CN114409509A - Lauryl alcohol purification method, polidocanol synthesis method and polidocanol injection - Google Patents
Lauryl alcohol purification method, polidocanol synthesis method and polidocanol injection Download PDFInfo
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- CN114409509A CN114409509A CN202210078630.5A CN202210078630A CN114409509A CN 114409509 A CN114409509 A CN 114409509A CN 202210078630 A CN202210078630 A CN 202210078630A CN 114409509 A CN114409509 A CN 114409509A
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- lauryl alcohol
- polidocanol
- filler
- steam
- purification method
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- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 title claims abstract description 98
- 238000000034 method Methods 0.000 title claims abstract description 52
- 229920001363 Polidocanol Polymers 0.000 title claims abstract description 47
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960002226 polidocanol Drugs 0.000 title claims abstract description 47
- 238000000746 purification Methods 0.000 title claims abstract description 38
- 229940025913 polidocanol injection Drugs 0.000 title claims abstract description 11
- 238000001308 synthesis method Methods 0.000 title abstract description 14
- 239000000945 filler Substances 0.000 claims abstract description 62
- 239000002994 raw material Substances 0.000 claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 16
- 239000007787 solid Substances 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims description 36
- 239000000919 ceramic Substances 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 238000006116 polymerization reaction Methods 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000018044 dehydration Effects 0.000 claims description 9
- 238000006297 dehydration reaction Methods 0.000 claims description 9
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 8
- 238000007872 degassing Methods 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical class O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 2
- 230000000274 adsorptive effect Effects 0.000 claims description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 3
- 238000003786 synthesis reaction Methods 0.000 claims 3
- 239000000499 gel Substances 0.000 claims 1
- 239000000377 silicon dioxide Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 19
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 24
- 238000012856 packing Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 6
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 6
- 238000009423 ventilation Methods 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229920002884 Laureth 4 Polymers 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 239000010457 zeolite Substances 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 1
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 description 1
- 206010046996 Varicose vein Diseases 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000003229 sclerosing agent Substances 0.000 description 1
- 238000007632 sclerotherapy Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/80—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by distillation
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
- C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
- C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
- C08G65/2609—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups containing aliphatic hydroxyl groups
Abstract
The invention relates to the technical field of pharmaceutical chemicals, in particular to a lauryl alcohol purification method, a polidocanol synthesis method and a polidocanol injection, which comprise the following steps: s1, introducing lauryl alcohol-dissolved steam into a filler containing micropores and/or mesopores, and keeping the temperature of the filler at 20-23 ℃; and S2, dissolving out the solid and the liquid condensed in the filler to obtain a solution, continuously heating the solution to prepare steam, continuously introducing the steam into the filler, keeping the temperature of the filler at 25-27 ℃, collecting the steam passing through the filler, condensing and distilling under reduced pressure to obtain a refined lauryl alcohol product. The method for purifying lauryl alcohol provided by the invention can effectively reduce the content of impurities in the lauryl alcohol raw material, and has high purification efficiency.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a lauryl alcohol purification method, a polidocanol synthesis method and a polidocanol injection.
Background
Polidocanol is a commonly used hardening agent in the treatment process, and is mainly suitable for hardening treatment of central veins, reticular veins and venules varicose veins of spider veins. Henschel in 1963 found that high concentrations of polidocanol injected into blood vessels can cause irritation to blood vessel walls, suggesting that polidocanol has a hardening effect on blood vessels. The first report of its use as a sclerosing agent and demonstrating therapeutic effects on scleroses began in the 60's of the 20 th century. Polidocanol is currently used in sclerotherapy in the form of injections or foams (cf. Li Chunmi et al, intravenous Endoluminal therapeutics [ M ], 2020, 215-220).
The existing polidocanol raw material generally synthesizes a large amount of byproducts in the polymerization reaction process due to the poor purity of the raw material lauryl alcohol, and meanwhile, the byproducts, such as the byproducts synthesized by the polymerization reaction of the lauryl alcohol and the tetradecanol and the ethylene oxide, are difficult to separate from the polidocanol, thereby affecting the quality of the polidocanol. Therefore, purification by starting with lauryl alcohol, which is a polidocanol, is an important step in existing polidocanol purification strategies.
The existing lauryl alcohol purification method generally comprises a reflux distillation method, a rectification method and a crystallization method. The invention adopts lauryl alcohol and toluene to be heated, refluxed and purified by distillation to obtain lauryl alcohol, and the method can effectively reduce the content of impurities such as lauryl alcohol, tetradecyl alcohol and the like in the lauryl alcohol to the limit range, but the lauryl alcohol has toluene residue, so certain safety risk exists.
The invention discloses a lauryl alcohol purification method and a polidocanol synthesis method by a rectification method, such as the patent with the publication number of CN113200821A, wherein the lauryl alcohol is obtained by adopting a vacuum rectification purification method, although the lauryl alcohol with higher purity can be obtained by the method, the rectification condition is carried out at 130-150 ℃ and minus 0.08MPa, and the industrial realization is difficult.
The invention discloses a refining process of lauryl alcohol and a process for preparing lauromacrogol by using the refined product as a raw material by a crystallization method, such as the patent with the publication number of CN113527060A, wherein the refined product of lauryl alcohol is obtained by recrystallizing lauryl alcohol in an organic solvent, although the purification process of the method is simple, the process conditions can be realized industrially, and the purity of the prepared lauryl alcohol is better, the method can obtain the lauryl alcohol with better purity only by repeated recrystallization industrially, and the solution after recrystallization still contains a large amount of lauryl alcohol, thus the purification efficiency of the lauryl alcohol is seriously reduced.
Therefore, there is a need in the industry for a method for purifying lauryl alcohol with good purification effect and high purification efficiency.
Disclosure of Invention
In order to overcome the defects of the prior art, the technical problems to be solved by the invention are as follows: the lauryl alcohol purification method has good lauryl alcohol purification effect and high purification efficiency;
further provides a synthesis method of the lauryl alcohol synthesized polidocanol prepared by the lauryl alcohol purification method;
still further provided is a polidocanol injection comprising polidocanol prepared by the above polidocanol synthesis method.
In order to solve the technical problem, the invention provides a lauryl alcohol purification method, which comprises the following steps:
s1, introducing lauryl alcohol-dissolved steam into a filler containing micropores and/or mesopores, and keeping the temperature of the filler at 20-23 ℃;
and S2, dissolving out the solid and the liquid condensed in the filler to obtain a solution, continuously heating the solution to prepare steam, continuously introducing the steam into the filler, keeping the temperature of the filler at 25-27 ℃, collecting the steam passing through the filler, condensing and distilling under reduced pressure to obtain a refined lauryl alcohol product.
Further provides a method for synthesizing polidocanol, which comprises the step of carrying out polymerization reaction on the refined lauryl alcohol product prepared by the lauryl alcohol purification method and ethylene oxide to obtain the polidocanol.
Further provides a polidocanol injection, which comprises polidocanol prepared by the polidocanol synthesis method.
The invention has the beneficial effects that: and repeatedly introducing lauryl alcohol-dissolved steam into the filler containing micropores and/or mesopores to intercept part of impurities with lower molecular weight through the micropores in the filler and intercept the impurities with lower freezing point by controlling the temperature of the filler. The lauryl alcohol purification method can effectively improve the purification efficiency of lauryl alcohol and the purity of a refined lauryl alcohol product, thereby further improving the purity of polidocanol and polidocanol injection, and avoiding certain safety risk caused by the fact that impurities exceed a limit range.
Detailed Description
In order to explain the technical content, the objects and the effects of the present invention in detail, the following description will be given with reference to the embodiments.
The lauryl alcohol purification method comprises the following steps:
s1, introducing lauryl alcohol-dissolved steam into a filler containing micropores and/or mesopores, and keeping the temperature of the filler at 20-23 ℃;
and S2, dissolving out the solid and the liquid condensed in the filler to obtain a solution, continuously heating the solution to prepare steam, continuously introducing the steam into the filler, keeping the temperature of the filler at 25-27 ℃, collecting the steam passing through the filler, condensing and distilling under reduced pressure to obtain a refined lauryl alcohol product.
Wherein the vapor in which the lauryl alcohol is dissolved is prepared by dissolving the lauryl alcohol raw material in an organic solvent and heating. Because the lauryl alcohol has volatility, when the organic solvent is heated to generate steam for volatilization, the lauryl alcohol can be volatilized along with the steam to generate the steam in which the lauryl alcohol is dissolved. When the steam dissolved with lauryl alcohol is firstly introduced into the filler containing micropores and/or mesopores, part of impurities with lower molecular weight can permeate into the micropores and/or mesopores of the filler and be intercepted, impurities with higher molecular weight and lauryl alcohol can move in gaps among filler particles, at the moment, the temperature of the filler is controlled to be 20-24 ℃, so that the impurities with higher condensation point and lauryl alcohol are condensed into solid on the surface of the filler, and the impurities with lower condensation point and organic solvent steam are discharged from the filler together, so that the impurities with lower molecular weight and the impurities with lower condensation point are separated from the lauryl alcohol raw material. And further dissolving out the solid and liquid condensed in the filler, wherein the specific dissolving mode can be that the solid and liquid are washed out of the filler by adopting an organic solvent, the organic solvent can be the same as the organic solvent for dissolving the lauryl alcohol raw material, or an appropriate organic solvent can be selected according to the solubility difference between the lauryl alcohol and other impurities, and in the technical scheme, in order to improve the purification efficiency of the lauryl alcohol and realize the recycling of the organic solvent, the organic solvent which is the same as the organic solvent for dissolving the lauryl alcohol raw material is preferably adopted.
Washing out the solid and liquid condensed in the packing material by the organic solvent, vaporizing the organic solvent while continuing to heat the organic solvent to promote dissolution of the solid, and further passing the resulting vapor into the packing material again, which may be fresh or recycled in S1. The temperature of the filler is controlled to be 25-27 ℃, impurities with higher condensation points are re-condensed in the filler, lauryl alcohol can be discharged from the filler along with steam, collected steam is condensed, and the solvent is removed through reduced pressure distillation, so that the lauryl alcohol with better purity can be obtained.
The reduced pressure distillation is specifically carried out by heating the recondensed organic solvent to 80-120 ℃, keeping the vacuum degree at 0.05MPa and carrying out reduced pressure distillation for 4-5 h.
In the present embodiment, in order to increase the yield of lauryl alcohol, it is preferable to perform separation by introducing steam in a closed cycle manner in S1 and S2. However, the temperature of the steam and the temperature inside the filler should be kept within appropriate ranges during the closed cycle to avoid the occurrence of a decrease in the yield of lauryl alcohol due to a decrease in the temperature inside the steam or the filler.
Further, the organic solvent is at least one of tetrahydrofuran, acetonitrile, n-pentane, cyclohexane, isooctane and petroleum ether. Preferably, a combination of tetrahydrofuran and acetonitrile is adopted, and the mass ratio of the lauryl alcohol raw material, the tetrahydrofuran and the acetonitrile is preferably 1: 1-2: 1 to 2.
Furthermore, the filler containing micropores is one of porous ceramics, synthetic zeolite, molecular sieve, silica gel and adsorptive polymer. Preferably, porous ceramics or synthetic zeolites are used, preferably T/NaY zeolites, the diameter of the micropores and/or mesopores being
Preferably, it is
Or
The method for synthesizing the polidocanol comprises the step of carrying out polymerization reaction on a refined lauryl alcohol product prepared by the lauryl alcohol purification method and ethylene oxide to obtain the polidocanol.
Specifically, the method for synthesizing polidocanol comprises the following steps:
s1, mixing and dehydrating the refined lauryl alcohol product and a catalyst to obtain a raw material A;
s2, carrying out polymerization reaction on the raw material A and ethylene oxide at the temperature of 100-140 ℃, and degassing to obtain the polidocanol.
Wherein, the catalyst is sodium hydroxide or potassium hydroxide. The addition amount of the catalyst is preferably 4-8 per mill of the addition amount of the refined lauryl alcohol product. Preferably, the dehydration condition is that the dehydration temperature is 90-130 ℃, the dehydration time is 1.1-1.4 h, and the vacuum degree is not more than-0.08 MPa. The preferable degassing condition is that the degassing temperature is 90-120 ℃, and the degassing time is 3-7 h. Meanwhile, the raw materials are continuously stirred in the dehydration process of the refined lauryl alcohol product, the polymerization reaction of the rest ethylene oxide and the degassing process, and the stirring speed can be selected according to actual needs, preferably 10-15 rpm.
Preferably, the method for synthesizing polidocanol further comprises the steps of adjusting the pH value of degassed polidocanol and performing precise pressure filtration of 0.22 mu m.
The polidocanol injection comprises polidocanol prepared by the polidocanol synthesis method.
Example 1
The lauryl alcohol purification method comprises the following steps:
dissolving 500g of lauryl alcohol raw material in 1000g of organic solvent (tetrahydrofuran to acetonitrile mass ratio of 1: 1), heating the organic solvent at 0.1MPa to generate steam, and passing the steam through porous ceramic (diameter)
) In the packing, the porous ceramic packing temperature was maintained at about 22 ℃. And after circulating ventilation for three times, collecting the porous ceramic filler, cleaning the porous ceramic filler by using the organic solvent, repeatedly cleaning the porous ceramic filler by using 500g of the organic solvent at 30 ℃ for three times, heating the organic solvent after collecting the organic solvent until steam is generated, repeatedly introducing the steam into the porous ceramic filler, and keeping the temperature of the porous ceramic filler at about 25 ℃. And (3) after circulating ventilation, collecting steam discharged from the porous ceramic filler, condensing the steam, heating the condensed product to 100 ℃, and distilling under reduced pressure for 5 hours under the vacuum degree of 0.05MPa to obtain a refined lauryl alcohol product. The refined lauryl alcohol product yield is 99.3%.
Example 2
The lauryl alcohol purification method comprises the following steps:
dissolving 500g of lauryl alcohol raw material in 1000g of organic solvent (tetrahydrofuran to acetonitrile mass ratio of 1: 2), heating the organic solvent at 0.1MPa to generate steam, and passing the steam through porous ceramic (diameter)
) In the packing, the porous ceramic packing temperature was maintained at about 23 ℃. After circulating ventilation for three times, collecting the porous ceramic filler, cleaning the porous ceramic filler by using the organic solvent, repeatedly cleaning the porous ceramic filler by using 500g of the organic solvent at 30 ℃ for three times, heating the organic solvent after collecting the organic solvent until steam is generated, repeatedly introducing the steam into the porous ceramic filler, and keeping the porous ceramic fillerThe ceramic packing temperature was about 26 ℃. And (3) after circulating ventilation, collecting steam discharged from the porous ceramic filler, condensing the steam, heating the condensed product to 80 ℃, and distilling under reduced pressure for 5 hours under the vacuum degree of 0.05MPa to obtain a refined lauryl alcohol product. The refined lauryl alcohol product yield is 99.6%.
Example 3
The lauryl alcohol purification method comprises the following steps:
dissolving 500g of lauryl alcohol raw material in 1000g of organic solvent (tetrahydrofuran to acetonitrile mass ratio of 2: 1), heating the organic solvent at 0.1MPa to generate steam, and passing the steam through porous ceramic (diameter)
) In the packing, the porous ceramic packing temperature was maintained at about 20 ℃. And after circulating ventilation for three times, collecting the porous ceramic filler, cleaning the porous ceramic filler by using the organic solvent, repeatedly cleaning the porous ceramic filler by using 500g of the organic solvent at 30 ℃ for three times, heating the organic solvent after collecting the organic solvent until steam is generated, repeatedly introducing the steam into the porous ceramic filler, and keeping the temperature of the porous ceramic filler at about 27 ℃. And (3) after circulating ventilation, collecting steam discharged from the porous ceramic filler, condensing the steam, heating the condensed product to 120 ℃, and distilling under reduced pressure for 5 hours under the vacuum degree of 0.05MPa to obtain a refined lauryl alcohol product. The refined lauryl alcohol product yield is 99.1%.
Example 4
The method for synthesizing polidocanol comprises the following steps:
stirring and mixing 500g of refined lauryl alcohol (prepared in example 1) and 4g of sodium hydroxide at the rotating speed of 10rpm, introducing nitrogen into a reaction kettle, and dehydrating at the dehydration temperature of 100 ℃ and the vacuum degree of 0.2MPa for 1.2 h; after dehydration is finished, adding epoxy ethane (8 times of the mol weight of refined lauryl alcohol), stirring and mixing, and carrying out polymerization reaction at the polymerization temperature of 120 ℃ and the polymerization pressure of 0.8 MPa; after the polymerization reaction is finished, the temperature of the reaction kettle is adjusted to be 100 ℃, and degassing is carried out for 5 hours to obtain the polidocanol.
Example 5
The synthesis method of polidocanol is different from the synthesis method of example 4 in that: the refined lauryl alcohol product was obtained by the method of example 2.
Example 6
The synthesis method of polidocanol is different from the synthesis method of example 4 in that: the refined lauryl alcohol product was obtained by the method of example 3.
Example 7
Polydocanol injection comprising 1g of polidocanol (prepared from example 4), 5mL of 96% ethanol, 0.05g of potassium dihydrogen nitrate, 0.05g of disodium hydrogen phosphate, and up to 100mL with water for injection.
Example 8
Polydocanol injection comprising 1g of polidocanol (prepared from example 5), 5mL of 96% ethanol, 0.05g of potassium dihydrogen nitrate, 0.05g of disodium hydrogen phosphate, and up to 100mL with water for injection.
Example 9
Polydocanol injection comprising 1g of polidocanol (prepared from example 6), 5mL of 96% ethanol, 0.05g of potassium dihydrogen nitrate, 0.05g of disodium hydrogen phosphate, and up to 100mL with water for injection.
Example of detection
The refined lauryl alcohol products prepared in examples 1 to 3 were tested according to the imported drug registration standard lauromacrogol injection (JX20120149), and the test results are shown in table 1.
TABLE 1
As can be seen from table 1, the refined product of lauryl alcohol obtained by purification according to the method for purifying lauryl alcohol provided by the present invention has significantly reduced residual amounts of n-decanol, unknown impurities and n-tetradecanol.
In summary, according to the lauryl alcohol purification method, the polidocanol synthesis method and the polidocanol injection provided by the invention, the steam dissolved with lauryl alcohol is repeatedly introduced into the filler containing micropores and/or mesopores, so that impurities with small molecular weight are intercepted by the micropores in the filler, and impurities with low freezing point are intercepted by controlling the temperature of the filler. The lauryl alcohol purification method can effectively improve the purification efficiency of lauryl alcohol and the purity of refined lauryl alcohol products, and remarkably reduce the residual quantity of impurities (n-decanol, unknown impurities and n-tetradecanol), thereby further improving the purity of polidocanol and polidocanol injection, and avoiding certain safety risk caused by the impurities exceeding the limit range.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or directly or indirectly applied to the related technical field are included in the scope of the present invention.
Claims (10)
1. The lauryl alcohol purification method is characterized by comprising the following steps:
s1, introducing lauryl alcohol-dissolved steam into a filler containing micropores and/or mesopores, and keeping the temperature of the filler at 20-23 ℃;
and S2, dissolving out the solid and the liquid condensed in the filler to obtain a solution, continuously heating the solution to prepare steam, continuously introducing the steam into the filler, keeping the temperature of the filler at 25-27 ℃, collecting the steam passing through the filler, condensing and distilling under reduced pressure to obtain a refined lauryl alcohol product.
2. The lauryl alcohol purification method according to claim 1, wherein said vapor containing dissolved lauryl alcohol is prepared by dissolving said lauryl alcohol raw material in an organic solvent and heating.
3. The lauryl alcohol purification method according to claim 2, wherein said organic solvent is at least one of tetrahydrofuran, acetonitrile, n-pentane, cyclohexane, isooctane, and petroleum ether.
4. The lauryl alcohol purification method of claim 1, wherein the filler containing micropores is one of porous ceramics, synthetic zeolites, molecular sieves, silica gels, and adsorptive polymers.
5. The lauryl alcohol purification method of claim 1 or 4, wherein the diameter of said micropores and/or mesopores is
6. The process for synthesizing polidocanol, characterized in that the refined lauryl alcohol product prepared by the lauryl alcohol purification method of any one of claims 1 to 5 is polymerized with ethylene oxide to obtain polidocanol.
7. The process for the synthesis of polidocanol according to claim 6, comprising the steps of:
s1, mixing and dehydrating the refined lauryl alcohol product and a catalyst to obtain a raw material A;
s2, carrying out polymerization reaction on the raw material A and ethylene oxide at the temperature of 100-140 ℃, and degassing to obtain the polidocanol.
8. The method for synthesizing polidocanol according to claim 7, wherein the dehydration condition is that the dehydration temperature is 90-130 ℃, the dehydration time is 1.1-1.4 h, and the vacuum degree is not more than-0.08 MPa.
9. The process for the synthesis of polidocanol as claimed in claim 7, wherein the catalyst is sodium hydroxide or potassium hydroxide.
10. Polidocanol injection, characterised in that it comprises polidocanol obtained by the polidocanol synthesis process according to any one of claims 6 to 9.
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