CN103664606A - Preparation methods of flurbiprofen axetil compound - Google Patents
Preparation methods of flurbiprofen axetil compound Download PDFInfo
- Publication number
- CN103664606A CN103664606A CN201310638812.4A CN201310638812A CN103664606A CN 103664606 A CN103664606 A CN 103664606A CN 201310638812 A CN201310638812 A CN 201310638812A CN 103664606 A CN103664606 A CN 103664606A
- Authority
- CN
- China
- Prior art keywords
- flurbiprofen
- ester compound
- adopt
- preparation
- alcohol
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses preparation methods of a flurbiprofen axetil compound. The methods comprise the steps: firstly dropwise adding an ester compound into a mixture of flurbiprofen, an acid catalyst and an organic solvent to form a reaction system, or directly mixing flurbiprofen, an alcohol and the acid catalyst, after a reaction is finished, thus obtaining a reaction system, then carrying out spin steaming concentration treatment under reduced pressure, adding ethyl acetate and water to fully dissolve, standing and layering to obtain an organic phase, washing the organic phase, drying, purifying by passing through a silica gel column, and thus obtaining the flurbiprofen axetil compound. The preparation methods have the advantages of simple reaction operation, low requirements on production personnel and production equipment, small pollution degree and low production cost, are safe and effective, can avoid use of high-risk and high-toxic materials, and can be used for mass production.
Description
Technical field
The present invention relates to medical synthesis technical field, be specifically related to a kind of preparation method of flurbiprofen ester compound.
Background technology
The molecular formula of flurbiprofen is fluoro-4 biphenyl of 2-(2-) propionic acid, be non-steroidal anti-inflammatory analgesics, there is good pain relieving, anti-inflammatory and refrigeration function, its antiinflammation is 250 times of acetylsalicylic acid, analgesic activity is 50 times of acetylsalicylic acid.Flurbiprofen passes through to suppress the activity of prostaglandin synthetase epoxidase, thereby plays the effect of anti-inflammatory analgesic, its better tolerance, and life-time service neither promotes also not suppress self metabolism.Flurbiprofen has been introduced a fluorine atom in molecular structure, due to the special performance that fluorine atom causes, it is acted in similar drugs stronger, and therapeutic dose is little, thereby possesses powerful anti-inflammatory, pain relieving and the function of bringing down a fever.The preparation of flurbiprofen only has oral preparation, but some patient cannot oral pharmaceutical, orally easily causes the untoward reactions such as gastrointestinal disturbance, and the exploitation that therefore changes the derivative that pharmaceutical dosage form and flurbiprofen are prodrug becomes one of direction of drug research.
Flurbiprofen axetil (refering in particular to the fluoro-4-xenyl of (±) 2-(2-) propionic acid-1-acetoxyl group ethyl ester) be a kind of nonsteroidal anti-inflammatory analgetic, it is the prodrug of flurbiprofen, after entering human body, can be gathered in operative incision and inflammation part by target, hydrolysis generates flurbiprofen.There is certain targeting, slow-releasing and fat-soluble, can reduce drug administration dosage, lower drug toxicity, improve the advantages such as medicine stability, replaced flurbiprofen and be widely used in the treatment of clinical inflammatory pain, pain caused by cancer and post-operative pain.The preparation of flurbiprofen axetil at present mainly contains following methods:
The patent No. is that 201110404346.4 Chinese patent discloses a kind of method of preparing flurbiprofen axetil compound, it is raw material that the method be take flurbiprofen and 1-bromoethanol acetic ester, the synthetic flurbiprofen axetil compound of reaction under the condition of esters solvent or ether solvent, having again the patent No. is the preparation method that 201210574448.5 Chinese patent discloses a kind of flurbiprofen axetil, the method is to using flurbiprofen and 1-chloroethanol acetic ester to prepare flurbiprofen axetil as raw material and by molecular distillation method of purification, yet need bromine or acetyl bromide in the preparation process of 1-bromoethanol acetic ester, in the preparation process of 1-chloroethanol acetic ester, need Acetyl Chloride 98Min. and paraldehyde, it is all very high to producers and equipment requirements, and there is larger hazardness, pollution level is large, 1-bromoethanol acetic ester and 1-chloroethanol acetic ester are volatile simultaneously, extremely unsettled material, be difficult for storage and transport.
The successful Application exploitation of flurbiprofen axetil impels the synthetic of flurbiprofen ester compound, yet the synthetic bibliographical information of the derivative of other flurbiprofen is very few.Patent EP2463263A1 has reported that flurbiprofen ester compound can be synthesized and obtain by flurbiprofen and alkane iodide under alkaline condition, or reacts and obtain with alcohol after flurbiprofen generation acyl chlorides.But this kind of method complex process, cost is expensive, is only suitable for laboratory study and uses.
Summary of the invention
The object of the invention is to propose a kind of preparation method of flurbiprofen ester compound, the method technique is simple, with low cost, is applicable to producing in enormous quantities.
In order to solve prior art problem, the present invention is achieved through the following technical solutions:
A preparation method for flurbiprofen ester compound, the method comprises the following steps:
1) by flurbiprofen and acid catalyst, be 1:(0.02 ~ 0.4 in molar ratio) ratio be placed in the reactor containing organic solvent, be heated to 20 ~ 150 ℃, then drip Ester, the addition of Ester is 0.9 ~ 8 times of flurbiprofen molar weight, isothermal reaction, to finishing, obtains reaction system;
2) reaction system is carried out to vacuum rotary steam concentration, then adding volume ratio is 1:(0.5 ~ 2) ethyl acetate and water dissolve, stratification obtains organic phase;
3) organic phase washing is extremely neutral, adopt desiccant dryness 2 ~ 16h, then carry out vacuum rotary steam concentration, obtain the thick product of flurbiprofen ester compound;
4) the thick product of flurbiprofen ester compound is crossed to silicagel column purification processes, adopt eluent wash-out, then adopt TLC point plate to follow the tracks of, after vacuum rotary steam concentration, obtain flurbiprofen ester compound.
A preparation method for flurbiprofen ester compound, the method comprises the following steps:
1) by flurbiprofen, acid catalyst and alcohol, be 1:(0.02 ~ 0.4 in molar ratio): the ratio of (0.8 ~ 20) is placed in reactor, is heated to 20 ~ 150 ℃, and isothermal reaction, to finishing, obtains reaction system;
2) reaction system is carried out to vacuum rotary steam concentration, then adding volume ratio is 1:(0.5 ~ 2) ethyl acetate and water dissolve, stratification obtains organic phase;
3) organic phase washing is extremely neutral, adopt desiccant dryness 2 ~ 16h, then carry out vacuum rotary steam concentration, obtain the thick product of flurbiprofen ester compound;
4) the thick product of flurbiprofen ester compound is crossed to silicagel column purification processes, adopt eluent wash-out, then adopt TLC point plate to follow the tracks of, after vacuum rotary steam concentration, obtain flurbiprofen ester compound.
Described Ester is 1,1-glycol diacetate, 1,1-glycol dipropionate, 1,1-ethylene glycol bisthioglycolate isobutyrate, 1,1-ethylene glycol bisthioglycolate pivalate, 1,1-propylene-glycol diacetate, methylene radical diacetate esters, methylene radical dipropionate, methylene radical diisobutyrate or methylene radical two pivalates.
Described organic solvent is tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, 2-methyltetrahydrofuran, ethyl acetate, sherwood oil, hexanaphthene, normal hexane, octane, methylene dichloride, N, any one or several combination in dinethylformamide, acetonitrile, acetone, toluene, dimethylbenzene and pyridine, the ratio of the volume of organic solvent and the quality of flurbiprofen is (0 ~ 30): 1.
Described alcohol is C
1~ C
18fatty alcohol or the aromatic alcohol of straight or branched, fatty alcohol is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, amylalcohol or Cetyl OH, aromatic alcohol is phenylethyl alcohol, phenylcarbinol, 2-pyridine propyl alcohol, phenol, L-AA or Eugenol.
Described acid catalyst is toluenesulphonic acids, xylene monosulfonic acid, Phenylsulfonic acid, sulfuric acid, hydrochloric acid or phosphoric acid.
The concrete steps of washing described in step 3) are: first adopt saturated sodium bicarbonate solution to organic phase washing 2 ~ 4 times, then adopt and be washed with water to neutrality.
The Heating temperature of described vacuum rotary steam concentration is that 40 ~ 90 ℃, vacuum tightness are-0.075 ~ 0.1mPa.
Described siccative is anhydrous sodium sulphate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous or calcium sulfate.
Described eluent is 1:(0 ~ 30 by volume ratio) ethyl acetate and alkanes form, alkanes is sherwood oil, hexanaphthene, normal hexane or octane.
Compared with prior art, beneficial effect of the present invention is as follows:
1), raw material of the present invention is industrialization product, easily obtains, and with low cost stable performance.
2), of the present invention simple to operate, avoided the use of high-risk high toxicity material.
3), hazardness of the present invention is little, pollution level is little, and to producers and production unit require lowly, production cost is low.
4) good product quality of the present invention, is applicable to producing in enormous quantities, meets suitability for industrialized production demand.
Embodiment
The present invention has disclosed a kind of preparation method of flurbiprofen ester compound, and the method comprises the following steps:
1) by flurbiprofen and acid catalyst, be 1:(0.02 ~ 0.4 in molar ratio) ratio be placed in the reactor containing organic solvent, be heated to 20 ~ 150 ℃, then drip Ester, the addition of Ester is 0.9 ~ 8 times of flurbiprofen molar weight, isothermal reaction, to finishing, obtains reaction system; In this step, there is esterification in the hydroxyl in flurbiprofen molecule under the effect of acid catalyst, and wherein, Ester slowly adds, and time for adding is controlled at 3 ~ 36h, and isothermal reaction, to finishing, obtains reaction system.
2) reaction system is carried out to vacuum rotary steam concentration, vacuum rotary steam concentration can be removed the solvent in reaction system, and then adding volume ratio is 1:(0.5 ~ 2) ethyl acetate and water dissolve, stratification obtains organic phase.
3) organic phase washing is extremely neutral, the concrete steps of washing are: first adopt saturated sodium bicarbonate solution to organic phase washing 2 ~ 4 times, adopt and be washed with water to neutrality, and then employing desiccant dryness 2 ~ 16h, carrying out vacuum rotary steam concentration to remove the solvent in organic phase, obtain the thick product of flurbiprofen ester compound.
4) the thick product of flurbiprofen ester compound is crossed to silicagel column purification processes, adopt eluent wash-out, then adopt TLC point plate to follow the tracks of, after vacuum rotary steam concentration, obtain flurbiprofen ester compound.
In above-mentioned steps, be all to adopt heating to carry out vacuum rotary steam concentration with Rotary Evaporators, this technique can be removed desolventizing, makes the quality of products obtained therefrom better.
A preparation method for flurbiprofen ester compound, the method comprises the following steps:
1) by flurbiprofen, acid catalyst and alcohol, be 1:(0.02 ~ 0.4 in molar ratio): the ratio of (0.8 ~ 20) is placed in reactor, is heated to 20 ~ 150 ℃, and isothermal reaction, to finishing, obtains reaction system; In this step, flurbiprofen is under the effect of acid catalyst, and direct and alcohol carries out esterification, and isothermal reaction, to finishing, obtains reaction system.
2) reaction system is carried out to vacuum rotary steam concentration, vacuum rotary steam concentration can be removed the solvent in reaction system, and then adding volume ratio is 1:(0.5 ~ 2) ethyl acetate and water dissolve, stratification obtains organic phase.
3) organic phase washing is extremely neutral, the concrete steps of washing are: first adopt saturated sodium bicarbonate solution to organic phase washing 2 ~ 4 times, adopt and be washed with water to neutrality, and then employing desiccant dryness 2 ~ 16h, carrying out vacuum rotary steam concentration to remove the solvent in organic phase, obtain the thick product of flurbiprofen ester compound;
4) the thick product of flurbiprofen ester compound is crossed to silicagel column purification processes, adopt eluent wash-out, then adopt TLC point plate to follow the tracks of, after vacuum rotary steam concentration, obtain flurbiprofen ester compound.
In above-mentioned steps, be all to adopt heating to carry out vacuum rotary steam concentration with Rotary Evaporators, this technique can be removed desolventizing, makes the quality of products obtained therefrom better.
In the present invention, Ester is 1,1-glycol diacetate, 1,1-glycol dipropionate, 1,1-ethylene glycol bisthioglycolate isobutyrate, 1,1-ethylene glycol bisthioglycolate pivalate, 1,1-propylene-glycol diacetate, methylene radical diacetate esters, methylene radical dipropionate, methylene radical diisobutyrate or methylene radical two pivalates.The mol ratio of Ester and flurbiprofen is (0.9 ~ 8): 1, and as a preferred embodiment of the present invention, the mol ratio of Ester and flurbiprofen is (1 ~ 4): 1.
In the present invention, organic solvent is tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, 2-methyltetrahydrofuran, ethyl acetate, sherwood oil, hexanaphthene, normal hexane, octane, methylene dichloride, N, any one or several combination in dinethylformamide, acetonitrile, acetone, toluene, dimethylbenzene and pyridine, the ratio of the volume of organic solvent and the quality of flurbiprofen is (0 ~ 30): 1.
In the present invention, alcohol is C
1~ C
18fatty alcohol or the aromatic alcohol of straight or branched, the preferably unitary fatty alcohol of the straight or branched of C1 ~ C15, more preferably methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, amylalcohol or Cetyl OH; The preferred phenylethyl alcohol of aromatic alcohol, phenylcarbinol, 2-pyridine propyl alcohol, phenol, L-AA or Eugenol.The mol ratio of alcohol and flurbiprofen is (0.8 ~ 20): 1, and as a preferred embodiment of the present invention, the mol ratio of alcohol and flurbiprofen is (1 ~ 10): 1.
In the present invention, acid catalyst is toluenesulphonic acids, xylene monosulfonic acid, Phenylsulfonic acid, sulfuric acid, hydrochloric acid or phosphoric acid, preferred tosic acid, the mol ratio of acid catalyst and flurbiprofen is (0.02 ~ 0.4): 1, as a preferred embodiment of the present invention, the mol ratio of acid catalyst and flurbiprofen is (0.05 ~ 0.2): 1.
Step 2) in, the ratio of ethyl acetate and the cumulative volume of water and the quality of flurbiprofen is (1 ~ 30): 1, preferably (3 ~ 10): 1, the volume ratio of ethyl acetate and water is 1:(0.5 ~ 2), preferred volume ratio is 1:1, and all identical with the consumption of ethyl acetate to the consumption of the water consumption in the washing process of organic phase and sodium hydrogen carbonate solution in step 3).The concrete steps of washing in step 3) are: first adopt saturated sodium bicarbonate solution to organic phase washing 2 ~ 4 times, then adopt and be washed with water to neutrality.
The present invention heating is carried out vacuum rotary steam concentration with Rotary Evaporators, the Heating temperature of vacuum rotary steam concentration is that 40 ~ 90 ℃, vacuum tightness are-0.075 ~ 0.1mPa, as a preferred embodiment of the present invention, the Heating temperature of vacuum rotary steam concentration is that 50 ~ 65 ℃, vacuum tightness are-0.090 ~ 0.1mPa.
In the present invention, siccative is anhydrous sodium sulphate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous or calcium sulfate, and described desiccant dryness, for adding siccative standing and drying 2 ~ 16h, then carries out suction filtration and obtains filtrate, and time of drying is 4 ~ 8h preferably.
In the present invention, eluent is 1:(0 ~ 30 by volume ratio) ethyl acetate and alkanes form, by volume ratio, be preferably 1:(4 ~ 10) ethyl acetate and alkanes form, wherein, alkanes is sherwood oil, hexanaphthene, normal hexane or octane.
According to the difference of used raw material, by preparation method of the present invention, can prepare flurbiprofen axetil, flurbiprofen methylene radical diacetate esters, flurbiprofen phenylglycollic ester, flurbiprofen isopropyl alcohol ester or flurbiprofen ethanol ester etc.
For those skilled in the art's understanding, below by specific embodiment, the present invention is done to further detailed description.
Embodiment 1: the preparation of flurbiprofen axetil.
The tosic acid of the flurbiprofen of 1.23mol and 0.15mol is placed in to the reactor containing 6.0L acetonitrile, is heated to 65 ℃, then slowly drip 1 of 2.25mol, 1-glycol diacetate, isothermal reaction, to finishing, obtains reaction system.
Reaction system is carried out to vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 50 ℃, vacuum tightness is-0.1mPa, then in the residue after vacuum rotary steam concentration, add the ethyl acetate of 3.0L and the water of 3.0L to dissolve, stratification obtains organic phase.
Adopt the saturated sodium bicarbonate solution of 3.0L to wash 3 times, use again the water washing 2 times of 3.0L to neutral, adopt the anhydrous sodium sulfate drying 8h of 30g, then carry out vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 50 ℃, vacuum tightness is-0.096mPa, obtain yellow dope 400.7g, its content is 98.2%.
Yellow dope is crossed to silicagel column purification processes, adopt ethyl acetate and hexanaphthene wash-out that volume ratio is 1: 10, then adopt TLC point plate to follow the tracks of, through vacuum rotary steam concentration, (Heating temperature is 55 ℃, vacuum tightness is-0.098mPa) after, obtain micro-yellow liquid 315.0g, i.e. flurbiprofen axetil 315.0g.
The structural formula of flurbiprofen axetil is:
As calculated, the productive rate of the present embodiment flurbiprofen axetil is 78.6%, content is 99.4%.Adopt nucleus magnetic resonance to confirm the structure of flurbiprofen axetil, confirm that result is as follows:
1H-NMR?（400MHz，CDC13，δ，ppm）：7.52?（d，2H），7.42（t，2H），7.37（d，1H），?7.35（t，1H），7.11（d，1H），7.07（d，1H），6.86（m，1H），3.72（m，1H），2.06（1.98）（?s，3H），1.51（d，3H），1.46（1.40）（d，3H）。
Embodiment 2: the preparation of flurbiprofen methylene radical diacetate esters.
The acid catalyst of the flurbiprofen of 0.13mol and 0.52mol is placed in to the reactor containing 0.6L acetonitrile, is heated to 88 ℃, then slowly drip the methylene radical diacetate esters of 0.49mol, isothermal reaction, to finishing, obtains reaction system.
Reaction system is carried out to vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 65 ℃, vacuum tightness is-0.086mPa, then in the residue after vacuum rotary steam concentration, add the ethyl acetate of 0.3L and the water of 0.3L to dissolve, stratification obtains organic phase.
Adopt the saturated sodium bicarbonate solution of 0.3L to wash 3 times, use again the water washing 2 times of 0.3L to neutral, adopt the dry 5h of calcium sulfate of 15g, then carry out vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 60 ℃, vacuum tightness is-0.088mPa, obtain yellow dope 41.4g, its content is 97.6%.
Yellow dope is crossed to silicagel column purification processes, adopt ethyl acetate and normal hexane wash-out that volume ratio is 1: 20, then adopt TLC point plate to follow the tracks of, through vacuum rotary steam concentration, (Heating temperature is 60 ℃, vacuum tightness is-0.088mPa) after, obtain micro-yellow liquid 33.4g, i.e. flurbiprofen methylene radical diacetate esters 33.4g.
The structural formula of flurbiprofen methylene radical diacetate esters is:
As calculated, the productive rate of the present embodiment flurbiprofen methylene radical diacetate esters is 81.2%, content is 99.0%.Adopt nucleus magnetic resonance to confirm the structure of flurbiprofen methylene radical diacetate esters, confirm that result is as follows:
1H-NMR（400MHz，CDC13，δ，ppm）：7.51（d，2H），7.42（t，2H），7.36（d，1H），7.34（t，1H），7.13（d，1H），7.09（d，1H），6.86（m，2H），3.74（m，1H），2.04（1.96）（s，3H），1.48（1.42）（d，3H）。
Embodiment 3: the preparation of flurbiprofen phenylglycollic ester.
The flurbiprofen of 0.21mol and 0.040mol Phenylsulfonic acid are placed in to the reactor containing 0.55L toluene, are heated to 108 ℃, then slowly drip 0.25mol phenylethyl alcohol, isothermal reaction, to finishing, obtains reaction system.
Reaction system is carried out to vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 90 ℃, vacuum tightness is-0.075mPa, then in the residue after vacuum rotary steam concentration, add the ethyl acetate of 0.4L and the water of 0.4L to dissolve, stratification obtains organic phase.
Adopt the saturated sodium bicarbonate solution of 0.4L to wash 3 times, use again the water washing 2 times of 0.4L to neutral, adopt the anhydrous magnesium sulfate drying 6h of 10g, then carry out vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 80 ℃, vacuum tightness is-0.080mPa, obtain yellow dope 72.8g, its content is 93.2%.
Yellow dope is crossed to silicagel column purification processes, adopt ethyl acetate and octane wash-out that volume ratio is 1: 1, then adopt TLC point plate to follow the tracks of, through vacuum rotary steam concentration, (Heating temperature is 85 ℃, vacuum tightness is-0.082mPa) after, obtain light yellow liquid 63.5g, i.e. flurbiprofen phenylglycollic ester 63.5g.
The structural formula of flurbiprofen phenylglycollic ester is:
As calculated, the productive rate of the present embodiment flurbiprofen phenylglycollic ester is 86.8%, content is 98.8%.Adopt nucleus magnetic resonance to confirm the structure of flurbiprofen phenylglycollic ester, confirm that result is as follows:
1H-NMR（400MHz，CDC13，δ，ppm）：7.53-7.48（m，2H），7.45-7.36?（m，4H），7.28-7.16（m，4H），7.14-7.07（m，3H），4.51（m，2H），3.86（t，J?=?6.7?Hz，1H），2.83（m，2H），1.27（t，J?=?6.7?Hz，3H）。
Embodiment 4: the preparation of flurbiprofen isopropyl alcohol ester.
The dehydrated alcohol of the flurbiprofen of 0.41mol, 0.0082mol sulfuric acid and 0.328mol is placed in to reactor, is heated to 82 ℃, isothermal reaction, to finishing, obtains reaction system.
Reaction system is carried out to vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 60 ℃, vacuum tightness is-0.096mPa, then in the residue after vacuum rotary steam concentration, add the ethyl acetate of 0.5L and the water of 0.5L to dissolve, stratification obtains organic phase.
Adopt the saturated sodium bicarbonate solution of 0.5L to wash 4 times, use again the water washing 3 times of 0.5L to neutral, adopt the dry 4h of Calcium Chloride Powder Anhydrous of 12g, then carry out vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 50 ℃, vacuum tightness is-0.096mPa, obtain yellow dope 112.8g, its content is 96.2%.
Yellow dope is crossed to silicagel column purification processes, adopt ethyl acetate and sherwood oil wash-out that volume ratio is 1: 30, then adopt TLC point plate to follow the tracks of, through vacuum rotary steam concentration, (Heating temperature is 55 ℃, vacuum tightness is-0.096mPa) after, obtain light yellow liquid 108.0g, i.e. flurbiprofen isopropyl alcohol ester 108.0g.
The structural formula of flurbiprofen isopropyl alcohol ester is:
As calculated, the productive rate of the present embodiment flurbiprofen isopropyl alcohol ester is 92.1%, content is 99.2%.Adopt nucleus magnetic resonance to confirm the structure of flurbiprofen isopropyl alcohol ester, confirm that result is as follows:
1H-NMR（400?MHz，CDC13，δ，ppm）：7.55-7.51（m，2H），7.46-7.32?（m，4H），7.14-7.07（m，2H），3.89（t，J?=?6.8?Hz，1H），3.94（t，J?=?6.8?Hz，1H），1.21（t，J?=?6.8?Hz，3H），0.99（t，J?=?6.8?Hz，6H）。
Embodiment 5: the preparation of flurbiprofen ethanol ester.
The dehydrated alcohol of the tosic acid of the flurbiprofen of 0.62mol, 0.062mol and 6.2mol is placed in to reactor, is heated to 20 ℃, isothermal reaction 36h, obtains reaction system.
Reaction system is carried out to vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 40 ℃, vacuum tightness is-0.096mPa, then in the residue after vacuum rotary steam concentration, add the ethyl acetate of 0.75L and the water of 0.75L to dissolve, stratification obtains organic phase.
Adopt the saturated sodium bicarbonate solution of 0.75L to wash 2 times, use again the water washing 2 times of 0.75L to neutral, adopt the anhydrous sodium sulfate drying 5h of 15g, then carry out vacuum rotary steam concentration to remove desolventizing, the concentrated Heating temperature of vacuum rotary steam is 50 ℃, vacuum tightness is-0.096mPa, obtain yellow dope 159.8g, its content is 95.8%.
Yellow dope is crossed to silicagel column purification processes, adopt ethyl acetate and hexanaphthene wash-out that volume ratio is 1: 8, then adopt TLC point plate to follow the tracks of, through vacuum rotary steam concentration, (Heating temperature is 55 ℃, vacuum tightness is-0.098mPa) after, obtain white powder 152.9g, i.e. flurbiprofen ethanol ester 152.9g.
The structural formula of flurbiprofen ethanol ester is:
As calculated, the productive rate of the present embodiment flurbiprofen ethanol ester is 91.3%, content is 99.3%.Adopt nucleus magnetic resonance to confirm the structure of flurbiprofen ethanol ester, confirm that result is as follows:
1H-NMR（400?MHz，CDC13，δ，ppm）：7.53?-?7.45（m，2H），7.44-?7.28?（m，4H），7.17?-?7.04（m，2H），4.08（m，2H），3.76（t，J?=?7.0?Hz，1H），1.54（d，J?=?7.2?Hz，3H），1.28（d，J?=?7.1?Hz，3H）。
According to the elaboration in above specification sheets, those skilled in the art in the invention can also carry out suitable change and modification to above-mentioned embodiment.Therefore, the content of mentioning in above-described embodiment is not limitation of the invention, is not departing under the prerequisite of inventive concept of the present invention, and any apparent replacement is all within protection scope of the present invention.
Claims (10)
1. a preparation method for flurbiprofen ester compound, the method comprises the following steps:
1) by flurbiprofen and acid catalyst, be 1:(0.02 ~ 0.4 in molar ratio) ratio be placed in the reactor containing organic solvent, be heated to 20 ~ 150 ℃, then drip Ester, the addition of Ester is 0.9 ~ 8 times of flurbiprofen molar weight, isothermal reaction, to finishing, obtains reaction system;
2) reaction system is carried out to vacuum rotary steam concentration, then adding volume ratio is 1:(0.5 ~ 2) ethyl acetate and water dissolve, stratification obtains organic phase;
3) organic phase washing is extremely neutral, adopt desiccant dryness 2 ~ 16h, then carry out vacuum rotary steam concentration, obtain the thick product of flurbiprofen ester compound;
4) the thick product of flurbiprofen ester compound is crossed to silicagel column purification processes, adopt eluent wash-out, then adopt TLC point plate to follow the tracks of, after vacuum rotary steam concentration, obtain flurbiprofen ester compound.
2. a preparation method for flurbiprofen ester compound, the method comprises the following steps:
1) by flurbiprofen, acid catalyst and alcohol, be 1:(0.02 ~ 0.4 in molar ratio): the ratio of (0.8 ~ 20) is placed in reactor, is heated to 20 ~ 150 ℃, and isothermal reaction, to finishing, obtains reaction system;
2) reaction system is carried out to vacuum rotary steam concentration, then adding volume ratio is 1:(0.5 ~ 2) ethyl acetate and water dissolve, stratification obtains organic phase;
3) organic phase washing is extremely neutral, adopt desiccant dryness 2 ~ 16h, then carry out vacuum rotary steam concentration, obtain the thick product of flurbiprofen ester compound;
4) the thick product of flurbiprofen ester compound is crossed to silicagel column purification processes, adopt eluent wash-out, then adopt TLC point plate to follow the tracks of, after vacuum rotary steam concentration, obtain flurbiprofen ester compound.
3. the preparation method of flurbiprofen ester compound according to claim 1, it is characterized in that: described Ester is 1,1-glycol diacetate, 1,1-glycol dipropionate, 1,1-ethylene glycol bisthioglycolate isobutyrate, 1,1-ethylene glycol bisthioglycolate pivalate, 1,1-propylene-glycol diacetate, methylene radical diacetate esters, methylene radical dipropionate, methylene radical diisobutyrate or methylene radical two pivalates.
4. the preparation method of flurbiprofen ester compound according to claim 1, it is characterized in that: described organic solvent is tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, 2-methyltetrahydrofuran, ethyl acetate, sherwood oil, hexanaphthene, normal hexane, octane, methylene dichloride, N, any one or several combination in dinethylformamide, acetonitrile, acetone, toluene, dimethylbenzene and pyridine, the ratio of the volume of organic solvent and the quality of flurbiprofen is (0 ~ 30): 1.
5. the preparation method of flurbiprofen ester compound according to claim 2, is characterized in that: described alcohol is C
1~ C
18fatty alcohol or the aromatic alcohol of straight or branched, fatty alcohol is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, amylalcohol or Cetyl OH, aromatic alcohol is phenylethyl alcohol, phenylcarbinol, 2-pyridine propyl alcohol, phenol, L-AA or Eugenol.
6. according to the preparation method of the flurbiprofen ester compound described in any one in claim 1 ~ 5, it is characterized in that: described acid catalyst is toluenesulphonic acids, xylene monosulfonic acid, Phenylsulfonic acid, sulfuric acid, hydrochloric acid or phosphoric acid.
7. according to the preparation method of the flurbiprofen ester compound described in any one in claim 1 ~ 5, it is characterized in that: the concrete steps of washing described in step 3) are: first adopt saturated sodium bicarbonate solution to organic phase washing 2 ~ 4 times, then adopt and be washed with water to neutrality.
8. according to the preparation method of the flurbiprofen ester compound described in any one in claim 1 ~ 5, it is characterized in that: the Heating temperature of described vacuum rotary steam concentration is that 40 ~ 90 ℃, vacuum tightness are-0.075 ~ 0.1mPa.
9. according to the preparation method of the flurbiprofen ester compound described in any one in claim 1 ~ 5, it is characterized in that: described siccative is anhydrous sodium sulphate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous or calcium sulfate.
10. according to the preparation method of the flurbiprofen ester compound described in any one in claim 1 ~ 5, it is characterized in that: described eluent is 1:(0 ~ 30 by volume ratio) ethyl acetate and alkanes form, alkanes is sherwood oil, hexanaphthene, normal hexane or octane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310638812.4A CN103664606B (en) | 2013-12-04 | 2013-12-04 | A kind of preparation method of flurbiprofen ester compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310638812.4A CN103664606B (en) | 2013-12-04 | 2013-12-04 | A kind of preparation method of flurbiprofen ester compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103664606A true CN103664606A (en) | 2014-03-26 |
| CN103664606B CN103664606B (en) | 2016-01-20 |
Family
ID=50303497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310638812.4A Active CN103664606B (en) | 2013-12-04 | 2013-12-04 | A kind of preparation method of flurbiprofen ester compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103664606B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104434813A (en) * | 2014-11-13 | 2015-03-25 | 广东嘉博制药有限公司 | Ibuprofen ester lipid microsphere preparation and preparation method thereof |
| CN105777544A (en) * | 2016-04-13 | 2016-07-20 | 成都倍特药业有限公司 | Method for preparing S-(+)-flurbiprofen axetil high in optical purity |
| CN113527098A (en) * | 2021-07-06 | 2021-10-22 | 山东威高药业股份有限公司 | Flurbiprofen axetil crystal form and preparation method thereof |
| CN114075109A (en) * | 2020-08-21 | 2022-02-22 | 北京泰德制药股份有限公司 | Preparation method of flurbiprofen axetil and prepared crystal form |
| CN114195642A (en) * | 2020-09-17 | 2022-03-18 | 武汉华谱生物科技有限公司 | Refining method of high-content flurbiprofen axetil |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01211550A (en) * | 1988-02-17 | 1989-08-24 | Kaken Pharmaceut Co Ltd | Production of 1-acetoxyethyl 2-(2-fluoro-4-biphenylyl) propionate |
| CN101892112A (en) * | 2010-07-15 | 2010-11-24 | 中国科学院新疆理化技术研究所 | Method for preparing phenolic ester type basic lubricating grease with oxygen resistance |
| CN102964250A (en) * | 2012-11-19 | 2013-03-13 | 吉林大学 | Flurbiprofen eugenol ester medical compound and preparation and preparation method thereof |
| CN103012144A (en) * | 2012-12-26 | 2013-04-03 | 哈药集团技术中心 | Preparation method of flurbiprofen axetil |
-
2013
- 2013-12-04 CN CN201310638812.4A patent/CN103664606B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01211550A (en) * | 1988-02-17 | 1989-08-24 | Kaken Pharmaceut Co Ltd | Production of 1-acetoxyethyl 2-(2-fluoro-4-biphenylyl) propionate |
| CN101892112A (en) * | 2010-07-15 | 2010-11-24 | 中国科学院新疆理化技术研究所 | Method for preparing phenolic ester type basic lubricating grease with oxygen resistance |
| CN102964250A (en) * | 2012-11-19 | 2013-03-13 | 吉林大学 | Flurbiprofen eugenol ester medical compound and preparation and preparation method thereof |
| CN103012144A (en) * | 2012-12-26 | 2013-04-03 | 哈药集团技术中心 | Preparation method of flurbiprofen axetil |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104434813A (en) * | 2014-11-13 | 2015-03-25 | 广东嘉博制药有限公司 | Ibuprofen ester lipid microsphere preparation and preparation method thereof |
| CN105777544A (en) * | 2016-04-13 | 2016-07-20 | 成都倍特药业有限公司 | Method for preparing S-(+)-flurbiprofen axetil high in optical purity |
| CN105777544B (en) * | 2016-04-13 | 2018-11-02 | 成都倍特药业有限公司 | A kind of preparation method of S- (+)-flurbiprofen axetil |
| CN114075109A (en) * | 2020-08-21 | 2022-02-22 | 北京泰德制药股份有限公司 | Preparation method of flurbiprofen axetil and prepared crystal form |
| CN114075109B (en) * | 2020-08-21 | 2024-05-03 | 北京泰德制药股份有限公司 | Preparation method of flurbiprofen axetil and prepared crystal form |
| CN114195642A (en) * | 2020-09-17 | 2022-03-18 | 武汉华谱生物科技有限公司 | Refining method of high-content flurbiprofen axetil |
| CN113527098A (en) * | 2021-07-06 | 2021-10-22 | 山东威高药业股份有限公司 | Flurbiprofen axetil crystal form and preparation method thereof |
| CN113527098B (en) * | 2021-07-06 | 2024-03-29 | 山东威高药业股份有限公司 | Flurbiprofen axetil crystal form and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103664606B (en) | 2016-01-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103664606B (en) | A kind of preparation method of flurbiprofen ester compound | |
| CN102766138B (en) | A kind of preparation method of Azilsartan | |
| CN101955481B (en) | A kind of preparation method of Valganciclovir hydrochloride | |
| CN111285760B (en) | Synthesis method and intermediate of pipadiric acid | |
| CN102060867A (en) | Method for preparing potassium trifluoroborate series compounds | |
| CN103613498B (en) | The synthetic method of Win-35833 | |
| CN101182319A (en) | Method for extracting epigallocatechin-3-gallate from tea polyphenol | |
| CN101172953B (en) | Method of preparing telmisartan midbody of angiotensin medicament for treating hypertension | |
| CN103374050B (en) | One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid | |
| CN102766088B (en) | Novel process for synchronizing 4,4'-dibromo-2,2'-bipyridyl | |
| CN106831397A (en) | A kind of anthraquinone analog compound and preparation method thereof and medical application | |
| CN104188978B (en) | The application in preparation treatment or preventing renal fibrosis medicine of O-(nafoxidine base) ethyl derivative of Cleistanone | |
| CN103664985B (en) | The stereoselectivity preparation method of β type hydroxyl sweet wormwood alkyl oxide | |
| CN103709039B (en) | Method for synthesizing methyl (ethyl) gallate through catalysis of Cu-mordenite | |
| BR112018005619B1 (en) | METHOD FOR PRODUCING A COMPOUND, COMPOUND AND USE OF A COMPOUND | |
| CN107235853B (en) | A kind of synthetic method being used to prepare Canton love-pea vine A prime and its isomers | |
| CN110128385A (en) | A kind of quercetin derivative and its synthetic method by lauroyl chloride chemical modification | |
| CN103374049B (en) | One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid | |
| CN104177327A (en) | Preparation method of 6-amino-2-thiospiro[3,3]heptane hydrochloride | |
| CN104909994A (en) | Method for synthesizing ciprofibrate intermediate and the intermediate | |
| CN102079691A (en) | Method for synthesizing trans-resveratrol by combining hydroxyl groups and protective groups | |
| CN107540640A (en) | A kind of reductive modification agent and its preparation method and application | |
| CN110862536B (en) | pH-sensitive lipid material and preparation method and application thereof | |
| CN104529726A (en) | Preparation method of hydroxyacetophenone | |
| CN111440059B (en) | Synthetic method of loxoprofen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |