Preparation method of creatinine phosphate disodium salt

Abstract

The invention provides a creatinine phosphate disodium salt preparation method, which comprises: under an inert gas atmosphere, using creatinine and trimethyl phosphate as raw materials, and under the catalysis effect of an MOFs crystal material, carrying out a reaction to obtain dimethyl creatinine phosphate, and reacting the creatinine phosphate dimethyl ester under the action of a demethylation reagent and alkali in sequence to obtain the creatinine phosphate disodium salt. Creatinine and trimethyl phosphate are adopted to react, phosphorus oxychloride is not used, the process conditions are mild, and the amplification requirement can be met; the MOFs crystal material is used for adsorbing methanol generated in the reaction, the yield of the reaction is remarkably improved, and in addition, the MOFs crystal material can be recycled and is environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing creatinine phosphate disodium salt. Background Art

[0002] As an important pharmaceutical intermediate, creatinine disodium salt is widely used in the pharmaceutical field. As a myocardial protective drug, it has been widely used in the prevention and adjuvant treatment of various heart diseases. Due to its good efficacy and no toxic side effects, its medical value ranks first among similar drugs. The preparation methods of creatinine disodium salt mainly include biological extraction method, enzyme method and chemical synthesis method.

[0003] Since the biological extraction method uses muscle tissue as raw material and the content of creatinine phosphate in muscle tissue is relatively low, the cost is relatively high; the reaction conditions of the enzymatic method are difficult to control, and the enzyme protein needs to be removed after the reaction, and the process operation is cumbersome; chemical synthesis is the main method for preparing disodium creatinine phosphate.

[0004] At present, creatinine phosphate disodium salt is mainly prepared by reacting creatinine with phosphorus oxychloride and then reacting with sodium hydroxide to form sodium salt to obtain the final product. This scheme requires the use of a large amount of phosphorus oxychloride, which causes serious environmental pollution. In addition, whether it is the raw materials, the feeding process, or the reaction process, the requirements for moisture are relatively strict, the conditions are harsh, there are many by-products, the product purity is low, and separation and purification are difficult, which makes it difficult to meet the needs of industrial scale-up production.

[0005] Prior art CN 112010895 A discloses reacting tetrabenzyl pyrophosphate with creatinine in a first solvent under the action of a first catalyst to obtain dibenzyl creatinine phosphate; step two, hydrogenating dibenzyl creatinine phosphate in a second solvent under the action of a second catalyst to remove the benzyl group to obtain creatinine phosphate; step three, using sodium hydroxide solution to open the creatinine phosphate, and salting to obtain sodium creatine phosphate. The reaction atom utilization rate in this patent is low, not only heavy metal catalysts are used to hydrogenate and remove the benzyl group, but also it is limited by the reaction equipment, which is not conducive to amplification production, and toluene is produced, which has a great negative impact on human health and the ecological environment. The general yield is less than 80%, and the average yield is about 60%.

[0006] Therefore, how to provide a method for preparing disodium phosphocreatinine salt which avoids the use of highly toxic phosphorus oxychloride, does not generate phosphorus-containing wastewater, has low reaction cost and high yield, and can meet the requirements of production scale-up has become an urgent problem to be solved. Summary of the invention

[0007] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for preparing disodium creatinine phosphate. The preparation method provided by the present invention avoids the use of highly toxic phosphorus oxychloride, does not generate phosphorus-containing wastewater, has low reaction cost and high yield, and can meet the requirements of production scale-up.

[0008] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0009] The first object of the present invention is to provide a method for preparing creatinine phosphate disodium salt, comprising the following steps:

[0010] (1) In an inert gas atmosphere, creatinine and trimethyl phosphate are used as raw materials, and dimethyl phosphate creatinine is obtained by reaction under the catalytic action of MOFs crystal materials;

[0011] (2) Creatinine phosphate dimethyl ester is reacted with a demethylating agent and a base in sequence to obtain the creatinine phosphate disodium salt.

[0012] Specifically, the MOFs crystal material is [Zn4O(L)3] n ; where L is R is one selected from H, halogen, trifluoromethoxy, and formyl.

[0013] Preferably, the preparation method of the MOFs crystal material comprises the following steps: adding a solvent to dissolve Zn(NO3)2·xH2O, and then adding The mixed reaction is followed by post-treatment to obtain a MOFs crystalline material, wherein x=4 or 6.

[0014] More preferably, the temperature of the mixed reaction is 80-120°C, and the reaction time is 48-120h; further preferably, the temperature of the mixed reaction can be 80°C, 90°C, 100°C, 110°C or 120°C, and the reaction time can be 48h, 50h, 60h, 70h, 80h, 90h, 100h, 110h or 120h, but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are equally applicable.

[0015] More preferably, the post-treatment is to slowly cool the mixture to 40-60° C. and filter the mixture under a nitrogen atmosphere to obtain the MOFs crystalline material.

[0016] More preferably, Zn(NO3)2·xH2O and The molar ratio of feed is 1:(0.65~0.75);

[0017] More preferably, the solvent is one or more selected from N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide;

[0018] More preferably, the volume of the solvent is 15-30 times the mass of Zn(NO3)2·xH2O.

[0019] Specifically, the mass ratio of creatinine to MOFs crystal material is 1:(0.5-1.0); the feeding molar ratio of creatinine to trimethyl phosphate is 1:(1-1.1).

[0020] Specifically, the demethylation agent is one selected from trimethylsilyl iodide, trimethylsilyl chloride and sodium iodide, trimethylsilyl chloride and lithium iodide, and the base is one selected from sodium bicarbonate, sodium carbonate, and sodium hydroxide;

[0021] Preferably, the molar ratio of the dimethyl creatinine phosphate to the demethylation agent is 1:(1-1.5).

[0022] Specifically, in step (1), the reaction temperature is 70-90°C, and the reaction time is 3-5h; preferably, the reaction temperature is 70°C, 75°C, 80°C, 85°C, or 90°C, and the reaction time can be 3.0h, 3.2h, 3.4h, 3.6h, 3.8h, 4.0h, 4.2h, 4.4h, 4.6h, 4.8h or 5.0h, but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable;

[0023] Preferably, in step (1), after the reaction, post-treatment is further included, wherein the MOFs crystal material is removed by hot filtration, and then the temperature is slowly cooled to room temperature, and a non-polar solvent is added dropwise to precipitate the product, and the product is filtered under a nitrogen atmosphere to obtain white crystals, which are placed in a vacuum drying oven at 40 to 50° C. and dried for 4 to 6 hours to obtain the dimethyl creatinine phosphate;

[0024] More preferably, the non-polar solvent is at least one selected from n-hexane, cyclohexane and n-heptane.

[0025] Specifically, in step (2), dimethyl creatinine phosphate needs to be dissolved in a mixed solvent first, and then reacted with a demethylation reagent for the next step;

[0026] Preferably, the mixed solvent comprises a first solvent and a second solvent, the first solvent is one or more selected from N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide; the second solvent is one selected from dichloromethane, chloroform and 1,1-dichloroethane;

[0027] More preferably, the volume ratio of the first solvent to the second solvent is 1:(0.8-2).

[0028] Specifically, in step (2), the demethylation reagent is added dropwise under the condition of ice bath and light avoidance, and the stirring reaction time is 3 to 6 hours; after the reaction, the reaction solution is concentrated, the third solvent is added to the concentrated solution, the pH of the reaction solution is adjusted to 6.0 to 8.0 with a base, and the fourth solvent is added dropwise to precipitate the product, and the product is filtered under nitrogen atmosphere, and the product is placed in a vacuum drying oven at 40 to 50° C. and dried for 3 to 6 hours to obtain the disodium creatinine phosphate;

[0029] Preferably, the third solvent is at least one selected from methanol, ethanol, and acetone; the fourth solvent is at least one selected from diethyl ether, tert-methyl ether, cyclopentyl methyl ether, tetrahydrofuran, and 1,4-dioxane.

[0030] Compared with the prior art, the present invention provides a method for preparing disodium creatinine phosphate, which has the following beneficial effects:

[0031] (1) Creatinine is reacted with trimethyl phosphate to avoid the use of phosphorus oxychloride. The process conditions are mild and can meet the needs of scale-up.

[0032] (2) The use of MOFs crystal materials to adsorb the methanol produced by the reaction significantly improves the yield of the reaction. In addition, MOFs crystal materials can be recycled, which is environmentally friendly and green. DETAILED DESCRIPTION

[0033] In order to further explain the technical means and effects adopted by the present invention, the technical solution of the present invention is further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0034] Example 1

[0035] This embodiment provides a method for preparing creatinine phosphate disodium salt, comprising the following steps:

[0036] Preparation of MOFs crystal material: DMF (300 mL) was added to Zn(NO3)2·6H2O (14.88 g, 0.05 mol, 1.00 eq) to dissolve, and then 1,4-benzenedicarboxylic acid (6.65 g, 0.038 mol, 0.75 eq) was added, stirred and mixed in a reaction bottle, heated to an internal temperature of 100°C, and the reaction was continued for 48 h, and then slowly cooled to 50°C. Filtered under nitrogen atmosphere, 8.37 g of MOFs crystal material was obtained, [Zn4O(L)3] n (L = 1,4-phthalic acid), yield 90.5%, set aside.

[0037] Characterization of MOFs crystalline materials:

[0038] Elemental Analysis: C, 39.19%; H, 1.38%; O, 23.95%.

[0039] The preparation method of creatinine phosphate disodium salt comprises the following steps:

[0040] (1) Under nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (5.0 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq), and the reaction was carried out under nitrogen atmosphere at an internal temperature of 80° C. for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25° C.). N-hexane (80 mL) was added dropwise to precipitate the product, and the product was filtered under nitrogen atmosphere to obtain white crystals, which were placed in a vacuum drying oven at 40-50° C. and dried for 6 h to obtain 16.7 g of dimethyl phosphocreatine, with a yield of 85.6%.

[0041] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry DMF:DCM (240 mL, volume ratio of 1:1), and trimethyl silane iodide (17.0 g, 0.085 mol, 1.25 eq) was added dropwise in an ice-water bath, and stirred at about 0°C in the dark for about 4 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then placed in a vacuum drying oven at 40-50°C for 6 h to obtain 14.5 g of disodium creatinine phosphate, with a yield of 89.7%.

[0042] Example 2

[0043] This embodiment provides a method for preparing creatinine phosphate disodium salt, comprising the following steps:

[0044] Preparation of MOFs crystal material: DMF (300 mL) was added to Zn(NO3)2·6H2O (14.88 g, 0.05 mol, 1.00 eq) to dissolve, and then 2-chloro-1,4-benzenedicarboxylic acid (8.02 g, 0.038 mol, 0.75 eq) was added, stirred and mixed in a reaction bottle, heated to an internal temperature of 100°C, and the reaction was continued for 70 h, and then slowly cooled to 50°C. Filtered under nitrogen atmosphere, 9.50 g of MOFs crystal material was obtained, [Zn4O(L)3] n (L = 2-chloro-1,4-phthalic acid), yield 90.1%, for future use.

[0045] Characterization of MOFs crystalline materials:

[0046] Elemental Analysis: C, 34.31%; H, 0.86%; O, 20.92%;

[0047] The preparation method of creatinine phosphate disodium salt comprises the following steps:

[0048] (1) Under nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (5.7 g) were added to creatinine (10 g, 0.088 mol, 1.00 eq), and the reaction was carried out under nitrogen atmosphere at an internal temperature of 80°C for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25°C). N-hexane (80 mL) was added dropwise to precipitate the product. The product was filtered under nitrogen atmosphere to obtain white crystals, which were placed in a vacuum drying oven at 40-50°C and dried for 6 h to obtain 17.2 g of dimethyl creatinine phosphate with a yield of 88.2%.

[0049] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry DMF:DCM (240 mL, volume ratio of 1:1), and trimethylsilyl iodide (17.0 g, 0.085 mol, 1.25 eq) was added dropwise in an ice-water bath, and stirred at about 0°C in the dark for about 4 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under a nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then placed in a vacuum drying oven at 40-50°C for 6 h to obtain 14.4 g of disodium creatinine phosphate, with a yield of 89.1%.

[0050] Example 3

[0051] This embodiment provides a method for preparing creatinine phosphate disodium salt, comprising the following steps:

[0052] Preparation of MOFs crystal material: DMF (300 mL) was added to Zn(NO3)2·6H2O (14.88 g, 0.05 mol, 1.00 eq) to dissolve, and then 2-bromo-1,4-benzenedicarboxylic acid (9.80 g, 0.038 mol, 0.75 eq) was added, stirred and mixed in a reaction bottle, heated to an internal temperature of 100°C, and the reaction was continued for 96 h, and then slowly cooled to 50°C. Filtered under nitrogen atmosphere, 10.80 g of MOFs crystal material was obtained, [Zn4O(L)3] n (L = 2-bromo-1,4-phthalic acid), yield 88.5%, for future use.

[0053] Characterization of MOFs crystalline materials:

[0054] Elemental Analysis: C, 29.68%; H, 0.75%; O, 18.06%;

[0055] The preparation method of creatinine phosphate disodium salt comprises the following steps:

[0056] (1) Under nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (6.61 g) were added to creatinine (10 g, 0.088 mol, 1.00 eq), and the reaction was carried out under nitrogen atmosphere at an internal temperature of 80°C for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25°C). N-hexane (80 mL) was added dropwise to precipitate the product, and the product was filtered under nitrogen atmosphere to obtain white crystals, which were placed in a vacuum drying oven at 40-50°C and dried for 6 h to obtain 17.5 g of dimethyl phosphocreatine, with a yield of 89.7%;

[0057] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry DMF:DCM (240 mL, volume ratio of 1:1), and trimethyl silane iodide (17.0 g, 0.085 mol, 1.25 eq) was added dropwise in an ice-water bath, and stirred at about 0°C in the dark for about 4 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under a nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then placed in a vacuum drying oven at 40-50°C for 6 h to obtain 14.6 g of disodium creatinine phosphate, with a yield of 90.3%.

[0058] Example 4

[0059] This embodiment provides a method for preparing creatinine phosphate disodium salt, comprising the following steps:

[0060] Preparation of MOFs crystal material: DMF (300 mL) was added to Zn(NO3)2·6H2O (14.88 g, 0.05 mol, 1.00 eq) to dissolve, and then 2-trifluoromethoxy-1,4-benzenedicarboxylic acid (10.01 g, 0.038 mol, 0.75 eq) was added, stirred and mixed in a reaction bottle, heated to an internal temperature of 100°C, and the reaction was continued for 108 h, and then slowly cooled to 50°C. Filtered under nitrogen atmosphere, 10.92 g of MOFs crystal material was obtained, [Zn4O(L)3] n (L = 2-trifluoromethoxy-1,4-phthalic acid), yield 88.1%, for future use.

[0061] Characterization of MOFs crystalline materials:

[0062] Elemental Analysis: C, 32.87%; H, 0.73%; O, 22.63%;

[0063] The preparation method of creatinine phosphate disodium salt comprises the following steps:

[0064] (1) Under nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (6.71 g) were added to creatinine (10 g, 0.088 mol, 1.00 eq), and the reaction was carried out under nitrogen atmosphere at an internal temperature of 80°C for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25°C). N-hexane (80 mL) was added dropwise to precipitate the product. The product was filtered under nitrogen atmosphere to obtain white crystals, which were placed in a vacuum drying oven at 40-50°C and dried for 6 h to obtain 17.6 g of dimethyl creatinine phosphate, with a yield of 90.1%;

[0065] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry DMF:DCM (240 mL, volume ratio of 1:1), and trimethyl silane iodide (17.0 g, 0.085 mol, 1.25 eq) was added dropwise in an ice-water bath, and stirred at about 0°C in the dark for about 4 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then placed in a vacuum drying oven at 40-50°C for 6 h to obtain 14.5 g of disodium creatinine phosphate, with a yield of 89.7%.

[0066] Example 5

[0067] This embodiment provides a method for preparing creatinine phosphate disodium salt, comprising the following steps:

[0068] Preparation of MOFs crystal material: DMF (300 mL) was added to Zn(NO3)2·6H2O (14.88 g, 0.05 mol, 1.00 eq) to dissolve, and then 2-formyl-1,4-benzenedicarboxylic acid (7.77 g, 0.038 mol, 0.75 eq) was added, stirred and mixed in a reaction bottle, heated to an internal temperature of 100°C, and the reaction was continued for 120 h, and then slowly cooled to 50°C. Filtered under nitrogen atmosphere, 9.40 g of MOFs crystal material was obtained, [Zn4O(L)3] n (L = 2-formyl-1,4-phthalic acid), yield 91.3%, for future use.

[0069] Characterization of MOFs crystalline materials:

[0070] Elemental Analysis: C, 39.54%; H, 1.25%; O, 27.33%;

[0071] The preparation method of creatinine phosphate disodium salt comprises the following steps:

[0072] (1) Under nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (5.57 g) were added to creatinine (10 g, 0.088 mol, 1.00 eq), and the reaction was carried out under nitrogen atmosphere at an internal temperature of 80°C for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25°C). N-hexane (80 mL) was added dropwise to precipitate the product, and the product was filtered under nitrogen atmosphere to obtain white crystals, which were placed in a vacuum drying oven at 40-50°C and dried for 6 h to obtain 17.9 g of dimethyl phosphocreatine, with a yield of 91.8%;

[0073] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry DMF:DCM (240 mL, volume ratio of 1:1), and trimethyl silane iodide (17.0 g, 0.085 mol, 1.25 eq) was added dropwise in an ice-water bath, and stirred at about 0°C in the dark for about 4 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under a nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then placed in a vacuum drying oven at 40-50°C for 6 h to obtain 14.6 g of disodium creatinine phosphate, with a yield of 90.3%.

[0074] Example 6

[0075] This embodiment provides a preparation method of creatinine phosphate disodium salt, which is basically the same as that of embodiment 1, except that, in the preparation of MOFs crystal material, N,N-diethylformamide (300 mL) was added to Zn(NO3)2·6H2O (14.88 g, 0.05 mol, 1.00 eq) to dissolve, and then 1,4-benzenedicarboxylic acid (5.40 g, 0.033 mol, 0.65 eq) was added, stirred and mixed in a reaction bottle, heated to an internal temperature of 100°C, continued to react for 72 h, slowly cooled to 50°C, and filtered under a nitrogen atmosphere to obtain 7.64 g of MOFs crystal material, [Zn4O(L)3] n (L = 1,4-phthalic acid), yield 82.6%, set aside.

[0076] Example 7

[0077] This embodiment provides a preparation method of creatinine phosphate disodium salt, which is basically the same as that of embodiment 1, except that, in the preparation of MOFs crystal material, N,N-dimethylacetamide (300 mL) was added to Zn(NO3)2·4H2O (14.88 g, 0.05 mol, 1.00 eq) to dissolve, and then 1,4-benzenedicarboxylic acid (5.82 g, 0.035 mol, 0.70 eq) was added, stirred and mixed in a reaction bottle, heated to an internal temperature of 80°C, continued to react for 84 h, slowly cooled to 50°C, and filtered under a nitrogen atmosphere to obtain 7.96 g of MOFs crystal material, [Zn4O(L)3] n (L = 1,4-phthalic acid), yield 86.1%, set aside.

[0078] Example 8

[0079] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0080] (1) Under a nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (7.5 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq). The mixture was heated to 80 °C in a nitrogen atmosphere and kept for reaction for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25 °C). N-hexane (80 mL) was added dropwise to precipitate the product. The product was filtered under a nitrogen atmosphere to obtain white crystals. The crystals were dried in a vacuum oven at 40-50 °C for 6 h to obtain 17.1 g of dimethyl creatinine phosphate with a yield of 87.8%.

[0081] Example 9

[0082] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0083] (1) Under a nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (10.0 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq). The temperature was raised to 80° C. in a nitrogen atmosphere and kept for reaction for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25° C.). N-hexane (80 mL) was added dropwise to precipitate the product. The product was filtered under a nitrogen atmosphere to obtain white crystals. The crystals were placed in a vacuum drying oven at 40-50° C. and dried for 6 h to obtain 17.4 g of dimethyl creatinine phosphate with a yield of 89.2%.

[0084] Example 10

[0085] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0086] (1) Under a nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (13.0 g, 0.093 mol, 1.05 eq), and the above-mentioned MOFs crystal material (5 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq). The temperature was raised to 80° C. in a nitrogen atmosphere and kept for reaction for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25° C.). N-hexane (80 mL) was added dropwise to precipitate the product. The product was filtered under a nitrogen atmosphere to obtain white crystals. The crystals were dried in a vacuum drying oven at 40-50° C. for 6 h to obtain 16.9 g of dimethyl creatinine phosphate with a yield of 86.6%.

[0087] Embodiment 11

[0088] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0089] (1) Under a nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (13.62 g, 0.097 mol, 1.1 eq), and the above-mentioned MOFs crystal material (5 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq). The temperature was raised to 80 °C in a nitrogen atmosphere and kept for reaction for 3 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25 °C). N-hexane (80 mL) was added dropwise to precipitate the product. The product was filtered under a nitrogen atmosphere to obtain white crystals. The crystals were placed in a vacuum drying oven at 40-50 °C and dried for 6 h to obtain 17.0 g of dimethyl creatinine phosphate with a yield of 87.1%.

[0090] Example 12

[0091] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0092] (1) Under a nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.0 eq) and the above-mentioned MOFs crystal material (5 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq). The temperature was raised to 60 °C in a nitrogen atmosphere and kept for reaction for 6 h. The MOFs crystal material was removed by hot filtration, and then the temperature was slowly lowered to room temperature (about 25 °C). N-hexane (80 mL) was added dropwise to precipitate the product. The product was filtered under a nitrogen atmosphere to obtain white crystals. The crystals were placed in a vacuum drying oven at 40-50 °C and dried for 4 h to obtain 16.6 g of dimethyl creatinine phosphate with a yield of 85.1%.

[0093] Example 13

[0094] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0095] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry N,N-diethylformamide:1,1-dichloroethane (240 mL, volume ratio of 1:1), and trimethylsilyl iodide (20.4 g, 0.102 mol, 1.50 eq) was added dropwise in an ice-water bath, and stirred at about 0°C in the dark for about 4 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then dried in a vacuum drying oven at 40-50°C for 6 h to obtain 14.4 g of disodium creatinine phosphate with a yield of 89.1%.

[0096] Embodiment 14

[0097] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0098] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry DMF:DCM (240 mL, volume ratio of 1:1), and trimethylsilyl iodide (13.57 g, 0.068 mol, 1.0 eq) was added dropwise in an ice-water bath, and stirred in the dark at about 0°C for about 4 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then placed in a vacuum drying oven at 40-50°C for 6 h to obtain 13.2 g of disodium creatinine phosphate, with a yield of 81.7%.

[0099] Embodiment 15

[0100] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0101] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry N,N-diethylacetamide:chloroform (270 mL, volume ratio of 1:0.8), and trimethylsilyl iodide (13.57 g, 0.068 mol, 1.0 eq) was added dropwise in an ice-water bath, and stirred at about 0°C in the dark for about 6 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under a nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then dried in a vacuum drying oven at 40-50°C for 6 h to obtain 13.3 g of disodium creatinine phosphate with a yield of 82.3%.

[0102] Example 16

[0103] This example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0104] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry DMF:DCM (360 mL, volume ratio of 1:2), and trimethyl silane iodide (13.57 g, 0.068 mol, 1.0 eq) was added dropwise in an ice-water bath, and stirred in the dark at about 0°C for about 6 h. After the reaction was completed, the reaction solution was concentrated; methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product, and the product was filtered under nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then placed in a vacuum drying oven at 40-50°C for 6 h to obtain 13.1 g of disodium creatinine phosphate, with a yield of 81.0%.

[0105] Comparative Example 1

[0106] This comparative example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0107] (1) Under a nitrogen atmosphere, DMF (40 mL) and trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq), and the mixture was stirred in a reaction flask. The internal temperature was raised to 80° C. in a nitrogen atmosphere and kept for reaction for 3 h. The temperature was then slowly lowered to room temperature (about 25° C.). The product was precipitated by dropwise addition of n-hexane (80 mL). The product was filtered under a nitrogen atmosphere to obtain white crystals. The crystals were placed in a vacuum drying oven at 40-50° C. and dried for 6 h to obtain 11.2 g of dimethyl creatinine phosphate with a yield of 57.4%.

[0108] Comparative Example 2

[0109] This comparative example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0110] Preparation of MOFs crystal material: DMF (300 mL) was added to Zn(NO3)2·6H2O (14.88 g, 0.05 mol, 1.00 eq) to dissolve, and then 2-amino-1,4-phthalic acid (6.79 g, 0.038 mol, 0.75 eq) was added, stirred and mixed in a reaction bottle, heated to an internal temperature of 100°C, and the reaction was continued for 84 h, and then slowly cooled to 50°C. Filtered under nitrogen atmosphere, 8.23 ​​g of MOFs crystal material was obtained, [Zn4O(L)3] n (L = 1,4-phthalic acid), yield 83.9%, set aside.

[0111] Characterization of MOFs crystalline materials:

[0112] Elemental Analysis: C, 36.94%; H, 1.66%; N, 5.43%; O, 22.50%;

[0113] The preparation method of creatinine phosphate disodium salt comprises the following steps:

[0114] (1) Under a nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (5.31 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq). The mixture was heated to 80 °C in a nitrogen atmosphere and kept for reaction for 3 h. The MOFs crystal material was removed by hot filtration and then the temperature was slowly cooled to room temperature (about 25 °C). The product was precipitated by adding n-hexane (80 mL) dropwise and filtered under a nitrogen atmosphere to obtain white crystals. The crystals were dried in a vacuum oven at 40-50 °C for 6 h to obtain 11.5 g of dimethyl creatinine phosphate with a yield of 58.9%.

[0115] Comparative Example 3

[0116] This comparative example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0117] (1) Under a nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (1.0 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq). The temperature was raised to 80° C. in a nitrogen atmosphere and kept for reaction for 3 h. The MOFs crystal material was removed by hot filtration and then the temperature was slowly lowered to room temperature (about 25° C.). The product was precipitated by dropwise addition of n-hexane (80 mL). The product was filtered under a nitrogen atmosphere to obtain white crystals. The crystals were dried in a vacuum drying oven at 40-50° C. for 6 h to obtain 13.3 g of dimethyl creatinine phosphate with a yield of 68.2%.

[0118] Comparative Example 4

[0119] This comparative example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0120] (1) Under a nitrogen atmosphere, DMF (40 mL), trimethyl phosphate (12.4 g, 0.088 mol, 1.00 eq) and the above-mentioned MOFs crystal material (7.5 g) were added to creatinine (10.0 g, 0.088 mol, 1.00 eq), and the reaction was carried out at room temperature (about 25° C.) in a nitrogen atmosphere for 48 h. The MOFs crystal material was filtered out, and the product was precipitated by adding n-hexane (80 mL) dropwise. The product was filtered out under a nitrogen atmosphere to obtain white crystals, which were placed in a vacuum drying oven at 40-50° C. and dried for 6 h to obtain 1.1 g of dimethyl creatinine phosphate with a yield of 5.6%.

[0121] Comparative Example 5

[0122] This comparative example provides a method for preparing creatinine phosphate disodium salt, which is basically the same as Example 1, except that:

[0123] (2) Dimethyl creatinine phosphate (15.0 g, 0.068 mol, 1.00 eq) was dissolved in dry DMF:DCM (240 mL, volume ratio of 1:1), and trimethyl silane iodide (17.0 g, 0.085 mol, 1.25 eq) was added dropwise at room temperature. The mixture was stirred at room temperature for about 4 h. After the reaction was completed, the reaction solution was concentrated. Methanol (45 mL) was added to the concentrate, and the pH of the reaction solution was adjusted to 6.0-8.0 with a saturated sodium bicarbonate aqueous solution. Methyl tert-ether (180 mL) was added dropwise to precipitate the product. The product was filtered under nitrogen atmosphere, rinsed with an appropriate amount of methyl tert-ether, and then dried in a vacuum drying oven at 40-50°C for 6 h to obtain 2.0 g of disodium creatinine phosphate with a yield of 12.4%.

[0124] The applicant declares that the present invention illustrates a method for synthesizing creatinine phosphate disodium salt through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0125] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0126] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for preparing creatinine phosphate disodium salt, characterized in that: The steps include: (1) In an inert gas atmosphere, creatinine and trimethyl phosphate are used as raw materials, and dimethyl phosphate creatinine is obtained by reaction under the catalytic action of MOFs crystal materials; (2) Creatinine phosphate dimethyl ester is reacted with a demethylating agent and a base in sequence to obtain the creatinine phosphate disodium salt.

2. The preparation method according to claim 1, characterized in that: The MOFs crystal material is [Zn4O(L)3] n ; where L is R is one selected from H, halogen, trifluoromethoxy, and formyl.

3. The preparation method according to claim 2, characterized in that: The preparation method of the MOFs crystal material comprises the following steps: adding a solvent to Zn(NO3)2·xH2O to dissolve it, and then adding The mixed reaction is followed by post-treatment to obtain a MOFs crystalline material, wherein x=4 or 6.

4. The preparation method according to claim 3, characterized in that: The temperature of the mixed reaction is 80-120°C and the reaction time is 48-120h; Preferably, the post-treatment is to slowly cool the mixture to 40-60° C. and filter the mixture under a nitrogen atmosphere to obtain the MOFs crystalline material.

5. The preparation method according to claim 3, characterized in that: Zn(NO3)2·xH2O and The molar ratio of feed is 1:(0.65~0.75); Preferably, the solvent is one or more selected from N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide; Preferably, the volume of the solvent is 15-30 times the mass of Zn(NO3)2·xH2O.

6. The preparation method according to claim 1, characterized in that: In step (1), the mass ratio of creatinine to MOFs crystal material is 1:(0.5-1.0), and the molar ratio of creatinine to trimethyl phosphate is 1:(1-1.1).

7. The preparation method according to claim 1, characterized in that: The demethylation agent is one selected from trimethylsilyl iodide, trimethylsilyl chloride and sodium iodide, trimethylsilyl chloride and lithium iodide, and the base is one selected from sodium bicarbonate, sodium carbonate, and sodium hydroxide; Preferably, the molar ratio of the dimethyl creatinine phosphate to the demethylation agent is 1:(1-1.5).

8. The preparation method according to claim 1, characterized in that: In step (1), the reaction temperature is 70-90° C. and the reaction time is 3-5 h; Preferably, in step (1), after the reaction, post-treatment is further included, wherein the MOFs crystal material is removed by hot filtration, and then the temperature is slowly cooled to room temperature, and a non-polar solvent is added dropwise to precipitate the product, and the product is filtered under a nitrogen atmosphere to obtain white crystals, which are placed in a vacuum drying oven at 40 to 50° C. and dried for 4 to 6 hours to obtain the dimethyl creatinine phosphate; More preferably, the non-polar solvent is at least one selected from n-hexane, cyclohexane and n-heptane.

9. The preparation method according to claim 1, characterized in that: In step (2), dimethyl creatinine phosphate needs to be dissolved in a mixed solvent first, and then reacted with a demethylation reagent for the next step; Preferably, the mixed solvent comprises a first solvent and a second solvent, the first solvent is one or more selected from N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide; the second solvent is one selected from dichloromethane, chloroform and 1,1-dichloroethane; More preferably, the volume ratio of the first solvent to the second solvent is 1:(0.8-2).

10. The preparation method according to claim 1, characterized in that: In step (2), the demethylation reagent is added dropwise under the condition of ice bath and light protection, and the stirring reaction time is 3 to 6 hours; after the reaction, the reaction solution is concentrated, the third solvent is added to the concentrated solution, the pH of the reaction solution is adjusted to 6.0 to 8.0 with a base, and the fourth solvent is added dropwise to precipitate the product, and the product is filtered under nitrogen atmosphere, and the product is placed in a vacuum drying oven at 40 to 50° C. and dried for 3 to 6 hours to obtain the disodium creatinine phosphate; Preferably, the third solvent is at least one selected from methanol, ethanol, and acetone; the fourth solvent is at least one selected from diethyl ether, tert-methyl ether, cyclopentyl methyl ether, tetrahydrofuran, and 1,4-dioxane.

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