SYNTHESIS AND APPLICATION OF HIGHLY FLUORORED OXOSULFONYL ISOCYANATES

Abstract

The present invention relates to the one-pot synthesis of novel highly fluorinated reaction intermediates of the oxosulfonyl isocyanate type. The compounds of the present invention have the general formula RF CH2 CH2 OSO2 NCO, where RF denotes a linear or branched perfluoroalkyl chain, and more particularly an F-butyl, F-hexyl, and F-octyl chain. Another aspect of the invention relates to the reactivity of these compounds with different classes of nucleophiles in order to obtain cationic or non-ionic surfactants or to produce new carbamate and urea-type synthons usable in the biomedical field.

Description

<Desc / Clms Page number 1> It has been shown in the literature that isocyanates, and more particularly oxosulfonyl isocyanates, are of great interest as reaction intermediates in organic synthesis or as raw materials in their own right. Indeed, they are found in many fields such as the plastics, resin, adhesives, and other coatings industries. [JL Harper, AH Thomas (WR Grace & Co), FR 1440591, 1965; NJ Hayes, WM. C. Ross (WR Grace & Co), FR 28970940, 1959; J. H. Saunders, RJ Slocombe, Chem. Rev., 43, 203, 1948], the textile, leather, and paper materials industry, as precursors of sulfonyl ureas which constitute a new generation of herbicides and pesticides. [D. Véga, J. Bastide, C. Poulain, Weed Res., 32, 149, 1992; E. Pichon, Phytoma, 48, 414, 1991; CD Monks, JW EMI1.1 [Wilcut, JS Richburg, Weed Technol., 7, 317, 1993] and finally the pharmaceutical industry, which constitutes the main application area for oxosulfonyl isocyanates. In this field, they are important precursors of sulfonamides, many of which are chemotherapeutic agents such as sulfonamides. It is also possible to access various series of acyl-CoA inhibitors of the urea, carbamate, and thiocarbamate type with IC50 values ​​< 1 M within the framework of lipid regulators. [JA Picard, P. O'Brien, J. Med. Chem., 39, 1243, 1996]. Still within the pharmaceutical industry, oxosulfonyl isocyanates are products of choice for the formation of P-lactam rings through [2+2] cycloaddition reactions with various alkenes. This provides access to a wide range of antibacterial agents such as penicillins, cephalosporins, nocardicins, carbapenems, and monobactams. [Z. Kaluza, W. Aabramski, Synlett, 539, 1994; AGBarrett, MJ Betto, J. Org. Chem., 50, 169, 1985]. From a structural point of view, the compounds described in the literature are generally composed of an arylized ArOSCNCO portion (Ar=Aryl) and sometimes an alkylated ROSO2NCO portion (R=alkyl). To our knowledge, no study reports the synthesis of fluorinated oxosulfonyl isocyanates. However, the introduction of a highly fluorinated chain generally enhances the properties of the resulting compounds: chemical and thermal inertness, low surface energy, low adsolubility, low viscosity, etc. <Desc / Clms Page number 2> With this in mind, we therefore focused on developing the synthesis of compounds with the general formula: EMI2.1 RpCH2CH2OSO2NCO in which RF denotes a linear or branched perfluoroalkyl chain CnH2n+1 (n=l to EMI2.2 22) and more specifically C4Fg, C6F13 and CSFI7. This synthetic strategy is based on the work of Lohaus carried out on the same type of compounds in the arylated series [G. Lohaus, Chem. Ber., 105.2791, 1972]. It is therefore possible to synthesize perfluoroalkylated isocyanate in a single step using chlorosulfonyl isocyanate (CSI) and 2-F-alkyl ethanol as starting materials. Initially, chlorosulfonyl carbamate (I) is formed at room temperature or slightly above. Subsequently, this reaction becomes reversible at higher temperatures, yielding oxosulfonyl isocyanate (II) (Table 1). EMI2.3 Table 1: Physico-chemical characteristics of oxosulfonyl isocyanates RFC2H4OSO2NCO EMI2.4 RF yield% yield ' % Teb at 10-2 mbar Tf EMI2.5 C4Fg - 95% 50 60-62 C CttF13 == 95% 72 100-102 C CsF17 == 95% 62 140-142 C 79-81 C - after distillation The second aspect of the present invention consists of studying the reactivity of the previously prepared oxosulfonyl isocyanates towards various classes of nucleophiles, and more particularly towards amines, alcohols, and polyfunctional compounds, with the aim of obtaining intermediates usable in the field <Desc / Clms Page number 3> biomedical or surfactants for the preparation of organized molecular systems. The present invention will be better understood with the aid of the following additional description. However, these examples are given solely to illustrate the objects of the invention and are in no way limiting. Example 1: Preparation of 2-F-hexylethyl oxosulfonyl isocyanate EMI3.1 C6Fi3C2H40SO2NCO In a setup placed under a nitrogen atmosphere, consisting of a 50 ml flask, a condenser and a magnetic stirrer, 5.46 g (0.015 mol) of 2-F-hexyl ethanol alcohol in solution in 30 ml of chlorobenzene is introduced. 2.15 g (0.015 mol) of chlorosulfonyl isocyanate is slowly added at 0°C. The mixture is heated to 130°C for 10 hours. Chlorobenzene is recovered by distillation under reduced pressure (60 mmHg, 53°C). The resulting oil is purified using a kugelrohr. A colorless oil is obtained. The yield is 72%. EMI3.2 IR: 2259 cm-l, 1412 cnf 1, 1100-1300 cin7'. 'H NMR (solvent CDC13 / TMS) 8 (ppm): 2.7 (Tt, 2H, 3JH~F =17.7 Hz, 3JH~g = 6.1 Hz); 4.7(t,2H,3JH-H = 6.1Hz). 19F NMR (solvent CDCl3 / CFC13) # (ppm): -81.0 (s, 3F); -113.5 (m, 2Fa); -121.9 (m, 2Fss); -122.8 (m, 2Fy); -123.5 (m, 2Fs); -126.2 (m, 2F#). Mass (IE 70 ev): m / z (%) 363 (1%); 169 (4%); 136 (100%); 131 (16%); 119 (12%); 106 (91%); 69(51%). Example 2: Preparation of type carbamates EMI3.3 After purging the setup with nitrogen, 1g (0.0021 mol) is placed in a two-necked flask equipped with a condenser, magnetic stirrer and topped with a bromine ampoule. EMI3.4 2-F-hexylethyl oxosulfonyl isocyanate (C6F13C2H40SOzNCO) is added dropwise at 0°C, along with 0.0018 mol of 2[2-[2-methoxyethyloxy]ethoxy]ethanol. The mixture <Desc / Clms Page number 4> is then heated to 40 C for two hours, the progress of the reaction is monitored by TLC or IR. After evaporation of the solvent, the product is purified by liquid chromatography. EMI4.1 (eluent: cyclohene / EtOH / CHCl3 1:1:1, detection: ninhydrin). The yield is 76%. IR: 3259 cidl, 2260 wax', 1758 crd', 1100-1300 cni'. RMN 'H (solvant CDC13 / TMS) 8 (ppm): 2,6 (Tt, 2H, 3JH~F= 17.7 Hz, 3JH~H = 7,OHz); 3,4 (s, 3H); 3,55-3,8 (m, 10 H); 4,25 (t, 2H,3JH-H= 2. 8 Hz); 4. 45 (t, 2H,3JH-H- 7,OHz). RMN 19F (solvant CDC13 / CFC13) 8 (ppm) : -81,0 (s, 3F);-113,5 (m, 2Fa); -121,9 (m, 2Fp); -122,8 (m, 2Fy); -123,5 (m, 2Fs); -126,2 (m, 2F#). Masse (IE 70ev) : m / z (%) 633 (< 1 %); 514 (54 %); 169 (1 %); 131 (4 %); 103 (12 %); 69 (10 %); 59 (100 %); 45 (50 %). Exemple 3 : Préparation d'urées de type: EMI4.2 After purging the apparatus with nitrogen, 1.3 g (0.0027 mol) of oxosulfonyl isocyanate in solution in 8 mL of freshly distilled anhydrous THF is introduced into a two-necked flask equipped with a condenser. At 0°C, 0.0024 mol of N,N-dimethyl-N'-decyl-[alpha],#-ethylenediamine is added dropwise. A white precipitate forms after one hour of stirring. The mixture is heated at 50°C for 12 hours to ensure that all the starting materials have reacted. The solvent is then evaporated, and the resulting solid is recrystallized from ether. The yield obtained is 78%. TF = 190-192°C. 1H NMR (CD30D solvent / TMS) # (ppm): 0.83 (t, 3H.3JH-H=7 Hz); 1.03-1.5 (m, EMI4.3 4 p.m.); 2.50 (Tt, 2H, 3JH-F = 17.7 Hz, 3JH-H 7.0 Hz); 2.8 (s, 6H); 3.05 (t, 2H, 3JH~H= 4.6 Hz); 3.25 (t, 2H, 3JH-h=5.6 Hz); 3.60 (t, 2H, 3JH~H= 5.6 Hz); 4.35 (t, 2H, 3JH~.I=7.0 Hz). <Desc / Clms Page number 5> 19F NMR (CDC13 / CFC13 solvent) # (ppm): -81.0 (s, 3F); -113.5 (m, 2Fa); -121.9 (m, 2Fp); -122.8 (m, 2Fy);-123.5 (m, 2Fs); -126.2 (m, 2F#). Mass (El 70 ev): m / z (%) 698 (< 1%); 161 (1%); 136 (38%); 131 (4%); 119 (3%); 72 (4%); 69(10%); 58 (100%); 44 (11%). Example 4: Urea prepared according to the procedure described in example 3, have a tertiary amine ending easily transformed into an ionic head, thus constituting precursors of choice for the preparation of new cationic surfactants belonging to the urea family. To access this category of F-alkylated single-chain amphiphiles, we quaternized the ureas with an excess of methyl iodide in chloroform at 40°C for 4 days. After evaporation of the solvent, the resulting yellow solid was washed several times with hot acetone and then purified by liquid chromatography (eluent: methanol). The product is then dried in a dryer under reduced pressure. The yield obtained is 70%. The product was identified by proton and fluorine NMR. Only protons close to the quaternized region underwent deshielding of 0.25 ppm compared to the starting amine.

Claims

DEMANDS 1) New fluorinated oxosulfonyl isocyanates with the general formula: RFCH2CH2OSO2NCO In which RF is a linear or branched fluorocarbon chain of Ci to C22 carbons. 2) Method for manufacturing the compounds according to claim (1), in which RF= C4F9, C6F13, CgFi7. 3) A manufacturing process according to claims 1 and 2, characterized in that they are prepared by the action of chlorosulfonyl isocyanate on 2-F-alkyl ethanol in a single step. 4) Application of the compounds according to claims 1 to 3 and their synthetic intermediates of the chlorosulfonyl carbamate and urethane type as precursors of mono or multipod cationic and non-ionic surfactants. 5) Use of the compounds according to claim 4 in the biomedical field as precursors of sulfonamides, antibacterials and lipid regulators. 6) Use of the compounds according to claim 4 in agronomy as precursors of herbicides and pesticides. 7) Use of the compounds according to claim 4 as precursors of surface coating agents for materials.