CN101220050A - Method for preparing (3R,4R)-3-[(1R)tert-butyl dimethyl silica ethyl]-4-acetoxy-2-aza ring butanone - Google Patents

Method for preparing (3R,4R)-3-[(1R)tert-butyl dimethyl silica ethyl]-4-acetoxy-2-aza ring butanone Download PDF

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CN101220050A
CN101220050A CNA2008100522519A CN200810052251A CN101220050A CN 101220050 A CN101220050 A CN 101220050A CN A2008100522519 A CNA2008100522519 A CN A2008100522519A CN 200810052251 A CN200810052251 A CN 200810052251A CN 101220050 A CN101220050 A CN 101220050A
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penicillanic acid
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CN101220050B (en
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章文军
赵昕
王亚琴
甘泉英
冯军利
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Hebei University of Technology
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Abstract

The invention discloses a preparation method of (3R, 4R) -3-[(1R) tert-butyl dimethylsilyloxy ethyl]-4-acetoxy-2-azetidinone. The method includes the procedures such as diazotization, bromination, esterification, Griganard reaction, reduction, hydroxyl protection, ring opening, oxidation, etc.; wherein through reaction time adjustment during the process of esterification, the reaction temperature is decreased in the ring opening and the application of pyridine as the solvent in the synthesis of (3S, 5R, 6S)-6-bromine-6-[(1R)-hydroxyethyl] penicillanic acid methyl ester of the Griganard procedure, the reaction of procedure 3) can be carried out ranging from minus 25 DEG C to minus 5 DEG C with equivalent total yield, thereby greatly reducing the equipment investment and energy consumption.

Description

(3R, 4R)-3-[(1R) tert-butyl dimethyl silica ethyl]-preparation method of 4-acetoxyl group-2-azetidinone
Technical field
The present invention relates to intermediate synthetic of penems and carbapenems medicine, specifically a kind of (3R, 4R)-3-[(1R) tert-butyl dimethyl silica ethyl]-preparation method of 4-acetoxyl group-2-azetidinone.
Background technology
Azetidinones (3R, 4R)-3-[(1R) tert-butyl dimethyl silica ethyl]-4-acetoxyl group-2-azetidinone is the key intermediate of synthesizing new high-efficiency antimicrobial medicine penem and carbapenem, its structural formula is:
Figure S2008100522519D00011
Compound I
The synthesis technique of this compound has bibliographical information, as document (Tetrahedron Letter., 1986,27 (47): 5751) report is the method for raw material utilization cycloaddition with the S-ethyl lactate, exist and be difficult for selecting good catalyzer or catalyzer to originate rare at home, low and the chiral separation of productive rate is difficult or the like, as Sandor Karady (J.Am.Chem.Soc., 1981,103 (22): 6765-6767) reported method is the character of prepared using diazonium compound with the penicillin G, reaction needed diisopropylamine-borine, trifluoracetic acid salt catalyst, but this catalyzer expensive price.Article (J.Org.Chem., 1977,42 (18): 2960-2965) report is that raw material carries out through diazotization, bromo-reaction in water with the 6-amino-penicillanic acid, but reaction dibromide yield is low, and speed of response is slow, and operation simultaneously is also complicated.And for example article (Li Shijie. synthetic [D] of the crucial medicine intermediate of penem---azetidinone. Hebei University of Technology, 2004) in the report, it adopts diazotization; bromo, esterification, grignard; reduction, hydroxyl protection, open loop; steps such as oxidation; wherein formatting step synthetic (3S, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] in the penicillanic acid methyl esters; because temperature of reaction too low (78 ℃) is unfavorable for suitability for industrialized production.
Summary of the invention
Purpose of the present invention overcomes in the current techniques, the shortcoming that yield is low or temperature of reaction is too low, provide a kind of (3R, 4R)-3-[(1R)-tert-butyl dimethyl silica ethyl]-4-acetoxyl group-2-azetidinone preparation method.The 3rd step was a solvent with the pyridine in this method, can make to be reflected under the temperature-25 ℃～-5 ℃ and can to carry out.
Technical scheme of the present invention be a kind of (3R, 4R)-3-[(1R)-tert-butyl dimethyl silica ethyl]-4-acetoxyl group-2-azetidinone preparation method, may further comprise the steps:
1) at CH 2Cl 2In the solution,-20～10 ℃ add phase-transfer catalyst poly(oxyethylene glycol) 400, bromine, sulfuric acid and Sodium Nitrite down, stir and add 6-amino-penicillanic acid down, be warming up to 12 ℃ after 1 hour, continue to react termination reaction after 4 hours, through washing, drying, underpressure distillation obtains faint yellow solid 6, the 6-dibromo penicillanic acid;
Wherein material proportion is: with the molar ratio computing bromine: 6-amino-penicillanic acid: sulfuric acid=1.3～1.8: 1: 0.67～1; In volume ratio bromine: CH 2Cl 2=0.03～0.06: 1; Poly(oxyethylene glycol) 400 by quality ratio: 6-amino-penicillanic acid: Sodium Nitrite=0.02～0.08: 1: 0.3～0.5;
2) in methyl alcohol, keep under-10～10 ℃ of temperature adding go up that the step obtains 6, the 6-dibromo penicillanic acid stirs then and adds aluminum chloride down, rises to room temperature reaction 12 hours, through washing, drying, oven dry obtains white solid 6,6-dibromo penicillanic acid methyl esters;
Wherein, methyl alcohol by quality ratio: aluminum chloride: 6,6-dibromo penicillanic acid=3～5: 0.03～0.06: 1;
3) under the argon shield-30 ℃ add in pyridine solution that the step makes 6,6-dibromo penicillanic acid methyl esters, add Tetramethyl Ethylene Diamine and Grignard reagent MeMgI again, after-30～0 ℃ of 2 hours following reaction times, drip anhydrous acetaldehyde and anhydrous diethyl ether, rise to stirring at room termination reaction after 12 hours after dropwising, extraction back organic phase obtains (3S after washing, dry, distillation, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters;
Wherein, with the anhydrous acetaldehyde of molar ratio computing: MeMgI: 6,6-dibromo penicillanic acid methyl esters=1～4: 1: 0.1～0.4; With quality than Tetramethyl Ethylene Diamine: 6,6-dibromo penicillanic acid methyl esters=0.02～0.07: 1; In the volume ratio pyridine: anhydrous acetaldehyde: anhydrous diethyl ether=13～15: 1: 1～3;
4) in methyl alcohol, add (the 3S that the step makes under the room temperature, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters, add zinc powder and saturated acetic acid ammonium solution, reacted 4 hours, and filtered, extract, organic phase obtains (3S through washing, drying and distilling and decolouring again, 5R, 6S)-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters;
Wherein, methyl alcohol by quality ratio: (3S, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters: zinc powder: ammonium acetate=8～13: 1: 0.29～0.97: 0.29～2.9;
5) under the room temperature at N, add in the dinethylformamide solution and go up (the 3S that the step makes, 5R, 6S)-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters, and TERT-BUTYL DIMETHYL CHLORO SILANE and imidazoles, reacted 12 hours, through washing, drying, air distillation obtains orange oily matter (3S, 5R, 6S)-6-[(1R)-tert-butyl dimethyl silica ethyl] the penicillanic acid methyl esters;
Wherein, N by quality ratio, dinethylformamide: (3S, 5R, 6S)-6-[(1R)-and hydroxyethyl] penicillanic acid methyl esters=3～7: 1; With the molar ratio computing imidazoles: (3S, 5R, 6S)-6-[(1R)-and hydroxyethyl] the penicillanic acid methyl esters: TERT-BUTYL DIMETHYL CHLORO SILANE=2.2～8.8: 0.6～1: 1;
6) in acetic acid solution, add (the 3S that the step makes, 5R, 6S)-6-[(1R)-and tert-butyl dimethyl silica ethyl] the penicillanic acid methyl esters adds mercuric acetate under 50～90 ℃ of temperature, reacted 1～7 hour, through underpressure distillation, filtration, washing, drying and column chromatography decolouring, obtain yellow oil (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-the 2-azetidinone.
Wherein, and by quality ratio (3S, 5R, 6S)-6-[(1R)-and tert-butyl dimethyl silica ethyl] the penicillanic acid methyl esters: acetate: mercuric acetate=0.29～0.59: 20～30: 1;
7) will go up (the 3R that the step makes, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-be dissolved in the acetone under the 2-azetidinone room temperature, add the aqueous solution that contains potassium permanganate and sodium periodate, the phosphate buffer solution that adds PH=7 again stirs reaction down 8～12 hours, through extraction, washing, underpressure distillation and column chromatography decolouring, generate target compound I
Wherein, the aqueous solution that contains potassium permanganate and sodium periodate in volume ratio: acetone: phosphate buffer solution=1～2: 1.5～3: 1; The concentration that contains the solution of sodium periodate and potassium permanganate is 8.16～11.1g sodium periodate/100ml aqueous solution; By quality ratio (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-the 2-azetidinone: sodium periodate: potassium permanganate=3～6: 8～11: 0.07.
Beneficial effect of the present invention:
1. in step 26, in 6-dibromo penicillanic acid methyl esters synthetic in the esterification reaction process by slow adding aluminum chloride and adjust the reaction times, make productive rate bring up to 97%, productivity ratio literature value (96.2%) (Li Shijie. the crucial medicine intermediate of penem---synthetic [D] of azetidinone. Hebei University of Technology, 2004) improve.
2. at step 6 (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-consider of the influence of the stability of tetra-atomic ring after the open loop in 2-azetidinone synthetic to yield, we reduce temperature of reaction (temperature is reduced to 60 ℃ by 90 ℃), and the yield that obtains compound is 80%.(Chinese Journal of Pharmaceuticals .1998,29 (3): 128-129) the report yield is 75% to document.
3. at step 3 (3S, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] compound 6 in penicillanic acid methyl esters synthetic, 6-dibromo penicillanic acid methyl esters in the presence of the methyl magnesium iodide, generate with acetaldehyde condensation reaction (3S, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters, be that solvent reacts under-78 ℃ with the tetrahydrofuran (THF) in the document, the condition harshness is unfavorable for suitability for industrialized production, and this experiment uses pyridine to make solvent, and temperature of reaction just can be carried out at-25 ℃～-5 ℃.
The present invention by a large amount of experiments, changes and choice of Solvent through reaction conditions on the prior art basis, and step 3 just can be carried out at-25 ℃～-5 ℃ in temperature of reaction, greatly reduces facility investment and energy consumption.Optimal yield is 35.88%.(literature value is 36%).
Embodiment
Embodiment one
1) adds methylene dichloride 70ml in the there-necked flask, be cooled to-5 ℃, add bromine (Br 2) 2.6ml (0.051mol), phase-transfer catalyst (poly(oxyethylene glycol) 400) 0.3g, concentration are the sulfuric acid 20ml of 1.25mol/L, under agitation disposable adding Sodium Nitrite 3.46g.Stir after 10 minutes, keep 0～5 ℃ to add 6-amino-penicillanic acid 7.5g (0.035mol), continue to stir 1 hour, heating up about 12 ℃ in the back, stirred 4 hours, drips saturated hypo solution in 0～7 ℃ and become faint yellow termination reaction until reaction solution, standing separation, organic phase is washed with saturated salt solution, anhydrous magnesium sulfate drying, suction filtration, with the filtrate rotary evaporation, get faint yellow solid 6,6-dibromo penicillanic acid 11.83g, productive rate are 95%.
2) add anhydrous methanol 50ml (39.55g) in the there-necked flask, be cooled to 0 ℃, add compound 6,6-dibromo penicillanic acid 12g, temperature is remained on add aluminum chloride total 0.6g in the 0-5 ℃ of scope in batches, add and stirred 20 minutes, rise under the room temperature and stirred 12 hours.The adularescent precipitation occurs, and filtration under diminished pressure obtains white solid, washes with water, obtains product 6 after the oven dry, 6-dibromo penicillanic acid methyl esters 12.09g, and yield is 97%.
3) use argon shield in the 250ml four-hole bottle; cryopump is cooled to-30 ℃; add new anhydrous pyridine 140ml of steaming and compound 6; 6-dibromo penicillanic acid methyl esters 5.25g (0.0141mo]); add Tetramethyl Ethylene Diamine (TMEDA) 0.3g; dripping methyl magnesium iodide MeMgI 30ml (0.056mol) controlled temperature reacted 2 hours down at-25 ℃; the adularescent precipitation is separated out; drip the mixed liquid of anhydrous acetaldehyde 10ml of new distillatory (0.175mol) and 10ml anhydrous diethyl ether again; dropwise; rise to room temperature; standing over night; be cooled to 0 ℃ and add saturated ammonium chloride solution until reaction solution change clarification termination reaction; organic phase is light yellow; the water ethyl acetate extraction; merge organic phase; it is washed with saturated salt solution; anhydrous magnesium sulfate drying, underpressure distillation obtains brown oil 5.0g; use sherwood oil: ethyl acetate=7: 3 is done elutriant; by column chromatography for separation, underpressure distillation obtains solid (3S, the 5R of white; 6S)-6-bromo-6-[(1R)-hydroxyethyl] penicillanic acid methyl esters 3.28g, productive rate is 69%.
4) in the there-necked flask will (3S, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] penicillanic acid methyl esters 5.0g (0.0148mol) is dissolved among the methyl alcohol 74ml (58.5g), adds 4.0g (0.061mol) zinc powder and saturated NH 4AC 8ml (8.6g) begins to stir, and solution is yellow, and temperature is controlled at room temperature, stirred 4 hours, static, solution decompression is filtered out zinc powder, filtrate obtains organic phase through ethyl acetate extraction, with saturated salt solution washing, anhydrous magnesium sulfate drying, air distillation is an elutriant with methylene dichloride, by the column chromatography decolouring, underpressure distillation obtains colorless oil (3S, 5R, 6S)-6-[(1R)-and hydroxyethyl] penicillanic acid methyl esters 3.64g, productive rate is 95%.
5) in the there-necked flask, at room temperature to the N of new steaming, add among the dinethylformamide 18ml (17g) (3S, 5R, 6S)-6-[(1R)-and hydroxyethyl] penicillanic acid methyl esters 4.3g (0.0166mol), imidazoles 4g (0.059mol) and TERT-BUTYL DIMETHYL CHLORO SILANE ( tBuMe 2SiCl) 4g (0.027mol) stirs reaction down 12 hours, adds ether 50ml dilution, solution washs with salt solution, anhydrous magnesium sulfate drying, air distillation, orange oily matter 6.2g, make elutriant with benzene, column chromatography decolouring, concentrating under reduced pressure, obtain yellow oil (3S, 5R, 6S)-6-[(1R)-tert-butyl dimethyl silica ethyl] penicillanic acid methyl esters 6.13g, productive rate is 99%.
6) add at 330ml (346.5g) acetic acid solution (3S, 5R, 6S)-6-[(1R)-and tert-butyl dimethyl silica ethyl] penicillanic acid methyl esters 6.5g (0.0174mol), water bath with thermostatic control is heated to 60 ℃, adds mercuric acetate 11.5g (0.0361mol) again, and the adularescent precipitation is separated out, restir 6 hours drops to room temperature, removes precipitation, the underpressure distillation acetic acid solution is 1/3 o'clock of cumulative volume, add ethyl acetate 100ml dilution, have precipitation to separate out, filter, filtrate water is washed, saturated NaHCO 3Washing produces up to no bubble, and is extremely neutral with the saturated common salt water washing.Use anhydrous magnesium sulfate drying at last, underpressure distillation, get scarlet oily matter, use sherwood oil: ethanol=8: 2 is made elutriant, the column chromatography decolouring, obtain the yellow oil product (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 5.56g, productive rate is 80%.
7) under the room temperature, with (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 5.43g is dissolved in the 220ml acetone, add sodium periodate 10g (containing potassium permanganate 0.07g) aqueous solution 90ml, 0.1mol/L phosphate buffered saline buffer 90ml (PH=7), stirred 12 hours, and filtered, filtrate concentrates, it is saturated to add NaCl, ethyl acetate extraction, washing, anhydrous magnesium sulfate drying, underpressure distillation obtains flaxen solid 3.16g, ether: normal hexane=3: 2 is an elutriant, column chromatography for separation, and underpressure distillation obtains the white needles solid
(3R, 4R)-the 4-acetoxy-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 2.93g, productive rate is 75%.
Total recovery is 35.88%
Embodiment two
1) adds methylene dichloride 70ml in the there-necked flask, be cooled to-5 ℃, add bromine (Br 2) 2.3ml (0.045mol), phase-transfer catalyst (poly(oxyethylene glycol) 400) 0.15g, concentration is 1.25mol/L sulfuric acid 20ml, under agitation disposable adding Sodium Nitrite 2.16g.Stir after 10 minutes, keep-10～-5 ℃ to add 6-amino-penicillanic acid 5.4g (0.025mol), continue to stir 1 hour, after be warmed up to about 12 ℃, stirred 4 hours, drip saturated hypo solution in 0-7 ℃ and become faint yellow termination reaction until reaction solution, standing separation, organic phase is washed with saturated salt solution, anhydrous magnesium sulfate drying, suction filtration, with the filtrate rotary evaporation, get faint yellow solid 6,6-dibromo penicillanic acid 8.34g, productive rate are 93%.
2) add anhydrous methanol 45ml (35.6g) in the there-necked flask, be cooled to 0 ℃, add compound 6,6-dibromo penicillanic acid 11.87g, temperature is remained on add aluminum chloride total 0.36g in-10～-5 ℃ of scopes in batches, add and stirred 20 minutes, rise under the room temperature and stirred 12 hours.The adularescent precipitation occurs, and filtration under diminished pressure obtains white solid, washes with water, obtains product 6 after the oven dry, 6-dibromo penicillanic acid methyl esters 11.9g, and yield is 96.5%.
3) use argon shield in the 250ml four-hole bottle; cryopump is cooled to-30 ℃; add new anhydrous pyridine 94ml of steaming and compound 6; 6-dibromo penicillanic acid methyl esters 6.96g (0.0187mol); add Tetramethyl Ethylene Diamine (TMEDA) 0.2g; drip methyl magnesium iodide MeMgI30ml (0.056mol); controlled temperature reacted 2 hours down at-5 ℃; the adularescent precipitation is separated out; drip the mixed liquid of anhydrous acetaldehyde 6.29ml of new distillatory (0.11mol) and 6.29ml anhydrous diethyl ether again; dropwise; rise to room temperature; standing over night; be cooled to 0 ℃ and add saturated ammonium chloride solution until reaction solution change clarification termination reaction; organic phase is light yellow; the water ethyl acetate extraction; merge organic phase, it is washed anhydrous magnesium sulfate drying with saturated salt solution; underpressure distillation; obtain brown oil 6.5g, use sherwood oil: ethyl acetate=do elutriant at 7: 3, pass through column chromatography for separation; underpressure distillation obtains the solid (3S of white; 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] penicillanic acid methyl esters 3.78g, productive rate is 60%.
4) in the there-necked flask will (3S, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] penicillanic acid methyl esters 5g (0.0148mol) is dissolved among the methyl alcohol 56ml (44.3g), adds 1.45g (0.022mol) zinc powder and saturated NH 4AC2.93ml (3.14g) begins to stir, and solution is yellow, and temperature is controlled at room temperature, stirred 4 hours, static, solution decompression is filtered out zinc powder, filtrate obtains organic phase through ethyl acetate extraction, with saturated salt solution washing, anhydrous magnesium sulfate drying, air distillation is an elutriant with methylene dichloride, by the column chromatography decolouring, underpressure distillation obtains colorless oil (3S, 5R, 6S)-6-[(1R)-and hydroxyethyl] penicillanic acid methyl esters 3.58g, productive rate is 93.5%.
5) in the there-necked flask, at room temperature, add (3S, 5R among the dinethylformamide 14ml (27.23g) to the N of new steaming, 6S)-6-[(1R)-and hydroxyethyl] penicillanic acid methyl esters 4.3g (0.0166mol), imidazoles 9.95g (0.146mol) and TERT-BUTYL DIMETHYL CHLORO SILANE ( tBuMe 2SiCl) 2.5g (0.0166mol) stirs reaction down 12 hours, adds ether 50ml dilution, organic salt solution that embraces washs anhydrous magnesium sulfate drying, air distillation, orange oily matter 6.5g, make elutriant with benzene, column chromatography decolouring, concentrating under reduced pressure, obtain yellow oil (3S, 5R, 6S)-6-[(1R)-tert-butyl dimethyl silica ethyl] penicillanic acid methyl esters 6.07g, productive rate is 98%.
6) add at 317ml (332.85g) acetic acid solution (3S, 5R, 6S)-6-[(1R)-and tert-butyl dimethyl silica ethyl] penicillanic acid methyl esters 6.5g (0.0174mol), water bath with thermostatic control is heated to 50 ℃, adds mercuric acetate 11.08g (0.0348mol) again, and the adularescent precipitation is separated out, restir 6 hours drops to room temperature, removes precipitation, the underpressure distillation acetic acid solution is 1/3 o'clock of cumulative volume, add ethyl acetate 100ml dilution, have precipitation to separate out, filter, filtrate water is washed, saturated NaHCO 3Washing produces up to no bubble, and is extremely neutral with the saturated common salt water washing.Use anhydrous magnesium sulfate drying at last, underpressure distillation, get scarlet oily matter, use sherwood oil: ethanol=8: 2 is made elutriant, the column chromatography decolouring, obtain faint yellow oily thing (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 5.46g, productive rate is 78.5%.
7) under the room temperature, with (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 3g is dissolved in the 132ml acetone, add sodium periodate 8g (containing potassium permanganate 0.07g) aqueous solution 98ml, 0.1mol/L phosphate buffered saline buffer 65ml (PH=7), stirred 12 hours, filter, filtrate concentrates, and it is saturated to add NaCl, and ethyl acetate is got by kingfisher, washing, anhydrous magnesium sulfate drying, underpressure distillation obtain flaxen solid 2g, ether: normal hexane=3: 2 is an elutriant, column chromatography for separation, underpressure distillation obtains the white needles solid, and (3R, 4R)-the 4-acetoxy-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 1.6g, productive rate is 74%.Total recovery is 28.7%
Embodiment three
1) adds methylene dichloride 70ml in the there-necked flask, be cooled to-5 ℃, add bromine (Br 2) 2.8ml (0.05mol), phase-transfer catalyst (poly(oxyethylene glycol) 400) 0.6g, concentration are the sulfuric acid 20ml of 1.25mol/L, under agitation disposable adding Sodium Nitrite 3g.Stir after 10 minutes, keep 5～10 ℃ to add 6-amino-penicillanic acid 8.1g (0.037mol), continue to stir 1 hour, heating up about 12 ℃ in the back, stirred 4 hours, drips saturated hypo solution in 0～7 ℃ and become faint yellow termination reaction until reaction solution, standing separation, organic phase is washed with saturated salt solution, anhydrous magnesium sulfate drying, suction filtration, with the filtrate rotary evaporation, get faint yellow solid 6,6-dibromo penicillanic acid 11.43g, productive rate are 85%.
2) add anhydrous methanol 75ml (59.32g) in the there-necked flask, be cooled to 0 ℃, add compound 6,6-dibromo penicillanic acid 11.86g, temperature is remained on add aluminum chloride total 0.71g in-5～0 ℃ of scopes in batches, add and stirred 20 minutes, rise under the room temperature and stirred 12 hours.The adularescent precipitation occurs, and filtration under diminished pressure obtains white solid, washes with water, obtains product 6 after the oven dry, 6-dibromo penicillanic acid methyl esters 11.09g, and yield is 90%.
3) use argon shield in the 250ml four-hole bottle; cryopump is cooled to-30 ℃; add new anhydrous pyridine 165ml of steaming and compound 6; 6-dibromo penicillanic acid methyl esters 4.17g (0.011mol); add Tetramethyl Ethylene Diamine (TMEDA) 0.13g; drip methyl magnesium iodide MeMgI30ml (0.056mol); controlled temperature reacted 2 hours down at-15 ℃; the adularescent precipitation is separated out; drip the mixed liquid of anhydrous acetaldehyde 12.6ml of new distillatory (0.22mol) and 25.2ml anhydrous diethyl ether again; dropwise; rise to room temperature; standing over night; be cooled to 0 ℃ and add saturated ammonium chloride solution until reaction solution change clarification termination reaction; organic phase is light yellow; the water ethyl acetate extraction; merge organic phase, it is washed anhydrous magnesium sulfate drying with saturated salt solution; underpressure distillation; obtain brown oil 4g, use sherwood oil: ethyl acetate=do elutriant at 7: 3, pass through column chromatography for separation; underpressure distillation obtains the solid (3S of white; 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] penicillanic acid methyl esters 2.27g, productive rate is 60%.
4) in the there-necked flask will (3S, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] penicillanic acid methyl esters 5g (0.0148mol) is dissolved among the methyl alcohol 82ml (64.8g), adds 4.83g (0.074mol) zinc powder and saturated NH 4AC3.26ml (3.49g) begins to stir, and solution is yellow, and temperature is controlled at room temperature, stirred 4 hours, static, solution decompression is filtered out zinc powder, filtrate obtains organic phase through ethyl acetate extraction, with saturated salt solution washing, anhydrous magnesium sulfate drying, air distillation is an elutriant with methylene dichloride, by the column chromatography decolouring, underpressure distillation obtains colorless oil (3S, 5R, 6S)-6-[(1R)-and hydroxyethyl] penicillanic acid methyl esters 3.1g, productive rate is 81%.
5) in the there-necked flask, at room temperature, add (3S among the dinethylformamide 23ml (21.7g) to the N of new steaming, 5R, 6S)-6-[(1R)-hydroxyethyl] penicillanic acid methyl esters 4.3g (0.0166mol), imidazoles (8g, 0.118mol) and TERT-BUTYL DIMETHYL CHLORO SILANE ( tBuMe 2SiCl) 4.17g (0.028mol) stirs reaction down 12 hours, adds ether 50ml dilution, filter, filtrate is washed with salt solution, anhydrous magnesium sulfate drying, air distillation, orange oily matter 6g makes elutriant with benzene, the column chromatography decolouring, concentrating under reduced pressure obtains yellow oil (3S, 5R, 6S)-6-[(1R)-and tert-butyl dimethyl silica ethyl] penicillanic acid methyl esters 5.58g, productive rate is 90%.
6) add at 422ml (443.1g) acetic acid solution (3S, 5R, 6S)-6-[(1R)-and tert-butyl dimethyl silica ethyl] penicillanic acid methyl esters 6.5g (0.0174mol), water bath with thermostatic control is heated to 60 ℃, adds mercuric acetate 22.17g (0.0695mol) again, and the adularescent precipitation is separated out, restir 6 hours drops to room temperature, removes precipitation, the underpressure distillation acetic acid solution is 1/3 o'clock of cumulative volume, add ethyl acetate l00ml dilution, have precipitation to separate out, filter, filtrate water is washed, saturated NaHCO 3Washing produces up to no bubble, and is extremely neutral with the saturated common salt water washing.Use anhydrous magnesium sulfate drying at last, underpressure distillation, get scarlet oily matter, use sherwood oil: ethanol=8: 2 is made elutriant, the column chromatography decolouring, obtain faint yellow oily thing (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 4.87g, productive rate is 70%.
7) under the room temperature, with (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 6g is dissolved in the 188ml acetone, add sodium periodate 11g (containing potassium permanganate 0.07g) aqueous solution 125ml, 0.1mol/L phosphate buffer 1 25ml (PH=7), stirred 12 hours, filter, filtrate concentrates, and it is saturated to add NaCl, ethyl acetate extraction, washing, anhydrous magnesium sulfate drying, underpressure distillation obtain flaxen solid 3.4g, ether: normal hexane=3: 2 is an elutriant, column chromatography for separation, underpressure distillation obtains the white needles solid, and (3R, 4R)-the 4-acetoxy-3-[(1R)-tert-butyl dimethyl silica ethyl]-2-azetidinone 2.59g, productive rate is 60%.
Total recovery is 14%.

Claims (1)

1., a kind of (3R, 4R)-3-[(1R)-tert-butyl dimethyl silica ethyl]-4-acetoxyl group-2-azetidinone preparation method, it is characterized by and may further comprise the steps:
1) at CH 2Cl 2In the solution,-20～10 ℃ add phase-transfer catalyst poly(oxyethylene glycol) 400, bromine, sulfuric acid and Sodium Nitrite down, stir and add 6-amino-penicillanic acid down, be warming up to 12 ℃ after 1 hour, continue to react termination reaction after 4 hours, through washing, drying, underpressure distillation obtains faint yellow solid 6, the 6-dibromo penicillanic acid;
Wherein material proportion is: with the molar ratio computing bromine: 6-amino-penicillanic acid: sulfuric acid=1.3～1.8: 1: 0.67～1; In volume ratio bromine: CH 2Cl 2=0.03～0.06: 1; Poly(oxyethylene glycol) 400 by quality ratio: 6-amino-penicillanic acid: Sodium Nitrite=0.02～0.08: 1: 0.3～0.5;
2) in methyl alcohol, keep under-10～10 ℃ of temperature adding go up that the step obtains 6, the 6-dibromo penicillanic acid stirs then and adds aluminum chloride down, rises to room temperature reaction 12 hours, through washing, drying, oven dry obtains white solid 6,6-dibromo penicillanic acid methyl esters;
Wherein, methyl alcohol by quality ratio: aluminum chloride: 6,6-dibromo penicillanic acid=3～5: 0.03～0.06: 1;
3) under the argon shield-30 ℃ add in pyridine solution that the step makes 6,6-dibromo penicillanic acid methyl esters, add Tetramethyl Ethylene Diamine and Grignard reagent MeMgI again, after-30～0 ℃ of 2 hours following reaction times, drip anhydrous acetaldehyde and anhydrous diethyl ether, rise to stirring at room termination reaction after 12 hours after dropwising, extraction back organic phase obtains (3S after washing, dry, distillation, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters;
Wherein, with the anhydrous acetaldehyde of molar ratio computing: MeMgI: 6,6-dibromo penicillanic acid methyl esters=1～4: 1: 0.1～0.4; With quality than Tetramethyl Ethylene Diamine: 6,6-dibromo penicillanic acid methyl esters=0.02～0.07: 1; In the volume ratio pyridine: anhydrous acetaldehyde: anhydrous diethyl ether=13～15: 1: 1～3;
4) in methyl alcohol, add (the 3S that the step makes under the room temperature, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters, add zinc powder and saturated acetic acid ammonium solution, reacted 4 hours, and filtered, extract, organic phase obtains (3S through washing, drying and distilling and decolouring again, 5R, 6S)-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters;
Wherein, methyl alcohol by quality ratio: (3S, 5R, 6S)-6-bromo-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters: zinc powder: ammonium acetate=8～13: 1: 0.29～0.97: 0.29～2.9;
5) under the room temperature at N, add in the dinethylformamide solution and go up (the 3S that the step makes, 5R, 6S)-6-[(1R)-hydroxyethyl] the penicillanic acid methyl esters, and TERT-BUTYL DIMETHYL CHLORO SILANE and imidazoles, reacted 12 hours, through washing, drying, air distillation obtains orange oily matter (3S, 5R, 6S)-6-[(1R)-tert-butyl dimethyl silica ethyl] the penicillanic acid methyl esters;
Wherein, N by quality ratio, dinethylformamide: (3S, 5R, 6S)-6-[(1R)-and hydroxyethyl] penicillanic acid methyl esters=3～7: 1; With the molar ratio computing imidazoles: (3S, 5R, 6S)-6-[(1R)-and hydroxyethyl] the penicillanic acid methyl esters: TERT-BUTYL DIMETHYL CHLORO SILANE=2.2～8.8: 0.6～1: 1;
6) in acetic acid solution, add (the 3S that the step makes, 5R, 6S)-6-[(1R)-and tert-butyl dimethyl silica ethyl] the penicillanic acid methyl esters adds mercuric acetate under 50～90 ℃ of temperature, reacted 1～7 hour, through underpressure distillation, filtration, washing, drying and column chromatography decolouring, obtain yellow oil (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-the 2-azetidinone
Wherein, and by quality ratio (3S, 5R, 6S)-6-[(1R)-and tert-butyl dimethyl silica ethyl] the penicillanic acid methyl esters: acetate: mercuric acetate=0.29～0.59: 20～30: 1;
7) will go up (the 3R that the step makes, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-be dissolved in the acetone under the 2-azetidinone room temperature, add the aqueous solution that contains potassium permanganate and sodium periodate, the phosphate buffer solution that adds PH=7 again stirs reaction down 8～12 hours, through extraction, washing, underpressure distillation and column chromatography decolouring generate target compound;
Wherein, the aqueous solution that contains potassium permanganate and sodium periodate in volume ratio: acetone: phosphate buffer solution=1～2: 1.5～3: 1; The concentration that contains the solution of sodium periodate and potassium permanganate is 8.16～11.1g sodium periodate/100ml aqueous solution; By quality ratio (3R, 4R)-4-acetoxyl group-1-(1-methoxycarbonyl-2-methyl isophthalic acid-propenyl)-3-[(1R)-tert-butyl dimethyl silica ethyl]-the 2-azetidinone: sodium periodate: potassium permanganate=3～6: 8～11: 0.07.
CN2008100522519A 2008-02-02 2008-02-02 Method for preparing (3R,4R)-3-[(1R)tert-butyl dimethyl silica ethyl]-4-acetoxy-2-aza ring butanone Expired - Fee Related CN101220050B (en)

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