JP2011051974A - Method for synthesizing sivelestat - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for conveniently synthesizing Sivelestat, a human neutrophil elastase inhibitor to be applied to treating acute pneumonia accompanying a systemic inflammatory response syndrome. <P>SOLUTION: The method of preparing Sivelestat (1), 2-(2-(4-(pivaloyloxy)phenylsulfonamido)benzamido)acetic acid, includes starting from sodium 4-hydroxybenzenesulfonate and isatoic anhydride. The method is conducted without isolating most intermediates and is particularly advantageous in terms of yields and productivity. Furthermore, the resulting Sivelestat is highly pure and can be conveniently transformed into Sivelestat sodium tetrahydrate. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a process for preparing civerestat (1), ie 2- (2- (4- (pivaloyloxy) phenylsulfonamido) benzamide) acetic acid, starting from sodium 4-hydroxybenzenesulfonate and isatoic anhydride. .

Cibelestat is a human neutrophil elastase that is indicated for the treatment of acute lung inflammation with systemic inflammatory response syndrome. More particularly, sivelestat sodium tetrahydrate is used for treatment. The synthesis of cibelestat is disclosed in EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134 (Ono Pharmaceutical Co., Ltd.). The main synthesis scheme of cibelestat is reported below.
Synthesis of sivelestat sodium tetrahydrate by EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134

  This method is based on a convergent synthesis in which intermediates 6 and 10 are obtained separately from the respective starting materials sodium 4-hydroxybenzenesulfonate 3 and 2-nitrobenzoic acid 7. Intermediate 6 reacts with intermediate 10 to give intermediate 11, which is then debenzylated to give sivelestat, which is then salified in the presence of water to give the tetrahydrate. Sodium salt 2 can be obtained. The method includes seven synthetic steps besides the final salification. Known methods include isolating and drying all intermediates, thereby affecting efficiency and productivity and greatly impacting the labor costs of the final product. The overall yield is less than 22% starting from sodium 4-hydroxybenzenesulfonate 3 and the process of synthesis of intermediate 5 is particularly low in yield and unsatisfactory for industrial processes. Furthermore, the synthesis of intermediate 5 is carried out in water and the next step (using thionyl chloride for the preparation of intermediate 6) is incompatible with water, so it is essential to recover and dry intermediate 5. For this reason, the process time is very long and the productivity is inefficient.

JP 09040692 (Ono Pharmaceutical Co., Ltd.) discloses a procedure for the synthesis of sivelestat and its tetrahydrate sodium salt according to the following scheme.
・ Synthesis of sivelestat sodium tetrahydrate according to JP 0904092

  The synthesis of cibelestat disclosed in JP 9040692 includes five synthesis steps in addition to the final salification. Compared to the synthetic procedure disclosed in EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134, one of the two starting materials for synthesis (2-nitrobenzoic acid 7) is Is replaced by commercially available anthranilic acid 12, which simplifies the process in terms of the number of steps, but the carboxyl group of glycine 14 in the state of trimethylsilyl derivative 15 using trimethylsilyl chloride, which is relatively expensive to react. It needs to be protected.

Another procedure for the synthesis of cibelestat and its tetrahydrate sodium salt disclosed in the patent application IN 2007MU01508 (Macleods Pharmaceuticals Ltd.) is reported in the following scheme.
・ Synthesis of sivelestat sodium tetrahydrate by IN 2007MU01508

  The synthesis includes six steps in addition to salification. This method involves the use of trimethylsilyl chloride, similar to that described in JP 9040692.

The following publications disclose methods for the preparation of sivelestat, sodium salt and tetrahydrate sodium salt as in 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.
・ Synthesis of Cibelestat. Zhongguo Yaowu Huaxue Zazhi (2006), 16 (2), 79-81, 111.
Hecheng Huaxue (2004), 12 (6), 580-582 describes a process for the preparation of sivelestat sodium salt based on the same synthetic scheme as JP 09040692.

European Patent No. 3472168 European Patent No. 539223 Specification Japanese Patent Laid-Open No. 09-040692 IN 2007MU01508

Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134 Huaxue Shijie (2004), 45 (1), 29-31, 25 Nanjing Gongye Daxue Xuebao, Ziran Kexueban (2005), 27 (1), 89-92 Zhongguo Yiyao Gongye Zazhi (2003), 34 (8), 369-370. 399 Zhongguo Yaowu Huaxue Zazhi (2006), 16 (2), 79-81, 111 Hecheng Huaxue (2004), 12 (6), 580-582

It has now been discovered that cyberestat and sivelestat sodium tetrahydrate can be prepared in an easy-to-use manner by the novel synthetic procedure reported below.
Synthesis of sivelestat sodium tetrahydrate according to the present invention

  The method of the present invention includes the following steps.

a) reacting sodium 4-hydroxybenzenesulfonate 3 with pivaloyl chloride in the presence of an organic base to obtain the corresponding 4-pivaloyloxybenzenesulfonate salt;
b) reacting the 4-pivaloyloxybenzenesulfonate obtained in a) with a halogenating agent to give 4- (halosulfonyl) phenyl pivalate;
c) reacting isatoic anhydride with benzyl glycinate to obtain 2- (2-aminobenzamido) acetic acid benzyl 10;
d) Benzyl 2- (2-aminobenzamido) acetate 10 is reacted with 4- (halosulfonyl) phenyl pivalate to give 4- (N- (2- (2- (benzyloxy) -2-oxoethyl) pivalate Obtaining carbamoyl) phenyl) sulfamoyl) phenyl 11;
e) a step of debenzylating 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl 11 of pivalic acid to obtain sivelestat 1; and
f) A step of chlorinating sivelestat 1 to obtain sivelestat tetrahydrate sodium salt 2.

  Alkyl, aryl or alkyl-arylamines such as triethylamine, benzylamine and the like are preferably used as the organic base.

  In this case, the synthesis of alkyl, aryl and alkyl-aryl ammonium 4-pivaloyloxybenzene sulfonates is carried out in an organic solvent, preferably an aromatic solvent such as toluene, in the presence of an organic base, preferably triethylamine. , Chlorinated solvents such as dichloromethane, and mixtures thereof. If triethylamine is used, intermediate 19 is obtained.

  The synthesis of 4- (halosulfonyl) phenyl pivalate is carried out using conventional halogenating agents such as thionyl chloride, oxalyl chloride, phosphorus oxychloride, preferably thionyl chloride. If thienyl chloride is used, intermediate 6 is obtained.

  Synthesis of benzyl 2- (2-aminobenzamido) acetate 10 is carried out using benzyl glycinate or a commercially available salt thereof such as hydrochloride or p-toluenesulfonate as a base.

  Intermediate 19 is novel and is also the subject of the present invention.

According to a preferred embodiment of the present invention, the method is performed as follows.
Step a
Typically, sodium 4-hydroxybenzenesulfonate 3 is added in the presence of 1.5-3.0 equivalents, preferably 2.0-2.5 equivalents of an organic base, preferably triethylamine, 1.0-2.0 equivalents, preferably 1.0-1.5 equivalents. React with pivaloyl chloride. The reaction is carried out in an aromatic solvent such as toluene, a chlorinated solvent such as dichloromethane, and mixtures thereof, preferably dichloromethane, preferably at a temperature between 0 ° C. and 40 ° C., preferably between 20 ° C. and 30 ° C. 2 to 15 volumes, preferably 4 to 8 volumes of solvent are used relative to the amount of sodium 4-hydroxybenzenesulfonate 3. The reaction is monitored by HPLC analysis using a C18 column and 0.05M monobasic phosphate buffer / acetonitrile as phase eluent. After completion of the reaction, triethylammonium 4-pivaloyloxybenzenesulfonate 19 can be obtained as an oil and can be stored for several days. Alternatively, according to a preferred embodiment of the present invention, the resulting solution is used directly in step b.

2-15 volumes of water are added, the phases are separated and the organic phase is concentrated until the solvent is completely removed to give 4-pivaloyloxybenzenesulfonic acid triethylammonium salt 19 as an oil. Triethylammonium 4-pivaloyloxybenzenesulfonate 19 is obtained as an oil.
Step b
Typically, triethylammonium 4-pivaloyloxybenzenesulfonate 19 from step a) (isolated as an oil or directly from the final reaction solution) is added to a catalytic amount (0.3 eq) of N, 1.0-3.0 equivalents, preferably 1.2-1.6 equivalents of thionyl chloride in an aromatic solvent such as toluene, a chlorinated solvent such as dichloromethane, and mixtures thereof, preferably dichloromethane, in the presence of N-dimethylformamide. Or preferably it can be reacted with oxalyl chloride. When using thionyl chloride, the reaction is carried out at a temperature between 0 ° C. and 40 ° C., preferably between 20 ° C. and 30 ° C., whereas when using oxalyl chloride, the reaction is carried out at a temperature between 0 ° C. and 10 ° C. 2 to 10 volumes, preferably 4 to 6 volumes of solvent are used relative to the amount of triethylammonium 4-pivaloyloxybenzenesulfonate 19. The reaction is monitored by HPLC analysis using a C18 column and 0.05M monobasic phosphate buffer / acetonitrile as phase eluent. After completion of the reaction, the intermediate 4- (chlorosulfonyl) phenyl pivalate 6 can be recovered as a solid and optionally dried, or the resulting solution can be used directly in step d.

The intermediate 4- (chlorosulfonyl) phenyl pivalate 6 is recovered as a solid upon evaporation of the solvent; if dichloromethane is used, the residue is dissolved in toluene and the suspension is filtered. When using toluene, after completion of the reaction, the turbid solution is filtered, and the resulting clear solution is concentrated and crystallized from n-hexane. The suspension is filtered and the product is dried under reduced pressure at 40 ° C. for 12 hours.
Process c
Typically, isatoic anhydride 4 is reacted with about 1 equivalent of benzyl glycinate as the free base or a salt thereof, such as the hydrochloride or paratoluenesulfonate, preferably paratoluenesulfonate. When benzyl glycinate is used as its salt, 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. 1 to 15 volumes, preferably 5 to 10 volumes of solvent are used relative to the amount of isatoic anhydride 4. The reaction is monitored by HPLC analysis using a C18 column and 0.05M monobasic phosphate buffer / acetonitrile as phase eluent. After completion of the reaction, if present, the organic solvent is removed by evaporation and 5 to 10 volumes of water are added to the amount of isatoic anhydride 4. The suspension is filtered, and the product is dried under reduced pressure at 60 ° C. for 12 hours to give 2- (2-aminobenzamido) benzyl acetate 10, which is collected and dried to a solid.
Step d
Typically, the intermediate from step c), benzyl 2- (2-aminobenzamido) acetate 10, is obtained directly from the final solution in step b), or the isolated intermediate 6 is like toluene. It is reacted with about 1 equivalent of 4- (chlorosulfonyl) phenyl pivalate obtained by dissolving in an aromatic solvent, a chlorinated solvent such as dichloromethane or a mixture thereof, preferably dichloromethane. The reaction is carried out in the presence of an organic base such as pyridine or triethylamine at a temperature of 0 ° C to 35 ° C, preferably 20 ° C to 25 ° C. The solvent is used in an amount of 2 to 15 volumes, preferably 5 to 10 volumes, relative to the amount of the intermediate 10-benzyl 2- (2-aminobenzamido) acetate. The reaction is monitored by HPLC analysis using a C18 column and 0.05M monobasic phosphate buffer / acetonitrile as phase eluent. After the reaction is complete, water is added and the phases are separated. The organic phase is washed with 10% hydrochloric acid and then with a saturated aqueous sodium chloride solution. The organic solvent is concentrated under reduced pressure. The resulting residue can be dissolved in 2-15 volumes of an alcohol solvent such as methanol and used directly in step e), or the residue is crystallized by addition of 2-10 volumes of diisopropyl ether. The suspension was filtered and the product was dried under reduced pressure at 60 ° C. for 12 hours to give 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate 11 is collected and dried to a solid.
Process e
Typically, the intermediate pivalate 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) obtained directly from the concentrated solution after evaporation of the solvent prior to isolation in d) The) sulfamoyl) phenyl 11 or isolated intermediate 11 is reacted under a hydrogen atmosphere in the presence of a metal catalyst, preferably Pd. The reaction is carried out in an alcohol solvent, preferably methanol, at a temperature of 10-60 ° C, preferably 20-25 ° C. 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl 11 pivalate 3 to 15 volumes, preferably 5 to 10 volumes, of solvent are used . After completion of the reaction, the catalyst is filtered off and the solvent is evaporated off. The product is crystallized by adding 5-10 volumes of toluene to the amount of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl 11 pivalate. Turn into. The suspension is filtered and the product is dried at 60 ° C. under reduced pressure for 12 hours to give Siberestat 1.
Process f
Typically, sivelestat 1 obtained in e) is salified with an inorganic base selected from sodium hydroxide, sodium carbonate or sodium bicarbonate. The salification is carried out at temperatures between 0 ° C. and 25 ° C. in water / tetrahydrofuran, as is known from the literature. After the addition of the base, the tetrahydrofuran is evaporated off and the resulting suspension is filtered. The product is washed with water and subsequently dried under reduced pressure at 25 ° C. to 40 ° C. for 12 hours to obtain sivelestat tetrahydrate sodium salt 2.

  The process of the present invention is particularly advantageous because it is carried out without isolation of most intermediates. In particular, the isolation of intermediates 19, 6 and 11 is avoided. A “one-pot” synthesis of intermediate 6 from sodium 4-hydroxybenzenesulfonate 3 can be performed because the novel intermediate 19 is soluble in organic solvents, contrary to the intermediate 5 of the known method. . Thus, both esterification with pivaloyl chloride and reaction with thionyl chloride can be performed using the same solvent without the need to isolate and dry the intermediate.

  This synthesis method is also very advantageous in that the intermediate 10 is synthesized in a single synthesis step compared to the three steps as disclosed in EP 3472168 and EP 539223. In addition, isatoic anhydride is a relatively inexpensive commercial starting material.

  The invention is illustrated in detail by the following examples.

Example 1
Sodium 4-pivaloyloxybenzenesulfonate (5) following the procedure disclosed in EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134

Addition of a solution of sodium 4-hydroxybenzenesulfonate (3) (107 g, 0.616 mol), water (300 ml), NaOH (52.8 g, 1.294 mol) and THF (200 ml) to pivaloyl chloride (82.6 g, 0.678 mol) Is carried out dropwise at 0-5 ° C. with mechanical stirring for 30 minutes. The mixture was kept stirring at 0-5 ° C. for 2 hours while monitoring by HPLC. After completion of the reaction, the mixture is filtered, washed with water (30 ml) and dried under reduced pressure at 45 ° C. for 16 hours to give 126.7 g (73.4%) of a white powdery solid.
LC-MS (APCI +) [M + H] ⁺ : 281
¹ H-NMR (in D ₂ O) (chemical shift expressed in ppm relative to the solvent signal at 4.7 ppm): 1.24 (9H, s, t-but); 7.14 and 7.81 (system AA'XX ', (4H, aromatic)
¹³ C-NMR (ppm): 26.1 (CH ₃ t-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) following the procedure disclosed in EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134

Addition of a suspension of sodium 4- (pivaloyloxy) benzenesulfonate (5) (1.5 g, 0.0054 mol) prepared according to Example 1 in DMF (7 ml) to thionyl chloride (0.78 g, 0.0065 mol) Perform dropwise at 0-5 ° C for 5 minutes. The mixture is kept stirring at this temperature for 1 hour while monitoring by HPLC, and then at room temperature for an additional 30 minutes. At the end of the reaction, water (10 ml) is added and the mixture is filtered, washed thoroughly with water and then dried under vacuum at 45 ° C. for 16 hours to give 1.2 g (81.6%) of a white solid.
LC-MS (APCI +) [M + H] ⁺ : 277
¹ H-NMR (in CDCl ₃ ) (chemical shift expressed in ppm relative to TMS signal): 1.40 (9H, s, t-but); 7.37 and 8.09 (system AA'XX ', 4H, aromatic)
¹³ C-NMR (ppm): 26.8 (CH ₃ t-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)
4-Pivaloyloxybenzenesulfonic acid triethylammonium salt (19)

Addition of a solution of sodium 4-hydroxybenzenesulfonate (3) (10 g, 0.049 mol), DCM (50 ml) and TEA (10.0 g, 0.098 mol) to pivaloyl chloride (8.9 g, 0.074 mol) Perform dropwise at about 30 minutes under magnetic stirring at ℃. The mixture is kept stirred at 20-25 ° C. for 2 hours while monitoring by HPLC. After completion of the reaction, water (30 ml) is added, the organic phase is separated and the solvent is removed by evaporation under reduced pressure to give 15.7 g (89%) of a clear oil.
LC-MS (APCI +) [M + H] ⁺ : 281
¹ H-NMR (in CDCl ₃ ) (chemical shift expressed in ppm relative to TMS signal): 1.33 (9H, t, J = 7.4 Hz, CH ₃ TEA); 1.35 (9H, s, t-but) 3.11 (6H, q, J = 7.4Hz, CH ₂ TEA); 7.04 and 7.88 (series AA'XX ', 4H, aromatic)
¹³ C-NMR (ppm): 8.9 (CH ₃ TEA); 26.7 (C t-but), 27.3 (CH ₃ t-but); 46.2 (CH ₂ TEA); 121.5 (aromatic CH); 127.6 (aromatic CH); 142.9 (CS); 152.4 (CO); 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 from non-isolated (19) (6)

  Add a solution of sodium 4-hydroxybenzenesulfonate (3) (1.0 g, 0.0049 mol), DCM (6 ml) and TEA (1.0 g, 0.0098 mol) to pivaloyl chloride (0.84 g, 0.0069 mol) 20-25 Perform dropwise at about 5 minutes with magnetic stirring. The mixture is kept stirred at 20-25 ° C. for 2 hours while monitoring by HPLC. After completion of the reaction, DMF (0.11 g, 0.0015 mol) is added and thionyl chloride (0.77 g, 0.0064 mol) is added dropwise at 20-25 ° C. over 15 minutes. The mixture is kept stirred at this temperature for 2 hours while monitoring by HPLC. After completion of the reaction, the solvent is evaporated off under reduced pressure, toluene (10 ml) is added, the salt is filtered off and the solvent is concentrated under reduced pressure. To the resulting residue is added 5 ml of n-hexane, then cooled to 0 ° C., the resulting suspension is filtered and the product is washed with n-hexane. 1.1 g (81.1%) of a pale yellow solid are obtained.

(Example 5)
2- (2-Aminobenzamide) benzyl acetate (10)

  Add a suspension of glycine benzyl ester hydrochloride (2.5 g, 0.012 mol), acetonitrile (15 ml) and triethylamine (1.3 g, 0.013 mol) to isatoic anhydride (2.0 g, 0.012 mol) with little Do this by adding one by one. The mixture is refluxed for 3 hours as monitored by HPLC. After completion of the reaction, the solvent is removed by evaporation and water (10 ml) is added. The mixture is filtered and the product is washed with water. The product is dried at 60 ° C. under reduced pressure for 12 hours. 2.92 g (85.6%) of a white peach colored solid are obtained.

(Example 6)
2- (2-Aminobenzamide) benzyl acetate (10)

  Addition of a suspension of glycine benzyl ester p-toluenesulfonate (10.0 g, 0.030 mol), acetonitrile (60 ml) and triethylamine (3.3 g, 0.032 mol) to isatoic anhydride (5.1 g, 0.030 mol) under stirring It is done by adding little by little. The mixture is refluxed for 2 hours as monitored by HPLC. After completion of the reaction, the solvent is evaporated off and water (50 ml) is added. The mixture is filtered and the product is washed with water and then dried under reduced pressure at 60 ° C. for 12 hours. 7.65 g (89.7%) of a white peach solid is obtained.

(Example 7)
2- (2-Aminobenzamide) benzyl acetate (10)

  The addition of a suspension of glycine benzyl ester p-toluenesulfonate (100.0 g, 0.296 mol), acetonitrile (500 ml) and triethylamine (31.4 g, 0.311 mol) to isatoic anhydride (48.3 g, 0.296 mol) Perform by adding little by little with stirring. The mixture is refluxed for 2 hours as monitored by HPLC. After completion of the reaction, the solvent is evaporated off and water (500 ml) is added. The mixture is filtered and the product is washed with water (50 ml) and then dried under reduced pressure at 60 ° C. for 12 hours. 77.5 g (92.1%) of a white peach solid is obtained.

(Example 8)
2- (2-Aminobenzamide) benzyl acetate (10)

Addition of a suspension of glycine benzyl ester p-toluenesulfonate (5.0 g, 0.015 mol), water (30 ml) and triethylamine (1.6 g, 0.016 mol) to isatoic anhydride (2.5 g, 0.015 mol) under stirring To add to. The mixture is kept stirred at room temperature for 6 hours while monitoring by HPLC. After the reaction is complete, the mixture is filtered and the product is washed with water and then dried at 60 ° C. under reduced pressure for 12 hours. 3.9 g (91.4%) of a white peach solid is obtained.
LC-MS (APCI +) [M + H] ⁺ : 285
¹ H-NMR (in CD ₃ COCD ₃ ) (chemical shift expressed in ppm relative to the TMS signal): 4.18 (d, J = 6 Hz, 2H, CH ₂ ); 5.20 (s, 2H, -CH ₂ OR) 6.29 (1H, bs, NH ₂ ); 6.59 (bt, J = 9Hz, 1H, H-4 aromatic); 6.78 (d, J = 9Hz, H-3); 7.18 (1H, dt, J = 8 , 1.5Hz, H-4 aromatic); 7.30-7.60 (m, 5H, aromatic); 7.60 (dd, 1H, J = 8, 1Hz, H-4 aromatic); 7.90 (1H, bt, NH)
¹³ C-NMR (in CD ₃ COCD ₃ ) (ppm): 40.6 (CH ₂ ); 65.6 (CH ₂ OR); 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)
Melting point: 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 (11) pivalic acid

  A solution of benzyl 2- (2-aminobenzamido) acetate (10) (1.0 g, 0.0035 mol) prepared according to Example 8 in pyridine (16 ml) 4- (4- (pivalic acid) prepared according to Example 4 Addition to (chlorosulfonyl) phenyl (6) (1.2 g, 0.0042 mol) is done in small portions at a temperature of 0-5 ° C. After the addition is complete, the mixture is warmed to 20-25 ° C., kept stirring for 16 hours, 50% sulfuric acid (70 ml) is 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 NaCl (20 ml). The solvent is evaporated off under reduced pressure. The residue is crystallized from n-hexane (10 ml), filtered and dried at 50 ° C. under reduced pressure. 1.51 g (82.2%) of yellow product is obtained.

(Example 10)
4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl (11) pivalic acid

Implementation of a suspension of benzyl 2- (2-aminobenzamido) acetate (10) (1.4 g, 0.0049 mol) prepared according to Example 8 in dichloromethane (9 ml) and pyridine (1.2 g, 0.015 mol) The addition to a solution of 4- (chlorosulfonyl) phenyl pivalate (6) (1.4 g, 0.0049 mol) prepared according to Example 4 in dichloromethane (7 ml) was added dropwise at 20-25 ° C. in about 30 minutes. Do. The mixture is kept stirring for 3 hours while monitoring by HPLC. After the reaction is complete, water (10 ml) is added and the phases are separated. The organic phase is then washed with 10% hydrochloric acid (10 ml) and saturated aqueous NaCl (10 ml). The mixture is crystallized from isopropyl ether (10 ml), filtered and dried at 40 ° C. under reduced pressure. 2.3 g (89.5%) of a white solid is obtained.
LC-MS (APCI +) [M + H] ⁺ : 525
¹ H-NMR (in CD ₃ COCD ₃ ) (chemical shift expressed in ppm relative to the TMS signal): 1.33 (9H, s, t-but); 4.18 (d, J = 6Hz, 2H, CH ₂ ); 5.25 (s, 2H, -CH ₂ OR); 7.15 (dt, J = 8, 1.5Hz, 1H, aromatic); 7.30-7.80 (m, 8H, aromatic); 7.33 and 7.80 (system AA'XX ' , 4H, aromatic); 8.41 (1H, bt, NH); 11.33 (1H, bs, NH)
¹³ C-NMR (in CD ₃ COCD ₃ ) (ppm): 27.5 (CH ₃ t-but); 40.1; 42.5 (CH ₂ ); 67.6 (CH ₂ OR); 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)
Melting point: 135 ° C
FT-IR (UATR, cm ^-1 ): 3423, 2976, 1748, 1638, 1493, 1154, 1091, 935, 753
(Example 11)
Cibelestat (1)

  Pivalic acid 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl (11) (1.0 g, 0.0019 mol), methanol (11 ml) obtained according to Example 9 ) And 10% Pd / C (0.11 g) are kept under stirring at 20-25 ° C. under a hydrogen atmosphere (1 atm) for 3 hours. The mixture is filtered and the solvent is evaporated off under reduced pressure. 0.77 g (93.3%) of a white solid is obtained.

(Example 12)
Cibelestat (1)

Pivalic acid 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl (11) (2.0 g, 0.0038 mol), methanol (20 ml) obtained according to Example 10 ) And 10% Pd / C (0.20 g) are placed in a steel autoclave and kept stirring at 20-25 ° C. under a hydrogen atmosphere (3 atm) for 2 hours. The mixture is filtered and the filter is washed thoroughly with methanol. Methanol is replaced with toluene (7 ml) as solvent. The mixture is kept stirred at 0-5 ° C. for about 30 minutes. 1.56 g (94.5%) of a white solid is obtained.
LC-MS (APCI +) [M + H] ⁺ : 435
¹ H-NMR (in DMSO) (chemical shift expressed in ppm relative to the TMS signal): 1.27 (9H, s, t-but); 3.91 (d, J = 6Hz, 2H, CH ₂ ); 7.16 (dt , J = 8, 1.5Hz, 1H, H-4 aromatic); 7.45-7.55 (2H, m, H-5 and H-6 aromatic); 7.30 and 7.83 (system AA'XX ', 4H, aromatic ); 7.75 (bd, 1H, J = 8Hz, H-3 aromatic); 9.27 (1H, bt, NH); 11.80 (2H, broad, NH eCOOH)
¹³ C-NMR (in DMSO) (ppm): 26.6 (CH ₃ t-but); 38.7; 41.3 (CH ₂ ); 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)
Melting point: 211-213 ℃
FT-IR (UATR, cm ^-1 ): 3431, 2979, 1747, 1718, 1645, 1521, 1152, 1104, 926, 756
(Example 13)
Cibelestat (1) from non-isolated (19), (6) and (11)

  Addition of a solution of sodium 4-hydroxybenzenesulfonate (3) (0.50 g, 0.0025 mol), DCM (3 ml) and TEA (0.50 g, 0.0049 mol) to pivaloyl chloride (0.42 g, 0.0035 mol) Perform dropwise at 20-25 ° C. with stirring for about 5 minutes. The mixture is kept stirred at 20-25 ° C. for 2 hours while monitoring by HPLC. After the reaction is complete, DMF (0.055 g, 0.00075 mol) is added, and then thionyl chloride (0.39 g, 0.0032 mol) is added dropwise at 20-25 ° C. over 15 minutes. The mixture is kept stirred at this temperature for 2 hours while monitoring by HPLC. After the reaction is complete, the solvent is evaporated off under reduced pressure, toluene (5 ml) is added, the salt is filtered off and dichloromethane (3 ml) is added. The resulting solution was then dissolved in 2- (2-aminobenzamido) benzyl acetate (10) (0.5 g, 0.0018 mol) prepared according to Example 8 in dichloromethane (4 ml) and pyridine (0.43 g, 0.0054 mol). Is added dropwise at 20 to 25 ° C. over about 30 minutes. The mixture is kept stirring for 3 hours while monitoring by HPLC. After the reaction is complete, water (5 ml) is added and the mixture is separated. The organic phase is then washed with 10% hydrochloric acid (5 ml) and saturated aqueous NaCl (5 ml). The solvent is replaced with methanol (10 ml) and 10% Pd / C (0.10 g) is added. The suspension is placed in a steel laboratory autoclave and stirring is continued for 2 hours at 20-25 ° C. under a hydrogen atmosphere (3 atm). The mixture is filtered and the filter is washed thoroughly with methanol. Replace the solvent with toluene (3 ml). The mixture is kept stirred at 0-5 ° C. for about 30 minutes. 0.80 g (73.6%) of a white solid is obtained.

(Example 14)
Cibelestat sodium tetrahydrate (2)

  Addition of a solution of Siverestat (1) obtained according to Example 12 (0.93 g, 0.0021 mol) in THF (5 ml) to 5N NaOH (0.44 ml, 0.0022 mol) dropwise at 0-5 ° C. Do. The mixture is kept stirred for 15 minutes at this temperature and then the solvent is evaporated off under reduced pressure. The residue is crystallized from water (4 ml), then filtered at 0-5 ° C, washed with cold water and dried at 25 ° C under reduced pressure. 0.83 g (74.8%) of a white solid is obtained.

(Example 15)
Sivelestat sodium tetrahydrate from Siberestat in Example 13

Addition of a solution of Siverestat (1) obtained in Example 13 (0.60 g, 0.0014 mol) in THF (3 ml) to 5N NaOH (0.29 ml, 0.0014 mol) dropwise at 0-5 ° C. To do. The mixture is kept stirring at this temperature for 1 hour and then the solvent is evaporated off under reduced pressure. The residue is crystallized from water (3 ml), filtered at 0-5 ° C, washed with cold water and dried at 25 ° C under reduced pressure. 0.60 g (84.1%) of a white solid is obtained.
LC-MS (APCI +) [M + H] ⁺ : 435
¹ H-NMR (in DMSO) (chemical shift expressed in ppm relative to the TMS signal): 1.28 (9H, s, t-but); 3.91 (s, 2H, CH2); 6.70 (bt, J = 8 Hz , 1H, H-4 aromatic); 7.11 (1H, dt, J = 8, 1.5Hz, H-5 aromatic); 7.14 and 7.76 (system AA'XX ', 4H, aromatic); 7.30 (1H, bd, J = 8Hz, H-6 aromatic); 7.84 (bd, 1H, J = 8Hz, H-3 aromatic); 10.90 (1H, bs, NH)
(2.50ppm: dmso, 4.20-4.50: H ₂ O)
¹³ C-NMR (in DMSO) (ppm): 26.6 (CH ₃ t-but); 38.6; 42.1 (CH ₂ ); 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 (6)

A process for preparing sivelestat and its tetrahydrate sodium salt, comprising:
a) Reaction of sodium 4-hydroxybenzenesulfonate 3 with pivaloyl chloride in the presence of an organic base to give the corresponding 4-pivaloyloxybenzenesulfonate,
b) Reaction of 4-pivaloyloxybenzene sulfonate with a halogenating agent to give 4- (halosulfonyl) phenyl pivalate,
c) Reaction of isatoic anhydride with benzyl glycinate to give benzyl 2- (2-aminobenzamido) acetate 10;
d) Benzyl 2- (2-aminobenzamido) acetate 10 is reacted with 4- (halosulfonyl) phenyl pivalate to give 4- (N- (2- (2- (benzyloxy) -2-oxoethyl) pivalate Reaction to give carbamoyl) phenyl) sulfamoyl) phenyl 11;
e) Debenzylation reaction of pivalic acid 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl 11 to give siberestat 1 and
f) Chlorination comprising the step of chlorinating sivelestat 1 to obtain sivelestat tetrahydrate sodium salt 2.   The process according to claim 1, wherein the organic base of step a) is alkyl, aryl or alkyl-arylamine.   The process of claim 2 wherein the amine is triethylamine.   The process according to any of claims 1 to 3, wherein in step b) thionyl chloride, oxalyl chloride or phosphorus oxychloride is used as the halogenating agent, preferably oxalyl chloride or thionyl chloride.   The method according to any one of claims 1 to 4, wherein in step c) benzyl glycinate or a salt thereof is used as a base.   Triethylammonium 4-pivaloyloxybenzenesulfonate.