Zalcitabine
- Iupac Name：4-amino-1-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
- CAS No.: 7481-89-2
- Molecular Weight：211.21782
- Modify Date.: 2022-11-10 22:46
- Introduction: Zalcitabine is an orally active dideoxynucleoside andog for combination use withzidovudine in advanced HIV infection and also as monotherapy for AIDS patients whocannot tolerate or have not responded to zidovudine. It has a similar mechanism ofaction (inhibition of reverse transcriptase) to didanosine. Like didanosine, its side effect profile includes peripheral neuropathy. Unlikezidovudine, zalcitabine does not cause bone marrow suppression.
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1. Names and Identifiers
- 1.1 Name
- Zalcitabine
- 1.2 Synonyms
[3H]-Zalcitabine 1-(2',3'-DIDEOXY-BETA-RIBOFURANOSYL)CYTOSINE 1-[(2R,5S)-5-(Hydroxymethyl)tetrahydro-2-furanyl]-4-imino-1,4-dihydro-2-pyrimidinol 2(1H)-Pyrimidinone, 4-amino-1-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furanyl]- 2',3'-DIDEOXYCYTIDINE 2'',3''-DIDEOXYCYTIDINE(ZALCITABINE) 2',3'-Dideoxycytidinene 2',3'-Dideoxy-D-cytidine 2-Pyrimidinol, 1,4-dihydro-4-imino-1-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furanyl]- 3'-Azido-3'-deoxythymidine 4-AMINO-1-[(2R,5S)-5-(HYDROXYMETHYL)OXOLAN-2-YL]PYRIMIDIN-2-ONE 4-Amino-1-[(2R,5S)-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone 4-Amino-1-[(2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin-2(1H)-on 4-Amino-1-[(2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin-2(1H)-one 4-amino-1-[(2R,5S)-5-(hydroxyméthyl)tétrahydrofuran-2-yl]pyrimidin-2(1H)-one CYTIDINE, 2',3'-DIDEOXY- Cytidine, 2',3'-dideoxy- (8CI, 9CI) Cytidine,2',3'-dideoxy D 2C DDC ddC (Antiviral) DDC (VAN) ddCyd Dideoxycytidine HIVID MFCD00012188 Zalcitibine
- 1.3 CAS No.
- 7481-89-2
- 1.4 CID
- 24066
- 1.5 EINECS(EC#)
- 620-762-3
- 1.6 Molecular Formula
- C9H13N3O3 (isomer)
- 1.7 Inchi
- InChI=1S/C9H13N3O3/c10-7-3-4-12(9(14)11-7)8-2-1-6(5-13)15-8/h3-4,6,8,13H,1-2,5H2,(H2,10,11,14)/t6-,8+/m0/s1
- 1.8 InChkey
- WREGKURFCTUGRC-POYBYMJQSA-N
- 1.9 Canonical Smiles
- C1CC(OC1CO)N2C=CC(=NC2=O)N
- 1.10 Isomers Smiles
- C1C[C@@H](O[C@@H]1CO)N2C=CC(=NC2=O)N
2. Properties
- 2.1 Density
- 1.57
- 2.1 Melting point
- 210-214℃
- 2.1 Boiling point
- 415 oC at 760 mmHg
- 2.1 Refractive index
- 78 ° (C=0.5, H2O)
- 2.1 Flash Point
- 204.8 oC
- 2.1 Precise Quality
- 211.09600
- 2.1 PSA
- 90.37000
- 2.1 logP
- 0.07660
- 2.1 Solubility
- 5-10 g/100 mL at 19 ºC
- 2.2 Appearance
- white to off-white crystalline powder
- 2.3 Storage
- Keep Cold.
- 2.4 Chemical Properties
- White to Off-White Cyrstalline Powder
- 2.5 Color/Form
- Crystals from ethanol and benzene
White to off-white powder
- 2.6 pKa
- 14.44±0.10(Predicted)
- 2.7 Water Solubility
- 5-10 g/100 mL at 19 oC
- 2.8 Spectral Properties
- UV max = 280 nm (epsilon=17720) 0.1N HCl; UV max = 280 nm (epsilon=8410) 0.1N NaOH
- 2.9 Stability
- Stable. Combustible. Incompatible with strong oxidizing agents.
- 2.10 StorageTemp
- Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
3. Use and Manufacturing
- 3.1 Definition
- ChEBI: A pyrimidine 2',3'-dideoxyribonucleoside compound having cytosine as the nucleobase.
- 3.2 General Description
- Zalcitabine, 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.
- 3.3 Usage
- ammonia detoxicant, diagnostic aid
4. Safety and Handling
- 4.1 Symbol
- GHS08
- 4.1 Hazard Codes
- Xn
- 4.1 Signal Word
- Warning
- 4.1 Risk Statements
- R40
- 4.1 Safety Statements
- S22;S36
- 4.1 Exposure Standards and Regulations
- The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl zalcitabine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
- 4.2 Octanol/Water Partition Coefficient
- log Kow = -1.30
- 4.3 Fire Hazard
- Flash point data for Zalcitabine are not available; however, Zalcitabine is probably combustible.
- 4.4 Other Preventative Measures
- PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological & cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer & hood should be devised before expt begun. When mixing diets, special protective clothing &, possibly, respirators may be required. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms & sides & fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, & monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type & amt of carcinogen & efficiency with which it can be removed. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors & benches, & ... interior of fume hoods & airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple & sensitive. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing & use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency & who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/
- 4.5 Hazard Declaration
- H351
- 4.5 Cleanup Methods
- PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/
- 4.6 DisposalMethods
- SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.
PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/
- 4.7 RIDADR
- OTH
- 4.7 Caution Statement
- P280
- 4.7 Formulations/Preparations
- Oral: Tablets, film-coated: 0.375 mg, HIVID, Roche, 0.75 mg, HIVID, Roche
- 4.8 WGK Germany
- 3
- 4.8 RTECS
- HA3870000
- 4.8 Safety
-
An experimental teratogen. Experimental reproductive effects. Mutation data reported.
The Hazard Codes of? Zalcitabine (7481-89-2): Xn?? 
The Risk Statements information of Zalcitabine (7481-89-2): 63
R63:Possible risk of harm to the unborn child.
The Safety Statements information of Zalcitabine (7481-89-2):?22-36/37
S22:Do not inhale dust;
S36/37:Wear suitable protective clothing and gloves.
?
- 4.9 Specification
-
?Zalcitabine's? first aid measures and others should be known. Such as: When on the skin: Immediately flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop.Secondly, get medical aid. Or in the eyes: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. Then get medical aid soon. While, it's inhaled:?Immediately leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used.?Then you have the ingesting of the product : If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and?immediatelty call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician.?
- 4.10 Toxicity
-
| 1. |
??? |
dni-hmn:lym 200?nmol/L
|
??? |
MOPMA3 ?? Molecular Pharmacology. 39 (1991),625. |
| 2. |
??? |
cyt-mus-orl 600?mg/kg/3D-C
|
??? |
EMMUEG ?? Environmental and Molecular Mutagenesis. 18 (1991),168. |
5. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
Carcinogenicity, Category 2
2.2 GHS label elements, including precautionary statements
| Pictogram(s) |  |
| Signal word | Warning |
| Hazard statement(s) | H351 Suspected of causing cancer |
| Precautionary statement(s) | |
| Prevention | P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P280 Wear protective gloves/protective clothing/eye protection/face protection. |
| Response | P308+P313 IF exposed or concerned: Get medical advice/ attention. |
| Storage | P405 Store locked up. |
| Disposal | P501 Dispose of contents/container to ... |
2.3 Other hazards which do not result in classification
none
6. Synthesis Route
7481-89-2Total: 69 Synthesis Route
8. Other Information
- 8.0 Merck
- 14,10109
- 8.1 BRN
- 654956
- 8.2 Target
- Value
- 8.3 Description
- Zalcitabine 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.
- 8.4 Description
- Zalcitabine is an analog of pyrimidine derived from deoxycytidine with the replacement of the hydroxyl group in position 3’ with a hydrogen.1 In cells, it is phosphorylated to the active triphosphate form, ddCTP, which acts as a substrate for HIV reverse transcriptase (Ki = 51 nM).2,3 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.4
- 8.5 Chemical Properties
- White to Off-White Cyrstalline Powder
- 8.6 Originator
- National Cancer Institute (NIH) (U.S.A.)
- 8.7 Uses
- ammonia detoxicant, diagnostic aid
- 8.8 Uses
- A pyrimidine nucleoside analogue with antiviral activity
- 8.9 Definition
- ChEBI: A pyrimidine 2',3'-dideoxyribonucleoside compound having cytosine as the nucleobase.
- 8.10 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.
- 8.11 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.
- 8.12 Brand name
- Hivid (Roche).
- 8.13 Therapeutic Function
- Antiviral, Immunosuppressive
- 8.14 General Description
- Zalcitabine, 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.
- 8.15 General Description
- White crystalline powder. Odorless.
- 8.16 Air & Water Reactions
- Water soluble.
- 8.17 Reactivity Profile
- Zalcitabine may be sensitive to prolonged exposure to light.
- 8.18 Fire Hazard
- Flash point data for Zalcitabine are not available; however, Zalcitabine is probably combustible.
- 8.19 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.
- 8.20 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.
- 8.21 Side effects
- It has side effects, such as stomatitis, rash, fever, malaise, arthritis, and arthralgia.
- 8.22 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."
- 8.23 Usage
- 2',3'-Dideoxycytidine 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. It is also is used as a DNA chain-terminating nucleotide for DNA sequencing methods based on the Sanger chain-termination method.
9. Computational chemical data
- Molecular Weight: 211.21782g/mol
- Molecular Formula: C9H13N3O3
- Compound Is Canonicalized: True
- XLogP3-AA: null
- Exact Mass: 211.09569129
- Monoisotopic Mass: 211.09569129
- Complexity: 327
- Rotatable Bond Count: 2
- Hydrogen Bond Donor Count: 2
- Hydrogen Bond Acceptor Count: 3
- Topological Polar Surface Area: 88.2
- Heavy Atom Count: 15
- Defined Atom Stereocenter Count: 2
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADccBzMAAAAAAAAAAAAAAAAAAAASAAAAAgAAAAAAAAAAAAAAAAHgAQCAAACBThgAYBAANABgCoACJmdACAAAEAAgAIAAAYABCBEAIAgAAOQAAEFgIDAACwMAIAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==
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ddC
- Purity:99%Packing: 200kg/bag FOB
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- Time: 2023/05/31
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