Lomefloxacin hydrochloride impurity and preparation method thereof

Abstract

The invention provides a lomefloxacin hydrochloride impurity and a preparation method thereof, 2, 3, 4-trifluoroaniline is used as a raw material to prepare trifluoroaniline lomefloxacin as the lomefloxacin hydrochloride impurity through ring formation, substitution, hydrolysis, acylation, condensation and other reactions, and an impurity reference substance is provided for external standard method quantitative detection of the trifluoroaniline lomefloxacin impurity in lomefloxacin hydrochloride. And the lomefloxacin hydrochloride impurity trifluoroaniline lomefloxacin synthesized by the method is high in yield and high in purity, and the detection accuracy of the impurity trifluoroaniline lomefloxacin in the bulk drug is improved.

Description

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to a lomefloxacin hydrochloride impurity and a preparation method thereof. Background technique

[0002] Quinolones are a class of synthetic antibacterial drugs whose mechanism of action is to target bacterial deoxyribose nucleic acid gyrase and inhibit the replication and transcription of bacterial DNA, thereby achieving antibacterial effects. Lomefloxacin hydrochloride is a third-generation fluoroquinolone drug developed by Hokuriku Corporation of Japan in 1985. It is a difluoroquinolic acid with a broad antibacterial spectrum and strong antibacterial effect. It is widely used in many infectious diseases Treatment. Lomefloxacin hydrochloride has a good oral absorption effect, has a strong antibacterial effect on Gram-negative bacteria, and has a rapid bactericidal effect on both the reproductive and stationary stages.

[0003] Trace impurities contained in drugs have always be...

Examples

Embodiment 1

[0027] Preparation of Compound II:

[0028] Add 135g of raw material I and 198.5g of EMME to a 2L reaction flask, stir and heat up to 115°C for 3 hours, add 0.8L of diphenyl ether to the feed liquid, stir and heat up to 243°C for 1h, cool down to 55°C, add 200mL THF, and stir It was filtered and dried to obtain 192.6 g of compound II. Yield 77%.

[0029] Preparation of compound III:

[0030] Add 165g of compound II and 1.3L of DMF to a 3L reaction flask, stir and heat up to 110°C, add 160g of potassium carbonate and 210g of bromoethane, stir and react at 115°C for 3h, after cooling down, add 1.3L of methyl tert-butyl ether and 1.3 L of purified water was stirred for crystallization, filtered, and dried to obtain 166.2 g of compound III. Yield 89%.

[0031] Preparation of Compound IV:

[0032] Add 145g of compound III and 900mL of glacial acetic acid into a 3L reaction flask, stir to raise the temperature to dissolve, add 300g of concentrated hydrochloric acid, stir and re...

Embodiment 2

[0038] Preparation of Compound II:

[0039] Add 140g of raw material I and 205.8g of EMME to a 2L reaction flask, stir and heat up to 112°C for 3 hours, add 1.6L of diphenyl ether to the feed liquid, stir and heat up to 243°C for 1h, cool down to 55°C, add 400mL of tetrahydrofuran, stir It was filtered and dried to obtain 199.2 g of compound II. Yield 76.8%.

[0040] Preparation of compound III:

[0041] Add 170g of compound II and 1.4L of DMF to a 3L reaction flask, stir and heat up to 110°C, add 165g of potassium carbonate and 212g of bromoethane, stir and react at 115°C for 3h, after cooling down, add 1.4L of methyl tert-butyl ether and 1.4 L of purified water was stirred for crystallization, filtered, and dried to obtain 167.4 g of compound III. Yield 88%.

[0042] Preparation of Compound IV:

[0043] Add 150g of compound III and 800mL of glacial acetic acid into a 3L reaction flask, stir to dissolve the liquid, add 305g of concentrated hydrochloric acid, stir and rea...

Embodiment 3

[0049] Preparation of Compound II:

[0050] Add 145g of raw material I and 213.2g of EMME to a 2L reaction flask, stir and heat up to 120°C for 3 hours, add 2L of diphenyl ether to the feed solution, stir and heat up to 243°C for 1h, cool down to 55°C, add 500mL of tetrahydrofuran, stir and filter , and dried to obtain 210 g of compound II. Yield 78.2%.

[0051] Preparation of compound III:

[0052] Add 175g of compound II and 1.42L of DMF to a 3L reaction flask, stir and heat up to 110°C, add 170g of potassium carbonate and 213.4g of bromoethane, stir and react at 115°C for 3h, add 1.42L of methyl tert-butyl ether and 1.42L of purified water was stirred and crystallized, filtered and dried to obtain 169.2g of compound III. Yield 87.5%.

[0053] Preparation of Compound IV:

[0054]Add 155g of compound III and 700mL of glacial acetic acid into a 3L reaction flask, stir to dissolve the liquid, add 315g of concentrated hydrochloric acid, stir and react at 104°C for 3h, cool ...

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to a lomefloxacin hydrochloride impurity and a preparation method thereof. Background technique

[0002] Quinolones are a class of synthetic antibacterial drugs whose mechanism of action is to target bacterial deoxyribose nucleic acid gyrase and inhibit the replication and transcription of bacterial DNA, thereby achieving antibacterial effects. Lomefloxacin hydrochloride is a third-generation fluoroquinolone drug developed by Hokuriku Corporation of Japan in 1985. It is a difluoroquinolic acid with a broad antibacterial spectrum and strong antibacterial effect. It is widely used in many infectious diseases Treatment. Lomefloxacin hydrochloride has a good oral absorption effect, has a strong antibacterial effect on Gram-negative bacteria, and has a rapid bactericidal effect on both the reproductive and stationary stages.

[0003] Trace impurities contained in drugs have always be...

Examples

Embodiment 1

[0027] Preparation of Compound II:

[0028] Add 135g of raw material I and 198.5g of EMME to a 2L reaction flask, stir and heat up to 115°C for 3 hours, add 0.8L of diphenyl ether to the feed liquid, stir and heat up to 243°C for 1h, cool down to 55°C, add 200mL THF, and stir It was filtered and dried to obtain 192.6 g of compound II. Yield 77%.

[0029] Preparation of compound III:

[0030] Add 165g of compound II and 1.3L of DMF to a 3L reaction flask, stir and heat up to 110°C, add 160g of potassium carbonate and 210g of bromoethane, stir and react at 115°C for 3h, after cooling down, add 1.3L of methyl tert-butyl ether and 1.3 L of purified water was stirred for crystallization, filtered, and dried to obtain 166.2 g of compound III. Yield 89%.

[0031] Preparation of Compound IV:

[0032] Add 145g of compound III and 900mL of glacial acetic acid into a 3L reaction flask, stir to raise the temperature to dissolve, add 300g of concentrated hydrochloric acid, stir and re...

Embodiment 2

[0038] Preparation of Compound II:

[0039] Add 140g of raw material I and 205.8g of EMME to a 2L reaction flask, stir and heat up to 112°C for 3 hours, add 1.6L of diphenyl ether to the feed liquid, stir and heat up to 243°C for 1h, cool down to 55°C, add 400mL of tetrahydrofuran, stir It was filtered and dried to obtain 199.2 g of compound II. Yield 76.8%.

[0040] Preparation of compound III:

[0041] Add 170g of compound II and 1.4L of DMF to a 3L reaction flask, stir and heat up to 110°C, add 165g of potassium carbonate and 212g of bromoethane, stir and react at 115°C for 3h, after cooling down, add 1.4L of methyl tert-butyl ether and 1.4 L of purified water was stirred for crystallization, filtered, and dried to obtain 167.4 g of compound III. Yield 88%.

[0042] Preparation of Compound IV:

[0043] Add 150g of compound III and 800mL of glacial acetic acid into a 3L reaction flask, stir to dissolve the liquid, add 305g of concentrated hydrochloric acid, stir and rea...

Embodiment 3

[0049] Preparation of Compound II:

[0050] Add 145g of raw material I and 213.2g of EMME to a 2L reaction flask, stir and heat up to 120°C for 3 hours, add 2L of diphenyl ether to the feed solution, stir and heat up to 243°C for 1h, cool down to 55°C, add 500mL of tetrahydrofuran, stir and filter , and dried to obtain 210 g of compound II. Yield 78.2%.

[0051] Preparation of compound III:

[0052] Add 175g of compound II and 1.42L of DMF to a 3L reaction flask, stir and heat up to 110°C, add 170g of potassium carbonate and 213.4g of bromoethane, stir and react at 115°C for 3h, add 1.42L of methyl tert-butyl ether and 1.42L of purified water was stirred and crystallized, filtered and dried to obtain 169.2g of compound III. Yield 87.5%.

[0053] Preparation of Compound IV:

[0054]Add 155g of compound III and 700mL of glacial acetic acid into a 3L reaction flask, stir to dissolve the liquid, add 315g of concentrated hydrochloric acid, stir and react at 104°C for 3h, cool ...

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