Process for the preparation of calcium d-glucarate

Abstract

The present application relates to a kind of new preparation methods of D-glucaric acid and its calcium salt tetrahydrate, the process route of the present application is prepared by one-pot method D-glucaric acid calcium, avoid in the lengthy separation process and the purification process of intermediate compound in post-processing process, to save time and resources and improve yield, with the advantages of few steps, simple operation, mild reaction, solvent has the recycling ability, suitable for large-scale mass production.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a novel method for preparing D-glucono-dicarboxylic acid calcium. Technical Background

[0002] Gluconic acid is naturally found in fruits such as grapefruit, apples, and oranges, as well as cruciferous vegetables. It is also secreted in a small number of mammals and humans, and is a non-toxic glucose derivative. Glucuronic acids may enhance the body's natural defense mechanisms and reduce the risk of cancer. With further research, gluconic acid has been found to have wide applications in the chemical and pharmaceutical fields. For example, it can be used as a basic unit in polymer synthesis to synthesize polyamides, hydroxylated nylon, and polydimethylsiloxane polyamides, as well as biodegradable polymers, slow-release fertilizers, and various films. It can also be used as a raw material to produce non-toxic, biodegradable phosphate substitutes for use in household detergents, preservatives, and concrete admixtures. Gluconic acid can also be used as a chelating agent for metal corrosion protection in electroplating. In 2004, the U.S. Department of Energy identified gluconic acid as one of the 12 "most valuable biorefining products," highlighting its significant economic value.

[0003] Calcium D-gluconate is readily converted to D-gluconate in the human body. D-gluconate plays multiple roles in metabolism, not only supplementing calcium but also fulfilling other important physiological functions. Furthermore, gluconate-1,4-lactone, an interconvertible form of D-gluconate, possesses strong detoxification and antioxidant properties. It can inhibit pancreatic β-cell apoptosis, alleviate alloxan-induced diabetes, and relieve intestinal mucosal damage caused by irinotecan hydrochloride. Since the content of gluconate in fruits and vegetables is minimal, the amount of gluconate ingested through diet is far below the level required to inhibit β-glucuronidase. Therefore, the body needs to supplement with D-gluconate and related derivatives to achieve preventative and therapeutic effects.

[0004] D-Calcium gluconate has four chiral centers and generally exists as a tetrahydrate, with the following structural formula:

[0005]

[0006] The key to synthesizing calcium D-gluconate tetrahydrate is the synthesis of D-gluconate. Currently, nitric acid oxidation and TEMPO oxidation are the most commonly used methods in the chemical industry. Both methods suffer from selectivity issues; glucose has too many reaction sites, and alcohol hydroxyl groups are difficult to oxidize, leading to low yields, purification difficulties, and a series of other problems.

[0007] Therefore, there is still a need in this field to develop a high-yield, low-cost method for preparing D-glucosidic acid and its calcium salt tetrahydrate that meets pharmaceutical excipient standards, is stable for storage, is suitable for pharmaceutical use, and has a simple, efficient, and scalable preparation process to meet market demand. Summary of the Invention

[0008] The purpose of this invention is to address the shortcomings of existing processes by providing a new method for preparing D-gluconic acid and its calcium salt tetrahydrate. This method features mild reaction conditions, low preparation cost, high yield, and is suitable for industrial production.

[0009] This invention provides a method for preparing calcium D-gluconate, specifically comprising the following steps:

[0010] (a) D-glucuronic acid is oxidized by adding an oxidizing agent to obtain D-gluconic acid;

[0011] (b) The prepared D-gluconic acid reacts with calcium salt to obtain calcium D-gluconic acid.

[0012] The present invention also provides a method for preparing D-glucuronic acid calcium, wherein D-glucuronic acid is added to calcium hypochlorite for oxidation to obtain D-glucuronic acid calcium.

[0013] Furthermore, in the above preparation method, D-glucuronic acid is obtained by alkaline hydrolysis of D-glucuronic acid-γ-lactone.

[0014] Furthermore, in the above preparation method, D-glucuronic acid-γ-lactone is first dissolved in water and then alkali is added. The mass-volume ratio of D-glucuronic acid-γ-lactone to water is 1:5 to 1:20, preferably 1:10 to 1:15, in g / ml or kg / L.

[0015] Furthermore, in the above preparation method, the alkali is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate, and the amount of alkali used is 1.0 to 3.0 eq of the molar amount of D-glucuronic acid-γ-lactone, preferably 1.0 to 1.5 eq.

[0016] Furthermore, in the above preparation method, the oxidant is selected from sodium hypochlorite or hydrogen peroxide.

[0017] Furthermore, in the above preparation method, the amount of oxidant or calcium hypochlorite used is 1.0 to 5.0 eq of the molar amount of D-glucuronic acid-γ-lactone, preferably 1.5 to 4.0 eq.

[0018] Furthermore, in the above preparation method, the oxidation reaction temperature is -30 to 50°C, the oxidation reaction time is 2 to 15 h, and preferably the oxidation reaction temperature is 20 to 50°C and the oxidation reaction time is 4 to 10 h.

[0019] Furthermore, in the above preparation method, the calcium salt is selected from one or more of calcium oxide, calcium hydroxide, calcium nitrate, calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium dihydrogen phosphate, calcium chloride, or calcium bicarbonate.

[0020] The preparation method described in this invention has the following advantages compared with existing processes:

[0021] 1) The process route of this invention prepares D-glucuronic acid calcium in a one-pot process, avoiding the lengthy separation process and purification process of intermediate compounds in the post-processing, thereby saving time and resources and improving the yield. It has the advantages of fewer steps, simple operation, mild reaction, and solvent recovery and reuse capability, making it suitable for large-scale mass production; 2) This invention uses D-glucuronic acid-γ-lactone as the starting material, which is inexpensive and readily available; 3) D-glucuronic acid is prepared by oxidizing D-glucuronic acid with common oxidants such as sodium hypochlorite, calcium hypochlorite, or hydrogen peroxide. Compared with the common enzymatic catalysis, the preparation cost of this invention is lower, the post-processing is simpler, and the product meets pharmaceutical grade standards. Attached Figure Description

[0022] Figure 1 The hydrogen spectrum of the white solid product obtained in Example 1. Detailed Implementation

[0023] The present invention will be further described below with reference to specific embodiments, based on common technical knowledge and conventional methods in the art. The following embodiments are only some preferred embodiments of the present invention and should not be regarded as limitations on the present invention. For those skilled in the art, several improvements can be made without departing from the scope of the present invention, and these improvements should also be considered within the protection scope of the present invention.

[0024] Example 1: Preparation of calcium D-gluconate tetrahydrate

[0025]

[0026] D-glucuronide-γ-lactone (100 g, 0.56 mol, 1 eq.) was dissolved in purified water (1000 mL). Lithium hydroxide (13.7 g, 0.56 mol, 1 eq.) was added in three portions at room temperature, and the mixture was stirred for 1 h. Calcium hypochlorite (174 g, 1.20 mol, 2.14 eq.) was added in three portions at 20–40 °C, and the mixture was stirred for 5 h at room temperature. After the reaction was complete, the mixture was filtered, the filter cake was washed three times with water and dried. The dried crude D-glucuronide was dissolved in purified water (1000 mL), heated to 50 °C, and the pH was adjusted to 5–6 with hydrochloric acid. The mixture was stirred for 12 h, filtered, the filter cake was washed three times with water and dried to obtain a white solid (89.0 g, 49.2%). The calcium content in the sample was 100.3%.

[0027] 1H-NMR (500MHz, D2O) δ = 4.44 (d, J = 2.8Hz, 1H), 4.32 (d, J = 5.2Hz, 1H), 4.11 (dd, J = 5.4, 3.0Hz, 1H), 3.94 (t, J = 5.2Hz, 1H);

[0028] 13 C-NMR (500MHz, D2O) δ = 70.65, 70.72, 71.00, 72.44, 174.91, 175.25ppm;

[0029] MS(ESI): m / z = 104.0112 [M-Ca 2+ ] 2- / 2 .

[0030] Example 2: Preparation of calcium D-gluconate tetrahydrate

[0031]

[0032] D-glucuronide-γ-lactone (100 g, 0.56 mol, 1 eq.) was dissolved in purified water (1000 mL). Lithium hydroxide (13.7 g, 0.56 mol, 1 eq.) was added in three portions at room temperature, and the mixture was stirred for 1 h. Hydrogen peroxide (63.4 g, 1.86 mol, 3.3 eq.) was added dropwise at 25–30 °C, and the mixture was stirred for 5 h at room temperature. After the reaction was complete, hydrochloric acid was added to adjust the pH to 2, and calcium oxide (79.5 g, 1.4 mol, 2.5 eq.) was added. The mixture was stirred for 10 h, and the pH was adjusted to 5. The reaction system was cooled to 0 °C, filtered, and the filter cake was washed three times with water and dried. The dried crude D-glucuronide was dissolved in purified water (1000 mL), heated to 50 °C, and hydrochloric acid was added to adjust the pH to 5–6. The mixture was stirred for 12 h, filtered, and the filter cake was washed three times with water and dried to obtain a white solid (73.0 g, 40.2%). The sample contained 99.5% calcium.

Claims

1. A method for preparing calcium D-gluconate, characterized in that... The preparation method includes the following steps: (a) D-glucuronic acid is oxidized by adding an oxidizing agent to obtain D-glucuronic acid, wherein the D-glucuronic acid is obtained by alkaline hydrolysis of D-glucuronic acid-γ-lactone, and the oxidizing agent is selected from sodium hypochlorite or hydrogen peroxide. (b) The prepared D-gluconic acid is reacted with calcium salt, calcium oxide or calcium hydroxide to obtain calcium D-gluconic acid.

2. A method for preparing calcium D-gluconate, characterized in that... D-glucuronic acid is oxidized by calcium hypochlorite to obtain calcium D-glucuronic acid, wherein the D-glucuronic acid is prepared by alkaline hydrolysis of D-glucuronic acid-γ-lactone.

3. The preparation method according to claim 1 or 2, characterized in that, D-glucuronic acid-γ-lactone is first dissolved in water and then alkali is added. The mass-volume ratio of D-glucuronic acid-γ-lactone to water is 1:5 to 1:20, expressed in g / ml or kg / L.

4. The preparation method according to claim 3, characterized in that, D-glucuronic acid-γ-lactone is first dissolved in water and then alkali is added. The mass-volume ratio of D-glucuronic acid-γ-lactone to water is 1:10 to 1:15, expressed in g / ml or kg / L.

5. The preparation method according to claim 3, characterized in that, The alkali is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

6. The preparation method according to claim 5, characterized in that, The amount of alkali used is 1.0~3.0 eq of the molar amount of D-glucuronic acid-γ-lactone.

7. The preparation method according to claim 5, characterized in that, The amount of alkali used is 1.0~1.5 eq of the molar amount of D-glucuronic acid-γ-lactone.

8. The preparation method according to claim 1 or 2, characterized in that, The amount of the oxidant or calcium hypochlorite used is 1.0~5.0 eq of the molar amount of D-glucuronic acid-γ-lactone.

9. The preparation method according to claim 1 or 2, characterized in that, The amount of the oxidant or calcium hypochlorite used is 1.5 to 4.0 eq of the molar amount of D-glucuronic acid-γ-lactone.

10. The preparation method according to claim 1 or 2, characterized in that, The oxidation reaction temperature is -30~50℃, and the oxidation reaction time is 2~15h.

11. The preparation method according to claim 1 or 2, characterized in that, The oxidation reaction temperature is 20~50℃, and the oxidation reaction time is 4~10h.

12. The preparation method according to claim 1, characterized in that, The calcium salt is selected from one or more of calcium nitrate, calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium dihydrogen phosphate, calcium chloride, or calcium bicarbonate.

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