy, in which case it should be discontinued. In some cases, pancreatitis occurs when given alone or in combination with ZDV."
DNA, SINGLE STRANDED, IMM. ON CELLULOSE, FROM CALF THYMUS* Dideoxyinosine Cytidine-5'-triphosphate disodium salt dihydrate N4-Acetylcytidine Citiolone Deoxynucleotide 1-beta-D-Arabinofuranosylcytosine hydrochloride Zalcitabine Floxuridine Neosperidin dihydrochalcone Cytosine 5-Azacytidine (+)-3',5'-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)cytidine Deoxidizer Cytarabine Fluorocytosine Cytidine 5-Fluorocytidine

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