CN104530113A - 2-fluorobenzoic acid compound and preparation method thereof - Google Patents
2-fluorobenzoic acid compound and preparation method thereof Download PDFInfo
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- CN104530113A CN104530113A CN201410831234.0A CN201410831234A CN104530113A CN 104530113 A CN104530113 A CN 104530113A CN 201410831234 A CN201410831234 A CN 201410831234A CN 104530113 A CN104530113 A CN 104530113A
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- UKODFQOELJFMII-UHFFFAOYSA-N CN(C)CCN(C)CCN(C)C Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a 2-fluorobenzoic acid compound used for a dye or medicine intermediate and a preparation method of the 2-fluorobenzoic acid compound. The synthetic route is as shown in the description. The preparation method comprises the following steps: by taking fluorine substituted benzene as a raw material, reacting fluorine substituted benzene with carbon dioxide at low temperature in the presence of n-butyllithium and an organic ligand, preferably pentamethyl di-ethanediamine, or sec-Butyllithium; then extracting an organic phase by utilizing an extracting agent, adjusting the pH of a water phase to be acidic with diluted hydrochloric acid, and then drying, filtering and concentrating the organic phase to obtain the 2-fluorobenzoic acid compound, wherein R is selected from hydrogen, halogen, hydroxy, C(1-6) alkoxy, unsubstituted or C(1-6) alkyl, halogen, hydroxy or C(1-6) alkoxy-substituted or polysubstituted C(3-6) naphthenic base, or unsubstituted or halogen- substituted or polysubstituted C(1-6) alkyl. The preparation method provided by the invention is less in steps, simple in process, simple in separation and purification methods, relatively high in productivity and good in selectivity and repeatability and can be prepared on a large scale.
Description
Technical field
The present invention relates to a kind of for dyestuff, medicine intermediate o-fluorobenzoic acid compounds and preparation method thereof.
Background technology
Fluorine element, because its superpower electronegativity and oxidation potential, has the physicochemical property of many uniquenesses, is mainly reflected in three aspects:
1, introduce in drug molecule fluorine atom can change significantly the richness of compound electrically, chemical property and the constitutional features such as moment of dipole and conformation, and then affect the character of compound;
2, the atomic radius due to fluorine atom is less, and the radius of a hydrogen atom is more or less the same, so can not cause the larger change of compound three-dimensional arrangement, so that affects its structure activity relationship;
3, because fluorine carbon bond is very stable, biological metabolism is less likely to occur, so the metabolism of this position can be suppressed at the position of easy metabolism introducing fluorine atom, increases the biologically stable of compound.
Since the fluohydrocortisone introducing fluorine atom in cortisone obtains success, dyestuff, the medicinal or agricultural chemical compound of band fluorine atom get more and more, and fluorochemicals has become the important compound of a class.
O-fluorobenzoic acid compounds is the important intermediate of the above-mentioned medicine as the pyridine of fluorine peace, and o-fluorobenzoic acid is white crystals body, and sterling fusing point is 123 DEG C, is slightly dissolved in hot water, can be dissolved in the organic solvent such as benzene,toluene,xylene, methylene dichloride.
The method preparing o-fluorobenzoic acid at present mainly contains:
(1) take anthranilic acid as raw material, by western graceful (Bults-schiemann) reaction preparation (Tsuyoshi Fuknhara, et al., synthetic communication, 1987,17 (6): 685-692), namely anthranilic acid diazotization in boron fluoride is used, generate NITRODIAZONIUM FLUOROBORATE, then pass through careful separating-purifying, in 130 DEG C of thermal degradation fluoro.Because this preparation process bothers, and yield is lower, and its yield is between 45%-55%.
(2) obtained by o Flurobenzonitrile hydrolysis.The raw material of this preparation method is difficult to obtain, and so there is no practical value.
(3) be oxidized preparation by o-fluorotobuene, the method take Ortho Toluidine as raw material, obtains o-fluorotobuene through western graceful reaction, and then oxidation obtains o-fluorobenzoic acid (Chen Hong hurricane etc., Chinese Journal of Pharmaceuticals, the 1st phase in 2002,6-7 page).This process prepared is also cumbersome, needs to obtain through polystep reaction.
(4) method by fluoridizing introduces fluorine atom.The fluoro reagent of the fluoro step of the method is expensive and operating process is dangerous, not easily prepares in a large number.
Summary of the invention
The present invention solves the aforementioned problems in the prior proposition.
The invention provides a kind of simple and practical preparation method of o-fluorobenzoic acid compounds, solve the technical problems such as the step of synthetic method in prior art is many, fluorination process is dangerous.
Present invention also offers a kind of o-fluorobenzoic acid compounds obtained by above-mentioned preparation method.
For achieving the above object, the present invention is by the following technical solutions:
First aspect of the present invention is to provide a kind of preparation method of o-fluorobenzoic acid compounds, and it is characterized in that, synthetic route is as follows:
Step comprises:
To replace fluorobenzene for raw material, under basic conditions, at low temperatures with carbon dioxide reaction, then use extraction agent extracted organic phase, aqueous phase dilute hydrochloric acid regulates pH to acid, organic phase is dry, filter, concentratedly obtain described o-fluorobenzoic acid compounds;
Wherein, R is selected from hydrogen, halogen, hydroxyl, C
1-6alkoxyl group, does not replace or by C
1-6alkyl, halogen, hydroxyl or C
1-6alkoxyl group one replaces or polysubstituted C
3-6cycloalkyl, or do not replace or replaced or polysubstituted C by halogen one
1-6alkyl.
In an embodiment of above-mentioned preparation method, preferably, described highly basic is n-Butyl Lithium.In this embodiment, preferably, also comprise interpolation organic ligand, described organic ligand is more preferably pentamethyl-diethylene triamine.
In another embodiment of above-mentioned preparation method, preferably, described highly basic is s-butyl lithium.
In above-mentioned preparation method, preferably, described low temperature is-50 DEG C to-100 DEG C, is more preferably-70 DEG C to-80 DEG C, such as-78 DEG C.
In above-mentioned preparation method, preferably, under described low temperature with carbon dioxide reaction at least half an hour after, be warming up to room temperature, release carbonic acid gas and nitrogen, then with frozen water quencher reaction.
In above-mentioned preparation method, preferably, described raw material replaces fluorobenzene and described highly basic is dissolved in the conventional organic solvent in this area, such as tetrahydrofuran (THF), toluene, methylene dichloride etc.
In above-mentioned preparation method, preferably, described extraction agent is the extraction agent that this area is commonly used, such as ethyl acetate, ether, tetracol phenixin etc.
Second aspect of the present invention is to provide a kind of preparation method of o-fluorobenzoic acid compounds, and it is characterized in that, synthetic route is as follows:
Step comprises:
To replace fluorobenzene for raw material, under n-Butyl Lithium and the organic ligand being preferably pentamethyl-diethylene triamine or s-butyl lithium existence, at low temperatures with carbon dioxide reaction, then extraction agent extracted organic phase is used, aqueous phase dilute hydrochloric acid regulates pH to acid, organic phase is dry, filter, concentratedly obtain described o-fluorobenzoic acid compounds;
Wherein, R is selected from hydrogen, halogen, hydroxyl, C
1-6alkoxyl group, does not replace or by C
1-6alkyl, halogen, hydroxyl or C
1-6alkoxyl group one replaces or polysubstituted C
3-6cycloalkyl, or do not replace or replaced or polysubstituted C by halogen one
1-6alkyl.
In above-mentioned preparation method, preferably, described low temperature is-50 DEG C to-100 DEG C, is more preferably-70 DEG C to-80 DEG C, such as-78 DEG C.
In above-mentioned preparation method, preferably, under described low temperature with carbon dioxide reaction at least half an hour after, be warming up to room temperature, release carbonic acid gas and nitrogen, then with frozen water quencher reaction.
In above-mentioned preparation method, preferably, described raw material replaces fluorobenzene and described highly basic is dissolved in the conventional organic solvent in this area, such as tetrahydrofuran (THF), toluene, methylene dichloride etc.
In above-mentioned preparation method, preferably, described extraction agent is the extraction agent that this area is commonly used, such as ethyl acetate, ether, tetracol phenixin etc.
3rd aspect of the present invention is to provide o-fluorobenzoic acid compounds prepared by a kind of above-mentioned arbitrary preparation method.
The present invention adopts technique scheme, compared with prior art, has following technique effect:
The step of the preparation method of o-fluorobenzoic acid compounds provided by the invention is few, technique simple, and separation purification method is simple, and productive rate is higher, and selectivity is good, reproducible, can prepare in enormous quantities.
Embodiment
The invention provides a kind of preparation method of o-fluorobenzoic acid compounds, it is characterized in that, synthetic route is as follows:
Step comprises:
To replace fluorobenzene for raw material, under n-Butyl Lithium and the organic ligand being preferably pentamethyl-diethylene triamine or s-butyl lithium existence, at low temperatures with carbon dioxide reaction, then extraction agent extracted organic phase is used, aqueous phase dilute hydrochloric acid regulates pH to acid, organic phase is dry, filter, concentratedly obtain described o-fluorobenzoic acid compounds;
Wherein, R is selected from hydrogen, halogen, hydroxyl, C
1-6alkoxyl group, does not replace or by C
1-6alkyl, halogen, hydroxyl or C
1-6alkoxyl group one replaces or polysubstituted C
3-6cycloalkyl, or do not replace or replaced or polysubstituted C by halogen one
1-6alkyl.
Carry out detailed and concrete introduction below by specific embodiment to the present invention, to make better to understand the present invention, but following embodiment does not limit the scope of the invention.
embodiment 1:
The present embodiment provides a kind of preparation method of o-fluorobenzoic acid compounds (1), and synthetic route is as follows:
Processing step comprises:
The chloro-triisopropylsilyl phenol (2g, 6.6mmol) of the fluoro-5-of 2-is dissolved in the tetrahydrofuran (THF) of 20mL drying, adds pentamethyl-diethylene triamine (1.15g, 6.6mmol).Solution nitrogen replacement three times, is cooled to-78 DEG C.The tetrahydrofuran solution (3.2mL, 7.9mmol) of slow dropping n-Butyl Lithium, after dripping, reaction solution stirs 1 hour at such a temperature.In solution, pass into carbon dioxide half an hour, continue reaction half an hour at-78 DEG C.Then be raised to room temperature gradually, release carbonic acid gas and nitrogen, react with frozen water cancellation.Add extraction into ethyl acetate and be separated organic phase.Aqueous phase dilute hydrochloric acid regulates pH to 4-5, adds extraction into ethyl acetate three times, organic phase anhydrous sodium sulfate drying.Filter, concentrate and obtain white solid product (1.8g, productive rate: 78.6%).
HNMR(d-DMSO,400MHz)δppm:7.55-7.57(dd,J
1＝2.8,J
2＝5.2,1H),7.15-7.18(dd,J
1＝2.8,J
2＝6.8,1H),1.28-1.34(m,3H)，1.13-1.14(d,J＝7.2,18H)。
embodiment 2:
The present embodiment provides a kind of preparation method of o-fluorobenzoic acid compounds (2), and synthetic route is as follows:
Processing step comprises:
The fluoro-5-methyl-triisopropylsilyl phenol (2g, 7.1mmol) of 2-is dissolved in the tetrahydrofuran (THF) of 20mL drying.Solution nitrogen replacement three times, is cooled to-78 DEG C.The tetrahydrofuran solution (6.5mL, 8.5mmol) of slow dropping s-butyl lithium, after dripping, reaction solution stirs 1 hour at such a temperature.In solution, pass into carbon dioxide half an hour, continue reaction half an hour at-78 DEG C.Then be raised to room temperature gradually, release carbonic acid gas and nitrogen, react with frozen water cancellation.Add extraction into ethyl acetate and be separated organic phase.Aqueous phase dilute hydrochloric acid regulates pH to 4-5, adds extraction into ethyl acetate three times, organic phase anhydrous sodium sulfate drying.Filter, concentrate and obtain white solid product (2.1g, productive rate: 90.9%).
HNMR(d-DMSO,400MHz)δppm:7.65-7.68(dd,J
1＝6.8,J
2＝2.0,1H),7.25-7.28(dd,J
1＝6.8,J
2＝2.0,1H),1.18-1.2(m,3H)，1.06-1.08(d,J＝7.2,18H)。
embodiment 3:
The present embodiment provides a kind of preparation method of o-fluorobenzoic acid compounds (3), and synthetic route is as follows:
Processing step comprises:
The fluoro-triisopropylsilyl phenol (5g, 20.5mmol) of 2,5-bis-is dissolved in the tetrahydrofuran (THF) of 60mL drying, adds pentamethyl-diethylene triamine (3.6g, 20.5mmol).Solution nitrogen replacement three times, is cooled to-78 DEG C.The tetrahydrofuran solution (9.8mL, 24.6mmol) of slow dropping n-Butyl Lithium, after dripping, reaction solution stirs 1 hour at such a temperature.In solution, pass into carbon dioxide half an hour, continue reaction half an hour at-78 DEG C.Then be raised to room temperature gradually, release carbonic acid gas and nitrogen, react with frozen water cancellation.Add extraction into ethyl acetate and be separated organic phase.Aqueous phase dilute hydrochloric acid regulates pH to 4-5, adds extraction into ethyl acetate three times, organic phase anhydrous sodium sulfate drying.Filter, concentrate and obtain yellow liquid product (3.5g, productive rate: 59.3%).
HNMR(d-DMSO,400MHz)δppm:7.45-7.49(t,J＝8.0,1H),7.28-7.33(dd,J
1＝7.2,J
2＝8.4,1H)，1.23-1.29(m,3H)，1.08-1.10(d,J＝7.2,18H)。
embodiment 4:
The present embodiment provides a kind of preparation method of o-fluorobenzoic acid compounds (4), and synthetic route is as follows:
Processing step comprises:
The fluoro-triisopropylsilyl phenol (2g, 7.0mmol) of 3,4-bis-is dissolved in the tetrahydrofuran (THF) of 20mL drying, adds pentamethyl-diethylene triamine (1.2g, 7.0mmol).Solution nitrogen replacement three times, is cooled to-78 DEG C.The tetrahydrofuran solution (3.4mL, 8.4mmol) of slow dropping n-Butyl Lithium, after dripping, reaction solution stirs 1 hour at such a temperature.In solution, pass into carbon dioxide half an hour, continue reaction half an hour at-78 DEG C.Then be raised to room temperature gradually, release carbonic acid gas and nitrogen, react with frozen water cancellation.Add extraction into ethyl acetate and be separated organic phase.Aqueous phase dilute hydrochloric acid regulates pH to 4-5, adds extraction into ethyl acetate three times, organic phase anhydrous sodium sulfate drying.Filter, concentrated.Rapid column chromatography (sherwood oil: methylene dichloride=4:1) obtains white solid product (1.5g, productive rate: 65.0%).
HNMR(d-DMSO,400MHz)δppm:7.17-7.22(m,1H),7.08-7.10(m,1H)，1.22-1.30(m,3H)，1.05-1.07(d,J＝7.2,18H)。
The step of the preparation method of o-fluorobenzoic acid compounds provided by the invention is few, technique simple, and separation purification method is simple, solves the technical problems such as the step of synthetic method in prior art is many, fluorination process is dangerous, and productive rate is higher, selectivity is good, reproducible, can prepare in enormous quantities.
Be described in detail specific embodiments of the invention above, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.
Claims (10)
1. a preparation method for o-fluorobenzoic acid compounds, is characterized in that, synthetic route is as follows:
Step comprises:
To replace fluorobenzene for raw material, under basic conditions, at low temperatures with carbon dioxide reaction, then use extraction agent extracted organic phase, aqueous phase dilute hydrochloric acid regulates pH to acid, organic phase is dry, filter, concentratedly obtain described o-fluorobenzoic acid compounds;
Wherein, R is selected from hydrogen, halogen, hydroxyl, C
1-6alkoxyl group, does not replace or by C
1-6alkyl, halogen, hydroxyl or C
1-6alkoxyl group one replaces or polysubstituted C
3-6cycloalkyl, or do not replace or replaced or polysubstituted C by halogen one
1-6alkyl.
2. preparation method according to claim 1, is characterized in that, described highly basic is n-Butyl Lithium.
3. preparation method according to claim 1, is characterized in that, described highly basic is s-butyl lithium.
4. preparation method according to claim 2, is characterized in that, in described synthesis step, also comprises interpolation organic ligand with during carbon dioxide reaction.
5. preparation method according to claim 4, is characterized in that, described organic ligand is pentamethyl-diethylene triamine.
6. preparation method according to claim 1, is characterized in that, described low temperature is-50 DEG C to-100 DEG C.
7. preparation method according to claim 1, is characterized in that, described low temperature is-70 DEG C to-80 DEG C.
8. preparation method according to claim 1, is characterized in that, under described low temperature with carbon dioxide reaction at least half an hour after, be warming up to room temperature, release carbonic acid gas and nitrogen, then with frozen water quencher reaction.
9. a preparation method for o-fluorobenzoic acid compounds, is characterized in that, synthetic route is as follows:
Step comprises:
To replace fluorobenzene for raw material, under n-Butyl Lithium and organic ligand or s-butyl lithium existence, at low temperatures with carbon dioxide reaction, then use extraction agent extracted organic phase, aqueous phase dilute hydrochloric acid regulates pH to acid, organic phase is dry, filter, concentratedly obtain described o-fluorobenzoic acid compounds;
Wherein, R is selected from hydrogen, halogen, hydroxyl, C
1-6alkoxyl group, does not replace or by C
1-6alkyl, halogen, hydroxyl or C
1-6alkoxyl group one replaces or polysubstituted C
3-6cycloalkyl, or do not replace or replaced or polysubstituted C by halogen one
1-6alkyl.
10. the o-fluorobenzoic acid compounds that as described in claim 1-9 any one prepared by preparation method.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1303365A (en) * | 1998-04-03 | 2001-07-11 | 三维药物公司 | Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors |
| WO2008029882A1 (en) * | 2006-09-07 | 2008-03-13 | Kyorin Pharmaceutical Co., Ltd. | 2-alkyl-6-(pyrazolopyridin-4-yl)pyridazinone derivative, addition salt thereof, and pde inhibitor comprising the derivative or the salt as active ingredient |
| US20100160335A1 (en) * | 2007-06-19 | 2010-06-24 | Kyorin Pharmaceutical Co., Ltd. | Pyridazinone derivative and pde inhibitor containing the same as active ingredient |
| CN103930396A (en) * | 2011-09-16 | 2014-07-16 | 弗维亚医药品公司 | Aniline derivatives,their preparation and their therapeutic application |
-
2014
- 2014-12-22 CN CN201410831234.0A patent/CN104530113A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1303365A (en) * | 1998-04-03 | 2001-07-11 | 三维药物公司 | Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors |
| WO2008029882A1 (en) * | 2006-09-07 | 2008-03-13 | Kyorin Pharmaceutical Co., Ltd. | 2-alkyl-6-(pyrazolopyridin-4-yl)pyridazinone derivative, addition salt thereof, and pde inhibitor comprising the derivative or the salt as active ingredient |
| US20100160335A1 (en) * | 2007-06-19 | 2010-06-24 | Kyorin Pharmaceutical Co., Ltd. | Pyridazinone derivative and pde inhibitor containing the same as active ingredient |
| CN103930396A (en) * | 2011-09-16 | 2014-07-16 | 弗维亚医药品公司 | Aniline derivatives,their preparation and their therapeutic application |
Non-Patent Citations (1)
| Title |
|---|
| KOJI OCHIAI等: "Phosphodiesterase inhibitors. Part 5: Hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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