药物Latanoprostene bunod(拉坦前列素硝酸酯)合成检索总结报告

药物Latanoprostene bunod（拉坦前列素硝酸酯）合

成检索总结报告

一、Latanoprostene bunod（拉坦前列素硝酸酯）简介

Latanoprostene bunod（拉坦前列素硝酸酯）于2017年11月在美国上市，主要用于降低伴有开角型青光眼或高眼压患者的眼内压。Latanoprostene bunod（拉坦前列素硝酸酯）不良反应有结膜充血、眼睛刺激、眼痛和滴注部位疼痛等等。

Latanoprostene bunod（拉坦前列素硝酸酯）分子结构式如下:

CAS:860005-21-6

英文名称：Latanoprostene bunod

中文名称：拉坦前列素硝酸酯

二、Latanoprostene bunod（拉坦前列素硝酸酯）合成路线

三、Latanoprostene bunod（拉坦前列素硝酸酯）合成检索总结报告

(一)Latanoprostene bunod（拉坦前列素硝酸酯）中间体2

合成

合成方法实验步骤参考文献

操作方法

一Into a10L three-necked bottle equipped with a thermometer

and mechanical stirring,add L-benzoylcolide1(500g,

1.81mol)and methylene chloride(5L),Then use the ice-salt

bath for the above mixing system,cool to an internal

temperature not higher than0°C,and stir at constant

temperature for10min;Next Dess Martin reagent(2.17mol)

was slowly added to the reaction system,and the reaction

temperature was controlled to be not higher than10°C.After

the addition of Dess Martin reagent was completed,the

mixture was stirred at constant temperature for2h.After the

reaction was completed,saturated Na2S2O3(1000mL)was

added to quench the reaction,and the aqueous phase was

extracted with dichloromethane(0.5L×2).The combined

organic phases were washed with a saturated sodium

chloride solution,dried over anhydrous sodium sulfate,

filtered,and concentrated to obtain a pale yellow compound

2(480g,1.75mol),which was directly applied to the next

reaction with a yield of96.7%

CN110483360;

(2019);(A)

操作方法

二A solution of1,3-diisopropylcarbodiimide(13.7g)in

dimethyl sulfoxide(38mL)contained in a

nitrogen-substituted flask was added dropwise with a

solution of[3aR-(3aα,4α,5α,6aα)]-5-(benzoyloxy)-

hexahydro-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one

1(14.9g)and orthophosphoric acid(1.1g)in dimethyl

sulfoxide.The mixture was stirred at about30°C for2hours,

and then added with methylene chloride,and the deposited

white solid was removed by filtration.The filtrate was

washed with water,dried over magnesium sulfate,then

filtered,and concentrated to obtain23.2g of an aldehyde

compound2.

EP1886992;

(2008);(A1)

English;

US2008/33176;

(2008);(A1)

English

A suspension of anhydrous chromium trioxide(20.8g,208

mmol)in methylene chloride(400mL)was stirred and

操作方法

三

cooled in an ice bath as

anhydrous pyridine (32.7mL,406mmol)was added.After 15min at 0°C.,the mixture was allowed to warm to ambient temperature for 2h.The reaction mixture was cooled to 0°C.and treated with a pre-cooled solution of (3aR,4S,5R,6aS)-5-(benzoyloxy)-hexahydro-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one 1(Corey lactone,9.4g,34mmol)in methylene chloride (400mL)After 5min,the reaction was diluted with toluene (240mL)and filtered.The solid was washed with toluene.The combined filtrate was concentrated to give (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-2-oxo-2H-cyclopenta[b]f uran-4-carboxaldehyde 2.Toluene was added to give about 300mL of https://www.360docs.net/doc/2d8473998.html,2008/242713;(2008);(A1)English;EP1975163;(2008);(A1)English;US2008/242714;(2008);(A1)English 操作方法

四Dess-Martin periodinane (27.63g)and dichloromethane (120mL)are charged into a round bottom flask under nitrogen atmosphere and stirred for 5-10minutes.The reaction mixture is cooled to 0-5°C.A solution of (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta [b]furan-5-yl benzoate 1(15g)in dichloromethane (90mL)is added to the reaction mixture at 0°C.The reaction mixture is maintained for 5hours.A solution of sodium thiosulphate pentahydrate (45g)and sodium bicarbonate (15g)in water (120mL)is added to the reaction mixture at 2°C.and maintained for 30minutes.The reaction mixture is heated to 16°C.and maintained for 30minutes.Both organic and aqueous layers are separated.The aqueous layer is extracted with dichloromethane (75mL).The combined organic layer is washed with 10%sodium chloride solution (75mL).The solvent from the organic layer is evaporated to 10volumes at 30-35°C.to afford 260mL of (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate https://www.360docs.net/doc/2d8473998.html,2013/184476;(2013);(A1)English

(二)Latanoprostene bunod （拉坦前列素硝酸酯）中间体4的合成合成方法实验步骤

参考文献To a suspension of 21g of LiCl (MW =42.39;4.4eq.)in 280mL of acetonitrile was added 37g of compound 3(MW =256.25;1.3eq.).The resulting mixture is cooled to -15°C