We applied process analytical technologies to solve the problem
of selectivity in the hydrogenation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (1) to (±)3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (2). We showed that both mid-IR and near-IR (NIR)
were suitable for in-line analysis of the hydrogenation. We chose
to use NIR in the production environment due to easier
implementation. We developed a NIR model by correlation of
NIR results with HPLC results for a laboratory-scale hydrogenation reactor, and we used production batch data to adjust
and confirm this model.
The
key macrocyclization step in the synthesis of simeprevir, a
hepatitis C virus (HCV) antiviral drug, was studied. N-Boc substitution on the diene precursor changes the site of insertion
of the metathesis catalyst and, consequently, the kinetic model of
the ring closing metathesis (RCM), enabling a further increase in
the macrocyclization efficiency under simulated high dilution (SHD)
conditions. NMR of the inserted species of both first and second generation
RCM catalysts are reported and discussed.
We describe in this paper the synthesis of compound 1 (R116301), which was developed to prepare pilot scale quantities (20-50 kg) of drug substance. The synthesis involves the s BuLi deprotonation of Boc-protected piperidone acetal 2, followed by benzaldehyde addition and ring closure to cyclic carbamate 4. Piperidine acetal 5 is resolved with Brown's acid and acylated. The ketone obtained after piperidine acetal deprotection undergoes reductive amination with N-benzyl piperazine, the most critical step in the synthesis. After debenzylation, final coupling and salt formation, compound 1 is obtained over 10 steps with 4% overall yield.
A practical process to make N-(2,6-dimethylphenyl)-2-piperazin-1-yl-acetamide 1 is described, starting from piperazine 2 and N-chloroacetyl-2,6-xylidine 3. The unwanted N,N′-bis-alkylated product 4 can be removed by simple filtration of the reaction mixture, while the excess of piperazine remains in the aqueous phase after extracting the filtrate with toluene at 70°C. The product precipitates from the organic phase with 68% active yield.
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