74441-18-2

Upstream product

• 2216-51-5 (-)-menthol 
• 68-11-1 mercaptoacetic acid 
• 125364-82-1 2-(2,6-dimethyl-5-heptenyl)-1,3-oxathiolan-5-one 

Downstream Products

• 490-99-3 DL-neomenthol 
• 15356-70-4 menthol 
• 125364-86-5 α-campholenic aldehyde acetal 
• 171775-17-0 Acetoxy-ethylsulfanyl-acetic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester 
• 200396-19-6 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-hydroxy-1,3-oxathiolane-2-carboxylate 
• 147126-62-3 (2R,5R)-5-hydroxy-1,3-oxathiolane-2-carboxylic acid (1R,2S,5R)-5-methyl-2-isopropylcyclohexyl ester 
• 147027-10-9 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5S)-5-(4-amino-2-oxo-1,2-dihydro-1-pyrimidinyl)-1,3-oxathiolane-2-carboxylate 

Relevant academic research and scientific papers

A Continuous Flow Sulfuryl Chloride-Based Reaction - Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine

We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines emtricitabine and lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm and evolution of hydrogen chloride and sulfur dioxide. Keeping gaseous byproducts in solution and controlling the temperature led to better outcomes. 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 system with a 141 g/h throughput.

Synthesis, crystal structure and oxidation of (R)-(+)-8,9-dimethoxy-6,10b-dihydro-5H-thiazolo[2,3-a]isoquinolin-3-one

(R)-(+)-8,9-Dimethoxy-6,10b-dihydro-5H-thiazolo[2,3-a]isoquinolin-3-one 1 has been synthesized from 6,7-dimethoxy-3,4-dihydroisoquinoline and menthyl thioglycolate. Compound 1 was obtained in the enantiomerically pure form (mp 150-153°C, [α]D +436) by a single crystallization of the crude reaction product (68% e.e.) from 96% ethanol. The absolute 10bR configuration was established by X-ray diffraction. Oxone oxidation of 1 resulted in a configurationally unstable dextrorotatory syn-sulfoxide 2 (mp 173-175°C, [α]D +62.8).

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 precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.