Preparation method of meropenem intermediate cyclization compound

A technology for temperature control and azetidinone, which is applied in the field of preparation of meropenem intermediates, can solve the problems of pollution and many metal-containing acidic wastewater, and achieves the effects of less wastewater, low price and mild reaction conditions

Active Publication Date: 2014-03-05
JIANGSU HANKUO BIOLOGICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Compared with using expensive lithium salts for reaction, this method has lower cost, so it is used more in actual production, but this method produces too much acidic wastewater containing metals and serious pollution

Method used

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  • Preparation method of meropenem intermediate cyclization compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Dissolve 0.36mol of (2R,3R)-N-(p-methoxyphenyl)-N-(2-oxo-propyl)-2,3-epoxybutyramide in tetrahydrofuran, add lithium chloride 0.05mol, lower the temperature to -10~0°C, add 0.72mol of sodium tert-butoxide to react, control the reaction temperature at 0°C, after the reaction is completed, concentrate, add 300ml of dichloromethane to the residue, add 400mL of 1N HCl solution and stir Wash for 10 min, separate the layers, wash the organic layer with saturated sodium bicarbonate until neutral, wash with saturated brine, and concentrate to remove the solvent to obtain (3S,4S)-1-p-methoxyphenyl-3-[(R)- 92 g of 1-hydroxyethyl]-4-acetyl-2-azetidinone. Yield: 82.4%, HPLC purity ≥ 85%.

[0027] The structure confirmation data of the product: 1 H-NMR (500MHz, CDCl 3 δ): 1.42(d,J=6.37Hz,3H),1.64(brs,1H),2.28(S,3H),3.2(dd,J=2.64and5.26Hz,1H),3.81(S,3H), 4.38(M,1H),4.58(d,J=2.64Hz,1H),6.90(d,J=6.87Hz,2H),7.25(d,J=6.8Hz,2H).

Embodiment 2

[0029] Dissolve 0.36mol of (2R,3R)-N-(p-methoxyphenyl)-N-(2-oxo-propyl)-2,3-epoxybutanamide in methyl tert-butyl ether , add 0.05mol of zinc chloride, lower the temperature to 0-10°C, add 0.76mol of potassium tert-butoxide, control the temperature at 20°C, after the reaction is completed, concentrate, add 300ml of dichloromethane to the residue, and add 500mL of 1N HCl solution Stir and wash for 10 min, separate layers, wash the organic layer with saturated sodium bicarbonate until neutral, wash with saturated brine, and concentrate to remove the solvent to obtain (3S,4S)-1-p-methoxyphenyl-3-[(R) - 91 g of 1-hydroxyethyl]-4-acetyl-2-azetidinone. Yield: 81.5%, HPLC purity ≥ 85%.

[0030] The structure confirmation data of the product: 1 H-NMR (500MHz, CDCl 3 δ): 1.42(d,J=6.37Hz,3H),1.64(brs,1H),2.28(S,3H),3.2(dd,J=2.64and5.26Hz,1H),3.81(S,3H), 4.38(M,1H),4.58(d,J=2.64Hz,1H),6.90(d,J=6.87Hz,2H),7.25(d,J=6.8Hz,2H).

Embodiment 3

[0032] Dissolve 0.36mol of (2R,3R)-N-(p-methoxyphenyl)-N-(2-oxo-propyl)-2,3-epoxybutanamide in toluene, add zinc chloride 0.05mol, lower the temperature to 0-10°C, add 1.08mol of sodium tert-butoxide, control the temperature at 50°C, after the reaction is completed, concentrate, add 300ml of dichloromethane, add 600mL of 1N HCl solution, stir and wash for 10min, separate layers , the organic layer was washed with saturated sodium bicarbonate until neutral, washed with saturated brine, and concentrated to remove the solvent to obtain (3S,4S)-1-p-methoxyphenyl-3-[(R)-1-hydroxyethyl ]-4-acetyl-2-azetidinone 83 g. Yield: 74.3%, HPLC purity ≥ 85%.

[0033] The structure confirmation data of the product: 1 H-NMR (500MHz, CDCl 3 δ): 1.42(d,J=6.37Hz,3H),1.64(brs,1H),2.28(S,3H),3.2(dd,J=2.64and5.26Hz,1H),3.81(S,3H), 4.38(M,1H),4.58(d,J=2.64Hz,1H),6.90(d,J=6.87Hz,2H),7.25(d,J=6.8Hz,2H).

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Abstract

The invention discloses a preparation method for synthesizing an intermediate (3S,4S)-p-methoxyphenyl-3-{(R)-1-hydroxy ethyl}-4-acetyl-2-azetidin-2-one of a meropenem intermediate cyclization compound (3R,4R)-3-{(R)-1-tert-butyl dimethyl silyloxy}-4-acetoxy-2-azetidin-2-one. The method comprises the following steps: dissolving (2R,3R)-N-(p-methoxyphenyl)-N-(2-oxo-propyl)-2,3-epoxy butyrylamide in an organic solvent, and adding lewis acid as a catalyst; cooling; and adding sodium tert-butoxide or potassium tert-butoxide to react so as to obtain the (3S,4S)-p-methoxyphenyl-3-{(R)-1-hydroxy ethyl}-4-acetyl-2-azetidin-2-one. The method disclosed by the invention is low in cost, high in reaction yield, moderate in reaction condition, little in pollution and environment-friendly, and raw materials are easily obtained.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of a meropenem intermediate. Background technique [0002] 4-AA, namely (3R,4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone, is a synthetic penem Key intermediates of drugs. In the process of synthesizing 4-AA, from (2R,3R)-N-(p-methoxyphenyl)-N-(2-oxo-propyl)-2,3-ring as shown in the following formula Preparation of (3S,4S)-1-p-methoxyphenyl-3-[(R)-1-hydroxyethyl]-4-acetyl-2-azetidinone from oxybutyramide (compound of formula Ⅱ) The cyclization reaction of (formula I cyclic compound) is a relatively critical step. [0003] [0004] The preparation of the above-mentioned compound of formula I generally needs to be completed in the presence of a basic reagent. Commonly used alkaline reagents mainly include the following categories: lithium amide compounds, such as lithium amide, lithium hexamethyldisilazide, lithium diiso...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08
CPCC07D205/08
Inventor 周熹王朝阳周卫国叶大志江雪峰
Owner JIANGSU HANKUO BIOLOGICAL
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