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Method for preparing 4 - acyloxo heterocyclic ketone compounds

A technology of heterocyclobutanone and acyloxy nitrogen, which is applied in the field of organic synthesis, can solve the problems of difficult post-processing, cumbersome operation, and high price, and achieve the effects of simple post-processing method, high yield and purity, and cost reduction

Active Publication Date: 2012-09-05
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome the existing method for preparing compound I using expensive m-chloroperoxybenzoic acid as an oxidizing agent, and the consumption is large, the post-treatment is difficult, the operation is cumbersome, and the defects of high production cost, and Provide a new method with low cost, simple operation and post-treatment, high yield and purity, and easy industrial production

Method used

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  • Method for preparing 4 - acyloxo heterocyclic ketone compounds
  • Method for preparing 4 - acyloxo heterocyclic ketone compounds
  • Method for preparing 4 - acyloxo heterocyclic ketone compounds

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1 (3R, 4R)-4-acetoxy-3-[(1R)-tert-butyldimethylsilyloxy]ethyl-1-(4-methoxyphenyl)-2-aza Cyclobutanone

[0022] (3R, 4R)-4-acetyl-3-[(1R)-tert-butyldimethylsilyloxy]ethyl-1-(4-methoxybenzene)-2-azetidinone 50g ( 0.132mol) was dissolved in acetic acid (500ml), added carbamide peroxide (37g, 0.40mol), reacted at 70°C for 2h (the reaction was detected by TLC), cooled to room temperature, added 2000ml of water, stirred at 0-10°C for 1h, and precipitated The white solid was filtered, washed with water, and dried under reduced pressure. The yield was 90%.

[0023] 1H-NMR (300MHz, CDCl 3 ): 0.01(s, 3H), 0.05(s, 3H), 0.73(s, 9H), 1.31(d, 3H), 2.11(s, 3H), 3.19(m, 1H), 3.77(s, 3H) 4.29(m, 1H), 6.65(s, 1H), 6.79(d, 2H), 7.32(d, 2H); m / z: 393.2; C 20 h 31 NO 5 Simp: 72-74°C

Embodiment 2

[0024] Example 2 (3R, 4R)-4-acetoxy-3-[(1R)-tert-butyldimethylsilyloxy]ethyl-1-(4-methoxyphenyl)-2-aza Cyclobutanone

[0025] (3R, 4R)-4-acetyl-3-[(1R)-tert-butyldimethylsilyloxy]ethyl-1-(4-methoxybenzene)-2-azetidinone 50g ( 0.132mol) was dissolved in chloroform (500ml), carbamide peroxide (620g, 6.6mol) was added, acetic anhydride (50ml) was reacted at 65°C for 48h (the reaction was detected by TLC), chloroform and acetic anhydride were recovered under reduced pressure, and N, N - 500ml of dimethylformamide, cooled to room temperature, added 3000ml of water, stirred at -5-10°C for 3h, a white solid precipitated, filtered, washed with water, dried under reduced pressure, yield 87%.

[0026] 1H-NMR (300MHz, CDCl3): 0.01(s, 3H), 0.05(s, 3H), 0.73(s, 9H), 1.31(d, 3H), 2.11(s, 3H), 3.19(m, 1H) , 3.77(s, 3H), 4.29(m, 1H), 6.65(s, 1H), 6.79(d, 2H), 7.32(d, 2H); m / z: 393.2; C 20 h 31 NO 5 Simp: 72-74°C

Embodiment 3

[0027] Example 3 (3R, 4R)-4-acetoxy-3-[(1R)-tert-butyldimethylsilyloxy]ethyl-1-(4-methoxyphenyl)-2-aza Cyclobutanone

[0028](3R, 4R)-4-acetyl-3-[(1R)-tert-butyldimethylsilyloxy]ethyl-1-(4-methoxybenzene)-2-azetidinone 50g ( 0.132mol) was dissolved in DMF (400ml), urea peroxide (50g, 0.53mol) was added, and acetic anhydride (50ml) was reacted at 125°C for 10h (TLC detected that the reaction was complete), the acetic anhydride and DMF were recovered under reduced pressure, and 1500ml of acetonitrile was added, Cool to room temperature, add 4000ml of water, stir at -5-0°C for 5h, a white solid precipitates, filter, wash the solid with water, dry under reduced pressure, yield 80%.

[0029] 1H-NMR (300MHz, CDCl3): 0.01(s, 3H), 0.05(s, 3H), 0.73(s, 9H), 1.31(d, 3H), 2.11(s, 3H), 3.19(m, 1H) , 3.77(s, 3H), 4.29(m, 1H), 6.65(s, 1H), 6.79(d, 2H), 7.32(d, 2H); m / z: 393.2; C 20 h 31 NO 5 Simp: 72-74°C

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Abstract

The invention discloses a method for preparing 4 - acyloxo heterocyclic ketone compounds, comprising the following steps: in acetic acid and / or acetic anhydride, carbamide peroxide is used as an oxidant, and a compound I is oxidized; wherein R1 is an H or hydroxyl protecting group; R2 is an H or N atom protecting group; and R3 is H, C1-C6 alkyl, C1-C6 naphthenic base, benzyl or substituted or unsubstituted C6 - C20 aryl. The method adopts the carbamide peroxide as the oxidant, so the reaction cost of the method is greatly reduced, and the cost of the need oxidant of products per kilogram is20-130 yuan. The invention has the advantages of simple post-processing method and high yield and purity.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for preparing 4-acyloxyazetidinone compounds. Background technique [0002] The 4-acyloxyazetidinone compound as shown in formula II is the key intermediate for the preparation of novel high-efficiency antibacterial drugs penem and carbapenem antibiotics, such as for the preparation of meropenem and imipenem ( J.Org.Chem.1992, 57(15), 4243-4249, Tetrahedron, 1991, 47(16-17), 2801-2820): [0003] [0004] There are three chiral centers in the structure of this compound, and there are 8 stereoisomers, which is relatively difficult to synthesize. The existing method for synthesizing 4-acyloxyazetidinone compounds shown in formula II is: in an organic solvent, using m-chloroperoxybenzoic acid as an oxidation reagent, subjecting compound I to a Baeyer-Villiger oxidation reaction , to obtain compound II, the reaction formula is as follows: [0005] [0006] Among them...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/08C07F7/18
CPCY02P20/55
Inventor 刘相奎朱雪焱王强袁哲东俞雄
Owner SHANGHAI INST OF PHARMA IND CO LTD