CN109879904B - Preparation method of penem medicine intermediate 4-AA precursor and intermediate 4-AA - Google Patents
Preparation method of penem medicine intermediate 4-AA precursor and intermediate 4-AA Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 48
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 title claims abstract description 46
- 239000002243 precursor Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 34
- 229940079593 drug Drugs 0.000 claims abstract description 24
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical group [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000007800 oxidant agent Substances 0.000 claims abstract description 22
- 230000001590 oxidative effect Effects 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 239000000543 intermediate Substances 0.000 claims description 49
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims 1
- 230000003115 biocidal effect Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 description 11
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 101710116957 D-alanyl-D-alanine carboxypeptidase Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 150000003952 β-lactams Chemical class 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
- 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
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 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
- 210000004027 cell Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229960002182 imipenem 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
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- XMFOQHDPRMAJNU-UHFFFAOYSA-N lead(II,IV) oxide Inorganic materials O1[Pb]O[Pb]11O[Pb]O1 XMFOQHDPRMAJNU-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 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
- 230000003287 optical effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000010405 reoxidation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a penem drug intermediate 4-AA precursor, which comprises the following steps: reacting a compound shown as a formula II in the presence of an oxidant to generate a penem drug intermediate 4-AA precursor shown as a formula I; wherein, the oxidant is ozone. The invention also provides a preparation method of the penem medicine intermediate 4-AA, (1) preparing a penem medicine intermediate 4-AA precursor shown in formula I; (2) preparing a penem medicine intermediate 4-AA by using a penem medicine intermediate 4-AA precursor shown in formula I; wherein, the step (1) adopts the method to prepare the penem medicine intermediate 4-AA precursor. The invention provides a safe and environment-friendly method for preparing a penem antibiotic intermediate compound shown as a formula I.
Description
Technical Field
The invention belongs to the field of production of beta-lactam drugs, and particularly relates to a novel key intermediate 4-AA precursor ((3R,4R) -4-acetoxyl-3- [ (R) -1-tert-butyldimethylsilyloxy-ethyl ] -N-methoxyphenyl-2-azetidinone) of a beta-lactam drug and a preparation method of the intermediate 4-AA thereof.
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 antibiotic has low toxicity to human cells, has no influence on human cells within the effective antibacterial concentration, and has the characteristics of ultra-broad spectrum, long half-life period, high-efficiency antibacterial activity and pharmacokinetics.
In the preparation process of the penem antibiotics, the key intermediate 4-AA plays a very important role, and all carbapenem drugs are further prepared through the key intermediate. There are various routes for preparing 4-AA, and among them, the route using threonine as a raw material has been regarded as a route in which the raw material is inexpensive and easily available. In 1984, M.Shiowuki (MAUO SHIOZAKI NOBORU ISHIDA, et al tetrahedron, 198440(10): 1795-; later, there were several reports of interest, such as Tae-subawang, et al, Korean peak Laid-Open No. 96-41141; LEE MI-JUNG et al, WO9807690A1; chromatogr.a., 1999, 832, 259; bull, koreanchem, soc, 1997, 18, 475, etc.
In all of these 4-AA preparations, the key precursor, the penem-like intermediate 4-AA precursor, commonly referred to as the oxide, is required to pass through. At present, there are two production methods of oxides, which are respectively the following two preparation methods:
the first preparation method utilizes Bayer-Virgilla oxidation to prepare oxide by inserting oxygen atom, and the second preparation method utilizes decarboxylation acetyl oxidation to prepare oxide. At present, both of these production methods face a great dilemma: the first preparation method needs to prepare the peroxyacetic acid in situ, which results in a large amount of acidic wastewater, and has high treatment difficulty and high cost; while the second preparation method requires the use of a highly toxic strong oxidant Pb3O4This is completely incompatible with green chemistry concepts and presents a high safety risk.
Based on the above discussion, there are serious environmental and safety hazards in the production of the current penem-type drug intermediate 4-AA precursor, which severely limit the production of the drug intermediate, and also generate negative uncertain factors for the long-term application of this important antibiotic, and a technical improvement on the process method is urgently needed.
Disclosure of Invention
In view of the above, the invention provides a safe and environment-friendly preparation method of a penem drug intermediate 4-AA precursor.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
the invention provides a preparation method of a penem drug intermediate 4-AA precursor, which comprises the following steps:
reacting a compound shown as a formula II in the presence of an oxidant to generate a penem drug intermediate 4-AA precursor shown as a formula I;
wherein the oxidant is ozone;
in the preparation process of the present invention, the inventors have found that the reaction rate of the system is affected by excessively low concentration of ozone, and that the yield is decreased by increasing the amount of over-oxidized products if excessively high concentration of ozone is introduced. In some specific embodiments, the volume concentration of the introduced ozone can be controlled to be 1-5%; in some preferred embodiments, the concentration of ozone is 2-4% by volume, for example, 3%. In the preparation process of the present invention, the ozone used can be obtained by a method known to those skilled in the art, for example, by electrolysis in an ozone generator.
In the invention, the compound shown in the formula II is dissolved in a mixed solvent and reacts, wherein the mixed solvent is a mixture of acetic acid and other solvents selected from dichloromethane and/or chloroform; the mixed solvent can be a mixed solvent of acetic acid and dichloromethane, a mixed solvent of acetic acid and chloroform or a mixed solvent of acetic acid, dichloromethane and chloroform. In some embodiments, the volume ratio of the acetic acid to the other solvent is 5:2 to 5:6, for example, 5: 3.
In the preparation process of the invention, the temperature of the reaction is controlled within the range of-20 ℃ to 10 ℃, preferably, within the range of-5 ℃ to 0 ℃.
In the invention, after the reaction is completed, a part of unreacted oxidant still remains in the reaction system, and in order to eliminate the influence of the unreacted oxidant on the subsequent reaction, after the reaction is completed, the residual oxidant is removed and drying treatment is carried out; for example, in some embodiments, a reducing solution is added thereto with stirring to bring the solution into sufficient contact with the residual oxidizing agent, and after standing and layering, an organic layer is obtained, which is then washed successively with saturated brine and dried over anhydrous sodium sulfate; after filtering sodium sulfate, evaporating the solvent to obtain a light yellow oily liquid which is the imipenem medicine intermediate 4-AA precursor. The above-mentioned evaporation method may be carried out by a method well known to those skilled in the art to remove the solvent, for example, distillation, etc.
In the present invention, a reducing solution is used to remove residual oxidizing agent from the system, and as is well known to those skilled in the art, a starch potassium iodide paper can be used as a method for detecting the presence of oxidizing substances; in some embodiments, the system from which the residual oxidizing agent is removed is tested for complete removal of the oxidizing agent using a potassium iodide starch test strip, and if not, the reducing solution can be added to the system until complete consumption of the oxidizing agent is detected.
In some specific embodiments, the reducing solution mentioned above may be an aqueous sodium sulfite solution with a concentration of 8% to 15%, for example, 10% by mass.
The second aspect of the invention provides a method for preparing a penem drug intermediate 4-AA, which comprises the following steps:
(1) preparing a penem medicine intermediate 4-AA precursor shown as a formula I;
(2) preparing a penem medicine intermediate 4-AA by using a penem medicine intermediate 4-AA precursor shown in formula I;
wherein, the method adopted in the step (1) is used for preparing the penem medicine intermediate 4-AA precursor shown in the formula I.
The penem medicine intermediate 4-AA obtained by the method is shown as the following formula:
in some embodiments, in the step (2), the intermediate 4-AA precursor shown in the formula I is reacted in the presence of an oxidizing agent to prepare the penem medicine intermediate 4-AA, and the reaction temperature can be controlled to be between-20 ℃ and-15 ℃; preferably, the oxidant is ozone, and the volume concentration of the ozone is 1-5%.
In the invention, in step (2), the intermediate 4-AA precursor shown in formula I is dissolved in an organic solvent and reacted, and in some specific implementations, the organic solvent is selected from methanol.
After the above reaction is completed, the residual oxidant in the system after the reoxidation reaction can be removed by post-treatment, which can be implemented by the means conventional in the art, such as: adding a sodium thiosulfate solution into the reaction solution, and stirring for 1-2 hours at 0-10 ℃; and adding thiourea into the mixture, heating to 40-50 ℃, reacting for 1-2 hours, evaporating to remove the solvent, adding distilled water into the mixture, crystallizing, filtering to obtain a crude product, and recrystallizing the crude product to obtain the penem medicine intermediate 4-AA.
In the present invention, the extent of the reaction can be determined by methods conventional in the art, and in some embodiments, the method of the present invention employs thin layer chromatography (abbreviated as TLC) in the preparation process.
By adopting the technical scheme, the method has the following technical effects:
according to the method for preparing the penem medicine intermediate 4-AA precursor, ozone is used as an oxidant for reaction, toxic and side effects are avoided, compared with other methods, a large amount of acidic wastewater and other byproducts are not generated, the green chemical concept is met, and the preparation method is safe.
Drawings
FIG. 1 is a chromatogram of the penem-type intermediate 4-AA precursor prepared in example 1.
Detailed Description
In order to better understand the technical solution of the present invention, the following examples are further provided to illustrate the present invention, but the present invention is not limited to the following examples.
The raw materials used in the examples or comparative examples are all commercial raw materials, specific information of part of the raw materials is described below (see table 1), products without marked supplier information are all reagents conventional in the art, and purity specifications are all analytical purity.
The compounds of formula II used in the following examples were prepared by the method of Tae-SubHwang, et al, Korean peak Laid-Open No.96-41141 or commercially available from Jiangsu Hankuo.
The following detection method is adopted in the following embodiments of the invention:
(1) the TCL detection method comprises the following steps: the adopted developing solvent is a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 2: 1;
(2) the purity determination method comprises the following steps: the purity of the product was determined by HPLC;
(3) the method for determining the yield comprises the following steps: actual product yield/theoretical product yield 100%;
(4) the detection method of ultraviolet-liquid phase combination comprises the following steps: detection wavelength: 254nm, flow rate: 1ml/min, the sample injection amount is 1 mu L; a chromatographic column: C184.6X 250mm, 5 μm, column temperature: at 30 ℃.
Example 1
Weighing 38.2g (0.1mol) of a compound shown as a formula II, adding the compound into a mixed solvent of 250ml dichloromethane and 150ml acetic acid, dissolving while stirring, cooling to a range of-5-0 ℃, slowly introducing ozone (the volume concentration of the ozone is 2%), and monitoring the complete reaction of raw materials by TLC after about 1 hour;
adding 200ml of sodium sulfite aqueous solution with the mass percent concentration of 10% into the mixture until the mixture does not change color in a starch potassium iodide test paper test, standing and layering the mixture to obtain an organic layer, washing the organic layer with 200ml of saturated salt water, drying the organic layer with anhydrous sodium sulfate, and filtering sodium sulfate; then distilling off the dichloromethane solvent under normal pressure distillation to obtain 38.5g of light yellow oily liquid, namely a penem drug intermediate 4-AA precursor; the purity was determined to be 98.3% and the yield 95%; after ultraviolet-liquid phase measurement, a chromatogram shown in fig. 1 is obtained, and specific information is shown in table 1.
TABLE 1
And comparing the spectrogram with a standard sample of a penem drug intermediate 4-AA precursor, wherein the peak-out time is the same, applying the spectrogram to preparation of the penem drug intermediate 4-AA, and detecting to obtain a product, namely the penem drug intermediate 4-AA.
Example 2
This example differs from example 1 in that: the mixed solvent used was 250ml of chloroform and 150ml of acetic acid, and 39.1g of a pale yellow oily liquid, which was the penem-type pharmaceutical intermediate 4-AA precursor, was obtained in 98.3% purity and 96.5% yield.
Example 3
This example differs from example 2 in that: the concentration of ozone fed was 3%, and after about 0.5 hour of feeding, TLC monitored the completion of the raw material reaction to obtain 39.3g of a pale yellow oily liquid, i.e., penem-like pharmaceutical intermediate 4-AA precursor, and the purity was 98.4% and the yield was 97.1% as measured.
Example 4
This example differs from example 2 in that: the concentration of the ozone introduced was 1%, and after about 3 hours of introduction, TLC monitored the completion of the reaction of the raw materials to obtain 28.5g of a pale yellow oily liquid, i.e., a penem-type drug intermediate 4-AA precursor, and the purity was 91% and the yield was 65.4% by detection.
Example 5
This example differs from example 2 in that: the concentration of ozone fed was 5%, and after about 0.5 hour of feeding, TLC monitored the completion of the raw material reaction to obtain 20.0g of a pale yellow oily liquid, i.e., penem-like pharmaceutical intermediate 4-AA precursor, and determined to have a purity of 73% and a yield of 36.7%.
Example 6
This example differs from example 2 in that: the reaction temperature is controlled between-15 ℃ and-10 ℃, TLC is used for monitoring the complete reaction of the raw materials after about 4 hours, 37g of light yellow oily liquid, namely the penem drug intermediate 4-AA precursor, is obtained, the purity is 96 percent and the yield is 89.2 percent.
Example 7
This example differs from example 2 in that: the reaction temperature is within the range of 5-10 ℃, TLC is used for monitoring the complete reaction of the raw materials after about 0.5 hour, 18g of light yellow oily liquid, namely the penem drug intermediate 4-AA precursor, is obtained, the purity is 88 percent and the yield is 40 percent.
The intermediate 4-AA is prepared from the penem medicine intermediate 4-AA precursor obtained in example 1 by the following method:
dissolving 20g of penem medicine intermediate 4-AA precursor by using 150ml of methanol, stirring at room temperature until the solution is clear, cooling to-20 ℃, introducing ozone with any concentration between 1 and 5 percent of volume concentration for reaction, and keeping the temperature between-20 and-15 ℃ until the TLC detection reaction is complete;
dropwise adding 110ml of 30% sodium thiosulfate solution into the reaction system, stirring for 1 hour at 0 ℃ after the dropwise adding is finished, and continuously adding 11.5g of thiourea into the reaction system in batches; heating to 40 ℃ for reaction for 2 hours, then decompressing and steaming most of methanol, adding 200ml of distilled water, crystallizing, filtering to obtain a crude product, recrystallizing the crude product with n-hexane to obtain the penem drug intermediate 4-AA, wherein the purity is 99% and the yield is 90%.
The penem medicine intermediate 4-AA obtained in the above embodiment is subjected to nuclear magnetic carbon spectrum (C:)13C-NMR), hydrogen spectrum (1H-NMR), infrared (IR (KBr)), optical rotation (. alpha.))]20 D) And a melting point (M.P.) test, wherein the specific data are shown in the specification, and the peak time comparison of HPLC is carried out on a standard sample of the intermediate 4-AA of the penem medicine, and all the information are compared with the intermediate of the penem medicineThe standards for body 4-AA were identical.
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℃。
in examples 2-7, the penem drug intermediate 4-AA is prepared by the method, and the purity and yield are shown in the following table 2 after detection.
TABLE 2
| Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | |
| Purity (%) | 99.1 | 99 | 98.1 | 95.3 | 98.5 | 96 |
| Yield (%) | 92 | 89 | 87 | 77 | 90 | 82 |
The method can efficiently prepare the penem medicine intermediate 4-AA precursor and the intermediate 4-AA thereof, and effectively solves the technical problems of large amount of acidic wastewater and high safety risk in the production process of the existing method.
It will be appreciated by those skilled in the art that modifications or adaptations to the invention may be made in light of the teachings of the present specification. Such modifications or adaptations are intended to be within the scope of the present invention as defined in the claims.
Claims (14)
1. A preparation method of a penem drug intermediate 4-AA precursor comprises the following steps:
reacting a compound shown as a formula II in the presence of an oxidant to generate a penem drug intermediate 4-AA precursor shown as a formula I;
wherein the oxidant is ozone;
the volume concentration of the ozone introduced in the preparation method is 1-5%;
the reaction temperature is controlled to be-20-10 ℃;
dissolving the compound shown in the formula II in a mixed solvent and carrying out the reaction, wherein the mixed solvent is a mixture of acetic acid and other solvents, and the other solvents are selected from dichloromethane and/or chloroform.
2. The method according to claim 1, wherein the concentration of ozone is 2 to 4% by volume.
3. The method according to claim 2, wherein the volume ratio of the acetic acid to the other solvent is 5:2 to 5: 6.
4. The method according to claim 3, wherein the volume ratio of the acetic acid to the other solvent is 5: 3.
5. The production method according to any one of claims 1 to 4, wherein the temperature of the reaction is controlled to be from-5 ℃ to 0 ℃.
6. The method according to claim 5, wherein after the reaction is completed, the residual oxidizing agent is removed and dried.
7. The process according to claim 6, wherein the reducing solution is added to the reaction mixture after completion of the reaction under stirring, the mixture is allowed to stand and separate into an organic layer, and the organic layer is washed with saturated brine and dried over anhydrous sodium sulfate in this order.
8. The method according to claim 7, wherein the reducing solution is an aqueous sodium sulfite solution having a concentration of 8 to 15% by mass.
9. A preparation method of a penem drug intermediate 4-AA is characterized by comprising the following steps:
(1) preparing a penem medicine intermediate 4-AA precursor shown as a formula I;
(2) preparing a penem medicine intermediate 4-AA by using a penem medicine intermediate 4-AA precursor shown in formula I;
wherein the penem-like pharmaceutical intermediate 4-AA precursor of formula I is prepared in step (1) by the method of any one of claims 1-8.
10. The method according to claim 9, wherein in step (2), the penem-like pharmaceutical intermediate 4-AA is prepared by reacting a penem-like pharmaceutical intermediate 4-AA precursor represented by formula I in the presence of an oxidizing agent.
11. The method of claim 10, wherein the oxidizing agent is ozone, and the concentration of ozone is 1-5% by volume.
12. The method according to claim 10, wherein in the step (2), the penem-like pharmaceutical intermediate 4-AA precursor represented by formula I is dissolved in an organic solvent and reacted.
13. The method according to claim 12, wherein the organic solvent is methanol.
14. The method according to any one of claims 10 to 13, wherein in the step (2), after the reaction is completed, a sodium thiosulfate solution is added thereto and stirred for 1 to 2 hours; and adding thiourea into the mixture, reacting for 1-2 hours, evaporating to remove the solvent, adding distilled water into the mixture, crystallizing, filtering to obtain a crude product, and recrystallizing the crude product to obtain the penem drug intermediate 4-AA.
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| 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 |
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| 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 |
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| 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 |
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