66734-13-2

Basic information

• Product Name: Alclometasone-17,21-dipropionate
• Synonyms: (7a,11b,16a)-7-chloro-11-hydroxy-16-methyl-17,21-bis(1-oxopropoxy)pregna-1,4-diene-3,20-dione;alclometasone-17,21-dipropionate;alclovate;(7-alpha,11-beta,16-alpha)-xy);pregna-1,4-diene-3,20-dione,7-chloro-11-hydroxy-16-methyl-17,21-bis(1-oxopropo;sch22219;ALCLOMETASONE DIPROPIONATE (300 MG);7alpha-chloro-11beta,17,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione 17,21-di(propionate)
• CAS NO: 66734-13-2
• Molecular Formula: C₂₈H₃₇ClO₇
• Molecular Weight: 521.04
• EINECS: 266-464-3
• Mol File: 66734-13-2.mol
• Article Data: 5

Chemical Properties

• Melting Point: 212-216°
• Boiling Point: 613.3°C (rough estimate)
• Flash Point: 338.4 °C
• Appearance: /
• Density: 1.0766 (rough estimate)
• Vapor Pressure: 7.55E-19mmHg at 25°C
• Refractive Index: 1.4429 (estimate)
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility: Chloroform (Slightly), DMF (Slightly), Methanol (Slightly)
• PKA: 13.70±0.70(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: Alclometasone-17,21-dipropionate(CAS DataBase Reference)
• NIST Chemistry Reference: Alclometasone-17,21-dipropionate(66734-13-2)
• EPA Substance Registry System: Alclometasone-17,21-dipropionate(66734-13-2)

Safety Data

• Hazardous Substances Data: 66734-13-2(Hazardous Substances Data)

Usage

Description

Alclometasone dipropionate (ACM) is a synthetic nonfluorinated corticosteroid which has been marketed since 1986 for the topical treatment of inflammatory and pruritic corticosteroid-responsive dermatoses. As esterification of the hydroxyl group at positions 17 and 21 of the alclometasone molecule enhances topical anti-inflammatory activity, the dipropionate salt of alclometasone is much more potent than alclometasone itself. It reduces cutaneous anaphylaxis reactions induced by tuberculin or albumin in mice when administered topically (20 μl of a 0.1% solution). ACM also inhibits androgen-dependent cytochrome P450 activity and the O-depropylation activity of 7-alkoxy-coumarin O-dealkylase in a dose-dependent manner in male rats but has no effect on hepatic drug metabolism in female rats or mice of both sexes. Formulations containing ACM have been used to treat radiation, allergic contact dermatitis and psoriasis.

Chemical Properties

Alclometasone dipropionate is a white powder, insoluble in water, slightly soluble in propylene glycol and moderately soluble in hexylene glycol. Crystallization from acetone-methanol-isopropyl ether.

Characteristics

The alclometasone dipropionate [7α-chloro-11β,17,21- trihydroxy-16α-methylpregna-1,4-dien-3,20-dione 17,21- dipropionate) molecule is obtained by insertion of a chlorine atom in position 7α of 16α-me thylprensoline 17,21-dipropionate. The unique properties of the compound result from the presence of a chlorine atom in position 7α instead of positions C6 or C9, which increases the potency of its effect without increasing the incidence of local and systemic adverse effects. Additionally, as a highly lipophilic compound, alclometasone dipropionate rapidly penetrates into the skin where its active metabolites bind to specific receptors.

Uses

Alclometasone dipropionate is a corticosteroid used topically for its glucocorticoid activity in the treatment of various skin disorders. It is usually used as a cream or ointment containing 0.05%. It is topically used in dermatology as an anti-inflammatory, antipruritic, antiallergic, antiproliferative and vasoconstrictive agent. Alclometasone dipropionate has been used since 1986 for the treatment of corticosteroid-responsive dermatoses. It is ranked in Group 6 based on potency and has been dassified as group D. According to the A-D grouping, patch-test reactions occur six to seven times more frequently within well-defined groups of structurally related chemicals than between corticosteroids of different groups.

Definition

ChEBI: Alclometasone dipropionate is a prednisolone compound having an alpha-chloro substituent at the 7-position, an alpha-methyl substituent at the 16-position and O-propanoyl groups at the 17- and 21-positions. It has a role as an anti-inflammatory drug. It is a 20-oxo steroid, an 11beta-hydroxy steroid, a glucocorticoid, a steroid ester, a propanoate ester, a 3-oxo-Delta(1),Delta(4)-steroid and a chlorinated steroid. It is functionally related to a prednisolone.

Preparation

Alclometasone dipropionate synthesis: The dehydrogenation of 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione-21-acetate (I) with dichlorodicyanobenzoquinone (II) in dioxane HCl gives 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-21-acetate (III), which is hydrolyzed with aqueous NaHCO3 to the corresponding free triol (IV). The reaction of (IV) with triethyl orthopropionate (A) by means of p-toluenesulfonic acid in DMSO yields 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17,21-ethylorthopropionate (V), which is hydrolyzed partially with acetic acid to 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17-propionate (VI). The acylation of (VI) with propionic anhydride affords 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17,21-dipropionate (VII), which is finally treated with dry HCl in dioxane.

Brand name

Aclovate (GlaxoSmithKline), Aclosone, Legederm, Almeta, Vaderm, Modrasone, Delonal.

Therapeutic Function

Antiinflammatory, Antiallergic

Side effects

The following local adverse reactions have been reported with alclometasone dipropionate cream in approximately 2% of patients: itching and burning, erythema, dryness, irritation, and papular rashes.The following local adverse reactions have been reported with alclometasone dipropionate ointment in approximately 1% of patients: itching, burning, and erythema. The following additional local adverse reactions have been reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in approximate decreasing order of occurrence: folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria.

Safety Profile

Alclometasone dipropionate has been classified as the FDA category C of drug safety during pregnancy (irrespective of the trimester of pregnancy), which means that it should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus. The safety of alclometasone use in paediatric patients below 1 year of age has not been established and there are no adequate, randomised studies in large patient groups.

Mode of action

At the cellular level, alclometasone dipropionate, like other glucocorticoids, after crossing the cell membrane binds to specific glucocorticoid receptors (GCR) in the cytoplasm. Subsequently, the glucocorticoid-GCR complex moves into the nucleus, where its binds to DNA at specific regions, known as the glucocorticoid response elements (GRE). At further stages, the expression of certain genes is either stimulated (transactivation) or inhibited (transuppression). In clinical practice, glucocorticoids are used for their anti-inflammatory, immunosuppressant and antiproliferative effects.

InChI:InChI=1/C28H37ClO7/c1-6-22(33)35-14-21(32)28(36-23(34)7-2)15(3)10-18-24-19(29)12-16-11-17(30)8-9-26(16,4)25(24)20(31)13-27(18,28)5/h8-9,11,15,18-20,24-25,31H,6-7,10,12-14H2,1-5H3/t15-,18+,19-,20+,24-,25+,26+,27+,28+/m1/s1

Synthetic route

16α-methyl-7,11-dihydroxy-17α,21-bispropionyloxypregna-4-ene-1,4-diene-3,20-dione → alclometasone dipropionate (66734-13-2)

Conditions	Yield
With pyridine; phosphorus trichloride In toluene at 40 - 45℃; Solvent; Reagent/catalyst; Green chemistry;	64.2%
With pyridine; phosphorus trichloride In toluene at 40 - 45℃; Solvent; Reagent/catalyst;	64.2 g

(7α,11β,16α)-7-hydroxy-11-hydroxy-16-methyl-17,21-bis(1-oxopropoxy)pregna-1,4-diene-3,20-dione → alclometasone dipropionate (66734-13-2)

Conditions	Yield
With pyridine; phosphorus trichloride In toluene at 40 - 45℃; Solvent; Reagent/catalyst;	64.2%

16α-methyl-11β,17α,21-trihydroxy-1,4,6-pregnatriene-3,20-dione 17,21-dipropionate (67212-74-2) → alclometasone dipropionate (66734-13-2)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane for 16h; Ambient temperature;	15%

16α-methyl-11β,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate (13209-52-4) → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 21 percent / HCl, DDQ / dioxane / 24 h / Ambient temperature 2: 53 percent / sat. aq. NaHCO3 / methanol / 2 h / Ambient temperature 3: TsOH*H2O / dimethylsulfoxide / 2 h / Ambient temperature 4: 1.) aq. AcOH, 2.) pyridine / 1.) RT, 1 h, 2.) RT, 3.5 h 5: 15 percent / HCl / dioxane / 16 h / Ambient temperature View Scheme

16α-methyl-11β,17α,21-trihydroxy-1,4,6-pregnatriene-3,20-dione (13954-10-4) → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: TsOH*H2O / dimethylsulfoxide / 2 h / Ambient temperature 2: 1.) aq. AcOH, 2.) pyridine / 1.) RT, 1 h, 2.) RT, 3.5 h 3: 15 percent / HCl / dioxane / 16 h / Ambient temperature View Scheme

16α-methyl-11β,17α,21-trihydroxy-1,4,6-pregnatriene-3,20-dione 21-acetate (13796-64-0) → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 53 percent / sat. aq. NaHCO3 / methanol / 2 h / Ambient temperature 2: TsOH*H2O / dimethylsulfoxide / 2 h / Ambient temperature 3: 1.) aq. AcOH, 2.) pyridine / 1.) RT, 1 h, 2.) RT, 3.5 h 4: 15 percent / HCl / dioxane / 16 h / Ambient temperature View Scheme

16α-methyl-11β,17α,21-trihydroxy-1,4,6-pregnatriene-3,20-dione 17α,21-ethylorthopropionate (67212-72-0) → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) aq. AcOH, 2.) pyridine / 1.) RT, 1 h, 2.) RT, 3.5 h 2: 15 percent / HCl / dioxane / 16 h / Ambient temperature View Scheme

3-ethylene ether-16α-methyl-17α,21-bispropionyloxy-pregnane-3,5-diene-7,11,20-trione → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / methanol / 25 - 30 °C / Green chemistry 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C / Green chemistry 3: pyridine; phosphorus trichloride / toluene / 40 - 45 °C / Green chemistry View Scheme
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate / methanol / 25 - 30 °C 1.2: 25 - 30 °C / pH 2 - 3 2.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 3.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; methanol / 25 - 30 °C 1.2: 25 - 30 °C / pH 2 - 3 2.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 3.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme

16α-methyl hydrocortisone → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: toluene-4-sulfonic acid / 20 - 25 °C / Green chemistry 2: acetic acid; chromium(VI) oxide / chloroform; water / 20 - 25 °C / Green chemistry 3: toluene-4-sulfonic acid / 30 - 35 °C / Green chemistry 4: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C / Green chemistry 5: sodium tetrahydroborate / methanol / 25 - 30 °C / Green chemistry 6: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C / Green chemistry 7: pyridine; phosphorus trichloride / toluene / 40 - 45 °C / Green chemistry View Scheme
Multi-step reaction with 7 steps 1.1: toluene-4-sulfonic acid / propionic acid / 20 - 25 °C 2.1: chromium(VI) oxide; water / chloroform / 20 - 25 °C 3.1: toluene-4-sulfonic acid / propionic acid / 30 - 35 °C 4.1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C 5.1: sodium tetrahydroborate / methanol / 25 - 30 °C 5.2: 25 - 30 °C / pH 2 - 3 6.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 7.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme
Multi-step reaction with 7 steps 1.1: toluene-4-sulfonic acid / 20 - 25 °C 2.1: acetic acid; chromium(VI) oxide / water / 20 - 25 °C 3.1: toluene-4-sulfonic acid / 30 - 35 °C 4.1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C 5.1: sodium tetrahydroborate; methanol / 25 - 30 °C 5.2: 25 - 30 °C / pH 2 - 3 6.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 7.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme

16α-methylhydrocortison-21-yl propionate → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: acetic acid; chromium(VI) oxide / chloroform; water / 20 - 25 °C / Green chemistry 2: toluene-4-sulfonic acid / 30 - 35 °C / Green chemistry 3: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C / Green chemistry 4: sodium tetrahydroborate / methanol / 25 - 30 °C / Green chemistry 5: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C / Green chemistry 6: pyridine; phosphorus trichloride / toluene / 40 - 45 °C / Green chemistry View Scheme
Multi-step reaction with 6 steps 1.1: chromium(VI) oxide; water / chloroform / 20 - 25 °C 2.1: toluene-4-sulfonic acid / propionic acid / 30 - 35 °C 3.1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C 4.1: sodium tetrahydroborate / methanol / 25 - 30 °C 4.2: 25 - 30 °C / pH 2 - 3 5.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 6.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme
Multi-step reaction with 6 steps 1.1: acetic acid; chromium(VI) oxide / water / 20 - 25 °C 2.1: toluene-4-sulfonic acid / 30 - 35 °C 3.1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C 4.1: sodium tetrahydroborate; methanol / 25 - 30 °C 4.2: 25 - 30 °C / pH 2 - 3 5.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 6.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme

C25H32O7 → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / 30 - 35 °C / Green chemistry 2: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C / Green chemistry 3: sodium tetrahydroborate / methanol / 25 - 30 °C / Green chemistry 4: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C / Green chemistry 5: pyridine; phosphorus trichloride / toluene / 40 - 45 °C / Green chemistry View Scheme
Multi-step reaction with 5 steps 1.1: toluene-4-sulfonic acid / propionic acid / 30 - 35 °C 2.1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C 3.1: sodium tetrahydroborate / methanol / 25 - 30 °C 3.2: 25 - 30 °C / pH 2 - 3 4.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 5.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme
Multi-step reaction with 5 steps 1.1: toluene-4-sulfonic acid / 30 - 35 °C 2.1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C 3.1: sodium tetrahydroborate; methanol / 25 - 30 °C 3.2: 25 - 30 °C / pH 2 - 3 4.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 5.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme

16α-methyl-17α,21-bispropionyloxy-pregna-4-ene-3,7,11,20-tetraone → alclometasone dipropionate (66734-13-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C / Green chemistry 2: sodium tetrahydroborate / methanol / 25 - 30 °C / Green chemistry 3: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C / Green chemistry 4: pyridine; phosphorus trichloride / toluene / 40 - 45 °C / Green chemistry View Scheme
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C 2.1: sodium tetrahydroborate / methanol / 25 - 30 °C 2.2: 25 - 30 °C / pH 2 - 3 3.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 4.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid / dichloromethane / 20 - 25 °C 2.1: sodium tetrahydroborate; methanol / 25 - 30 °C 2.2: 25 - 30 °C / pH 2 - 3 3.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 75 - 80 °C 4.1: pyridine; phosphorus trichloride / toluene / 40 - 45 °C View Scheme

alclometasone dipropionate (66734-13-2) → 7α-chloro-16α-methylprednisolone (67452-97-5)

Conditions	Yield
With sodium hydrogencarbonate In methanol for 4h; Ambient temperature;	35%

alclometasone dipropionate (66734-13-2) → 7α-chloro-16α-methylprednisolone 17-propionate

Conditions	Yield
In ethanol for 312h; Ambient temperature; malt diastase in water;

alclometasone dipropionate (66734-13-2) → 7α-chloro-16α-methylprednisolone 17-butyrate

Conditions	Yield
Multi-step reaction with 3 steps 1: 35 percent / NaHCO3 (aq.) / methanol / 4 h / Ambient temperature 2: p-TsOH*H2O / dimethylsulfoxide / 3 h / Ambient temperature 3: acetic acid / H2O / 1 h / Ambient temperature View Scheme

alclometasone dipropionate (66734-13-2) → 7α-chloro-16α-methylprednisolone 17,21-ethylorthobutyrate (76576-31-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 35 percent / NaHCO3 (aq.) / methanol / 4 h / Ambient temperature 2: p-TsOH*H2O / dimethylsulfoxide / 3 h / Ambient temperature View Scheme

alclometasone dipropionate (66734-13-2) → 7α-Chloro-11β,17α,21-trihydroxy-16α-methyl-5β-pregnane-3,20-dione 17,21-dipropionate

Upstream product

• 67212-74-2 16α-methyl-11β,17α,21-trihydroxy-1,4,6-pregnatriene-3,20-dione 17,21-dipropionate 
• 13954-10-4 16α-methyl-11β,17α,21-trihydroxy-1,4,6-pregnatriene-3,20-dione 
• 13796-64-0 16α-methyl-11β,17α,21-trihydroxy-1,4,6-pregnatriene-3,20-dione 21-acetate 
• 67212-72-0 16α-methyl-11β,17α,21-trihydroxy-1,4,6-pregnatriene-3,20-dione 17α,21-ethylorthopropionate 
• 13209-52-4 16α-methyl-11β,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate 

Downstream Products

• 67452-97-5 alclometasone 

Relevant articles and documents

Method for preparing etherified intermediate for alclometasone dipropionate

The invention provides a method for preparing an etherified intermediate for alclometasone dipropionate. 16a-methylhydrocortisone used as a raw material undergoes a four-step reaction comprising propionation at the 21-position, double oxidation at 7- and 11-positions into double ketones, propionation at the 17-position and enolification and etherification protection at the 3-position to synthesizethe etherified intermediate for alclometasone dipropionate. The method for preparing the etherified intermediate for alclometasone dipropionate from the 16a-methylhydrocortisone through the four-stepreaction has the advantages of short synthesis route, economical and environmentally-friendly process, simplicity in production operation, and high product yield; and the solvent used in production can be recovered and recycled, and so the method achieves easy industrial production.

Method of reduced intermediate used for alclometasone-17,21-dipropionate

The invention provides a method of a reduced intermediate used for alclometasone-17,21-dipropionate. The method comprises the steps that 16alpha-methlhydrocortisone as a raw material is subjected to 21-position propionic esterification, 7- and 11-position double oxidation to form diketone, 17-position propionic esterification, 3-position enolization etherification protection and 7- and 11-positiondiketone reduction and acid hydrolysis deprotection, and then the reduced intermediate used for the alclometasone-17,21-dipropionate is synthesized. In the method, the 16alpha-methlhydrocortisone serves as the raw material and is subjected to reactions in five steps to form the reduced intermediate used for the alclometasone-17,21-dipropionate, the technology has the advantages of being short insynthesis route, economical, environmentally friendly, simple in production operation and high in product yield; the solvent used in the production process can be recycled, and industrial production is easily implemented.

7α-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor

Novel 3,20-dioxo-7α-halogeno-1,4-pregnadienes are described and their use as anti-inflammatory agents. Preferred are 7α-bromo- and 7α-chloro- derivatives, particularly 7α-bromo- and 7α-chloro-1,4-pregnadienes-11β,17α,21-triol-3,20-dione 17,21-dihydrocarboncarboxylates, the 16-methyl and 16-methylene derivatives thereof being particularly valuable as topical anti-inflammatory agents.