CN105585532B - The post-processing approach of l-ornidazole reaction solution - Google Patents
The post-processing approach of l-ornidazole reaction solution Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 51
- 229960002313 ornidazole Drugs 0.000 title claims abstract description 39
- 238000012805 post-processing Methods 0.000 title claims abstract description 17
- 238000013459 approach Methods 0.000 title claims abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 68
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000002798 polar solvent Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 239000007787 solid Substances 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 6
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 3
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- 150000003851 azoles Chemical class 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 2
- 239000004575 stone Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 230000015556 catabolic process Effects 0.000 abstract description 4
- 238000006731 degradation reaction Methods 0.000 abstract description 4
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 abstract description 3
- 230000004308 accommodation Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000006386 neutralization reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- VYDWQPKRHOGLPA-UHFFFAOYSA-N 5-nitroimidazole Chemical compound [O-][N+](=O)C1=CN=CN1 VYDWQPKRHOGLPA-UHFFFAOYSA-N 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000007605 air drying Methods 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- 239000004411 aluminium Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- -1 nitre azoles Chemical class 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
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- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
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- 206010024652 Liver abscess Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010033119 Ovarian abscess Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003103 anti-anaerobic effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940058965 antiprotozoal agent against amoebiasis and other protozoal diseases nitroimidazole derivative Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000002682 general surgery Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000004957 nitroimidazoles Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- 239000011435 rock Substances 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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.
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