KR20110013293A - Process for the synthesis of sivelestat - Google Patents
Process for the synthesis of sivelestat Download PDFInfo
- Publication number
- KR20110013293A KR20110013293A KR1020100073263A KR20100073263A KR20110013293A KR 20110013293 A KR20110013293 A KR 20110013293A KR 1020100073263 A KR1020100073263 A KR 1020100073263A KR 20100073263 A KR20100073263 A KR 20100073263A KR 20110013293 A KR20110013293 A KR 20110013293A
- Authority
- KR
- South Korea
- Prior art keywords
- phenyl
- mol
- benzyl
- solvent
- aromatic
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
Abstract
Description
The present invention relates to 2- (2- (4- (pivaloyloxy) phenylsulfonamido) benzamido) acetic acid (2-, starting from sodium 4-hydroxybenzenesulfonate and isatoic anhydride) The present invention relates to a method for preparing Sibelesstat (1), which is (2- (4- (pivaloyloxy) phenylsulfonamido) benzamido) acetic acid).
Cibelesat is a human neutrophil elastase that is prescribed for the treatment of acute pulmonary inflammation associated with inflammatory systemic response syndrome. More precisely, Cibelestate Sodium Tetrahydrate is used for this treatment.
The synthesis of Cibelesat is disclosed in EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134 (Ono Pharmaceutical Co., Ltd).
A summary of the main synthesis of Cibelestat is reported as follows:
The synthesis method is based on the convergence synthesis of intermediates (6) and (10) separately obtained from the starting materials sodium 4-hydroxybenzenesulfonate (3) and 2-nitrobenzene acid (7), respectively. Intermediate (6) is reacted with intermediate (10) to give intermediate (11), which is fmf then debenzylate to give Cibelest, which is then chlorided in the presence of water to give tetra Hydrate sodium salt (2) may be provided. The method includes seven synthetic steps in addition to the final salification. Known methods include the isolation and drying of all intermediates, which greatly affects the labor cost of the final product and affects efficiency and productivity. Overall yield is lower than 22% starting with sodium 4-hydroxybenzenesulfonate (3); The step for the synthesis of intermediate (5) has a particularly low yield, which is unsatisfactory for industrial processes. In addition, the synthesis of the intermediate (5) is carried out in water: the following steps (with thionyl chloride for the preparation of the intermediate (6)) are incompatible with water, so it is essential to recover and dry the intermediate (5) And therefore entails a very long process time and production inefficiency.
JP 09040692 (Ono Pharmaceutical Co., Ltd.) discloses a process for the synthesis of cebelesate and its tetrahydrate sodium salt according to the following reaction scheme:
The synthesis of the Sibelesate disclosed in JP 9040692 includes five synthetic steps in addition to the final chloride. Compared to the synthetic methods disclosed in EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), 2115-2134, one of two starting materials for synthesis (2-nitrobenzoic acid (7)) is commercially available. Form of trimethylsilyl derivative (15) using trimethylsilyl chloride, which is a relatively expensive reactant, although the process is simpler in terms of the number of steps replaced with commercially available anthranilic acid (12). It requires a step of protection.
Another method for the synthesis of cibelesatate and its tetrahydrate sodium salts disclosed in patent application IN 2007MU01508 (Macleods Pharmaceuticals Ltd) is reported in the following reaction scheme:
The synthesis includes six steps in addition to chloride. Similar to that described in JP 9040692, the method involves the use of trimethylsilyl chloride.
The following publications disclose methods for the preparation of cibelesat and its sodium salt and tetrahydrate sodium salt similar to those of the first reaction 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 describe a method for the preparation of cibelesate sodium salt based on the same as the synthetic scheme of JP 09040692.
It has been found that the Cibelestate and Cibelestate Sodium Tetrahydrates can be conveniently prepared by the novel synthesis procedure reported below:
The method of the present invention includes:
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 salt obtained in step a) with a halogenating agent to obtain 4- (halosulfonyl) phenyl pivalate;
c) reacting isatoic anhydride with benzyl glycinate to obtain benzyl 2- (2-aminobenzamido) acetate (10)
d) benzyl 2- (2-aminobenzamido) acetate (10) with 4- (halosulfonyl) phenyl pivalate to react 4- (N- (2- (2- (benzyloxy) -2-oxo Obtaining ethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate (11);
e) Debenzylation of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate (11) to give Cibelesstat (1) Making;
f) the Cibelestate tetrahydrate sodium salt (2) by chlorideing the Cibelestate (1) Obtaining.
Preferably alkyl amines, aryl amines or alkyl-aryl amines such as triethylamine, benzylamine and the like are used as the organic base.
In this case, the synthesis of alkyl, aryl and alkyl-aryl ammonium 4-pivaloyloxybenzenesulfonate salts is carried out in the presence of an organic base, preferably triethylamine, in an aromatic solvent such as an organic solvent, preferably toluene, In 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, preferably thionyl chloride, such as thionyl chloride, oxalyl chloride, phosphorus oxychloride. If thienyl chloride is used, intermediate (6) is obtained.
The synthesis of benzyl 2- (2-aminobenzamido) acetate (10) is carried out using benzyl glycinate or its commercially available salts such as hydrochloride or p-toluenesulfonate as base.
Intermediate 19 is novel and is an object of the present invention.
According to a preferred embodiment of the invention, the process of the invention is carried out as follows:
Step a
Typically 1.0 to 2.0 equivalents of pivaloyl chloride in the presence of sodium 4-hydroxybenzenesulfonate (3) in an amount comprising from 1.5 to 3.0 equivalents, preferably from 2.0 to 2.5 equivalents, of an organic base, preferably triethylamine Preferably it is reacted with 1.0-1.5 equivalents. The reaction is carried out in an aromatic solvent such as toluene, a chlorinated solvent such as dichloromethane and mixtures thereof, preferably in dichloromethane at a temperature of 0 ° C.-40 ° C., preferably 20 ° C.-30 ° C. 2-15 volumes of solvent, preferably 4-8 volumes, are used for the amount of sodium 4-hydroxybenzenesulfonate (3). The reaction is monitored by HPLC analysis using 0.05M monobasic phosphate buffer / acetonitrile with a C18 column and phase eluent. After the reaction is completed, triethylammonium 4-pivaloyloxy benzenesulfonate (19) can be obtained as an oil which can be stored for several days. Alternatively, according to a preferred embodiment of the invention, the resulting solution is used directly in step b.
Add 2-15 volumes of water, separate the phases and concentrate the organic phase until the solvent is completely removed to give triethylammonium 4-pivaloyloxybenzenesulfonate salt (19) as an oil.
Step b
Usually, in an aromatic solvent such as toluene, chlorinated solvent such as dichloromethane and mixtures thereof, preferably in dichloromethane, in the presence of a catalytic amount of N, N-dimethylformamide (0.3 equiv), separated as an oil, or the final reaction Triethylammonium 4-pivaloyloxybenzenesulfonate (19) from step a, derived directly from the solution, with 1.0-3.0 equivalents, preferably 1.2-1.6 equivalents of thionyl chloride or preferably oxalyl chloride Can react. When using thionyl chloride, the reaction is carried out at a temperature of 0 ° C to 40 ° C, preferably 20 ° C to 30 ° C; On the other hand, when using oxalyl chloride, the reaction is carried out at a temperature of 0 ℃ ~ 10 ℃. 2 to 10 volumes, preferably 4 to 6 volumes of solvent are used for the amount of triethylammonium 4-pivaloyloxybenzenesulfonate (19). The reaction is monitored by HPLC analysis using 0.05M monobasic phosphate buffer / acetonitrile with C18 column and phase eluent. After completion of the reaction, 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.
Intermediate 4- (chlorosulfonyl) phenyl pivalate (6) is recovered as a solid after evaporation of the solvent; If dichloromethane is used, the residue is dissolved in toluene and the suspension is filtered. If toluene is used, after completion of the reaction, the turbidity is filtered and the resulting clear solution is concentrated to crystallize from n-hexane. The suspension is filtered and the product is dried at 40 ° C. for 12 h under vacuum.
Step c
Typically, isatoic anhydride 4 is reacted with about 1 equivalent of hydrochloride or benzyl glycinate as a free base or salt thereof, such as para-toluenesulfonate, preferably para-toluenesulfonate. When benzyl glycinate is used in the form of its salts, the reaction is carried out in an organic solvent such as acetonitrile or in water, preferably water, in the presence of an organic base such as triethylamine, at a temperature of 20 ° C. to 100 ° C. do. 1-15 volumes, preferably 5-10 volumes of solvent are used for the amount of isatoic anhydride 4. The reaction is monitored by HPLC analysis using 0.05M monobasic phosphate buffer / acetonitrile with C18 column and phase eluent. After completion of the reaction, the organic solvent is evaporated, if any, and 5-10 volumes of water is added to the amount of isatoic anhydride 4. The suspension is filtered and the product is dried under vacuum at 60 ° C. for 12 hours to give recovered and solid dried benzyl 2- (2-aminobenzamido) acetate (10).
Step d
Typically, the intermediate benzyl 2- (2-aminobenzamido) acetate (10) from step c is obtained directly from the final solution in step b or the isolated intermediate (6) is prepared with an aromatic solvent such as toluene, dichloromethane. Reaction is carried out with about 1 equivalent of 4- (chlorosulfonyl) phenyl pivalate (6) dissolved in the same chlorinated solvent, or mixtures 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. 2-15 volumes, preferably 5-10 volumes of solvent are used for the amount of intermediate benzyl 2- (2-aminobenzamido) acetate (10). The reaction is monitored by HPLC analysis using 0.05M monobasic phosphate buffer / acetonitrile with C18 column and phase eluent. After the reaction is completed, water is added and the phases are separated. The organic phase is washed with 10% hydrochloric acid and washed with saturated aqueous sodium chloride solution. The organic solvent is concentrated under reduced pressure. The resulting residue can be dissolved in 2-15 volumes of alcohol solvent, such as methanol, and used directly in step e or the residue is crystallized by the addition of 2-10 volumes of diisopropyl ether. The suspension was filtered and the product dried under vacuum at 60 ° C. for 12 hours to recover and dry to solid (4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfa. Moyl) phenyl pivalate (11) is obtained.
Step e
Intermediate 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) -phenyl) sulfamoyl) obtained in step d directly from the concentrated solution, usually after evaporation of the solvent before separation Phenyl pivalate (11) or isolated intermediate (11) is reacted in the presence of a metal catalyst, preferably Pd, in a hydrogen atmosphere. The reaction is carried out in an alcohol solvent, preferably methanol, at a temperature of 10 to 60 ° C., preferably 20 to 25 ° C. 3-15 volumes, preferably 5-10, to the amount of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate (11) Use a volume of solvent. After completion of the reaction, the catalyst is filtered off and the solvent is evaporated. The product was added by addition of 5-10 volumes of toluene to the amount of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate (11). Crystallize. The suspension is filtered and the product is dried under vacuum at 60 ° C. for 12 hours to give Cibelesat (1).
Step f
Typically the Cibelestate (1) obtained from step e is chlorided with an inorganic base selected from sodium hydroxide, sodium carbonate or sodium bicarbonate. The chloride is carried out in water / tetrahydrofuran at a temperature of 0 ° C.-25 ° C. as can be seen in the literature. After addition of the base, tetrahydrofuran is evaporated and the resulting suspension is filtered. The product is washed with water and then dried under vacuum at 25 ° C.-40 ° C. for 12 hours to give the Cibelestate tetrahydrate sodium salt (2).
The process of the invention is particularly advantageous because it is carried out without the need to isolate most intermediates. In particular, isolation of intermediates (19), (6) and (11) is avoided. The "one pot" synthesis of intermediate (6) from sodium 4-hydroxybenzenesulfonate (3) differs from the solubility in organic solvents of the novel intermediate (19), unlike intermediate (5) of the known process. Thanks to this. Thus esterification with pivaloyl chloride and reaction with thionyl chloride can be achieved without the need to isolate and dry the intermediate in the same solvent.
The present synthesis method is also very advantageous in that the intermediate 10 is synthesized in a single synthesis step compared to the three steps disclosed in EP 3472168 and EP 539223. Isatoic anhydride is also a rather inexpensive and commercially available starting material.
The invention is illustrated in more detail by the following examples.
Example One: EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), sodium 4- according to the method disclosed in 2115-2134 Pivaloyloxybenzenesulfonate (5)
Pivaloyl chloride (82.6 g, in 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) 0.678 mol) was droppedwise for 30 minutes with mechanical stirring at 0-5 ° C. The mixture was stirred at 0-5 ° C. for 2 hours while monitoring by HPLC. After completion of the reaction, the mixture was filtered, washed with water (30 ml) and dried under vacuum at 45 ° C. for 16 hours to give 126.7 g (73.4%) of white powder solid.
LC-MS (APCI +) [M + H] + : 281
1 H-NMR (in D 2 O) (chemical shift is given in ppm relative to the signal of the solvent at 4.7 ppm): 1.24 (9H, s , t- but); 7.14 and 7.81 (system AA'XX '4H, directional).
13 C-NMR in 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: EP 3472168, EP 539223 and Biorganic & Medicinal Chemistry (1996), 4 (12), 4- (according to the method disclosed in 2115-2134). Chlorosulfonyl ) Phenyl Pivalate (6)
Thionyl chloride (0.78) for 5 minutes at 0-5 ° C. in a suspension of sodium 4- (pivaloyloxy) benzenesulfonate ( 5) (1.5 g, 0.0054 mol) prepared according to Example 1 in DMF (7 ml). g, 0.0065 mol) was added dropwise. The mixture was stirred for 1 hour at the same temperature while monitoring by HPLC and for 30 minutes at room temperature. After completion of the reaction, water was added (10 ml), the mixture was filtered, washed thoroughly with water and 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 (CDCl 3 Medium) (chemical shifts are given in ppm relative to the signal of TMS): 1.40 (9H, s , t- but); 7.37 and 8.09 (system AA'XX '4H, directional).
13 C-NMR in 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: Triethylammonium 4- Pivaloyloxybenzenesulfonate (19)
To a solution of sodium 4-hydroxybenzenesulfonate ( 3 ) (10 g, 0.049 mol), DCM (50 ml), TEA (10.0 g, 0.098 mol) was added 20-pivaloyl chloride (8.9 g, 0.074 mol). It was added dropwise for about 30 minutes with magnetic stirring at 25 ℃. The mixture was stirred at 20-25 ° C. for 2 hours while monitoring by HPLC. After completion of the reaction, water was added (30 ml), the organic phase was separated and the solvent was evaporated under reduced pressure to give 15.7 g (89%) of a clear oil.
LC-MS (APCI +) [M + H] + : 281
1 H-NMR (CDCl 3 Medium) (chemical shifts are given in ppm relative to the signal of TMS): 1.33 (9H, t , J = 7.4 Hz, CH 3 TEA); 1.35 (9H, s , t -but); 3.11 (6H, q, J = 7.4 Hz, CH 2 TEA); 7.04 and 7.88 (system AA'XX '4H, directional).
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 (C- S ); 152.4 (CO); 177.1 (COOR).
FT-IR (UATR, cm −1 ): 2978, 2704, 2511, 1808, 1746, 1592, 1479,1119, 1005, 898, 696.
Example 4: Not isolated 4- from 19 Chlorosulfonyl ) Phenyl Pivalate (6)
To a solution of sodium 4-hydroxybenzenesulfonate ( 3 ) (1.0 g, 0.0049 mol), DCM (6 ml), TEA (1.0 g, 0.0098 mol) was added 20-pivaloyl chloride (0.84 g, 0.0069 mol). At 25 ° C., dropwise added for about 5 minutes with magnetic stirring. The mixture was stirred at 20-25 ° C. for 2 hours while monitoring by HPLC. After completion of the reaction, DMF (0.11 g, 0.0015 mol) was added and thionyl chloride (0.77 g, 0.0064 mol) was then added dropwise at 20-25 ° C. for 15 minutes. The mixture was stirred at the same temperature for 2 hours while monitoring by HPLC. After completion of the reaction, the solvent was evaporated under reduced pressure, toluene (10 ml) was added and the salts were filtered off and the solvent was concentrated under reduced pressure. 5 ml of n-hexane was added to the resulting residue, then cooled to 0 ° C., the resulting suspension was filtered and the product washed with n-hexane. 1.1 g (81.1%) of a pale yellow solid were obtained.
Example 5: benzyl 2- (2- Aminobenzamido Acetate (10)
Isatoic anhydride (2.0 g, 0.012 mol) was added portionwise with stirring a suspension of glycine benzyl ester hydrochloride (2.5 g, 0.012 mol), acetonitrile (15 ml) and triethylamine (1.3 g, 0.013 mol). The mixture was refluxed for 3 hours while monitoring by HPLC. After completion of the reaction, the solvent was evaporated and water was added (10 ml). The mixture was filtered and the product washed with water. The product was dried under vacuum at 60 ° C. for 12 hours. 2.92 g (85.6%) of white-pink solid were obtained.
Example 6: benzyl 2- (2- Aminobenzamido Acetate (10)
To a suspension of glycine benzyl ester para-toluenesulfonate (10.0 g, 0.030 mol), acetonitrile (60 ml) and triethylamine (3.3 g, 0.032 mol), slowly stirring isatoic anhydride (5.1 g, 0.030 mol) with stirring Added. The mixture was refluxed for 2 hours while monitoring by HPLC. After completion of the reaction, the solvent was evaporated and water was added (50 ml). The mixture was filtered and the product was washed with water and then dried at 60 ° C. for 12 h under vacuum. 7.65 g (89.7%) of a pinkish solid were obtained.
Example 7: benzyl 2- (2- Aminobenzamido Acetate (10)
Mechanical stirring of isatoic anhydride (48.3 g, 0.296 mol) in a suspension of glycine benzyl ester para-toluenesulfonate (100.0 g, 0.296 mol), acetonitrile (500 ml) and triethylamine (31.4 g, 0.311 mol) Little by little while adding. The mixture was refluxed for 2 hours while monitoring by HPLC. After completion of the reaction, the solvent was evaporated and water was added (500 ml). The mixture was filtered and the product washed with water (50 ml) and dried at 60 ° C. for 12 h under vacuum. 77.5 g (92.1%) of a pinkish solid were obtained.
Example 8: benzyl 2- (2- Aminobenzamido Acetate (10)
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) was added with stirring isatoic anhydride (2.5 g, 0.015 mol). . The mixture was stirred at rt for 6 h while monitoring by HPLC. After completion of the reaction, the mixture was filtered and the product was washed with water and then dried under vacuum at 60 ° C. for 12 hours. 3.9 g (91.4%) of a pink solid were obtained.
LC-MS (APCI +) [M + H] + : 285
1 H-NMR (CD 3 COCD 3 Medium) (chemical shifts are given in ppm relative to the signal of TMS): 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 = 9 Hz, 1H, H-4 directional); 6.78 ( d , J = 9 Hz, H-3); 7.18 (1H, doublet of doublets , J = 8, 1.5 Hz, H-4 directional); 7.30-7.60 ( m , 5H, directional); 7.60 ( dd , 1H, J = 8, 1 Hz, H-4 directional); 7.90 (1 H, bt , NH).
13 C-NMR (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 ℃
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 ) - Sulfa Mole ) Phenyl Pivalate (11)
4- (chlorosulfonyl) prepared according to Example 4 in a solution of benzyl 2- (2-aminobenzamido) acetate ( 10 ) (1.0 g, 0.0035 mol) prepared according to Example 8 in pyridine (16 ml) ) Phenyl pivalate ( 6 ) (1.2 g, 0.0042 mol) was added in portions at 0-5 ° C. After the addition was complete, the mixture was warmed to 20-25 ° C. and stirred for 16 h, 50% sulfuric acid (70 ml) was added and extracted with ethyl acetate (40 ml). The organic phase was then washed with water (20 ml), 10% sodium bicarbonate (20 ml), water (20 ml) and saturated aqueous NaCl solution (20 ml). The solvent was evaporated under reduced pressure, the residue was crystallized from n-hexane (10 ml), filtered and dried at 50 ° C. under vacuum. 1.51 g (82.2%) of a yellowish material were obtained.
Example 10: 4- (N- (2- (2- ( Benzyloxy )-2- Oxoethylcarbamoyl ) Phenyl ) - Sulfa Mole ) Phenyl Pivalate (11)
Dichloromethane in 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) A solution of 4- (chlorosulfonyl) phenyl pivalate ( 6 ) (1.4 g, 0.0049 mol) prepared according to Example 4 in (7 ml) was added dropwise at 20-25 ° C. for about 30 minutes. The mixture was stirred for 3 h while monitoring by HPLC. After completion of the reaction, water was added (10 ml) and the phases were separated. The organic phase was then washed with 10% hydrochloric acid (10 ml) and saturated aqueous NaCl solution (10 ml). The mixture was crystallized from isopropyl ether (10 ml), filtered and dried in vacuo at 40 ° C. 2.3 g (89.5%) of a white solid were obtained.
LC-MS (APCI +) [M + H] + : 525
1 H-NMR (CD 3 COCD 3 Medium) (chemical shifts are given in ppm relative to the signal of TMS): 1.33 (9H, s , t- but); 4.18 ( d , J = 6 Hz, 2H, CH 2 ); 5.25 ( s , 2H, -CH 2 OR); 7.15 ( dt , J = 8, 1.5 Hz, 1H, directional); 7.30-7.80 ( m , 8H, aromatic); 7.33 and 7.80 (system AA'XX '4H, directional); 8.41 (1H, bt , NH); 11.33 (1 H, bs , NH).
13 C-NMR (CD 3 COCD 3 Medium) (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 ℃
FT-IR (UATR, cm −1 ): 3423, 2976, 1748, 1638, 1493, 1154, 1091, 935, 753.
Example 11: Cibelestat (One)
4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) -sulfamoyl) phenyl pivalate ( 11 ) obtained according to example 9 (1.0 g, 0.0019 mol) , A mixture of methanol (11 ml) and 10% Pd / C (0.11 g) was stirred at 20-25 ° C. under hydrogen atmosphere (1 atm) for 3 hours. The mixture was filtered and the solvent was evaporated under reduced pressure. 0.77 g (93.3%) of a white solid were obtained.
Example 12: Cibelestat (One)
4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) -sulfamoyl) phenyl pivalate ( 11 ) (2.0 g, 0.0038 mol) obtained according to Example 10. , A mixture of methanol (20 ml) and 10% Pd / C (0.20 g) was placed in a steel autoclave and stirred at 20-25 ° C. under hydrogen atmosphere (3 atm) for 2 hours. The mixture was filtered and the filter was washed thoroughly with methanol. The solvent was replaced with toluene (7 ml) in methanol. The mixture was stirred at 0-5 ° C. for about 30 minutes. 1.56 g (94.5%) of white solid were obtained.
LC-MS (APCI +) [M + H] + : 435
1 H-NMR (in DMSO) (chemical shift is given in ppm relative to the signal of TMS): 1.27 (9H, s , t- but); 3.91 ( d , J = 6 Hz, 2H, CH 2 ); 7.16 ( dt , J = 8, 1.5 Hz, 1H, H-4 directional); 7.45-7.55 (2H, m , H-5 and H-6 aromatics); 7.30 and 7.83 (system AA'XX '4H, directional); 7.75 ( bd , 1H, J = 8 Hz, H-3 directional); 9.27 (1H, bt , NH); 11.80 (2H, broad (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: from unisolated (19), (6) and (11) Cibelestat (One)
To a solution of sodium 4-hydroxybenzenesulfonate ( 3 ) (0.50 g, 0.0025 mol), DCM (3 ml), TEA (0.50 g, 0.0049 mol) add pivaloyl chloride (0.42 g, 0.0035 mol) to 20-. It was added dropwise for about 5 minutes with magnetic stirring at 25 ℃. The mixture was stirred at 20-25 ° C. for 2 hours while monitoring by HPLC. After completion of the reaction, DMF (0.055 g, 0.00075 mol) was added, and thionyl chloride (0.39 g, 0.0032 mol) was then added dropwise at 20-25 ° C. for 15 minutes. The mixture was stirred at the same temperature for 2 hours while monitoring by HPLC. After completion of the reaction, the solvent was evaporated under reduced pressure and toluene (5 ml) was added, the salt was filtered off and dichloromethane (3 ml) was added. The resulting solution was benzyl 2- (2-aminobenzamido) -acetate ( 10 ) suspension (0.5 g, 0.0018 mol) prepared according to Example 8 in dichloromethane (4 ml) and pyridine (0.43 g, 0.0054 mol). ) Was added dropwise at 20-25 ° C. for about 30 minutes. The mixture was stirred for 3 h while monitoring by HPLC. After completion of the reaction, water was added (5 ml) and the mixture was separated. The organic phase was then washed with 10% hydrochloric acid (5 ml) and saturated aqueous NaCl solution (5 ml). The solvent was replaced with methanol (10 ml) and 10% Pd / C (0.10 g) was added. The suspension was placed in a steel laboratory autoclave and stirred at 20-25 ° C. under hydrogen gas (3 atm). The mixture was filtered and the filter washed thoroughly with methanol. The solvent was replaced with toluene (3 ml). The mixture was stirred at 0-5 ° C. for about 30 minutes. 0.80 g (73.6%) of a white solid were obtained.
Example 14: Cibelestat Sodium Tetrahydrate (2)
To a solution of Cibelestat (1) (0.93 g, 0.0021 mol) obtained according to Example 12 in THF (5 ml) was added dropwise 5N NaOH (0.44 ml, 0.0022 mol) at 0-5 ° C. The mixture was stirred at the same temperature for 15 minutes, after which the solvent was evaporated under reduced pressure. The residue was crystallized from water (4 ml), then filtered at 0-5 ° C., washed with cold water and dried at 25 ° C. under vacuum. 0.83 g (74.8%) of a white solid were obtained.
Example 15: Example 13's From Cibelestat Cibelestat Sodium Tetrahi Drate
To a solution of Cibelestat (1) (0.60 g, 0.0014 mol) obtained according to Example 13 in THF (3 ml) was added dropwise 5N NaOH (0.29 ml, 0.0014 mol) at 0-5 ° C. The mixture was stirred at the same temperature for 1 hour, after which the solvent was evaporated under reduced pressure. The residue was crystallized from water (3 ml), filtered at 0-5 ° C., washed with cold water and dried at 25 ° C. under vacuum. 0.60 g (84.1%) of a white solid were obtained.
LC-MS (APCI +) [M + H] + : 435
1 H-NMR (in DMSO) (chemical shifts are given in ppm relative to the signal of TMS): 1.28 (9H, s , t- but); 3.91 ( s , 2 H, CH 2 ); 6.70 ( bt , J = 8 Hz, 1H, H-4 directional); 7.11 (1H, doublet of doublets , J = 8, 1.5 Hz, H-5 directional); 7.14 and 7.76 (system AA'XX '4H, directional); 7.30 (1H, bd , J = 8 Hz, H-6 directional); 7.84 ( bd , 1H, J = 8 Hz, H-3 directional); 10.90 (1H, bs , NH).
(2.50 ppm: 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)
b) reacting the 4-pivaloyloxybenzenesulfonate salt with a halogenating agent to yield 4- (halosulfonyl) phenyl pivalate;
c) reacting isatoic anhydride with benzyl glycinate to obtain benzyl 2- (2-aminobenzamido) acetate (10);
d) benzyl 2- (2-aminobenzamido) acetate (10) with 4- (halosulfonyl) phenyl pivalate to react 4- (N- (2- (2- (benzyloxy) -2-oxo Obtaining ethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate (11);
e) Debenzylation of 4- (N- (2- (2- (benzyloxy) -2-oxoethylcarbamoyl) phenyl) sulfamoyl) phenyl pivalate (11) to give sievelesate (1) Obtaining;
f) chlorideing the Cibelestate (1) to obtain the Cibelestate tetrahydrate sodium salt (2);
Cibelesate and its tetrahydrate sodium salt production method comprising a.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2009A001363A IT1395124B1 (en) | 2009-07-30 | 2009-07-30 | PROCESS FOR SIVELESTAT SYNTHESIS |
| ITMI2009A001363 | 2009-07-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20110013293A true KR20110013293A (en) | 2011-02-09 |
Family
ID=41728480
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020100073263A KR20110013293A (en) | 2009-07-30 | 2010-07-29 | Process for the synthesis of sivelestat |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP5746484B2 (en) |
| KR (1) | KR20110013293A (en) |
| IT (1) | IT1395124B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116354855B (en) * | 2022-11-10 | 2024-02-02 | 江苏百奥信康医药科技有限公司 | Preparation method of cilansetrot sodium |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0320253A (en) * | 1988-06-13 | 1991-01-29 | Ono Pharmaceut Co Ltd | Para-substituted phenyl pivalate derivatives, their production and elastase inhibitor containing the same |
| EP0539223A1 (en) * | 1991-10-25 | 1993-04-28 | Ono Pharmaceutical Co., Ltd. | Glycine derivative monosodium salt tetrahydrate having an inhibitory effect on elastase |
| JPH05194366A (en) * | 1991-10-25 | 1993-08-03 | Ono Pharmaceut Co Ltd | Glycine derivative-monosodium salt-tetrahydrate, its production, medicine containing the same and production of intermediate for the same derivative |
-
2009
- 2009-07-30 IT ITMI2009A001363A patent/IT1395124B1/en active
-
2010
- 2010-07-29 KR KR1020100073263A patent/KR20110013293A/en not_active Application Discontinuation
- 2010-07-29 JP JP2010170367A patent/JP5746484B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2011051974A (en) | 2011-03-17 |
| ITMI20091363A1 (en) | 2011-01-31 |
| IT1395124B1 (en) | 2012-09-05 |
| JP5746484B2 (en) | 2015-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI797082B (en) | Novel Diphenylmethane Protectant | |
| CN104540807B (en) | For the method preparing pyrazole carboxylic acid derivant | |
| JP2014205682A (en) | Method for manufacture of pharmaceutically active compounds | |
| JP2015180665A (en) | Synthetic intermediate of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthoamide and pharmaceutically acceptable salt and application of the same | |
| RU2742005C2 (en) | Methods for producing 4-alkoxy-3-(acyl or alkyl)oxypicolinamides | |
| KR20200100048A (en) | New alkyldiphenylmethane protective agent | |
| JP4299677B2 (en) | Method for producing combretastatin | |
| JP6726801B2 (en) | Method for preparing avibactam preparation material compound represented by formula II | |
| KR20110013293A (en) | Process for the synthesis of sivelestat | |
| WO2018032586A1 (en) | Method for synthesizing 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid, and intermediates thereof | |
| KR100663167B1 (en) | Process for preparing itopride hydrochloride | |
| KR20230043107A (en) | Method for preparing aminofuran | |
| EP0490970B1 (en) | New route of synthesis for protected nitrogen mustard prodrugs | |
| CN112272665A (en) | Process for preparing sitagliptin | |
| EP1002798A1 (en) | An improved process for preparing a therapeutically active pyrazolopyrimidinone derivative | |
| CN110878097B (en) | Preparation method of feigninib | |
| EP1698611A1 (en) | Process for producing phenylacetic acid derivative | |
| JPH0759558B2 (en) | Process for producing 1,3-dialkylpyrazole-4-aldehydes | |
| JP3526606B2 (en) | Method for producing N-substituted pyrazinecarboxamides | |
| JPS60139672A (en) | Production of amide derivative | |
| JPH0759557B2 (en) | Method for producing 1,3-dialkylpyrazole-4-aldehyde derivative | |
| JP2023512000A (en) | Process for the production of haloalkyl-substituted pyridine compounds | |
| JP2002265426A (en) | Dicarboxylic acid diester derivative and method for producing the same | |
| JPS58164573A (en) | Manufacture of 1-(4-chlorobenzoyl)-5-methoxy- 2-methyl-3-indole acetoxyacetic acids | |
| JPH054987A (en) | Production of pyrazolopyridine derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E601 | Decision to refuse application |