CN100408542C - Synthesis of 2,4,5-trifluoro-3-methoxybenzoic acid - Google Patents
Synthesis of 2,4,5-trifluoro-3-methoxybenzoic acid Download PDFInfo
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- CN100408542C CN100408542C CNB2005100293836A CN200510029383A CN100408542C CN 100408542 C CN100408542 C CN 100408542C CN B2005100293836 A CNB2005100293836 A CN B2005100293836A CN 200510029383 A CN200510029383 A CN 200510029383A CN 100408542 C CN100408542 C CN 100408542C
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Abstract
The present invention relates to a method for synthesizing 2, 4, 5-trifluorine-3-methoxybenzoic acid. Firstly, tetrafluorine phthalic acid is used for carrying out defluorination methoxylation in a mixing alkali system of CaOH2 and NaOH in return temperature and an alcohol solvent, and 2, 4, 5-fluorine 3-methoxy phthalic acid is obtained; then, the 2, 4, 5-fluorine 3-methoxy phthalic acid and tributylamine react in xylene or toluene solvent under return temperature, and 2, 4, 5-trifluorine-3-methoxybenzoic acid is obtained. The method of the present invention has the advantages of short synthetic route, mild reaction condition and little side reaction. The defect that extreme toxic substance dimethyl sulfate is used for carrying out methylation by a traditional method for synthesizing 2, 4, 5-trifluorine-3-methoxybenzoic acid can be eliminated, and the present invention develops a technological line with the advantages of economic value and friendly environment.
Description
Technical field
The present invention is a kind of Synthetic 2 of practicality, 4, and the method for 5-three fluoro-3-methoxybenzoic acids, this method route is short, environmental pollution is light and eco-friendly synthetic method.
Technical background
Anti-infectives market is huge in the world, and in being worth more than 3,000 hundred million dollars pharmaceutical market every year, anti-infectives occupies about 10%.Domestic anti-infectives accounts for whole pharmaceutical market more than 30%, and quinolones has has a broad antifungal spectrum, strong, simple in structure, the convenient drug administration of antimicrbial power, curative effect-price compares advantages of higher, become the focus medicine of competitively producing and using, only the fluoroquinolone medicine market share in recent years accounts for 20% of anti-infectives.The antibacterials of quinolone generic chemosynthesis behind nineteen sixty synthetic first-generation quinolones naphthoic acid, have been synthesized s-generation quinolone medicine pipemidic acid etc. in 1973, synthesized third generation quinolone medicine in 1978.The common feature of third generation quinolones is a piperazine ring continuously on 7 of chemical structures, 6 places have introduced fluorine atom again, thereby improved the bacterium activity greatly, broadening antimicrobial spectrum, evident in efficacy, side effect simultaneously is also little, because of in the third generation quinolones structure fluorine atom being arranged all, so claim fluoroquinolones (fluoroquinolones) again.Also have the people it to be divided into four-stage according to the anti-microbial effect of quinolones, side effect etc.:
Fs is meant the Nalidixic Acid and the minaline of 1962-1969 listing, and they have activity to most of Lan Shi negative bacterium, but to gram-positive microorganism and Pseudomonas aeruginosa non-activity.This medicine oral absorption is good, and in vivo by metabolism and deactivation, the rate of recovery is 50%-90% in the twenty-four-hour urine; And former medicine and active metabolite only account for about 10% of dosage.However, because concentration is higher in urinary tract, biliary tract and enteron aisle, can treats these systems and infect.
Subordinate phase is represented with pipemidic acid and cinoxacin master at 1970-1977, this type of has activity to Gram-negative bacteria, aspect antimicrobial spectrum, compares with the fs medicine, Pseudomonas aeruginosa there is certain effect, has highly drug-fast bacterial strain that activity is also arranged Nalidixic Acid and minaline.This type of medicine internal metabolism is stable, has in the urine 24 hours rate of recovery nearly 90%, its Central Plains medicine content＞50%, and tissue permeability is good, except that treatment urinary tract, biliary tract and intestinal tract infections, also is used for the infection at positions such as ear, nose.
On behalf of medicine, the phase III norfloxicin, Ofloxacine USP 23, ring Xisha star, Nuo Meisha magnitude are arranged at 1978-1964; Antimicrobial spectrum is expanded as the non-glycolysis bacterium of G+ bacterium, G-bacterium and glucose.This type of medical instrument has the favorable tissue perviousness, except that cerebral tissue and cerebrospinal fluid, various organizing is all had good distribution, thus antimicrobial spectrum is widely not only arranged, and indication is widely arranged.
The quadravalence section refers to some quinolones of being gone on the market later in 1986, compares with former classes, and they have the antimicrobial spectrum aspect, and some medicine all has good effect to staphylococcus, streptococcus pneumoniae, bacteroides fragilis, mycoplasma, chlamydozoan, legionella etc.; Some medicine to the activity of mycobacterium tuberculosis be the phase III quinolone 3-30 doubly, suitable with different cigarette calf with Rifampin.This type of medicine is owing to absorb rapidly, it is good to distribute, and Plasma Concentration is big, long half time, the bioavailability height is so clinically can be applicable to infection such as urinary tract infection, respiratory tract infection, digestive tract infection, skin and soft tissue infection, Eye Ear Nose And Throat section, Stomatological Department.
The Novel Quinolone class medicine of developing after the nineties, numerous, roughly have: lomefloxacin, Tosulfloxacin, temafloxacin, rufloxacin, fleroxacin, Sparfloxacin, the husky star in sodium ground, levofloxacin, grepafloxacin, the husky star of curve, alafloxacin, Gatifloxacin, baloxacin, Pazufloxacin, Clinafloxacin, lattice are for husky star, prulifloxacin and Moxifloxacin etc.As
2,4,5-three fluoro-3-methoxybenzoic acids are synthetic Gatifloxacins (gatifloxacin), the key intermediate Fertel of baloxacin third generation carbostyril family antibacterial drugs such as (baloxa cin), Lawrence B.; Derwin, William S.Method of making 3-methoxy-2,4,5-trifluorobenzoic acid.US5380926.; Derwin, William S.Preparation of 3-hydroxy-2,4,5-trifluorobenzoic acid useful as anintermediate for quinolone antibacterials.US 5233082.].2,4,5-three fluoro-3-methoxybenzoic acids are for CAS number 112811-65-1, and molecular formula is C
8H
5F
3O
3, fusing point is the 115-116 degree, white crystalline powder, and structural formula is as follows:
The route of its synthetic route and suitable industrialization growth is concluded and is mainly contained following three:
Route one [Fertel, Lawrence B.; Derwin, William S.Method of making3-methoxy-2,4,5-trifluorobenzoic acid.US5380926.; Derwin, William S.Preparation of3-hydroxy-2,4,5-trifluorobenzoic acid useful as an intermediate for quinoloneantibacterials.US 5233082.]:
Route two [N.Ishikawa et al.Nippon Kagaku Kaishi 1976.1.200-202.]:
Route three [Tian Zhiming, Liu Mingliang, Guo Huiyuan.2,4, preparation [J] Chinese Journal of Pharmaceuticals .20000.31 (12) .557-558 of 5-three fluoro-3-methoxybenzoic acids; Ataka, Kikuo; Oku, Masayoshi.Manufacture of2,4,5-trifluoro-3-hydroxybenzoic acid.JP 03127755; Yoshida, Masahiko; Miyata, Kazuyoshi; Shibabuchi, Hiroshi; Imai, Yasushi.Preparation of 4-hydroxy-3,5,6-trifluorophthalic acid and 3-hydroxy-2,4,5-trifluorobenzoic acid.JP 03232838; Pfirmann, Ralf; Papenfuhs, Theodor.Preparation of 3-alkoxy-2,4,5-trifluorophthalicand-benzoic acids.EP 667334.]:
Above route is nearest 20 years domestic and foreign literature report Synthetic 2s, and 4,5-three fluoro-3-methoxybenzoic acid routes, each bar route all has its characteristics, but its deficiency is all arranged.Route one defluorinate that in alkaline aqueous solution, is hydrolyzed, but to separate 2,4 after the hydrolysis, 5-three fluoro-3-hydroxy-benzoic acids, operational path is long; Adopt the environmental pollution that methylates of highly toxic substance methyl-sulfate methylating reagent serious.Route two adopts methyl alcohol to carry out methylating reagent, has solved the pollution problem of methyl-sulfate, but has utilized methyl alcohol that carboxyl is protected, and operational path is loaded down with trivial details, industrialization cost height.Route three is that present domestic great majority produce 2,4, the technology that 5-three fluoro-3-methoxybenzoic acid producers are adopted, and this operational path is shorter, but the decarboxylic reaction side reaction under alkaline condition of this route is more, causes the refining difficulty of target product; Because use the highly toxic substance methyl-sulfate as methylating reagent, environmental problem is deviate from, and also easily product is polluted in addition.
Summary of the invention
The object of the invention has provided a kind of new preparation 2,4, the synthetic method of 5-three fluoro-3-methoxybenzoic acids.
The present invention has designed one, and route is short, the gentle side reaction of reaction conditions is few; Got rid of the traditional method Synthetic 2,4,5-three fluoro-3-methoxybenzoic acids utilize the highly toxic substance methyl-sulfate to carry out methylated drawback, have developed an economically valuable, eco-friendly operational path.Shown in following two steps of design reaction scheme:
Reaction one:
Reaction two:
The first step uses ptfe phthalate at Ca (OH) in reflux temperature and methanol solvate
2With carried out the defluorinate methoxylation 1～24 hour in the NaOH mixed base system, recommended 5～8 hours, obtain 2,4,5-three fluoro-3-methoxyl group phthalic acids, described ptfe phthalate, Ca (OH)
2With the mol ratio of NaOH be 1: 0.8-2.2: 1-4.0, the recommendation ratio is 1: 2: 4 or 1: 2.2: 4.Method of the present invention has been got rid of the use of hypertoxic methyl-sulfate.Compare reduction reaction one usefulness Ca (OH) with former technology
2Replace comparatively expensive LiOH with NaOH suitable proportion mixed base, production cost reduces, and because of Ca
2+In conjunction with F
-Generate the CaF that the utmost point is difficult to water
2, and make defluorination reaction accelerate, also avoided F
-Cause environmental pollution and equipment corrosion.The modified reaction follow the tracks of to be detected fully at 7-8 hour once liquid phase, comparing the reaction times with document shortens 2 hours, and reaction conversion ratio is more than 95%, and side reaction is less than 5%.
The mixed solvent of second step with dimethylbenzene and tri-n-butylamine replaces dichlorobenzene to extract and decarboxylic reaction.Make this technology more rationally perfect, yield improves, and the target product production cost is lower.
The second step reaction adopts tri-n-butylamine to exist down, the decarboxylic reaction that replaces dichlorobenzene to extract and follow with dimethylbenzene or toluene solvant.
In the backflow temperature of dimethylbenzene or toluene solvant, 2,4,5-three fluoro-3-methoxyl group phthalic acids and tri-n-butylamine reaction obtained 2,4 in 0.5～4 hour, 5-three fluoro-3-methoxybenzoic acids, described 2,4, the mol ratio of 5-three fluoro-3-methoxyl group phthalic acids and tri-n-butylamine is 1: 0.1～10, more tri-n-butylamine is to not influence of reaction, and recommending mol ratio is 1: 0.1～2.This mixed solvent of tri-n-butylamine and dimethylbenzene or toluene is fine to compound (2) effect of extracting, and usage quantity reduces about 30% than simple when using a kind of solvent, can prolong four hours with the reaction time, thereby decarboxylic reaction can very steadily carry out, the decarboxylation selectivity is good, greatly reduces through Liquid Detection reaction side reaction.Reaction back with 10～35% hydrochloric acid conditioned reaction liquid acidity to pH=1-2, xylene extraction, drying, concentrated, recrystallization
Two step total recoverys are more than 70%, be much higher than 66% of document, through simple recrystallization processing target product (3) is white crystalline powder, fusing point 115-116 degree, purity can be used for synthetic Gatifloxacin (gatifloxacin), baloxacin carbostyril family antibacterial drugs such as (baloxacin) more than 99% (HPLC).
Table-1: the amount of calcium hydroxide and sodium hydroxide is to the influence of the methoxylation of ptfe phthalate
| Batch | Temperature | Reaction times | Ptfe phthalate (mole) | Ca(OH) 2/ NaOH (moles/mole) | Transformation efficiency (%) |
| 1 | Reflux | 5 | 1 | 0.8/1 | 65 |
| 2 | Reflux | 8 | 1 | 1/2 | 85 |
| 3 | Reflux | 10 | 1 | 1.5/3.2 | 95.6 |
| 4 | Reflux | 12 | 1 | 2/4.0 | 98 |
| 5 | Reflux | 12 | 1 | 2.2/4.0 | 99 |
Table-2:2,4, the preparation of 5-three fluoro-3-methoxybenzoic acids
| Batch | Temperature | Reaction times | Ptfe phthalate (mole) | Tributylamine (mole) | Transformation efficiency (%) |
| 1 | Reflux | 1 | 1 | 0.1 | 67 |
| 2 | Reflux | 1 | 1 | 0.2 | 75 |
| 3 | Reflux | 1 | 1 | 0.4 | 82 |
| 4 | Reflux | 1 | 1 | 0.5 | 84 |
| 5 | Reflux | 1 | 1 | 1.0 | 85 |
| 6 | Reflux | 1 | 1 | 1.2 | 88 |
| 7 | Reflux | 1.2 | 1 | 1.5 | 90 |
| 8 | Reflux | 4 | 1 | 2 | 95 |
Method route of the present invention is short, the gentle side reaction of reaction conditions is few; Got rid of the traditional method Synthetic 2,4,5-three fluoro-3-methoxybenzoic acids utilize the highly toxic substance methyl-sulfate to carry out methylated drawback, have developed an economically valuable, eco-friendly operational path.
Embodiment
Help to understand the present invention by following exemplary embodiments, do not get content but do not limit the present invention.
In a 1L three-necked flask that reflux exchanger is housed, add tetra fluoro benzene dioctyl phthalate 95.2g (0.4mol), methyl alcohol 150mL, sodium hydroxide 64g (1.6mol), calcium hydroxide 59.2g (0.8mol).Under mechanical stirring, back flow reaction 12hr.The cooling reaction solution slowly adds 35% hydrochloric acid 230mL (2.6mol), the insoluble CaF of elimination
2, obtain containing 2 the aqueous solution, to wherein adding 400ml dimethylbenzene and 74g Bu
3N, under mechanical stirring, back flow reaction 1-2 hour, with 35% hydrochloric acid conditioned reaction liquid acidity to pH=1-2, xylene extraction, drying concentrates, the white solid 73.7g of recrystallization, productive rate 89%.M.p.115-116 ℃ (literature value 115.6-116.4 ℃).
Claims (4)
1. Synthetic 2,4, the method for 5-three fluoro-3-methoxybenzoic acids; It is characterized in that adopting the reaction of two steps:
(1), in reflux temperature and methanol solvate, use ptfe phthalate at Ca (OH)
2With carried out the defluorinate methoxylation 1～24 hour in the NaOH mixed base system, then carry out acidifying, obtain 2,4,5-three fluoro-3-methoxyl group phthalic acids, described ptfe phthalate, Ca (OH)
2With the mol ratio of NaOH be 1: 0.8-2.2: 1-4.0;
(2), in dimethylbenzene or toluene solvant and under the reflux temperature, 2,4,5-three fluoro-3-methoxyl group phthalic acids and tri-n-butylamine reaction obtained 2,4 in 0.5～4 hour, 5-three fluoro-3-methoxybenzoic acids, described 2,4, the mol ratio of 5-three fluoro-3-methoxyl group phthalic acids and tri-n-butylamine is 1: 0.1～10.
2. a kind of Synthetic 2 as claimed in claim 1,4, the method for 5-three fluoro-3-methoxybenzoic acids is characterized in that the ptfe phthalate described in the method (1), Ca (OH)
2With the mol ratio of NaOH be 1: 2: 4 or 1: 2.2: 4.
3. a kind of Synthetic 2 as claimed in claim 1,4, the method for 5-three fluoro-3-methoxybenzoic acids is characterized in that the reaction times described in the method (1) is 5～8 hours.
4. a kind of Synthetic 2 as claimed in claim 1,4, the method for 5-three fluoro-3-methoxybenzoic acids is characterized in that 2,4 described in the method (2), the mol ratio of 5-three fluoro-3-methoxyl group phthalic acids and tri-n-butylamine is 1: 0.1～2.
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| CNB2005100293836A CN100408542C (en) | 2005-09-02 | 2005-09-02 | Synthesis of 2,4,5-trifluoro-3-methoxybenzoic acid |
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| CN102531887B (en) * | 2012-01-05 | 2014-05-14 | 连云港威远精细化工有限公司 | Method for preparing 2,4,5-trifluoro-3-methyl benzoic acid |
| CN114736133B (en) * | 2022-04-14 | 2023-03-24 | 内蒙古源宏精细化工有限公司 | Preparation of 2,4, 5-trifluoro-3-methoxybenzoic acid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03232838A (en) * | 1990-02-07 | 1991-10-16 | Nippon Carbide Ind Co Inc | Production of 4-hydroxy-3,5,6-trifluorophthalic acid and 3-hydroxy-2,4,5-trifluorobenzoic acid |
| JPH03279348A (en) * | 1990-03-28 | 1991-12-10 | Kyorin Pharmaceut Co Ltd | Production of 2,4,5-trifluoro-3-alkoxybenzoic acid |
| US5488152A (en) * | 1994-02-12 | 1996-01-30 | Hoechst Aktiengesellschaft | Process for the preparation of 4-alkoxy-3,5,6-trifluoro-phthalic acids and 3-alkoxy-2,4,5-trifluorobenzoic acids |
| CN1118344A (en) * | 1994-02-23 | 1996-03-13 | 旭硝子株式会社 | Processes for producing tetrafluorophthalic anhydride and fluorobenzoic acids |
| JPH1059898A (en) * | 1997-05-23 | 1998-03-03 | Nippon Carbide Ind Co Inc | Production of 2,4,5-trifluoro-3-hydroxybenzoic acid and production of 2,4,5-trifluoro-3-alkoxybenzoic acid |
-
2005
- 2005-09-02 CN CNB2005100293836A patent/CN100408542C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03232838A (en) * | 1990-02-07 | 1991-10-16 | Nippon Carbide Ind Co Inc | Production of 4-hydroxy-3,5,6-trifluorophthalic acid and 3-hydroxy-2,4,5-trifluorobenzoic acid |
| JPH03279348A (en) * | 1990-03-28 | 1991-12-10 | Kyorin Pharmaceut Co Ltd | Production of 2,4,5-trifluoro-3-alkoxybenzoic acid |
| US5488152A (en) * | 1994-02-12 | 1996-01-30 | Hoechst Aktiengesellschaft | Process for the preparation of 4-alkoxy-3,5,6-trifluoro-phthalic acids and 3-alkoxy-2,4,5-trifluorobenzoic acids |
| CN1118344A (en) * | 1994-02-23 | 1996-03-13 | 旭硝子株式会社 | Processes for producing tetrafluorophthalic anhydride and fluorobenzoic acids |
| JPH1059898A (en) * | 1997-05-23 | 1998-03-03 | Nippon Carbide Ind Co Inc | Production of 2,4,5-trifluoro-3-hydroxybenzoic acid and production of 2,4,5-trifluoro-3-alkoxybenzoic acid |
Non-Patent Citations (4)
| Title |
|---|
| 《2，4，5－三氟－3－甲氧基苯甲酸合成路线图解》. 刘明亮，郭惠元.《中国医药工业杂志》，第30卷第4期. 1999 |
| 《2，4，5－三氟－3－甲氧基苯甲酸合成路线图解》. 刘明亮，郭惠元.《中国医药工业杂志》，第30卷第4期. 1999 * |
| 《2，4，5－三氟－3－甲氧基苯甲酸的制备》. 田治明等.《中国医药工业杂志》，第31卷第12期. 2000 |
| 《2，4，5－三氟－3－甲氧基苯甲酸的制备》. 田治明等.《中国医药工业杂志》，第31卷第12期. 2000 * |
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