CN107759626B - Method for preparing 4-AA by reducing inorganic reducing agent - Google Patents
Method for preparing 4-AA by reducing inorganic reducing agent Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 43
- 239000003638 chemical reducing agent Substances 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000006722 reduction reaction Methods 0.000 claims abstract description 38
- 229910052751 metal Inorganic materials 0.000 claims abstract description 31
- 239000002184 metal Substances 0.000 claims abstract description 31
- 239000000843 powder Substances 0.000 claims abstract description 31
- 239000000243 solution Substances 0.000 claims abstract description 31
- 230000002829 reductive effect Effects 0.000 claims abstract description 23
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 17
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006385 ozonation reaction Methods 0.000 claims abstract description 14
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 13
- -1 -tert-butyl dimethyl silicon Chemical compound 0.000 claims abstract description 8
- 239000012670 alkaline solution Substances 0.000 claims abstract description 8
- 239000003929 acidic solution Substances 0.000 claims abstract description 7
- 230000003213 activating effect Effects 0.000 claims abstract description 5
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 7
- 230000004913 activation Effects 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 5
- GXDHCNNESPLIKD-UHFFFAOYSA-N 2-methylhexane Natural products CCCCC(C)C GXDHCNNESPLIKD-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 239000011135 tin Substances 0.000 claims description 2
- 229910052718 tin Inorganic materials 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 239000002351 wastewater Substances 0.000 abstract description 35
- 230000009467 reduction Effects 0.000 abstract description 20
- 230000008569 process Effects 0.000 abstract description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 14
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 abstract description 14
- 239000011593 sulfur Substances 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 4
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- 239000002994 raw material Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 11
- 239000004473 Threonine Substances 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000012153 distilled water Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 239000011259 mixed solution Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 101710116957 D-alanyl-D-alanine carboxypeptidase Proteins 0.000 description 2
- GWHDKFODLYVMQG-UBHAPETDSA-N [(2r,3r)-3-[(1r)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxoazetidin-2-yl] acetate Chemical compound CC(C)(C)[Si](C)(C)O[C@H](C)[C@@H]1[C@@H](OC(C)=O)NC1=O GWHDKFODLYVMQG-UBHAPETDSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Treatment Of Water By Oxidation Or Reduction (AREA)
Abstract
Preparation of (3R,4R) -4-acetoxyl-3- [ (R) -1-tert-butyl dimethyl silicon oxo-ethyl by reduction of inorganic reducing agentBase of]-a process for 2-azetidinone, said inorganic reducing agent being a reducing metal powder, said process comprising the steps of: (1) pretreatment of inorganic reducing agent: activating the reductive metal powder in an acidic or alkaline solution to obtain activated metal powder; (2) introducing ozone into the solution of the compound I to carry out oxidation reaction to obtain ozonization reaction liquid; (3) adding the activated metal powder obtained in the step (1) into the ozonization reaction liquid obtained in the step (2) for reduction reaction to obtain (3R,4R) -4-acetoxyl-3- [ (R) -1-tert-butyl dimethyl silicon oxo-ethyl]-2-azetidinone; wherein, the structural formula of the compound I is as follows:
Description
Technical Field
The invention relates to a beta-lactam drug, in particular to the production field of penem antibiotics, and specifically relates to a method for preparing a penem antibiotic intermediate (3R,4R) -4-acetoxyl-3- [ (R) -1-tert-butyldimethylsilyloxy-ethyl ] -2-azetidinone (namely, 4-AA) by reducing with an inorganic reducing agent.
Background
The penem antibiotics are antibiotics with the widest antibacterial spectrum and the strongest antibacterial effect in the known antibacterial drugs. These antibiotics selectively bind to Penicillin Binding Protein (PBP) on bacterial membranes and cause them to be non-cross-linked, thereby causing cell wall defects and bacterial cell rupture and death. The penem antibiotics have low toxicity to human cells, and have no influence on human cells within the effective antibacterial concentration. Has the advantages of broad spectrum, long half-life period, high-efficiency antibacterial activity and pharmacokinetic property.
In the preparation of penem antibiotics, the key mother nucleus 4-AA plays a very important role, and all carbapenem drugs are prepared by further reaction through the 4-AA. There are many methods for preparing 4-AA known in the prior art, among which, the method using threonine as a raw material has been regarded as cheap and easy, and this route was first reported in 1984 by M.Shiowuki (MAUO SHIOZAKI NOBORU ISHIDA, equivalent.tetrahedron, 198440 (10):1795-1802), and later, there are many reports related thereto, such as Tae-sublHwang, equivalent.Korean brand-Open No. 96-41141; LEE MI-JUNG et al, wo 9807690a1; chromatogr.a.,1999,832,259; bull. Korean chem. Soc, 1997,18,475, etc.
In the above process, threonine is first reacted in a plurality of steps to obtain threonineThe intermediate compound I is subjected to N-alkyl (alkyl is methoxyphenyl) removal to finally obtain 4-AA. Wherein the removal of N-alkyl groups from the compounds I is an unavoidable reaction unit. In the prior production process, the method of firstly oxidizing by ozone and then reducing is adopted when N-alkyl in the compound I is removed. In previous studies, researchers usually focused on the screening of oxidants and oxidation conditions, but considered less reduction, mainly because the current process and mechanism for removing N-alkyl by ozone oxidation is not clear, 4-AA is not present in ozonization reaction liquid obtained after ozone oxidation, 4-AA can be detected after reduction, and it is suspected that intermediate compound iii may be generated during reduction, and compound iii is reduced to obtain 4-AA, and the structural formula of compound iii is:
the structural formula of 4-AA is:
the research difficulty is large due to unknown mechanism. In the actual production, the reduction part is two-step reduction, namely, excessive sodium thiosulfate solution is added for reduction, and excessive thiourea is added for continuous reduction, so that the ammonia nitrogen (1.6 wt%) and sulfur (8 wt%) in the wastewater generated in the preparation of the 4-AA have high content, high COD value (more than 2000mg/L), strong smell and high environmental protection pressure. And the two-step reduction process of the reduction part has the largest wastewater discharge amount in the whole 4-AA production process, and the environmental safety is seriously harmed.
Disclosure of Invention
The invention aims to provide a method for preparing (3R,4R) -4-acetoxyl-3- [ (R) -1-tert-butyl dimethyl silicon oxo-ethyl ] -2-azetidinone by reducing an inorganic reducing agent, which only needs one-step reduction and can reduce the amount of wastewater, reduce the contents of ammonia nitrogen and sulfur in the wastewater and reduce the COD value of the wastewater.
The technical scheme of the invention is as follows:
a process for the preparation of (3R,4R) -4-acetoxy-3- [ (R) -1-tert-butyldimethylsilyloxy-ethyl ] -2-azetidinone by reduction with an inorganic reducing agent which is a reducing metal powder, comprising the steps of:
(1) pretreatment of inorganic reducing agent: activating the reductive metal powder in an acidic or alkaline solution to obtain activated metal powder;
(2) introducing ozone into the solution of the compound I to carry out oxidation reaction to obtain ozonization reaction liquid;
(3) adding the activated metal powder obtained in the step (1) into the ozonization reaction liquid obtained in the step (2) for reduction reaction to obtain (3R,4R) -4-acetoxyl-3- [ (R) -1-tert-butyl dimethyl silicon oxo-ethyl ] -2-azetidinone;
wherein, the structural formula of the compound I is as follows:
in order to complete the reaction, stirring or the like may be added during the respective reaction.
The inorganic reducing agent-reducing metal powder is used for one-step reduction, so that the amount of the generated wastewater can be reduced, the use of organic reducing agents sodium thiosulfate and thiourea is avoided, the generated wastewater does not contain ammonia nitrogen and sulfur, the COD value is low, and the environmental protection pressure is relieved.
Preferably, the reducing metal powder comprises any one or more of iron, nickel, zinc, tin or aluminium; further preferably, the mesh number of the reducing metal powder is 50-300 mesh, preferably 60-200 mesh, such as 100 mesh.
Preferably, in the step (1), the activation temperature is 0 to 100 ℃, preferably 10 to 40 ℃, for example 25 ℃, and the activation time is 0.5 to 8 hours, preferably 6 hours, so as to ensure that the reducing metal powder is fully activated, remove oxides on the surface of the reducing metal powder, improve the reducing capability of the reducing metal powder, facilitate the subsequent reduction reaction, and improve the reaction rate and the reaction effect of the reduction reaction.
Preferably, in the step (1), the acidic solution includes any one of a hydrochloric acid solution, a sulfuric acid solution, an acetic acid solution, a formic acid solution, or an ammonium chloride solution, and the pH of the acidic solution is 1 to 3. The adding amount of the acid solution is 3-6 times of the mass of the reducing metal powder so as to ensure the full activation of the reducing metal powder.
Preferably, in the step (1), the alkaline solution comprises an ammonia solution or a sodium hydroxide solution, and the pH of the alkaline solution is 13 to 14. The adding amount of the alkaline solution is 3-6 times of the mass of the reducing metal powder so as to ensure the full activation of the reducing metal powder.
In the step (1), the activated metal powder can be obtained by filtration, and preferably, the reduced metal powder after filtration is washed with water until the washing liquid becomes neutral, and then dried in vacuum.
In the step (2), the compound I is separated from a reaction solution containing the compound I obtained in the process of producing 4-AA by taking threonine as a raw material.
The process route for producing 4-AA by taking threonine as a raw material is as follows:
as can be seen from the above-mentioned process route, in the conventional process for producing 4-AA starting from threonine, the intermediate compound I is produced.
In the step (2), the compound I can be obtained from the process of producing (3R,4R) -4-acetoxyl group-3- [ (R) -1-tert-butyl dimethyl silicon oxo-ethyl ] -2-azetidinone (namely 4-AA) by taking threonine as a raw material, and can also be obtained from other approaches. Currently, the compound I can only be obtained from the process of producing 4-AA by taking threonine as a raw material. The invention mainly aims to solve the problem of wastewater pollution when 4-AA is obtained by reducing ozonization reaction liquid in the process of producing 4-AA by taking threonine as a raw material, so that the compound I obtained in the process of producing 4-AA by taking threonine as a raw material can be directly used. The method comprises the steps of obtaining a reaction liquid containing a compound I in the process of producing the 4-AA by taking threonine as a raw material, extracting and separating the compound I to obtain the compound I, dissolving the compound I in a solvent (such as methanol) to obtain a solution of the compound I, introducing ozone into the solution of the compound I to perform catalytic oxidation to obtain an ozonized reaction liquid, and reducing the ozonized reaction liquid by one step by using the method of the invention to obtain the 4-AA, namely replacing two-step reduction of a reduction part in a traditional process route by one-step reduction of the invention.
The traditional technology for producing 4-AA by taking threonine as a raw material is mature, equipment and a flow form the scale of industrial large-scale production, the invention only improves the reduction part of the traditional technology, can reduce the amount of generated wastewater, ensures that the generated wastewater does not contain ammonia nitrogen and sulfur, has a lower COD value, and can also directly use the production equipment and the production line of the traditional technology, thereby avoiding the large-scale modification of the production equipment and the production line and reducing the capital investment brought by the process change.
Preferably, in the step (2), the oxidation reaction temperature is-30-0 ℃, and the oxidation reaction time is 5-30 hours. So as to ensure the full progress of the oxidation reaction and the yield of the 4-AA. The introduction amount of the ozone is based on the complete reaction of the raw materials.
Whether the oxidation reaction in step (2) was completed was judged by observing gradual disappearance of spots of the raw material by thin layer chromatography (TLC detection).
Preferably, in the step (3), the reduction reaction temperature is-25-45 ℃, preferably-10-10 ℃, such as 0 ℃; the reduction reaction time is 0.5-5 h. So as to ensure the full progress of the reduction reaction and improve the yield of the 4-AA.
Preferably, in the step (3), the molar ratio of the activated metal powder to the compound I is 10-70:1, preferably 10-25:1, and more preferably 11:1, so as to ensure sufficient reduction of the ozonized reaction solution and improve the yield of 4-AA. The metal powder is generally added in an excess amount to ensure sufficient reduction, and the excess amount of metal powder hardly adversely affects the reduction reaction.
In the step (3), the reaction solution after the reduction reaction is filtered, the filtrate is distilled under reduced pressure, and the obtained solvent is crystallized by adding water, so that the 4-AA is obtained. The reducing metal powder can be recovered during filtering, and can be recycled after simple treatment (such as cleaning and drying), so that the cost is reduced. The pressure during the reduced pressure distillation is set at 60-80 deg.C, such as 70 deg.C.
Preferably, step (3) is followed by a recrystallization step (4). Preferably, in the recrystallization step (4), the solvent for recrystallization is a low-polarity alkane solvent including one or more of n-pentane, n-heptane, isoheptane, n-octane, isooctane or n-hexane.
The invention has the beneficial effects that:
in the process of producing (3R,4R) -4-acetoxyl group-3- [ (R) -1-tert-butyl dimethyl silicon oxo-ethyl ] -2-azetidinone (namely 4-AA) by using a compound I as a raw material, an inorganic reducing agent is used for replacing organic reducing agents of sodium thiosulfate and thiourea for reduction, the sulfur content in the generated wastewater is reduced to 0 from the original 8 wt%, the ammonia nitrogen content is reduced to 0 from the original 1.6 wt%, the COD value is reduced to less than 100mg/L from the original more than 2000mg/L, the treatment is easier, the wastewater treatment cost is reduced by more than 80%, the 4-AA yield is improved to 95 from the original 41.8%, and the method has obvious environmental protection and economic values.
Detailed Description
The technical solution and the effects of the present invention are further described by the following specific examples. The following examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention. Simple modifications of the invention applying the inventive concept are within the scope of the invention as claimed.
Example 1
(1) 100g of zinc powder with the mesh number of 100 meshes are put into 0.5mol/L NH4Activating in Cl aqueous solution, stirring for 2 hours at normal temperature, filtering, washing with distilled water to be neutral, and performing vacuum drying at 70 ℃ under reduced pressure to obtain activated zinc powder for later use;
(2) adding 20.0 g of compound I into a 250ml three-necked bottle, adding 150ml of methanol, stirring at room temperature until the mixture is clear (to obtain a solution of the compound I), cooling the system to-20 ℃, introducing ozone for reaction, keeping the temperature between-20 ℃ and-15 ℃, detecting by TLC (thin layer chromatography) until the raw material point disappears (to obtain ozonization reaction liquid), slowly adding 35g of the activated zinc powder obtained in the step (1) in batches for reduction reaction, slowly heating to 0 ℃, and reacting for 1.5 hours to obtain a mixed solution;
(3) filtering the mixed solution obtained in the step (2), washing a filter cake with a small amount of methanol, distilling the filtrate under reduced pressure to obtain 130ml of methanol, adding 200ml of distilled water, standing, precipitating crystals, and filtering to obtain a 4-AA crude product;
(4) and (4) recrystallizing the crude product of 4-AA obtained in the step (3) by using n-hexane to obtain 4-AA.
The yield of 4-AA is 92 wt%, the generated wastewater is about 200g (can be converted into 20 tons of wastewater/ton of product), the sulfur content in the wastewater is 0, the ammonia nitrogen content is 0, and the COD value is less than 100 mg/L.
Example 2
(1) Activating 100g of 80-mesh iron powder in 0.5mol/L HAc aqueous solution, stirring for 2 hours at 50 ℃, filtering, washing with distilled water to be neutral, and performing vacuum drying at 70 ℃ under reduced pressure to obtain activated iron powder for later use;
(2) adding 20.0 g of compound I into a 250ml three-necked bottle, adding 150ml of methanol, stirring at room temperature until the mixture is clear (to obtain a solution of the compound I), cooling the system to-20 ℃, introducing ozone for reaction, keeping the temperature between-20 ℃ and-15 ℃, detecting by TLC (thin layer chromatography) until the raw material point disappears (to obtain ozonization reaction liquid), slowly adding 23g of activated iron powder obtained in the step (1) in batches for reduction reaction, slowly heating to 0 ℃, and reacting for 2.5 hours to obtain a mixed solution;
(3) filtering the mixed solution obtained in the step (2), washing a filter cake with a small amount of methanol, distilling the filtrate under reduced pressure to obtain 130ml of methanol, adding 200ml of distilled water, standing, precipitating crystals, and filtering to obtain a 4-AA crude product;
(4) and (4) recrystallizing the crude product of 4-AA obtained in the step (3) by using n-hexane to obtain 4-AA.
The yield of 4-AA is 94 wt%, the generated wastewater is about 200g (can be converted into 20 tons of wastewater/ton of product), the sulfur content in the wastewater is 0, the ammonia nitrogen content is 0, and the COD value is less than 100 mg/L.
Example 3
(1) 80g of aluminum powder with the mesh number of 100 meshes are put into 0.5mol/L NH3·H2Activating in O water solution, stirring at 50 deg.C for 2 hr, filtering, washing with distilled water to neutralDrying under reduced pressure at 70 deg.C under vacuum to obtain activated aluminum powder;
(2) adding 20.0 g of compound I into a 250ml three-necked bottle, adding 150ml of methanol, stirring at room temperature until the mixture is clear (to obtain a solution of the compound I), cooling the system to-20 ℃, introducing ozone for reaction, keeping the temperature between-20 ℃ and-15 ℃, detecting by TLC (thin layer chromatography) until the raw material point disappears (to obtain ozonization reaction liquid), slowly adding 20g of activated aluminum powder obtained in the step (1) in batches for reduction reaction, slowly heating to 0 ℃, and reacting for 1.5 hours to obtain a mixed solution;
(3) filtering the mixed solution obtained in the step (2), washing a filter cake with a small amount of methanol, distilling the filtrate under reduced pressure to obtain 130ml of methanol, adding 200ml of distilled water, standing, precipitating crystals, and filtering to obtain a 4-AA crude product;
(4) and (4) recrystallizing the crude product of 4-AA obtained in the step (3) by using n-hexane to obtain 4-AA.
The yield of 4-AA is 95 wt%, the generated wastewater is about 200g (can be converted into 20 tons of wastewater/ton of product), the sulfur content in the wastewater is 0, the ammonia nitrogen content is 0, and the COD value is less than 100 mg/L.
Example 4
(1) Putting 120g of nickel powder with the mesh number of 180 meshes into 0.5mol/L NaOH aqueous solution for activation, stirring for 2 hours at normal temperature, filtering, washing with distilled water to be neutral, and performing vacuum drying at 70 ℃ under reduced pressure to obtain activated nickel powder for later use;
(2) adding 20.0 g of compound I into a 250ml three-necked bottle, adding 150ml of methanol, stirring at room temperature until the mixture is clear (to obtain a solution of the compound I), cooling the system to-20 ℃, introducing ozone for reaction, keeping the temperature between-20 ℃ and-15 ℃, detecting by TLC (thin layer chromatography) until the raw material point disappears (to obtain ozonization reaction liquid), slowly adding 45g of the activated nickel powder obtained in the step (1) in batches for reduction reaction, slowly heating to 0 ℃, and reacting for 1.5 hours to obtain a mixed solution;
(3) filtering the mixed solution obtained in the step (2), washing a filter cake with a small amount of methanol, distilling the filtrate under reduced pressure to obtain 130ml of methanol, adding 200ml of distilled water, standing, precipitating crystals, and filtering to obtain a 4-AA crude product;
(4) and (4) recrystallizing the crude product of 4-AA obtained in the step (3) by using n-hexane to obtain 4-AA.
The yield of 4-AA is 85 wt%, the generated wastewater is about 200g (can be converted into 20 tons of wastewater/ton of product), the sulfur content in the wastewater is 0, the ammonia nitrogen content is 0, and the COD value is less than 100 mg/L.
Example 5
(1) Activating 110g of 80-mesh tin powder in 1.5mol/L HCl aqueous solution, stirring at normal temperature for 5 hours, filtering, washing with distilled water to be neutral, and vacuum drying at 70 ℃ under reduced pressure to obtain activated tin powder for later use;
(2) adding 20.0 g of compound I into a 250ml three-necked bottle, adding 150ml of methanol, stirring at room temperature until the mixture is clear (to obtain a solution of the compound I), cooling the system to-20 ℃, introducing ozone for reaction, keeping the temperature between-20 ℃ and-15 ℃, detecting by TLC (thin layer chromatography) until the raw material point disappears (to obtain ozonization reaction liquid), slowly adding 58g of the activated tin powder obtained in the step (1) in batches for reduction reaction, slowly heating to 0 ℃, and reacting for 1.5 hours to obtain a mixed solution;
(3) filtering the mixed solution obtained in the step (2), washing a filter cake with a small amount of methanol, distilling the filtrate under reduced pressure to obtain 130ml of methanol, adding 200ml of distilled water, standing, precipitating crystals, and filtering to obtain a 4-AA crude product;
(4) and (4) recrystallizing the crude product of 4-AA obtained in the step (3) by using n-hexane to obtain 4-AA.
The yield of 4-AA is 78 wt%, the generated wastewater is about 200g (can be converted into 20 tons of wastewater/ton of product), the sulfur content in the wastewater is 0, the ammonia nitrogen content is 0, and the COD value is less than 100 mg/L.
Comparative example 1
Adding 20.0 g of compound I into a 250ml three-necked bottle, adding 150ml of methanol, stirring at room temperature until the mixture is clear (obtaining a solution of the compound I), cooling the system to-20 ℃, introducing ozone for reaction, keeping the temperature between-20 ℃ and-15 ℃, detecting by TLC (thin layer chromatography) until the raw material point disappears (obtaining an ozonization reaction liquid), dropwise adding 110ml of 30% sodium thiosulfate solution into the subsequent phase reaction system, stirring at 0 ℃ for 1 hour after dropping, adding 11.5g of thiourea in batches, heating to 40 ℃ for reaction for 2 hours, decompressing and evaporating most of methanol after the reaction is finished, adding 200ml of distilled water, crystallizing, filtering, recrystallizing the crude product by using normal hexane to obtain 4-AA, wherein the yield is 90 wt%. The produced wastewater is about 200g (can be converted into 20 tons of wastewater per ton of product), the sulfur content in the wastewater is 8 wt%, the ammonia nitrogen content is 1.6 wt%, and the COD value is more than 2000 mg/L.
The products 4-AA obtained in the above examples 1-5 and comparative example 1 were all subjected to nuclear magnetic carbon spectrum (C:)13C-NMR), hydrogen spectrum (1H-NMR), infrared (IR (KBr)), optical rotation (. alpha.))]20 D) And melting point (M.P.) tests were performed for structural confirmation and comparison to HPLC peak times for the 4-AA standard, all consistent with the 4-AA standard. Wherein,
13C-NMR：170.7,166.4,74.9,64.8,63.7,25.6,20.8,20.5,17.8,-4.4,-5.1；
1H-NMR：0.01(d,J＝6.0,6H),0.8(s,9H),1.20(d,J＝6.4,3H),2.04(s,3H),3.1(t,J＝2.4,1H),4.14(m,1H),5.76(s,1H),7.04(s,1H)；
IR(KBr)：v3200,2958,2929,2890,2855,1782,1745,1470,1377,1363,1340,1300,1255,1234,1163,1135,1107,1080,1039,984,945,896,877cm-1；
[α]20 D：+51.5°(C＝1.0,CHCl3)；
M.P.：104℃。
as can be seen from the comparison of the results of examples 1-5 and comparative example 1, the yield of 4-AA in the method of the present invention can reach 95 wt%, and the produced wastewater has a sulfur content of 0, an ammonia nitrogen content of 0, and a COD value of less than 100mg/L, and compared with the wastewater of comparative example 1, which has a sulfur content of 8 wt%, an ammonia nitrogen content of 1.6 wt%, and a COD value of more than 2000mg/L, the wastewater produced in the method of the present invention is easier to treat, and the treatment cost is low.
Claims (12)
1. A method for preparing (3R,4R) -4-acetoxyl group-3- [ (R) -1-tert-butyl dimethyl silicon oxo-ethyl ] -2-azetidinone by reducing an inorganic reducing agent, wherein the inorganic reducing agent is a reducing metal powder, and the method comprises the following steps:
(1) pretreatment of inorganic reducing agent: activating the reductive metal powder in an acidic or alkaline solution to obtain activated metal powder;
(2) introducing ozone into the solution of the compound I to carry out oxidation reaction to obtain ozonization reaction liquid;
(3) adding the activated metal powder obtained in the step (1) into the ozonization reaction liquid obtained in the step (2) for reduction reaction to obtain (3R,4R) -4-acetoxyl-3- [ (R) -1-tert-butyl dimethyl silicon oxo-ethyl ] -2-azetidinone;
wherein, the structural formula of the compound I is as follows:
2. the method of claim 1, wherein the reducing metal powder comprises any one or more of iron, nickel, zinc, tin, or aluminum.
3. The method of claim 2, wherein the reducing metal powder has a mesh size of 50-300 mesh.
4. The method according to claim 1, wherein in the step (2), the oxidation reaction temperature is-30 to 0 ℃ and the oxidation reaction time is 5 to 30 hours.
5. The method of claim 1, wherein in step (3), the molar ratio of the activated metal powder to the compound i is 10-25: 1.
6. The method according to claim 5, wherein in the step (3), the reduction reaction temperature is-25-45 ℃ and the reduction reaction time is 0.5-5 h.
7. The method according to claim 6, wherein in the step (3), the reduction reaction temperature is-10 to 10 ℃.
8. The method according to any one of claims 1 to 7, wherein in the step (1), the activation temperature is 0 to 100 ℃ and the activation time is 0.5 to 8 hours.
9. The method according to claim 8, wherein in the step (1), the acidic solution comprises any one of a hydrochloric acid solution, a sulfuric acid solution, an acetic acid solution, a formic acid solution or an ammonium chloride solution, and the acidic solution has a pH of 1-3.
10. The method according to claim 8, wherein in the step (1), the alkaline solution comprises an ammonia solution or a sodium hydroxide solution, and the pH of the alkaline solution is 13-14.
11. The method of claim 1, wherein step (3) is further followed by a recrystallization step (4).
12. The method according to claim 11, wherein in the recrystallization step (4), the solvent for recrystallization is a low-polarity alkane solvent comprising one or more of n-pentane, n-heptane, isoheptane, n-octane, isooctane, or n-hexane.
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