Preparation method and application of doripenem side chain disulfide

Abstract

The invention discloses a preparation method and application of doripenem side chain disulfide. The doripenem side chain disulfide, serving as a reference substance of a standard impurity, is used for purifying an important intermediate doripenem side chain in preparation of doripenem, provides a reliable reference index, improves the purity of the doripenem side chain, and finally improves a purification process of a doripenem medicine.

Description

technical field

[0001] The invention relates to a preparation method and application of doripenem side chain disulfide. It belongs to the field of organic chemistry and medicine. Background technique

[0002] Doripenem (S-4661) is a new broad-spectrum carbapenem antibiotic developed by Japan Shioyagi Company. It has the characteristics of broad antibacterial spectrum and stability to most β-lactamases. Johnson & Johnson obtained the right to develop and market the drug from Shionogi Corporation of Japan. In September 2005, doripenem was launched in Japan for the first time under the product name Finibax. In October 2007, the US FDA approved the drug injection for the clinical treatment of complicated intra-abdominal infection and complicated urinary tract infection. Its chemical name is: (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoylaminomethylpyrrolidin-3-yl ] Thio-1-methyl-1-carbo-2-penem-3-carboxylic acid, monohydrate. The structural formula is as follows:...

Examples

Embodiment 1

[0044] A preparation method of doripenem side chain disulfide, comprising the following steps:

[0045] 1) Dissolving 10 grams of doripenem side chains in 40 grams of methanol to form a methanol solution of A; adding 3 grams of 30% sodium methoxide-methanol solution to the resulting methanol solution of doripenem side chains, The dropping rate was 0.3 g / min, mechanically stirred at a speed of 100 rpm, and reacted at 20° C. for 1.2 hours to obtain a pale yellow clear liquid, which was sampled for HPLC to detect the reaction;

[0046] 2) Dissolve 2 grams of ferric chloride in 8 grams of methanol to obtain a suspension, add the resulting suspension to the light yellow clear liquid obtained in step 1), and stir mechanically at a temperature of 20°C at a speed of 100 rpm to form a mixed solution;

[0047] 3) Introduce oxygen into the mixed liquid, keep the oxygen pressure at 0.08MPa, react at 20°C for 3 to 4 hours, and the HPLC test shows that the reaction is complete, and the rea...

Embodiment 2

[0052] A preparation method of doripenem side chain disulfide, comprising the following steps:

[0053] 1) Dissolving 20 grams of doripenem side chains in 40 grams of methanol to form a methanol solution of A; adding 3.5 grams of 30% sodium methoxide-methanol solution to the resulting methanol solution of doripenem side chains, The rate of addition was 0.4 g / min, and the speed was 300 r / min with mechanical stirring, and reacted at 30° C. for 1.5 hours to obtain a light yellow clear liquid, which was sampled for HPLC to detect the reaction;

[0054] 2) Dissolve 5 grams of ferric chloride in 10 grams of methanol to obtain a suspension, add the resulting suspension to the light yellow clear liquid obtained in step 1), and stir mechanically at a temperature of 30°C at a speed of 100 rpm to form a mixed solution;

[0055] 3) Introduce oxygen into the mixed liquid, keep the oxygen pressure at 0.12MPa, react at 30°C for 2.5h, and the HPLC test shows that the reaction is complete, an...

Embodiment 3

[0060] A preparation method of doripenem side chain disulfide, comprising the following steps:

[0061] 1) Dissolving 30 grams of doripenem side chains in 180 grams of methanol to form a methanol solution of A; adding 3.2 grams of 30% sodium methoxide-methanol solution to the resulting methanol solution of doripenem side chains, The rate of addition was 0.35 g / min, and the speed was 200 r / min with mechanical stirring, and reacted at 25°C for 1.3 hours to obtain a light yellow clear liquid, which was sampled for HPLC to detect the reaction;

[0062] 2) Dissolve 7.5 grams of ferric chloride in 18 grams of methanol to obtain a suspension, which is added to the light yellow clear liquid obtained in step 1), and mechanically stirred at a temperature of 28°C at a speed of 200 rpm to form a mixed solution;

[0063] 3) Introduce oxygen into the mixed liquid, keep the oxygen pressure at 0.10 MPa, react at 25°C for 2.8 hours, and the reaction is complete as detected by HPLC, and the re...

technical field

[0001] The invention relates to a preparation method and application of doripenem side chain disulfide. It belongs to the field of organic chemistry and medicine. Background technique

[0002] Doripenem (S-4661) is a new broad-spectrum carbapenem antibiotic developed by Japan Shioyagi Company. It has the characteristics of broad antibacterial spectrum and stability to most β-lactamases. Johnson & Johnson obtained the right to develop and market the drug from Shionogi Corporation of Japan. In September 2005, doripenem was launched in Japan for the first time under the product name Finibax. In October 2007, the US FDA approved the drug injection for the clinical treatment of complicated intra-abdominal infection and complicated urinary tract infection. Its chemical name is: (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoylaminomethylpyrrolidin-3-yl ] Thio-1-methyl-1-carbo-2-penem-3-carboxylic acid, monohydrate. The structural formula is as follows:...

Examples

Embodiment 1

[0044] A preparation method of doripenem side chain disulfide, comprising the following steps:

[0045] 1) Dissolving 10 grams of doripenem side chains in 40 grams of methanol to form a methanol solution of A; adding 3 grams of 30% sodium methoxide-methanol solution to the resulting methanol solution of doripenem side chains, The dropping rate was 0.3 g / min, mechanically stirred at a speed of 100 rpm, and reacted at 20° C. for 1.2 hours to obtain a pale yellow clear liquid, which was sampled for HPLC to detect the reaction;

[0046] 2) Dissolve 2 grams of ferric chloride in 8 grams of methanol to obtain a suspension, add the resulting suspension to the light yellow clear liquid obtained in step 1), and stir mechanically at a temperature of 20°C at a speed of 100 rpm to form a mixed solution;

[0047] 3) Introduce oxygen into the mixed liquid, keep the oxygen pressure at 0.08MPa, react at 20°C for 3 to 4 hours, and the HPLC test shows that the reaction is complete, and the rea...

Embodiment 2

[0052] A preparation method of doripenem side chain disulfide, comprising the following steps:

[0053] 1) Dissolving 20 grams of doripenem side chains in 40 grams of methanol to form a methanol solution of A; adding 3.5 grams of 30% sodium methoxide-methanol solution to the resulting methanol solution of doripenem side chains, The rate of addition was 0.4 g / min, and the speed was 300 r / min with mechanical stirring, and reacted at 30° C. for 1.5 hours to obtain a light yellow clear liquid, which was sampled for HPLC to detect the reaction;

[0054] 2) Dissolve 5 grams of ferric chloride in 10 grams of methanol to obtain a suspension, add the resulting suspension to the light yellow clear liquid obtained in step 1), and stir mechanically at a temperature of 30°C at a speed of 100 rpm to form a mixed solution;

[0055] 3) Introduce oxygen into the mixed liquid, keep the oxygen pressure at 0.12MPa, react at 30°C for 2.5h, and the HPLC test shows that the reaction is complete, an...

Embodiment 3

[0060] A preparation method of doripenem side chain disulfide, comprising the following steps:

[0061] 1) Dissolving 30 grams of doripenem side chains in 180 grams of methanol to form a methanol solution of A; adding 3.2 grams of 30% sodium methoxide-methanol solution to the resulting methanol solution of doripenem side chains, The rate of addition was 0.35 g / min, and the speed was 200 r / min with mechanical stirring, and reacted at 25°C for 1.3 hours to obtain a light yellow clear liquid, which was sampled for HPLC to detect the reaction;

[0062] 2) Dissolve 7.5 grams of ferric chloride in 18 grams of methanol to obtain a suspension, which is added to the light yellow clear liquid obtained in step 1), and mechanically stirred at a temperature of 28°C at a speed of 200 rpm to form a mixed solution;

[0063] 3) Introduce oxygen into the mixed liquid, keep the oxygen pressure at 0.10 MPa, react at 25°C for 2.8 hours, and the reaction is complete as detected by HPLC, and the re...

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