Sulfinamides were synthesized from sulfonyl chlorides using a procedure involving the in situ reduction of sulfonyl chlorides. The reaction is broad in scope and easy to perform.Sulfinamides, especially chiral sulfinamides, play vital roles in the modern asymmetric chemistry. 1 Furthermore, sulfinamides can also act as N-sulfinyl protecting group in ease of removal under mild conditions. 2 Even though there are various procedures reported for the preparation of sulfinamides from sulfinic acids 3 , sulfinates 4 , sulfinyl chlorides 5 , disulfides 6 , and homolytic substitution at the sulfur atom 7 , these reactions often require two or more synthetic steps. A one-step process would be useful and increase the exploration of sulfinamide chemistry.Sulfinamides are useful compounds and can be transformed to a number of other important functional groups. 8 For example, they can be converted to sulfonimidoyl chlorides, whose chemistry is both interesting and useful. 9 We reported that benzothiazines can be prepared from N-aryl sulfinamides by oxidation with t-butyl hypochlorite and subsequent treatment with an alkene or alkyne in the presence of a Lewis acid. (Scheme 1). 10 The requisite sulfinamide was prepared from a sulfinyl choride in high yield. While sulfinyl chlorides are not exceptionally difficult to make, they are sensitive to hydrolysis and require preparation using noxious reagents such as thionyl chloride. We thought that a procedure to quickly access sulfinamides would be useful in both exploring sulfinamide chemistry and derivatives such as sulfonimidoyl chlorides.A number of years ago Sharpless 11 reported the synthesis of sulfinate esters from sulfonyl chlorides by a one-pot reductive esterification reaction using either phosphites as the reducing agent. Attempts to prepare sulfinamides by the Sharpless group were not successful. We thought however, that the modification of the synthesis of sulfinate esters introduced by Toru 12 , which used triarylphophines as the reductant, would be suitable for the synthesis of such compounds. This letter reports the realization of that idea.We began our studies by simply using Toru's procedure for sulfinate ester formation. 11 The results are summarized in Table 1. When a CH 2 Cl 2 solution of triphenylphosphine was added to the mixture of TsCl, TEA (10 equivalents) and BzNH 2 in CH 2 Cl 2 at 0 °C, only sulfonamide 6 and PPh 3 were detected by the NMR analysis of the crude mixture (entry 1). However, a small change in the addition sequence offered an encouraging result. When PPh 3 and benzylamine in CH 2 Cl 2 were added to a mixture of triethylamine and tosyl chloride, the desired HarmataM@Missouri.edu.
NIH Public Access
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sulfinamide was isolated in 62% yield, (entry 2). Only a 14% yield of sulfinamide, accompanied by 40% sulfonamide, was isolated when the reaction was performed by the addition of PPh 3 to TsCl in CH 2 Cl 2 over 1 hour followed by addition of a mixture of BzNH 2 and T...
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.
Introduction
Fatty acid amide hydrolase (FAAH) is responsible for the enzymatic degradation of the fatty acid amide family of signaling lipids, including the endogenous cannabinoid (endocannabinoid) anandamide. The involvement of the endocannabinoid system in pain and other nervous system disorders has made FAAH an attractive target for drug development. Companion molecular imaging probes are needed, however, to assess FAAH inhibition in the nervous system in vivo. We report here the synthesis and in vivo evaluation of [18F]PF-9811, a novel PET ligand for non-invasive imaging of FAAH in the brain.
Methods
The potency and selectivity of unlabeled PF-9811 were determined by activity-based protein profiling (ABPP) both in vitro and in vivo. [18F]PF-9811 was synthesized in a 3-step, one-pot reaction sequence, followed by HPLC purification. Biological evaluation was performed by biodistribution and dynamic PET imaging studies in male rats. The specificity of [18F]PF-9811 uptake was evaluated by pre-administration of PF-04457845, a potent and selective FAAH inhibitor, 1 h prior to radiotracer injection.
Results
Biodistribution studies show good uptake (SUV∼0.8 at 90 min) of [18F]PF-9811 in rat brain, with significant reduction of the radiotracer in all brain regions (37%–73% at 90 min) in blocking experiments. Dynamic PET imaging experiments in rat confirmed the heterogeneous uptake of [18F]PF-9811 in brain regions with high FAAH enzymatic activity, as well as statistically significant reductions in signal following pre-administration of the blocking compound PF-04457845.
Conclusions
[18F]PF-9811 is a promising PET imaging agent for FAAH. Biodistribution and PET imaging experiments show that the tracer has good uptake in brain, regional heterogeneity, and specific binding as determined by blocking experiments with the highly potent and selective FAAH inhibitor, PF-04457845.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.