Synthesis Of Istradefylline

Parkinson's disease is one of the most common degenerative diseases of the elderly.The incidence of Parkinson's disease increases with age.The aging problem in China is becoming serious,the number of patients suffering from Parkinson's disease also showed a rising trend year by year.Parkinson's disease hasn't been cured yet,because it's slow onset,complicated pathogenesis and the unknown cause.The initial symptoms of Parkinson's disease often was ignored by people because of its high heterogeneous..The main symptoms of the disease are divided into motor symptoms and non-motor symptoms.Motor symptoms include resting tremor,muscle rigidity,slow movement and posture gait abnormalities.Non-motor symptoms include cognitive disorders,sleep disorders,anxiety and so on.Most of the anti-Parkinson's disease medicines on the market can only relieved the symptoms of the disease,slow the deterioration of the disease,and yet can't cure the disease.The long-term use of these drugs will lead to motor complications,and will seriously affect the quality of life of patients and their families.Faced with such a grim situation,the development of better anti-Parkinson's disease drugs become significant.Istradefylline,named as?E?-8-?3,4-dimethoxystyryl?-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione,was developed by Kyowa Hakko Kirin Co.,Ltd.,Japan,and published in Japan on March 25,2013 under the trade name Nouriast^?.However,the drug is still in stage?clinical research in the United States.As a first selective adenosine A_2A receptor antagonist,Istradefylline can significantly improve motor complications,which are caused due to long-term use of dopamine receptor drugs such as levodopa.Istradefylline can also protect dopaminergic nerves and reduce“off-period”phenomena.In this paper,we mainly study on the synthesis of Istradefylline and conditions optimization.By reviewing lots of literatures and comprehensive analysis,we believed that the preparation of Istradefylline mainly includes the synthesis of1,3-diethyl-5,6-diaminouracil and?E?-3,4-dimethoxyphenylacrylic acid.Most of the literature adapted expensive raw materials to synthesize Istradefylline,and the post-treatment is also tedious.Based on the reported routes,this paper improved and perfected the synthetic route and process,and obtains an efficient synthesis method.The process conditions are mild,the reaction cycle is short,the yield is high,the cost is reduced,and it is suitable for industrial production.In this method,firstly,1,3-diethylurea 2 was produced under high pressure using dimethyl carbonate and 70%ethylamine as raw materials.2 and cyanoacetic acid are condensed to give 1,3-diethyl-6-aminouracil 3.3 and sodium nitrite were prepared by nitrosylation to give 1,3-diethyl-6-amino-5-nitrosyluracil 4.4 is reduced by Raney nickel and hydrazine hydrate to 1,3-diethyl-5,6-diaminouracil 5.The other intermediate?E?-3,4-dimethoxyphenylacrylic acid 6 was prepared by Knoevenagel condensation using 3,4-dimethoxybenzaldehyde and malonic acid as starting materials.5 and 6 are subjected to condensation reaction to give?E?-1,3-diethyl-6-amino-5-?3,4-dimethoxyphenylacryloyl?aminouracilatroom temperature 7.7 was heated in the alkaline conditions under cyclization reaction to give?E?-8-[2-?3,4-dimethoxyphenyl?ethylene]-1,3-diethyl-3,7-dihydro-1H-purine-2,6-dione 8,which was finally methylated with dimethyl carbonate to give 1.The overall yield was 26.2%.This synthesis method has the following advantages,such as cheap raw materials,mild reaction condition,simple operation,suitability for industrial production.The chemical structures of the target products and important intermediates were confirmed by MS,¹H-NMR and¹³C-NMR.