A preparation method of medicinal creatinine

Abstract

The invention discloses a preparation method of medicinal creatinine, comprising the following steps: (1) ethyl 2-(cyanomethylamino)acetate and a polar solvent are sequentially added to a reaction vessel, stirred and dissolved; an alkaline catalyst is added; the temperature is cooled to 0-10 DEG C, 7M ammonia methanol solution is added dropwise, stirring is continued, and a reaction solution containing creatinine is obtained; (2) a macroporous strongly acidic cation exchange resin activated by hydrochloric acid is added to the reaction solution containing creatinine, the temperature is raised, stirring is performed, hot filtration is performed, and filter cake is recycled and regenerated, and filtrate is collected; (3) the filtrate obtained by step (2) is concentrated under reduced pressure, solid is precipitated, and filter cake is obtained; (4) the filter cake obtained by step (3) is immersed in a polar solvent, beating is performed, and a beating mixed solution is obtained; filtering, filter cake is washed with a polar solvent, and reduced pressure drying is performed to obtain medicinal creatinine. The method of the present invention is simple to operate, raw materials are easily available, operation safety is high, environmentally friendly and pollution-free, and it is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceuticals, and particularly relates to a method for preparing medicinal creatinine. Background Art

[0002] Creatinine, also known as creatinine or 2-amino-1-methylimidazoline-4-one, is a white crystal with a molecular formula of C4H7N3O. It is a polar organic nitrogen-containing compound with a low molecular weight (Mr = 113.12). It decomposes when heated to 300°C, is soluble in water, slightly soluble in ethanol, and almost insoluble in ether, acetone and chloroform. Creatinine is the end product of creatine metabolism in mammals. This metabolic process mainly occurs in skeletal muscle and releases energy at the same time. The concentration of creatinine in body fluids is mainly related to the glomerular filtration rate (GFR). In clinical practice, the concentration of creatinine is used as an indicator to measure the glomerular filtration rate and evaluate kidney function. Therefore, the determination of creatinine content is a key biochemical indicator in clinical testing.

[0003] Creatinine has many applications in the pharmaceutical field. First, creatinine can be used as a biomarker in drug development to evaluate drug metabolism and renal clearance. Second, creatinine can also be used as an evaluation indicator of drug stability and compatibility to help pharmaceutical companies optimize drug preparations and formulations.

[0004] Pharmaceutical creatinine has been included in the United States Pharmacopoeia as a pharmaceutical excipient. At the same time, creatinine is used as a pharmaceutical excipient in a variety of pharmaceutical preparations approved for marketing by the U.S. Food and Drug Administration (FDA), such as sunscreen cream (trade name: Regeneration Wrinkle Control Cream SPF 15) and dexamethasone sodium phosphate solution (trade name: Dexamethasone Sodium Phosphate).

[0005] The existing creatinine preparation technology mainly uses creatine as a raw material and undergoes intramolecular acid-amine condensation under acidic conditions. Creatinine and the inorganic acid are salted with inorganic acid, and alkali needs to be added for post-treatment to neutralize and remove inorganic salt ions. The invention patent with Chinese patent number CN109438360A discloses a method for synthesizing creatinine using creatine as a raw material under the action of low-level saturated fatty acids containing 2-5 carbons. Although this method uses organic acids to replace inorganic acids, the boiling point of organic acids is high, and organic acids are easy to remain, and the removal cost is high. Because the acid-amine condensation reaction is reversible, it is difficult to convert completely, and side reactions are prone to occur to obtain intermolecular condensation products, and the yield is low. The creatinine obtained by the traditional method contains chlorides, organic acid salts, moisture, organic solvents, creatine and other impurities, and the quality is poor. However, domestic pharmaceutical customers have put forward higher requirements for the pharmaceutical quality standards of creatinine based on the existing production technology of creatinine. In addition to the content, impurities, and loss on drying test items specified by the United States Pharmacopoeia USP-NF2024, they have also added acid value, chloride, moisture, residue on ignition, residual solvents, heavy metals and other test items.

[0006] Therefore, in order to improve the quality of pharmaceutical creatinine products and meet the needs of formulation customers, it is urgent to develop a preparation method for pharmaceutical creatinine with few by-products, low impurity content, no acid salt residue, good quality, high yield, low production cost, and suitable for industrial production. Summary of the invention

[0007] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing medicinal creatinine with simple process, high conversion rate, low impurity content, mild reaction conditions, low cost and product quality standards that meet enterprise standards.

[0008] The technical solution of the present invention is summarized as follows:

[0009] A method for preparing medicinal creatinine comprises the following steps:

[0010] (1) adding ethyl 2-(cyanomethylamino)acetate (I) and a polar solvent in a mass ratio of 1:5.5 to 12.5 to a reaction vessel, stirring and dissolving; adding a basic catalyst equivalent to 1.2% to 5.0% of the molar amount of ethyl 2-(cyanomethylamino)acetate; cooling to 0 to 10° C., adding dropwise a 7M ammonia methanol solution, continuing stirring, reacting at 10 to 30° C. for 0.5 to 1.5 hours, and obtaining a reaction solution containing creatinine (II); the molar ratio of ethyl 2-(cyanomethylamino)acetate to 7M ammonia methanol solution is 1:1.6 to 4.2;

[0011] The reaction equation is:

[0012]

[0013] (2) adding a macroporous strongly acidic cation exchange resin activated by hydrochloric acid to a reaction solution containing creatinine (II), heating to 40 to 70° C., stirring for 0.5 to 1 hour, filtering at 40 to 70° C., recovering and regenerating the filter cake, and collecting the filtrate;

[0014] (3) the filtrate obtained in step (2) is concentrated under reduced pressure to 10% to 15% of the volume of the filtrate, solid is precipitated, and filtered to obtain a filter cake;

[0015] (4) Immersing the filter cake obtained in step (3) in a polar solvent, stirring and beating at 0-30° C. for 0.5-1.5 hours to obtain a beating mixture; filtering, washing the filter cake with a polar solvent, and drying under reduced pressure for 2-4 hours to obtain medicinal creatinine.

[0016] Preferably, in step (1), the molar ratio of ethyl 2-(cyanomethylamino)acetate to 7M ammonia methanol solution is 1:2.5-3.3.

[0017] Preferably, the alkaline catalyst in step (1) is sodium methoxide, sodium ethoxide or potassium methoxide.

[0018] Preferably, the amount of the macroporous strongly acidic cation exchange resin activated by hydrochloric acid added is equivalent to 6 to 10 times the mass of the alkaline catalyst.

[0019] The macroporous strongly acidic cation exchange resin is preferably: D002 macroporous strongly acidic styrene cation exchange resin, 011×7 macroporous strongly acidic acrylic acid cation exchange resin or HD-8 macroporous strongly acidic cation exchange resin.

[0020] Preferably, the polar solvent in step (1) is dichloromethane, tetrahydrofuran, methanol or ethanol; and the polar solvent in step (4) is dichloromethane, tetrahydrofuran, methanol or ethanol.

[0021] Preferably, the temperature of the reduced pressure drying in step (4) is 40 to 75°C.

[0022] Advantages of the present invention:

[0023] 1. The method of the present invention is to use ethyl 2-(cyanomethylamino)acetate as a raw material, and then undergo nucleophilic addition with 7M ammonia methanol solution and then undergo amine ester exchange ring closing reaction to obtain creatinine, with mild reaction conditions, fast reaction rate and high reaction yield;

[0024] 2. The present invention selects dichloromethane, tetrahydrofuran, methanol or ethanol as the reaction and purification solvent according to the difference in solubility. The impurities such as unreacted raw materials and by-products in the reaction solution can be effectively removed by the pulping method, and the obtained creatinine content is more than 99.9%;

[0025] 3. The present invention uses a macroporous strongly acidic cation exchange resin activated by hydrochloric acid to neutralize the alkaline catalyst, thereby avoiding creatinine salt formation, and the product has no chloride and acid salt residues. The post-treatment is simple, the macroporous strongly acidic cation exchange resin can be recycled and regenerated, and no waste solid is generated;

[0026] 4. Compared with the traditional production process, the medicinal creatinine prepared by the method of the present invention has higher creatinine content, no acid salt residue, low moisture, high yield, simple operation, and product quality standards fully meet the enterprise standards (quality standards refer to USP-NF2024, and other test items are supplemented as enterprise standards), meeting the medicinal needs;

[0027] 5. The production process used in the present invention is simple to operate, the raw materials are readily available, the operation is highly safe, the environment is friendly and pollution-free, and it is suitable for industrial production. DETAILED DESCRIPTION

[0028] The present invention is further described in detail below through specific examples, which should not be construed as limiting the claims of the present invention.

[0029] The macroporous strongly acidic cation exchange resin used in the present invention is:

[0030] D002 macroporous strongly acidic styrene cation exchange resin (Hebei Chaoyan Energy Saving Technology Co., Ltd.), 011×7 macroporous strongly acidic acrylic acid cation exchange resin (Shanghai Jinkai Resin Co., Ltd.) or HD-8 macroporous strongly acidic cation exchange resin (Shanghai Xuanya Biotechnology Co., Ltd.) are taken as examples, but the present invention is not limited thereto.

[0031] Preparation of macroporous strongly acidic cation exchange resin activated by hydrochloric acid:

[0032] Take 100g of macroporous strongly acidic cation exchange resin, add it to 300mL of saturated salt water, soak it for 6 hours, filter it, and wash it with 300mL of distilled water; soak it with 300mL of 3% sodium hydroxide aqueous solution for 2 hours, filter it, and wash it with distilled water until it is neutral; soak it with 300mL of 5% hydrochloric acid aqueous solution for 2 hours, filter it, and wash it with distilled water until it is neutral; finally, dry it in an oven at 70°C for 4 hours for use.

[0033] Example 1

[0034] A method for preparing medicinal creatinine comprises the following steps:

[0035] (1) Add ethyl 2-(cyanomethylamino)acetate (I) (1 kg, 7.04 mol) to a reaction vessel, add 5.5 kg of methanol, and stir to dissolve; add sodium methoxide (4.56 g, 0.084 mol); cool to 10° C., and dropwise add 7M ammonia methanol solution (1.61 L, 11.27 mol); continue stirring, heat to 30° C., and react for 0.5 hours to obtain a reaction solution containing creatinine (II);

[0036] (2) adding 45.6 g of HD-8 macroporous strong acidic cation exchange resin activated by hydrochloric acid to the reaction solution containing creatinine (II), heating to 60° C., stirring for 0.5 hour, filtering at 60° C., recovering the filter cake, and collecting the filtrate;

[0037] (3) The filtrate obtained in step (2) is concentrated under reduced pressure to 10% of the volume of the filtrate, solid is precipitated, and filtered to obtain a filter cake;

[0038] (4) The filter cake obtained in step (3) is immersed in 800 mL of methanol, stirred and slurried at 30° C. for 0.5 hours to obtain a slurried mixture; filtered, the filter cake is washed with 300 mL of methanol, and dried under reduced pressure for 4 hours at a drying temperature of 40° C. to obtain medicinal creatinine.

[0039] After sampling and testing, the product was qualified and then packaged and stored. 769.31g of medicinal creatinine was obtained, and the purification yield was 96.67%. After inspection, the quality indicators all met the enterprise standards, as shown in Table 1.

[0040] Example 2

[0041] A method for preparing medicinal creatinine comprises the following steps:

[0042] (1) Add ethyl 2-(cyanomethylamino)acetate (I) (1 kg, 7.04 mol) to a reaction vessel, add 12.5 kg of dichloromethane, and stir to dissolve; add sodium ethoxide (19.01 g, 0.352 mol); cool to 0°C, and dropwise add 7M ammonia methanol solution (4.22 L, 29.54 mol); continue stirring, heat to 10°C, and react for 1.5 hours to obtain a reaction solution containing creatinine (II);

[0043] (2) adding 114.05 g of D002 macroporous strong acid styrene cation exchange resin activated by hydrochloric acid to the reaction solution containing creatinine (II), heating to 40° C., stirring for 1 hour, filtering at 40° C., recovering the filter cake, and collecting the filtrate;

[0044] (3) the filtrate obtained in step (2) is concentrated under reduced pressure to 15% of the volume of the filtrate, solid is precipitated, and filtered to obtain a filter cake;

[0045] (4) The filter cake obtained in step (3) is immersed in 800 mL of dichloromethane, stirred and slurried at 0° C. for 1.5 hours to obtain a slurried mixture; filtered, the filter cake is washed with 300 mL of dichloromethane, and dried under reduced pressure for 2 hours at a drying temperature of 75° C. to obtain medicinal creatinine.

[0046] After sampling and testing, the product was qualified and then packaged and stored. 764.85g of medicinal creatinine was obtained, and the purification yield was 96.12%. After inspection, the quality indicators all met the enterprise standards, as shown in Table 1.

[0047] Example 3

[0048] A method for preparing medicinal creatinine comprises the following steps:

[0049] (1) Add ethyl 2-(cyanomethylamino)acetate (I) (1 kg, 7.04 mol) to a reaction vessel, add 8.6 kg of tetrahydrofuran, and stir to dissolve; add sodium methoxide (9.50 g, 0.176 mol); cool to 4°C, and dropwise add 7M ammonia methanol solution (3.32 L, 23.24 mol); continue stirring, heat to 20°C, and react for 1 hour to obtain a reaction solution containing creatinine (II);

[0050] (2) adding 76 g of 011×7 macroporous strongly acidic acrylic acid cation exchange resin activated by hydrochloric acid to the reaction solution containing creatinine (II), heating to 65° C., stirring for 0.8 hours, filtering at 65° C., recovering the filter cake, and collecting the filtrate;

[0051] (3) the filtrate obtained in step (2) is concentrated under reduced pressure to 13% of the volume of the filtrate, solid is precipitated, and the solid is filtered to obtain a filter cake;

[0052] (4) The filter cake obtained in step (3) is immersed in 800 mL of tetrahydrofuran, stirred and slurried at 20° C. for 1 hour to obtain a slurried mixture; filtered, the filter cake is washed with 300 mL of tetrahydrofuran, and dried under reduced pressure for 3 hours at a drying temperature of 60° C. to obtain medicinal creatinine.

[0053] After sampling and testing, the product was qualified and then packaged and stored. 775.99g of medicinal creatinine, purification yield 97.51%. After inspection, the quality indicators all met the enterprise standards, see Table 1.

[0054] Example 4

[0055] A method for preparing medicinal creatinine comprises the following steps:

[0056] (1) Add ethyl 2-(cyanomethylamino)acetate (I) (1 kg, 7.04 mol) to a reaction vessel, add 10 kg of ethanol, and stir to dissolve; add potassium methoxide (11.39 g, 0.211 mol); cool to 10° C., and dropwise add 7M ammonia methanol solution (2.51 L, 17.60 mol); continue stirring, raise the temperature to 10° C., and react for 1.5 hours; obtain a reaction solution containing creatinine (II);

[0057] (2) adding 68.34 g of D002 macroporous strong acid styrene cation exchange resin activated by hydrochloric acid to the reaction solution containing creatinine (II), heating to 70° C., stirring for 0.5 hour, filtering at 70° C., recovering the filter cake, and collecting the filtrate;

[0058] (3) the filtrate obtained in step (2) is concentrated under reduced pressure to 13% of the volume of the filtrate, solid is precipitated, and the solid is filtered to obtain a filter cake;

[0059] (4) The filter cake obtained in step (3) is immersed in 800 mL of ethanol, stirred and slurried at 30° C. for 1.5 hours to obtain a slurried mixture; filtered, the filter cake is washed with 300 mL of ethanol, and dried under reduced pressure for 3 hours at a drying temperature of 70° C. to obtain medicinal creatinine.

[0060] After sampling and testing, the product was qualified and then packaged and stored. 774.55g of medicinal creatinine was obtained, and the purification yield was 97.33%. After inspection, the quality indicators all met the enterprise standards, as shown in Table 1.

[0061] Example 5

[0062] A method for preparing medicinal creatinine comprises the following steps:

[0063] (1) Add ethyl 2-(cyanomethylamino)acetate (I) (1 kg, 7.04 mol) to a reaction vessel, add 7 kg of methanol, and stir to dissolve; add sodium ethoxide (13.28 g, 0.246 mol); cool to 10° C., and dropwise add 7 M ammonia methanol solution (1.61 L, 11.27 mol); continue stirring, raise the temperature to 25° C., and react for 1 hour; obtain a reaction solution containing creatinine (II);

[0064] (2) adding 132.8 g of 011×7 macroporous strongly acidic acrylic acid cation exchange resin activated by hydrochloric acid to the reaction solution containing creatinine (II), heating to 50° C., stirring for 0.5 hour, filtering at 50° C., recovering the filter cake, and collecting the filtrate;

[0065] (3) the filtrate obtained in step (2) is concentrated under reduced pressure to 12% of the volume of the filtrate, solid is precipitated, and filtered to obtain a filter cake;

[0066] (4) The filter cake obtained in step (3) is immersed in 800 mL of methanol, stirred and slurried at 15° C. for 1 hour to obtain a slurried mixture; filtered, the filter cake is washed with 300 mL of methanol, and dried under reduced pressure for 4 hours at a drying temperature of 55° C. to obtain medicinal creatinine.

[0067] After sampling and testing, the product was qualified and then packaged and stored. 772.01g of medicinal creatinine was obtained, and the purification yield was 97.01%. After inspection, the quality indicators all met the enterprise standards, as shown in Table 1.

[0068] Table 1 Enterprise standards and test results of creatinine

[0069]

[0070] Note: ﹡ refers to the USP-NF2024 creatinine quality standard.

Claims

1. A method for preparing medicinal creatinine, characterized in that The following steps are involved: (1) adding ethyl 2-(cyanomethylamino)acetate and a polar solvent to a reaction vessel in a mass ratio of 1:5.5-12.5, stirring and dissolving; adding a basic catalyst equivalent to 1.2%-5.0% of the molar amount of ethyl 2-(cyanomethylamino)acetate; cooling to 0-10° C., adding dropwise a 7M ammonia methanol solution, continuing stirring, reacting at 10-30° C. for 0.5-1.5 hours, and obtaining a reaction solution containing creatinine; the molar ratio of ethyl 2-(cyanomethylamino)acetate to 7M ammonia methanol solution is 1:1.6-4.2; (2) adding a macroporous strongly acidic cation exchange resin activated by hydrochloric acid to the reaction solution containing creatinine, heating to 40 to 70° C., stirring for 0.5 to 1 hour, filtering at 40 to 70° C., recovering the filter cake, and collecting the filtrate; (3) the filtrate obtained in step (2) is concentrated under reduced pressure to 10% to 15% of the volume of the filtrate, solid is precipitated, and filtered to obtain a filter cake; (4) immersing the filter cake obtained in step (3) in a polar solvent, stirring and beating at 0 to 30° C. for 0.5 to 1.5 hours to obtain a beating mixture; filtering, washing the filter cake with a polar solvent, and drying under reduced pressure for 2 to 4 hours to obtain medicinal creatinine; In the step (1), the alkaline catalyst is sodium methoxide, sodium ethoxide or potassium methoxide.

2. The method for preparing a medicinal creatinine according to claim 1, characterized in that In the step (1), the molar ratio of ethyl 2-(cyanomethylamino)acetate to 7M ammonia methanol solution is 1:2.5-3.

3.

3. The method for preparing a medicinal creatinine according to claim 1, characterized in that The amount of the macroporous strongly acidic cation exchange resin activated by hydrochloric acid is equivalent to 6 to 10 times the mass of the alkaline catalyst.

4. A method for preparing a medicinal creatinine according to claim 1 or 3, characterized in that The macroporous strongly acidic cation exchange resin is D002 macroporous strongly acidic styrene cation exchange resin, 011×7 macroporous strongly acidic acrylic acid cation exchange resin or HD-8 macroporous strongly acidic cation exchange resin.

5. The method for preparing a medicinal creatinine according to claim 1, characterized in that The polar solvent in step (1) is dichloromethane, tetrahydrofuran, methanol or ethanol; the polar solvent in step (4) is dichloromethane, tetrahydrofuran, methanol or ethanol.

6. The method for preparing a medicinal creatinine according to claim 1, characterized in that The temperature of the reduced pressure drying in the step (4) is 40 to 75°C.

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