ITMI20091363A1 - PROCESS FOR SIVELESTAT SYNTHESIS - Google Patents

Description

â € œPROCESS FOR THE SYNTHESIS OF SIVELESTATâ €

The present invention relates to a process for the synthesis of Sivelestat (1), 2- (2- (4- (pivaloyloxy) phenylsulfonamido) benzamido) acetic acid starting from sodium 4-hydroxybenzenesulphonate and isatoic anhydride.

BACKGROUND OF THE INVENTION

Sivelestat is a human neutrophilic elastase inhibitor and is indicated for the treatment of acute lung inflammation associated with systemic inflammatory response syndrome. In particular, Sivelestat sodium tetrahydrate is used in therapy.

The synthesis of Sivelestat is described in EP 3472168, EP 539223 and in Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134 (Ono Pharmaceutical Co., Ltd).

The main synthesis scheme of Sivelestat is shown in the following scheme:

The process is based on a convergent synthesis in which the intermediates 6 and 10 are produced separately starting from the raw materials respectively sodium 4-hydroxybenzenesulphonate 3 and 2-nitrobenzoic acid 7. The intermediate 6 reacts with the intermediate 10 to to obtain the intermediate 11, which in turn is debenzilated thus producing the Sivelestat, which can then be salified in the presence of water to give the sodium tetrahydrate 2 salt. This process involves seven synthesis stages in addition to the final salification. The known process involves the isolation and drying of all the intermediates, thus affecting efficiency and productivity, with a strong impact on the cost of labor on the finished product. The overall yield is less than 22% starting from sodium 4-hydroxybenzenesulphonate 3 and in particular the synthesis stage of intermediate 5 has a low yield, unsatisfactory for an industrial process. Furthermore, the synthesis of intermediate 5 is carried out in water: since the subsequent synthesis stage (with thionyl chloride for the preparation of intermediate 6) is incompatible with water, intermediate 5 must must be isolated and dried, thus entailing very long process times and production inefficiencies.

JP 09040692 (Ono Pharmaceutical Co., Ltd.) describes a synthesis procedure of Sivelestat and its sodium tetrahydrate salt according to the following scheme:

The synthesis of Sivelestat described in JP 9040692 involves five synthesis stages in addition to the final salification. Compared to the synthesis method described in EP 3472168, EP 539223 and in Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134, one of the two starting raw materials of the synthesis (2-nitrobenzoic acid 7) It has been replaced by the commercially available anthranilic acid 12, and this makes the process simpler from the point of view of the number of stages, but makes it mandatory to protect the carboxylic group of glycine 14 as trimethylsilyl derivative 15 by means of trimethylsilyl chloride, a reactive relatively expensive.

Another synthesis method of Sivelestat and its sodium tetrahydrate salt, described in patent application IN 2007MU01508 (Macleods Pharmaceuticals Ltd), is shown in the following scheme:

This synthesis involves six stages in addition to salification. The process, like that described by JP 9040692, involves the use of trimethylsilyl chloride.

The following publications describe the preparation processes of Sivelestat and its sodium salt and sodium salt tetrahydrate analogous to those of the first scheme reported above:

Synthesis of sivelestat sodium. Huaxue Shijie (2004), 45 (1), 29-31, 25; Preparation of sivelestat sodium hydrate. Nanjing Gongye Daxue Xuebao, Ziran Kexueban (2005), 27 (1), 89-92;

Synthesis of sivelestat sodium. Zhongguo Yiyao Gongye Zazhi (2003), 34 (8), 369-370, 399;

Synthesis of sivelestat. Zhongguo Yaowu Huaxue Zazhi (2006), 16 (2), 79-81, 111;

Hecheng Huaxue (2004), 12 (6), 580-582 describes a preparation process of Sivelestat sodium salt based on the same synthesis scheme of JP 09040692.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that Sivelestat and Sivelestat sodium tetrahydrate can be conveniently produced by means of a new synthesis method reported below:

The process of the invention includes:

a) reaction of sodium 4-hydroxybenzenesulfonate 3 with pivaloyl chloride in the presence of an organic base to produce the corresponding 4-pivaloyloxybenzenesulphonate salt;

b) reaction of the 4-pivaloyloxybenzenesulfonate salt obtained in a) with halogenating agent to produce 4- (halosulfonyl) phenyl pivalate; c) reaction of isatoic anhydride with benzyl glycinate to produce 2- (2-aminobenzamido) benzyl acetate 10;

d) reaction of 2- (2-aminobenzamido) benzyl acetate 10 with 4- (halosulfonyl) phenyl pivalate to produce 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11;

e) debenzylation reaction of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11 to produce Sivelestat 1;

f) salification of Sivelestat 1 to produce Sivelestat sodium salt tetrahydrate 2

As the organic base, an alkyl, aryl or alkyl-aryl amine is preferably used, for example triethylamine, benzylamine and the like.

In this case, the synthesis of the 4-pivaloyloxybenzenesulphonate salt of alkyl, aryl and alkyl-aryl ammonium is carried out in an organic solvent, preferably an aromatic solvent such as toluene, a chlorinated solvent such as dichloromethane and their mixtures, in the presence of an organic base, preferably triethylamine . In the case of using triethylamine, the intermediate 19 is obtained.

The synthesis of 4- (halosulfonyl) phenyl pivalate is carried out by using commonly used halogenating agents such as thionyl chloride, oxalyl chloride, phosphorus oxychloride, preferably thionyl chloride. In the case of use of thienyl chloride, the intermediate 6 is obtained.

The synthesis of benzyl 2- (2-aminobenzamido) acetate 10 is carried out using benzyl glycinate in the form of a base or one of its commercially available salts such as for example hydrochloride or p-toluenesulfonate.

Intermediate 19 is new and is also the subject of the present invention. According to a preferred version of the invention, the process is performed as follows:

Stage a

Typically sodium 4-hydroxybenzenesulphonate 3 is reacted with 1.0 Ã · 2.0 equivalents of pivaloyl chloride, preferably 1.0 Ã · 1.5 equivalents, in the presence of an organic base, preferably triethylamine, in an amount between 1.5 Ã · 3.0 equivalents, preferably 2.0 Ã · 2.5 equivalent. The reaction is carried out in an aromatic solvent such as toluene, a chlorinated solvent such as dichloromethane and their mixtures, preferably dichloromethane at a temperature of 0 ° C Ã · 40 ° C, preferably at a temperature of 20 ° C Ã · 30 ° C. 2 Ã · 15 volumes of solvent are used, preferably 4 Ã · 8 volumes with respect to the quantity of sodium 4-hydroxybenzenesulphonate 3. The reaction is controlled by HPLC analysis using a C18 column and monobasic phosphate buffer 0.05M / acetonitrile as eluent phase . When the reaction is over, the triethylammonium 4-pivaloyloxybenzenesulphonate 19 can be obtained as an oil for storage at room temperature for several days or, according to a preferred version of the invention, the solution obtained is used directly in the step b.

To obtain the 4-pivaloyloxybenzenesulphonate salt of triethylammonium 19 as oil, 2 to 15 volumes of water are added, the phases are separated and the organic phase is concentrated until the solvent is completely eliminated. Triethylammonium 19 4-pivaloyloxybenzenesulphonate is obtained as oil.

Stage b

Typically the triethylammonium 4-pivaloyloxybenzenesulphonate 19 obtained in a), isolated as an oil or directly from the end-of-reaction solution, is reacted with 1.0 à 3.0 equivalents of thionyl chloride, preferably 1.2 à 1.6 equivalents, in the presence of a catalytic of N, N-dimethylformamide (0.3 equivalents) in an aromatic solvent such as toluene, a chlorinated solvent such as dichloromethane and their mixtures, preferably dichloromethane. The reaction is carried out at a temperature of 0 ° C Ã · 40 ° C, preferably at a temperature of 20 ° C Ã · 30 ° C. 2 Ã · 10 volumes of solvent are used, preferably 4 Ã · 6 volumes with respect to the amount of triethylammonium 4-pivaloyloxybenzenesulphonate 19. The reaction is controlled by HPLC analysis using a C18 column and monobasic phosphate buffer 0.05M / acetonitrile as eluent phase . When the reaction is over, the intermediate 4- (chlorosulfonyl) phenyl pivalate 6 can be obtained as an isolated and optionally dried solid, or it is possible to proceed using the solution obtained directly in step d.

To obtain the intermediate 4- (chlorosulfonyl) phenyl pivalate 6 as an isolated solid, the solvent is evaporated; if dichloromethane is used, the residue is dissolved in toluene and the suspension is filtered. In the case of using toluene, the slurry is simply filtered at the end of the reaction. The clear solution obtained is concentrated and crystallized from n-hexane. The suspension is filtered and the product is dried at 40 ° C for 12 hours under vacuum

Stage c

Typically, isatoic anhydride 4 is reacted with about 1 equivalent of benzyl glycinate in the form of a free base or a salt thereof such as for example hydrochloride or paratoluenesulfonate, preferably paratoluenesulfonate. The reaction is carried out in an organic solvent, such as acetonitrile, or in water, preferably in water at a temperature of 20 ° C to 100 ° C, in the presence of an organic base, such as triethylamine, in the case of using benzyl glycinate in the form of its salt. 1 Ã · 15 volumes of solvent are used, preferably 5 Ã · 10 volumes with respect to the amount of isatoic anhydride 4. The reaction is controlled by HPLC analysis using a C18 column and monobasic phosphate buffer 0.05M / acetonitrile as eluent phase. When the reaction is over, the organic solvent is evaporated, if carried out in an organic solvent, and 5 ÷ 10 volumes of water are added with respect to the amount of isatoic anhydride 4. The suspension is filtered and the product is dried at 60 ° C for 12 hours under vacuum to obtain 2- (2-aminobenzamido) benzyl acetate 10 as an isolated and dried solid.

Stage d

Typically the intermediate 2- (2-aminobenzamido) benzyl acetate 10 obtained in c) is reacted with about 1 equivalent of 4- (chlorosulfonyl) phenyl pivalate 6, obtained in b) directly from the end-of-reaction solution or from the dissolution of the isolated intermediate 6 in an aromatic solvent such as toluene, in a chlorinated solvent such as dichloromethane and their mixtures, preferably dichloromethane. The reaction is carried out at a temperature of 0 ° C Ã · 35 ° C, preferably at a temperature of 20 ° C Ã · 25 ° C, in the presence of an organic base such as pyridine or triethylamine. 2 Ã · 15 volumes of solvent are used, preferably 5 Ã · 10 volumes with respect to the quantity of the intermediate 2- (2-aminobenzamido) benzyl acetate 10. The reaction is controlled by HPLC analysis using a C18 column and phosphate buffer monobasic 0.05M / acetonitrile as eluent phase. When the reaction is over, water is added and the phases are separated. The organic phase is washed with 10% hydrochloric acid and then with a saturated aqueous solution of sodium chloride. The organic solvent is concentrated under reduced pressure. The residue obtained can be dissolved in 2 15 volumes of alcoholic solvent, such as methanol and be directly used in step e, or the residue is crystallized by adding 2 10 volumes of diisopropyl ether. The suspension is filtered and the product is dried at 60 ° C for 12 hours under vacuum to obtain 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11 as an isolated solid and dried.

Stadium e

Typically the intermediate 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11 obtained in d, directly from the concentrated solution after evaporation of the solvent before isolation or The isolated intermediate 11 is reacted in a hydrogen atmosphere in the presence of a metal catalyst, preferably Pd. The reaction is carried out in an alcoholic solvent, preferably methanol, at the temperature of 10 ÷ 40 ° C, preferably at the temperature of 20 ÷ 25 ° C. 3 × 15 volumes of solvent are used, preferably 5 × 10 volumes with respect to the amount of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11. When the reaction At the end, the catalyst is filtered and the solvent is evaporated. The product is crystallized by adding 5 ÷ 10 volumes of toluene with respect to the quantity of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11. The suspension it is filtered and the product is dried at 60 ° C for 12 hours under vacuum to obtain Sivelestat 1.

Stadium f

Typically Sivelestat 1 obtained in e) is salified with an inorganic base chosen from sodium hydroxide, sodium carbonate or sodium bicarbonate. Salification is carried out, as known from the literature, in water / tetrahydrofuran at a temperature of 0 ° C Ã · 25 ° C. After the addition of the base, the tetrahydrofuran is evaporated and the suspension obtained is filtered. The product is washed with water and subsequently dried at 25 ° C ÷ 40 ° C for 12 hours under vacuum to obtain Sivelestat sodium salt tetrahydrate 2.

The invention process is particularly advantageous as it is conducted without the isolation of most of the intermediates. In particular, the isolation of intermediates 19, 6 and 11 is avoided. The â € œone potâ € synthesis of the intermediate 6 from sodium 4-hydroxybenzenesulphonate 3 is possible thanks to the solubility of the new intermediate 19 in organic solvent, difference of intermediate 5 of the known processes. In this way, both the esterification with pivaloyl chloride and the reaction with thionyl chloride are carried out with the same solvent, without the need to isolate and dry the intermediate.

The synthesis process is also very advantageous in that the intermediate 10 is synthesized in a single synthesis stage, contrary to the three stages reported in EP 3472168 and EP 539223. Furthermore, isatoic anhydride is a raw material available commercially at very low prices.

The invention is illustrated in detail in the following examples.

Example 1: Sodium 4-Pivaloyloxybenzenesulphonate (5) as per procedure described in EP 3472168, EP 539223 and in Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134

A solution of sodium 4-hydroxybenzenesulphonate (3) (107 g, 0.616 mol), water (300 ml), NaOH (52.8 g, 1.294 mol) and THF (200 ml) is dropped at 0-5 ° C under mechanical stirring in 30 minutes pivaloyl chloride (82.6 g, 0.678 mol). It is left under stirring for 2 hours at 0-5 ° C and is checked by HPLC. At the end of the reaction it is filtered and washed with water (30 ml). It is dried under vacuum at 45 ° C for 16 hours to obtain 126.7 g (73.4%) of a white powdery solid.

LC-MS (APCI +) [M + H] <+>: 281

<1> H-NMR (in D2O) (chemical shifts expressed in ppm with respect to the solvent signal at 4.7 ppm): 1.24 (9H, s, t-but); 7.14 and 7.81 (AAâ € ™ XXâ € ™ system, 4H, aromatic).

<13> C-NMR (ppm): 26.1 (CH3t-but); 38.8; 122.0 (aromatic CH); 127.3 (aromatic CH); 140.4; 152.4; 180.1 (COOR).

FT-IR (UATR, cm <-1>): 2970, 1746, 1591, 1235, 1185, 1117, 1044, 1010, 900, 698.

Example 2: 4- (Chlorosulfonyl) phenyl pivalate (6) as per procedure described in EP 3472168, EP 539223 and in Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134

SO2Cl

OR

6

OR

To a suspension of sodium 4- (pivaloyloxy) benzenesulfonate (5) prepared according to example 1 (1.5 g, 0.0054 mol) in DMF (7 ml) thionyl chloride is dropped at 0-5 ° C in 5 minutes (0.78 g, 0.0065 mol). It is left under stirring at this temperature for 1 hour and then at room temperature for another 30 minutes. It is controlled by HPLC. At the end of the reaction, water (10 ml) is added, filtered and washed abundantly with water. It is dried under vacuum at 45 ° C for 16 hours to obtain 1.2 g (81.6%) of a white solid.

LC-MS (APCI +) [M + H] <+>: 277

<1> H-NMR (in CDCl3) (chemical shifts expressed in ppm with respect to the TMS signal): 1.40 (9H, s, t-but); 7.37 and 8.09 (AA 'XX', 4H, aromatic system).

<13> C-NMR (ppm): 26.8 (CH3t-but); 39.2 122.8 (aromatic CH); 128.7 (aromatic CH); 140.9; 156.2; 175.9 (COOR).

FT-IR (UATR, cm <-1>): 2981, 1748, 1590, 1576, 1479, 1370, 1100, 844, 682.

Example 3: Triethylammonium 4-Pivaloyloxybenzenesulphonate (19)

A solution of sodium 4-hydroxybenzenesulphonate (3) (10 g, 0.049 mol), DCM (50 ml), TEA (10.0 g, 0.098 mol) is dropped at 20-25 ° C under magnetic stirring in about 30 minutes pivaloyl chloride (8.9 g, 0.074 mol). It is left under stirring for 2 hours at 20-25 ° C and is checked by HPLC. At the end of the reaction, water (30 ml) is added. It is separated and the solvent is removed from the organic phase at reduced pressure, obtaining 15.7 g (89%) of transparent oil.

LC-MS (APCI +) [M + H] <+>: 281

<1> H-NMR (in CDCl3) (chemical shifts expressed in ppm with respect to the TMS signal): 1.33 (9H, t, J = 7.4 Hz, CH3TEA); 1.35 (9H, s, t-but); 3.11 (6H, q, J = 7.4 Hz, CH2TEA); 7.04 and 7.88 (AAâ € ™ XXâ € ™ system, 4H, aromatic).

<13> C-NMR (ppm): 8.9 (CH3TEA); 26.7 (C t-but), 27.3 (CH3t-but); 46.2 (CH2TEA) 121.5 (aromatic CH); 127.6 (aromatic CH); 142.9 (C-S); 152.4 (C-O); 177.1 (COOR).

FT-IR (UATR, cm <-1>): 2978, 2704, 2511, 1808, 1746, 1592, 1479,1119, 1005, 898, 696.

Example 4: 4- (Chlorosulfonyl) phenyl pivalate (6) from (19) not isolated

SO2Cl

OR

6

OR

A solution of sodium 4-hydroxybenzenesulphonate (3) (1.0 g, 0.0049 mol), DCM (6 ml), TEA (1.0 g, 0.0098 mol) is dropped at 20-25 ° C under magnetic stirring in about 5 minutes pivaloyl chloride (0.84 g, 0.0069 mol). It is left under stirring for 2 hours at 20-25 ° C and is checked by HPLC. At the end of the reaction, DMF (0.11 g, 0.0015 mol) is added and thionyl chloride (0.77 g, 0.0064 mol) is dropped at 20-25 ° C in 15 minutes. It is left under stirring at this temperature for 2 h and is checked by HPLC. At the end of the reaction the solvent is removed at reduced pressure and toluene is added (10 ml), the salts are filtered and the solvent is concentrated under reduced pressure and 5 ml of n-hexane are added to the residue obtained. It is cooled to 0 ° C and the suspension is filtered, washing the product with n-hexane. 1.1 g (81.1%) of a pale yellow solid are obtained.

Example 5: 2- (2-Aminobenzamido) benzyl acetate (10)

Isatoic anhydride (2.0 g, 0.012) is added to a suspension of glycine benzyl ester hydrochloride (2.5 g, 0.012 mol), acetonitrile (15 ml) and triethylamine (1.3 g, 0.013 mol). mol). The mixture is refluxed for 3 hours and monitored by HPLC. At the end of the reaction the solvent is evaporated and water (10 ml) is added. It is filtered by washing the product with water. The product is dried at 60 ° C under vacuum for 12 hours. 2.92 g (85.6%) of white-pink solid are obtained.

Example 6: 2- (2-Aminobenzamido) benzyl acetate (10)

To a suspension of glycine benzyl ester paratoluenesulfonate (10.0 g, 0.030 mol), acetonitrile (60 ml) and triethylamine (3.3 g, 0.032 mol), isatoic anhydride (5.1 g, 0.030) is added in stirred portions. mol). The mixture is refluxed for 2 hours and monitored by HPLC. At the end of the reaction the solvent is evaporated and water (50 ml) is added. It is filtered by washing the product with water. The product is dried at 60 ° C under vacuum for 12 hours. 7.65 g (89.7%) of white-pink solid are obtained.

Example 7: 2- (2-Aminobenzamido) benzyl acetate (10)

To a suspension of glycine benzyl ester paratoluenesulfonate (100.0 g, 0.296 mol), acetonitrile (500 ml) and triethylamine (31.4 g, 0.311 mol), isatoic anhydride (48.3 g, 0.296 mol). The mixture is refluxed for 2 hours and monitored by HPLC. At the end of the reaction the solvent is evaporated and water (500 ml) is added. It is filtered by washing the product with water (50 ml). The product is dried at 60 ° C under vacuum for 12 hours. 77.5 g (92.1%) of white-pink solid are obtained.

Example 8: 2- (2-Aminobenzamido) benzyl acetate (10)

Isatoic anhydride (2.5 g, 0.015) is added under stirring to a suspension of glycine benzyl ester para-toluenesulfonate (5.0 g, 0.015 mol), water (30 ml) and triethylamine (1.6 g, 0.016 mol). mol). It is left under stirring at room temperature for 6 h and monitored by HPLC. At the end of the reaction it is filtered by washing the product with water. The product is dried at 60 ° C under vacuum for 12 hours. 3.9 g (91.4%) of white-pink solid are obtained.

LC-MS (APCI +) [M + H] <+>: 285

<1> H-NMR (in CD3COCD3) (chemical shifts expressed in ppm with respect to the TMS signal): 4.18 (d, J = 6 Hz, 2H, CH2); 5.20 (s, 2H, -CH2OR); 6.29 (1H, bs, NH2); 6.59 (bt, J = 9 Hz, 1H, aromatic H-4); 6.78 (d, J = 9 Hz, H-3); 7.18 (1H, dt, J = 8.1.5 Hz, aromatic H-4); 7.30 - 7.60 (m, 5H, aromatics); 7.60 (dd, 1H, J = 8.1 Hz, aromatic H-4); 7.90 (1H, bt, NH).

<13> C-NMR (in CD3COCD3) (ppm): 40.6 (CH2); 65.6 (CH2OR); 113.9; 114.6 (aromatic CH); 116.3 (aromatic CH); 127.3 (CH); 127.5 (CH); 127.9 (CH); 131.7 (aromatic CH); 135.9; 149.7; 169.0 (CONR); 169.4 (COOR). mp: 142 ° C

FT-IR (UATR, cm <-1>): 3451, 3339, 2928, 1742, 1635, 1528, 1198, 1166, 971, 750, 739.

Example 9: 4- (N- (2- (2- (Benzyloxy) -2-oxoethylcarbamoyl) phenyl) -sulfamoyl) phenyl pivalate (11)

To a solution of benzyl 2- (2-aminobenzamido) acetate (10), prepared according to example 8, (1.0 g, 0.0035 mol) in pyridine (16 ml), is added in portions at the temperature of 0-5 ° C 4- (chlorosulfonyl) phenyl pivalate (6), prepared according to example 4, (1.2 g, 0.0042 mol). Once the addition is complete, the mixture is brought to 20-25 ° C and left under stirring for 16 hours. 50% sulfuric acid (70 ml) is then added and extracted with ethyl acetate (40 ml). The organic phase is then washed with water (20 ml), 10% sodium bicarbonate (20 ml), water (20 ml) and saturated aqueous solution of NaCl (20 ml). The solvent is evaporated under reduced pressure. It is crystallized from n-hexane (10 ml), filtered and dried at 50 ° C under vacuum. 1.51 g (82.2%) of yellow solid are obtained.

Example 10: 4- (N- (2- (2- (Benzyloxy) -2-oxoethylcarbamoyl) phenyl) -sulfamoyl) phenyl pivalate (11)

To a suspension of benzyl 2- (2-aminobenzamido) acetate (10), prepared according to example 8, (1.4 g, 0.0049 mol) in dichloromethane (9 ml) and pyridine (1.2 g, 0.015 mol), a solution of 4- (chlorosulfonyl) phenyl pivalate (6), prepared according to example 4, (1.4 g, 0.0049 mol) is dropped in about 30 minutes at 20-25 ° C dichloromethane (7 ml). It is left under stirring for 3 hours and monitored by HPLC. At the end of the reaction, water (10 ml) is added and separated. The organic phase is then washed with 10% hydrochloric acid (10 ml) and saturated aqueous solution of NaCl (10 ml). It crystallizes from isopropylether (10 ml). It is filtered and dried under vacuum at 40 ° C. 2.3 g (89.5%) of white solid are obtained.

LC-MS (APCI +) [M + H] <+>: 525

<1> H-NMR (in CD3COCD3) (chemical shifts expressed in ppm with respect to the TMS signal): 1.33 (9H, s, t-but); 4.18 (d, J = 6 Hz, 2H, CH2); 5.25 (s, 2H, -CH2OR); 7.15 (dt, J = 8, 1.5 Hz, 1H, aromatic); 7.30 â € “7.80 (m, 8H, aromatic); 7.33 and 7.80 (AA 'XX', 4H, aromatic system); 8.41 (1H, bt, NH); 11.33 (1H, bs, NH).

<13> C-NMR (in CD3COCD3) (ppm): 27.5 (CH3t-but); 40.1; 42.5 (CH2); 67.6 (CH2OR); 121.7 (aromatic CH); 122.0; 123.8 (aromatic CH); 124.9 (aromatic CH); 129.2 (aromatic CH); 129.3 (aromatic CH); 129.4 (aromatic CH); 129.7 (aromatic CH); 130.1 (aromatic CH); 134.1 (aromatic CH); 137.4; 137.8; 140.3; 155.9; 170.3 (CONHR 170.3 (COOR); 177.0 (COOR).

mp: 135 ° C

FT-IR (UATR, cm <-1>): 3423, 2976, 1748, 1638, 1493, 1154, 1091, 935, 753.

Example 11: Sivelestat (1)

A mixture of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) -sulfamoyl) phenyl pivalate (11), obtained according to example 9, (1.0 g, 0.0019 mol), methanol (11 ml) and 10% Pd / C (0.11 g) are left under stirring in a hydrogen atmosphere (1 atm) at 20-25 ° C for 3 h. The solvent is filtered and removed under reduced pressure. 0.77 g (93.3%) of white solid are obtained.

Example 12: Sivelestat (1)

A mixture of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) -sulfamoyl) phenyl pivalate (11), obtained according to example 10, (2.0 g, 0.0038 mol), methanol (20 ml) and 10% Pd / C (0.20 g) are loaded into a steel autoclave and left under stirring in a hydrogen atmosphere (3 atm) at 20-25 ° C for 2 hours. The filter is filtered and washed abundantly with methanol. The solvent is replaced with toluene (7 ml). It is left under stirring at 0-5 ° C for about 30 minutes. 1.56 g (94.5%) of white solid are obtained.

LC-MS (APCI +) [M + H] <+>: 435

<1> H-NMR (in DMSO) (chemical shifts expressed in ppm with respect to the TMS signal): 1.27 (9H, s, t-but); 3.91 (d, J = 6 Hz, 2H, CH2); 7.16 (dt, J = 8.1.5 Hz, 1H, aromatic H-4); 7.45 â € “7.55 (2H, m, H-5 and H-6 aromatic); 7.30 and 7.83 (AAâ € ™ XXâ € ™ system, 4H, aromatic); 7.75 (bd, 1H, J = 8 Hz, aromatic H-3); 9.27 (1H, bt, NH); 11.80 (2H, broad, NH and COOH).

<13> C-NMR (in DMSO) (ppm): 26.6 (CH3t-but); 38.7; 41.3 (CH2); 119.4 (aromatic CH); 120.2; 122.8 (aromatic CH); 123.5 (aromatic CH); 128.5 (aromatic CH); 128.7 (aromatic CH); 132.8 (aromatic CH); 135.9; 138.4; 154.1; 168.5 (CONR); 170.8 (COOH); 175.8 (COOR).

mp: 211-213 ° C

FT-IR (UATR, cm <-1>): 3431, 2979, 1747, 1718, 1645, 1521, 1152, 1104, 926, 756.

Example 13: Sivelestat (1) from (19), (6) and (11) not isolated

A solution of sodium 4-hydroxybenzenesulphonate (3) (0.50 g, 0.0025 mol), DCM (3 ml), TEA (0.50 g, 0.0049 mol) is dropped at 20-25 ° C under magnetic stirring in about 5 minutes pivaloyl chloride (0.42 g, 0.0035 mol). It is left under stirring for 2 hours at 20-25 ° C and is checked by HPLC. At the end of the reaction add DMF (0.055 g, 0.00075 mol) and thionyl chloride (0.39 g, 0.0032 mol) is dropped at 20-25 ° C in 15 minutes. It is left under stirring at this temperature for 2 h and is checked by HPLC. At the end of the reaction the solvent is eliminated under reduced pressure and toluene is added (5 ml), the salts are filtered and dichloromethane (3 ml) is added.

The solution thus obtained is then dropped into a suspension of benzyl 2- (2-aminobenzamido) acetate (10), prepared according to example 8, (0.5 g, 0.0018 mol) in dichloromethane (4 ml) and pyridine (0.43 g, 0.0054 mol), in about 30 minutes at 20-25 ° C. It is left under stirring for 3 hours and monitored by HPLC. At the end of the reaction, water (5 ml) is added and separated. The organic phase is then washed with 10% hydrochloric acid (5 ml) and saturated aqueous solution of NaCl (5 ml). The solvent is replaced with methanol (10 ml) and 10% Pd / C (0.10 g) is added The suspension is loaded into a laboratory autoclavine in steel and left under stirring in a hydrogen atmosphere (3 atm) at 20- 25 ° C for 2 hours. The filter is filtered and washed abundantly with methanol. The solvent is replaced with toluene (3 ml). It is left under stirring at 0-5 ° C for about 30 minutes. 0.80 g (73.6%) of white solid are obtained.

Example 14: Sivelestat sodium tetrahydrate (2)

To a solution of Sivelestat (1), obtained according to example 12, (0.93 g, 0.0021 mol) in THF (5 ml), 5N NaOH (0.44 ml, 0.0022 mol). The mixture is left under stirring at this temperature 15 'and the solvent is removed under reduced pressure. The residue is crystallized from water (4 ml). It is filtered at 0-5 ° C and washed with cold water. It is dried at 25 ° C under vacuum. 0.83 g (74.8%) of white solid are obtained.

Example 15: Sivelestat sodium tetrahydrate from Sivelestat of example 13 To a solution of Sivelestat (1), obtained according to example 13, (0.60 g, 0.0014 mol) in THF (3 ml) is dropped to 0-5 ° C 5N NaOH (0.29 ml, 0.0014 mol). The mixture is left under stirring at this temperature for 1 h and the solvent is removed under reduced pressure. The residue is crystallized from water (3 ml). It is filtered at 0-5 ° C and washed with cold water. It is dried at 25 ° C under vacuum. 0.60 g (84.1%) of white solid are obtained.

LC-MS (APCI +) [M + H] <+>: 435

<1> H-NMR (in DMSO) (chemical shifts expressed in ppm with respect to the TMS signal): 1.28 (9H, s, t-but); 3.91 (s, 2H, CH2); 6.70 (bt, J = 8 Hz, 1H, aromatic H-4); 7.11 (1H, dt, J = 8.1.5 Hz, aromatic H-5); 7.14 and 7.76 (AAâ € ™ XXâ € ™ system, 4H, aromatic); 7.30 (1H, bd, J = 8 Hz, aromatic H-6); 7.84 (bd, 1H, J = 8 Hz, aromatic H-3); 10.90 (1H, bs, NH).

[2.50 ppm: dmso, 4.20 - 4.50: H2O)

<13> C-NMR (in DMSO) (ppm): 26.6 (CH3t-but); 38.6; 42.1 (CH2); 118.2 (aromatic CH); 119.4 (aromatic CH); 121.5; 121.8 (aromatic CH); 128.0 (aromatic CH); 129.6 (aromatic CH); 131.1 (aromatic CH); 141.6; 146.0; 152.2; 167.2 (CONR); 171.9 (COO-); 176.0 (COOR).

FT-IR (UATR, cm <-1>): 3439, 3303, 2979, 1754, 1624, 1586, 1547, 1271, 1152, 1123, 941, 751.

KF: 13.6%

Claims (5)

CLAIMS 1. Process for the preparation of sivelestat and its tetrahydrate sodium salt, which includes: a) reaction of sodium 4-hydroxybenzenesulfonate 3 with pivaloyl chloride in the presence of an organic base to produce the corresponding 4-pivaloyloxybenzenesulphonate salt; b) reaction of the 4-pivaloyloxybenzenesulfonate salt with a halogenating agent to produce 4- (halosulfonyl) phenyl pivalate; c) reaction of isatoic anhydride with benzyl glycinate to produce 2- (2-aminobenzamido) benzyl acetate 10; d) reaction of 2- (2-aminobenzamido) benzyl acetate 10 with 4- (halosulfonyl) phenyl pivalate to produce 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11; e) debenzylation reaction of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11 to produce Sivelestat 1; f) salification of Sivelestat 1 to produce Sivelestat sodium salt tetrahydrate 2. 2. Process according to claim 1 wherein the organic base of step a) is an alkyl, aryl or alkyl-aryl amine. 3. Process according to claim 2 wherein the amine is triethylamine. 4. Process according to any one of claims 1 to 3 wherein in step b) thionyl chloride, oxalyl chloride, phosphorus oxychloride, preferably thionyl chloride, are used as halogenating agent. 5. Process according to any one of claims 1 to 4 wherein in step c) benzyl glycinate in the form of base or one of its salts is used. 6. Triethylammonium 4-Pivaloyloxybenzenesulphonate.