Adapalene, CD-271, Differin, Differine, -Drug Synthesis Database

【结构式】

【药物名称】Adapalene, CD-271, Differin, Differine

【化学名称】6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid
　　　　　　6-(4-Methoxy-3-(tricyclo[3.3.1.1(3,7)]dec-1-yl)phenyl)-2-naphthoic acid

【CA登记号】106685-40-9

【分子式】C₂₈H₂₈O₃

【分子量】412.53356

【开发单位】Galderma (Originator), Sanofi-synthélabo (Licensee)

【药理作用】Acne Therapy, DERMATOLOGIC DRUGS, Immunologic Neuromuscular Disorders, Treatment of, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, Retinoids

合成路线1 合成路线2

合成路线1

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).

参考文献中间体

【1】 Charpentier, B.; et al.; Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. J Med Chem 1995, 38, 26, 4993.
【2】 Shroot, B.; Eustache, J.; Bernardon, J.M. (Laboratoires Galderma SA); Benzonaphthalenic acid derivs., process for their preparation and their use in pharmacy and cosmetics. AU 9047961; EP 0199636; US 4717720; US 5098895; US 5183889 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	25313	4-bromophenol	106-41-2	C₆H₅BrO	详情	详情
(II)	52642	1-Adamantanol; 1-Hydroxyadamantane; Tricyclo[3.3.1.1]decan-1-ol	768-95-6	C₁₀H₁₆O	详情	详情
(III)	59536	2-(1-adamantyl)-4-bromophenol		C₁₆H₁₉BrO	详情	详情
(IV)	59537	1-(5-bromo-2-methoxyphenyl)adamantane; 2-(1-adamantyl)-4-bromophenyl methyl ether		C₁₇H₂₁BrO	详情	详情
(V)	59538	[3-(1-adamantyl)-4-methoxyphenyl](bromo)magnesium		C₁₇H₂₁BrMgO	详情	详情
(VI)	59539	6-Bromo-2-naphthoic acid methyl ester; Methyl 6-bromo-2-naphthoate	33626-98-1	C₁₂H₉BrO₂	详情	详情
(VII)	59540	methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate		C₂₉H₃₀O₃	详情	详情

合成路线2

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.

参考文献中间体

【1】 Shroot, B.; Darmon, M. (Laboratoires Galderma SA); Novel tritium marked cpds., its preparation and application for finding of retinoid nuclear receptors. CA 2021550; EP 0409740; FR 2649976; JP 1991063246; US 5073361; US 5149631 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	62999	methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate; methyl 6-[4-(methyloxy)-3-tricyclo[3.3.1.1~3,7~]dec-1-ylphenyl]-2-naphthalenecarboxylate	C₂₉H₃₀O₃	详情	详情
(II)	63000	methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate; methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate	C₂₉H₂₈Br₂O₃	详情	详情
(III)	63001	methyl 6-[4-(methyloxy)-3-tricyclo[3.3.1.1~3,7~]dec-1-ylphenyl]-2-naphthalenecarboxylate; methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate	C₂₉H₃₀O₃	详情	详情

Extended Information