CN116789678A - Continuous flow preparation method of cyclic anhydride - Google Patents
Continuous flow preparation method of cyclic anhydride Download PDFInfo
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- CN116789678A CN116789678A CN202310437954.8A CN202310437954A CN116789678A CN 116789678 A CN116789678 A CN 116789678A CN 202310437954 A CN202310437954 A CN 202310437954A CN 116789678 A CN116789678 A CN 116789678A
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- -1 cyclic anhydride Chemical class 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims abstract description 25
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 20
- 238000011049 filling Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 11
- 239000002516 radical scavenger Substances 0.000 claims abstract description 9
- 239000000758 substrate Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 238000005086 pumping Methods 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims description 55
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000012024 dehydrating agents Substances 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 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 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 239000012527 feed solution Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 abstract description 9
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000002347 injection Methods 0.000 description 38
- 239000007924 injection Substances 0.000 description 38
- 239000000047 product Substances 0.000 description 25
- 238000003860 storage Methods 0.000 description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 230000014759 maintenance of location Effects 0.000 description 17
- 239000002994 raw material Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 229910001220 stainless steel Inorganic materials 0.000 description 10
- 239000010935 stainless steel Substances 0.000 description 10
- 239000012046 mixed solvent Substances 0.000 description 9
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000007599 discharging Methods 0.000 description 6
- 238000005265 energy consumption Methods 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 229930003756 Vitamin B7 Natural products 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 239000011735 vitamin B7 Substances 0.000 description 2
- 235000011912 vitamin B7 Nutrition 0.000 description 2
- RRRHSSRMQAVLCO-UHFFFAOYSA-N 4,5-dihydro-1h-imidazole-4,5-dicarboxylic acid Chemical class OC(=O)C1NC=NC1C(O)=O RRRHSSRMQAVLCO-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000006004 Quartz sand Substances 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000005112 continuous flow technique Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910000856 hastalloy Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000005341 toughened glass Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- 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
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a continuous flow preparation method of cyclic anhydride. The invention adopts a micro-reaction system, which comprises a feed pump, a micro-channel reactor and a back pressure valve; the preparation method comprises the steps of filling a water scavenger into a microchannel reactor; pumping substrate of cyclic acid (II) into a microchannel reactor by a feed pump to carry out continuous dehydration reaction; the mixed materials flowing out of the microchannel reactor are led out and collected through a back pressure valve, and the target product is obtained through pressure concentration treatment; the invention has the advantages of shortened reaction time to several minutes, high product yield of more than 99%, high continuous automation degree of the process, high space-time yield, simple operation, no need of separation of reaction liquid and water removing agent, no production of kettle-type process waste acid, low cost and easy industrialized production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a continuous flow preparation method of cyclic anhydride.
Background
(+) -biotin, also known as vitamin H, coenzyme R, is a water-soluble vitamin of the vitamin B group. The cyclic anhydride (I) is an important intermediate for industrial synthesis of (+) -biotin. The structural formula is as follows:
wherein R is 1 Is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl or the like, ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl, biphenyl, naphthyl or the like.
The chemical name of the cyclic anhydride (I) is cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ] imidazole-2, 4,6 (3H) -trione. In 1949, US patent 2489232 discloses the synthesis of cyclic anhydride by dehydration of cyclic acid with acetic anhydride for the first time. The research of the compound denier university Chen Fener group finds that the yield of the cyclic anhydride by reflux dehydration of acetic anhydride is only 90%, the residual cyclic acid of the reaction is difficult to separate, the process is optimized to be that the mixed solvent of the acetic anhydride and the catalytic amount of phosphoric acid and the cyclic acid are subjected to reflux dehydration, the cyclic anhydride is obtained in 98% yield (the university chemical report, 2001,22,1141), but the cyclic anhydride and the acetic anhydride can completely react when the molar ratio of the cyclic anhydride to the acetic anhydride is 1:3, and a large amount of acetic acid can be generated by using the acetic anhydride as a dehydrating agent, and the byproduct acetic acid has obvious residues and corrodes reaction equipment. World patent WO 2008071696 discloses that the use of catalytic amounts of organic or inorganic acids to dehydrate Guan Huange to cyclic anhydrides with cyclic acids has the disadvantages of longer reaction times, lower yields, incomplete conversion of cyclic acids, complex post-treatment operations, low process efficiency, etc. Chinese patent CN 101245069 discloses that cyclic anhydride is synthesized by reflux dehydration of cyclic acid and acetyl chloride, and stoichiometric acetyl chloride is required to be used to generate a large amount of waste acid, which has the disadvantages of potential safety hazard and serious harm to human body. Chinese patent CN 101519407 discloses azeotropic dehydration of benzene solvent and cyclic acid to synthesize cyclic anhydride, which has long reaction time, high energy consumption, low efficiency of process, and complicated separation of incomplete residual cyclic acid. Chen Fener reports that cyclic acid and thionyl chloride are dehydrated by reflux to obtain cyclic anhydride in 98% yield, and the reaction process requires excessive thionyl chloride, sulfur dioxide and hydrogen chloride gas are generated in the reaction process, so that the environment is polluted, the reaction equipment is corroded, and the potential safety hazard is large (Tetrahedron Asymmetry,2010,21,665). In the process of synthesizing cyclic anhydride from cyclic acid in an intermittent reaction kettle, an acid dehydrating agent is required to be used under a reflux condition, and the defects of long reaction time, complex operation, high potential safety hazard, high energy consumption, low process efficiency and the like exist. Therefore, based on a plurality of problems existing in the existing kettle-type preparation of the cyclic anhydride, a method for continuously preparing the cyclic anhydride is developed, which has the advantages of short reaction time, low energy consumption, high efficiency of the technological process and safety.
Disclosure of Invention
The invention aims to provide a continuous preparation method of cyclic anhydride type, which has the advantages of short reaction time, low energy consumption, high efficiency and good safety.
The invention provides a method for continuously preparing cyclic anhydride, which adopts a micro-reaction system, wherein the micro-reaction system comprises a feed pump, a micro-channel reactor and a back pressure valve; the outlet of the feed pump is connected with the inlet of the micro-channel reactor, the outlet of the micro-channel reactor is connected with the inlet of the back pressure valve, and the micro-channel reactor is filled with molecular sieve; the preparation method comprises the following specific steps:
(1) Filling a water scavenger into the microchannel reactor;
(2) Pumping substrate liquid of cyclic acid (II) into the microchannel reactor of the water removing agent in the step (1) by a feed pump to carry out continuous dehydration reaction;
(3) The mixed material flowing out of the microchannel reactor then enters an adjustable back pressure valve, the reaction mixed liquid is led out from an outlet of the adjustable back pressure valve and is collected, and the target product formula (I) is obtained through decompression concentration treatment.
Wherein, the reaction formula is:
the compound shown in the formula (I) is cyclic anhydride, and the compound shown in the formula (II) is cyclic acid;
wherein R is 1 Is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl or the like, ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl, biphenyl, naphthyl or the like.
In the step (1), the water scavenger is10Z MS, 13Z MS, Y MS, anhydrous sodium sulfate, anhydrous calcium chloride or anhydrous magnesium sulfate, preferably, the water scavenger in the step (1) is And the mixture is formed by stirring and mixing 10Z MS, 13Z MS, Y MS, anhydrous sodium sulfate, anhydrous calcium chloride and anhydrous magnesium sulfate with inert solid medium particles (such as quartz sand, diatomite, glass beads, stainless steel beads and the like).
In the step (2), the substrate solution containing the cyclic acid (II) is prepared by dissolving the cyclic acid (II) in a solvent; the solvent is a single organic solvent or a mixed solvent composed of two or more such liquids of one or more organic solvents; preferably, the organic solvent is one or a combination of several of dichloromethane, chloroform, ethyl acetate, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, anisole, acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, 1, 3-dimethyl-2-imidazolidinone and hexamethylphosphoric triamide; preferably, the solvent may be a mixed solvent composed of two or more such liquids of one or more organic solvents; for example, the mixed solvent may be a mixed solvent composed of acetonitrile and tetrahydrofuran in any ratio, or the mixed solvent may be a mixed solvent composed of N, N-dimethylformamide and tetrahydrofuran in any ratio, or the mixed solvent may be a mixed solvent composed of chloroform, ethyl acetate and tetrahydrofuran in any ratio.
The concentration of the substrate solution of the cyclic acid (II) in the step (2) is 0.1-2.0M; preferably, the concentration of the substrate solution of cyclic acid (II) is 0.5-1.5M.
The residence time of the reaction material in the microchannel reactor in the step (2) is controlled to be 0.1-10 minutes. The residence time is preferably from 2 to 8 minutes.
In the step (2), the temperature of the reaction material in the sample injection pump is controlled at 25-100 ℃.
In the step (2), the temperature of the reaction material in the microchannel reactor is controlled between 50 and 180 ℃.
The microchannel reactor in step (2) is a tubular microchannel reactor, or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 micrometers-50 millimeters; the hydraulic diameter of the reaction fluid channel of the plate-type micro-channel reactor is 100 micrometers-50 millimeters.
And (3) controlling the pressure of the back pressure valve to be 0.1-3.0 Mpa.
The invention also provides a micro-reaction system for continuously preparing cyclic anhydride (I), which comprises a feed pump, a micro-channel reactor and a back pressure valve; the inlet of the sample injection pump is connected with the substrate liquid (II), the inlet of the micro-channel reactor is connected with the outlet of the sample injection pump, the outlet of the micro-channel reactor is connected with the controllable back pressure valve, and the pressure adjustable range of the connected back pressure valve is 0.1-3.0 Mpa. The micro-channel reactor is filled with a molecular sieve; the feed pump directly enters the micro-channel reactor to carry out continuous dehydration reaction, the mixed material flowing out of the micro-channel reactor then enters the adjustable back pressure valve, the reaction mixed liquid is led out from the outlet of the adjustable back pressure valve and is collected, and the target product formula (I) is obtained through decompression concentration treatment.
The invention has the beneficial effects that:
compared with the existing synthesis method adopting the traditional batch reaction kettle, the invention has the following advantages:
1. the continuous synthesis from raw materials to products is realized, the process is continuously carried out, the automation process is high, the kettle type of organic acid or inorganic acid to the reaction kettle is avoided, various potential safety hazards in the kettle type production process are avoided, external treatment is not needed, the space-time efficiency is high, the number of operators and the labor intensity are greatly reduced, and the production cost is remarkably reduced;
2. the dehydration reaction of the cyclic acid (II) is completed in a reaction fluid channel of the microchannel reactor, and the total volume of the reaction fluid channel is small, so that the online liquid holdup is small, and the reaction process is intrinsically safe;
3. the microchannel reactor has excellent mass transfer and heat transfer and material mixing properties, so that the dehydration reaction time of the cyclic acid (II) is greatly shortened, and the reaction time is shortened from a few hours to a few minutes in the traditional intermittent kettle type reaction;
4. the continuous flow process based on the microchannel reactor does not need to separate the reaction liquid from the water scavenger, so that the reaction system can run continuously for a long time, the efficiency and the space-time yield of the process are greatly improved, the product yield is high (more than 99%), and the waste of single use of a large amount of acid in the batch kettle type reaction process, the time for separation, economy and labor cost are saved;
5. one or more solvents in the reaction process are mixed, mass transfer and the reaction process are completed in a reaction fluid channel of the microchannel reactor, a stirring device is not needed, and the energy consumption of the process is greatly reduced.
Drawings
FIG. 1 is a schematic diagram of a micro-reaction system according to an embodiment of the present invention.
Reference numerals in the drawings: 1 is cyclic anhydride product collection liquid, 2 is a reaction liquid storage tank, 3 is a feed pump, 4 is a microchannel reactor, 5 is a water scavenger, 6 is a back pressure valve, and 7 is a liquid storage tank.
Detailed Description
The invention will be further illustrated with reference to specific examples.
The micro-reaction system used in the embodiment has a structure shown in figure 1, and comprises 1 a cyclic anhydride product collecting liquid, 2 a reaction liquid storage tank, 3 a feed pump, 4 a micro-channel reactor, 5 a water scavenger, 6 a back pressure valve, 7 a product liquid storage tank.
The inlet of the feed pump 3 is connected with the reaction liquid storage tank 2, the outlet of the feed pump 3 is connected with the inlet of the micro-channel reactor 4, the outlet of the micro-channel reactor 4 is connected with the inlet of the back pressure valve 6, and the outlet of the back pressure valve 6 is connected with the product liquid storage tank.
The working process is as follows:
(A) Filling the microchannel reactor 4 with a water scavenger; preparing a reaction solution containing the formula (II), and placing the reaction solution in a reaction solution storage tank 2;
(B) The reaction solution containing the formula (II) is connected with an inlet of the feed pump 3 by the feed pump 3, an outlet of the feed pump 3 is directly connected with an inlet of the micro-channel reactor 4, an outlet of the micro-channel reactor 4 is connected with an inlet of the back pressure valve 6, an outlet of the back pressure valve 6 is connected with a product liquid storage tank, and the reaction mixed solution is collected and subjected to reduced pressure concentration treatment to obtain a target product formula (I).
Example 1
30g ofThe MS was filled in a stainless steel tube microchannel reactor (length 20cm, inner diameter 2 cm). Dissolving cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) in 300ml tetrahydrofuran solution, connecting the raw material liquid with inlet of sample injection pump, controlling sample injection temperature to 50deg.C, and connecting outlet of sample injection pump to the above filling>The inlet of the tubular microchannel reactor of MS, the retention volume in the microchannel reactor is 10ml, and the temperature in the microchannel reactor is controlled to be 120 DEG CThe back pressure value of the back pressure valve is set to be 1.5Mpa, the reaction retention time is 2.5 minutes, the reaction material flows out from the outlet of the micro-channel reactor, the product liquid is collected in a liquid storage tank, white flocculent solid is obtained after decompression and concentration, and the cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid is completely converted after analysis, so as to obtain the cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ]]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
Example 2
30g ofThe MS was packed in a stainless steel tube-type microchannel reactor (length 20cm, inner diameter 2 cm). Cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) was dissolved in 300ml of a mixed solution of tetrahydrofuran and N, N-dimethylformamide (1:1), then the raw material liquid was connected to the inlet of a sample injection pump, the sample injection temperature was controlled to 25 ℃, and the outlet of the sample injection pump was connected to the above-mentioned filling->The method comprises the steps of (1) collecting product liquid in a liquid storage tank, concentrating under reduced pressure to obtain white flocculent solid, and analyzing to obtain cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid, wherein the retention volume in the microchannel reactor is 10ml, the temperature in the microchannel reactor is controlled to be 130 ℃, the back pressure value of a back pressure valve is set to be 1.5Mpa, the reaction retention time is 1.5 min, the reaction material flows out of the outlet of the microchannel reactor, and the product liquid is completely converted into cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
Example 3
30g ofThe MS was packed in a stainless steel tube-type microchannel reactor (length 20cm, inner diameter 2 cm). Cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) was dissolved in 300ml of acetonitrile, and then the raw material liquid was connected to the inlet of a sample pump,controlling the sample injection temperature to 55 ℃, and connecting the outlet of the sample injection pump with the filling +.>The method comprises the steps of (1) collecting product liquid in a liquid storage tank, concentrating under reduced pressure to obtain white flocculent solid, and analyzing to obtain cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid, wherein the retention volume in the microchannel reactor is 10ml, the temperature in the microchannel reactor is controlled to be 150 ℃, the back pressure value of a back pressure valve is set to be 1.0Mpa, the reaction retention time is 2.0 min, the reaction material flows out of the outlet of the microchannel reactor, and the product liquid is completely converted into cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
Example 4
30g ofThe MS was filled in a stainless steel tube microchannel reactor (length 20cm, inner diameter 2 cm). Cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) was dissolved in 300ml of a mixed solution of acetone and tetrahydrofuran (1:1), then the raw material liquid was connected to the inlet of a sample injection pump, the sample injection temperature was controlled to 40 ℃, and the outlet of the sample injection pump was connected to the above-mentioned filling->The method comprises the steps of (1) collecting product liquid in a liquid storage tank, concentrating under reduced pressure to obtain white flocculent solid, and analyzing to obtain cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid, wherein the retention volume in the microchannel reactor is 10ml, the temperature in the microchannel reactor is controlled to be 100 ℃, the back pressure value of a back pressure valve is set to be 1.5Mpa, the reaction retention time is 1.5 min, the reaction material flows out of the outlet of the microchannel reactor, and the product liquid is completely converted into cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
Example 5
20g will beMS and 10g of anhydrous magnesium sulfate were uniformly mixed and then packed in a stainless steel tube type microchannel reactor (length: 20cm, inner diameter: 2 cm). Dissolving cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) in 300ml of tetrahydrofuran solution, connecting the raw material liquid with an inlet of a sample injection pump, controlling the sample injection temperature to be 40 ℃, connecting an outlet of the sample injection pump with an inlet of the filled tubular microchannel reactor, keeping the retention volume in the microchannel reactor to be 10ml, controlling the temperature in the microchannel reactor to be 140 ℃, setting the back pressure value of a back pressure valve to be 1.3Mpa, keeping the reaction retention time to be 1.2 minutes, discharging the reaction material from an outlet of the microchannel reactor, collecting the product liquid in a liquid storage tank, decompressing and concentrating to obtain white flocculent solid, and analyzing to obtain cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid for complete conversion to obtain cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ]]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
Example 6
30g of anhydrous sodium sulfate was filled in a stainless steel tube type microchannel reactor (length: 20cm, inner diameter: 2 cm). Dissolving cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) in 300ml of acetonitrile solution, connecting raw material liquid with an inlet of a sample injection pump, controlling the sample injection temperature to be 55 ℃, connecting an outlet of the sample injection pump with an inlet of a tubular microchannel reactor filled with anhydrous sodium sulfate, keeping the volume in the microchannel reactor to be 10ml, controlling the temperature in the microchannel reactor to be 150 ℃, setting the back pressure value of a back pressure valve to be 1.8Mpa, keeping the reaction time to be 2.0 min, discharging reaction materials from an outlet of the microchannel reactor, collecting product liquid from a liquid storage tank, decompressing and concentrating to obtain white flocculent solid, and analyzing to obtain the cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid with the yield of cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ] imidazole-2, 4,6 (3H) -trione with the purity of more than 99%.
Example 7
30g of 10Z MS was packed in a stainless steel tube microchannel reactor (length 20cm, inner diameter 2 cm). Dissolving cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) in 300ml of N-methylpyrrolidone solution, connecting the raw material liquid with the inlet of a sample injection pump, controlling the sample injection temperature to be 40 ℃, connecting the outlet of the sample injection pump with the inlet of the filling pipe type micro-channel reactor, setting the retention volume in the micro-channel reactor to be 10ml, controlling the temperature in the micro-channel reactor to be 170 ℃, setting the back pressure value of a back pressure valve to be 1.2Mpa, reacting for 2.5 minutes, discharging the reaction material from the outlet of the micro-channel reactor, collecting the product liquid in a liquid storage tank, decompressing and concentrating to obtain white flocculent solid, and analyzing to obtain the cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid with the yield of cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ] imidazole-2, 4,6 (3H) -trione with the purity of 99 percent.
Example 8
30g of 13Z MS was packed in a stainless steel tube microchannel reactor (length 20cm, inner diameter 2 cm). Dissolving cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) in 400ml of 1, 4-dioxane solution, connecting the raw material liquid with an inlet of a sample injection pump, controlling the sample injection temperature to be 30 ℃, connecting an outlet of the sample injection pump with an inlet of the filling pipe type micro-channel reactor, setting the retention volume in the micro-channel reactor to be 10ml, controlling the temperature in the micro-channel reactor to be 100 ℃, setting the back pressure value of a back pressure valve to be 1.6Mpa, reacting for 1.3 minutes, discharging the reaction material from an outlet of the micro-channel reactor, collecting the product liquid in a liquid storage tank, decompressing and concentrating to obtain white flocculent solid, and analyzing to obtain the cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid with the yield of the cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ] imidazole-2, 4,6 (3H) -trione with the purity of more than 99%.
Example 9
15g of Y MS and 15gThe MS was filled in a stainless steel tube microchannel reactor (length 20cm, inner diameter 2 cm). Cis-1, 3-dibenzyl-2-oxoimidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) was dissolved in 300ml ethylene glycolThe mixed solution of dimethyl ether and 1, 2-dichloroethane (1:1), then connect raw material liquid with inlet of the sample injection pump, control the sample injection temperature to 40 deg.C, the outlet of the sample injection pump connects the inlet of the above-mentioned filling tube type microchannel reactor, the retention volume in the microchannel reactor is 10ml, the temperature in the microchannel reactor is controlled to 135 deg.C, the back pressure value of the back pressure valve is set to 2.2Mpa, the reaction retention time is 0.9 minute, the reaction material flows out from the outlet of the microchannel reactor, collect the product liquid in the liquid storage tank, get white flocculent solid after decompressing and concentrating, through analysis, cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid is completely converted, the cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ] is obtained]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
Example 10
10g will beMS was packed in a hastelloy tube microchannel reactor (length 20cm, inner diameter 1 cm). Dissolving cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) in 300ml acetonitrile solution, connecting raw material liquid with an inlet of a sample injection pump, controlling the sample injection temperature to be 50 ℃, connecting an outlet of the sample injection pump with an inlet of the filling pipe type microchannel reactor, controlling the retention volume in the microchannel reactor to be 6ml, controlling the temperature in the microchannel reactor to be 160 ℃, setting the back pressure value of a back pressure valve to be 2.5Mpa, reacting for 1.1 min, discharging reaction materials from an outlet of the microchannel reactor, collecting product liquid in a liquid storage tank, decompressing and concentrating to obtain white flocculent solid, and analyzing to obtain cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid for complete conversion to obtain cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ]]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
Example 11
30g ofThe MS was packed in a polytetrafluoroethylene tube-type microchannel reactor (length 20cm, inner diameter 2 cm). Cis-1, 3-dibenzyl-2-oxoDissolving substituted imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) in 300ml acetonitrile solution, connecting the raw material liquid with the inlet of a sample injection pump, controlling the sample injection temperature to be 50 ℃, connecting the outlet of the sample injection pump with the inlet of the filling pipe type microchannel reactor, controlling the retention volume in the microchannel reactor to be 10ml, controlling the temperature in the microchannel reactor to be 180 ℃, setting the back pressure value of a back pressure valve to be 2.0Mpa, reacting for 0.8 min, flowing out the reaction material from the outlet of the microchannel reactor, collecting the product liquid in a liquid storage tank, concentrating under reduced pressure to obtain white flocculent solid, and completely converting the cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid to obtain cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ]]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
Example 12
Will be 14gThe MS was filled in a tempered glass tube type microchannel reactor (length: 20cm, inner diameter: 1 cm). Dissolving cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid (33.6, 0.1 mol) in a mixed solution of 300ml acetonitrile and chloroform (1:1), connecting the raw material liquid with an inlet of a sample injection pump, controlling the sample injection temperature to be 45 ℃, connecting an outlet of the sample injection pump with an inlet of the filling pipe type microchannel reactor, setting the retention volume in the microchannel reactor to be 5ml, controlling the temperature in the microchannel reactor to be 140 ℃, setting the back pressure value of a back pressure valve to be 1.8Mpa, reacting for 2.2 minutes, discharging the reaction material from an outlet of the microchannel reactor, collecting the product liquid in a liquid storage tank, concentrating under reduced pressure to obtain white flocculent solid, and completely converting the cis-1, 3-dibenzyl-2-oxo-imidazoline-4, 5-dicarboxylic acid to obtain cis-1, 3-disubstituted imidazoline-1H-furo [3,4-d ]]The yield of the imidazole-2, 4,6 (3H) -trione is 99 percent, and the purity is more than 99 percent.
The continuous flow micro-channel reaction does not need a stirring device, so that the energy consumption is greatly reduced, the technological process is continuously carried out, the operation is simple and convenient, the automation degree is high, and the efficiency is greatly improved. In addition, the micro-reaction continuous flow synthesis mode has small online liquid holdup and the excellent mass and heat transfer characteristics of the micro-channel reactor, so that the process is intrinsically safe, and the problem of high potential safety hazard of catalytic hydrogenation in the traditional intermittent kettle type synthesis method is effectively solved.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.
Claims (8)
1. A method for continuously preparing cyclic anhydride, which is characterized by adopting a micro-reaction system, wherein the micro-reaction system comprises a feed pump, a micro-channel reactor and a back pressure valve; the outlet of the feed pump is connected with the inlet of the micro-channel reactor, the outlet of the micro-channel reactor is connected with the inlet of the back pressure valve, and the micro-channel reactor is filled with molecular sieve; the preparation method comprises the following specific steps:
(1) Filling a water scavenger into the microchannel reactor;
(2) Pumping substrate liquid of cyclic acid (II) into the microchannel reactor of the water removing agent in the step (1) by a feed pump to carry out continuous dehydration reaction;
(3) The mixed material flowing out of the microchannel reactor then enters an adjustable back pressure valve, the reaction mixed liquid is led out from an outlet of the adjustable back pressure valve and is collected, and the target product formula (I) is obtained through reduced pressure concentration treatment;
wherein, the reaction formula is:
the compound shown in the formula (I) is cyclic anhydride, and the compound shown in the formula (II) is cyclic acid;
wherein R is 1 Is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyAnd Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl, biphenyl or naphthyl.
2. The process according to claim 1, wherein the dehydrating agent in step (1) is 10Z MS, 13Z MS, Y MS, anhydrous sodium sulfate, anhydrous calcium chloride, anhydrous magnesium sulfate, or a combination of one or more thereof.
3. The method according to claim 1, wherein the substrate solution of the cyclic acid (II) in step (2) is prepared by dissolving the cyclic acid (II) in a solvent; the solvent is one or more of dichloromethane, chloroform, ethyl acetate, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, anisole, acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, 1, 3-dimethyl-2-imidazolidinone and hexamethylphosphoric triamide.
4. The method of claim 1, wherein the concentration of the feed solution in step (2) is 0.1-2.0M.
5. The process according to claim 1, wherein the residence time of the reaction mass in the microchannel reactor in step (2) is controlled between 0.1 and 30 minutes.
6. The process of claim 1, wherein the microchannel reactor reaction temperature in step (2) is from 70 to 200 ℃.
7. The method of claim 1, wherein the microchannel reactor in step (2) is a tubular microchannel reactor, or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 0.1-50 mm; the inner diameter of the reaction fluid channel of the plate-type microchannel reactor is 0.1-50 mm, and the length is 5-50 m.
8. The method of claim 1, wherein the back pressure valve is controlled to a pressure of 0.1 to 3.0Mpa.
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