CN100462362C - Preparing process of 2-(10-oxy-10,11-dihydrodibenz [b,f]-thiotropilium-2-yl) propionic acid - Google Patents
Preparing process of 2-(10-oxy-10,11-dihydrodibenz [b,f]-thiotropilium-2-yl) propionic acid Download PDFInfo
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Abstract
The improved preparation process of zaltoprofen, named chemically as 2-(10-oxy-10, 11-dihydrodibenz [b, f]-thiotrppilium-2-yl) propionic acid, includes the following steps: rearrangement reaction of 5-propionyl-2-thiophenyl phenylacetate, iodine and triamyl orthoformate in the presence or absence of catalyst to obtain 5-(1-alkoxycarbonylethyl)-2-thiophenyl phenylacetate; hydrolyzing the said reaction product in water solution of alkali metal hydroxide and acidifying to obtain 5-(1-carboxylethyl)-2-thiophenyl phenylacetate; and the cyclization of 5-(1-carboxylethyl)-2-thiophenyl phenylacetate in the presence of polyphosphate to obtain the ultimate product. The present invention has low cost, less reaction steps, high yield, simple operation and no environmental pollution.
Description
Technical field
The present invention relates to a kind of preparation method of zaltoprofen, its chemical name is 2-(10-oxo-10,11 dihydro-dibenzo [b, a f] thia
-2-yl) propionic acid (1).
Background technology
Zaltoprofen is a kind of potent non-steroidal anti-inflammatory, analgesia, febrifuge.Its selectively acting is in inflammation part, and other organ such as stomach and kidney are not had effect.Compare with similar medicine such as Naproxen Base, Ibuprofen BP/EP, have characteristics such as efficient, that the stomach side effect is little.Its structural formula is as follows:
The synthetic route of zaltoprofen is a lot, now disclosed synthetic route is listed below:
One, be the feedstock production zaltoprofen with 5-propionyl-2-thiophenyl methyl phenylacetate (2)
1, Japanese kokai publication sho 61-251682 communique
Under the vitriol oil, get 5-(1-methoxycarbonyl ethyl)-2-thiophenyl methyl phenylacetate (3) with 5-propionyl-2-thiophenyl methyl phenylacetate (2) with trimethyl orthoformate, two acetic acid iodobenzene generation rearrangement reactions; (3) hydrolysis gets 5-(1-propyloic)-2-thiophenyl toluylic acid (4), and (4) closed loop under polyphosphoric acid (PPA) gets object-zaltoprofen (1).Reaction formula is as follows:
The two acetic acid iodobenzene price height that use in this method are difficult for reclaiming, the cost height, and operation steps is many, and need the solubilizing agent extraction, washing etc. separate step, aftertreatment complexity, the a large amount of vitriol oils of reaction needed are discharged a large amount of waste sulfuric acid solutions, contaminate environment through the aftertreatment meeting simultaneously.This patent is through testing and change experimental verification such as proportioning repeatedly: less than 1%, be not suitable for suitability for industrialized production by (2) preparation (4) yield.
2, clear No. 6310756 and EP0309626 communique are opened in Japanese kokai publication sho 62-2292780 number, spy
With 5-propionyl-2-thiophenyl methyl phenylacetate (2) is that raw material carries out bromo with bromine and gets (5), (5) and trimethyl orthoformate react ketal (6), (6) are at ZnBr
2Reset then under the catalysis that hydrolysis gets (4), (4) closed loop gets zaltoprofen (1).Reaction formula is as follows:
This method needs experience bromo, ketalization, rearrangement, hydrolysis four-step reaction by (2) synthetic (4).Reactions steps is long, during wherein by (2) preparations (4), owing in (2) two central carbon atom that contain active hydrogen are arranged, product complexity during bromo, purifying be difficulty very, brings the content of (4) very low, through recrystallization repeatedly, also can't solve the problem of purification difficult, yield is very low, also is not suitable for suitability for industrialized production.
Two, be the feedstock production zaltoprofen with 5-ethanoyl-2-thiophenyl methyl phenylacetate (1)
No. 57171991 communiques of Japanese kokai publication sho by 5-ethanoyl-2-thiophenyl methyl phenylacetate (1) and KBH4 reduce (8), (8) get (9) with Hydrogen bromide bromo, KCN cyaniding, (9) closed loop under PPA gets (10), (10) hydrolysis gets zaltoprofen (1).Reaction formula is as follows:
This method need be used the high POTASSIUM BOROHYDRIDE of price, and heavy-polluted Hydrogen bromide and highly toxic product potassium cyanide are restricted reaction, and reactions steps is long, and total recovery is low, also is not suitable for suitability for industrialized production.
As mentioned above, known that the multiple method for preparing zaltoprofen is arranged.But from the availability of raw material, the controllability of production operation, yield, environmental problem are considered, still wish to have more improved method.
Summary of the invention
The object of the present invention is to provide a kind of yield height, cost is lower and practicality is more excellent and helps the preparation method of the zaltoprofen of environment protection, more be applicable to suitability for industrialized production.
Realize that purpose technical scheme of the present invention is: a kind of 2-(10-oxo-10,11 dihydro-dibenzo [b, f] thia
-2-yl) preparation method of propionic acid (1) is characterized in that in turn including the following steps:
A) 5-propionyl-2-2-thiophenyl phenylacetate (18) is carried out rearrangement reaction with iodine, ortho-formate under the situation that catalyzer or catalyst-free are arranged, obtain 5-(1-alkoxy carbonyl ethyl)-2-2-thiophenyl phenylacetate (19);
B) this reaction product (19) hydrolysis in alkali metal hydroxide aqueous solution, acidifying gets 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4) then;
C) this compound (4) carries out cyclization in the presence of polyphosphoric acid, gets final product (1).
Described ortho-formate CH (OR)
3In R be C
1～C
6Alkyl.
Also use catalyzer in the described rearrangement reaction.
The catalyzer of described rearrangement reaction is selected from cupric oxide, Red copper oxide, Benzoyl Peroxide, Peracetic Acid, hydrogen peroxide or Lewis acid.Described Lewis acid is cupric bromide or cuprous bromide, cupric chloride or cuprous chloride.
The catalyzer of described rearrangement reaction is preferably cuprous chloride.
Described rearrangement reaction also can add Sulfothiorine after finishing, to remove iodine wherein.
Described 5-propionyl-2-2-thiophenyl phenylacetate (18) is to carry out esterification by 5-propionyl-2-thiophenyl toluylic acid (13) and alcohol to make.
Described 5-propionyl-2-thiophenyl toluylic acid (13) is to carry out the Ullmann condensation reaction by 5-propionyl-2-chlorobenzene acetic acid salt (17) and thiophenol under catalyzer to make.
Described Ullmann condensation reaction adopts dewatering agent to carry out under anhydrous state and normal pressure.
Described dewatering agent is selected from oil of mirbane, dimethylbenzene or primary isoamyl alcohol.Described dewatering agent is preferably primary isoamyl alcohol, is that toxicity is low because primary isoamyl alcohol is a spices, and solvability is good, and boiling point is also high, and reaction effect is good, the yield height.
Described Ullmann condensation reaction is carried out under 140～160 ℃.When being lower than 140 ℃, reaction not exclusively; When being higher than 160 ℃, because solvent steams manyly, reaction mass becomes sticky thick, and weak effect also the coking phenomenon can occur.
Described 5-propionyl-2-chlorobenzene acetic acid salt (17) is by the hydrolysis and making in alkali metal hydroxide aqueous solution of 5-propionyl-2-chlorobenzene acetic acid ester (16).
Described 5-propionyl-2-chlorobenzene acetic acid ester (16) be by o-chlorobenzene acetic acid ester (15) under the effect of anhydrous Lewis acid catalyst, carry out Friedel-Crafts reaction with propionyl chloride and make.
Described Friedel-Crafts is reflected in the solvent and carries out.Adopt solvent to add reaction system, can make reaction even, gentle, and convenient post-treatment.
The solvent that described Friedel-Crafts reaction is adopted is selected from oil of mirbane, tetracol phenixin or chloroform.Described solvent is preferably tetracol phenixin, and in all solvents, the tetracol phenixin effect is best, and yield is the highest.
Described anhydrous Lewis acid catalyst is aluminum trichloride (anhydrous) or FERRIC CHLORIDE ANHYDROUS.
Described o-chlorobenzene acetic acid ester (15) is a starting raw material with o-chlorobenzene acetic acid (14), under vitriolic catalysis, carries out esterification with alcohol and makes.
In above-mentioned preparation method's step a), reset owing to adopt the lower iodine of price to replace two high acetic acid iodobenzenes of price, not only step is short, and the yield height, and practicality easy and simple to handle does not need again not pollute the environment with a large amount of vitriol oils simultaneously.Japanese kokai publication sho 61-251682 communique adopts two high acetic acid iodobenzenes of price to reset, and, contaminate environment low except that yield, the cost height, the iodobenzene that generates that also responds reclaims difficulty, needs rectifying, hydrogen peroxide oxidation, aceticanhydride acidylate just can make.In addition, the present invention adopts iodine to reset, and the by product sodium iodide that reaction generates directly can be recycled.
Thereby the present invention compared with prior art has the superiority that cost is lower, yield is high, practicality is stronger and help environment protection, is more suitable in suitability for industrialized production.
Realize that the further technical scheme of purpose of the present invention is: in above-mentioned preparation method, described rearrangement reaction also can add catalyzer.
After adding catalyzer, can reduce the consumption of iodine in the rearrangement reaction, make cost lower, more help suitability for industrialized production.
Realize purpose of the present invention further technical scheme be: in above-mentioned preparation method, described rearrangement reaction also can add Sulfothiorine after finishing, to remove wherein unreacted iodine.
Added Sulfothiorine is 10% hypo solution.
After rearrangement reaction finishes, add Sulfothiorine, can remove wherein unreacted iodine, further improve the quality of the finished product, the color and luster of the finished product is improved.And all right regeneration of the sodium iodide in the waste liquid, thereby can further reduce cost, be more suitable in suitability for industrialized production.If do not remove wherein unreacted iodine, also be fine, iodine wherein can slowly vapor away.
Show that in sum the present invention can be a starting raw material with o-chlorobenzene acetic acid (14), under vitriolic catalysis, carry out esterification with alcohol and get o-chlorobenzene acetic acid ester (15); Compound (15) carries out the Friedel-Crafts reaction under the catalysis of anhydrous Lewis acid catalyst, get 5-propionyl-2-chlorobenzene acetic acid ester (16); Compound (16) is hydrolyzed to 5-propionyl-2-chlorobenzene acetic acid salt (17) in alkali metal hydroxide aqueous solution; Compound (17) carries out the Ullmann condensation reaction with thiophenol and gets 5-propionyl-2-thiophenyl toluylic acid (13) under catalyzer, compound (13) gets 5-propionyl-2-2-thiophenyl phenylacetate (18) with pure esterification under vitriolic catalysis; Compound (18) carries out rearrangement reaction with iodine, trimethyl orthoformate under catalyzer or the catalyst-free and gets 5-(1-alkoxy carbonyl ethyl)-2-2-thiophenyl phenylacetate (19) having; Compound (19) hydrolysis in alkali metal hydroxide aqueous solution, acidifying get 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4); Compound (4) carries out cyclization in the presence of polyphosphoric acid, get object-zaltoprofen (1).Reaction formula is as follows:
In above-mentioned reaction formula, R is C
1～C
6Alkyl, Cat represents catalyzer.
For further understanding content of the present invention, each step process is described below:
1, the preparation of o-chlorobenzene acetic acid ester (15)
Reaction formula:
(annotate: R is C
1～C
6Alkyl)
This step is for esterification, and compound (14), alcohol, the vitriol oil were added in the reactor back flow reaction 6～12 hours, and normal pressure steams and removes excessive alcohol and water then, cools off to add water, layering, drying, underpressure distillation and get compound (15).
In this step reaction, alcohol can adopt C
1～C
6Alcohol as methyl alcohol, ethanol, propyl alcohol, butanols etc., the temperature when temperature of reaction is back flow reaction will be determined according to the alcohol that reaction is adopted.
O-chlorobenzene acetic acid: alcohol: the vitriol oil=1:(5～20): (0.1～1) (mol/mol/mol)
2,5-propionyl-2-chlorobenzene acetic acid ester (16) preparation
Reaction formula:
This step reaction is acylation reaction, compound (15) is added to stirs anhydrous Lewis acid catalyst down and have in the reactor of solvent, after adding, in 0～20 ℃ of temperature of reaction dropping propionyl chloride down, drip off the back and carried out back flow reaction 2～8 hours in 40～60 ℃, be incubated 5 hours; Separate compound (16).
The solvent that is adopted in acylation reaction can be selected oil of mirbane, tetracol phenixin or chloroform for use, and preferred solvent is a tetracol phenixin.In all solvents, the tetracol phenixin effect is best, and yield is the highest.
Anhydrous Lewis acid catalyst can be selected aluminum trichloride (anhydrous) or FERRIC CHLORIDE ANHYDROUS etc. for use, preferred aluminum trichloride (anhydrous).
O-chlorobenzene acetic acid ester: propionyl chloride: anhydrous Lewis acid catalyst: solvent=1:(1.2～2.5): (1.2～3.0): (3～10) (mol/mol/mol/mol)
3, the preparation of 5-propionyl-2-thiophenyl toluylic acid (13)
Reaction formula:
Earlier by (16) in the presence of alkali metal hydroxide, be hydrolyzed compound (17), then add dewatering agent and carry out dehydration reaction, in the presence of catalyzer, carry out the Ullmann condensation reaction with thiophenol more then, use hcl acidifying, separation at last, get off-white color crystalline compounds (13).
During to (17), temperature of reaction is back flow reaction (about 100 ℃) by (16) hydrolysis in this reaction.
The dewatering agent that dehydration reaction adopted can be dimethylbenzene, oil of mirbane, primary isoamyl alcohol etc., and dewatering agent is preferably primary isoamyl alcohol.This is that toxicity is low because primary isoamyl alcohol is a spices, and solvability is good, and boiling point is also high, and reaction effect is good, the yield height.
The temperature of reaction of Ullmann condensation reaction: 140-160 ℃, when being lower than 140 ℃, reaction not exclusively; When being higher than 160 ℃, because solvent steams manyly, reaction mass becomes sticky thick, and weak effect also the coking phenomenon can occur.
Reaction times: 10-15 hour,
Catalyst system therefor can be cupric chloride, cuprous chloride, oxo copper, copper powder, and catalyzer is preferably copper powder.
Alkali metal hydroxide can be sodium hydroxide or potassium hydroxide etc.
5-propionyl-2 chlorobenzene acetic acid ester (16): alkali metal hydroxide: thiophenol: catalyzer=1:(2～2.4): (1～1.4): (0-0.10) mol/mol/mol/mol, dewatering agent and water add arbitrarily.
4,5-propionyl-2-2-thiophenyl phenylacetate (18) preparation
Reaction formula:
This step is esterification, and with the vitriol oil of 5-propionyl-2-thiophenyl toluylic acid (13), alcohol (ROH) and catalytic amount, back flow reaction is 8～10 hours in the input reactor, and steaming dewaters, alcohol, and separation and purification gets compound (18).
Alcohol can be C
1～C
6Alcohol, as methyl alcohol, ethanol, propyl alcohol, butanols, amylalcohol, hexanol etc.Temperature of reaction: back flow reaction, when using primary isoamyl alcohol reflux temperature: 140-160 ℃.
5-propionyl-2-thiophenyl acetate (13): alcohol: the vitriol oil=1:(5～10): (0.1～0.5) mol/mol/mol.
5, the preparation of 5-(1-alkoxy carbonyl ethyl)-2-2-thiophenyl phenylacetate (19)
Reaction formula:
This step is rearrangement reaction.In reactor, add ortho-formate, 5-propionyl-2-2-thiophenyl phenylacetate (18), catalyzer and iodine; slowly heat up and carried out back flow reaction 6～16 hours; after reaction finishes; add 10% Sulfothiorine to remove unreacted iodine; phase-splitting; organic phase removes low-boiling-point substance under reduced pressure, gets resistates compound (19).Also can not add Sulfothiorine, directly phase-splitting, organic phase removes low-boiling-point substance under reduced pressure, gets resistates compound (19).
Ortho-formate CH (OR)
3R be C
1～C
6Alkyl, can be trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, triamyl orthoformate etc.
The catalyzer of rearrangement reaction can be cupric oxide, Red copper oxide, Benzoyl Peroxide, Peracetic Acid, hydrogen peroxide, Lewis acid.Lewis acid can be cupric bromide, cuprous bromide, cupric chloride, cuprous chloride etc.The catalyzer of rearrangement reaction is preferably cuprous chloride.Temperature of reaction is 60～90 ℃ of back flow reaction temperature.
5-propionyl-2-2-thiophenyl phenylacetate (18): ortho-formate: iodine: catalyzer=1:(1～2.5): (1～2): (0.01～0.2) (mol/mol/mol/mol)
6, the preparation of 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4)
Reaction formula:
This step is hydrolysis reaction.In reactor, drop into alcohol, alkali metal hydroxide, water, 5-(1-alkoxy carbonyl ethyl)-2-2-thiophenyl phenylacetate (19), carried out back flow reaction 3～5 hours at 40～100 ℃, steam to remove alcohol, add water dissolution, use acidifying, separate, collect compound (4).In this step reaction, also can not add alcohol.
Alkali metal hydroxide can be sodium hydroxide or potassium hydroxide etc., is preferably potassium hydroxide.
5-(1-alkoxy carbonyl ethyl)-2-2-thiophenyl phenylacetate (19): alkali metal hydroxide=1:(2～3) (mol/mol)
7, the preparation of zaltoprofen (1)
Reaction formula:
This step reaction is the dehydration closed-loop reaction.Under violent stirring, drop into 82～84% polyphosphoric acid (PPA) and 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4), ethylene dichloride, be heated to 80～90 ℃, refluxed 6～8 hours, reaction finishes cooling, splash into the unnecessary PPA of water decomposition, the dehydration of layering organic phase, steaming desolventizes, and separation and purification gets compound zaltoprofen (1).
Temperature of reaction: 80～90 ℃.
5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4): PPA=1:(4～8) (mol/mol)
Technique effect of the present invention:
Improvement master of the present invention more is to adopt in the rearrangement reaction step the lower iodine of price to replace two high acetic acid iodobenzenes of price.
Japanese kokai publication sho 61-251682 communique adopts two high acetic acid iodobenzenes of price to reset, and, contaminate environment low except that yield, the cost height, the iodobenzene that generates that also responds reclaims difficulty, needs rectifying, hydrogen peroxide oxidation, aceticanhydride acidylate just can make.Through experimental verification yield less than 1%.Also have bibliographical information to adopt the bromo ketal to reset, step is long, and the bromination product complexity not only influenced quality product, and yield is low.
And in preparation method's rearrangement reaction step of the present invention, reset owing to adopt the lower iodine of price to replace two high acetic acid iodobenzenes of price, not only step is short, and yield height, practicality easy and simple to handle does not need again not pollute the environment with a large amount of vitriol oils simultaneously.And the by product sodium iodide that reaction generates directly can be recycled.
Thereby the present invention compared with prior art has the superiority that cost is lower, yield is high, practicality is stronger and help environment protection.Thereby help suitability for industrialized production.
If in the rearrangement reaction step, also use catalyzer, then can further reduce the consumption of iodine, make cost lower, more help suitability for industrialized production.
If after rearrangement reaction finishes, add Sulfothiorine, remove wherein unreacted iodine, then can further improve the quality of the finished product, the color and luster of the finished product is improved.And all right regeneration of the sodium iodide in the waste liquid, thereby can further reduce cost, be more suitable in suitability for industrialized production.
The every kind of solvent that uses in building-up process can reclaim use, greatly reduces cost especially, through test determination, and the reliable product quality that the present invention obtains, stable performance.Product of the present invention is made zaltoprofen, has the good result of antipyretic-antalgic.
Embodiment
Below in conjunction with embodiment, the present invention is further described in detail, but is not limited to this.
Embodiment 1:
1, the preparation of o-chlorobenzene acetic acid methyl esters (15)
Raw material specification and charging capacity
| Raw material (molecular weight) | Specification | Charging capacity |
| O-chlorobenzene acetic acid (170.5) | The industry first grade has acetate smell white powder.MP95～97 ℃ | 10Kg |
| Methyl alcohol (32) | The inflammable volatile polar liquid of water white transparency 〉=99% | 19Kg |
| The vitriol oil (98) | Colourless transparent oil liquid, deep-etching, content 〉=98% | 1.14Kg |
Feed ratio (mol ratio):
O-chlorobenzene acetic acid: methyl alcohol: the vitriol oil=1:10.12:0.20
Add o-chlorobenzene acetic acid, methyl alcohol respectively in reactor, stir, cooling drips the vitriol oil, temperature rising reflux 10 hours, precipitation down.Add water, layering, organic layer neutralization, washing, dry, distillation obtains product 9.4Kg, content 99.3% (measuring with gas-chromatography GC method).
2, the preparation of 5-propionyl-2-chlorophenyl acetate (16)
Raw material specification and charging capacity
| Raw material (molecular weight) | Specification | Charging capacity |
| O-chlorobenzene acetic acid methyl esters (184.5) | The white oily liquids, content is greater than 99% | 8Kg |
| Aluminum trichloride (anhydrous) (133.3) | The industry first grade, content is greater than 98% easy deliquescence | 11.6Kg |
| Propionyl chloride (92) | Colourless liquid has strong tearing property and corrodibility, content 〉=98.5% | 8Kg |
| Tetracol phenixin | Colourless liquid, content 〉=98.5% | 20Kg |
Feed ratio (mol ratio):
O-chlorobenzene acetic acid methyl esters: aluminum trichloride (anhydrous): propionyl chloride: tetracol phenixin=1:2:2:3
The frozen water cooling drops into tetracol phenixin and aluminum trichloride (anhydrous) down in reactor, suction o-chlorobenzene acetic acid methyl esters drips propionyl chloride at 10～20 ℃, drips off the back in 50～60 ℃ of insulations 5 hours.After reaction finishes, reactant is slowly poured in 5% dilute hydrochloric acid, layering, is neutralized to PH=5～6, washing, precipitation, recrystallization, product 9.4Kg, content is more than or equal to 95%.
3, the preparation of 5-propionyl-2-thiophenyl toluylic acid (13)
Raw material specification and charging capacity
| Raw material (molecular weight) | Specification | Charging capacity |
| 5-propionyl-2-chlorophenyl acetate (240.5) | Faint yellow crystallization, content 〉=95% | 9.4Kg |
| Potassium hydroxide (56) | White plates GB1919-80 content 90%, easy deliquescence | 4.6Kg |
| Water | Tap water | Arbitrarily |
| Thiophenol (110) | Colourless liquid, has the garlic stink | 4.5Kg |
| Primary isoamyl alcohol | Colourless liquid has apple brandy fragrance and sharp flavor GB2760-86 content 99% | Arbitrarily |
| Catalyzer (copper powder) (64) | Powder | 0.089Kg |
Feed ratio (mol ratio):
5-propionyl-2-chlorophenyl acetate: potassium hydroxide: thiophenol: copper powder=1:2.22:1.1054:0.035, dewatering agent isoamyl alcohol and water adds arbitrarily.
Add entry in reactor, stirring down, adding potassium hydroxide, 5-propionyl-2-chlorophenyl acetate refluxed 0.5 hour.Cooling adds primary isoamyl alcohol and dewaters to anhydrous state, and is cold slightly, adds thiophenol, catalyst copper powder, and timing refluxes and is incubated 10 hours, 140～160 ℃ of reflux temperatures.Primary isoamyl alcohol, Jia Shui, filtration, accent PH=1 are taken off in cooling, decompression, and filtration, recrystallization, oven dry get product 6Kg, 106～108 ℃ of Mp.
4, the preparation of 5-propionyl-2-thiophenyl methyl phenylacetate (18)
Raw material specification and charging capacity
| Raw material (molecular weight) | Specification | Charging capacity |
| 5-propionyl-2-thiophenyl toluylic acid (300) | White, needle-shaped crystals, content 〉=98% | 5.6Kg |
| Sulfuric acid (98) | Content 〉=98.5% | 0.36Kg |
| Methyl alcohol (32) | Content 〉=99% | 12Kg |
Feed ratio (mol ratio):
5-propionyl-2-thiophenyl toluylic acid: sulfuric acid: methyl alcohol=1:0.2:10
In reactor, drop into methyl alcohol, 5-propionyl-2-thiophenyl toluylic acid, cooling drips the vitriol oil, refluxes 4 hours, desolventizing, adding recrystallizing methanol, freezing and filtering must 5Kg, 59～60 ℃ of mp.
5, the preparation of 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4)
Raw material specification and charging capacity
| Raw material (molecular weight) | Specification | Charging capacity |
| 5-propionyl-2-thiophenyl methyl phenylacetate (314) | The white plates crystallization, content 〉=99% | 4.84Kg |
| Iodine (256) | The crystallization of atropurpureus squamous is corrosive, easily distillation.Technical grade 〉=98% | 3.95Kg |
| Trimethyl orthoformate (106) | Colourless liquid, the fragrance that ester is arranged, content 〉=98% | 23Kg |
| Catalyzer (cuprous chloride) (99.5) | 0.020Kg | |
| Potassium hydroxide (56) | Strong basicity white plates GB1919-80 content 90%, easy deliquescence | 3.9Kg |
| Chloroform solvent (extraction is used) | ||
| Water | Tap water | 30Kg |
| Sulfothiorine (248) | Water white transparency monocline body xln HG 1-210-79 content 〉=98% | 12Kg |
Feed ratio (mol ratio):
5-propionyl-2-thiophenyl methyl phenylacetate: iodine: trimethyl orthoformate: catalyzer: potassium hydroxide: water: Sulfothiorine=1:1:14:0.013:4.5:108:3.14
In reactor, add 5-propionyl-2-thiophenyl methyl phenylacetate, trimethyl orthoformate, cuprous chloride, the slow temperature rising reflux of iodine respectively; be incubated 5 hours; adding chloroform, water, Sulfothiorine stir half an hour, filtration, layering, washing, precipitation; add methyl alcohol, water, potassium hydroxide, refluxed 2 hours.Precipitation, Jia Shui transfer PH=1, and filtration, crystallization obtain 2.7Kg, 145～148 ℃ of mp.
6, the preparation of zaltoprofen (1)
Raw material specification and charging capacity
| Raw material (molecular weight) | Specification | Charging capacity |
| 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (316) | White powder crystallization, mp145～148 ℃ | 2Kg |
| PPA(338) | Colorless transparent viscous liquid, easy deliquescence, company standard 〉=80% | 8Kg |
| Ethylene dichloride | Water white transparency volatile liquid content 99% | 26Kg |
Feed ratio (mol ratio):
5-(1-carboxy ethyl)-2-thiophenyl toluylic acid: PPA: ethylene dichloride=1:3.74:45
In reactor, add PPA, ethylene dichloride, 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid, refluxed 8 hours, drip water, static layering, organic phase washing, steaming desolventizes, and recrystallization obtains product 1.1Kg, mp132～136 ℃, content 〉=99%.
Preparation (not adding catalyzer) raw material specification and the charging capacity of embodiment 2:5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4)
| Raw material (molecular weight) | Specification | Charging capacity |
| 5-propionyl-2-thiophenyl methyl phenylacetate (314) | The white plates crystallization, content 〉=99% | 4.84Kg |
| Iodine (256) | The crystallization of atropurpureus squamous is corrosive, easily distillation.Technical grade 〉=98% | 7.9Kg |
| Trimethyl orthoformate (106) | Colourless liquid, the fragrance that ester is arranged, content 〉=98% | 23Kg |
| Potassium hydroxide (56) | Strong basicity white plates GB1919-80 content 90%, easy deliquescence | 3.9Kg |
| Chloroform solvent (extraction is used) | ||
| Water | Tap water | 30Kg |
| Sulfothiorine (248) | Water white transparency monocline body xln HG 1-210-79 content 〉=98% | 12Kg |
Feed ratio (mol ratio): 5-propionyl-2-thiophenyl methyl phenylacetate: iodine: trimethyl orthoformate: potassium hydroxide: water: Sulfothiorine=1:2:14:4.5:108:3.14
In reactor, add 5-propionyl-2-thiophenyl methyl phenylacetate, trimethyl orthoformate, the slow temperature rising reflux of iodine respectively; be incubated 5～8 hours; after reaction finishes; adding chloroform, water, Sulfothiorine stir half an hour, filtration, layering; washing, precipitation; adding, water, potassium hydroxide refluxed 2 hours.Precipitation, Jia Shui transfer PH=1, and filtration, crystallization obtain 2.64Kg, 145～148 ℃ of mp.
Preparation (not adding Sulfothiorine) raw material specification and the charging capacity of embodiment 3:5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4)
| Raw material (molecular weight) | Specification | Charging capacity |
| 5-propionyl-2-thiophenyl methyl phenylacetate (314) | The white plates crystallization, content 〉=99% | 4.84Kg |
| Iodine (256) | The crystallization of atropurpureus squamous is corrosive, easily distillation.Technical grade 〉=98% | 3.95Kg |
| Trimethyl orthoformate (106) | Colourless liquid, the fragrance that ester is arranged, content 〉=98% | 23Kg |
| Catalyzer (cuprous chloride) (99.5) | 0.020Kg | |
| Potassium hydroxide (56) | Strong basicity white plates GB1919-80 content 90%, easy deliquescence | 3.9Kg |
| Chloroform solvent (extraction is used) | Technical grade | |
| Water | Tap water | 30Kg |
Feed ratio (mol ratio): 5-propionyl-2-thiophenyl methyl phenylacetate: iodine: trimethyl orthoformate: catalyzer (cuprous chloride): potassium hydroxide: water=1:1:14:0.013:4.5:108
In reactor, add 5-propionyl-2-thiophenyl methyl phenylacetate, trimethyl orthoformate, cuprous chloride, the slow temperature rising reflux of iodine respectively; be incubated 5 hours, add chloroform, water, stir half an hour, filtration, layering, washing, precipitation; add methyl alcohol, water, potassium hydroxide, refluxed 2 hours.Precipitation, Jia Shui transfer PH=1, and filtration, crystallization obtain 2.69Kg, 145～148 ℃ of mp.
Embodiment 4
The preparation of 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4) (do not add catalyzer and do not add Sulfothiorine) raw material specification and charging capacity
| Raw material (molecular weight) | Specification | Charging capacity |
| 5-propionyl-2-thiophenyl methyl phenylacetate (314) | The white plates crystallization, content 〉=99% | 4.84Kg |
| Iodine (256) | The crystallization of atropurpureus squamous is corrosive, easily distillation.Technical grade 〉=98% | 7.9Kg |
| Trimethyl orthoformate (106) | Colourless liquid, the fragrance that ester is arranged, content 〉=98% | 23Kg |
| Potassium hydroxide (56) | Strong basicity white plates GB1919-80 content 90%, easy deliquescence | 3.9Kg |
| Chloroform solvent (extraction is used) | ||
| Water | Tap water | 30Kg |
Feed ratio (mol ratio): 5-propionyl-2-thiophenyl methyl phenylacetate: iodine: trimethyl orthoformate: potassium hydroxide: water=1:2:14:4.5:108
In reactor, add 5-propionyl-2-thiophenyl methyl phenylacetate, trimethyl orthoformate, the slow temperature rising reflux of iodine respectively, be incubated 5～8 hours, after reaction finishes; adding chloroform, water stir half an hour, filtration, layering; washing, precipitation, adding, water, potassium hydroxide refluxed 2 hours.Precipitation, Jia Shui transfer PH=1, and filtration, crystallization obtain 2.60Kg, 145～148 ℃ of mp.
Claims (9)
1. 2-(10-oxo-10,11 dihydro-dibenzo [b, f] thia
-2-yl) preparation method of propionic acid (1) is characterized in that in turn including the following steps:
A) with 5-propionyl-2-2-thiophenyl phenylacetate (18) under the situation that catalyzer or catalyst-free are arranged with iodine, ortho-formate CH (OR)
3Carry out rearrangement reaction, obtain 5-(1-alkoxy carbonyl ethyl)-2-2-thiophenyl phenylacetate (19), described ortho-formate CH (OR)
3In R be C
1～C
6Alkyl;
B) this reaction product (19) hydrolysis in alkali metal hydroxide aqueous solution, acidifying gets 5-(1-carboxy ethyl)-2-thiophenyl toluylic acid (4) then;
C) this compound (4) carries out cyclization in the presence of polyphosphoric acid, gets final product (1).
2. 2-according to claim 1 (10-oxo-10,11 dihydro-dibenzo [b, f] thia
-2-yl) preparation method of propionic acid (1) is characterized in that: also use catalyzer in the described rearrangement reaction.
3. 2-according to claim 2 (10-oxo-10,11 dihydro-dibenzo [b, f] thia
-2-yl) preparation method of propionic acid (1) is characterized in that: the catalyzer of described rearrangement reaction is selected from cupric oxide, Red copper oxide, Benzoyl Peroxide, Peracetic Acid, hydrogen peroxide or Lewis acid.
4. preparation method according to claim 3 is characterized in that: described Lewis acid is cupric bromide or cuprous bromide, cupric chloride or cuprous chloride.
5. preparation method according to claim 4 is characterized in that: described Lewis acid is cuprous chloride.
6. according to claim 1 or 2 or 3 or 4 or 5 described preparation methods, it is characterized in that: described rearrangement reaction also adds Sulfothiorine after finishing, to remove iodine wherein.
7. preparation method according to claim 1 is characterized in that: 5-propionyl-2-2-thiophenyl phenylacetate (18) is to carry out esterification by 5-propionyl-2-thiophenyl toluylic acid (13) and alcohol to make.
8. preparation method according to claim 7 is characterized in that: 5-propionyl-2-thiophenyl toluylic acid (13) is to carry out the Ullmann condensation reaction by 5-propionyl-2-chlorobenzene acetic acid salt (17) and thiophenol under catalyst action to make.
9. preparation method according to claim 8 is characterized in that: 5-propionyl-2-chlorobenzene acetic acid salt (17) is to be starting raw material with o-chlorobenzene acetic acid (14), under vitriolic catalysis, carries out esterification with alcohol and gets o-chlorobenzene acetic acid ester (15); Compound (15) carries out the Friedel-Crafts reaction under the catalysis of anhydrous Lewis acid catalyst, get 5-propionyl-2-chlorobenzene acetic acid ester (16); Compound (16) hydrolysis and making in alkali metal hydroxide aqueous solution.
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| CNB2005100225805A CN100462362C (en) | 2005-12-20 | 2005-12-20 | Preparing process of 2-(10-oxy-10,11-dihydrodibenz [b,f]-thiotropilium-2-yl) propionic acid |
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| CNB2005100225805A CN100462362C (en) | 2005-12-20 | 2005-12-20 | Preparing process of 2-(10-oxy-10,11-dihydrodibenz [b,f]-thiotropilium-2-yl) propionic acid |
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| CN104098540B (en) * | 2014-06-24 | 2016-02-17 | 浙江亚太药业股份有限公司 | A kind of method preparing Zaltoprofen |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0309626A1 (en) * | 1987-09-30 | 1989-04-05 | Nippon Chemiphar Co., Ltd. | Process for the preparation of dibenzothiepin derivative |
| US4891433A (en) * | 1986-06-10 | 1990-01-02 | Nippon Chemiphar Co., Ltd. | Process for the preparation of dibenzothiepin derivative |
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2005
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4891433A (en) * | 1986-06-10 | 1990-01-02 | Nippon Chemiphar Co., Ltd. | Process for the preparation of dibenzothiepin derivative |
| EP0309626A1 (en) * | 1987-09-30 | 1989-04-05 | Nippon Chemiphar Co., Ltd. | Process for the preparation of dibenzothiepin derivative |
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