CN113493379A - Preparation method of calcium glucarate - Google Patents
Preparation method of calcium glucarate Download PDFInfo
- Publication number
- CN113493379A CN113493379A CN202010258771.6A CN202010258771A CN113493379A CN 113493379 A CN113493379 A CN 113493379A CN 202010258771 A CN202010258771 A CN 202010258771A CN 113493379 A CN113493379 A CN 113493379A
- Authority
- CN
- China
- Prior art keywords
- calcium
- gluconate
- glucarate
- salt
- producing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/21—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen
- C07C51/23—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups
- C07C51/235—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups of —CHO groups or primary alcohol groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Abstract
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of calcium glucarate. The preparation method of the calcium glucarate comprises the steps of adding D-gluconate into a reaction container, cooling to-30-50 ℃, adding a catalyst, a solvent and an oxidant, and carrying out catalytic oxidation reaction to obtain a glucarate solution; reacting the glucose diacid salt solution with calcium salt to obtain calcium glucose diacid; wherein the D-gluconate is D-sodium gluconate, D-lithium gluconate, D-potassium gluconate, D-calcium gluconate, D-magnesium gluconate or D-zinc gluconate. The method adopts the D-gluconate as the raw material, has the advantages of less consumption of the oxidant, simple operation, high yield, low production cost and less industrial three wastes, meets the quality requirements of domestic and foreign pharmaceutic adjuvants, is suitable for industrial production and has no pollution to the environment.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of calcium glucarate.
Background
Glucaric acid naturally exists in fruits such as grapefruit, apple, orange and the like and cruciferous vegetables, is secreted in a small amount of mammals and human bodies, and is a nontoxic glucose derivative. The uronic acid substances can improve the natural defense mechanism of human body and reduce the risk of cancer. With the gradual deepening and development of research, people find that glucaric acid also has wide application value in the chemical field and the medical field. For example, the polymer can be used as a basic unit for polymer synthesis to synthesize polyamides, hydroxylated nylon and polydimethylsiloxane polyamide, to synthesize biodegradable polymers, slow-release fertilizers, various films and the like, and can also be used as a raw material to produce nontoxic and biodegradable phosphate substitutes for household detergents, preservatives, concrete admixtures and the like. Glucaric acid can also act as a chelating agent for metal preservation in electroplating. In 2004, glucaric acid was identified by the U.S. department of energy as one of the 12 "most valuable biorefinery products" with enormous economic value.
The structural formula of the calcium glucarate is as follows:
the calcium glucarate is a compound containing 4 chiral carbon atoms, is easy to be converted into glucaric acid in a human body, has multiple functions in the metabolism of the glucaric acid in the human body, can supplement calcium of the human body, and can play other important physiological roles. In addition, the glucaric acid-1, 4-lactone capable of being converted by glucaric acid has strong detoxification and oxidation resistance, can inhibit islet beta cell apoptosis to relieve diabetes induced by alloxan and relieve intestinal mucosa injury caused by irinotecan hydrochloride. Because the content of glucaric acid in fruits and vegetables is very low, the content of glucaric acid taken by diet is far lower than the level capable of inhibiting beta-glucuronidase, so that the body needs to take D-glucaric acid and related derivatives additionally to achieve the effects of preventing and treating diseases.
The key point of synthesizing the calcium glucarate is to synthesize glucaric acid, and the current methods comprise a nitric acid oxidation method and a TEMPO oxidation method, which are relatively universal methods in the field of chemical industry. The raw materials adopted by the two methods are monohydrate glucose, although the monohydrate glucose is cheaper, a large amount of oxidant is consumed in the preparation process, more waste water is generated, the reaction time is long, the yield is low, and the environmental impact is large.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide the preparation method of the calcium glucarate, which adopts D-gluconate as a raw material, has the advantages of small using amount of an oxidant, simple operation and high yield, meets the quality requirements of pharmaceutical auxiliary materials at home and abroad, has low production cost and less industrial three wastes, is suitable for industrial production and has no pollution to the environment.
Adding D-gluconate into a reaction container, cooling to-30-50 ℃, adding a catalyst, a solvent and an oxidant, and carrying out catalytic oxidation reaction to obtain a glucarate solution;
reacting the glucose diacid salt solution with calcium salt to obtain calcium glucose diacid;
wherein the D-gluconate is D-sodium gluconate, D-lithium gluconate, D-potassium gluconate, D-calcium gluconate, D-magnesium gluconate or D-zinc gluconate.
When the D-gluconate is D-calcium gluconate, the D-calcium gluconate does not need to react with calcium salt, and the calcium gluconate is directly obtained through catalytic oxidation reaction.
When the D-gluconate is D-sodium gluconate, D-lithium gluconate or D-potassium gluconate, the calcium salt is one or more of calcium oxide, calcium nitrate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium chloride or calcium bicarbonate.
When the D-gluconate is D-magnesium gluconate or D-zinc gluconate, the pH value of the glucarate solution is adjusted to be less than or equal to 3 by using acid before the D-gluconate reacts with the calcium salt, and the calcium salt is one or more of calcium oxide, calcium nitrate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium chloride or calcium bicarbonate.
The catalyst is tempo and bromide salt, and the using amount of the tempo is 0.5-20% of the molar amount of the D-gluconate, and the preferential amount is 5%; the amount of the bromide salt is 1 to 50 mol%, preferably 5 mol% of the D-gluconate salt.
The bromide salt is preferably sodium bromide.
The solvent is water.
The oxidant is sodium hypochlorite aqueous solution or chlorine and sodium hydroxide solution.
The using amount of the sodium hypochlorite aqueous solution is 2-10 times of the molar weight of the D-gluconate, and the sodium hypochlorite aqueous solution is dripped into the reaction system within 1-10 hours.
When the oxidizing agent adopts chlorine and sodium hydroxide solution, the chlorine and the sodium hydroxide solution are directly introduced into the reaction solution.
The temperature of the catalytic oxidation reaction is-30-50 ℃, and 0 ℃ is preferred; the pH value during the reaction is 4-14, preferably 7-12; the time is 2 to 15 hours, preferably 10 hours.
The calcium salt is one or more of calcium oxide, calcium hydroxide, calcium nitrate, calcium carbonate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium chloride or calcium bicarbonate, preferably calcium oxide, and has the best effect when calcium oxide is adopted.
The glucose diacid salt solution is adjusted to pH value less than or equal to 3 by acid and then reacts with calcium salt to obtain the glucose diacid calcium.
The acid is at least one of hydrochloric acid, nitric acid, acetic acid or sulfuric acid, and hydrochloric acid is preferred.
The calcium glucarate is pulped and purified at the temperature of 40-100 ℃, the pulping temperature is preferably 50 ℃, the solvent adopted for pulping is at least one of ethanol, methanol, isopropanol or water, preferably water, and the effect is best when pure water is adopted.
The pulping purification specifically comprises the following steps: pulping the crude product of calcium glucarate at 40-100 ℃, and filtering when the temperature is reduced to room temperature to obtain the pure product of calcium glucarate.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention adopts D-gluconate to prepare glucarate, and then the glucarate is converted into calcium glucarate. The preparation method is simple to operate, and the total yield of the reaction is improved by controlling the reaction conditions. The catalyst of the invention can be repeatedly used, and the production cost is reduced. Reduces the use of oxidant, has less industrial three wastes, is suitable for industrial production and has no pollution to the environment.
2. The calcium content of the calcium glucarate product prepared by the invention is 98.5-102.0%, and the calcium glucarate product meets the quality requirements of domestic and foreign pharmaceutic adjuvants.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a product obtained in example 1 of the present invention;
FIG. 2 is a mass spectrum of the product obtained in example 1 of the present invention.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.
All the starting materials used in the examples are commercially available, except where otherwise indicated.
In the present invention, g represents g, mL represents mL, mol/L represents mol/L, h represents hour, min represents minute, and tempo represents 2,2,6, 6-tetramethylpiperidine oxide.
The Nuclear Magnetic Resonance (NMR) hydrogen spectrum detection method and conditions are as follows: the instrument comprises the following steps: bruker 400MHz nuclear magnetic resonance; solvent: deuterated water.
Example 1
Adding 100mmol of D-sodium gluconate (D-lithium gluconate, D-potassium gluconate), 1% tempo, 5% sodium bromide and 200mL of water into a reaction bottle, cooling to-10-50 ℃, dropwise adding a sodium hypochlorite aqueous solution, keeping the pH value at 7-12, and continuing to react for 2 hours after dropwise adding. After the reaction, the temperature was lowered to room temperature, 200mmol of calcium chloride was added to the reaction solution, the pH was adjusted to 14, and the mixture was stirred for 10 hours. And (3) cooling the mixture to 0 ℃, filtering, adding the solid into a reaction kettle, adding water, stirring for 1 hour, carrying out suction filtration, washing the filter cake with water for three times, and drying. Pouring 27.8g (25.7g, 25.3g) of dried crude calcium glucarate into 300mL of purified water, heating to 50 ℃, adjusting the pH to 0.5 by using hydrochloric acid, then adding calcium oxide and calcium hydroxide to adjust the pH to 8-9 (wherein the effect of adding calcium oxide is better), stirring overnight, performing suction filtration, pulping a filter cake at 50 ℃ for 2h by using pure water, cooling to room temperature, stirring for 30min, performing suction filtration, leaching the filter cake for three times by using pure water, and drying to obtain 20.7g (19.2g, 18.7g) of white solid, wherein the yield is 64.7% (60.0%, 58.4%) and the calcium content is 100.5% (99.6%, 100.1%).
Example 2
Adding 100mmol of D-calcium gluconate, 1% of tempo, 5% of sodium bromide and 200mL of water into a reaction tank, cooling to-30-50 ℃, dropwise adding a sodium hypochlorite aqueous solution, keeping the pH value at 7-12, and continuing to react for 2 hours after dropwise adding. After the reaction, the temperature is reduced to room temperature, the solution is filtered, and the solid is washed with purified water for three times and dried. Pouring 29.7g of dried crude calcium glucarate into 300mL of purified water, heating to 50 ℃, adjusting the pH to 0.5 by using hydrochloric acid, then adding sodium hydroxide to adjust the pH to 8-9, stirring overnight, performing suction filtration, pulping a filter cake at 50 ℃ for 2h by using pure water, cooling to room temperature, stirring for 30min, performing suction filtration, leaching the filter cake for three times by using pure water, and drying to obtain 26.5g of white solid, wherein the yield is 82.8%, and the calcium content is 100.2%.
Example 3
Adding 100mmol of D-magnesium gluconate (D-zinc gluconate), 1% tempo, 5% sodium bromide and 200mL of water into a reaction tank, cooling to-30-50 ℃, dropwise adding a sodium hypochlorite aqueous solution, keeping the pH value at 7-12, and continuing to react for 2 hours after dropwise adding. After the reaction, the temperature is reduced to room temperature, hydrochloric acid is added to adjust the pH value to 1.5, then 200mmol of calcium oxide is added to adjust the pH value to 14, and the mixture is stirred for 10 hours. And (3) cooling the mixture to 0 ℃, filtering, adding the solid into a reaction kettle, adding water, stirring for 1 hour, carrying out suction filtration, washing the filter cake with water for three times, and drying. Pouring 18.7g of dried crude calcium glucarate into 150mL of pure water, heating to 50 ℃, adjusting the pH to 0.5-1.5 by using hydrochloric acid, then adding calcium phosphate, calcium hydrogen phosphate and calcium dihydrogen phosphate to adjust the pH to 8-9, stirring overnight, performing suction filtration, pulping a filter cake at 50 ℃ by using pure water for 2 hours, cooling to room temperature, stirring for 30 minutes, performing suction filtration, leaching the filter cake for three times by using pure water, and drying to obtain 16.5g of white solid, wherein the yield is 51.6% and the calcium content is 99.8%.
Example 4
And (3) adding 100mmol of D-calcium gluconate, 1% of tempo, 5% of sodium bromide and 200mL of water into a reaction tank, cooling to-30-50 ℃, introducing chlorine into the reaction system, simultaneously dropwise adding a sodium hydroxide aqueous solution, keeping the pH value at 7-12, adding methanol after the intermediate control reaction is finished, and continuing to react for 2 hours. Cooled to room temperature, filtered, and the solid washed three times with purified water and dried. Pouring 27.6g of dried crude calcium glucarate into 300mL of purified water, adjusting the pH to 0.5 by using hydrochloric acid, then adding solid calcium carbonate, calcium nitrate and calcium bicarbonate to adjust the pH to 8-9, stirring overnight, performing suction filtration, pulping a filter cake for 2 hours at 100 ℃ by using pure water, cooling to room temperature, stirring for 1 hour, performing suction filtration, leaching the filter cake for three times by using pure water, and drying to obtain 23.2g of white solid, wherein the yield is 72.5% and the calcium content is 99.6%.
The calcium glucarate tetrahydrate products obtained in the examples were tested according to the methods related to the United states pharmacopoeia and European pharmacopoeia, and the test results are shown in Table 1.
TABLE 1 test results
Claims (10)
1. A preparation method of calcium glucarate is characterized by comprising the following steps: adding D-gluconate into a reaction container, cooling to-30-50 ℃, adding a catalyst, a solvent and an oxidant, and carrying out catalytic oxidation reaction to obtain a glucarate solution;
reacting the glucose diacid salt solution with calcium salt to obtain calcium glucose diacid;
wherein the D-gluconate is D-sodium gluconate, D-lithium gluconate, D-potassium gluconate, D-calcium gluconate, D-magnesium gluconate or D-zinc gluconate.
2. The method for producing calcium glucarate according to claim 1, characterized in that: the catalyst is tempo and bromide salt, the dosage of the tempo is 0.5-20% of the molar weight of the D-gluconate, and the dosage of the bromide salt is 1-50% of the molar weight of the D-gluconate.
3. The method for producing calcium glucarate according to claim 1, characterized in that: the solvent is water.
4. The method for producing calcium glucarate according to claim 1, characterized in that: the oxidant is sodium hypochlorite aqueous solution or chlorine and sodium hydroxide solution.
5. The method for producing calcium glucarate according to claim 4, characterized in that: the using amount of the sodium hypochlorite aqueous solution is 2-10 times of the molar weight of the D-gluconate, and the sodium hypochlorite aqueous solution is dripped into the reaction system within 1-10 hours.
6. The method for producing calcium glucarate according to claim 1, characterized in that: the temperature of the catalytic oxidation reaction is-30-50 ℃, the pH value of the reaction is 4-14, and the time is 2-15 hours.
7. The method for producing calcium glucarate according to claim 1, characterized in that: the calcium salt is one or more of calcium oxide, calcium hydroxide, calcium nitrate, calcium carbonate, calcium hydrophosphate, calcium phosphate, calcium dihydrogen phosphate, calcium chloride or calcium bicarbonate.
8. The method for producing calcium glucarate according to claim 1, characterized in that: the glucose diacid salt solution is adjusted to pH value less than or equal to 3 by acid and then reacts with calcium salt to obtain the glucose diacid calcium.
9. The method for producing calcium glucarate according to claim 8, characterized in that: the acid is at least one of hydrochloric acid, nitric acid, acetic acid or sulfuric acid.
10. The method for producing calcium glucarate according to claim 1 or 8, characterized in that: the calcium gluconate diphosphate is pulped and purified at the temperature of 40-100 ℃, and the solvent adopted by pulping is at least one of ethanol, methanol, isopropanol or water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010258771.6A CN113493379A (en) | 2020-04-03 | 2020-04-03 | Preparation method of calcium glucarate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010258771.6A CN113493379A (en) | 2020-04-03 | 2020-04-03 | Preparation method of calcium glucarate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113493379A true CN113493379A (en) | 2021-10-12 |
Family
ID=77995084
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010258771.6A Pending CN113493379A (en) | 2020-04-03 | 2020-04-03 | Preparation method of calcium glucarate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113493379A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101503434A (en) * | 2008-12-11 | 2009-08-12 | 江苏天士力帝益药业有限公司 | Method for synthesizing glucurolactone |
| JP2016060712A (en) * | 2014-09-17 | 2016-04-25 | 旭化成株式会社 | Method for producing compound having two or more carboxyl groups from primary alcohol, and catalyst used therefor |
| CN107188795A (en) * | 2017-06-05 | 2017-09-22 | 中国石油大学(华东) | A kind of method that low-temperature catalytic oxidation method prepares saccharic acid |
| CN109678695A (en) * | 2019-01-21 | 2019-04-26 | 江苏东南纳米材料有限公司 | A kind of preparation method of antacidin |
| CN110256234A (en) * | 2019-07-02 | 2019-09-20 | 扬州中宝药业股份有限公司 | A kind of preparation method of calcium gluconate |
-
2020
- 2020-04-03 CN CN202010258771.6A patent/CN113493379A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101503434A (en) * | 2008-12-11 | 2009-08-12 | 江苏天士力帝益药业有限公司 | Method for synthesizing glucurolactone |
| JP2016060712A (en) * | 2014-09-17 | 2016-04-25 | 旭化成株式会社 | Method for producing compound having two or more carboxyl groups from primary alcohol, and catalyst used therefor |
| CN107188795A (en) * | 2017-06-05 | 2017-09-22 | 中国石油大学(华东) | A kind of method that low-temperature catalytic oxidation method prepares saccharic acid |
| CN109678695A (en) * | 2019-01-21 | 2019-04-26 | 江苏东南纳米材料有限公司 | A kind of preparation method of antacidin |
| CN110256234A (en) * | 2019-07-02 | 2019-09-20 | 扬州中宝药业股份有限公司 | A kind of preparation method of calcium gluconate |
Non-Patent Citations (3)
| Title |
|---|
| MATHIAS IBERT等: "Improved preparative electrochemical oxidation of D-glucose to D-glucaric acid", ELECTROCHIMICA ACTA, vol. 55, pages 3589 - 3594, XP026965244 * |
| 仇钰莹等: "葡萄糖二酸研究进展", 生物工程学报, vol. 31, no. 4, pages 481 - 490 * |
| 朱俏俏等: "生物质基葡萄糖二酸的研究与展望", 工业催化, vol. 27, no. 9, pages 13 - 18 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102250261B (en) | New method for producing iron dextran | |
| CN109678695B (en) | Preparation method of calcium glucarate | |
| CN114031551B (en) | Fluopicolide and synthesis method thereof | |
| CN113493379A (en) | Preparation method of calcium glucarate | |
| CN102827015B (en) | Preparation method of 5-aminolevulinic acid (ALA) hydrochloride | |
| CN101781264B (en) | Production method of 1-methyl-5-mercapto-1,2,3,4-tetrazole | |
| SU843749A3 (en) | Method of preparing 4a,9b-trans-hexahydro-gamma-carboline | |
| CN114890999B (en) | Preparation method of PQQ | |
| US4041079A (en) | Bicyclic compounds | |
| CN111518156B (en) | One-step preparation method of astragaloside | |
| CN100519514C (en) | Method of preparing D-p-hydroxyphenylglycine | |
| CN114213335A (en) | Carnosine intermediate and preparation and application of carnosine | |
| CN111574387A (en) | P-aminomethyl benzoic acid and preparation method thereof | |
| CN113735798A (en) | Preparation method of roxatidine acetate hydrochloride | |
| CN117623903A (en) | Preparation method of D-calcium glucarate | |
| CN115286593B (en) | Preparation method of dibenzothiazyl disulfide serving as rubber vulcanization accelerator | |
| SU576937A3 (en) | Method of preparing mono-o-b-oxoethyl-7-rutine | |
| CN115403461B (en) | Method for synthesizing benzoic acid by oxidizing ethylbenzene | |
| CN109956886B (en) | Preparation method of ethyl (Z) - [ (4-methoxyphenyl) hydrazono ] chloroacetate | |
| CN109761801B (en) | Novel method for preparing ketovaline calcium | |
| CN110105362B (en) | Safe and green folic acid synthesis method catalyzed by heteropoly acid | |
| CN112142705B (en) | Method for synthesizing cromolyn sodium key intermediate 7-hydroxy-4-methylcoumarin | |
| CN111499531B (en) | Method for preparing dimethyl aminophthalate | |
| CN111499533B (en) | Method for preparing acetamino dimethyl phthalate | |
| JP2009062392A (en) | Cyclization process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |