CN108586250B - Sodium stearyl fumarate auxiliary material and preparation method thereof - Google Patents
Sodium stearyl fumarate auxiliary material and preparation method thereof Download PDFInfo
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- CN108586250B CN108586250B CN201810695287.2A CN201810695287A CN108586250B CN 108586250 B CN108586250 B CN 108586250B CN 201810695287 A CN201810695287 A CN 201810695287A CN 108586250 B CN108586250 B CN 108586250B
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 229940045902 sodium stearyl fumarate Drugs 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000000463 material Substances 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000003513 alkali Substances 0.000 claims abstract description 27
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims abstract description 26
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000011734 sodium Substances 0.000 claims abstract description 20
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 20
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 19
- 238000001816 cooling Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000007670 refining Methods 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 11
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 11
- 239000002798 polar solvent Substances 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000004537 pulping Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 9
- 235000013305 food Nutrition 0.000 abstract description 9
- 239000012043 crude product Substances 0.000 abstract description 4
- 238000010438 heat treatment Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000013067 intermediate product Substances 0.000 abstract description 2
- 238000001514 detection method Methods 0.000 description 8
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- 239000000203 mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- -1 but not limited to Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical group [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000012019 baked potatoes Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 1
- STFSJTPVIIDAQX-TVWXOORISA-M sodium;(z)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C([O-])=O STFSJTPVIIDAQX-TVWXOORISA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/593—Dicarboxylic acid esters having only one carbon-to-carbon double bond
- C07C69/60—Maleic acid esters; Fumaric acid esters
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a sodium stearyl fumarate auxiliary material and a preparation method thereof, wherein the preparation method comprises the following steps: s1, mixing maleic anhydride, octadecanol and a reaction solvent, and heating for ring-opening reaction; s2, adding a conversion agent for conversion reaction; s3, cooling, dropwise adding a sodium-containing alkali solution, stirring, reacting, cooling, and crystallizing to obtain a crude product; and S4, refining to obtain a sodium stearyl fumarate product. The sodium stearyl fumarate is prepared by a one-pot method, and each intermediate product does not need to be separated, so that the preparation process and the post-treatment step are greatly simplified, and the reaction condition is mild; meanwhile, the total yield and purity are obviously improved, and the method is suitable for being used as a medicine and food auxiliary material and industrial production.
Description
Technical Field
The invention belongs to the technical field of auxiliary material preparation, and particularly relates to a sodium stearyl fumarate auxiliary material and a preparation method thereof.
Background
Stearyl fumarate sodium (C)22H39NaO4) Is an important medicine and food auxiliary material with wide application. During the metabolism process of the sodium stearyl fumarate in animal bodies, most of the sodium stearyl fumarate can be absorbed, and the sodium stearyl fumarate is hydrolyzed to generate stearyl alcohol and stearic acid, and a small part of the sodium stearyl fumarate can be directly and rapidly metabolized, so that the sodium stearyl fumarate is non-toxic and non-irritant. In the field of medicine, sodium stearyl fumarateThe compound can be added into a pharmaceutical preparation, can be used as a lubricant for tablets and capsules, can also form a protective film in effervescent tablets, can solve the problems of stearate lubricants, and can play roles in improving the disintegration of the medicine and promoting the dissolution of the medicine. In the food field, sodium stearyl fumarate is permitted by the FDA to be directly added into foods for human consumption as a regulator and a stabilizer, such as various baked foods, flour-thickened foods, baked potatoes, processed grains and the like, and the addition amount of the sodium stearyl fumarate can be 0.2-1.0% of the weight of the foods.
In the prior art, stearyl alcohol and maleic anhydride are usually used as raw materials to prepare sodium stearyl fumarate, but various solid intermediate products are often required to be prepared in sequence in the preparation process, so that the preparation steps are more, the synthesis process is complicated, the production cost and time are increased, more solvent usage and waste liquid are caused, the environmental protection pressure is higher, and the industrial production is not facilitated.
Disclosure of Invention
The invention aims to solve the technical problem of providing a sodium stearyl fumarate auxiliary material and a preparation method thereof, and the method has simple synthesis steps and high yield and high purity.
The invention provides a preparation method of a sodium stearyl fumarate auxiliary material, which comprises the following steps:
s1, mixing maleic anhydride, octadecanol and a reaction solvent, and carrying out ring-opening reaction at the temperature of 80 ℃ or above;
s2, adding a conversion agent into the reaction system to carry out conversion reaction;
s3, cooling to 40-50 ℃, dropwise adding a sodium-containing alkali solution into the reaction system, stirring, reacting, cooling, and crystallizing to obtain a crude sodium stearyl fumarate;
and S4, refining the crude sodium stearyl fumarate to obtain a sodium stearyl fumarate product.
Preferably, in step S1, the reaction solvent is one or more of toluene, cyclohexane and n-heptane; the reaction temperature of the ring-opening reaction is 80-100 ℃, and the reaction time is 8-24 hours.
Preferably, in step S2, the conversion agent includes a hydrochloric acid/thiourea solution, the hydrochloric acid/thiourea solution is made of thiourea and an acid solution, the mass ratio of the thiourea to the acid solution is 1:1, and the acid solution includes 1-12mol/L hydrochloric acid and/or sulfuric acid; the reaction temperature of the conversion reaction is 70-85 ℃, and the reaction time is 15-24 hours.
Preferably, in step S3, the sodium-containing alkali solution includes an alkali component and a first solvent, the mass percentage of the alkali component in the sodium-containing alkali solution is 5-20%, and the alkali component includes a sodium-containing inorganic salt.
Preferably, the alkali component is selected from one or more of sodium hydroxide, sodium carbonate and sodium bicarbonate; the first solvent comprises water and/or alcohol, and the alcohol is low-carbon alcohol with 1-4 carbon atoms.
Preferably, the dropping time of the sodium-containing alkali solution is 0.5 to 2 hours.
Preferably, in step S4, the refining process includes a pulping purification process in a polar solvent, and the polar solvent is one or more of ethanol, methanol, isopropanol and water.
Preferably, in step S4, the refining step includes: placing the crude sodium stearyl fumarate into a polar solvent, pulping for 2-10 hours at 40-50 ℃, cooling, and then sequentially stirring, filtering, washing and drying; the polar solvent is one or more of ethanol, methanol, isopropanol and water.
Preferably, the mass ratio of the maleic anhydride to the octadecanol is 1-1.1, and the mass ratio of the reaction solvent to the maleic anhydride is 4-11; the amount of material of the conversion agent is 5-15% of the amount of material of the maleic anhydride; the mass ratio of the maleic anhydride to the alkali component in the sodium-containing alkali solution is 0.8-1.
In another aspect of the invention, sodium stearyl fumarate is prepared by any one of the preparation methods.
The invention has at least the following beneficial effects:
compared with the prior art, the sodium stearyl fumarate is prepared by adopting a one-pot method, and each intermediate is not required to be separated and purified, so that the preparation process and the post-treatment steps are greatly simplified, and the reaction condition is mild; meanwhile, the total yield is obviously improved, the types and the scales of the used solvents are reduced, the residual components of the solvents are few, and the prepared product can obtain the purity of not less than 99 percent without column chromatography purification. Compared with the prior preparation process, the yield is improved, the preparation process is more environment-friendly, and the preparation process is suitable for being used as a medicine and food auxiliary material and industrial production.
Drawings
FIG. 1 is a flow chart of a method for preparing a sodium stearyl fumarate adjuvant according to an embodiment of the present invention;
FIG. 2 is a GC spectrum of the product obtained in example 1;
FIG. 3 is a GC spectrum of the product obtained in example 3;
FIG. 4 is an NMR spectrum of the product obtained in example 3;
FIG. 5 is an IR spectrum of the product obtained in example 3.
Detailed Description
For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims.
All the following raw materials and reagents of the present invention are commercially available.
As shown in fig. 1, the invention provides a preparation method of a sodium stearyl fumarate auxiliary material, which comprises the following steps:
s1, mixing maleic anhydride, octadecanol and a reaction solvent, and carrying out ring-opening reaction at the temperature of 80 ℃ or above;
s2, adding a conversion agent into the reaction system to carry out conversion reaction;
s3, cooling to 40-50 ℃, dropwise adding a sodium-containing alkali solution into the reaction system, stirring, reacting, cooling, and crystallizing to obtain a crude sodium stearyl fumarate;
and S4, refining the crude sodium stearyl fumarate to obtain a sodium stearyl fumarate product.
The process route of the invention is as follows:
in one embodiment, in step S1, maleic anhydride and octadecanol are used as raw materials, the raw materials are placed in a reaction solvent, the temperature is raised to 80 ℃ or above under the condition of no catalyst, and the maleic anhydride is subjected to a ring opening reaction under the action of octadecanol to generate an intermediate I. In the present invention, the reaction solvent is an inert solvent, for example including but not limited to one or more of toluene, cyclohexane, n-heptane, preferably toluene. The reaction temperature of the ring-opening reaction is preferably 80 to 100 ℃ and more preferably 85 to 95 ℃. The reaction time of the ring-opening reaction is 8 to 24 hours, preferably 10 to 18 hours. The mass ratio of the maleic anhydride to the octadecanol is 1-1.2, preferably 1-1.1, and more preferably 1.05-1.1. The mass ratio of the reaction solvent to the maleic anhydride is 3-15, preferably 4-11, and more preferably 4-8.
In the present invention, there is no need to perform a separate crystallization and purification process step on the intermediate I generated in step S1 before performing step S2.
Next, after the reaction in step S1 is completed, in step S2, a conversion agent is added to the reaction system, so that intermediate I is isomerized to obtain intermediate II. The conversion agent includes, but is not limited to, thiourea and thiourea containing acid. The amount of substance of the conversion agent is 5-15% of the amount of substance of the maleic anhydride, preferably 10% of the amount of substance of the maleic anhydride. In the present invention, the conversion agent is a hydrochloric acid/thiourea solution. The hydrochloric acid/thiourea solution is prepared from thiourea and an acid solution, and specifically, the hydrochloric acid/thiourea solution can be a physical mixed solution of thiourea and the acid solution. The mass ratio of the thiourea to the acid solution is 1: 1. The acid solution comprises 1-12mol/L hydrochloric acid and/or sulfuric acid, and is preferably a hydrochloric acid solution. The reaction temperature of the conversion reaction is 70 to 100 ℃, preferably 75 to 88 ℃, and more preferably 80 ℃. The reaction time of the conversion reaction is 8 to 36 hours, preferably 15 to 24 hours.
In the present invention, there is no need to perform a separate crystallization and purification process step on the intermediate II generated in step S2 before performing step S3.
And then, after the reaction in the step S2 is finished, cooling to 40-50 ℃, preferably to 40-45 ℃, dropwise adding a sodium-containing alkali solution into the reaction system to produce sodium salt, cooling to 20-25 ℃ after the stirring reaction is finished, crystallizing, and filtering to obtain a crude product of the sodium stearyl fumarate. The dropping time of the sodium-containing alkali solution is 0.5-2 hours. The sodium containing base solution includes a base component and a first solvent, and the base component may include sodium containing inorganic salts including, but not limited to, one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate. The first solvent is a solvent capable of dissolving the base component, preferably water and/or an alcohol. The alcohol is a low-carbon alcohol with 1-4 carbon atoms, and includes but is not limited to at least one of methanol, ethanol, propanol, butanol and ethylene glycol. The mass percentage of the alkali component in the alkali solution containing sodium is 5-20%, preferably 5-15%, and more preferably 10%. The mass ratio of the maleic anhydride to the alkali component in the sodium-containing alkali solution can be 0.8-1, and preferably 0.8-0.95.
In step S4, the crude sodium stearyl fumarate is subjected to a refining process. The refining treatment comprises a pulping purification treatment in a polar solvent, and of course, the refining treatment can also comprise other purification treatment steps. In the invention, the refining treatment is only pulping purification treatment, and a product with the purity of not less than 99 percent can be obtained without chromatography purification treatment.
The refining treatment comprises the following specific steps: placing the crude sodium stearyl fumarate into a polar solvent, pulping at 40-50 deg.C for 2-10 hr, cooling to 20-25 deg.C, stirring for 1-3 hr, filtering, washing, and drying. The washing treatment is preferably carried out by using a common reagent such as ethanol, and washing may be carried out by using a plurality of reagents alternately. The drying treatment is preferably air drying. The polar solvent includes, but is not limited to, one or more of ethanol, methanol, isopropanol, and water, preferably ethanol. The mass ratio of the polar solvent to the crude sodium stearyl fumarate is 2-20: 1, and preferably 3-10: 1. The stirring speed is 20 to 150rpm, preferably 30 to 80 rpm.
The sodium stearyl fumarate is prepared by a one-pot method, and each intermediate is not required to be separated and purified, so that the preparation process and the post-treatment steps are greatly simplified, and the reaction conditions are mild; meanwhile, the total yield is obviously improved, the types and the scales of the used solvents are reduced, the residual components of the solvents are few, and the prepared product can obtain the purity of not less than 99 percent without column chromatography purification. Compared with the prior preparation process, the yield is improved, the preparation process is more environment-friendly, and the preparation process is suitable for being used as a medicine and food auxiliary material and industrial production.
In order to further illustrate the present invention, the following detailed description of the invention refers to specific examples.
Example 1 preparation of sodium stearyl fumarate
In a reaction vessel, 103.0g of maleic anhydride, 270.00g of octadecanol and 1000mL of toluene were added, and the mixture was heated to 85 ℃ to react for 12 hours. Adding 10% hydrochloric acid/thiourea solution (the mass ratio of the hydrochloric acid to the thiourea is 1:1) into the reaction system, reacting for 16 hours at 80 ℃, and detecting by a gas phase: intermediate II/intermediate I was 99.5%. Then, the temperature is reduced to 45 ℃, 320mL of aqueous solution containing 51.5g of sodium hydroxide is dropwise added into the reaction system, after 1 hour, the dropwise addition is finished, the stirring is continued for 1 hour, the temperature is reduced to room temperature, the stirring is carried out for 1 hour, and the crude sodium stearyl fumarate is obtained by filtering. Adding the crude product and 2Kg of ethanol into a reaction vessel, heating to 50 ℃, pulping at the temperature for 7 hours, cooling to 20 ℃, filtering, washing with ethanol, and vacuum-drying the obtained solid for 24 hours to obtain white solid sodium stearyl fumarate 327.6g, the yield is 83.9%, and the HPLC purity is 99.24%.
Example 2 preparation of sodium stearyl fumarate
In a reaction vessel, 324.06g of maleic anhydride and 1200mL of cyclohexane were added, and the mixture was heated to 90 ℃ and reacted for 15 hours. To the reaction system, 8% hydrochloric acid/thiourea solution (mass ratio of hydrochloric acid to thiourea was 1:1) was added and reacted at 72 ℃ for 10 hours. Then, the temperature is reduced to 48 ℃, 650mL of aqueous solution containing 49.5g of sodium hydroxide is dropwise added into the reaction system, after 1 hour, the dropwise addition is finished, the stirring is continued for 1 hour, the temperature is reduced to the room temperature, the stirring is carried out for 2 hours, and the crude sodium stearyl fumarate is obtained by filtering. Adding the crude product and 4.2Kg of ethanol into a reaction vessel, heating to 50 ℃, pulping at the temperature for 5 hours, cooling to 22 ℃, filtering, washing with ethanol, and carrying out vacuum freeze drying on the obtained solid for 24 hours to obtain white solid sodium stearyl fumarate, wherein the yield is 82.3%, and the HPLC purity is 99.17%.
Example 3 preparation of sodium stearyl fumarate
10.0kg of maleic anhydride, 26.2kg of octadecanol and 42kg of toluene are added into a reaction vessel, after the mixture is heated to 85 ℃ and reacts for 12 hours, 10% hydrochloric acid/thiourea solution (the mass ratio of hydrochloric acid to thiourea is 1:1) is added, the mixture reacts for 16 hours at 80 ℃, and the intermediate II/the intermediate I is 99.5% through gas phase detection. Then, the temperature is reduced to 50 ℃, 23.8L of aqueous solution containing 4.4kg of sodium hydroxide is dripped, after 1.5 hours of dripping, the mixture is continuously stirred for 2 hours, the temperature is reduced to room temperature, the mixture is stirred for 1 hour, filtration is carried out to obtain crude sodium stearyl fumarate, the crude sodium stearyl fumarate and 80kg of ethanol are added into a reaction vessel, the temperature is raised to 50 ℃, the mixture is pulped for 10 hours at the temperature, the temperature is reduced to 25 ℃, filtration and ethanol washing are carried out, and the obtained solid is dried in vacuum for 24 hours to obtain 31.5kg of white solid sodium stearyl fumarate with the yield of 83.2%. HPLC purity 99.94%.
Example 4 preparation of sodium stearyl fumarate
This embodiment is different from embodiment 3 in that: the aqueous solution containing sodium hydroxide was replaced with an ethanol solution containing sodium hydroxide.
Example 5 preparation of sodium stearyl fumarate
This embodiment is different from embodiment 3 in that: replacing the aqueous solution containing sodium hydroxide with a mixed solution of ethanol and water containing sodium hydroxide, wherein the volume ratio of the ethanol to the water is 1: 2.
Example 6 gas chromatography detection
The detection method and conditions of gas chromatography detection (GC detection) are as follows: the type of the chromatographic column: agilent HP-1 column (0.53 x 15m x 0.15 μm); a detector: a FID detector; maintaining the column temperature at 180 ℃ for 1 minute, raising the temperature to 320 ℃ at a temperature rise rate of 7 ℃ per minute, and maintaining the column temperature for 5 minutes, wherein the carrier gas is helium and the flow rate is 2mL per minute; the injection port temperature is 250 ℃, the split ratio is 25:1, and the detection temperature is 320 ℃ by using a hydrogen flame ionization detector. Taking 1.0mg of each of a sodium stearyl maleate reference substance and a sodium stearyl fumarate reference substance, adding 1mL of a silanization solution [ taking 2mL of N, O-bis (trimethylsilyl) trifluoroacetamide, adding 0.02mL of trimethylsilane, uniformly mixing ] to seal, heating at 70 ℃ for 1 hour, filtering, precisely taking 2 μ L of a subsequent filtrate, injecting into a gas chromatograph, and recording a chromatograph diagram, wherein the separation degree of a stearic trimethylsilane maleate peak and a stearic trimethylsilane fumarate peak is not less than 1.5.
The sodium stearyl fumarate products prepared in examples 1 and 3 were subjected to GC tests, and the test patterns are shown in fig. 2 and 3, respectively, with the following specific results:
determining the retention time of each product according to the reference: the retention time of the product prepared in example 1 was 11.420 min; the product prepared in example 3 had a retention time of 11.401 min.
Example 7 mapping assay
The Nuclear Magnetic Resonance (NMR) hydrogen spectrum detection method and conditions are as follows: the instrument is a Bruker400MHz nuclear magnetic resonance instrument; the solvent is deuterated methanol.
The product prepared in example 3 was subjected to NMR measurement and IR measurement, and its measurement NMR spectrum and IR spectrum are shown in fig. 4 and 5, respectively. According to the test result, the prepared product is sodium stearyl fumarate.
Example 8 product testing
The sodium stearyl fumarate product obtained in example 3 was examined in accordance with the methods associated with the United states Pharmacopoeia (USP 35-NF 30) and the European Pharmacopoeia (European Pharmacopoeia 8.0) and the results are as follows:
according to the detection results, all indexes of the prepared sodium stearyl fumarate accord with the regulations in the field of medicine, and the sodium stearyl fumarate is suitable for being used as a medicine auxiliary material.
The invention also provides sodium stearyl fumarate which is prepared by any one of the preparation methods.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (5)
1. A preparation method of a sodium stearyl fumarate auxiliary material is characterized in that the sodium stearyl fumarate auxiliary material is prepared by a one-pot method, and comprises the following steps:
s1, mixing maleic anhydride, octadecanol and a reaction solvent, and carrying out a ring-opening reaction under the condition of no catalyst; the reaction solvent is toluene; the reaction temperature of the ring-opening reaction is 85-100 ℃, and the reaction time is 8-24 hours; the mass ratio of the reaction solvent to the maleic anhydride is 4-11;
s2, adding a conversion agent into the reaction system to carry out conversion reaction; the conversion agent is prepared from thiourea and an acid solution in a mass ratio of 1:1, wherein the acid solution is selected from 1-12mol/L hydrochloric acid and/or sulfuric acid; the reaction temperature of the conversion reaction is 70-85 ℃, and the reaction time is 15-24 hours; the amount of substance of the conversion agent is 5-15% of the amount of substance of the maleic anhydride;
s3, cooling to 40-50 ℃, dropwise adding a sodium-containing alkali solution into the reaction system, stirring, reacting, cooling, and crystallizing to obtain a crude sodium stearyl fumarate; the mass ratio of the maleic anhydride to the alkali component in the sodium-containing alkali solution is 0.8-1; the sodium-containing alkali solution comprises an alkali component and a first solvent, wherein the mass percent of the alkali component in the sodium-containing alkali solution is 5-20%; the alkali component is selected from one or more of sodium hydroxide, sodium carbonate and sodium bicarbonate;
s4, refining the crude sodium stearyl fumarate to obtain a sodium stearyl fumarate product, wherein the refining is pulping and purifying in a polar solvent, and the polar solvent is one or more of ethanol, methanol, isopropanol and water; the purity of the prepared sodium stearyl fumarate product is not less than 99%.
2. The preparation method according to claim 1, wherein the first solvent is selected from water or a mixed solution of water and alcohol, and the alcohol is a lower alcohol having 1 to 4 carbon atoms.
3. The production method according to claim 1 or 2, wherein the dropping time of the sodium-containing alkali solution is 0.5 to 2 hours.
4. The production method according to claim 1, wherein in step S4, the step of refining treatment includes: and (3) placing the crude sodium stearyl fumarate into a polar solvent, pulping for 2-10 hours at 40-50 ℃, cooling, and then sequentially stirring, filtering, washing and drying.
5. The method according to claim 1, wherein the mass ratio of maleic anhydride to octadecanol is 1 to 1.1.
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| US5783428A (en) * | 1994-07-19 | 1998-07-21 | Mitsubishi Chemical Corporation | Method of producing fumaric acid |
| JP2001220365A (en) * | 2000-02-09 | 2001-08-14 | Honshu Chem Ind Co Ltd | Monoesters of fumaric acid and method for producing alkali metal salts thereof |
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