CN110143861A - A kind of preparation method of brufen - Google Patents
A kind of preparation method of brufen Download PDFInfo
- Publication number
- CN110143861A CN110143861A CN201910471790.4A CN201910471790A CN110143861A CN 110143861 A CN110143861 A CN 110143861A CN 201910471790 A CN201910471790 A CN 201910471790A CN 110143861 A CN110143861 A CN 110143861A
- Authority
- CN
- China
- Prior art keywords
- added
- brufen
- temperature
- acid solution
- liquid separation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000926 separation method Methods 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910001385 heavy metal Inorganic materials 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 47
- 239000007788 liquid Substances 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000012044 organic layer Substances 0.000 claims description 26
- 239000010410 layer Substances 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 239000000010 aprotic solvent Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 239000012670 alkaline solution Substances 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000005727 Friedel-Crafts reaction Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 abstract 1
- QXWDAKBZLIENSO-UHFFFAOYSA-N propyl 2-[4-(2-methylpropyl)phenyl]propanoate Chemical group CCCOC(=O)C(C)C1=CC=C(CC(C)C)C=C1 QXWDAKBZLIENSO-UHFFFAOYSA-N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000013517 stratification Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010583 slow cooling Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- VLVILBSSXMZZCB-UHFFFAOYSA-N 1-[4-(2-methylpropyl)phenyl]ethanol Chemical compound CC(C)CC1=CC=C(C(C)O)C=C1 VLVILBSSXMZZCB-UHFFFAOYSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 229920013683 Celanese Polymers 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C51/285—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with peroxy-compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention discloses a kind of preparation methods of brufen, this method is using isobutyl-benzene as starting material, key intermediate ibuprofen propyl alcohol is prepared through Friedel-Crafts reaction with propylene oxide, the intermediate is directly aoxidized to obtain brufen without separation, and the preparation method further comprises purification.The route is not necessarily to heavy metal catalyst, and synthetic route step is few, and used material is easy to get, and easy to operate, reaction condition is mild, environmental-friendly, at low cost, and atom utilization is high, is suitble to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to a kind of preparation method of brufen, and specifically this method includes Fu
Gram reaction and oxidation reaction, further comprise purification.
Background technique
Brufen is a kind of non-steroidal anti-inflammatory drugs (NSAID) of Boots company exploitation, is that WHO, FDA uniquely recommend jointly
Children's antipyretic.The compound is found and was applied for a patent in 1961, structure the 1960s by Boots Group
As shown in following formula I:
。
Industrializing synthesis route is Boots method to brufen earlier: it includes 6 steps, using isobutyl-benzene as raw material, warp
Friedel-crafts acylation reaction, by generating α after react up to ginseng with ethyl chloroacetate, beta epoxide acid esters, epoxy acid ester is by taking off
Carboxylic reaction, hydrolysis generate unstable free acid, it is easy to lose carbon dioxide, become enol, then mutually make a variation through keto-enol
Structure generates aldehyde.Aldehyde and azanol reaction are converted into nitrile after generating oxime, and generate brufen by hydrolysis.This method synthesis step is more,
Reaction time is long, and raw material availability is low, and production cost is high.
In the 1990s, Hoechst-Celanese company, the U.S. and Boots company cooperative research and development go out new brufen
Synthetic method passes through 1-(4-Isobutylphenyl)ethanol plus carbonyl reaction realization brufen industrial production (referred to as BHC method).It should
Method is also through Friedel-Crafts reaction, catalytic hydrogen reduction and to add carbonyl reaction that brufen is prepared using isobutyl-benzene as raw material.This
Synthesis path obtains the honor of Presidential Green Chemistry Challenge Awards in 1997.Its Atom economy is substantially improved by 35%
To 80%.After similar acylation reaction, after generating alcohol using Raney's nickel as catalyst, it is coupled with palladium chtalyst and carries out carbonyl
Glycosylation reaction.The synthetic method is the problem is that the separation and recovery and circulation of the precious metals pd catalyst of crucial oxonation are sharp
With.
To solve the above problems, the present invention provides it is a kind of it is easier, be more suitable for industrialized production and environmentally protective conjunction
At route, the synthetic route totally two step, heavy metal free catalyst, atom utilization is high, and reaction mass and reagent are easy to get.
Summary of the invention
It is described the preparation method is as follows: a kind of brufen for preparing the present invention provides a kind of preparation method of brufen
Preparation method,
Include the following steps:
1) lewis acid is added into reactor, propylene oxide is slowly added to isobutylbenzene, after reaction, organic solvent is added
I, liquid separation obtain organic layer I；
2) acid solution 1 is added in the organic layer I into step 1), is slowly added to hydrogen peroxide, after fully reacting, is added organic molten
Agent II, liquid separation obtain organic layer II；Alkaline solution is added in resulting organic layer II, and liquid separation obtains water layer；Gained water layer is added organic molten
Agent III, is added acid solution 2, and liquid separation obtains organic layer III；Cool down crystallization, filters to obtain brufen.
The method further includes step 3) by above-mentioned steps 2) resulting brufen is dissolved in organic solvent I V and water,
Cool down crystallization, and brufen is obtained by filtration.
Wherein the molar ratio of isobutyl-benzene and propylene oxide is 1:0.8 ~ 1, preferably 1:0.9 ~ 1 in step 1).
Wherein the molar ratio of isobutyl-benzene and propylene oxide is 1:1 ~ 1.2, preferably 1:1 ~ 1.1 in step 1).
Wherein lewis acid is alchlor in step 1).
Temperature is for 30 DEG C hereinafter, preferably 20 DEG C hereinafter, more preferably 10 DEG C when propylene oxide being wherein added in step 1)
Below.
After wherein adding propylene oxide in step 1), 0.5h ~ 3h is stirred.
Temperature is 0 ~ 40 DEG C, preferably 5 ~ 15 DEG C when isobutylbenzene being wherein added in step 1).
Wherein add water or salt water in step 1) into reaction solution after reaction, temperature control is at 80 DEG C hereinafter, it is preferred that 60
DEG C hereinafter, more preferable 50 DEG C or less.
Wherein organic solvent I is aprotic solvent in step 1), and the aprotic solvent is selected from petroleum ether, dichloromethane
Or mixtures thereof one of alkane, toluene, dimethylbenzene.
Wherein organic layer obtained in step 1) makes to be washed with brine, and the salt water is sodium chloride solution, the matter of solution
Measuring score is 10 ~ 26.5%, the sodium chloride solution being preferably saturated.
Wherein acid solution 1 is inorganic acid solution in step 2, and it is molten that the inorganic acid solution is selected from sulfuric acid solution, hydrochloric acid
Or mixtures thereof one of liquid, wherein the mass concentration of solution is 5% ~ 50%.
After acid solution 1 wherein is added in step 2, it is warming up to 40 ~ 80 DEG C.
Wherein the mass concentration of hydrogen peroxide is 25% ~ 45% in step 2.
Wherein organic solvent II described in step 2 be aprotic solvent, the aprotic solvent be selected from petroleum ether,
Or mixtures thereof one of methylene chloride, toluene, dimethylbenzene.
After organic solvent II wherein is added in step 2, liquid separation is stirred, resulting water layer continues to be extracted with organic solvent II,
Merge organic layer, obtains organic layer II.
Wherein alkaline solution described in step 2 is inorganic alkali solution, and the inorganic alkali solution is that sodium hydroxide is molten
One of liquid, potassium hydroxide solution, lithium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution are several
Kind, wherein the mass concentration of solution is 5% ~ 40%.
Wherein organic layer II is added the resulting organic layer of alkaline solution liquid separation and continuously adds alkaline solution, liquid separation in step 2
Combining water layer.
Wherein organic solvent II I described in step 2 be aprotic solvent, the aprotic solvent be selected from petroleum ether,
Or mixtures thereof one of methylene chloride, toluene, dimethylbenzene.
Wherein acid solution 2 described in step 2 be inorganic acid solution, the inorganic acid solution be selected from sulfuric acid solution,
Or mixtures thereof one of hydrochloric acid solution, hydrobromic acid solution, hydroiodic acid solution, wherein the mass concentration of solution is 5% ~ 50%.
Acid solution 2 is wherein added in step 2, the resulting water layer of liquid separation is added organic solvent II I extraction, merges organic
Layer, obtains organic layer III.
Wherein organic layer III obtained in step 2 makes to be washed with brine, and the salt water is sodium chloride solution, preferably
The sodium chloride solution of saturation.
Wherein in step 2 crystallization temperature be 20 DEG C hereinafter, it is preferred that 10 DEG C hereinafter, more preferably 0 ~ 5 DEG C.
Wherein in step 2 filter after, can also include drying, drying temperature be 30 DEG C ~ 60 DEG C, preferably 30 ~ 50 DEG C,
More preferably 35 DEG C ~ 50 DEG C.
Wherein organic solvent I V described in step 3) is proton solvent, and the proton solvent is selected from the alcohol of C1 ~ C5
Or mixtures thereof one kind, preferably one or more of methanol, ethyl alcohol, isopropanol.
Wherein brufen is dissolved in organic solvent I V in step 3), can also add decolorising agent, and the decolorising agent is to live
Property charcoal, preferably medicinal carbon.
Wherein in step 3) crystallization temperature be 30 DEG C hereinafter, it is preferred that 20 DEG C hereinafter, more preferably 0 ~ 10 DEG C.
It further include drying after wherein being filtered in step 3), drying mode is dried under reduced pressure for step temperature, first dry in temperature 1
For a period of time, it increases the temperature to temperature 2 and continues drying.The temperature 1 be 20 DEG C ~ 40 DEG C, preferably 20 ~ 30 DEG C, more preferably
It is 20 DEG C ~ 25 DEG C；Temperature 2 is 45 DEG C ~ 65 DEG C, preferably 50 DEG C ~ 60 DEG C.
What is not yet explicitly indicated is all conventionally.
Detailed description of the invention
4 brufen HPLC purity spectrogram of Fig. 1 embodiment
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies specific material proportion, process conditions and its result described in example and is merely to illustrate the present invention, without that should will not limit
The present invention described in detail in claims processed.
The preparation of 1 brufen of embodiment
Aluminum trichloride (anhydrous) 298g is added into reactor, in 20 ~ 30 DEG C or less investment propylene oxide 104g, after adding 20 ~
30 DEG C of reaction 0.5h stirred below are kept the temperature at 30-40 DEG C anti-then in 30-40 DEG C of dropwise addition isobutylbenzene 300g, after being added dropwise
It answers.After reaction, slowly add water 1300g, temperature controls within 80 DEG C.Petroleum ether 900g is added after adding water, stands
Layering, for organic layer with 20% brine It 2 times, liquid separation obtains organic layer.
50% sulfuric acid solution 100g is added to above-mentioned organic layer, is warming up to 60 ~ 70 DEG C, 65 ~ 80 DEG C of temperature control, is slowly added to
35% hydrogen peroxide 350g, is stirred to react 5h, and after fully reacting, petroleum ether 600ml is added, stirs 0.5h, stands liquid separation；Continue to add
Enter 450ml petroleum ether extraction, stands liquid separation；20% sodium hydroxide solution 200ml is added, stirs 0.5h, liquid separation；Continue to add in upper layer
Enter 20% sodium hydroxide solution 200ml, stirs 0.5h, liquid separation.Combining water layer is added petroleum ether 350ml, is slowly added to hydrochloric acid about
Petroleum ether 250ml extraction, liquid separation is added in 250g, stratification, water layer；Merge petroleum ether layer, with saturated common salt water washing 2 times,
Liquid separation；Slow cooling is stirred to react 3h to 0 ~ 5 DEG C, and filtering, drying obtain brufen, yield 83%.
The preparation of 2 brufen of embodiment
Alchlor 286g is added into reactor, in 10 ~ 20 DEG C or less investment propylene oxide 104g, at 10 ~ 20 DEG C after adding
Reaction 3h stirred below, then in 10-20 DEG C of dropwise addition isobutylbenzene 240g, after being added dropwise at 15 ~ 25 DEG C insulation reaction.Reaction
After, slowly plus water 1700g, temperature control within 60 DEG C.Add and methylene chloride 1000g is added after water, stratification,
For organic layer with 10% brine It 2 times, liquid separation obtains organic layer.
30% hydrochloric acid solution 100g is added to above-mentioned organic layer, is warming up to 40 ~ 50 DEG C, 60 ~ 70 DEG C of temperature control, is slowly added to
45% hydrogen peroxide 670g, is stirred to react, and reaction terminates, and methylene chloride 1000g is added, and stirring stands liquid separation and obtains organic layer, has
35% potassium hydroxide solution 500g is added in machine layer, stands liquid separation and obtains water layer, toluene 400g is added, and is slowly added to dilute sulfuric acid and adjusts pH,
Stratification, liquid separation obtain toluene layer, are washed with 20% sodium chloride solution, liquid separation；To 10 DEG C, stirring and crystallizing filters slow cooling
Obtain brufen, yield 85%.
The preparation of 3 brufen of embodiment
Into reactor be added alchlor 288g(1.21mol), in 0 ~ 10 DEG C or less investment propylene oxide 104g, after adding
0 ~ 10 DEG C of reaction 1h stirred below, then in 5-15 DEG C of dropwise addition isobutylbenzene 264g(1.1mol), after being added dropwise at 5-15 DEG C
Insulation reaction.After reaction, slowly add water 1450g, temperature controls within 50 DEG C.Dimethylbenzene is added after adding water
900g, stratification, organic layer are washed with saturated sodium chloride solution, and liquid separation obtains toluene layer.
10% sulfuric acid solution 600g is added to above-mentioned toluene layer, is warming up to 35 ~ 45 DEG C, 50 ~ 60 DEG C of temperature control, is slowly added to
25% hydrogen peroxide 610g, is stirred to react, and after fully reacting, dimethylbenzene 500ml is added, stirring stands liquid separation；Continuously add 500ml
Xylene extraction stands liquid separation；20% sodium carbonate liquor 800g is added, stirs, stands liquid separation；Toluene continuously adds 20% carbon layer by layer
Sour sodium sodium solution 800g, stirring stand liquid separation.Combining water layer is added dimethylbenzene 400g, is slowly added to hydrobromic acid tune pH, stands
Xylene extraction, liquid separation is added in layering, water layer；Merge diformazan benzene layer, is washed with saturated sodium chloride solution, liquid separation；Slow cooling
To 10 ~ 15 DEG C, stirring and crystallizing, filtering, drying obtain brufen, yield 82%.
The purification of 4 brufen of embodiment
It takes and brufen 100g is prepared according to embodiment 1, ethyl alcohol 200g, water 10g is added, heat up 50 DEG C of upper dissolutions, while hot mistake
Filter is cooled at 30 DEG C and stirs a period of time, continues to be cooled to 10 DEG C of crystallizations, filter to obtain brufen wet product；It is depressurized at 30 ~ 40 DEG C
Dry 5h, is to slowly warm up to 55 ~ 65 DEG C and is dried under reduced pressure 12h, obtain brufen, yield 91%, purity 99.78%.
The purification of 5 brufen of embodiment
It takes and brufen 100g is prepared according to embodiment 2, isopropanol 400g, water 25g is added, active carbon 0.5g, heating is added
50 DEG C of upper dissolutions, are filtered, cool down 10 DEG C of crystallizations, filters to obtain brufen wet product while hot；A period of time is dried under reduced pressure at 20 ~ 30 DEG C,
It is to slowly warm up to 50 ~ 60 DEG C to be dried under reduced pressure, obtains brufen, yield 85%, purity 99.92%.
The purification of 6 brufen of embodiment
It takes and brufen 100g is prepared according to embodiment 3, methanol 300g, water 28g is added, active carbon 1g is added, heat up 50 DEG C
Upper dissolution, is filtered while hot, be cooled at 20 DEG C stir a period of time, continue to be cooled to 5 DEG C or less crystallizations, filter brufen is wet
Product；It is dried under reduced pressure at 20 ~ 25 DEG C, is to slowly warm up to 45 ~ 55 DEG C and is dried under reduced pressure, obtain brufen, yield 90%, purity 99.84%.
Claims (10)
1. a kind of preparation method of brufen, it is characterised in that include the following steps:
1) lewis acid is added into reactor, propylene oxide is slowly added to isobutylbenzene, after reaction, organic solvent is added
I, liquid separation obtain organic layer I；
2) acid solution 1 is added in the organic layer I into step 1), is slowly added to hydrogen peroxide, after fully reacting, is added organic molten
Agent II, liquid separation obtain organic layer II；Alkaline solution is added in resulting organic layer II, and liquid separation obtains water layer；Gained water layer is added organic molten
Agent III, is added acid solution 2, and liquid separation obtains organic layer III；Cool down crystallization, filters to obtain brufen；
Wherein heavy metal free reagent in the method.
2. according to the method described in claim 1, characterized by further comprising step 3) by above-mentioned steps 2) resulting brufen
It is dissolved in organic solvent I V and water, cool down crystallization, and brufen is obtained by filtration.
3. according to the method described in claim 2, characterized by further comprising resulting brufen is dried.
4. according to the method described in claim 3, it is characterized in that the drying is step temperature drying, the step temperature
Degree is the drying at temperature I, is then warming up under temperature II dry；The temperature I is 20 DEG C ~ 40 DEG C, the temperature II
It is 45 DEG C ~ 65 DEG C.
5. the method according to claim 3 or 4, which is characterized in that the drying is to be dried under reduced pressure.
6. any method according to claim 1 ~ 5, it is characterised in that lewis acid described in step 1) is tri-chlorination
Aluminium.
7. any method according to claim 1 ~ 6, it is characterised in that add after reaction into reaction solution in step 1)
Water or salt water, temperature control at 80 DEG C hereinafter, it is preferred that 60 DEG C hereinafter, more preferable 50 DEG C or less.
8. any method according to claim 1 ~ 7, it is characterised in that acid solution 1 is inorganic acid solution in step 2,
The inorganic acid solution is selected from or mixtures thereof one of sulfuric acid solution, hydrochloric acid solution, and wherein the mass concentration of solution is
5%~50%。
9. any method according to claim 1 ~ 8, it is characterised in that the brufen in step 2 is dried, dry
Temperature is 30 DEG C ~ 60 DEG C, preferably 30 ~ 50 DEG C, more preferably 35 DEG C ~ 50 DEG C.
10. any method according to claim 1 ~ 9, it is characterised in that organic solvent I, organic solvent II and organic molten
Agent III is aprotic solvent, the aprotic solvent be selected from one of petroleum ether, methylene chloride, toluene, dimethylbenzene or
Its mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910471790.4A CN110143861A (en) | 2019-06-03 | 2019-06-03 | A kind of preparation method of brufen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910471790.4A CN110143861A (en) | 2019-06-03 | 2019-06-03 | A kind of preparation method of brufen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110143861A true CN110143861A (en) | 2019-08-20 |
Family
ID=67590053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910471790.4A Pending CN110143861A (en) | 2019-06-03 | 2019-06-03 | A kind of preparation method of brufen |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110143861A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110642705A (en) * | 2019-09-30 | 2020-01-03 | 福建太平洋制药有限公司 | Method for extracting ibuprofen from tailings in production process of ibuprofen sustained-release capsule |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5154527A (en) * | 1974-10-14 | 1976-05-13 | Kanebo Ltd | Arufua * 44 isopuchirufueniru * puropion |
| JPS5156428A (en) * | 1974-11-12 | 1976-05-18 | Kanebo Ltd | Arufua * 44 isopuchirufueniru * puropionsanno seizoho |
| JPS5726254B2 (en) * | 1973-05-01 | 1982-06-03 | ||
| CN101456808A (en) * | 2009-01-06 | 2009-06-17 | 长沙理工大学 | Method for preparing ibuprofen |
| CN108947803A (en) * | 2018-03-19 | 2018-12-07 | 山东润博生物科技有限公司 | A kind of preparation method of phenoxy carboxylic acid substance |
-
2019
- 2019-06-03 CN CN201910471790.4A patent/CN110143861A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5726254B2 (en) * | 1973-05-01 | 1982-06-03 | ||
| JPS5154527A (en) * | 1974-10-14 | 1976-05-13 | Kanebo Ltd | Arufua * 44 isopuchirufueniru * puropion |
| JPS5156428A (en) * | 1974-11-12 | 1976-05-18 | Kanebo Ltd | Arufua * 44 isopuchirufueniru * puropionsanno seizoho |
| CN101456808A (en) * | 2009-01-06 | 2009-06-17 | 长沙理工大学 | Method for preparing ibuprofen |
| CN108947803A (en) * | 2018-03-19 | 2018-12-07 | 山东润博生物科技有限公司 | A kind of preparation method of phenoxy carboxylic acid substance |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110642705A (en) * | 2019-09-30 | 2020-01-03 | 福建太平洋制药有限公司 | Method for extracting ibuprofen from tailings in production process of ibuprofen sustained-release capsule |
| CN110642705B (en) * | 2019-09-30 | 2022-04-05 | 福建太平洋制药有限公司 | Method for extracting ibuprofen from tailings in production process of ibuprofen sustained-release capsule |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104892509B (en) | Nuo get Si Ta preparation method | |
| CN103980263B (en) | The synthesis technique of canagliflozin | |
| CN101891649B (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN106478504A (en) | The method preparing Roxadustat intermediate | |
| CN107011404B (en) | A method of using cholic acid as Material synthesis lithocholic acid | |
| CN108191830B (en) | A kind of Vonoprazan fumarate intermediate IV and preparation method thereof | |
| CN102617587A (en) | Synthesis method for 2,3,6,7-triptycene tetracarboxylic dianhydride | |
| CN104817443B (en) | Benzoin dimethyl ether synthesis process | |
| CN113402511A (en) | Preparation method of topramezone | |
| CN102863408B (en) | Preparation method of andrographolide | |
| CN110143861A (en) | A kind of preparation method of brufen | |
| CN110156684A (en) | A kind of synthesis technology of demethyl coclaurine and its pharmaceutical salts | |
| CN112250546B (en) | Synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene | |
| CN103833820A (en) | Synthetic method of 3- succinic acid-30-stearyl alcohol glycyrrhetinate | |
| CN104003934B (en) | The synthesis of the fluoro-2-pyridine carboxylic acid of the chloro-3-of 6- | |
| CN107827742A (en) | A kind of CO2The method that direct carboxylation method prepares aromatic acid | |
| CN103880674A (en) | Synthetic process of L-menthyl glyoxylate | |
| CN113336764B (en) | Bipyridine ligand with axial chirality and synthetic method thereof | |
| CN110922373A (en) | Synthesis method of methyl platinolate | |
| CN102372687A (en) | Production method for spirodiclofen | |
| CN105601517B (en) | A kind of synthetic method of 3,3,3 trifluoroacetic acid methyl esters | |
| CN107118088A (en) | A kind of preparation method of m-hydroxy acetophenone | |
| CN106565522A (en) | Method for preparing alkyloxy aromatic compound from fluoroaromatic compound | |
| CN104447252A (en) | Method for preparing 6-methoxyl-2-naphthaldehyde | |
| CN105801482A (en) | Method for preparing 1-cyclopropyl-4-oxo-7-bromine-8-difluoromethoxy-1,4-dihydro-quinoline-3-nonanoic acid-ethyl ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |