Dissertation > Medicine, health > Pharmacy > Drug basic science > Medicinal Chemistry

Gliclazide key intermediates cis-1 ,2 - cyclopentane- dicarboximide Synthesis

Author ZhangKeHua
Tutor ZhouHouYuan
School Shanghai Institute of Pharmaceutical Industry
Course Medicinal Chemistry
Keywords Dicarboximide Key intermediates Gliclazide Cyclopentane carboxylic acid Cis configuration Cyclopentadiene Dichloroacetyl chloride Isolation and Identification Oral hypoglycemic agents Leuckart reaction
CLC R914
Type PhD thesis
Year 2001
Downloads 383
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Gliclazide, a second generation sulfonylurea hypoglycaemic agent, is used in the treatment of Type II diabetes mellitus. 3-azabicyclo[3.3.0]octane 1 is a key intermediate of synthesizing gliclazide. The difficult problem of the synthetic approach to gliclazide is to build the cis-bicyclic compound. In China an eight-step approach to the cis-bicyclic amine was adopted, including five-step route to cyclopentane- 1 ,2-dicarboxylic acid and three-step reactions for formation of 1. Therefore, it is of necessity and significance to study and develop a novel synthetic method of 1 and its intermediates. Based on the commercially available and realatively cheap starting materials di- cyclopentandiene and dichloroacetyl chloride, the new synthetic routes of cis-cyclo- pentane-1,2-dicarboximide 4 and 3-azabicyclo[3.3.0]octan-2-one 5 were designed. 0 0 / I NH NH NH I 5 The 2+2 cycloaddition between dichloroketene produced in situ from dichlo- roacetyl chloride/triethylamine and cyclopentadiene from its dimer via cracking afforded 7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one 38. Thus, one-step reaction cons- tructed the seven-carbon skeleton of target compounds. Ring-opening reaction of 38 in aqueous sodium hydroxide resulted in cis-2- dichloromethylcyclopent-3-enecarboxylic acid 40, and then hydrogenation of olefinic bond yielded cis-cyclopentane-1,2-dicarboxylic acid 41. The preparation of key intermediate 41 with cis-configuration was performed successfully in overall three- step reactions. 0 COOH / - - COOH I / 38 CHCI2 41 CHCI2 40 Hydrolysis of 41 in 70-80% formic acid gave 2-formylcyclopentanecarboxylic acid and its tautomer in high yield. On the other hand, 41 underwent reductive amination and ring-closing reaction, converted to 5. The two promising experimental results laid the foundation of functional group conversion of dichloromethyl group of 41. 41 reacted with hydroxylamine in water to give cis-N-hydroxy- 1 ,2-cyclopent- anedicarboximide 56 in 80% yield. The reaction is characterized by cheap solvent, convenient operation and simple purification process. These advantages make the new method not only approach industrial production but also become a practical method of synthesizing azacyclopentanes. Low pressure hydrogenation of 56 prepared 4. -3. 0 0 000H 1 NH I I / / ?-~ ~CHCI2 <1 41 56 a o The conversion of 41 to 56 is a novel synthetic method. The reaction mechanism includes substitution of dichloroinethyl group of 41 by hydroxylamine, oxidation state change of carbon atom and ring-closure. The intermediate 3-hydroxy-4- hydroxyimino-3-azabicyelo[3.3.Ojoctan-2-one 69 was separated and identified, gives a proof that 41 to 56 involved one-step oxidation process; two

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