Development Of New Synthetic Processes For Antibacterial Iclaprim And Anti-WHIM Syndrome Drug Mavorixafor

The development of new synthetic process suitable for industrialization with own property rights is particularly important in the layout of generic drug so that the pharmaceutical companies can produce and sell the generic drug as soon as the compound patent is expired.Based on the layout strategy of generic drug development,new synthetic processes were developed for the DHFR inhibitor Iclaprim(antibacterial agent)and chemokine receptor 4 antagonist Mavorixafor(treatment of WHIM syndrome),which have excellent performance in phase III clinical and market prospects.It is expected to obtain the new synthetic process routes of Iclaprim and Mavorixafor with independent intellectual property rights and potential for industrialized production.A new synthetic route of Iclaprim was developed in six steps.The aminoprotection and Friedel-Crafts acetylation were simultaneously completed by one-step synthesis from trimethoprim(TMP)to obtain 2,4-diacetamido-5-(2-acetyl-3,4,5trimethoxybenzyl)pyrimidine(2-37)in a 96%yield,followed by deprotection,demethylation,cyclization reduction and elimination to provide Iclaprim with a total yield of 21%,approximately five fold as much as the original process.The Knoevenagel condensation of 2,4-bdiamino-5-(2-acetyl-3-hydroxy-4,5dimethoxybenzyl)pyrimidine(2-40)with cyclopropyl carboxaldehyde followed by the intramolecular Michael addition in the buffer system(pyrrolidine/acetic acid)gave 2cyclopropyl-5-[(2,4-diaminopyrimidin-5-yl)methyl]-7,8-dimethoxychroman-4-one(241).In the elimination,an impurity named 5-cyclopropyl-2,3-dimethoxy-4,5,6,6a,7,12hexahydronaphtho[l,8-bc]pyrimido[5,4-f]azepin-9-amine(2-1a)was identified and used as the reference for monitoring the reaction process so that it was minimized in the optimized process.All intermediates including 2-37,2-39,2-40,2-41 and 2-42 and impurity 2-1a have not been found in the literature.Additionally,recrystallization was the only involved purification method in our process,without any column chromatography.A novel and practical synthesis of mavorixafor(3-1)was described from 8-chloro5,6,7,8-tetrahydroquinoline(3-24)and 1,4-diaminobutane,instead of 8-amino-5,6,7,8tetrahydroquinoline(3-8)and N,N-di-protected aminobutyraldehyde,so that our route not only avoided the fatigue preparation for the materials but also reduced the cost for production.The preparation of N1-[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4butanediamine(3-30)by resolution with N-acetyl-L-leucine was first reported.The one-pot synthesis from 3-30 to 3-1 was developed that involved the protection,condensation and subsequent hydrolysis.In addition,the final product with a satisfactory purity(>99.5%,detected by both achiral and chiral HPLC)was obtained by simple operation(salification)without column chromatographic purification.