CN100338039C - Ornidazole optical antimer preparation and purification method - Google Patents
Ornidazole optical antimer preparation and purification method Download PDFInfo
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- CN100338039C CN100338039C CNB2005101270333A CN200510127033A CN100338039C CN 100338039 C CN100338039 C CN 100338039C CN B2005101270333 A CNB2005101270333 A CN B2005101270333A CN 200510127033 A CN200510127033 A CN 200510127033A CN 100338039 C CN100338039 C CN 100338039C
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- ornidazole
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- optical enantiomorph
- enantiomorph according
- epoxy chloropropane
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Abstract
The present invention provides a preparation and purification method for an ornidazole optical antimer. In the method, 2-methyl-5-nitroimidazole reacts with epoxy chloropropane (S-(+)-epoxy chloropropane or R-(-)-epoxy chloropropane) with optical activity to obtain an intermediate product; the obtained intermediate product is then hydrolyzed, acidified and neutralized to obtain the ornidazole with optical activity; the ornidazole with optical activity is purified to obtain pure S-(-)-ornidazole or R-(+)-ornidazole. The present invention has the advantages of easy operation and high purity of products and suitability for industrial mass production.
Description
Technical field
The present invention relates to the preparation and the purification process of ornidazole optical enantiomorph.
Background technology
Ornidazole (Ornidazole, CAS 16773-42-5) is nitro imidazole derivatives, be the medicine that a kind of powerful anaerobe resistant and protozoacide infect, also be that the curative effect that newly is developed into is higher, the course of treatment is shorter, tolerance is better behind metronidazole, the wider third generation nitro imidazole derivatives of distribution in the body.Its chemistry 1-(3-chloro-2-hydroxypropyl) by name-2-methyl-5-nitro imidazoles, molecular formula: C
7H
10ClN
3O
3, molecular weight: 219.6.The anti-microbial effect of ornidazole is to be reduced into amino by the nitro in its molecule in oxygen-free environment, or interacts by the formation and the cellular constituent of free radical, thereby causes the death of microorganism.Prior art has and splits to such an extent that left and rightly revolve ornidazole (seeing CN 1400312A) from the ornidazole raceme by enzyme process, but thus method to get the required cost of ornidazole optical enantiomorph bigger, and be not suitable for big production.
Summary of the invention
The purpose of this invention is to provide can make the purity height, outward appearance is good and the preparation and the purification process of ornidazole optical enantiomorph that be applicable to suitability for industrialized production.
The present invention realizes by following technical measures:
With 2-methyl-5-nitro imidazoles with have optically active epichlorohydrin reaction, intermediate product hydrolysis again, promptly get the active ornidazole of respective optical.Specific as follows:
S-(-)-ornidazole is prepared as follows:
S-(+)-epoxy chloropropane
S-(-)-ornidazole
R-(+)-ornidazole is prepared as follows:
R-(-)-epoxy chloropropane
R-(+)-ornidazole
The present invention adopts following experiment to obtain the higher ornidazole optical enantiomorph of purity altogether, this method comprises drip S-(+)-epoxy chloropropane in the ethyl acetate solution of 2-methyl-5-nitro imidazoles, carry out condensation reaction, and then the reaction that is hydrolyzed generates S-(-)-ornidazole, carry out acidifying subsequently, neutralization reaction gets S-(-)-ornidazole finished product, recrystallization gets pure product S-(-)-ornidazole again; Perhaps
In the ethyl acetate solution of 2-methyl-5-nitro imidazoles, drip R-(-)-epoxy chloropropane, carry out condensation reaction, and then the reaction that is hydrolyzed generates R-(+)-ornidazole, carries out acidifying subsequently, neutralization reaction gets R-(+)-ornidazole finished product, and recrystallization gets pure product R-(+)-ornidazole again.
More particularly, above-mentioned condensation reaction is to carry out under the katalysis of Lewis acid, and control reaction temperature is-10～20 ℃ (being preferably 0～10 ℃); Add the back in 0～20 ℃ of (being preferably 5～10 ℃) insulation reaction 1～5 hour (being preferably 2.5 hours); Then, reactant adds the water reaction that is hydrolyzed, and controlled temperature is 0～40 ℃ (being preferably 20～30 ℃), stirs 0.5～2 hour (being preferably 1 hour); With reacting liquid filtering, the filtrate standing demix adds mineral acid after getting organic addition water again, carries out acidification reaction, makes pH 0.5～2.0 (being preferably 1.0), standing demix, and it is mutually stand-by to fetch water; In aqueous phase solution, add ethyl acetate and weak base, carry out neutralization reaction, make pH at 6.5～8.0 (being preferably 7.0～7.5), standing demix; Get organic phase siccative drying, get crude product behind the concentrating under reduced pressure; Get pure product with the organic solvent recrystallization.When adopting S-(+)-epoxy chloropropane, obtain S-(-)-ornidazole for raw material; When adopting R-(-)-epoxy chloropropane, obtain R-(+)-ornidazole for raw material.The present invention is easy and simple to handle, yield is high, quality product is better.
The acid of Lewis described in the present invention can be iron(ic) chloride, zinc chloride or aluminum chloride, is preferably aluminum chloride.
The mineral acid that acidification reaction described in the present invention adopts can be concentrated hydrochloric acid or 40%～60% sulfuric acid, is preferably concentrated hydrochloric acid or 50% sulfuric acid.
The weak base that neutralization reaction described in the present invention adopts can be sodium bicarbonate, triethylamine, diethylamine or ammoniacal liquor etc., is preferably ammoniacal liquor.
The used organic solvent of recrystallization described in the present invention can be toluene, ethyl acetate, ethanol or methyl alcohol etc., is preferably toluene.
According to the method for the invention, adopt S-(+)-epoxy chloropropane to make S-(-)-ornidazole, adopt R-(-)-epoxy chloropropane to make R-(+)-ornidazole.
The present invention is easy and simple to handle, and product purity can reach more than 99.5%.
Embodiment
Embodiment 1
In 1000 liters of enamel reactors of exsiccant, drop into 52.5 kilograms of 500 liters of ethyl acetate and 2-methyl-5-nitro imidazoles, stirring is reduced to 0 ℃, and 80 kilograms aluminum chloride are added in the reactor in batches, and controlled temperature must not be above 10 ℃, be cooled to 5 ℃ after adding, keep and stirred 1 hour; 50 liters of S-(+)-epoxy chloropropane is dropped in the reactor, and controlled temperature is no more than 10 ℃, adds the 5-10 ℃ of insulation reaction in back 2.5 hours; 300 liters of frozen water slowly are added in the reaction solution, and controlled temperature is no more than 30 ℃, adds the 20-30 ℃ of insulation reaction in back 1 hour; With reacting liquid filtering, the filtrate standing demix, get 200 liters in organic addition water after restir add about 50 liters of concentrated hydrochloric acid, making pH value is 1.0, standing demix is fetched water and is added to 500 liters of ethyl acetate, dropping ammonia, making pH is 7.0-7.5, standing demix; Get the organic phase anhydrous magnesium sulfate drying, obtain S-(-)-ornidazole crude product behind the concentrating under reduced pressure, use the toluene recrystallization, 29.3 kilograms of S-(-)-ornidazole, [α]
D 20-68.2 (c1.0, CH
2Cl
2), yield is 68%, purity is 99.6%, (reclaiming 12.5 kilograms of 2-methyl-5-nitro imidazoles).
Embodiment 2
In 1000 liters of enamel reactors of exsiccant, drop into 500 liters of ethyl acetate and 52.5 kilograms of 2-methyl-5-nitro imidazoles (kg), stirring is reduced to 0 ℃, and the iron(ic) chloride of 80kg is added in the reactor in batches, and controlled temperature must not be above 10 ℃, be cooled to 5 ℃ after adding, keep and stirred 1 hour; 50 liters of R-(-)-epoxy chloropropane is dropped in the reactor, and controlled temperature is no more than 10 ℃, adds the 5-10 ℃ of insulation reaction in back 3 hours; 300 liters of frozen water slowly are added in the reaction solution, and controlled temperature is no more than 30 ℃, adds the 20-30 ℃ of insulation reaction in back 1.5 hours; With reacting liquid filtering, the filtrate standing demix, get 200 liters in organic addition water after restir add about 50 liters of concentrated hydrochloric acid, making pH value is 1.5, standing demix, water intaking is added to 500 liters of ethyl acetate, the dropping triethylamine, making pH is 7.0-7.5, standing demix; Get the organic phase anhydrous sodium sulfate drying, obtain R-(+)-ornidazole crude product behind the concentrating under reduced pressure, use the toluene recrystallization, get R-(+)-ornidazole 29.1kg, [α]
D 20+ 68.4 (c0.8, CH
2Cl
2), yield is 67%, purity is 99.7%, (reclaiming 2-methyl-5-nitro imidazoles 12.8kg).
Embodiment 3
The purifying of goods.By the S-(-) that makes among the embodiment 1-ornidazole crude product (impurity 13%) 200 gram (g) and 2000 milliliters of input reaction flasks of toluene, stirring is warming up to 60 ℃, insulated and stirred is filtered while hot after 15 minutes, filtrate is placed crystallization in 12 hours down in-5 ℃, filter solid 160g (impurity 2%), the ethanol of dried solid and 128 milliliter 75% is dropped into reaction flask, stirring is warming up to 55 ℃, treat to add gac 2g after the solid dissolving, insulated and stirred is filtered while hot after 20 minutes, and filtrate is placed crystallization in 12 hours for 5 ℃, filters, the gained solid is with cold ethanol drip washing, dry S-(-)-ornidazole 112g (impurity 0.2%).
Embodiment 4
S-(-)-ornidazole that makes by embodiment 1,2 and the HPLC of R-(+)-ornidazole differentiate
Chromatographic condition is as follows: chromatographic column: OB-H; Moving phase: Virahol-normal hexane-methyl tertiary butyl ether-Glacial acetic acid (2: 90: 8: 0.2); Measure wavelength: 314nm.As a result, the retention time of S-(-)-ornidazole is 48.6min, and the retention time of R-(+)-ornidazole is 43.6min.
Embodiment 5
S-(-)-ornidazole, R-(+)-ornidazole and the racemization ornidazole specific optical rotation in different solutions relatively
The digital automatic polarimeter of instrument: WZZ-2S; Temperature: 20 ℃; Humidity: 50%.Learn from else's experience 60 ℃ of drying under reduced pressure of Vanadium Pentoxide in FLAKES to S-(-)-ornidazole, R-(+)-ornidazole and the racemization ornidazole of constant weight, press two appendix VIE of Chinese Pharmacopoeia version in 2000 angle-of-rotation measuring method and measure specific optical rotation.The results are shown in Table 1.
Table 1. specific optical rotation measurement result
| Solvent | S-(-)-ornidazole | R-(+)-ornidazole | The racemization ornidazole |
| The water methanol dichloromethane ethanol | -40.2° -32.4° -45.3° -68.2° | +41.3° +33.2° +45.3° +68.4° | 0° 0° 0° 0° |
Claims (20)
1. the preparation method of ornidazole optical enantiomorph, this method comprises carries out condensation reaction with 2-methyl-5-nitro imidazoles and S-(+)-epoxy chloropropane, and the hydrolysis again of gained intermediate product, acidifying, neutralization obtain S-(-)-ornidazole, if necessary, repurity gets pure product S-(-)-ornidazole; Perhaps
With 2-methyl-5-nitro imidazoles and R-(-)-epichlorohydrin reaction, the hydrolysis again of gained intermediate product, acidifying, neutralization obtain R-(+)-ornidazole, and if necessary, repurity gets pure product R-(+)-ornidazole.
2. the preparation method of ornidazole optical enantiomorph according to claim 1, wherein concrete steps are:
Under the katalysis of Lewis acid, in the ethyl acetate solution of 2-methyl-5-nitro imidazoles, drip S-(+)-epoxy chloropropane, add the back and carried out condensation reaction 1～5 hour 0～20 ℃ of insulation, reactant adds water and is hydrolyzed, hydrolysis afterreaction liquid is filtered, and the filtrate standing demix adds mineral acid after getting organic addition water again, standing demix, it is mutually stand-by to fetch water; In aqueous phase solution, add ethyl acetate and weak base, standing demix; Get organic phase siccative drying, get S-(-)-ornidazole behind the concentrating under reduced pressure; Perhaps
Under the katalysis of Lewis acid, in the ethyl acetate solution of 2-methyl-5-nitro imidazoles, drip R-(-)-epoxy chloropropane, add the back 0～20 ℃ of heat-preserving condensation reaction 1～5 hour, reactant adds water and is hydrolyzed, hydrolysis afterreaction liquid is filtered, and the filtrate standing demix adds mineral acid after getting organic addition water again, standing demix, it is mutually stand-by to fetch water; In aqueous phase solution, add ethyl acetate and weak base, standing demix; Get organic phase siccative drying, get R-(+)-ornidazole behind the concentrating under reduced pressure.
3. the preparation method of ornidazole optical enantiomorph according to claim 2 is characterized in that described condensation reaction is 2.5 hours.
4. the preparation method of ornidazole optical enantiomorph according to claim 2 is characterized in that described Lewis acid is iron(ic) chloride, zinc chloride or aluminum chloride.
5. the preparation method of ornidazole optical enantiomorph according to claim 4 is characterized in that described Lewis acid is aluminum chloride.
6. the preparation method of ornidazole optical enantiomorph according to claim 2, control reaction temperature is at-10～20 ℃ when it is characterized in that dripping S-(+)-epoxy chloropropane or R-(-)-epoxy chloropropane.
7. the preparation method of ornidazole optical enantiomorph according to claim 6, control reaction temperature is at 0～10 ℃ when it is characterized in that dripping S-(+)-epoxy chloropropane or R-(-)-epoxy chloropropane.
8. the preparation method of ornidazole optical enantiomorph according to claim 2 is characterized in that the condensation reaction holding temperature is 5～10 ℃.
9. the preparation method of ornidazole optical enantiomorph according to claim 2 is characterized in that hydrolysis temperature is 0～40 ℃, and hydrolysis time is 0.5～2 hour.
10. the preparation method of ornidazole optical enantiomorph according to claim 9 is characterized in that hydrolysis temperature is 20～30 ℃.
11. the preparation method of ornidazole optical enantiomorph according to claim 9 is characterized in that hydrolysis time is 1 hour.
12. the preparation method of ornidazole optical enantiomorph according to claim 2 is characterized in that used mineral acid is concentrated hydrochloric acid or 40%～60% sulfuric acid, add acid to pH 0.5～2.0.
13. the preparation method of ornidazole optical enantiomorph according to claim 12 is characterized in that used mineral acid is concentrated hydrochloric acid or 50% sulfuric acid.
14. the preparation method of ornidazole optical enantiomorph according to claim 12, it is characterized in that adding acid to pH be 1.0.
15. the preparation method of ornidazole optical enantiomorph according to claim 2 is characterized in that used weak base is sodium bicarbonate, triethylamine, diethylamine or ammoniacal liquor; Add weak base to pH 6.5～8.0.
16. the preparation method of ornidazole optical enantiomorph according to claim 15 is characterized in that used weak base is ammoniacal liquor.
17. the preparation method of ornidazole optical enantiomorph according to claim 15, it is characterized in that adding weak base to pH be 7.0～7.5.
18., wherein further carry out purifying with the organic solvent recrystallization according to the preparation method of each described ornidazole optical enantiomorph of claim 1-17.
19. the preparation method of ornidazole optical enantiomorph according to claim 18 is characterized in that the used organic solvent of described recrystallization is toluene, ethyl acetate, ethanol or methyl alcohol.
20. the preparation method of ornidazole optical enantiomorph according to claim 18 is characterized in that the used organic solvent of described recrystallization is a toluene.
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|---|---|---|---|
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| CN 200410095900 CN1651415A (en) | 2004-11-29 | 2004-11-29 | Preparation and purification method of ornidazole optical antipode |
| CNB2005101270333A CN100338039C (en) | 2004-11-29 | 2005-11-29 | Ornidazole optical antimer preparation and purification method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539745A (en) * | 2013-10-11 | 2014-01-29 | 黄冈赛康药业有限公司 | Preparation method of secnidazole |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101817786A (en) * | 2010-04-13 | 2010-09-01 | 陕西合成药业有限公司 | Method for preparing (S)-ornidazole |
| CN105585532B (en) * | 2014-10-24 | 2018-05-01 | 山东齐都药业有限公司 | The post-processing approach of l-ornidazole reaction solution |
| CN112125851A (en) * | 2020-08-28 | 2020-12-25 | 石家庄四药有限公司 | Preparation method of ornidazole with optical activity |
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| US3493582A (en) * | 1965-05-19 | 1970-02-03 | Hoffmann La Roche | 1-(2,3-epoxypropyl)-5(4)-nitroimidazoles and a process for their preparation |
| CN1400312A (en) * | 2002-08-23 | 2003-03-05 | 中国科学院上海有机化学研究所 | Enzyme method resolution method of racemic ornidazole |
| WO2004035547A1 (en) * | 2002-10-15 | 2004-04-29 | Otsuka Pharmaceutical Co., Ltd. | 1-substituted 4-nitroimidazole compound and process for producing the same |
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2005
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3493582A (en) * | 1965-05-19 | 1970-02-03 | Hoffmann La Roche | 1-(2,3-epoxypropyl)-5(4)-nitroimidazoles and a process for their preparation |
| CN1400312A (en) * | 2002-08-23 | 2003-03-05 | 中国科学院上海有机化学研究所 | Enzyme method resolution method of racemic ornidazole |
| WO2004035547A1 (en) * | 2002-10-15 | 2004-04-29 | Otsuka Pharmaceutical Co., Ltd. | 1-substituted 4-nitroimidazole compound and process for producing the same |
Non-Patent Citations (1)
| Title |
|---|
| 奥硝唑的合成 张峻松等，中国医药工业杂志，第35卷第11期 2004 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539745A (en) * | 2013-10-11 | 2014-01-29 | 黄冈赛康药业有限公司 | Preparation method of secnidazole |
| CN103539745B (en) * | 2013-10-11 | 2015-09-02 | 黄冈赛康药业有限公司 | A kind of preparation method of secnidazole |
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| CN1800166A (en) | 2006-07-12 |
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Application publication date: 20060712 Assignee: Xu Xin Assignor: Nanjing Sanhome Pharmaceutical Co., Ltd. Contract record no.: 2013320000796 Denomination of invention: Preparation and purification method of ornidazole optical antipode Granted publication date: 20070919 License type: Common License Record date: 20131127 Application publication date: 20060712 Assignee: Xie Tong Assignor: Nanjing Sanhome Pharmaceutical Co., Ltd. Contract record no.: 2013320000798 Denomination of invention: Preparation and purification method of ornidazole optical antipode Granted publication date: 20070919 License type: Common License Record date: 20131127 |
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Address after: 210038 No. 9 Hui Middle Road, Nanjing economic and Technological Development Zone, Jiangsu Patentee after: NANJING SANHOME PHARMACEUTICAL CO., LTD. Address before: 210038, Nanjing economic and Technological Development Zone, Jiangsu Hui Road, No. 9 Patentee before: Nanjing Sanhome Pharmaceutical Co., Ltd. |