97-77-8

Basic information

• Product Name: Disulfiram
• Synonyms: ethylthiudad;ethyltuex;Etyl Tuex;Exhoran;Exhorran;Formamide, 1,1'-dithiobis(N,N-diethylthio)-;Hoca;Hocakrotenalnci-C02959
• CAS NO: 97-77-8
• Molecular Formula: C₁₀H₂₀N₂S₄
• Molecular Weight: 296.54
• EINECS: 202-607-8
• Product Categories: Miscellaneous Emzyme;Aliphatics;Amines;Sulfur & Selenium Compounds;Antabuse, Antabus;Other APIs
• Mol File: 97-77-8.mol
• Article Data: 52

Chemical Properties

• Melting Point: 69-71 °C(lit.)
• Boiling Point: 117°C
• Flash Point: 117°C/17mm
• Appearance: Light yellow/Crystals, Crystalline Powder or Granules
• Density: 1.27
• Vapor Pressure: 0Pa at 25℃
• Refractive Index: 1.5500 (estimate)
• Storage Temp.: Store at +4°C
• Solubility: 0.004g/l
• PKA: 0.86±0.50(Predicted)
• Water Solubility: 0.02 g/100 mL
• Stability: Stable. Incompatible with strong oxidants.
• Merck: 14,3364
• BRN: 1712560
• CAS DataBase Reference: Disulfiram(CAS DataBase Reference)
• NIST Chemistry Reference: Disulfiram(97-77-8)
• EPA Substance Registry System: Disulfiram(97-77-8)

Safety Data

• Hazard Codes: Xn,N
• Statements: 22-43-48/22-50/53
• Safety Statements: 24-37-60-61
• RIDADR: UN 3077 9/PG 3
• WGK Germany: 3
• RTECS: JO1225000
• TSCA: Yes
• HazardClass: 9
• PackingGroup: III
• Hazardous Substances Data: 97-77-8(Hazardous Substances Data)

Usage

General Introduction

Alcohol dependence is a chronic disorder that may have multiple relapses and remissions, increased mortality and low long-term abstinence rates that lead to increased psychosocial losses. Many drugs have been used in the treatment of this disorder such as the anti-craving agents, acamprosate, naltrexone and the aversive agent, disulfiram[1, 2]. Disulfiram (trade name: Antabuse) has been in use since the early 1940s for the treatment of alcohol dependence and is the first FDA-approved medication for the treatment of this disorder[3,4,5]. Disulfiram has thus completed almost 60 years of use in alcohol use disorders and has stood the test of time[6]. A large number of studies have been done on this molecule, ever since some proving its superiority over other drugs while others negating it.

Uses

Different sources of media describe the Uses of 97-77-8 differently. You can refer to the following data:
1. Disulfiram , is a sulfur- and nitrogen-containing compound with several industrial uses, including applications as a rubber accelerator and vulcanizer, fungicide, and seed disinfectant. It is most commonly known as antabuse, a therapeutic agent for the treatment of alcohol abuse that causes nausea, vomiting, and other adverse effects when ethanol is ingested. Disulfiram is an inhibitor of aldehyde dehydrogenase so that it allows for buildup of the acetaldehyde metabolite of ethanol, causing unpleasant effects that are a deterrent to the ingestion of alcohol. Because of the buildup of acetaldehyde, disulfiram should be given with extreme caution, especially to individuals suffering from liver cirrhosis.
2. It is used as rubber accelerator; vulcanizer; seed disinfectant; fungicide; alcohol deterrent.
3. Alcohol deterrent;Dopamine beta-hydroxylase inhibitor;For the treatment and management of chronic alcoholism.
4. Disulfiram is a copper and zinc chelator and an irreversible inhibitor of aldehyde dehydrogenase (IC50 = 0.1 mM) that has been indicated for the treatment of alcohol dependence. It also inhibits the copper-dependent enzyme dopamine β-hydroxylase, which prevents the breakdown of dopamine and has been considered as a treatment for cocaine dependence. When in complex with copper, disulfiram has been shown to inhibit purified 20S proteasome (IC50 = 7.5 μM) and 26S proteasome (IC50 = 20 μM) from MDA-MB-0231 breast cancer cells. Because disulfiram targets the ubiquitin-proteasome pathway, it has been investigated as an anti-cancer agent. Furthermore, at 250 nM it has been shown to induce reactive oxygen species, to activate JNK and p38 pathways, and to inhibit NF-κB activity, which suppresses self-renewal in cancer stem cells.

Indications

Disulfiram is used as a second line treatment of alcohol dependence, behind acamprosate and naltrexone[8]. It is an aid for the management of selected chronic alcohol patients who want to remain in a state of enforced sobriety so that supportive and psychotherapeutic treatment may be applied to best advantage. However, it should be noted that disulfiram is not a cure for alcoholism. When used alone, without proper motivation and supportive therapy, it is unlikely that it will have any substantive effect on the drinking pattern of the chronic alcoholic dependence[5]. Disulfiram should not be taken if alcohol has been consumed in the last 12 hours[9]. Recently, more and more studies have shown that disulfiram has the potential for the treatment of cancer[12, 13] and HIV infections[10, 11]. Disulfiram (DSF) can reactivate latent HIV-1 expression in a primary cell model of virus latency and has the potential to deplete the latent HIV-1 reservoir in patients on combination antiretroviral therapy. DSF can reactivate latent HIV-1 expression via the Akt signaling pathway through depletion of PTEN[10]. Recent studies have disclosed a surprising, but mechanistically consistent, anticancer activity of disulfiram. Disulfiram has been successfully used to suppress hepatic metastases originating from ocular melanoma[12]. The anticancer mechanism of disulfiram is through inhibiting the 26S proteasome (The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis)[12-14]. Moreover, disulfiram was also found to have specific activity against zinc fingers and RING-finger ubiquitin E3 ligases that play an important role in cancer development[12, 13].

Mode of action

Ethanol undergoes metabolism in the liver initially by alcohol dehydrogenase (ADH) forming acetaldehyde; this is removed from the body primarily by oxidation into acetate by acetaldehyde dehydrogenase (ALDH)[15], which finally enters the citric acid cycle. Disulfiram acts by inhibiting the enzyme ALDH via its metabolite S-methyl N, N-diethyl-dithio-carbamate-sulphoxide[16], leading to accumulation of acetaldehyde in blood. This gives rise to various manifestations of disulfiram-alcohol reaction (DER)[17]. Since the inhibition of ALDH by disulfiram is irreversible, the DER will get terminated only after production of new ALDH oncedisulfiram is stopped. The new ALDH takes about a week’s time to be produced. Hence patients should be advised to take alcohol only after 2 weeks of stopping disulfiram[18]. In addition to this, disulfiram also acts on the dopaminergic system, both disulfiram and its metabolite carbon disulfide leading to inhibition of dopamine beta-hydroxylase (DBH) that leads to increase in the levels of dopamine. This may give rise to several neuropsychiatric manifestations such as delirium, paranoia, impairment of memory, ataxia, dysarthria and frontal lobe release signs[19]. Besides this action, disulfiram is also known to inhibit dopamine beta-hydroxylase leading to an increase in dopamine concentrations but decreased norepinephrine in the brain[20]. This may suggest an anti-craving role of disulfiram in alcohol dependence[21].

Adverse reactions

In severe cases, hepatitis such as both cholestatic and fulminant hepatitis, as well as hepatic failure resulting in transplantation or death, could occur upon treatment of disulfiram[5]. In a small number of patients, side effects include a transient mild drowsiness, fatigability, impotence, headache, acneform eruptions, allergic dermatitis, or a metallic or garlic-like aftertaste during the first two weeks of therapy. These reactions often disappear spontaneously with the continuation of therapy, or with reduced dosage. High dosage, combined toxicity (with metronidazole or isoniazid), or to the unmasking of underlying psychoses can cause psychotic reactions[5].

Warning and precaution

The following tips should be pay attention during administration of disulfiram[9]. Disulfiram is not allowed if the patients have consumed alcohol within the past 12 hours. Do not drink alcohol while taking disulfiram and for up to 14 days after stop taking disulfiram. It is not known whether disulfiram will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine. It is not known whether disulfiram passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine. People less than 18 years old should also disabled. Disulfiram should not be used in the following cases: Allergic people; those who have recently taken metronidazole (Flagyl) or paraldehyde; or have consumed any foods or products that contain alcohol; People of the following cases should consult the doctors: Liver or kidney disease; heart disease, high blood pressure, history of heart attack or stroke; Underactive thyroid; diabetes; seizures or epilepsy; head injury or brain damage; a history of mental illness or psychosis; an allergy to rubber; or taking phenytoin (Dilantin), tuberculosis medicine, or a blood thinner (warfarin, Coumadin, Jantoven).

Mechanism of action

Disulfiram is an oral drug used for treating alcoholism. Alcohol is converted in the body into acetaldehyde by an enzyme called alcohol dehydrogenase. Another enzyme called acetaldehyde dehydrogenase then converts acetaldehyde into acetic acid. Disulfiram prevents acetaldehyde dehydrogenase from converting acetaldehyde into acetic acid, leading to a buildup of acetaldehyde levels in the blood.

Pharmacodynamics

Disulfiram irreversibly inhibits aldehyde dehydrogenase, which prevents the oxidation of alcohol after the acetaldehyde stage. It interacts with ingested alcohol to produce acetaldehyde levels five to ten times higher than are produced by normal alcohol metabolism. Excess acetaldehyde produces a highly unpleasant reaction (nausea and vomiting) to even a small quantity of alcohol. Tolerance to disulfiram doesn’t occur; rather, sensitivity to alcohol increases with longer duration of therapy.

Interactions

Some individuals should never take disulfiram, and others should use extra caution when taking the drug. Do not take disulfiram if you have a nickel allergy, a sulfur allergy or a hypersensitivity to disulfiram or other derivatives of thiuram, which are commonly found in rubber.

References

Bouza, C., Angeles, M., Mu?oz, A., & Amate, J. M. (2015). Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction, 99(7), 811-828. Laaksonen, E., Koskij?nnes, A., Salaspuro, M., Ahtinen, H., & Alho, H. (2008). A randomized, multicentre, open-label, comparative trial of disulfiram, naltrexone and acamprosate in the treatment of alcohol dependence. Alcohol & Alcoholism, 43(1), 53. Petrakis, I.L., Nich, C. and Ralevski, E. (2006) Psychotic spectrum disorders and alcohol abuse: A review of pharmacotherapeutic strategies and a report on the effective-ness of naltrexone and disulfiram. Schizophrenia Bulletin, 32, 644-654. De Sousa, A. (2010) The pharmacotherapy of alcohol dependence: A state of the art review. Mens Sana Monographs, 8, 69-82. https://www.rxlist.com/antabuse-drug.htm Krampe, H., & Ehrenreich, H. (2010). Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design, 16(19), (60 years) Johansson, B. (1992) A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatrica Scandanavica, 362, 15-26. https://www.ncbi.nlm.nih.gov/books/NBK459340/ https://www.drugs.com/pro/disulfiram.html Doyon, G., Zerbato, J., Mellors, J. W., & Sluiscremer, N. (2013). Disulfiram reactivates latent hiv-1 expression through depletion of the phosphatase and tensin homolog. Aids, 27(2), F7-F11. Rasmussen, TA; Lewin, SR (July 2016). "Shocking HIV out of hiding: where are we with clinical trials of latency reversing agents?". Current Opinion in HIV and AIDS. Cvek, B., & Dvorak, Z. (2008). The value of proteasome inhibition in cancer: can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor?. Drug Discovery Today, 13(15), 716-722. Kona, F. R., Buac, D., & A, M. B. (2011). Disulfiram, and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies. Current Cancer Drug Targets, 11(3). Rajkumar, S. V., Richardson, P. G., Hideshima, T., & Anderson, K. C. (2005). Proteasome inhibition as a novel therapeutic target in human cancer. Journal of Clinical Oncology, 23(3), 630-639. Deitrich, R.A., Petersen, D. and Vasiliou, V. (2007) Removal of acetaldehyde from the body. Novartis Foundation Symposia, 285, 23-40. Pike, M.G., Mays, D.C., Macomber, D.W. and Lipsky, J.J. (2001) Metabolism of a disulfiram metabolite S-methyl N,N-diethyldithiocarbamate by flavinmonooxygenase in human renal microsomes. Drug Metabolism & Disposition, 29, 127-132. Larsen, V. (1948) The effects on experimental animals of antabuse (tetraethylthiuram disulfide) in combination with alcohol. Acta Pharmacologica Toxicology, 4, 321-332.? Krampe, H. and Ehrenreich, H. (2010) Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design, 16, 2076-2090.? Fuller, R.K. and Gordis, E. (2004) Does disulfiram have a role in alcoholism treatment today? Addiction, 99, 21-24.? Vaccari, A., Saba, P.L., Ruiu, S., Collu, M. and Devoto, P. (1996) Disulfiram and diethyldithiocarbamate intoxica-tion affects the storage and release of striatal dopamine. Toxicology & Applied Pharmacology, 139, 102-108.? Muller, C.A. and Banas, R. (2011) Disulfiram: An anti-craving substance? American Journal of Psychiatry, 168, 98.

Description

Disulfiram was first synthesized in the 1800s to improve the manufacturing process of rubber. A physician working in a rubber factory plant first observed in 1937 that factory workers who were exposed to disulfiram were intolerant to ethanol. In the 1940s, two scientists rediscovered the disulfiram– ethanol effects while researching antiparasitic therapies. This finding eventually led to the approval of the medication to be used as an ethanol deterrent by the Food and Drug Administration in 1951.

Chemical Properties

yellow-white crystals or grey powder

Originator

Esperal,Millot Solac,France,1950

Definition

ChEBI: An organic disulfide that results from the formal oxidative dimerisation of N,N-diethyldithiocarbamic acid. A multi-enzyme inhibitor that is used in alcohol aversion therapy and also exhibits anticancer properties.

Manufacturing Process

Disulfiram may be made by the reaction of diethyl amine with carbon disulfide in the presence of sodium hydroxide. The (C2H5)2NCSSNa intermediate is oxidatively coupled using hydrogen peroxide to give disulfiram.

Brand name

Antabuse (Odyssey) .

Therapeutic Function

Alcohol deterrent

General Description

Odorless or almost odorless white or almost white to tan powder. Unpleasant taste with metallic or garlic aftertaste. pH of a solution obtained by shaking 1 g with 30 mL of water is 6 to 8.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Disulfiram is sensitive to light. Disulfiram is incompatible with strong acids, strong oxidizers and nitrosating agents (e.g. N-Nitrosodiphenylamine). .

Hazard

Toxic symptoms when ingested with alcohol; animal teratogen. Vasodilation and nausea. Questionable carcinogen.

Health Hazard

Disulfiram affects the central nervous system, thyroid, and skin; in combination with alcohol it causes an “Antabusealcohol” syndrome. Small doses of disulfiram reportedly can cause effects on thyroid iodine uptake and thyroid gland hypertrophy. It may also produce dermatitis and acneform rashes.

Fire Hazard

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

Flammability and Explosibility

Notclassified

Biological Activity

Inhibitor of aldehyde dehydrogenase that displays antialcoholism activity. Shown to reversibly stimulated Ca 2+ -ATPase activity and inhibit V-ATPase (EC 50 = 26 μ M). Also inhibits expression of MMP-2 and MMP-9 and displays anti-invasive activity.

Contact allergens

TETD is a rubber accelerator of the thiuram group, contained in “thiuram mix.” It can cross-react with other thiurams, especially TMTD. TETD is used to aid those trying to break their dependence on alcohol. The disulfiram-alcohol reaction is not allergic but due to the accumulation of toxic levels of acetaldehyde. The implanted drug can, however, lead to local or generalized dermatitis, for example ingested disulfiram, mainly in previously rubber-sensitized patients. As an adjunctive treatment of alcoholism, it caused occupational contact dermatitis in a nurse.

Clinical Use

Adjunct in the treatment of chronic alcohol dependence

Safety Profile

A human poison by ingestion. An experimental poison by intraperitoneal route. Toxic symptoms when accompanied by ingestion of alcohol. Human systemic effects by ingestion: jaundtce, joint changes. An experimental teratogen. Other experimental reproductive effects. Questionable carcinogen with experimental neoplastigenic data. See also THIRAM.

Drug interactions

Potentially hazardous interactions with other drugsAlcohol: risk of severe disulfiram reaction.Anticoagulants: enhanced anticoagulant effect with coumarins.Antiepileptics: inhibition of metabolism of fosphenytoin and phenytoin (increased risk of toxicity).Paraldehyde: increased risk of toxicity with paraldehyde.

Carcinogenicity

In a lifetime carcinogenicity bioassay, disulfiram was not carcinogenic in either rats or mice when fed in the diet. The highest doses were 600 ppm in rats and 2000ppm in mice. Increased fetal resorptions, but no teratogenic effects, were seen in rats exposed at 100mg/kg/day from day 3 of gestation. A weak genotoxic response was observed in mice treated in vivo as evidenced by an increase in sister chromatid exchanges in bone marrow and spermatogonial cells.9 The 2003 ACGIH threshold limit valuetime- weighted average (TLV-TWA) is 2mg/m3.

Metabolism

Disulfiram is rapidly reduced to diethyldithiocarbamate, mainly by the glutathione reductase system in erythrocytes; reduction may also occur in the liver.Diethyldithiocarbamate is metabolised in the liver to its glucuronide and methyl ester and to diethylamine, carbon disulfide, and sulfate ions. Metabolites are excreted mainly in the urine; carbon disulfide is exhaled in the breath.

Toxicity evaluation

Disulfiram has multiple mechanisms of toxicity. Its most welldefined action is inhibition of aldehyde dehydrogenase, which thereby diminishes the breakdown of acetaldehyde. Accumulation of carbon disulfide, a disulfiram metabolite, as well as inhibition of dopamine-b-hydroxylase has also been associated with its toxicity in particular related to use for cocaine dependence.

InChI:InChI=1/C10H20N2O3S/c1-5-11(6-2)9(13)14-10(16)15-12(7-3)8-4/h5-8H2,1-4H3

Synthetic route

Diethyldithiocarbamic acid (147-84-2) → disulfiram (97-77-8)

Conditions	Yield
With oxygen In ethanol at 20 - 30℃; under 3000.3 Torr; for 0.1h; Time; Flow reactor;	99.8%
With 3,6-di(2'-pyridyl)-1,2,4,5-tetrazine In ethanol; water at 40℃; for 0.5h; Temperature;	98%
With morpholine; iodine In tetrahydrofuran; benzene at 10 - 20℃; for 0.25h;	97%

diethylamine (109-89-7) → disulfiram (97-77-8)

Conditions	Yield
With triphenyl antimony oxide In acetonitrile for 24h; Ambient temperature;	99%

carbon disulfide (75-15-0) + diethylamine (109-89-7) → disulfiram (97-77-8)

Conditions	Yield
With oxygen In isopropyl alcohol at 50℃; under 1275.13 Torr; for 1.5h; Autoclave;	98.5%
Stage #1: carbon disulfide; diethylamine With haematoxylin In ethanol at 20 - 30℃; for 0.1h; Stage #2: In ethanol for 0.0333333h; Temperature; Irradiation;	98.99%
With carbon tetrabromide In N,N-dimethyl-formamide at 20℃; for 1h; Cooling with ice;	96%

sodium N,N-diethyldithiocarbamate (148-18-5) → disulfiram (97-77-8)

Conditions	Yield
With 1,3,5-trichloro-2,4,6-triazine; dimethyl sulfoxide In dichloromethane at 20℃; for 2h;	96%
With iodine In methanol at 0℃;	95%
With oxygen; sodium hydroxide In water at 25℃; for 1.08333h; pH=10; Kinetics; pH-value; Reagent/catalyst;	94%

N,N-diethyl-S-(α,α-dimethyl-α-acetic acid)dithiocarbamate (548761-51-9) + N-(2-methyl-2-propyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)aminoxyl (188526-94-5) → disulfiram (97-77-8) + N-(2-methyl-2-propyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)-O-(2-carboxyprop-2-yl)hydroxylamide (654636-62-1)

Conditions	Yield
In ethanol at 20℃; for 4h; Product distribution / selectivity; Inert atmosphere; Photolysis;	A n/a B 90%

diethylammonium oxotrithiotungstate (112296-52-3) → W2O2(μ-S)2(S2CNEt2)2 + disulfiram (97-77-8)

Conditions	Yield
With carbon disulfide In N,N-dimethyl-formamide byproducts: H2S; refluxing (4 h); addn. of 2-propanol and ether, filtn., crystn. (room temp., overnight), washing (water, ethanol, ether), recrystn. (CH2Cl2/petroleum ether); elem. anal.;	A 38% B n/a

diethylammonium tetrathiotungstate(VI) → W2OS(μ-S)2(S2CNEt2)2 + disulfiram (97-77-8)

Conditions	Yield
With carbon disulfide; air In N,N-dimethyl-formamide byproducts: H2S; refluxing (4 h) in presence of air; addn. of 2-propanol and ether, filtn., crystn. (room temp., overnight), washing (water, ethanol, ether), recrystn. (CH2Cl2/petroleum ether), chromy. (silica gel, Ch2Cl2/petroleum ether 75:25); elem. anal.;	A 30% B n/a

diethylammonium tetrathiotungstate(VI) → W2S2(μ-S)2(S2CNEt2)2 + disulfiram (97-77-8)

Conditions	Yield
With carbon disulfide In N,N-dimethyl-formamide byproducts: H2S; N2 atmosphere, refluxing (absence of light, 4 h); addn. of 2-propanol and ether to the cold soln., filtn., crystn. (room temp., 24 h), washing (water, ethanol, ether), recrystn. (CH2Cl2/petroleum ether), chromy. (silica gel, CH2Cl2/petroleum ether 75:25); elem. anal.;	A 28% B n/a

carbon disulfide (75-15-0) + N,N,N',N'-tetraethylthioamine (3768-61-4) → disulfiram (97-77-8)

N,N,N',N'-tetraethylthioamine (3768-61-4) → disulfiram (97-77-8)

Conditions	Yield
With carbon disulfide

sodium diethyldithiocarbamate trihydrate (20624-25-3) + cyclohexylamine (108-91-8) → disulfiram (97-77-8) + N,N-diethylthiocarbamoyl-N'-cyclohexylsulfenamide (52185-80-5)

Conditions	Yield
at 30℃; anschliessend mit NaOCl bei pH 12-12.5;

diethyldithiocarbamate (392-74-5) → disulfiram (97-77-8)

Conditions	Yield
With sodium nitrate; 3Na(1+)*C8N8W(3-) In water; acetone at 25℃; Equilibrium constant; Rate constant; Mechanism; ΔH(excit.), Σ(excit.), other dithiocarbamate anions, var. metal complexes and salts;

sodium N,N-diethyldithiocarbamate (148-18-5) + C8H15NOS4 (327989-09-3) → disulfiram (97-77-8) + sodium O-ethyl dithiocarbonate (140-90-9)

Conditions	Yield
With sodium nitrate; C8MoN8(3-)*3Na(1+) In water; acetone at 25℃; Equilibrium constant; μ 0.2 mol/l;

sodium N,N-diethyldithiocarbamate (148-18-5) + C12H24N2S4 → disulfiram (97-77-8) + sodium N,N'-diisopropyldithiocarbamate (4092-82-4)

Conditions	Yield
With sodium nitrate; potassium hexacyanoferrate(III) In water; acetone at 25℃; Rate constant; Equilibrium constant; μ 0.2 mol/l;

diethyldithiocarbamate radical (54451-16-0) → disulfiram (97-77-8)

Conditions	Yield
With sodium nitrate In water; acetone at 25℃; Equilibrium constant; var. metal complexes and salts;
In methanol at 21.85℃; Kinetics; Further Variations:; Solvents; Temperatures; Recombination;

bis(chlorothiocarbonyl)disulfide (88245-23-2) + diethylamine (109-89-7) → disulfiram (97-77-8)

Conditions	Yield
In tetrachloromethane at 5℃;

diethylamine (109-89-7) + 35S containing CS2 → disulfiram (97-77-8)

Conditions	Yield
With potassium hydroxide bei folgendes Oxydation mit Na2S4O6; Darstellung von 35S-markiertem Tetraaethyl-thiuramdisulfid;

N.N-diethyl-dithiocarbamidacidic diethylamine → disulfiram (97-77-8)

Conditions	Yield
Electrolysis.an der Anode;

sodium diethyl dithiocarbamate → disulfiram (97-77-8)

Conditions	Yield
With ammonium peroxydisulfate; water
With sodium nitrite
With water; chlorine at 5 - 8℃;
With sodium nitrite

bis(diethyldithiocarbamato)selenium (136-92-5) + sodium diethyl dithiocarbamate → disulfiram (97-77-8)

Conditions	Yield
With ethanol

diethylamine (109-89-7) + CS2 → disulfiram (97-77-8) + bis(diethyldithiocarbamato)selenium (136-92-5)

Conditions	Yield
With selenium(IV) oxide; isopropyl alcohol

N.N-diethyl-dithiocarbamidacidic diethylamine → disulfiram (97-77-8) + di-ethylamine hydroiodide (19833-78-4)

Conditions	Yield
With ethanol; iodine

ethanol (64-17-5) + chloroform (67-66-3) + bis(diethyldithiocarbamato)selenium (136-92-5) + potassium ethyl xanthogenate (140-89-6) → disulfiram (97-77-8) + selenium

ethanol (64-17-5) + chloroform (67-66-3) + bis(diethyldithiocarbamato)selenium (136-92-5) + sodium diethyl dithiocarbamate → disulfiram (97-77-8) + selenium

iodine (7553-56-2) + diethylammonium diethyldithiocarbamate (1518-58-7) → disulfiram (97-77-8) + di-ethylamine hydroiodide (19833-78-4)

bromocyane (506-68-3) + sodium N,N-diethyldithiocarbamate (148-18-5) → disulfiram (97-77-8)

Conditions	Yield
With potassium iodide In water pH:6.2-6.7; in aqueous and non aqueous medium; titration method;

octacyanomolybdate(V) + Diethyldithiocarbamic acid (147-84-2) → octacyanomolybdate(IV) ion + disulfiram (97-77-8)

Conditions	Yield
With sodium perchlorate In dimethyl sulfoxide Kinetics; Electrochem. Process; 25°C;
With sodium nitrate In water; acetone Kinetics; Electrochem. Process; 30% aq.acetone, 25°C, at different pH (9-12);

Fe(imid)(CN)5(2-) + Diethyldithiocarbamic acid (147-84-2) → [Fe(CN)5(imidazole)](3-) + disulfiram (97-77-8)

Conditions	Yield
With sodium nitrate In water; acetone Kinetics; Electrochem. Process; 25°C, 30% aq.acetone, at different pH (9-12);

(pyrazine)pentcyanidoferrate(III) + Diethyldithiocarbamic acid (147-84-2) → pentacyano(pyrazine)ferrate(II)(3-) (40299-78-3) + disulfiram (97-77-8)

Conditions	Yield
With sodium nitrate In water; acetone Kinetics; Electrochem. Process; 25°C, 30% aq.acetone, at different pH (9-12);

disulfiram (97-77-8) + 4-(pivaloylamino)pyridine (70298-89-4) → <4-<(2,2-dimethyl-1-oxopropyl)amino>-3-pyridinyl>diethylcarbamodithioate (129333-20-6)

Conditions	Yield
Stage #1: 4-N-pivaloylaminopyridine With n-butyllithium In tetrahydrofuran; hexane at -10 - 1℃; for 2h; Stage #2: disulfiram In tetrahydrofuran; hexane at -10 - 20℃;	100%
Stage #1: 4-N-pivaloylaminopyridine With n-butyllithium Stage #2: disulfiram	98%
With n-butyllithium 1) THF, hexane, -10 to 0 deg C, 2) THF, 0 deg C to room temperature; Yield given. Multistep reaction;

2-bromopyrazine (56423-63-3) + disulfiram (97-77-8) → pyrazin-2-yl diethylcarbamodithioate

Conditions	Yield
With copper(I) oxide; caesium carbonate In dimethyl sulfoxide at 110℃; for 48h; Sealed tube;	96%

disulfiram (97-77-8) + 2-chloro-5-nitrobenzoic acid (2516-96-3) → 2-chloro-5-nitro-N,N-diethylbenzamide (67272-98-4)

Conditions	Yield
With di-tert-butyl peroxide; copper(I) bromide In ethyl acetate at 120℃;	95%

disulfiram (97-77-8) + 1-bromomethyl-4-nitro-benzene (100-11-8) → (4-nitrophenyl)methyl diethyldithiocarbamate (28371-57-5)

Conditions	Yield
With potassium carbonate In water at 100℃; for 0.5h; Sealed tube; Green chemistry;	94%

disulfiram (97-77-8) + cyclohexylamine (108-91-8) → N,N-diethylthiocarbamoyl-N'-cyclohexylsulfenamide (52185-80-5) + Diethyl-dithiocarbamic acid; compound with cyclohexylamine

Conditions	Yield
at 20℃; for 3h;	A 93% B n/a

disulfiram (97-77-8) + methyl (triphenylphosphoranylidene)acetate (21204-67-1) → Diethylthiocarbamoylsulfanyl-(triphenyl-λ5-phosphanylidene)-acetic acid methyl ester (110637-87-1)

Conditions	Yield
In benzene Heating;	93%

disulfiram (97-77-8) + 3-nitrobenzoic acid (121-92-6) → 3-nitro-N,N-diethylbenzamide (2433-21-8)

Conditions	Yield
With di-tert-butyl peroxide; copper(I) bromide In ethyl acetate at 120℃;	93%

disulfiram (97-77-8) + 1-triphenylphosphoranylidene-2-propanone (1439-36-7) → Diethyl-dithiocarbamic acid 2-oxo-1-(triphenyl-λ5-phosphanylidene)-propyl ester (110637-84-8)

Conditions	Yield
In benzene Heating;	92%

disulfiram (97-77-8) + diethyl 2,2'-azobis(2-methylpropionate) (3879-07-0) → S-(1-methyl-1-ethoxycarbonylethyl) N,N-diethyl-dithiocarbamate (120924-70-1)

Conditions	Yield
In ethyl acetate for 18h; Heating;	92%

dodecacarbonyl triosmium (15696-40-9) + disulfiram (97-77-8) + hexane (110-54-3) → cis-Os(CO)2(S2CNEt2)2*0.25C6H14

Conditions	Yield
In toluene under N2 atm. using Schlenk technique; soln. refluxed for 4 h; solvent removed under vac.; residue washed with hexanes;	92%

disulfiram (97-77-8) + 1-bromomethyl-4-bromobenzene (589-15-1) → 4-bromobenzyl diethylcarbamodithioate (28371-58-6)

Conditions	Yield
With potassium carbonate In water at 100℃; for 0.5h; Sealed tube; Green chemistry;	92%

bismuth (7440-69-9) + disulfiram (97-77-8) → tris(N,N-diethyldithiocarbamato)bismuth(III) (1000068-52-9, 20673-31-8)

Conditions	Yield
In toluene metal and S-compd. were refluxed in 1:1.5 molar ratio in toluene for 3 h; soln. was filtered, concd. to 1/3 of its original vol., cooled to room temp., solid was filtered off, washed with petroleum ether (b.p. 60-80 °C), dried in vac., elem. anal.;	91%

disulfiram (97-77-8) → N,N-diethylcarbamyl chloride (88-10-8)

Conditions	Yield
Stage #1: disulfiram With chlorine In dichloromethane at 24 - 26℃; for 7h; Cooling with ice; Stage #2: With water; sodium hydrogencarbonate In dichloromethane Cooling with ice;	90.3%

disulfiram (97-77-8) → N-ethyl-N-(trifluoromethyl)ethanamine (1481-55-6)

Conditions	Yield
With silver fluoride In various solvent(s) at 20℃; for 3h;	90%
With dialkylaminosulfurtrifluoride In diethyl ether at 20℃; for 0.25h;

disulfiram (97-77-8) + Rh((C6H5)2PCSNC6H5)(P(C6H5)3)2 (65595-22-4, 65585-33-3) → Rh[(C6H5)2PCSNC6H5][(C2H5)2NCSS]2*0.3C7H8

Conditions	Yield
In toluene Rh-complex and ligand were dissolved in toluene for 2 h, diluted with n-hexane at room temp.; elem. anal.;	90%

disulfiram (97-77-8) + 1-Bromo-2-bromomethyl-benzene (3433-80-5) → 2-bromobenzyl diethylcarbamodithioate (30742-31-5)

Conditions	Yield
With potassium carbonate In water at 100℃; for 0.5h; Sealed tube; Green chemistry;	90%

disulfiram (97-77-8) + Methyl 4-(bromomethyl)benzoate (2417-72-3) → methyl 4-{[(diethylcarbamothioyl)thio]methyl}benzoate

Conditions	Yield
With potassium carbonate In water at 100℃; for 0.5h; Sealed tube; Green chemistry;	90%

bismuth (7440-69-9) + disulfiram (97-77-8) + iodine (7553-56-2) → (NN-diethyldithiocarbamato)di-iodo-bismuth(III) (78403-74-4)

Conditions	Yield
In toluene metal, S-compd. and I2 were refluxed in 1:1:1 molar ratio in toluene for3.5 h; soln. was filtered in hot, solid was washed with petroleum ether (b.p. 60-80 °C), dried in vac., elem. anal.;	89%

dichloro(1,2-bis(diphenylphosphino)ethane)cobalt(II) (15168-81-7, 18498-01-6) + cadmium(II) diethyldithiocarbamate (14239-68-0) + disulfiram (97-77-8) → di(N,N-diethyldithiocarbamato)[1,2-bis(diphenylphosphino)ethane]cobalte(III) tetrachlorocadmate

Conditions	Yield
In dichloromethane stirred for 30 min at room temp.; filtered, concd. (vac.), added diethyl ether, ppt. filtered, washed (ethanol, diethyl ether), dried (vac.); elem. anal., NMR;	89%

disulfiram (97-77-8) → N,N-diethylcarbamyl chloride (88-10-8) + N,N-diethylthiocarbamoyl chloride (88-11-9)

Conditions	Yield
With sulfuryl dichloride In benzene at 50℃; for 6h;	A 1.3% B 87%
With sulfuryl dichloride In benzene at 60℃; for 4h;	A 1.3% B 87%

bismuth (7440-69-9) + disulfiram (97-77-8) + iodine (7553-56-2) → bis(NN-diethyldithiocarbamato)-iodo-bismuth(III) (59196-65-5)

Conditions	Yield
In toluene metal, S-compd. and I2 were refluxed in 1:1.5:0.5 molar ratio in toluenefor 3.5 h; soln. was filtered in hot, solid was washed with petroleum ether (b.p. 60-80 °C), dried in vac., elem. anal.;	87%

tin (7440-31-5) + disulfiram (97-77-8) → tetrakis(N,N-diethyldithiocarbamato)tin (33790-72-6, 12367-48-5, 442849-67-4, 34431-16-8)

Conditions	Yield
In toluene metal and S-compd. were refluxed in 1:2 molar ratio in toluene for 5 h; mixt. was evapd. in vac., residue was triturated with n-pentane, solid was filtered off, dried in vac., elem. anal.;	87%

bis(cyclopentadienylchromium tricarbonyl) + disulfiram (97-77-8) → (cyclopentadienyl)Cr(CO)2(η2-S(S)CN(C2H5)2) (377078-60-9)

Conditions	Yield
In toluene stoich., at ambient temp., concd.; elem. anal.;	87%
In toluene N2 or Ar; stirring of Cr complex and ligand in toluene at ambient temp. for 1 h; filtering, concn. the filtrate, crystn. by addn. of hexane and overnightcooling at -29°C; elem. anal.;	86.7%

disulfiram (97-77-8) + 3-chlorobenzoate (535-80-8) → 3-chloro-N,N-diethylbenzamide (15952-65-5)

Conditions	Yield
With di-tert-butyl peroxide; copper(I) bromide In ethyl acetate at 120℃;	87%

disulfiram (97-77-8) + 4-tolyl iodide (624-31-7) → diethyl dithiocarbamic acid p-tolyl ester (109720-10-7)

Conditions	Yield
With copper(I) oxide; caesium carbonate In dimethyl sulfoxide at 80℃; for 18h; Sealed tube;	87%
With potassium carbonate; copper dichloride; zinc In dimethyl sulfoxide at 110℃; for 18h; Sealed tube;	83%
With copper acetylacetonate; tetrabutylammomium bromide; sodium carbonate In water at 100℃; for 12h; Sealed tube;	80%

Upstream product

• 54451-16-0 diethyldithiocarbamate radical 
• 147-84-2 Diethyldithiocarbamic acid 
• 2391-78-8 N,N-diethyldithiocarbamate triethylamine salt 
• 3699-30-7 potassium diethyldithiocarbamate 
• 548761-51-9 N,N-diethyl-S-(α,α-dimethyl-α-acetic acid)dithiocarbamate 
• 188526-94-5 N-(2-methyl-2-propyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)aminoxyl 
• 112296-52-3 diethylammonium oxotrithiotungstate 
• 22337-23-1 Fe(bpy)(CN)4^(1-) 
• 506-68-3 bromocyane 
• 148-18-5 sodium N,N-diethyldithiocarbamate 

Downstream Products

• 38331-55-4 Ph₃PAuSC(S)NEt₂ 
• 14267-17-5 nickel(II) diethyldithiocarbamate 
• 14239-68-0 cadmium(II) diethyldithiocarbamate 
• 13963-59-2 tris(N,N-diethyldithiocarbamato)iron(III) 
• 38351-46-1 silver diethyldithiocarbamate 
• 83399-40-0 chlorobis(diethyldithiocarbamato)(p-tolylnitrene)rhenium 
• 15952-65-5 N,N-diethyl-m-chlorobenzamide 
• 2433-21-8 N,N-diethyl-3-nitrobenzamide 
• 13577-84-9 N,N-diethyl-2-naphthamide 
• 67272-98-4 2-chloro-N,N-diethyl-5-nitrobenzamide 
• 16906-74-4 diethyl dithiocarbamic acid 4-chlorophenyl ester 

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