CN1321121C - Preparation and post-treatment method of levofloxacin - Google Patents
Preparation and post-treatment method of levofloxacin Download PDFInfo
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- CN1321121C CN1321121C CNB2005100252751A CN200510025275A CN1321121C CN 1321121 C CN1321121 C CN 1321121C CN B2005100252751 A CNB2005100252751 A CN B2005100252751A CN 200510025275 A CN200510025275 A CN 200510025275A CN 1321121 C CN1321121 C CN 1321121C
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- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 title claims abstract description 58
- 229960003376 levofloxacin Drugs 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims description 22
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 7
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- -1 carboxylic acid fluoride Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000009413 insulation Methods 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000003472 neutralizing effect Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 150000001298 alcohols Chemical class 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- CAOOISJXWZMLBN-PPHPATTJSA-N htn0d03vrz Chemical compound Cl.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 CAOOISJXWZMLBN-PPHPATTJSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 4
- 229960001699 ofloxacin Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- ONDRRTIAGBDDKP-PPHPATTJSA-N 294662-18-3 Chemical compound CC(O)C(O)=O.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 ONDRRTIAGBDDKP-PPHPATTJSA-N 0.000 description 1
- CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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Abstract
The invention provides a post-treatment method for preparing levofloxacin. The method directly recovers the solvent after the reaction with the piperazine, and adopts the method of salifying and then neutralizing with alkali, so that the high-purity levofloxacin is effectively obtained. The method is simple and convenient and is suitable for industrial production.
Description
Technical field:
The present invention relates to pharmaceutical chemistry, be specifically related to a kind of levofloxacin preparation and post-treating method.
Background technology:
Fluoroquinolones is efficient with it, the antimicrobial characteristic of wide spectrum, low toxicity, obtaining immense success aspect the clinical anti-infective therapy, the Ofloxacine USP 23 (Ofloxacin) of Japanese first drugmaker exploitation and levofloxacin (Levofloxacin) are outstanding kinds wherein.Levofloxacin is the S enantiomorph of racemize Ofloxacine USP 23, and the anti-microbial activity of Ofloxacine USP 23 mainly belongs to the S enantiomorph.
Levofloxacin is the fluorinated quinolones structure with chirality, and its chemical name is S-(-) 9-fluoro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen--2, and 3-dihydro-7H-pyrido-[1,2,3 ,-de] [1,4] benzoxazine-6-carboxylic acid semihydrate (CAS registration number 100986-85-4).The chemical structure of levofloxacin as shown in Equation 1.
Formula 1
The synthetic method of levofloxacin and intermediate thereof has a lot of bibliographical informations, as U.S. Pat 4382892, US5053407, US5051505, US5155223, Chinese patent CN01134024.X, CN200410155139.X etc., less about the document of reporting the post-treating method that levofloxacin prepares.Disclose by being controlled at the water-content that dissolves a kind of water-containing solvent of levofloxacin during the crystallization therein as U.S. Pat 5545737 and optionally to have produced Levofloxacin semihydrate or monohydrate.U.S. Pat 60334316 discloses the novel method of coming the purifying levofloxacin with the crystallization of high temperature polar solvent.
China is since the levofloxacin Lactate listing of approval Xinchang, Zhejiang pharmaceutical factory in 1997, and the derivative of approval listing also has levofloxacin hydrochloride and Levofloxacin M. S. A, and the post-treating method of these products as shown in Figure 1.
But the yield of this method can not be satisfactory, and the yield from left carboxylic acid fluoride to finished product is usually less than 70%.Afterwards, Xinchang pharmaceutical factory had developed the salt derivative that levofloxacin is produced in technical process shown in Figure 2.Also available in addition prepared levofloxacin finished product shown in Figure 3, but this method raises the relative substance content in the finished product relatively.
Summary of the invention:
Particular problem to be solved by this invention is to overcome above-mentioned weak point, designs a kind of more effective aftertreatment purification process.
The inventor has proposed the scheme of two kinds of solutions.
First kind of scheme is the crystallization that increases once moisture dehydrated alcohol; Second kind of scheme is at first with the crude product salify, and then obtains finished product with the alkali neutralization.The technical process of second method as shown in Figure 4.
Data presentation by experiment, two kinds of methods can both obtain highly purified levofloxacin, but the product purity that second kind of scheme obtains is better, and both have significant difference.Statistics is as shown in table 1.
Two kinds of methods of table 1 produce the impurity situation of levofloxacin
| Levofloxacin lot number (method | Single impurity maximum value | Total impurities | Levofloxacin lot number (method | Single impurity maximum value | Total impurities |
| One) | Two) | ||||
| D050102A | 0.15 | 0.3 | J050101 | 0.03 | 0.08 |
| D050101A | 0.11 | 0.2 | J050102 | 0.09 | 0.1 |
| D050106 | 0.11 | 0.14 | J050103 | 0.1 | 0.2 |
| D050201 | 0.11 | 0.2 | J050104 | 0.06 | 0.1 |
| Mean value | 0.12 | 0.21 | Mean value | 0.07 | 0.12 |
The product that above-mentioned two kinds of methods obtain shows mutually isomorphous crystallization through infrared result with X ray powder diffraction.
The invention provides in the preparation of a kind of levofloxacin post-treating method as shown in Figure 4.This method comprises the following steps:
(1) preparation crude preparation of levofloxacin: in the dimethyl sulfoxide solvent of 2～5 times (w/w), 80～100 ℃ of reactions of the N methyl piperazine of left side carboxylic acid fluoride and 0.5～1.5 times (w/w) 4～8 hours, reclaim under reduced pressure N methyl piperazine and dimethyl sulfoxide (DMSO), in product, add entry, regulating pH is 6.0～6.5, the dissolving back adds gac, keep 45～75 ℃ to stir 20～60 minutes, filter, filtrate is heated to 45～75 ℃, regulating pH is 9.5～10.0, add gac, keep 45～75 ℃ to stir 20～60 minutes, filter, it is 7.0～8.0 that filtrate is regulated pH, with chloroform re-extract 6～10 times, combining extraction liquid, reclaim chloroform, the anhydrous alcohol solution post crystallization that in residue, adds 5～8 times (w/w), filter crude preparation of levofloxacin;
(2) salify: the dehydrated alcohol that in crude preparation of levofloxacin, adds 5～8 times (w/w), be warmed up to 65～75 ℃, after the dissolving fully, add EDTA and gac, 65～75 ℃ of scope insulations 20～60 minutes, filter, add a certain amount of acid in the filtrate, crystallisation by cooling, filter levofloxacin salt;
(3) preparation levofloxacin: the dehydrated alcohol and a certain amount of alkali lye that in levofloxacin salt, add 5～8 times (w/w), after intensification is waited to dissolve, add EDTA and gac, 60～75 ℃ of scopes are incubated 20～60 minutes, filter, the filtrate crystallisation by cooling, crystallization promptly got levofloxacin in 2～3 hours in 50～55 ℃ of drying under reduced pressure.
The acid that adds during the inventive method step (2) salify is hydrochloric acid, sulfuric acid or Glacial acetic acid, preferred hydrochloric acid.The alkali that adds during step (3) preparation levofloxacin is ammoniacal liquor, sodium hydroxide or sodium bicarbonate, preferred ammoniacal liquor.
Advantage of the present invention is: directly reclaim solvent in last first piperazine reaction back, not only improved yield, reduced the solvent unit consumption, and avoided the original centrifugal environmental problem that filters in the journey of getting rid of, in subsequent disposal, adopt first salify simultaneously, the back has obtained the constant highly purified levofloxacin of crystalline form effectively with alkali neutral method.
Description of drawings:
Fig. 1: prior art prepares the post-treating method of levofloxacin salt.
Fig. 2: prior art prepares the post-treating method of levofloxacin salt.
Fig. 3: prior art prepares the aftertreatment scheme of levofloxacin.
Fig. 4: levofloxacin post-treating method of the present invention.
Embodiment:
Embodiment one:
Left carboxylic acid fluoride 100 grams are dropped into reaction flask, add 400 milliliters of dimethyl sulfoxide (DMSO), 100 milliliters of N methyl piperazines then, add 85 ℃ of reactions of the interior temperature of thermal control 5 hours; After the TLC analysis is qualified, reclaim under reduced pressure N methyl piperazine and dimethyl sulfoxide (DMSO), temperature is lower than 100 ℃ in keeping.The water that adds 400 milliliters in the product of gained is regulated PH=6.0～6.5, and it is molten refining that dissolving back adding gac 1.5 gram insulated and stirred were carried out acid in 30 minutes.Filter then, be heated to 65～75 ℃, transfer PH to 9.5～10.0 with sodium hydroxide solution, it is molten refining that adding gac 1.5 gram insulated and stirred were carried out alkali in 30 minutes, refilters.Add appropriate hydrochloric acid in the stirring and transfer PH=7.0～8.0, adds 200 milliliters of chloroform extractions, repeat chloroform extraction 6～10 times, combining extraction liquid reclaims chloroform to doing, and adds the anhydrous alcohol solution post crystallization again, filter crude preparation of levofloxacin, weight in wet base 168 restrains.
In the wet product of levofloxacin, add 600 milliliters of dehydrated alcohols, heating in water bath heats up, after the dissolving fully, add a small amount of EDTA and gac,, filter 60～75 ℃ of scope insulations 30 minutes, add about 30 milliliters of concentrated hydrochloric acid in the filtrate, crystallisation by cooling, filter the levofloxacin hydrochloride, weight in wet base 172 gram.
In the wet product of levofloxacin hydrochloride hydrochloride, add 25 milliliters of 550 milliliters of dehydrated alcohols and 5% ammoniacal liquor, heating in water bath heats up, after treating dissolving fully, add a small amount of EDTA and gac, 60～75 ℃ of scopes are incubated 30 minutes, filter, the filtrate crystallisation by cooling filters the gained crystallization and uses water pump drying under reduced pressure 2.0～3.0 hours, and temperature is between 50～55 ℃, get levofloxacin, dry weight 101 grams.
Embodiment two,
The left carboxylic acid fluoride of 100 grams feeds intake, and is prepared into crude preparation of levofloxacin as described in embodiment one, weight in wet base 163 grams.
In the wet product of levofloxacin, add 600 milliliters of dehydrated alcohols, heating in water bath heats up, after the dissolving fully, add a small amount of EDTA and gac,, filter 60～75 ℃ of scope insulations 30 minutes, add about 30 milliliters of 15% sulfuric acid in the filtrate, crystallisation by cooling, filter levofloxacin vitriol, weight in wet base 185 gram.
In the wet product of levofloxacin hydrochloride vitriol, add 25 milliliters of 550 milliliters of dehydrated alcohols and 5% ammoniacal liquor, heating in water bath heats up, after treating dissolving fully, add a small amount of EDTA and gac, 60～75 ℃ of scopes are incubated 30 minutes, filter, the filtrate crystallisation by cooling filters the gained crystallization and uses water pump drying under reduced pressure 2.0～3.0 hours, and temperature is between 50～55 ℃, get levofloxacin, dry weight 98 grams.
Embodiment three:
The left carboxylic acid fluoride of 100 grams feeds intake, and is prepared into crude preparation of levofloxacin as described in embodiment one, weight in wet base 167 grams.
In the wet product of levofloxacin, add 600 milliliters of dehydrated alcohols, heating in water bath heats up, after the dissolving fully, add a small amount of EDTA and gac,, filter 60～75 ℃ of scope insulations 30 minutes, add about 30 milliliters of concentrated hydrochloric acid in the filtrate, crystallisation by cooling, filter the levofloxacin hydrochloride, weight in wet base 170 gram.
In the wet product of levofloxacin hydrochloride, add 550 milliliters of dehydrated alcohols, regulate PH to 7.5～8.0 with saturated sodium bicarbonate solution, heating in water bath heats up, treat dissolving fully after, add a small amount of EDTA and gac, 60～75 ℃ of scopes are incubated 30 minutes, filter the filtrate crystallisation by cooling, filter the gained crystallization and use water pump drying under reduced pressure 2.0～3.0 hours, temperature gets levofloxacin between 50～55 ℃, dry weight 92 grams.
Claims (3)
1, a kind of levofloxacin preparation and post-treating method is characterized in that this method comprises the following steps:
(1) preparation crude preparation of levofloxacin: in the dimethyl sulfoxide solvent of 2～5 times of w/w, 80～100 ℃ of reactions of the N methyl piperazine of left side carboxylic acid fluoride and 0.5～1.5 times of w/w 4～8 hours, reclaim under reduced pressure N methyl piperazine and dimethyl sulfoxide (DMSO), in product, add entry, regulating pH is 6.0～6.5, the dissolving back adds gac, keep 45～75 ℃ to stir 20～60 minutes, filter, filtrate is heated to 45～75 ℃, regulating pH is 9.5～10.0, add gac, keep 45～75 ℃ to stir 20～60 minutes, filter, it is 7.0～8.0 that filtrate is regulated pH, with chloroform re-extract 6～10 times, combining extraction liquid, reclaim chloroform, the anhydrous alcohol solution post crystallization that in residue, adds 5～8 times of w/w, filter crude preparation of levofloxacin;
(2) salify: in crude preparation of levofloxacin, add the dehydrated alcohol of 5～8 times of w/w, be warmed up to 65～75 ℃, after the dissolving fully, add EDTA and gac,, filter 65～75 ℃ of scope insulations 20～60 minutes, add a certain amount of acid in the filtrate, crystallisation by cooling, filter levofloxacin salt;
(3) preparation levofloxacin: the dehydrated alcohol and a certain amount of alkali lye that in levofloxacin salt, add 5～8 times of w/w, after intensification is waited to dissolve, add EDTA and gac, 60～75 ℃ of scopes are incubated 20～60 minutes, filter, the filtrate crystallisation by cooling, crystallization promptly got levofloxacin in 2～3 hours in 50～55 ℃ of drying under reduced pressure.
2, a kind of levofloxacin preparation according to claim 1 and post-treating method, used acid is hydrochloric acid, sulfuric acid or Glacial acetic acid when it is characterized in that wherein said step (2) salify.
3, a kind of levofloxacin preparation according to claim 1 and post-treating method is characterized in that the used alkali of wherein said step (3) preparation levofloxacin is ammoniacal liquor, sodium hydroxide or sodium bicarbonate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746320A (en) * | 2011-04-20 | 2012-10-24 | 上虞京新药业有限公司 | Levofloxacin hydrochloride crystal forms and preparation methods thereof |
| CN103420938A (en) * | 2012-05-25 | 2013-12-04 | 浙江京新药业股份有限公司 | Method for recovering piperazine after piperazine condensation reaction in quinolone medicine preparation |
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| CN103113388B (en) * | 2013-02-01 | 2016-02-10 | 浙江国邦药业有限公司 | A kind of preparation method of levofloxacin |
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