Study On Synthesis Of Tenofovir Disoproxil Fumarate And Tenofovir Alafenamide Fumarate

China has a large number of AIDS and hepatitis B virus infections.Carriers of the hepatitis B virus are about 100 million people.There are 758,610 HIV-infected people living with HIV and AIDS in our country.The infection rate and number of patients have risen significantly this year.Tenofovir disoproxil fumarate(TDF)is a nucleoside reverse transcriptase inhibitor primarily used for anti-HIV-1 virus infection.It was approved by the FDA in October 2001 and listed in China in August 2013.TDF is the first line of AIDS antiviral drugs recommended by the World Health Organization(WHO)AIDS treatment guidelines,and it is listed as the first-line drug for national free AIDS antiviral treatment in China.Tenofovir Alafenamide Fumarate(TAF)is a nucleoside reverse transcriptase inhibitor primarily used to treat chronic hepatitis B virus infection in adults with compensated liver disease.On November 2016,it received FDA approval for listing.On December 2016,PMDA was approved for listing.On December 2017,it was approved by the EMA for listing.It became the first and the only hepatitis B drug approved for listing in Europe in the last 10 years.Its market prospects are widely optimistic.In this thesis,the synthesis reasearch and process optimization of tenofovir disoproxil fumarate and tenofovir alafenamide fumarate were performed.The main research contents and results are as follows: The reasearch on synthesis process of tenofovir disoproxil fumarateThrough the route analysis and comparison,this thesis chose the original research process for the synthesis of tenofovir disoproxil fumarate.Using adenine 25 and R-propylene carbonate 16 as raw materials,we obtain the key intermediate tenofovir 3 through condensation,nucleophilic substitution and hydrolysis.After the condensation of 3 and chloromethyl isopropyl carbonate,we affoded enofovir disoproxil 2.And finally after salt formation we afforded tenofovir disoproxil fumarate 1.The average total yield is 28.1%,the HPLC purity is greater than 99.4%,ee%=100%,the monoester is less than 0.6%,and the other single impurities are all less than 0.1%.The sample quality meets the requirements for drug registration.Specific improvements and optimizations are as follows: 1)During the preparation of intermediate 9,toluene was used instead of methanol/isopropanol mixed solution as a crystallization solvent,and the yield was substantially increased to 90.8%(literal yield 65%).2)During the preparation of intermediate 5,magnesium tert-butoxide was used instead of lithium tert-butoxide used in the original patent.Optimizing the molar ratio of compound 9 : magnesium tert-butoxide to 1 : 1.5 to increase the reaction conversion rate;DMF was selected as the reaction solvent.And the reaction time was shortened to 3 hours.The obtained 5 was directly used in the next step without purification.3)During the preparation of key intermediate 3,the acetonitrile solvent was used to optimize the molar charge ratio of 5 : trimethylsilyl bromide to 1 : 3.2,and the crude product was recrystallized in water to obtain high-quality tenofovir 3,its HPLC purity is greater than 99.7%,mono-aza is less than 0.1%,and the yield is stable to 51.4%.4)During the preparation of the final product 1,the recrystallization refining operation was performed,and a high-quality product was obtained by using a stages of temperature-reducing crystallization method.The HPLC purity was greater than 99.4%,and the yield was stable to 56.4%.The resulting crystalline form is a medicinal crystalline form and has been characterized and reported in the patent.5)Six impurities of tenofovir disoproxil fumarate were studied and synthesized.The study of impurities facilitates the quality control of the final product and the verification of analytical methods.It also lays the foundation for the drug registration.The reasearch on synthesis process of tenofovir alafenamide fumarateIn this thesis,through the analysis and comparison of routes,the synthesis of tenofovir alafenamide fumarate was studied and some of the reaction steps were optimized.The starting material is tenofovir 3,which is first condensed with phenol and then chlorinated with thionyl chloride to obtain intermediate 43.After condensation of 43 and L-alanine isopropyl ester hydrochloride and the salification of isomers,we afforded 41,and then we use fumaric to preparation the salt tenofovir alaranamine fumarate 40.The total yield of 17.27%(based on compound 3).The chemical purity of the obtained product was 99.94%,and the single impurity was less than 0.1%.The non-equivalent is not detected,and the sample quality reached the CFDA drug application requirements.Specific improvements and optimizations are as follows: 1)During the preparation of compound 44,NMP was used as a solvent,and the reaction temperature was optimized to increase to 150° C.The reaction time was shortened to 1.5 hours and the yield was 60%.(literature yield 55%)2)During the preparation of compound 42,screening of the mixed solvent,preferably a mixed solvent of toluene and acetonitrile(volume ratio 4:1),not only improves the reaction stirring state and product properties,but also improves the purity and the traits of the product.Selectively,the resulting 42 was a high purity diastereomer(RSS: RRS=82%:18%)with a chemical purity of 99.11% and was used in the subsequent reaction without purification.3)During the preparation of compound 41,intermediate 42 was used as a raw material,and the high-purity crude product 41(RSS: RRS=97.8%: 2.18%)was obtained by the dynamic resolution of crystals induced by DBU and phenol,and then recrystallized from acetonitrile.Chemical purity and optical purity reached 100% and the yield was 52.09%.In this thesis,the synthetic study and process optimization of tenofovir disoproxil fumarate and tenofovir alafenamide fumarate were carried out,which laid a solid foundation for the drug application and industrialization of the two varieties.