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Process for stereoselective preparation of 4-bma using a chiral auxiliary

A technology of selection and solvent, which is applied in the field of stereoselective preparation of 4-BMA using chiral auxiliaries

Inactive Publication Date: 2010-03-17
DAEWOONG PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0026] Accordingly, the present inventors have studied extensively to address the shortcomings of earlier methods of synthesizing 4-BMA of formula (6)

Method used

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  • Process for stereoselective preparation of 4-bma using a chiral auxiliary
  • Process for stereoselective preparation of 4-bma using a chiral auxiliary
  • Process for stereoselective preparation of 4-bma using a chiral auxiliary

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1: Preparation of (S)-4-isopropyloxazolidin (isopropyloxazolidin)-2-ketone (2)

[0064]

[0065] The raw material L-valinol (150 g) was added to diethyl carbonate (227 ml), and then potassium carbonate (20 g) was added, while stirring the mixture at room temperature. The reaction solution was refluxed at 120-130° C. for 5 hours. The reaction solution was cooled to 0°C, 1.5N hydrochloric acid (450 ml) and ethyl acetate (450 ml) were added, and the resulting two phases were separated. The aqueous phase was extracted twice with ethyl acetate (450ml), the organic phase was washed with aqueous sodium chloride (450ml), the phases were separated, dried, filtered and distilled. Diisopropyl ether (225 ml) was added to produce crystals, to which n-hexane (225 ml) was added. The mixture was stirred at 0 °C for 1 h, then filtered and dried to give the title compound (170 g, 85% yield).

[0066] 1 H NMR (300MHz, CDCl 3 )δ4.4(t, 1H), 4.1(m, 1H), 3.6(q, 1H), 1.7(m, ...

Embodiment 2

[0067] Example 2: Preparation of (S)-4-isopropyl-3-propionyl oxazolidin-2-one (3)

[0068]

[0069] Compound (2) (100 g) prepared in Example 1 was dissolved in tetrahydrofuran (300 ml), and cooled to 0°C. Lithium chloride (36 g) was added followed by triethylamine (101 g) slowly and the resulting mixture was stirred for 30 min. Propionic anhydride (106 g) was slowly added over a period of 30 min. The reaction mixture was slowly warmed to room temperature and stirred for 1-1.5 h. The reaction solution was cooled, 1N aqueous sodium chloride solution (300 ml) was added, and the mixture was stirred for 30 min. Ethyl acetate (300ml) was added, the phases were separated and extracted once more with ethyl acetate (300ml). After washing with 1.5N hydrochloric acid (300ml), the organic phase was washed once more with aqueous sodium chloride (300ml), dried, filtered and distilled to give the title compound (142g, 99% yield).

[0070] 1 H NMR (300MHz, CDCl 3 )δ4.4(m, 1H), 4.3-4....

Embodiment 3

[0071] Example 3: (S)-3-((R)-2-(3-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-4-oxoazepine Preparation of cyclobutan-2-yl)propionyl)-4-isopropyloxazolidin-2-one (5)

[0072]

[0073] Compound (3) (44 g) prepared in Example 2 was dissolved in dichloromethane (890 ml), and cooled to 0°C. Titanium chloride (55 g) was added slowly. After 1 h, diisopropylethylamine (40 g) was added followed by 4-AA (50 g). The resulting mixture was reacted at room temperature for 3 h and cooled. Water (890ml) was added to separate the phases, and 1.5N hydrochloric acid (500ml) was added thereto. The phases were separated and washed once more with aqueous sodium bicarbonate, with aqueous sodium chloride (100ml), dried over magnesium sulfate and distillation to yield the title compound (95g) contaminated with some impurities.

[0074] 1 H NMR (300MHz, CDCl 3 )δ5.96(s, 1H), 4.44(m, 1H), 4.30(m, 4H), 3.96(m, 1H), 3.05(m, 1H), 2.30(m, 1H), 1.25(dd, 6H ), 0.92(m, 15H), 0.07(d, 6H)

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Abstract

The present invention relates to a process for preparing (3R,4S)-3-[[[R]-V-t- butyldimethylsilyloxy] ethyl] -4- [(R)- l'-carboxyethyl]-2-azetidinone [4-BMA: formula (6)], a key intermediate for the synthesis of carbapenem and penem antibiotics. Specifically, the present invention relates to a process comprising first, the preparation of a chiral auxiliary from cheap L-Valinol, and then the preparation of 4-BMA in high yield and high selectivity, under industrially mild conditions.

Description

technical field [0001] The present invention relates to the stereoselective preparation of compounds of formula (6) wherein R represents hydrogen or a hydroxy-protecting group: [0002] [0003] In particular, (3R,4S)-3-[[[R]-1'-tert-butyldimethylsilyloxy]ethyl]-4-[(R)-1"-carboxyethyl] - A new method of 2-azetidinone (β-methylazetidin-2-one; 4-BMA), which can be used as an intermediate in the synthesis of penems or carbapenems The present invention also relates to the preparation of following formula (3) compound: [0004] [0005] This compound can be effectively used as a chiral auxiliary for the stereoselective preparation of compounds of formula (6) in high yields under mild conditions. Background technique [0006] The compound of formula (6) is known in the art as an intermediate in the synthesis of 1β-methylcarbapenems which exhibit potent antibacterial activity. Many types of carbapenems can be prepared from the compound of formula (6), a typical example of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08
CPCC07D205/08C07D263/04Y02P20/55
Inventor 申东昀洪明燦李元求河炫俊文星哲宋忠炫李庆镐韩彰完金钟赫李炳具宋润石
Owner DAEWOONG PHARM CO LTD
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