Development of an Efficient Large-Scale Synthesis for a 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide Derivative for Depression and Anxiety

Abstract

The development and scale-up of an optimized synthesis for a novel drug candidate for depression and anxiety is presented. The updated synthesis represents a convergent and efficient four-stage approach to the API, overcoming high cost of goods (COG), general lack of convergence, and low yield of previous routes. A lower cost of goods resulted from using 3-nitrosalicylaldehyde as a starting material and introducing the expensive side chain (2-methyl-5-(piperazin-1-yl)quinoline) at a later stage. Green chemistry principles were applied when a direct amidation enabled a straightforward conversion of the 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate to the corresponding amide in the last step. In addition, the total number of stages was reduced from seven to four, and solvent usage was greatly minimized. The modified synthesis was demonstrated on a kilogram pilot scale, allowing the isolation of the API in 17% overall yield with the required purity.

Green Solvents for Eco-Friendly Synthesis of Dimethindene: A Forward-Looking Approach

“…According to a recent ICH guidance Q3C (R8) [ 27 ], 2-MeTHF and CPME belong to solvent classes 3 and 2, respectively. Thus, they are recognized as “greener alternatives” to VOCs [ 28 , 29 ], and their use has been strongly advocated in the synthesis of drugs and drug intermediates by the ACS Green Chemistry Pharmaceutical Roundtable [ 30 , 31 , 32 ]. On this basis, we focused on the use of these solvents for the total synthesis of dimethindene ( 6 ).…”

A Practical and Scalable Method for Manufacturing JAK Inhibitor ASP3627

“…That washing with aqueous Rochelle salt after hydrolysis resulted in poor separation of layers suggested that the order in which these processes were performed was very important for ease of operation and reducing the reaction time (Table , entry 3). In the Wittig reaction ( 6 → 7 ), removal of the byproduct triphenylphosphine oxide is typically a serious problem . We developed an efficient purification method that employed crystallization with n -heptane.…”

Efficient Synthesis of Novel Tricyclic Benzoxazine Derivative via Ring Opening of Epoxide Along the Mp and DFT Studies of Structural, Spectroscopic (Ir, Raman, Uv-Vis), Thermodynamic, Orbitals and Nlo Properties of Desired Tricyclic Benzoxazine Derivative

“…The second order perturbation energy (E 2 ) is the quantitative measure of interactions between donor and acceptors in NBO and is also known as stabilization energy. The higher value of E (2) is reflecting stronger interactions of donor and acceptor and the higher extend of conjugation [25]. The value of E (2) depends on occupancy of donor (i) and acceptor (j), the diagonal elements (orbital energies) and and the off-diagonal Fork matix element, ( , ) [54].…”

“…The E (2) analysis of selected donor and acceptor orbitals of S11 in gas phase are given in the Table 4. It shows the pi conjugation resonance in the first benzene ring (arising from pi electrons delocalization) and the primary as well as secondary hyper-conjugation.…”

“…The benzoxazine moiety is a fascinating scaffold which constitutes important structural feature of different pharmaceutically important drugs such as Bemoradan (1) (vasodilator agent), Azasetron (2) (serotonin 3 antagonistic) and Levofloxacin (3) (antibiotic) [1] (Figure 1). Various 1,4-benzoxazine derivatives have the ability to act as central nervous system depressants [2,3], antipsychotic agents [4], calcium antagonists [5] and antibacterial agents [6,7]. Promoted by the pharmacological properties exhibited by benzoxazine bearing molecules, various novel methods for the synthesis of this scaffold have been reported such as iodocyclization [8], tandem reduction-oxirane opening of 2nitroaroxymethyloxiranes [9], Baeyer-Villiger oxidation reaction [10] and Pdcatalyzed aerobic oxidation of o-aminophenols with isocyanides [11].…”