CN117343067A - Continuous flow production process of antiviral agent TZV - Google Patents
Continuous flow production process of antiviral agent TZV Download PDFInfo
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- 239000003443 antiviral agent Substances 0.000 title claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 239000007788 liquid Substances 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000012954 diazonium Substances 0.000 claims abstract description 21
- FTKASJMIPSSXBP-UHFFFAOYSA-N ethyl 2-nitroacetate Chemical compound CCOC(=O)C[N+]([O-])=O FTKASJMIPSSXBP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 239000012043 crude product Substances 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 13
- 150000001989 diazonium salts Chemical class 0.000 claims abstract description 12
- 238000007670 refining Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 239000000463 material Substances 0.000 claims description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 238000005112 continuous flow technique Methods 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 9
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 230000014759 maintenance of location Effects 0.000 claims description 9
- 229910017604 nitric acid Inorganic materials 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000003860 storage Methods 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 3
- 239000002351 wastewater Substances 0.000 abstract description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052804 chromium Inorganic materials 0.000 abstract description 2
- 239000011651 chromium Substances 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- DARSMUGUKCGKHQ-UHFFFAOYSA-M chembl1256733 Chemical compound O.O.[Na+].[N-]1N=C([N+]([O-])=O)C(=O)N2N=C(SC)N=C21 DARSMUGUKCGKHQ-UHFFFAOYSA-M 0.000 description 27
- 239000007864 aqueous solution Substances 0.000 description 10
- 230000001276 controlling effect Effects 0.000 description 10
- 241000700605 Viruses Species 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000006193 diazotization reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- XGWWZKBCQLBJNH-UHFFFAOYSA-N 3-methylsulfanyl-1h-1,2,4-triazol-5-amine Chemical compound CSC1=NN=C(N)N1 XGWWZKBCQLBJNH-UHFFFAOYSA-N 0.000 description 5
- 239000003651 drinking water Substances 0.000 description 5
- 235000020188 drinking water Nutrition 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- -1 3-amino-5-methylthio-1H-1, 2, 4-triazole hydrochloride Chemical compound 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- IDVQGNMSSHPZSJ-UHFFFAOYSA-N 7-methylsulfanyl-3-nitro-6h-[1,2,4]triazolo[5,1-c][1,2,4]triazin-4-one Chemical compound N1=C([N+]([O-])=O)C(=O)N2NC(SC)=NC2=N1 IDVQGNMSSHPZSJ-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 2
- DAKKWKYIQGMKOS-UHFFFAOYSA-N diethyl 2-nitropropanedioate Chemical compound CCOC(=O)C([N+]([O-])=O)C(=O)OCC DAKKWKYIQGMKOS-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- HFTNNOZFRQLFQB-UHFFFAOYSA-N ethenoxy(trimethyl)silane Chemical compound C[Si](C)(C)OC=C HFTNNOZFRQLFQB-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010062106 Respiratory tract infection viral Diseases 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 229940124401 anti-hepatitis virus drug Drugs 0.000 description 1
- 229940124397 anti-herpes virus drug Drugs 0.000 description 1
- 229940124393 anti-influenza virus drug Drugs 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000029578 entry into host Effects 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000013102 re-test Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000017610 release of virus from host Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- 229960004072 thrombin Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a continuous flow production process of antiviral drug TZV, belonging to the technical field of pharmaceutical intermediates. The method comprises the following steps: continuous flow preparation of ethyl nitroacetate, continuous flow preparation of Me-AMT diazonium salt, preparation of TZV crude product and refining of TVZ product. According to the invention, the micro-channel reaction is used for replacing the ethyl nitroacetate reaction, so that not only is the potential safety hazard of the process reduced, but also the generation of chromium-containing wastewater is avoided, and the key intermediate NEE with the content of more than or equal to 95% is successfully prepared through the micro-channel reaction, so that the production cost is greatly reduced; simultaneously, the micro-channel continuous flow reaction is adopted to prepare Me-AMT diazonium salt feed liquid, so that the potential safety hazard is reduced, and the obtained diazonium salt feed liquid is more beneficial to the next ring closing reaction; provides a new idea for the amplified production of an antiviral drug TZV.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical intermediates, and particularly relates to a continuous flow production process of an antiviral drug TZV.
Background
The development and production of effective antiviral drugs is still a very urgent problem in order to cope with the future possible outbreaks of new and reappeared viral epidemic situations, which seriously threatens the life health and social development of human beings. Antiviral drugs are a class of drugs used to specifically treat viral infections. Most diseases caused by viruses are main infectious diseases of human beings, and the viruses can invade different tissues and organs to infect cells to cause the diseases. Antiviral drugs are classified into anti-herpes virus drugs, anti-AIDS virus drugs, anti-influenza virus drugs, anti-hepatitis virus drugs, broad-spectrum antiviral drugs, etc. according to the diseases caused by viruses. There are many ways of inhibiting viral infection, such as directly inhibiting or killing viruses, interfering with viral adsorption, preventing viral penetration into cells, inhibiting viral biosynthesis, inhibiting viral release or enhancing host antiviral ability, etc. The effect of antiviral drugs is mainly achieved by affecting a certain link of the viral replication cycle. Broad-spectrum antiviral drugs can exert broad-spectrum antiviral effects and reduce the occurrence of drug resistance by targeting host proteins critical for viral replication, acting on multiple viruses or multiple genotypes of the same virus.
Triazavirine (TZV) is a novel broad-spectrum antiviral drug developed by Russian Ula national institute of chemical technology in 2014, which is helpful for delay treatment of acute respiratory viral infection and influenza, improving health condition on the first day, reducing possibility of complications, rapidly stopping clinical symptoms of coronavirus infection, preventing disease deterioration, and effectively resisting RNA viral infection.
TZV is similar to Abidol hydrochloride, has good in-vitro and in-vivo anti-influenza activity, and also has good inhibitory activity on amantadine-resistant virus strains, and the specific action mechanism is unknown. TZV HAs been reported to bind specifically to the thrombin (HA) of the virus and inhibit early stages of viral invasion into host cells. In view of the special structure and pharmacological properties of TZV, the novel compound can be probably marketed as non-patent medicines in China like Abidol hydrochloride in the future, the research on the synthesis process of the novel compound is developed, industrialization is accelerated, and the novel compound has important significance for preventing and treating influenza in China.
TZV has a complex structure, and few reports on the literature about the synthetic process route are about the structure, and the structure is mainly obtained by a two-step reaction through a one-pot reaction. At present, the national Shandong university Liu Tao's Studies on optimizing the synthesis process of Triazavirin and researching the design, synthesis and antiviral activity of novel nucleoside analogues' have been designed and discussed aiming at the synthetic route of Triazavirin. The first technical route is adopted by Shandong university Liu Tao, 3-amino-5-methylsulfanyl-1H-1, 2, 4-triazole is taken as a raw material to prepare a nitrate diazonium aqueous solution of 3-amino-5-methylsulfanyl-1H-1, 2, 4-triazole, a TZV crude product is prepared by adopting a one-pot method under alkaline conditions, and then a TZV finished product is obtained by adopting 60% acetic acid aqueous solution for crystallization. Although the yield of the above route is improved compared with that of the original route, the nitrate system is still adopted to prepare the diazonium salt aqueous solution of the 3-amino-5-methylthio-1H-1, 2, 4-triazole, and the diazonium salt is unstable and has the risk of potential safety hazard during the industrial scale-up production.
The method adopts two routes for research production at home and abroad, the first route adopts 3-amino-5-methylthio-1H-1, 2, 4-triazole as a starting material, 3-amino-5-methylthio-1H-1, 2, 4-triazole hydrochloride diazotization is obtained after diazotization, and the diazotization aqueous solution is cyclized with ethyl nitroacetate under alkaline condition to obtain TZV crude product, and acetic acid aqueous solution is adopted for recrystallization. The method has high atom utilization rate, but the diazotization aqueous solution of the 3-amino-5-methylthio-1H-1, 2, 4-triazole hydrochloride is unstable, and the obtained product has high impurity content and is not easy to industrialize. The second route is the same as the first route, namely, the method for preparing 3-amino-5-methylthio-1H-1, 2, 4-triazole hydrochloride diazotization aqueous solution is that diethyl nitromalonate is added into aqueous solution of propanol, diazonium salt aqueous solution is added, and TZV crude product is obtained after reaction for 1-2 hours at room temperature, and then the crude product is crystallized in acetic acid aqueous solution to obtain the finished product. The diethyl nitromalonate is expensive, has low atom utilization rate and is not easy to industrialize.
Disclosure of Invention
The microchannel reactor is essentially a continuous flow pipeline reactor, and comprises a mixer, a heat exchanger, a reaction controller and the like which are required by a chemical unit, and the microchannel reactor is very suitable for strong exothermic reactions, such as diazotization reactions and oxidation reactions which are mainly regulated, because the interior of the microchannel reactor has good heat and mass transfer characteristics, the reaction temperature can not be excessively accumulated, and the reaction temperature can be accurately controlled within a certain range.
Comprehensive research on the technological route of the broad-spectrum antiviral drug TZV at home and abroad is performed, and the large-scale production process of the broad-spectrum antiviral drug TZV is optimized, and mainly comprises the following two points:
1. the preparation process of the ethyl Nitroacetate (NEE) in the original large production process belongs to an oxidation process under national key supervision, potential safety hazards exist in the preparation process, sodium dichromate dihydrate is used in raw materials, waste water generated by the sodium dichromate dihydrate is not easy to treat, the reaction is replaced by a micro-channel reaction, the potential safety hazards of the process are reduced, the generation of chromium-containing waste water is avoided, and a key intermediate NEE with the content of more than or equal to 95% is successfully prepared through the micro-channel reaction, so that the production cost is greatly reduced.
2. In the original large-scale production process, the preparation of Me-AMT (5-amino-3-methylthio-1, 2, 4-triazole) diazonium salt feed liquid belongs to a dangerous process of national key supervision, and has great potential safety hazard in large-scale production.
The TZV continuous flow production process provided by the invention comprises the following steps: continuous flow preparation of ethyl nitroacetate, continuous flow preparation of Me-AMT diazonium salt, preparation of TZV crude product and refining of TVZ product.
1. A continuous flow process for the preparation of ethyl nitroacetate comprising the steps of; ethyl acetoacetate, concentrated sulfuric acid and concentrated nitric acid are used as raw materials, the flow rate of the raw materials is controlled in the presence of an organic solvent, the raw materials react under heating through a microchannel tubular reactor, and continuously produced feed liquid is concentrated to obtain ethyl nitroacetate. The reaction equation is expressed as follows:
further, in the technical scheme, the concentrated sulfuric acid and the concentrated nitric acid are prepared into a mixed acid solution according to a molar ratio of 1:3, and the mixed acid solution is marked as a material A; the organic solvent is selected from dichloromethane, chloroform or dichloroethane. Ethyl acetoacetate was dissolved in an organic solvent and designated as material B.
Further, in the technical scheme, the flow rate of the material A is 0.1-1.0L/min, and the flow rate of the material B is 0.1-4.0L/min.
Further, in the above technical scheme, the reaction temperature of the microchannel reactor is selected from 40-80 ℃; the retention time in the microchannel reactor was 3min.
Further, in the optimized case, a typical NEE microchannel production preparation procedure is as follows:
preparing a material A: concentrated sulfuric acid (98%) and nitric acid (65%) at low temperature (5 ℃) in a molar ratio of 1:3 preparing a mixed acid solution for standby.
Preparing a material B: dissolving the acetoacetic ester in an organic solvent for standby.
Micro-reaction conditions: material a flow rate: 0.14L/min,1.90mol/min; material B flow rate: 0.40L/min,0.40mol/min; microreactor reaction temperature: 60-70 ℃.
Post-treatment: GC detection reaction liquid
Microreaction attempts method:
(1) Reactor temperature: 35 ℃, 60 ℃, 75 ℃;
(2) Flow rate: 1.4L/min for material A and 4L/min for material B;
(3) Retention time: 3min;
(4) 98% sulfuric acid mass: 65% nitric acid mass 1:1.9;
(5) Ethyl acetoacetate to organic solvent volume ratio 1:6, preparing a base material;
(6) The intermediate content is 95-98% after discharging and concentrating.
2. The continuous flow preparation method of Me-AMT diazonium salt comprises the following steps: water and glycol are used as solvents, me-AMT, 50% fluoboric acid and sodium nitrite are used as raw materials, the flow rate of the raw materials is controlled, and the raw materials pass through a microchannel tubular reactor to react at a set temperature, so that diazonium salt feed liquid is continuously produced. The reaction equation is expressed as follows:
further, in the technical scheme, the ratio of water to glycol is 1:2; the ratio of sodium nitrite to water is 1:2. The flow rate of the material C is 3L/min, and the flow rate of the material D is 0.3L/min.
Further, in the technical scheme, the temperature of the micro-channel reactor is-9 ℃ and the retention time is 2min.
Further, in the above technical scheme, the storage temperature of the diazonium salt solution is-10 ℃ to-12 ℃.
Further, in the optimized case, a typical NEE microchannel production and preparation method is as follows:
preparing a material C: mixing water, glycol and Me-AMT, cooling to-5-0 ℃, and dripping 50% tetrafluoroboric acid solution to obtain colorless transparent solution.
Preparing a material D: stirring and dissolving water and sodium nitrite, and preparing light yellow transparent solution.
Micro-reaction conditions: material C flow rate: 2.0L/min; material D flow rate: 0.2L/min; microreactor reaction temperature: -9 ℃.
Post-treatment: the reaction was checked by HPLC.
Microreaction attempts method:
(1) Reactor temperature: -9 ℃;
(2) Flow rate: material C flow rate: 1.0L/min material D flow rate: 0.1L/min
(3) Retention time: 2min
(4) Diazonium feed solution storage temperature: -11 DEG C
2. The preparation method of the TZV crude product comprises the following steps: and (3) dropwise adding ethyl nitroacetate prepared by micro-channel reaction under an alkaline condition by taking water as a solvent, dropwise adding diazonium salt feed liquid stored in a low-temperature reaction kettle, adding an acidifying reagent to adjust the pH of the feed liquid to crystallize after the reaction is closed, and centrifuging by a centrifuge to obtain a crude product TZV. The reaction equation is expressed as follows:
further, in the above technical scheme, the base is selected from sodium carbonate or potassium carbonate; the temperature of the process of dripping the ethyl nitroacetate is 5-15 ℃; the temperature of the process of adding the nitrogen liquid is 0-5 ℃; the temperature of the ring closing reaction is 5-25 ℃; the acidifying reagent is acetic acid; feed liquid crystallization ph=5.5-7.0.
Typical operations are as follows: adding water and sodium carbonate into a reaction kettle, stirring and dissolving, controlling the temperature to be 10 ℃, dropwise adding the ethyl nitroacetate prepared in the step 1 into the kettle, cooling to be 2 ℃ after the dripping, dropwise adding the diazonium salt feed liquid prepared in the step 2 into the kettle, after the dripping, keeping the temperature to be 5 ℃ for reaction for 2 hours, heating to be 15 ℃ for reaction for 2 hours, and then heating to be 25 ℃ for reaction for 1 hour. Acetic acid is dripped, the pH value of the feed liquid is regulated to be=6.0, when the pH value of the feed liquid is in place, the dripping is stopped, and stirring is kept for 30min to retest the pH value; stirring and cooling to 10 ℃ and centrifuging to obtain crude product TZV.
4. TZV product refining method comprises the following steps: purified water is used as a solvent, activated carbon is used as a decoloring agent, the temperature is raised to 80-95 ℃ for decoloring after the crude product is added, filtering is carried out, a filter cake of the activated carbon is washed by hot purified water, the filtrate and the washing liquid are combined to a crystallization kettle for cooling and crystallization, and finally, centrifugation and material drying are carried out, thus obtaining the finished product TZV.
Typical operations are as follows: adding water, crude product TZV and medical active carbon into a reaction kettle, stirring and heating to 90 ℃, decoloring for 30 minutes, filtering, washing a filter cake with hot water, then mixing filtrate and washing liquid into a crystallization kettle, cooling and crystallizing, and centrifugally drying to obtain a finished product TZV.
Detailed Description
Example 1: preparation of ethyl Nitroacetate (NEE)
And (3) preparing a material A: 68kg (0.69 Kmol) of concentrated sulfuric acid and 200kg (2.06 Kmol) of concentrated nitric acid are added into a 200L reaction kettle, and the mixture is stirred and cooled to 5 ℃ for standby.
And (3) preparing a material B: 65L (0.52 Kmol) of ethyl acetoacetate and 400L of methylene dichloride are added into a 500L reaction kettle, and the mixture is stirred and mixed uniformly for later use.
Microchannel reaction: opening the micro-channel reactor, regulating the micro-reaction temperature to 35 ℃, controlling the flow rate of the material A to be 0.14L/min, controlling the flow rate of the material B to be 0.4L/min, and entering the micro-channel reactor for reaction, wherein the reaction retention time is about 3min.
Post-treatment: collecting the outlet feed liquid, standing for layering, separating out an organic phase, adding 200L of drinking water to wash the organic phase, standing for layering, separating out the organic phase, drying 20kg of anhydrous magnesium sulfate for 30 minutes, filtering, washing a filter cake with 50L of dichloromethane, mixing the filtrate and the washing liquid, and concentrating in a concentrating kettle to obtain 28kg of ethyl nitroacetate with the content of 82%.
Example 2
And (3) preparing a material A: 68kg (0.69 Kmol) of concentrated sulfuric acid and 200kg (2.06 Kmol) of concentrated nitric acid are added into a 200L reaction kettle, and the mixture is stirred and cooled to 5 ℃ for standby.
Preparation of a material B: 65L (0.52 Kmol) of ethyl acetoacetate and 400L of chloroform are added into a 500L reaction kettle, and the mixture is stirred and mixed uniformly for later use.
Microchannel reaction: opening the micro-channel reactor, regulating the micro-reaction temperature to 60 ℃, controlling the flow rate of the material A to be 0.14L/min, controlling the flow rate of the material B to be 0.4L/min, and entering the micro-channel reactor for reaction, wherein the reaction retention time is about 3min.
Post-treatment: collecting the outlet feed liquid, standing for layering, separating out an organic phase, adding 200L of drinking water to wash the organic phase, standing for layering, separating out the organic phase, drying 20kg of anhydrous magnesium sulfate for 30 minutes, filtering, washing a filter cake with 50L of chloroform, mixing the filtrate and the washing liquid, and concentrating in a concentrating kettle to obtain 42kg of ethyl nitroacetate with the content of 97%.
Example 3
And (3) preparing a material A: 68kg (0.69 Kmol) of concentrated sulfuric acid and 200kg (2.06 Kmol) of concentrated nitric acid are added into a 200L reaction kettle, and the mixture is stirred and cooled to 5 ℃ for standby.
And (3) preparing a material B: 65L (0.52 Kmol) of ethyl acetoacetate and 400L of dichloroethane are added into a 500L reaction kettle, and the mixture is stirred and mixed uniformly for standby.
Microchannel reaction: opening the micro-channel reactor, regulating the micro-reaction temperature to 75 ℃, controlling the flow rate of the material A to be 0.14L/min, controlling the flow rate of the material B to be 0.4L/min, and entering the micro-channel reactor for reaction, wherein the reaction retention time is about 3min.
Post-treatment: collecting the outlet feed liquid, standing for layering, separating out an organic phase, adding 200L of drinking water to wash the organic phase, standing for layering, separating out the organic phase, drying 20kg of anhydrous magnesium sulfate for 30 minutes, filtering, washing a filter cake with 50L of chloroform, mixing the filtrate and the washing liquid, and concentrating in a concentrating kettle to obtain 34kg of ethyl nitroacetate with the content of 95%.
According to the yield and content of the ethyl nitroacetate prepared by the three batches of micro-channel reactions, the scheme of the embodiment 2 is preferred, chloroform is adopted as a reaction solvent, and the reaction temperature is 60 ℃.
Example 4: me-AMT diazotization procedure
And (3) preparing a material C: 120kg of drinking water, 240kg of ethylene glycol and Me-AMT are added into a 500L reaction kettle: 48kg, stirring and cooling to 0 ℃, and then dropwise adding 130kg of 50% fluoboric acid, wherein the solution is colorless and transparent.
And (3) preparing a material D: 55kg of water and 27.5kg of sodium nitrite are added into a 200L reaction kettle, and the mixture is stirred and dissolved for later use.
Microchannel reaction: opening a micro-channel reactor, adjusting the micro-reaction temperature to-9 ℃, and controlling the material C: flow rate 2L/min, control material D: the flow rate is 0.2L/min, and the reaction is carried out in a micro-channel reactor for 2min.
Post-treatment: and directly transferring the outlet feed liquid into a storage kettle, and controlling the temperature to-11 ℃ for storage for standby.
Example 5: TZV crude product preparation procedure
Adding 350kg of drinking water into a 1000L reaction kettle, stirring and adding 85kg of sodium carbonate, cooling to 5 ℃, starting to dropwise add 40kg of ethyl nitroacetate, stirring and cooling to 0 ℃ after the dropwise adding, starting to dropwise add the Me-AMT diazonium salt feed liquid prepared in the example 4, controlling the temperature in the dropwise adding process not to exceed 5 ℃, keeping the temperature of the feed liquid at 5 ℃ after the dropwise adding, stirring and reacting for 2 hours, heating to 15 ℃, stirring and reacting for 2 hours, and heating to 25 ℃ and reacting for 1 hour. And (3) dropwise adding acetic acid to quench the reaction, stopping dropwise adding acetic acid when the pH value of the feed liquid is=6.5, stirring for 30min, and repeatedly measuring the pH value of the feed liquid without changing. And (3) cooling is started, and when the temperature of the crystallization feed liquid is 10 ℃, centrifugation is started to obtain a crude product with wet weight of 110kg.
Example 6: TZV refinement procedure
Adding 680kg of purified water into a 1000L reaction kettle, stirring and putting 110kg of TZV wet product, 15kg of 767 needle-shaped medical active carbon in example 5, heating to 90-95 ℃, stirring and decoloring for half an hour, filtering while hot, top-washing an active carbon filter cake with 80kg of purified water at 90 ℃, then merging filtrate and top-washing liquid into a crystallization kettle, cooling and crystallizing, keeping stirring for 2h and centrifuging when the temperature of the crystallization liquid is 20 ℃, and drying to obtain 60kg of light yellow TZV finished product with the content of 99.5%.
The foregoing embodiments illustrate the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.
Claims (10)
1. A continuous flow production process of antiviral agent TZV, comprising the steps of: continuous flow preparation of ethyl nitroacetate, continuous flow preparation of Me-AMT diazonium salt, preparation of TZV crude product and refining of TVZ product.
2. The continuous flow process of antiviral agent TZV according to claim 1, wherein: the continuous flow preparation of the ethyl nitroacetate is carried out by taking ethyl acetoacetate, concentrated sulfuric acid and concentrated nitric acid as raw materials, controlling flow rate of raw materials in the presence of organic solvent, reacting under heating by micro-channel tubular reactor, and concentrating continuously-produced feed liquid to obtain the ethyl nitroacetate.
3. The continuous flow process of antiviral agent TZV according to claim 2, wherein: the concentrated sulfuric acid and the concentrated nitric acid are prepared into a mixed acid solution according to a molar ratio of 1:3, and the mixed acid solution is marked as a solvent A; the organic solvent is selected from dichloromethane, chloroform or dichloroethane; ethyl acetoacetate was dissolved in an organic solvent and designated as material B.
4. The continuous flow process of antiviral agent TZV according to claim 3, wherein: the flow rate of the material A is 0.1-1L/min, and the flow rate of the material B is 0.1-4L/min; the reaction temperature of the microchannel reactor is 40-80 ℃; the retention time in the microchannel reactor was 3min.
5. The continuous flow process of antiviral agent TZV according to claim 1, wherein: the Me-AMT diazonium salt continuous flow is prepared by taking water and ethylene glycol as solvents, taking methyl-AMT, 50% fluoboric acid and sodium nitrite as raw materials, controlling the flow rate of the raw materials, and carrying out reaction at a set temperature through a microchannel tubular reactor to continuously produce diazonium salt feed liquid.
6. The continuous flow process of antiviral agent TZV of claim 5, wherein: mixing water, glycol and Me-AMT, cooling to-5-0 ℃, and dropwise adding 50% fluoboric acid to obtain a colorless transparent solution, wherein the colorless transparent solution is marked as a material C; stirring and dissolving water and sodium nitrite to prepare a pale yellow transparent solution, and marking the solution as a material D; the flow rate of the material C is 3L/min, and the flow rate of the material D is 0.3L/min.
7. The continuous flow process of antiviral agent TZV of claim 6, wherein: the temperature of the microchannel reactor is-9 ℃ and the retention time is 2min; the storage temperature of the produced diazonium salt feed liquid is minus 10 ℃ to minus 12 ℃.
8. The continuous flow process of antiviral agent TZV according to claim 1, wherein: the TZV crude product is prepared by taking water as a solvent, dropwise adding ethyl nitroacetate prepared by micro-channel reaction under alkaline condition, then dropwise adding diazonium salt feed liquid stored in a low-temperature reaction kettle, adding an acidifying reagent to adjust pH of the feed liquid for crystallization after closing a ring, and centrifuging by a centrifuge to obtain the crude product TZV.
9. The continuous flow process of antiviral agent TZV of claim 8, wherein: the base is selected from sodium carbonate or potassium carbonate; the temperature of the process of dripping the ethyl nitroacetate is 5-15 ℃; the temperature of the process of adding the nitrogen liquid is 0-5 ℃; the temperature of the ring closing reaction is 5-25 ℃; the acidifying reagent is acetic acid; feed liquid crystallization ph=5.5-7.0.
10. The continuous flow process of antiviral agent TZV according to claim 1, wherein: the TZV product is refined by taking purified water as a solvent, taking active carbon as a decoloring agent, stirring and heating to 80-95 ℃ for decoloring after the crude product is added, filtering, washing an active carbon filter cake with hot purified water, combining filtrate and washing liquid to a crystallization kettle for cooling and crystallizing, and finally centrifuging and drying to obtain a finished product TZV.
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