CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 202141026463 filed on June 14, 2021.

FIELD OF THE INVENTION

The present invention relates to process for the preparation of pure Salcaprozate sodium free of color impurity.

BACKGROUND OF THE INVENTION

Salcaprozate sodium is chemically known as N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium and its represented by Formula 1. Which is also known as SNAC sodium.

Formula 1

The preparation of SNAC sodium may lead to product which includes color-bodies. US patent 7544833 discloses avoiding or reducing the production of a color impurity therein comprising the step of hydrolyzing 2,4-dioxo-l,3-benzoxazinyloctanoic acid ethyl ester by admixing 2,4-dioxo-l,3-benzoxazinyloctanoic acid ethyl ester with sodium hydroxide, water, and a member selected from the group consisting of ethylenediamine tetra acetic acid (EDTA), ascorbic acid, NaHSCE, and triphenylpho sphine .

SUMMARY OF THE INVENTION

The main aspect of the present invention relates to process for the preparation of pure Salcaprozate sodium free of color impurity.

In one aspect, the present invention relates to process for the preparation of Salcaprozate acid comprising the steps of: a) hydrolyzing 2,4-dioxo-l,3-benzoxazinyloctanoic acid ethyl ester in the presence of sodium hydroxide, water and reducing agent, and b) isolating white Salcaprozate acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of pure Salcaprozate sodium free of color impurity.

In one embodiment, the present invention provides a process for the preparation of Salcaprozate acid comprising the steps of: a) hydrolyzing 2,4-dioxo-l,3-benzoxazinyloctanoic acid ethyl ester in the presence of sodium hydroxide, water and reducing agent, and b) isolating white Salcaprozate acid.

Within the context of this embodiment, hydrolysis of 2,4-dioxo-l,3- benzoxazinyloctanoic acid ethyl ester may be carried out using water, sodium hydroxide and catalytic amount of reducing agent and the reaction mass may be heated to about 70-100°C for 2-4 hours. After completion of the reaction, the reaction mass may be cooled to room temperature, followed by adjusting the pH to 4.0 to 4.5 with hydrochloric acid and maintained for 2 to 20 hours. The resultant solid may be filtered to obtain white Salcaprozate acid.

Within the context of this embodiment, reducing agents are selected from Sodium borohydride, sodium sulfite or Zinc powder.

Within the context of this embodiment, hydrolysis of 2,4-dioxo-l,3- benzoxazinyloctanoic acid ethyl ester may be carried out using water which may be degassed with vacuum followed by releasing of vacuum with Nitrogen purging and sodium hydroxide. The reaction mass may be heated to about 70-100°C for 2-4 hours. After completion of the reaction, the reaction mass may be cooled to room temperature, followed by adjusting the pH to 4.0 to 4.5 with hydrochloric acid and stirred for 2 to 4 hours. The resultant solid may be filtered to obtain white Salcaprozate acid.

Within the context of this embodiment, hydrolysis of 2,4-dioxo-l,3- benzoxazinyloctanoic acid ethyl ester may be carried out using ethanol, sodium hydroxide and the reaction mass may be heated to about 70-90°C, maintained for 2-12 hours. Water may be added to the reaction mass followed by adjusting the pH to 4.0 to 4.5 with hydrochloric acid and maintained for 2 to 4 hours. The resultant solid may be filtered to obtain white Salcaprozate acid.

In another embodiment, present invention provides a process for the preparation of Salcaprozate sodium comprising the steps of: a) contacting white Salcaprozate acid with sodium hydroxide in ethanol, b) adding an anti-solvent, and c) isolating Salcaprozate sodium.

Within the context of this embodiment, white Salcaprozate acid reacts with sodium hydroxide in ethanol at about 30°C and the reaction mass may be maintained for 45- 60 minutes. After completion of reaction, the reaction mass may be filtered and washed with ethanol. To the resultant filtrate, an anti-solvent such as di-isopropyl ether may be added and maintained for about 3 hours at room temperature. The resultant solid may be filtered to obtain pure Salcaprozate sodium.

Within the context of this embodiment, the present invention encompasses reverse addition of resultant filtrate into the anti-solvent such as di-isopropyl ether and isolation of Salcaprozate sodium.

Salcaprozate sodium is used as an excipient in the preparation of pharmaceutical compositions along with drug substance for increasing the solubility.

The pure Salcaprozate sodium prepared according to the present invention is used as an excipient in the preparation of Semaglutide.

Advantages

1. Using reducing agents such as Sodium sulfite, Zinc or Sodium borohydride, the color of obtained Salcaprozate Acid is white to off-white and free from pink shade.

2. Existing reported literature process of Salcaprozate sodium involves usage of n-Heptane by which the filtration of material is very slow. The use of di-isopropyl ether provides good crystalline material which is filtered very fast and ultimately reduces overhead cost. Reported literature (US7544833) shows usage of Acetone along with NaHS03. The pink color is because of oxidation and it is observed that when the reaction is carried out with nitrogen purging there is reduction in the pink color, however using sodium sulfite, Zinc and other reagents like sodium borohydride the color of the Salcaprozate-Acid is white even without nitrogen.

Comparison of Sodium sulfite and sodium bisulfite.

In view of the above description and the examples below, one of the ordinary skills in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES:

Example 1: Preparation of Salcaprozate-Acid

Water (140 mL) was taken into to the flask sodium hydroxide (16.8g) was charged to it (temperature raised to 50°C). Sodium sulfite (1.4 g, NaiSCL) was charged to reaction mass and maintained temperature 50-60°C for 1 hour. Reaction mass was cooled to 40-45°C. Ethyl, 8-(2,4-dioxo-2H-l,3-benzoxazin- 3(4H)-yl) octanoate (35 g) was charged to the solution and heated to 90-94°C. Reaction mass was maintained for 2 hours and cooled to 27°C. pH of the reaction mass was adjusted to 4.1 with Hydrochloric acid (46g). Reaction mass was stirred for 16 hours at room temperature, filtered the reaction mass, washed with water (105 mL). Finally, material was dried and obtained 28g of white material of Salcaprozate Acid.

Example 2: Preparation of Salcaprozate-Acid

Water (40 mL) and Zinc (0.5g) was taken into the flask and heated to 50°C. After heating for 30 minutes, it was cooled to 40°C. sodium hydroxide (9.6g) was charged to it (temperature raised to 45°C). Reaction mass temperature was reduced to 29°C and Ethyl, 8-(2,4-dioxo-2H-l,3-benzoxazin-3(4H)-yl) octanoate (20 g) is charged and heated to 93-94°C. Water (40mL) was added to reaction mass and maintained for 2 hours; reaction mass was cooled to 40°C. Reaction mass was filtered, and pH of the filtrate was adjusted to 4.3 with Hydrochloric acid (30g). Reaction mass was stirred for 2 hours at room temperature, filtered, and washed with water (60mL). Finally, material was dried and obtained 15.8g of white material of Salcaprozate Acid.

Example 3: Preparation of Salcaprozate-Acid

Water (80 mL) was taken into the flask sodium hydroxide (9.6g) was charged to it (temperature raised to 52°C). Sodium borohydride (0.1 g, NaBH4) was charged to reaction mass and maintained temperature for 1 hour at 50-52°C. Reaction mass temperature was reduced to 30-35°C and Ethyl, 8-(2,4-dioxo-2H-l,3- benzoxazin-3(4H)-yl) octanoate (20 g) was charged and heated to 92-94°C. Reaction mass was maintained for 2 hours and cooled to 27°C. pH of the reaction mass was adjusted to 4.3 with Hydrochloric acid. Reaction mass was stirred for 4 hours at room temperature, filtered, and washed with water (60 mL). Finally, material was dried and obtained 16g of white material of Salcaprozate Acid.

Example 4: Preparation of Salcaprozate-Acid

Water (100 mL) was into the flask. Water was degassed with vacuum followed by releasing of vacuum with Nitrogen purging. It was repeated two times and sodium hydroxide (24g) is charged to it (temperature raised to 60°C). Reaction mass was cooled to 35°C and Ethyl, 8-(2,4-dioxo-2H-l,3-benzoxazin-3(4H)-yl) octanoate (50 g) was charged and heated to 91-94°C. Reaction mass was maintained for 2 hours and cooled to 30°C and water (lOOmL) was added to the reaction mass. pH of the reaction mass was adjusted to 4.3 with Hydrochloric acid (68g). Reaction mass was raised to 50°C and stirred for 30 minutes followed by cooling to 27 °C and stirred for 3 hours at room temperature, filtered and washed with 150 ml of water. Finally, material was dried and obtained 40g of Off-white material of Salcaprozate Acid.

Example 5: Preparation of Salcaprozate acid

Ethanol (100 mL) was taken into the flask sodium hydroxide (4.8g) and Ethyl, 8- (2,4-dioxo-2H-l,3-benzoxazin-3(4H)-yl) octanoate (10 g) were charged to the flask and heated to reflux at 74-76°C. Water (20 mL) was added to it and maintained for 10 hours and cooled to 30°C and added water (lOOmL). pH of the reaction mass was adjusted to 4.12 with Hydrochloric acid (12g). Reaction mass was stirred for 2 hours at room temperature, filtered the reaction mass, washed with water (30 mL). Finally, material was dried and obtained 7.0g of Salcaprozate Acid with Off-white color (No pink tinge is observed).

Example 6: Preparation of Salcaprozate Sodium

Salcaprozate Acid (25 g) and Ethanol (88 mL) were taken into the flask. Temperature was raised to 30°C and then sodium hydroxide solution (3.5 lg of sodium hydroxide dissolved in 10 ml of water) was added to the reaction mass. Reaction mass was stirred for 45 minutes and then filtered followed by washing of Ethanol (12.5 mL). Into the filtrate of Di-isopropyl ether (325 mL) was added and stirred for 3 hours at room temperature. Finally filtered and dried under vacuum to get Salcaprozate sodium (25g).