CN101768167B - Method for synthesizing piperazine of levofloxacin - Google Patents
Method for synthesizing piperazine of levofloxacin Download PDFInfo
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- CN101768167B CN101768167B CN2010100400650A CN201010040065A CN101768167B CN 101768167 B CN101768167 B CN 101768167B CN 2010100400650 A CN2010100400650 A CN 2010100400650A CN 201010040065 A CN201010040065 A CN 201010040065A CN 101768167 B CN101768167 B CN 101768167B
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Abstract
The invention provides a method for synthesizing piperazine of levofloxacin and belongs to the technical field of medicine synthetics. The method solves the problem that the levofloxacin piperazine reaction requires a high boiling point solvent and the polar solvents such as DMSO, triethylamine, pyridine, and the like have strong smell and strong pungency which are harmful to the health of human. The method comprises the following steps of: A) adding N-methyl piperazine in lavo-ofloxacin carboxylic acid to react and concentrating and recycling N-methyl piperazine after finishing the reaction so as to obtain residue, and B) adding water in the residue, and then adding alkali to neutralize so as to obtain the crude products of lavo-ofloxacin after filtering. The method of the invention does not use the high boiling point solvent like DMSO and the organic base like triethylamine or pyridine, so the smell is slight during the production process, the pungency is soft and the damage on the environment and the harm to the health of human are greatly decreased.
Description
Technical field
The present invention relates to the compound method of fluoroquinolone antibacterial agent thing, relate in particular to the piperazine compound method that contracts of levofloxacin; Belong to technical field of medicine synthesis.
Background technology
Levofloxacin (Levofloxacin) chemistry is by name: (S)-(-)-9-fluoro-2, and 3-dihydro-3-methyl isophthalic acid 0-[4-methyl isophthalic acid-piperazinyl]-7-oxo-7-pyridinium hydroxide also [1,2; 3-de] [1; 4] benzoxazine-6-carboxylic acid, CAS accession number: 100986-85-4, the 4th generation the fluoroquinolone antibacterial agent thing; Have has a broad antifungal spectrum, characteristics that toxicity is low; Gram-positive microorganism, Gram-negative bacteria and part anerobes are all had anti-microbial effect, and its antibacterial strength is 2 times of ordinary oxygen Flucloxacillin, is 8-128 times of right Flucloxacillin; Toxicity is lower than Ofloxacine USP 23, is widely used in the treatment of respiratory tract infection, urinary tract infection, gynecological infection, the infection of liver road, ophthalmology infection and intestinal tract infections clinically.Wherein the chemical structural formula of levofloxacin is as follows:
The preparation technology of levofloxacin and midbody thereof is mature on the whole, and the report document is a lot, the space but the piperazine reaction of contracting of final step still is improved, and the piperazine that contracts at present reaction mainly contains following two kinds of methods:
Method one: like USP (publication number: US5539110); International monopoly (publication number: WO2006048889); Chinese patent (publication number: CN1687074) and Chinese patent (publication number: CN 1594320) open be raw material with the levofloxacin carboxylic acid, at polar solvent such as methyl-sulphoxide, DMAC N,N, tetramethylene sulfone, ethylene glycol monoethyl ether, isopropylcarbinol, propyl carbinol; Primary isoamyl alcohol, dioxane and YLENE; With alkali such as triethylamine, pyridine, salt of wormwood and yellow soda ash etc. and N methyl piperazine prepared in reaction levofloxacin, wherein reaction expression is as follows:
Method two: international monopoly (publication number: WO2002070726); International monopoly (publication number: WO2001018005) and European patent (publication number: EP0368410A2) disclosed method earlier changes into midbody (4) with levofloxacin carboxylic acid (2) with boron trifluoride solution; Again with N methyl piperazine (3) prepared in reaction levofloxacin, wherein reaction expression is as follows:
Wherein raw material boron trifluoride cost is higher and be difficult to reclaim in the method two, is method one so existing suitability for industrialized production mainly adopts; But the deficiency of method one to need to be all high boiling solvent do reaction solvent, causes recovery difficult big, and picture DMSO, triethylamine, and pyridine isopolarity solvent odor is bigger, and pungency is stronger, and environment and people's health is had bigger harm.
Summary of the invention
The present invention is directed to the existing in prior technology defective, a kind of piperazine compound method that contracts of levofloxacin is provided, this method does not need high boiling solvent to do reaction solvent, and reaction cost is lower, and pungency is less, and environment and people's Health hazard property is reduced greatly.
Above-mentioned purpose of the present invention can realize through following technical proposal: a kind of piperazine compound method that contracts of levofloxacin, and this method may further comprise the steps:
A, in levofloxacin carboxylic acid, add N methyl piperazine and react, the reaction back concentrates reclaims N methyl piperazine and obtains residue;
B, residue add water, transfer to alkali then and obtain crude preparation of levofloxacin after neutrality is filtered.
The liquid phase of the present invention's reaction is a N methyl piperazine; The inventor is through studying for a long period of time and testing discovery; N methyl piperazine both can be as reaction reagent; Again can be as acid binding agent and solvent, need to add in addition high boiling solvent as reaction solvent technology prejudice thereby overcome in the piperazine building-up process that contracts of existing levofloxacin, greatly reduce reaction cost and to environment and people's Health hazard property.
In the piperazine compound method that contracts of above-mentioned levofloxacin, the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1 in the steps A: 2.5-6.As preferably, the mol ratio of described levofloxacin carboxylic acid and N methyl piperazine is 1: 3-4.The mol ratio of levofloxacin carboxylic acid and N methyl piperazine is influential with stirring to the speed of reaction, and it is insufficient that N methyl piperazine reacts stirring very little, and the reaction times prolongs: N methyl piperazine is too many, and cost strengthens, and recovery difficult strengthens.
In the piperazine compound method that contracts of above-mentioned levofloxacin, the temperature when reacting in the steps A is 75-110 ℃, and the reaction times is 8-15 hour.As preferably, the temperature in the steps A during reaction is 85-95 ℃, and the reaction times is 10-12 hour.The too high meeting of temperature of reaction causes by product more, and reaction temperature is spent low reaction will be incomplete; Equally, the reaction times, long meeting caused by product more, and the reaction times, very few reaction will be incomplete.
In the piperazine compound method that contracts of above-mentioned levofloxacin, the temperature when concentrating in the steps A is lower than 110 ℃.As preferably, the temperature when concentrating in the steps A is lower than 95 ℃.
In the piperazine compound method that contracts of above-mentioned levofloxacin, the volume ratio of residue and water is 1 among the step B: 2-6.As preferably, the volume ratio of residue and water is 1 among the step B: 3-4.The volume of water what directly influence the weight content and the yield of the finished product levofloxacin, adds water and causes in the product inorganic salt residual too much and defective very little, and the water yield is too many, then product loss yield reduction greatly.
In the piperazine compound method that contracts of above-mentioned levofloxacin, the alkali described in the step B is a kind of in ammoniacal liquor, sodium hydroxide, sodium hydrogencarbonate, yellow soda ash, the salt of wormwood.As preferably, described alkali is ammoniacal liquor.Ammoniacal liquor is compared with other alkali, and mother liquor is residual less, and product yield is higher.
The reaction expression of the piperazine compound method that contracts of levofloxacin of the present invention is as follows:
In sum, the present invention has the following advantages:
The piperazine compound method that contracts of levofloxacin of the present invention is not used reaction solvent, does acid binding agent without organic bases, and raw materials cost reduces, and need not comparatively complicated recovery technology, and technical process is simple.
The piperazine compound method that contracts of levofloxacin of the present invention has reduced the reactant volume greatly, compares former technology and has improved production capacity greatly, and operation cost is also thereupon with low.
The piperazine compound method that contracts of levofloxacin of the present invention need not look like the high boiling solvent of DMSO and so on and the organic bases of triethylamine or pyridine and so on, and the production period smell reduces, and pungency is lower, and the harm of environmental pollution and HUMAN HEALTH reduces greatly.
Embodiment
Through specific embodiment, do further bright specifically below to technical scheme of the present invention; But the present invention is not limited to these embodiment.
Embodiment 1
Levofloxacin carboxylic acid (2) 28.1 grams are added N methyl piperazine (3) 30 grams (wherein the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1: 3); 90-95 ℃ was reacted 12 hours; Less than 90 ℃ reactant is concentrated into the dried residue that obtains, residue adds water 84mL (wherein the volume ratio of residue and water is 1: 3), uses concentration to transfer to neutrality as 25-28% ammoniacal liquor; Filtration obtains faint yellow solid levofloxacin (1) bullion 30.3g, yield: 84.0%.Detected result is as follows:
MS(ESI)：(M
++H
+)362
1H-NMR(CDCl
3)：8.65(s，1H)，7.47(d，J＝12.2Hz，1H)，4.66(d，1H)，4.42(m，2H)，3.31-3.41(m，4H)，2.51(s，4H)，2.32(s，3H)，1.56(d，3H)
[α]
D 20＝-96.7°(c＝0.027，CH
3OH)。
Embodiment 2
Levofloxacin carboxylic acid (2) 28.1 grams are added N methyl piperazine (3) 40 grams (wherein the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1: 4); 85-90 ℃ was reacted 10 hours; Less than 90 ℃ reactant is concentrated into the dried residue that obtains, residue adds water 112mL (wherein the volume ratio of residue and water is 1: 4), uses concentration to transfer to neutrality as 25-28% ammoniacal liquor; Filtration obtains faint yellow solid levofloxacin (1) bullion 29.6g, yield: 82.0%.
Embodiment 3
Levofloxacin carboxylic acid (2) 28.1 grams are added N methyl piperazine (3) 50 grams (wherein the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1: 5); 80-85 ℃ was reacted 12 hours; Less than 90 ℃ reactant is concentrated into the dried residue that obtains, residue adds water 141mL (wherein the volume ratio of residue and water is 1: 5), and using concentration is that 10% sodium hydroxide transfers to neutrality; Filtration obtains faint yellow solid levofloxacin (1) bullion 28.5g, yield: 79.0%.
Embodiment 4
Levofloxacin carboxylic acid (2) 28.1 grams are added N methyl piperazine (3) 60 grams (wherein the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1: 6); 75-80 ℃ was reacted 12 hours; Less than 90 ℃ reactant is concentrated into the dried residue that obtains, residue adds water 169mL (wherein the volume ratio of residue and water is 1: 6), and using concentration is that 10% yellow soda ash transfers to neutrality; Filtration obtains faint yellow solid levofloxacin (1) bullion 27.1g, yield: 75.0%.
Embodiment 5
Levofloxacin carboxylic acid (2) 28.1 grams are added N methyl piperazine (3) 50 grams (wherein the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1: 5); 95-100 ℃ was reacted 10 hours; Less than 100 ℃ reactant is concentrated into the dried residue that obtains, residue adds water 112mL (wherein the volume ratio of residue and water is 1: 4), and using concentration is that 10% sodium hydrogencarbonate transfers to neutrality; Filtration obtains faint yellow solid levofloxacin (1) bullion 28.9g, yield: 80.0%.
Embodiment 6
Levofloxacin carboxylic acid (2) 28.1 grams are added N methyl piperazine (3) 40 grams (wherein the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1: 4); 100-105 ℃ was reacted 10 hours; Less than 100 ℃ reactant is concentrated into the dried residue that obtains, residue adds water 84mL (wherein the volume ratio of residue and water is 1: 3), and using concentration is that 10% salt of wormwood transfers to neutrality; Filtration obtains faint yellow solid levofloxacin (1) bullion 29.2g, yield: 81.0%.
Embodiment 7
Levofloxacin carboxylic acid (2) 28.1 grams are added N methyl piperazine (3) 30 grams (wherein the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1: 3); 105-110 ℃ was reacted 12 hours; Less than 100 ℃ reactant is concentrated into the dried residue that obtains, residue adds water 56mL (wherein the volume ratio of residue and water is 1: 2), uses concentration to transfer to neutrality as 25-28% ammoniacal liquor; Filtration obtains faint yellow solid levofloxacin (1) bullion 29.2g, yield: 81.0%.
Specific embodiment described in the present invention only is that the present invention's spirit is illustrated.Person of ordinary skill in the field of the present invention can make various modifications or replenishes or adopt similar mode to substitute described specific embodiment, but can't depart from spirit of the present invention or surmount the defined scope of appended claims.
Although the present invention has been made detailed explanation and has quoted some specific embodiments as proof, to those skilled in the art, only otherwise leave that the spirit and scope of the present invention can be done various variations or correction is obvious.
Claims (7)
1. the piperazine compound method that contracts of a levofloxacin is characterized in that this method may further comprise the steps:
A, in levofloxacin carboxylic acid, add N methyl piperazine and react, the reaction back concentrates reclaims N methyl piperazine and obtains residue; This reaction only uses N methyl piperazine as solvent and acid binding agent;
B, residue add water, transfer to alkali then and obtain crude preparation of levofloxacin after neutrality is filtered.
2. the piperazine compound method that contracts of levofloxacin according to claim 1, it is characterized in that: the mol ratio of levofloxacin carboxylic acid and N methyl piperazine is 1 in the steps A: 2.5-6.
3. the piperazine compound method that contracts of levofloxacin according to claim 1 and 2 is characterized in that: the temperature in the steps A during reaction is 75-110 ℃, and the reaction times is 8-15 hour.
4. the piperazine compound method that contracts of levofloxacin according to claim 1 and 2 is characterized in that: the temperature when concentrating in the steps A is lower than 110 ℃.
5. the piperazine compound method that contracts of levofloxacin according to claim 3 is characterized in that: the temperature when concentrating in the steps A is lower than 110 ℃.
6. the piperazine compound method that contracts of levofloxacin according to claim 1, it is characterized in that: the volume ratio of residue and water is 1 among the step B: 2-6.
7. according to the piperazine compound method that contracts of claim 1 or 6 described levofloxacins, it is characterized in that: the alkali described in the step B is a kind of in ammoniacal liquor, sodium hydroxide, sodium hydrogencarbonate, yellow soda ash, the salt of wormwood.
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| CN2010100400650A CN101768167B (en) | 2010-01-15 | 2010-01-15 | Method for synthesizing piperazine of levofloxacin |
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| CN101768167B true CN101768167B (en) | 2012-07-04 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101880288B (en) * | 2010-07-12 | 2012-02-22 | 浙江东亚药业有限公司 | Synthesis method for ofloxacin |
| CN103420938B (en) * | 2012-05-25 | 2015-07-29 | 浙江京新药业股份有限公司 | A kind of method preparing contracting piperazine reaction rear recovery piperazine in quinolone medicine |
| CN104277052A (en) * | 2014-08-19 | 2015-01-14 | 天方药业有限公司 | Synthetic method of levofloxacin or ofloxacin |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042538A (en) * | 1988-11-07 | 1990-05-30 | 吉斯特·布罗卡德斯股份有限公司 | Opticity benzoxazine and benzothiazine and Stereoselective preparation method thereof |
| CN1181381A (en) * | 1997-11-18 | 1998-05-13 | 中国科学院上海药物研究所 | Synthetizing and application of laevo-rotation ofloxacin analogue |
| CN1379779A (en) * | 1999-09-08 | 2002-11-13 | 第一制药株式会社 | Process for preparation of benzoxazine derivatives and intermediates therefor |
| CN101337934A (en) * | 2007-05-24 | 2009-01-07 | 百科达公司 | Method for preparing fluoroquinolone compound |
| CN101514208A (en) * | 2008-10-17 | 2009-08-26 | 浙江京新药业股份有限公司 | Green synthesizing process for ofloxacin |
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2010
- 2010-01-15 CN CN2010100400650A patent/CN101768167B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042538A (en) * | 1988-11-07 | 1990-05-30 | 吉斯特·布罗卡德斯股份有限公司 | Opticity benzoxazine and benzothiazine and Stereoselective preparation method thereof |
| CN1181381A (en) * | 1997-11-18 | 1998-05-13 | 中国科学院上海药物研究所 | Synthetizing and application of laevo-rotation ofloxacin analogue |
| CN1379779A (en) * | 1999-09-08 | 2002-11-13 | 第一制药株式会社 | Process for preparation of benzoxazine derivatives and intermediates therefor |
| CN101337934A (en) * | 2007-05-24 | 2009-01-07 | 百科达公司 | Method for preparing fluoroquinolone compound |
| CN101514208A (en) * | 2008-10-17 | 2009-08-26 | 浙江京新药业股份有限公司 | Green synthesizing process for ofloxacin |
Non-Patent Citations (1)
| Title |
|---|
| 顾海宁等.左旋氧氟沙星合成的新工艺研究.《高校化学工程学报》.2005,第19卷(第5期),708-711. * |
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