A 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt and its preparation method and application

Abstract

The present invention provides a 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt and a preparation method and application thereof, belonging to the technical field of 3,4,5,6-tetrahalophenolsulfonphthalein salt formation. The tetrahalophenolsulfonphthalein alkali metal salt described in the present invention is tetrahalophenolsulfonphthalein lithium salt, tetrahalophenolsulfonphthalein sodium salt and tetrahalophenolsulfonphthalein potassium salt; the preparation method of the tetrahalophenolsulfonphthalein alkali metal salt is: tetrahalophenolsulfonphthalein and alkali metal salt are subjected to salt formation reaction in an aprotic solvent, crystallized to obtain a crude product, and then recrystallized in an aprotic solvent to obtain a pure tetrahalophenolsulfonphthalein alkali metal salt. The preparation method of a tetrahalophenolsulfonphthalein alkali metal salt provided by the present invention overcomes the problem of poor water solubility of existing tetrahalophenolsulfonphthalein, and the preparation process is simple, the conditions are mild, the product purity is high, the yield is high, the cost is low, and it can be mass-produced, which is beneficial to further application in acid-base indicators and albumin diagnostic reagents.

Description

Technical Field

[0001] The invention relates to the technical field of 3,4,5,6-tetrahalophenolsulfonphthalein salt formation, and in particular to a 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt and a preparation method and application thereof. Background Art

[0002] 3,4,5,6-Tetrahalophenolsulfonphthalein is an important acid-base indicator and is used as a protein error indicator in clinical diagnostic reagents. Its English name is 3,4,5,6-Tetrahalophenolsulfonphthalein and its structural formula is as follows:

[0003]

[0004] Since 3,4,5,6-tetrahalophenolsulfonphthalein is poorly soluble in water, a large amount of organic solvents are often used to dissolve it during use, which wastes reagents and increases costs. This problem affects the further research and application of 3,4,5,6-tetrahalophenolsulfonphthalein.

[0005] Therefore, how to overcome the shortcomings of the existing technology and increase the water solubility of 3,4,5,6-tetrahalophenolsulfonphthalein to achieve the purpose of convenient use is a technical problem that needs to be solved at present. Summary of the invention

[0006] The purpose of the present invention is to provide an alkali metal salt of 3,4,5,6-tetrahalophenolsulfonphthalein and a preparation method and application thereof, so as to solve the technical problem that 3,4,5,6-tetrahalophenolsulfonphthalein is poorly soluble in water and limits its use.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides a 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt, and the structural formula of the 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is as follows:

[0009]

[0010] Wherein, X is independently Cl, Br or I; M is Li, Na or K.

[0011] The present invention provides a method for preparing 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt, comprising the following steps:

[0012] 1) salt formation: 3,4,5,6-tetrahalophenolsulfonphthalein and an alkali metal salt are mixed in a solvent to carry out a salt formation reaction to obtain a crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt;

[0013] 2) Recrystallization: The crude product of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is mixed with a solvent for recrystallization to obtain 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt.

[0014] Furthermore, in the step 1), the temperature of the salt-forming reaction is 30 to 80° C., and the time of the salt-forming reaction is 0.5 to 24 h.

[0015] Furthermore, in the step 1), the solvent is an aprotic solvent, and the aprotic solvent includes one or more of tetrahydrofuran, acetone, acetonitrile, dioxane, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, ether, petroleum ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether and ethylene glycol dimethyl ether.

[0016] Furthermore, in the step 1), the alkali metal salt is one or more of alkali metal carbonate, alkali metal acetate and alkali metal bicarbonate; and the molar ratio of the 3,4,5,6-tetrahalophenolsulfonphthalein to the alkali metal salt is 1:0.9-1.8.

[0017] Furthermore, in the step 1), the mass volume ratio of the crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt to the solvent used for the first recrystallization is 1g:1-20mL, and the mass volume ratio of the crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt to the solvent used for the second recrystallization is 1g:1-20mL.

[0018] Furthermore, in the step 2), the recrystallization is performed twice, the solvent used for the first recrystallization is ethyl acetate, dichloromethane, chloroform or carbon tetrachloride, and the solvent used for the second recrystallization is ether, petroleum ether, n-propyl ether or isopropyl ether;

[0019] The recrystallization temperature is 30-80° C., and the recrystallization time is 0.5-24 h.

[0020] Furthermore, in the step 2), the mass volume ratio of the crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt to the solvent is 1 g: 1-20 mL.

[0021] The invention provides an application of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt as an acid-base indicator.

[0022] The invention provides application of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt in an albumin detection reagent.

[0023] Beneficial effects of the present invention:

[0024] The invention obtains 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt by salting and recrystallizing 3,4,5,6-tetrahalophenolsulfonphthalein, thereby overcoming the problem of poor water solubility of the existing 3,4,5,6-tetrahalophenolsulfonphthalein. The invention also has simple preparation method, mild conditions, high product purity, high yield, low cost, and can be mass-produced, which is beneficial to further application in acid-base indicators and protein indicators. DETAILED DESCRIPTION

[0025] The present invention provides a 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt, and the structural formula of the 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is as follows:

[0026]

[0027] Wherein, X is independently Cl, Br or I; M is Li, Na or K.

[0028] In the present invention, the 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is preferably 3,4,5,6-tetrachlorophenolsulfonphthalein sodium salt, 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt, 3,4,5,6-tetraiodophenolsulfonphthalein sodium salt, 3,4,5,6-tetrachlorophenolsulfonphthalein lithium salt, 3,4,5,6-tetrabromophenolsulfonphthalein lithium salt, 3,4,5,6-tetraiodophenolsulfonphthalein lithium salt, 3,4,5,6-tetrachlorophenolsulfonphthalein potassium salt, 3,4,5,6-tetrabromophenolsulfonphthalein potassium salt or 3,4,5,6-tetraiodophenolsulfonphthalein potassium salt.

[0029] The present invention provides a method for preparing 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt, comprising the following steps:

[0030] 1) salt formation: 3,4,5,6-tetrahalophenolsulfonphthalein and an alkali metal salt are mixed in a solvent to carry out a salt formation reaction to obtain a crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt;

[0031] 2) Recrystallization: The crude product of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is mixed with a solvent for recrystallization to obtain 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt.

[0032] In the present invention, the reaction formula for the synthesis of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is as follows:

[0033]

[0034] Wherein, X is Cl, Br or I; M is Li, Na or K.

[0035] In the present invention, in the step 1), the temperature of the salt-forming reaction is 30 to 80° C., preferably 35 to 75° C., and more preferably 40 to 70° C.; the time of the salt-forming reaction is 0.5 to 24 h, preferably 1 to 12 h, and more preferably 2 to 10 h.

[0036] In the present invention, in the step 1), the solvent is an aprotic solvent, and the aprotic solvent comprises one or more of tetrahydrofuran, acetone, acetonitrile, dioxane, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, ethyl ether, petroleum ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether and ethylene glycol dimethyl ether, preferably one or more of tetrahydrofuran, acetone, acetonitrile and dioxane.

[0037] In the present invention, if the salt-forming reaction solvent used is a protic solvent, it will affect the formation of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt, the yield is low, and it is not suitable for use; the selected solvent is a non-protic solvent, the yield of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is higher, and it can be used.

[0038] In the present invention, in the step 1), the alkali metal salt is one or more of alkali metal carbonate, alkali metal acetate and alkali metal bicarbonate, preferably alkali metal carbonate; the molar ratio of the 3,4,5,6-tetrahalophenolsulfonphthalein to the alkali metal salt is 1:0.9-1.8, preferably 1:1-1.6, and more preferably 1:1.2-1.4.

[0039] In the present invention, in the step 1), the mass volume ratio of the 3,4,5,6-tetrahalophenolsulfonphthalein to the solvent is 1 g: 1 to 20 mL, preferably 1 g: 2 to 16 mL, and more preferably 1 g: 5 to 10 mL.

[0040] In the present invention, after the salt-forming reaction, the crude product yield of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is 93.0% and the purity is 94.0%.

[0041] In the present invention, if the recrystallization solvent used is a protic solvent, it will affect the purification effect of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt, resulting in lower purity and yield, and is not suitable for use; the selected solvent is an aprotic solvent, which has a higher yield and can be used.

[0042] In the present invention, in the step 2), the recrystallization is completed twice, the solvent used for the first recrystallization is ethyl acetate, dichloromethane, chloroform or carbon tetrachloride, preferably dichloromethane; the solvent used for the second recrystallization is ether, petroleum ether, n-propyl ether or isopropyl ether, preferably petroleum ether.

[0043] In the present invention, in step 2), in the first recrystallization, the 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is insoluble in the solvent, while the 3,4,5,6-tetrahalophenolsulfonphthalein is easily soluble, so that the remaining 3,4,5,6-tetrahalophenolsulfonphthalein in the reaction can be removed; in the second solvent recrystallization, the small polar impurities contained in the 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt are easily soluble in the solvent, while the 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is insoluble, thereby achieving the removal of impurities; therefore, the recrystallization uses two different aprotic solvents for each recrystallization, and the effect is better.

[0044] In the present invention, in step 2), after two recrystallizations using aprotic solvents of different properties, the purity of the 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt product is as high as 98.0% or more, and the total yield of the two recrystallizations is as high as 88.0%.

[0045] In the present invention, the recrystallization temperature is 30 to 80° C., preferably 35 to 75° C.; the recrystallization time is 0.5 to 24 h, preferably 1 to 12 h.

[0046] In the present invention, when the recrystallization temperature is lower than 35°C, dissolution and dispersion are not sufficient; when the recrystallization temperature is higher than 75°C, impurities are generated in the product; when the recrystallization temperature is 35-75°C, the recrystallization is relatively sufficient and the effect is better. When the recrystallization time is less than 1 hour, dissolution and dispersion are not sufficient; when the recrystallization time is greater than 12 hours, impurities are generated in the product.

[0047] In the present invention, the mass volume ratio of the crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt to the solvent used for the first recrystallization is 1g:1-20mL, preferably 1g:2-16mL; the mass volume ratio of the crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt to the solvent used for the second recrystallization is 1g:1-20mL, preferably 1g:2-16mL.

[0048] In the present invention, when the mass volume ratio of the crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt to the solvent is too large, the recrystallization is insufficient and the purification effect is poor; when the mass volume ratio is too small, the reagent is wasted and the yield is reduced.

[0049] The invention provides an application of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt as an acid-base indicator.

[0050] The invention provides application of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt in an albumin detection reagent.

[0051] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0052] The 3,4,5,6-tetrahalophenolsulfonphthalein used in the following experimental examples and embodiments is a commercially available raw material, wherein the purity of 3,4,5,6-tetrachlorophenolsulfonphthalein is 93.23%, the purity of 3,4,5,6-tetrabromophenolsulfonphthalein is 92.05%, and the purity of 3,4,5,6-tetraiodophenolsulfonphthalein is 90.15%.

[0053] Experimental Example 1

[0054] Comparison of salt-forming reaction effects

[0055] (1) 3,4,5,6-Tetrabromophenolsulfonphthalein sodium salt

[0056] Take 3,4,5,6-tetrabromophenolsulfonphthalein raw material, weigh 4 portions, each 67.0 g (0.1 mol), add them to the reactor respectively, then weigh 1.1 eq of sodium hydroxide, sodium carbonate, sodium bicarbonate, and sodium acetate respectively, add them to the reactor respectively, add 280 mL of acetonitrile respectively, stir and react at 55°C for 6 hours, stop the reaction, cool to room temperature, filter, dry the filter cake, weigh it, and obtain a crude product. Relevant experimental data are shown in Table 1.

[0057] Table 1 Selection of alkali metal salts

[0058]

[0059] The data in Table 1 show that: when sodium hydroxide is used as a reaction base, the alkalinity is too strong, the product yield and purity are low; when sodium carbonate, sodium acetate, and sodium bicarbonate are used as reaction bases, the alkalinity is moderate, the yield and purity are high. It can be seen that specific alkali metal salts are required to achieve the technical effect of the present application.

[0060] (2) Alkali metal salt equivalent

[0061] Take 3,4,5,6-tetrabromophenolsulfonphthalein raw material, weigh 5 portions, each portion 67.0 grams (0.1 mol), add them to the reactor respectively, then weigh 0.9eq, 1.0eq, 1.4eq, 1.6eq and 1.8eq of sodium bicarbonate respectively, add them to the reactor respectively, add 350mL of acetone respectively, stir and react at 40°C for 8 hours, stop the reaction, cool to room temperature, filter, dry the filter cake, weigh it, and obtain a crude product. Relevant experimental data are shown in Table 2.

[0062] Table 2 Selection of alkali metal salt feed equivalent

[0063]

[0064] The data in Table 2 show that when the feed ratio of sodium bicarbonate to 3,4,5,6-tetrahalophenolsulfonphthalein is 0.9eq, the reaction is incomplete and the yield is low; when the feed ratio is 1.8eq, the amount of alkali is too much and the product purity is low; when the feed ratio is 0.9eq to 1.6eq, the yield is high and the purity is high.

[0065] (3) Salt-forming solvent

[0066] Take 3,4,5,6-tetrabromophenolsulfonphthalein raw material, weigh 6 portions, each portion 67.0 grams (0.1 moL), add them to the reactor respectively, then weigh 1.15eq of sodium bicarbonate respectively, add them to the reactor in sequence, add 300mL of tetrahydrofuran, acetone, acetonitrile, dioxane, and methanol respectively, react at 45°C for 8 hours, filter after the reaction is completed, dry the filter cake, weigh it, and obtain a crude product. Relevant experimental data are shown in Table 3.

[0067] Table 3 Selection of salt-forming solvents

[0068]

[0069]

[0070] The data in Table 3 show that when the reaction solvent is tetrahydrofuran, acetone, acetonitrile or dioxane, the yield can reach more than 93% and the purity can reach more than 94%; when the reaction solvent is methanol (protic solvent), the yield and purity are lower.

[0071] (4) Amount of salt-forming solvent used

[0072] Take 3,4,5,6-tetrabromophenolsulfonphthalein raw material, weigh 5 portions, each portion is 67.0 grams (0.1 moL), and add them to the reactor respectively, then weigh 1.2 eq of sodium bicarbonate, add them to the reactor respectively, add acetonitrile according to the mass volume ratio of 1:1, 1:2, 1:6, 1:16, 1:18 respectively, stir and react at 50°C for 5 hours, stop the reaction, cool to room temperature, filter, dry the filter cake, weigh it, and obtain a crude product. Relevant experimental data are shown in Table 4.

[0073] Table 4 Selection of the amount of salt-forming solvent used

[0074]

[0075] The data in Table 4 show that when the mass volume ratio of raw material to acetonitrile is 1g:1mL, the reaction is incomplete and the purity is low; when the mass volume ratio is 1g:18mL, the yield is too low; when the mass volume ratio is 1g:2-18mL, the crude product yield is higher and the purity is higher.

[0076] (5) Salt formation temperature

[0077] Take 3,4,5,6-tetrabromophenolsulfonphthalein raw material, weigh 5 portions, each portion 67.0 g (0.1 mol), add them to the reactor respectively, weigh 1.3 eq of sodium bicarbonate respectively, add them to the reactor respectively, add them to 500 mL of acetonitrile respectively, stir and react at 30°C, 35°C, 50°C, 75°C, 80°C for 6 hours, stop the reaction, cool to room temperature, filter, dry the filter cake, weigh it, and obtain a crude product. Relevant experimental data are shown in Table 5.

[0078] Table 5 Selection of salt formation temperature

[0079]

[0080] The data in Table 5 show that when the reaction temperature is 30°C, the reaction is incomplete, the yield is low, and the purity is low; when the reaction temperature is 80°C, the side reactions increase, the yield is low, and the purity is low; when the reaction temperature is 35°C to 75°C, the yield of the obtained crude product is high and the purity is high.

[0081] (6) Salt-forming reaction time

[0082] Take 3,4,5,6-tetrabromophenolsulfonphthalein raw material, weigh 5 portions, each portion 67.0 g (0.1 mol), add them to the reactor respectively, weigh 1.3 eq of sodium bicarbonate respectively, add them to the reactor respectively, add them to 500 mL of dioxane respectively, stir and react at 50°C for 0.5 hour, 1 hour, 6 hours, 12 hours, 13 hours respectively, stop the reaction, cool to room temperature, filter, dry the filter cake, weigh it, and obtain a crude product. Relevant experimental data are shown in Table 6.

[0083] Table 6 Selection of salt-forming reaction time

[0084]

[0085]

[0086] The data in Table 6 show that when the reaction time is 0.5 hours, the reaction is not complete, the yield is low, and the purity is low; when the reaction time is 13 hours, the side reactions increase, the yield is low, and the purity is low; when the reaction time is 1 to 12 hours, the yield of the obtained crude product is high and the purity is high.

[0087] Experimental Example 2

[0088] Comparison of recrystallization effects

[0089] Salt-forming reaction: Take 3,4,5,6-tetrabromophenolsulfonphthalein raw material, weigh 3349.8 g (5.0 mol), add it to the reactor, add 504.1 g of sodium bicarbonate, add 12 L of acetonitrile, stir and react at 60 ° C for 4 hours, stop stirring, cool to room temperature, filter, dry the filter cake, collect, and obtain 3293.6 g of crude product with a yield of 95.2% and a purity of 95.36%, which will be used in the next experiment;

[0090] (1) First recrystallization solvent

[0091] Take the crude sodium salt of 3,4,5,6-tetrabromophenolsulfonphthalein obtained in the previous step, weigh 5 portions, each 100 g, add them to the reactor, add 400 mL of ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, and methanol, stir at 50°C for 3 hours, stop stirring, cool to room temperature, filter, dry the filter cake, weigh it, and obtain the pure product. Relevant experimental data are shown in Table 7.

[0092] Table 7 Selection of the first recrystallization solvent

[0093]

[0094]

[0095] The data in Table 7 show that when the first recrystallization solvent is ethyl acetate, dichloromethane, or chloroform, the product yield and purity are higher, and when the solvent is carbon tetrachloride, the product yield and purity are slightly lower; when the solvent is methanol, the product yield and purity are both lower.

[0096] (2) Second recrystallization solvent

[0097] First recrystallization: Take the crude product of 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt obtained in the previous step, weigh 600.0 g, add it to the reactor, add 1.8 L of ethyl acetate, stir at 50 ° C for 3 hours, stop stirring, cool to room temperature, filter, dry the filter cake, weigh it, and obtain 571.2 g of product with a yield of 95.2% and a purity of 97.22%, which is used in the next experiment;

[0098] Second recrystallization: Take the first recrystallization product of the previous step, weigh 5 portions, 100 grams each, and add them into the reactor respectively. Then add 500 mL of ether, isopropyl ether, isobutyl ether, n-propyl ether, and ethanol respectively. Stir at 35°C for 10 hours, stop stirring, cool to room temperature, filter, dry the filter cake, weigh it, and obtain a pure product. Relevant experimental data are shown in Table 8.

[0099] Table 8 Selection of solvent for the second recrystallization

[0100]

[0101] The data in Table 8 show that when the second recrystallization solvent is diethyl ether, isobutyl ether, isopropyl ether, and n-propyl ether, the purity of the obtained pure products is above 99%, and the second recrystallization yield is above 94%; when the second recrystallization solvent is methanol, the purity and yield of the obtained product are both lower.

[0102] (3) Amount of recrystallization solvent used

[0103] Take the crude product of 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt obtained in the previous step, weigh 5 portions, 100 grams each, and add them into the reactor respectively, then add ethyl acetate according to the mass volume ratio of 1:1, 1:2, 1:6, 1:16, and 1:18 respectively, stir at 60°C for 2 hours, stop stirring, cool to room temperature, filter, dry the filter cake, weigh it, and obtain the product. The relevant experimental data are shown in Table 9.

[0104] Table 9 Selection of the amount of recrystallization solvent used

[0105]

[0106] The data in Table 9 show that: when the mass volume ratio of crude 3,4,5,6-tetrabromophenolsulfonphthalein to ethyl acetate is 1g:1mL, the stirring and dispersion are not sufficient, and the product purity is low; when the mass volume ratio is 1g:18mL, the product yield is too low; when the mass volume ratio is 1g:2~18mL, the yield is higher and the purity is higher.

[0107] (4) Recrystallization temperature

[0108] Take the crude product of 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt obtained in the previous step, weigh 5 portions, 100 g each, and add them into the reactor respectively, add 500 mL of chloroform respectively, stir at 30°C, 35°C, 55°C, 75°C, and 80°C for 4 hours, stop stirring, cool to room temperature, filter, dry the filter cake, weigh it, and obtain the product. The relevant experimental data are shown in Table 10.

[0109] Table 10 Selection of recrystallization temperature

[0110]

[0111]

[0112] The data in Table 10 show that when the recrystallization temperature is 30°C, the recrystallization is not sufficient and the purity is low; when the temperature is 80°C, the purity decreases; when the reaction temperature is 35-75°C, the product yield is high and the purity is high.

[0113] (5) Recrystallization time

[0114] Take the crude product of 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt obtained in the previous step, weigh 5 portions, 100 grams each, and add them into the reactor in sequence, then add ethyl acetate according to the mass volume ratio of 1g:2mL, stir for 0.5 hour, 1 hour, 6 hours, 12 hours, and 13 hours respectively, stop stirring, cool to room temperature, filter, dry the filter cake, weigh it, and obtain the product. The relevant experimental data are shown in Table 11.

[0115] Table 11 Selection of recrystallization time

[0116]

[0117] The data in Table 11 show that: when the recrystallization time is 0.5 hours, the recrystallization is not sufficient, the purity is not improved, and the purity is low; when the recrystallization time is 13 hours, new impurities are generated in the product and the purity decreases; when the recrystallization time is 1 to 12 hours, the product yield is high and the purity is high.

[0118] Example 1

[0119] Preparation of 3,4,5,6-Tetrahalophenolsulfonphthalein Lithium Salt

[0120] 1) Preparation of 3,4,5,6-Tetrachlorophenolsulfonphthalein Lithium Salt

[0121] Salt formation: weigh 49.2 g (0.1 mol) of 3,4,5,6-tetrachlorophenolsulfonphthalein and add it to the reactor, add 1.1 eq of lithium bicarbonate, add 300 mL of tetrahydrofuran, stir and react at 65 ° C for 3 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain 47.3 g of crude product;

[0122] Recrystallization: Add all the crude product obtained in the previous step to the reactor, add 300 mL of dichloromethane, stir at 40°C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 300 mL of isopropyl ether, stir at 60°C for 1 hour, stop stirring, cool to room temperature, filter, dry, collect, and obtain 42.2 grams of 3,4,5,6-tetrachlorophenolsulfonphthalein lithium salt, with a total yield of 84.8% and a purity of 99.32%.

[0123] 2) Preparation of 3,4,5,6-tetrabromophenolsulfonphthalein lithium salt

[0124] Salt formation: weigh 67.0 g (0.1 mol) of 3,4,5,6-tetrabromophenolsulfonphthalein and add it to the reactor, add 1.2 eq of lithium bicarbonate, add 250 mL of acetone, stir and react at 40°C for 5 hours, stop stirring, cool to room temperature, filter, dry and collect to obtain 64.2 g of crude product;

[0125] Recrystallization: Add all the crude product obtained in the previous step to the reactor, add 300 mL of dichloromethane, stir at 40°C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 300 mL of isopropyl ether, stir at 60°C for 1 hour, stop stirring, cool to room temperature, filter, dry, collect, and obtain 55.6 grams of 3,4,5,6-tetrabromophenolsulfonphthalein lithium salt, with a total yield of 82.3% and a purity of 99.37%.

[0126] 3) Preparation of 3,4,5,6-tetraiodophenolsulfonphthalein lithium salt

[0127] Salt formation: weigh 85.8 g (0.1 mol) of 3,4,5,6-tetraiodophenolsulfonphthalein and add it to the reactor, add 1.2 eq of lithium bicarbonate, add 250 mL of acetone, stir and react at 40°C for 5 hours, stop stirring, cool to room temperature, filter, dry and collect to obtain 81.5 g of crude product;

[0128] Recrystallization: Add all the crude product obtained in the previous step to the reactor, add 300 mL of dichloromethane, stir at 40°C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 300 mL of isopropyl ether, stir at 60°C for 1 hour, stop stirring, cool to room temperature, filter, dry, collect, and obtain 69.8 grams of 3,4,5,6-tetraiodophenolsulfonphthalein lithium salt, with a total yield of 81.4% and a purity of 99.51%.

[0129] Example 2

[0130] Preparation of 3,4,5,6-Tetrahalophenolsulfonphthalein Sodium Salt

[0131] 1) Preparation of 3,4,5,6-tetrachlorophenolsulfonphthalein sodium salt

[0132] Salt formation: weigh 49.2 g (0.1 mol) of 3,4,5,6-tetrachlorophenolsulfonphthalein and add it to the reactor, add 1.0 eq of sodium carbonate, add 300 mL of dioxane, stir and react at 75 ° C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain 48.3 g of crude product;

[0133] Recrystallization: add all the crude product obtained in the previous step to the reactor, add 200 mL of chloroform, stir at 50°C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 300 mL of isopropyl ether, stir at 60°C for 1 hour, stop stirring, cool to room temperature, filter, dry, collect, and obtain 42.9 grams of 3,4,5,6-tetrachlorophenolsulfonphthalein sodium salt, with a total yield of 83.4% and a purity of 99.32%.

[0134] 2) Preparation of 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt

[0135] Salt formation: weigh 67.0 g (0.1 mol) of 3,4,5,6-tetrabromophenolsulfonphthalein and add it to the reactor, add 1.2 eq of sodium carbonate, add 350 mL of acetonitrile, stir and react at 40°C for 5 hours, stop stirring, cool to room temperature, filter, dry and collect to obtain 63.6 g of crude product;

[0136] Recrystallization: add all the crude product obtained in the previous step to the reactor, add 200 mL of carbon tetrachloride, stir at 40°C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 200 mL of ether, stir at 35°C for 11 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain 56.7 grams of 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt, with a total yield of 81.9% and a purity of 99.47%.

[0137] 3) Preparation of 3,4,5,6-tetraiodophenolsulfonphthalein sodium salt

[0138] Salt formation: weigh 85.8 g (0.1 mol) of 3,4,5,6-tetraiodophenolsulfonphthalein and add it to the reactor, add 1.4 eq of sodium carbonate, add 400 mL of acetone, stir and react at 40°C for 5 hours, stop stirring, cool to room temperature, filter, dry, and collect to obtain 80.9 g of crude product;

[0139] Recrystallization: add all the crude product obtained in the previous step to the reactor, add 250 mL of ethyl acetate, stir at 40°C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 200 mL of n-propyl ether, stir at 60°C for 3 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain 73.1 grams of 3,4,5,6-tetraiodophenolsulfonphthalein sodium salt, with a total yield of 83.1% and a purity of 99.53%.

[0140] Example 3

[0141] Preparation of 3,4,5,6-Tetrahalophenolsulfonphthalein Potassium Salt

[0142] 1) Preparation of 3,4,5,6-Tetrachlorophenolsulfonphthalein Potassium Salt

[0143] Salt formation: weigh 49.2 g (0.1 mol) of 3,4,5,6-tetrachlorophenolsulfonphthalein and add it to the reactor, add 1.2 eq of potassium acetate, add 300 mL of acetone, stir and react at 40°C for 12 hours, stop stirring, cool to room temperature, filter, dry, and collect to obtain 49.3 g of crude product;

[0144] Recrystallization: add all the crude product obtained in the previous step to the reactor, add 200 mL of chloroform, stir at 55°C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 200 mL of isopropyl ether, stir at 55°C for 1 hour, stop stirring, cool to room temperature, filter, dry, collect, and obtain 43.1 grams of 3,4,5,6-tetrachlorophenolsulfonphthalein potassium salt, with a total yield of 81.2% and a purity of 99.41%.

[0145] 2) Preparation of 3,4,5,6-tetrabromophenolsulfonphthalein potassium salt

[0146] Salt formation: weigh 67.0 g (0.1 mol) of 3,4,5,6-tetrabromophenolsulfonphthalein and add it to the reactor, add 1.4 eq of potassium acetate, add 250 mL of acetonitrile, stir and react at 60°C for 2 hours, stop stirring, cool to room temperature, filter, dry and collect to obtain 65.8 g of crude product;

[0147] Recrystallization: Add all the crude product obtained in the previous step to the reactor, add 150 mL of carbon tetrachloride, stir at 75°C for 2 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 200 mL of ether, stir at 35°C for 12 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain 58.5 grams of 3,4,5,6-tetrabromophenolsulfonphthalein potassium salt, with a total yield of 82.6% and a purity of 99.35%.

[0148] 3) Preparation of 3,4,5,6-tetraiodophenolsulfonphthalein potassium salt

[0149] Salt formation: weigh 85.8 g (0.1 mol) of 3,4,5,6-tetraiodophenolsulfonphthalein and add it to the reactor, add 1.6 eq of potassium acetate, add 200 mL of tetrahydrofuran, stir and react at 60°C for 5 hours, stop stirring, cool to room temperature, filter, dry, and collect to obtain 84.2 g of crude product;

[0150] Recrystallization: add all the crude product obtained in the previous step to the reactor, add 200 mL of ethyl acetate, stir at 50°C for 3 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain the product; add all the product obtained in the previous step to the reactor, add 200 mL of isopropyl ether, stir at 60°C for 3 hours, stop stirring, cool to room temperature, filter, dry, collect, and obtain 72.7 grams of 3,4,5,6-tetraiodophenolsulfonphthalein potassium salt, with a total yield of 81.1% and a purity of 99.19%.

[0151] Test Case

[0152] The solubility of 3,4,5,6-tetrahalophenolsulfonphthalein lithium salt, 3,4,5,6-tetrahalophenolsulfonphthalein sodium salt, 3,4,5,6-tetrahalophenolsulfonphthalein potassium salt and 3,4,5,6-tetrahalophenolsulfonphthalein obtained in Examples 1 to 3 was tested. The relevant data comparison results are shown in Table 12.

[0153] Table 12 Solubility of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salts obtained in Examples 1 to 3

[0154]

[0155] Definitions of terms used to describe solubility:

[0156] Very soluble: refers to the fact that 1g (mL) of solute can be dissolved in less than 1mL of solvent;

[0157] Soluble: refers to the solute 1g (mL) can be dissolved in 1 to less than 10mL of solvent;

[0158] Solubility: refers to the solute 1g (mL) can be dissolved in 10 to less than 30mL of solvent;

[0159] Slightly soluble: refers to the solute 1g (mL) can be dissolved in 30 to less than 100mL of solvent;

[0160] Slightly soluble: refers to the solute 1g (mL) can be dissolved in 100 to less than 1000mL of solvent;

[0161] Very slightly soluble: Soluble means that 1g (mL) of solute can be dissolved in 1000 to less than 10000mL of solvent;

[0162] Almost insoluble or insoluble: Soluble means that 1g (mL) of the solute cannot be completely dissolved in 10000mL of the solvent;

[0163] As can be seen from Table 12, the solubility of 3,4,5,6-tetrahalophenolsulfonphthalein lithium salt, 3,4,5,6-tetrahalophenolsulfonphthalein sodium salt and 3,4,5,6-tetrahalophenolsulfonphthalein potassium salt in water increased significantly.

[0164] Example 4

[0165] Application of 3,4,5,6-tetrahalophenolsulfonphthalein lithium salt in detection reagents

[0166] 1) Solution preparation: Color solution preparation: weigh 0.35 g of 3,4,5,6-tetrachlorophenolsulfonphthalein lithium salt and 0.45 g of sodium dodecylsulfonate, add to 100 mL of distilled water, stir evenly and set aside; Albumin standard solution preparation: weigh human serum albumin, dissolve it in distilled water, and prepare concentration gradients of 0.1, 0.2, 0.4, 0.8, 1.6, and 3.2 g / L respectively, set aside; Buffer solution preparation: prepare 100 mL of pH 3.0 citric acid-sodium citrate buffer solution, stir evenly and set aside;

[0167] 2) Determination of albumin content: In 7 colorimetric tubes, add 4.0 mL of citric acid-sodium citrate buffer solution, add 100 μL of colorimetric solution, add 100 μL of 6 concentrations of human serum albumin standard solution, add 100 μL of the protein standard solution to be tested, and the established standard curve can directly measure the albumin content in the sample to be tested.

[0168] Example 5

[0169] Application of 3,4,5,6-tetrahalophenolsulfonphthalein sodium salt in detection reagents

[0170] 1) Solution preparation: Color solution preparation: Weigh 0.38 g of 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt and 0.40 g of sodium dodecylsulfonate respectively, add to 100 mL of distilled water, stir evenly and set aside; Albumin standard solution preparation: Weigh human serum albumin, dissolve it in distilled water, and prepare concentration gradients of 0.1, 0.2, 0.4, 0.8, 1.6, and 3.2 g / L respectively, set aside; Buffer solution preparation: Prepare 100 mL of pH 3.0 citric acid-sodium citrate buffer solution, stir evenly and set aside;

[0171] Determination of albumin content: In 7 colorimetric tubes, add 4.5 mL of citric acid-sodium citrate buffer solution, add 100 μL of colorimetric solution, add 100 μL of 6 concentrations of human serum albumin standard solution, add 100 μL of the protein standard solution to be tested, and the established standard curve can directly measure the albumin content in the sample to be tested.

[0172] Example 6

[0173] Application of 3,4,5,6-tetrahalophenolsulfonphthalein potassium salt in detection reagents

[0174] 1) Solution preparation: Color development solution preparation: Weigh 0.42 g of 3,4,5,6-tetraiodophenolsulfonphthalein potassium salt and 0.42 g of sodium dodecylsulfonate respectively, add to 100 mL of distilled water, stir evenly and set aside; Albumin standard solution preparation: Weigh human serum albumin, dissolve it in distilled water, and prepare concentration gradients of 0.1, 0.2, 0.4, 0.8, 1.6, and 3.2 g / L respectively, set aside; Buffer solution preparation: Prepare 100 mL of pH 3.0 citric acid-sodium citrate buffer solution, stir evenly and set aside;

[0175] 2) Determination of albumin content: In 7 colorimetric tubes, add 3.7 mL of citric acid-sodium citrate buffer solution, add 100 μL of colorimetric solution, add 100 μL of 6 concentrations of human serum albumin standard solution, add 100 μL of the protein standard solution to be tested, and the established standard curve can directly measure the albumin content in the sample to be tested.

[0176] Example 7

[0177] Application of 3,4,5,6-tetrahalophenolsulfonphthalein lithium salt in acid-base indicator

[0178] Weigh 0.5 g of 3,4,5,6-tetrachlorophenolsulfonphthalein lithium salt, 15 g of polyethylene glycol 6000, 12 mL of sodium dodecyl sulfate, 0.1 g of bromothymol blue, and 15 mL of methyl red, add them into 1000 mL of aqueous solution in sequence, stir for 0.5 hour, then soak the solution with filter paper, dry it, cut it, and stick it on a film to make pH test paper for later use.

[0179] Example 8

[0180] Application of 3,4,5,6-tetrahalophenolsulfonphthalein sodium salt in acid-base indicator

[0181] Weigh 0.5 g of 3,4,5,6-tetrabromophenolsulfonphthalein sodium salt, 15 g of polyethylene glycol 6000, 12 mL of sodium dodecyl sulfate, 0.1 g of bromothymol blue, and 15 mL of methyl red, add them into 1000 mL of aqueous solution in sequence, stir for 0.5 hour, then soak the solution with filter paper, dry it, cut it, and stick it on a film to make pH test paper for later use.

[0182] Example 9

[0183] Application of 3,4,5,6-tetrahalophenolsulfonphthalein potassium salt in acid-base indicator

[0184] Weigh 0.5 g of 3,4,5,6-tetraiodophenolsulfonphthalein lithium salt, 15 g of polyethylene glycol 6000, 12 mL of sodium dodecyl sulfate, 0.1 g of bromothymol blue, and 15 mL of methyl red, add them into 1000 mL of aqueous solution in sequence, stir for 0.5 hour, then soak the solution with filter paper, dry it, cut it, and stick it on a film to make pH test paper for later use.

[0185] It can be seen from the above embodiments that the present invention provides a 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt and its preparation method and application. The present invention obtains 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt by salting and recrystallizing 3,4,5,6-tetrahalophenolsulfonphthalein, thereby overcoming the problem of poor water solubility of the existing 3,4,5,6-tetrahalophenolsulfonphthalein. The purity of the finally obtained 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt product reaches 99.0%, and the total yield reaches 80%. The preparation process is simple, the conditions are mild, the product purity is high, the yield is high, the cost is low, and it can be mass-produced, which is beneficial to further application in albumin detection reagents and hair dyes.

[0186] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt, characterized in that: The following steps are involved: 1) Salt formation: 3,4,5,6-tetrahalophenolsulfonphthalein and an alkali metal salt are mixed in a solvent to carry out a salt formation reaction to obtain a crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt; 2) Recrystallization: The crude product of 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is mixed with a solvent for recrystallization to obtain 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt; In the step 1), the solvent is an aprotic solvent, and the aprotic solvent is selected from one or more of tetrahydrofuran, acetone, acetonitrile, dioxane, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, ether, petroleum ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether and ethylene glycol dimethyl ether; In the step 1), the alkali metal salt is one or more of alkali metal carbonate, alkali metal acetate and alkali metal bicarbonate; The structural formula of the 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt is as follows: ； wherein X is independently Cl, Br or I; M is Li, Na or K; In the step 2), the recrystallization is performed twice, the solvent used for the first recrystallization is ethyl acetate, dichloromethane, chloroform or carbon tetrachloride, and the solvent used for the second recrystallization is ether, petroleum ether, n-propyl ether or isopropyl ether; The recrystallization temperature is 30-80° C., and the recrystallization time is 0.5-24 h.

2. The preparation method according to claim 1, characterized in that: In the step 1), the temperature of the salt-forming reaction is 30-80° C., and the time of the salt-forming reaction is 0.5-24 h.

3. The preparation method according to claim 2, characterized in that: In the step 1), the molar ratio of the 3,4,5,6-tetrahalophenolsulfonphthalein to the alkali metal salt is 1:0.9-1.

8.

4. The preparation method according to any one of claims 1 to 3, characterized in that In the step 1), the mass volume ratio of the 3,4,5,6-tetrahalophenolsulfonphthalein to the solvent is 1 g: 1-20 mL.

5. The preparation method according to claim 4, characterized in that: In the step 2), the mass volume ratio of the crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt to the solvent used for the first recrystallization is 1 g: 1-20 mL, and the mass volume ratio of the crude 3,4,5,6-tetrahalophenolsulfonphthalein alkali metal salt to the solvent used for the second recrystallization is 1 g: 1-20 mL.

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