ADAPALENE

ADAPALENE

• Molecular FormulaC₂₈H₂₈O₃
• Average mass412.520 Da
• CD 271
• CD-271

CD-271, Differin, Differine

Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions.^[1] Studies have found adapalene is as effective as other retinoids, while causing less irritation.^[2] It also has several advantages over other retinoids. The adapalene molecule is more stable compared to tretinoin and tazarotene, which leads to less concern for photodegradation.^[2] It is also chemically more stable compared to the other two retinoids, allowing it to be used in combination with benzoyl peroxide.^[2] Due to its effects on keratinocyte proliferation and differentiation, adapalene is superior to tretinoin for the treatment of comedonal acne and is often used as a first-line agent. ^[3]

Adapalene is a third-generation topical retinoid with anti-comedogenic, comedolytic, and anti-inflammatory properties used to treat acne vulgaris in adolescents and adults.

SYN

AU 9047961; EP 0199636; US 4717720; US 5098895; US 5183889

J Med Chem 1995,38(26),4993

Friedel-Crafts condensation of 4-bromophenol (I) with 1-adamantanol (II) in the presence of H2SO4 yielded the adamantyl phenol (III). Subsequent alkylation of the sodium phenoxide of (III) with iodomethane produced the methyl ether (IV). The Grignard reagent (V), prepared from aryl bromide (IV), was converted to the organozincate derivative, and then subjected to a nickel-catalyzed cross-coupling with methyl 6-bromo-2-naphthoate (VI) to furnish adduct (VII). The target carboxylic acid was finally obtained by saponification of the methyl ester (VII).

SYN

CA 2021550; EP 0409740; FR 2649976; JP 1991063246; US 5073361; US 5149631

The bromination of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester (I) with Br2 in dichloromethane gives the dibromo derivative (II), which is hydrogenated with tritium gas over Pd/C in THF containing TEA to yield the bis tritiated ester (III). Finally, ester (III) is hydrolyzed with NaOH in refluxing methanol to afford the target tritiated naphthoic acid.

SYN

doi:10.1071/CH9732303c US4717720

SYN

Adapalene (CAS NO.: 106685-40-9), with its systematic name of 2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo(3.3.1.1(sup 3,7))dec-1-ylphenyl)-, could be produced through many synthetic methods.

Following is one of the synthesis routes:
Firstly, Friedel-Crafts condensation of 4-bromophenol (I) with 1-adamantanol (II) in the presence of H₂SO₄ yields the adamantyl phenol (III). Next, subsequent alkylation of the sodium phenoxide of (III) with iodomethane produces the methyl ether (IV). The Grignard reagent (V), prepared from aryl bromide (IV), is converted to the organozincate derivative, and then subjects to a nickel-catalyzed cross-coupling with methyl 6-bromo-2-naphthoate (VI) to furnish adduct (VII). Finally, the target carboxylic acid is obtained by saponification of the methyl ester (VII).

Synthesis Reference

Graziano Castaldi, Pietro Allegrini, Gabriele Razzetti, Mauro Ercoli, “Process for the preparation of adapalene.” U.S. Patent US20060229465, issued October 12, 2006.

US20060229465

PATENT

https://patents.google.com/patent/US8119834B2/en

The compound 6-[3-(l – Adamantyl) – 4 – methoxy phenyl] – 2 – naphthoic acid of Formula – I known as Adapalene is used in dermatology, particularly in the treatment of acne vulgaris and psoriasis.

Formula – 1

Adapalene was first time disclosed in the US patent No. 4,717,720 (herein after referred as ‘720) describe the preparation of compound of Formula – I using Negishi cross Coupling. In this reaction, 2-(l-adamantyl)-4-bromoanisole is converted to its organomagnesium compound followed by conversion to organozinc compound using zinc chloride and reacted with 6-bromo-2-methylnaphthoate employing transition metal as reaction catalyst such as palladium or nickel or one of its complexes with various phosphines. The reaction sequence is as shown in scheme – 1 below:

Scheme – 1 Another US patent No. 5,015,758 describe the process for preparation of 6[3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoate a penultimate step for preparation of Adapalene using Friedel – Crafts alkylation by reacting 1 – acetoxy adamantane with methyl – 6 – (4 – hydroxyphenyl) – 2 – naphthoate in presence of cone. Sulfuric acid in solvent n – heptane.

Another improved process was published in the journal, Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. The process involves the preparation of intermediates followed by Negishi cross Coupling, where in 2-(l-adamantyl)-4-bromophenol was prepared using 1 – adamentol and 4- bromo phenol in presence of 98% sulphuric acid and acetic acid, which on methylation with dimethyl sulfate and potassium carbonate in dry acetone yields 2-(l -adamantyl)-4-bromoanisole. The compound is reacted with magnesium to form Grignard reagent and then coupled with 6-bromo-2-methylnaphthoate in presence of novel Pd – Zn double metal catalyst to yield ester, which on saponification followed by treatment with acid yields Adapalene.

The recent published application WO 2006/108717 describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – 1. The application describes the preparation of 3-adamantyl-4-methoxyphenyl boronic acid from 2-(l-adamantyl)-4- bromoanisole using n-Butyl Lithium and triisopropyl borate in solvent tetrahydrofuran. Finally 3-adamantyl-4-methoxyphenyl boronic acid is reacted with 6-bromo-2-naphthoic acid involving Suzuki coupling in presence of Palladium acetate catalyst, a ligand 2 – (dicyclohexyl – phosphino) biphenyl, an inorganic base in solvent to get the compound adapalene.

Some of the drawbacks of the prior art processes include:

– The reported process in US patent 4717720, using Negishi cross coupling involves Grignard reaction. This requires anhydrous condition and a possibility of runaway reaction during Grignard reagent formation. Also the reaction involves the addition of fused ZnC12 and the preparation of the catalyst NiC12 (DPPE) complex, which needs to be freshly prepared increases the reaction step and has to be thoroughly dried before its use for coupling. Further the coupling reaction, results in the formation of dimer impurities during the organozinc compound reaction, with 2-(I -adamantyl)-4-bromoanisole and 6-bromo-2-methylnaphthoate respectively, which are difficult to remove. All these operations make the entire synthesis extremely sensitive and difficult to handle.

Some of the above drawbacks were addressed by the authors in the article published in Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. But the use of Pd catalyst with the ligand like PdCl₂ (PPh₃)₂ for the direct conversion of Grignard reagent employing ZnCYl in catalytic amount has its own limitations. The use of Grignard reagent, palladium catalyst with ligand and hygroscopic ZnCl₂ demerits this process for industrial application.

The recent published application WO 2006/108717; describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – I. The use of organo boronic acids for the Suzuki reaction has some limitations because of the indeterminate stoichiometry associated with the use of boronic acid, and its difficulty in purification and the byproducts formed during the reaction.

Therefore there remains a need for an improved process for preparing adapalene that eliminates or substantially reduces the impurities, decreases the number of steps, and employs a more robust process which is convenient and cost efficient.

Examples:

Example 1: Preparation of 3 – Adamantyl – 4 – methoxy phenyl potassium trifluoroborate:

In a 2.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 100.0 gm of 2-(l- adamantyl) 4-bromo anisole was charged in 600 ml tetrahydrofuran. The reaction mixture was cooled to -55 ± 5⁰C and 302 ml of 1.6 M n – butyl Lithium was slowly added and stirred. 87 ml of tri isopropyl borate was then charged and stirring was continued for 30 minutes at -55 ± 5°C. Cooling was removed and the temperature raised slowly to 25 – 30⁰C. 1.0 L of 1.2N hydrochloric acid was then charged and reaction mass was stirred for 30 minutes and separated the organic layer. The organic layer was charged in 1.0 L round bottom flask and freshly prepared aqueous solution of potassium hydrogen difluoride (230 gm, in 700 ml water) was added at 25 – 30⁰C and stirring was maintained till white precipitate is obtained. The mixture was continued under stirring and cooled to 0 – 5⁰C. The product, 3 – adamantyl – 4 – methoxyphenyl potassium trifluoroborate obtained was filtered, washed with 100 ml of ethyl acetate. The product was dried at 60 – 65°C till constant weight. Yield: 90.5 gm (83%), Purity: 99.0 % by HPLC.

Example 2: Preparation of 6 – [3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid:

In a 1.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 50.0 gm of 3 – Adamantyl – 4 – methoxyphenyl potassium trifluoroborate, 23 gm of 6- bromo -2-methyl napthoate in 300 ml tetrahydrofuran (THF) was charged. Stirred for 15 min and charged 3.0 gm of 5% Pd / C was and aqueous potassium hydroxide solution (50.0 gm in 300 ml water). Stirring was continued and the temperature was raised to reflux. The reaction mass was maintained for 10 hours at reflux and after the completion of the reaction, 200 ml of tetrahydrofuran: water (1 : 1) mixture was added and then filtered through hyflow bed at 45-50⁰C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-50⁰C. 500 ml water was charged and the reaction mass was stirred. The aqueous layer was acidified with 1.2N hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH. The solid product obtained was dried at 70 – 75°C till constant weight to get 6 – [3-(l- adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid.

The dried product was taken in 300 ml of tetrahydrofuran and stirred. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and cooled the reaction mass to 25 – 30⁰C. 500 ml of n – heptane was charged to the reaction mass and stirred for 30 minutes. The reaction mass was then chilled to 0 – 5°C and maintained stirring at 0 – 5°C temperature for 2.0 hours. The precipitated solid was filtered and washed with n – heptane. The pure crystalline 6 – [3-(l- adamantyl) – 4 methoxyphenyl] – 2 – naphthoic acid thus obtained was then dried till constant weight. Yield = 40 – 42 gms (68 – 72 %)

PATENT

https://pubs.acs.org/doi/10.1021/op050223f

Strategies that were adopted during the process development of adapalene to achieve a cost-effective commercial-scale synthesis are described herein. These included (1) the use of AcOH/H₂SO₄ to afford 2-(1-adamantyl)-4-bromophenol in quantitative yield; (2) the dimethyl sulfate methylation to enhance the yield of methylation to 95%; (3) direct conversion of the Grignard reagent into methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoate by the catalysis of both PdCl₂(PPh₃)₂ and ZnCl₂ in high yield; (4) the use of EDTA-disodium salt dihydrate to ensure the heavy metal’s content within acceptable limits; (5) the use of toluene to simplify the original chromatographic purification to recrystallization. The pilot-scale synthesis of adapalene is described in detail in the Experimental Section.

6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic Acid (Adapalene, 1). Compound 7 (213 g, 0.5 mol) was treated with 2 N NaOH solution (8 L) in methanol under reflux for 8 h. After evaporation of methanol (7 L) and addition of water (1.5 L), the mixture was acidified until pH 1 with 6 N HCl and filtrated through Celite. The residue was washed with water (3 × 5 L), and recrystallized twice in THF (194 g/2 L/time) to give pure (99% HPLC) 1 (177 g, 85%), mp 320-322 °C.1 H NMR (400 MHz, DMSO-d6) δ 1.77 (6 H,s, H on 1-adamantyl), 2.07 (3 H, s, H on 1-adamantyl), 2.14 (6 H, s, H on 1-adamantyl), 3.87 (3 H, s, H on ArOCH3), 7.12 (1 H, d, J ) 8.4 Hz, 5-phenyl H), 7.58 (1 H, d, J ) 2.0 Hz, 2-phenyl H), 7.65 (1 H, dd, J ) 8.4 Hz, J ) 2.0 Hz, 6-phenyl H), 7.89 (1 H, d, J ) 8.8 Hz, 7-naphthyl H), 7.98 (1 H, d, J ) 8.8 Hz, 4-naphthyl H), 8.08 (1 H, d, J ) 8.8 Hz, 8-naphthyl H), 8.15 (1 H, d, J ) 8.8 Hz, 3-naphthyl H), 8.22 (1 H, s, 5-naphthyl H), 8.60 (1 H, s, 1-naphthyl H), 13.05 (1 H, s, -COOH); 13C NMR (100 MHz, DMSO-d6) δ 28.32, 36.47, 40.09, 55.28, 112.68, 123.99, 124.99, 125.38, 125.68, 125.85, 127.55, 128.25, 129.72, 130.13, 130.83, 131.46, 135.38, 138.00, 140.13, 158.53, 167.34.

Adapalene, namely 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, having the following chemical formula:

is disclosed in U.S. Pat. No. 4,717,720 and used in dermatology, in particular for the treatment of acne vulgaris and psoriasis.

According to U.S. Pat. No. 4,717,720 the synthesis is carried out by a coupling reaction between a magnesium, lithium or zinc derivative of a compound of formula (A) and a compound of formula (B), wherein X and Y are Cl, Br, F or I; R is hydrogen or alkyl; and Ad is 1-adamantyl

in an anhydrous solvent, in the presence of a metal transition or a complex thereof as a catalyst.

A number of alternative synthetic approaches have been suggested in order to reduce the preparation costs. Surprisingly, particularly advantageous proved the alternative synthesis of the invention, which makes use of easily-available, low-cost 6-hydroxy-2-naphthoic acid alkyl esters as intermediates, and provides good yields.

EXAMPLE 1Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester [adapalene methyl ester]

A round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (20 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added to the mixture, which is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (7-g; 24.4 mmol), water (0.88 g; 48.8 mmol) and THF (50 ml). The mixture is heated under reflux for 24 hours, then cooled to a temperature ranging from 50 to 55° C. and added with water, adjusting pH to a value below 7 with acetic acid. After cooling to a temperature of 15° C., the resulting product is filtered, thereby obtaining crystalline adapalene methyl ester (8.5 g; 20.08 mmol) in 82% yield.

¹H NMR: (300 MHz, DMSO), δ 8.6 (s, 1H), δ 8.3-7.8 (m, 6H), δ 7.7-7.5 (m, 2H), δ 7.1 (d, 1H), δ 3.9 (s, 3H), δ 3.85 (s, 3H), δ 2 (m, 9H), δ 1.7 (m, 6H).

EXAMPLE 2Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid sodium salt [adapalene sodium salt]

A round-bottom flask is loaded with adapalene methyl ester (7 g; 16.41 mmol), THF (42 ml), water (7 ml) and a 50% w/w sodium hydroxide aqueous solution (1.44 g; 18.05 mmol). The mixture is refluxed for 6 hours, then added with water (133 ml) and THF is distilled off to a residual content of approx. 5% w/w, heated to a temperature of about 80° C. until complete dissolution of the solid, then cooled to 15° C. The crystallized product is filtered and dried under vacuum in a static dryer at a temperature of 50° C., thereby obtaining adapalene sodium salt (6.7 g; 15.42 mmol) in 94% yield.

EXAMPLE 3Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid [adapalene]

A round-bottom flask is loaded with adapalene sodium salt (6.7 g; 15.42 mmol), THF (40 ml) and water (7 ml) and the mixture is refluxed until complete dissolution of the solid. The resulting solution is dropped into a 3% w/w acetic acid aqueous solution, keeping the temperature above 60-70° C., to precipitate adapalene acid (6.3 g; 15.27 mmol), which is filtered and dried under vacuum at a temperature of 50-60° C. The yield is 95%.

EXAMPLE 4Synthesis of adapalene methyl ester

A round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (20 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added. The mixture is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (9.1 g; 31.8 mmol), water (10.53 g; 585.3 mmol) and THF (50 ml). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C., added with water, and adjusted to pH lower than 7 with acetic acid. After cooling to 15° C., the resulting product is filtered, thereby obtaining adapalene methyl ester (9 g; 21.2 mmol) in 86% yield.

EXAMPLE 5Synthesis of adapalene methyl ester

A round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (15 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added. The mixture is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium carbonate (6.75 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (9.1 g; 31.8 mmol), water (8.11 g; 450.5 mmol) and THF (30 ml). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C., added with water, and adjusted to pH lower than 7 with acetic acid. After cooling to 15° C., the resulting product is filtered, thereby obtaining adapalene methyl ester (9.37 g; 21.96 mmol) in 90% yield.

EXAMPLE 6Synthesis of adapalene methyl ester

A round-bottom flask is loaded with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), THF (70 ml), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (7 g; 24.4 mmol), nickel chloride complexed with tri(cyclohexyl)phosphine (0.83 g; 1.2 mmol) and tri(cyclohexyl)phosphine (1.37 g; 4.88 mmol). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C. and added with water, then cooled to 15° C. The resulting product is filtered, thereby obtaining adapalene methyl ester (8.1 g; 19.0 mmol) in 78% yield.

PATENT

https://patents.google.com/patent/WO2008126104A2/en

The compound 6-[3-(l – Adamantyl) – 4 – methoxy phenyl] – 2 – naphthoic acid of Formula – I known as Adapalene is used in dermatology, particularly in the treatment of acne vulgaris and psoriasis.

Formula – 1

Adapalene was first time disclosed in the US patent No. 4,717,720 (herein after referred as ‘720) describe the preparation of compound of Formula – I using Negishi cross Coupling. In this reaction, 2-(l-adamantyl)-4-bromoanisole is converted to its organomagnesium compound followed by conversion to organozinc compound using zinc chloride and reacted with 6-bromo-2-methylnaphthoate employing transition metal as reaction catalyst such as palladium or nickel or one of its complexes with various phosphines. The reaction sequence is as shown in scheme – 1 below:

Scheme – 1 Another US patent No. 5,015,758 describe the process for preparation of 6[3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoate a penultimate step for preparation of Adapalene using Friedel – Crafts alkylation by reacting 1 – acetoxy adamantane with methyl – 6 – (4 – hydroxyphenyl) – 2 – naphthoate in presence of cone. Sulfuric acid in solvent n – heptane.

Another improved process was published in the journal, Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. The process involves the preparation of intermediates followed by Negishi cross Coupling, where in 2-(l-adamantyl)-4-bromophenol was prepared using 1 – adamentol and 4- bromo phenol in presence of 98% sulphuric acid and acetic acid, which on methylation with dimethyl sulfate and potassium carbonate in dry acetone yields 2-(l -adamantyl)-4-bromoanisole. The compound is reacted with magnesium to form Grignard reagent and then coupled with 6-bromo-2-methylnaphthoate in presence of novel Pd – Zn double metal catalyst to yield ester, which on saponification followed by treatment with acid yields Adapalene.

The recent published application WO 2006/108717 describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – 1. The application describes the preparation of 3-adamantyl-4-methoxyphenyl boronic acid from 2-(l-adamantyl)-4- bromoanisole using n-Butyl Lithium and triisopropyl borate in solvent tetrahydrofuran. Finally 3-adamantyl-4-methoxyphenyl boronic acid is reacted with 6-bromo-2-naphthoic acid involving Suzuki coupling in presence of Palladium acetate catalyst, a ligand 2 – (dicyclohexyl – phosphino) biphenyl, an inorganic base in solvent to get the compound adapalene.

Some of the drawbacks of the prior art processes include:

– The reported process in US patent 4717720, using Negishi cross coupling involves Grignard reaction. This requires anhydrous condition and a possibility of runaway reaction during Grignard reagent formation. Also the reaction involves the addition of fused ZnC12 and the preparation of the catalyst NiC12 (DPPE) complex, which needs to be freshly prepared increases the reaction step and has to be thoroughly dried before its use for coupling. Further the coupling reaction, results in the formation of dimer impurities during the organozinc compound reaction, with 2-(I -adamantyl)-4-bromoanisole and 6-bromo-2-methylnaphthoate respectively, which are difficult to remove. All these operations make the entire synthesis extremely sensitive and difficult to handle.

Some of the above drawbacks were addressed by the authors in the article published in Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. But the use of Pd catalyst with the ligand like PdCl₂ (PPh₃)₂ for the direct conversion of Grignard reagent employing ZnCYl in catalytic amount has its own limitations. The use of Grignard reagent, palladium catalyst with ligand and hygroscopic ZnCl₂ demerits this process for industrial application.

The recent published application WO 2006/108717; describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – I. The use of organo boronic acids for the Suzuki reaction has some limitations because of the indeterminate stoichiometry associated with the use of boronic acid, and its difficulty in purification and the byproducts formed during the reaction.

Therefore there remains a need for an improved process for preparing adapalene that eliminates or substantially reduces the impurities, decreases the number of steps, and employs a more robust process which is convenient and cost efficient.

The present inventors have come out with a novel process which ameliorates the problems in the prior art with a one – pot process for the preparation of adapalene by employing Suzuki – Miyaura coupling involving the use of novel reactant 3-adamantyl-4- methoxyphenyl potassium trifiuoroborate.

The novel compound 3 – Adamantyl – 4 – methoxy phenyl potassium trifiuoroborate, exhibit superb behavior in the Suzuki-Miyaura reaction and provides a powerful method for the preparation of 6 – [3-(I – Adamantyl) – 4 – methoxy phenyl] – 2 – naphthoic acid, the compound of Formula – I.

Formula – 1

Potassium organotrifluoroborates are air and moisture-stable crystalline solids which can be stored for extended periods of time making it more industrial friendly to use on large scale production.

The other advantage of the present invention is in the use of methyl ester of 6 – Bromo – 2 -naphthoic acid and isolating adapalane directly from the reaction instead of its methyl ester, the above process becomes more robust and eliminates the saponification step as reported in prior art. Also the use of readily and cheaply available Pd catalyst on carbon over the conventional and costlier Pd-catalyst with ligands offers further advantage to the current process.

Examples:

Example 1: Preparation of 3 – Adamantyl – 4 – methoxy phenyl potassium trifluoroborate:

In a 2.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 100.0 gm of 2-(l- adamantyl) 4-bromo anisole was charged in 600 ml tetrahydrofuran. The reaction mixture was cooled to -55 ± 5⁰C and 302 ml of 1.6 M n – butyl Lithium was slowly added and stirred. 87 ml of tri isopropyl borate was then charged and stirring was continued for 30 minutes at -55 ± 5°C. Cooling was removed and the temperature raised slowly to 25 – 30⁰C. 1.0 L of 1.2N hydrochloric acid was then charged and reaction mass was stirred for 30 minutes and separated the organic layer. The organic layer was charged in 1.0 L round bottom flask and freshly prepared aqueous solution of potassium hydrogen difluoride (230 gm, in 700 ml water) was added at 25 – 30⁰C and stirring was maintained till white precipitate is obtained. The mixture was continued under stirring and cooled to 0 – 5⁰C. The product, 3 – adamantyl – 4 – methoxyphenyl potassium trifluoroborate obtained was filtered, washed with 100 ml of ethyl acetate. The product was dried at 60 – 65°C till constant weight. Yield: 90.5 gm (83%), Purity: 99.0 % by HPLC.

Example 2: Preparation of 6 – [3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid:

In a 1.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 50.0 gm of 3 – Adamantyl – 4 – methoxyphenyl potassium trifluoroborate, 23 gm of 6- bromo -2-methyl napthoate in 300 ml tetrahydrofuran (THF) was charged. Stirred for 15 min and charged 3.0 gm of 5% Pd / C was and aqueous potassium hydroxide solution (50.0 gm in 300 ml water). Stirring was continued and the temperature was raised to reflux. The reaction mass was maintained for 10 hours at reflux and after the completion of the reaction, 200 ml of tetrahydrofuran: water (1 : 1) mixture was added and then filtered through hyflow bed at 45-50⁰C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-50⁰C. 500 ml water was charged and the reaction mass was stirred. The aqueous layer was acidified with 1.2N hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH. The solid product obtained was dried at 70 – 75°C till constant weight to get 6 – [3-(l- adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid.

The dried product was taken in 300 ml of tetrahydrofuran and stirred. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and cooled the reaction mass to 25 – 30⁰C. 500 ml of n – heptane was charged to the reaction mass and stirred for 30 minutes. The reaction mass was then chilled to 0 – 5°C and maintained stirring at 0 – 5°C temperature for 2.0 hours. The precipitated solid was filtered and washed with n – heptane. The pure crystalline 6 – [3-(l- adamantyl) – 4 methoxyphenyl] – 2 – naphthoic acid thus obtained was then dried till constant weight. Yield = 40 – 42 gms (68 – 72 %)

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Medical uses

Per the recommendations of the Global Alliance on Improving Outcomes of Acne, retinoids such as adapalene are considered first-line therapy in acne treatment and are to be used either independently or in conjunction with benzoyl peroxide and/or an antimicrobial agent, like clindamycin, for maximum efficacy.^[4][5] Furthermore, adapalene, like other retinoids, increases the efficacy and penetration of other topical acne medications that are used in conjunction with topical retinoids as well as hastens the improvement of the post-inflammatory hyperpigmentation caused by acne.^[4] In the long term, it can be used as maintenance therapy.^[4]

Off-label uses

Adapalene has the unique ability to inhibit keratinocyte differentiation and decrease keratin deposition. This property makes adapalene an effective treatment for keratosis pilaris and callus. It may be used by men undergoing foreskin restoration to reduce excess keratin that forms a layer on the exterior of the human penis after circumcision. Other non-FDA approved indications that have been reported in the literature include treatment of warts, molluscum contagiosum, Darier disease, photoaging, pigmentary disorders, actinic keratoses and alopecia areata.^[6]

Side effects

Adapalene is known to cause mild adverse effects such as photosensitivity, irritation, redness, dryness, itching, and burning.^[2] It is common (between 1% and 10% of users)^[7] to experience a brief sensation of warmth or stinging, as well as dry skin, peeling and redness during the first 2–4 weeks of using the medication.^[4][8] These effects are considered mild and generally decrease over time.^[4][8] Any serious allergic reaction is rare.^[8] Furthermore, of the three topical retinoids, adapalene is often regarded as the most tolerable.^[6]

In pregnancy

Use of topical adapalene in pregnancy has not been well studied, but has a theoretical risk of retinoid embryopathy.^[9] Thus far, there is no evidence that the cream causes problems in the baby if used during pregnancy. Use is at the consumer’s own risk.^[10]

According to the Drugs and Lactation Database, topical adapalene has poor systemic absorption and results in low blood levels (less than 0.025 mcg/L) despite long term use, suggesting that there is low risk of harm for a nursing infant.^[11] However, it is recommended that the topical medication should not be applied to the nipple or any other area that may come into direct contact with the infant’s skin.^[11]

Interactions

Adapalene has been shown to enhance the efficacy of topical clindamycin, although adverse effects are also increased.^[12][13] Application of adapalene gel to the skin 3–5 minutes before application of clindamycin enhances penetration of clindamycin into the skin, which may enhance the overall efficacy of the treatment as compared to clindamycin alone.^[14]

Pharmacology

Unlike the retinoid tretinoin (Retin-A), adapalene has also been shown to retain its efficacy when applied at the same time as benzoyl peroxide due to its more stable chemical structure.^[15] Furthermore, photodegradation of the molecule is less of a concern in comparison to tretinoin and tazarotene.^[6]

Pharmacokinetics

Absorption of adapalene through the skin is low. A study with six acne patients treated once daily for five days with two grams of adapalene cream applied to 1,000 cm² (160 sq in) of skin found no quantifiable amounts, or less than 0.35 ng/mL of the drug, in the patients’ blood plasma.^[16] Controlled trials of chronic users of adapalene have found drug levels in the patients’ plasma to be 0.25 ng/mL.^[9]

Pharmacodynamics

Adapalene is highly lipophilic. When applied topically, it readily penetrates hair follicles and absorption occurs 5 minutes after topical application.^[2] After penetration into the follicle, adapalene binds to nuclear retinoic acid receptors (namely retinoic acid receptor beta and gamma).^[5][9] These complexes then bind to the retinoid X receptor which induces gene transcription by binding to specific DNA sites, thus modulating downstream keratinocyte proliferation and differentiation.^[2][9] This results in normalization of keratinocyte differentiation, allowing for decreased microcomedone formation, decreased clogging of pores, and increased exfoliation by increasing cell turnover.^[6][9][17] Adapalene is also regarded as an anti-inflammatory agent, as it suppresses the inflammatory response stimulated by the presence of Cutibacterium acnes,^[6] and inhibits both lipoxygenase activity and the oxidative metabolism of arachidonic acid into prostaglandins.^[9]

Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma when applied to epithelial cells such as those found in the skin.^[18] Its agonism of the gamma subtype is largely responsible for adapalene’s observed effects. In fact, when adapalene is applied in conjunction with a retinoic acid receptor gamma antagonist, adapalene loses clinical efficacy.^[19]

Retinization is a common temporary phenomenon reported by patients when initiating use of retinols.^[20] Within the initial period of treatment, skin can become red, irritated, dry and may burn or itch from retinol application; however, this tends to resolve within four weeks with once a day use.^[20]

History

Adapalene is a research product of Galderma Laboratories, France.^[21] Adapalene was approved in 1996 by the U.S. Food and Drug Administration (FDA) for use in the treatment of acne.^[22]

Research

A study has concluded that adapalene can be used to treat plantar warts and may help clear lesions faster than cryotherapy.^[23]

References

External links

• “Adapalene”. Drug Information Portal. U.S. National Library of Medicine.

Adapalene

Clinical data
Trade names	Differin, Pimpal, Gallet, Adelene, Adeferin
AHFS/Drugs.com	Monograph
MedlinePlus	a604001
License data	US DailyMed: Adapalene
Pregnancy category	AU: D
Routes of administration	Topical
Drug class	Retinoids
ATC code	D10AD03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) / S3 CA: ℞-only UK: POM (Prescription only) US: OTC / Rx-only
Pharmacokinetic data
Bioavailability	Very low[medical citation needed]
Excretion	Bile
Identifiers
show IUPAC name
CAS Number	106685-40-9
PubChem CID	60164
IUPHAR/BPS	5429
DrugBank	DB00210
ChemSpider	54244
UNII	1L4806J2QF
KEGG	D01112
ChEBI	CHEBI:31174
ChEMBL	ChEMBL1265
CompTox Dashboard (EPA)	DTXSID5046481
ECHA InfoCard	100.149.379
Chemical and physical data
Formula	C28H28O3
Molar mass	412.529 g·mol−1
3D model (JSmol)	Interactive image
show SMILES
show InChI
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/////////////////ADAPALENE, CD 271, CD-271, ANTIACNE, Differin, Differine

COC1=C(C=C(C=C1)C1=CC2=C(C=C1)C=C(C=C2)C(O)=O)C12CC3CC(CC(C3)C1)C2