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

A technology of tert-butyldimethylsiloxyethyl and azetidinone, which is applied in the field of synthesis of intermediates, can solve the problems of scarcity of catalysts or catalyst sources, expensive catalysts, and slow reaction speeds, etc.

Inactive Publication Date: 2008-07-16
HEBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The synthetic technique of this compound has bibliographical information, as bibliographical information (Tetrahedron Letter., 1986,27 (47): 5751) report is that raw material utilizes the method for cycloaddition with S-ethyl lactate, exists and is difficult for selecting excellent catalyzer or catalyst Scarcity of domestic sources, low yield and difficulties in chiral resolution, etc., such as the method reported by Sandor Karady (J.Am.Chem.Soc., 1981, 103 (22): 6765-6767) uses penicillin G as raw material utilization The nature of the diazo compound, the reaction requires diisopropylamine-borane, trifluoroacetate catalyst, but this catalyst is expensive
Article (J.Org.Chem., 1977, 42 (18): 2960-2965) reports that 6-aminopenicillanic acid is used as a raw material in water for diazotization and bromination reactions, but the reaction dibromide yield Low, slow response, and complicated operation

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1) Add 70ml of dichloromethane into the three-necked flask, cool to -5°C, add bromine (Br 2 ) 2.6ml (0.051mol), phase transfer catalyst (polyethylene glycol 400) 0.3g, concentration are 20ml of sulfuric acid of 1.25mol / L, add sodium nitrite 3.46g at one time under stirring. After stirring for 10 minutes, keep 0~5℃ and add 7.5g (0.035mol) of 6-aminopenicillanic acid, continue stirring for 1 hour, then raise the temperature at about 12℃, stir for 4 hours, add saturated Sodium thiosulfate solution until the reaction solution turns light yellow to terminate the reaction, stand for separation, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter with suction, and rotate the filtrate to obtain a light yellow solid 6,6- Dibromopenicillanic acid 11.83g, yield rate 95%.

[0029] 2) Add 50ml of anhydrous methanol (39.55g) into the three-necked flask, cool to 0°C, add 12g of compound 6,6-dibromopenicillanic acid, keep the temperature within th...

Embodiment 2

[0038] 1) Add 70ml of dichloromethane into the three-necked flask, cool to -5°C, add bromine (Br 2 ) 2.3ml (0.045mol), phase transfer catalyst (polyethylene glycol 400) 0.15g, concentration is 1.25mol / L sulfuric acid 20ml, under stirring, add sodium nitrite 2.16g in one go. After stirring for 10 minutes, add 5.4g (0.025mol) of 6-aminopenicillanic acid at -10~-5℃, continue stirring for 1 hour, then raise the temperature to about 12℃, stir for 4 hours, and add dropwise at 0-7℃ Saturated sodium thiosulfate solution until the reaction solution turns light yellow to terminate the reaction, stand and separate, the organic phase is washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate is rotary evaporated to obtain a light yellow solid 6, 8.34 g of 6-dibromopenicillanic acid, the yield is 93%.

[0039] 2) Add 45ml (35.6g) of anhydrous methanol into the three-necked flask, cool to 0°C, add 11.87g of compound 6,6-dibromopenicillan...

Embodiment 3

[0046] 1) Add 70ml of dichloromethane into the three-necked flask, cool to -5°C, add bromine (Br 2 ) 2.8ml (0.05mol), phase transfer catalyst (polyethylene glycol 400) 0.6g, concentration are 20ml of sulfuric acid of 1.25mol / L, add sodium nitrite 3g at one time under stirring. After stirring for 10 minutes, keep 5-10°C and add 8.1g (0.037mol) of 6-aminopenicillanic acid, continue to stir for 1 hour, then raise the temperature at about 12°C, stir for 4 hours, and add saturated Sodium thiosulfate solution until the reaction solution turns light yellow to terminate the reaction, stand for separation, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter with suction, and rotate the filtrate to obtain a light yellow solid 6,6- Dibromopenicillanic acid 11.43g, yield rate 85%.

[0047]2) Add 75ml (59.32g) of anhydrous methanol into the three-necked flask, cool to 0°C, add 11.86g of the compound 6,6-dibromopenicillanic acid, keep the temperature w...

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Abstract

The invention discloses a method for preparation of (3R, 4R) -3-[(1R)-(tert-butyl dimethylsilyloxy) ethyl]-4-acetoxy-2-azetidinone. The method contains 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, reaction temperature decrease in ring opening and application of pyridine as the solvent in synthesis of (3S, 5R, 6S)-6-bromine-6-[(1R)-hydroxyethyl] penicillanic acid methyl ester of the Griganard reaction, 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

technical field [0001] The present invention relates to the synthesis of intermediates of penems and carbapenems, specifically a (3R, 4R)-3-[(1R) tert-butyldimethylsiloxyethyl]- Process for the preparation of 4-acetoxy-2-azetidinone. Background technique [0002] The azetidinone compound (3R, 4R)-3-[(1R) tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone is a new type of high-efficiency antibacterial drug The key intermediate of penem and carbapenem, its structural formula is: [0003] [0004] Compound I [0005] The synthetic technique of this compound has bibliographical information, as bibliographical information (Tetrahedron Letter., 1986,27 (47): 5751) report is that raw material utilizes the method for cycloaddition with S-ethyl lactate, exists and is difficult for selecting good catalyst or catalyst Scarcity of domestic sources, low yield and difficulties in chiral resolution, etc., such as the method reported by Sandor Karady (J.Am...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
Inventor 章文军赵昕王亚琴甘泉英冯军利
Owner HEBEI UNIV OF TECH
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