Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint Driven Innovation

A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low cost, widely available starting materials – we refer to this as supply centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precurors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate and water to produce the oxathiolane.

A CONTINUOUS FLOW SULFURYL CHLORIDE BASED REACTION – SYNTHESIS OF A KEY INTERMEDIATE IN A NEW ROUTE TOWARD EMTRICITABINE AND LAMIVUDINE

<p>We demonstrate a continuous two-step sequence where a sulfenyl chloride is formed, trapped by vinyl acetate and chlorinated further via a Pummerer rearrangement. This sequence produces a key intermediate in our new approach to the oxathiolane core used to prepare the anti-retroviral medicines Emtricitabine and Lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm, temperature and pressure sensitivity, and evolution of hydrogen chloride and sulfur dioxide. These reactions are ideal candidates for implementation in a continuous, mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein, we discuss the flow implementation and the final reactor design that led to a 141g/h throughput system. </p>

A CONTINUOUS FLOW SULFURYL CHLORIDE BASED REACTION – SYNTHESIS OF A KEY INTERMEDIATE IN A NEW ROUTE TOWARD EMTRICITABINE AND LAMIVUDINE

<p>We demonstrate a continuous two-step sequence where a sulfenyl chloride is formed, trapped by vinyl acetate and chlorinated further via a Pummerer rearrangement. This sequence produces a key intermediate in our new approach to the oxathiolane core used to prepare the anti-retroviral medicines Emtricitabine and Lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm, temperature and pressure sensitivity, and evolution of hydrogen chloride and sulfur dioxide. These reactions are ideal candidates for implementation in a continuous, mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein, we discuss the flow implementation and the final reactor design that led to a 141g/h throughput system. </p>

Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint Driven Innovation

A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low cost, widely available starting materials – we refer to this as supply centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precurors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate and water to produce the oxathiolane.

A theoretical study of styrene and sulfenyl chloride reaction mechanism

The classical description of sulfenyl halides additions to olefins proposes the formation of an episulfonium ion intermediate during the reaction path. However, a careful analysis of experiments performed in the past suggests that there should not be a single mechanistic picture of sulfenyl halide additions to substituted olefins. Our work is the first theoretical study of detailed insights into the mechanism of methylsulfenchloride addition to styrene. The reaction potential energy profile has been calculated by means of the B3LYP functional with the 6-31++G(d, p) basis set. Mixing of the molecular orbital shapes of reaction stationary points has been described. The addition proceeds as a single step reaction from the methylsulfenchloride and styrene reactants via the concerted transition state (TS) to the final product along the reaction path estimated by the calculation of the intrinsic reaction coordinate. The reaction intermediate was not detected by calculations. The polar solvent has a significant effect on the decrease of reaction activation energy barriers. The large charge separation of the S–Cl bond in TS implies that the addition reaction should proceed through the ionic TS.

Crystal structures of (N-methyl-N-phenylamino)(N-methyl-N-phenylcarbamoyl)sulfide and the corresponding disulfane

The title compounds, (N-methyl-N-phenylamino)(N-methyl-N-phenylcarbamoyl)sulfide, C15H16N2OS, (I), and (N-methyl-N-phenylamino)(N-methyl-N-phenylcarbamoyl)disulfane, C15H16N2OS2, (II), are stable derivatives of (chlorocarbonyl)sulfenyl chloride and (chlorocarbonyl)disulfanyl chloride, respectively. The torsion angle about the S—S bond in (II) is −92.62 (6)°, which is close to the theoretical value of 90°. In the crystal of (II), non-classical intermolecular C—H...O hydrogen bonds form centrosymmetric cyclic dimers [graph setR22(10)], while inter-dimer C—H...S interactions generate chains extending along thebaxis.