The Synthesis Process Research Of 2,3,4-tri-O-benzyl-5-O-allyl-D-ribitol

Haemophilus influenzae(HIB)belongs to Gram-negative bacteria,who can cause kinds of purulent diseases that are even life-threatening on a global scale.It is reported that 3.3 million children under 5 years old are inf-ected by HIB every year,among whom,about 380-500 thousand children die.In the surviving children,there are about 30-40%of children with disability or serious complications.Fortunately.HIB vaccine can effectively prevent HIB infection.HIB vaccine used clinically are classified into three categories:HIB capsular polysaccharide vaccine,HIB protein binding vaccine,and the new-type HIB protein combination vaccine.However,HIB capsular polysaccharide vaccine is ineffective due to weak immunogenicity and HIB protein binding vaccine is not stable due to polysaccharide intermittent instability.The new-type HIB protein binding vaccine is a synthetic HIB polysaccharide binding to carrier protein,ef'fective in preventing HIB infection while HIB capsular polysaccharide is a ribose-ribitol polysaccharide.In this paper.our goal is to solve problem of preparation of the key intermediates used for HIB capsular polysaccharide.such as 5-O-allyl-2,3,4-tri-O-benzyl-D-ribitol.There are three synthetic routes for 2.3.4-tri-O-benzyl-5-O-allyl-D-ribitol reported previously.Vicente Guillermo et al.reported that the desired product was obtained from D-ribose as the starting material via a sequence of 10 steps including protection,allylation,deprotection,benzylation,reduction,trityl protection,benzylation and hydrolysis,in an overall yield of 25.9%.However,the synthetic route is obviously not economical due to its too long route and poor yield.George Erich et al.used D-ribose as the starting material to prepare the desired product via a sequence of 6 steps including protection of ethanethiol,acylation with methoxytrityl chloride,benzylation,deprotection,allylation and reduction.This synthetic route,however,is not enviormentl friendly since application of the toxic reagents such as ethanethiol and mercuric chloride,etc.Eduard C et al.used ribosyl lactone as starting materials to obtain the desired product through a sequence of 7 steps including the protection,allylation,reduction,decrimidine,trityl protection,benzylation,and deprotection.Unfortunately,ribosyl lactone is too expensive,leading to excessive cost of this route.We established a new synthetic route from the starting material D-ribose in a sequence of 7 steps with overall yield of 47%.In first step,D-ribose reacted with methanol to get l-O-methyl-?-D-ribopyranose.In particular,the application of mother liquid recycle in this step reduced the by-products of other configurations,leading to up to the yield of 95%.In second step.reaction of 1-O-methyl-?-D-ribopyranose with benzyl chloride in the presence of potassium hydroxide gave l-O-methyl-2,3,4-tri-O-benzyl-?-D-ribopyranose in 90%yield.Dangerous reagent sodium hydride was avoided in this step.In third step,hydrolysis of l-O-methyl-2,3.4-tri-O-benzyl-?-D-ribopyranose using sulfuric acid produced 2.3,4-tri-O-benzyl-?-D-ribopyranose in 80%yield.In fourth step,2.3.4-tri-O-benzyl-?-D-ribopyranose reacted with methoxyamine hydrochloride to get 2.3,4-tri-O-benzyl-D-ribose-O-methyloxime with the yield of 90%,In fifth step.2.3,4-tri-O-benzyl-D-ribose-O-methyloxime reacted with allyl bromide to get 2.3,4-tri-O-benzyl-5-O-allyl-D-ribose-O-methyloxime in 90%yield.Finally.2.3.4-tri-O-benzyl-D-ribose-O-methyloxime reacted with formaldehyde to obtain 2.3.4-tri-O-benzyl-5-O-allyl-D-ribose,followed by subquent reacton with sodium borohydride to prepare 2,3,4-tri-O-benzyl-5-O-allyl-D-ribitol in a yield of 85%for the two steps.The product was confirmed by nuclear magnetic resonance spectroscopy and infrared spectra.The synthetic route established above was amplified in an industrial scale in Jinan Shengquan Group and produced 100kg product of export orders with sales income of 3 million yuan,which amply demonstrated that the synthetic route in this thesis was a suitable route for industrial scale.With the expansion of foreign markets,2,3.4-tri-O-benzyl-5-O-allyl-D-ribitol will bring greater economic benefits for our Group.