CN102952111A - Method for synthesizing Naproxen ketal intermediate compound through steam penetration and coupling technology - Google Patents
Method for synthesizing Naproxen ketal intermediate compound through steam penetration and coupling technology Download PDFInfo
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Abstract
The invention provides a method for synthesizing a Naproxen ketal intermediate compound through a steam penetration and coupling technology. According to the method, a steam penetration membrane device and a ketal reaction process are coupled, and a steam penetration membrane separation technology is utilized to remove the byproduct water in the synthesis reaction system of the Naproxen ketal intermediate compound, thereby upsetting the reaction balance and improving the reaction conversion rate. According to the method, the steam penetration membrane device and a reactor separately works, so that the reaction can be performed at the optimal reaction temperature, thereby eliminating the influence on the separation temperature, enhancing the reaction selectivity and improving the yield. The method provided by the invention can reduce the energy consumption in the synthesis process and obviously improve the reaction yield, thereby improving the utilization efficiency of raw materials.
Description
Technical field
The present invention relates to a kind of novel methodology of organic synthesis, be specifically related to utilize membrane reactor to carry out the synthetic of Naproxen Base ketal intermediate.
Technical background
Naproxen Base is one of the most effective non-steroid antiinflammatory drug, especially a kind of antipyretic-antalgic, anti-inflammatory and antiheumatic basic chemicals.Naproxen Base is usually used in the treatment of rheumatic and rheumatoid arthritis, also is used for the treatment of the chronic disease sex change disease of osteoarthritis, ankylosing spondylitis, gout, motor system and light, moderate pain etc.
Synthetic main 1, the 2-aryl tropic rearrangement method that adopts of domestic industrialized Naproxen Base, the method be raw material first through halogenation, by the synthetic route of ketal, this processing method technique is simple, yield is high, therefore becomes the main technique of producing Naproxen Base.
In the method, the synthetic of ketal intermediate is a step crucial in the whole synthesis step.Its building-up reactions equation as shown in Figure 1.Wherein, reactant is 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene and neopentyl glycol, take tosic acid as catalyzer; toluene is solvent; the product that generates be 2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5,5-dimethyl-1,3-dioxane and water.In reaction, except generating target ketal product, generated simultaneously water byproduct.Naproxen Base ketal intermediate building-up reactions equation is as follows:
In the traditional synthesis, for improving the transformation efficiency of reaction, adopt the heating feed liquid by the water trap reflux dewatering, the water byproduct in the reaction is removed, break molecular balance, reaction is carried out to the direction that generates the ketal product.But the power consumption of this technique is huge, in order to remove the water of minute quantity, and needs the whole feed liquids of distillation, has increased production cost; And temperature of reaction can only be confined to be with water temp, i.e. the boiling point of azeotropic system, but this temperature is generally, is not the optimum temps of reaction.For overcoming the above problems, the present invention utilizes water vapour penetration technology and the synthetic Naproxen Base ketal intermediate of the mode of reaction coupling.
Water vapour penetration is take steam as charge raw material, under the poor promotion of each component vapor partial pressure of mixture, utilizes each component to dissolve different with diffusion in film, thereby realizes the mixture separation process.The water vapour penetration technology is having its unique advantage aspect the separation of constant boiling point system, nearly boiling point system and isomers.Simultaneously, can also be coupled with biology and chemical reaction, the micromolecular compound that generates in the reaction is constantly removed, reaction is moved to the goal response direction, transformation efficiency obviously improves.It is technical and economy is with the obvious advantage, has broad application prospects in the industrial circles such as petrochemical complex, medicine, food, environmental protection.
Document 1: Hu Aixi, Yuan Shuai, the king deposits the lady in the moon, and Cao Sheng spring .2-haloethyl-2-(6-methoxyl group-2-naphthyl)-4-methyl isophthalic acid, 3-dioxolane reset synthetic racemic modification Naproxen Base [J]. applied chemistry, 2002,19 (2): 149-152.Synthetic 1, the 2-aryl tropic rearrangement method that adopts of Naproxen Base in ketal reaction, in order to improve the transformation efficiency of reaction, adopts reflux band water in the literary composition, through water trap water byproduct is separated and removes.
Document 2:Benedict D J, Parulekar S J, Tsai S P Pervaporation-assisted esterification of lactic and succinic acids with downstream ester recovery[J] .Journal of Membrane Science, 2006,281,435-445. adopt Pervaporation Technology in the literary composition, utilize the esterification of the auxiliary ethyl succinate of Pervaporation membrane reactor and ethyl lactate synthetic, remove the water that generates in the reaction system, break molecular balance and move to the direction that generates ester.Successful realization in the membrane reactor with the coupling of reaction, improved the transformation efficiency of reaction.
The water vapour penetration coupling technique is that membrane module is coupled in the reaction process, and breaks molecular balance to obtain novel, the high efficiency reactor of higher yield and speed of reaction by infiltration evaporation.It integrates reaction and separation processes, and not only energy efficient can also improve reaction yield, Reaction time shorten.Than traditional rectifying obvious economic advantages are arranged.But utilize at present the synthetic Naproxen Base ketal intermediate of water vapour penetration coupling technique to yet there are no bibliographical information.
Summary of the invention
The object of the present invention is to provide a kind of method of utilizing the synthetic Naproxen Base ketal intermediate of water vapour penetration coupling technique.Namely utilizing air lift that the material in the ketal reaction system is brought to membrane separation apparatus separates, make water vapour penetration process and reaction coupling, remove Trace water in the reaction system, therefore reaction and separate all and can carry out under its suitableeest Parameter Conditions has solved the problem that the intermediates of naproxen productive rate is low, cost is high.
The centrifugation of vapor permeable membrane is because film has the selection perviousness to material, utilize this technique original position to remove Trace water in the reaction solution, be that a small amount of removing substances is vaporized at the film rear side, avoided in the distillation band water conservancy project skill feed liquid integral body being distilled, technique is more energy-conservation.
Utilize the concrete preparation method of the synthetic intermediates of naproxen of water vapour penetration coupling ketal reaction as follows:
A. be 1-0.25 with raw material 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene and neopentyl glycol according to mol ratio: 1 adds in the reactor, adds the Catalyzed by p-Toluenesulfonic Acid agent, adds toluene solvant again; The material in reactor temperature is controlled at 60-100 ℃, opens stirring, dissolve the formation homogeneous system fully to material; The add-on of tosic acid is the 1-10% of 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene quality; Wherein the add-on of toluene solvant be reactor Raw total mass 8-10 doubly.
B. reactor and vapor permeable membrane device are connected into the loop, gas can be circulated in two equipment; When steps A begins to react, with gas pump the steam in the reactor is delivered to the vapor permeable membrane device, the circulation velocity of control gas is 6-30L/h, the vacuum pump of opening again the film rear side makes the film front and back produce pressure reduction, film rear side vacuum tightness is between the 30-50kPa, permeable membrane separates the moisture in the circulation gas, and the water that is penetrated into the film rear side is discharged by vacuum system; The not separated gas in film front side passes through in the Returning reactor of loop; Circulation 4-12 hour stopped reaction like this.Wherein the working temperature of vapor permeable membrane device remains on 50-70 ℃.
Used permeable membrane is comprised of supporting layer and separating layer, and the material of supporting layer can be polysulfones, polyethersulfone, tetrafluoroethylene, polyvinylidene difluoride (PVDF) or Mierocrystalline cellulose; Described separating layer can be polyvinyl alcohol, chitosan, sodium alginate or inorganic zeolite.Permeable membrane has stronger water separation capability, and it is fixed on by tightness systems such as wear ring, packing rings and steams in the permeable membrane device.
Whole device relies on the water vapour penetration composite membrane to the selection perviousness of water, and the water in the reaction system is constantly separated, and the chemical equilibrium of reaction is constantly carried out to the direction that generates the ketal product.
After reaction finishes, take a sample by thief hole, utilize efficient liquid phase chromatographic analysis, productive rate reaches 50-85%.
Water vapour penetration coupling device of the present invention is as shown in Figure 1: major parts is ketal reaction device (1), it is furnished with agitator (2), and reactor links and consist of the loop of a closure by gas recycle pump (3) and water vapour penetration film device (6).Be provided with vapor permeable membrane (5) in the vapor permeable membrane apparatus (6), vapor permeable membrane apparatus (6) is connected with vacuum system (7).
The invention has the beneficial effects as follows:
1. utilize the water vapour penetration coupling device, can original position remove the water that produces in the ketal reaction, break the original chemical equilibrium of reaction, improved the transformation efficiency of reaction, and because in time removing of water reduced the side reaction in the system, improved simultaneously productive rate.
2. vapor permeable membrane has high selectivity, only has component to be separated to pass through in a large number, and other materials then are trapped, its main energy consumption is the latent heat of vaporization in the penetrant process of osmosis, so the power consumption of water vapour penetration process is few, has greatly reduced and has produced power consumption, thereby the saving cost, save energy.
3. reaction of the present invention-separation coupling equipment separates sepn process and reaction process, thereby makes the not restriction of the factors such as boiling point of tape aqua of temperature of reaction, and ketal reaction is carried out being lower than under boiling point, the only temperature of reaction.
Description of drawings
Fig. 1 is water vapour penetration coupling device synoptic diagram: wherein: (1) reactor; (2) agitator; (3) gas recycle pump; (4) under meter; (5) vapor permeable membrane; (6) vapor permeable membrane apparatus; (7) vacuum system.
Embodiment
Embodiment 1
Adopt water vapour penetration coupling device as shown in Figure 1, and take polyvinyl alcohol/polyethersulfone composite membrane as the water vapour penetration separatory membrane, its membrane area is 19.63cm
2
Adding 4.9g 6-methoxyl group-2-in reactor (2 '-the bromine propionyl) naphthalene, 2.6g neopentyl glycol, 0.34g tosic acid, 52mL toluene.Open heating and temperature controlling device and make the interior temperature of charge of reactor remain on 80 ℃, open agitator, open simultaneously gas recycle pump, the adjustments of gas circulation velocity is 30L/h.Open vacuum pump, keep film rear side vacuum tightness 30kPa, the temperature in the film device is made as 60 ℃, reacted 12 hours.From feed liquid, take a sample, utilize high performance liquid chromatography that the intermediates of naproxen productive rate is analyzed.The transformation efficiency of 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene be 83%, 2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5,5-dimethyl-1,3-dioxane productive rate is 78%.
Under similarity condition; do not adopt the mode of coupling dehydration to compare reaction experiment; the transformation efficiency of 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene is 23%; 2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5; 5-dimethyl-1, the productive rate of 3-dioxane are 20%.
As can be seen from the above data, the transformation efficiency of coupling experiment is higher than the not transformation efficiency of coupling experiment far away, utilizes the synthetic effect of water vapour penetration coupling Naproxen Base ketal reaction good, and good using value is arranged.
Embodiment 2
Test used separatory membrane, medicine with example 1, temperature of reaction is 70 ℃, and other operate with embodiment 1, and reaction utilizes high performance liquid chromatography that the intermediates of naproxen productive rate is analyzed after finishing.The transformation efficiency of 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene is 77%, 2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5,5-dimethyl-1, and the productive rate of 3-dioxane is 69%.
Under similarity condition; do not adopt the mode of coupling dehydration to compare reaction experiment; the transformation efficiency of 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene is 18%; 2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5; 5-dimethyl-1, the productive rate of 3-dioxane are 12%.
Embodiment 3
Test used separatory membrane and catalyst content with example 1, adding 4.9g 6-methoxyl group-2-in reactor (2 '-the bromine propionyl) naphthalene, 1.74g neopentyl glycol, 0.34g tosic acid.Other operations are with embodiment 1, and reaction utilizes high performance liquid chromatography that the intermediates of naproxen productive rate is analyzed after finishing.2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5,5-dimethyl-1, the productive rate of 3-dioxane are 57%.
Under similarity condition, do not adopt the mode of coupling dehydration to compare reaction experiment, 2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5,5-dimethyl-1, the productive rate of 3-dioxane are 10%.
Embodiment 4
Test used separatory membrane and raw material add-on with example 1, add the quality 0.44g of catalyzer, other operate with embodiment 1, and reaction utilizes high performance liquid chromatography that the intermediates of naproxen productive rate is analyzed after finishing.2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5,5-dimethyl-1, the productive rate of 3-dioxane are 82%.
Under similarity condition, do not adopt the mode of coupling dehydration to compare reaction experiment, 2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5,5-dimethyl-1, the productive rate of 3-dioxane are 18%.
Embodiment 5
Test used separatory membrane, raw material add-on and catalyzer add-on with example 1, the gas circulation flow velocity is 6L/h, and other operate with embodiment 1, and reaction utilizes high performance liquid chromatography that the intermediates of naproxen productive rate is analyzed after finishing.2-(1 '-bromotrifluoromethane)-2-(6 '-methoxyl group-2 '-naphthyl)-5,5-dimethyl-1, the productive rate of 3-dioxane are 54%.
Claims (3)
1. method of utilizing the synthetic Naproxen Base ketal intermediate of water vapour penetration coupling technique, concrete steps are as follows:
A. be 1-0.25 with raw material 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene and neopentyl glycol according to mol ratio: 1 adds in the reactor, adds the Catalyzed by p-Toluenesulfonic Acid agent, adds toluene solvant again; The material in reactor temperature is controlled at 60-100 ℃, opens stirring, dissolve the formation homogeneous system fully to material; The add-on of tosic acid is the 1-10% of 6-methoxyl group-2-(2 '-bromine propionyl) naphthalene quality; Wherein the add-on of toluene solvant be reactor Raw total mass 8-10 doubly;
B. reactor and vapor permeable membrane device are connected into the loop, gas can be circulated in two equipment; When steps A begins to react, with gas pump the steam in the reactor is delivered to the vapor permeable membrane device, the circulation velocity of control gas is 6-30L/h, the vacuum pump of opening again the film rear side makes the film front and back produce pressure reduction, film rear side vacuum tightness is between the 30-50kPa, permeable membrane separates the moisture in the circulation gas, and the water that is penetrated into the film rear side is discharged by vacuum system; The not separated gas in film front side passes through in the Returning reactor of loop; Circulation 4-12 hour stopped reaction like this; Permeable membrane used in the vapor permeable membrane device is comprised of supporting layer and separating layer.
2. the method for utilizing the synthetic Naproxen Base ketal intermediate of water vapour penetration coupling technique according to claim 1 is characterized in that the working temperature of the described vapor permeable membrane device of step B remains on 50-70 ℃.
3. the method for utilizing the synthetic Naproxen Base ketal intermediate of water vapour penetration coupling technique according to claim 1, the supporting layer that it is characterized in that the described vapor permeable membrane of step B is polysulfones, polyethersulfone, tetrafluoroethylene, polyvinylidene difluoride (PVDF) or Mierocrystalline cellulose; Described separating layer is polyvinyl alcohol, chitosan, sodium alginate or inorganic zeolite.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101139290A (en) * | 2007-09-14 | 2008-03-12 | 浙江工商大学 | Method for producing vitamin C by esterification reaction-infiltration evaporation barrier separation integral process |
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| CN101139290A (en) * | 2007-09-14 | 2008-03-12 | 浙江工商大学 | Method for producing vitamin C by esterification reaction-infiltration evaporation barrier separation integral process |
Non-Patent Citations (5)
| Title |
|---|
| DANIEL J. BENEDICT ET AL.: "Pervaporation-assisted esterification of lactic and succinic acids with downstream ester recovery", 《JOURNAL OF MEMBRANE SCIENCE》 * |
| 李洪亮等: "蒸汽渗透技术及其应用", 《膜科学与技术》 * |
| 熊贤强等: "DL-萘普生合成工艺研究", 《中国医药工业杂志》 * |
| 胡艾希等: "2-卤乙基-2-( 6 -甲氧基-2 -萘基) -4-甲基-1, 3-二氧杂环戊烷重排合成外消旋体萘普生", 《应用化学》, vol. 19, no. 2, 28 February 2002 (2002-02-28), pages 149 - 152 * |
| 胡艾希等: "2-卤乙基-2-( 6-甲氧基-2-萘基) -4-甲基-1, 3-二氧杂环戊烷重排合成外消旋体萘普生", 《应用化学》 * |
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