CN107759626A - A kind of method that inorganic reducing agent reduction prepares 4 AA - Google Patents
A kind of method that inorganic reducing agent reduction prepares 4 AA Download PDFInfo
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- CN107759626A CN107759626A CN201610683079.1A CN201610683079A CN107759626A CN 107759626 A CN107759626 A CN 107759626A CN 201610683079 A CN201610683079 A CN 201610683079A CN 107759626 A CN107759626 A CN 107759626A
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 239000003638 chemical reducing agent Substances 0.000 title claims abstract description 16
- 230000009467 reduction Effects 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 239000000843 powder Substances 0.000 claims abstract description 31
- 238000006722 reduction reaction Methods 0.000 claims abstract description 31
- 239000000243 solution Substances 0.000 claims abstract description 31
- 229910052751 metal Inorganic materials 0.000 claims abstract description 30
- 239000002184 metal Substances 0.000 claims abstract description 30
- 239000007788 liquid Substances 0.000 claims abstract description 20
- 238000006385 ozonation reaction Methods 0.000 claims abstract description 17
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000012670 alkaline solution Substances 0.000 claims abstract description 7
- -1 acetoxyl group Chemical group 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 230000004913 activation Effects 0.000 claims description 12
- 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
- 230000003647 oxidation Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 239000004411 aluminium Substances 0.000 claims description 5
- 229910052782 aluminium Inorganic materials 0.000 claims description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- GXDHCNNESPLIKD-UHFFFAOYSA-N 2-methylhexane Natural products CCCCC(C)C GXDHCNNESPLIKD-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-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
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 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
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 235000019270 ammonium chloride 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
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 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
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- 239000002351 wastewater Substances 0.000 abstract description 35
- 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
- 239000005864 Sulphur Substances 0.000 abstract description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000002994 raw material Substances 0.000 description 20
- 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
- 238000004821 distillation Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000001914 filtration 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000003115 biocidal effect Effects 0.000 description 7
- 230000006837 decompression Effects 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000000428 dust Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 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
- 230000002411 adverse Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 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
- 230000006872 improvement Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
- 238000003911 water pollution 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
A kind of inorganic reducing agent reduction prepares (3R, 4R) the method for 4 acetoxyl group 3 [(R) 1 tertiary butyl dimethyl Si is for ethyl] 2 aza cyclo-butanones, the inorganic reducing agent is reducing metal powder, be the described method comprises the following steps：(1) pretreatment of inorganic reducing agent：Reducing metal powder is placed in acid or alkaline solution and activated, obtains activated metal powder；(2) ozone progress oxidation reaction is passed through into the solution of chemical compounds I and obtains ozonization liquid；(3) the activated metal powder that step (1) obtains is added in the ozonization liquid of step (2) and carries out reduction reaction, produce (3R, 4R) 4 acetoxyl group 3 [(R) 1 tertiary butyl dimethyl Si is for ethyl] 2 aza cyclo-butanones；Wherein, the structural formula of chemical compounds I is as follows：
Description
Technical field
The present invention relates to Beta-lactam medicine, the production field of southern class antibiotic is particularly trained, specifically a kind of nothing
Prepared by the reduction of machine reducing agent trains southern class antibiotic intermediates (3R, 4R) -4- acetoxy-3s-[(R) -1- tert-butyldimethyl silyls
Oxo-ethyl] -2- aza cyclo-butanones (that is, 4-AA) method.
Background technology
It is a kind of antibiotic that antimicrobial spectrum is most wide in hitherto known antibacterials, antibacterial action is most strong to train southern class antibiotic.
This kind of antibiotic can be combined optionally with the PBP (PBP) on bacterial membrane, be allowed to be crosslinked, and be caused thin
The defect of cell wall, cause bacterial cell rupture and it is dead.The toxicity that southern class antibiotic is trained to human body cell is very low, effectively anti-at it
On human body cell without influence in bacteria concentration.It is special with super wide spectrum, long half time, dynamical antibacterial activity and pharmacokinetics
Property.
In the preparation for training southern class antibiotic, crucial parent nucleus 4-AA has very important effect, all carbapenems
Class medicine will further react preparation by 4-AA.The method for preparing 4-AA known in the art has a lot, wherein, with
Threonine for raw material method always with raw material attention cheap and easy to get, 1984, M.Shiowuki (MAUO SHIOZAKI
NOBORU ISHIDA,etal.Tetrahedron,1984 40(10):This route of having reported for work first such as 1795-1802), after
Come, there are multiple related reports again, e.g., Tae-subHwang, etal.Korean Patant Laid-Open_No.96-
41141；LEE MI-JUNG etal.WO9807690A1；J.Chromatogr.A.,1999,832,259；
Bull.KoreanChem.Soc., 1997,18,475 etc..
In the above method, the chemical compounds I as intermediate first is obtained by multiple step reactions by threonine, afterwards to changing
N- alkyl (alkyl is anisyl) in compound I carries out removing and finally gives 4-AA.The removing of N- alkyl wherein in chemical compounds I
It is inevitable reaction member.And, when the N- alkyl in chemical compounds I removes, used in production technology at present
The method that first ozone oxidation restores.In research before, researcher generally only puts forth effort on the sieve of oxidant and oxidizing condition
Choosing, and to reduce part consideration it is less, this mainly due at present to ozone oxidation remove N- alkyl process and mechanism still
It is unclear, do not have 4-AA in the ozonization liquid obtained after ozone oxidation, 4-AA can be just detected after reduction, conjecture is also
There may be intermediate-compound III, compound III during original to obtain 4-AA through reduction, and the structural formula of compound III is：4-AA structural formula is：Mechanism is not clear to be caused
It is big to study difficulty.In actual production, reduction part reduces for two steps, i.e., first adds excessive hypo solution reduction, then
Add excessive thiocarbamide to continue to reduce, this causes to prepare in waste water caused by 4-AA, ammonia nitrogen (1.6wt%) and sulphur (8wt%)
Content is very big, and COD value is very high (being more than 2000mg/L), and smell is big, and environmental protection pressure is big.And the two step reduction processes for reducing part exist
In whole 4-AA production processes, wastewater discharge is maximum, has seriously endangered Environmental security.
The content of the invention
It is an object of the invention to provide a kind of inorganic reducing agent reduction prepare (3R, 4R) -4- acetoxy-3s-[(R) -
1- tertiary butyl dimethyl Sis generation-ethyl] -2- aza cyclo-butanones method, this method only needs a step to reduce, and can reduce waste water
Amount, the content of ammonia nitrogen and sulphur in waste water is reduced, reduce the COD value of waste water.
Technical scheme is as follows：
A kind of inorganic reducing agent reduction prepare (3R, 4R) -4- acetoxy-3s-[(R) -1- tertiary butyl dimethyl Sis generation -
Ethyl] -2- aza cyclo-butanones method, the inorganic reducing agent is reducing metal powder, be the described method comprises the following steps：
(1) pretreatment of inorganic reducing agent：Reducing metal powder is placed in acid or alkaline solution and activated, must be activated
Metal dust；
(2) ozone progress oxidation reaction is passed through into the solution of chemical compounds I and obtains ozonization liquid；
(3) the activated metal powder that step (1) obtains is added in the ozonization liquid of step (2) and reduce instead
Should, produce (3R, 4R) -4- acetoxy-3s-[(R) -1- tertiary butyl dimethyl Sis generation-ethyl] -2- aza cyclo-butanones；
Wherein, the structural formula of chemical compounds I is as follows：
In order that reaction is complete, stirring etc. can be aided with each course of reaction.
A step reduction is carried out with inorganic reducing agent-reducing metal powder, caused wastewater flow rate can be not only reduced, keep away simultaneously
Exempted from the use of organic reducing agent sodium thiosulfate and thiocarbamide so that do not contain ammonia nitrogen and sulphur in caused waste water, COD value compared with
It is low, alleviate environmental protection pressure.
Preferably, the reducing metal powder includes any of iron, nickel, zinc, tin or aluminium or a variety of；It is further excellent
Selection of land, the mesh number of the reducing metal powder are 50-300 mesh, preferably 60-200 mesh, such as 100 mesh.
Preferably, in the step (1), activation temperature is 0-100 DEG C, preferably 10-40 DEG C, such as 25 DEG C, soak time
For 0.5-8h, preferably 6 hours, to ensure that reducing metal powder fully activates, the oxidation on reducing metal powder surface is removed
Thing, the reducing power of reducing metal powder is improved, contribute to the progress of sequential reduction reaction, improve the reaction speed of reduction reaction
Rate and reaction effect.
Preferably, in the step (1), the acid solution includes hydrochloric acid solution, sulfuric acid solution, acetum, formic acid
Any of solution or ammonium chloride solution, the pH of the acid solution is 1-3.The addition of acid solution is reducing metal
3-6 times of quality of powder, to ensure the abundant activation to reducing metal powder.
Preferably, in the step (1), the alkaline solution includes ammonia spirit or sodium hydroxide solution, the alkalescence
The pH of solution is 13-14.The addition of alkaline solution is 3-6 times of quality of reducing metal powder, to ensure to reproducibility gold
Belong to the abundant activation of powder.
, can be by being filtrated to get activated metal powder in the step (1), the reducing metal powder after preferably filtering is used
Washing lotion is washed in neutrality, is then dried in vacuo again.
In step (2), the chemical compounds I be from using threonine as raw material produce 4-AA during obtain contain compound
It is isolated in I reaction solution.
The process route that 4-AA is produced using threonine as raw material is as follows：
It can be seen that by above-mentioned process route, during 4-AA traditional handicraft is produced as raw material using threonine, generate
Intermediate compound I.
In the step (2), the chemical compounds I can produce (3R, 4R) -4- acetyl oxygen from by raw material of threonine
Obtained during base -3- [(R) -1- tertiary butyl dimethyl Sis generation-ethyl] -2- aza cyclo-butanones (i.e. 4-AA), can also
Obtained from other approach.At present, the acquisition of chemical compounds I can only obtain during 4-AA is produced as raw material using threonine.
The present invention is primarily to solve that ozonization liquid is reduced to obtain 4- during producing 4-AA as raw material using threonine
Waste water pollution problem during AA, therefore the chemical compounds I obtained during 4-AA is produced as raw material using threonine can be used directly.
I.e. during 4-AA is produced as raw material using threonine, after obtaining the reaction solution containing chemical compounds I, chemical compounds I is extracted
Separation, obtains chemical compounds I, then chemical compounds I is dissolved in solvent (such as methanol) and obtains the solution of chemical compounds I, to chemical combination
Ozone is passed through in the solution of thing I catalysis oxidation is carried out to it, obtain ozonization liquid, then with the step of method one of the invention also
Former ozonization liquid, 4-AA is obtained, i.e., the step for the two step reduction present invention that part will be reduced in conventional processing routes is also
Originally replace.
Traditional technique that 4-AA is produced using threonine as raw material is ripe, and equipment and flow have all formd industry
Change the scale produced greatly, reduction part progress of the present invention only to the traditional handicraft such as improvement of the present invention, can not only reduce generation
Wastewater flow rate, make caused by do not contain ammonia nitrogen and sulphur in waste water, COD value is relatively low, while also can directly continue to use the life of traditional handicraft
Equipment and production line are produced, production equipment is avoided and produces the large-scale redevelopment of circuit, reduce the fund input that technique change is brought.
Preferably, in the step (2), oxidizing reaction temperature is -30-0 DEG C, and oxidation time is 5-30 hours.With
Ensure the abundant progress of oxidation reaction, ensure 4-AA yield.The intake of ozone is defined completely by raw material reaction.
Using the progressively disappearance of thin-layer chromatography (TLC detections) observation raw material spot come the oxidation reaction in judgment step (2)
Whether complete.
Preferably, in the step (3), reduction reaction temperature is -25-45 DEG C, preferably -10-10 DEG C, such as 0 DEG C；Reduction
Reaction time is 0.5-5h.To ensure that reduction reaction is fully carried out, 4-AA yield is improved.
Preferably, in the step (3), the mol ratio of the activated metal powder and the chemical compounds I is 10-70:1,
It is preferred that 10-25:1, further preferred 11:1, to ensure the abundant reduction to ozonization liquid, improve 4-AA yield.In order to
Ensure fully reduction, the addition of metal dust is generally excess, and excessive metal dust does not almost have to reduction reaction
Adverse effect.
It is that the reacting liquid filtering after reduction reaction, filtrate decompression distillation, obtained solvent are added into water in the step (3)
Crystallization, and then obtain 4-AA's.Recyclable reducing metal powder during filtering, simple process (such as cleaning, drying) are recycled afterwards
Use, reduce cost.Pressure in vacuum distillation process is arranged to 60-80 DEG C, such as 70 DEG C.
Preferably, re-crystallization step (4) is also included after step (3).Preferably, in the re-crystallization step (4), tie again
Brilliant solvent is low polarity alkane solvent, including in pentane, normal heptane, isoheptane, normal octane, isooctane or n-hexane
It is one or more.
The beneficial effects of the present invention are：
It is that raw material produces (3R, 4R) -4- acetoxy-3s-[(R) -1- tertiary butyl dimethyl Si generation-second in chemical compounds I
Base] during -2- aza cyclo-butanones (i.e. 4-AA), organic reducing agent sodium thiosulfate and thiocarbamide are replaced using inorganic reducing agent
Being reduced, sulfur content drops to 0 by original 8wt% in caused waste water, and ammonia nitrogen amount drops to 0 by original 1.6wt%,
COD value drops to below 100mg/L by original more than 2000mg/L, it is easier to handles, and cost for wastewater treatment reduces by 80%
More than, 4-AA yields bring up to 95% by original 41.8%, have significant environmental protection and economic value.
Embodiment
Technical scheme and its effect are described further below by way of specific embodiment.Following examples are only
For illustrating present disclosure, the protection domain that is not intended to limit the invention.Design using the present invention is entered to the present invention
Capable simple change is all in the scope of protection of present invention.
Embodiment 1
(1) 100g mesh numbers are placed in 0.5mol/L NH for the zinc powder of 100 mesh4Activated in the Cl aqueous solution, stirring at normal temperature 2 is small
When, filtering, distillation are washed in neutrality, and depressurize 70 DEG C of vacuum drying, obtain activated zinc powder, standby；
(2) 20.0 grams of chemical compounds I is added in 250ml there-necked flask, methanol 150ml is added, stirs to clarify at room temperature
(solution for obtaining chemical compounds I), system temperature is down to -20 DEG C, is passed through ozone reaction, between -20--15 DEG C of keeping temperature,
TLC detections reaction to raw material point disappears (obtaining ozonization liquid), and the activated zinc powder that step (1) obtains slowly is added portionwise
35g carries out reduction reaction, is to slowly warm up to 0 DEG C, reacts 1.5 hours, that is, obtains mixed liquor；
(3) mixed liquor for obtaining step (2) filters, and washs filter cake with a small amount of methanol, filtrate decompression distillation, obtains
130ml methanol, distilled water 200ml is added thereto, stood, separate out crystal, filter to obtain 4-AA crude products；
(4) the 4-AA crude products that step (3) obtains are recrystallized with n-hexane, obtains 4-AA.
4-AA yield is 92wt%, and caused waste water about 200g (can convert 20 tons of waste water/ton product), sulphur in waste water
Content is 0, and ammonia nitrogen amount is 0, and COD value is less than 100mg/L.
Embodiment 2
(1) 100g mesh numbers are placed in the 0.5mol/L HAc aqueous solution for the iron powder of 80 mesh and activated, 50 DEG C are stirred 2 hours,
Filtering, distillation are washed in neutrality, and depressurize 70 DEG C of vacuum drying, obtain activation iron powder, standby；
(2) 20.0 grams of chemical compounds I is added in 250ml there-necked flask, methanol 150ml is added, stirs to clarify at room temperature
(solution for obtaining chemical compounds I), system temperature is down to -20 DEG C, is passed through ozone reaction, between -20--15 DEG C of keeping temperature,
TLC detections reaction to raw material point disappears (obtaining ozonization liquid), and the activation iron powder that step (1) obtains slowly is added portionwise
23g carries out reduction reaction, is to slowly warm up to 0 DEG C, reacts 2.5 hours, that is, obtains mixed liquor；
(3) mixed liquor for obtaining step (2) filters, and washs filter cake with a small amount of methanol, filtrate decompression distillation, obtains
130ml methanol, distilled water 200ml is added thereto, stood, separate out crystal, filter to obtain 4-AA crude products；
(4) the 4-AA crude products that step (3) obtains are recrystallized with n-hexane, obtains 4-AA.
4-AA yield is 94wt%, and caused waste water about 200g (can convert 20 tons of waste water/ton product), sulphur in waste water
Content is 0, and ammonia nitrogen amount is 0, and COD value is less than 100mg/L.
Embodiment 3
(1) 80g mesh numbers are placed in 0.5mol/L NH for the aluminium powder of 100 mesh3·H2Activated in the O aqueous solution, 50 DEG C of stirrings 2
Hour, filtering, distillation are washed in neutrality, and depressurize 70 DEG C of vacuum drying, obtain activation aluminium powder, standby；
(2) 20.0 grams of chemical compounds I is added in 250ml there-necked flask, methanol 150ml is added, stirs to clarify at room temperature
(solution for obtaining chemical compounds I), system temperature is down to -20 DEG C, is passed through ozone reaction, between -20--15 DEG C of keeping temperature,
TLC detections reaction to raw material point disappears (obtaining ozonization liquid), and the activation aluminium powder that step (1) obtains slowly is added portionwise
20g carries out reduction reaction, is to slowly warm up to 0 DEG C, reacts 1.5 hours, that is, obtains mixed liquor；
(3) mixed liquor for obtaining step (2) filters, and washs filter cake with a small amount of methanol, filtrate decompression distillation, obtains
130ml methanol, distilled water 200ml is added thereto, stood, separate out crystal, filter to obtain 4-AA crude products；
(4) the 4-AA crude products that step (3) obtains are recrystallized with n-hexane, obtains 4-AA.
4-AA yield is 95wt%, and caused waste water about 200g (can convert 20 tons of waste water/ton product), sulphur in waste water
Content is 0, and ammonia nitrogen amount is 0, and COD value is less than 100mg/L.
Embodiment 4
(1) 120g mesh numbers are placed in the 0.5mol/L NaOH aqueous solution for the nickel powder of 180 mesh and activated, stirring at normal temperature 2 is small
When, filtering, distillation are washed in neutrality, and depressurize 70 DEG C of vacuum drying, obtain activation nickel powder, standby；
(2) 20.0 grams of chemical compounds I is added in 250ml there-necked flask, methanol 150ml is added, stirs to clarify at room temperature
(solution for obtaining chemical compounds I), system temperature is down to -20 DEG C, is passed through ozone reaction, between -20--15 DEG C of keeping temperature,
TLC detections reaction to raw material point disappears (obtaining ozonization liquid), and the activation nickel powder that step (1) obtains slowly is added portionwise
45g carries out reduction reaction, is to slowly warm up to 0 DEG C, reacts 1.5 hours, that is, obtains mixed liquor；
(3) mixed liquor for obtaining step (2) filters, and washs filter cake with a small amount of methanol, filtrate decompression distillation, obtains
130ml methanol, distilled water 200ml is added thereto, stood, separate out crystal, filter to obtain 4-AA crude products；
(4) the 4-AA crude products that step (3) obtains are recrystallized with n-hexane, obtains 4-AA.
4-AA yield is 85wt%, and caused waste water about 200g (can convert 20 tons of waste water/ton product), sulphur in waste water
Content is 0, and ammonia nitrogen amount is 0, and COD value is less than 100mg/L.
Embodiment 5
(1) 110g mesh numbers are placed in 1.5mol/L HCl/water solution for the glass putty of 80 mesh and activated, stirring at normal temperature 5 hours,
Filtering, distillation are washed in neutrality, and depressurize 70 DEG C of vacuum drying, obtain activation glass putty, standby；
(2) 20.0 grams of chemical compounds I is added in 250ml there-necked flask, methanol 150ml is added, stirs to clarify at room temperature
(solution for obtaining chemical compounds I), system temperature is down to -20 DEG C, is passed through ozone reaction, between -20--15 DEG C of keeping temperature,
TLC detections reaction to raw material point disappears (obtaining ozonization liquid), and the activation glass putty that step (1) obtains slowly is added portionwise
58g carries out reduction reaction, is to slowly warm up to 0 DEG C, reacts 1.5 hours, that is, obtains mixed liquor；
(3) mixed liquor for obtaining step (2) filters, and washs filter cake with a small amount of methanol, filtrate decompression distillation, obtains
130ml methanol, distilled water 200ml is added thereto, stood, separate out crystal, filter to obtain 4-AA crude products；
(4) the 4-AA crude products that step (3) obtains are recrystallized with n-hexane, obtains 4-AA.
4-AA yield is 78wt%, and caused waste water about 200g (can convert 20 tons of waste water/ton product), sulphur in waste water
Content is 0, and ammonia nitrogen amount is 0, and COD value is less than 100mg/L.
Comparative example 1
20.0 grams of chemical compounds I is added in 250ml there-necked flask, methanol 150ml is added, stirs to clarify at room temperature (i.e.
Obtain the solution of chemical compounds I), system temperature is down to -20 DEG C, is passed through ozone reaction, between -20--15 DEG C of keeping temperature, TLC
Detection reaction to raw material point disappears (obtaining ozonization liquid), and 30% sodium thiosulfate is added dropwise in subsequent phase reaction system
Solution 110ml, 0 DEG C is stirred 1 hour after dripping off, and thiocarbamide 11.5g is added portionwise, and is warming up to 40 DEG C and is reacted 2 hours, after reaction terminates
Decompression steams most of methanol, adds distilled water 200ml, crystallization, filters, crude product is recrystallized with n-hexane, produces 4-AA, yield
90wt%.Caused waste water about 200g (can convert 20 tons of waste water/ton product), and sulfur content is 8wt% in waste water, and ammonia nitrogen amount is
1.6wt%, COD value are more than 2000mg/L.
By the product 4-AA obtained in above-described embodiment 1-5 and comparative example 1, composed by nuclear-magnetism carbon (13C-NMR), hydrogen
Spectrum (1H-NMR), infrared (IR (KBr)), optical activity ([α]20 D) and fusing point (M.P.) test carried out structural identification, and and 4-AA
The appearance time that standard items have carried out HPLC compares, and all information are consistent with 4-AA standard items.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 ° of (C=1.0, CHCl3)；
M.P.：104℃.
From the results contrast of embodiment 1-5 and comparative example 1, in method of the invention, 4-AA yields can reach
95wt%, and sulfur content is 0 in caused waste water, ammonia nitrogen amount is 0, COD value is less than 100mg/L, relative to the waste water of comparative example 1
Middle sulfur content is 8wt%, ammonia nitrogen amount is 1.6wt%, COD value is more than 2000mg/L, and caused waste water is more in method of the invention
It is easily processed, and processing cost is low.
Claims (10)
1. a kind of inorganic reducing agent reduction prepares (3R, 4R) -4- acetoxy-3s-[(R) -1- tertiary butyl dimethyl Si generation-second
Base] -2- aza cyclo-butanones method, it is characterised in that the inorganic reducing agent is reducing metal powder, and methods described includes
Following steps：
(1) pretreatment of inorganic reducing agent：Reducing metal powder is placed in acid or alkaline solution and activated, obtains activated metal
Powder；
(2) ozone progress oxidation reaction is passed through into the solution of chemical compounds I and obtains ozonization liquid；
(3) the activated metal powder that step (1) obtains is added in the ozonization liquid of step (2) and carries out reduction reaction, i.e.,
Obtain (3R, 4R) -4- acetoxy-3s-[(R) -1- tertiary butyl dimethyl Sis generation-ethyl] -2- aza cyclo-butanones；
Wherein, the structural formula of chemical compounds I is as follows：
2. according to the method for claim 1, it is characterised in that the reducing metal powder include iron, nickel, zinc, tin or
Any of aluminium is a variety of；Preferably, the mesh number of the reducing metal powder is 50-300 mesh.
3. according to the method for claim 1, it is characterised in that in the step (2), oxidizing reaction temperature is -30-0 DEG C,
Oxidation time is 5-30 hours.
4. according to the method for claim 1, it is characterised in that in the step (3), the activated metal powder with it is described
The mol ratio of chemical compounds I is 10-25:1.
5. according to the method for claim 4, it is characterised in that in the step (3), reduction reaction temperature is -25-45
DEG C, preferably -10-10 DEG C；The reduction reaction time is 0.5-5h.
6. according to the method any one of claim 1-5, it is characterised in that in the step (1), activation temperature 0-
100 DEG C, soak time 0.5-8h.
7. according to the method for claim 6, it is characterised in that in the step (1), it is molten that the acid solution includes hydrochloric acid
Any of liquid, sulfuric acid solution, acetum, formic acid solution or ammonium chloride solution, the pH of the acid solution is 1-3.
8. according to the method for claim 6, it is characterised in that in the step (1), it is molten that the alkaline solution includes ammoniacal liquor
Liquid or sodium hydroxide solution, the pH of the alkaline solution is 13-14.
9. according to the method for claim 1, it is characterised in that also include re-crystallization step (4) after step (3).
10. according to the method for claim 8, it is characterised in that in the re-crystallization step (4), the solvent of recrystallization
For low polarity alkane solvent, including one kind or more in pentane, normal heptane, isoheptane, normal octane, isooctane or n-hexane
Kind.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113549102A (en) * | 2021-09-22 | 2021-10-26 | 凯莱英医药集团（天津）股份有限公司 | Method for removing p-methoxyphenyl protecting group on amide group |
| CN115385950A (en) * | 2022-10-27 | 2022-11-25 | 天津凯莱英医药科技发展有限公司 | System and method for preparing 4-acetoxyazetidinone through continuous ozone oxidation |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1120834A (en) * | 1993-12-28 | 1996-04-17 | 大塚化学株式会社 | Ozonide reducing agent |
| CN101265271A (en) * | 2008-04-30 | 2008-09-17 | 寿光富康制药有限公司 | Method for synthesizing penem-like pharmaceutical intermediate 4AA |
| CN101407486A (en) * | 2008-11-18 | 2009-04-15 | 浙江新东港药业股份有限公司 | Process for synthesizing 4- acetoxy-2-azetidinone |
| CN102336696A (en) * | 2011-07-15 | 2012-02-01 | 浙江海翔川南药业有限公司 | Intermediate for synthesizing 4-AA and preparation method and application thereof |
| CN102432632A (en) * | 2011-09-16 | 2012-05-02 | 上海悦昂化学有限公司 | Method for preparing (3R,4R)-3-[(1R)tert-butyl-dimethyl-silyloxyethyl]-4-acetoxyl-2-azetidinone |
-
2016
- 2016-08-17 CN CN201610683079.1A patent/CN107759626B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1120834A (en) * | 1993-12-28 | 1996-04-17 | 大塚化学株式会社 | Ozonide reducing agent |
| CN101265271A (en) * | 2008-04-30 | 2008-09-17 | 寿光富康制药有限公司 | Method for synthesizing penem-like pharmaceutical intermediate 4AA |
| CN101407486A (en) * | 2008-11-18 | 2009-04-15 | 浙江新东港药业股份有限公司 | Process for synthesizing 4- acetoxy-2-azetidinone |
| CN102336696A (en) * | 2011-07-15 | 2012-02-01 | 浙江海翔川南药业有限公司 | Intermediate for synthesizing 4-AA and preparation method and application thereof |
| CN102432632A (en) * | 2011-09-16 | 2012-05-02 | 上海悦昂化学有限公司 | Method for preparing (3R,4R)-3-[(1R)tert-butyl-dimethyl-silyloxyethyl]-4-acetoxyl-2-azetidinone |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113549102A (en) * | 2021-09-22 | 2021-10-26 | 凯莱英医药集团（天津）股份有限公司 | Method for removing p-methoxyphenyl protecting group on amide group |
| CN115385950A (en) * | 2022-10-27 | 2022-11-25 | 天津凯莱英医药科技发展有限公司 | System and method for preparing 4-acetoxyazetidinone through continuous ozone oxidation |
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