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Synthesis method of 4-acetoxyl-2-azetidinone

A technology of -acetoxy- and azetidinone, which is applied in the field of synthesis of penem drug intermediate 4-acetoxy-2-azetidinone, can solve the problem of high cost of raw materials and large environmental pollution , the problem of high cost, to overcome the high cost of raw materials, shorten the reaction cycle, and achieve the effect of low cost

Active Publication Date: 2013-10-02
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0011] This process uses p-methoxyphenyl (PMP) as the protective group of N, and finally uses a large amount of cerium ammonium nitrate (Cerium Ammonium Nitr, referred to as CAN) to remove the protective group, which is costly and pollutes the environment.
And Pd(PPh 3 ) 4 Also an expensive reagent, Pb(OAc) 4 Serious environmental pollution, not suitable for industrial production
The process routes of the prior art have their own disadvantages. In the 4AA synthesis process, there are problems such as high raw material cost, long cycle and serious environmental pollution.

Method used

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  • Synthesis method of 4-acetoxyl-2-azetidinone
  • Synthesis method of 4-acetoxyl-2-azetidinone
  • Synthesis method of 4-acetoxyl-2-azetidinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (1) Add 200mL chloroform, 37.4g (0.12mol) (R) 3-tert-butyldimethylsilyloxy-thiobutyric acid-S-2-pyridyl ester, 30mL triethylamine to 500mL tetra In the mouth bottle, cool down to -10~-20°C, add 19g TiCl dropwise under the protection of nitrogen 4 , and then added 17.7g (0.1mol) of N-p-methoxyphenyl-N-(acetyl)methylimine, and reacted at 0-5°C for 5h. After the reaction, the nitrogen protection was stopped, followed by 50mL 1N NaOH, 80mL saturated NaHCO 3 solution and washed with 100 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain (3S, 4S)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetyl-1- p-methoxyphenyl-2-azetidinone 27.6g, yield 73.4%, mp: 81-83°C, purity: 98.8% (HPLC detection).

[0045]

[0046] (2) Add 150mL ethyl acetate to a 500mL three-necked flask, and 27.6g (0.073mol) (3S, 4S)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4- Acetyl-1-p-methoxyphenyl-2-azetidinone was dissol...

Embodiment 2

[0051] (1) Add 200mL chloroform, 46.7g (0.15mol) (R) 3-tert-butyldimethylsilyloxy-thiobutyric acid-S-2-pyridyl ester, 30mL triethylamine to 500mL tetra In the mouth bottle, cool down to -10~-20°C, add 19g TiCl dropwise under the protection of nitrogen 4 , add 17.7g (0.1mol) of N-p-methoxyphenyl-N-(acetyl)methylimine, react at 0~5℃ for 5h. After the reaction, the nitrogen protection was stopped, followed by 50mL 1N NaOH, 80mL saturated NaHCO 3 solution and washed with 100 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain (3S, 4S)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetyl-1- p-methoxyphenyl-2-azetidinone 28.9g, yield 76.8% (based on compound I, yield calculation formula is the same as Example 1), mp: 81-83°C, purity: 98.6% (HPLC detection).

[0052] (2) Add 150mL ethyl acetate to a 500mL three-necked flask, and 28.9g (0.077mol) (3S, 4S)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4- Diss...

Embodiment 3

[0055] (1) Add 200mL chloroform, 40.5g (0.13mol) (R) 3-tert-butyldimethylsilyloxy-thiobutyric acid-S-2-pyridyl ester, 30mL triethylamine to 500mL tetra In the mouth bottle, cool down to -10~-20°C, add 19g TiCl dropwise under the protection of nitrogen 4 , add 17.7g (0.1mol) of N-p-methoxyphenyl-N-(acetyl)methylimine, react at 0~5℃ for 5h. After the reaction, the nitrogen protection was stopped, followed by 50mL 1N NaOH, 80mL saturated NaHCO 3 solution and washed with 100 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain (3S, 4S)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetyl-1- p-Methoxyphenyl-2-azetidinone 28.4g, yield 75.5% (based on compound I, yield calculation formula is the same as Example 1), mp: 81-83°C, purity: 98.5% (HPLC detection).

[0056] (2) Add 150mL ethyl acetate to a 500mL three-necked flask, and 28.4g (0.075mol) (3S, 4S)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4- Diss...

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Abstract

A synthesis method of 4-acetoxyl-2-azetidinone comprises the following steps of: (1) taking N-p-methoxypheny-N-(acetyl) methyleneimine as a raw material and carrying out cyclization reaction with (R)3-tert-butyldimethylsilyloxy-sulfo-butyrate-S-2-pyridinyl ester to obtain (3S,4S)-3-[(1'R)-tert-butyldimethylsilyloxyethyl]-4-acetyl-1-p-methoxyphenyl-2-azetidinone; (2) preparing (3R,4R)-3-[(1'R)-tert-butyldimethylsilyloxyethyl]-4-acetoxyl -1-p-methoxyphenyl-2-azetidinone from peroxyacetic acid through oxidization in the presence of Na3PO4 and a phase transfer catalyst; and (3) removing protective groups to obtain a final product (3R,4R)-3-[(1'R)-tert-butyldimethylsilyloxyethyl]-4-acetoxyl-2-azetidinone. The invention has the advantages of shortening reaction period, improving reaction total yield, and improving reaction yield and product purity by introducing the phase transfer catalyst in the step (2). The method is simple, causes small pollution and has great application value and economic benefit.

Description

technical field [0001] The invention relates to a method for synthesizing 4-acetoxy-2-azetidinone, an intermediate of penem drugs. Background technique [0002] 4-Acetoxy-2-azetidinone, chemical name (3R,4R)-3-[(1'R)-tert-butyldimethylsiloxyethyl]-4-acetoxy-2 - Azetidinone. [0003] English name: (3R, 4R)-4-Acetoxy-3-[(1’R)-(tert-butyldimethylsilyloxy)-ethyl]-2-azetidinone; 4AA for short in the industry; [0004] As an important pharmaceutical intermediate, it is an indispensable intermediate product for the production of penem antibiotics such as imipenem, meropenem, panipenem and doripenem. [0005] In the prior art, there are many synthetic routes of 4-acetoxy-2-azetidinone. [0006] In 1983, Shiozaki M. et al. (Chemistry Letters, 1983, 2, 169-172) used 6-aminopenicillanic acid (6-APA) as raw material through bromination, esterification, Grignard reaction, reduction, hydroxyl protection, 4AA was synthesized by ring opening and oxidative cleavage. The synthesis route ...

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 张谨贺丽丽于金平周磊
Owner YIYUAN XINQUAN CHEM
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