A process for the preparation of salcaprozate sodium

Abstract

The present invention provides a process for the preparation of Salcaprozate sodium of Formula-I having high yield and purity. The present invention also provides a process for the purification of Salcaprozic acid of Formula-II having high yield and purity.

Description

[0001] A PROCESS FOR THE PREPARATION OF SALCAPROZATE SODIUM

[0002] FIELD OF THE INVENTION:

[0003] The present invention relates to an efficient and industrially advantageous process for the preparation of Salcaprozate sodium of Formula-I.

[0004] The present invention also relates to process for the purification of Salcaprozic acid of Formula-II.

[0005] BACKGROUND OF THE INVENTION:

[0006] Salcaprozate sodium is chemically known as Sodium A-[8-(2- hydroxybenzoyl)amino]caprylate (SNAC), having the structure of Formula-I.

[0007] [Formula-I]

[0008] Salcaprozic acid or a salt thereof has been developed by Emisphere Technologies, Inc. Salcaprozate sodium is commonly used as a pharmaceutically acceptable excipient for the preparation of pharmaceutical dosage form, for example it is used as an excipient for the preparation of dosage form of Semaglutide.

[0009] The US patent number US 5650386 (hereinafter US ‘386) firstly discloses Salcaprozic acid or a salt thereof. US ‘386 also discloses process for preparation of Salcaprozic acid comprising reacting cyclooctanone with hydroxylamine- O- sulfonic acid in presence of formic acid to obtain 2-azacyclononanone. Resulting 2-azacyclononanone further reacts with O-acetylsalicyloyl chloride in presence of aqueous sodium hydroxide followed by recrystallization using 65% methanol and water to obtain Salcaprozic acid having 42% yield.

[0010] US ‘386 process suffer from the major drawback such as, during reaction of 2- azacyclononanone with O-acetylsalicyloyl chloride, 8-[[8-[(2-hydroxybenzoyl)amino]-l- oxooctyl] amino] octanoic acid is generates as a side product, which is difficult to remove from the Salcaprozic acid or salt thereof, which may affect quality of the product. Further, during the recrystallization process using 65% methanol and water, impurity namely methyl 8-(2-hydroxybenzamido)octanoate is generated, which is difficult to remove from Salcaprozic acid or salt thereof and thus it requires additional / multiple purification to remove methyl 8-(2-hydroxybenzamido)octanoate. Therefore, US ‘386 is not attractive option for large scale industrial production of Salcaprozic acid or salt thereof as it is not economically viable.

[0011] The US patent number US11667614 (hereinafter US ‘614) discloses the process for preparation of Salcaprozic acid using hydrazine, sodium borohydride, or benzotriazole.

[0012] US ‘614 process require costly reagent such as hydrazine, sodium borohydride, or benzotriazole which may result in the formation of genotoxic impurities. Therefore, the process as disclosed in US ‘614 is not an attractive option for large scale industrial production of Salcaprozic acid or salt thereof.

[0013] Prior art process results into Salcaprozate sodium with lower yield and purity. Also the process of prior art are either silent about purity of Salcaprozate sodium or required multiple purification methods. Therefore, there is an urgent need to develop an improved process for preparation of Salcaprozate sodium having high yield and purity which solves the problem of prior art.

[0014] OBJECT OF THE INVENTION:

[0015] The main object of the present invention is to provide a process for the preparation of Salcaprozate sodium of Formula-I having higher yield and purity.

[0016] Another object of the present invention is to provide a process for purification of Salcaprozic acid of Formula-II having higher yield and purity.

[0017] SUMMARY OF INVENTION:

[0018] First aspect of the present invention is to provide a process for preparation of Salcaprozate sodium of Formula-I,

[0019] [Formula-I] comprising the steps of: a) treating Salcaprozic acid of Formula-II,

[0020] [Formula-II] with n-propanol or isopropanol or 2-butanol or n-butanol or mixture thereof to obtain a pure Salcaprozic acid of Formula-II; and b) reacting pure Salcaprozic acid of Formula-II with sodium source in presence of aromatic hydrocarbon solvent and butanol solvent to obtain Salcaprozate sodium of Formula-I.

[0021] Second aspect of the present invention is to provide a process for purification of

[0022] Salcaprozic acid of Formula-II,

[0023] [Formula-II] comprising treating Salcaprozic acid of Formula-II with n-propanol or isopropanol or 2- butanol or n-butanol or mixture thereof to obtain pure Salcaprozic acid of Formula-II.

[0024] Third aspect of the present invention is to provide a process for preparation of Salcaprozate sodium of Formula-I,

[0025] [Formula-I] comprising reacting Salcaprozic acid of Formula-II,

[0026] [Formula-II] with sodium source in presence of aromatic hydrocarbon solvent and butanol solvent to obtain Salcaprozate sodium of Formula-I. Fourth aspect of the present invention is to provide a Salcaprozate sodium of Formula-I,

[0027] [Formula-I] having less than 0.1% 8-[[8-[(2-hydroxybenzoyl)amino]-l-oxooctyl]amino]octanoic acid of Formula- III,

[0028] [Formula-Ill].

[0029] Fifth aspect of the present invention is to provide a Salcaprozate sodium of Formula-I,

[0030] [Formula-I] having less than 0.1% 8-[[8-[(2-hydroxybenzoyl)amino]-l-oxooctyl]amino]octanoic acid of Formula- III,

[0031] [Formula-Ill] and devoid of salicylic acid of Formula- IV,

[0032] [Formula-IV] and 8-acetamidooctanoic acid of Formula- V,

[0033] [Formula- V].

[0034] Sixth aspect of the present invention is to provide a process for the preparation of 2- azacyclononanone of Formula- VI,

[0035] [Formula- VI] comprising the steps of: a) reacting cyclooctanone of Formula- VII,

[0036] [Formula- VII] with hydroxylamine hydrochloride to obtain in-situ cyclooctanone oxime hydrochloride of Formula- VIII,

[0037] [Formula- VIII] b) reacting in-situ obtained cyclooctanone oxime hydrochloride of Formula- VIII with base in presence of aromatic hydrocarbon solvent to obtain in-situ cyclooctanone oxime of Formula-IX,

[0038] [Formula-IX] c) adding in-situ obtained cyclooctanone oxime of Formula-IX to polyphosphoric acid and simultaneously removing the aromatic hydrocarbon solvent to obtain a 2- azacyclononanone of Formula- VI.

[0039] DETAILED DESCRIPTION OF INVENTION:

[0040] In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.

[0041] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.

[0042] As used in this specification the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0043] The use of the word ‘devoid’ refers to the absence of impurity or below the level of limit of detection (LOD), wherein LOD can be less than 0.0015% by High-performance liquid chromatography (HPLC). The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.

[0044] The best methods and materials of performing the present invention are described here.

[0045] According to first embodiment, the present invention provides a process for preparation of Salcaprozate sodium of Formula-I,

[0046] [Formula-I] comprising the steps of: treating Salcaprozic acid of Formula-II,

[0047] [Formula-II] with n-propanol or isopropanol or 2-butanol or n-butanol or mixture thereof to obtain a pure Salcaprozic acid of Formula- II; and b) reacting pure Salcaprozic acid of Formula- II with sodium source in presence of aromatic hydrocarbon solvent and butanol solvent to obtain Salcaprozate sodium of Formula-I.

[0048] In the first embodiment of step a), the crude Salcaprozic acid of Formula-II can be prepared by a process known in the prior art.

[0049] In the first embodiment of step a), the treatment of Salcaprozic acid of Formula-II with n- propanol or isopropanol or 2-butanol or n-butanol or mixture thereof can be carried out at temperature of 40°C to reflux temperature of the solvent used.

[0050] In the first embodiment of step a), the solvent n-propanol or isopropanol or 2-butanol or n- butanol or mixture thereof can be used in the ratio of 1 volume to 15 volumes with respect to Salcaprozic acid of Formula-II. In the first embodiment of step a), the treatment of Salcaprozic acid of Formula-II with n- propanol or isopropanol or 2-butanol or n-butanol or mixture thereof can be carried out by methods such as slurry wash or by heating the mixture obtained from 40°C to reflux temperature followed by cooling to obtain pure Salcaprozic acid of Formula-II.

[0051] Generally, pure Salcaprozic acid of Formula-II can be prepared by heating Salcaprozic acid of Formula-II with n-propanol or isopropanol or 2-butanol or n-butanol or mixture thereof at temperature of 40°C to reflux temperature of the solvent used. Activated carbon can be added to the resulting mixture. Resulting mixture can be filtered to remove the color impurities. Resulting filtrate can be distilled out under vacuum to remove the solvent and to obtain pure Salcaprozic acid of Formula-II.

[0052] In the first embodiment of step a), the obtained pure Salcaprozic acid of Formula-II can be substantially free from colored impurities.

[0053] In the first embodiment of step a), the obtained pure Salcaprozic acid of Formula-II may have purity greater than 99.9% by High-performance liquid chromatography (HPLC).

[0054] In the first embodiment of step b), the sodium source can be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium tert-butoxide.

[0055] In the first embodiment of step b), the reaction of pure Salcaprozic acid of Formula-II with sodium source can be carried out at temperature of 30°C to reflux temperature of the solvent used.

[0056] In the first embodiment of step b), the reaction of pure Salcaprozic acid of Formula-II with sodium source can be carried out in presence of aromatic hydrocarbon solvent and butanol solvent to obtain Salcaprozate sodium of Formula-I.

[0057] In the first embodiment of step b), aromatic hydrocarbon solvent can be selected from toluene, o-xylene, m-xylene, p-xylene, mixture of xylene or mixture thereof.

[0058] In the first embodiment of step b), butanol solvent can be n-butanol or 2-butanol or mixture thereof.

[0059] In the first embodiment of step b), the mixture of aromatic hydrocarbon solvent and butanol solvent can be used in the ratio of 1 volume to 15 volumes with respect to Salcaprozic acid of Formula-II. In the first embodiment of step b), percentage of aromatic hydrocarbon solvent can be in the range of 0.5% to 10% with respect to butanol solvent.

[0060] In the first embodiment of step b), the obtained Salcaprozate sodium of Formula-I may have purity greater than 99.9% by High-performance liquid chromatography (HPLC).

[0061] According to second embodiment, the present invention provides a process for purification of Salcaprozic acid of Formula-II,

[0062] [Formula-II] comprising treating Salcaprozic acid of Formula-II with n-propanol or isopropanol or 2- butanol or n-butanol or mixture thereof to obtain pure Salcaprozic acid of Formula-II.

[0063] In the second embodiment, the crude Salcaprozic acid of Formula-II can be prepared by process known in the prior art.

[0064] In the second embodiment, the treatment of Salcaprozic acid of Formula-II with n- propanol or isopropanol or 2-butanol or n-butanol or mixture thereof can be carried out at temperature of 40°C to reflux temperature of the solvent used.

[0065] In the second embodiment, the solvent n-propanol or isopropanol or 2-butanol or n- butanol or mixture thereof can be used in the ratio of 1 volume to 15 volumes with respect to Salcaprozic acid of Formula-II.

[0066] In the second embodiment, the treatment of Salcaprozic acid of Formula-II with n- propanol or isopropanol or 2-butanol or n-butanol or mixture thereof can be carried out by methods such as slurry wash or by heating the mixture obtained from 40°C to reflux temperature followed by cooling to obtain pure Salcaprozic acid of Formula-II.

[0067] Generally, pure Salcaprozic acid of Formula-II can be prepared by heating Salcaprozic acid of Formula-II with n-propanol or isopropanol or 2-butanol or n-butanol or mixture thereof at temperature of 40°C to reflux temperature of the solvent used. Activated carbon can be added to the resulting mixture. Resulting mixture can be filtered to remove the color impurities. Resulting filtrate can be distilled out under vacuum to remove the solvent and to obtain pure Salcaprozic acid of Formula-II. In the second embodiment, the obtained pure Salcaprozic acid of Formula-II can be substantially free from colored impurities.

[0068] In the second embodiment, the obtained pure Salcaprozic acid of Formula-II may have purity greater than 99.9% by High-performance liquid chromatography (HPLC).

[0069] According to third embodiment, the present invention provides a process for preparation of Salcaprozate sodium of Formula-I,

[0070] [Formula-I] comprising reacting Salcaprozic acid of Formula-II,

[0071] [Formula-II] with sodium source in presence of aromatic hydrocarbon solvent and butanol solvent to obtain Salcaprozate sodium of Formula-I.

[0072] In the third embodiment, the sodium source can be selected from sodium source can be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium tert- butoxide.

[0073] In the third embodiment, the reaction of Salcaprozic acid of Formula-II with sodium source can be carried out at temperature of 30°C to reflux temperature of the solvent used.

[0074] In the third embodiment, the reaction of Salcaprozic acid of Formula-II with sodium source can be carried out in presence of aromatic hydrocarbon solvent and butanol solvent to obtain Salcaprozate sodium of Formula-I.

[0075] In the third embodiment, aromatic hydrocarbon solvent can be selected from toluene, o- xylene, m-xylene, p-xylene, mixture of xylene or mixture thereof.

[0076] In the third embodiment, butanol solvent can be n-butanol or 2-butanol or mixture thereof. In the third embodiment, the mixture of aromatic hydrocarbon solvent and butanol solvent can be used in the ratio of 1 volume to 15 volumes with respect to Salcaprozic acid of Formula-II.

[0077] In the third embodiment, percentage of aromatic hydrocarbon solvent can be in the range of 0.5% to 10% with respect to butanol solvent.

[0078] In the third embodiment, the obtained Salcaprozate sodium of Formula-I may have purity greater than 99.9% by High-performance liquid chromatography (HPLC).

[0079] According to fourth embodiment, the present invention provides a Salcaprozate sodium of

[0080] Formula-I,

[0081] [Formula-I] having less than 0.1% 8-[[8-[(2-hydroxybenzoyl)amino]-l-oxooctyl]amino]octanoic acid of Formula- III,

[0082] [Formula-Ill]

[0083] In the fourth embodiment, Salcaprozate sodium of Formula-I may have less than 0.1% 8- [[8-[(2-hydroxybenzoyl)amino]-l-oxooctyl]amino]octanoic acid of Formula- III, preferably less than 0.05% of compound of the Formula-Ill, more preferably less than 0.03% of compound of the Formula-Ill.

[0084] According to fifth embodiment, the present invention provides a Salcaprozate sodium of Formula-I, having less than 0.1% 8-[[8-[(2-hydroxybenzoyl)amino]-l-oxooctyl]amino]octanoic acid of Formula- III,

[0085] [Formula-Ill] and devoid of salicylic acid and 8-acetamidooctanoic acid.

[0086] According to sixth embodiment, the present invention provides a process for the preparation of 2-azacyclononanone of Formula- VI,

[0087] [Formula- VI] comprising the steps of: a) reacting cyclooctanone of Formula- VII, [Formula- VII] with hydroxylamine hydrochloride to obtain in-situ cyclooctanone oxime hydrochloride of Formula- VIII,

[0088] [Formula- VIII] b) reacting in-situ obtained cyclooctanone oxime hydrochloride of Formula- VIII with base in presence of aromatic hydrocarbon solvent to obtain in-situ cyclooctanone oxime of Formula-IX,

[0089] [Formula-IX] c) adding in-situ obtained cyclooctanone oxime of Formula-IX to polyphosphoric acid and simultaneously removing the aromatic hydrocarbon solvent to obtain a 2- azacyclononanone of Formula- VI.

[0090] In the sixth embodiment, reaction of cyclooctanone of Formula- VII with hydroxylamine hydrochloride is in presence of alcohol solvent.

[0091] In the sixth embodiment, the alcohol solvent can be selected from methanol, ethanol, n- propanol, isopropanol, butanol or 2-butanol.

[0092] In the sixth embodiment, the reaction of cyclooctanone of Formula- VII with hydroxylamine hydrochloride can be carried out at temperature of 50°C to 80°C.

[0093] In the sixth embodiment, the reaction of in-situ obtained cyclooctanone oxime hydrochloride of Formula- VIII with base in presence of aromatic hydrocarbon solvent can be carried out at 0°C to 30°C.

[0094] In the sixth embodiment, base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonates, sodium bicarbonate, potassium carbonate or cesium carbonate. In the sixth embodiment, in-situ obtained cyclooctanone oxime of Formula-IX can be added to polyphosphoric acid and simultaneously aromatic hydrocarbon solvent can be removed by using distillation set-up.

[0095] In the sixth embodiment, aromatic hydrocarbon solvent can be selected from toluene, o- xylene, m-xylene, p-xylene, mixture of xylene or mixture thereof.

[0096] In the sixth embodiment, in-situ obtained cyclooctanone oxime of Formula-IX can be added to polyphosphoric acid at temperature up to reflux temperature of the solvent used.

[0097] Generally, in-situ obtained cyclooctanone oxime of Formula-IX can be added to polyphosphoric acid at temperature up to reflux temperature by simultaneously removing solvent using distillation assembly and maintaining it for 3 hours. Resulting mixture can be cooled at 75 °C to 95 °C and purified water can be added followed by further cooling at 0°C to 5°C. Ammonia can be added to resulting mixture at 0°C to 35°C. Halogenated solvent like methylene chloride can be added to the resulting mixture at 0°C to 15 °C and mixture can be stirred for 30 minutes at the same temperature. The resulting mixture can be filtered and resulting wet material can be washed with halogenated solvent. Resulting filtrate can be allowed to separate aqueous and organic layers. The resulting organic layer- 1 can be kept aside. Halogenated solvent can be added to the obtained aqueous layer and wet material and can be stirred at 0°C to 15 °C. Resulting mixture can be filtered and wet material can be washed with halogenated solvent. Resulting filtrate can be allowed to separate aqueous and organic layers. Resulting organic layer-2 can be kept aside and halogenated solvent can be added to aqueous layer and wet material and can be further stirred at 0°C to 15 °C. Resulting mixture can be filtered and wet material can be washed with halogenated solvent. Resulting filtrate can be collected and allowed to separate aqueous and organic layers. Resulting organic layer-3 can be kept aside and halogenated solvent can be added to aqueous layer and wet material, followed by stirring at 0°C to 15°C. Resulting mixture can be filtered and wet material can be washed with halogenated solvent. Resulting filtrate can be collected and allowed to separate aqueous and organic layers. The resulting organic layer-4 can be combined with organic layers 1 to 3. All the combined organic layer can be distilled out under reduced pressure to obtain a 2- azacyclononanone of Formula- VI. When cyclooctanone oxime of Formula-IX is reacted with polyphosphoric acid using normal set-up, strong exotherm observed. Thus, present inventors found a specific reaction set-up and mode of addition wherein in-situ obtained cyclooctanone oxime of Formula-IX can be added to polyphosphoric acid at temperature up to reflux temperature by simultaneously removing solvent using distillation assembly. This not only solves the problem of prior art for controlling exothermicity but also results into smooth process to obtained a 2-azacyclononanone of Formula- VI in a safer way.

[0098] The present invention also provides a highly pure Salcaprozate sodium which controls impurities.

[0099] EXAMPLES:

[0100] The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

[0101] Example 01: Preparation of 2-azacyclononanone of Formula- VI

[0102] To a stirred mixture of cyclooctanone (250 g) and methanol (1000 mL), hydroxylamine hydrochloride (212.5 g) was added at temperature of 25°C to 35°C. Resulting mixture was heated at 65°C to 70°C for 3 hours. After completion of reaction, reaction mixture was distilled out under vacuum and toluene (500.0 mL) was added to resulting mixture at 80°C to 90°C. Resulting mixture was distilled out under vacuum. Toluene (500 mL) was added and to the obtained mixture and cooled the mixture slowly to temperature of 20°C to 25°C. Purified water (1000 mL) was added to resulting mixture and further cooled at 0°C to 10°C. Caustic soda lye (300 g) was added to the obtained mixture at same temperature and pH of the mixture was adjusted to 12. The resulting mixture was allowed to separate aqueous and organic layers. The resulting aqueous layer was extracted with toluene (3 x 125 mL). All the organic layers were combined and added into the polyphosphoric acid (700 g) at 110°C to 130°C by simultaneously removing solvent using distillation assembly and maintaining it for 3 hours. Resulting mixture was cooled at 75°C to 95°C and purified water (250 mL) followed by further cooling at 0°C to 5°C. 20% aqueous ammonia (1950 mL) was added to resulting mixture at 0°C to 35°C. Methylene chloride (1500 mL) was added to the resulting mixture at 0°C to 15°C and stirred for 30 minutes at the same temperature. The resulting mixture was filtered and obtained wet material was washed with methylene chloride (3 x 500 mL). Resulting filtrate was allowed to separate aqueous and organic layers. The resulting organic layer- 1 was kept aside. Methylene chloride (1000 mL) was added to the obtained aqueous layer and wet material and stirred at 0°C to 15°C. Resulting mixture was filtered and wet material was washed with methylene chloride (3 x 250 mL). Resulting filtrate was allowed to separate aqueous and organic layers. Resulting organic layer-2 was kept aside and methylene chloride (1000 mL) was added to aqueous layer and wet material further stirred at 0°C to 15°C. Resulting mixture was filtered and wet material was washed with methylene chloride (3 x 250 mL). Resulting filtrate was collected and allowed to separate aqueous and organic layers. Resulting organic layer-3 was kept aside and methylene chloride (1000 mL) was added to aqueous layer and wet material, further stirred at 0°C to 15°C. Resulting mixture was filtered and wet material was washed with methylene chloride (3 x 250 mL). Resulting filtrate was collected and allowed to separate aqueous and organic layers. The resulting organic layer-4 were combined with organic layers 1 to 3. All the combined organic layer were distilled out under reduced pressure to obtain a title compound (223.4 g) having Gas Chromatography (GC) purity of 99.42%

[0103] Appearance: White color solid

[0104] Cyclooctanone: 0.03%

[0105] \ -cyclooctadiene hydroxylamine: Not detected

[0106] Dichloromethane Content: Not detected

[0107] Example 02: Preparation of 2-(chlorocarbonyl)phenyl acetate

[0108] To a stirred mixture of acetylsalicylic acid (400 g) and methylene chloride (400 mL), triphenylphosphine (4 g) was added at 25°C to 35°C. Resulting mixture was heated at 35°C to 40°C and thionyl chloride (360 gm) was slowly added at 30°C to 40°C. The resulting mixture was stirred for 4 hours at the same temperature. Thionyl chloride (40 g) was slowly added to the resulting mixture at 30°C to 40°C and stirred for 2 hours at 35°C to 40°C. After completion of reaction, distilled out methylene chloride under reduced pressure to obtain a title compound (418.4 g).

[0109] GC Purity: 96.40%

[0110] Example 03: Preparation of Salcaprozic acid of Formula-II To a stirred mixture of 2-azacyclononanone (150.0 g) and purified water (930.0 mL), caustic soda flakes (240.0 g) were added at 20°C to 100°C. The resulting mixture was stirred for 6 hours at 100°C to 105°C. After completion of reaction, purified water (300.0 mL) was added at 40°C to 50°C. Resulting mixture was filtered through hyflow, washed with purified water (900.0 mL). Resulting mixture was cooled to -5°C to 5°C. 2- (chlorocarbonyl)phenyl acetate (255.0 g) was added to resulting mixture at -5°C to 15°C and further stirred for 3.0 hours at 0°C to 5°C. Temperature of resulting mixture was stirred at 10°C to 15 °C for 3.0 hours. The obtained mixture was stirred for 3.0 hours at 20°C to 25°C followed by further stirring for 3.0 hours at 25°C to 35°C. Hydrochloric acid (360.0 g) was added to the resulting mixture at 25°C to 35°C and pH of the mixture was adjusted to 4.0 to 4.5. The resulting mixture was filtered and wet material was washed with purified water (2 X 150.0 mL). Purified water (2153.0 mL) and caustic soda flakes (160.5 g) were added to the obtained wet material at 25°C to 50°C. Resulting mixture was heated at 80°C to 85°C for 12 hours. The obtained mixture was cooled at 25°C to 35°C. Hydrochloric acid (425.0 g) was added to the mixture at 25 °C to 35 °C and stirred the mixture for 1 hour at same temperature. The resulting mixture was filtered and obtained wet material was washed with purified water (2 x 75.0 mL) to obtain the title compound.

[0111] Example 04: Purification of Salcaprozic acid of Formula-II

[0112] Isopropyl alcohol (1800.0 mL) was added to Salcaprozic acid obtained in Example-03 at 25 °C to 35 °C. Resulting mixture was heated at 65 °C to 70°C and activated carbon slurry (37.5 g activated carbon in 262.2 mL of isopropyl alcohol) was added to resulting mixture at 65°C to 70°C. Resulting mixture was stirred for 60 minutes at same temperature. Resulting mixture was filtered, washed with isopropyl alcohol (900.0 mL). The resulting filtrate was distilled under vacuum below 55°C. Purified water (1050.0 mL) was added to the distilled mass 50°C to 55°C and stirred for 30 minutes. Resulting mixture was cooled slowly at 25°C to 35°C. Resulting mixture was filtered, washed with purified water (2 x 90.0 mL) to obtain solid. The resulting solid was dried under vacuum at 60°C to 65°C for 8 hours to obtain title compound (168 g) having HPLC Purity of 99.94%

[0113] 2-Azacyclononanone content: 0.03%

[0114] Salicylic acid content: Not detected

[0115] Acetyl salicylic acid content: Not detected

[0116] Triphenylphosphine oxide content: Not detected Methyl 8-(2-hydroxybenzamido)octanoate content: Not detected

[0117] 8-acetamidooctanoic acid content: Not detected

[0118] Example 05: Preparation of Salcaprozate sodium of Formula-I

[0119] [Formula-I]

[0120] To a stirred mixture of Salcaprozic acid (150.0 g) and 2-butanol (895.5 mL), toluene (4.5 mL) was added at 25°C to 35°C. Resulting mixture was stirred for 15 minutes at same temperatures. Resulting mixture was heated at 65 °C to 70°C and activated carbon slurry (7.5 g activated carbon in 52.5 mL 2-butanol) was added at 65°C to 70°C. The obtained mixture was stirred and maintained for 40 minutes at 65 °C to 70°C. Resulting mixture was filtered over hyflow, washed with mixture of 2-butanol and toluene. To the resulting filtrate caustic soda solution (21.9 g caustic soda in 48.0 g purified water) was added at 40°C to 50°C. Resulting mixture was stirred for 10 minutes at 40°C to 50°C. n-heptane (570.0 mL) was added to resulting mixture at 40°C to 50°C and stirred for 35 minutes at 40°C to 50°C. Resulting mixture was cooled slowly to 25°C to 35°C and filtered, washed with n-heptane (2 x 75.0 mL) at 25°C to 35°C to obtain solid. The resulting solid was dried under vacuum at 80°C to 85°C for 8 hours to obtain title compound (154 g).

[0121] Appearance: Off white powder

[0122] HPLC Purity: 99.94 %

[0123] Water content: 1.0%

[0124] Sodium content: 7.6%

[0125] Salicylic acid content: Not detected

[0126] 8-[[8-[(2-hydroxybenzoyl)amino]-l-oxooctyl]amino]octanoic acid content: 0.02% 8-acetamidooctanoic acid content: Not detected

[0127] Methyl 8-(2-hydroxybenzamido)octanoate content: Not detected

Claims

We Claim:

1. A process for preparation of Salcaprozate sodium of Formula-I,[Formula-I] comprising the steps of: a) treating Salcaprozic acid of Formula-II,[Formula-II] with n-propanol or isopropanol or 2-butanol or n-butanol or mixture thereof to obtain a pure Salcaprozic acid of Formula-II; and b) reacting pure Salcaprozic acid of Formula-II with sodium source in presence of aromatic hydrocarbon solvent and butanol solvent to obtain Salcaprozate sodium of Formula-I.

2. The process as claimed in claim 1, wherein step a) is carried out at temperature of 40°C to reflux temperature of the solvent used; and step b) is carried out using aromatic hydrocarbon solvent selected from toluene, o-xylene, m-xylene, p-xylene, mixture of xylene or mixture thereof; butanol and sodium source selected from sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium tert-butoxide.

3. A process for purification of Salcaprozic acid of Formula-II,[Formula-II]comprising treating Salcaprozic acid of Formula-II with n-propanol or isopropanol or 2- butanol or n-butanol or mixture thereof to obtain pure Salcaprozic acid of Formula- II.

4. The process as claimed in claim 3, wherein the obtained pure Salcaprozic acid of Formula-II is having purity greater than 99.9% by High-performance liquid chromatography (HPLC).

5. A process for preparation of Salcaprozate sodium of Formula-I,[Formula-I] comprising reacting Salcaprozic acid of Formula-II,[Formula-II] with sodium source in presence of aromatic hydrocarbon solvent and butanol solvent to obtain Salcaprozate sodium of Formula-I.

6. The process as claimed in claim 5, wherein sodium source is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium tert-butoxide; and aromatic hydrocarbon solvent is selected from toluene, o-xylene, m-xylene, p-xylene, mixture of xylene or mixture thereof.

7. A Salcaprozate sodium of Formula-I,[Formula-I]having less than 0.1% 8-[[8-[(2-hydroxybenzoyl)amino]-l-oxooctyl]amino]octanoic acid of Formula- III,[Formula-Ill].

8. A Salcaprozate sodium of Formula-I,having less than 0.1% 8-[[8-[(2-hydroxybenzoyl)amino]-l-oxooctyl]amino]octanoic acid of Formula- III,[Formula-Ill] and devoid of salicylic acid of Formula-IV,[Formula-IV] and 8-acetamidooctanoic acid of Formula- V,[Formula- V].

9. A process for the preparation of 2-azacyclononanone of Formula- VI,[Formula- VI] comprising the steps of: a) reacting cyclooctanone of Formula- VII,[Formula- VII] with hydroxylamine hydrochloride to obtain in-situ cyclooctanone oxime hydrochloride of Formula- VIII,[Formula- VIII] b) reacting in-situ obtained cyclooctanone oxime hydrochloride of Formula- VIII with base in presence of aromatic hydrocarbon solvent to obtain in-situ cyclooctanone oxime of Formula- IX,[Formula-IX] c) adding in-situ obtained cyclooctanone oxime of Formula-IX to polyphosphoric acid and simultaneously removing the aromatic hydrocarbon solvent to obtain a 2- azacyclononanone of Formula- VI.

10. The process as claimed in claim 9, wherein base is selected from sodium hydroxide, potassium hydroxide, sodium carbonates, sodium bicarbonate, potassium carbonate or cesium carbonate; and aromatic hydrocarbon solvent is selected from toluene, o- xylene, m-xylene, p-xylene, mixture of xylene or mixture thereof.

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