Renin inhibitors. Synthesis of transition-state analog inhibitors containing phosphorus acid derivatives at the scissile bond

The synthesis of α-aminophosphonates on a large scale is not always straightforward. One of the described methodologies has now been adjusted for use in a microreactor system. The CPC College System was used to investigate the continuous production of α-aminophosphonates. This technology couples miniaturisation to optimal reaction conditions for the production of chemical and pharmaceutical intermediates. The reaction of an imine with a dialkyl phosphite in different solvents was optimised, since the use of a solvent is necessary when using a microreactor. When methanol was used, a considerable reduction of the reaction time was noticed in comparison with other commonly used solvents. Subsequently, several reaction parameters were optimised in batch and compared with the continuous process in the microreactor. Similar yields and purities were obtained compared to the batch reaction. Using the microreactor system, the scale-up problems were avoided and large amounts of α-aminophosphonates could be generated in a short time.

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Straightforward continuous synthesis of α-aminophosphonates under microreactor conditions

Meenen¹,

Moonen²,

Acke³

et al. 2005

“…The benzyl group was cleaved using hydrogen and palladium hydroxide as catalyst, giving the difluoromethylphosphonate 12 analogue of FR-900098-ester (95% yield). The hydrolysis of the phosphonate ester using trimethylsilyl bromide, 28,29 followed by methanolysis at room temperature, did not afford pure phosphonic acid 3. Otherwise, another attempt by acidolysis of 12 and neutralization, followed by N-acetylation also revealed not convincing for a clean access to phosphonic acid 3 (Scheme 3).…”

Section: Scheme 1 Retrosynthetic Pathwaymentioning

confidence: 99%

Preparation of gem-difluorinated retrohydroxamic-fosmidomycin

Volle¹,

Midrier²,

Blanchard³

et al. 2015

From several decades, some organophosphorus compounds specifically designed to alter biological systems were introduced on market as agrochemicals (ie glyphosate and glufosinate as herbicides). Nevertheless, it becomes necessary to find new compounds in order to counter plant resistances already observed with glyphosate. Fosmidomicyn and its N-acetyl analogues FR-900098 were perceived as starting points for elaboration of new herbicide candidates, targeting the second enzyme of the non-mevalonate pathway in plants, the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DOXP reductoisomerase or DXR). It is expected that the enhancement of bioactivity compared to the parent compounds, might be reached by insertion of two fluorine atoms close to the phosphonate function. Indeed, the presence of both fluorine atoms could improve the lipophilicity, affect the pKa of the phosphonic acid function and then induce better activities. Herein, the synthesis of gem-difluorinated analogues of retrohydroxamic fosmidomycin and FR-900098-ester is reported using a radical addition mediated by a cobaloxime complex.

“…A new class of α-aminophosphonates structurally resembling α-amino acids 1 has attracted much interest as enzyme inhibitors, 2 antibiotics, pharmacological agents, 3 and herbicides. 4 A large number of α-aminophosphonates have been synthesized by using acyclic hydrogen phosphites over the past few years under different reaction conditions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, and antimicrobial activity of 2,10-dichloro–6- substituted aminobenzyl–12H –dibenzo [d, g][1,3,2]dioxaphosphocin– 6–oxides

Kumar¹,

Reddy²,

Reddy³

et al. 2007

Novel 2,10-dichloro-6-substituted aminobenzyl-12H-dibenzo [d,g][1,3,2] dioxaphosphocin-6-oxides (5a-n) have been synthesized in excellent yields from three component one-pot reaction of aldehydes, anilines and 2,10-dichloro-12H-dibenzo [d,g][1,3,2] dioxaphosphorobromodite(3)/corresponding cyclic hydrogen phosphite(4) in dry toluene. The title compounds were characterized by elemental analysis, IR, 1 H, 13 C, and 31 P NMR spectroscopy, and mass spectral studies and exhibited moderate antimicrobial activity.