CN113979960B - Preparation method of bilastine intermediate - Google Patents
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- CN113979960B CN113979960B CN202111607486.1A CN202111607486A CN113979960B CN 113979960 B CN113979960 B CN 113979960B CN 202111607486 A CN202111607486 A CN 202111607486A CN 113979960 B CN113979960 B CN 113979960B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Abstract
The invention relates to the technical field of medicine preparation, in particular to a preparation method of a bilastine intermediate, which comprises the following steps in sequence: mixing and stirring a compound 7, dichloromethane and anhydrous aluminum trichloride, then dropwise adding a compound 1, mixing and stirring a product after reaction with trifluoroacetic acid, then adding triethylsilane, mixing and stirring a product after the mixture is heated and reacted with DMSO and water, mixing and stirring the product after the mixture is heated and reacted with 2-amino-2-methylpropane-1-ol and toluene, heating and stirring for reaction to obtain a white-like solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol, and finally reacting with p-toluenesulfonyl chloride to obtain a bilastine intermediate final product; the preparation method has the advantages of simple operation, mild reaction conditions, easy purification of the intermediate, reduction of three wastes and reduction of industrial cost.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method of a bilastine intermediate.
Background
Bilastine (Bilastine) is a 2 nd generation antihistamine developed by the pharmaceutical company Spanish FASE, and inhibits the release of histamine and IL-4 from mast cell nuclei and peripheral granulocytes in addition to its antagonistic effect on the H1 histamine receptor. Is suitable for symptomatic treatment of seasonal or perennial allergic rhinoconjunctivitis and urticaria. The chemical name of Bilastine (Bilastine) is: 2- [4- [2- [4- [1- (2-ethoxyethyl) -1H-benzo [ d ] imidazol-2-yl ] piperidin-1-yl ] ethyl ] phenyl ] -2-methylpropionic acid having the formula:
according to literature investigations, the synthesis of bilastine requires the following intermediates:
wherein the compound II is 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate, and the synthetic route reported in the literature mainly comprises the following components:
the synthesis methods reported in patents US5877187 and ES2151442 are as follows:
the method comprises the steps of taking 4-bromobenzoate methyl ester as a raw material, firstly reacting with methyl iodide to generate a compound 9, then hydrolyzing with NaOH to generate a compound 10, reacting with thionyl chloride to generate an acyl chloride intermediate state, then reacting with 2-amino-2-methylpropane-1-ol to form amide, dehydrating and closing a ring to generate a compound 11, using n-butyl lithium to extract bromine from the compound 11 and reacting with ethylene oxide at low temperature to generate a compound 5, and reacting the compound 5 with p-toluenesulfonyl chloride to obtain a compound 6, namely 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate. Thionyl chloride is used twice in the synthesis of the compound 11 in the route, a large amount of waste acid and waste gas are generated, the operation is complex, and side reactions are more; the compound 5 needs ultralow temperature, no water and no oxygen in the synthesis process, and the ethylene oxide is a flammable and explosive toxic carcinogen, has low boiling point, is volatile, has harsh reaction conditions, complex operation, more side reactions and lower overall yield, and is not suitable for the requirement of industrial production.
In order to solve the problems of difficult operation, large three wastes and low yield of the existing 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate and simultaneously avoid using a dangerous reagent ethylene oxide, the invention aims to provide a novel preparation method of a bilastine intermediate, which has the advantages of cheap and easily obtained raw materials, no dangerous reagent, reduced by-products, reduced production cost, simple and convenient operation and easy industrial production.
Disclosure of Invention
The purpose of the invention is: overcomes the defects in the prior art, and provides a preparation method of the bilastine intermediate, which has the advantages of cheap and easily obtained raw materials, no dangerous reagent, less by-products, low production cost and easy industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for preparing a bilastine intermediate, comprising the steps of:
wherein X is a chloro or bromo leaving group;
r is methyl, ethyl, isopropyl or n-propyl.
Further, the specific steps in the step 1 are as follows: mixing and stirring the compound 7, dichloromethane and anhydrous aluminum trichloride, then dropwise adding the compound 1, and stirring and reacting the mixture after dropwise adding; the reaction solution is post-treated and concentrated to obtain yellow oily 2- (4- (2-halogenated acetyl) phenyl) -2-methyl propionate, namely the compound 2.
Further, the mole ratio of the compound 1, the compound 7 and the anhydrous aluminum trichloride in the step 1 is 1: 1.5-2.5: 1.1-1.2.
Further, the specific steps in the step 2 are as follows: and mixing and stirring the compound 2 and trifluoroacetic acid, adding triethylsilane, heating and stirring the mixture for reaction, carrying out post-treatment and concentration on the reaction solution to obtain a yellow oily 2- (4- (2-halogenated ethyl) phenyl) -2-methylpropionate, namely a compound 3, wherein the molar ratio of the compound 2, the trifluoroacetic acid to the triethylsilane is 1: 6-8: 3-4.
Further, the specific steps in step 3 are as follows: and mixing and stirring the compound 3, DMSO and water, heating to 150 ℃, stirring for reaction, and concentrating a post-treated organic phase after the reaction is finished until the organic phase is dried to obtain a light yellow oily 2- (4- (2-hydroxyethyl) phenyl) -2-methyl propionate, namely a compound 4.
Further, the volume ratio of the compound 3 to the DMSO to the water is 1: 3-4.
Further, the specific steps in the step 4 are as follows: mixing the compound 4, 2-amino-2-methylpropane-1-alcohol and toluene, heating and stirring for reaction, then configuring a water separator, heating to reflux and stirring, adding toluene while dividing water until the total solvent amount is constant, treating and concentrating after the reaction is finished to obtain a white solid, and recrystallizing the solid by using a mixed solvent of ethanol and water to obtain the white solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol.
Further, the molar ratio of the compound 4 to the 2-amino-2-methylpropane-1-ol is 1: 1.5-3.
Further, the specific steps in the step 5 are as follows: dissolving the solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol obtained in the step 4 in dichloromethane, adding triethylamine, then adding p-toluenesulfonyl chloride in batches, stirring for reaction, carrying out post-treatment and concentration on the reaction liquid after the reaction is finished to obtain a light yellow solid, and recrystallizing the solid by using isopropanol to obtain a white-like solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate.
Further, in the step 5, the molar ratio of the 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol, the triethylamine and the p-toluenesulfonyl chloride is 1: 1.3-1.5: 1.1-1.2.
The technical scheme adopted by the invention has the beneficial effects that:
the invention has the technical effects and advantages that: the preparation method has the advantages of simple operation, mild reaction conditions, easy purification of the intermediate, reduction of three wastes and reduction of industrial cost.
The preparation method disclosed by the invention avoids the use of toxic substances such as methyl iodide, ethylene oxide and the like, is mild in reaction conditions, safer to operate, free of thionyl chloride, simple to operate, less in side reaction and suitable for industrial production, and avoids the generation of a large amount of waste acid and waste gas.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum (DMSO) of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol prepared by the present invention;
FIG. 2 is a mass spectrum of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol prepared by the present invention;
FIG. 3 is a nuclear magnetic hydrogen spectrum (DMSO) of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate made in accordance with the present invention;
FIG. 4 is a mass spectrum of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate made in accordance with the present invention.
Detailed Description
The following will further describe a preparation method of a bilastine intermediate in the present invention with reference to specific embodiments.
The specific compound name of the bilastine intermediate in the invention is as follows: 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate.
The novel preparation method of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate according to the present invention has the following preparation scheme:
wherein X is a chloro or bromo leaving group;
r is methyl or ethyl;
the method comprises the following steps in sequence:
1. and mixing and stirring the compound 7, dichloromethane and anhydrous aluminum trichloride, then dropwise adding the compound 1, and stirring and reacting the mixture after dropwise adding. After the reaction, water was added to quench the reaction. Washing organic phase with water and NaHCO3Washing the solution, and concentrating an organic phase to obtain a yellow oily substance 2- (4- (2-halogenated acetyl) phenyl) -2-methyl propionate, namely a compound 2;
2. mixing the compound 2 obtained in the above step with trifluoroacetic acid, stirring, adding triethylsilane, and mixingThe mixture is heated and stirred for reaction, and water is added for quenching the reaction after the reaction is finished. Extraction with dichloromethane, washing of the organic phase with water and NaHCO3Washing the solution, and concentrating to obtain yellow oily 2- (4- (2-halogenated ethyl) phenyl) -2-methyl propionate, namely a compound 3;
3. mixing and stirring the compound 3 obtained in the step, DMSO and water, heating to 150 ℃, stirring for reaction, cooling after the reaction is finished, adding water into the reaction liquid for dilution, extracting by using ethyl acetate, washing the organic phase by using water, washing the organic phase by using salt water, and concentrating the organic phase to be dry to obtain light yellow oily 2- (4- (2-hydroxyethyl) phenyl) -2-methyl propionate, namely a compound 4;
4. mixing the compound 4 obtained in the above steps, 2-amino-2-methylpropane-1-ol and toluene, heating and stirring for reaction, then configuring a water separator, heating to reflux and stirring, adding toluene while dividing water until the total solvent amount is constant, cooling after the reaction is finished, adding water to quench and react, standing and layering, and using NaHCO to react an organic phase3Washing the solution, washing with saturated brine, drying the organic phase, filtering, concentrating to obtain a white-like solid, and recrystallizing the solid with a mixed solvent of ethanol and water to obtain a white-like solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl]Phenyl ethyl alcohol;
5. dissolving the solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol obtained in the step in dichloromethane, adding triethylamine, adding p-toluenesulfonyl chloride in batches, stirring for reaction, adding water after the reaction is finished, quenching, separating liquid, washing an organic phase with water, concentrating the organic phase to obtain a light yellow solid, and recrystallizing the solid with isopropanol to obtain the white-like solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate.
The preparation method disclosed by the invention avoids the use of toxic substances such as methyl iodide, ethylene oxide and the like, is mild in reaction conditions, safer to operate, free of thionyl chloride, simple to operate, less in side reaction and suitable for industrial production, and avoids the generation of a large amount of waste acid and waste gas.
Example 1:
preparation of methyl 2- (4- (2-chloroacetyl) phenyl) -2-methylpropionate
Adding 126.7 g (1122 mmol) of chloroacetyl chloride, 300 mL of dichloromethane and 89.8 g (673 mmol) of anhydrous aluminum trichloride into a reaction bottle in sequence, cooling the mixture to 0 ℃, stirring for 20min, then dropwise adding 100 g (561 mmol) of raw material 2, 2-dimethyl phenylacetic acid methyl ester at 10 ℃, heating to 30 ℃ after dropwise adding, stirring for reaction for 2h, after TLC (thin layer chromatography) monitoring reaction is complete, adding 300 mL of dichloromethane for dilution, cooling the reaction solution to 10 ℃, dropwise adding 600 mL of water for stirring and quenching, standing for liquid separation, dropwise adding 600 mL of saturated NaHCO into the organic phase, stirring and quenching, then, standing for liquid separation, and dropwise adding 600 mL of saturated NaHCO into the organic phase3The solution was washed once and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration of the organic phase gave 138.6 g of a yellow oil, 97% yield, methyl 2- (4- (2-chloroacetyl) phenyl) -2-methylpropionate;
example 2:
preparation of ethyl 2- (4- (2-bromoacetyl) phenyl) -2-methylpropionate
Adding 78.7 g (390 mmol) of bromoacetyl bromide, 150 mL of dichloromethane and 38.1 g (286 mmol) of anhydrous aluminum trichloride into a reaction bottle in sequence, cooling the mixture to 0 ℃, stirring for 20min, then dropwise adding 50 g (260 mmol) of raw material 2, 2-dimethyl phenylacetic acid ethyl ester at 0 ℃, stirring and reacting for 1h at 10 ℃ after finishing dropping, adding 150 mL of dichloromethane for dilution after TLC (thin layer chromatography) monitoring reaction is completed, cooling the reaction liquid to 0 ℃, dropwise adding 300 mL of water for stirring and quenching, standing and separating liquid, and dropwise adding 300 mL of saturated NaHCO into an organic phase3The solution was washed once and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration of the organic phase gave 74.1 g of a yellow oil, 91% yield, ethyl 2- (4- (2-bromoacetyl) phenyl) -2-methylpropionate;
example 3:
preparation of methyl 2- (4- (2-chloroethyl) phenyl) -2-methylpropionate
Adding 101.9 g (400 mmol) of methyl 2- (4- (2-chloroacetyl) phenyl) -2-methylpropionate and 273.7 g (2400 mmol) of trifluoroacetic acid into a three-necked bottle, mixing and stirring, adding 139.5 g (1200 mmol) of triethylsilane, heating the mixture to 50 ℃, stirring and reacting for 7h, monitoring by TLC to complete reaction, cooling to 0 ℃, adding 800 mL of water into the reaction solution, quenching, extracting with dichloromethane for 2 times (400 mL each time), combining organic phases, washing with 600 mL of water once, washing with 600 mL of saturated NaHCO3 once, concentrating the organic phases to dryness to obtain 96.3 g of yellow oily matter with the yield of 94%, wherein the yellow oily matter is methyl 2- (4- (2-chloroethyl) phenyl) -2-methylpropionate;
example 4:
preparation of ethyl 2- (4- (2-bromoethyl) phenyl) -2-methylpropionate
Adding 70.2 g (224 mmol) of ethyl 2- (4- (2-bromoacetyl) phenyl) -2-methylpropionate and 153.2 g (1344 mmol) of trifluoroacetic acid into a three-neck flask, mixing and stirring, adding 104.2 g (896 mmol) of triethylsilane, heating the mixture to 40 ℃, stirring and reacting for 15h, monitoring by TLC (thin layer chromatography), cooling to 0 ℃, adding 700 mL of water into the reaction solution, quenching, extracting with dichloromethane for 2 times (300 mL each time), combining the organic phases, washing with 300 mL of water, washing with 300 mL of saturated NaHCO3 solution, concentrating the organic phases until the organic phases are dried to obtain 60.3 g of yellow oily matter, wherein the yield is 90 percent, and the yellow oily matter is ethyl 2- (4- (2-bromoethyl) phenyl) -2-methylpropionate;
example 5:
preparation of methyl 2- (4- (2-hydroxyethyl) phenyl) -2-methylpropionate
70 g (291 mmol) of methyl 2- (4- (2-chloroethyl) phenyl) -2-methylpropionate, 210 mL of DMSO and 210 mL of water are added into a three-necked bottle to be mixed, the temperature is raised to 150 ℃, the mixture is stirred and reacted for 25 hours, TLC monitors that the reaction is complete, the mixture is cooled to room temperature, 420 mL of water is added into the reaction solution, ethyl acetate is used for extraction for 2 times, each time, 420 mL of water is added, organic phases are combined and washed twice by 420 mL of water, then, the organic phases are washed by 420 mL of saturated saline water once, the organic phases are concentrated to dryness to obtain 58.8 g of light yellow oily matter, and the yield is 91 percent, namely methyl 2- (4- (2-hydroxyethyl) phenyl) -2-methylpropionate;
example 6:
preparation of ethyl 2- (4- (2-hydroxyethyl) phenyl) -2-methylpropionate
Adding 57.7 g (193 mmol) of ethyl 2- (4- (2-bromoethyl) phenyl) -2-methylpropionate, 230 mL of DMSO and 230 mL of water into a three-necked flask, mixing, heating to 125 ℃, stirring for reaction for 16h, monitoring by TLC (thin layer chromatography), cooling to room temperature, adding 460 mL of water into a reaction solution, extracting with ethyl acetate for 2 times, each time 460 mL of water, combining organic phases, washing with 460 mL of water twice, washing with 460 mL of saturated saline once, concentrating the organic phases to dryness to obtain 42.4 g of light yellow oily matter with the yield of 93%, wherein the yield is ethyl 2- (4- (2-hydroxyethyl) phenyl) -2-methylpropionate;
example 7:
preparation of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol
Adding 50.0 g (225 mmol) of 2- (4- (2-hydroxyethyl) phenyl) -2-methyl propionic acid methyl ester, 40.1 g (450 mmol) of 2-amino-2-methylpropane-1-ol and 250 mL of toluene into a three-necked bottle, mixing and stirring, heating to 60 ℃, reacting for 5h, configuring a water separator, heating to reflux and stirring for 6h, adding toluene while dividing water until the total solvent amount is 250 mL, monitoring by TLC after the reaction is finished, cooling to room temperature, adding 250 mL of water to quench and kill the reaction, standing, washing an organic phase with 250 mL of saturated NaHCO3 aqueous solution, washing with 250 mL of saturated salt water, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate until the filtrate is dried to obtain 58.7g of light yellow solid, recrystallizing the solid with a mixed solvent of ethanol and water (3:2) to obtain 48.2 g of white-like solid, yield 82% of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol;
example 8:
preparation of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol
Adding 39.0 g (165 mmol) of ethyl 2- (4- (2-hydroxyethyl) phenyl) -2-methylpropionate, 22.1 g (248 mmol) of 2-amino-2-methylpropane-1-ol and 200 mL of methylbenzene into a three-neck flask, mixing and stirring, heating to 70 ℃, reacting for 6h, configuring a water separator, heating to reflux and stirring for 10h, adding methylbenzene while dividing water until the total solvent amount is 200 mL, monitoring by TLC that the reaction is finished, cooling to room temperature, adding 200 mL of water, quenching the reaction, separating, and adding 200 mL of saturated NaHCO into an organic phase3Washing with an aqueous solution, washing with 200 mL of saturated brine, drying the organic phase over anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness to obtain 45.6g of a pale yellow solid, and recrystallizing the solid with a mixed solvent of ethanol and water (3:2) to obtain 32.7 g of an off-white solid with a yield of 76% of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl group]Phenyl ethyl alcohol;
example 9:
preparation of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate
40.0 g (153 mmol) of 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol was dissolved in 320 mL of dichloromethane, then 23.3 g (230 mmol) of triethylamine is added, 35.0 g (184 mmol) of p-toluenesulfonyl chloride is added in batches, the mixture is stirred and reacted for 5 hours at the temperature of 25 ℃, TLC detection reaction is finished, 320 mL of water is added for quenching, standing and liquid separation are carried out, the organic phase is washed once by 320 mL of water, the organic phase is concentrated to obtain a white-like solid, the solid is recrystallized by 120 mL of isopropanol to obtain 57.2 g of the white-like solid with the yield of 90 percent, the solid was 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate.
It should be understood that although the description is made in terms of embodiments, not every embodiment includes only a single claim, and such description is for clarity only, and those skilled in the art will recognize that the embodiments described in the various embodiments can be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (10)
2. The method for preparing a bilastine intermediate as claimed in claim 1, wherein the method comprises the following steps: the specific steps in the step 1 are as follows: mixing and stirring the compound 7, dichloromethane and anhydrous aluminum trichloride, then dropwise adding the compound 1, and stirring and reacting the mixture after dropwise adding; the reaction solution is post-treated and concentrated to obtain yellow oily 2- (4- (2-halogenated acetyl) phenyl) -2-methyl propionate, namely the compound 2.
3. The method for preparing a bilastine intermediate as claimed in claim 2, wherein: the molar ratio of the compound 1, the compound 7 and the anhydrous aluminum trichloride in the step 1 is 1: 1.5-2.5: 1.1-1.2.
4. The method for preparing a bilastine intermediate as claimed in claim 1, wherein the method comprises the following steps: the specific steps in the step 2 are as follows: and mixing and stirring the compound 2 and trifluoroacetic acid, adding triethylsilane, heating and stirring the mixture for reaction, carrying out post-treatment and concentration on the reaction solution to obtain a yellow oily 2- (4- (2-halogenated ethyl) phenyl) -2-methylpropionate, namely a compound 3, wherein the molar ratio of the compound 2, the trifluoroacetic acid to the triethylsilane is 1: 6-8: 3-4.
5. The method for preparing a bilastine intermediate as claimed in claim 1, wherein the method comprises the following steps: the specific steps in the step 3 are as follows: and mixing and stirring the compound 3, DMSO and water, heating to 150 ℃, stirring for reaction, and concentrating a post-treated organic phase after the reaction is finished until the organic phase is dried to obtain a light yellow oily 2- (4- (2-hydroxyethyl) phenyl) -2-methyl propionate, namely a compound 4.
6. The method for preparing a bilastine intermediate as claimed in claim 5, wherein: the volume ratio of the compound 3 to the DMSO to the water is 1: 3-4.
7. The method for preparing a bilastine intermediate as claimed in claim 1, wherein the method comprises the following steps: the specific steps in the step 4 are as follows: mixing the compound 4, 2-amino-2-methylpropane-1-alcohol and toluene, heating and stirring for reaction, then configuring a water separator, heating to reflux and stirring, adding toluene while dividing water until the total solvent amount is constant, treating and concentrating after the reaction is finished to obtain a white solid, and recrystallizing the solid by using a mixed solvent of ethanol and water to obtain the white solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol.
8. The method for preparing a bilastine intermediate as claimed in claim 7, wherein: the molar ratio of the compound 4 to the 2-amino-2-methylpropane-1-ol is 1: 1.5-3.
9. The method for preparing a bilastine intermediate as claimed in claim 1, wherein the method comprises the following steps: the specific steps in the step 5 are as follows: dissolving the solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol obtained in the step 4 in dichloromethane, adding triethylamine, then adding p-toluenesulfonyl chloride in batches, stirring for reaction, carrying out post-treatment and concentration on the reaction liquid after the reaction is finished to obtain a light yellow solid, and recrystallizing the solid by using isopropanol to obtain a white-like solid 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol p-toluenesulfonate.
10. The method for preparing a bilastine intermediate as claimed in claim 9, wherein: in the step 5, the molar ratio of the 4- [1- (4, 5-dihydro-4, 4-dimethyl-2-oxazolyl) -1-methylethyl ] phenethyl alcohol to the triethylamine to the p-toluenesulfonyl chloride is 1: 1.3-1.5: 1.1-1.2.
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