CN117531462B - Continuous synthesis system and continuous synthesis method of PEGn cyclic sulfite - Google Patents
Continuous synthesis system and continuous synthesis method of PEGn cyclic sulfite Download PDFInfo
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- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 46
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 43
- 125000004122 cyclic group Chemical group 0.000 title claims abstract description 37
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000001308 synthesis method Methods 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 239000007788 liquid Substances 0.000 claims abstract description 59
- 238000010791 quenching Methods 0.000 claims abstract description 48
- 230000000171 quenching effect Effects 0.000 claims abstract description 45
- 238000000605 extraction Methods 0.000 claims abstract description 33
- 239000002994 raw material Substances 0.000 claims abstract description 31
- 238000000926 separation method Methods 0.000 claims abstract description 25
- 239000000243 solution Substances 0.000 claims description 90
- 239000000047 product Substances 0.000 claims description 86
- 229920001223 polyethylene glycol Polymers 0.000 claims description 71
- 239000002202 Polyethylene glycol Substances 0.000 claims description 70
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 63
- 239000012074 organic phase Substances 0.000 claims description 43
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 30
- 239000011259 mixed solution Substances 0.000 claims description 29
- 239000003513 alkali Substances 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000008346 aqueous phase Substances 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 230000007935 neutral effect Effects 0.000 claims description 9
- 239000010409 thin film Substances 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 239000007795 chemical reaction product Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 239000011780 sodium chloride Substances 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 description 11
- KXSKAZFMTGADIV-UHFFFAOYSA-N 2-[3-(2-hydroxyethoxy)propoxy]ethanol Chemical compound OCCOCCCOCCO KXSKAZFMTGADIV-UHFFFAOYSA-N 0.000 description 6
- 101000693243 Homo sapiens Paternally-expressed gene 3 protein Proteins 0.000 description 6
- 102100025757 Paternally-expressed gene 3 protein Human genes 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000003321 amplification Effects 0.000 description 3
- 239000010408 film Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 238000010539 anionic addition polymerization reaction Methods 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 238000010924 continuous production Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
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- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- 239000010808 liquid waste Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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- 239000000178 monomer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
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- 238000006116 polymerization reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D1/00—Evaporating
- B01D1/22—Evaporating by bringing a thin layer of the liquid into contact with a heated surface
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D11/00—Solvent extraction
- B01D11/04—Solvent extraction of solutions which are liquid
- B01D11/0492—Applications, solvents used
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses continuous synthesis system and continuous synthesis method of PEGn cyclic sulfite relates to the chemical industry field, and above-mentioned continuous synthesis system includes from feeding to ejection of compact in proper order: the continuous raw material supply unit, the continuous reaction unit, the continuous quenching unit, the continuous liquid separation unit, the first continuous concentration unit, the continuous extraction unit and the second continuous concentration unit. The continuous synthesis system can accurately control the reaction temperature and time, has high reaction stability and less side reaction, is convenient to operate, and can greatly improve the productivity and the yield.
Description
Technical Field
The application belongs to the field of chemical industry, and particularly relates to a continuous synthesis system and a continuous synthesis method of PEGn cyclic sulfite.
Background
Polyethylene glycol (PEG) has excellent biocompatibility, and functionalized polyethylene glycol can modify bioactive molecules, and after the functionalized polyethylene glycol is grafted to bioactive molecules such as medicines, the water solubility, biocompatibility and stability of the functionalized polyethylene glycol can be improved, toxicity is reduced, and the functionalized polyethylene glycol is an important intermediate for realizing medicine transmission and controlled release.
The molecular weight of the monodisperse polyethylene glycol is consistent, the molecular weight distribution is narrow, the consistency and the stability are high, and the monodisperse polyethylene glycol has more controllable property in practical application and wide application in the fields of biomedicine, chemical synthesis, material science and the like. The preparation method of the short-chain monodisperse polyethylene glycol is mature, but the preparation difficulty of the long-chain monodisperse polyethylene glycol is relatively high, and at present, the preparation method mainly comprises the following steps: is realized by strictly controlling the anionic polymerization process, purifying and separating by gel chromatography, and synthesizing the monodisperse polyethylene glycol from the head by a chemical synthesis method.
For the anionic polymerization process, the purity of the polymerization monomer ethylene oxide needs to be strictly controlled, and the process has larger process risks and health safety risks, so that industrialization is not easy to realize; the gel chromatography purification and separation method has limited capacity and can not realize the production of hundred kilograms. For chemical synthesis, it is known to synthesize high-purity PEGn cyclic sulfite or PEGn cyclic sulfate (PEGn cyclic sulfate can be synthesized from PEGn cyclic sulfite) from short-chain monodisperse polyethylene glycol, and long-chain monodisperse polyethylene glycol and monofunctional long-chain monodisperse polyethylene glycol can be efficiently synthesized by nucleophilic ring opening reaction of PEGn cyclic sulfate or PEGn cyclic sulfite, and the specific principle is as follows: in the presence of strong alkali, ring opening is performed on cyclic sulfate or cyclic sulfite by nucleophilic attack of shorter chain polyethylene glycol, and finally the monosulfate obtained by hydrolysis can obtain long chain monodisperse polyethylene glycol. This method essentially corresponds to a modified single-ended extension method or double-ended extension method. Compared with the traditional coupling method, the method has high synthesis efficiency and easy purification, and can meet the synthesis of the monofunctional asymmetric and symmetric monodisperse polyethylene glycol.
There is no report on industrial production of PEGn cyclosulfite, and the existing production method often needs long-time dripping and purification to improve the yield and has low production efficiency. Accordingly, there is a need to provide an efficient process for the production of PEGn cyclosulfite.
Disclosure of Invention
The main purpose of the application is to provide a continuous synthesis system and a continuous synthesis method of PEGn cyclic sulfite, so as to solve the problem that the prior art cannot realize the purpose of industrial production of PEGn cyclic sulfite.
In order to achieve the above object, according to one aspect of the present application, there is provided a continuous synthesis system of PEGn cyclosulfite having the structural formula shown in formula I:
i is a kind of
Wherein n represents an integer of 3 to 8;
the continuous synthesis system comprises:
a raw material continuous supply unit for continuously supplying a polyethylene glycol-containing solution, an alkali-containing solution, and a thionyl chloride solution as reaction raw materials; the polyethylene glycol-containing solution also contains a catalyst;
the continuous reaction unit is provided with a reaction raw material inlet and a reaction product outlet, the reaction raw material inlet is connected with the raw material continuous supply unit, and the continuous reaction unit is used for carrying out continuous ring-closing reaction on the reaction raw material to obtain liquid to be quenched;
the continuous quenching unit is provided with a to-be-quenched object inlet and a quenched product outlet, the to-be-quenched object inlet is connected with the reaction product outlet, and the continuous quenching unit is used for carrying out continuous quenching treatment on the to-be-quenched liquid so as to quench the to-be-quenched liquid to be neutral to obtain a quenched product;
the continuous liquid separation unit is provided with a to-be-separated object inlet and a liquid separation product outlet, the to-be-separated object inlet is connected with the quenching product outlet, the liquid separation product outlet comprises an organic phase outlet and an aqueous phase outlet, and the continuous liquid separation unit is used for continuously separating the quenching product to obtain a first organic phase and a first aqueous phase;
a first continuous concentration unit having a first inlet to be concentrated and a first concentrated product outlet, the first inlet to be concentrated being connected to the organic phase outlet for continuously concentrating the first organic phase to obtain a concentrated product;
a continuous extraction unit having an extract inlet and an extraction product outlet, the extract inlet being connected to the first concentrated product outlet; the extraction product outlet comprises a first extraction product outlet and a second extraction product outlet, wherein the first extraction product is an organic phase, and the second extraction product is a water phase; the continuous extraction unit is used for continuously extracting the concentrated product to obtain a second organic phase;
and a second continuous concentration unit, having a second inlet to be concentrated and a second outlet for concentrated product, wherein the second inlet to be concentrated is connected with the first outlet for extracted product and is used for continuously concentrating the second organic phase to obtain the PEGn cyclic sulfite.
Further, the continuous reaction unit is also connected with a tail gas absorption unit; and/or, the continuous synthesis system further comprises a continuous stirring unit and a pH regulator supply unit, wherein the water phase outlet in the continuous liquid separation unit is connected with the continuous stirring unit, and the outlet of the pH regulator supply unit is connected with the continuous stirring unit.
Further, the raw material continuous supply unit comprises at least two feeding pipes, and the feeding pipes are connected with the reaction raw material inlets of the continuous reaction units; and/or, each of the continuous reaction unit and the continuous quenching unit is independently provided with a continuous stirring reactor or a plug flow reactor; and/or the continuous liquid separator is arranged in the continuous liquid separation unit and the continuous extraction unit; and/or, the first continuous concentration unit and the second continuous concentration unit are provided with a thin film evaporator.
According to another aspect of the present application, there is provided a continuous synthesis method of PEGn cyclic sulfite, which employs the above continuous synthesis system, and the structural formula of the PEGn cyclic sulfite is shown in formula I:
i is a kind of
Wherein n represents an integer of 3 to 8;
and the synthesis method comprises the following steps:
s1, mixing a polyethylene glycol-containing solution, an alkali-containing solution and a thionyl chloride solution under a continuous stirring condition, and continuously carrying out a ring-closing reaction to obtain a solution to be quenched; the polyethylene glycol-containing solution and the alkali-containing solution are mixed in advance or not, and the polyethylene glycol-containing solution also contains a catalyst;
s2, continuously quenching the liquid to be quenched by using a quenching liquid, and quenching the liquid to be quenched to be neutral to obtain a quenched product;
s3, carrying out continuous liquid separation treatment on the quenching product to obtain a first organic phase and a first aqueous phase;
s4, continuously concentrating the first organic phase to obtain a concentrated product;
s5, continuously extracting the concentrated product by using an extract liquid to obtain a second organic phase;
and S6, continuously concentrating the second organic phase to obtain the PEGn cyclic sulfite.
Further, in S1, inert gas is introduced in the reaction process for protection; and/or, the pH value of the first aqueous phase is continuously adjusted to 6.5-7.5.
Further, in S1, the reaction temperature is-10 ℃ to 60 ℃, alternatively, the reaction temperature is 30 ℃ to 35 ℃.
Further, concentrating the first and second organic phases by a thin film evaporator; and/or, after S4 is finished, recovering the solvent.
Further, in S1, the polyethylene glycol is H (OCH) 2 CH 2 ) 3 OH、H(OCH 2 CH 2 ) 4 OH、H(OCH 2 CH 2 ) 5 One of OH; and/or
The base is at least one of triethylamine, diisopropylethylamine, pyridine, potassium carbonate and 4-dimethylaminopyridine; and/or
The catalyst is 4-dimethylaminopyridine; and/or
The solvent of the polyethylene glycol-containing solution, the alkali-containing solution and the thionyl chloride solution is the same, and the solvent is at least one of dichloromethane, dichloroethane, tetrahydrofuran, dimethyl sulfoxide and acetonitrile; and/or
The quenching liquid is at least one of sodium chloride solution, sodium carbonate solution, potassium carbonate solution, sodium bicarbonate solution, potassium bicarbonate solution, sodium dihydrogen phosphate solution, potassium dihydrogen phosphate solution, disodium hydrogen phosphate solution and dipotassium hydrogen phosphate solution, and the solvent in the quenching agent is water; and/or
The volume ratio of the n-heptane to the methyl tertiary butyl ether is 1: the mixed solution of (2-3).
Further, in S1, a polyethylene glycol-containing solution and an alkali-containing solution are mixed in advance to obtain a mixed solution, and then the mixed solution is mixed with a thionyl chloride solution to carry out a cyclization reaction; the mixed solution and the thionyl chloride solution are simultaneously introduced into a continuous reaction unit at the same volume flow; the mole ratio of polyethylene glycol, alkali and catalyst in the mixed solution is 1: (1-5): (0.08-0.5), and the concentration of polyethylene glycol in the mixed solution is 0.1-0.11 mmol/L; the concentration of thionyl chloride in the thionyl chloride solution is 0.15-0.55 mmol/L; and/or
In S5, the volume ratio of the extract to the concentrated product is (2-5): 1.
further, the polyethylene glycol is H (OCH) 2 CH 2 ) 3 When in OH, the alkali is diisopropylethylamine, and the catalyst is 4-dimethylaminopyridine; polyethylene glycol is H (OCH) 2 CH 2 ) 4 In the case of OH, the base is triethylamine and the catalyst is 4-dimethylaminopyridine.
By adopting the technical scheme, continuous production of PEGn cyclic sulfite is realized through continuous reaction units, continuous quenching units, continuous liquid separation units, first continuous concentration units, continuous extraction units and second continuous concentration units, the reaction temperature and time can be accurately controlled, the reaction is stable, the side reaction is less, the operation is convenient, and the productivity and the yield are greatly improved.
Drawings
FIG. 1 is a block diagram of a continuous synthesis system provided in accordance with an exemplary embodiment of the present invention;
FIG. 2 is a block diagram of a continuous synthesis system provided in accordance with a preferred embodiment of the present invention;
wherein the above figures include the following reference numerals:
10. a raw material continuous supply unit; 20. a continuous reaction unit; 30. a continuous quenching unit; 40. a continuous liquid separation unit; 50. a first continuous concentration unit; 60. a continuous extraction unit; 70. a second continuous concentration unit; 21. a tail gas absorption unit; 41. a continuous stirring unit; 42. and a pH adjuster supply unit.
Detailed Description
It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other. The present application will be described in detail with reference to examples.
As mentioned in the background art of the application, the production of PEGn cyclic sulfite in the prior art generally needs to increase the yield through long-time dripping and purification, and the reaction system has the advantages of large solvent consumption, obvious amplification effect and low production efficiency, and is not suitable for industrial production.
Based on the above, the application provides a continuous synthesis system of PEGn cyclic sulfite, wherein the structural formula of the PEGn cyclic sulfite is shown as formula I:
i is a kind of
Wherein n represents an integer of 3 to 8.
In one exemplary embodiment of the present application, as shown in FIG. 1, a continuous synthesis system of PEGn cyclic sulfite comprises:
a raw material continuous supply unit 10 for continuously supplying a polyethylene glycol-containing solution, an alkali-containing solution, and a thionyl chloride solution as reaction raw materials; the polyethylene glycol-containing solution also contains a catalyst;
a continuous reaction unit 20 having a reaction raw material inlet and a reaction product outlet, the reaction raw material inlet being connected to the raw material continuous supply unit 10, the continuous reaction unit 20 being configured to perform a continuous ring-closure reaction of the reaction raw material to obtain a liquid to be quenched;
the continuous quenching unit 30 is provided with a to-be-quenched object inlet and a quenched product outlet, the to-be-quenched object inlet is connected with the reaction product outlet, and the continuous quenching unit 30 is used for carrying out continuous quenching treatment on the to-be-quenched liquid so as to quench the to-be-quenched liquid to be neutral to obtain a quenched product;
the continuous liquid separation unit 40 is provided with a to-be-separated object inlet and a liquid separation product outlet, the to-be-separated object inlet is connected with the quenching product outlet, the liquid separation product outlet comprises an organic phase outlet and an aqueous phase outlet, and the continuous liquid separation unit 40 is used for continuously separating the quenching product to obtain a first organic phase and a first aqueous phase;
a first continuous concentration unit 50 having a first inlet to be concentrated and a first concentrated product outlet, the first inlet to be concentrated being connected to the organic phase outlet for continuously concentrating the first organic phase to obtain a concentrated product;
a continuous extraction unit 60 having an extract inlet and an extraction product outlet, the extract inlet being connected to the first concentrated product outlet; the extraction product outlet comprises a first extraction product outlet and a second extraction product outlet, wherein the first extraction product is an organic phase, and the second extraction product is a water phase; the continuous extraction unit 60 is configured to continuously extract the concentrated product to obtain a second organic phase;
a second continuous concentration unit 70 having a second inlet for concentrate and a second outlet for concentrated product, the second inlet for concentrate being connected to the first outlet for extracted product for continuous concentration of the second organic phase to obtain the PEGn cyclosulfite.
The reaction time and temperature can be precisely controlled through the continuous reaction unit 20, the reaction is quenched to be neutral in the continuous quenching unit 30 after the reaction is finished, the stability of a system can be improved, the generation of side reactions is avoided, the yield is improved, the separation of an organic phase and a water phase can be realized by introducing the product of the continuous quenching unit 30 into the continuous liquid separation unit 40, the solvent can be directly recovered after the organic phase is introduced into the first continuous concentration unit 50, the recycling of the solvent is facilitated, the raw material cost can be reduced, and the purity of PEGn cyclosulfite can be improved by at least 10 percent after the treatment of the first continuous concentration unit 50, the continuous extraction unit 60 and the second continuous concentration unit 70.
In a preferred embodiment of the present application, as shown in fig. 2, the continuous reaction unit is further connected to an exhaust gas absorption unit 21; and/or, the continuous synthesis system further comprises a continuous stirring unit 41 and a pH regulator supply unit 42, wherein an outlet of the water phase in the continuous liquid separation unit 40 is connected with the continuous stirring unit 41, and an outlet of the pH regulator supply unit 42 is connected with the continuous stirring unit 41. The pH of the aqueous phase in the continuous stirring unit 41 can be adjusted to be neutral so that it directly meets the discharge standard. The block diagram of the continuous synthesis system is shown in fig. 2.
The safety of the reaction process can be improved by connecting the continuous reaction unit 20 with the tail gas absorption unit 21, the safety risk is greatly reduced, and the system is simple and convenient, and the working strength and the labor cost can be reduced.
In a preferred embodiment of the present application, the raw material continuous supply unit 10 comprises at least two feeding pipes connected to the reaction raw material inlets of the continuous reaction unit 20; and/or, each of the continuous reaction unit 20, the continuous quenching unit 30 is independently configured with a continuous stirred reactor (CSTRs) or a Plug Flow Reactor (PFR); and/or, the continuous liquid separator is arranged in each of the continuous liquid separating unit 40 and the continuous extraction unit 60; and/or, the first continuous concentration unit 50 and the second continuous concentration unit 70 are each provided with a thin film evaporator.
By using the PEGn cyclosulfite continuous synthesis system, the feeding speed of the reaction raw materials can be adjusted according to the required quantity of the products, no obvious influence is caused on the yield of the reaction products, and the defect that the traditional PEGn cyclosulfite needs to be prepared through a long-time dropping process is overcome.
In another exemplary embodiment of the present application, a continuous synthesis of a PEGn cyclosulfite is provided, the PEGn cyclosulfite having a structural formula as shown in formula I:
i is a kind of
Wherein n represents an integer of 3 to 8.
The synthesis method adopts the continuous synthesis system, and comprises the following steps:
s1, mixing a polyethylene glycol-containing solution, an alkali-containing solution and a thionyl chloride solution under a continuous stirring condition, and continuously carrying out a ring-closing reaction to obtain a solution to be quenched; the polyethylene glycol-containing solution and the alkali-containing solution are mixed in advance or not, and the polyethylene glycol-containing solution also contains a catalyst;
s2, continuously quenching the liquid to be quenched by using a quenching liquid, and quenching the liquid to be quenched to be neutral to obtain a quenched product;
s3, carrying out continuous liquid separation treatment on the quenching product to obtain a first organic phase and a first aqueous phase;
s4, continuously concentrating the first organic phase to obtain a concentrated product;
s5, continuously extracting the concentrated product by using an extract liquid to obtain a second organic phase;
and S6, continuously concentrating the second organic phase to obtain the PEGn cyclic sulfite.
The continuous synthesis method of the PEGn cyclic sulfite realizes continuous production of the PEGn cyclic sulfite, the reaction conditions can be accurately controlled, and the serious amplification effect generated during the amplification production can be effectively avoided, namely, the yield is reduced along with the increase of the feeding amount.
In a preferred embodiment of the present application, in S1, inert gas is introduced during the reaction process to perform protection; and/or, the pH value of the first aqueous phase is continuously adjusted to 6.5-7.5.
The potential safety hazard can be reduced by introducing inert gas; in addition, the waste liquid or solid waste generated by the reaction can be directly transferred after the pH value is regulated on line, so that a reaction kettle, a post-treatment kettle and three-waste treatment equipment used in the process of amplified production can be greatly reduced.
In a preferred embodiment, in S1, the reaction temperature is from-10℃to 60℃and, more preferably, the reaction temperature is from 30℃to 35 ℃. The continuous synthesis method can be used for production in a larger temperature range, and refrigeration equipment is not necessarily required to be provided; preferably 30-35 ℃, not only can stably prepare the required PEGn cyclic sulfite, but also can improve the reaction rate and reduce the time cost.
In a preferred embodiment, the first and second organic phases are concentrated by a thin film evaporator; and/or, after S4 is finished, recovering the solvent. In S4, the solvent can be recovered after concentration, which is helpful for reducing the production cost. The adoption of the thin film evaporator for concentration can save energy consumption and also is beneficial to reducing the production cost.
In a preferred embodiment, in S1, the polyethylene glycol is H (OCH) 2 CH 2 ) 3 OH、H(OCH 2 CH 2 ) 4 OH、H(OCH 2 CH 2 ) 5 One of OH, [ OCH ] 2 CH 2 ]When the number of the repeating units is less than 5, the monodisperse polyethylene glycol is easy to prepare, the raw materials are easy to obtain, and the high-purity PEGn cyclic sulfite can be prepared.
Typically, but not by way of limitation, the base includes at least one of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, 4-dimethylaminopyridine; the catalyst is 4-dimethylaminopyridine; the solvents of the polyethylene glycol-containing solution, the alkali-containing solution and the thionyl chloride solution are the same, and organic solvents commonly used in the field can be selected, and the solvents are at least one of dichloromethane, dichloroethane, tetrahydrofuran, dimethyl sulfoxide and acetonitrile; the quenching liquid is one of a salt solution or a buffer solution, and illustratively, the quenching liquid is at least one of a sodium chloride solution, a sodium carbonate solution, a potassium carbonate solution, a sodium bicarbonate solution, a potassium bicarbonate solution, a sodium dihydrogen phosphate solution, a potassium dihydrogen phosphate solution, a disodium hydrogen phosphate solution and a dipotassium hydrogen phosphate solution, and the solvent of the quenching liquid is water; the volume ratio of the n-heptane to the methyl tertiary butyl ether is 1: the mixed solution of (2-3). Experiments show that for the continuous synthesis method of the PEGn cyclic sulfite, the yield of the PEGn cyclic sulfite can be effectively improved by adding the catalyst 4-dimethylaminopyridine.
In a preferred embodiment, in S1, a polyethylene glycol-containing solution and an alkali-containing solution are mixed in advance to obtain a mixed solution, and then mixed with a thionyl chloride solution to perform a ring-closure reaction; the mixed solution and the thionyl chloride solution are simultaneously introduced into the continuous reaction unit 20 at the same volume flow rate; the mole ratio of polyethylene glycol, alkali and catalyst in the mixed solution is 1: (1-5): (0.08-0.5), and the concentration of polyethylene glycol in the mixed solution is 0.1-0.11 mmol/L; the concentration of thionyl chloride in the thionyl chloride solution is 0.15-0.55 mmol/L; and/or, in S5, the volume ratio of the extract to the concentrated product is (2-5): 1. when the conditions are met, polyethylene glycol can fully react with thionyl chloride, and the product has less impurity phase and high yield.
In a preferred embodiment, when the polyethylene glycol is H (OCH) 2 CH 2 ) 3 When OH (PEG 3), the alkali is diisopropylethylamine, and the catalyst is 4-dimethylaminopyridine; when the polyethylene glycol is H (OCH) 2 CH 2 ) 4 In the case of OH (PEG 4), the base is triethylamine and the catalyst is 4-dimethylaminopyridine. For different polyethylene glycols, the reaction conditions are different to a certain extent, and when the types of the components meet the conditions, the PEG3 cyclic sulfite and the PEG4 cyclic sulfite can be prepared respectively and efficiently.
The present application is described in further detail below in conjunction with specific embodiments, which should not be construed as limiting the scope of the claims.
Performance testing
1) Yield: the mass of the separated product/the theoretical product amount calculated according to the addition amount of the raw materials is 100 percent;
2) Purity: HPLC-CAD detection is carried out, and the area ratio of the product peak to all peaks is taken as a purity value.
Example 1
An embodiment of a continuous synthesis method of PEGn cyclosulfite in the present application, the continuous synthesis method adopts a continuous synthesis system with a structural block diagram as shown in fig. 1, and the continuous synthesis method is as follows:
s1, pre-mixing a polyethylene glycol-containing solution and an alkali-containing solution to obtain a mixed solution, then simultaneously introducing the mixed solution and a sulfoxide chloride solution into a continuous reaction unit 20 through two feeding pipes of a raw material continuous supply unit 10 respectively at the same volume flow, and continuously carrying out a ring-closing reaction under the action of a continuous stirring reactor, wherein the reaction temperature is controlled at 30 ℃ to obtain a solution to be quenched; the mixed solution contains polyethylene glycol, alkali, a catalyst and a solvent, wherein the polyethylene glycol is PEG4, the alkali is diisopropylethylamine, the catalyst is 4-dimethylaminopyridine, the solvent is dichloromethane, and the molar ratio of the polyethylene glycol, the diisopropylethylamine and the 4-dimethylaminopyridine in the mixed solution is 1:2.5:0.08; the concentration of polyethylene glycol in the mixed solution is 0.1mmol/L, the thionyl chloride solution contains thionyl chloride and a solvent, the solvent is methylene dichloride, and the concentration of thionyl chloride is 0.15mmol/L.
S2, continuously quenching the liquid to be quenched in the S1 to be neutral by using the quenching liquid in a continuous quenching unit 30 to obtain a quenching product; the quenching liquid is saturated sodium chloride water solution.
S3, continuously separating the quenching product of the step S2 in a continuous liquid separating unit 40 by using a continuous liquid separator to obtain a first organic phase;
s4, continuously performing film concentration on the first organic phase by using a film evaporator in a first continuous concentration unit 50 to obtain a concentrated product;
s5, continuously extracting the concentrated product by using an extracting solution in a continuous extraction unit 60 and separating the concentrated product to obtain a second organic phase; the extract is a mixed solution with the volume ratio of n-heptane to methyl tertiary butyl ether of 1:2, and the volume of the extract is 2.5 of the volume of the concentrated product;
s6, continuously concentrating the second organic phase by using a thin film evaporator in a second continuous concentration unit 70 to obtain a product of PEG4 cyclosulfite.
The yield of the continuous synthesis method of example 1 was 76% and the purity was 89%.
Example 2
An example of a continuous synthesis of PEGn cyclosulfite of the present application differs from example 1 only in that the base is triethylamine.
The yield of the continuous synthesis method of example 2 was 83% and the purity was 88%.
Example 3
An example of a continuous synthesis of PEGn cyclosulfite in this application differs from example 1 only in that PEG3 is substituted for PEG4 and the synthesized product is PEG3 cyclosulfite.
The yield of the continuous synthesis method of example 3 was 76% and the purity was 83%.
Example 4
An example of a continuous synthesis of PEGn cyclosulfite in this application differs from example 3 only in that the base is triethylamine and the product synthesized is PEG3 cyclosulfite.
The yield of the continuous synthesis method of example 4 was 72% and the purity was 78%.
Example 5
An example of a continuous synthesis of PEGn cyclosulfite of the present application differs from example 1 only in that diisopropylethylamine is used instead of 4-dimethylaminopyridine.
The yield of the continuous synthesis method of example 5 was 70% and the purity was 75%.
Example 6
An embodiment of the continuous synthesis method of PEGn cyclosulfite in the present application is different from embodiment 1 in that a continuous synthesis system with a structural block diagram shown in fig. 2 is adopted, inert gas is introduced into S1 for protection, and an exhaust gas absorption unit 21 is used for controlling odor in a reaction process in a continuous reaction unit 20; s3, introducing the water phase obtained by continuous liquid separation into a continuous stirring unit 41, and directly transferring after on-line pH value adjustment; s4, concentrating the first organic phase by a continuous film, and then guiding out the solvent, recycling the solvent to the batching device for recycling.
The yield of the continuous synthesis method of example 6 was 76% and the purity was 88%.
Examples 7 to 10
Examples 7 to 10 of the continuous synthesis method of PEGn cyclosulfite of the present application differ from example 2 in that in S5, the volume ratio of n-heptane to methyl tert-butyl ether in the extract is different, specifically:
in example 7, the volume ratio of n-heptane to methyl tert-butyl ether was 1:2.5; the yield is 81% and the purity is 86%;
in example 8, the volume ratio of n-heptane to methyl tert-butyl ether was 1:3; the yield is 80% and the purity is 85%;
in example 9, the volume ratio of n-heptane to methyl tert-butyl ether was 1:1.5; the yield is 77% and the purity is 77%;
in example 10, the volume ratio of n-heptane to methyl tert-butyl ether was 1:3.5; the yield thereof was found to be 76% and the purity thereof was found to be 75%.
Examples 11 to 12
Examples 11 to 12 of the continuous synthesis method of PEGn cyclic sulfite in the present application are different from example 2 in that in S1, the molar ratio of polyethylene glycol, triethylamine, and 4-dimethylaminopyridine in the mixed solution is different, and the concentration of polyethylene glycol in the mixed solution and the concentration of thionyl chloride in the thionyl chloride solution are different, specifically as follows:
example 11: in the mixed solution, the mol ratio of polyethylene glycol to triethylamine to 4-dimethylaminopyridine is 1:5:0.5, the concentration of polyethylene glycol in the mixed solution is 0.1mmol/L, and the concentration of thionyl chloride in the thionyl chloride solution is 0.2mmol/L; the yield is 82% and the purity is 85%;
example 12: in the mixed solution, the mol ratio of polyethylene glycol to triethylamine to 4-dimethylaminopyridine is 1:3:0.08, the concentration of polyethylene glycol in the mixed solution is 0.11mmol/L, and the concentration of thionyl chloride in the thionyl chloride solution is 0.55mmol/L; the yield thereof was found to be 81% and the purity thereof was found to be 88%.
Comparative example 1
A continuous synthesis process for PEGn cyclic sulfite which differs from example 1 only in that S4 is omitted.
The yield of the continuous synthesis method of comparative example 1 was 65% and the purity was 74%.
According to the test results, the continuous synthesis system and the continuous synthesis method of the PEGn cyclic sulfite can be used for efficiently synthesizing the PEGn cyclic sulfite, the yield and the productivity are high, and industrial production can be realized.
In addition, the test results of comparative examples 1 and examples 2 to 4 show that the yield of diisopropylethylamine as the base is higher when PEG3 is selected as the polyethylene glycol and the yield of triethylamine as the base is higher when PEG4 is selected as the polyethylene glycol; meanwhile, when PEG4 is selected as polyethylene glycol, the yield of the product is generally higher than that of PEG3.
The test results of comparative example 1 and example 5 show that the product yield is relatively high for the continuous synthesis process of the present application using 4-dimethylaminopyridine as catalyst.
Furthermore, the results of the tests of comparative example 2 and examples 7 to 10 show that the composition of the extract also has a large influence on the yield and purity of the product, wherein when the volume ratio of n-heptane to methyl tert-butyl ether in the extract is 1: (2-3) having an optimum combination of properties.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A continuous synthesis system of PEGn cyclosulfite, characterized in that the structural formula of the PEGn cyclosulfite is shown as formula I:
i is a kind of
Wherein n represents an integer of 3 to 8;
the continuous synthesis system comprises:
a raw material continuous supply unit (10) for continuously supplying a polyethylene glycol-containing solution, an alkali-containing solution, and a thionyl chloride solution as reaction raw materials; the polyethylene glycol-containing solution also contains a catalyst, wherein the catalyst is 4-dimethylaminopyridine;
a continuous reaction unit (20) having a reaction raw material inlet and a reaction product outlet, the reaction raw material inlet being connected to the raw material continuous supply unit (10), the continuous reaction unit (20) being configured to perform a continuous ring-closing reaction of the reaction raw material to obtain a liquid to be quenched;
the continuous quenching unit (30) is provided with a to-be-quenched object inlet and a quenched product outlet, the to-be-quenched object inlet is connected with the reaction product outlet, and the continuous quenching unit (30) is used for carrying out continuous quenching treatment on the to-be-quenched liquid so as to quench the to-be-quenched liquid to be neutral to obtain a quenched product;
a continuous liquid separation unit (40) having a to-be-separated inlet connected to the quenched product outlet and a separated product outlet comprising an organic phase outlet and an aqueous phase outlet, the continuous liquid separation unit (40) being configured to continuously separate the quenched product to obtain a first organic phase and a first aqueous phase;
a first continuous concentration unit (50) having a first inlet to be concentrated and a first concentrated product outlet, the first inlet to be concentrated being connected to the organic phase outlet for continuously concentrating the first organic phase to obtain a concentrated product;
a continuous extraction unit (60) having an extract inlet and an extraction product outlet, the extract inlet being connected to the first concentrated product outlet; the extraction product outlet comprises a first extraction product outlet and a second extraction product outlet, wherein the first extraction product is an organic phase, and the second extraction product is a water phase; -said continuous extraction unit (60) is adapted to perform a continuous extraction of said concentrated product to obtain a second organic phase;
a second continuous concentration unit (70) having a second inlet for concentrate and a second outlet for concentrated product, said second inlet for concentrate being connected to said first outlet for extracted product for continuous concentration of said second organic phase to obtain said PEGn cyclosulfite.
2. Continuous synthesis system according to claim 1, characterized in that the continuous reaction unit (20) is also connected to an off-gas absorption unit (21); and/or, the continuous synthesis system further comprises a continuous stirring unit (41) and a pH regulator supply unit (42), wherein the water phase outlet in the continuous liquid separation unit (40) is connected with the continuous stirring unit (41), and the outlet of the pH regulator supply unit (42) is connected with the continuous stirring unit (41).
3. Continuous synthesis system according to claim 1 or 2, characterized in that the raw materials continuous supply unit (10) comprises at least two feed pipes connected to the reaction raw materials inlet; and/or, each of the continuous reaction unit (20) and the continuous quenching unit (30) is independently provided with a continuous stirring reactor or a plug flow reactor; and/or a continuous liquid separator is arranged in each of the continuous liquid separation unit (40) and the continuous extraction unit (60); and/or, a thin film evaporator is arranged in each of the first continuous concentration unit (50) and the second continuous concentration unit (70).
4. A continuous synthesis process of PEGn cyclosulfite, characterized in that a continuous synthesis system according to any one of claims 1 to 3 is employed, the structural formula of the PEGn cyclosulfite being shown as formula I:
i is a kind of
Wherein n represents an integer of 3 to 8;
and the continuous synthesis method comprises:
s1, mixing a polyethylene glycol-containing solution, an alkali-containing solution and a thionyl chloride solution under a continuous stirring condition, and continuously carrying out a ring-closing reaction to obtain a solution to be quenched; the polyethylene glycol-containing solution and the alkali-containing solution are pre-mixed or not mixed;
s2, continuously quenching the liquid to be quenched by using a quenching liquid, and quenching the liquid to be quenched to be neutral to obtain a quenched product;
s3, carrying out continuous liquid separation treatment on the quenching product to obtain a first organic phase and a first aqueous phase;
s4, continuously concentrating the first organic phase to obtain a concentrated product;
s5, continuously extracting the concentrated product by using an extract liquid to obtain a second organic phase;
and S6, continuously concentrating the second organic phase to obtain the PEGn cyclic sulfite.
5. The continuous synthesis method according to claim 4, wherein in S1, inert gas is introduced for protection during the reaction; and/or in the step S3, the pH value of the first water phase is continuously adjusted to be 6.5-7.5.
6. The continuous synthesis process according to claim 4 or 5, wherein the first and second organic phases are concentrated by a thin film evaporator; and/or, recovering the solvent after the S4 is finished.
7. The continuous synthesis process according to claim 4 or 5, wherein in S1,
the polyethylene glycol is H (OCH) 2 CH 2 ) 3 OH、H(OCH 2 CH 2 ) 4 OH、H(OCH 2 CH 2 ) 5 OH、H(OCH 2 CH 2 ) 6 OH、H(OCH 2 CH 2 ) 7 OH、H(OCH 2 CH 2 ) 8 One of OH; and/or
The alkali is at least one of triethylamine, diisopropylethylamine, pyridine, potassium carbonate and 4-dimethylaminopyridine; and/or
The solvent of the polyethylene glycol-containing solution, the alkali-containing solution and the thionyl chloride solution is the same, and the solvent is at least one of dichloromethane, dichloroethane, tetrahydrofuran, dimethyl sulfoxide and acetonitrile; and/or
The quenching liquid is at least one of sodium chloride solution, sodium carbonate solution, potassium carbonate solution, sodium bicarbonate solution, potassium bicarbonate solution, sodium dihydrogen phosphate solution, potassium dihydrogen phosphate solution, disodium hydrogen phosphate solution and dipotassium hydrogen phosphate solution; and/or
The extract liquid is a mixed solution of n-heptane and methyl tertiary butyl ether with the volume ratio of 1 (2-3).
8. The continuous synthesis process according to claim 7, wherein,
in the step S1, the polyethylene glycol-containing solution and the alkali-containing solution are mixed in advance to obtain a mixed solution, and then the mixed solution is mixed with the thionyl chloride solution to carry out the cyclization reaction; the mixed solution and the thionyl chloride solution are simultaneously introduced into the continuous reaction unit (20) at the same volume flow rate; the molar ratio of the polyethylene glycol to the alkali to the catalyst in the mixed solution is 1: (1-5): (0.08-0.5), wherein the concentration of the polyethylene glycol in the mixed solution is 0.1-0.11 mmol/L; the concentration of the thionyl chloride in the thionyl chloride solution is 0.15-0.55 mmol/L; and/or
In the step S5, the volume ratio of the extract to the concentrated product is (2-5): 1.
9. the continuous synthesis process according to claim 8, wherein the polyethylene glycol is H (OCH) 2 CH 2 ) 3 OH, the base is diisopropylethylamine.
10. According to the weightsThe continuous synthesis process according to claim 8, wherein the polyethylene glycol is H (OCH) 2 CH 2 ) 4 OH, and the base is triethylamine.
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| WO2011016440A1 (en) * | 2009-08-04 | 2011-02-10 | 和光純薬工業株式会社 | Method for producing cyclic sulfonic acid ester and intermediate thereof |
| CN103613576A (en) * | 2013-12-06 | 2014-03-05 | 武汉大学 | Novel macrocyclic cyclic sulfate, and preparation method and application thereof |
| CN107629032A (en) * | 2017-10-25 | 2018-01-26 | 上海康鹏科技有限公司 | A kind of preparation method of cyclic sulfates |
| CN108129267A (en) * | 2018-01-11 | 2018-06-08 | 吉林凯莱英医药化学有限公司 | Low temperature Total continuity reaction system and application |
| CN113979990A (en) * | 2021-11-23 | 2022-01-28 | 山东鹏润新材料有限公司 | Preparation method of sulfite |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011016440A1 (en) * | 2009-08-04 | 2011-02-10 | 和光純薬工業株式会社 | Method for producing cyclic sulfonic acid ester and intermediate thereof |
| CN103613576A (en) * | 2013-12-06 | 2014-03-05 | 武汉大学 | Novel macrocyclic cyclic sulfate, and preparation method and application thereof |
| CN107629032A (en) * | 2017-10-25 | 2018-01-26 | 上海康鹏科技有限公司 | A kind of preparation method of cyclic sulfates |
| CN108129267A (en) * | 2018-01-11 | 2018-06-08 | 吉林凯莱英医药化学有限公司 | Low temperature Total continuity reaction system and application |
| CN113979990A (en) * | 2021-11-23 | 2022-01-28 | 山东鹏润新材料有限公司 | Preparation method of sulfite |
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