CN114591266A - Preparation process of compound containing sulfonic group - Google Patents
Preparation process of compound containing sulfonic group Download PDFInfo
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- CN114591266A CN114591266A CN202210106045.1A CN202210106045A CN114591266A CN 114591266 A CN114591266 A CN 114591266A CN 202210106045 A CN202210106045 A CN 202210106045A CN 114591266 A CN114591266 A CN 114591266A
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention relates to the technical field of biological buffer reagent synthesis, and discloses a preparation process of a sulfonic acid group-containing compound and a salt thereof, which comprises the following preparation steps: reacting the compound 1 with the compound 2 to obtain a compound 3; reacting the compound 3 with an M-containing reagent to obtain a M-containing salt crude product corresponding to a sulfonic acid group-containing compound 4; after the acidification reaction, a crude product of the compound 4 containing sulfonic acid groups is obtained. And finally, purifying the crude product of the compound 4 containing sulfonic acid groups and the salt thereof to obtain the high-purity compound 4 containing sulfonic acid groups and the salt thereof. The preparation method disclosed by the invention has the advantages that the cost of the raw materials used in the preparation method is low, the operation is simple, the purity of the obtained product is higher, the yield of the product is improved, the application cost of the product is reduced, the preparation method is suitable for industrial production, and the obtained product can meet the requirements of the field of biological buffers on the purity, the impurity content and the cost of the biological buffers.
Description
Technical Field
The invention belongs to the technical field of biological buffer reagent synthesis, and particularly relates to a preparation process of a compound containing sulfonic groups.
Background
The compounds containing sulfonic acid groups, such as PIPES, MOPS, HEPES, MES and corresponding sodium salts PIPES-2Na, MOPS-Na, HEPES-Na and MES-Na, are important hydrogen ion buffers, have good buffering capacity in a certain pH range, and can maintain the pH constant for a long time. In general, the culture solution containing 20mmol/L concentration of sulfonic acid group-containing compound as a buffer has good buffering capacity, and the sulfonic acid group-containing compound has no toxic effect on cells.
Chinese patent CN110683995A discloses two methods for preparing piperazine ethanesulfonic acid derivatives, wherein the reaction is initiated by preheating in the early stage of charging, and the side reaction of 2-hydroxyethyl piperazine and 2-chloroethyl sodium sulfonate is controlled by heating after the reaction is self-heated to a certain degree, so that the reaction is relatively thorough; the amount of supplemented NaOH solution is reduced in the reaction process, the generation of NaCl in the reaction system is reduced, and triethylamine hydrochloride which is soluble in water and ethanol is formed in a subsequent salt forming mode with triethylamine and can be directly removed from the system, so that the desalting process using ion exchange resin is reduced; the mixed solution of ethanol/water is adopted for recrystallization, so that the residue of inorganic salts is effectively reduced, and the finally obtained product has relatively high purity.
However, in general, the number of patents relating to sodium salt products in sulfonic acid group-containing compounds is relatively small, and the preparation process in the prior patents has various problems: the raw materials of the product are not easy to obtain, the manufacturing cost is high, the three wastes are more, and the like. Thus preventing the large-scale application of sulfonic acid group compounds, especially preventing them from becoming materials in the field of biological buffering agents.
Based on the defects and shortcomings, the application aims to disclose a preparation process of a sulfonic acid group-containing compound, so that the sulfonic acid group-containing compound has important industrial application value in the fields of biological buffer reagents and the like.
Disclosure of Invention
In order to overcome the defects of the prior art, the first object of the present invention is to provide a preparation process of a sulfonic acid group-containing compound, the preparation process is simple, the used raw materials are easy to obtain, the product manufacturing cost is low, the yield of the prepared product is high, and the prepared sulfonic acid group-containing compound is purified to obtain a high-purity sulfonic acid group-containing compound refined product, which meets the requirements of the biological buffer reagent field on the purity, impurity content, cost and the like.
The first purpose of the invention can be achieved by adopting the following technical scheme:
a preparation process of a compound containing sulfonic group and salt thereof comprises the following preparation steps:
preparation step S1: reacting the compound 1 with the compound 2 to obtain a compound 3;
preparation step S2: reacting the compound 3 with an M-containing reagent to obtain a M-containing salt crude product corresponding to a sulfonic acid group-containing compound 4, and acidifying to obtain a sulfonic acid group-containing compound 4 crude product;
wherein, the structural formula of the compound 1 is a general structure shown in a formula I:
the structural formula of the compound 2 is a general structure shown in a formula II:
H2C＝CH-Cm-2H2(m-2)-SO2-O-R1；
formula II
Y is one of O, NH and NR; r is C which is saturated or unsaturated, contains straight chain or branched chain, contains heteroatoms or does not contain heteroatoms and can be substituted by one of sulfonate, hydroxyl and sulfonate at the tail end1-C30One of the hydrocarbon groups; r is1Is saturated or unsaturated, straight-chain or branched, heteroatom-containing or heteroatom-free C1-C30One of the hydrocarbon groups; m is an integer greater than or equal to 2; when m is 2, compound 2 is H2C＝CH-SO2-OR1(ii) a M in the reagent containing M is NH4 +One of metal elements;
the structural formula of the compound 3 is a general structure shown in a formula III:
the structural formula of the compound 4 is a general structure shown in a formula IV:
further, the corresponding M-containing salt of sulfonic acid group-containing compound 4 also includes a hydrate of the corresponding M-containing salt of sulfonic acid group-containing compound 4;
further, the sulfonic acid group-containing compound 4 also includes a hydrate corresponding to the sulfonic acid group-containing compound 4.
Wherein the general structure of the M-containing salt corresponding to the compound with the general structure shown in formula IV is shown as formula IV':
when Y in the compound 4 is N-CmH2m-SO2when-OH, Compound 1 has the general structure
At least one of (a);
in the preparation step S1, reacting the compound 1 with the compound 2 to prepare a compound with a general formula structure shown as a formula V; wherein the general structure shown in formula V is:
in the preparation step S2, reacting the compound having the general formula structure of formula V with a reagent containing M to obtain a crude salt corresponding to the compound having a sulfonic acid group having the general formula structure of formula VI; after acidification reaction, a sulfonic acid group-containing compound with a general structure of formula VI or a corresponding hydrate is obtained; the general structure shown in formula VI is:
wherein the general structure of the M-containing salt corresponding to the compound having the general structure shown in formula VI is shown in formula VI':
further, the sulfonic acid group-containing compound is piperazine-N, N '-bis (2-ethanesulfonic acid), 3-morpholinopropanesulfonic acid, 4-hydroxyethylpiperazine ethanesulfonic acid, 2-morpholinoethanesulfonic acid, or a sodium salt of said piperazine-N, N' -bis (2-ethanesulfonic acid), 3-morpholinopropanesulfonic acid, 4-hydroxyethylpiperazine ethanesulfonic acid, 2-morpholinoethanesulfonic acid.
Further, when Y is NR, R is C whose end is substituted with one of sulfonate, hydroxy and sulfonate1-C30One of the hydrocarbon radicals, Y being N-CmH2m-SO2-OH、N-CmH2m-OH、N-CmH2m-CO-OH。
Further, the M reagent is one or a composition of more than two of simple substance containing M, alkali containing M, oxide containing M, salt containing M or precursor, double salt, hydrate, solvent complex and hydrogen halide complex thereof.
Further, in the preparation step S1, the reaction temperature is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours; in the preparation step S2, the reaction temperature is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours.
Further, in the preparation step S1, the molar ratio of compound 1 to compound 2 is 1: (0.1-10); in preparation step S2, the molar ratio of compound 3 to M-containing reagent is 1: (0.1-10).
Further, the reaction is carried out using at least one of a catalyst or an auxiliary in the preparation step S1.
Further, in the preparation step S1, the compound 1 is reacted with a reagent containing M in a reaction solvent a, wherein the reaction solvent a is at least one of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethyl sulfoxide; in the preparation step S2, the compound 3 is reacted with the M-containing reagent in the reaction solvent B, which is at least one of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethyl sulfoxide.
Further, the method also comprises a purification step, wherein the purification step comprises the following steps:
the sulfonic acid group-containing compound or its salt obtained as the crude product in the preparation step S2 is dissolved in a purification solvent under dry conditions using a dry sealed apparatus or under dry gas purge, followed by recrystallization, filtration, and drying to obtain a purified sulfonic acid group-containing compound.
Further, the purifying solvent is one or a combination of more than two of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide and dimethyl sulfoxide.
Compared with the prior art, the invention has the beneficial effects that:
1. the preparation process of the sulfonic acid group-containing compound and the salt thereof has the advantages of simple preparation method, easily obtained raw materials, low water content and dryness of the prepared product, improves the yield of the product, integrally reduces the cost of the product, and is suitable for industrial production and application in the fields of life science, in-vitro diagnosis, medicine and the like.
2. According to the preparation process of the sulfonic group-containing compound and the salt thereof, the generated by-products and impurities are easy to purify and separate, so that the purification process is simple, the impurities in the product can reach the high-purity practical application standard without a complex purification process, and a high-purity sulfonic group-containing compound fine product is obtained after purification, so that the requirements on the aspects of purity, impurity content, cost and the like of the compound in the field of biological buffer reagents are met. The preparation process of the product is simplified, the product yield is high, the product purity is high, and the requirements on yield and quality of large-scale application can be met.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment. It is noted that the terminology used in the examples is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. In addition, the raw materials used in the invention are generally common commercial products, so that the sources of the raw materials do not need to be particularly limited.
The pressure values mentioned in this patent application, unless otherwise specified, are gauge pressures, which refer to the total absolute pressure exceeding the ambient atmospheric pressure or the pressure at a point in the liquid above atmospheric pressure.
The yield, as a percentage ratio of actual product mass to theoretical product mass, and theoretical product mass, were calculated as the raw materials in the reaction equation were not in excess.
The reaction temperature is generally referred to as the oil bath temperature of the reaction unless otherwise specified.
The purity of the product was analyzed by acid-base titration.
Nuclear magnetic analysis was performed using a Bruker (AVANCE 400 mega nuclear magnetic resonance spectrometer from Bruker).
Example 1: preparation of disodium piperazine-N, N' -bis (2-ethanesulfonate) (PIPES-2Na)
The preparation method of piperazine-N, N' -di (2-ethanesulfonic acid) disodium comprises the following preparation steps:
preparation step S1:
adding 100g of a compound 1, a compound 2 and a reaction solvent acetonitrile into a 1L dry reactor under the condition of stirring, wherein the compound 1 is piperazine, and the compound 2 is vinyl ethyl sulfonate; the molar ratio of the compound 1 to the compound 2 is 1:4, the reaction temperature is 70 ℃, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 4 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude compound 3.
Preparation step S2:
adding 100g of the compound 3, a reaction solvent methanol and an M-containing reagent into a 1L dry reactor under the condition of stirring, wherein the M-containing reagent is sodium hydroxide; the molar ratio of compound 3 to M-containing reagent is 1: 3, the reaction temperature is 30 ℃, the reaction pressure is 0MPa (gauge pressure), and the reaction time is 5 h.
And after the reaction is finished, cooling to normal temperature, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a piperazine-N, N' -di (2-ethanesulfonic acid) disodium crude product with the yield of 75%.
Preparation step S3:
under a dry condition, dissolving the crude piperazine-N, N' -di (2-ethanesulfonic acid) disodium obtained in the step S2 in a purification solvent diethyl carbonate under a dry closed device, recrystallizing, crystallizing at a low temperature, filtering, and drying to obtain a refined compound containing sulfonic groups; the purity of the product was 99.8%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.8ppm，2.9ppm，2.6ppm，2.0ppm。
example 2: preparation of piperazine-N, N' -bis (2-ethanesulfonic acid) (PIPES)
The preparation of the 3-morpholine propanesulfonic acid comprises the following preparation steps:
preparation step S1:
adding 100g of compound 1, compound 2 and a reaction solvent acetone into a 1L dry reactor under the condition of stirring; wherein, the compound 1 is piperazine, and the compound 2 is vinyl propyl sulfonate; the molar ratio of the compound 1 to the compound 2 is 1:10, the reaction temperature is 40 ℃, the reaction pressure is 0.2MPa (gauge pressure), and the reaction time is 15 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude compound 3.
Preparation step S2:
adding 100g of the compound 3, a reaction solvent of tetrahydrofuran and an M-containing reagent into a 1L dry reactor under stirring; wherein the M-containing reagent is sodium bicarbonate, and the molar ratio of the compound 3 to the M-containing reagent is 1:1, the reaction temperature is 65 ℃, the reaction pressure is 0.2MPa (gauge pressure), and the reaction time is 1 h.
And after the reaction is finished, cooling to normal temperature, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude piperazine-N, N' -di (2-ethanesulfonic acid) disodium product.
Preparation step S3:
dissolving the crude piperazine-N, N '-di (2-ethanesulfonic acid) disodium product prepared in the step S2 in ethanol, adjusting the pH to 4-5 by using glacial acetic acid, stirring, cooling to clean crystals, filtering, and drying to obtain piperazine-N, N' -di (2-ethanesulfonic acid).
Preparation step S4:
under the drying condition, dissolving the piperazine-N, N' -bis (2-ethanesulfonic acid) obtained in the step S3 in a purified solvent ethanol by using a drying closed device, recrystallizing at low temperature, filtering, and drying to obtain a refined compound containing sulfonic groups; the yield of piperazine-N, N' -bis (2-ethanesulfonic acid) was 70%, and the purity of the product was 99.9%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.5ppm、3.4ppm。
example 3: preparation of sodium 3-morpholinopropanesulfonate (MOPS-Na)
The preparation process of the 3-morpholine sodium propanesulfonate comprises the following preparation steps:
preparation step S1:
adding 100g of compound 1, compound 2 and a reaction solvent N, N-dimethylformamide into a 1L dry reactor under stirring; wherein, the compound 1 is morpholine, and the compound 2 is methyl allylsulfonate; the molar ratio of the compound 2 to the compound 3 is 1:1.5, the reaction temperature is 100 ℃, the reaction pressure is 0.4MPa (gauge pressure), and the reaction time is 1 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude compound 3.
Preparation step S2:
adding 100g of the compound 3, a reaction solvent, dimethyl sulfoxide and an M-containing reagent into a 1L dry reactor under stirring; wherein the M-containing reagent is sodium carbonate; the molar ratio of compound 3 to M-containing reagent is 1: 5, the reaction temperature is 60 ℃, the reaction pressure is 0MPa (gauge pressure), and the reaction time is 5 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude product of the 3-sodium morpholine propanesulfonate, wherein the yield of the crude product of the 3-sodium morpholine propanesulfonate is 72%.
Preparation step S3:
under the drying condition, dissolving the crude product of the 3-morpholine sodium propanesulfonate obtained in the preparation step S2 in a purified solvent dimethyl carbonate under a drying closed device, recrystallizing, crystallizing at low temperature, filtering, and drying to obtain a refined compound containing sulfonic groups; the purity of the product was 99.6%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.8ppm，2.9ppm，2.6ppm，2.0ppm。
example 4: preparation of 3-morpholinopropanesulfonic acid (MOPS)
Dissolving the crude product of the sodium 3-morpholine propanesulfonate prepared in the embodiment 3 in methanol, adjusting the pH value to 4-5 by using a dilute hydrochloric acid solution, stirring, cooling to clean crystals, filtering, and drying to obtain the crude product of the 3-morpholine propanesulfonic acid;
under the drying condition, dissolving the crude product of 3-morpholine propanesulfonic acid in a purified solvent methanol by using drying closed equipment, recrystallizing, crystallizing at low temperature, filtering, and drying to obtain a refined product; the total yield of 3-morpholinopropanesulfonic acid was 71% (total yield of synthesis and purification), with a purity of 99.6%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ4.2ppm，3.9ppm，3.6ppm，3.4ppm，3.3ppm，3.1ppm，2.3ppm。
example 5: preparation of sodium 4-hydroxyethyl piperazineethanesulfonate (HEPES-Na)
A preparation process of a compound containing sulfonic groups comprises the following preparation steps:
preparation step S1:
adding 100g of compound 1, compound 2 and a reaction solvent dioxane into a 1L dry reactor under stirring; wherein the compound 1 is 4-hydroxyethyl piperazine, and the compound 2 is n-hexyl vinylsulfonate; the molar ratio of the compound 1 to the compound 2 is 1:1, the reaction temperature is 140 ℃, the reaction pressure is 1MPa (gauge pressure), and the reaction time is 24 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude compound 3.
Preparation step S2:
adding 100g of the compound 3, a reaction solvent of dimethyl carbonate and an M-containing reagent into a 1L dry reactor under the condition of stirring; wherein, the M-containing reagent is sodium methoxide; the molar ratio of compound 3 to M-containing reagent is 1:10, the reaction temperature is 30 ℃, the reaction pressure is 0MPa (gauge pressure), and the reaction time is 24 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude product of the 4-hydroxyethyl piperazine ethanesulfonic acid sodium salt, wherein the yield of the crude product of the 4-hydroxyethyl piperazine ethanesulfonic acid sodium salt is 69%.
Preparation step S3:
under a drying condition, dissolving the crude 4-hydroxyethyl piperazine ethanesulfonic acid sodium salt obtained in the step S2 in a purification solvent diethyl carbonate under a drying closed device, recrystallizing, crystallizing at a low temperature, filtering, and drying to obtain a refined 4-hydroxyethyl piperazine ethanesulfonic acid sodium salt; the purity was 99.7%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.7ppm，3.1ppm，2.8ppm，2.6ppm。
example 6: preparation of 4-hydroxyethyl piperazine ethanesulfonic acid (HEPES)
The preparation process of the 4-hydroxyethyl piperazine ethanesulfonic acid comprises the following preparation steps:
preparation step S1:
adding 100g of compound 1, compound 2 and reaction solvent diethyl ether into a 1L dry reactor under the condition of stirring; wherein the compound 1 is 4-hydroxyethyl piperazine, and the compound 2 is ethyl vinylsulfonate; the molar ratio of the compound 1 to the compound 2 is 1:7, the reaction temperature is 25 ℃, the reaction pressure is 0MPa (gauge pressure), and the reaction time is 72 h.
And after the reaction is finished, cooling to normal temperature, performing rotary evaporation under reduced pressure to remove the solvent, and concentrating to obtain a crude product of the compound 3.
Preparation step S2:
to a 1L dry reactor, 100g of the above compound 3, a reaction solvent N, N-dimethylformamide, and a reagent containing M were charged with stirring; wherein the M-containing reagent is potassium carbonate; the molar ratio of compound 3 to M-containing reagent is 1:4, the reaction temperature is 100 ℃, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 36 h.
And cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude product of the 4-hydroxyethyl piperazine potassium ethanesulfonate.
Preparation step S3:
and (4) dissolving the potassium 4-hydroxyethyl piperazine ethanesulfonate prepared in the step (S2) in methanol, adjusting the pH to 4-5 by using dilute sulfuric acid, stirring, cooling to clean crystals, filtering, and drying to obtain the 4-hydroxyethyl piperazine ethanesulfonic acid with the yield of 71%.
And 4, a preparation step:
under the drying condition, dissolving the crude product of the 4-hydroxyethyl piperazine ethanesulfonic acid obtained in the step S3 in a purification solvent of diethyl carbonate by using drying closed equipment, recrystallizing, crystallizing at low temperature, filtering, and drying to obtain a refined product; the purity of the 4-hydroxyethyl piperazine ethanesulfonic acid product is 99.7%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ4.0ppm，3.3ppm，3.2ppm，3.1ppm。
example 7: preparation of 2-morpholine potassium ethanesulfonate (MES-K)
The preparation process of the 2-morpholine potassium ethanesulfonate comprises the following preparation steps:
preparation step S1:
adding 100g of compound 1, compound 2 and a reaction solvent N, N-dimethylformamide into a 1L dry reactor under stirring; wherein, the compound 1 is morpholine, and the compound 2 is methyl vinylsulfonate; the molar ratio of the compound 1 to the compound 2 was 1:1, the reaction temperature was 25 ℃, the reaction pressure was 0.1MPa (gauge pressure), and the reaction time was 54 hours.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude compound 3.
Preparation step S2:
adding 100g of the compound 3, dioxane as a reaction solvent and an M-containing reagent into a 1L dry reactor under stirring; wherein, the M-containing reagent is potassium hydroxide; the molar ratio of compound 3 to M-containing reagent is 1:1.5, the reaction temperature is 80 ℃, the reaction pressure is 0.2MPa (gauge pressure), and the reaction time is 15 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude product of the 2-morpholine potassium ethanesulfonate with the yield of 76%.
Preparation step S3:
under the drying condition, dissolving the crude product of the 2-morpholine potassium ethanesulfonate obtained in the step S2 in a purification solvent diethyl carbonate under a drying closed device, recrystallizing, crystallizing at low temperature, filtering, and drying to obtain a refined product; the purity of the potassium 2-morpholine ethanesulfonate product is 99.5%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ3.8ppm，3.2ppm，2.9ppm，2.7ppm。
example 8: preparation of 2-morpholinoethanesulfonic acid (MES)
The preparation process of the 2-morpholine ethanesulfonic acid comprises the following preparation steps:
preparation step S1:
adding 100g of compound 1, compound 2 and tetrahydrofuran as a reaction solvent into a 1L dry reactor under stirring; wherein, the compound 1 is morpholine, and the compound 2 is vinyl propyl sulfonate; the molar ratio of the compound 1 to the compound 2 is 1:1.5, the reaction temperature is 50 ℃, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 24 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude compound 3.
Preparation step S2:
adding 100g of the compound 3, a reaction solvent ethanol and an M-containing reagent into a 1L dry reactor under stirring; wherein, the reagent containing M is ammonia water; the molar ratio of compound 3 to M-containing reagent is 1: 2, the reaction temperature is 50 ℃, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 12 h.
And (3) cooling to normal temperature after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid to remove the solvent, and concentrating to obtain a crude product of the 2-morpholine ammonium ethanesulfonate with the yield of 68%.
Preparation step S3:
and (4) dissolving the crude product of the 2-morpholine ethanesulfonic acid ammonium salt prepared in the step (S2) in ethanol, adjusting the pH value to 4-5 by using glacial acetic acid, stirring, cooling to clean crystals, filtering, and drying to obtain the crude product of the 2-morpholine ethanesulfonic acid.
Preparation step S4:
under the drying condition, dissolving the crude product of the 2-morpholine ethanesulfonic acid obtained in the step S3 in a purification solvent of dimethyl carbonate under a drying closed device, recrystallizing, crystallizing at low temperature, filtering, and drying to obtain a refined compound containing sulfonic groups; the purity of the product was 99.6%.
The nmr characterization data is as follows:1H NMR(400MHz,D2O):δ4.2ppm，3.9ppm，3.6ppm，3.4ppm，3.3ppm。
the experiments show that the compound containing sulfonic group prepared in the embodiment has high purity and low impurity content, and can meet the requirements of the application field, the product yield of the preparation method can reach 76 percent at most, the product yield is improved, and the product purity can reach 99.9 percent at most.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (12)
1. A process for preparing a sulfonic acid group-containing compound and salts thereof,
preparation step S1: reacting the compound 1 with the compound 2 to obtain a compound 3;
preparation step S2: reacting the compound 3 with an M-containing reagent to obtain a M-containing salt crude product corresponding to a sulfonic acid group-containing compound 4; after acidification reaction, a crude product of a compound 4 containing sulfonic acid groups is obtained;
wherein, the structural formula of the compound 1 is a general structure shown in a formula I:
the structural formula of the compound 2 is a general structure shown in a formula II:
H2C＝CH-Cm-2H2(m-2)-SO2-O-R1；
formula II
Y is one of O, NH and NR; r is C which is saturated or unsaturated, contains straight chain or branched chain, contains heteroatoms or does not contain heteroatoms and can be substituted by one of sulfonate, hydroxyl and sulfonate at the tail end1-C30One of the hydrocarbon groups; r1Is saturated or unsaturated, straight-chain or branched, heteroatom-containing or heteroatom-free C1-C30One of the hydrocarbon groups; m is an integer greater than or equal to 2; when m is 2, compound 2 is, H2C＝CH-SO2-OR1(ii) a M in the reagent containing M is NH4 +One of metal elements;
the structural formula of the compound 3 is a general structure shown in a formula III:
the structural formula of the compound 4 is a general structure shown in a formula IV:
2. the process according to claim 1 for preparing a sulfonic acid group-containing compound or a salt thereof,
y in the compound 4 is N-CmH2m-SO2when-OH, Compound 1 has the general structure
At least one of (a);
in the preparation step S1, reacting the compound 1 with the compound 2 to prepare a compound with a general formula structure shown as a formula V;
the general structure shown in formula V is:
in the preparation step S2, reacting the compound with the general formula structure as formula V with a reagent containing M to obtain a crude salt corresponding to the compound containing sulfonic group with the general formula structure as formula VI; after acidification reaction, a sulfonic acid group-containing compound with a general structure of formula VI or a corresponding hydrate is obtained;
the general structure shown in formula VI is:
3. the process for producing a sulfonic acid group-containing compound and its salt according to claim 1-2,
the M-containing salt corresponding to the sulfonic acid group-containing compound 4 also includes a hydrate of the M-containing salt corresponding to the sulfonic acid group-containing compound 4;
the sulfonic acid group-containing compound 4 also includes a hydrate corresponding to the sulfonic acid group-containing compound 4.
4. The process for preparing a sulfonic acid group-containing compound and its salt according to claims 1-2, wherein the sulfonic acid group-containing compound is one of piperazine-N, N '-bis (2-ethanesulfonic acid), 3-morpholinopropanesulfonic acid, 4-hydroxyethylpiperazine ethanesulfonic acid, 2-morpholinoethanesulfonic acid or the sodium salts of piperazine-N, N' -bis (2-ethanesulfonic acid), 3-morpholinopropanesulfonic acid, 4-hydroxyethylpiperazine ethanesulfonic acid, 2-morpholinoethanesulfonic acid.
5. The process according to claims 1-2, wherein when Y is NR, R is C whose end is substituted with a group selected from sulfonate, hydroxy, sulfonate1-C30One of the hydrocarbon radicals, Y being N-CmH2m-SO2-OH、N-CmH2m--OH、N-CmH2m-CO-OH。
6. The process according to claims 1 to 2, wherein the M reagent is one or a combination of two or more of a simple substance containing M, a base containing M, an oxide containing M, a salt containing M, or a precursor, a double salt, a hydrate, a solvent complex, and a hydrogen halide complex thereof.
7. The process for preparing a sulfonic acid group-containing compound or salt thereof as claimed in claims 1-2, wherein in the step of S1, the reaction temperature is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours; in the preparation step S2, the reaction temperature is-50-200 ℃, the reaction pressure is-0.05-1 MPa, and the reaction time is 0.1-72 hours.
8. The process according to claims 1 to 2, wherein the molar ratio of compound 1 to compound 2 in the preparation step S1 is 1: (0.1-10); in preparation step S2, the molar ratio of compound 3 to M-containing reagent is 1: (0.1-10).
9. The process for preparing a sulfonic acid group-containing compound or salt thereof according to claims 1-2, wherein in the step S1, compound 1 is reacted with compound 2 in a reaction solvent a which is at least one of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethylsulfoxide; in the preparation step S2, the compound 3 is reacted with the M-containing reagent in the reaction solvent B, which is at least one of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethyl sulfoxide.
10. The process according to claims 1 to 2, wherein at least one of the catalyst and the auxiliary is used in the step S1.
11. The process for preparing sulfonic acid group-containing compounds and salts thereof according to claims 1-10, further comprising the steps of:
the sulfonic acid group-containing compound or its salt obtained as the crude product in the preparation step S2 is dissolved in a purification solvent under dry conditions using a dry sealed apparatus or under dry gas purge, followed by recrystallization, filtration, and drying to obtain a purified sulfonic acid group-containing compound.
12. The process according to claim 11, wherein the purification solvent is one or a combination of two or more selected from methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl ether, acetonitrile, dioxane, N-dimethylformamide, and dimethylsulfoxide.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20060089509A1 (en) * | 2003-09-16 | 2006-04-27 | Carroll Glenn T | Preparation of substituted alkanesulfonates from 2-hydroxyalkanesulfonates |
| CN104803949A (en) * | 2015-05-19 | 2015-07-29 | 山东理工大学 | Method for preparing high-purity 4-hydroxyethyl piperazine ethane sulfonic acid |
| CN109836399A (en) * | 2017-11-27 | 2019-06-04 | 荆楚理工学院 | A kind of synthetic method of biological buffer-morpholinoethanesulfonic acid |
| CN110683995A (en) * | 2019-09-17 | 2020-01-14 | 苏州亚科科技股份有限公司 | Piperazine ethanesulfonic acid derivative preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060089509A1 (en) * | 2003-09-16 | 2006-04-27 | Carroll Glenn T | Preparation of substituted alkanesulfonates from 2-hydroxyalkanesulfonates |
| CN104803949A (en) * | 2015-05-19 | 2015-07-29 | 山东理工大学 | Method for preparing high-purity 4-hydroxyethyl piperazine ethane sulfonic acid |
| CN109836399A (en) * | 2017-11-27 | 2019-06-04 | 荆楚理工学院 | A kind of synthetic method of biological buffer-morpholinoethanesulfonic acid |
| CN110683995A (en) * | 2019-09-17 | 2020-01-14 | 苏州亚科科技股份有限公司 | Piperazine ethanesulfonic acid derivative preparation method |
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| WO2023142797A1 (en) * | 2022-01-28 | 2023-08-03 | 苏州亚科科技股份有限公司 | Preparation process for sulfonic acid-containing compound |
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