CN109053793B - Method for preparing penem drug intermediate 4-AA by removing N-alkyl through photocatalysis - Google Patents
Method for preparing penem drug intermediate 4-AA by removing N-alkyl through photocatalysis Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 33
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 23
- 238000007146 photocatalysis Methods 0.000 title claims abstract description 20
- 230000001699 photocatalysis Effects 0.000 title claims abstract description 20
- 229940079593 drug Drugs 0.000 title claims abstract description 11
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000004408 titanium dioxide Substances 0.000 claims abstract description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000004809 thin layer chromatography Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims abstract description 10
- 239000008367 deionised water Substances 0.000 claims abstract description 9
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 9
- 238000005286 illumination Methods 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000001953 recrystallisation Methods 0.000 claims abstract description 9
- 230000008034 disappearance Effects 0.000 claims abstract description 7
- 238000004821 distillation Methods 0.000 claims abstract description 7
- 239000004473 Threonine Substances 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- 229960002898 threonine Drugs 0.000 claims abstract description 5
- 230000001678 irradiating effect Effects 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- 238000005119 centrifugation Methods 0.000 claims abstract description 3
- 239000000463 material Substances 0.000 claims abstract description 3
- 238000005374 membrane filtration Methods 0.000 claims abstract description 3
- 238000007670 refining Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 239000000047 product Substances 0.000 claims description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 230000005587 bubbling Effects 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052753 mercury Inorganic materials 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 230000020335 dealkylation Effects 0.000 claims description 2
- 238000006900 dealkylation reaction Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 238000001514 detection method Methods 0.000 abstract description 7
- 239000002351 wastewater Substances 0.000 abstract description 7
- 230000007547 defect Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- SOQBVABWOPYFQZ-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical compound [O-2].[O-2].[Ti+4] SOQBVABWOPYFQZ-UHFFFAOYSA-N 0.000 description 5
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000110 cooling liquid Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 239000002699 waste material Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 description 1
- 229960003169 biapenem Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- 229960000379 faropenem Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- -1 methoxyphenyl Chemical group 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229950011346 panipenem Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 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
- 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)
- Catalysts (AREA)
Abstract
A method for preparing a penem drug intermediate 4-AA by removing N-alkyl through photocatalysis comprises the following preparation steps: preparing a compound I into a solution by using an alcohol solvent or an alcohol aqueous solution;adding a titanium dioxide catalyst into the solution in the step (1); irradiating the reaction material in the step (2) by using an ultraviolet lamp, controlling the temperature within 10 ℃, and then controlling the illumination reaction time according to the disappearance speed of the raw material points by thin layer chromatography (TLC detection); after the reaction is finished, the titanium dioxide catalyst is separated out through membrane filtration or centrifugation, part of solvent is recovered through reduced pressure distillation, then deionized water is added, a product is separated out, and the target product is obtained through recrystallization and refining. The method can overcome the defect that the last step of removing N-alkyl in the preparation of 4-AA by an L-threonine route is complex, is simple and efficient, has no metal pollution and no wastewater discharge, reduces the synthesis cost of 4-AA, and has obvious effect on reducing the environmental pressure; the reaction equation is as follows:
Description
the technical field is as follows:
the invention relates to beta lactam drugs, in particular to the production field of penem antibiotics. In particular to a method for preparing a penem antibiotic intermediate (3R, 4R) -4-acetoxyl-3- [ (R-1-tert-butyl dimethyl silicon oxo-ethyl) -2-azetidinone (namely 4-AA or 4-AA) by titanium dioxide catalytic ultraviolet irradiation C-N bond rupture.
Background art:
the penem medicine is a novel beta lactam antibiotic. The penem medicines in the current market comprise imipenem, panipenem, faropenem, ertapenem, biapenem and the like. 4-AA is a key intermediate for synthesizing all penem medicines, is a mother nucleus of the penem medicines and plays a role in the synthesis related bonds of the penem medicines. The most mature route for synthesizing 4-AA in the market at present is to use L-threonine as a raw material, obtain an intermediate compound I after multi-step reaction, and then carry out removal reaction on N-alkyl (methoxyphenyl) in the compound I to finally obtain 4-AA (M.Shiowuki, Tetrahedron,1984,40(10): 1795-. In actual production, the method for removing the compound I includes an ozone method and a cerium ammonium nitrate method. In the ammonium cerium nitrate method, 5 times of ammonium cerium nitrate is used, a large amount of waste residue and waste water are generated in the reaction, a large amount of substrates are adsorbed, the separation yield is low, and the pollution is serious. The ozone method is carried out in two steps, after the ozone is introduced for reaction, excessive sodium thiosulfate solution is added for reduction, and excessive thiourea is added for continuous reduction, so that a large amount of wastewater is generated during the preparation of 4AA, the smell is large, and the environmental protection pressure is large.
The invention content is as follows:
aiming at the defects in the prior art, the invention provides the method for preparing the penem medicine intermediate 4-AA by removing the N-alkyl through photocatalysis, which can overcome the defect that the last step of removing the N-alkyl in the preparation of the 4-AA through an L-threonine route is complex, is simple and efficient, has no metal pollution and no wastewater discharge, reduces the synthesis cost of the 4-AA, and has a remarkable effect on reducing the environmental pressure.
In order to solve the technical problems, the invention adopts the technical scheme that: a method for preparing a penem drug intermediate 4-AA by removing N-alkyl through photocatalysis has the following reaction equation:
the method for preparing the penem medicine intermediate 4-AA by removing N-alkyl through photocatalysis comprises the following specific preparation processes: taking compound I synthesized by taking L-threonine as a raw material as a starting material, and adding titanium dioxide (TiO)2) Under catalysis, ultraviolet irradiation and dealkylation protection to obtain the target compound 4-AA.
Specifically, the method for preparing the penem drug intermediate 4-AA by removing N-alkyl through photocatalysis comprises the following specific preparation steps:
1) preparing a compound I into a solution by using an alcohol solvent or an alcohol aqueous solution;
2) adding a titanium dioxide catalyst into the solution in the step (1);
3) irradiating the reaction material in the step (2) by using an ultraviolet lamp, controlling the temperature within 10 ℃, and then controlling the illumination reaction time according to the disappearance speed of the raw material points by thin layer chromatography (TLC detection);
4) after the reaction is finished, the titanium dioxide catalyst is separated out through membrane filtration or centrifugation, part of solvent is recovered through reduced pressure distillation, then deionized water is added, a product is separated out, and the target product is obtained through recrystallization and refining.
Wherein the alcohol solvent used in step (1) for dissolving compound I, such as methanol, ethanol solvent; the alcohol in the aqueous alcohol solution is methanol or ethanol. The thinner the concentration of the solution prepared, the better the water content in the solution (because water has a reaction promoting effect in titanium dioxide photocatalysis). The alcoholic solution of compound I is generally formulated to a solution concentration of 0.5% to 5% by mass (i.e., the mass percentage content of compound I in the mixed solution). The aqueous alcoholic solution is prepared by adding water to compound I, and gradually adding methanol while stirring until the solution is clear.
Wherein in the step (2), the titanium dioxide catalyst is rutile crystal type titanium dioxide powder, preferably more than 1000 mesh titanium dioxide powder, preferably rutile titanium dioxide with the particle size of 100nm-1000 nm. The amount of catalyst used is 0.1-0.5% of compound I (0.1-0.5% by weight of compound I), the catalyst being suspended in the solution. The finer the titanium dioxide powder is, the better the effect is if the titanium dioxide powder is in the nanometer range.
In the operation step (3), the ultraviolet light source is generally a high-pressure mercury lamp or an LED lamp with a wavelength of more than 300 nm. The light irradiation reaction temperature is preferably controlled within 5 ℃; excessive temperatures can break other chemical bonds of the compound and produce byproducts. The reaction temperature can be controlled by a jacket device, and the structure can realize cooling water circulation so as to reduce the reaction temperature.
In the above operation step (4), the solvent used for recrystallization is a low-polarity solvent, such as one or more of n-hexane, n-pentane, n-heptane, etc.
In the operation step (4), after the reaction is finished, most of the solvent can be directly distilled and recovered by only using alcohol as the solvent, then deionized water is added to precipitate the product, and the product is filtered and recrystallized. And (3) directly distilling the alcohol-water mixed solvent until a large amount of precipitate is separated out, then filtering, and recrystallizing to obtain the product.
Stirring or introducing nitrogen gas in a bubbling mode to disturb the reaction in the whole system reaction so as to increase the reaction rate.
The light irradiation reaction time is controlled by the speed of disappearance of the raw material point by thin layer chromatography (TLC detection) in the reaction process until the disappearance of the raw material point is the reaction end point.
The invention has the advantages and beneficial effects that:
1. the method adopts the photocatalysis method for removing the N-alkyl for the first time, has simple operation, adopts less solvent in the actual operation process, and does not need a large amount of ammonium ceric nitrate, thereby overcoming the technical defects of generating a large amount of waste residue and waste water in the reaction, absorbing a large amount of substrates, having low separation yield and serious pollution; meanwhile, the technical defects that excessive sodium thiosulfate solution is added for reduction and excessive thiourea is added for continuous reduction in an ozone method to generate a large amount of wastewater, the smell is large, the environmental protection pressure is large and the like are overcome.
2. In addition, the method has the beneficial effects that the original conventional method for removing N-alkyl by using a chemical reagent is avoided, and the method for breaking C-N bonds by using nano titanium dioxide photocatalysis is used. The method does not basically generate waste water, waste gas and waste residue, is a pure green method, has obvious environmental protection and economic values, and has high yield of target products.
The specific implementation mode is as follows:
the present invention is further illustrated by the following examples, which should be construed as limiting the scope of the invention.
Example 1
Firstly, 1g of compound I is weighed, then 100g of methanol is added, the mixture is stirred and dissolved completely, then the mixture is added into a 250ml reaction tube with a jacket, and then 0.1g of nano titanium dioxide is added. Then introducing nitrogen, slightly bubbling, opening cooling liquid, cooling to 0 ℃, and irradiating by a 500w high-pressure mercury lamp; TLC detection reaction is carried out until the raw material point disappears, about 2 hours, illumination is finished, reaction liquid is obtained, and methanol is recovered by reduced pressure distillation; and adding 20ml of deionized water into the reduced pressure slurry, filtering, and adding n-hexane into filter residues for recrystallization to obtain the product 4-AA. Yield WT 96% (96% yield).
Example 2
First, 1g of compound I was added, then 100g of methanol was added, dissolved with stirring, and added to a 250ml jacketed reaction tube, and then 0.1g of nano-titanium dioxide was added. Introducing nitrogen, slightly bubbling, opening the cooling liquid, and cooling to 0 ℃. 40w360nm wavelength LED lamp illumination. TLC detection reaction is carried out until the raw material point disappears, about 5h, illumination is finished, reaction liquid is obtained, and methanol is recovered by reduced pressure distillation. And adding 20ml of deionized water into the reduced pressure slurry, filtering, and adding n-hexane into filter residues for recrystallization to obtain the product 4-AA. Yield WT 98% (98% yield).
Example 3
5g of the compound I, 100g of methanol, stirring and dissolving are added into a 250ml reaction tube with a jacket, and then 0.5g of nano titanium dioxide is added. Introducing nitrogen, slightly bubbling, opening the cooling liquid, and cooling to 0 ℃. 500w high-pressure mercury lamp. TLC detection reaction is carried out until the raw material point disappears, about 3h, illumination is finished, reaction liquid is obtained, and methanol is recovered by reduced pressure distillation. And adding 20ml of deionized water into the reduced pressure slurry, filtering, and adding n-hexane into filter residues for recrystallization to obtain the product 4-AA. Yield WT 90% (90% yield).
Example 4
5g of the compound I, 100g of methanol, stirring and dissolving are added into a 250ml reaction tube with a jacket, and then 0.5g of nano titanium dioxide is added. Introducing nitrogen, slightly bubbling, opening the cooling liquid, and cooling to 0 ℃. 40w360nm wavelength LED lamp illumination. . TLC detection reaction is carried out until the raw material point disappears, about 6 hours, illumination is finished, reaction liquid is obtained, and methanol is recovered by reduced pressure distillation. And adding 20ml of deionized water into the reduced pressure slurry, filtering, and adding n-hexane into filter residues for recrystallization to obtain the product 4-AA. Yield WT 98% (98% yield).
The product is compared with a standard 4-AA sample by H-NMR, and the information is consistent with the standard sample, so that the method provided by the invention has the advantages that the target product is obtained, the yield is high, the preparation method is simple, and the pollution is small:
H-NMR：
0.01(d,6H),0.8(s,9H),1.20(d,3H),2.04(s,3H),3.1(t,1H),4.14(m,1H),5.76(s,1H),7.04(s,1H)M.P:104℃。
Claims (10)
1. a method for preparing a penem drug intermediate 4-AA by removing N-alkyl through photocatalysis is characterized by comprising the following steps: the reaction equation is as follows:
2. the method for preparing penem medicine intermediate 4-AA by removing N-alkyl through photocatalysis according to claim 1, which is characterized in that: the specific preparation process comprises the following steps: synthesizing a compound I by taking L-threonine as a raw material, and then carrying out ultraviolet irradiation and dealkylation protection under the catalysis of titanium dioxide to obtain a target compound 4-AA.
3. The method for preparing penem medicine intermediate 4-AA by removing N-alkyl through photocatalysis according to claim 2, which is characterized in that: the preparation method comprises the following specific steps:
1) preparing a compound I into a solution by using an alcohol solvent or an alcohol aqueous solution;
2) adding a titanium dioxide catalyst into the solution in the step (1);
3) irradiating the reaction material in the step (2) by using an ultraviolet lamp, controlling the temperature within 10 ℃, and controlling the illumination reaction time by detecting the disappearance speed of the raw material point by thin-layer chromatography (TLC);
4) after the reaction is finished, the titanium dioxide catalyst is separated out through membrane filtration or centrifugation, part of solvent is recovered through reduced pressure distillation, then deionized water is added, the product is separated out, and the product is obtained through recrystallization and refining.
4. The method for preparing penem medicine intermediate 4-AA by removing N-alkyl under photocatalysis according to claim 3, which is characterized in that: in the step (1), the alcohol used for dissolving the compound I is methanol or ethanol.
5. The method for preparing penem medicine intermediate 4-AA by removing N-alkyl under photocatalysis according to claim 4, which is characterized in that: the alcoholic solution of the compound I has a solution concentration of 0.5 to 5 percent by mass.
6. The method for preparing penem medicine intermediate 4-AA by removing N-alkyl under photocatalysis according to claim 3, which is characterized in that: in the step (2), the titanium dioxide catalyst is rutile crystal form titanium dioxide powder, and the particle size of the titanium dioxide powder is larger than 1000 meshes; the titanium dioxide powder is rutile titanium dioxide with the particle size of 100nm-1000 nm; the dosage of the catalyst is 0.1-0.5%.
7. The method for preparing penem medicine intermediate 4-AA by removing N-alkyl under photocatalysis according to claim 3, which is characterized in that: in the step (3), the light source of the ultraviolet lamp is a high-pressure mercury lamp or an LED lamp with the wavelength being more than 300 nm; the reaction temperature of light irradiation is controlled within 5 ℃.
8. The method for preparing penem medicine intermediate 4-AA by removing N-alkyl under photocatalysis according to claim 3, which is characterized in that: in the step (4), the solvent adopted for recrystallization is a low-polarity solvent; the low-polarity solvent is one or more of n-hexane, n-pentane and n-heptane.
9. The method for preparing penem medicine intermediate 4-AA by removing N-alkyl under photocatalysis according to claim 3, which is characterized in that: in the operation step (4), after the reaction is finished, most of the solvent can be directly distilled and recovered by only using alcohol as the solvent, then deionized water is added to precipitate the product, and the product is filtered and recrystallized. And (3) directly distilling the alcohol-water mixed solvent until a large amount of precipitate is separated out, then filtering, and recrystallizing to obtain the product.
10. The method for preparing penem medicine intermediate 4-AA by removing N-alkyl under photocatalysis according to claim 3, which is characterized in that: stirring or introducing nitrogen for bubbling in the reaction process to disturb the reaction so as to increase the reaction rate; in the reaction process, the light irradiation reaction time is controlled by the disappearance speed of the thin-layer chromatography raw material point until the disappearance of the raw material point is the reaction end point.
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| CN112010889B (en) * | 2020-09-14 | 2023-09-19 | 中国科学院上海营养与健康研究所 | Preparation method of 4-hydroxy-2-azetidinone compound |
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| JP2002281993A (en) * | 2001-03-27 | 2002-10-02 | Toray Ind Inc | Method for producing shikimic acid |
| CN102936262A (en) * | 2012-11-07 | 2013-02-20 | 凯莱英医药集团（天津）股份有限公司 | Preparation method for imipenem medicine intermediate 4AA |
| CN108069998A (en) * | 2017-12-29 | 2018-05-25 | 浙江工商大学 | A kind of synthetic method of penem-like pharmaceutical intermediate |
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| JP2002281993A (en) * | 2001-03-27 | 2002-10-02 | Toray Ind Inc | Method for producing shikimic acid |
| CN102936262A (en) * | 2012-11-07 | 2013-02-20 | 凯莱英医药集团（天津）股份有限公司 | Preparation method for imipenem medicine intermediate 4AA |
| CN108069998A (en) * | 2017-12-29 | 2018-05-25 | 浙江工商大学 | A kind of synthetic method of penem-like pharmaceutical intermediate |
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