EP0925280A1

EP0925280A1 - Novel n-protected alpha-amino sulphinic acid salts, method for preparing same, and sulphonopeptides derived therefrom

Info

Publication number: EP0925280A1
Application number: EP97931852A
Authority: EP
Inventors: Michel Mulliez
Original assignee: Universite Toulouse III Paul Sabatier
Current assignee: Universite Toulouse III Paul Sabatier
Priority date: 1996-07-31
Filing date: 1997-07-03
Publication date: 1999-06-30
Also published as: WO1998004522A1; FR2751973B1; FR2751973A1

Abstract

A method for preparing N-protected α-amino sulphinic acid salts having formula Y - NH - CR'R - SO2-, M+ is disclosed. An intermediate compound Y - NH - CR'R - R1 is reacted with a sulphinic hydroxyacid salt in a strongly basic medium. The resulting salts, wherein Y is an acyl grouping other than R' SO¿2?, where R' is methyl or PCH3C6H4, R is a halogenated carbon group, alkyl or aryl, R' is hydrogen, a halogenated carbon group, alkyl or aryl, and M?+¿ is a cation, are also disclosed. Furthermore, stable sulphonopeptides derived from said salts by electrophilic amination are disclosed.

Description

NOVEL PROTEIN N SALTS OF α-AMINO SULFINIC ACID, THEIR PROCESS FOR OBTAINING SULFONOPEPTIDES AND THE SAME

The analogues of the transition state of the hydrolysis of the peptide bond (falling into the class of pseudopeptides) can act as false non-degradable substrates or as protease inhibitors, and therefore have great therapeutic interest, in particular for obtaining antibiotics, antihypertensives, analgesics, HIV protease inhibitors ...

We have already successfully synthesized phosphorous analogs of peptides. However, these analogs are imperfect in view of the brittleness of the P-N bond in an acid medium.

In addition, it was considered until now that the synthesis of α sulfonopeptides (chain of α-amino acids comprising at least one α-aminosulfonamide acid residue) was very difficult due to the fundamental instability of α aminosulfonamides (for example "Azasulfonamidopeptides as Peptide Bond Hydrolysis Transition State Analogues. Part 1. Synthetic Approaches, Thi othy J. Cheeseright et al, J. Chem. Soc. Perkin Trans. 1, 1994, p. 1595;" So e Studies on peptide Analogues Involving the sulphinamide Group ", David Merricks et al, J. Chem. Soc. Perkin Trans. 1., 1991, p. 2169;" Synthesis of Sulfonamido-Pseudopeptides: New Chiral Unnatural Oligomers ", Cesare Gennari et al, Angew. Chem. Int. Ed. Engl. 1994, 33, n ° 20, p. 2067; "alpha-amino sulphonamides", Journal of Organic Chemistry, WF Gilmore et al., Vol. 43, n ° 23, 10.11.78, p. 4535 ; "alpha- A inosulphonopeptides as possible functional analogues of pennicillin: evidence for their extreme instability" , S. Paik et al., Tetrahedron, vol. 52, n ° 15, 8.04.96, p. 5303; "Synthesis of derivatives substituted in 3 and 4 by acylating cyclization of chloromethylsufonyliso-ureas and isothio-ureas", A. Etienne et al., Bull. Soc. Chi. de France 1974, n ° 7-8, p. 1580). On the other hand, the β or y sulfonopeptides have been described as being very stable (for example "Synthesis of Peptides containing a Sulfinamide or a Sulfonamide Transition-State Isostere",. J. MOREE et al, Tetrahedron, 1993, vol. 49, n ° 5, p 1133). However, these compounds are not exactly analogs of the transition state of the hydrolysis of the peptide bond, that is to say of the group: H OH

HN - C _α - C - NH

R OH they have little or no therapeutic activity. The publication "Synthesis of salts of sulfuric α-amino acids substituted for nitrogen by a Methane or p-Toluene-Sulfonyl group", M. MULLIEZ and C. NAUDY, Tetrahedron, 1994, vol. 50, No. 18, p 5401, teaches the synthesis of the compounds R''Sθ2 - NH - CHR - SÛ2Na, R '' being Me or pMeC5H4. It was already envisaged in this document that these compounds should allow the synthesis of α sulfona ide peptide analogs by electrophilic amination. However, these sulfonyl groups R '' SO2 are difficult to eliminate, so that obtaining the α sulfonopeptides from these compounds comes up against the problem of the simultaneous destruction of the α sulfonamide function that can be formed. It is difficult to generalize the method to other protective groups than esyl or tosyle ("Study of the coupling of rongalite with various amino compounds", F. LEURQUIN and M. MULLIEZ, Phosphorus Sulfur and Silicon, 1994, vol 92, p. 201).

Furthermore, the rare derivatives of α-sulfinic amino acids described are not protected on nitrogen by an acyl protecting group, are not substituted at α, and are unstable.

The invention therefore aims to overcome these drawbacks by proposing protected N acid salts α, amino sulfinic synthesized, stable, isolated or capable of being isolated, and the process for obtaining them. By stable, we mean that we can keep them at least 8 hours - notably several days - without alteration. More particularly, the invention aims to propose a process making it possible to obtain said salts, the nitrogen substituent of which can be freely chosen, in particular from traditional acyl protective groups (Cbz, Boc, acetyl, etc.), and by particular distinct from the tosyle (PCH3C5H4SO2) and mesyl (CH3SO2) groups, so that the said salts can serve as precursors of α sulfonopeptides.

The invention aims more particularly to provide salts as mentioned above in which the α carbon is substituted, in particular by a halogenated carbon group, and their process for obtaining.

The invention thus aims to propose these salts which are precursors of sulfonopeptides, or even of sulfinopeptides, but which can also be isolated and used as such, in particular as N acylated analogs of natural α-amino carboxylic acids.

The invention further aims to provide stable sulfonopeptics, namely, the stable synthesized α-sulfonopeptides, isolated or capable of being isolated, derived from these salts according to the invention.

Throughout the present application, the following terminologies and abbreviations are used to denote the substituent groups:

- sulfonopeptide: any chain of amino acids comprising at least one α-amino sulfonamide residue,

- acyl: any group or function of acyl type derived from an oxoacid in general, that is to say not only a carboxylic or thiocarboxylic acyl stricto sensu, but also groups or functions of acyl type derived from mineral acids such that sulfonic, phosphoric, thiophosphoric, phosphonic, or phosphinic acids, - ester: esters derived from acyls as mentioned above,

- amide: the aids originating from acyls as mentioned above, - CBz or Z: Benzyloxycarbonyl,

- Boc: tert-butyloxycarbonyl,

- Tos: tosyle (pMeC * 5H4S02),

- My: mesyle (MeSθ2),

- Me: methyl, - And: ethyl,

- Ac: acetyl,

- halogenated carbon group: any group comprising at least one carbon atom and at least one halogen atom. The invention therefore relates to a process for obtaining protected N salts of α-amino sulfinic acid of formula:

Y - NH - CR'R - Sθ2 ^~ , M ⁺ where: Y is an acyl - in particular a protective group adapted to be able to be substituted by a peptide group, and / or a peptide or pseudopeptide peptide group (for example sulfonopeptide) itself protected N, R and R ′ may be chosen from hydrogen, a halogenated carbon group directly linked by a carbon atom to the α carbon of the salt, an alkyl or an aryl,

M ⁺ is a cation, characterized in that:. an intermediate compound corresponding to the linear formula is chosen or prepared:

Y - NH - CR'R - R1 where R1 is an electron-withdrawing group, or to cyclic analogs of this formula, such as:

Y - N - CR'R

\ I R-, Y - NH - CR - R- *

I / R '

Y - NH (R-j being confused with Y) \ I

CR'R. this intermediate compound is reacted in a strongly basic medium with a sulfinic hydroxyacid salt of formula:

HO - CH - S0 ₂ ^~ M ' ⁺ IR ₂ where R2 is hydrogen or an organic group linked by a carbon atom in the sulfinic hydroxyacid salt, and M ^{, +} is a cation, identical or not to M ⁺ . Advantageously and according to the invention, R1 is chosen to promote the formation of the corresponding imine Y - N = CR 'R in basic medium during the reaction of said intermediate compound with the basic solution. It then suffices to choose Y, R, and R 'so that this imine reacts only on the sulfinate function. In particular, it has been found that it is possible to choose Y, R and R ¹ so that the imine reacts selectively on the sulfinate function, even in an aqueous medium.

Advantageously and according to the invention, R1 is chosen from:

an -0-acyl ester function originating from an acyl as defined above, in particular a carboxylic ester function such as: O // -O- C or -O-SO3-, especially when R is -CF3,

\ ^CF 3

an ether -O-alkyl function, in particular when R is hydrogen,

an amide -N-acyl function originating from an acyl as defined above, that is to say a carboxylic amide or originating from an oxoacid,

- halogen.

Advantageously and according to the invention, R is a fluorinated or chlorinated carbon group, in particular -CF3. Advantageously and according to the invention, R 'is hydrogen. To react the intermediate compound, several variants are possible.

In a first variant according to the invention, said intermediate compound is added dropwise to an aqueous solution of HO - CH - SO2 Na rongalite.

In another variant according to the invention, R2 is an organic group chosen from an alkyl; aryl; or a halogenated carbon group, in particular a fluorinated or chlorinated carbon group, more particularly a halogenated carbon group linked by a carbon to the carbon of the sulfinic hydroxyacid salt, advantageously -CF3. Advantageously and according to the invention, said intermediate compound is reacted in an anhydrous organic medium with a salt of sulfinic hydroxy acid of formula: HO - CH - S0 ₂ ^~ , B ⁺

C ₃ where B is an organic base such as an amine. Advantageously and according to the invention, B is an aliphatic amine, such as NH (CgH- * - |) 2 •

According to the invention, to prepare said intermediate compound, the aldehyde or the ketone is first reacted: 0 // R - C with the amide Y - NH2.

\

R 'is preferably hydrogen, the aldehyde being generally more reactive than the ketone.

Following this reaction, two situations (1) and 2) below) may arise, depending on the stable products obtained, the nature of which depends on the groups R, R 'and Y considered.

1) When the reaction of the aldehyde or ketone with the amide provides a stable carbinolamine Y - NH - CR'R - OH, this carbinolamine is activated in a second step, by reacting it on a donor compound of a halogen, an acyl or an alkyl, so as to obtain said intermediate compound where R1 is a halogen, an ester function or an ether function. In particular and according to the invention, the carbinolamine is activated by reacting it with the trifluoroacetic anhydride CF3 - CO - O - CO - CF3, so as to obtain said intermediate compound where Ri is the ester:

0

II - 0 - C - CF3

As a variant and according to the invention, the carbinolamine is activated by reacting it on a sulfonic acyl so as to obtain said intermediate compound where R1 is a sulfonic ester, in particular - O - SO3H or the corresponding anion - O - SO3-. In particular, the SO3 - Py complex is used where Py represents Pyridine. With this last variant, after reaction, the protected salt N is separated from α-amino sulfinic acid by adding a water-soluble salt of dicyclohexylamrnoniurn (in particular a citrate), selective extraction in an organic solvent and evaporation. In fact, the dicyclohexylamrnoniurn salt formed with the aminosulfinate is selectively extracted in an organic extraction solvent (such as chloroform), while the other salts remain in the aqueous phase.

This first situation and the corresponding variants of the process according to the invention are particularly applicable when Y is a protective group, distinct from tosyl and mesyl groups, and chosen to be able to be eliminated at least in part subsequently (and substituted by a peptide group) without destroying the sulfonamide function which can be formed from the salt, in particular under milder conditions than the tosyl and mesyl groups, and in particular when Y is chosen from benzyloxycarbonyl or tert-butyloxycarbonyl.

2) When the reaction of the aldehyde or ketone with the amide provides a linear amine diacyl, such as Y - NH - CR 'R - NH - Y, or cyclic, this aminal diacyl is used directly as an intermediate compound ( with R1 being a -NH-acyl function). This situation is encountered in particular when Y is the tosyle group.

The process according to the invention makes it possible to obtain stable, synthesized or even isolated salts,

N protected from α-amino sulfinic acid, and in particular the new stable salts synthesized according to the invention of formula:

Y - NH - CR'R - S0 ₂ -, M ⁺ where:

Y is an acyl group, distinct from R ' ¹ S0 ₂ , R''being methyl or PCH3C6H4,

R is a halogenated carbon group directly linked by a carbon atom to the carbon α of the salt, or an alkyl or an aryl,

R 'is chosen from hydrogen, a halogenated carbon group directly linked by a carbon atom to the carbon α of the salt, an alkyl or an aryl, M ⁺ is a cation. It should be noted that R is distinct from hydrogen. Advantageously and according to the invention, R is a fluorinated or chlorinated carbon group, in particular -CF3. Advantageously, R 'is hydrogen. In addition, advantageously and according to the invention, Y is a protective group distinct from the tosyl and mesyl groups. Y is chosen so that it can be eliminated at least in part (and subsequently substituted by a peptide group) without destruction of the sulfonamide function which can be formed from the salt, in particular under milder conditions than the tosyl and mesyl groups. Y is in particular a group chosen from benzyloxycarbonyl or tert-butyloxycarbonyl. It should also be noted that Y is an acyl group which can itself incorporate an α-amino acid residue N protected, in particular by an acyl function, or even a protected peptide or pseudo-peptide chain (for example sulfonopeptide) N, in particular by an acyl function. In this case, only the protective part of Y is eliminated. Thus, the salts according to the invention are then already themselves of sulfonopeptide nature.

The new salts according to the invention are stable and can be isolated. They constitute analogs N acyls of the natural α-amino carboxylic acids and have in themselves the properties, in particular therapeutic, corresponding to this structure.

The new salts according to the invention also make it possible to obtain particularly stable synthesized sulfonopeptides. To do this, the stable salts according to the invention are subjected to an electrophilic amination of the type: Y-NH-CR'R-S0 ₂ ^~ , M ⁺ + H ₂ N-0-S0 ₂ -0H -> Y-NH -CR'R-S0 ₂ -NH2 + HS0 - ^~ , M «„ +

Y-NH-CR'R-S02-NH2 is then used in conventional peptide synthesis reactions.

The invention thus makes it possible to obtain the synthesized stable sulfonopeptides incorporating at least one residue of α-amino sulfonamide:

- NH - CR'R - S0 - N ^ where R is a halogenated carbon group linked directly by a carbon atom to the carbon α of the residue; and R 'is chosen among hydrogen, a halogenated carbon group directly linked by a carbon atom to the carbon α of the residue, an alkyl or an aryl. In particular, R is a fluorinated or chlorinated carbon group, in particular -CF3. Likewise, R ′ is in particular hydrogen, so that the sulfonopeptide is a natural peptide analog. The sulfonopeptides according to the invention are easy to isolate. The invention therefore also extends to these isolated sulfonopeptides.

It should be noted that the use, according to the invention, of a fluorinated carbon group R such as -CF3 provides numerous advantages: it does not disturb the steric hindrance of the salt or of the sulfonopeptide; it can be easily followed by nuclear magnetic resonance and therefore constitutes a tracer element; it gives the molecule an ability to cross cell membranes and improves its therapeutic effectiveness ...

The invention also relates to a process for obtaining the new salts and the sulfonopeptides comprising in combination all or part of the characteristics mentioned above or below.

The following description provides examples of implementation of the process according to the invention, and new salts and sulfonopeptides according to the invention. In the examples, all the syntheses were carried out under argon and with degassed solvents. The products were fully characterized by ¹ H, ¹³ C, possibly ¹⁹ F NMR (Bruker AC 80 device) and by IR (Perkin-elmer 257 device). The elementary analyzes were carried out on a Carlo Erba 11-06 device. The melting points were measured in capillary tubes (Bϋchi device from Dr. Tottoli) and are not corrected. EXAMPLE 1 Synthesis of the salt Z-NH-CHCF ₃ S02 ^~ H ₂ N ⁺ (C ₆ H- _| - *) ₂

In this salt, Y is Z, R is CF3, R 'is H, M ⁺ is H ₂ N ⁺ (C ₆ H- | - |) ₂ .

To a solution of 0.32 g (1.28 mmol) of carbinolamine Z-NH-CHCF3OH (Chem. Ber. 1966, 99, 1933) in 3 g of anhydrous pyridine, is added dropwise, 3 min, at 4 ° C, with good magnetic stirring, 0.2 cm ³ (1.41 mmol, 10% excess) of trifluoroacetic anhydride.

The solution obtained from the intermediate compound Z-NH-CHCF3-OCOCF3 obtained, kept at 4 ° C., is added dropwise over 7 min to an alkaline solution of 0.56 g (3.63 mmol) of rongalite in 9 g of water, vigorously stirred at 4 ° C. 0.26 g (1.43 mmol) of dicyclohexylamine is then added and four extractions are carried out with approximately 20 cm ³ of chloroform. The ⁹ F NMR shows that the product is contaminated with approximately 50% of trifluoroacetate. The combined CHCI3 extracts are thus washed four times with approximately 20 cm ³ of water. After drying (Na2SO4) and concentration to dryness, 0.49 g (yield 79%) is obtained of product which crystallizes, the melting point of which is 120 ° C. to 123 ° C. after recrystallization from MeCN. Analysis: C22H33F3N2O4S, M - 478.564

Theoretical% calculated: C: 55.21; H: 6.95; N: 5.86% experimental found: C: 54.8; H: 6.9; N: 5.8. EXAMPLE 2 Synthesis of the salt Boc-NH-CHCF3S02 ^~ HN ⁺ (CQU - - *) ₂ In this salt, Y is Boc; R is -CF3; R 'is H; M ⁺ is H ₂ N ⁺ (C ₆ H- * - *) ₂ -

To a solution of 0.86 g (3.98 mmol) of carbinolamine B0CNH-CHCF3OH (Chem. Ber. 1967, 3838) in 3 g of anhydrous pyridine, 0.95 g (6 mmol) of SO3 complex are added. pyridine. After three days of stirring, the finally obtained solution of the intermediate compound Boc-NH-CHCF3-0-S03 PyH ⁺ is added dropwise, over 2 min, to a well stirred solution, at 4 ° C. of 0.74 g (4.80 mmol 1.2 equivalent) of rongalite in 12 g of water. After treatment as in Example 1, but with only two washes with water, in which the product is partially soluble, the residue is obtained by crystallization from 10 g of 60% alcohol, 1.12 g (yield 63 %) of crystallized product, the melting point of which is 157 ° C. to 159 ° C. after recrystallization from water.

Analysis: C * ι 9H5F3N2O4S, M = 444.554 theoretical% calculated: C: 51.33; H: 7.94; N: 6.30 % experimental found: C: 51.1; H: 8; N: 6, 2.

When operating, not with the SO3 complex. pyridine, but with trifluoroacetic anhydride as in Example 1, only 37% of product is obtained due to the losses during the aqueous washes necessary to remove the trifluoroacetate. EXAMPLE 3 Synthesis of the Tos-NH-CHCF ₃ salt Sθ2 ^~ H2N ⁺ (CQH- _] - ^→ ) ₂

In this salt, Y is Tos; R is CF3; R 'is H; M ⁺ is H ₂ N ⁺ (C ₆ H-ι - ^* ) ₂ * A 0.41 g (1.19 mmol, 1.5 eq.) Of the sulfinic hydroxyacid HOCHCF ₃ Sθ2 ^~ H2N ⁺ (C6H-- - *) ₂ (R2 is - -CF3 and M 'is identical to M; Tetrahedron 1993, 2469) and 0.29 g (0.75 mmol) of the diacylaminal (TosNH) ₂ CHCF3 (Chem. Ber. 1964, 97 , 483), 7 g of the solvent CH2Cl2 are added and, to the solution obtained, 0.45 g (4.5 mmol) of NEt3- The NMR spectrum of ⁹ F shows that the reaction is practically completed within a few hours. Concentrate to dryness and dissolve the residue with slight heating in 3 g of absolute EtOH. The product crystallizes after a few days at −15 ° C.: 0.43 g (yield 73%), the melting point of which is 162 ° C. to 165 ° C. (to be compared with the yield of 16%, and with the point of melting from 168 ° C to 169 ° C described earlier in the above publication).

When rongalite is used as sulfinate, in aqueous medium, the ¹⁹ F NMR spectra show the formation of the product and then its conversion in a few hours to fluorine hydrate. After extraction with AcOEt, a single equivalent of TosNH _{2 is} recovered. After adding an equivalent of DCHA citrate, TosNHCH2S0 ₂ -H ₂ N (C6H- | i) ₂ crystallizes, the melting point of which is from 141 ° C to 145 ° C (to be compared with the melting point described previously from 142 ° C to 143 ° C) and is isolated by filtration with a yield of 62%.

We thus note the interest there is in using either the fluorinated hydroxysulfinate or the unsubstituted hydroxysulfinate according to the final salt which it is desired to obtain. EXAMPLE 4 Synthesis of the Tos Monosulfonopeptide Protected

NHCH2S0 ₂ H ₂ by electrophilic amination

To a solution cooled to 4 ° C of 4.53 g

(15.6 mmol) of TosNHCH ₂ S02Na monohydrate (obtained from the salt of Example 3) in 10 g of water, 1.54 g is added

(17.2 mmol) of NH2OSO3H with stirring, in 2 min. After

5 min, the product begins to precipitate. After a few hours, the thick suspension is filtered, the insoluble material is rinsed thoroughly with water and dried in the presence of P2O5 • 3.8 g (92% yield) are isolated of product with a melting point of 87 ° C.

Analysis: CgH- ^* _{2 2} 0 S2 * M = 264.32

Theoretical% calculated: C: 36.75; H: 4.58; N: 10.60;

S: 24.26% experimental found: C: 36.3,; H: 4.5; N: 10.7;

S: 24.4.

The product can be recrystallized, without heating, from a MeCN-CHCl3 mixture. On the other hand, in the MeCN-H 0 mixture the product is hydrolyzed in less than an hour and after addition of dicyclohexylamine, it is isolated with an almost quantitative yield, TosNHCH2S03 ^_ H2N (C5H- _| - *) 2 whose melting point is from 180 ° C to 181 ° C (the previously described melting point being from 180 ° C to 183 ° C). It can thus be seen that the protected monosulfonopeptide is in this case not very stable.

EXAMPLE 5 Synthesis of the Protected Monosulfonopeptide Z-NH-

CHCF3SO2NH2 by electrophilic amination

By proceeding as for the derivative of Example 4 but with the salt Z-NH-CHCF3SO2Na obtained from the salt of Example 1, the sulfonamide is obtained with a yield of 82%, the melting point of which is

148 ° C.

Analysis: C- * ₀ H- | -j F3N2O4S, M = 312.274

Theoretical% calculated: C: 38.46; H: 3.55; N: 8.97% experimental found: C: 38.0,; H: 3.5; N: 8.8.

The product is stable in MeCN-H2θ solution and is recognized quantitatively after 24 h by adding an excess of water. The protective group Z is easy to remove, for example by catalytic hydrogenation, to obtain the new sulfonopeptide according to the invention in salt form: N ⁺ H ₃ - CH CF ₃ - SO2 - NH ₂ - A ^~

This alanine analog is of major therapeutic interest, in particular as an antibiotic.

These examples 4 and 5 demonstrate that it is possible to carry out an electrophilic amination in order to obtain the protected monosulfonopeptides derived from the sulfinate salts obtained according to the invention.

In addition, it is found that the new monosulfonopeptides of the invention are stable, in particular when one chooses -CF3 for the group R.

Claims

CLAIMS 1 / - Process for obtaining protected N salts of α-amino sulfinic acid of formula:

Y - NH - CR'R - S0 ₂ ^~ - M ⁺ where:

Y is an acyl group,

R and R 'may be chosen from hydrogen, a halogenated carbon group directly linked by a carbon atom to the carbon α of the salt, an alkyl or an aryl, M ⁺ is a cation, characterized in that:

. an intermediate compound corresponding to the linear formula is chosen or prepared:

Y - NH - CR'R - R1 where RI is an electron-attracting group, or to cyclic analogs of this formula,

. this intermediate compound is reacted in a strongly basic medium with a sulfinic hydroxyacid salt of formula:

HO - CH - S0 ^~ M ' ⁺ I

* 2 where R2 is hydrogen or an organic group linked by a carbon atom in the salt of hydroxy acid sulfinic, and

M ' ⁺ is a cation.

2 / - Process according to claim 1, characterized in that R is a fluorinated or chlorinated carbon group. 3 / - Method according to one of claims

1 and 2, characterized in that R is -CF3.

4 / - Method according to one of claims

1 to 3, characterized in that R1 and chosen from an -0-acyl ester function, an -0-alkyl ether function, an amide -N-acyl carboxylic or oxoacid function, or a halogen.

5 / - Method according to one of claims

1 to 3, characterized in that RI is: 0 / / -O- C

\ ^CF 3

6 / - Method according to one of claims 1 to 3, characterized in that R1 is -O- Sθ3 ^~ . it - Method according to one of claims 1 to 6, characterized in that said intermediate compound is added dropwise to an aqueous solution of HO - CH ₂ - SO2 Na rongalite.

8 / - Method according to one of claims 1 to 6, characterized in that R2 is an organic group chosen from an alkyl, an aryl, or a halogenated carbon group.

9 / - Method according to one of claims 1 to 6, characterized in that R2 is a fluorinated or chlorinated carbon group.

10 / - Method according to one of claims 1 to 6, characterized in that R2 is -CF3.

11 / - Method according to one of claims 1 to 6, characterized in that said intermediate compound is reacted in an anhydrous organic medium with a salt of sulfinic hydroxyacid of formula: HO - CH - Sθ2 ^~ , B ⁺

CF ₃ where B is an organic base such as an amine.

12 / - Process according to claim 11, characterized in that B is an aliphatic amine, such as NHfCgH-n) ₂ .

13 / - Method according to one of claims 1 to 12, characterized in that the said intermediate compound is prepared by reacting the aldehyde or the ketone: 0 // R - C with the amide Y - NH ₂ . \ ^R '

14 / - Process according to claim 13, characterized in that when the reaction of the aldehyde or of the ketone with the amide provides a stable carbinolamine Y - NH - CR'R - OH, this carbinolamine is activated in a second step , so as to obtain said intermediate compound where R1 is a halogen, an ester function or an ether function.

15 / - Process according to claim 14, characterized in that the carbinolamine is activated by reacting it with trifluoroacetic anhydride

CF3 - CO - O - CO - CF3, so as to obtain said intermediate compound where R1 is the ester function:

0

II 0 - C CF3

16 / - Process according to claim 14, characterized in that the carbinolamine is activated by reacting it on a sulfonic acyl so as to obtain said intermediate compound where R1 is a sulfonic ester. 17 / - Process according to claim 16, characterized in that sulfonic acyl SO3-Py is used where Py represents Pyridine.

18 / - Method according to one of claims 16 and 17, characterized in that after reaction, the protected salt N is separated from α-amino sulfinic acid by addition of a water-soluble salt of dicyclohexylamrnoniurn and extraction .

19 / - Method according to one of claims 1 to 18, characterized in that Y is a protective group distinct from the tosyle and mesyl groups, chosen to be able to be eliminated at least in part subsequently without destruction of the sulfonamide function which can be formed at from salt. 20 / - Method according to one of claims 1 to 19, characterized in that Y is chosen from benzyloxycarbonyl or tert-butyloxycarbonyl.

21 / - Process according to claim 13, characterized in that when the reaction of the aldehyde or of the ketone with the amide provides an aminal diacyl, this aminal diacyl is used directly as an intermediate compound.

22 / - Method according to claim 21, characterized in that Y is the tosyle group.

23 / - New stable synthesized salts N protected with α-amino sulfinic acid of formula:

Y - NH - CR'R - S0 ₂ ^" , M ⁺ where: Y is an acyl group, distinct from R '' SO2, R ¹ 'being methyl or PCH3C5H4,

R is a halogenated carbon group directly linked by a carbon atom to the α carbon of the salt, an alkyl or an aryl, R ′ is chosen from hydrogen, a halogenated carbon group directly linked by a carbon atom to the α carbon of the salt , alkyl, or aryl, M ⁺ is a cation.

24 / - New salts according to claim 23, characterized in that R is a fluorinated or chlorinated carbon group.

25 / - New salts according to claim 23, characterized in that R is -CF3.

26 / - New salts according to one of claims 23 to 25, characterized in that Y is a group, distinct from the tosyl or mesyl groups, chosen to be able to be removed subsequently without destruction of the sulfonamide function which can be formed from the salt . 27 / - New salts according to one of claims 23 to 26, characterized in that Y is a group chosen from benzyloxycarbonyl or tert-butyloxycarbonyl. 28 / - Synthetic stable sulfonopeptides incorporating at least one residue of α-amino sulfonamide:

- NH - CR'R - S0 ₂ - NC where R is a halogenated carbon group directly linked by a carbon atom to the carbon α of the salt, and R 'is chosen from hydrogen, a halogenated carbon group directly linked by an atom from carbon to carbon α of the salt, an alkyl or an aryl.

29 / - Sulfonopeptides according to claim 28, characterized in that R is a fluorinated or chlorinated carbon group.

30 / - Sulfonopeptides according to claim 26, characterized in that R is -CF3.