106685-41-0

Basic information

• Product Name: Mehtyl 6-[3-(1-adamanty)-4-methoxy phenyl]-2-naphthoate
• Synonyms: METHYL 6-[3-(1-ADAMANTYL)-4-METHOXYPHENYL]-2-NAPHTHOATE;Mehtyl 6-[3-(1-adamanty)-4-methoxy phenyl]-2-naphthoate;Mehtyl 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoate;6-[3-(1-Adamantyl-4-methoxyphenyl]-2-naphthatemethylester;Methyl6-[3-(1-adamanty)-4-methoxyphenyl]-2-naphthoate;Mehtyl 6-[3-(1-adamanty)-4-methoxy phenyl]-2-naphthoate(Adapalene);METYL 6-[3-(1-ADAMANTYL)-4-METHOXY PHENYL]-2-NAPHTHOATE;Mehtyl 6-[3-(1-adamanty)-4-methoxy
• CAS NO: 106685-41-0
• Molecular Formula: C₂₉H₃₀O₃
• Molecular Weight: 426.55
• EINECS: 1806241-263-5
• Product Categories: APIs Intermediate;ADAPALENE;(intermediate of adapalene);Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;Heterocycles
• Mol File: 106685-41-0.mol
• Article Data: 16

Chemical Properties

• Melting Point: 223-225°C
• Boiling Point: 589.632 °C at 760 mmHg
• Flash Point: 258.722 °C
• Appearance: white to off white crystal
• Density: 1.186 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.627
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly)
• CAS DataBase Reference: Mehtyl 6-[3-(1-adamanty)-4-methoxy phenyl]-2-naphthoate(CAS DataBase Reference)
• NIST Chemistry Reference: Mehtyl 6-[3-(1-adamanty)-4-methoxy phenyl]-2-naphthoate(106685-41-0)
• EPA Substance Registry System: Mehtyl 6-[3-(1-adamanty)-4-methoxy phenyl]-2-naphthoate(106685-41-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/38
• Safety Statements: 26
• Hazardous Substances Data: 106685-41-0(Hazardous Substances Data)

Usage

Chemical Properties

White to Off-White Solid

Uses

Adapalene intermediate

InChI:InChI=1/C29H30O3/c1-31-27-8-7-24(14-26(27)29-15-18-9-19(16-29)11-20(10-18)17-29)22-3-4-23-13-25(28(30)32-2)6-5-21(23)12-22/h3-8,12-14,18-20H,9-11,15-17H2,1-2H3

Synthetic route

3-(1-adamantyl)-4-methoxyphenylboronic acid (459423-32-6) + methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With sodium carbonate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In tetrahydrofuran; water Product distribution / selectivity; Suzuki-Miyaura cross-coupling; Inert atmosphere; Reflux;	92%
Suzuki-Miyaura coupling;

3-(1-adamantyl)-4-methoxyphenylboronic acid (459423-32-6) + 2-methoxycarbonyl-6-(p-tolylsulfonyl)naphthalene (366799-67-9) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: tris(3-hydroxypropyl)phosphine; nickel dichloride In tetrahydrofuran for 1h; Heating / reflux; Stage #2: 3-(1-adamantyl)-4-methoxyphenylboronic acid; 2-methoxycarbonyl-6-(p-tolylsulfonyl)naphthalene With water; potassium carbonate In tetrahydrofuran at 50℃; for 24h; Product distribution / selectivity; Heating / reflux;	90%
Stage #1: tris(3-hydroxypropyl)phosphine; nickel dichloride In tetrahydrofuran for 1h; Heating / reflux; Stage #2: 3-(1-adamantyl)-4-methoxyphenylboronic acid; 2-methoxycarbonyl-6-(p-tolylsulfonyl)naphthalene With potassium phosphate; water In tetrahydrofuran at 50℃; for 24h; Product distribution / selectivity; Heating / reflux;	82%
With potassium phosphate; bis(tricyclohexylphosphine)nickel(II) dichloride; tricyclohexylphosphine In tetrahydrofuran for 24h; Product distribution / selectivity; Heating / reflux;	78%

methyl 6-bromo-2-naphthoate (33626-98-1) + 2-(1-adamantyl)-4-bromoanisole (104224-63-7) → 3,3'-diadamantyl-4,4'-dimethoxybiphenyl (932033-57-3) + 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: 2-(1-adamantyl)-4-bromoanisole With magnesium; ethylene dibromide In tetrahydrofuran at 45 - 55℃; for 1.5h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 20 - 25℃; for 1h; Stage #3: methyl 6-bromo-2-naphthoate; 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In tetrahydrofuran at 20℃; for 2h;	A n/a B 88.83%

2-(3-adamantan-1-yl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1036766-56-9) + methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With potassium phosphate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate In tetrahydrofuran; water Product distribution / selectivity; Suzuki-Miyaura cross-coupling; Inert atmosphere; Reflux;	87%
With sodium carbonate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In tetrahydrofuran; water Product distribution / selectivity; Suzuki-Miyaura coupling; Inert atmosphere;	85%

methyl 6-bromo-2-naphthoate (33626-98-1) + 2-(1-adamantyl)-4-bromoanisole (104224-63-7) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: 2-(1-adamantyl)-4-bromoanisole With iodine; magnesium In tetrahydrofuran at 40℃; for 1h; Inert atmosphere; Stage #2: methyl 6-bromo-2-naphthoate With bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride In tetrahydrofuran at 55℃; for 0.75h; Negishi Coupling;	86%
Stage #1: 2-(1-adamantyl)-4-bromoanisole With magnesium; ethylene dibromide In tetrahydrofuran at 20 - 40℃; for 0.5h; Heating / reflux; Stage #2: With zinc(II) chloride In tetrahydrofuran for 1.25h; Heating / reflux; Stage #3: methyl 6-bromo-2-naphthoate; 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In tetrahydrofuran for 2.16667h;	50%
With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; iodine; magnesium; zinc(II) chloride Yield given. Multistep reaction;

C19H25BO3 (1036766-57-0) + methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With potassium carbonate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In tetrahydrofuran; water Product distribution / selectivity; Suzuki-Miyaura cross-coupling; Inert atmosphere; Reflux;	86%

3-(1-adamantyl)-4-methoxybenzene magnesium bromide (1036766-54-7) + methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride at 55℃; for 0.75h; Negishi coupling reaction;	86%

methyl 6-iodonaphthalene-2-carboxylate (5042-98-8) + lithium [3-(1-adamantyl)-4-methoxyphenyl]trimethoxyborate → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
for 21h; Suzuki-Miyaura Coupling; Flow reactor;	86%

2-(4’-methoxyphenyl)naphthalene-6-methyl ester + 1-adamanthanol (768-95-6) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With sulfuric acid In chloroform at 20℃; Solvent;	83%

6-(3-adamantan-1-yl-4-hydroxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-43-2) + methyl iodide (74-88-4) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: 6-(3-adamantan-1-yl-4-hydroxyphenyl)naphthalene-2-carboxylic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 1.5h;	82%

adapalene (106685-40-9) + diazomethyl-trimethyl-silane (18107-18-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
In tetrahydrofuran; methanol at 0 - 20℃; for 1h;	79%

methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: bis(pinacol)diborane; palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 100 °C 1.2: 80 - 100 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C 2.2: 1.5 h / 20 °C View Scheme

4-bromo-phenol (106-41-2) + p-bromo-anisole (?) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 86 percent / conc. H2SO4 / CH2Cl2 / 8 h / Ambient temperature 2: 1.) NaH / 1.) DMF, RT, 1 h, 2.) DMF, 20 deg C, 2 h 3: 1.) Mg, I2, 2.) ZnCl2, 3.) NiCl2*1,2-bis(diphenylphosphino)ethane View Scheme

1-adamanthanol (768-95-6) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 86 percent / conc. H2SO4 / CH2Cl2 / 8 h / Ambient temperature 2: 1.) NaH / 1.) DMF, RT, 1 h, 2.) DMF, 20 deg C, 2 h 3: 1.) Mg, I2, 2.) ZnCl2, 3.) NiCl2*1,2-bis(diphenylphosphino)ethane View Scheme
Multi-step reaction with 4 steps 1: sulfuric acid; acetic acid / 48 h / 20 °C 2: potassium carbonate / acetone / 8 h / Reflux 3: magnesium / tetrahydrofuran / 1 h / 40 °C 4: bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride / 0.75 h / 55 °C View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid; acetic acid / 4.17 h / 20 - 70 °C 2.1: potassium carbonate / acetone / 4.25 - 6.25 h / 20 °C / Heating / reflux 3.1: magnesium; ethylene dibromide / tetrahydrofuran / 0.5 h / 20 - 40 °C / Heating / reflux 3.2: 1.25 h / Heating / reflux 3.3: 2.17 h View Scheme

2-(1-adamantyl)-4-bromophenol (104224-68-2) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) NaH / 1.) DMF, RT, 1 h, 2.) DMF, 20 deg C, 2 h 2: 1.) Mg, I2, 2.) ZnCl2, 3.) NiCl2*1,2-bis(diphenylphosphino)ethane View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 8 h / Reflux 2: magnesium / tetrahydrofuran / 1 h / 40 °C 3: bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride / 0.75 h / 55 °C View Scheme
Multi-step reaction with 2 steps 1.1: bis(pinacol)diborane; palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 100 °C 1.2: 80 - 100 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C 2.2: 1.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetone / 4.25 - 6.25 h / 20 °C / Heating / reflux 2.1: magnesium; ethylene dibromide / tetrahydrofuran / 0.5 h / 20 - 40 °C / Heating / reflux 2.2: 1.25 h / Heating / reflux 2.3: 2.17 h View Scheme

Conditions	Yield
With sulfuric acid In ethanol; cyclohexane; nitrogen

Conditions	Yield
Stage #1: 6-(3-adamantan-1-yl-4-hydroxyphenyl)naphthalene-2-carboxylic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 1.5h;

→ 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With sodium carbonate In water at 80℃; for 4h; Inert atmosphere;

4-bromo-phenol (106-41-2) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid; acetic acid / 48 h / 20 °C 2: potassium carbonate / acetone / 8 h / Reflux 3: magnesium / tetrahydrofuran / 1 h / 40 °C 4: bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride / 0.75 h / 55 °C View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid; acetic acid / 4.17 h / 20 - 70 °C 2.1: potassium carbonate / acetone / 4.25 - 6.25 h / 20 °C / Heating / reflux 3.1: magnesium; ethylene dibromide / tetrahydrofuran / 0.5 h / 20 - 40 °C / Heating / reflux 3.2: 1.25 h / Heating / reflux 3.3: 2.17 h View Scheme

2-(1-adamantyl)-4-bromoanisole (104224-63-7) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium / tetrahydrofuran / 1 h / 40 °C 2: bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride / 0.75 h / 55 °C View Scheme
Multi-step reaction with 2 steps 1: n-butyllithium 2: 21 h / Flow reactor View Scheme

adapalene (106685-40-9) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 4 h / 80 °C 2: potassium carbonate / ethyl acetate; water / 4 h / 0 - 20 °C View Scheme

6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid chloride (106685-64-7) + N-methoxylamine hydrochloride (593-56-6) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With potassium carbonate In water; ethyl acetate at 0 - 20℃; for 4h;

2-methoxycarbonyl-6-naphthol p-toluenesulfonate → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium phosphate tribasic trihydrate; bis(triphenylphosphine)nickel(II) chloride; 1-n-butyl-3-methylimidazolim bromide / toluene / 6 h / 110 °C / Inert atmosphere 2: sulfuric acid / chloroform / 20 °C View Scheme

4-methoxyphenylboronic acid (5720-07-0) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium phosphate tribasic trihydrate; bis(triphenylphosphine)nickel(II) chloride; 1-n-butyl-3-methylimidazolim bromide / toluene / 6 h / 110 °C / Inert atmosphere 2: sulfuric acid / chloroform / 20 °C View Scheme

6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid potassium salt

Conditions	Yield
With potassium hydroxide; tetrabutylammomium bromide In methanol; toluene for 3h; Heating / reflux;	99.18%
With potassium hydroxide; water In tetrahydrofuran; 1,4-dioxane at 90℃; for 6h; Product distribution / selectivity; Heating / reflux;	94%
With potassium hydroxide; water In 1,4-dioxane for 2.25 - 4.25h; Product distribution / selectivity; Heating / reflux;

6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → adapalene (106685-40-9)

Conditions	Yield
Stage #1: 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester With ethylene glycol; sodium hydroxide Stage #2: With hydrogenchloride In water Product distribution / selectivity;	97%
Stage #1: 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester With ethylene glycol; sodium hydroxide Stage #2: With hydrogenchloride In water Product distribution / selectivity;	96%
With water; sodium hydroxide In propylene glycol	89%

6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid sodium salt

Conditions	Yield
With sodium hydroxide; water In tetrahydrofuran for 6h; Heating / reflux;	94%
With sodium hydroxide; water In tetrahydrofuran; 1,4-dioxane at 90℃; for 6h; Heating / reflux;	94%

3-(1-adamantyl)-4-methoxyphenylboronic acid (459423-32-6) + methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With sodium carbonate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In tetrahydrofuran; water Product distribution / selectivity; Suzuki-Miyaura cross-coupling; Inert atmosphere; Reflux;	92%
Suzuki-Miyaura coupling;

3-(1-adamantyl)-4-methoxyphenylboronic acid (459423-32-6) + 2-methoxycarbonyl-6-(p-tolylsulfonyl)naphthalene (366799-67-9) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: tris(3-hydroxypropyl)phosphine; nickel dichloride In tetrahydrofuran for 1h; Heating / reflux; Stage #2: 3-(1-adamantyl)-4-methoxyphenylboronic acid; 2-methoxycarbonyl-6-(p-tolylsulfonyl)naphthalene With water; potassium carbonate In tetrahydrofuran at 50℃; for 24h; Product distribution / selectivity; Heating / reflux;	90%
Stage #1: tris(3-hydroxypropyl)phosphine; nickel dichloride In tetrahydrofuran for 1h; Heating / reflux; Stage #2: 3-(1-adamantyl)-4-methoxyphenylboronic acid; 2-methoxycarbonyl-6-(p-tolylsulfonyl)naphthalene With potassium phosphate; water In tetrahydrofuran at 50℃; for 24h; Product distribution / selectivity; Heating / reflux;	82%
With potassium phosphate; bis(tricyclohexylphosphine)nickel(II) dichloride; tricyclohexylphosphine In tetrahydrofuran for 24h; Product distribution / selectivity; Heating / reflux;	78%

methyl 6-bromo-2-naphthoate (33626-98-1) + 2-(1-adamantyl)-4-bromoanisole (104224-63-7) → 3,3'-diadamantyl-4,4'-dimethoxybiphenyl (932033-57-3) + 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: 2-(1-adamantyl)-4-bromoanisole With magnesium; ethylene dibromide In tetrahydrofuran at 45 - 55℃; for 1.5h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 20 - 25℃; for 1h; Stage #3: methyl 6-bromo-2-naphthoate; 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In tetrahydrofuran at 20℃; for 2h;	A n/a B 88.83%

2-(3-adamantan-1-yl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1036766-56-9) + methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With potassium phosphate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate In tetrahydrofuran; water Product distribution / selectivity; Suzuki-Miyaura cross-coupling; Inert atmosphere; Reflux;	87%
With sodium carbonate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In tetrahydrofuran; water Product distribution / selectivity; Suzuki-Miyaura coupling; Inert atmosphere;	85%

methyl 6-bromo-2-naphthoate (33626-98-1) + 2-(1-adamantyl)-4-bromoanisole (104224-63-7) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: 2-(1-adamantyl)-4-bromoanisole With iodine; magnesium In tetrahydrofuran at 40℃; for 1h; Inert atmosphere; Stage #2: methyl 6-bromo-2-naphthoate With bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride In tetrahydrofuran at 55℃; for 0.75h; Negishi Coupling;	86%
Stage #1: 2-(1-adamantyl)-4-bromoanisole With magnesium; ethylene dibromide In tetrahydrofuran at 20 - 40℃; for 0.5h; Heating / reflux; Stage #2: With zinc(II) chloride In tetrahydrofuran for 1.25h; Heating / reflux; Stage #3: methyl 6-bromo-2-naphthoate; 1,2-bis(diphenylphosphino)ethane nickel(II) chloride In tetrahydrofuran for 2.16667h;	50%
With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; iodine; magnesium; zinc(II) chloride Yield given. Multistep reaction;

C19H25BO3 (1036766-57-0) + methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With potassium carbonate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In tetrahydrofuran; water Product distribution / selectivity; Suzuki-Miyaura cross-coupling; Inert atmosphere; Reflux;	86%

3-(1-adamantyl)-4-methoxybenzene magnesium bromide (1036766-54-7) + methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride at 55℃; for 0.75h; Negishi coupling reaction;	86%

methyl 6-iodonaphthalene-2-carboxylate (5042-98-8) + lithium [3-(1-adamantyl)-4-methoxyphenyl]trimethoxyborate → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
for 21h; Suzuki-Miyaura Coupling; Flow reactor;	86%

2-(4’-methoxyphenyl)naphthalene-6-methyl ester + 1-adamanthanol (768-95-6) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With sulfuric acid In chloroform at 20℃; Solvent;	83%

6-(3-adamantan-1-yl-4-hydroxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-43-2) + methyl iodide (74-88-4) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: 6-(3-adamantan-1-yl-4-hydroxyphenyl)naphthalene-2-carboxylic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 1.5h;	82%

adapalene (106685-40-9) + diazomethyl-trimethyl-silane (18107-18-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
In tetrahydrofuran; methanol at 0 - 20℃; for 1h;	79%

methyl 6-bromo-2-naphthoate (33626-98-1) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: bis(pinacol)diborane; palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 100 °C 1.2: 80 - 100 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C 2.2: 1.5 h / 20 °C View Scheme

4-bromo-phenol (106-41-2) + p-bromo-anisole (?) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 86 percent / conc. H2SO4 / CH2Cl2 / 8 h / Ambient temperature 2: 1.) NaH / 1.) DMF, RT, 1 h, 2.) DMF, 20 deg C, 2 h 3: 1.) Mg, I2, 2.) ZnCl2, 3.) NiCl2*1,2-bis(diphenylphosphino)ethane View Scheme

1-adamanthanol (768-95-6) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 86 percent / conc. H2SO4 / CH2Cl2 / 8 h / Ambient temperature 2: 1.) NaH / 1.) DMF, RT, 1 h, 2.) DMF, 20 deg C, 2 h 3: 1.) Mg, I2, 2.) ZnCl2, 3.) NiCl2*1,2-bis(diphenylphosphino)ethane View Scheme
Multi-step reaction with 4 steps 1: sulfuric acid; acetic acid / 48 h / 20 °C 2: potassium carbonate / acetone / 8 h / Reflux 3: magnesium / tetrahydrofuran / 1 h / 40 °C 4: bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride / 0.75 h / 55 °C View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid; acetic acid / 4.17 h / 20 - 70 °C 2.1: potassium carbonate / acetone / 4.25 - 6.25 h / 20 °C / Heating / reflux 3.1: magnesium; ethylene dibromide / tetrahydrofuran / 0.5 h / 20 - 40 °C / Heating / reflux 3.2: 1.25 h / Heating / reflux 3.3: 2.17 h View Scheme

2-(1-adamantyl)-4-bromophenol (104224-68-2) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) NaH / 1.) DMF, RT, 1 h, 2.) DMF, 20 deg C, 2 h 2: 1.) Mg, I2, 2.) ZnCl2, 3.) NiCl2*1,2-bis(diphenylphosphino)ethane View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 8 h / Reflux 2: magnesium / tetrahydrofuran / 1 h / 40 °C 3: bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride / 0.75 h / 55 °C View Scheme
Multi-step reaction with 2 steps 1.1: bis(pinacol)diborane; palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 100 °C 1.2: 80 - 100 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C 2.2: 1.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetone / 4.25 - 6.25 h / 20 °C / Heating / reflux 2.1: magnesium; ethylene dibromide / tetrahydrofuran / 0.5 h / 20 - 40 °C / Heating / reflux 2.2: 1.25 h / Heating / reflux 2.3: 2.17 h View Scheme

2-(4’-methoxyphenyl)naphthalene-6-methyl ester + 1-acetyloxyadamantane (22635-62-7) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With sulfuric acid In ethanol; cyclohexane; nitrogen

methyl iodide (74-88-4) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Stage #1: 6-(3-adamantan-1-yl-4-hydroxyphenyl)naphthalene-2-carboxylic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 1.5h;

2-(3-adamantan-1-yl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1036766-56-9) + methyl 6-bromonaphthalene-1-carboxylate (93353-66-3) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With sodium carbonate In water at 80℃; for 4h; Inert atmosphere;

4-bromo-phenol (106-41-2) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid; acetic acid / 48 h / 20 °C 2: potassium carbonate / acetone / 8 h / Reflux 3: magnesium / tetrahydrofuran / 1 h / 40 °C 4: bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride / 0.75 h / 55 °C View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid; acetic acid / 4.17 h / 20 - 70 °C 2.1: potassium carbonate / acetone / 4.25 - 6.25 h / 20 °C / Heating / reflux 3.1: magnesium; ethylene dibromide / tetrahydrofuran / 0.5 h / 20 - 40 °C / Heating / reflux 3.2: 1.25 h / Heating / reflux 3.3: 2.17 h View Scheme

2-(1-adamantyl)-4-bromoanisole (104224-63-7) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium / tetrahydrofuran / 1 h / 40 °C 2: bis-triphenylphosphine-palladium(II) chloride; zinc(II) chloride / 0.75 h / 55 °C View Scheme
Multi-step reaction with 2 steps 1: n-butyllithium 2: 21 h / Flow reactor View Scheme

adapalene (106685-40-9) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 4 h / 80 °C 2: potassium carbonate / ethyl acetate; water / 4 h / 0 - 20 °C View Scheme

6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid chloride (106685-64-7) + N-methoxylamine hydrochloride (593-56-6) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
With potassium carbonate In water; ethyl acetate at 0 - 20℃; for 4h;

2-methoxycarbonyl-6-naphthol p-toluenesulfonate → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium phosphate tribasic trihydrate; bis(triphenylphosphine)nickel(II) chloride; 1-n-butyl-3-methylimidazolim bromide / toluene / 6 h / 110 °C / Inert atmosphere 2: sulfuric acid / chloroform / 20 °C View Scheme

4-methoxyphenylboronic acid (5720-07-0) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium phosphate tribasic trihydrate; bis(triphenylphosphine)nickel(II) chloride; 1-n-butyl-3-methylimidazolim bromide / toluene / 6 h / 110 °C / Inert atmosphere 2: sulfuric acid / chloroform / 20 °C View Scheme

6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid potassium salt

Conditions	Yield
With potassium hydroxide; tetrabutylammomium bromide In methanol; toluene for 3h; Heating / reflux;	99.18%
With potassium hydroxide; water In tetrahydrofuran; 1,4-dioxane at 90℃; for 6h; Product distribution / selectivity; Heating / reflux;	94%
With potassium hydroxide; water In 1,4-dioxane for 2.25 - 4.25h; Product distribution / selectivity; Heating / reflux;

6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → adapalene (106685-40-9)

Conditions	Yield
Stage #1: 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester With ethylene glycol; sodium hydroxide Stage #2: With hydrogenchloride In water Product distribution / selectivity;	97%
Stage #1: 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester With ethylene glycol; sodium hydroxide Stage #2: With hydrogenchloride In water Product distribution / selectivity;	96%
With water; sodium hydroxide In propylene glycol	89%

6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid sodium salt

Conditions	Yield
With sodium hydroxide; water In tetrahydrofuran for 6h; Heating / reflux;	94%
With sodium hydroxide; water In tetrahydrofuran; 1,4-dioxane at 90℃; for 6h; Heating / reflux;	94%

C22H22N4O7 + 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → C50H49N5O9

Conditions	Yield
With silver hexafluoroantimonate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium acetate In 1,2-dichloro-ethane at 140℃; for 18h; Inert atmosphere;	54%

phenylacetonitrile (140-29-4) + 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → (3r,5r,7r)-1-(2-methoxy-5-(6-((E)-styryl)naphthalen-2-yl)phenyl)adamantane

Conditions	Yield
Stage #1: 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester With lithium aluminium tetrahydride Stage #2: phenylacetonitrile	40%

6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester (106685-41-0) → 6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid hydroxyamide

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / methanol / 8 h / Reflux 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; hydroxylamine hydrochloride / 20 °C / Inert atmosphere View Scheme

Upstream product

• 459423-32-6 3-(1-adamantyl)-4-methoxyphenylboronic acid 
• 33626-98-1 methyl 6-bromo-2-naphthoate 
• 1036766-57-0 C₁₉H₂₅BO₃ 
• 106685-40-9 adapalene 
• 106685-64-7 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid chloride 
• 593-56-6 N-methoxylamine hydrochloride 
• 768-95-6 1-adamanthanol 
• 5720-07-0 4-methoxyphenylboronic acid 
• 18107-18-1 diazomethyl-trimethyl-silane 
• 5042-98-8 methyl 6-iodonaphthalene-2-carboxylate 
• 106685-43-2 6-(3-adamantan-1-yl-4-hydroxyphenyl)naphthalene-2-carboxylic acid methyl ester 
• 74-88-4 methyl iodide 
• 104224-63-7 2-(1-adamantyl)-4-bromoanisole 
• 106-41-2 4-bromo-phenol 

Downstream Products

• 106685-40-9 adapalene 

Relevant articles and documents

Preparation method of adapalene

The invention discloses a preparation method of adapalene. According to the preparation method of adapalene, 2-methoxycarbonyl-6-naphthol p-toluenesulfonate and 4-methoxyphenylboronic acid which are low in price and easy to obtain are used as raw materials and bis (triphenylphosphine) nickel chloride is used as a catalyst, Suzuki coupling is performed to obtain 6-(4-methoxyphenyl)-2-methyl naphthoate, then alkylation reaction with 1-adamantanol is made to obtain 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-methyl naphthoate, and finally ester hydrolysis is performed to obtain the target product adapalene. The method is simple in process, raw materials are available, the yield is high and the cost is low, and the quality can reach a satisfactory level.

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To investigate the influence of the adamantyl group on the biological properties of known HDAC inhibitors with a 4-phenylcinnamic skeleton, a series of compounds having the adamantyl moiety in the cap structure were synthesized and compared to the corresponding hydroxamic acids lacking this group. An unexpected finding was the substantial reduction of inhibitory activity toward the tested enzymes, in particular HDAC6, following the introduction of the adamantyl group. In spite of the reduced ability to function as HDAC inhibitors, the compounds containing the adamantyl moiety still retained a good efficacy as antiproliferative and proapoptotic agents. A selected compound (2c; ST3056) of this series exhibited an appreciable antitumor activity against the colon carcinoma xenograft HCT116.