药物Obeticholic acid(奥贝胆酸)合成检索总结报告

药物Obeticholic acid（奥贝胆酸）合成检索总结报告
一、Obeticholic acid（奥贝胆酸）简介
Obeticholic acid（奥贝胆酸）于2016年5月在美国上市，主要用于成人单药治疗应答不佳的原发性胆汁性胆管炎。

Obeticholic acid（奥贝胆酸）常见的不良反应有瘙痒、疲劳、腹部疼痛、皮疹、口咽痛、头晕、便秘等等。

Obeticholic acid（奥贝胆酸）分子结构式如下:
英文名称：Obeticholic acid
中文名称：奥贝胆酸
本文主要对Obeticholic acid（奥贝胆酸）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。

二、Obeticholic acid（奥贝胆酸）合成路线
三、Obeticholic acid （奥贝胆酸）合成检索总结报告
(一)Obeticholic acid （奥贝胆酸）中间体2
的合成合成方法
实验步骤参考文献操作方法
一
To a solution of 7-ketolithocholic acid 1(5g,12.8mmol),dissolved in 100mL of dry methanol was added p-toluenesulfonic acid (1.1g,64.1mmol).The solution was left to stand at room temperature for 2h.The mixture was quenched by addition of NaHCO 3saturated solution.After the evaporation of the methanol,the residue was extracted with EtOAc (3×150mL).The combined extract was washed with brine,dried with Na 2SO 4,and evaporated to give the methyl ester 2as amorphous solid (5.13g,quantitative yield).WO2015/181275;(2015);(A1)English 操作方法
二To a three-necked flask was added 3α-hydroxy-7-carbonyl-cholanic acid 1(32.7g,83.7mmol),120mL of anhydrous methanol,2mL of hydrochloric acid (containing 22.52mmol hydrochloric acid),after the addition of reflux reaction 4.0h,TLC detection of the reaction was complete.Then the methanol was removed under reduced pressure,and the residue was dissolved in 200mL of dichloromethane.The organic phase was washed with 100mL of saturated sodium bicarbonate solution,100mL of water and 100mL of saturated brine respectively,dried over anhydrous sodium sulfate and filtered.The mixture was evaporated under reduced pressure to give 33.2g of a white powder (2),yield:98%.The product was directly transferred into the next reaction without purification.
CN106478757;(2017);(A)Chinese 3a-hydroxy-7-keto-5P-cholan-24-oic acid 1(KLCA;500.0g,1.28mol)was esterified using methyl alcohol (2500mL),in the presence of acidic catalysis (sulfuric acid,1.0mL)and was heated up to 62°C to 64°C for approximately 3hours,to yield 3a-hydroxy-7-keto-5p-cholan-24-oic acid methyl ester (2).In this reaction,the methyl alcohol acts as the methylating reagent as well as the reaction solvent.For the work-up,the pH-value was adjusted with sodium hydroxide solution (2N)to pH 7.0to 7.5.The solution was treated with activated carbon (25g)for approximately 30minutes and
WO2013/192097;
操作方法
三filtered to remove the carbon solids.Alternatively,the
solution was not treated with activated carbon.To precipitate
the product,water(625mL)at10°C to15°C was added over
15minutes and seeding material was added.The reaction
mixture is stirred for1hour at10°C to15°C.Another
portion of water(1875mL)was added over about20to25
minutes.The product suspension was stirred for30minutes
at10°C to15°C.The product was isolated with a centrifuge
and washed with a mixture of methanol and water(1:1,350
mL).The water content of the wet material was quantified by
Karl Fischer(KF).The material was dried in a tumble dryer
under vacuum at NMT70°C.The material can also be used
in the next step without drying.The yield(calculated on
dried product)is501.4g(1.24mol,96.8%).
(2013);(A1)
English
操作方法
四500g of3α-hydroxy-7-keto-5β-cholanic acid(1)was
weighed into a5000mL three-necked flask,Then,2500mL
of methanol and1mL of sulfuric acid with98%mass
fraction were added,stirred,At this time the reaction
solution was white emulsion;The reaction solution was
heated to60°C for3hours to8hours,and the reaction
solution was transparent and clear when TLC was used.Raw
material reaction is complete;The reaction system was
adjusted to pH7.0to7.5using2mol/L sodium hydroxide
solution.System cooling to10~15°C,the system slowly
adding625mL of water and seed,Stirring vigorously1h;
then add1875ml of water to the system,the system
precipitated a large number of solid,System to keep10~
15°C stirring0.5h;The above system of liquid pumping
filter,filter cake with methanol and water mixed solution
(volume ratio of1:1,350mL)Rinse;The rinsed filter cake
was dried in vacuum at50°C for24h,To obtain
3α-hydroxy-7-keto-5β-cholanic acid methyl ester(2).The
crude crude product was recrystallized using ethyl
acetate/n-hexane(500ml and1000ml volumes).And finally
dried to give500g of the intermediate product of methyl
3α-hydroxy-7-keto-5β-cholinate(2)The yield was96%and
the purity was99%.
CN106986909;
(2017);(A)
Chinese
操作方法
五17.0kg of3α-hydroxy-7-keto-5β-cholanic acid1,68kg of
methanol and0.17kg of methansulphonic acid were charged
into a reactor.The reaction mixture was then heated to
30-60°C.for1hour and25.5kg of demineralised water was
added.The mixture obtained was then stirred,cooled to
20-25°C.until a good precipitation was obtained,then
cooled further to0-15°C.The precipitate was filtered and
US2014/148428;
(2014);(A1)
English;
WO2017/53428;。