CN106928046B - A kind of salicylic preparation method of 3,4,5,6- tetrafluoro - Google Patents
A kind of salicylic preparation method of 3,4,5,6- tetrafluoro Download PDFInfo
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- CN106928046B CN106928046B CN201710275807.XA CN201710275807A CN106928046B CN 106928046 B CN106928046 B CN 106928046B CN 201710275807 A CN201710275807 A CN 201710275807A CN 106928046 B CN106928046 B CN 106928046B
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/31—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation of cyclic compounds with ring-splitting
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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Abstract
The invention discloses one kind 3,4,5, the salicylic preparation method of 6- tetrafluoro, with 2,3,4,5,6- phenyl-pentafluoride formyl chlorides are raw material, by obtaining intermediate product with ethyl acetoacetate condensation complex copper ion, acidified again, heating cyclization obtains product 5,6,7,8- tetra- fluoro- 2- methyl -4- oxo -4H- chromene -3- carboxylic acid, ethyl esters；Above-mentioned product stirs in sodium hydroxide solution, is slowly added dropwise excess hydrogen peroxide solution, insulated and stirred, the then end of reaction after TLC detection discovery is without above-mentioned product；It adds sodium thiosulfate and removes excess hydrogen peroxide, heat up 1h, is cooled to room temperature and salt acid for adjusting pH is added, and methyl tertiary butyl ether(MTBE) is extracted, is dried over anhydrous sodium sulfate, and 3,4,5,6- tetra- fluorosalicylic acids are made through recrystallize with dichloromethane in filtrate distillation, crude product.The present invention is low for equipment requirements, and by-product is that water is pollution-free, and yield 78-83%, crude product purity is up to 97%.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of 3,4,5,6- salicylic preparation methods of tetrafluoro.
Background technique
Tuberculosis (TB) is still serious disease in the world now, and Global Health Organization has 9,600,000 people within 2015
With tuberculosis, wherein there is 1,500,000 people to die of tuberculosis, 27% dead crowd is the tuberculosis for dying of HIV infection formation.This
Outside, 480,000 multidrug resistance tuberculosis of the tissue registration, wherein 10% is extensive drug resistance (MDR) tuberculosis.
Mycobacterium is pathogen lungy.In TB treatment, most widely used MDR drug is PAS
(PAS), PAS is salicylic analogue, and PAS is to the inhibiting effect of mycobacteria biosynthesis, in cell membrane building
It is responsible for the biosynthesis of mycobactin and carboxyl colistin.
It is found that salicylic acid containing fluorine atom becomes apparent from mycobacterium inhibiting effect, fluorine atom is also successfully applied to drug
Chemistry becomes lead compound in drug excavation process.In fact, about 20% drug used has at least in the structure
One fluorine atom, and it is aromatic series fluorine.
The mechanism of action of polyfluoro salicylic acid compounds is rarely known by the people, but has irreplaceable work in its bioactivity
With many polyfluoro salicylamides are patented as anti-coagulants, as polyfluoro salicylic acid N- alkyl-alkyl sulfonamide can be used as resisting
Fat agent and diabetes；Polyfluorizated N- { [the fluoro- 7- of 4- oxo -6- (cyclohexyl-amine) -1- cyclopenta -1,4- dihydroquinoline -3-
Base] methyl -2- hydroxy-benzoyIamide require be used as platelet aggregation inhibitor and P2Y12 receptor；Polyfluoro salicylic acid simultaneously can
As actinic material intermediate etc..
Several known polyfluoro salicylic acid synthetic methods are currently, there are, but it is various scarce as existing for them
Point, they all do not have preparation value.In the presence of n-BuLi, in -75 DEG C, CO2Under environment, by 2,3,4,5- phenyl tetrafluorides
Phenol obtains 3,4,5,6- tetra- fluorosalicylic acids, yield 85%, but with the variation of reaction condition and organolithium reagent, area can be obtained
The polyfluoro salicylic acid of domain isomery, yield 61-93%.Although the yield of target acid is high, the method for the carboxylation containing fluorophenol has
Some significant disadvantages, such as fairly expensive polyfluoro phenol and the complex instrument for low temperature synthesis process.
A.T.Prudchenko,L.P.Vovdenko,V.A.Barkhash,and N.N.Vorozhtsov,Jr.Kh -
Involved in imiya Geterotsiklicheskikh Soedinenii, Vol.4, No.6, the pp.967-969,1968. technology
Obtain tetrafluoro water through oxydrolysis using the fluoro- 2- methyl -4- oxo -4H- chromene -3- carboxylic acid, ethyl ester of 5,6,7,8- tetra- as raw material
Poplar acid, this method in acetone, add 5,6,7,8- tetra- fluoro- 2- methyl -4- oxo -4H- chromene -3- carboxylic acid, ethyl ester dissolutions
The acetone soln for entering potassium permanganate, is stirred at room temperature 16h or more, solvent is distilled off, boiling is added to boil, filtering, after cooling acidification, second
Ether extracts to obtain tetra- fluorosalicylic acid of 3,4,5,6-:
This method uses potassium permanganate as strong oxidizer, but a large amount of metal byproducts can be generated in actual production process
Object, environmental pollution is serious, and its oxidation is violent, reacts higher for temperature control requirement, yield is also relatively low, only
63%.
Summary of the invention
For disadvantage existing in the prior art and problem, the purpose of the present invention is to provide a kind of 3,4,5,6- tetrafluoro water
The preparation method of poplar acid, this method replace potassium permanganate using hydrogen peroxide oxidation method, react easy to control, to equipment requirement
Low, by-product is water no pollution to the environment.
The salicylic structural formula of 3,4,5,6- tetrafluoro is as follows:
Technical solution provided by the invention are as follows:
This method preparation process are as follows: with 2,3,4,5,6- phenyl-pentafluoride formyl chlorides (B) for raw material, process and ethyl acetoacetate
Condensation complex copper ion obtains compound (C), obtains 5,6,7,8- tetra- fluoro- 2- methyl -4- oxo -4H- by heating cyclization after acidification
Chromene -3- carboxylic acid, ethyl ester (D).
Further, in the step of prepare compound (C), need to be added metal alkoxide catalyst Mg (OCH2CH3)2With it is molten
Agent benzene；The solution of copper ion is acetic acid copper solution, and concentration is 0.92mol/L~1.0mol/L；Five fluorine of 2,3,4,5,6-
The mass ratio of chlorobenzoyl chloride and ethyl acetoacetate is 1.55:1~1.58:1.
Further, the reagent of the acidification is ethanol solution hydrochloride, and mass percent is 25%~35%；Preferably
The mass percent for being ethanol solution hydrochloride is 30%；The heating cyclization is 100-110 DEG C of heating 1h.
Prepare 3,4,5,6- tetra- fluorosalicylic acids: compound (D) is maintained at 20-25 in 2~3mol/L sodium hydroxide solution
DEG C stirring, is slowly added dropwise the hydrogenperoxide steam generator that mass percent is 25%~30%, drips off insulated and stirred 3-4h, TLC (EA:
PE=1:1) detection is added a small amount of slightly hot removing excess hydrogen peroxide of sodium thiosulfate, then rises without raw material (D), end of reaction
Temperature boils 1h, is cooled to room temperature and hydrochloric acid adjusting pH=1~2 are added, methyl tertiary butyl ether(MTBE) extracts, and extracting solution is dry through anhydrous sodium sulfate
Dry, 3,4,5,6- tetra- fluorosalicylic acids of high-purity are made through recrystallize with dichloromethane in filtrate distillation, crude product.The preparation method
Process route is as follows:
Further, insulated and stirred 3-4h is extracted with ethyl acetate reaction solution to after the time, then with ethyl acetate layer into
Row TLC.
Further, it is 40~45 DEG C that the slightly hot temperature of sodium thiosulfate, which is added,；The mass percent of hydrochloric acid be 20~
30%.
The device have the advantages that as follows:
This method replaces potassium permanganate using hydrogen peroxide oxidation method, reacts easy to control.Improved oxydrolysis without
Cumbersome operation is needed, low for equipment requirements, required raw material inexpensively easily obtains, and by-product is water no pollution to the environment, and in original
There is on Process ba- sis yield be increased to 78-83% from 63%, the purity of crude product has reached 97%.
Detailed description of the invention
Fig. 1 is the LC-MS figure of compound (D): (a) being mass spectrogram；It (b) is liquid phase figure；(c) exist for corresponding mass spectrum
The karyoplasmic ratio (M/Z) of the molecule fragment of appearance when 13.02min；
Fig. 2 is the salicylic HPLC figure of final product 3,4,5,6- tetrafluoro: (a) curve graph；It (b) is data analysis chart；
Fig. 3 is the salicylic nuclear magnetic resonance figures of final product 3,4,5,6- tetrafluoro: (a) being nuclear magnetic resonance " hydrogen " spectrogram；(b)
For nuclear magnetic resonance " fluorine " spectrogram；
Fig. 4 is the salicylic mass spectrogram of final product 3,4,5,6- tetrafluoro: (a) MS schemes；(b) exist for corresponding MS
7.05min goes out the molecule fragment karyoplasmic ratio (M/Z) of peak position.
Specific embodiment
It is further to the present invention combined with specific embodiments below to be illustrated.
Embodiment 1:
Compound (C) preparation: the metal alkoxide catalyst Mg (OCH of 13.5g is added into 250ml reaction flask2CH3)2With
The mixing of 15ml solvent benzol, stirring at normal temperature are added dropwise 19.1g ethyl acetoacetate, drip off in 50 DEG C of stirring 1h；It is cooled to room temperature, is added dropwise
The 2 of 30g, 3,4,5,6- phenyl-pentafluoride formyl chlorides (compound B) drip off holding and are stirred at room temperature after 1h then at 50 DEG C of stirring 15min,
Heating is closed, is subsequently agitated for that acetic acid copper solution (11g copper acetate is dissolved in 4.7g acetic acid and 50ml water) is added simultaneously, jelly is fast
Instant clear aobvious blue, continues to stir 20min, is transferred to separatory funnel layering, and water layer is merged with the extraction of 30x3ml methyl tertiary butyl ether(MTBE)
Organic layer, vacuum distillation remove organic solvent, and 10ml methanol is added in blue solid fraction residue, then constantly add water and stir solid to being precipitated
Body is complete, and suction filtration dries to obtain 33.9g blue fluffy powder solid chemical compound (C).
Compound (D) preparation: 100ml dry reaction bottle puts into 30g compound (C), 30ml solvent methyl t-butyl ether, protects
It holds room temperature under dry environment and 30% ethanol solution hydrochloride of 15g (mass percent) is added dropwise, solution becomes faint yellow clear by blue
Clearly, stirring at normal temperature 20min is dripped, rear reaction solution vacuum distillation is added dropwise and removes solvent, residue is heated in 100-110 DEG C
1h, paleness brown；It is cooled to room temperature, 30ml methyl tertiary butyl ether(MTBE) and 30ml water is added, water layer continues with 20x3ml methyl- tert fourth
Base ether extracts, and merges organic phase, pure water to neutrality, it is light to obtain 22.1g for vacuum distillation removing solvent after anhydrous sodium sulfate is dry
Yellow solid compound (D), molar yield 89%, LC-MS detection data are detailed in Fig. 1: (a) being mass spectrogram；It (b) is liquid phase
Figure, indicates the purity of each substance in the component；It (c) is the karyoplasmic ratio of corresponding mass spectrogram molecule fragment of appearance in 13.02min
(M/Z), in cation, the substance karyoplasmic ratio is 305.6, and actual molecular weight is the molecular weight one of 304.6 with compound D
It causes.
The preparation of compound (A): sodium hydroxide solution, the 20gization of 65ml 2mol/L are added in 150ml cleaning reaction flask
It closes object (D) and 2g PEG-400,20-25 DEG C of stirring is added dropwise 30% hydrogenperoxide steam generator of 15g (mass percent), drips off heat preservation
Stir 3-4h；It to after the time, extracts reaction solution and (extracts reaction solution with a small amount of ethyl acetate), ethyl acetate layer carries out TLC TLC
(EA:PE=1:1) it if detection adds 5g sodium thiosulfate to reaction solution, be heated to 40 DEG C of stirring 30min without compound (D), rises
1h is boiled in temperature to reflux；It is cooled to room temperature, stirring while dropwise addition 30% hydrochloric acid (mass percent) adjust pH=1-2, stirring
5min repetition measurement pH is constant to be continued to stir 30min, and 50ml methyl tertiary butyl ether(MTBE) is added and extracts, 20x3ml methyl tertiary butyl ether(MTBE) repeats to mention
It taking, merging organic layer dries, filters filtrate decompression with anhydrous sodium sulfate and solvent is distilled off, faint yellow solid crude product 11.3g is obtained,
Yield is 82%.The crude product is detected through HPLC, as shown in Fig. 2, the salicylic peak retention time of main component tetrafluoro is
17.937min, the corresponding peak area i.e. purity of the ingredient are 97.974%.
Crude product obtains 3,4,5,6- tetra- fluorosalicylic acids of 8.7g colorless crystalline solid through recrystallize with dichloromethane, and final purity reaches
99%, fusing point is 170-172 DEG C.
Fig. 3 is the salicylic nuclear magnetic resonance map of 3,4,5,6- tetrafluoro of preparation: (a) (1H-NMR-CDCl3) it is tetrafluoro water
Poplar acid nuclear magnetic resonance " hydrogen " is composed, and the corresponding chemical shift of appearance indicates there is position hydrogeneous at 2 on carboxyl and hydroxyl in structure at two
It sets；(b) is schemed for nuclear magnetic resonance " fluorine " spectrum, and the correspondence chemical shift δ of 4 position fluorine is respectively -133, -144, -161, -168, four
A appearance indicates on the benzene ring structure containing four asymmetric position fluorine atoms.
Fig. 4 is 3,4,5, the 6- salicylic mass spectrograms of tetrafluoro of preparation, in corresponding 7.05min appearance under the conditions of anion
The molecule fragment karyoplasmic ratio (m/z) of position is 209.4, actual molecular weight 210.4, and 3,4,5,6- tetra- fluorosalicylic acid molecular weight
Unanimously.
Embodiment 2:
Compound (C) preparation: the metal alkoxide catalyst Mg (OCH of 22.5g is added into 250ml reaction flask2CH3)2With
The mixing of 25ml solvent benzol, stirring at normal temperature are added dropwise 31.8g ethyl acetoacetate, drip off in 50 DEG C of stirring 1h；It is cooled to room temperature, is added dropwise
The 2 of 50g, 3,4,5,6- phenyl-pentafluoride formyl chlorides (compound B) drip off holding and are stirred at room temperature after 1h then at 50 DEG C of stirring 15min,
Heating is closed, is subsequently agitated for being added simultaneously acetic acid copper solution (18.3g copper acetate is dissolved in 7.8g acetic acid and 84ml water), it is faint yellow
The quick dissolved clarification of jelly shows navy blue, continues to stir 20min, is transferred to separatory funnel layering, water layer is with 50x3ml methyl tertbutyl
Ether extracts, merging organic layer, and vacuum distillation removes organic solvent, and 15ml methanol is added in blue solid fraction residue, then constantly adds water
Stirring is complete to solid is precipitated, and suction filtration dries to obtain 56.1g blue fluffy powder solid chemical compound (C).
Compound (D) preparation: consistent with embodiment 1.
The preparation of compound (A): sodium hydroxide solution, the 40.9g of 133ml 2mol/L are added in 500ml cleaning reaction flask
Compound (D) and 4g PEG-400,20-25 DEG C of stirring are added dropwise 30% hydrogenperoxide steam generator of 31g (mass percent), drip off guarantor
Temperature stirring 3-4h；To after the time, extracts reaction solution and (extract reaction solution with a small amount of ethyl acetate), ethyl acetate layer progress TLC (EA:
PE=1:1 it) if detection adds 10g sodium thiosulfate to reaction solution, be heated to 40 DEG C of stirring 30min without compound (D), heats up
1h is boiled to reflux；25 DEG C are cooled to room temperature, stir while 30% hydrochloric acid (mass percent) is added dropwise, adjusts pH=1-2, stirring
5min repetition measurement pH is constant to be continued to stir 30min, and 100ml methyl tertiary butyl ether(MTBE) is added and extracts, 40x3ml methyl tertiary butyl ether(MTBE) repeats
It extracts, merging organic layer dries, filters filtrate decompression with anhydrous sodium sulfate and solvent is distilled off, and obtains faint yellow solid crude product
22.8g, yield 80.7%, the crude product obtain 3,4,5,6- tetrafluoro water of 17.0g colorless crystalline solid through recrystallize with dichloromethane
Poplar acid, fusing point are 170-172 DEG C, purity 99%.
Claims (9)
1. 3,4,5, the 6- salicylic preparation method of tetrafluoro of one kind, which is characterized in that the preparation method includes the following steps:
(1) with 2,3,4,5,6- phenyl-pentafluoride formyl chlorides for raw material, by being condensed with ethyl acetoacetate, and complex copper ion is made
Intermediate product；
(2) above-mentioned intermediate product is acidified, and 5,6,7,8- tetra- fluoro- 2- methyl -4- oxo -4H- benzos are made by heating cyclization
Pyrans -3- carboxylic acid, ethyl ester；
(3) the fluoro- 2- methyl -4- oxo -4H- chromene -3- carboxylic acid, ethyl ester of above-mentioned 5,6,7,8- tetra- is in sodium hydroxide solution
Stirring, is slowly added dropwise excessive hydrogenperoxide steam generator, drips off insulated and stirred 3-4h, through TLC (ethyl acetate: petroleum ether=1:1)
Detection discovery is without then end of reaction after the fluoro- 2- methyl -4- oxo -4H- chromene -3- carboxylic acid, ethyl ester of the 5,6,7,8- tetra-；
The slightly hot excessive hydrogen peroxide of removing of sodium thiosulfate is added, then heat up 1h, is cooled to room temperature and salt acid for adjusting pH is added
=1~2, methyl tertiary butyl ether(MTBE) extracts, and extracting solution is dried over anhydrous sodium sulfate, and filtrate distillation, crude product is most afterwards through methylene chloride weight
3,4,5,6- tetra- fluorosalicylic acids of high-purity are made in crystallization.
2. 3,4,5, the 6- salicylic preparation methods of tetrafluoro of one kind as described in claim 1, which is characterized in that the step
(1) in, need to be added metal alkoxide catalyst Mg (OCH2CH3)2And solvent benzol；The copper ion is acetic acid copper solution, concentration
For 0.92mol/L~1.0mol/L.
3. 3,4,5, the 6- salicylic preparation methods of tetrafluoro of one kind as described in claim 1, which is characterized in that the step
(1) in, the mass ratio of described 2,3,4,5,6- phenyl-pentafluoride formyl chlorides and ethyl acetoacetate is 1.55:1~1.58:1.
4. 3,4,5, the 6- salicylic preparation method of tetrafluoro of one kind as described in claim 1-3 is one of any, which is characterized in that
In the step (2), the reagent of the acidification is ethanol solution hydrochloride, and mass percent is 25%~35%；The heating
Cyclization is 100~110 DEG C of heating 1h.
5. 3,4,5, the 6- salicylic preparation methods of tetrafluoro of one kind as claimed in claim 4, which is characterized in that the hydrochloric acid second
The mass percent of alcoholic solution is 30%.
6. 3,4,5, the 6- salicylic preparation method of tetrafluoro of one kind as described in claim 1-3 is one of any, which is characterized in that
In the step (3), the concentration of the sodium hydroxide solution is 2~3mol/L；The temperature stirred in sodium hydroxide solution is
20~25 DEG C.
7. 3,4,5, the 6- salicylic preparation method of tetrafluoro of one kind as described in claim 1-3 is one of any, which is characterized in that
In the step (3), the mass percent 25%~30% of the hydrogenperoxide steam generator.
8. 3,4,5, the 6- salicylic preparation method of tetrafluoro of one kind as described in claim 1-3 is one of any, which is characterized in that
In the step (3), 3~4h of insulated and stirred is extracted with ethyl acetate reaction solution, then carried out with ethyl acetate layer to after the time
TLC。
9. 3,4,5, the 6- salicylic preparation method of tetrafluoro of one kind as described in claim 1-3 is one of any, which is characterized in that
In the step (3), adding the slightly hot temperature of sodium thiosulfate is 40~45 DEG C；1h is boiled in heating；The quality hundred of hydrochloric acid
Score is 20~30%.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1227352A (en) * | 1967-01-26 | 1971-04-07 |
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2017
- 2017-04-24 CN CN201710275807.XA patent/CN106928046B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1227352A (en) * | 1967-01-26 | 1971-04-07 |
Non-Patent Citations (2)
| Title |
|---|
| 《A convenient and efficient approach to polyfluorosalicylic acids and their tuberculostatic activity》;Evgeny V. Shchegol’kov et al;《Bioorganic & Medicinal Chemistry Letters》;20160331;第26卷;2455–2458 * |
| 《New Fluoroaryl-containing b,b`-Dioxoesters in the Synthesis of Fluorobenzopyran-2(4)-ones》;S. P. Kisil et al;《Russian Journal of Organic Chemistry》;20011231;第37卷(第10期);1455-1462 * |
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