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(3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and preparation method of same

A technology of azetidinone and hydroxyethyl, which is applied in the field of medicinal chemistry, can solve problems such as difficult separation, difficult synthesis, and difficult availability in the market, and achieve the effects of simple post-treatment, mild reaction, and concise route

Inactive Publication Date: 2010-11-24
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The 4-AA molecule contains 3 chiral centers, which is difficult to synthesize
[0016] Compared with method (1) and (2), method (3) raw material is easy to get, easy and simple to operate, but has the following problems: 1. starting material needs to use methyl cyclopropyl ketone, and the market is not easy to get
2. Due to the high water solubility of the deprotected product, it is soluble in water together with p-toluenesulfonic acid and is not easy to separate

Method used

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  • (3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and preparation method of same
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  • (3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and preparation method of same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of (2R, 3R)-N-benzhydryl-N-(2-oxopropyl) epoxybutanamide (formula (I) compound)

[0042] In a 250 mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7.9 g of sodium (2R,3R)-2,3-epoxybutyrate and 100 mL of tetrahydrofuran. After cooling to -15°C, add 3.7 mL of oxalyl chloride dropwise, stir at this temperature for 2 hours, add 5.3 mL of anhydrous pyridine, 6.4 g of 1-benzhydrylamino-2-propanone, stir for 1 hour and then rise to Stirring was continued at room temperature for 2 hours, 100 mL of ethyl acetate was added, washed with 5% sodium bicarbonate solution, the organic phase was washed with brine after liquid separation, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated, and the compound (I) was obtained by silica gel column chromatography 7.2 g, yield 85.6%.

[0043]MS: 324.2 (M+H);

[0044] 1 HNMR: (400MHz, CDCl 3 )1.18(3H, m), 2.13(3H, s), 2.93(1H, m), 3.47(1H, m),...

Embodiment 2

[0045] Embodiment 2: the preparation of (2R, 3R)-N-benzhydryl-N-(2-oxopropyl) epoxybutyramide (formula (I) compound)

[0046] In a 250 mL four-necked round bottom flask equipped with a magnetic stirrer and a thermometer, 7.9 g of sodium (2R,3R)-2,3-epoxybutyrate and 100 mL of dichloromethane were added. After cooling to -20°C, add 4.9 g of thionyl chloride dropwise, stir at this temperature for 2 hours, add 10.5 g of triethylamine, 6.4 g of 1-benzhydrylamino-2-propanone, and stir for 1 hour Heat up to reflux reaction for 2 hours, add 100mL ethyl acetate, wash with 5% sodium bicarbonate solution, wash the organic phase with brine after liquid separation, dry over anhydrous magnesium sulfate, evaporate the solvent after filtration, and obtain compound (I )7.2g, yield 82.0%.

[0047] MS: 324.2 (M+H);

[0048] 1 HNMR: (400MHz, CDCl 3 )1.18(3H, m), 2.13(3H, s), 2.93(1H, m), 3.47(1H, m), 4.38(1H, s), 6.16(1H, s), 7.10-7.33(10H, m ).

Embodiment 3

[0049] Example 3: (3S, 4S)-1-benzhydryl-3-((R)-1-hydroxyethyl)-4-acetyl-2-azetidinone (compound of formula (II)) preparation of

[0050] In a 500 mL four-necked round bottom flask equipped with a magnetic stirrer and a thermometer, 7.0 g of the compound of formula (I) and 250 mL of dichloromethane were added. After cooling to -20°C, add LDA (1mol / L) 26.4mL dropwise, heat up to reflux for 3 hours after the dropwise addition, add 1N HCl 30mL, ethyl acetate 150mL, and use 5% sodium bicarbonate solution for the organic phase after liquid separation Washing, washing with brine, drying over anhydrous magnesium sulfate, filtering and distilling off the solvent, silica gel column chromatography to obtain compound (II) 5.4g, yield 77.4%.

[0051] MS: 324.2(M+H), 346(M+Na)

[0052] 1 HNMR: (400MHz, CDCl 3 )1.28(3H, m), 1.80(3H, s), 2.96(1H, m), 4.24(1H, m), 4.56(1H, s), 5.90(1H, s), 7.25-7.33(10H, m )

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Abstract

The invention provides (3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and a preparation method of the same. The invention further provides the intermediates of (2R,3R)-N-benzhydryl-N-(2-oxopropyl)epoxy butyramide (I) and (3S,4S)-1-benzhydryl-3-((R)-1-hydroxyethyl)-4-acetyl-2-azetidinone (II) of the (3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and preparation methods thereof. The method has the advantages of low-cost of easily obtained raw material, high yield, simple and convenient operation, environment friendliness and easy achievement of mass production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the compound (3S, 4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and a preparation method thereof. Involving its intermediates (2R, 3R)-N-benzhydryl-N-(2-oxopropyl) epoxybutanamide and (3S, 4S)-1-benzhydryl-3-((R )-1-hydroxyethyl)-4-acetyl-2-azetidinone and its preparation method. Background technique [0002] Penem and carbapenem antibiotics are atypical β-lactam antibiotics developed in the 1970s. It has strong antibacterial effect and is stable to β-lactamase. It occupies an important position in the current clinical anti-infection treatment, especially in the treatment of infections caused by drug-resistant bacteria. [0003] (3R, 4R)-3-((R)-1-tert-butyldimethylsiloxyethyl)-4-acetoxy-2-azetidinone (4-AA for short) is the preparation of Penicillium The key intermediate of alkene and carbapenem antibiotics, its structural formula is as shown in formula (VI): [0004] ...

Claims

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Application Information

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IPC IPC(8): C07D205/08C07D303/48B01J31/02
Inventor 张福利梁小敏王环
Owner SHANGHAI INST OF PHARMA IND
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