4,4'-Diaminodiphenylsulfone Chemical Properties

Melting point:

175-177 °C(lit.)

Boiling point:

511.7±35.0 °C(Predicted)

Density 

1.2701 (rough estimate)

vapor pressure 

0.004Pa at 25℃

refractive index 

1.5950 (estimate)

storage temp. 

2-8°C

solubility 

0.38g/l

form 

Crystalline Powder

pka

pKb 13.0(at 25℃)

color 

White to beige

PH

5.5-7.5 (H2O, 20℃)(saturated aqueous solution)

Water Solubility 

<0.1 g/100 mL at 20 ºC

Merck 

14,2822

BRN 

788055

BCS Class

4,2

Stability:

Stable. Combustible. Incompatible with strong oxidizing agents.

InChIKey

MQJKPEGWNLWLTK-UHFFFAOYSA-N

LogP

0.97 at 25℃

CAS DataBase Reference

80-08-0(CAS DataBase Reference)

NIST Chemistry Reference

Dapsone(80-08-0)

IARC

3 (Vol. 24, Sup 7) 1987

EPA Substance Registry System

Dapsone (80-08-0)

Safety Information

Hazard Codes 

Xn

Risk Statements 

22

Safety Statements 

22

RIDADR 

3249

WGK Germany 

1

RTECS 

BY8925000

TSCA 

Yes

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

29051620

HS Code 

29309070

Hazardous Substances Data

80-08-0(Hazardous Substances Data)

Toxicity

LD50 orally in Rabbit: 1000 mg/kg LD50 dermal Rabbit > 4000 mg/kg

MSDS

• Language:English Provider:Dapsonum
• Language:English Provider:SigmaAldrich
• Language:English Provider:ACROS
• Language:English Provider:ALFA

4,4'-Diaminodiphenylsulfone Usage And Synthesis

Chemical Properties

Off -White Crystalline Solid

Originator

Avlosulfon,Ayerst,US,1957

Uses

An antibacterial used in the treatment of dermatitis herpetiformis

Uses

antibacterial, leprostatic, dermatitis herpetiformis suppressant

Uses

4,4'-diaminodiphenylsulfone be used for preparation polyimide and epoxy resin material.

Uses

Hardening agent in the curing of epoxy resins.

Definition

ChEBI: A sulfone that is diphenylsulfone in which the hydrogen atom at the 4 position of each of the phenyl groups is substituted by an amino group. It is active against a wide range of bacteria, but is mainly employed for its actions against Mycobacteriu leprae, being used as part of multidrug regimens in the treatment of all forms of leprosy.

Indications

Although dapsone (Avlosulfon) is most often used as an antimicrobial agent, it has important antiinflammatory properties in many noninfectious skin diseases. The mechanism of action of dapsone in skin disease is not clear.Most of the cutaneous diseases for which it is effective manifest inflammation and are characterized by an infiltration of neutrophils; the drug’s antiinflammatory effect may arise from its inhibition of intracellular neutrophil reactions mediated by myeloperoxidase and hydrogen peroxide or from its scavenging of reactive oxygen species, which inhibits inflammation.

Indications

Although dapsone (Avlosulfon) was once used in the treatment and prophylaxis of chloroquine-resistant P. falciparum malaria, the toxicities associated with its administration (e.g., agranulocytosis, methemoglobinemia, hemolytic anemia) have severely reduced its use. Occasionally dapsone has been added to the usual chloroquine therapeutic regimen for the prophylaxis of chloroquine-resistant P. falciparum malaria. It is also used in combination therapy for leprosy.

Manufacturing Process

p-Chloronitrobenzene is reacted with NaSO2C6H5NHCOCH3 to give as an intermediate, O2NC6H5SO2C6H5NHCOCH3 which is then reduced and deacetylated to give the product, dapsone. Alternatively, benzene and sulfuric acid react to give phenyl sulfone which is nitrated, then reduced to give dapsone.

brand name

Hansolar (ParkeDavis).

Therapeutic Function

Antibacterial (leprostatic)

Synthesis Reference(s)

Synthesis, p. 640, 1981 DOI: 10.1055/s-1981-29557

Antimicrobial activity

Dapsone is active against many bacteria and some protozoa. Fully susceptible strains of M. leprae are inhibited by a little as 0.003 mg/L. It is predominantly bacteristatic. Resistance is associated with mutations in the folP1 gene involved in the synthesis of para-aminobenzoic acid.

Acquired resistance

Resistance to high levels is acquired by several sequential mutations. As a result of prolonged use of dapsone monotherapy, acquired resistance emerged in patients with multibacillary leprosy in many countries. Initial resistance also occurs in patients with both paucibacillary and multibacillary leprosy. Thus, leprosy should always be treated with multidrug regimens. Resistance of M. leprae to dapsone (and other anti-leprosy drugs) may now be determined by use of DNA microarrays.

General Description

Odorless white or creamy white crystalline powder. Slightly bitter taste.

Air & Water Reactions

Sensitive to oxidation and light. Insoluble in water.

Reactivity Profile

4,4'-Diaminodiphenylsulfone can neutralize acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated in combination with strong reducing agents, such as hydrides. Incompatible with strong oxidizing agents. Also incompatible with epoxy resins under uncontrolled conditions .

Fire Hazard

4,4'-Diaminodiphenylsulfone is probably combustible.

Pharmaceutical Applications

The most effective of a number of sulfonamide derivatives to be tested against leprosy. The dry powder is very stable. It is only slightly soluble in water.

Pharmacokinetics

Oral absorption: >90%
C_max 100 mg oral: c. 2 mg/L after 3–6 h
Plasma half-life: 10–50 h
Plasma protein binding: c. 50%
It is slowly but almost completely absorbed from the intestine and widely distributed in the tissues, but selectively retained in skin, muscle, kidneys and liver. It is metabolized by N-oxidation and also by acetylation, which is subject to the same genetic polymorphism as isoniazid. The elimination half-life is consequently very variable, but on standard therapy the trough levels are always well in excess of inhibitory concentrations. It is mostly excreted in the urine: in the unchanged form (20%), as N-oxidation products (30%) and as a range of other metabolites.

Clinical Use

Dapsone (4,4 -sulfonylbisbenzeneamine; 4,4 -sulfonyldianiline;p,p -diaminodiphenylsulfone; or DDS [Avlosulfon])occurs as an odorless, white crystalline powder that is veryslightly soluble in water and sparingly soluble in alcohol.The pure compound is light stable, but traces of impurities,including water, make it photosensitive and thus susceptibleto discoloration in light. Although no chemical change is detectablefollowing discoloration, the drug should be protectedfrom light.
Dapsone is used in the treatment of both lepromatous andtuberculoid types of leprosy. Dapsone is used widely for allforms of leprosy, often in combination with clofazimine andrifampin. Initial treatment often includes rifampin with dapsone,followed by dapsone alone. It is also used to preventthe occurrence of multibacillary leprosy when given prophylactically.Dapsone is also the drug of choice for dermatitis herpetiformisand is sometimes used with pyrimethamine for treatmentof malaria and with trimethoprim for PCP.
Serious side effects can include hemolytic anemia,methemoglobinemia, and toxic hepatic effects. Hemolyticeffects can be pronounced in patients with glucose-6-phosphatedehydrogenase deficiency. During therapy, all patientsrequire frequent blood counts.

Clinical Use

Dapsone is approved for the treatment of an autoimmune blistering skin disease, dermatitis herpetiformis. This intensely pruritic eruption is characterized histologically by a dense dermal infiltration of neutrophils and subepidermal blisters. Other skin diseases in which dapsone is helpful are linear immunoglobulin A (IgA) dermatosis, subcorneal pustular dermatosis, leukocytoclastic vasculitis, and a variety of rarer eruptions in which neutrophils predominate, including some forms of cutaneous lupus erythematosus.

Clinical Use

Leprosy (multidrug regimens)
Prophylaxis of malaria, treatment of chloroquine-resistant malaria (in combination with pyrimethamine)
Prophylaxis of toxoplasmosis (in combination with pyrimethamine)
Prophylaxis (monotherapy) and treatment (in combination with trimethoprim) of Pneumocystis jirovecii pneumonia
Dermatitis herpetiformis and related skin disorders

Side effects

Although usually well tolerated at standard doses, gastrointestinal upsets, anorexia, headaches, dizziness and insomnia may occur. Less frequent reactions include skin rashes, exfoliative dermatitis, photosensitivity, peripheral neuropathy (usually in non-leprosy patients), tinnitus, blurred vision, psychoses, hepatitis, nephrotic syndrome, systemic lupus erythematosus and generalized lymphadenopathy.
The term ‘dapsone syndrome’ is applied to a skin rash and fever occurring 2–8 weeks after starting therapy and sometimes accompanied by lymphadenopathy, hepatomegaly, jaundice and/or mononucleosis.
Blood disorders include anemia, methemoglobinemia, sulfhemoglobinemia, hemolysis (notably in patients with glucose- 6-phosphate dehydrogenase deficiency), mononucleosis, leukopenia and, rarely, agranulocytosis. Severe anemia should be treated before patients receive dapsone.
The incidence of adverse reactions declined in the 1960s but reappeared around 1982 when multidrug therapy was introduced, and may represent an unexplained interaction with rifampicin.

Safety Profile

Poison by ingestion, intraperitoneal, and subcutaneous routes. Human systemic effects by ingestion: agranulocytosis, change in tubules and other kidney changes, cyanosis, effect on joints, hemolysis with or without anemia, jaundice, methemoglobinemiacarboxyhemoglobinemia, retinal changes, somnolence. Experimental reproductive effects. Can cause hepatitis, dermatitis, and neuritis. Questionable carcinogen with experimental carcinogenic and neoplastigenic data. Human mutation data reported. Used in leprosy treatment and veterinary medicine. When heated to decomposition it emits very toxic fumes of NOx and SOx. See also SULFONATES.

Synthesis

Dapsone, 4,4-diaminodiphenylsulfone (34.2.3), is synthesized from either 4-chloronitrobenzene or from the sodium salt of 4-acetamidobenzenesulfonic acid. Reacting 4-chloronitrobenzene with sodium sulfide gives 4,4-dinitrodiphenylthioester (34.2.1), and oxidation of the sulfur atom in this compound using potassium dichromate in sulfuric acid gives 4,4-dinitrodiphenylsulfone (34.2.2). Reduction of the nitro group in the resulting compound using tin dichloride in hydrochloric acid makes the desired dapsone.
It has also been suggested to reduce the nitro group to an amino group, protect it with an acetyl protection, oxidize the sulfur atom to a sulfone using potassium dichromate, and then remove the protective acetyl group by hydrolysis.

Another way of the synthesis of dapsone begins with 4-acetamidobenzenesulfonic acid, which is reacted with 4-chloronitrobenzene at high temperatures to give 4-acetamido-4- nitrodiphenylsulfone (34.2.4). Reducing the nitro group in this compound with tin dichloride in hydrochloric acid along with the simultaneous hydrolysis of the acetyl group under the reaction conditions gives the desired dapsone.

Drug interactions

Potentially hazardous interactions with other drugs
Antivirals: increased risk of ventricular arrhythmias with saquinavir - avoid.

Metabolism

Dapsone undergoes enterohepatic recycling. Dapsone is acetylated to monoacetyldapsone, the major metabolite, and other mono and diacetyl derivatives. Acetylation shows genetic polymorphism. Hydroxylation is the other major metabolic pathway resulting in hydroxylamine dapsone, which may be responsible for dapsoneassociated methaemoglobinaemia and haemolysis. Dapsone is mainly excreted in the urine, only 20% of a dose as unchanged drug.

4,4'-Diaminodiphenylsulfone(80-08-0)Related Product Information

• Phenyl sulfoxide
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• Diphenyl sulfone
• Bis(4-hydroxyphenyl) Sulfone
• (3,4-Diaminophenyl)phenylmethanone
• 4,4'-Oxydianiline
• 3,4'-DIAMINODIPHENYLMETHANE
• Tetradifon
• solasulfone
• BIS(4-NITROPHENYL) SULFONE
• ISOTHIOCYANATOPHENYL SULFONE
• DAPSONE HYDROXYLAMINE
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• Amidapsone
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• 3,3'-Sulfonyldianiline
• N-[5-amino-2-(4-aminophenyl)sulfonyl-phenyl]sulfonylacetamide