CN1400312A - Enzyme method resolution method of racemic ornidazole - Google Patents
Enzyme method resolution method of racemic ornidazole Download PDFInfo
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- CN1400312A CN1400312A CN 02136622 CN02136622A CN1400312A CN 1400312 A CN1400312 A CN 1400312A CN 02136622 CN02136622 CN 02136622 CN 02136622 A CN02136622 A CN 02136622A CN 1400312 A CN1400312 A CN 1400312A
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Abstract
The present invention relates to a method of preparing optical pure (S)-(-)-ornidazole or/and (R)-(+)-ornidazole by utilizing enzymatic resolution of recemate of ornidazole, and is characterized by that under the action of chiral synthetic lypase the racemate of ornidazole is reacted with vinyl acetate to produce acetate of (S)-(-)-ornidazole, said acetate is purified, hydrolyzed and converted into optical pure (S)-(-)-ornidazole, (R)-(+)-ornidazole is not reacted, can be obtained by purifying mother liquor; or the racement of ornidazole can be prepared into acetate firstly, under the action of chiral synthetic lypase the acetate can be selectively hydrolyzed to obtain the optical pure (S)-(-)-ornidazole, and the (R)-(+)-ornidazole is still exists in the form of acetate, said acetate can be hydrolyzed and converted into (R)+(+)-ornidazole.
Description
Technical field
The present invention relates to a kind of raceme utilize enzyme process to split preparation optically pure (S)-(-)-ornidazole or/and (R)-(+)-method of ornidazole from ornidazole.Be that a kind of raceme of ornidazole that makes reacts the acetic ester that generates (S)-(-)-ornidazole with vinyl acetate furtherly under the effect of chirality synthetic fat enzyme, this ester of purifying, hydrolysis is converted into optically pure (S)-(-)-ornidazole, (R)-(+)-ornidazole be because not reaction can obtain by the purifying mother liquor; Perhaps elder generation is prepared into acetic ester with the raceme of ornidazole, make acetic ester under the effect of chirality synthetic fat enzyme, carry out selective hydrolysis and obtain optically pure (S)-(-)-ornidazole, (R)-(+)-and ornidazole then still exists with the form of acetic ester, and this acetic ester hydrolysis is converted into optically pure (R)-(+)-ornidazole.
Background technology
Ornidazole is a novel 5-nitro glyoxaline microbiotic, has the activity of good trichomonacide, amoeba worm, giardia lamblia, anaerobic infection, and sale and clinical application is its raceme in the market.
Article about the pharmacologically active difference of (S)-(-)-ornidazole and (R)-(+)-ornidazole does not see that report is arranged, just have one piece of document (Bone, W., et al, Int.J.Andrology, 1997,
20, 347) and the side effect of mentioning them do not have notable difference.
The report of preparation ornidazole optical enantiomorph seldom has only Skupin, R. etc. (Skupin, R., et al, Tetrahedron:Asymmetry, 1997,
8, 2453) and utilize the asymmetric one-tenth ester of chirality synthetic fat enzyme PS (Lipase PS) to obtain a certain optical antipode.
Summary of the invention
Purpose of the present invention utilizes enzyme process to split the method for preparation optically pure (S)-(-)-ornidazole and (R)-(+)-ornidazole with regard to providing a kind of raceme from ornidazole.
Method of the present invention is to make the raceme of ornidazole react the acetic ester that generates (S)-(-)-ornidazole with vinyl acetate under the effect of chirality synthetic fat enzyme, this ester of purifying, hydrolysis is converted into optically pure (S)-(-)-ornidazole, (R)-(+)-ornidazole be because not reaction can obtain by the purifying mother liquor; Perhaps elder generation is prepared into acetic ester with the raceme of ornidazole, make acetic ester under the effect of chirality synthetic fat enzyme, carry out selective hydrolysis and obtain optically pure (S)-(-)-ornidazole, (R)-(+)-and ornidazole then still exists with the form of acetic ester, and this acetic ester hydrolysis is converted into optically pure (R)-(+)-ornidazole.
Method of the present invention is that the raceme with ornidazole is dissolved in the vinyl acetate, adds chirality synthetic fat enzyme, 10～50 ℃ of reactions 1～40 day, and the recommendation response temperature is 25～35 ℃, the reaction times is as the criterion with detection.The raceme of described ornidazole and vinyl acetate mol ratio are 1: 1～100, because vinyl acetate can be used as solvent in the present invention, so adopt more vinyl acetate to not influence of result of the present invention.The weight ratio of the raceme of described ornidazole and chirality synthetic fat enzyme is 1: 0.1～10, and recommending weight ratio is 1: 0.5-2.
Reaction is finished, elimination chirality synthetic fat enzyme, and reaction solution is concentrated into dried, column chromatography for separation gets optically pure (S)-(-)-ornidazole acetic ester and (R)-(+)-ornidazole.
(S)-(-)-and the ornidazole acetic ester is with mineral acid or its aqueous hydrolysis, after reaction finishes, adds the basic solution neutralization, and the water-insoluble organic solvent extraction can obtain optically pure (S)-(-)-ornidazole.
The optical purity of above-mentioned (S)-(-)-ornidazole acetic ester, (S)-(-)-ornidazole or (R)-(+)-ornidazole is not if reach requirement, can carry out repeatedly recrystallization till reach requirement in organic solvent.
Optical purity does not reach requirement (S)-(-)-ornidazole (contain a small amount of (R)-(+)-ornidazole) also can be again and vinyl acetate reaction repeated preparation (S)-(-)-ornidazole acetic ester according to the method described above, column chromatography for separation is removed a spot of (R)-(+)-ornidazole, (S)-(-) that will make again-ornidazole acetic ester hydrolysis gets optically pure (S)-(-)-ornidazole.
Optical purity does not reach requirement (R)-(+)-ornidazole (contain a small amount of (S)-(-)-ornidazole) also can be again and vinyl acetate reaction repeated according to the method described above, make residual a small amount of (S)-(-)-ornidazole generate acetic ester, column chromatography for separation is removed a spot of (S)-(-)-ornidazole acetic ester, optically pure (R)-(+)-ornidazole.
The all right elder generation of method of the present invention is with the raceme document (Skupin of ornidazole, R., et al, Tetrahedron:Asymmetry, 1997,8,2453) described method is prepared into acetic ester, also the raceme and the excess acetyl chloride of ornidazole can be prepared into acetic ester, also can add a small amount of nitrogenous compound, as pyridine, hexahydropyridine, triethylamine etc. as catalyzer.
The acetic ester of ornidazole raceme and chirality synthetic fat enzyme are in phosphoric acid buffer (pH=5.0～9.0), and 10～50 ℃ were reacted 1～40 day, and the recommendation response temperature is 25～35 ℃, and the reaction times is as the criterion with detection.The weight ratio of the acetic ester of described ornidazole raceme and chirality synthetic fat enzyme is 1: 0.1～10, and recommending weight ratio is 1: 0.5-2.
Reaction is finished, and adds the water-insoluble organic solvent extraction, elimination chirality synthetic fat enzyme, combining extraction liquid, be evaporated to dried, column chromatography for separation gets optically pure (S)-(-)-ornidazole and (R)-(+)-ornidazole acetic ester.(R)-(+)-and the hydrolysis under acidic conditions of ornidazole acetic ester, get optically pure (R)-(+)-ornidazole.
The optical purity of above-mentioned (S)-(-)-ornidazole, (R)-(+)-ornidazole acetic ester or (R)-(+)-ornidazole is not if reach requirement, can carry out repeatedly recrystallization till reach requirement in organic solvent.
Optical purity does not reach requirement (S)-(-)-ornidazole (containing a small amount of (R)-(+)-ornidazole) can be prepared into acetic ester with ordinary method earlier, with (S)-(-)-ornidazole acetic ester of making secondary response more according to the method described above, column chromatography for separation is removed unreacted a small amount of (R)-(+)-ornidazole acetic ester, gets optically pure (S)-(-)-ornidazole.
Optical purity do not reach requirement (R)-(+)-ornidazole acetic ester (contain a small amount of (S)-(-)-ornidazole acetic ester) can be according to the method described above secondary response again, column chromatography for separation is removed a small amount of (S)-(-)-ornidazole that has reacted, with unreacted (R)-(+)-ornidazole acetic ester hydrolysis, get optically pure (R)-(+)-ornidazole.
Described chirality synthetic fat enzyme comprises lipase A K (Lipase AK, fromPseudomonas fluorescens), lipase ay S (Lipase AYS, from Candida rugosa), lipase A S (Lipase AS, from Aspergillus niger), lipase PS-C (Lipase PS-C, fromPseudomonas cepacia), lipase PS-D (Lipase PS-D, from Pseudomonas cepacia), porcine pancreatic lipase (Porcine Pancreas Lipase, PPL), lipase A (Lipase A, from Aspergillusniger), lipase F-AP15 (Lipase F-AP15, from Rhizopus oryzae), lipase G (Lipase G, from Penicillium camemberti), lipase M (Lipase M, from Mucor javanicus), lipase PS-C I (Lipase PS-C I, be fixed on the pottery), lipase PS-C II (Lipase PS-C II, be fixed on the pottery), lipase PS-D I (Lipase PS-D I, be fixed on the pottery) and lipase CAL (Candidaantarctica Lipase, Novozym 435), be recommended as lipase A K.
Described mineral acid can be sulfuric acid, hydrochloric acid, phosphoric acid etc., is recommended as concentrated hydrochloric acid;
Described alkali can be yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, strong aqua, sodium hydroxide solution, potassium hydroxide solution etc., recommends to use strong aqua;
Described water-insoluble organic solvent can be chloroform, methylene dichloride, ethyl acetate, ether etc., is recommended as ethyl acetate.
Described chirality synthetic fat enzyme and vinyl acetate are recyclable.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1:(S)-(-)-preparation of ornidazole
Ornidazole 13.2g, lipase A K 7.0g, vinyl acetate 100ml mixes, 28 ℃ of stirring reactions 18 days, HPLC detection reaction process.Reaction is finished, elimination lipase, the ethyl acetate washing, be concentrated into dried, oily matter.Column chromatography for separation gets faint yellow solid (S)-(-)-ornidazole acetic ester 6.77g and faint yellow oily thing (R)-(+)-ornidazole 6.9g.
Above-mentioned gained (S)-(-)-ornidazole acetic ester gets fine acicular near-white crystallization 5.5g ([α] twice with ethyl acetate-sherwood oil recrystallization
D 20=-69.3 ° of (c=1.01, CH
2Cl
2)), the ee value is 0.95.This crystallization is dissolved in the 50ml concentrated hydrochloric acid, stirring at room hydrolysis in 18 hours, neutralize with strong aqua, ethyl acetate extraction, combined ethyl acetate extraction liquid, washing, anhydrous sodium sulfate drying, filtering and concentrating to do oily matter, about 0 ℃ of placement solidify faint yellow solid 4.1g, with twice of ethyl acetate-sherwood oil recrystallization the short prism-shaped crystal 2 .88g ([α] of (S)-(-)-ornidazole
D 20=-66.7 ° of (c=0.99, CH
2Cl
2)), the ee value is 0.99, yield is 43.6% (based on (S)-enantiomorph).
Embodiment 2:(R)-(+)-preparation of ornidazole
Embodiment 1 gained (R)-(+)-ornidazole 6.9g gets white prism-shaped crystal 3 .9g ([α] three times with ethyl acetate-sherwood oil (1: 1) recrystallization
D 20=+65.3 ° of (c=1.08, CH
2Cl
2)), the ee value is 0.99, yield is 59.1% (based on (R)-enantiomorph).
Embodiment 3:(S)-(-)-preparation of ornidazole
Press embodiment 1 method, ornidazole 11.4g, lipase PS-C 7.0g, vinyl acetate 85ml, hybrid reaction 30 days, (S)-(-)-ornidazole acetic ester 5.45g and (R)-(+)-ornidazole 6.15g.(S)-(-)-and ornidazole acetic ester recrystallization twice, hydrolysis, recrystallization gets (S)-(-)-ornidazole 2.23g ([α] twice again
D 20=-67.1 ° of (c=1.03, CH
2Cl
2)), the ee value is 0.99, yield is 39.1% (based on (S)-enantiomorph).
Embodiment 4:(R)-(+)-preparation of ornidazole
Embodiment 3 gained (R)-(+)-ornidazole 6.15g gets white prism-shaped crystal 2 .85g ([α] four times with ethyl acetate-sherwood oil (1: 1) recrystallization
D 20=+64.9 ° of (c=0.99, CH
2Cl
2)), the ee value is 0.99, yield is 50.0% (based on (R)-enantiomorph).
Embodiment 5:(S)-(-)-preparation of ornidazole
Press embodiment 1 method, ornidazole 12.5g, porcine pancreatic lipase 6.5g, vinyl acetate 100ml, hybrid reaction 30 days, (S)-(-)-ornidazole acetic ester 3.12g and (R)-(+)-ornidazole 9.18g (containing a small amount of (S)-(-)-ornidazole).(S)-(-)-and ornidazole acetic ester recrystallization twice, hydrolysis, recrystallization gets (S)-(-)-ornidazole 1.29g ([α] twice again
D 20=-66.8 ° of (c=1.00, CH
2Cl
2)), the ee value is 0.99, yield is 20.6% (based on (S)-enantiomorph).
Embodiment 6:(R)-(+)-preparation of ornidazole
Embodiment 5 gained (R)-(+)-ornidazole 9.18g gets white prism-shaped crystal 4 .41g ([α] four times with ethyl acetate-sherwood oil (1: 1) recrystallization
D 20=+34.2 ° of (c=1.05, CH
2Cl
2)), the ee value is 0.53, yield is 70.6% (based on (R)-enantiomorph).
Embodiment 7:(S)-(-)-preparation of ornidazole
Press embodiment 1 method, ornidazole 11.4g, lipase A K 6.4g, vinyl acetate 85ml mixes, 28 ℃ of stirring reactions 18 days.Reaction is finished, elimination lipase, the ethyl acetate washing, be concentrated into dried, oily matter.Column chromatography for separation gets (S)-(-)-ornidazole acetic ester 5.71g and (R)-(+)-ornidazole 5.83g.
Above-mentioned gained (S)-(-)-ornidazole acetic ester 5.71g gets (S)-(-)-ornidazole 4.49g with concentrated hydrochloric acid hydrolysis, dissolve with the 35ml vinyl acetate, add lipase A K 2.8g, repeat aforesaid operations, get (S)-(-)-ornidazole acetic ester 4.45g, hydrolysis, ethyl acetate-sherwood oil recrystallization get (S)-(-)-ornidazole 3.05g ([α]
D 20=-67.5 ° of (c=0.97, CH
2Cl
2)), the ee value is 0.99, yield is 53.5% (based on (S)-enantiomorph).
Embodiment 8:(R)-(+)-preparation of ornidazole
Embodiment 7 gained (R)-(+)-ornidazole 5.83g, with the dissolving of 45ml vinyl acetate, add lipase A K 3.3g, hybrid reaction 18 days, column chromatography for separation gets (R)-(+)-ornidazole 4.42g, and ethyl acetate-sherwood oil recrystallization gets (R)-(+)-ornidazole 3.72g ([α]
D 20=+64.7 ° of (c=1.02, CH
2Cl
2)), the ee value is 0.99, yield is 65.3% (based on (R)-enantiomorph).
Embodiment 9: the preparation of the ornidazole acetic ester of racemization
10.98g the raceme of ornidazole, the 37.8ml aceticanhydride, the 4ml pyridine, mixed at room temperature stirred 1 hour.Add the 100ml frozen water, white solid is separated out, the frozen water washing, and filtration drying gets 11.9g near-white solid, gets the ornidazole acetic ester 9.3g of racemization with re-crystallizing in ethyl acetate, and yield is 70.8%.
Embodiment 10:(S)-(-)-preparation of ornidazole
Ornidazole acetic ester 5.76g, lipase A K 5.0g, 1M phosphoric acid buffer (pH=7) 400ml mixes, 28 ℃ of stirring reactions 20 days, HPLC detection reaction process.Reaction is finished, and adds the 400ml ethyl acetate, stirs, elimination lipase, water are again with ethyl acetate collection twice, combined ethyl acetate extraction liquid, be evaporated to driedly, column chromatography for separation gets (S)-(-)-ornidazole 1.84g and (R)-(+)-ornidazole acetic ester 3.16g.
Above-mentioned gained (S)-(-)-ornidazole is with ethyl acetate-sherwood oil recrystallization three times, (S)-(-)-ornidazole prism-shaped crystal 1.13g ([α]
D 20=-66.9 ° of (c=1.10, CH
2Cl
2)), the ee value is 0.99, yield is 46.9% (based on (S)-enantiomorph).
Embodiment 11:(R)-(+)-preparation of ornidazole
Embodiment 10 gained (R)-(+)-ornidazole acetic ester 3.16g are pressed embodiment 1 method, recrystallization twice, and hydrolysis, recrystallization gets (R)-(+)-ornidazole 1.23g ([α] twice again
D 20=+65.3 ° of (c=0.99, CH
2Cl
2)), the ee value is 0.99, yield is 51.1% (based on (R)-enantiomorph).
Embodiment 12:(S)-(-)-preparation of ornidazole
Press embodiment 10 methods, ornidazole acetic ester 5.36g, porcine pancreatic lipase 3.2g, 1M phosphoric acid buffer (pH=7) 400ml, hybrid reaction 30 days, (S)-(-)-ornidazole 1.63g and (R)-(+)-ornidazole acetic ester 3.04g.
Above-mentioned gained (S)-(-)-ornidazole is with ethyl acetate-sherwood oil recrystallization three times, (S)-(-)-ornidazole prism-shaped crystal 1.02g ([α]
D 20=-67.2 ° of (c=1.03, CH
2Cl
2)), the ee value is 0.99, yield is 45.5% (based on (S)-enantiomorph).
Embodiment 13:(R)-(+)-preparation of ornidazole
Embodiment 12 gained (R)-(+)-ornidazole acetic ester 3.04g are pressed embodiment 1 method, recrystallization three times, and hydrolysis, recrystallization gets (R)-(+)-ornidazole 0.99g ([α] twice again
D 20=+65.1 ° of (c=1.01, CH
2Cl
2)), the ee value is 0.99, yield is 44.2% (based on (R)-enantiomorph).
Embodiment 14:(S)-(-)-preparation of ornidazole
Press embodiment 10 methods, ornidazole acetic ester 5.23g, lipase A K 2.8g, 1M phosphoric acid buffer (pH=7) 400ml, hybrid reaction 20 days, (S)-(-)-ornidazole 1.67g and (R)-(+)-ornidazole acetic ester 2.69g.
Above-mentioned gained (S)-(-)-ornidazole 1.67g makes (S)-(-)-ornidazole acetic ester 1.43g by embodiment 9 methods, add 1M phosphoric acid buffer (pH=7) 100ml and lipase A K 0.8g, repeat aforesaid operations, get (S)-(-)-ornidazole 0.92g, ethyl acetate-sherwood oil recrystallization gets (S)-(-)-ornidazole 0.82g ([α]
D 20=-66.3 ° of (c=0.98, CH
2Cl
2)), the ee value is 0.99, yield is 37.5% (based on (S)-enantiomorph).
Embodiment 15:(R)-(+)-preparation of ornidazole
Embodiment 14 gained (R)-(+)-ornidazole acetic ester 2.69g, lipase A K 1.6g, 1M phosphoric acid buffer (pH=7) 200ml, hybrid reaction 20 days, the reaction product column chromatography for separation gets (R)-(+)-ornidazole 2.23g, hydrolysis, ethyl acetate-sherwood oil recrystallization get (R)-(+)-ornidazole 1.49g ([α]
D 20=+65.0 ° of (c=1.04, CH
2Cl
2)), the ee value is 0.99, yield is 68.1% (based on (R)-enantiomorph).
Embodiment 16:(S)-(-)-preparation of ornidazole
Press embodiment 1 method, ornidazole 11.9g, the lipase A K6.3g of recovery, the vinyl acetate 90ml of recovery, hybrid reaction 18 days, (S)-(-)-ornidazole acetic ester 5.97g and (R)-(+)-ornidazole 6.13g.(R)-(-)-and Saikexiaozuo acetic ester recrystallization twice, hydrolysis, recrystallization gets (S)-(-)-ornidazole 2.42g ([α] twice again
D 20=-66.6 ° of (c=1.04, CH
2Cl
2)), the ee value is 0.99, yield is 40.7% (based on (S)-enantiomorph).
Ee value among the above embodiment is the HPLC method, and (high-pressure liquid phase method records.
Claims (10)
1. the raceme from ornidazole or its acetic ester prepares optically pure (S)-(-)-ornidazole or/and (R)-(+)-method of ornidazole, it is characterized in that by following (1), (1) and (2), and (3), or (3) and (4) four kinds of methods make respectively:
(1). the raceme of ornidazole is dissolved in the vinyl acetate, add chirality synthetic fat enzyme, 10～50 ℃ were reacted 1～40 day, elimination chirality synthetic fat enzyme, concentrate, column chromatography for separation gets optically pure (S)-(-)-ornidazole acetic ester and (R)-(+)-ornidazole, the weight ratio of the raceme of described ornidazole and chirality synthetic fat enzyme is 1: 0.1～10;
(2). above-mentioned optically pure (S)-(-)-ornidazole acetic ester after the reaction, adds the basic solution neutralization with mineral acid or its aqueous hydrolysis, and the water-insoluble organic solvent extraction can obtain optically pure (S)-(-)-ornidazole;
(3). the acetic ester of ornidazole raceme and chirality synthetic fat enzyme are in the phosphoric acid buffer of pH=5.0～9.0,10～50 ℃ of reactions 1～40 day, add the water-insoluble organic solvent extraction again, elimination chirality synthetic fat enzyme, combining extraction liquid, concentrate column chromatography for separation gets optically pure (S)-(-)-ornidazole and (R)-(+)-ornidazole acetic ester;
(4). above-mentioned optically pure (R)-(+)-ornidazole acetic ester after reaction finishes, adds the basic solution neutralization with mineral acid or its aqueous hydrolysis, and the water-insoluble organic solvent extraction can obtain optically pure (R)-(+)-ornidazole.
2. preparation method as claimed in claim 1 is characterized in that described chirality synthetic fat enzyme comprises lipase A K, lipase ay S, lipase A S, lipase PS-C, lipase PS-D, porcine pancreatic lipase, lipase A, lipase F-AP15, lipase G, lipase M, lipase PS-CI, lipase PS-CII, lipase PS-DI and lipase CAL.
3. preparation method as claimed in claim 1 is characterized in that described (S)-(-)-ornidazole, (S)-(-)-ornidazole acetic ester, (R)-(+)-ornidazole or (R)-(+)-ornidazole acetic ester is through recrystallization.
4. preparation method as claimed in claim 1, it is characterized in that described (S)-(-) in method (1) and (2)-ornidazole again with vinyl acetate according to (1) the method repetitive operation identical with (2), be further purified (S)-(-)-ornidazole.
5. preparation method as claimed in claim 1, it is characterized in that described (R)-(+) of method (1)-ornidazole again with vinyl acetate according to (1) identical method repetitive operation, be further purified (R)-(+)-ornidazole.
6. preparation method as claimed in claim 1 is characterized in that described (S)-(-) of method (3)-ornidazole is prepared into acetic ester, according to (3) identical method repetitive operation, is further purified (S)-(-)-ornidazole again.
7. preparation method as claimed in claim 1 is characterized in that described (R)-(+) in method (3) and (4)-ornidazole acetic ester again according to (3) and (4) same procedure repetitive operation, is further purified (R)-(+)-ornidazole.
8. preparation method as claimed in claim 1 is characterized in that described mineral acid is sulfuric acid, hydrochloric acid, phosphoric acid.
9. preparation method as claimed in claim 1 is characterized in that described alkali is carbonate, supercarbonate, oxyhydroxide and the aqueous solution thereof or the ammoniacal liquor of monovalence metal.
10. preparation method as claimed in claim 1 is characterized in that adopting chirality synthetic fat enzyme and the vinyl acetate that reclaims gained.
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| CN 02136622 CN1212405C (en) | 2002-08-23 | 2002-08-23 | Enzyme method resolution method of racemic ornidazole |
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|---|---|---|---|
| CN 02136622 CN1212405C (en) | 2002-08-23 | 2002-08-23 | Enzyme method resolution method of racemic ornidazole |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005041853A3 (en) * | 2003-10-28 | 2005-08-04 | Ems Sa | Antibacterial and/or antiprotozoal nitroimidazole derivative compounds with urease inhibitor activity, process for preparing these compounds and use in pharmaceutical compositions and medicines. |
| WO2006114042A1 (en) | 2005-04-28 | 2006-11-02 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Application of levo-ornidazole in preparation of anti-anaerobic bacteria infection medicine |
| WO2007006197A1 (en) * | 2005-07-08 | 2007-01-18 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Use of levo-ornidazole for preparing antiparasitic infection drug |
| CN1332662C (en) * | 2005-04-29 | 2007-08-22 | 南京圣和药业有限公司 | Levo ornidazole vein administration agent and its preparation method |
| CN100338039C (en) * | 2004-11-29 | 2007-09-19 | 南京圣和药业有限公司 | Ornidazole optical antimer preparation and purification method |
| CN100368402C (en) * | 2005-11-16 | 2008-02-13 | 沈阳中海生物技术开发有限公司 | Preparation method for optical enantiomer of ornidaxole |
| CN100451023C (en) * | 2006-01-06 | 2009-01-14 | 陕西新安医药科技有限公司 | Levo-ornidazole phosphate, preparing process and use thereof |
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2002
- 2002-08-23 CN CN 02136622 patent/CN1212405C/en not_active Expired - Fee Related
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005041853A3 (en) * | 2003-10-28 | 2005-08-04 | Ems Sa | Antibacterial and/or antiprotozoal nitroimidazole derivative compounds with urease inhibitor activity, process for preparing these compounds and use in pharmaceutical compositions and medicines. |
| US7608724B2 (en) | 2003-10-28 | 2009-10-27 | Ems S.A. | Antibacterial and/or antiprotozoal nitromidazole derivative compounds with urease inhibitor activity, process for preparing these compounds and use in pharmaceutical compositions and medicines |
| CN100338039C (en) * | 2004-11-29 | 2007-09-19 | 南京圣和药业有限公司 | Ornidazole optical antimer preparation and purification method |
| WO2006114042A1 (en) | 2005-04-28 | 2006-11-02 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Application of levo-ornidazole in preparation of anti-anaerobic bacteria infection medicine |
| CN1314396C (en) * | 2005-04-28 | 2007-05-09 | 南京圣和药业有限公司 | Application of levoornidazole in preparation of anti anaerobic bacteria infection medicine |
| EP1875910A4 (en) * | 2005-04-28 | 2008-09-17 | Nanjing Sanhome Pharmaceutical | Application of levo-ornidazole in preparation of anti-anaerobic bacteria infection medicine |
| US8530507B2 (en) | 2005-04-28 | 2013-09-10 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Use of levo-ornidazole in the preparation of anti-anaerobic bacteria infection drugs |
| CN1332662C (en) * | 2005-04-29 | 2007-08-22 | 南京圣和药业有限公司 | Levo ornidazole vein administration agent and its preparation method |
| WO2007006197A1 (en) * | 2005-07-08 | 2007-01-18 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Use of levo-ornidazole for preparing antiparasitic infection drug |
| CN1305469C (en) * | 2005-07-08 | 2007-03-21 | 南京圣和药业有限公司 | Use of levo-ornidazole for preparing anti-parasitic-infectious drug |
| CN100368402C (en) * | 2005-11-16 | 2008-02-13 | 沈阳中海生物技术开发有限公司 | Preparation method for optical enantiomer of ornidaxole |
| CN100451023C (en) * | 2006-01-06 | 2009-01-14 | 陕西新安医药科技有限公司 | Levo-ornidazole phosphate, preparing process and use thereof |
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| Publication number | Publication date |
|---|---|
| CN1212405C (en) | 2005-07-27 |
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