CN117534593A - Preparation method of high-purity docusate sodium - Google Patents
Preparation method of high-purity docusate sodium Download PDFInfo
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- CN117534593A CN117534593A CN202311543958.0A CN202311543958A CN117534593A CN 117534593 A CN117534593 A CN 117534593A CN 202311543958 A CN202311543958 A CN 202311543958A CN 117534593 A CN117534593 A CN 117534593A
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- sodium
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- docusate
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- docusate sodium
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 title claims abstract description 84
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 title claims abstract description 82
- 229960000878 docusate sodium Drugs 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 58
- -1 di (2-ethyl) hexyl maleate Chemical compound 0.000 claims abstract description 57
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims abstract description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 235000010265 sodium sulphite Nutrition 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 24
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims abstract description 24
- 229940001584 sodium metabisulfite Drugs 0.000 claims abstract description 24
- 235000010262 sodium metabisulphite Nutrition 0.000 claims abstract description 24
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims abstract description 10
- BWDBEAQIHAEVLV-UHFFFAOYSA-N 6-methylheptan-1-ol Chemical compound CC(C)CCCCCO BWDBEAQIHAEVLV-UHFFFAOYSA-N 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000006277 sulfonation reaction Methods 0.000 abstract description 39
- 230000035484 reaction time Effects 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 239000012752 auxiliary agent Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 239000001301 oxygen Substances 0.000 abstract description 2
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 238000003756 stirring Methods 0.000 description 34
- 239000008213 purified water Substances 0.000 description 32
- 239000012074 organic phase Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 30
- 239000000203 mixture Substances 0.000 description 25
- 239000007788 liquid Substances 0.000 description 20
- 238000010992 reflux Methods 0.000 description 14
- 239000002994 raw material Substances 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- ONBWNNUYXGJKKD-UHFFFAOYSA-N 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonic acid;sodium Chemical compound [Na].CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC ONBWNNUYXGJKKD-UHFFFAOYSA-N 0.000 description 8
- 238000005886 esterification reaction Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of high-purity docusate sodium, belonging to the technical field of drug synthesis. The method comprises the following steps: firstly, maleic anhydride and isooctanol react in toluene under the catalysis of first acid to generate di (2-ethyl) hexyl maleate; then, the di (2-ethyl) hexyl maleate, sodium sulfite and sodium metabisulfite react in ethanol and water to generate sodium docusate; the molar ratio of the addition amount of sodium metabisulfite to the di (2-ethyl) hexyl maleate is (0.5-2.0): 1, and the molar ratio of the di (2-ethyl) hexyl maleate to the sodium sulfite is (1.0-1.2). The sulfonation step of the invention uses sodium sulfite and sodium metabisulfite, the sulfonation yield is high, the process is simple, the reaction conditions are not harsh, and the sulfonation reaction is not required to be carried out in the environments of no oxygen, high pressure and the like; no other auxiliary agent is introduced, so that the impurity is less, and the method is more suitable for the industrialized production of medicines; the invention has short reaction time, short production period and relatively low production cost; the finally obtained docusate sodium has high purity.
Description
Technical Field
The invention relates to a preparation method of high-purity docusate sodium, belonging to the technical field of drug synthesis.
Background
Sodium Docusate (Docusate sodium), also known as dioctyl sodium sulfosuccinate, is chemically known as sodium 1, 4-di (2-ethylhexyl) sulfosuccinate, and has a chemical structural formula shown in formula I:
docusate sodium is a surfactant which, after oral administration, allows water and fatty substances to soak into the faeces and soften them, and is suitable for patients suffering from faecal weakness such as anus, rectum or postoperative patients.
The synthesis of docusate sodium usually adopts a two-step method, wherein the first step is to carry out esterification reaction on maleic anhydride and isooctyl alcohol under the action of acid; and the second step is to carry out sulfonation reaction on the obtained ester and sodium bisulphite in an aqueous solution to obtain docusate sodium.
At present, related researches on a preparation method of the docusate sodium are few, for example, publication No. CN102702040B discloses a preparation method of the high-purity docusate sodium, but the method has the defects of low yield (sulfonation yield is lower than 75 percent), complex process (a catalyst is used, high-pressure environment is adopted in sulfonation reaction, and the like), long time consumption, and the like. Publication No. CN104829503A also discloses a method for preparing high-purity docusate sodium, but in order to prevent oxidation in the production process, nitrogen protection is needed, and the production cost is increased; and the esterification step is carried out in two stages, and the operation is complicated. The publication No. CN105753747B discloses an industrial production new method for preparing high-purity sodium docusate PEG solution, which requires vacuum reaction and obtains the sodium docusate PEG solution.
Therefore, it is very necessary to provide a synthetic method for preparing high-purity docusate sodium with simple process, low cost and high yield.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of high-purity docusate sodium, which comprises the following specific technical scheme:
the preparation method of the high-purity docusate sodium comprises the following steps:
step 1, carrying out esterification reaction on maleic anhydride and isooctanol under the catalysis of concentrated sulfuric acid to generate di (2-ethyl) hexyl maleate, wherein the reaction formula is as follows:
step 2, sulfonating the intermediate di (2-ethyl) hexyl maleate obtained in the step 1 by using water and ethanol as solvents in the presence of sodium sulfite and sodium metabisulfite to generate sodium docusate, wherein the reaction formula is as follows:
further improvement, the specific implementation of the step 1 is as follows: the maleic anhydride and isooctanol are adopted to react under the catalysis of concentrated sulfuric acid to generate di (2-ethyl) hexyl maleate which is a crude product and needs to be purified; the purification step is to obtain the high-purity di (2-ethyl) hexyl maleate through alkali washing, water washing and distillation in sequence.
The specific method of the step 2 is as follows: in the presence of sodium sulfite and sodium metabisulfite, the intermediate di (2-ethyl) hexyl maleate obtained in the step 1 is sulfonated by using water and ethanol as solvents to generate sodium docusate, and the crude product is obtained by sequentially extracting, salt washing, water washing and distilled water removal after post-treatment; and obtaining the high-purity docusate sodium through recrystallization.
In the present invention, the esterification and sulfonation steps are both carried out without inert gas protection and without high-pressure reaction, and the sulfonation step is carried out without the presence of a catalyst (ion exchange resin, phase transfer catalyst, etc.).
In the esterification step of the step 1, the acid used is concentrated sulfuric acid, and the dosage is 4-10% of the mass of maleic anhydride, preferably 6-8%; the molar ratio of maleic anhydride to isooctyl alcohol is 1:2.5-3.5, preferably 1:2.8-3.2; the alkaline washing solution is 10% potassium carbonate solution, and the dosage is 1-4 times of the volume of the reaction solution, preferably 1-2 times of the reaction solution.
The inventor finds that the different dosage of the metabisulfite in the sulfonation step can directly influence the efficiency and quality of the sulfonation reaction, when the dosage of the metabisulfite is 0, the reaction is abnormal, a target product cannot be obtained, and the intermediate di (2-ethyl) hexyl maleate can be subjected to massive hydrolysis to generate massive isooctanol; when the molar ratio of the amount of sodium metabisulfite to the di (2-ethyl) hexyl maleate is 0.5:1, no abnormal reaction occurs, but the sulfonation yield is low, the yield is reduced to below 85%, and a small amount of di (2-ethyl) hexyl maleate is hydrolyzed. In order to avoid the occurrence of the above situations as much as possible, the inventors conducted extensive studies on the sulfonation reaction step, and finally found that the reaction can be smoothly conducted when the molar ratio of the amount of sodium metabisulfite to di (2-ethyl) hexyl maleate added is 0.5 to 2.0:1, preferably 0.8 to 1.2:1; the molar ratio of the di (2-ethyl) hexyl maleate to the sodium sulfite is 1:1.0-1.2, the final sulfonation yield can reach more than 92%, and the purity of the docusate sodium reaches more than 99.5%.
At present, when di (2-ethyl) hexyl maleate is sulfonated to produce docusate sodium, the sulfonation reagent used is sodium bisulphite, and if sodium bisulphite is singly used, high pressure conditions are required, and the yield is only about 70%; alternatively, sodium bisulphite is singly used for sulfonation, nitrogen protection is needed under normal pressure, and the yield is low; if it is desired to increase the yield, it is also desired to use a catalyst.
The invention adopts the combination of sodium sulfite and sodium metabisulfite, has better sulfonation reaction effect than the single use of sodium sulfite or sodium metabisulfite, and plays a role in coordination and synergy; the sulfonation reaction can be carried out under the condition of normal pressure and no nitrogen protection, and a new catalyst is not required to be additionally introduced, so that the process is simpler, the yield and the purity are very high, and the method is more suitable for industrial production.
In the sulfonation step of step 2, the solvent used is a mixed solvent of water and ethanol. The inventor finds that the difference of the ethanol content in the solvent in the sulfonation step directly influences the efficiency and quality of the sulfonation reaction, and when only purified water is used as the solvent, the reaction system is layered, the reaction time is long (the reaction is required for 12 hours, and the sulfonation yield is 85 percent); when only 95% ethanol (95% by volume) was used as a solvent, the reaction system was not layered, but the reaction was found to be still slow, and the reaction was still not completed for 15.0 hours, leaving a large amount of raw materials. When 40% ethanol is used as a solvent, the system has obvious layering phenomenon, the reaction time is 4 hours, and the sulfonation yield is 92%; when 50% ethanol is used as a solvent, the system is uniform, the reaction time is 3 hours, and the sulfonation yield is 94%; the ethanol concentration was increased to 60%, the reaction time was 5 hours, and the sulfonation yield was 87%.
When the result of examining the concentration of the ethanol shows that the concentration of the ethanol is higher, sodium sulfite participating in the reaction is not easy to participate in the reaction, so that the reaction time is relatively prolonged; when the concentration of the ethanol is low, the system has layering phenomenon, the reaction system is not uniform, and the reaction time is relatively long, so that the optimal concentration of the ethanol is 49-51% through multiple experiments.
In the screening of the solvent used in the sulfonation reaction of step 2, isopropanol and acetonitrile were examined in addition to ethanol and water. When ethanol is replaced with isopropanol (i.e., an aqueous isopropanol solution having a concentration of about 50% is used), the reaction time becomes long, and about 6 hours is required for the starting material to react. If ethanol is replaced with acetonitrile (i.e., an aqueous acetonitrile solution having a concentration of about 50% is used), the raw material is not reacted even if it is reacted for 12 hours.
The invention has the beneficial effects that:
1. the sodium sulfite and sodium metabisulfite auxiliary agent are used in the sulfonation step, the sulfonation yield is high, the process is simple, the reaction conditions are not harsh, the sulfonation reaction is not required to be carried out in the environments of no oxygen, high pressure and the like, the equipment requirement is low, and the production cost is reduced; and no other auxiliary agent (such as a phase transfer catalyst and the like) is introduced, so that the method has less impurities and is more suitable for industrial production of medicines.
2. The invention is suitable for large-scale industrial production and has great popularization value.
3. The invention has high yield of the esterification step and simple process.
4. The invention has short reaction time, short production period and relatively low production cost; the finally obtained docusate sodium has high purity.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
1. Preparation of di (2-ethyl) hexyl maleate
398.56g (3.0 mol) of isooctanol, 6.0g (98% of mass dispersion) of concentrated sulfuric acid and 200g of toluene are added into a reaction bottle with a water diversion device, stirring is started, 100.02g (1.0 mol) of maleic anhydride is added, heating is started after the addition, the temperature is raised to reflux (100-120 ℃), and the temperature is kept for stirring reaction. The reaction is terminated when the separated moisture is about 85% or more of the theoretical produced moisture. After the reaction is finished, the temperature of the system is reduced to room temperature, 200ml of 10% potassium carbonate solution is slowly added for washing once, the solution is separated, the organic phase is washed once again by 200ml of purified water, the organic phase is distilled under reduced pressure until no fraction flows out, and 330.24g of colorless and transparent di (2-ethyl) hexyl maleate is obtained, and the esterification yield is 95%.
2. Preparation of crude docusate sodium
50.01g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 120ml of purified water, 130ml of 95% ethanol are added into a reaction flask, stirring is started, 20.3g (0.16 mol,1.1 eq) of sodium sulfite and 0g of sodium metabisulfite are added, heating is carried out until reflux (80-90 ℃) is carried out, stirring reaction is carried out at the temperature for 12 hours, and the residual quantity of di (2-ethyl) hexyl maleate in a TLC monitoring system is carried out until a point is basically disappeared. TLC monitoring, no docusate sodium was produced.
Example 2
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.01g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 120ml of purified water and 130ml of 95% ethanol are added into a reaction bottle, stirring is started, 20.3g (0.16 mol,1.1 eq) of sodium sulfite and 14.2g (0.075 mol,0.5 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80-90 ℃) after the addition, stirring reaction is carried out at the temperature for 3 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate while the system is hot, stirred and dissolved, the mixture is stood for liquid separation, the aqueous phase is extracted once again by 100ml of ethyl acetate, the organic phases are combined, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined sodium docusate (purified sodium docusate)
Heating and dissolving the crude docusate sodium product with 200ml acetonitrile, cooling and crystallizing, separating the upper liquid layer, and drying the lower white solid layer in a vacuum drying oven to obtain 58.9g of white waxy solid docusate sodium with 90% sulfonation yield.
Example 3
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.03g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 120ml of purified water and 130ml of 95% ethanol are added into a reaction flask, stirring is started, 20.02g (0.16 mol,1.1 eq) of sodium sulfite and 22.32g (0.12 mol,0.8 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80-90 ℃) after the addition, stirring is carried out at the temperature for 3 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 100ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
The crude docusate sodium is heated and dissolved by 200ml acetonitrile, cooled and crystallized, the upper liquid is separated, the lower white solid is dried in a vacuum drying oven, 61.01g of white waxy solid docusate sodium is obtained, and the sulfonation yield is 93%.
Example 4
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.37g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 120ml of purified water and 130ml of 95% ethanol are added into a reaction bottle, stirring is started, 20.3g (0.16 mol,1.1 eq) of sodium sulfite and 25.30g (0.13 mol,0.9 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80-90 ℃) after the addition, and the reaction is carried out at the temperature with stirring for 3 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 100ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
Heating and dissolving the crude docusate sodium product with 200ml acetonitrile, cooling and crystallizing, separating the upper liquid layer, drying the lower white solid layer in a vacuum drying oven to obtain 61.07g of white waxy solid docusate sodium, and the sulfonation yield is 93%.
Example 5
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.02g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 120ml of purified water and 130ml of 95% ethanol are added into a reaction flask, stirring is started, 20.0g (0.16 mol,1.1 eq) of sodium sulfite and 27.94g (0.15 mol,1.0 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80 ℃ to 90 ℃) after the mixture is added, and the reaction is carried out at the temperature with stirring for 3 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 100ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
The crude docusate sodium is heated and dissolved by 200ml acetonitrile, cooled and crystallized, the upper liquid is separated, the lower white solid is dried in a vacuum drying oven, and 60.28g of white waxy solid docusate sodium is obtained, and the sulfonation yield is 92%.
Example 6
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.4g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 120ml of purified water and 130ml of 95% ethanol are added into a reaction flask, stirring is started, 20.6g (0.16 mol,1.1 eq) of sodium sulfite and 33.5g (0.18 mol,1.2 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80-90 ℃) after the addition, stirring is carried out at the temperature for 3 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 100ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
The crude docusate sodium is heated and dissolved by 200ml acetonitrile, cooled and crystallized, the upper liquid is separated, the lower white solid is dried in a vacuum drying oven, 61.9g of white waxy solid docusate sodium is obtained, and the sulfonation yield is 94%.
Example 7
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.0g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above and 250ml of purified water are added into a reaction flask, stirring is started, 20.9g (0.16 mol,1.1 eq) of sodium sulfite and 25.9g (0.14 mol,0.9 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80 ℃ C. -90 ℃ C.) after the mixture is heated to reflux, stirring is carried out at the temperature for 12 hours, and the residual quantity of di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 100ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
Heating and dissolving the crude docusate sodium product with 200ml acetonitrile, cooling and crystallizing, separating the upper liquid layer, and drying the lower white solid layer in a vacuum drying oven to obtain 56.7g of white waxy solid docusate sodium with 85% sulfonation yield.
Example 8
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.0g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above and 250ml of 95% ethanol are added into a reaction bottle, stirring is started, 20.4g (0.16 mol,1.1 eq) of sodium sulfite and 25.8g (0.14 mol,0.9 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80-90 ℃) after the addition, the reaction is carried out at the temperature with stirring for 15 hours, and a large amount of di (2-ethyl) hexyl maleate is remained in a TLC monitoring system.
Example 9
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.0g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 146ml of purified water and 104ml of 95% ethanol are added into a reaction bottle, stirring is started, 20.4g (0.16 mol,1.1 eq) of sodium sulfite and 24.7g (0.13 mol,0.9 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80-90 ℃) after the addition, stirring is carried out at the temperature for 4 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 100ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
The crude docusate sodium is heated and dissolved by 200ml acetonitrile, cooled and crystallized, the upper liquid is separated, the lower white solid is dried in a vacuum drying oven, and 61.3g of white waxy solid docusate sodium is obtained, and the sulfonation yield is 92%.
Example 10
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.0g (0.15 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 94ml of purified water and 156ml of 95% ethanol are added into a reaction flask, stirring is started, 20.4g (0.16 mol,1.1 eq) of sodium sulfite and 24.7g (0.13 mol,0.9 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80-90 ℃) after the addition, stirring is carried out at the temperature for 5 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 100ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
Heating and dissolving the crude docusate sodium product by using 200ml of acetonitrile, cooling and crystallizing, separating upper liquid, drying lower white solid in a vacuum drying oven to obtain 58.1g of white waxy solid docusate sodium, wherein the sulfonation yield is 87%.
Example 11
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
50.0g (0.15 mol,1.0 eq) of the prepared di (2-ethyl) hexyl maleate, 120ml of purified water and 130ml of 95% ethanol are added into a reaction bottle, stirring is started, 30.4g (0.16 mol,1.1 eq) of sodium metabisulfite is added, the mixture is heated to reflux (80-90 ℃) after the mixture is added, the mixture is stirred at the temperature for 8 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in a TLC monitoring system is carried out until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 150ml of ethyl acetate and 100ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 100ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
Heating and dissolving the crude docusate sodium product with 200ml acetonitrile, cooling and crystallizing, separating the upper liquid layer, and drying the lower white solid layer in a vacuum drying oven to obtain 56.6g of white waxy solid docusate sodium with 85% sulfonation yield.
Example 12
1. Di (2-ethyl) hexyl maleate was prepared as in example 1.
2. Preparation of crude docusate sodium
100.3g (0.29 mol,1.0 eq) of di (2-ethyl) hexyl maleate prepared above, 240ml of purified water and 260ml of 95% ethanol are added into a reaction flask, stirring is started, 40.3g (0.32 mol,1.1 eq) of sodium sulfite and 50.3g (0.26 mol,0.9 eq) of sodium metabisulfite are added, the mixture is heated to reflux (80-90 ℃) after the addition, stirring is carried out at the temperature for 3 hours, and the residual quantity of the di (2-ethyl) hexyl maleate in the system is monitored by TLC until the raw material point is basically disappeared. After the reaction is finished, the temperature of the system is reduced to room temperature, then the system is decompressed and concentrated to be solid, 300ml of ethyl acetate and 200ml of purified water are respectively added into the concentrate for stirring and dissolution, the mixture is stood for liquid separation, the aqueous phase is extracted once by 200ml of ethyl acetate, the organic phases are combined, the organic phases are washed once by 200ml of purified water, and the organic phases are concentrated to be dry, so as to obtain the crude docusate sodium.
3. Preparation of refined docusate sodium
The crude docusate sodium is heated and dissolved by 400ml acetonitrile, cooled and crystallized, the upper liquid is separated, the lower white solid is dried in a vacuum drying oven, 122.5g of white waxy solid docusate sodium is obtained, the sulfonation yield is 95%, and the purity is 99.74%.
Example 13
The effect of sodium sulfite amount on sulfonation reaction was examined, and the results are shown in Table 1:
TABLE 1 influence of sodium sulfite usage on experimental results
From the viewpoint of the amplification effect and the cost, 1.1 equivalent is preferable.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (10)
1. The preparation method of the high-purity docusate sodium is characterized by comprising the following steps of:
step 1, maleic anhydride and isooctanol react in a first solvent under the catalysis of a first acid to generate di (2-ethyl) hexyl maleate;
step 2, the di (2-ethyl) hexyl maleate, sodium sulfite and sodium metabisulfite react in a second solvent to generate sodium docusate.
2. The method for preparing high-purity docusate sodium according to claim 1, wherein: in the step 2, the molar ratio of the addition amount of sodium metabisulfite to the di (2-ethyl) hexyl maleate is (0.5-2.0): 1, and the molar ratio of the di (2-ethyl) hexyl maleate to the sodium sulfite is (1.0-1.2).
3. The method for preparing high-purity docusate sodium according to claim 1, wherein: in step 2, the second solvent is ethanol and water.
4. A method for preparing high purity docusate sodium according to claim 3, wherein: the volume fraction of the ethanol in the second solvent is 49% -51%.
5. The method for preparing high-purity docusate sodium according to claim 1, wherein: in the step 1, the reaction temperature is 100-120 ℃; in step 2, the reaction temperature is 80-90 ℃.
6. The method for preparing high-purity docusate sodium according to claim 1, wherein: in the step 1, the first acid is concentrated sulfuric acid, and the dosage is 4-10% of the mass of maleic anhydride; the molar ratio of maleic anhydride to isooctyl alcohol is 1 (2.5-3.5).
7. The method for preparing high-purity docusate sodium according to claim 1, wherein: the di (2-ethyl) hexyl maleate produced in step 1 is further purified by alkali washing, water washing, and distillation.
8. The method for preparing high-purity docusate sodium according to claim 1, wherein: the sodium docusate produced in step 2 is also purified by recrystallisation and drying.
9. The method for preparing high-purity docusate sodium according to claim 1, wherein: in step 1, the first acid is one or more of concentrated sulfuric acid and p-toluenesulfonic acid.
10. The method for preparing high-purity docusate sodium according to claim 1, wherein: the first solvent is toluene.
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