Preparation method of 7-chloro-2-oxoheptanoic acid ethyl ester

Abstract

The invention discloses a preparation method of 7-chloro-2-oxoheptanoic acid ethyl ester. The method comprises the steps as follows: firstly, 1-bromo-5-chloropentane and magnesium perform a Grignard reaction in a benzene dissolvent containing organic base; secondly, an obtained Grignard solution and ethyloxalylmonochloride perform an addition reaction; lastly, a product obtained from the addition reaction performs an acid hydrolysis reaction to obtain the 7-chloro-2-oxoheptanoic acid ethyl ester. The product, namely the 7-chloro-2-oxoheptanoic acid ethyl ester, obtained via the preparation method disclosed by the invention, has purity over 98 percent, is higher in yield, and remarkably lowers the production cost.

Description

technical field

[0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of ethyl 7-chloro-2-oxoheptanoate. Background technique

[0002] Ethyl 7-chloro-2-oxoheptanoate is an important starting material for the synthesis of cilastatin. Cilastatin is a renal dehydrodiphthalase inhibitor developed by Merck & Co. of the United States. It can inhibit the renal metabolism of imipenem, a broad-spectrum antimicrobial drug currently in clinical use, and has the effect of reducing nephrotoxicity. At the same time, it can increase the blood inhibitory concentration of imipenem in the body, and the curative effect is very significant. Therefore, in the past ten years, domestic and foreign chemists have carried out a lot of research work on how to improve the purity and yield of synthetic cilastatin. Because ethyl 7-chloro-2-oxoheptanoate is an important starting material for the synthesis of cilastatin, and the purity of the raw m...

Examples

Embodiment 1

[0049] According to the preparation method of this example, using 1-bromo-5-chloropentane as the starting material, 7-chloro-2-oxoheptanoic acid ethyl ester was prepared through the following steps:

[0050](1) Add 15g (0.625mol) of magnesium into a 500ml four-neck flask, add 20ml of anhydrous THF and 1ml of 1-bromo-5-chloropentane and stir to initiate the reaction. 100g (0.54mol) of 1-bromo-5-chloropentane was mixed with 400ml of anhydrous THF, and then added dropwise to the four-necked flask. During the dropwise addition, the temperature of the material in the four-necked flask was kept at -10°C to -15°C After dropping, react until the magnesium powder completely disappears to obtain Grignard solution, detect 1-bromo-5-chloropentane residual ≤ 1%, seal it for use;

[0051] (2) In another dry four-neck flask, under mechanical stirring and nitrogen protection, add THF100ml and oxalic acid monoethyl chloride 85g (0.62mol), cool down to -15℃~-10℃, add dropwise 1) For the above-...

Embodiment 2

[0054] According to the preparation method of this example, using 1-bromo-5-chloropentane as the starting material, 7-chloro-2-oxoheptanoic acid ethyl ester was prepared through the following steps:

[0055] (1) Add 24g (1mol) of magnesium into a 500ml four-neck flask, add 20ml of anhydrous THF and 1ml of 1-bromo-5-chloropentane and stir to initiate the reaction. Mix 168g (0.9mol) of 1-bromo-5-chloropentane with 600ml of methyl tetrahydrofuran and add it dropwise into a four-necked flask. During the dropwise addition, the temperature of the material in the four-necked flask is kept at -10°C to -15°C After dropping, react until the magnesium powder completely disappears to obtain Grignard solution, detect 1-bromo-5-chloropentane residual ≤ 1%, seal it for use;

[0056] (2) In a dry 1L four-neck flask, under mechanical stirring and nitrogen protection, add 200ml of methyl tetrahydrofuran and 150g (1.1mol) of monoethyl oxalate chloride, cool down to -10°C ~ -15°C, dropwise add F...

technical field

[0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of ethyl 7-chloro-2-oxoheptanoate. Background technique

[0002] Ethyl 7-chloro-2-oxoheptanoate is an important starting material for the synthesis of cilastatin. Cilastatin is a renal dehydrodiphthalase inhibitor developed by Merck & Co. of the United States. It can inhibit the renal metabolism of imipenem, a broad-spectrum antimicrobial drug currently in clinical use, and has the effect of reducing nephrotoxicity. At the same time, it can increase the blood inhibitory concentration of imipenem in the body, and the curative effect is very significant. Therefore, in the past ten years, domestic and foreign chemists have carried out a lot of research work on how to improve the purity and yield of synthetic cilastatin. Because ethyl 7-chloro-2-oxoheptanoate is an important starting material for the synthesis of cilastatin, and the purity of the raw m...

Examples

Embodiment 1

[0049] According to the preparation method of this example, using 1-bromo-5-chloropentane as the starting material, 7-chloro-2-oxoheptanoic acid ethyl ester was prepared through the following steps:

[0050](1) Add 15g (0.625mol) of magnesium into a 500ml four-neck flask, add 20ml of anhydrous THF and 1ml of 1-bromo-5-chloropentane and stir to initiate the reaction. 100g (0.54mol) of 1-bromo-5-chloropentane was mixed with 400ml of anhydrous THF, and then added dropwise to the four-necked flask. During the dropwise addition, the temperature of the material in the four-necked flask was kept at -10°C to -15°C After dropping, react until the magnesium powder completely disappears to obtain Grignard solution, detect 1-bromo-5-chloropentane residual ≤ 1%, seal it for use;

[0051] (2) In another dry four-neck flask, under mechanical stirring and nitrogen protection, add THF100ml and oxalic acid monoethyl chloride 85g (0.62mol), cool down to -15℃~-10℃, add dropwise 1) For the above-...

Embodiment 2

[0054] According to the preparation method of this example, using 1-bromo-5-chloropentane as the starting material, 7-chloro-2-oxoheptanoic acid ethyl ester was prepared through the following steps:

[0055] (1) Add 24g (1mol) of magnesium into a 500ml four-neck flask, add 20ml of anhydrous THF and 1ml of 1-bromo-5-chloropentane and stir to initiate the reaction. Mix 168g (0.9mol) of 1-bromo-5-chloropentane with 600ml of methyl tetrahydrofuran and add it dropwise into a four-necked flask. During the dropwise addition, the temperature of the material in the four-necked flask is kept at -10°C to -15°C After dropping, react until the magnesium powder completely disappears to obtain Grignard solution, detect 1-bromo-5-chloropentane residual ≤ 1%, seal it for use;

[0056] (2) In a dry 1L four-neck flask, under mechanical stirring and nitrogen protection, add 200ml of methyl tetrahydrofuran and 150g (1.1mol) of monoethyl oxalate chloride, cool down to -10°C ~ -15°C, dropwise add F...

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