N-[3-(4-乙氧基苄基)-4-氯苯基]-1-脱氧野尻霉素的合成及其降血糖作用
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摘要
以具有降血糖活性的达格列净、卡格列净和脱氧野尻霉素为参照,设计合成了新化合物N-[3-(4-乙氧基苄基)-4-氯苯基]-1-脱氧野尻霉素(A)。以2-氯-5-硝基苯甲酸为原料,先将羧酸转化为酰氯、再经Friedel-Crafts酰基化、羰基还原及硝基还原,合成了中间体2-氯-5-氨基-4'-乙氧基二苯基甲烷;另一方面,以单丙酮葡萄糖为原料,经选择性氧化和水解反应得到5-氧化-D-葡萄糖。该化合物和2-氯-5-氨基-4'-乙氧基二苯基甲烷发生双还原胺化反应得到化合物A的粗品。将粗品A与乙酸酐反应,经柱色谱分离得到高纯度的四乙酰基-N-[3-(4-乙氧基苄基)-4-氯苯基]-1-脱氧野尻霉素(B),再将其水解制得纯的化合物A。将化合物A口服给药SD大鼠后,发现该化合物可以降低SD大鼠血糖,增加尿量和葡萄糖从尿液中的排出。
By using hypoglycemic drugs dapagliflozin,canagliflozin and 1-deoxynojirimycin as reference,the target compound N-[( 3-( 4-ethoxybenzyl)-4-chlorophenyl]-1-deoxynojirimycin( A) was firstly designed and synthesized. Herein,the intermediate 2-chloro-5-amino-4'-ethoxy diphenyl methane was prepared from 2-chloro-5-nitro benzoic acid through a synthetic route including chlorination of carboxylic acid,Friedel-Crafts acylation,reduction of carbonyl and reduction of nitro. On the other hand,5-keto-D-glucose was gotten from 1,2-Oisopropylidene-D-glucofuranose by selective oxidation and hydrolysis. The crude A was obtained by the double reductive amination of 2-chloro-5-amino-4'-ethoxy diphenyl methane and 5-keto-D-glucose. The crude A was treated with acetic anhydride to yield tetraacetyl N-[( 3-( 4-ethoxybenzyl)-4-chlorophenyl]-1-deoxynojirinmycin( B). B was purified by column chromatography. Then the hydrolyzation of B gave the pure compound A. It was found that the compound A can effectively decrease the SD rats' blood glucose,increase urine volume and the excretion of urine glucose after dosing orally the compound A to SD rats.
By using hypoglycemic drugs dapagliflozin,canagliflozin and 1-deoxynojirimycin as reference,the target compound N-[( 3-( 4-ethoxybenzyl)-4-chlorophenyl]-1-deoxynojirimycin( A) was firstly designed and synthesized. Herein,the intermediate 2-chloro-5-amino-4'-ethoxy diphenyl methane was prepared from 2-chloro-5-nitro benzoic acid through a synthetic route including chlorination of carboxylic acid,Friedel-Crafts acylation,reduction of carbonyl and reduction of nitro. On the other hand,5-keto-D-glucose was gotten from 1,2-Oisopropylidene-D-glucofuranose by selective oxidation and hydrolysis. The crude A was obtained by the double reductive amination of 2-chloro-5-amino-4'-ethoxy diphenyl methane and 5-keto-D-glucose. The crude A was treated with acetic anhydride to yield tetraacetyl N-[( 3-( 4-ethoxybenzyl)-4-chlorophenyl]-1-deoxynojirinmycin( B). B was purified by column chromatography. Then the hydrolyzation of B gave the pure compound A. It was found that the compound A can effectively decrease the SD rats' blood glucose,increase urine volume and the excretion of urine glucose after dosing orally the compound A to SD rats.
引文
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[2]J S Wu,Y H Peng,J M Wu et al.J.Med.Chem.,2010,53(24):8770~8774.
[3]P Malla,R Kumar,M KMahapatra et al.Med.Res.Rev.,2014,34(6):1146~1167.
[4]Y Ohtake,T Sato,T Kobayashi et al.J.Med.Chem.,2012,55(17):7828~7840.
[5]A B Hughes,A J Rudge.Nat.Prod.Rep.,1994,11(2):135~162.
[6]孙宝丽,张娅玲,王丽丽等.应用化学,2015,32(9):987~993.
[7]Y Tsuda,M Hanajima,N Matsuhira et al.Chem.Pharm.Bull.,1989,37(9):2344~2350.
[8]S P Han,D L Hagan,J R Taylor et al.Diabetes,2008,57(6):1723~1729.
[9]Z J Xin,Z Jia,D He et al.Adv.Mat.Res.,2013,634:1371~1375.
[10]W Meng,A E Bruce,A N Alexandra et al.J.Med.Chem.,2008,51(5):1145~1149.
[11]T Hirashima,O Manabe.Chem.Lett.,1975,259~260.
[12]J M Riordan,P E Morris,D E Kiely.J.Carbohyd.Chem.,1993,12(7):865~879.
[13]E W Baxter,A B Reitz.J.Org.Chem.,1994,59:3175~3185.
[14]A F Abdel-Magid,M Chisholm,S Mehrman.WO:2009035969 A1,2009.