Preparation method of novel diammonium pyrophosphate with low moisture absorption

Abstract

The invention discloses a preparation method of novel diammonium pyrophosphate with low moisture absorption. The method comprises the steps of pyrophosphoric acid pretreatment, pyrophosphoric acid solution preparation, salt forming reaction, drying and the like. The diammonium pyrophosphate prepared by the preparation method disclosed by the invention is not easy to absorb moisture, can keep a low-moisture powder state during weighing and transferring, and cannot be adhered to a weighing appliance, so that the problem of strong water absorption of ammonium pyrophosphate is solved.

Description

Technical Field

[0001] The invention relates to the technical field of compound preparation, and in particular to a method for preparing a novel diammonium pyrophosphate salt with low hygroscopicity. Background Art

[0002] In the prior art, since it is difficult to obtain anhydrous free pyrophosphate, and low-moisture ammonium pyrophosphate salts have low water content and high solubility in organic solvents, low-moisture ammonium pyrophosphate salts are often used to generate triphosphates with nucleoside monophosphonyl dichloride. The more mature commercially available ammonium pyrophosphate salt is a solid tri-n-butylammonium pyrophosphate salt, but this type of ammonium pyrophosphate salt has poor stability and needs to be stored at low temperatures. In addition, due to its strong water absorption, moisture will be brought into the material during weighing and transfer, and then into the reaction system, and nucleoside monophosphonyl dichloride will be quenched by water to produce nucleoside monophosphate impurities. In addition, the production process of tri-n-butylammonium pyrophosphate solid is complicated and expensive. For example, the preparation of tributylammonium pyrophosphate is as follows: tetrasodium pyrophosphate (26.6 g, 0.1 mol) is dissolved in deionized water (500 mL), the aqueous solution passes through a strong ion exchange column (pk216 proton type), the fractions containing pyrophosphate are combined, and tri-n-butylamine (37 Chemicalbook.1 g, 0.2 mol) is used to form salts. The above eluent is concentrated into an oily substance by a rotary evaporator, and the oily substance is hydrated by 1,4-dioxane (100 mL), and the hydration is repeated 3 times to obtain tri-n-butylammonium pyrophosphate (quantitative) as an oily substance; it can be seen that its preparation is relatively cumbersome and the cost of using ion exchange resin is high. Therefore, it is urgent to seek a preparation method of ammonium pyrophosphate salt that is cheap, has low water absorption and is easy to store. Summary of the invention

[0003] In view of this, the technical problem to be solved by the present invention is to provide a method for preparing a novel diammonium pyrophosphate salt with low hygroscopicity. The diammonium pyrophosphate salt prepared by the preparation method of the present invention is not easy to absorb moisture, can maintain a low-moisture powder state during weighing and transfer, and will not adhere to weighing utensils, thereby solving the problem of strong water absorption of ammonium pyrophosphate salt.

[0004] The specific technical solution adopted by the present invention is:

[0005] A method for preparing a novel diammonium pyrophosphate salt with low hygroscopicity comprises the following steps:

[0006] (1) Pyrophosphoric acid pretreatment: 95% pyrophosphoric acid is mixed with ether, and concentrated under reduced pressure to remove water to obtain low-water pyrophosphoric acid;

[0007] (2) preparing a pyrophosphoric acid solution: dissolving low-water pyrophosphoric acid in anhydrous acetonitrile to prepare a pyrophosphoric acid solution;

[0008] (3) Salt-forming reaction: the diamine compound is dissolved in ethyl acetate, diluted, and added to the pyrophosphoric acid solution with stirring to generate a white suspension;

[0009] (4) The white suspended matter suspension is filtered and washed to obtain a wet product of diammonium pyrophosphate, the wet product is collected and a water-carrying agent is added, and the wet product is concentrated and dried under reduced pressure to obtain dried diammonium pyrophosphate.

[0010] Furthermore, the diamine compound contains two tertiary amines in a single molecule.

[0011] Furthermore, the diamine compound is selected from one of triethylenediamine, N,N-dimethylpiperazine, tetramethylpropylenediamine, N,N,N',N'-tetramethyl-1,6-hexanediamine, and N,N,N',N'-tetramethyl-1,3-diaminobutane.

[0012] Furthermore, the ratio of the 95% pyrophosphoric acid to ether in step (1) is 1:10 (m / V); the reduced pressure concentration and water removal in step (1) is: under 30° C. water bath conditions, reduced pressure concentration until the vacuum degree of the system is 20 mbar, and the low-water pyrophosphoric acid obtained is 97%-99% pyrophosphoric acid.

[0013] Furthermore, the ratio of the 95% pyrophosphoric acid to anhydrous acetonitrile is 1:5 (m / V).

[0014] Furthermore, the volume of ethyl acetate used in step (3) is equal to that of anhydrous acetonitrile used in step (2), and the ratio of the diamine compound to ethyl acetate is 0.6-1.1:5 (m / V).

[0015] Furthermore, the washing described in step (4) is specifically carried out as follows: the filter cake obtained by suction filtration is washed twice with ethyl acetate at a ratio of 0.8-1.2:1 (m / V).

[0016] Furthermore, the ratio of the wet product to the added water-carrying agent is 1:5-10 (m / V).

[0017] Furthermore, the water-carrying agent is a solvent that can form an azeotrope with water, including but not limited to: ether and dioxane.

[0018] Furthermore, the reduced pressure concentration and drying in step (4) is: concentrated under reduced pressure in a water bath at 30-60° C. until the vacuum degree of the system is below 10 mbar.

[0019] The beneficial effects of the present invention are:

[0020] The diammonium pyrophosphate prepared by the method of the invention is not easy to absorb moisture, can maintain a powder state with low moisture content during weighing and transfer, and will not adhere to a weighing device, thus solving the problem of strong water absorption of the ammonium pyrophosphate salt.

[0021] The preparation method of the present invention does not need to use ion exchange resin, and does not need to spend a large amount of strong acid aqueous solution to regenerate the ion exchange resin, and has good atom economy.

[0022] A single molecule of the diamine compound used in the preparation method of the present invention has two tertiary amines, and thus has two salt-forming sites. A single molecule can form two ionic bonds with pyrophosphate, making it easier to form stable crystals (solid salts). BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the H NMR spectrum of pyrophosphate-dimethylpiperazine prepared in Example 1;

[0024] Figure 2 This is the H NMR spectrum of tetramethylpropane diammonium pyrophosphate prepared in Example 2;

[0025] Figure 3 This is the H NMR spectrum of tetramethylhexanediammonium pyrophosphate prepared in Example 3;

[0026] Figure 4 This is the H NMR spectrum of pyrophosphate-triethyl diammonium salt prepared in Example 4;

[0027] Figure 5 This is the H NMR spectrum of the pyrophosphate-tetramethyl-1,3-diammonium butane salt prepared in Example 5;

[0028] Figure 6 is the moisture absorption rate of different types of ammonium pyrophosphate salts;

[0029] Figure 7-11 1 is a series of mass spectra of the guanosine triphosphate analogue synthesized from the pyrophosphate-dimethylpiperazine salt prepared in Example 1. DETAILED DESCRIPTION

[0030] In order to explain the technical content, structural features, achieved objectives and effects of the technical solution in detail, the following is a detailed description in conjunction with specific embodiments and accompanying drawings.

[0031] Example 1

[0032] Preparation of pyrophosphate-dimethylpiperazine salt:

[0033] (1) Pretreatment: 1.0 g of 95% pyrophosphoric acid was mixed with 10 mL of ether, and the mixture was decompressed to a vacuum of 20 mbar in a water bath at 30°C and azeotropically removed for three times to obtain 97%-99% pyrophosphoric acid;

[0034] (2) preparing a pyrophosphoric acid solution: dissolving the pretreated pyrophosphoric acid in 5 mL of anhydrous acetonitrile to prepare a pyrophosphoric acid solution;

[0035] (3) Salt-forming reaction: Take 0.7 g of N,N-dimethylpiperazine and dissolve it in 5 ml of ethyl acetate, dilute it, and add it to the above pyrophosphoric acid solution with stirring to generate a white suspension;

[0036] (4) After reacting for 10 minutes, the white suspension was filtered, and the filter cake was washed twice with 2 mL of ethyl acetate. The filter cake was collected to obtain a wet product of the target compound, and then the wet product was transferred to a single-mouth bottle, 16 mL of ether was added, and the product was concentrated under reduced pressure in a 30-60°C water bath until the vacuum degree of the system was below 10 mbar to obtain 1.56 g of the dried target compound. The H NMR spectrum of the target compound is shown in Figure 1 The hydrogen spectrum data are as follows:

[0037] 1 H NMR(400MHz,Deuterium Oxide)δ3.62(s,8H),2.97(s,6H)

[0038] The target compound was identified as dimethylpiperazine pyrophosphate salt.

[0039] Example 2

[0040] Preparation of tetramethylpropane diammonium pyrophosphate:

[0041] (1) Pretreatment: 1.0 g of 95% pyrophosphoric acid was mixed with 10 mL of ether, and the mixture was decompressed to a vacuum of 20 mbar in a water bath at 30°C and azeotropically removed for three times to obtain 97%-99% pyrophosphoric acid;

[0042] (2) preparing a pyrophosphoric acid solution: dissolving the pretreated pyrophosphoric acid in 5 mL of anhydrous acetonitrile to prepare a pyrophosphoric acid solution;

[0043] (3) Salt-forming reaction: 0.797 g of tetramethylpropylenediamine was dissolved in 5 ml of ethyl acetate and added to the pyrophosphoric acid solution with stirring to generate a white suspension;

[0044] (4) The white suspension was filtered, and the filter cake was washed twice with 2 mL of ethyl acetate. The filter cake was collected to obtain a wet product of the target compound, and then the wet product was transferred to a single-mouth bottle, 17 mL of ether was added, and the product was concentrated under reduced pressure in a 30-60°C water bath until the vacuum degree of the system was below 10 mbar to obtain 1.64 g of the target compound after drying. The H NMR spectrum of the target compound is shown in Figure 2 The hydrogen spectrum data are as follows:

[0045] 1 H NMR (400MHz, Deuterium Oxide) δ3.22–3.13(m,4H),2.87(s,12H),2.23–2.12(m,2H).

[0046] The target compound was identified as tetramethylpropanediammonium pyrophosphate.

[0047] Example 3

[0048] Preparation of tetramethylhexane diammonium pyrophosphate:

[0049] (1) Pretreatment: 1.0 g of 95% pyrophosphoric acid was mixed with 10 mL of ether, and the mixture was decompressed to a vacuum of 20 mbar in a water bath at 30°C and azeotropically removed for three times to obtain 97%-99% pyrophosphoric acid;

[0050] (2) preparing a pyrophosphoric acid solution: dissolving the pretreated pyrophosphoric acid in 5 mL of anhydrous acetonitrile to prepare a pyrophosphoric acid solution;

[0051] (3) Salt-forming reaction: 1.06 g of N,N,N',N'-tetramethyl-1,6-hexanediamine was dissolved in 5 mL of ethyl acetate and added to the pyrophosphoric acid solution with stirring to generate a white suspension;

[0052] (4) The white suspension was filtered, and the filter cake was washed twice with 2 mL of ethyl acetate. The filter cake was collected to obtain a wet product of the target compound, and then the wet product was transferred to a single-mouth bottle, 20 mL of ether was added, and the product was concentrated under reduced pressure in a 30-60°C water bath until the vacuum degree of the system was below 10 mbar to obtain 1.76 g of the target compound after drying. The H NMR spectrum of the target compound is shown in Figure 3 The hydrogen spectrum data are as follows:

[0053] 1 H NMR (400MHz, Deuterium Oxide) δ3.10–3.01(m,4H),2.80(s,12H),1.72–1.61(m,4H),1.39–1.29(m,4H).

[0054] The target compound was identified as tetramethylhexanediammonium pyrophosphate.

[0055] Example 4

[0056] Preparation of triethyl diammonium pyrophosphate:

[0057] (1) Pretreatment: 1.0 g of 95% pyrophosphoric acid was mixed with 10 mL of ether, and the mixture was decompressed to a vacuum of 20 mbar in a water bath at 30°C and azeotropically removed for three times to obtain 97%-99% pyrophosphoric acid;

[0058] (2) preparing a pyrophosphoric acid solution: dissolving the pretreated pyrophosphoric acid in 5 mL of anhydrous acetonitrile to prepare a pyrophosphoric acid solution;

[0059] (3) Salt-forming reaction: 0.687 g of triethylenediamine was dissolved in 5 mL of ethyl acetate and added to the pyrophosphoric acid solution with stirring to generate a white suspension;

[0060] (4) The white suspension was filtered, and the filter cake was washed twice with 1.7 mL of ethyl acetate. The filter cake was collected to obtain a wet product of the target compound, and then the wet product was transferred to a single-mouth bottle, 17 mL of ether was added, and the product was concentrated under reduced pressure in a 30-60°C water bath until the vacuum degree of the system was below 10 mbar to obtain 1.54 g of the target compound after drying. The H NMR spectrum of the target compound is shown in Figure 4 The hydrogen spectrum data are as follows:

[0061] 1 H NMR (400MHz, Deuterium Oxide) δ3.72 (d, J = 1.5Hz, 12H).

[0062] The target compound was identified as triethyl diammonium pyrophosphate.

[0063] Example 5

[0064] Preparation of tetramethyl-1,3-diaminium pyrophosphate butane salt:

[0065] (1) Pretreatment: 1.0 g of 95% pyrophosphoric acid was mixed with 10 mL of ether, and the mixture was decompressed to a vacuum of 20 mbar in a water bath at 30°C and azeotropically removed for three times to obtain 97%-99% pyrophosphoric acid;

[0066] (2) preparing a pyrophosphoric acid solution: dissolving the pretreated pyrophosphoric acid in 5 mL of anhydrous acetonitrile to prepare a pyrophosphoric acid solution;

[0067] (3) Salt-forming reaction: 0.883 g of N,N,N',N'-tetramethyl-1,3-diaminobutane was dissolved in 5 mL of ethyl acetate and added to the pyrophosphoric acid solution with stirring to generate a white suspension;

[0068] (4) The white suspension was filtered, and the filter cake was washed twice with 1.8 mL of ethyl acetate. The filter cake was collected to obtain a wet product of the target compound, and then the wet product was transferred to a single-mouth bottle, 19 mL of ether was added, and the product was concentrated under reduced pressure in a 30-60°C water bath until the vacuum degree of the system was below 10 mbar to obtain 1.62 g of the target compound after drying. The H NMR spectrum of the target compound is shown in Figure 5The hydrogen spectrum data are as follows:

[0069] 1 H NMR(400MHz,Deuterium Oxide)δ3.44(dqd,J=10.0,6.6,3.3Hz,1H),3.20(dd,J=9.4,7.4Hz,2H),2.86(d ,J=4.3Hz,6H),2.78(d,J=13.1Hz,6H),2.17(tdd,J=10.2,7.7,3.5Hz,1H),2.07–

[0070]

[0071] The target compound was identified as tetramethyl-1,3-diammonium pyrophosphate butane salt.

[0072] Ammonium pyrophosphate water absorption experiment:

[0073] Water absorption calculation formula: W = (B n -B0) / G×100%

[0074] Where W is the water absorption, expressed as a percentage, G is the weight of the sample after drying, in grams, B0 is the initial weight of the sample and the small petri dish, and B n The weight of the sample including water and the small petri dish, in grams.

[0075] Water absorption time: T = Tn-T1

[0076] Where T is the water absorption time, in hours (h); T1 is the time to start the water absorption experiment, Tn is the time to take out, n>1.

[0077] Experimental materials: culture dish, cotton wool, purified water, tributylammonium pyrophosphate (purchased from Sigma-Aldrich), dimethylpiperazine pyrophosphate prepared in Examples 1-5, tetramethylpropanediammonium pyrophosphate, tetramethylhexanediammonium pyrophosphate, triethyldiammonium pyrophosphate, tetramethyl-1,3-diammonium pyrophosphate butane, and a thousandth balance.

[0078] Experimental operation:

[0079] 1. Weigh the weight B0 of a small glass culture dish using a 1 / 1000 balance, and then accurately weigh G = 100 mg of ammonium pyrophosphate and place it in the small culture dish.

[0080] 2. Place the above-mentioned small culture dish into a medium-sized dry glass culture dish, and place cotton wool moistened with pure water between the small and medium-sized culture dishes.

[0081] 3. Cover the medium-sized culture dish with the large culture dish to create a windless and humid environment, and record the time T1.

[0082] 4. After a period of time, take out the small petri dish, record the time T2, wipe the bottom of the small petri dish with a paper towel, and weigh it with a 1 / 1000 balance to get B1. Then, put the small petri dish back into the above medium petri dish and cover the large petri dish.

[0083] 5. After a while, take out the small petri dish, record the time T3, wipe the bottom of the small petri dish dry with a paper towel, and weigh it with a 1 / 1000 balance to get B2. Then, put the small petri dish back into the medium petri dish and cover the large petri dish. Repeat this step to get B n

[0084] The mass changes of each ammonium pyrophosphate salt are shown in Table 1:

[0085] Table 1

[0086]

[0087] The moisture absorption rate of each ammonium pyrophosphate salt is as follows Figure 6 As shown in Table 2:

[0088]

[0089] It can be seen that the water absorption rate of the pyrophosphate-diammonium salt obtained by the present invention is much lower than that of the commercially available tributylammonium pyrophosphate salt. Experimental study on the synthesis of guanosine triphosphate analogs using diammonium pyrophosphate salt:

[0090] Experimental materials: guanylate analog (N-(3-(7-((2R,4S,5R)-4-(azidomethoxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-(((E)-(dimethylamino)methylene)amino)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-yn-1-yl)-2,2,2-trifluoroacetamide, homemade), pyrophosphate-dimethylpiperazine salt (prepared in Example 1), phosphorus oxychloride (Annaiji), trimethyl phosphate (Leyan), proton sponge (Aladdin), DMF (Chinese name dimethylformamide, Anaiji anhydrous solvent), triethylamine (Kermiou), polytetrafluoroethylene magnet.

[0091] Experimental operation:

[0092] 1. Mix guanylate analog (100 mg, 1.0 equivalent) with trimethyl phosphate (1.0 mL) and proton sponge (41 mg, 1.0 equivalent) in a 50 mL single-mouth bottle, add tetrafluoroethylene magnetic particle and replace nitrogen gas three times, put into a low temperature tank with an external temperature of -15°C to cool for 5 minutes, then drop phosphorus oxychloride (102 mg, 3 equivalents) and keep stirring at low temperature for 1 hour.

[0093] 2. Mix dimethylpiperazine pyrophosphate (130 mg, 2.5 equivalents) with triethylamine (109 mg, 6 equivalents) and DMF (1 mL), and add dropwise to the above reaction solution at -15°C. After the addition is complete, move the mixture to room temperature and react for 2 hours.

[0094] 3. The reaction solution was cooled to 0°C, quenched with TEAB (1 mol / L, pH=8.0) solution to pH=7.0, and concentrated under reduced pressure at room temperature to obtain a light yellow viscous oil. Figure 7-11 As shown, it can be seen that the mass spectrum value of the target product (guanosine triphosphate analogue) can be seen in LCMS.

[0095] Although the above embodiments have been described, once those skilled in the art know the basic creative concepts, they can make additional changes and modifications to these embodiments. Therefore, the above description is only an embodiment of the present invention and does not limit the patent protection scope of the present invention. Any equivalent structure or equivalent process transformation made by using the contents of the specification and drawings of the present invention, or directly or indirectly used in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for preparing a novel diammonium pyrophosphate with low hygroscopicity, characterized in that: The steps include: (1) Pyrophosphoric acid pretreatment: 95% pyrophosphoric acid is mixed with ether, and concentrated under reduced pressure to remove water to obtain low-water pyrophosphoric acid; (2) preparing a pyrophosphoric acid solution: dissolving low-water pyrophosphoric acid in anhydrous acetonitrile to prepare a pyrophosphoric acid solution; (3) Salt-forming reaction: the diamine compound is dissolved in ethyl acetate, diluted, and added to the pyrophosphoric acid solution with stirring to generate a white suspension; (4) The white suspended matter suspension is filtered and washed to obtain a wet product of diammonium pyrophosphate, the wet product is collected and a water-carrying agent is added, and the wet product is concentrated and dried under reduced pressure to obtain dried diammonium pyrophosphate.

2. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 1, characterized in that: The diamine compound has two tertiary amines in a single molecule.

3. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 2, characterized in that: The diamine compound is selected from one of triethylenediamine, N,N-dimethylpiperazine, tetramethylpropylenediamine, N,N,N',N'-tetramethyl-1,6-hexanediamine, and N,N,N',N'-tetramethyl-1,3-diaminobutane.

4. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 1, characterized in that: The ratio of the 95% pyrophosphoric acid to ether in step (1) is 1:10 (m / V); the reduced pressure concentration and water removal in step (1) is: under a 30° C. water bath condition, reduced pressure concentration until the vacuum degree of the system is 20 mbar, and the low-water pyrophosphoric acid obtained is 97%-99% pyrophosphoric acid.

5. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 1, characterized in that: The ratio of the 95% pyrophosphoric acid to anhydrous acetonitrile is 1:5 (m / V).

6. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 1, characterized in that: The volume of ethyl acetate used in step (3) is equal to that of anhydrous acetonitrile used in step (2), and the ratio of the diamine compound to ethyl acetate is: 0.6-1.1:5(m / V).

7. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 1, characterized in that: The washing described in step (4) is specifically carried out as follows: the filter cake obtained by suction filtration is washed twice with ethyl acetate at a ratio of 0.8-1.2:1 (m / V).

8. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 1, characterized in that: The ratio of the wet product to the added water-carrying agent is 1:5-10 (m / V).

9. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 8, characterized in that: The water-carrying agent is a solvent that can form an azeotrope with water, including but not limited to: ether and dioxane.

10. The method for preparing the novel low hygroscopic diammonium pyrophosphate according to claim 1, characterized in that: The reduced pressure concentration and drying in step (4) is: concentrated under reduced pressure in a water bath at 30-60° C. until the vacuum degree of the system is below 10 mbar.

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