* 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.
Stage #1: With sodium hydroxide In tetrahydrofuran; ethanol at 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; ethanol for 1 h; Reflux
To a solution of ethyl-6-[(3-adamantyl-4-methoxyphenyl)]-2-naphthoate (1c) (10.85 g, 0.025 mol) in tetrahydrofuran (100 mL), a solution of sodium hydroxide (1.3 g, 0.027 mol) in absolute ethanol (25 mL) was added at room temperature. The solution was kept under stirring overnight at room temperature and glacial acetic acid (21.0 g, 20.0 mL, 0.35 mol) was added and the solution refluxed (1 h). The insoluble residue was filtered-off on celite from the hot solution, washed with tetrahydrofuran (50 mL) then cooled to 25 °C. The solution was concentrated at reduced pressure at ambient temperature, treated with methanol (100 mL) and warmed-up at 60 °C for 15 min. After cooling at room temperature and filtration, the solid residue was suspended in methanol (100 mL) then treated with triethylamine (10.9 g, 15 mL, 0.11 mol) and activated charcoal (1 h at room temperature). After filtration on celite and washing with methanol, the filtrate was poured into a flask and refluxed (65 °C). To this warm solution, a solution of glacial acetic acid (21.0 g, 20.0 mL, 0.35 mol) in methanol (20 mL) was added dropwise and a white precipitate was formed. After cooling to room temperature, the solid was filtrated and washed with methanol to obtain pure 6-[(3-adamantyl-4-metoxyphenyl)]-2-naphthoic acid (1a) (7.08 g, 0.017 mol, 70percent yield).CommentMp 320-322 °C; 1H NMR (DMSO-d6) δ = 1.74 (6 H, s, H on 1-adamantyl), 2.05 (3 H, s, H on 1-adamantyl), 2.12 (6 H, s, H on 1-adamantyl), 3.85 (3 H, s, ArOCH3), 7.10 (1 H, d, J = 8.5 Hz, 5-phenyl H), 7.56 (1 H, d, J = 2.0 Hz, 2-phenyl H), 7.62 (1 H, dd, J = 8.5 and 2.0 Hz, 6-phenyl H), 7.87 (1 H, d, J = 8.5 Hz, 7-naphthyl H), 7.98 (1 H, d, J = 8.5 Hz, 4-naphthyl H), 8.05 (1 H, d, J = 8.6 Hz, 8-naphthyl H), 8.13 (1 H, d, J = 8.6 Hz, 3-naphthyl H), 8.20 (1 H, s, 5-naphthyl H), 8.59 (1 H, s, 1-naphthyl H), 13.01 (1 H, s, COOH); 13C NMR (125.76 MHz, DMSO-d6) δ = 28.57, 36.73, 40.24, 55.50, 112.90, 124.24, 125.24, 125.66, 125.89, 126.09, 127.75, 128.48, 129.97, 130.42, 131.08, 131.68, 135.64, 138.19, 140.38, 158.75, 167.63. Anal. Calcd for C29H32O3: C, 81.27; H, 7.53; O, 11.20. Found: C, 81.36percent; H, 7.48percent.
Stage #1: With potassium carbonate In tetrahydrofuran; water for 8 h; Heating / reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran for 1 h;
Example 3 :Preparation of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2- naphthoic acid (I) :20 ml (12 vol) of tetrahydrofuran, 2 g (7 mmol) of 3-adamantyl-4-methoxyphenylboronic acid (II), 1.65 g (6.6 mmol) of 6 -broτno-2 -naphthoic acid (III) and 20 mL of a 2 M aqueous potassium carbonate solution are introduced into a round-bottomed flask equipped with EPO <DP n="13"/>stirring and under a nitrogen stream. 0.7 g (5percent) of 10percent palladium on carbon (50percent wet; Keraeus type K-0218) is then introduced.The medium is heated under reflux for 8 hours. The catalyst is filtered on a cartridge, and then slowly poured over 30 ml of a 1 N aqueous hydrochloric acid solution.The medium is kept stirring for one hour. The precipitate is filtered, washed with water and then dried under reduced pressure. 2.06 g of 6- [3- (1- adamantyl) -4-methoxyphenyl] -2-naphthoic acid are obtained in the form of a white solid whose purity, determined by HPLC, is 99.9percent (yield = 79percent; m.p. 321°C) .
99%
Stage #1: With potassium hydroxide In tetrahydrofuran; water at 55℃; for 2 h; Heating / reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran at 20℃;
Example 2 :Preparation of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2- naphthoic acid (I) :80 g (0.319 mol) of 6-bromo-2 -naphthoic acid, 95.7 g (0.335 mol, 1.05 eq) of 3 -adamantyl-4 -methoxyphenyl- boronic acid, 0.8 g of 5percent palladium on carbon (50percent wet,Degussa type E105CA/W) and 800 ml of tetrahydrofuran(10 vol) are introduced into a 4 litre reactor. The medium is heated to 55°C. 85 g (1.05 mol, 3.3 eq) of potassium hydroxide at 85percent are dissolved in 240 ml of water (3 vol) .The solution obtained is poured over the reaction medium. The addition is exothermic. The reaction medium reaches the reflux temperature. The reflux is EPO <DP n="12"/>maintained for about 2 hours .The reaction medium is filtered at about 35-400C on a cartridge and rinsed with 400 ml of a THF/water mixture (1/1) .The medium is cooled to 200C and 100 ml of HCl at 35percent in 600 ml of water are added. 6- [3- (1-adamantyl) -4- methoxyphenyl] -2-naphthoic acid precipitates. It is filtered and washed with 4 litres of water. The pH of the washings is about 6-7. The product is dried under vacuum at 1000C for 24 hours.131 g of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2 -naphtho- ic acid are obtained (crude yield = 99percent) .This crude material is dissolved in 15 to 22 volumes of THF under reflux. After filtration in the hot state, 15 to 22 volumes of heptane are added and the medium is cooled to about 50C for 1 to 2 hours.The 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid is filtered on sintered glass and it is rinsed with 1 to 2 volumes of heptane.108 g of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid are obtained in the form of a white solid whose purity, determined by HPLC, is 99.9percent (yield = 82percent; m.p. = 320-3220C) .
94.8%
Stage #1: With potassium carbonate In tetrahydrofuran; water for 2 - 4 h; Heating / reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran for 1 h;
b) - Preparation of 6- [3- (1-adamantyl) -4-methoxy- phenyl] -2-naphthoic acid (I):20 mL of tetrahydrofuran (12 vol) , 2 g (7 mmol) of 3 -adamantyl-4-methoxyphenylboronic acid (II), 1.65 g (6.6 mmol) of 6-bromo-2 -naphthoic acid (III) and 20 mL of a 2 M aqueous potassium carbonate solution are introduced into a round-bottomed flask equipped with stirring and under a nitrogen stream. 15 mg (1percent) of palladium acetate and 46 mg (2percent) of 2- (dicyclohexyl- phosphino) biphenyl are then introduced. The medium is EPO <DP n="11"/>heated under reflux for 2 hours. Kinetic monitoring by HPLC indicates that the percent of 6- [3- (i-adamantyi) -4- methoxyphenyl] -2 -naphthoic acid formed is 94percent after one hour and 98percent after 2 h.After returning to room temperature, the catalyst is filtered on a cartridge, and then slowly poured over 30 ml of a 1 N aqueous hydrochloric acid solution.The medium is kept stirring for one hour. The precipitate is filtered, washed with water and then dried under reduced pressure. 2.68 g of 6-[3-(l- adamantyl) -4-methoxyphenyl] -2 -naphthoic acid are obtained in the form of a white solid whose purity, determined by HPLC, is 99.9percent (yield = 94.8percent; m.p. = 3210C) .The following melting points (m.p.) exist in the literature: m.p. = 319°-322°C (B. Charpentier et al . , J. Med. Chem., 1995, 38, 4993-5006) and m.p. = 325°-327°C (EP 0 199 636) .
Step D: Basic hydrolysis of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoateExample 13; Into a 600 mL beaker is introduced 10 g of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate, 300 mL of ethylene glycol and heated almost to boiling. The obtained clear solution is added 15 g of sodium hydroxide in 3 portions and vigorously stirred for 20 min.The hot reaction mixture is slowly added with vigorous stirring to a cold 5percent solution of aqueous hydrochloric acid.The suspension thus obtained is stirred for 30 min and filtered off. The precipitate is pressed on filter, washed with 3.x.500 mL of hot water and dried at 100° C. for 16 h. 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, 9.3 g (96percent) with m.p. 320° C. and purity over 97percent is obtained.NMR (500 MHz, DMSO δ: 1.79 (s, 6H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.76 (d, 1H, J=9 Hz), 7.92 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H), 12.7 (s, 1H).Using 1,2-propanediol instead of ethylene glycol the concentration of the hydrolyzed methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate in solution can be increased by 50percent.
96%
Stage #2: With hydrogenchloride In water
Step D: Basic hydrolysis of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate; EXAMPLE 18; Into a 600 mL beaker 10 g of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate is introduced, 300 mL of ethylene glycol added and heated almost to boiling. To the obtained clear solution 15 g of sodium hydroxide is added in 3 portions and vigorously stirred for 20 min. The hot reaction mixture is slowly added with vigorous stirring to cold 5percent solution of aqueous hydrochloric acid. The suspension thus obtained is stirred for 30 min and filtered off. The precipitate is pressed on filter, washed with 3.x.500 mL of hot water. Dried at 100° C. for 16 h. 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoic acid, 9.3 g (96percent) with m.p. 320° C. and purity over 97percent is obtained.NMR (500 MHz, DMSO D6 δ: 1.79 (s, 6H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.76 (d, 1H, J=9 Hz), 7.92 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H), 12.7 (s, 1H).Using 1,2-propanediol instead of ethylene glycol the concentration of the hydrolized methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoate in solution can be increased by 50percent.
Reference：
[1] Patent: US2010/76219, 2010, A1, . Location in patent: Page/Page column 4
[2] Patent: US2010/160677, 2010, A1, . Location in patent: Page/Page column 5-6
[3] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4690 - 4694
[4] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[5] Organic Process Research and Development, 2006, vol. 10, # 2, p. 285 - 288
[6] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[7] Patent: WO2007/383, 2007, A1, . Location in patent: Page/Page column 19; 20
[8] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
[9] Patent: WO2007/125542, 2007, A2,
[10] Patent: WO2007/125542, 2007, A2,
Stage #1: With tert.-butyl lithium; sodium hydride In tetrahydrofuran; pentane at -60 - 20℃; for 0.666667 h; Stage #2: at -60 - 20℃; for 1.5 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; pentane for 0.166667 h;
A mixture of 6-[3-(1 -adamantyl)-4-methoxyphenyl]-2-bromonaphthalene (50 mg, 0,11 mmol) in THF (1 ml) was introduced into a Schlenk tube and was heated until its complete dissolution. Next, NaH (4,5 mg, 60percent dispersion in mineral oil, 0,11 mmol) was added under argon atmosphere and at room temperature, and the mixture was stirred for 10 minutes. The obtained mixture was cooled to -60 0C and t-BuLi (1 ,7 M in penthane, 0,22 mmol) was added, dropwise, during a period of 30 minutes. Next, and at the same temperature, a continuous mild flow of CO2 (anhydrous gas) was introduced in the reaction for 1 h. After bringing the reaction to room temperature during 30 minutes with continuous flow of CO2, the mixture was diluted with aq HCI (5 ml, 2 M) and was vigorously stirred for 10 minutes. The resulting mixture was extracted with CHCI3 (3 x 5 ml) and the joined organic phases were evaporated to dryness once dried with Na2SO4, giving the crude of Adapalene.The obtained crude was dissolved in dichloromethane (DCM) (3 ml_) and H2O (3 ml_) and NaOH (75 μl_, 1 eq., 1 ,5 M) was added. The mixture was brought at 55 0C and kept at reflux for 20 minutes. Next, extractions with H2O (2 x 3 ml_) were carried out. The aqueous phase was washed with DCM (2 x 3 ml_).DCM (3 ml_) was added again and the mixture was stirred at reflux for 10 minutes once acidified with HCI (1 M) until pH = 3-4. Finally, the phases were separated and the aqueous one was extracted with DCM (2 x 3 ml_). The joined organic phases were dried with Na2SO4 and were evaporated to dryness giving Adapalene (19 mg, 41 percent).
30%
Stage #1: With n-butyllithium; sodium hydride In tetrahydrofuran; hexane at -40 - 20℃; for 0.666667 h; Stage #2: at -40 - 20℃; for 1.5 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexane for 0.166667 h;
A mixture of 6-[3-(1 -adamantyl)-4-methoxyphenyl]-2-bromonaphthalene (50 mg, 0,11 mmol), THF (1 ml) was introduced into a Schlenk tube and was heated until its complete dissolution. Next, NaH (4,5 mg, 60percent dispersion in mineral oil, 0,11 mmol) was added under argon atmosphere and at room <n="17"/>temperature, and the mixture was stirred for 10 minutes. The solution was cooled to -40 0C and n-BuLi (139,5 μl, 1 ,6 M in hexane, 0,22 mmol) was added, dropwise, during 30 minutes. At the same temperature, a continuous mild flow of CO2 (anhydrous gas) was introduced in the reaction for 1 h. After bringing the reaction to room temperature during 30 minutes with continuous flow of CO2, the mixture was diluted with aq HCI (5 ml, 2 M) and was vigorously stirred for 10 minutes. The resulting mixture was extracted with CHCI3 (3 x 5 ml) and the joined organic phases were dried with Na2SO4 and next were evaporated to dryness, giving the crude of Adapalene. The crude was purified in the same way as that of the Example 8. 15 mg of Adapalene were obtained (30 percent) as a white solid.
Step D: Basic hydrolysis of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoateExample 13; Into a 600 mL beaker is introduced 10 g of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate, 300 mL of ethylene glycol and heated almost to boiling. The obtained clear solution is added 15 g of sodium hydroxide in 3 portions and vigorously stirred for 20 min.The hot reaction mixture is slowly added with vigorous stirring to a cold 5% solution of aqueous hydrochloric acid.The suspension thus obtained is stirred for 30 min and filtered off. The precipitate is pressed on filter, washed with 3×500 mL of hot water and dried at 100 C. for 16 h. 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, 9.3 g (96%) with m.p. 320 C. and purity over 97% is obtained.NMR (500 MHz, DMSO delta: 1.79 (s, 6H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.76 (d, 1H, J=9 Hz), 7.92 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H), 12.7 (s, 1H).Using 1,2-propanediol instead of ethylene glycol the concentration of the hydrolyzed methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate in solution can be increased by 50%.
96%
Step D: Basic hydrolysis of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate; EXAMPLE 18; Into a 600 mL beaker 10 g of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate is introduced, 300 mL of ethylene glycol added and heated almost to boiling. To the obtained clear solution 15 g of sodium hydroxide is added in 3 portions and vigorously stirred for 20 min. The hot reaction mixture is slowly added with vigorous stirring to cold 5% solution of aqueous hydrochloric acid. The suspension thus obtained is stirred for 30 min and filtered off. The precipitate is pressed on filter, washed with 3×500 mL of hot water. Dried at 100 C. for 16 h. 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoic acid, 9.3 g (96%) with m.p. 320 C. and purity over 97% is obtained.NMR (500 MHz, DMSO D6 delta: 1.79 (s, 6H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.76 (d, 1H, J=9 Hz), 7.92 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H), 12.7 (s, 1H).Using 1,2-propanediol instead of ethylene glycol the concentration of the hydrolized methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoate in solution can be increased by 50%.
Methyl 6-(3-adamantyl-4-hydroxyphenyl)naphtoate (506 mg, 1.23 mmol) was added to an ice-cooled suspension of NaH (80 mg, 60%) in dry DMF, the mixture stirred 1 h at O0C, then added with 245 mg (1.7 mmol) of CH3I, and left 90 min at r.t. Taking up with 80 ml of cold water, repeated extraction with CH2CI2, then with EtOAc, drying and evaporating the joined organic phases, and chromatography (silicagel, hexane/EtOAc 9/1 ) gave 300 mg of methyl 6-(3-adamantyl-4-methoxyphenyl)naphtoate. This compound (235 mg) was suspended in a 1 M solution of NaOH in MeOH and the mixture was refluxed 8 h. Evaporation, taking up with water, addition of HCI and filtration gave 227 mg of 6-(3-adamantyl-4-methoxyphenyl)naphtoic acid, mp >300C.This compound (100 mg, 0.24 mmol) was dissolved under nitrogen in 2.4 ml of DMF, then 92 mg (0.24 mmol) of HATU and 0.2 ml (1.21 mmol) of DIPEA were added and EPO <DP n="21"/>the solution thus obtained was kept under stirring at room temperature for 2 min. After addition of hydroxylamine hydrochloride (84 mg , 1.21 mmol), the mixture was stirred 2 h at r.t.. DMF was removed under reduced pressure and the residue was washed with water to obtain, after filtration, 111 mg of crude product, that was purified by flash chromatography (silicagel, MeOH/H2O 85:15), mp. 2220C, 1H NMR: (DMSO-d6)delta: 1.76 (s, 6H, Adam.), 2.03 (s, 3H, Adam), 2.14 (s, 6H, Adam), 3.86 (s, 3H, OCH3), 7.12 (d, 1 H, 1Ar,J = 8.56), 7.57 (d, 1 H, 1Ar, J = 1.86), 7.65 (dd, 1 H, 1Ar, J = 1.86, 8.93), 7.83 (dd, 1 H, 1Ar, J = 8.56, 1.86), 7.88 (dd, 1 H, 1Ar, J = 8.56, 1.86), 8.00-8.10 (m, 2H, 2Ar), 8.19 (s, 1 H, 1Ar), 8.35 (s, 1 H, 1Ar), 9.40 (s, 1 H), 11.35 (s, 1 H).
With sodium hydroxide; In methanol; for 8h;Reflux;
The above ester (235 mg, 0.551 mmol) was suspended in a 1M solution of NaOH in MeOH (22 mL) and the mixture was refluxed 8h. Evaporation, taking up with water, addition of HCl and filtration gave 15 as a white solid Mp> 300 C. 1H NMR (DMSO-d6) 13.10 (1H, brs); 8.59 (1H, d, J = 1.9 Hz); 8.21 (1H, d, J = 1.9 Hz); 8.13 (1H, d, J = 8.6 Hz); 8.07 (1H, d, J = 8.6 Hz); 7.96 (1H, dd, J = 8.6, 1.9 Hz); 7.88 (1H, dd, J = 8.6, 1.9 Hz); 7.64 (1H, dd, J = 8.6, 1.9 Hz); 7.58 (1H, d, J = 1.9 Hz); 7.11 (1H, d, J = 8.6 Hz); 3.88 (3H, s); 2.21-2.00 (9H, m); 1.78 (6H, s).
In tetrahydrofuran; toluene; at 65℃; for 1.25h;Purification / work up;
Example 10; Purification of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2 naphthoic acid (I); To a solution of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2 naphthoic acid (25g, 60.6 mmol) in THF (550 ml) was stirred at 650C. Then toluene (225 ml) was added in dropwise manner for 15 min. The reaction mixture was heated at 65 C for 1 h. The organic solvent was partially distilled from reaction mixture. Then the reaction mixture was cooled at 15-20 0C. The solid obtain was filtered and dried.[Yield: 15 g,60 %, Purity 99.6%].
Exemplary retinoids bearing a phenol or naphthol function, particularly representative are the following compounds: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid; methyl 6-[3-(1-adamantyl)-hydroxyphenyl]-2-naphthoate; 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid; 6-[3-(1-adamantyl)-4-acetoxyphenyl]-2-naphthoic acid; [3-[3-(1-adamantyl)-4-methoxyphenyl]-2H-1-benzopyran]-7-carboxylic acid; [3-[3-(1-adamantyl)-4-hydroxyphenyl]-2H-1-benzopyran]-7-carboxylic acid; [3-[3-(1-adamantyl)-4-acetoxyphenyl]-2H-1-benzopyran]-7-carboxylic acid; [2-[3-(1-adamantyl)-4-hydroxyphenyl]benzimidazole]-5-carboxylic acid; ?2-[3-(1-adamantyl)-4-hydroxyphenyl]benzothiophene-6-carboxylic acid; ...
(c) The preceding tritiated product (96 mCi) is dissolved in 5 ml of methanol. 6 mul of 5N soda are added and the resulting mixture is heated at reflux for 3 hours, cooled, acidified using 2 ml of 6N HCl and then extracted with 50 ml of ethyl ether. The ether phase is decanted, washed with water, dried on anhydrous magnesium sulfate and the solvents evaporated under reduced pressure. The resulting residue is dissolved in 2 ml of ether and purified by high performance liquid chromatography (eluant: 100% ethyl ether).
In tetrahydrofuran; n-heptane; at 0 - 30℃; for 3h;Heating / reflux;Purification / work up;
The dried product was taken in 300 ml of tetrahydrofuran and stirred. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and cooled the reaction mass to 25 - 300C. 500 ml of n - heptane was charged to the reaction mass and stirred for 30 minutes. The reaction mass was then chilled to 0 - 5C and maintained stirring at 0 - 5C temperature for 2.0 hours. The precipitated solid was <n="12"/>filtered and washed with n - heptane. The pure crystalline 6 - [3-(l- adamantyl) - 4 methoxyphenyl] - 2 - naphthoic acid thus obtained was then dried till constant weight. Yield = 40 - 42 gms (68 - 72 %)
EXAMPLE 3 Composition 3 Specifications at T0 Macroscopic appearance: Thick, supple, white ointment with slight yellow tints Microscopic appearance: Absence of hydroquinone crystals, dispersion of adapalene <2.5 mum to 5 mum.
EXAMPLE 4 Composition 4 Specifications at T0 Macroscopic appearance: Thick, supple, white ointment with slight yellow tints Microscopic appearance: Absence of hydroquinone crystals, dispersion of adapalene <2.5 mum to 5 mum
EXAMPLE 5 Composition 5 Specifications at T0 Macroscopic appearance: Glossy white ointment Microscopic appearance: Absence of rucinol crystals, dispersion of adapalene <2.5 mum to 5 mum.
2. Preparation of Adapalene Phase Sodium decussate and POLOXAMER124 were dissolved in glycerin at about 55-60 C.
2. Preparation of Adapalene Phase POLOXAMER124 was dissolved in propylene glycol at about 55-60 C.
2. Preparation of Adapalene Phase POLOXAMER124 was dissolved in propylene glycol at about 55-60 C.
7
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid sodium salt[ No CAS ]
[ 106685-40-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With acetic acid; In tetrahydrofuran; water; at 60 - 70℃;Heating / reflux;
A round-bottom flask is loaded with adapalene sodium salt (6.7 g; 15.42 mmol), THF (40 ml) and water (7 ml) and the mixture is refluxed until complete dissolution of the solid. The resulting solution is dropped into a 3% w/w acetic acid aqueous solution, keeping the temperature above 60-70C, to precipitate adapalene acid (6.3 g; 15.27 mmol), which is filtered and dried under vacuum at a temperature of 50-60C. The yield is 95%.
80%
With hydrogenchloride; In water;pH 3 - 4;Product distribution / selectivity;
Example 9; Preparation of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (I); A mixture of sodium salt of 6-[3-(l-adamantyl)-4~methoxy phenyl]-2 naphthoic acid (20 g, 58 mmol) in water (200 ml) and concentrated HCl (5 ml) was added slowly till pH becomes 3 to 4. The solid was separated, filtered, washed with water and dried.[Yield: 15 g, 80 %].
Example 3 :Preparation of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2- naphthoic acid (I) :20 ml (12 vol) of tetrahydrofuran, 2 g (7 mmol) of 3-adamantyl-4-methoxyphenylboronic acid (II), 1.65 g (6.6 mmol) of 6 -brotauno-2 -naphthoic acid (III) and 20 mL of a 2 M aqueous potassium carbonate solution are introduced into a round-bottomed flask equipped with EPO <DP n="13"/>stirring and under a nitrogen stream. 0.7 g (5%) of 10% palladium on carbon (50% wet; Keraeus type K-0218) is then introduced.The medium is heated under reflux for 8 hours. The catalyst is filtered on a cartridge, and then slowly poured over 30 ml of a 1 N aqueous hydrochloric acid solution.The medium is kept stirring for one hour. The precipitate is filtered, washed with water and then dried under reduced pressure. 2.06 g of 6- [3- (1- adamantyl) -4-methoxyphenyl] -2-naphthoic acid are obtained in the form of a white solid whose purity, determined by HPLC, is 99.9% (yield = 79%; m.p. 321C) .
99%
Example 2 :Preparation of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2- naphthoic acid (I) :80 g (0.319 mol) of 6-bromo-2 -naphthoic acid, 95.7 g (0.335 mol, 1.05 eq) of 3 -adamantyl-4 -methoxyphenyl- boronic acid, 0.8 g of 5% palladium on carbon (50% wet,Degussa type E105CA/W) and 800 ml of tetrahydrofuran(10 vol) are introduced into a 4 litre reactor. The medium is heated to 55C. 85 g (1.05 mol, 3.3 eq) of potassium hydroxide at 85% are dissolved in 240 ml of water (3 vol) .The solution obtained is poured over the reaction medium. The addition is exothermic. The reaction medium reaches the reflux temperature. The reflux is EPO <DP n="12"/>maintained for about 2 hours .The reaction medium is filtered at about 35-400C on a cartridge and rinsed with 400 ml of a THF/water mixture (1/1) .The medium is cooled to 200C and 100 ml of HCl at 35% in 600 ml of water are added. 6- [3- (1-adamantyl) -4- methoxyphenyl] -2-naphthoic acid precipitates. It is filtered and washed with 4 litres of water. The pH of the washings is about 6-7. The product is dried under vacuum at 1000C for 24 hours.131 g of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2 -naphtho- ic acid are obtained (crude yield = 99%) .This crude material is dissolved in 15 to 22 volumes of THF under reflux. After filtration in the hot state, 15 to 22 volumes of heptane are added and the medium is cooled to about 50C for 1 to 2 hours.The 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid is filtered on sintered glass and it is rinsed with 1 to 2 volumes of heptane.108 g of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid are obtained in the form of a white solid whose purity, determined by HPLC, is 99.9% (yield = 82%; m.p. = 320-3220C) .
94.8%
b) - Preparation of 6- [3- (1-adamantyl) -4-methoxy- phenyl] -2-naphthoic acid (I):20 mL of tetrahydrofuran (12 vol) , 2 g (7 mmol) of 3 -adamantyl-4-methoxyphenylboronic acid (II), 1.65 g (6.6 mmol) of 6-bromo-2 -naphthoic acid (III) and 20 mL of a 2 M aqueous potassium carbonate solution are introduced into a round-bottomed flask equipped with stirring and under a nitrogen stream. 15 mg (1%) of palladium acetate and 46 mg (2%) of 2- (dicyclohexyl- phosphino) biphenyl are then introduced. The medium is EPO <DP n="11"/>heated under reflux for 2 hours. Kinetic monitoring by HPLC indicates that the % of 6- [3- (i-adamantyi) -4- methoxyphenyl] -2 -naphthoic acid formed is 94% after one hour and 98% after 2 h.After returning to room temperature, the catalyst is filtered on a cartridge, and then slowly poured over 30 ml of a 1 N aqueous hydrochloric acid solution.The medium is kept stirring for one hour. The precipitate is filtered, washed with water and then dried under reduced pressure. 2.68 g of 6-[3-(l- adamantyl) -4-methoxyphenyl] -2 -naphthoic acid are obtained in the form of a white solid whose purity, determined by HPLC, is 99.9% (yield = 94.8%; m.p. = 3210C) .The following melting points (m.p.) exist in the literature: m.p. = 319-322C (B. Charpentier et al . , J. Med. Chem., 1995, 38, 4993-5006) and m.p. = 325-327C (EP 0 199 636) .
6-(3-adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid hydroxyamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; at 20℃;Inert atmosphere;
A solution of HATU (55mg, 0.14mmol), acid 10a (60mg, 0.14mmol) and DIPEA (0.05mL, 0.23mmol) was stirred for 2min under nitrogen. NH2OH·HCl (40mg, 0.58mmol) was added and the resulting solution was stirred at room temperature overnight. The solvent was evaporated, water was added and the suspension was stirred 1h at room temperature. The white solid formed was filtered. Yield: 65% M.p. 211-213C. 1H NMR (DMSO-d6) delta: 10.75 (1H, s); 9.04 (1H, s); 7.68-7.52 (4H, m); 7.47 (1H, d, J=16.0Hz); 7.03 (1H, d, J=2.1Hz); 7.00 (1H, d, J=2.1Hz); 6.47 (1H, d, J=16.0Hz); 4.27 (4H, s); 2.10 (6H, s); 2.05 (3H, s); 1.74 (6H, s). 13C NMR (DMSO-d6) delta: 162.8, 144.0, 142.7, 141.2, 138.7, 138.0, 133.3, 131.6, 128.0, 126.7, 118.6, 116.6, 113.2, 63.7, 63.5, 36.7, 36.5, 28.4. Anal. Calcd for C27H29NO4: C, 75.15; H, 6.77; N, 3.25. Found: C, 75.25; H, 6.73; N, 3.21.
Methyl 6-(3-adamantyl-4-hydroxyphenyl)naphtoate (506 mg, 1.23 mmol) was added to an ice-cooled suspension of NaH (80 mg, 60%) in dry DMF, the mixture stirred 1 h at O0C, then added with 245 mg (1.7 mmol) of CH3I, and left 90 min at r.t. Taking up with 80 ml of cold water, repeated extraction with CH2CI2, then with EtOAc, drying and evaporating the joined organic phases, and chromatography (silicagel, hexane/EtOAc 9/1 ) gave 300 mg of methyl 6-(3-adamantyl-4-methoxyphenyl)naphtoate. This compound (235 mg) was suspended in a 1 M solution of NaOH in MeOH and the mixture was refluxed 8 h. Evaporation, taking up with water, addition of HCI and filtration gave 227 mg of 6-(3-adamantyl-4-methoxyphenyl)naphtoic acid, mp >300C.This compound (100 mg, 0.24 mmol) was dissolved under nitrogen in 2.4 ml of DMF, then 92 mg (0.24 mmol) of HATU and 0.2 ml (1.21 mmol) of DIPEA were added and EPO <DP n="21"/>the solution thus obtained was kept under stirring at room temperature for 2 min. After addition of hydroxylamine hydrochloride (84 mg , 1.21 mmol), the mixture was stirred 2 h at r.t.. DMF was removed under reduced pressure and the residue was washed with water to obtain, after filtration, 111 mg of crude product, that was purified by flash chromatography (silicagel, MeOH/H2O 85:15), mp. 2220C, 1H NMR: (DMSO-d6)delta: 1.76 (s, 6H, Adam.), 2.03 (s, 3H, Adam), 2.14 (s, 6H, Adam), 3.86 (s, 3H, OCH3), 7.12 (d, 1 H, 1Ar,J = 8.56), 7.57 (d, 1 H, 1Ar, J = 1.86), 7.65 (dd, 1 H, 1Ar, J = 1.86, 8.93), 7.83 (dd, 1 H, 1Ar, J = 8.56, 1.86), 7.88 (dd, 1 H, 1Ar, J = 8.56, 1.86), 8.00-8.10 (m, 2H, 2Ar), 8.19 (s, 1 H, 1Ar), 8.35 (s, 1 H, 1Ar), 9.40 (s, 1 H), 11.35 (s, 1 H).
A mixture of 6-[3-(1 -adamantyl)-4-methoxyphenyl]-2-bromonaphthalene (50 mg, 0,11 mmol) in THF (1 ml) was introduced into a Schlenk tube and was heated until its complete dissolution. Next, NaH (4,5 mg, 60% dispersion in mineral oil, 0,11 mmol) was added under argon atmosphere and at room temperature, and the mixture was stirred for 10 minutes. The obtained mixture was cooled to -60 0C and t-BuLi (1 ,7 M in penthane, 0,22 mmol) was added, dropwise, during a period of 30 minutes. Next, and at the same temperature, a continuous mild flow of CO2 (anhydrous gas) was introduced in the reaction for 1 h. After bringing the reaction to room temperature during 30 minutes with continuous flow of CO2, the mixture was diluted with aq HCI (5 ml, 2 M) and was vigorously stirred for 10 minutes. The resulting mixture was extracted with CHCI3 (3 x 5 ml) and the joined organic phases were evaporated to dryness once dried with Na2SO4, giving the crude of Adapalene.The obtained crude was dissolved in dichloromethane (DCM) (3 ml_) and H2O (3 ml_) and NaOH (75 mul_, 1 eq., 1 ,5 M) was added. The mixture was brought at 55 0C and kept at reflux for 20 minutes. Next, extractions with H2O (2 x 3 ml_) were carried out. The aqueous phase was washed with DCM (2 x 3 ml_).DCM (3 ml_) was added again and the mixture was stirred at reflux for 10 minutes once acidified with HCI (1 M) until pH = 3-4. Finally, the phases were separated and the aqueous one was extracted with DCM (2 x 3 ml_). The joined organic phases were dried with Na2SO4 and were evaporated to dryness giving Adapalene (19 mg, 41 %).
30%
A mixture of 6-[3-(1 -adamantyl)-4-methoxyphenyl]-2-bromonaphthalene (50 mg, 0,11 mmol), THF (1 ml) was introduced into a Schlenk tube and was heated until its complete dissolution. Next, NaH (4,5 mg, 60% dispersion in mineral oil, 0,11 mmol) was added under argon atmosphere and at room <n="17"/>temperature, and the mixture was stirred for 10 minutes. The solution was cooled to -40 0C and n-BuLi (139,5 mul, 1 ,6 M in hexane, 0,22 mmol) was added, dropwise, during 30 minutes. At the same temperature, a continuous mild flow of CO2 (anhydrous gas) was introduced in the reaction for 1 h. After bringing the reaction to room temperature during 30 minutes with continuous flow of CO2, the mixture was diluted with aq HCI (5 ml, 2 M) and was vigorously stirred for 10 minutes. The resulting mixture was extracted with CHCI3 (3 x 5 ml) and the joined organic phases were dried with Na2SO4 and next were evaporated to dryness, giving the crude of Adapalene. The crude was purified in the same way as that of the Example 8. 15 mg of Adapalene were obtained (30 %) as a white solid.
6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid potassium salt[ No CAS ]
[ 106685-40-9 ]
Yield
Reaction Conditions
Operation in experiment
89.29%
With hydrogenchloride; In methanol; water; at 40℃; for 1.5h;
In 500 mL of methanol was added 49.59 g (1.10×10-1 mol, dry equivalent amount) of the wet solid obtained in Example/Step 2, and the mixture was heated to reflux for 30 minutes and cooled to approximately 40 C. Next, 33.17 g of concentrated HCl was slowly added over approximately 1 hour with gentle stirring in order to ensure homogeneity, followed by the slow addition of 248 mL of water. The resulting mixture was stirred for approximately 30 additional minutes at approximately 40 C. and then cooled to room temperature, filtered and washed with methanol. The wet solid was then suspended with 1020 mL of tetrahydrofuran and heated to reflux for approximately 10 minutes or until complete dissolution. The solution was then cooled to approximately 35 C., the solid particles were removed by filtration, and the filter was washed with tetrahydrofuran.The collected mother liquors were heated to reflux, and 654 g of tetrahydrofuran was removed by distillation. The mixture was then cooled to approximately 55-60 C. Thereafter, 650 mL of methanol was added over approximately 10 minutes, and the mixture heated to reflux for approximately 30 minutes, cooled, and filtered. The resulting solid was filtered with methanol and dried at 80 C. in a vacuum oven to yield 40.54 g of adapalene (9.83×10-2 mol; yield: 89.29% (from adapalene potassium salt); 88.56% (from adapalene methyl ester); and 78.67% (from methyl 6-bromo-2-naphthoate)). Analytical data: HPLC Purity (HPLC at 272 nm): 100.00%; Assay: 99.99%; Residue on Ignition: 0.02%; IR: matches reference.
With hydrogenchloride; In 1,4-dioxane; methanol; water;
Preparation of AdapaleneTo a mixture of 6-[3-(1 -adamantyl)-4-methoxyphenyl]-2-cyanonaphthalene(125 mg, 0.32 mmol), dioxane (2 ml_), MeOH (2 ml_) and H2O (0.8 ml_), was added KOH (222 mg, 3.97 mmol) and the reaction mixture was stirred at reflux temperature for 24 h. The mixture was acidified with HCI (5 ml_, 2M) was extracted with EtOAc (3 x 10 ml_). The combined organic phases were evaporated to dryness once dried with Na2SO4, giving crude Adapalene (164 mg). Recrystallization from toluene yielded Adapalene (122 mg, 58%) as a white solid.
With hydrogenchloride; In water;Product distribution / selectivity;
Example 11; Preparation of 6-[3-(l-adamantyl)-4methoxy phenyl]-2 naphthoic acid (Adapalene) (I): The compound (V) (9.45 g, 22mmol) was dissolved in 1,4-Dioxane (95 ml) at reflux temperature and KOH (6.3 g, 11 mmol in 30 ml water) was added in a drop wise manner for 15 min. The reaction mixture was refluxed for 2-4 hrs and then cooled when the <n="19"/>potassium salt of adapalene is precipitated, filtered and washed with methanol (25 ml). This salt of adapalene was acidified with 2 N HCl, solid separated, filtered and dried to obtain crude adapalene. The crude was recrystallized from THF-ethyl acetate. [Yield: 5.0 g, 81 %; Purity: HPLC > 99 %]
3-adamantyl-4-methoxyphenyl potassium trifluoroborate[ No CAS ]
[ 33626-98-1 ]
[ 106685-40-9 ]
Yield
Reaction Conditions
Operation in experiment
Example 2: Preparation of 6 - [3-(l- Adamantyl) - 4 - methoxyphenyl] - 2 - naphthoic acid:In a 1.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 50.0 gm of 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate, 23 gm of 6- bromo -2-methyl napthoate in 300 ml tetrahydrofuran (THF) was charged. Stirred for 15 min and charged 3.0 gm of 5% Pd / C was and aqueous potassium hydroxide solution (50.0 gm in 300 ml water). Stirring was continued and the temperature was raised to reflux. The reaction mass was maintained for 10 hours at reflux and after the completion of the reaction, 200 ml of tetrahydrofuran: water (1 : 1) mixture was added and then filtered through hyflow bed at 45-500C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-500C. 500 ml water was charged and the reaction mass was stirred. The aqueous layer was acidified with 1.2N hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH. The solid product obtained was dried at 70 - 75C till constant weight to get 6 - [3-(l- adamantyl) - 4 - methoxyphenyl] - 2 - naphthoic acid.
To a solution of ethyl-6-[(3-adamantyl-4-methoxyphenyl)]-2-naphthoate (1c) (10.85 g, 0.025 mol) in tetrahydrofuran (100 mL), a solution of sodium hydroxide (1.3 g, 0.027 mol) in absolute ethanol (25 mL) was added at room temperature. The solution was kept under stirring overnight at room temperature and glacial acetic acid (21.0 g, 20.0 mL, 0.35 mol) was added and the solution refluxed (1 h). The insoluble residue was filtered-off on celite from the hot solution, washed with tetrahydrofuran (50 mL) then cooled to 25 C. The solution was concentrated at reduced pressure at ambient temperature, treated with methanol (100 mL) and warmed-up at 60 C for 15 min. After cooling at room temperature and filtration, the solid residue was suspended in methanol (100 mL) then treated with triethylamine (10.9 g, 15 mL, 0.11 mol) and activated charcoal (1 h at room temperature). After filtration on celite and washing with methanol, the filtrate was poured into a flask and refluxed (65 C). To this warm solution, a solution of glacial acetic acid (21.0 g, 20.0 mL, 0.35 mol) in methanol (20 mL) was added dropwise and a white precipitate was formed. After cooling to room temperature, the solid was filtrated and washed with methanol to obtain pure 6-[(3-adamantyl-4-metoxyphenyl)]-2-naphthoic acid (1a) (7.08 g, 0.017 mol, 70% yield).CommentMp 320-322 C; 1H NMR (DMSO-d6) delta = 1.74 (6 H, s, H on 1-adamantyl), 2.05 (3 H, s, H on 1-adamantyl), 2.12 (6 H, s, H on 1-adamantyl), 3.85 (3 H, s, ArOCH3), 7.10 (1 H, d, J = 8.5 Hz, 5-phenyl H), 7.56 (1 H, d, J = 2.0 Hz, 2-phenyl H), 7.62 (1 H, dd, J = 8.5 and 2.0 Hz, 6-phenyl H), 7.87 (1 H, d, J = 8.5 Hz, 7-naphthyl H), 7.98 (1 H, d, J = 8.5 Hz, 4-naphthyl H), 8.05 (1 H, d, J = 8.6 Hz, 8-naphthyl H), 8.13 (1 H, d, J = 8.6 Hz, 3-naphthyl H), 8.20 (1 H, s, 5-naphthyl H), 8.59 (1 H, s, 1-naphthyl H), 13.01 (1 H, s, COOH); 13C NMR (125.76 MHz, DMSO-d6) delta = 28.57, 36.73, 40.24, 55.50, 112.90, 124.24, 125.24, 125.66, 125.89, 126.09, 127.75, 128.48, 129.97, 130.42, 131.08, 131.68, 135.64, 138.19, 140.38, 158.75, 167.63. Anal. Calcd for C29H32O3: C, 81.27; H, 7.53; O, 11.20. Found: C, 81.36%; H, 7.48%.
Example 5 - Formula 135 - Examples 5a & 5bIntermediate B: (6-(3-(Adamantan-1 -yl)-4-methoxyphenyl)naphthalen-2-yl)methanol A solution of compound A (2.00 g, 4.85 mmol, 1 eq) in THF (180 mL) was cooled to 0 C before adding BH3.THF (1 M solution in THF, 14.6 mL, 14.6 mmol, 3 eq) dropwise. The reaction mixture was warmed to room temperature and stirred for 3 h then diluted with water and extracted with CH2CI2 (30 mL x 3). The organic layers were combined, washed with brine and dried over anhydrous MgS04. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (CH2CI2 /Pet. ether, 1/2, v/v) to give (6-(3-(adamantan-1 -yl)-4-methoxyphenyl)naphthalen-2-yl)methanol (1 .90 g, 98%) as a white solid.LC-MS (Agilent): Rt 4.1 1 min; m/z calculated for C28H3o02 [M+Na]+ 421 .5, found [M+Na]+ 421 .21H NMR: (400 MHz, CDCI3) delta (ppm): 8.00 (s, 1 H), 7.92-7.75 (m, 4H), 7.62 (d, J = 2.4 Hz, 1 H), 7.57-7.51 (m, 2H), 7.01 (d, J = 8.4 Hz, 1 H), 4.90 (s, 2H), 3.93 (s, 3H), 2.21 (s, 6H), 2.13 (s, 3H), 1 .83 (m, 6H).
98%
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3h;
A solution of compound A (2.00 g, 4.85 mmol, 1 eq) in THF (180 mL) was cooled to 0 C. before adding BH3.THF (1 M solution in THF, 14.6 mL, 14.6 mmol, 3 eq) dropwise. The reaction mixture was warmed to room temperature and stirred for 3 h then diluted with water and extracted with CH2Cl2 (30 mL*3). The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (CH2Cl2/Pet. ether, ½, v/v) to give (6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalen-2-yl)methanol (1.90 g, 98%) as a white solid. LC-MS (Agilent): Rt 4.11 min; m/z calculated for C28H30O2 [M+Na]+ 421.5. found [M+Na]+ 421.2 1H NMR: (400 MHz, CDCl3) delta (ppm): 8.00 (s, 1H), 7.92-7.75 (m, 4H), 7.62 (d, J=2.4 Hz, 1H), 7.57-7.51 (m, 2H), 7.01 (d, J=8.4 Hz, 1H), 4.90 (s, 2H), 3.93 (s, 3H), 2.21 (s, 6H), 2.13 (s, 3H), 1.83 (m, 6H).
79%
With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃; for 2h;
To a solution of lithium aluminum hydride (LAH) (5.05 mg, 0.133 mmol) in Et20 (1 mL) at 0 C was added <strong>[106685-40-9]adapalene</strong> (50 mg, 0.121 mmol) in Et20 (0.5 mL). The reaction was warmed to room temperature and stirred for 2 hours. The reaction was cooled to 0 C and H20 (1 mL) was added slowly followed by IN NaOH (1 mL). The resulting slurry was filtered over Celite and washed with EtOAc. The aqueous layer was extracted with EtOAc 3x and the combined organics were washed with water and brine, dried over Na2S04, filtered, and concentrated; yielding the title compound as a white solid (38 mg, 79% yield). JH NMR (500 MHz, CDCh) delta 7.98 (d, J = 1.1 Hz, 1H), 7.88 (t, J = 8.5 Hz, 2H), 7.82 (s, 1H), 7.74 (dd, J = 8.5, 1.8 Hz, 1H), 7.60 (d, J = (0563) 2.3 Hz, 1H), 7.53 (dd, J = 8.4, 2.3 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 6.99 (d, J = (0564) 8.4 Hz, 1H), 4.87 (s, 2H), 3.90 (s, 3H), 2.20 (s, 6H), 2.11 (s, 3H), 1.81 (s, 6H); 13C NMR (125 MHz, CDCh) delta 158.72, 139.19, 139.01, 138.09, 133.44, 133.20, 132.29, 128.64, 128.36, 126.17, 126.01, 125.70, 125.65, 125.40, 124.98, 112.22, 65.69, 55.31, 40.76, 37.28, 29.26; HRMS Accurate mass (ES+): Found 421.2141, C28H3i02Na (M+Na+) requires 421.2143.
With dipotassium hydrogenphosphate; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; triphenylphosphine; In dichloromethane; water; at 20℃; for 48h;Inert atmosphere; Irradiation;
Firstly weighing (41.2 mg, 0.1 mmol),photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6(2.3 mg, 0.002 mmol), K2HPO4(3.5 mg, 0 . 02 mmol),and Ph3P (31.5 mg, 0.12 mmol)are added to a reaction tube, pumping air through the vacuum line three times, in the argon atmosphere, adding DCM/H2O (2.0 ml, 4:1 v/v), then carefully added (15.8 mg, 0 . 15 mmol),then put into 5W blue LEDs lamp irradiation, react at room temperature for 48 h.Add 20 ml water, and the DCM extraction (3x 10 ml) the aqueous phase, combined with the organic phase. The organic phase by absolute Na2SO4 after drying and steaming and to remove the solvent, dry sample, column chromatography (300 - 400 item of chromatographic analysis silica gel) (petroleum ether - ethyl acetate) to obtain the product 24.0 mg, Yield 48%.
6-(3-(adamantan-1-yl)-4-methoxyphenyl)-2-naphthamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[106685-40-9]adapalene</strong> (50 mg, 0.121 mmol) in CH2C12 (3 mL) and DMF (one drop, cat.) was added oxalyl chloride (2M in CH2C12, 0.15 mL, 0.30 mmol), and the reaction was stirred at room temperature 2 hours. The reaction was concentrated and dissolved in 8: 1 EtOAc/NH4OH (5 mL) and stirred at 0C for 30 minutes. The reaction was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc 3x. The combined organic layers were washed with water and brine, dried over Na2S04, filtered, and concentrated, yielding the title compound as a white solid (49 mg, quant.). JH NMR (500 MHz, CDCh) delta 8.36 (s, 1H), 8.02 (s, 1H), 8.00 - 7.93 (m, 2H), 7.87 (dd, J = 8.5, 1.8 Hz, 1H), 7.81 (dd, J = 8.5, 1.8 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.4, 2.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 2.19 (s, 6H), 2.11 (s, 3H), 1.80 (s, 6H); 13C NMR (125 MHz, CDCh) delta 170.04, 159.00, 141.20, 139.11, 135.53, 132.60, 131.39, 129.97, 129.49, 128.68, 128.09, 126.77, 126.03, 125.79, 124.79, 124.11, 112.22, 55.26, 40.69, 37.20, 29.19; HRMS Accurate mass (ES+): Found 434.2085, CisFfeNOiNa (M+Na+) requires 434.2096.
6-(3-(adamantan-1-yl)-4-methoxyphenyl)-2-naphthaldehyde-formyl-d<SUB>1</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With dipotassium hydrogenphosphate; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; 2,4,6-Triisopropylthiophenol; water-d2; triphenylphosphine; In dichloromethane; at 20℃; for 36h;Irradiation; Inert atmosphere; Sealed tube;
Weighed first (41.2mg, 0.1mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.3mg, 0.002mmol), Kappa2EtaRhoOmicron4 (34.8mg, 1.0equinu.), and Rhoh3Rho (0.11mmol, 28.8mg, 1.1equiv.) was added to the reaction tube, and the gas was exchanged three times through a vacuum line. Under an argon atmosphere, DCM/D2O (2.0 mL, 1: 1 nu/nu) was added. Then, 2,4,6-triisopropylthiophenol (0.03 mmol, 7.1 mg) was carefully added, and then the tube was sealed and placed under a 5W blue LEDs lamp and allowed to react at room temperature for 36 hours. At the end of the reaction. The reaction completed, the mixture was quenched with water, and extracted with DCM (3x10mL). Rotary evaporated organic phase was dried over anhydrous Na2SO4 the solvent was removed by dry-like, column chromatography (300-400 mesh silica gel chromatography) (eluent: petroleum ether - ethyl acetate, volume ratio: 40-10: 1) to give 29 mg, 73% yield of product.
diethyl (6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalen-2-yl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate; In 1,4-dioxane; at 130℃; for 18h;Schlenk technique; Inert atmosphere; Glovebox;
Weigh 1.2 times equivalent of <strong>[106685-40-9]adapalene</strong> (0.48mmol), take 1.0 times equivalent of diethoxyphosphine HP (O) (OEt) 2 and 10mol% Pd (OAc) 2, 10mol% dppp, 2.5 times the equivalent of CyNMe2 and 1.5 times the equivalent of Boc2O were sequentially added to the Schlenk reaction tube, and then, under a nitrogen atmosphere, 3 ml of dioxane solvent was added, and the reaction was continued at 130 C for 18 hours. After the reaction was completed, it was cooled to room temperature and separated by column chromatography to obtain the target product: <strong>[106685-40-9]adapalene</strong> modified with diethoxyphosphoric oxide. The yield was 72%.
(6-(3-((3r,5r,7r)-adamantan-1-yl)-4-methoxyphenyl)naphthalen-2-yl)diphenylphosphine oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With di-tert-butyl dicarbonate; N,N-dimethyl-cyclohexanamine; 1,3-bis-(diphenylphosphino)propane; palladium diacetate; In 1,4-dioxane; at 115℃; for 18h;Schlenk technique; Inert atmosphere; Glovebox;
Weigh 1.2 times equivalent of <strong>[106685-40-9]adapalene</strong> (0.48mmol), take 1.0 times equivalent of diphenylphosphine HP (O) Ph2), 10mol% Pd (OAc) 2, 10mol% dppp, 2.0 times equivalent in the glove box CyNMe2 and 1.4 times the equivalent of Boc2O were sequentially added to the Schlenk reaction tube. Subsequently, 3 ml of dioxane solvent was added under a nitrogen atmosphere, and the reaction was continued at 115 C for 18 hours. After the reaction was completed, the mixture was cooled to room temperature and separated by column chromatography to obtain the target product: <strong>[106685-40-9]adapalene</strong> modified with diphenylphosphine oxide with a yield of 68%.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
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