* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium carbonate In N,N-dimethyl-formamide for 2 h;
To a stirred mixture of the product of Step A (0.5 g; 1.62 mmol) and K2CO3 (0.335 g; 2.42 mmol) in danhydrous DMF (5 ml) CH3I (1 ml) was added. The reaction mixture was stirred for 2 h and then diluted to 100 ml with H2O and extracted with EtOAc (100 ml). The organic layer was dried over MgSO4 and filtered. The filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the title compound (0.49 g, 94percent), as light yellow green solid. 1H-NMR (CDCI3) 7.27 - 7.22 (m, 2H); 6.31 (d, 1 H, J = 6.5 Hz); 3.78 (s, 3H); 2.04 (s, 10H); 1.74 (b, 5H).
78%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: at 20℃; for 2 h;
To a suspension of sodium hydride (60percent in mineral oil, 0.402g, 10.1 mmol) in 11 mL of DMF, 2-(1-adamantyl)-4-bromophenol 2 (2.75 g, 8.38 mmol) was slowly added, while maintaining the temperature at 20°C. The mixture was stirred at room temperature for 1 h, then methyl iodide (0.73 mL, 11.7 mmol) was added. After having stirred for additional 2 h at 20°C, the solution was poured into water and extracted with diethyl ether. The organic phase was dried and evaporated. The residue was purified by flash chromatography (hexane) to give 2.1 g (78percent) of 4-bromo-1-methoxy-2-(adamantan-1-yl)-benzene, mp 136°C. 1H NMR (300 MHz, CDCl3) : 1.75 (6H, s, 6Ad), 2.05 (9H, s, 9Ad), 3.80 (3H, s, OMe), 6.72 (1H, d, 1Ar, J = 8.0 Hz), 7.24 (1H, dd, 1Ar, J = 8.0, 2.2 Hz), 7.28 (1H, d, 1Ar, J = 2.2 Hz).
Reference：
[1] Patent: WO2010/43000, 2010, A1, . Location in patent: Page/Page column 80
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 14, p. 4863 - 4875
[3] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
[4] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[5] Patent: US4717720, 1988, A,
3
[ 104-92-7 ]
[ 768-95-6 ]
[ 104224-63-7 ]
Yield
Reaction Conditions
Operation in experiment
75%
With sulfuric acid In dichloromethane at 20℃; for 20 h;
1-(5-Bromo-2-methoxyphenyl)-adamantane [0145] [0146] Reagent grade concentrated H2S04 (11 mL) was added dropwise to a solution of 1- adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgS04 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder. [0147] Yield: 65 g (75percent) ; white solid; Rf= 0.9 in 25percent EtOAc-hexane. 1H NMR (CDC13, 300 MHz) No. 1.78 (s, 6H), 2.08 (s, 9H), 3.81 (s, 3H), 6.72 (d, 1H), 7.24 (dd, 1H), 7.28 (m, 1H)
75%
With sulfuric acid In dichloromethane at 20℃; for 20 h;
Reagent grade concentrated H2SO4 (11 mL) was added dropwise to a solution of 1- adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgSO4 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder.[0157] Yield: 48 g (75percent); white solid; Rf= 0.9 in 25percent EtOAc-hexane. IH NMR (CDC13, 300 MHz) D 1.78 (s, 6H)3 2.08 (s, 9H), 3.81 (s, 3H), 6.72 (d, IH)5 7.24 (dd, IH)5 7.28 (m, IH).
72%
With sulfuric acid In dichloromethane for 5 h;
Step A. 2-(1-adamantyl)-4-bromoanisoleExample 1; In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to separating funnel and the organic layer collected, which is neutralized by two portions of 100 mL 10percent sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72percent) with m.p. 140-141° C. is obtained.NMR (500 MHz, DMSO D6) δ: 1.75 (s, 6H), 2.03 (s, 9H), 3.81 (s, 3H), 6.82 (d, 1H, J=8 Hz), 7.17 (s, 1H), 7.23 (d, 1H, J=8 Hz).Scaling the synthesis up 10 times did not change either the yield or quality of the 2-(1-adamantyl)-4-bromoanisole.
72%
With sulfuric acid In dichloromethane for 5 h;
Step A. 2-(1-adamantyl)-4-bromoanisole; EXAMPLE 1In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) of sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to a separating funnel and the organic layer collected. It is neutralized by two portions of 100 mL 10percent sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at about 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72percent) with m.p. 140-141° C. is obtained.NMR (500 MHz, DMSO D6)δ: 1.75 (s, 6H), 2.03 (s, 9H), 3.81 (s, 3H), 6.82 (d, 1H, J=8 Hz), 7.17 (s, 1H), 7.23 (d, 1H, J=8 Hz).Scaling the synthesis up 10 times did not change either the yield or quality of the 2-(1-adamantyl)-4-bromoanisole
With potassium carbonate In acetone at 20℃; for 4.25 - 6.25 h; Heating / reflux
Example 4; Preparation of 2-(l-adamantyl)-4-bromoanisole (IV): A mixture of 2-(l-adamantyl)-4-bromophenol (III) (50 g, 162 mmol) and potassium carbonate (33.7 g, 216 mmol) in acetone (250 ml) was stirred at room temperature. Then dimethylsulphate (20.16 ml, 240 mmol) was added drop wise for 15 min at room temperature. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water, acidified with dilute HCl. The solid separated was filtered and washed with water. The solid was dissolved in dichloromethane (200 ml) and washed with water. The organic layer was dried over sodium sulphate, evaporated and the solid obtain was purified with ethyl acetate (200ml).[Yield: 30 g, 58 percent]; Example 5; Preparation of 2-(l-adamantyl)-4-bromoanisole (IV): To a solution of 2-(l-adamantyl)-4-Bromophenol (III) (50 g, 162 mmol) in acetone 200 ml, Potassium carbonate (33.7 g, 216 mmol) was added and stirred at RT. Dimethyl sulphate (20.53 ml, 244 mmol) was added dropwise for 15 min at RT. The reaction mixture was then refluxed for 4 hrs. The reaction mixture was further cooled to RT5 water was added, and the solid separated, was filtered and washed with acetone. The solid was then treated with 3N HCl till pH is about 5 to 6, filtered and washed with water and acetone and then finally dried to obtain compound (IV).[Yield: 38g, 73percent] [44 g, 84percent]
Reference：
[1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[2] Organic Process Research and Development, 2006, vol. 10, # 2, p. 285 - 288
[3] Patent: WO2007/125542, 2007, A2, . Location in patent: Page/Page column 15
5
[ 768-95-6 ]
[ 104224-63-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[2] Patent: WO2007/125542, 2007, A2,
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuran at 20 - 40℃; for 0.5 h; Heating / reflux Stage #2: With zinc(II) chloride In tetrahydrofuran for 1.25 h; Heating / reflux Stage #3: for 2.16667 h;
Example 6; Preparation of methyl ester of 6-[3-(l-adamantyl)-4methoxy phenyl]-2 naphthoate (V): A mixture of magnesium turnings (1.26 g, 51.85 mmol) in THF (10 ml) was stirred at room temperature and 2-(l-adamantyl)-4-bromoanisole (IV) (1.4 g, 4.36 mmol) and 1,2- dibromoethane (0.56 ml) were added under nitrogen atmosphere. The reaction mixture was heated at 40°C for initiation, and then 2-(l-adamantyl)-4-bromoanisole (12.6 g, 39.25 mmol) in tetrahydrofuran (40 ml) was added in a drop wise manner for 30 min at reflux temperature. Purified Zinc chloride (8.4 g, 61 mmol) in tetrahydrofuran (30 ml) was added in a drop wise manner for 15 min at reflux temperature. The reaction mixture was refluxed for 1 hr. Methyl 6-bromo-2-naphthoate (8.0 g, 30mmol) was added, stirred for 10 min, followed by the addition of NiCl2ZDPPE catalyst (0.21 g). The reaction mixture was stirred at same temperature for 2 hrs and concentrated to obtain a residue, which was treated with dichloromethane (100 ml) and 1 N HCl (100 ml). The dichloromethane layer washed with 10 percent EDTA disodium salt, water, dried over anhydrous sodium sulfate and distilled to obtained crude compound. The crude compound was stirred in ethyl acetate (140 ml) for 1 hr at 7O0C, cool at 15 0C for l*h and the solid obtained was filtered and dried. [Yield: 9.45 g, 50percent]
Reference：
[1] Organic Process Research and Development, 2006, vol. 10, # 2, p. 285 - 288
[2] Patent: WO2007/125542, 2007, A2, . Location in patent: Page/Page column 16
[3] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
8
[ 33626-98-1 ]
[ 104224-63-7 ]
[ 932033-57-3 ]
[ 106685-41-0 ]
Yield
Reaction Conditions
Operation in experiment
88.83%
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuran at 45 - 55℃; for 1.5 h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 20 - 25℃; for 1 h; Stage #3: at 20℃; for 2 h;
To a 2 L, five-necked cylindrical reaction vessel equipped with a reflux condenser, heat-transfer jacket, compensated-pressure addition funnel, anchor impeller and purged with nitrogen, were added 1.13 g of 1-(5-bromo-2-methoxyphenyl) adamantane (3.52.x.10-3 mol), 3.75 g of magnesium granules (1.54.x.10-1 mol) and 90 mL of tetrahydrofuran. Into the compensated-pressure addition funnel was added a previously prepared solution of 36.37 g of 1-(5-bromo-2-methoxyphenyl)adamantane (1.13.x.10-1 mol) and 270 mL of tetrahydrofuran. The reaction mixture was then heated to approximately 45° C., at which point 2.50 g of 1,2-dibromoethane (1.33.x.10-2 mol) was charged to the mixture. During the addition, the internal temperature increased and bubbling was observed, indicating initiation of the reaction.At approximately 50° C., addition of the solution in the compensated-pressure addition funnel was initiated and continued over approximately 45 minutes during which time the internal temperature of the solution was maintained between approximately 50 and 55° C. Following the addition, the reaction mixture was stirred for approximately 45 minutes at approximately 50° C. and then cooled to approximately 20-25° C. To the cooled suspension was added 18.18 g of anhydrous zinc chloride (1.33.x.10-1 mol) and an increase in temperature was observed within a few seconds. The mixture was permitted to cool and was stirred for approximately 1 hour at approximately 20-25° C. Thereafter, 1.05 g of 1,2-[bis(diphenylphosphino)ethane] dichloronickel(II) (2.20.x.10-3 mol) was charged to the reaction mixture followed by the addition of 24.00 g of methyl 6-bromo-2-naphtoate (9.05.x.10-2 mol). The mixture was permitted cool and was stirred for approximately two hours at room temperature.Next, 50 mL of water was slowly added and the mixture was stirred for approximately 15 minutes, at which point 200 mL of 1N HCl was slowly added. The mixture was then stirred overnight at room temperature or until the excess of magnesium pellets were dissolved. The mixture was then filtered, and the cake was washed with methyl ethyl ketone ("MEK"). The resulting solid was next suspended in 500 mL of 1N HCl and 125 mL of MEK. The resulting suspension was then stirred at room temperature for approximately 1 hour. The mixture was then filtered, and the cake was washed with MEK. The resulting solid was next suspended in 270 mL of MEK and the mixture was heated to reflux for approximately 30 minutes, cooled and filtered. The resulting cake was then washed with MEK.The wet solid obtained was suspended in 184 mL of tetrahydrofuran and was heated to approximately 50-60° C. for approximately 30 minutes, cooled and precipitated by addition of 300 mL of methanol. The precipitate was then filtered and dried at approximately 60° C. in a vacuum oven to yield 34.31 g of adapalene methyl ester (8.044.x.10-2 mol; yield: 88.83percent) as an off-white powder. Analytical data: HPLC Purity (HPLC at 272 nm): 97.32percent; Impurity (i.e., 3,3'-diadamantyl-4,4'-dimethoxybiphenyl) area percent (HPLC at 272 nm): 2.05percent.The product may also contain a small amount of an unidentified impurity, which is more polar than the final product. This unidentified impurity, when observed, as well as the 3,3'-diadamantyl-4,4'-dimethoxybiphenyl impurity, are eliminated from the synthetic pathway during the work-up described in the Example/Step 2 (below).
Reference：
[1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[2] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4690 - 4694
10
[ 104224-63-7 ]
[ 459423-32-6 ]
Yield
Reaction Conditions
Operation in experiment
12%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.0833333 h; Stage #2: With triethyl borate In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃;
1-(5-Boronic acid-2-methoxyphenyl)-adamantane [0149] To a solution of 1-(5-bromo-2-methoxyphenyl)-adamantane (4 g, 12.5 mmol) in 40 mL of THF was added a 2.5M solution of n-BuLi in hexane (5 mL, 12.5 mmol) at-78°C, under nitrogen. The mixture was stirred for 5 minutes at-78°C, triethylborate (1.88g, 12.9 mmol) was added and the mixture was stirred for an additional 30 minutes at -78°C. The reaction was allowed to slowly warm to room temperature and was quenched by addition of IN HCl (30 mL). The mixture was diluted with Et20, washed with water and brine, dried over Na2S04, filtered thru a pad of silica gel and the solvent was removed to yield the crude product which was recrystallized from chloroform. [0150] Yield: 0.45 g (12percent); solid; 1H NMR (CDCl3-MeOD 10:1, 300 MHz) 8 1.74 (s, 6H), 2.08 (m, 9H), 2.9 (s, 2H), 3.81 (s, 3H), 6.82 (d, 1H), 7.52 (m, 2H)
12%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.0833333 h; Stage #2: With triethyl borate In tetrahydrofuran; hexane; water at -78℃; for 0.5 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water
To a solution of l-(5-bromo-2-methoxyphenyl)-adamantane (4 g, 12.5 mmol) in 40 mL of THF was added a 2.5M solution of n-BuLi in hexane (5 mL, 12.5 mmol) at -780C, under nitrogen. The mixture was stirred for 5 minutes at -780C, triethylborate (1.88g, 12.9 mmol) was added and the mixture was stirred for an additional 30 minutes at -780C. The reaction was allowed to slowly warm to room temperature and was quenched by addition of IN HCl (30 mL). The mixture was diluted with Et2O, washed with water and brine, dried over Na2SO4, filtered thru a pad of silica gel and the solvent was removed to yield the crude product which was recrystallized from chloroform.[0159] Yield: 0.45 g (12percent); white solid; IH NMR (CDC13-MeOD 10:1, 300 MHz) D 1.74 (s, 6H), 2.08 (m, 9H), 2.9 (s, 2H)5 3.81 (s, 3H), 6.82 (d, IH), 7.52 (m, 2H)
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuranReflux; Inert atmosphere Stage #2: at -50 - -40℃; for 0.5 h; Inert atmosphere Stage #3: With hydrogenchloride; water In tetrahydrofuran
EXAMPLE 1 Into a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel 8 g (0.33 M) of magnesium filings are introduced and 200 mL of dry tetrahydrofuran added. The air in the flask is displaced by argon and all further operations conducted under a slight stream of the inert gas. Under vigorous stirring 11 g (5 mL, 0.06 M) of 1,2-dibromoethane is added. After the vigorous reaction had subsided, the hot reaction mixture is treated with a solution of 50 g (0.16 M) 2-(1-adamantyl)-4-bromoanisole in 400 mL of dry tetrahydrofuran with such speed that a slight reflux is supported. After the adding of all solution of 2-(1-adamantyl)-4-bromoanisole, the reaction mixture is refluxed for another 30 min. Stirring is discontinued and the solution of the prepared Grignard's reagent decanted from the residual magnesium into a conical flask with ground stopper flushed in advance with argon. For further functionalization reactions trimethylborate, a standard reactant for preparing phenylboronic acids was used. In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel a solution of 33 g (36 mL, 0.35 M) of trimethylborate in 100 mL of dry tetrahydrofuran is prepared, the solution cooled to -50° C. and under vigorous stirring the solution of the Grignard's reagent is added within 30 min at -40to -50° C. The reaction mixture is decomposed with a solution of 50 mL of hydrochloric acid in 50 mL water with vigorous stirring without external cooling. The mixture is transferred to separating funnel and the water and organic layers separated. To the water layer 200 mL of water is added and then extracted twice with 100 mL of diethylether. The pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed in vacuo at about 50° C. in the water bath. The residue is treated with 200 mL of hexane and left in the freezer overnight. The precipitate is filtered off, washed with cold ethyl acetate and is dried at 100° C. 3-(1-adamantyl)-4-methoxyphenylboronic acid with m.p. ~300° C. is obtained, yield 2.5 g (5.7percent). The gas chromatographic analysis of the reaction mixture showed one main product. The yield, according to gas chromatography data is 78percent. The compound was isolated and identified as 2-(1-adamantyl)anisole. The preparative yield is 67percent, m.p. 100-102° C.
Stage #1: With magnesium; ethylene dibromide; lithium chloride In tetrahydrofuran at 0℃; Inert atmosphere; Reflux Stage #2: at -70℃; Inert atmosphere Stage #3: With hydrogenchloride; water In tetrahydrofuran
Step B. 3-(1-adamantyl)-4-methoxyphenylboronic acidEXAMPLE 2In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 8 g (0.33 M) magnesium filings and 200 mL of dry tetrahydrofuran is stirred. 8 g (0.19 M) of pulverised anhydrous lithium chloride is added. The air in the flask is displaced by argon and all further operations performed under a slight stream of this inert gas. Under intense stirring 11 g (5 mL, 0.06 M) of 1,2-dibromoethane is added in one portion. After the vigorous reaction had subsided, the hot reaction mixture is treated with a solution of 50 g (0.16 M) 2-(1-adamantyl)-4-bromoanisole in 400 mL tetrahydrofuran with such speed that a slight reflux is supported. After adding the solution of 2-(1-adamantyl)-4-bromoanisole the reaction mixture is stirred and heated to slow reflux for another 30 min. The stirring is discontinued and the Grignard's reagent thus obtained is decanted from is the residual magnesium into a conical flask, flushed in advance with argon, closed with a ground stopper and kept at 0° C. for 2 h.In a 1 L flask equipped with a stirrer, a reflux condener and a dropping funnel a mixture of 33 g (36 mL, 0.35 M) of trimethylborate and 100 mL of dry tetrahydrofuran is prepared. The solution thus obtained is cooled to 0-+5° C. (by ice water) and under vigorous stirring treated with the previously prepared Grignard's reagent within 10 min. The reaction mixture is left overnight (16 h) in the refrigerator at 0-+5° C. The reaction mixture is decomposed with a solution of 50 mL of hydrochloric acid in 50 mL of water with vigorous stirring without external cooling. The mixture is transferred to a separating funnel and the layers separated. To the water layer 200 mL of water is added and extracted twice with 100 mL of diethyl ether. The pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed under vacuo at about 50° C. in the water bath. The residue is treated with 200 mL of ethyl acetate and left in the refrigerator overnight. The precipitate is filtered off and dried at 100° C. 3-(1-adamantyl)-4-methoxyphenylboronic acid, 30 g (68percent) with m.p.300° C. is obtained.; EXAMPLE 10Reaction is performed as described in Example 2. The interaction of 3-(1-adamantyl)-4-methoxyphenylmagnesium bromide solution with trimethylborate is performed at -70° C. 3-(1-Adamantyl)-4-methoxyphenylboronic acid, 30.6 g (69percent) is obtained.
Reference：
[1] Russian Journal of General Chemistry, 2010, vol. 80, # 4, p. 868 - 869
[2] Russian Journal of General Chemistry, 2010, vol. 80, # 4, p. 868 - 869
[3] Patent: US2010/160677, 2010, A1, . Location in patent: Page/Page column 3-4
Example 6; Preparation of methyl ester of 6-[3-(l-adamantyl)-4methoxy phenyl]-2 naphthoate (V): A mixture of magnesium turnings (1.26 g, 51.85 mmol) in THF (10 ml) was stirred at room temperature and 2-(l-adamantyl)-4-bromoanisole (IV) (1.4 g, 4.36 mmol) and 1,2- dibromoethane (0.56 ml) were added under nitrogen atmosphere. The reaction mixture was heated at 40C for initiation, and then 2-(l-adamantyl)-4-bromoanisole (12.6 g, 39.25 mmol) in tetrahydrofuran (40 ml) was added in a drop wise manner for 30 min at reflux temperature. Purified Zinc chloride (8.4 g, 61 mmol) in tetrahydrofuran (30 ml) was added in a drop wise manner for 15 min at reflux temperature. The reaction mixture was refluxed for 1 hr. Methyl 6-bromo-2-naphthoate (8.0 g, 30mmol) was added, stirred for 10 min, followed by the addition of NiCl2ZDPPE catalyst (0.21 g). The reaction mixture was stirred at same temperature for 2 hrs and concentrated to obtain a residue, which was treated with dichloromethane (100 ml) and 1 N HCl (100 ml). The dichloromethane layer washed with 10 % EDTA disodium salt, water, dried over anhydrous sodium sulfate and distilled to obtained crude compound. The crude compound was stirred in ethyl acetate (140 ml) for 1 hr at 7O0C, cool at 15 0C for l*h and the solid obtained was filtered and dried. [Yield: 9.45 g, 50%]
With potassium carbonate; In N,N-dimethyl-formamide; for 2h;
To a stirred mixture of the product of Step A (0.5 g; 1.62 mmol) and K2CO3 (0.335 g; 2.42 mmol) in danhydrous DMF (5 ml) CH3I (1 ml) was added. The reaction mixture was stirred for 2 h and then diluted to 100 ml with H2O and extracted with EtOAc (100 ml). The organic layer was dried over MgSO4 and filtered. The filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the title compound (0.49 g, 94%), as light yellow green solid. 1H-NMR (CDCI3) 7.27 - 7.22 (m, 2H); 6.31 (d, 1 H, J = 6.5 Hz); 3.78 (s, 3H); 2.04 (s, 10H); 1.74 (b, 5H).
78%
To a suspension of sodium hydride (60% in mineral oil, 0.402g, 10.1 mmol) in 11 mL of DMF, 2-(1-adamantyl)-4-bromophenol 2 (2.75 g, 8.38 mmol) was slowly added, while maintaining the temperature at 20C. The mixture was stirred at room temperature for 1 h, then methyl iodide (0.73 mL, 11.7 mmol) was added. After having stirred for additional 2 h at 20C, the solution was poured into water and extracted with diethyl ether. The organic phase was dried and evaporated. The residue was purified by flash chromatography (hexane) to give 2.1 g (78%) of 4-bromo-1-methoxy-2-(adamantan-1-yl)-benzene, mp 136C. 1H NMR (300 MHz, CDCl3) : 1.75 (6H, s, 6Ad), 2.05 (9H, s, 9Ad), 3.80 (3H, s, OMe), 6.72 (1H, d, 1Ar, J = 8.0 Hz), 7.24 (1H, dd, 1Ar, J = 8.0, 2.2 Hz), 7.28 (1H, d, 1Ar, J = 2.2 Hz).
In tetrahydrofuran; dichloromethane;
(b) 2-(1-adamantyl)-4-bromoanisole. To a suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50 ml of THF, there are slowly added, while maintaining the temperature at 20 C., 36.8 g (120 mmol) of 2-(1-adamantyl)-4-bromophenol. The mixture is stirred for 1 hour at ambient temperature at which point 9 ml (144 mmol) of methyl iodide are added. The mixture is then stirred for 2 hours at 20 C., poured into water, extracted with ether, dried and evaporated. The product is purified by passage through a silica column (10*30 cm), eluding with a mixture of hexane (90%) and dichloromethane (10%). On evaporation, 26.2 g of a white solid are obtained. Yield-68%. Melting point: 138-139 C.
With potassium carbonate; In acetone; at 20℃; for 4.25 - 6.25h;Heating / reflux;Product distribution / selectivity;
Example 4; Preparation of 2-(l-adamantyl)-4-bromoanisole (IV): A mixture of 2-(l-adamantyl)-4-bromophenol (III) (50 g, 162 mmol) and potassium carbonate (33.7 g, 216 mmol) in acetone (250 ml) was stirred at room temperature. Then dimethylsulphate (20.16 ml, 240 mmol) was added drop wise for 15 min at room temperature. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water, acidified with dilute HCl. The solid separated was filtered and washed with water. The solid was dissolved in dichloromethane (200 ml) and washed with water. The organic layer was dried over sodium sulphate, evaporated and the solid obtain was purified with ethyl acetate (200ml).[Yield: 30 g, 58 %]; Example 5; Preparation of 2-(l-adamantyl)-4-bromoanisole (IV): To a solution of 2-(l-adamantyl)-4-Bromophenol (III) (50 g, 162 mmol) in acetone 200 ml, Potassium carbonate (33.7 g, 216 mmol) was added and stirred at RT. Dimethyl sulphate (20.53 ml, 244 mmol) was added dropwise for 15 min at RT. The reaction mixture was then refluxed for 4 hrs. The reaction mixture was further cooled to RT5 water was added, and the solid separated, was filtered and washed with acetone. The solid was then treated with 3N HCl till pH is about 5 to 6, filtered and washed with water and acetone and then finally dried to obtain compound (IV).[Yield: 38g, 73%] [44 g, 84%]
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; for 2h;Reflux; Inert atmosphere;
To a solution of 1.95g (6.06 mmol) of <strong>[104224-63-7]4-bromo-1-methoxy-2-(adamantan-1-yl)-benzene</strong> in 12.2 mL of toluene, 6.06 mL (12.1 mmol) of 2M aqueous Na2CO3, 0.210 g (0.182 mmol) of tetrakis-triphenylphosphine-palladium and a solution of 1g (6.67 mmol) of 4-formylbenzeneboronic acid in 2.83 mL of ethanol were added. The mixture was refluxed for 2 h under a stream of nitrogen, then it was cooled at room temperature, diluted with dichloromethane and washed with brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography (hexane/ethyl acetate 85: 15) to give 1.5 g (72%) of the desired aldehyde, mp 196C. 1H NMR (300 MHz, CDCl3) : 1.80 (6H, s, 6Ad), 2.10 (9H, s, 9Ad), 3.90 (3H, s, OMe), 6.98 (1H, d, 1Ar, J = 8.0 Hz), 7.47 (1H, dd, 1Ar, J = 8.0, 2.2 Hz), 7.48 (1H, d, J = 2.2 Hz), 7.70 (2H, d, 2Ar, J = 8.3 Hz), 7.90 (2H, d, 2Ar, J = 8.3 Hz), 10.0 (1H, s).
34%
With potassium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; water;
The intermediate 4-[3-(1-adamantyl)-4-methoxyphenyl]benzaldehyde was prepared as follows: A mixture of 3-(1-adamantyl)-4-methoxy-1-bromobenzene (1.000 g, 3.11 mmol, prepared in a similar manner as described by Charpentier, B. et al. in J. Med. Chem. 1995, 38, 4993-5006), 4-formylphenylboronic acid (0.559 g, 3.73 mmol) and potassium carbonate (1.719 g, 12.44 mmol) in 10.5 mL of DME and 1.5 mL of water was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.16 mmol) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:ethyl acetate, 95:5) to give 0.372 g of 4-[3-(1-adamantyl)-4-methoxyphenyl]benzaldehyde (34%). 1H NMR (300 MHz; CDCl3): delta1.80 (s, 6 H), [2.10 (brs), 216 (s), 9 H], 3.91 (s, 3 H), 6.98 (d, J=8.4 Hz, 1 H), 7.48 (dd, J1=8.4 Hz, J2=2.4 Hz, 1 H), 7.51 (d, J=2.4 Hz, 1 H), 7.73 (d, J=8.7 Hz, 2 H), 7.93 (d, J=8.7 Hz, 2 H), 10.04 (s, 1 H).
1-(5-Boronic acid-2-methoxyphenyl)-adamantane [0149] To a solution of 1-(5-bromo-2-methoxyphenyl)-adamantane (4 g, 12.5 mmol) in 40 mL of THF was added a 2.5M solution of n-BuLi in hexane (5 mL, 12.5 mmol) at-78C, under nitrogen. The mixture was stirred for 5 minutes at-78C, triethylborate (1.88g, 12.9 mmol) was added and the mixture was stirred for an additional 30 minutes at -78C. The reaction was allowed to slowly warm to room temperature and was quenched by addition of IN HCl (30 mL). The mixture was diluted with Et20, washed with water and brine, dried over Na2S04, filtered thru a pad of silica gel and the solvent was removed to yield the crude product which was recrystallized from chloroform. [0150] Yield: 0.45 g (12%); solid; ¹H NMR (CDCl3-MeOD 10:1, 300 MHz) 8 1.74 (s, 6H), 2.08 (m, 9H), 2.9 (s, 2H), 3.81 (s, 3H), 6.82 (d, 1H), 7.52 (m, 2H)
12%
To a solution of l-(5-bromo-2-methoxyphenyl)-adamantane (4 g, 12.5 mmol) in 40 mL of THF was added a 2.5M solution of n-BuLi in hexane (5 mL, 12.5 mmol) at -780C, under nitrogen. The mixture was stirred for 5 minutes at -780C, triethylborate (1.88g, 12.9 mmol) was added and the mixture was stirred for an additional 30 minutes at -780C. The reaction was allowed to slowly warm to room temperature and was quenched by addition of IN HCl (30 mL). The mixture was diluted with Et2O, washed with water and brine, dried over Na2SO4, filtered thru a pad of silica gel and the solvent was removed to yield the crude product which was recrystallized from chloroform.[0159] Yield: 0.45 g (12%); white solid; IH NMR (CDC13-MeOD 10:1, 300 MHz) D 1.74 (s, 6H), 2.08 (m, 9H), 2.9 (s, 2H)5 3.81 (s, 3H), 6.82 (d, IH), 7.52 (m, 2H)
n-BuLi (9 ml, 22,4 mmol, 2,5 M in hexane) was added to a solution of 3-(1 -adamantyl)-1 -bromo-4-methoxybenzene (6 g, 18,7 mmol) in THF (90 ml) at -78 0C and under inert atmosphere during a period of 10 minutes. The reaction mixture was stirred at the same temperature during one hour, during this time a white precipitate was formed. The precipitate was dissolved with the addition of B(O-I-Pr)3 (15 ml, 65,4 mmol) at -78 0C. After one hour of stirring at -78 0C, the reaction mixture was brought at room temperature and was agitated during 16 h. Next, the mixture was cooled at 0 0C and H2O (6 ml) and HCI (6 ml, 2M) were added. After 5 minutes, HCI (120 ml, 2M) was added again and it was kept at vigorous stirring during 10 minutes. Finally, extractions with AcOEt (3 x 100 ml) were carried out. The joined organic phases were dried with Na2SO4, filtered and after evaporation to dryness the crude 3-(1 -adamantyl)-4-methoxyphenylboronic acid was obtained (6,46 g, which contains some trimer) as a yellow solid. <n="13"/>The obtained solid was suspended on hexane (60 ml) and the obtained suspension was heated at 50 0C during 30 minutes. Next, the suspension was allowed to cool at room temperature, was filtered and the solid was washed with hexane (30 ml). Once vacuum dried, the title compound was obtained (5,53 g) as a white solid which was used in the following Suzuki couplings without previous purification. IR (KBr) 3228, 2902, 2846, 1597, 1453, 1400, 1339, 1281 , 1235, 1181 , 1138, 1100, 1022, 820, 758 y 724. 1H RMN (400 MHz, CDCI3) 8,15 (s, 1 H), 8,05 (d, J = 8,4 Hz, 1 H), 7,00 (d, J = 8,4 Hz, 1 H), 3,92 (s, 3 H), 2,21 (s, 6 H), 2,10 (s, 3 H) y 1 ,82 (s, 6 H).
With sulfuric acid; In dichloromethane; at 20℃; for 20h;
1-(5-Bromo-2-methoxyphenyl)-adamantane [0145] [0146] Reagent grade concentrated H2S04 (11 mL) was added dropwise to a solution of 1- adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgS04 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder. [0147] Yield: 65 g (75%) ; white solid; Rf= 0.9 in 25% EtOAc-hexane. ¹H NMR (CDC13, 300 MHz) No. 1.78 (s, 6H), 2.08 (s, 9H), 3.81 (s, 3H), 6.72 (d, 1H), 7.24 (dd, 1H), 7.28 (m, 1H)
75%
With sulfuric acid; In dichloromethane; at 20℃; for 20h;
Reagent grade concentrated H2SO4 (11 mL) was added dropwise to a solution of 1- adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgSO4 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder.[0157] Yield: 48 g (75%); white solid; Rf= 0.9 in 25% EtOAc-hexane. IH NMR (CDC13, 300 MHz) D 1.78 (s, 6H)3 2.08 (s, 9H), 3.81 (s, 3H), 6.72 (d, IH)5 7.24 (dd, IH)5 7.28 (m, IH).
72%
With sulfuric acid; In dichloromethane; for 5h;
Step A. 2-(1-adamantyl)-4-bromoanisoleExample 1; In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to separating funnel and the organic layer collected, which is neutralized by two portions of 100 mL 10% sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at 0 C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100 C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72%) with m.p. 140-141 C. is obtained.NMR (500 MHz, DMSO D6) delta: 1.75 (s, 6H), 2.03 (s, 9H), 3.81 (s, 3H), 6.82 (d, 1H, J=8 Hz), 7.17 (s, 1H), 7.23 (d, 1H, J=8 Hz).Scaling the synthesis up 10 times did not change either the yield or quality of the 2-(1-adamantyl)-4-bromoanisole.
72%
With sulfuric acid; In dichloromethane; for 5h;
Step A. 2-(1-adamantyl)-4-bromoanisole; EXAMPLE 1In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) of sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to a separating funnel and the organic layer collected. It is neutralized by two portions of 100 mL 10% sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at about 0 C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100 C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72%) with m.p. 140-141 C. is obtained.NMR (500 MHz, DMSO D6)delta: 1.75 (s, 6H), 2.03 (s, 9H), 3.81 (s, 3H), 6.82 (d, 1H, J=8 Hz), 7.17 (s, 1H), 7.23 (d, 1H, J=8 Hz).Scaling the synthesis up 10 times did not change either the yield or quality of the 2-(1-adamantyl)-4-bromoanisole
With ammonium chloride; dihydrogen peroxide; iodine; magnesium; In tetrahydrofuran; diethyl ether; hexane; water;
(a) 3-(1-Adamantyl)-4-methoxyphenol. 4.2 g (0.17 mol) of magnesium, a crystal of iodine and 50 ml of THF are introduced into a three-necked flask. A solution of 50 g (0.156 mol) of <strong>[104224-63-7]2-(1-adamantyl)-4-bromoanisole</strong> in 200 ml of THF is added dropwise and the mixture is heated to reflux for three hours. This solution is added dropwise at 0 C. to a solution of 19.2 ml (0. 172 mol) of trimethyl borate in 400 ml of ethyl ether, the mixture is then stirred at room temperature for one hour, 200 ml of water are added and the reaction medium is evaporated to dryness. The residue is cooled to 10 C. and a solution of 40 g of ammonium chloride dissolved in 150 ml of water and then 100 ml of hydrogen peroxide (30%) are added successively, and the mixture is stirred at room temperature for six hours. The solid is filtered off, washed with water, dried over phosphorus pentoxide, ground in 400 ml of hexane heated to reflux and filtered off. 22.9 g (57%) of the expected phenol, melting point 167-169 C., are collected.
(b) From 1-adamantanol In a ten-liter flask equipped with an agitation mechanism and a cooler are placed 750 g of 1-adamantanol and 2.4 1 of n-heptane, under nitrogen. With good agitation, 18.3 g of concentrated sulfuric acid are slowly added and then 573.5 g of acetic anhydride. During the addition, the temperature rises from 21.C to approximately 37 C. Agitation is continued for 15 hours at approximately 21 C. and then 241.5 g of concentrated sulfuric acid are added. The temperature goes from 21 C. to 28 C. Once the temperature has returned to 21 C., 921.3 g of 4-bromoanisole are added and agitation is continued for 24 hours. 3 liters of denatured ethanol are added and one agitates for one hour. The solid product is collected by filtration and it is washed on the filter with 1 liter of absolute ethanol.
16
[ 104224-63-7 ]
[ 107430-91-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; magnesium; In tetrahydrofuran; hexane; dichloromethane; N,N-dimethyl-formamide;
(a) 3-(1-adamantyl)-4-methoxy benzaldehyde 11.09 g (37 mmoles) of 2-(1-adamantyl)-4-bromo anisole dissolved in 85 ml of THF are slowly added to 1 g of magnesium and an iodine crystal. At the beginning of the addition, the reaction mixture is heated until the reaction begins, then the remainder of the solution is added in a manner to maintain a regular reflux. This reaction mixture is heated at reflux for 30 minutes after the end of the addition at which point 2.70 g (37 mmoles) of dry DMF are added. The reaction mixture is then stirred for 30 minutes without heating and then poured into 300 ml of mixture of 2N aqueous HCl and dichloromethane. The organic phase is decanted and the aqueous phase is extracted with dichloromethane. The organic extracts are combined, washed with a saturated solution of sodium bicarbonate, then with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and the solvents evaporated. The resulting residue is purified by passage through a silica column (eluant: 60:40 mixture of dichloromethane and hexane). After evaporation of the solvents the expected aldehyde, 8.0 g (80% yield) in the form of a light yellow powder which melts at 180 C. is obtained.
(a) 3-(1-adamantyl)-4-methoxybenzoic acid. In a round bottomed flask, there are introduced 5.4 g (225 m atom g) of magnesium turnings, and 30 ml of THF. To this mixture there is added, dropwise, a solution of 48.3 g (150 mmoles) of 2-adamantyl-4-bromo anisole, and 6 ml (70 mmoles) of 1,2-dibromoethane in 300 ml of THF. This mixture is heated at reflux for 2 hours and then cooled to -70 C. A current of CO2 is passed therethrough for 1 hour. The temperature of the mixture is then permitted to rise to 20 C. at which point it is poured into water, acidified to pH 1 with concentrated HCl and extracted with ethyl ether. The organic phase is decanted and dried on magnesium sulfate. The solvents are evaporated. The resulting solid is recyrstallized in ethyl acetate (3.7 g, 86%). Melting point: 238-239 C.
In tetrahydrofuran; at -78℃; for 1h;Product distribution / selectivity;
Preparation of 6-[3-(1 -adamantiv)-4-methoxyphenyl1-2- cvanonaphthaleneTo a mixture of 3-(1 -adamantyl)-1 -bromo-4-methoxybenzene (62 mg, 0.19 mmol), and THF anh. (1 ml) under Ar atmosphere and at -78 0C, t-BuLi (197 mul, 1.4 M, 0.27 mmol) was added, dropwise, and the mixture was stirred for 1 hour. After this time, the reaction was allowed to warm to room temperature, a solution of ZnCI2 (26 mg, 0.19 mmol) in anhydrous THF (0.4 ml_) was added and stirring was continued for another hour. A solution of 6- cyanonaphthalenyl thfluoromethanesulfonate (50 mg, 0.17 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and anhydrous THF (0.2 ml) was added and the reaction was maintained for 18 h at room temperature and for 5 h at 50 0C. Finally, the reaction was neutralized with HCI (1 M) and extractions were performed with Et2O (3 x 2 ml). The organic phase was washed with NaCI sat (3 x 3 ml) and H2O (3 x 3 ml), was dried with MgSO4 and evaporated to dryness. A crude <n="25"/>product was obtained (88 mg) in the form of an orange oil, which after purification by column chromatography (SiO2, CH2CI2:cyclohexane 8/2) yielded the title compound (11 mg, 18%) as a white solid. The spectroscopic data coincide with those of Example 11.
In tetrahydrofuran; hexane; at -78℃; for 1.16667h;Product distribution / selectivity;
Preparation of 2,4,6-tris[3-(1 -adamantyl)-4-methoxyphenyl1- 1 ,3,5,2,4,6-trioxatriborinaneTo a solution of 3-(1 -adamantyl)-1 -bromo-4-methoxybenzene (6 g, 18.7 mmol) in THF (90 ml) at -78 0C and under an inert atmosphere, n-BuLi (9 ml, 22.4 mmol, 2.5 M in hexane) was added during a period of 10 min. The reaction mixture was stirred at the same temperature for an hour, during which time a white precipitate formed. With the addition of B(O-I-Pr)3 (15 ml, 65.4 mmol) at -78 0C the precipitate dissolved. After an hour of stirring at -78 0C, the reaction mixture was brought to room temperature and was stirred for 16 h. Next, the mixture was cooled to 0 0C and H2O (6 ml) and HCI (6 ml, 2 M) were added. After 5 minutes, HCI (120 ml, 2 M) was again added and a vigorous stirring was maintained for 10 minutes. Finally, extractions were performed with EtOAc (3 x 100 ml). The combined organic phases were dried with Na2SO4, were filtered and after evaporation to dryness crude 3-(1 - adamantyl)-4-rnethoxyphenylboronic acid (6.46 g, that contains some trimer) was obtained as a yellow solid.The solid obtained was suspended in hexane (60 ml) and the suspension obtained was heated to 50 0C for 30 min. Next, the suspension was left to cool to room temperature, it was filtered and the solid was washed with hexane (30 ml). Once dried in vacuum, the title compound was obtained (5.53 g) as a white solid that was used in subsequent Suzuki couplings without prior purification. IR (KBr) 3228, 2902, 2846, 1597, 1453, 1400, 1339, 1281 , 1235, 1181 , 1138, 1100, 1022, 820, 758 and 724. 1H NMR (400 MHz, CDCI3)8.15 (s, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 3.92 (s, 3 H), 2.21 (s, 6 H), 2.10 (s, 3 H) and 1.82 (s, 6 H).
In tetrahydrofuran; at 20℃; for 2.04167h;Heating / reflux;Product distribution / selectivity;
Preparation of 6-[3-(1 -adamantyl)-4-methoxyphenyl1-2- cvanonaphthaleneA previously prepared solution of 3-(1 -adamantyl)-1 -bromo-4- methoxybenzene (50 mg, 0.156 mmol), dibromoethane (13 mul, 0.155 mmol) and anhydrous THF (0.4 ml) was added over a suspension of Mg (56.4 mg, 2.322 mmol) in anhydrous THF (1 ml), and the mixture was stirred at room temperature until the reaction was activated (2.5 min). Once the reaction was activated, a solution of 3-(1 -adamantyl)-1 -bromo-4-methoxybenzene (0.45 g, 1.402 mmol) in anhydrous THF (3 ml) was added dropwise and the reaction mixture was stirred at reflux temperature for 2 hours resulting in the organic magnesium compound. Next, the solution was cooled to room temperature and a fraction of said organic magnesium compound solution (0.858 ml, 0.304 mmol, 0.354 M) was added over ZnCI2 (21.5 mg, 0.304 mmol) (previously melted under vacuum and cooled to room temperature under inert atmosphere) and the mixture was stirred at room temperature for 1 h resulting in the organic zinc derivative.The previously prepared solution of the organic zinc derivative was added over a previously deoxygenated (3 freeze/unfreeze cycles) mixture of 6- cyano-2-naphthalenyl methanesulfonate (50 mg, 0.202 mmol), NiCI2(PPh3)2 (13 mg, 0.020 mmol) and PPh3 (11 mg, 0.040 mmol), and the mixture was stirred at room temperature for 16h.Next, the solution was diluted with H2O (2 ml) and extractions were carried out with CH2CI2 (3 x 5 ml). The organic phase was washed with NaCI sat (3 x 3 ml), the organic phase was dried over MgSO4 and was concentrated dryness resulting in a yellowish crude (115 mg). The purification by column chromatography (SiO2, CH2CI2:cyclohexane, 40/60) resulted in the title compound (47 mg, 59%) in the form of a white solid. Spectroscopic data coincide with those of Example 11.
In tetrahydrofuran; at 20 - 67℃; for 1.16667h;Product distribution / selectivity;
Preparation of 6-[3-(1 -adamantyl)-4-methoxyphenyl1-2- cvanonaphthalene3.5 ml of a previously prepared solution of 3-(1 -adamantyl)-1 -bromo-4- methoxybenzene (2 g, 6.23 mmol) in anhydrous THF (7 ml) was added to a suspension of Mg (166 mg, 6.83 mmol) in anhydrous THF (4 ml), and the mixture was stirred at room temperature for 10 min and then at 670C until the reaction was activated. Once the reaction was activated, the remaining solution of 3-(1 -adamantyl)-1 -bromo-4-methoxybenzene in anhydrous THF was added dropwise, and the reaction mixture was stirred at 670C for 1 hour resulting in the organic magnesium derivative. The solution was cooled to room temperature.The previously prepared organic magnesium derivative (0.748 ml, 0.62 M, 0.464 mmol) was added to a mixture of cyanonaphthalenyl toluenesulfonate (50 mg, 0.155 mmol), NiCI2(PPh3)2 (5 mg, 0.007 mmol) and PPh3 (2 mg, 0.007 mmol) under inert atmosphere, and the solution was stirred at 8O0C for 72 h. <n="27"/>The solution was cooled to room temperature, diluted in CH2CI2 (3 ml), filtered and washed with CH2CI2. The combined filtrates were dried over MgSO4 and were concentrated to dryness resulting in a crude in the form of an orange oil (170 mg). Purification by column chromatography (SiO2, CH2CI2:cyclohexane, 60/40) resulted in the title compound (7 mg, 11 %). Spectroscopic data coincide with those of Example 11.
3-adamantyl-4-methoxyphenyl potassium trifluoroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
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 <n="11"/>slowly added and stirred. 87 ml of tri isopropyl borate was then charged and stirring was continued for 30 minutes at -55 +/- 5C. 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 - 65C till constant weight. Yield: 90.5 gm (83%), Purity: 99.0 % by HPLC.
To a 100 mL rounded bottom reaction vessel equipped with a magnetic stirrer, thermometer, reflux condenser, pressure compensated addition funnel, were added 0.15 g of 1-(5-bromo-2-methoxyphenyl)adamantane, 0.47 g of magnesium turnings and 7 mL of tetrahydrofuran. The mixture was heated to approximately 35 C., and 0.13 mL of 1,2-dibromoethane were added to the mixture. Reaction exothermy self-heated the mixture. Next, a solution of 4.85 g of 1-(5-bromo-2-methoxyphenyl)adamantane and 28 mL of tetrahydrofuran was added to the mixture dropwise. During this addition, the temperature of the mixture dropped from reflux temperature to approximately 45 C. The reaction was then stirred for approximately 45 additional minutes at approximately 45 C. and was permitted to cool to approximately 22 C. Next, 2.3 g of ZnCl2 was added to the mixture, resulting in an exothermic reaction that raised the temperature of the mixture to approximately 38 C. The mixture was then permitted to cool to approximately 22 C. and was stirred for approximately 1 hour at this temperature.Next, 0.03 g of Pd(OAc)2 and 3.5 g of 1-(5-bromo-2-methoxyphenyl) adamantane were added to the mixture, followed by 25 mL of tetrahydrofuran in order to improve agitation, and the mixture was heated at reflux for approximately 24 hours. The resulting mixture was then evaporated to dryness and poured into 103 mL of 0.015 N HCl. Next, 150 mL of dichloromethane and 100 mL of water were added to yield a mixture consisting of a solid, an aqueous layer and an organic layer. The mixture was then filtered to separate the solid, the aqueous layer was discarded, and the organic layer was washed with 200 mL of water and decanted again. This process was repeated twice on the filtered solid. The three collected organic layers were evaporated to dryness, washed in methanol, and dried to yield 2.1 g of 3,3'-diadamantyl-4,4'-dimethoxybiphenyl (yield: 39.9%). Analytical data: Melting point: 288.1-289.1 C.; Elemental analysis: C 83.63%, H 8.73%; 1H-NMR (300 MHz, CDCl3): delta 1.78 (broad s, 12H), 2.08 (broad s, 6H), 2.15 (broad s, 12H), 3.86 (s, 6H), 6.92 (dm, 2H, J=8.1 Hz), 7.34 (dd, 2H, J=2.4, 8.1 Hz), 7.39 (d, 2H, J=2.4 Hz); 13C-NMR (75.4 MHz, CDCl3): delta 29.2, 37.1, 37.2, 40.6, 55.1, 111.9, 125.0, 125.5, 134.0, 138.5, 157.8; MS (EI, 70 eV): m/z=484 (6), 483 (36), 412 (1,100), 410 (5), 347 (8), 135 (22), 107 (7), 93 (14), 79 (17), 67 (9), 55 (6); IR (Selected absorption bands): 2992, 2964, 2898, 2850, 1603 cm-1.
To a 2 L, five-necked cylindrical reaction vessel equipped with a reflux condenser, heat-transfer jacket, compensated-pressure addition funnel, anchor impeller and purged with nitrogen, were added 1.13 g of 1-(5-bromo-2-methoxyphenyl) adamantane (3.52×10-3 mol), 3.75 g of magnesium granules (1.54×10-1 mol) and 90 mL of tetrahydrofuran. Into the compensated-pressure addition funnel was added a previously prepared solution of 36.37 g of 1-(5-bromo-2-methoxyphenyl)adamantane (1.13×10-1 mol) and 270 mL of tetrahydrofuran. The reaction mixture was then heated to approximately 45 C., at which point 2.50 g of 1,2-dibromoethane (1.33×10-2 mol) was charged to the mixture. During the addition, the internal temperature increased and bubbling was observed, indicating initiation of the reaction.At approximately 50 C., addition of the solution in the compensated-pressure addition funnel was initiated and continued over approximately 45 minutes during which time the internal temperature of the solution was maintained between approximately 50 and 55 C. Following the addition, the reaction mixture was stirred for approximately 45 minutes at approximately 50 C. and then cooled to approximately 20-25 C. To the cooled suspension was added 18.18 g of anhydrous zinc chloride (1.33×10-1 mol) and an increase in temperature was observed within a few seconds. The mixture was permitted to cool and was stirred for approximately 1 hour at approximately 20-25 C. Thereafter, 1.05 g of 1,2-[bis(diphenylphosphino)ethane] dichloronickel(II) (2.20×10-3 mol) was charged to the reaction mixture followed by the addition of 24.00 g of methyl 6-bromo-2-naphtoate (9.05×10-2 mol). The mixture was permitted cool and was stirred for approximately two hours at room temperature.Next, 50 mL of water was slowly added and the mixture was stirred for approximately 15 minutes, at which point 200 mL of 1N HCl was slowly added. The mixture was then stirred overnight at room temperature or until the excess of magnesium pellets were dissolved. The mixture was then filtered, and the cake was washed with methyl ethyl ketone (?MEK?). The resulting solid was next suspended in 500 mL of 1N HCl and 125 mL of MEK. The resulting suspension was then stirred at room temperature for approximately 1 hour. The mixture was then filtered, and the cake was washed with MEK. The resulting solid was next suspended in 270 mL of MEK and the mixture was heated to reflux for approximately 30 minutes, cooled and filtered. The resulting cake was then washed with MEK.The wet solid obtained was suspended in 184 mL of tetrahydrofuran and was heated to approximately 50-60 C. for approximately 30 minutes, cooled and precipitated by addition of 300 mL of methanol. The precipitate was then filtered and dried at approximately 60 C. in a vacuum oven to yield 34.31 g of adapalene methyl ester (8.044×10-2 mol; yield: 88.83%) as an off-white powder. Analytical data: HPLC Purity (HPLC at 272 nm): 97.32%; Impurity (i.e., 3,3'-diadamantyl-4,4'-dimethoxybiphenyl) area percent (HPLC at 272 nm): 2.05%.The product may also contain a small amount of an unidentified impurity, which is more polar than the final product. This unidentified impurity, when observed, as well as the 3,3'-diadamantyl-4,4'-dimethoxybiphenyl impurity, are eliminated from the synthetic pathway during the work-up described in the Example/Step 2 (below).
Example 7; Reaction is performed as in Example 6. As the source of Pd(0) to tris(dibenzylydeneacetone)dipalladium(0) (Pd2(dba)3) is used.3-(1-Adamantyl)-4-methoxyphenylboronic acid pinacol ester, 29 g (49.5%) is obtained.Using as the ligand dichloropalladium 1,1'-bis(diphenylphosphino)-ferrocene [PdCl2(dppf)CH2Cl2] or 2,2'-bis(diphenylphosphino)diphenylether (DPEphos) does not cause a lower yield of the end product (gas chromatography data).
Step B. 3-(1-adamantyl)-4-methoxyphenylboronic acid pinacol esterExample 2; Into a 2 L double-necked flask equipped with a stirrer, a reflux condenser and a gas-inlet adapter is introduced 800 mL of dioxan, 100 g (0.31 M) of <strong>[104224-63-7]2-(1-adamantyl)-4-bromoanisole</strong>, 94 g (130 mL, 0.93 M) of triethylamine, 3.5 g (0.0155 M, 5 mol %) of palladium acetate and 16.7 g (0.031 M, 10 mol %) of 2,2'-bis-(diphenylphosphino)diphenylether (DPEphos). The solution is stirred for 30 min and under a slight stream or argon 60 g (68 mL, 0.47 M) of pinacol borane solution in 300 mL of dioxan added. The reaction mixture is refluxed under stirring for 12 h, the solvent distilled off in vacuo at water-bath temperature of 60 C. The residue is dissolved in 500 mL of warm ethyl acetate, filtered and concentrated to 300 mL. The solution is left for 16 h at about 0 C. The precipitate is filtered off, washed with a minimal volume of cold ethyl acetate and dried at 80 C.3-(1-Adamantyl)-4-methoxyphenylboronic acid pinacol ester, 71 g (62%) with m.p. 162-164 C. is obtained.1H NMR (500 MHz, DMSO D6) delta: 1.30 (s, 12H), 1.76 (s, 6H), 2.07 (s, 3H), 2.09 (s 6H), 3.85 (s, 3H), 6.83 (d, 1H, J=8 Hz), 7.49 (s, 1H), 7.50 (d, 1H, J=8 Hz).Using as a ligand 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos) instead of DPEphos does not substantially influence the yield of the final product.The yield is also not influenced by replacing tris(dibenzylidene-acetone)dipalladium(0) (Pd2(dba)3) by palladium acetate as Pd(0) source.
EXAMPLE 1 Into a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel 8 g (0.33 M) of magnesium filings are introduced and 200 mL of dry tetrahydrofuran added. The air in the flask is displaced by argon and all further operations conducted under a slight stream of the inert gas. Under vigorous stirring 11 g (5 mL, 0.06 M) of 1,2-dibromoethane is added. After the vigorous reaction had subsided, the hot reaction mixture is treated with a solution of 50 g (0.16 M) <strong>[104224-63-7]2-(1-adamantyl)-4-bromoanisole</strong> in 400 mL of dry tetrahydrofuran with such speed that a slight reflux is supported. After the adding of all solution of <strong>[104224-63-7]2-(1-adamantyl)-4-bromoanisole</strong>, the reaction mixture is refluxed for another 30 min. Stirring is discontinued and the solution of the prepared Grignard's reagent decanted from the residual magnesium into a conical flask with ground stopper flushed in advance with argon. For further functionalization reactions trimethylborate, a standard reactant for preparing phenylboronic acids was used. In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel a solution of 33 g (36 mL, 0.35 M) of trimethylborate in 100 mL of dry tetrahydrofuran is prepared, the solution cooled to -50 C. and under vigorous stirring the solution of the Grignard's reagent is added within 30 min at -40to -50 C. The reaction mixture is decomposed with a solution of 50 mL of hydrochloric acid in 50 mL water with vigorous stirring without external cooling. The mixture is transferred to separating funnel and the water and organic layers separated. To the water layer 200 mL of water is added and then extracted twice with 100 mL of diethylether. The pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed in vacuo at about 50 C. in the water bath. The residue is treated with 200 mL of hexane and left in the freezer overnight. The precipitate is filtered off, washed with cold ethyl acetate and is dried at 100 C. 3-(1-adamantyl)-4-methoxyphenylboronic acid with m.p. ~300 C. is obtained, yield 2.5 g (5.7%). The gas chromatographic analysis of the reaction mixture showed one main product. The yield, according to gas chromatography data is 78%. The compound was isolated and identified as 2-(1-adamantyl)anisole. The preparative yield is 67%, m.p. 100-102 C.
EXAMPLE 6 Grignard's reagent was prepared from 51 g (0.16 M) of <strong>[104224-63-7]2-(1-adamantyl)-4-bromoanisole</strong> as in Example 1. In the next step into a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel 17 g (16.5 mL, 0.16 M) of benzaldehyde and 100 mL of dry tetrahydrofuran was introduced, the solution cooled to 0 C. and under stirring the solution of the Grignard's reagent added within 10 min. The mixture was left for 16 h in a refrigerator at about 0 C. The reaction mixture is decomposed with a solution of 25 mL of hydrochloric acid in 25 mL of water with vigorous stirring without external cooling. The mixture is transferred to separating funnel and the water and organic layers separated, the water layer extracted with 2 portions of 100 mL of diethyl ether. The pooled organic layers were dried over sodium sulfate. The yield of 3-(1-adamantyl)-4-methoxyphenylmethanol according to gas chromatography data is 11%.
3-(1-adamantyl)-(4-methoxyphenyl)phenylmethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%Chromat.
EXAMPLE 11; Into a 100 mL flask equipped with a magnetic stirrer, a reflux condenser and a dropping funnel 1 g (0.042 M) of magnesium filings are introduced and 20 mL of dry tetrahydrofuran added. Pulverized anhydrous lithium chloride, 0.81 g (0.019 M) is added. The air in the flask is displaced by argon and all further operations conducted under a slight stream of the is inert gas. Under vigorous stirring 1.1 g (0.5 mL, 0.006 M) of 1,2-dibromoethane is added. After the vigorous reaction had subsided, the hot reaction mixture is treated dropwise within 30 min with 5.14 g (0.016 M) of <strong>[104224-63-7]2-(1-adamantyl)-4-bromoanisole</strong> in 40 mL of dry tetrahydrofuran, keeping the reaction mixture at 55-60 C. The mixture is then kept at slight reflux for another 30 min. Stiring is discontinued and the solution of the prepared Grignard's reagent decanted from the residual magnesium into a conical flask with ground stopper flushed in advance with argon. The flask is closed with a stopper and kept at 0 C. for 2 h.Into a 250 mL flask equipped with a magnetic stirrer, a reflux condenser and a dropping funnel a solution of 3.4 g (3.3 mL, 0.032 M) of benzaldehyde in 20 mL of dry tetrahydrofuran is introduced, the solution cooled to 0 C. and under constant stirring the solution of the Grignard's reagent is added within 10 min. The mixture is left in a refrigerator at about 0 C. for 16 h.The reaction mixture is decomposed with a solution of 5 mL of HCl in 5 mL of water with vigorous stirring without external cooling. The mixture is transferred to separating funnel and the water and organic layers separated, the water layer extracted with 2 portions of 20 mL of diethyl ether. The pooled organic layers were dried over sodium sulfate. 3-(1-Adamantyl)-4-methoxyphenyl)phenylethanol, 88% (gas chromatography data) is obtained.Experimentally the optimal rate of the substituted adamantylarylhalide and lithium chloride in the Grignard's reaction was determined as 1:1.2. The results in Table 1 (Examples 4, 10, 11-12) show that increasing of the molar rate of lithium chloride from 0.1 to 1.2 the yield of the Grignard's reagent increases, but the further increase to 2 equivalents does not substantially increase the yield of Grignard's reagent.
Step B. 3-(1-adamantyl)-4-methoxyphenylboronic acidEXAMPLE 2In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 8 g (0.33 M) magnesium filings and 200 mL of dry tetrahydrofuran is stirred. 8 g (0.19 M) of pulverised anhydrous lithium chloride is added. The air in the flask is displaced by argon and all further operations performed under a slight stream of this inert gas. Under intense stirring 11 g (5 mL, 0.06 M) of 1,2-dibromoethane is added in one portion. After the vigorous reaction had subsided, the hot reaction mixture is treated with a solution of 50 g (0.16 M) <strong>[104224-63-7]2-(1-adamantyl)-4-bromoanisole</strong> in 400 mL tetrahydrofuran with such speed that a slight reflux is supported. After adding the solution of <strong>[104224-63-7]2-(1-adamantyl)-4-bromoanisole</strong> the reaction mixture is stirred and heated to slow reflux for another 30 min. The stirring is discontinued and the Grignard's reagent thus obtained is decanted from is the residual magnesium into a conical flask, flushed in advance with argon, closed with a ground stopper and kept at 0 C. for 2 h.In a 1 L flask equipped with a stirrer, a reflux condener and a dropping funnel a mixture of 33 g (36 mL, 0.35 M) of trimethylborate and 100 mL of dry tetrahydrofuran is prepared. The solution thus obtained is cooled to 0-+5 C. (by ice water) and under vigorous stirring treated with the previously prepared Grignard's reagent within 10 min. The reaction mixture is left overnight (16 h) in the refrigerator at 0-+5 C. The reaction mixture is decomposed with a solution of 50 mL of hydrochloric acid in 50 mL of water with vigorous stirring without external cooling. The mixture is transferred to a separating funnel and the layers separated. To the water layer 200 mL of water is added and extracted twice with 100 mL of diethyl ether. The pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed under vacuo at about 50 C. in the water bath. The residue is treated with 200 mL of ethyl acetate and left in the refrigerator overnight. The precipitate is filtered off and dried at 100 C. 3-(1-adamantyl)-4-methoxyphenylboronic acid, 30 g (68%) with m.p.300 C. is obtained.; EXAMPLE 10Reaction is performed as described in Example 2. The interaction of 3-(1-adamantyl)-4-methoxyphenylmagnesium bromide solution with trimethylborate is performed at -70 C. 3-(1-Adamantyl)-4-methoxyphenylboronic acid, 30.6 g (69%) is obtained.
5-(4-bromophenyl)-penta-2,4-dienoic acid (tetrahydropyran-2-yloxy)-amide[ No CAS ]
[ 104224-63-7 ]
5-(3'-adamantan-1-yl-4'-methoxybiphenyl-4-yl)penta-2,4-dienoic acid (tetrahydropyran-2-yloxy)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
To a solution of 6 (68mg, 0.21mmol) in dioxane (1.5mL) bis(pinacolato)diboron (59mg, 0.23mmol), KOAc (62mg, 0.63mmol) and PdCl2(dppf) (5mg, 0.006mmol) were added. The mixture was refluxed for 1.45h under nitrogen. The solution was cooled at room temperature, then compound 8 (144mg, 0.41mmol), 2M Na2CO3 (270muL, 0.53mmol) and PdCl2(dppf) (5mg, 0.006mmol) were added. The resulting mixture was refluxed for 4h. After addition of ethyl acetate, the organic phase was washed with water, brine, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give a crude which was purified by flash chromatography (hexane/ethyl acetate 60:40) to obtain 91mg of 9. Yield: 86%. M.p. 190-192C
With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 105℃; for 2h;
10 parts of 2- (1-adamantyl) -4-bromoanisole (manufactured by Tokyo Chemical Industry Co., Ltd.),4 parts of 3-aminoanisole (manufactured by Tokyo Chemical Industry Co., Ltd.),0.35 parts of palladium acetate (manufactured by Tokyo Chemical Industry Co., Ltd.),0.90 parts of 4,5'-bis (diphenylphosphino) -9,9'-dimethylxanthene (manufactured by Tokyo Chemical Industry Co., Ltd.),Sodium tert-butoxide(Tokyo Chemical Industry Co., Ltd.) 6 parts toluene(Kanto Chemical Co., Ltd.) dissolved in 180 parts,The mixture was heated under reflux at 105 C for 2 hours.After the reaction, add water,Extract the organic layer,By concentrating, 25 parts of the compound represented by the formula (1-63) was obtained.
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