Study On The Synthesis Of Tocapine Citrate

The main research contents include the following three parts:1 Study on the synthesis of TofacitinibTofacitinib is a kind of JAK3(Janus kinase 3) inhibitor, and it is being developed for the treatment of rheumatoidarthritis (RA). On the basis of literature, we designed ten steps synthesis of Tofacitinib by using 4-methyl-3-pyridinamine as the starting material. At first,4-methyl-3-pyridinamine and dimethyl carbonate generated amide in the presence of alkali to produce pyridine salt with benzyl bromide. Then the salt was partially reduced in the system of sodium borohydride and methanol. The unsaturated double bond of this structure was continuously reduced by Pd/C via hydrogenation. The completely reduced product reductive amination with benzaldehyde in the presence of sodium triacetoxyborohydride, soon afterwards, the product into salt through the concentrated hydrochloric acid treatment, then the hydrochloride was reduced by LAH, the product with concentrated hydrochloric acid into the hydrochloric acid salt. The hydrochloride split out the bis-(3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)-methyl-amine-di-p-toluoyl-L-tartaric acid in the presence of resolving agent di-p-toluoyl-L-tartaric acid. The important intermediate occurs in coupling reaction with 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine, then N-methyl-N-(3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was formed with benzyl group and the chloro group was removed under the atmosphere of hydrogen, finally, tofacitinib was obtained via the amidation of the intermediate. The main innovation points:not only the final yield was improved but also the cost of raw materials was reduced by the optimization of the reactions. The target product was received in high purity to reach the requirement of the drug registration.2 Study on the synthesis of ApixabanApixaban, jointly developed by Pfizer and Bristol Myers Squibb, is an oral selective activetion factor X inhibitor. It is for the prevention of thrombosis of patients who received hip or knee replacement operation. This paper explores a four-step synthetic progress of Apixaban by 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydr -o-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. Firstly, by the catalysis of palladium on carbon, the nitro group is reduced to an amino group, which then starts the substitution reaction with 5-chloro-pentanoylchlorid. Thirdly, the ring is closed under the effect of sodium hydride. Finally, Apixaban is formed after amidation reaction. Every step of the process has been optimized to improve the yield; the synthetic process is of low toxicity and good safety performance, and is suitable for industrial production.3 The synthesis of β-naphthalene sulfonic acid formaldehyde condensateβ-naphthalene sulfonic acid formaldehyde condensate is a separant with excellent performance. This paper studies the naphthalene sulfonated at high temperature in the presence of concentrated sulfuric acid. We accept the a-naphthalene sulfonic acid by use the hydrolysis method, and than adding concentrated sulfuric acid to improve the system acidity. Finally, we choose a more appropriate ratio of the naphthalene and formaldehyde condensation reaction through the exploration of naphthalene ratio, and get the standard consistent naphthalene sulfonic acid sodium salt formaldehyde condensate. This paper use one-step synthesis and use the concentrated sulfuric acid that easy to get as the sulfonated reagent.