Convenient Synthesis of Novel N-Acylsulfonamides Containing Phosphonate Moiety

GRAPHICAL ABSTRACT Abstract The present study describes a convenient method for the synthesis of new N-acylsulfonamides containing phosphonate moiety. The N-acylsulfonamides were prepared starting from chlorosulfonyl isocyanate (CSI) in four steps (carbamoylation, sulfamoylation, deprotection, and acylation). Trimethylphosphite has been used to introduce the phosphonate moiety into N-acylsulfonamides via Arbuzov reaction.


INTRODUCTION
N-acylsulfonamides derivatives are well-known pharmaceutical agents since this group has been the main functional part of most of the drug structures due to stability and tolerance in human beings. These molecules have gained much attention due to their diverse biological activities in pharmaceutical as antibacterial inhibitors of tRNA synthetases, 1 antagonists for Angiotensin II 2 and Leukotriene D 4 -receptors. 3 New N-acylsulfonamides were described such as 1 ( Figure 1); these compounds are the prodrugs of celecoxib 4 nonsteroidal, antiinflammatory, and selective COX-2 inhibitor used in the treatment of osteoarthritis and rheumatoid arthritis. Compound 2 (Figure 1), which is a prodrug of valdecoxib 5 that is marketed for the hospital treatment of postoperative pain, also exemplifies this principle.
On the other hand, phosphonates have a variety of biological activities and may act as antibiotics and antiviral agents as well as insecticides and herbicides. 6,7 The phosphonate functionality has been incorporated into a range of clinically useful drugs. In addition, acyclic nucleoside phosphonates have shown potential as therapeutics for pathogenic  species. 8 For example, Tenofovir disoproxil fumarate (PMPA) is an approved agent for the treatment of HIV in humans, and has shown efficacy in the treatment of hepatitis B (HBV). 9 The phosphonate moiety is also found in HIV protease inhibitors showing an enhanced resistance profile compared to that of the nonphosphonylated parent compounds. 10 Phosphonate containing protease inhibitors also have shown great potential for the treatment of Hepatitis C virus. 11 Alafosfalin-an antibiotic with a broad spectrum of activity-has been developed and demonstrates the ability to inhibit cell wall biosynthesis. 12 It has proved to be potentially useful in the treatment of gastroenteritis and bacterial urinary tract infections. 13 Introduction of phosphonate esters into a molecule intended as a possible drug candidate enhances the water solubility, which changes its bioavailability. Such organophosphorus compounds have found practical application in medicine, 14 agriculture, 15 industry, 16 and organic synthesis. 17 In the literature, novel phosphonates containing sulfonamide moiety have been described and have interesting biological properties. New phosphonosulfonamides were described such as compound 3, which is used in the treatment of HIV protease, 18 and compound 4, which was discovered to be potent inhibitor of protein tyrosine phosphatase 1B 19 ( Figure 2).
Several methods have been utilized by our group 20,21 for the synthesis of phosphonate esters 5-7 ( Figure 3), most notably the Michaelis-Arbuzov reaction.
Here we describe the synthesis of a new series of modified N-acylsulfonamides containing phosphonate moiety starting from chlorosulfonyl isocyanate (CSI), primary amines, and trimethylphosphite.

RESULTS AND DISCUSSION
There are several approaches toward the synthesis of phosphonates, which focus on the formation of the crucial C-P bond. Of these methods, the Abramov, Pudovik, Michaelis-Becker, and Michaelis-Arbuzov (commonly called the "Arbuzov Reaction") are the most well studied and documented. 22 A search of the literature shows that the Arbuzov reaction is commonly used to form phosphonates, and in fact is the most common method of phosphorylation employed. 23 The general method, which is employed to prepare the final compounds, is outlined in Scheme 1. The N-acylsulfonamides presented here were obtained in four steps by a simple and efficient methodology described below. The sulfonamides 24 (8a-f) were prepared by reaction of tert-butanol and CSI in anhydrous methylene chloride at 0 • C. After 30 min, the N-chlorosulfonyl carbamate and triethylamine were added to a solution of the primary amine in the same solvent. After completion of the reaction, the mixture was washed with 0.1 N HCl and then with water. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to give sulfonamides 8a-f as white powders in excellent yields. The deprotection reaction of sulfonamides 8a-f was carried out in distilled water at 100 • C for 30-60 min to give sulfonamides 9a-f in quantitative yields. The preparation of the N-acylsulfonamides 10a-f includes the reaction of sulfonamides 9a-f with chloroacetyl chloride in toluene in the presence of a Lewis acid catalyst at 110 • C for 3 h.
Phosphorylation of N-acylsulfonamides 10a-f was easily achieved by Arbuzov reaction in the presence of a large excess of trimethylphosphite under reflux conditions.
In this study, we obtained some new N-acylsulfonamides containing phosphonate moiety in good to moderate yield. The structures of the synthesized compounds are confirmed by elemental analysis as well as by IR and 1 H, 13 C, and 31 P NMR spectral data.

EXPERIMENTAL PART
1 H, 13 C, and 31 P NMR spectra were obtained with a Bruker AC 250 spectrometer in CDCl 3 as solvent. Chemical shifts are referred to TMS ( 1 H, 13 C) as internal standard and to 85% H 3 PO 4 ( 31 P) as external standard. All coupling constants (J) are reported in Hertz. Multiplicity is indicated as s (singlet), d (doublet), t (triplet), m (multiplet), and combination of these signals. IR spectra were recorded in potassium bromide pellets with a Perkin-Elmer FT-600 spectrometer. Melting points were measured in open capillary tubes on an Electro thermal apparatus and are uncorrected. Elemental analyses were performed with a Perkin-Elmer 2400 C, H, N analyzer and the determined values were within the acceptable limits of the calculated values. All reactions were monitored by TLC on silica Merck h60 F254 (Art. 5554) precoated aluminum plates and were developed by spraying with ninhydrin solution.

Preparation of N-Acylsulfonamides 10a-f
In a three-neck round bottomed flask equipped with a magnetic stirring bar and reflux condenser, sulfonamide (9a-f) (2 mmol) was dissolved in toluene (10 mL). Chloroacetyl chloride (0.41 g, 0.29 mL, 2 equiv., 4 mmol) and Lewis acid catalyst (0.4 g, 1.5 equiv., 3 mmol) were added dropwise with stirring. The reaction mixture was kept at a temperature of 50 • C for 30 min and then heated to reflux for 3 h. After completing the reaction, the reaction mixture was cooled down to room temperature. The excess of chloroacetyl chloride was washed with water and the organic layer was separated. The solvent was removed under reduced pressure. The precipitated white product was filtered and recrystallized from diethyl ether.

General Procedure for the Arbuzov Reaction
The trimethylphosphite (5 equiv., 4.96 mmol) and the corresponding compound 10a-f (1.1 equiv., 4.96 mmol) were heated at 110 • C under argon and the resulting solution was heated to reflux for additional 5 h. The undesired products were removed by distillation. The residue was then purified by column chromatography on silica gel to give the corresponding compound 11a-f in good yield.