CN111960957A - Preparation method of pranlukast intermediate - Google Patents
Preparation method of pranlukast intermediate Download PDFInfo
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- CN111960957A CN111960957A CN202010943914.7A CN202010943914A CN111960957A CN 111960957 A CN111960957 A CN 111960957A CN 202010943914 A CN202010943914 A CN 202010943914A CN 111960957 A CN111960957 A CN 111960957A
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- hydroxyacetophenone
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- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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Abstract
The application relates to the field of drug synthesis, and particularly discloses a preparation method of pranlukast intermediate. The preparation method of the pranlukast intermediate comprises the following steps: 4-phenylbutoxybenzoic acid and 3-amino-2-hydroxyacetophenone are used as raw materials, a phosphotungstic acid catalyst is added into a reaction system, and amidation reaction is carried out to obtain a target product 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone. The preparation method has the advantage of environmental protection on the premise of ensuring the yield and purity of the target product.
Description
Technical Field
The application relates to the field of drug synthesis, in particular to a preparation method of pranlukast intermediate.
Background
Pranlukast is a drug for the treatment of bronchial asthma, which selectively binds and antagonizes leukotriene receptors to thereby inhibit bronchoconstriction, vascular hyperpermeability, mucosal edema and airway allergic reaction.
At present, 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone, an important intermediate of pranlukast, is generally prepared by a two-step method, 4-phenylbutoxybenzoic acid and 3-amino-2-hydroxyacetophenone are used as raw materials, and amidation reaction is carried out by the following specific reaction steps:
the 4-phenylbutoxybenzoic acid is generally activated with thionyl chloride and other active agents to form mixed acid, and then amidated with amino on the 3-amino-2-hydroxyacetophenone to obtain the target product 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone. Because the activating agent used in the two-step method is a toxic substance, the decomposition of the activating agent can generate toxic gas, which causes great pollution to the environment and limits the industrial application of the activating agent to a certain extent.
In the related art, a method for preparing 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone which is an important intermediate of pranlukast by using 4-phenylbutoxy benzoic acid and 3-amino-2-hydroxyacetophenone as raw materials through a one-step method is not reported.
Disclosure of Invention
In order to solve the problem of serious environmental pollution caused by a two-step method, the application provides a preparation method of pranlukast intermediate.
The preparation method of the pranlukast intermediate provided by the application adopts the following technical scheme:
4-phenylbutoxy benzoic acid and 3-amino-2-hydroxyacetophenone are used as raw materials to perform amidation reaction to obtain a target product 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone, and a phosphotungstic acid catalyst is added into a reaction system.
By adopting the technical scheme, the phosphotungstic acid catalyst is adopted to reduce the reaction activation energy between the 4-phenylbutoxybenzoic acid and the 3-amino-2-hydroxyacetophenone, so that the carboxyl of the 4-phenylbutoxybenzoic acid and the amino of the 3-amino-2-hydroxyacetophenone can be directly condensed, the generated byproduct is water, and meanwhile, the added catalyst is an environment-friendly catalyst, so that the environmental pollution is less. The 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone is prepared by a one-step method, the yield is more than 77%, the purity of the prepared 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone is more than 98%, and the problem of serious environmental pollution generated by the two-step method is solved while the process steps are simplified.
Preferably, the mass ratio of the 4-phenylbutoxybenzoic acid to the phosphotungstic acid catalyst in the step S1 is 1: (0.009-0.01).
By adopting the technical scheme, the phosphotungstic acid catalyst has the best catalytic effect in the range, and the yield of the target product is higher.
Preferably, the method comprises the following steps:
s1, dissolving 4-phenylbutoxybenzoic acid and 3-amino-2-hydroxyacetophenone in liquid-phase polyethylene glycol;
s2, adding a phosphotungstic acid catalyst, heating to 160 ℃ under the protection of nitrogen, and preserving heat to obtain a reaction mixture;
s3, cooling the reaction mixture to 5-10 ℃, adding ether, mixing uniformly, standing for layering, and keeping a lower polyethylene glycol layer;
s4, adding acid into the separated polyethylene glycol layer to adjust the pH value of the polyethylene glycol layer to be less than 7, separating out crystals, and separating to obtain the finished product of the 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone.
By adopting the technical scheme, the target product can be directly prepared in one step, and the used solvents are low-toxicity or non-toxic solvents, so that the problem of serious environmental pollution generated by a two-step method is solved.
Preferably, the mass ratio of the 4-phenylbutoxybenzoic acid to the 3-amino-2-hydroxyacetophenone in the step S1 is 1: (0.67-0.78).
By adopting the technical scheme, the generation of the target product can be promoted by the excessive 3-amino-2-hydroxyacetophenone, and the yield of the target product is improved.
Preferably, the mass ratio of the polyethylene glycol to the 4-phenylbutoxybenzoic acid in the step S1 is (3-4): 1.
by adopting the technical scheme, the polyethylene glycol and the phosphotungstic acid catalyst have a synergistic effect, so that the catalytic effect of phosphotungstic acid is improved, and the yield of a target product is improved.
Preferably, the reaction temperature in the step S2 is 130-140 ℃.
By adopting the technical scheme, the phosphotungstic acid catalyst has the best activity in the reaction temperature range, so that the reaction temperature range can effectively improve the yield of the target product.
Preferably, the heat preservation time in the step S2 is 6-8 h.
Through the technical scheme, the yield of the target product is obviously improved within the reaction time range, the yield of the target product is reduced below the time range, and the yield of the target product is almost unchanged above the time range.
Preferably, toluene is added in step S2 and the toluene is refluxed.
By adopting the technical scheme, the amidation reaction is a reversible reaction, and the water in the reaction can be removed in time by adopting a toluene azeotropic reflux water removal method, so that the yield and the purity of the target product 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone are increased.
Preferably, the ether layer obtained by separation in the step S3 is subjected to rotary evaporation to recover the phosphotungstic acid catalyst.
By adopting the technical scheme, the ethyl ether is removed by rotary evaporation, so that the phosphotungstic acid catalyst can be recycled, and the method is environment-friendly.
Preferably, the 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone in step S4 is washed and purified to obtain a finished product.
By adopting the technical scheme, the purity of the 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone can be improved by purifying the crude product in the step S4.
In summary, the present application has the following beneficial effects:
1. according to the method, the phosphotungstic acid catalyst is adopted to reduce the reaction activity of 4-phenylbutoxybenzoic acid and 3-amino-2-hydroxyacetophenone, so that the activation energy of amidation reaction is reduced, direct condensation can be realized, and the generated byproduct is water, thereby solving the problem of serious environmental pollution in the two-step synthesis process.
2. The application preferably adopts polyethylene glycol as a solvent and polyethylene glycol as a catalyst promoter of phosphotungstic acid, effectively reduces the reaction activity in the catalysis of phosphotungstic acid, improves the reaction yield and has a synergistic effect.
Detailed Description
3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone is an important intermediate in the pranlukast synthesis process. The synthesis principle of 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone is that 4-phenylbutoxybenzoic acid and 3-amino-2-hydroxyacetophenone are used as raw materials to carry out amidation reaction, but because the direct amidation of carboxylic acid and amino is difficult, the reaction is generally carried out by adopting a two-step method, namely, an active agent is added firstly to carry out activation, and then amidation is carried out. The activating agent usually adopts thionyl chloride and the like which have high toxicity, generate more byproducts and cause serious pollution to the environment.
Based on the situation, the method aims to add a green and environment-friendly phosphotungstic acid catalyst into a reaction system, reduce the activation energy required by amidation reaction, complete the reaction in one step on the premise of ensuring the yield and purity of a target product 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone, ensure that the phosphotungstic acid catalyst does not react with reactants in the reaction system, generate water as a byproduct, and solve the problem of environmental pollution generated by a two-step method.
In addition, the solvents of polyethylene glycol and phosphotungstic acid used in the method are green, environment-friendly and low-toxicity substances, and can be safely discharged in industrial production.
Meanwhile, the phosphotungstic acid catalyst is dissolved in the ether layer, and after the ether is removed by rotary evaporation, the phosphotungstic acid catalyst is easy to recycle.
Examples
Example 1
A preparation method of pranlukast intermediate, comprising the following steps:
s1, weighing 100g of 4-phenylbutoxybenzoic acid, putting the 4-phenylbutoxybenzoic acid into a three-neck flask with the capacity of 1L, adding 3-amino-2-hydroxyacetophenone, wherein the mass ratio of the 4-phenylbutoxybenzoic acid to the 3-amino-2-hydroxyacetophenone is 1:0.56, and adding 200g of polyethylene glycol-400 for dissolving;
s2, adding a phosphotungstic acid catalyst, wherein the mass ratio of the added phosphotungstic acid catalyst to the 4-phenylbutoxy benzoic acid is 0.008: 1, stirring and uniformly mixing, heating to 150 ℃ under the protection of nitrogen, and carrying out heat preservation reaction for 10 hours;
s3, after the reaction is finished, cooling to 8 ℃, adding 400mL of diethyl ether for extraction, standing for layering, retaining a lower polyethylene glycol layer, performing rotary evaporation on a separated upper diethyl ether layer, and recovering a phosphotungstic acid catalyst;
s4, adding dilute nitric acid with the concentration of 0.05 wt% into the polyethylene glycol layer to adjust the pH value of the solution to 6.5, and performing suction filtration to separate a precipitated crude product;
s5, adding 500mL of distilled water to the crude product, washing, and filtering to obtain 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone.
Examples 2 to 10
Examples 2 to 10 each relate to a method for preparing a pranlukast intermediate, based on example 1, with the difference that: the mass ratio of the 4-phenylbutoxy benzoic acid to the phosphotungstic acid catalyst, the mass ratio of the 4-phenylbutoxy benzoic acid to the 3-amino-2-hydroxyacetophenone, and the mass ratio of the polyethylene glycol to the 4-phenylbutoxy benzoic acid in the step S1 are different, and specific numerical values are shown in the following table:
table 1 specific values of the mass ratio of 4-phenylbutoxy benzoic acid to phosphotungstic acid catalyst, the mass ratio of 4-phenylbutoxy benzoic acid to 3-amino-2-hydroxyacetophenone, and the mass ratio of polyethylene glycol to 4-phenylbutoxy benzoic acid:
examples 11 to 18
Examples 11 to 18 all relate to a process for the preparation of a pranlukast intermediate, based on example 10, with the following differences: the reaction temperature and the reaction time in step S2 were varied, and the specific values are shown in the following table:
table 2 reaction temperature and reaction time in step S2:
example 19
Example 19 relates to a process for the preparation of pranlukast intermediate, based on example 18, with the following differences: in step S2, 300mL of toluene was added to the three-necked flask, a water separator was connected between the condenser and the three-necked flask, and water generated by the reaction was removed by azeotropic distillation of toluene with water during heating.
Comparative example
Comparative example 1
A preparation method of pranlukast intermediate, based on example 1, with the difference that: in step S1, a phosphotungstic acid catalyst is not added, and in step S1, polyethylene glycol is added and replaced by toluene with equal mass.
Comparative example 2
A preparation method of pranlukast intermediate, based on example 1, with the difference that: in step S1, a phosphotungstic acid catalyst is not added.
Comparative example 3
A preparation method of pranlukast intermediate, based on example 1, with the difference that: the polyethylene glycol added in step S1 was replaced with an equal volume of toluene.
Comparative example 4
A preparation method of pranlukast intermediate, based on example 1, with the difference that: the phosphotungstic acid catalyst added in the step S1 is replaced by phenylboronic acid with equal mass.
Comparative example 5
A preparation method of pranlukast intermediate, comprising the following steps:
p1, adding 100g of 4-phenylbutoxybenzoic acid into a three-neck flask with the capacity of 1L, adding 100g of thionyl chloride, keeping the temperature at 50 ℃ for reaction for 3 hours, recovering thionyl chloride under reduced pressure after the reaction is finished, introducing nitrogen into the three-neck flask to blow off the thionyl chloride, cooling to room temperature, and adding 100g of dichloromethane to prepare a standby solution;
p2, adding 100g of 3-amino-2-hydroxyacetophenone into another 1L three-neck flask, adding 150g of dichloromethane for dissolution, adding 110g of pyridine, dropwise adding the standby liquid at 0 ℃, wherein the dropwise adding speed is 1d/s, the dropwise adding temperature is not more than 10 ℃ in the dropwise adding process, after the dropwise adding is finished, keeping the temperature at 10 ℃ for reaction for 2 hours;
and P3, after the reaction is finished, adding 0.05 wt% of dilute nitric acid into the reaction system to adjust the pH value of the solution to 2-3, separating, washing a dichloromethane layer to be neutral, drying the dichloromethane layer by using anhydrous sodium sulfate, filtering, evaporating and concentrating to obtain a reddish brown solid, and recrystallizing ethyl acetate to obtain the target product 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone.
The specifications and production locations of the raw materials in examples 1 to 19 and comparative examples 1 to 5 are shown in the following table:
TABLE 3 raw material specifications and production locations in examples 1-19 and comparative examples 1-5:
performance test
1. Yield: the mass of the target product 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone of high purity obtained after the washing and the total mass of the reactants 4-phenylbutoxy benzoic acid and 3-amino-2-hydroxyacetophenone were calculated according to the following formula:
2. purity: purity check was performed on HPLC instruments.
The result of the detection
The yield and purity test data for comparative examples 1-5 and examples 1-19 are as follows:
TABLE 4 yield and purity of comparative examples 1-5 and examples 1-19:
combining example 1 and comparative example 1 and table 4, it can be seen that the yield of the target product can be significantly improved by using phosphotungstic acid as a catalyst and polyethylene glycol as a solvent.
Combining example 1 and comparative examples 2-4 and table 4, it can be seen that the polyethylene glycol and phosphotungstic acid catalysts have a synergistic effect.
As can be seen by combining example 19 with comparative example 5 and by combining Table 4, the preparation of example 19 gives a higher yield and purity of the product than the preparation of activation followed by amidation.
Example 19 is the best method of preparation, as can be seen by combining examples 1-19 with table 4.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A preparation method of pranlukast intermediate takes 4-phenylbutoxybenzoic acid and 3-amino-2-hydroxyacetophenone as raw materials to perform amidation reaction to obtain a target product 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone, and is characterized in that: adding a phosphotungstic acid catalyst into a reaction system.
2. The method for preparing pranlukast intermediate according to claim 1, characterized in that: the mass ratio of the 4-phenylbutyloxybenzoic acid to the phosphotungstic acid catalyst is 1: (0.009-0.01).
3. The method for preparing pranlukast intermediate according to claim 1 or 2, characterized in that: the method comprises the following steps:
s1, dissolving 4-phenylbutoxybenzoic acid and 3-amino-2-hydroxyacetophenone in liquid-phase polyethylene glycol;
s2, adding a phosphotungstic acid catalyst, heating to 160 ℃ under the protection of nitrogen, and preserving heat to obtain a reaction mixture;
s3, cooling the reaction mixture to 5-10 ℃, adding ether, mixing uniformly, standing for layering, and keeping a lower polyethylene glycol layer;
s4, adding acid into the separated polyethylene glycol layer to adjust the pH value of the polyethylene glycol layer to be less than 7, separating out crystals, and separating to obtain the 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone.
4. The method for preparing pranlukast intermediate according to claim 3, characterized in that: in the step S1, the mass ratio of 4-phenylbutoxybenzoic acid to 3-amino-2-hydroxyacetophenone is 1: (0.67-0.78).
5. The method for preparing pranlukast intermediate according to claim 4, characterized in that: the mass ratio of the polyethylene glycol to the 4-phenylbutoxybenzoic acid in the step S1 is (3-4): 1.
6. the method for preparing pranlukast intermediate according to claim 5, characterized in that: the reaction temperature in the step S2 is 130-140 ℃.
7. The method for preparing pranlukast intermediate according to claim 6, characterized in that: the heat preservation time in the step S2 is 6-8 h.
8. The method for preparing pranlukast intermediate according to claim 7, characterized in that: toluene was added in step S2, and the toluene was refluxed.
9. The method for preparing pranlukast intermediate according to claim 1, characterized in that: and (4) rotationally evaporating the ether layer separated in the step S3, and recovering the phosphotungstic acid catalyst.
10. The method for preparing pranlukast intermediate according to claim 1, characterized in that: and (3) washing and purifying the 3- [4- (4-phenylbutoxy) benzoylamino ] -2-hydroxyacetophenone in the step S4 to obtain a finished product.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| WO2010002075A1 (en) * | 2008-07-02 | 2010-01-07 | Pharmacostech Co., Ltd. | Methods for preparing amide derivatives |
| CN106588897A (en) * | 2017-02-28 | 2017-04-26 | 上海微巨实业有限公司 | New preparation method of Pranlukast |
| CN110452160A (en) * | 2019-09-26 | 2019-11-15 | 江苏欣舟化工科技有限公司 | The preparation method of bis- (2,2,6,6- tetramethyl -4- the piperidyl) -1,3- benzenedicarboxamides of N, N ' - |
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- 2020-09-09 CN CN202010943914.7A patent/CN111960957A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010002075A1 (en) * | 2008-07-02 | 2010-01-07 | Pharmacostech Co., Ltd. | Methods for preparing amide derivatives |
| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| CN106588897A (en) * | 2017-02-28 | 2017-04-26 | 上海微巨实业有限公司 | New preparation method of Pranlukast |
| CN110452160A (en) * | 2019-09-26 | 2019-11-15 | 江苏欣舟化工科技有限公司 | The preparation method of bis- (2,2,6,6- tetramethyl -4- the piperidyl) -1,3- benzenedicarboxamides of N, N ' - |
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