CN105585532B - The post-processing approach of l-ornidazole reaction solution - Google Patents

The post-processing approach of l-ornidazole reaction solution Download PDF

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Publication number
CN105585532B
CN105585532B CN201410579006.9A CN201410579006A CN105585532B CN 105585532 B CN105585532 B CN 105585532B CN 201410579006 A CN201410579006 A CN 201410579006A CN 105585532 B CN105585532 B CN 105585532B
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China
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ornidazole
reaction solution
post
processing approach
ethyl acetate
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CN201410579006.9A
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Chinese (zh)
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CN105585532A (en
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杨学谦
王朋
刘文坤
张涛
李靖
原江涛
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山东齐都药业有限公司
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Abstract

The invention discloses a kind of post-processing approach of l-ornidazole reaction solution, belong to technical field of medicine synthesis.2 methyl, 5 nitroimidazole is added in ethyl acetate, under Aluminium Trichloride as Catalyst, adds S epoxychloropropane, reacted, after reaction, obtain reaction solution, reaction solution is added in frozen water and is quenched, then separates ethyl acetate phase, be concentrated under reduced pressure to obtain grease after dry;Then organic solvent being added into grease to be beaten, and adding small polar solvent and further separate out solid, filtration drying, obtains l-ornidazole.The post-processing approach of l-ornidazole reaction solution of the present invention, does not use the method for adding acid-base accommodation pH value, and so as to avoid because the generation of thermal degradation impurity caused by acid-base neutralization heat release, and easy to operate, yield is higher, more suitable for industrialized production.

Description

The post-processing approach of l-ornidazole reaction solution

Technical field

The present invention relates to a kind of post-processing approach of l-ornidazole reaction solution, belong to technical field of medicine synthesis.

Background technology

L-ornidazole, entitled S- (-) -1- (the chloro- 2- hydroxypropyls of the 3-) -2- 5-nitro imidazoles of chemistry, are Ornidazoles Levo form, Ornidazole are nitro imidazole derivatives, are a kind of medicines of strength anaerobe resistant and antigen insect infection, and after first The effect of being newly developed into after nitre azoles higher, the course for the treatment of is shorter, tolerance is more preferable, is distributed wider array of third generation nitro glyoxaline in vivo spreads out Biology.The anti-microbial effect of Ornidazole is that amino is reduced into oxygen-free environment by the nitro in its molecule, or by certainly Interacted by the form and cell component of base, so as to cause the death of microorganism.Commercially available Ornidazole preparation is disappeared with Ornidazole Rotation body is main ingredient.Clinical test (see patent CN1686117A) research finds l-ornidazole pharmacokinetic properties better than right nitre difficult to understand Azoles and racemization Ornidazole, and maincenter toxicity is less than right Ornidazole and racemization Ornidazole, therefore l-ornidazole is used to prepare anti-anaerobism Bacterium infection medicine has more practicality.Clinically mainly it is suitable for peritonitis, bacterial liver abscess, endometritis, defeated ovum Pipe ovarian abscess, periodontitis, periapical inflammation, cellulitis, meningitis, septicemia, department of infectious disease, Neurology, the department of stomatology, Gynemetrics, liver and gall surgical department, department of general surgery.Its structural formula is as follows:

L-ornidazole is that Nanjing of China is holy and pharmaceutcal corporation, Ltd is in exploitation in 2009 as anti anaerobic bacteria infection medicine City, the famous-brand and high-quality promise peace of commodity.

The post processing of l-ornidazole is reported in the patents such as CN1800166A, CN101817786A, CN101633643A Method, after mainly carrying out catalytic synthesis with lewis acid, water process on the rocks, then adjusts pH value by adding soda acid The excessive S- epoxychloropropane of reaction is removed, obtains l-ornidazole.

Reported in patent CN102643238 by 2- 5-nitro imidazoles and epoxychloropropane formic acid catalysis Under reacted, post processing is also to add acid to remove excessive S- epoxychloropropane in reaction to adjust pH value, is then added Alkali is adjusted to neutrality and obtains l-ornidazole.

The report of current all about last handling process, be by adding different acid-base accommodation solution ph, with up to To the purpose for removing excess epoxy chloropropane in reaction.During adjusting, due to acid-base neutralization reaction easily heat release, a left side is caused Ornidazole degradation, and thermal degradation impurity is produced, influence product purity;Therefore, after the present invention is with regard to l-ornidazole reaction solution Processing method is further studied.

The content of the invention

The present invention provides a kind of post-processing approach of l-ornidazole reaction solution, easy to operate, yield is higher, more suitable for Industrialized production.

The post-processing approach of l-ornidazole reaction solution of the present invention is as follows:

2- 5-nitro imidazoles are added in ethyl acetate, under Aluminium Trichloride as Catalyst, add S- epoxychloropropane, Reacted, after reaction, obtain reaction solution, reaction solution is added in frozen water and is quenched, then separates ethyl acetate phase, Be concentrated under reduced pressure to obtain grease after drying;Then into grease add organic solvent be beaten, and add small polar solvent into One step separates out solid, and filtration drying, obtains l-ornidazole.

2- 5-nitro imidazoles, S- epoxychloropropane, alchlor, the mass ratio of ethyl acetate in the reaction For 5-6:7-8:9-10:45-46, preferably 5:7.185:9:45.1.

The organic solvent is ethyl acetate, methyl acetate, dichloromethane, chloroform, acetone, tetrahydrofuran or ethanol One or more, ethyl acetate.

The dosage of the organic solvent is organic solvent:2- 5-nitro imidazoles are 1-2mL/g.

The small polar solvent is petroleum ether, isopropyl ether, methyl tertiary butyl ether(MTBE), hexamethylene, normal heptane or isooctane One or more, preferably petroleum ether.

The dosage of the small polar solvent is 10 times of organic solvent volume.

The principle of the present invention is as follows:

After dried organic phase has been concentrated, it is beaten, the grease after concentration can be had by adding ethyl acetate Disperseing for effect, adds small polar solvent, changes the polarity of system so that and l-ornidazole smoothly separates out, and by reaction process Excessive S- epoxychloropropane is stayed in mother liquor.And the processing method, and the once purifying to l-ornidazole, in crystallization During, it can be very good to remove caused 1- (2,3- glycidyl) -2- 5-nitro imidazoles in synthetic reaction process (impurity I) and 1- (2- oxopropyls) -2- 5-nitro imidazoles (impurity II) the two major impurities.

Compared with prior art, the invention has the advantages that:

The post-processing approach of l-ornidazole reaction solution of the present invention, does not use the method for adding acid-base accommodation pH value, So as to avoid because the generation of thermal degradation impurity caused by acid-base neutralization heat release, and easy to operate, yield is higher, more suitable for Industrialized production.

Embodiment

With reference to embodiment, the invention will be further described:

Embodiment 1

2- 5-nitro imidazole 50g are added in ethyl acetate 500mL, are cooled to 3 ± 1 DEG C, then, add trichlorine Change aluminium 90g, 5 ± 2 DEG C of controlling reaction temperature is slow added into S- epoxychloropropane 85mL, controlling reaction temperature 5 in adition process ± 2 DEG C, finish, 3 ± 1 DEG C of reactions of temperature control.Reaction is finished, and reaction solution is directly added into 2L mixture of ice and water, and control temperature is 10 ± 2 DEG C are stirred 30 minutes, separate ethyl acetate layer, with anhydrous sodium sulfate drying 4 it is small when, then at 45 ± 1 DEG C, -0.08MPa It is concentrated under reduced pressure under~-0.10MPa, is concentrated into dripless and drips, adds 50mL ethyl acetate and be beaten 30 minutes, then add stone Oily ether 500mL, separates out solid, filtering, l-ornidazole 75.6g, off-white color knot are obtained by filter cake when 45 ± 1 DEG C of heated-air dryings 8 are small Crystalline substance, yield 87.5%.

Embodiment 2

2- 5-nitro imidazole 50g are added in ethyl acetate 500mL, are cooled to 3 ± 1 DEG C, then, add trichlorine Change aluminium 90g, controlling reaction temperature is less than 5 ± 2 DEG C, is slow added into S- epoxychloropropane 85mL, reaction is controlled in adition process 5 ± 2 DEG C of temperature, finishes, 3 ± 1 DEG C of reactions of temperature control.Reaction is finished, and reaction solution is directly added into 2L mixture of ice and water, controls temperature 10 ± 2 DEG C stir 30 minutes, stir 30 minutes, separate ethyl acetate layer, with anhydrous sodium sulfate drying 4 it is small when, then 45 ± 1 DEG C, it is concentrated under reduced pressure under -0.08MPa~-0.10MPa, is concentrated into dripless and drips, adds 50mL dichloromethane mashing 30 Minute, normal heptane 500mL is then added, separates out solid, filtering, l-ornidazole is obtained by filter cake when 45 ± 1 DEG C of heated-air dryings 8 are small 73.5g, off-white color crystallization, yield 85.0%.

Embodiment 3

2- 5-nitro imidazole 50g are added in ethyl acetate 500mL, are cooled to 3 ± 1 DEG C, then, add trichlorine Change aluminium 90g, controlling reaction temperature is less than 5 ± 2 DEG C, is slow added into S- epoxychloropropane 85mL, reaction is controlled in adition process 5 ± 2 DEG C of temperature, finishes, 3 ± 1 DEG C of reactions of temperature control.Reaction is finished, and reaction solution is directly added into 2L mixture of ice and water, controls temperature Stirred 30 minutes at 10 ± 2 DEG C, separate ethyl acetate layer, dried with anhydrous sodium sulfate, then at 45 ± 1 DEG C, -0.08MPa It is concentrated under reduced pressure under~-0.10MPa, is concentrated into dripless and drips, adds 50mL acetone and be beaten 30 minutes, then add hexamethylene 500mL, separates out solid, filtering, obtains l-ornidazole 76.2g, off-white color crystallization, is received by filter cake when 45 ± 1 DEG C of heated-air dryings 8 are small Rate 88.2%.

Embodiment 4

2- 5-nitro imidazole 50g are added in ethyl acetate 500mL, are cooled to 3 ± 1 DEG C, then, add trichlorine Change aluminium 90g, controlling reaction temperature is less than 5 ± 2 DEG C, is slow added into S- epoxychloropropane 85mL, reaction is controlled in adition process 5 ± 2 DEG C of temperature, finishes, 3 ± 1 DEG C of reactions of temperature control.Reaction is finished, and reaction solution is directly added into 2L mixture of ice and water, controls temperature Stirred 30 minutes at 10 ± 2 DEG C, separate ethyl acetate layer, dried with anhydrous sodium sulfate, then at 45 ± 1 DEG C, -0.08MPa It is concentrated under reduced pressure under~-0.10MPa, is concentrated into dripless and drips, adds 50mL tetrahydrofurans and be beaten 30 minutes, then add different Propyl ether 500mL, separates out solid, filtering, l-ornidazole 71.6g, off-white color knot are obtained by filter cake when 45 ± 1 DEG C of heated-air dryings 8 are small Crystalline substance, yield 82.9%.

Claims (7)

1. a kind of post-processing approach of l-ornidazole reaction solution, is included in addition 2- 5-nitro imidazoles in ethyl acetate, Under Aluminium Trichloride as Catalyst, S- epoxychloropropane is added, is reacted, after reaction, obtains reaction solution, it is characterised in that first Reaction solution is added in frozen water and is quenched, then separates ethyl acetate phase, be concentrated under reduced pressure to obtain grease after dry;Most backward oil Organic solvent is added in shape thing to be beaten, and adds small polar solvent and further separates out solid, and filtration drying, obtains left nitre difficult to understand Azoles;
Organic solvent is one kind or more in ethyl acetate, methyl acetate, dichloromethane, chloroform, acetone, tetrahydrofuran or ethanol Kind;
Small polar solvent is one kind or more in petroleum ether, isopropyl ether, methyl tertiary butyl ether(MTBE), hexamethylene, normal heptane or isooctane Kind.
2. the post-processing approach of l-ornidazole reaction solution according to claim 1, it is characterised in that 2- methyl in reaction- 5- nitroimidazoles, S- epoxychloropropane, alchlor, the mass ratio of ethyl acetate are 5-6:7-8:9-10:45-46.
3. the post-processing approach of l-ornidazole reaction solution according to claim 2, it is characterised in that 2- methyl in reaction- 5- nitroimidazoles, S- epoxychloropropane, alchlor, the mass ratio of ethyl acetate are 5:7.185:9:45.1.
4. the post-processing approach of l-ornidazole reaction solution according to claim 1, it is characterised in that organic solvent is acetic acid Ethyl ester.
5. the post-processing approach of the l-ornidazole reaction solution according to claim 1 or 4, it is characterised in that organic solvent Dosage is that the ratio of organic solvent and 2- 5-nitro imidazoles is 1-2, and organic solvent is in terms of mL, 2- methyl-5-nitro miaows Azoles is in terms of g.
6. the post-processing approach of l-ornidazole reaction solution according to claim 1, it is characterised in that small polar solvent is stone Oily ether.
7. the post-processing approach of l-ornidazole reaction solution according to claim 6, it is characterised in that the use of small polar solvent Measure as 10 times of organic solvent volume.
CN201410579006.9A 2014-10-24 2014-10-24 The post-processing approach of l-ornidazole reaction solution CN105585532B (en)

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US3435049A (en) * 1965-05-19 1969-03-25 Hoffmann La Roche Nitroimidazole derivatives
CN1651415A (en) * 2004-11-29 2005-08-10 南京圣和药业有限公司 Preparation and purification method of ornidazole optical antipode
CN1800166A (en) * 2004-11-29 2006-07-12 南京圣和药业有限公司 Ornidazole optical antimer preparation and purification method
CN1923817A (en) * 2005-11-16 2007-03-07 沈阳中海生物技术开发有限公司 Preparation method for optical enantiomer of ornidaxole
CN101633643A (en) * 2009-08-14 2010-01-27 海南美大制药有限公司 Ornidazole compound in new path
CN101781293A (en) * 2010-03-03 2010-07-21 本溪瑞圣康药物开发有限公司 Antibacterial compound, preparation method and application thereof
CN101817786A (en) * 2010-04-13 2010-09-01 陕西合成药业有限公司 Method for preparing (S)-ornidazole
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CN102643238A (en) * 2012-04-06 2012-08-22 陕西合成药业有限公司 Preparation and purification method for new ornidazole optical antimer

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CN1651415A (en) * 2004-11-29 2005-08-10 南京圣和药业有限公司 Preparation and purification method of ornidazole optical antipode
CN1800166A (en) * 2004-11-29 2006-07-12 南京圣和药业有限公司 Ornidazole optical antimer preparation and purification method
CN1923817A (en) * 2005-11-16 2007-03-07 沈阳中海生物技术开发有限公司 Preparation method for optical enantiomer of ornidaxole
CN101633643A (en) * 2009-08-14 2010-01-27 海南美大制药有限公司 Ornidazole compound in new path
CN101781293A (en) * 2010-03-03 2010-07-21 本溪瑞圣康药物开发有限公司 Antibacterial compound, preparation method and application thereof
CN101817786A (en) * 2010-04-13 2010-09-01 陕西合成药业有限公司 Method for preparing (S)-ornidazole
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Inventor after: Yang Xueqian

Inventor after: Wang Peng

Inventor after: Liu Wenkun

Inventor after: Zhang Tao

Inventor after: Li Jing

Inventor after: Yuan Jiangtao

Inventor before: Yang Xueqian

Inventor before: Cao Peng

Inventor before: Liu Wenkun

Inventor before: Zhang Tao

Inventor before: Gong Xiaowei

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Denomination of invention: After-treatment method for levornidazole reaction liquid

Effective date of registration: 20181213

Granted publication date: 20180501

Pledgee: CITIC Bank, Limited by Share Ltd, Zibo branch

Pledgor: Qidu Pharmaceutical Co., Ltd., Shandong Prov.

Registration number: 2018370000224