Method for preparing doripenem intermediate compound

A technology for doripenem and compounds, applied in the field of preparation of doripenem intermediate compounds, can solve the problems of cumbersome operation, high cost, and many products, and achieve simple operation, high product purity and yield, and product separation easy effect

Active Publication Date: 2012-07-04
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The technical problem to be solved by the present invention is to overcome the defects of more impurities in the product, cumbersome operation, higher cost and lower yield in the existing process for preparing the key intermediate of doripenem, and provide a The method for preparing the key intermediate of doripenem, the preparation method of the present invention has higher product yield, higher purity, simple operation, simple post-treatment and cost saving, and is easy to realize industrialization

Method used

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  • Method for preparing doripenem intermediate compound
  • Method for preparing doripenem intermediate compound
  • Method for preparing doripenem intermediate compound

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Experimental program
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Effect test

Embodiment 1

[0039] Embodiment 1: the synthesis of compound (I)

[0040] Under the protection of nitrogen, add white powder compound of formula (II) (10.9g, 0.0179mol), add about 80ml of DMF to dissolve and mix, cool in ice bath to about 0°C, add compound (III) (5.28g, 0.0179mol) in DMF (15ml) solution, cooled to 0°C, gradually added triethylamine (2.54g, 0.025mol) dropwise, after the addition, stirred at -5°C to 0°C for 10 hours to complete the reaction, then added ethyl acetate Ethyl acetate, extracted with water, washed the ethyl acetate layer with one equivalent of dilute hydrochloric acid, adjusted the pH to about 3, added saturated aqueous sodium bicarbonate solution to wash, adjusted the pH value to 7-8, washed twice with saturated saline, and separated the ethyl acetate Layers were evaporated to dryness under reduced pressure to obtain off-white foamy solid (I), dried under reduced pressure, about 6.57g, yield: 67.5%.

[0041] The property determination result of compound (I): 1 ...

Embodiment 2

[0042] Embodiment 2: the synthesis of compound (I)

[0043]Under the protection of nitrogen, add white powder compound of formula (II) (10.9g, 0.0179mol), add about 54.5ml of DMF to dissolve and mix, cool to about 0°C in an ice bath, add compound (III) (5.28g , 0.0179mol) in DMF (15ml) solution, cooled to 0°C, gradually added dropwise N-methylmorpholine (2.53g, 0.025mol), after adding, -5°C~0°C, stirred for 10 hours and the reaction was complete , add ethyl acetate, extract with water, wash the ethyl acetate layer with one equivalent of dilute hydrochloric acid, adjust the pH to about 3, add saturated aqueous sodium bicarbonate solution to wash, adjust the pH to 7-8, wash twice with saturated saline, divide The ethyl acetate layer was removed and evaporated to dryness under reduced pressure to obtain off-white foamy solid (I), which was dried under reduced pressure, about 5.86 g, yield: 60.2%.

[0044] The property determination result of compound (I): 1 H-NMR δ 1.16(d, 3H),...

Embodiment 3

[0045] Embodiment 3: the synthesis of compound (I)

[0046] Under the protection of nitrogen, add white powder compound of formula (II) (10.9g, 0.0179mol), add about 163.5ml of acetonitrile to dissolve and mix, cool in ice bath to about 0°C, add compound (III) (5.28g , 0.0179mol) in acetonitrile (15ml) solution, cooled to 0°C, gradually added diisopropylethylamine (3.23g, 0.025mol) dropwise, after adding, stirred at -5°C to 0°C for 10 hours to react Complete, add ethyl acetate, extract with water, wash the ethyl acetate layer with one equivalent of dilute hydrochloric acid, adjust the pH to about 3, add saturated aqueous sodium bicarbonate solution to wash, adjust the pH to 7-8, wash twice with saturated saline, The ethyl acetate layer was separated and evaporated to dryness under reduced pressure to obtain off-white foamy solid (I), dried under reduced pressure, about 5.85 g, yield: 60.1%.

[0047] The property determination result of compound (I): 1 H-NMR δ 1.16(d, 3H), 1....

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Abstract

The invention discloses a method for preparing a doripenem intermediate compound (I), which comprises the following step: under the protection of inert gas, in a polar aprotic solvent, reacting a compound (II) with a compound (III) at the temperature of between -60 and 25 DEG C under the action of organic base, wherein AOC is allyloxycarbonyl group. The preparation method has the advantages of high yield and high purity of the product, simple operation, simple posttreatment, cost conservation and easy realization of industrialization.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate compound, in particular to a preparation method of a doripenem intermediate compound. Background technique [0002] So far, there have been a large number of reports of natural or synthetic β-lactam inhibitors. From the structure of the compound, they can be divided into oxypenems, penems, carbapenems and monocyclic β-lactam inhibitors. Lactam oxypenems, among which carbapenems, especially β-methyl carbapenems, such as imipenem, meropenem, and biapenem have good antibacterial effects on many drug-resistant bacteria, In particular, it has a fairly strong inhibitory effect on B-type enzymes, and is a series of unique β-lactamase inhibitors. Since the discovery of thiamycin's current antibacterial activity against Gram-negative and Gram-positive bacteria, research on the synthesis of carbapenem or penem derivatives similar to thiamycin has been extensively carried out. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D477/20
Inventor 曹旭峰袁哲东朱雪焱刘相奎俞雄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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