CN103539813B - A kind of preparation method of 4-AA compounds - Google Patents
A kind of preparation method of 4-AA compounds Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of 4-AA compounds. Prior art severe reaction conditions, the shortcoming such as processing procedure is loaded down with trivial details, cost is high, environmental pollution is serious, is unfavorable for industrialized production. The inventive method, taking 4-carboxyl-2-azetidinones I as raw material, at dehydrating agent N, under the condition that N ˊ-dicyclohexylcarbodiimide and oxidant Peracetic acid exist, obtains 4-AA compounds II through oxidation deacidification. Oxidative deamination process of the present invention avoids using heavy metal oxidant or catalyst, greatly reduces residual, discharge and the pollution to environment of heavy metal. The recovery and reuse easily of accessory substance in course of reaction, reduce production costs to a great extent, more outstanding aspect economy. The method reaction condition gentleness, easy and simple to handle, product is easy to separation and purification, and yield is high, is applicable to large-scale production.
Description
Technical field
The invention belongs to organic synthesis and chemical medical preparing technical field, relate to a kind of 4-acetylThe preparation method of oxygen base-2-azetidinones, specifically a kind of for the preparation of training southThe preparation method of class pharmaceutical intermediate 4-AA compounds.
Technical background
The southern class of synthetic training suc as formula the 4-AA compounds shown in IIThe important intermediate of medicine. Penem-like pharmaceutical is one group of novel beta-lactam antibiotic, isThe class antibiotic that in the antibacterials of exploitation, antimicrobial spectrum is the widest, antibacterial action is the strongest so far. FromSince finding thiomycin from 1976, the existing very large development of the research of penem-like pharmaceutical, so farTill the present, the training south of having gone on the market in the whole world mainly contains Imipenem (Imipenem), Panipenem(Panipenem), Meropenem (Meropenem), also have and much carrying out clinical testingKind. Therefore study the synthetic significant of penem-like pharmaceutical intermediate.
Synthetic method suc as formula the 4-AA compounds shown in II is groundStudy carefully always all very active, existing many documents and patent report. Wherein topmost synthetic sideMethod is to introduce carboxyl by 4 of azacyclo-s, then at Pb (OAc)4、Hg(OAc)2、Cu(OAc)2、TI(OAc)3Make Deng oxidative deamination under material effect. As: Georg etc.（GundaI.Georg;JoydeepKantandHarpalS.Gill,J.Am.Chem.Soc.1987,109,1129-1135.) report (3S, 4S)-3-[(1 ' R)-tertiary butyl dimethyl SiEthyl]-4-formoxyl-1-p-methoxyphenyl-2-aza cyclo-butanone first obtains corresponding through oxidationCarboxylic acid, then carboxylic acid is at Pb (OAc)4The lower oxidative deamination of effect obtains 4-acetoxyl group-2-azepineCyclobutanone compounds. And for example Lee, the people such as M.J. (Kwon, H.; Lee, M.J.; Lee,I．H．；Lee，S．J.;Yoon,T．H.；Hwang,T．S.Bull．KoreanChem.Soc．1997，18，475-478；LeeM.J.,etal.WO9807690(A1);Rathod,P.D., etal.WO2007004028 etc.) report the 2-azetidin keto carboxylic acid replacing with differenceEster obtains corresponding carboxylic acid through hydrolysis, and then carboxylic acid is at Pb (OAc)4The lower oxidative deamination of effect obtainsTo 4-AA compounds. In recent years, the people such as Yang Lei(CN101265271A.) also reported the R with compound (3S, 4S)-3-[(1 ')-tert-butyl group diformazanBase silica ethyl]-4-carboxyl-1-p-methoxyphenyl-2-aza cyclo-butanone is raw material, with mangano-porphyrinComplex compound is that catalyst obtains 4-AA class through oxidant oxidative deaminationCompound.
In the synthetic method of above-mentioned report major part be with metal oxide or salt participate in catalysis andOxidative deamination process, especially with lead salt Pb (AcO)4Use the most extensively. In reactionIn process, Pb (AcO)4Have catalysis and oxidation double action concurrently, after oxidation, become the lead of lower valencyCompound, cannot recover to use, and therefore the method will be brought insoluble heavy-metal residualProblem, and Pb in process3O4Consumption is excessive, and heavy metal pollution is serious, is unfavorable for environment guarantorProtect. In addition, in oxidative deamination course of reaction, also use slaine or catalysis that some is difficult to preparationAgent, this slaine or catalyst require harsh (as conditions such as anhydrous, anaerobics) to reaction condition,Expensive, and be difficult for reclaiming and reusing. In a word, said method exists reaction conditionHarshness, the shortcoming such as processing procedure is loaded down with trivial details, cost is high, environmental pollution is serious, is unfavorable for industrializationLarge production.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, through more deep research, for training southern class medicineThing intermediate 4-AA compounds provides a kind of reaction condition gentleness,High and the eco-friendly new synthetic method of yield.
The object of the invention is to disclose the important intermediate 4-synthetic for penem-like pharmaceuticalThe preparation method of acetoxy-2-azetidinone compounds (II).
The structural formula of 4-AA compounds (II) is as follows:
R in formula1For hydroxyl protecting groupWherein R3、R4、R5Be independently separatelyC1～C6 alkyl;
R2For N protecting atom base, this N protecting atom base is 4-methoxyphenyl, 4-firstBase phenyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, two (4-methoxybenzeneBase) methyl or pi-allyl.
As preferably, R1For-Si (CH3)3、-Si(CH3)2CH2CH3Or-Si (CH3)2C(CH3)3。
In synthetic route of the present invention, taking 4-carboxyl-2-azetidinones (I) asRaw material, at dehydrating agent N, N'-dicyclohexylcarbodiimide (DCC) and oxidant Peracetic acidUnder the condition existing, obtain 4-AA class through oxidation deacidificationCompound (II), synthetic route is as follows:
The inventive method is specifically:
In 4-carboxyl-2-azetidinones (I), join in solvent, then addEnter concentration and be the Peracetic acid of 18～35 ﹪ as oxidant, then add N, N'-dicyclohexyl carbonDiimine (DCC), as dehydrating agent, is oxidized depickling reaction at 0～25 DEG C, untilReactant all runs out of, and finally obtains 4-AA compounds（II）。
Described Peracetic acid and 4-carboxyl-2-azetidinones (I) mol ratio are1.1～1.3:1; N, the mol ratio of N'-dicyclohexylcarbodiimide (DCC) and Peracetic acidFor 1:1; In every mole of 4-carboxyl-2-azetidinones (I), add 1.5～2LSolvent.
Described solvent is carrene, chloroform or ethyl acetate;
As preferably, described solvent is carrene or chloroform,
As preferably, the concentration of described Peracetic acid is 20 ﹪ or 35 ﹪.
The present invention has carried out deep optimization by great many of experiments to this technique, and this technique is now hadReaction condition gentleness, the characteristic such as feasible easy and simple to handle, thus realize product yield, produce effectRates etc. improve greatly; Equipment investment, energy consumption, environmental pollution and production cost etc. are realized greatlyReduce.
The present invention is by entering the synthetic method of 4-AA compoundsGo further research, invented one and utilized 4-carboxyl-2-azetidinones(I) for the synthetic 4-AA compounds (II) of key intermediateNew method, the method for this invention and the contrast of existing method have the following advantages:
1) oxidative deamination process is avoided using heavy metal oxidant or catalyst, greatly reduces heavilyResidual, the discharge of metal and pollution to environment. 2) accessory substance in course of reaction can facilitateGround recovery and reuse, reduce production costs to a great extent, more outstanding aspect economy.3) the method reaction condition gentleness, easy and simple to handle, and product is easy to separation and purification, and yield is high,Be applicable to large-scale production.
Detailed description of the invention
Further illustrate the present invention below in conjunction with embodiment, but do not limit the present invention.
Embodiment 1. (3S, 4S)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-acetoxyl groupSynthesizing of-1-(4-methoxyphenyl)-2-aza cyclo-butanone
In the there-necked flask of 500mL, add successively (3S, 4S)-3-[(R)-1-tert-butyl group dimethyl-siliconOxygen ethyl]-4-carboxyl-1-(4-methoxyphenyl)-2-aza cyclo-butanone 37.9g (0.1mol), dichloroMethane (200mL), is placed under condition of ice bath, then slowly adds the peroxide second of 23.9g35 ﹪Acid (0.11mol), after Peracetic acid adds, then adds 22.7g (0.11mol) N, N'-bis-hexamethylenesBase carbodiimide (DCC), insulation reaction 1～2h at 0～5 DEG C. TLC monitors reaction, reactionAfter end, first reactant mixture is filtered, filtrate is washed with the water of 300mL at every turn,Wash altogether 3 times, after washing, the organic layer of gained is again through saturated NaHCO3Washing, anhydrous Na2SO4Dry, pressure reducing and steaming solvent, crude product obtains 37.7g white solid product after recrystallization, producesProduct have carried out structural confirmation through nuclear magnetic resoance spectrum, mass spectrum, infrared spectrum to it, are our orderMark product. Yield is 96.0 ﹪.
Embodiment 2. (3S, 4S)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-acetoxyl groupSynthesizing of-1-(4-methoxyphenyl)-2-aza cyclo-butanone
In the there-necked flask of 500mL, add successively (3S, 4S)-3-[(R)-1-tert-butyl group dimethyl-siliconOxygen ethyl]-4-carboxyl-1-(4-methoxyphenyl)-2-aza cyclo-butanone 37.9g (0.1mol), chloroform(150mL), be placed under condition of ice bath, then slowly add the Peracetic acid of 49.4g20 ﹪(0.13mol), after Peracetic acid adds, then add 26.8g (0.13mol) N, N'-dicyclohexyl carbonDiimine (DCC), insulation reaction 1～2h at 25 DEG C. TLC monitors reaction, after reaction finishes,First reactant mixture is filtered, filtrate is washed with the water of 300mL at every turn, wash altogether 3 times,After washing, the organic layer of gained is again through saturated NaHCO3Washing, anhydrous Na2SO4Dry, subtractPressure boils off solvent, and crude product obtains 37.0g white solid product after recrystallization, and product is through nuclear-magnetismResonance spectrum, mass spectrum, infrared spectrum have carried out structural confirmation to it, are our target product.Yield is 94.1 ﹪.
Embodiment 3. (3S, 4S)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-acetoxyl groupSynthesizing of-1-(4-methoxy-benzyl)-2-aza cyclo-butanone
In the there-necked flask of 500mL, add successively (3S, 4S)-3-[(R)-1-tert-butyl group dimethyl-siliconOxygen ethyl]-4-carboxyl-1-(4-methoxy-benzyl)-2-aza cyclo-butanone 39.3g (0.1mol), dichloroMethane (200mL), is placed under condition of ice bath, then slowly adds the peroxide second of 26.1g35 ﹪Acid (0.12mol), after Peracetic acid adds, then adds 24.8g (0.12mol) N, N'-bis-hexamethylenesBase carbodiimide (DCC), insulation reaction 1～2h at 15 DEG C. TLC monitors reaction, reaction knotShu Hou, first filters reactant mixture, and filtrate is washed with the water of 300mL at every turn, altogetherWash 3 times, after washing, the organic layer of gained is again through saturated NaHCO3Washing, anhydrous Na2SO4Dry, pressure reducing and steaming solvent, crude product obtains 36.6g white solid product after recrystallization, producesProduct have carried out structural confirmation through nuclear magnetic resoance spectrum, mass spectrum, infrared spectrum to it, are our orderMark product. Yield is 90.0 ﹪.
Embodiment 4. (3S, 4S)-3-[(R)-1-ethyl dimethyl silica ethyl]-4-acetoxyl groupSynthesizing of-1-(4-aminomethyl phenyl)-2-aza cyclo-butanone
In the there-necked flask of 500mL, add successively (3S, 4S)-3-[(R)-1-ethyl dimethyl silicaEthyl]-4-carboxyl-1-(4-aminomethyl phenyl)-2-aza cyclo-butanone 36.5g (0.1mol), carrene(200mL), be placed under condition of ice bath, then slowly add the Peracetic acid of 41.8g20 ﹪(0.11mol), after Peracetic acid adds, then add 22.7g (0.11mol) N, N'-dicyclohexyl carbonDiimine (DCC), insulation reaction 1～2h at 0～5 DEG C. TLC monitors reaction, and reaction finishesAfter, first reactant mixture to be filtered, filtrate is washed with the water of 300mL at every turn, washes altogether3 times, after washing, the organic layer of gained is again through saturated NaHCO3Washing, anhydrous Na2SO4DryDry, pressure reducing and steaming solvent, crude product obtains 33.7g white solid product, product after recrystallizationThrough nuclear magnetic resoance spectrum, mass spectrum, infrared spectrum, it having been carried out to structural confirmation, is our targetProduct. Yield is 89.0 ﹪.
Embodiment 5. (3S, 4S)-3-[(R)-1-ethyl dimethyl silica ethyl]-4-acetoxyl group-1-(3,4-dimethoxy-benzyl)-2-aza cyclo-butanone synthetic
In the there-necked flask of 500mL, add successively (3S, 4S)-3-[(R)-1-ethyl dimethyl silicaEthyl]-4-carboxyl-1-(3,4-dimethoxy-benzyl)-2-aza cyclo-butanone 39.5g (0.1mol), twoChloromethanes (200mL), is placed under condition of ice bath, then slowly adds the peroxide of 23.9g35 ﹪Acetic acid (0.11mol), after Peracetic acid adds, then adds 22.7g (0.11mol) N, and N'-bis-encirclesHexyl carbodiimide (DCC), insulation reaction 1～2h at 0～5 DEG C. TLC monitors reaction, anti-After should finishing, first reactant mixture is filtered, filtrate is washed with the water of 300mL at every turn,Wash altogether 3 times, after washing, the organic layer of gained is again through saturated NaHCO3Washing, anhydrous Na2SO4Dry, pressure reducing and steaming solvent, crude product obtains 37.8g white solid product after recrystallization, producesProduct have carried out structural confirmation through nuclear magnetic resoance spectrum, mass spectrum, infrared spectrum to it, are our orderMark product. Yield is 92.5 ﹪.
Embodiment 6. (3S, 4S)-3-[(R)-1-trimethyl silica ethyl]-4-acetoxyl group-1-benzylSynthesizing of-2-aza cyclo-butanone
In the there-necked flask of 500mL, add successively (3S, 4S)-3-[(R)-1-trimethyl silica secondBase]-4-carboxyl-1-benzyl-2-aza cyclo-butanone 32.1g (0.1mol), carrene (200mL),Be placed under condition of ice bath, then slowly add the Peracetic acid (0.11mol) of 23.9g35 ﹪,After Peracetic acid adds, then add 22.7g (0.11mol) N, N'-dicyclohexylcarbodiimide(DCC), insulation reaction 1～2h at 0～5 DEG C. TLC monitors reaction, after reaction finishes, firstReactant mixture is filtered, and filtrate is washed with the water of 300mL at every turn, wash altogether 3 times,After washing, the organic layer of gained is again through saturated NaHCO3Washing, anhydrous Na2SO4Dry, subtractPressure boils off solvent, and crude product obtains 29.1g white solid product after recrystallization, and product is through nuclear-magnetismResonance spectrum, mass spectrum, infrared spectrum have carried out structural confirmation to it, are our target product.Yield is 87.0 ﹪.
Embodiment 7. (3S, 4S)-3-[(R)-1-trimethyl silica ethyl]-4-acetoxyl group-1-[bis-(4-methoxyphenyl) methyl]-2-aza cyclo-butanone synthetic
In the there-necked flask of 500mL, add successively (3S, 4S)-3-[(R)-1-trimethyl silica secondBase]-4-carboxyl-1-[bis-(4-methoxyphenyl) methyl]-2-aza cyclo-butanone 45.7g (0.1mol),Carrene (200mL), is placed under condition of ice bath, then slowly adds the mistake of 23.9g35 ﹪Fluoroacetic acid (0.11mol), after Peracetic acid adds, then adds 22.7g (0.11mol) N, N'-bis-Carbodicyclo hexylimide (DCC), insulation reaction 1～2h at 0～5 DEG C. TLC monitors reaction,After reaction finishes, first reactant mixture is filtered, filtrate is washed with the water of 300mL at every turnWash, wash altogether 3 times, after washing, the organic layer of gained is again through saturated NaHCO3Washing, anhydrousNa2SO4Dry, pressure reducing and steaming solvent, crude product obtains 42.8g white solid and produces after recrystallizationProduct, product has carried out structural confirmation through nuclear magnetic resoance spectrum, mass spectrum, infrared spectrum to it, is meTarget product. Yield is 91.0 ﹪.
Embodiment 8. (3S, 4S)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-acetoxyl groupSynthesizing of-1-pi-allyl-2-aza cyclo-butanone
In the there-necked flask of 500mL, add successively (3S, 4S)-3-[(R)-1-tertiary butyl dimethyl Si secondBase]-4-carboxyl-1-pi-allyl-2-aza cyclo-butanone 31.3g (0.1mol), carrene(200mL), be placed under condition of ice bath, then slowly add the Peracetic acid of 41.8g20 ﹪(0.11mol), after Peracetic acid adds, then add 22.7g (0.11mol) N, N'-dicyclohexyl carbonDiimine (DCC), insulation reaction 1～2h at 0～5 DEG C. TLC monitors reaction, and reaction finishesAfter, first reactant mixture to be filtered, filtrate is washed with the water of 300mL at every turn, washes altogether3 times, after washing, the organic layer of gained is again through saturated NaHCO3Washing, anhydrous Na2SO4DryDry, pressure reducing and steaming solvent, crude product obtains 28.8g white solid product, product after recrystallizationThrough nuclear magnetic resoance spectrum, mass spectrum, infrared spectrum, it having been carried out to structural confirmation, is our targetProduct. Yield is 88.0 ﹪.
Above-described embodiment is not for restriction of the present invention, and the present invention is not limited only to above-mentioned realityExecute example, as long as meet requirement of the present invention, all belong to protection scope of the present invention.
Claims (3)
1. the preparation method of a 4-AA compounds, it is characterized in that the method is taking 4-carboxyl-2-azetidinones I as raw material, at dehydrating agent N, under the condition that N'-dicyclohexylcarbodiimide DCC and oxidant Peracetic acid exist, obtain 4-AA compounds II through oxidation deacidification, synthetic route is as follows:
R in formula1For hydroxyl protecting group-Si (CH3)3Or-Si (CH3)2CH2CH3；
R2For N protecting atom base, this N protecting atom base is benzyl, 3,4-dimethoxy-benzyl or two (4-methoxyphenyl) methyl;
The method is specifically: 4-carboxyl-2-azetidinones I joins in solvent, then adding concentration is that the Peracetic acid of 18～35 ﹪ is as oxidant, add again N, N'-dicyclohexylcarbodiimide DCC is as dehydrating agent, at 0～25 DEG C, be oxidized depickling reaction, until reactant all runs out of, finally obtain 4-AA compounds II;
Described Peracetic acid and 4-carboxyl-2-azetidinones I mol ratio are 1.1～1.3:1; N, the mol ratio of N'-dicyclohexylcarbodiimide DCC and Peracetic acid is 1:1; In every mole of 4-carboxyl-2-azetidinones I, add 1.5～2L solvent;
Described solvent is carrene, chloroform or ethyl acetate.
2. the preparation method of a kind of 4-AA compounds as claimed in claim 1, is characterized in that described solvent is carrene or chloroform.
3. the preparation method of a kind of 4-AA compounds as claimed in claim 1, is characterized in that the concentration of described Peracetic acid is 20 ﹪ or 35 ﹪.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747250A (en) * | 2008-12-16 | 2010-06-23 | 上海医药工业研究院 | Method for preparing 4 - acyloxo heterocyclic ketone compounds |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101747250A (en) * | 2008-12-16 | 2010-06-23 | 上海医药工业研究院 | Method for preparing 4 - acyloxo heterocyclic ketone compounds |
| 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 |
Non-Patent Citations (1)
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| Scope and limitations of oxidative decarboxylation of α-(acylamino) acids by peroxy acids: conversion of a 2-azetidinone-4-carboxylic acid to a carbapenem;Masao Shiozaki;《synthesis》;19900831;第8卷;第691页左栏图A，图B，第692页左栏最后一段至右栏第一段 * |
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