阿达帕林结构如下 合成路线信息 实验操作 2-(1-Adamantyl)-4-bromophenol (4). 3 (1730 g, 10 mol)
and 2 (1520 g, 10 mol) were dissolved in CH2Cl2 (5 L). To
the resulting solution was slowly added the mixture of 98%
H2SO4 (0.55 L) and AcOH (2.75 L). The resulting mixture
was stirred for 2 days at room temperature, poured into water
(2.5 L), neutralized to pH 6 with saturated sodium bicarbonate solution, extracted with CH2Cl2 (3 × 5 L). The organic
phase was washed with water (2 × 10 L), dried over
anhydrous sodium sulfate, filtrated through Celite, and
evaporated in vacuo. The recycled CH2Cl2 could subsequently be used again after anhydration with anhydrous
calcium chloride. After recrystallization in isooctane (3078
g/35 L), 4 was obtained as a pure white (99% HPLC) solid
(3050 g, 99%)小编：投料比1:1，傅克烷基化反应，后处理，重结晶后收率能做到99%，非常牛掰，只是不知道重现性如何？
2-(1-Adamatyl)-4-bromoanisole (5).Dimethyl sulfate
(100 mL, 1.05 mol) was added to a suspension of 4 (307 g,
1 mol) and anhydrous potassium carbonate (415 g, 3 mol)
in dry acetone (9 L). The mixture was refluxed for 8 h. After
cooling, the solid was removed by suction filtration. The
solvent was recycled in vacuo, and the residue was washed
with 5% aqueous sodium hydroxide (5 L). Then the mixture
was extracted with ethyl ether (3 × 2.5 L). The organic layer
was successively washed with water (3 × 2.5 L) and brine
(2.5 L), dried with anhydrous sodium sulfate, filtrated
through Celite, and concentrated in vacuo. The resultant (314
g) was recrystallized from ethyl acetate (1.5 L) to give the
pure (99.5% HPLC) white solid 5 (305 g, 95%)小编：这步烷基化，收率这么高，感觉很正常。 6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic Acid
(Adapalene, 1). Compound 7 (213 g, 0.5 mol) was treated
with 2 N NaOH solution (8 L) in methanol under reflux for
8 h. After evaporation of methanol (7 L) and addition of
water (1.5 L), the mixture was acidified until pH 1 with 6 N
HCl and filtrated through Celite. The residue was washed
with water (3 × 5 L), and recrystallized twice in THF (194
g/2 L/time) to give pure (99% HPLC) 1 (177 g, 85%),小编：最后一步，基于原料药控制，收率85%是可以接受的，但是如果不是基于API，这个收率不高。 参考文献Organic Process Research & Development 2006, 10, 285−288
