CN104098540B - A kind of method preparing Zaltoprofen - Google Patents
A kind of method preparing Zaltoprofen Download PDFInfo
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- CN104098540B CN104098540B CN201410287231.5A CN201410287231A CN104098540B CN 104098540 B CN104098540 B CN 104098540B CN 201410287231 A CN201410287231 A CN 201410287231A CN 104098540 B CN104098540 B CN 104098540B
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- zaltoprofen
- ethyl acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/14—[b,f]-condensed
Abstract
The present invention relates to the preparation method of Zaltoprofen, disclose a kind of method preparing Zaltoprofen, comprise with 5-(1-propionyl)-2-thiophenyl toluylic acid for initiator, prepare Zaltoprofen through rearrangement, hydrolysis, cyclization.The rearrangement reaction of 5-of the present invention (1-propionyl)-2-thiophenyl toluylic acid adopts illumination heating, illumination effect is deep into atom, electronics is had an impact, reduce the required activation energy of reaction, reaction efficiency is high, and the effect of illumination simultaneously makes iodine distil as gaseous state, gaseous iodine can contact more fully with substrate, more thoroughly rapidly, decrease the impact of methyl iodide on rearrangement reaction, yield is higher in reaction; Present method is simple to operate, environmental protection, is applicable to industrialized production.
Description
Technical field
The present invention relates to the preparation method of Zaltoprofen, particularly relate to a kind of method preparing Zaltoprofen.
Background technology
Zaltoprofen (10,11-dihydro-Alpha-Methyl-10-oxygen dibenzo [b, f] thiophene pinane-2-acetic acid), molecular formula is C
17h
14o
3s, molecular weight is 298.36, and its structural formula is:
Zaltoprofen is the COX nonspecific inhibitor of new generation developed by Japanese Chemiphar and Zeria company, is a kind of potent non-steroidal antalgic anti-inflammatory agent.The compound relevant with pharmacological action is as compared with Ibuprofen BP/EP, indomethacin, loxoprofen sodium, diclofenac sodium etc., the analgesic activity of Zaltoprofen, especially comparatively strong, simultaneously also stronger to effect that is acute, subacute and chronic inflammatory diseases to the pain reaction effect excited by bradykinin.Also have the safety index of Zaltoprofen higher, extremely low to GI detrimental effect, occur that the probability of great untoward reaction as acute renal insufficiency, hepatic insufficiency and peptide ulceration etc. is lower than < 0.1%.Therefore, Zaltoprofen has the feature of high-efficiency low-toxicity, the anti-inflammatory analgesic etc. after being widely used in chronic rheumatoid arthritis, deformability arthrodynia, lumbago diseases, scapulohumeral periarthritis, neck shoulder wrist syndrome and Post operation, wound clinically, after exodontia.
The preparation method of existing Zaltoprofen for starting raw material, prepares Zaltoprofen through rearrangement, hydrolysis, cyclization with 5-(1-propionyl)-2-thiophenyl toluylic acid.But the method does not consider the impact of the generation of methyl iodide for W-response yield in rearrangement reaction.And in ring-closure reaction, adopting polyphosphoric acid and organic solvent dichloromethane mixing reaction, two-phase is immiscible on the one hand, can affect carrying out smoothly of reaction in large production; On the other hand do not consider methylene dichloride yet and refining time the feature not easily removed of normal hexane in actual production that adopt, considerably increase workload; And the space that yield is also improved.
Therefore, existing technology can not be applicable to large production and this target of environmental protection preferably, still needs to make and improves and innovation.
Summary of the invention
The present invention is directed to existing Zaltoprofen preparation method yield low, large produce in reaction carry out slowly, impurity such as not easily to go out at the shortcoming simultaneously, provides a kind of yield high, easily refine, is applicable to the preparation method of the Zaltoprofen of industrialized production.
In order to solve the problems of the technologies described above, the present invention is solved by following technical proposals:
Prepare a method for Zaltoprofen, comprise the steps:
Step a, 5-(1-propionyl)-2-thiophenyl toluylic acid is carried out rearrangement reaction when Red copper oxide makees catalyzer with iodine, triethyl orthoformate, first reaction process adopts illumination to be heated to 55 DEG C, continuous light heats, stirring reaction 2 ~ 5h;
Step b, reactor are cooled to room temperature, add sodium thiosulfate solution, continue stirring 2 ~ 5h, are extracted with ethyl acetate, combined ethyl acetate phase, and washing ethyl acetate phase, steams except ethyl acetate, obtain intermediate compound I;
Step c, in intermediate compound I, add ethanol and alkali lye, with hydrochloric acid neutralization after backflow 1 ~ 5h, reaction solution is extracted with ethyl acetate again, combined ethyl acetate phase, and washing ethyl acetate phase is dry, adds normal hexane, crystallization, obtains intermediate II;
Steps d, intermediate II, polyphosphoric acid and phosphoric acid to be mixed, be heated to 80 ~ 90 DEG C of reaction 22 ~ 26h, reactor is placed in frozen water, agitation and filtration obtains solid, then dissolves gained solid with methylene dichloride, uses sodium hydrogen carbonate solution, aqueous salt solu-tion neutral to pH successively, dry, concentrating under reduced pressure solvent to volume is 1/3 ~ 1/4 before concentrating, and cooling crystallization, filters and obtain Zaltoprofen crude product;
Step e, Zaltoprofen crude product is added methylene dichloride, heating, activated carbon decolorizing, filtered while hot, crystallization, suction filtration, obtains Zaltoprofen.
In step a, adopt illumination heating, illumination is different from traditional heating, and illumination effect provides photon, and the frequency of illumination is high, and energy is strong, and the zone of action is deep among atom, has an impact to electronics, and reduce reaction activity, reaction efficiency is high; Meanwhile, in step a, illumination heats up and iodine element is distilled as gaseous state, and gaseous iodine can contact more fully with substrate, and more thoroughly rapidly, can also reduce the impact of methyl iodide on rearrangement reaction, yield is higher in reaction.In addition, due to this reaction very exothermic, once after reaction startup, can steep temperature rise be caused, and under traditional heating condition, be difficult to lower the temperature rapidly, thus this reaction is caused to produce the reaction of a large amount of high temperature secondary and plurality of impurities.Therefore, while adopting the convenient actual large production operation of illumination heating, also add safety and reliability.
In steps d, ring-closure reaction adopts phosphoric acid to make solvent, adopts higher temperature of reaction, after having reacted, cooling and crystallize out, do not adopt normal hexane crystallization in traditional technology, decreases the removal operation of normal hexane in subsequent step, on the one hand, reduce technology difficulty, reduce workload; On the other hand, because normal hexane is difficult to remove, does not add normal hexane in operation, avoid the introducing of impurity, be conducive to the purity improving finished product.
Adopt methylene dichloride to make solvent in step e, adopt the operation of heat filtering decrease temperature crystalline, reduce the usage quantity of normal hexane, avoid the introducing of impurity, be conducive to the purity improving finished product.
As preferably, in step a, intensity of illumination is 2000 ~ 4000lx.
As preferably, in step a, illumination heating adopts infrared lamp to go deep into reaction solution to irradiate heating.
As preferably, in step b and step c, adopt massfraction be 5% ~ 10% aqueous NaCl wash ethyl acetate phase.
As preferably, alkali lye is sodium hydroxide solution or potassium hydroxide solution.
As preferably, in step c, in dry crystallization operation, adopt the mixed solution crystallization of normal hexane and ethyl acetate, the volume ratio of normal hexane and ethyl acetate is 1:(0.8 ~ 1.5).Dry crystallization operation adopts the mixed solution of normal hexane and ethyl acetate, can reduce the usage quantity of normal hexane, reduces the introduction volume being difficult to the normal hexane taken out, and is conducive to the purity improving finished product.
The present invention, owing to have employed above technical scheme, adopts illumination heating to promote that reaction is carried out, is swift in response thoroughly, decreases the impact of methyl iodide on rearrangement reaction, obtain higher yield; In addition, due to this reaction very exothermic, once after reaction startup, can steep temperature rise be caused, and under traditional heating condition, be difficult to lower the temperature rapidly, thus this reaction is caused to produce the reaction of a large amount of high temperature secondary and plurality of impurities; And while adopting illumination to heat convenient actual large production operation, also add safety and reliability; Ring-closure reaction adopts phosphoric acid to make solvent, and reacted rear direct cooling crystallization, avoid the introducing of normal hexane, impurity is few, simple to operate.Of the present inventionly prepare improving one's methods of Zaltoprofen, enormously simplify production technique, be applicable to industrialized production, meet the requirement of environmental protection.
Accompanying drawing explanation
Fig. 1 is the hydrogen spectrogram of the Zaltoprofen synthesized of improving one's methods according to Zaltoprofen of the present invention.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Embodiment 1
Prepare a method for Zaltoprofen, comprise the steps:
Step a, with 5-(1-propionyl)-2-thiophenyl toluylic acid for starting raw material, rearrangement reaction is carried out with iodine, triethyl orthoformate when Red copper oxide makees catalyzer, will with 5-(1-propionyl)-2-thiophenyl toluylic acid 1125g, iodine 1947g, triethyl orthoformate 4200ml, Red copper oxide 108g, join in there-necked flask, first illumination is adopted to be heated to 55 DEG C, continue illumination, stirring reaction 2h, wherein, illumination heating adopts 100W infrared lamp deeply to reaction solution heating, and intensity of illumination is 2000lx;
Step b, reactor are cooled to room temperature, add the sodium thiosulfate solution that massfraction is 40%, continue to stir 5h, be extracted with ethyl acetate, combined ethyl acetate phase, employing massfraction is the aqueous NaCl wash ethyl acetate phase of 26.5%, steam except ethyl acetate, obtain intermediate compound I;
Step c, in intermediate compound I, add the potassium hydroxide solution 4400mL of 4400mL ethanol and 2mol/L, neutralize with hydrochloric acid after back flow reaction 5h, reaction solution is extracted with ethyl acetate again, combined ethyl acetate phase, adopts the sodium chloride solution washing ethyl acetate phase of 26.5%, dry, add normal hexane, crystallization, obtains intermediate II 1024.9g, and yield is 91.10%;
Steps d, intermediate II 1024.9g, polyphosphoric acid 6480g and phosphoric acid 810mL to be mixed, be heated to 80 ~ 90 DEG C of reaction 26h, reactor is placed in frozen water, agitation and filtration obtains solid, then dissolves gained solid with methylene dichloride, washs to pH neutral successively with sodium hydrogen carbonate solution, 10% sodium chloride solution, dry, concentrating under reduced pressure solvent to volume is 1/4 before concentrating, and cooling crystallization, filters and obtain Zaltoprofen crude product 903.5g;
Step e, Zaltoprofen crude product is added methylene dichloride, heating, activated carbon decolorizing, filtered while hot, crystallization, suction filtration, obtains off-white color solid 797.6g, i.e. Zaltoprofen, and mass yield is 70.89%.
Embodiment 2
Prepare a method for Zaltoprofen, comprise the steps:
Step a, with 5-(1-propionyl)-2-thiophenyl toluylic acid for starting raw material, rearrangement reaction is carried out with iodine, triethyl orthoformate when Red copper oxide makees catalyzer, will with 5-(1-propionyl)-2-thiophenyl toluylic acid 1125g, iodine 1947g, triethyl orthoformate 4200ml, Red copper oxide 108g, join in there-necked flask, first illumination is adopted to be heated to 55 DEG C, continue illumination, stirring reaction 5h, wherein, illumination heating adopts 100W infrared lamp to be immersed into reaction solution heating, and intensity of illumination is 4000lx;
Step b, reactor are cooled to room temperature, add the sodium thiosulfate solution that massfraction is 40%, continue to stir 2h, be extracted with ethyl acetate, combined ethyl acetate phase, employing massfraction is the aqueous NaCl wash ethyl acetate phase of 5%, steam except ethyl acetate, obtain intermediate compound I;
Step c, in intermediate compound I, add the sodium hydroxide solution 4400mL of 4400mL ethanol and 2mol/L, neutralize with hydrochloric acid after back flow reaction 1h, reaction solution is extracted with ethyl acetate again, combined ethyl acetate phase, adopts the sodium chloride solution washing ethyl acetate phase of 10%, dry, add normal hexane, crystallization, obtains intermediate II 1029.7g, and yield is 91.53%;
Steps d, intermediate II 1029.7g, polyphosphoric acid 6518g and phosphoric acid 812.9mL to be mixed, be heated to 80 ~ 90 DEG C of reaction 22h, reactor is placed in frozen water, agitation and filtration obtains solid, then dissolves gained solid with methylene dichloride, washs to pH neutral successively with sodium hydrogen carbonate solution, 10% sodium chloride solution, dry, concentrating under reduced pressure solvent to volume is 1/4 before concentrating, and cooling crystallization, filters and obtain Zaltoprofen crude product 904.7g;
Step e, Zaltoprofen crude product is added methylene dichloride, heating, activated carbon decolorizing, filtered while hot, crystallization, suction filtration, obtains off-white color solid 800.1g, i.e. Zaltoprofen, and mass yield is 71.12%.
Embodiment 3
Prepare a method for Zaltoprofen, comprise the steps:
Step a, with 5-(1-propionyl)-2-thiophenyl toluylic acid for starting raw material, rearrangement reaction is carried out with iodine, triethyl orthoformate when Red copper oxide makees catalyzer, will with 5-(1-propionyl)-2-thiophenyl toluylic acid 1125g, iodine 1947g, triethyl orthoformate 4200ml, Red copper oxide 108g, join in there-necked flask, first illumination is adopted to be heated to 55 DEG C, continue illumination, stirring reaction 4h, wherein, illumination heating adopts 100W infrared lamp deeply to reaction solution heating, and intensity of illumination is 3000lx;
Step b, reactor are cooled to room temperature, add the sodium thiosulfate solution that massfraction is 40%, continue to stir 4h, be extracted with ethyl acetate, combined ethyl acetate phase, employing massfraction is the aqueous NaCl wash ethyl acetate phase of 15%, steam except ethyl acetate, obtain intermediate compound I;
Step c, in intermediate compound I, add the potassium hydroxide solution 4400mL of 4400mL ethanol and 2mol/L, neutralize with hydrochloric acid after back flow reaction 3h, reaction solution is extracted with ethyl acetate again, combined ethyl acetate phase, adopts the sodium chloride solution washing ethyl acetate phase of 15%, dry, add the equal-volume mixed solution of normal hexane and ethyl acetate, crystallization, obtains intermediate II 1026.9g, and yield is 91.28%;
Steps d, intermediate II 1026.9g, polyphosphoric acid 6500g and phosphoric acid 810mL to be mixed, be heated to 80 ~ 90 DEG C of reaction 24h, reactor is placed in frozen water, agitation and filtration obtains solid, then dissolves gained solid with methylene dichloride, washs to pH neutral successively with sodium hydrogen carbonate solution, 20% sodium chloride solution, dry, concentrating under reduced pressure solvent to volume is 1/4 before concentrating, and cooling crystallization, filters and obtain Zaltoprofen crude product 903.5g;
Step e, Zaltoprofen crude product is added methylene dichloride, heating, activated carbon decolorizing, filtered while hot, crystallization, suction filtration, obtains off-white color solid 797.6g, i.e. Zaltoprofen, and mass yield is 70.89%.
Embodiment 4
Embodiment 4 is identical with embodiment 3, and difference is in step c, after drying, adds the mixed solution crystallization of normal hexane and ethyl acetate, and the volume ratio of normal hexane and ethyl acetate is 1:0.8.
Embodiment 5
Embodiment 5 is identical with embodiment 3, and difference is in step c, after drying, adds the mixed solution crystallization of normal hexane and ethyl acetate, and the volume ratio of normal hexane and ethyl acetate is 1:1.5.
In a word, the foregoing is only preferred embodiment of the present invention, all equalizations done according to the present patent application the scope of the claims change and modify, and all should belong to the covering scope of patent of the present invention.
Claims (5)
1. prepare a method for Zaltoprofen, it is characterized in that, comprise the steps:
Step a, 5-(1-propionyl)-2-thiophenyl toluylic acid is made catalyzer at Red copper oxide condition under carry out rearrangement reaction with iodine, triethyl orthoformate, first reaction process adopts illumination to be heated to 55 DEG C, continuous light heats, illumination heating adopts infrared lamp deeply to reaction solution heating, stirring reaction 2 ~ 5h;
Step b, reactor are cooled to room temperature, add sodium thiosulfate solution, continue stirring 2 ~ 5h, are extracted with ethyl acetate, combined ethyl acetate phase, and washing ethyl acetate phase, steams except ethyl acetate, obtain intermediate compound I;
Step c, in intermediate compound I, add ethanol and alkali lye, with hydrochloric acid neutralization after backflow 1 ~ 5h, reaction solution is extracted with ethyl acetate again, combined ethyl acetate phase, and washing ethyl acetate phase is dry, adds normal hexane, crystallization, obtains intermediate II;
Steps d, intermediate II, polyphosphoric acid and phosphoric acid to be mixed, be heated to 80 ~ 90 DEG C of reaction 22 ~ 26h, reactor is placed in frozen water, agitation and filtration obtains solid, then dissolves gained solid with methylene dichloride, uses sodium hydrogen carbonate solution, aqueous salt solu-tion neutral to pH successively, dry, concentrating under reduced pressure solvent to volume is 1/3 ~ 1/4 before concentrating, and cooling crystallization, filters and obtain Zaltoprofen crude product;
Step e, Zaltoprofen crude product add methylene dichloride, and heating, activated carbon decolorizing, filtered while hot, crystallization, suction filtration, obtains Zaltoprofen.
2. a kind of method preparing Zaltoprofen according to claim 1, is characterized in that: in step a, and intensity of illumination is 2000 ~ 4000lx.
3. a kind of method preparing Zaltoprofen according to claim 1, is characterized in that: in step b, step c and steps d, and employing massfraction is the aqueous NaCl wash organic phase of 5% ~ 26.5%.
4. a kind of method preparing Zaltoprofen according to claim 1, is characterized in that: in step c, and alkali lye is sodium hydroxide solution or potassium hydroxide solution.
5. a kind of method preparing Zaltoprofen according to claim 1, it is characterized in that: in step c, in dry crystallization operation, adopt the mixed solution crystallization of normal hexane and ethyl acetate, the volume ratio of normal hexane and ethyl acetate is 1:(0.8 ~ 1.5).
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| CN110407804A (en) * | 2019-07-18 | 2019-11-05 | 河南后羿制药有限公司 | The cyclisation method of application and Zaltoprofen of the micro passage reaction in the cyclization reaction of Zaltoprofen |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1986542A (en) * | 2005-12-20 | 2007-06-27 | 常州市康瑞化工有限公司 | Preparing process of 2-(10-oxy-10,11-dihydrodibenz [b,f]-thiotropilium-2-yl) propionic acid |
| CN101812049A (en) * | 2009-02-19 | 2010-08-25 | 严洁 | Method for preparing zaltoprofen |
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| IT1175572B (en) * | 1984-07-13 | 1987-07-01 | Blaschim Spa | PROCEDURE FOR PREPARING ARILALCANOIC ACIDS THROUGH OXIDATIVE REARRANGEMENT OF ARILALCANONI |
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| CN1986542A (en) * | 2005-12-20 | 2007-06-27 | 常州市康瑞化工有限公司 | Preparing process of 2-(10-oxy-10,11-dihydrodibenz [b,f]-thiotropilium-2-yl) propionic acid |
| CN101812049A (en) * | 2009-02-19 | 2010-08-25 | 严洁 | Method for preparing zaltoprofen |
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