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

Kashinath, K.; Snead, David R.; Burns, Justina M.; Stringham, Rodger W.; Gupton, B. Frank; McQuade, D. Tyler

doi:10.1021/acs.oprd.0c00145

Cited by 14 publications

(11 citation statements)

References 28 publications

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“…The use of 2 equiv is necessary to support the multiple chlorinations (steps 1 and 2; Figure 1 ), and we presume that the 10% excess is needed due to reagent decomposition. 2 The heat released during the formation of sulfenyl chloride 4 (step 1) is 242 kJ/mol. The vinyl acetate addition (step 2) is also exothermic, involving both the addition of 4 to 5 and the chlorination at the position α to the ester in 6 to yield the desired dichloride 7 .…”

Section: Resultsmentioning

confidence: 99%

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

Souza

Berton

Snead

et al. 2020

Org. Process Res. Dev.

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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.

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Section: Resultsmentioning

confidence: 99%

“…The process begins with a Fischer esterification between l -menthol ( 1 ) and thioglycolic acid ( 2 ). 2 The menthyl thioglycolate ( 3 ) is then treated with SO 2 Cl 2 to produce sulfenyl chloride intermediate 4 . 3 The reaction between the thioglycolate 3 and SO 2 Cl 2 is exothermic, as is the reaction of 4 with vinyl acetate ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

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

Souza

Berton

Snead

et al. 2020

Org. Process Res. Dev.

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“…Kashinath and co-workers [54] also identified an innovative route to access an oxathiolane intermediate, which was further used for the synthesis of lamivudine (1) as well as emtricitabine (2). They presented an efficient reaction path that utilized commonly available and inexpensive starting materials.…”

Section: Kraus and Attardomentioning

confidence: 99%

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

Aher¹,

Srivastava²,

Singh³

et al. 2021

Beilstein J. Org. Chem.

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Sugar-modified nucleosides have gained considerable attention in the scientific community, either for use as molecular probes or as therapeutic agents. When the methylene group of the ribose ring is replaced with a sulfur atom at the 3’-position, these compounds have proved to be structurally potent nucleoside analogues, and the best example is BCH-189. The majority of methods traditionally involves the chemical modification of nucleoside structures. It requires the creation of artificial sugars, which is accompanied by coupling nucleobases via N-glycosylation. However, over the last three decades, efforts were made for the synthesis of 1,3-oxathiolane nucleosides by selective N-glycosylation of carbohydrate precursors at C-1, and this approach has emerged as a strong alternative that allows simple modification. This review aims to provide a comprehensive overview on the reported methods in the literature to access 1,3-oxathiolane nucleosides. The first focus of this review is the construction of the 1,3-oxathiolane ring from different starting materials. The second focus involves the coupling of the 1,3-oxathiolane ring with different nucleobases in a way that only one isomer is produced in a stereoselective manner via N-glycosylation. An emphasis has been placed on the C–N-glycosidic bond constructed during the formation of the nucleoside analogue. The third focus is on the separation of enantiomers of 1,3-oxathiolane nucleosides via resolution methods. The chemical as well as enzymatic procedures are reviewed and segregated in this review for effective synthesis of 1,3-oxathiolane nucleoside analogues.

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“…Our route relies on a sulfuryl chloride (SO2Cl2) mediated chloro-thioene reaction (Scheme 1). The process begins with a Fischer esterification between L-menthol (1) and thioglycolic acid (2). 2 The menthyl thioglycolate (3) is then treated with SO2Cl2 to produce a sulfenyl chloride intermediate 4.…”

Section: Introductionmentioning

confidence: 99%

“…The process begins with a Fischer esterification between L-menthol (1) and thioglycolic acid (2). 2 The menthyl thioglycolate (3) is then treated with SO2Cl2 to produce a sulfenyl chloride intermediate 4. 3 The reaction between the thioglycolate 3 and SO2Cl2 is exothermic and so is the reaction of 4 with vinyl acetate (5).…”

Section: Introductionmentioning

confidence: 99%

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

Souza¹,

Berton²,

Snead

et al. 2020

Preprint

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<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>

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

Cited by 14 publications

References 28 publications

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

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

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

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

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