7481-89-2

Usage

Uses

Used in Pharmaceutical Industry:
Zalcitabine is used as an antiviral agent for the treatment of advanced HIV infection and AIDS. It is used in combination with zidovudine or as monotherapy for patients who cannot tolerate or have not responded to zidovudine. Its mechanism of action involves the inhibition of reverse transcriptase, similar to didanosine, and it is effective in terminating viral DNA chain elongation.
Used as an Ammonia Detoxicant:
In some applications, Zalcitabine is used as an ammonia detoxicant, helping to reduce the levels of ammonia in the body, which can be beneficial in certain medical conditions.
Used as a Diagnostic Aid:
Zalcitabine can also be used as a diagnostic aid in medical procedures, assisting in the identification and assessment of specific conditions or responses to treatment.

Originator

National Cancer Institute (NIH) (U.S.A.)

Indications

Zalcitabine (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 Process

Bromoacetylation 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.

Therapeutic Function

Antiviral, Immunosuppressive

Air & Water Reactions

Water soluble.

Reactivity Profile

Zalcitabine may be sensitive to prolonged exposure to light.

Fire Hazard

Flash point data for Zalcitabine are not available; however, Zalcitabine is probably combustible.

Pharmacokinetics

Zalcitabine (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.

Pharmacology

Peripheral 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 effects

It has side effects, such as stomatitis, rash, fever, malaise, arthritis, and arthralgia.

Metabolism

Dideoxyuridine 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."

Upstream product

• 3416-05-5 3'-Deoxythymidine 
• 65-46-3 CYTIDINE 
• 32780-06-6 (5S)-5-(hydroxymethyl)-2-oxo-tetrahydrofuran 
• 5983-09-5 2',3'-Dideoxyuridine 

Downstream Products

• 5983-09-5 2',3'-Dideoxyuridine 
• 130006-19-8 5',4N-bis<(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl>-2',3'-dideoxycytidine 
• 120885-60-1 N⁴-benzoyl-2',3'-dideoxycytidine 
• 170164-18-8 5'-<(tert-butyldiphenyl)silyl>-N⁴-suberyl-2',3'-dideoxycytidine 
• 170164-17-7 5'-<(tert-butyldiphenyl)silyl>-N⁴-adipyl-2',3'-dideoxycytidine 
• 170164-16-6 5'-<(tert-butyldiphenyl)silyl>-N⁴-succinyl-2',3'-dideoxycytidine 
• 129533-24-0 2,2-Dimethyl-propionic acid (2S,5R)-5-(4-benzyloxycarbonylamino-2-oxo-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethoxymethyl ester 
• 120885-73-6 Carbonic acid (2S,5R)-5-(4-benzyloxycarbonylamino-2-oxo-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl ester ethyl ester 
• 120885-64-5 [1-((2R,5S)-5-Hydroxymethyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-carbamic acid benzyl ester 
• 143840-02-2 5'-<(tert-butyldiphenyl)silyl>-2',3'-dideoxycytidine 
• 107036-57-7 2',3'-dideoxy-5-bromocytidine 
• 114748-57-1 5-iodo-2',3'-dideoxycytidine 
• 139300-67-7 Oxalic acid (2S,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl ester 4-nitro-phenyl ester 

Relevant academic research and scientific papers

Lactobacillus Fermentum N-Desoxyribosyl Transferases and the Use Thereof for Enzymatic Synthesis of 2', 3' - Didesoxynucleosides and 2',3'- Didehydro-2',3'- Didesoxynucleosides

The inventive method for evaluating an X protein encoded by an Lactobacillus fermentum (L. fermentum ) ntd gene in such a way that the characteristics thereof are modified consists a) in obtaining the Lactobacillus fermentum (L. fermentum ) ntd gene mutants by random mutagenesis, b) in transforming cells containing a [P-] phenotype provided with vectors containing mutated nucleic acids obtained at the stage a) coding for the thus modified X* proteins, wherein P- means that said cells are auxotrophic for a substance P produced by the action of X on a natural substrate S, c) in culturing said cells in a medium comprising a substrate S*, wherein S* is an analog to the natural substrate S of the protein X and d) in selecting the cells [P-::X*] which survived at the stage c) and ijn which the proteins X* are capable of carrying out the biosynthesis of the product P based on the substrate S*. The mutated L. fermentum N-desoxyribosyl transferases have an N-didesoxyribosyl transferase activity, corresponding nucleic acids, expression vectors, host cells containing said vectors and an application for the enzymatic synthesis of 2′,3′-didesoxynucleosides and 2′,3′-didehydro-2′,3′-didesoxynucleosides.

Expeditious syntheses of sugar-modified nucleosides and collections thereof exploiting furan-, pyrrole-, and thiophene-based siloxy dienes

A series of individual sugar-modified pyrimidine nucleosides including enantiomerically enriched 2',3'-dideoxynucleosides 14a-c (α and β anomers of L- and D-series), 2',3'-dideoxy-4'-thionucleosides 21a-c (α and β anomers of L- and D-series), and 2',3'-dideoxy-4'-azanucleosides 28a-c (β anomers of L- and D-series) were synthesized, with uniform chemistry and high stereochemical efficiency, exploiting a triad of versatile heterocyclic siloxy dienes, namely, 2-(tert-butyldimethylsiloxy)furan (TBSOF), 2-(tert- butyldimethylsiloxy)thiophene (TBSOT), and N-(tert-butoxycarbonyl)-2-(tert- butyldimethylsiloxy)pyrrole (TBSOP). The synthetic procedure advantageously used both enantiomers of glyceraldehyde acetonide (D-1 and L-1) as sources of chirality and as synthetic equivalents of the formyl cation. The outlined chemistry also allowed for the rapid assemblage of a 30-member collection of racemic nucleosides (D,L-L) as well as one 15-member ensemble of chiral analogues (L-L), along with some related sublibraries.

A Highly Stereoselective Synthesis of Anti-HIV 2',3'-Dideoxy- and 2',3'-Didehydro-2',3'-dideoxynucleosides

A general total synthesic method for the stereocontrolled synthesis of 2',3'-dideoxy- as well as 2',3'-didehydro-2',3'-dideoxynucleosides is presented.Introduction of an α-phenylselenenyl group at the 2-position of 2,3-dideoxyribosyl acetate directs the glycosyl bond formation to give >/=95percent β-isomer.This 2'-phenylselenenyl nucleoside may be converted to either the 2',3'-dideoxynucleoside by treatment with n-Bu3SnH and Et3B at room temperature or to the unsaturated derivative by treatment with H2O2/cat. pyridine.The application of this method to the syntheses of pyrimidines (ddU, ddT, ddC), 6-substituted purines (ddA, ddI, 6-chloro-ddP, N6-Me-ddA), and 2,6-disubstituted purines (2-F-ddA, 6-chloro-2-amino-ddP) as well as selected 2',3'-didehydro-2',3'-dideoxy derivatives is reported.

Synthesis of the Dideoxynucleosides ddC and CNT from Glutamic Acid, Ribonolactone, and Pyrimidine Bases

2,3-Dideoxyribose in suitably protected form was prepared from glutamic acid and coupled with silylated cytosine to give a mixture of the α-and β-anomers of 2',3'-dideoxycitidine.The anomer ratio depended on the Lewis acid used in the coupling, with EtAlCl2 favoring the β-anomer ddC, a potent anti-HIV drug.Conjugate addition of cyanide to a 4-butenolide prepared from D-ribonolactone gave a mixture of (racemic) α- and β-3-cyanobutyrolactones.Both isomers were reduced to lactols and coupled with thymine to give α/β-anomer pairs.The α-cyano lactone, the struct ure of which was established by X-ray crystallography, afforded an authentic sample of the putative (but in fact inactive) anti-HIV substance known in AIDS research as CNT.