CN106380441B - Synthetic method of fexofenadine intermediate - Google Patents
Synthetic method of fexofenadine intermediate Download PDFInfo
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Abstract
The invention provides a synthesis method of a fexofenadine intermediate 2- [4- [4- [4- (hydroxy diphenylmethyl) -1-piperidyl ] -butyryl ] phenyl ] -2-methyl propionic acid methyl ester, which comprises the following steps of taking benzyl cyanide as a raw material, and carrying out methylation, alkaline hydrolysis, weinreb amide reaction, Friedel-crafts reaction, acid hydrolysis, ester formation and condensation. The invention has the advantages of cheap and easily obtained raw and auxiliary materials, high yield, low cost, no meta-isomer, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the technical field of organic synthesis route design and preparation of medical intermediates thereof, and particularly relates to a synthesis method of fexofenadine intermediate 2- [4- [4- [4- (hydroxy benzhydryl) -1-piperidyl ] -butyryl ] phenyl ] -2-methyl propionate.
Background
The chemical name of fexofenadine is 2- [4- [ 1-hydroxy-4- [4- (hydroxy diphenylmethyl) -1-piperidyl]Butyl radical]Phenyl radical]-2-methylpropionic acid with the molecular formula C32H39NO4. Its racemic hydrochloride is used clinically. Fexofenadine, a new generation of receptor-type antagonists without sedative and lethargy effects, was developed by Hemerole (HMR) in germany and was first marketed in the united states after approval by the FDA in 1996 under the trade name Allegra, and subsequently in countries such as the united kingdom, sweden, australia, and the like, and is now on the market in china in increasing quantities. Fexofenadine is a safe substitute and has good economic and social benefits.
Fexofenadine is prepared from 2- [4- [4- [4- (hydroxy-diphenylmethyl) -1-piperidyl ] -butyryl ] phenyl ] -2-methyl-propionic acid methyl ester (VII) through hydrolysis, reduction and salification. Many documents and patents relating to the fexofenadine intermediate methyl 2- [4- [4- [4- (hydroxybenzyl) -1-piperidinyl ] -butyryl ] phenyl ] -2-methylpropionate (VII) have been reported, and mainly:
1. US 4254129 and DE 3007498 take alpha, alpha-dimethyl benzene acetic acid as raw material, and are obtained through esterification, Friedel-crafts reaction and condensation. The method has the disadvantages that para-isomer and meta-isomer appear in the Friedel-crafts reaction, and the separation of the two products is difficult, so that the post-treatment is troublesome and the purity of the product is not high.
2. US 6348597B2 and the literature (chinese journal of pharmaceutical chemistry, 2004, 14(2), 96) use a, a-dimethyl phenylacetic acid as a raw material, chlorinate with thionyl chloride, and then aminated with N, O-dimethyl hydroxylamine hydrochloride, in order to utilize steric hindrance effect to produce only para-product during friedel-crafts reaction with 4-chlorobutyl chloride, resulting in improved product purity. However, the product obtained by Friedel-crafts reaction in the method can not be purified, and the impurities in the product can react with diphenyl-4-piperidinemethanol, thereby reducing the purity and yield of the subsequent step and the reaction product. In addition, the yield of amide hydrolysis in the hydrolysis step is not high, and unhydrolyzed amide is difficult to separate from the product.
3. U.S. Pat. No. 4, 0198233 starts from 4-bromo (a, a-dimethyl) phenylacetate at (Ph)3P)4Pd/CuBr2Under the catalytic action of the catalyst, the catalyst is subjected to coupling reaction with 3-butyne-1-alcohol, then is subjected to substitution reaction with diphenyl-4-piperidine methanol, and finally is selectively oxidized into triple bonds by using Pt as a catalyst. However, the method selects the expensive Pt and (Ph)3P)4Pd catalyst, increasing production costs.
4. The Chinese patent with application number CN 200910153475.3 also takes 2-methyl-2-phenylpropionic acid as a raw material, and improves the method of US 6348597B2 and the literature (Chinese journal of pharmaceutical chemistry, 2004, 14(2), 96), and the method is obtained by firstly carrying out Weilnereb (weinreb) amide reaction, Friedel-crafts reaction, hydrolysis into ester and condensation. However, the hydrolysis of the product into ester is carried out by a one-pot method, which causes the generated impurities to be difficult to separate, and has great influence on the subsequent condensation, thus the purity is not improved.
Disclosure of Invention
In order to overcome the defects or existing problems mentioned above, the invention provides a synthetic method which has no meta-isomer, simple process steps, low production cost, high purity of the final product and is suitable for industrial production.
According to the invention, the synthesis method of the fexofenadine intermediate 2- [4- [4- [4- (hydroxybenzophenone) -1-piperidyl ] -butyryl ] phenyl ] -2-methyl propionic acid methyl ester is provided according to the following synthesis route:
the synthesis method comprises the following steps:
step 1: taking benzyl cyanide as a raw material, and reacting the benzyl cyanide with dimethyl sulfate under an alkaline condition to generate 2-methyl-2-phenylpropionitrile (I);
step 2: hydrolyzing 2-methyl-2-phenylpropanenitrile (I) to 2-methyl-2-phenylpropionic acid (II) under alkaline conditions;
and step 3: 2-methyl-2-phenylpropionic acid (II) is reacted by Weininranulamide to generate N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III);
and 4, step 4: the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) generates 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV) through Friedel-crafts reaction;
and 5: 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV) is hydrolyzed to 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid (V);
step 6: reacting 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid (V) with methanol to produce methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI);
and 7: condensation of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) with diphenyl-4-piperidinemethanol produced methyl 2- [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -butyryl ] phenyl ] -2-methylpropionate (VII).
Wherein the alkali used in the step 1 is sodium hydroxide and potassium hydroxide, and the molar weight ratio of the phenylacetonitrile to the dimethyl sulfate to the alkali is 1: 2.1-3: 4-6.
Wherein, the alkali used for hydrolysis in the step 2 is sodium hydroxide and potassium hydroxide.
The step 3 comprises the steps of firstly, reacting 2-methyl-2-phenylpropionic acid (II) with thionyl chloride to generate acyl chloride, and then, reacting the acyl chloride with N, O-dimethylhydroxylamine hydrochloride to synthesize N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) under the alkaline condition, wherein the specific synthetic route is as follows:
wherein the alkali used in the step 3 is potassium carbonate, cesium carbonate and sodium carbonate, and the molar weight ratio of the 2-methyl-2-phenylpropionic acid (II), the N, O-dimethylhydroxylamine hydrochloride and the alkali is 1: 1.1-1.5: 2-3.
Wherein, in the step 4, the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) reacts with 4-chlorobutyryl chloride under the action of a catalyst of aluminum trichloride to generate 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV).
Wherein in the step 4, the molar weight ratio of the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III), the 4-chlorobutyryl chloride and the aluminum trichloride is 1: 1.1-1.5: 2-2.5, and the reaction temperature is 20-25 ℃.
Wherein, the step 5 is to hydrolyze by 6N hydrochloric acid, the 6N hydrochloric acid is prepared by adding water into industrial grade 31 percent hydrochloric acid, and the heating temperature is 90-100 ℃.
Wherein the step 6 comprises the steps of heating 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid (V) and thionyl chloride in a methanol solution for 2 hours, evaporating the methanol to dryness, and introducing hydrochloric acid gas to prepare 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid methyl ester (VI), wherein the heating temperature is 55-65 ℃, and the specific synthetic route is as follows:
wherein the catalyst used in the step 7 is potassium iodide, the base used is potassium bicarbonate and sodium bicarbonate, the molar weight ratio of the methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) to the potassium iodide to the base is 1: 0.05-0.15: 2-2.5, and the reaction temperature is 80-95 ℃.
The synthesis method has the advantages of cheap and easily obtained raw and auxiliary materials, high yield, low cost, no meta-isomer, suitability for industrial production and the like.
In order to make the aforementioned and other objects, features and advantages of the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below.
Detailed Description
1. Synthesis of 2-methyl-2-phenylpropionic acid (II)
Example 1: adding 50g of benzyl cyanide, 140g of potassium hydroxide and 250mL of dimethyl sulfoxide into a 1000mL reaction bottle, stirring at room temperature for 1h, dropwise adding 132g of dimethyl sulfate, controlling the temperature to be 35-40 ℃, reacting at the temperature for 1h after the addition is finished, and monitoring by HPLC; after the reaction is completed, pouring the reaction solution into 1000g of a stirred ice-water mixture, extracting 200mL of 2 by using dichloromethane, combining organic phases, washing with water and saturated salt in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a red liquid; and adding the obtained red liquid into a reaction bottle, sequentially adding 250mL of water and 85g of sodium hydroxide, heating and refluxing for 48 hours, monitoring by HPLC (high performance liquid chromatography), cooling to 20-25 ℃ after the reaction is completed, extracting impurities by using 100mL of dichloromethane 2, discarding, acidifying a water layer by using concentrated hydrochloric acid until the pH value is 1-2, separating out a large amount of solid, filtering, washing with water, and drying to obtain 63g of pale yellow solid 2-methyl-2-phenylpropionic acid (II), wherein the purity is 96%, and the yield of two steps is 90%. Wherein the molar weight ratio of the phenylacetonitrile to the dimethyl sulfate to the alkali is 1:2.4: 5.6.
Example 2: adding 50g of benzyl cyanide, 102.4g of sodium hydroxide and 250mL of dimethyl sulfoxide into a 1000mL reaction bottle, stirring at room temperature for 1h, dropwise adding 118.3g of dimethyl sulfate, controlling the temperature to be 35-40 ℃, reacting at the temperature for 1h after the addition is finished, and monitoring by HPLC; after the reaction is completed, pouring the reaction solution into 1000g of a stirred ice-water mixture, extracting 200mL of 2 by using dichloromethane, combining organic phases, washing with water and saturated salt in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a red liquid; and adding the obtained red liquid into a reaction bottle, sequentially adding 250mL of water and 85g of sodium hydroxide, heating and refluxing for 48 hours, monitoring by HPLC (high performance liquid chromatography), cooling to 20-25 ℃ after the reaction is completed, extracting impurities by using 100mL of dichloromethane 2, discarding, acidifying a water layer by using concentrated hydrochloric acid until the pH value is 1-2, separating out a large amount of solid, filtering, washing by water, and drying to obtain light yellow solid 2-methyl-2-phenylpropionic acid (II)55g, wherein the purity is 95%, and the yield in two steps is 78.6%. Wherein the molar weight ratio of the phenylacetonitrile to the dimethyl sulfate to the alkali is 1:2.1: 6.
Example 3: adding 50g of benzyl cyanide, 95.8g of potassium hydroxide and 250mL of dimethyl sulfoxide into a 1000mL reaction bottle, stirring at room temperature for 1h, dropwise adding 161.5g of dimethyl sulfate, controlling the temperature to be 35-40 ℃, reacting at the temperature for 1h after the addition is finished, and monitoring by HPLC; after the reaction is completed, pouring the reaction solution into 1000g of a stirred ice-water mixture, extracting 200mL of 2 by using dichloromethane, combining organic phases, washing with water and saturated salt in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a red liquid; and adding the obtained red liquid into a reaction bottle, sequentially adding 250mL of water and 85g of sodium hydroxide, heating and refluxing for 48 hours, monitoring by HPLC (high performance liquid chromatography), cooling to 20-25 ℃ after the reaction is completed, extracting impurities by using 100mL of dichloromethane 2, discarding, acidifying a water layer by using concentrated hydrochloric acid until the pH value is 1-2, separating out a large amount of solid, filtering, washing with water, and drying to obtain 63g of light yellow solid 2-methyl-2-phenylpropionic acid (II), wherein the purity is 95%, and the yield of two steps is 90%. Wherein the molar weight ratio of the phenylacetonitrile to the dimethyl sulfate to the alkali is 1:3: 4.
Example 4: adding 50g of benzyl cyanide, 85.4g of sodium hydroxide and 250mL of dimethyl sulfoxide into a 1000mL reaction bottle, stirring at room temperature for 1h, dropwise adding 132g of dimethyl sulfate, controlling the temperature to be 35-40 ℃, reacting at the temperature for 1h after the addition is finished, and monitoring by HPLC; after the reaction is completed, pouring the reaction solution into 1000g of a stirred ice-water mixture, extracting 200mL of 2 by using dichloromethane, combining organic phases, washing with water and saturated salt in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a red liquid; and adding the obtained red liquid into a reaction bottle, sequentially adding 250mL of water and 85g of sodium hydroxide, heating and refluxing for 48 hours, monitoring by HPLC (high performance liquid chromatography), cooling to 20-25 ℃ after the reaction is completed, extracting impurities by using 100mL of dichloromethane 2, discarding, acidifying a water layer by using concentrated hydrochloric acid until the pH value is 1-2, separating out a large amount of solid, filtering, washing by water, and drying to obtain 58g of pale yellow solid 2-methyl-2-phenylpropionic acid (II), wherein the purity is 95%, and the yield in two steps is 82.9%. Wherein the molar weight ratio of the phenylacetonitrile to the dimethyl sulfate to the alkali is 1:2.5: 5.
2. Synthesis of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III)
Example 5: adding 63g of 2-methyl-2-phenylpropionic acid (II), 250mL of toluene and 150g of thionyl chloride into a 500mL reaction flask, heating and refluxing for 2h, monitoring the reaction by HPLC to be complete, evaporating the solvent and the excessive thionyl chloride under reduced pressure, adding 100mL of toluene for dissolving, cooling to 0-5 ℃, slowly adding a potassium carbonate (117 g)/water (180g) solution dropwise, keeping the temperature and stirring for 10min, adding a N, O-dimethylhydroxylamine hydrochloride (40 g)/water (80g) solution dropwise, after the addition is completed, naturally heating to room temperature for reaction for 2h, monitoring the reaction by HPLC to be complete, separating an organic layer, extracting 200mL of 2 with dichloromethane for a water layer, combining the organic layer, washing with 1N hydrochloric acid, a saturated sodium bicarbonate solution and a saturated salt solution respectively, drying with anhydrous sodium sulfate, filtering and concentrating to obtain an oily substance, distilling under reduced pressure, collecting a fraction with bp of 112-3 mmHg, 73g of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) was obtained with a purity of 98% and a yield of 91.8%. Wherein the molar weight ratio of the 2-methyl-2-phenylpropionic acid (II), the N, O-dimethylhydroxylamine hydrochloride and the alkali is 1:1.1: 2.2.
Example 6: adding 63g of 2-methyl-2-phenylpropionic acid (II), 250mL of toluene and 150g of thionyl chloride into a 500mL reaction flask, heating and refluxing for 2h, monitoring the reaction by HPLC to be complete, evaporating the solvent and the excessive thionyl chloride under reduced pressure, adding 100mL of toluene for dissolving, cooling to 0-5 ℃, slowly dropwise adding a cesium carbonate (375 g)/water (180g) solution, keeping the temperature and stirring for 10min, dropwise adding a N, O-dimethylhydroxylamine hydrochloride (40 g)/water (80g) solution, after the addition, naturally heating to room temperature for reaction for 2h, monitoring the reaction by HPLC to be complete, separating an organic layer, extracting 200mL of 2 with dichloromethane for a water layer, combining the organic layer, washing with 1N hydrochloric acid, a saturated sodium bicarbonate solution and a saturated salt solution respectively, drying with anhydrous sodium sulfate, filtering and concentrating to obtain an oily substance, distilling under reduced pressure, collecting a fraction with bp of 112-115 ℃/3mmHg, 75g of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) was obtained with a purity of 98% and a yield of 94.3%. Wherein the molar weight ratio of the 2-methyl-2-phenylpropionic acid (II), the N, O-dimethylhydroxylamine hydrochloride and the alkali is 1:1.1: 3.
Example 7: adding 63g of 2-methyl-2-phenylpropionic acid (II), 250mL of toluene and 150g of thionyl chloride into a 500mL reaction flask, heating and refluxing for 2h, monitoring the reaction to be complete by HPLC, evaporating the solvent and the excessive thionyl chloride under reduced pressure, adding 100mL of toluene for dissolving, cooling to 0-5 ℃, slowly dropwise adding a solution of sodium carbonate (81.3 g)/water (180g), keeping the temperature and stirring for 10min, dropwise adding a solution of N, O-dimethylhydroxylamine hydrochloride (56.1 g)/water (80g), naturally heating to room temperature for reaction for 2h, monitoring the reaction to be complete by HPLC, separating an organic layer, extracting 200mL of 2 with dichloromethane for a water layer, combining the organic layer, washing with 1N hydrochloric acid, a saturated sodium bicarbonate solution and saturated mmHg respectively, drying with anhydrous sodium sulfate, filtering and concentrating to obtain an oily substance, distilling under reduced pressure, collecting a fraction with bp of 112-115 ℃/3, 60g of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) was obtained with a purity of 94% and a yield of 75.5%. Wherein the molar weight ratio of the 2-methyl-2-phenylpropionic acid (II), the N, O-dimethylhydroxylamine hydrochloride and the alkali is 1:1.5: 2.
Example 8: adding 63g of 2-methyl-2-phenylpropionic acid (II), 250mL of toluene and 150g of thionyl chloride into a 500mL reaction flask, heating and refluxing for 2h, monitoring the reaction to be complete by HPLC, evaporating the solvent and the excessive thionyl chloride under reduced pressure, adding 100mL of toluene for dissolving, cooling to 0-5 ℃, slowly dropwise adding a solution of potassium carbonate (132.4 g)/water (180g), keeping the temperature and stirring for 10min, dropwise adding a solution of N, O-dimethylhydroxylamine hydrochloride (48.6 g)/water (80g), naturally heating to room temperature for reaction for 2h, monitoring the reaction to be complete by HPLC, separating an organic layer, extracting 200mL of 2 with dichloromethane for a water layer, combining the organic layer, washing with 1N hydrochloric acid, a saturated sodium bicarbonate solution and saturated mmHg respectively, drying with anhydrous sodium sulfate, filtering and concentrating to obtain an oily substance, distilling under reduced pressure, collecting a fraction with bp of 112-115 ℃/3, 74g of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) was obtained with a purity of 98% and a yield of 93.1%. Wherein the molar weight ratio of the 2-methyl-2-phenylpropionic acid (II), the N, O-dimethylhydroxylamine hydrochloride and the alkali is 1:1.3: 2.5.
3. Synthesis of 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV)
Example 9: adding 60g of anhydrous aluminum trichloride and 125mL of dichloromethane into a 500mL reaction bottle, cooling to-5-0 ℃, dropwise adding a solution of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) (100 g)/dichloromethane (90mL) at a controlled temperature, keeping the temperature and reacting for 1h after the addition is finished, thus obtaining a solution for later use; adding 90g of anhydrous aluminum trichloride and 125mL of dichloromethane into a 1000mL reaction bottle, cooling to-5-0 ℃, dropwise adding a 4-chlorobutyryl chloride (95 g)/dichloromethane (90mL) solution at a controlled temperature, keeping the temperature for reaction for 1h, cooling to 0-5 ℃, dropwise adding the solution, keeping the temperature for 0-5 ℃, keeping the temperature for reaction for 1h after the addition is finished, naturally heating to room temperature (20-25 ℃) for reaction for 48h, monitoring by HPLC (high performance liquid chromatography) until the reaction is complete, slowly pouring the reaction solution into 1500g of stirred ice-water mixture for quenching, separating an organic layer, extracting a water layer by using dichloromethane for 200mL & gt2, combining the organic layers, washing by using a saturated sodium bicarbonate solution, washing by using saturated salt, drying by using anhydrous sodium sulfate, and concentrating to obtain a black oily substance. After the cyclohexane was added to dissolve out the product, cyclohexane was concentrated to obtain 128g of 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV) with a purity of 92% and a yield of 85%. Wherein the molar weight ratio of the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III), the 4-chlorobutyryl chloride and the aluminum trichloride is 1:1.4: 2.5.
Example 10: adding 70.8g of anhydrous aluminum trichloride and 125mL of dichloromethane into a 500mL reaction bottle, cooling to-5-0 ℃, dropwise adding a solution of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) (100 g)/dichloromethane (90mL) at a controlled temperature, and reacting for 1h under a heat preservation condition to obtain a solution for later use; adding 90g of anhydrous aluminum trichloride and 125mL of dichloromethane into a 1000mL reaction bottle, cooling to-5-0 ℃, dropwise adding a 4-chlorobutyryl chloride (74.8 g)/dichloromethane (90mL) solution at a controlled temperature, keeping the temperature for reaction for 1h, cooling to 0-5 ℃, dropwise adding the solution, keeping the temperature for 0-5 ℃, keeping the temperature for reaction for 1h after the addition is finished, naturally heating to room temperature (20-25 ℃) for reaction for 48h, monitoring by HPLC (high performance liquid chromatography) until the reaction is complete, slowly pouring the reaction solution into 1500g of stirred ice water mixture for quenching, separating an organic layer, extracting a water layer by using dichloromethane for 200mL & lt 2 & gt, combining the organic layers, washing by using a saturated sodium bicarbonate solution, washing by using saturated salt, drying by using anhydrous sodium sulfate, and concentrating to obtain a black oily substance. After the cyclohexane was added to dissolve out the product, cyclohexane was concentrated to obtain 107g of 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV) with a purity of 89% and a yield of 71.1%. Wherein the molar weight ratio of the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III), the 4-chlorobutyryl chloride and the aluminum trichloride is 1:1.1: 2.5.
Example 11: adding 38.7g of anhydrous aluminum trichloride and 125mL of dichloromethane into a 500mL reaction bottle, cooling to-5-0 ℃, dropwise adding a solution of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) (100 g)/dichloromethane (90mL) at a controlled temperature, and reacting for 1h under a heat preservation condition to obtain a solution for later use; adding 90g of anhydrous aluminum trichloride and 125mL of dichloromethane into a 1000mL reaction bottle, cooling to-5-0 ℃, dropwise adding a 4-chlorobutyryl chloride (102 g)/dichloromethane (90mL) solution at a controlled temperature, keeping the temperature for reaction for 1h, cooling to 0-5 ℃, dropwise adding the solution, keeping the temperature for 0-5 ℃, keeping the temperature for reaction for 1h after the addition is finished, naturally heating to room temperature (20-25 ℃) for reaction for 48h, monitoring by HPLC (high performance liquid chromatography) until the reaction is complete, slowly pouring the reaction solution into 1500g of stirred ice-water mixture for quenching, separating an organic layer, extracting a water layer by using dichloromethane for 200mL & gt2, combining the organic layers, washing by using a saturated sodium bicarbonate solution, washing by using saturated salt, drying by using anhydrous sodium sulfate, and concentrating to obtain a black oily substance. After the cyclohexane was added to dissolve out the product, cyclohexane was concentrated to obtain 126g of 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV), purity 92%, yield 83.8%. Wherein the molar weight ratio of the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III), the 4-chlorobutyryl chloride and the aluminum trichloride is 1:1.5: 2.
Example 12: adding 60g of anhydrous aluminum trichloride and 125mL of dichloromethane into a 500mL reaction bottle, cooling to-5-0 ℃, dropwise adding a solution of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) (100 g)/dichloromethane (90mL) at a controlled temperature, keeping the temperature and reacting for 1h after the addition is finished, thus obtaining a solution for later use; adding 90g of anhydrous aluminum trichloride and 125mL of dichloromethane into a 1000mL reaction bottle, cooling to-5-0 ℃, dropwise adding a 4-chlorobutyryl chloride (88.4 g)/dichloromethane (90mL) solution at a controlled temperature, keeping the temperature for reaction for 1h, cooling to 0-5 ℃, dropwise adding the solution, keeping the temperature for 0-5 ℃, keeping the temperature for reaction for 1h after the addition is finished, naturally heating to room temperature (20-25 ℃) for reaction for 48h, monitoring by HPLC (high performance liquid chromatography) until the reaction is complete, slowly pouring the reaction solution into 1500g of stirred ice water mixture for quenching, separating an organic layer, extracting a water layer by using dichloromethane for 200mL & lt 2 & gt, combining the organic layers, washing by using a saturated sodium bicarbonate solution, washing by using saturated salt, drying by using anhydrous sodium sulfate, and concentrating to obtain a black oily substance. After the cyclohexane was added to dissolve out the product, cyclohexane was concentrated to obtain 125g of 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV) with a purity of 92% and a yield of 83.1%. Wherein the molar weight ratio of the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III), the 4-chlorobutyryl chloride and the aluminum trichloride is 1:1.3: 2.3.
4. Synthesis of 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid (V)
Example 13: 121g of 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV), 484mL of dioxane and 242g of 6N HCl are sequentially added into a 1000mL reaction bottle, the mixture is heated to 90-100 ℃ and subjected to reflux reaction for 20 hours, HPLC (high performance liquid chromatography) is used for monitoring the reaction to be complete, the mixture is cooled to room temperature, the reaction solution is poured into 400mL of water, 200mL of x 3 is extracted by toluene, organic layers are combined, washed by water, washed by saturated common salt water, dried by anhydrous sodium sulfate and concentrated to obtain a brownish red oily substance, and the brownish red oily substance is recrystallized by cyclohexane to obtain 95g of yellow powdery solid 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionic acid (V), the purity is 94%, and the yield is 91%.
5. Synthesis of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI)
Example 14: adding 49.2g of 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid (V), 150mL of toluene and 65g of thionyl chloride into a 500mL reaction bottle, heating to 55-65 ℃ for refluxing for 2h, monitoring the reaction by HPLC (high performance liquid chromatography), evaporating the toluene and the excessive thionyl chloride under reduced pressure, dissolving the residue by using 150mL of toluene, cooling to 0-5 ℃, dropwise adding 100mL of anhydrous methanol under controlled temperature, heating to room temperature, stirring for 2h, monitoring the reaction by HPLC, introducing HCl gas to saturation, stirring for 1h, monitoring reaction completion by HPLC, concentrating toluene and methanol under reduced pressure, dissolving the residue in 150mL of toluene, washing with water, washing with saturated saline, drying over anhydrous sodium sulfate, and concentrating to obtain 53g of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI), purity 90%, yield 92%.
6. Synthesis of methyl 2- [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -butyryl ] phenyl ] -2-methylpropionate (VII)
Example 15: adding 55.4g of diphenylpiperidine methanol, 42.1g of potassium bicarbonate, 3.1g of potassium iodide and 310mL of toluene into a 1000mL reaction bottle in sequence, heating to 80 ℃, starting to slowly dropwise add a 2- (4- (4-chlorobutyryl) phenyl) -2-methyl propionate (VI) (53.3 g)/toluene solution (150mL), carrying out reflux reaction for about 30 hours after the addition is finished, monitoring the reaction completion by HPLC, cooling the reaction solution to 10-15 ℃, filtering, and concentrating the filtrate to obtain 107g of crude product; heating, refluxing and dissolving the mixture to be clear by using 250mL of absolute ethyl alcohol, dripping 80mL of water, refluxing for 30min, naturally cooling to 10-15 ℃, preserving heat, stirring for 4h, filtering to obtain a white-like solid, and drying 90g of the white-like solid; recrystallization from EA gave 77.4g of methyl 2- [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -butyryl ] phenyl ] -2-methylpropionate (VII) as a white solid with a purity of 99.5% and a yield of 80%. Wherein the molar weight ratio of the methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) to the potassium iodide to the alkali is 1:0.1: 2.23.
Example 16: adding 55.4g of diphenylpiperidine methanol, 47.1g of potassium bicarbonate, 1.6g of potassium iodide and 310mL of toluene into a 1000mL reaction bottle in sequence, heating to 85 ℃, starting to slowly dropwise add a 2- (4- (4-chlorobutyryl) phenyl) -2-methyl propionate (VI) (53.3 g)/toluene solution (150mL), carrying out reflux reaction for about 30 hours after the addition is finished, monitoring the reaction completion by HPLC, cooling the reaction solution to 10-15 ℃, filtering, and concentrating the filtrate to obtain 107g of crude product; heating, refluxing and dissolving the mixture to be clear by using 250mL of absolute ethyl alcohol, dripping 80mL of water, refluxing for 30min, naturally cooling to 10-15 ℃, preserving heat, stirring for 4h, filtering to obtain a white-like solid, and drying 89 g; recrystallization from EA gave 75g of methyl 2- [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -butyryl ] phenyl ] -2-methylpropionate (VII) as a white solid with a purity of 99.3% and a yield of 77.5%. Wherein the molar weight ratio of the methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) to the potassium iodide to the alkali is 1:0.05: 2.5.
Example 17: adding 55.4g of diphenyl piperidine methanol, 31.7g of sodium bicarbonate, 4.7g of potassium iodide and 310mL of toluene into a 1000mL reaction bottle in sequence, heating to 90 ℃, starting to slowly dropwise add methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) (53.3 g)/toluene solution (150mL), refluxing for about 30 hours after the addition is finished, monitoring the reaction completion by HPLC, cooling the reaction solution to 10-15 ℃, filtering, and concentrating the filtrate to obtain 107g of crude product; heating, refluxing and dissolving the mixture to be clear by using 250mL of absolute ethyl alcohol, dripping 80mL of water, refluxing for 30min, naturally cooling to 10-15 ℃, preserving heat, stirring for 4h, filtering to obtain a white-like solid, and drying 85 g; recrystallization from EA gave 70g of methyl 2- [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -butyryl ] phenyl ] -2-methylpropionate (VII) as a white solid with a purity of 99% and a yield of 72.3%. Wherein the molar weight ratio of the methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) to the potassium iodide to the base is 1:0.15: 2.
Example 18: adding 55.4g of diphenyl piperidine methanol, 34.8g of sodium bicarbonate, 3.1g of potassium iodide and 310mL of toluene into a 1000mL reaction bottle in sequence, heating to 95 ℃, starting to slowly dropwise add methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) (53.3 g)/toluene solution (150mL), refluxing for about 30 hours after the addition is finished, monitoring the reaction completion by HPLC, cooling the reaction solution to 10-15 ℃, filtering, and concentrating the filtrate to obtain 107g of crude product; heating, refluxing and dissolving the mixture to be clear by using 250mL of absolute ethyl alcohol, dripping 80mL of water, refluxing for 30min, naturally cooling to 10-15 ℃, preserving heat, stirring for 4h, filtering to obtain a white-like solid, and drying 86 g; recrystallization from EA gave 71g of methyl 2- [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -butyryl ] phenyl ] -2-methylpropionate (VII) as a white solid with a purity of 99% and a yield of 73.3%. Wherein the molar weight ratio of the methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) to the potassium iodide to the alkali is 1:0.1: 2.2.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (9)
1. A synthetic method of fexofenadine intermediate 2- [4- [4- [4- (hydroxy benzhydryl) -1-piperidyl ] -butyryl ] phenyl ] -2-methyl propionic acid methyl ester is characterized by comprising the following synthetic route:
the synthesis method comprises the following steps:
step 1: taking benzyl cyanide as a raw material, and reacting the benzyl cyanide with dimethyl sulfate under an alkaline condition to generate 2-methyl-2-phenylpropionitrile (I);
step 2: hydrolyzing 2-methyl-2-phenylpropanenitrile (I) to 2-methyl-2-phenylpropionic acid (II) under alkaline conditions;
and step 3: 2-methyl-2-phenylpropionic acid (II) is reacted by Weininranulamide to generate N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III);
and 4, step 4: the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) generates 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV) through Friedel-crafts reaction, wherein in the step 4, the N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) reacts with 4-chlorobutyryl chloride under the action of catalyst aluminum trichloride to generate 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV), and the method specifically comprises the following steps: firstly, adding a part of aluminum trichloride into a reaction bottle, cooling dichloromethane to-5-0 ℃, dropwise adding an N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III)/dichloromethane solution at a controlled temperature, and after the addition is finished, carrying out heat preservation reaction for a period of time to obtain a solution for later use; then adding the rest aluminum trichloride and dichloromethane into another reaction bottle, cooling to-5-0 ℃, dropwise adding a 4-chlorobutyryl chloride/dichloromethane solution at a controlled temperature, after the addition is finished, carrying out heat preservation reaction for a period of time, cooling to 0-5 ℃, dropwise adding the solution, keeping the temperature at 0-5 ℃, after the addition is finished, carrying out heat preservation reaction for a period of time, and naturally heating to 20-25 ℃ for reaction;
and 5: 2- (4- (4-chlorobutyryl) phenyl) -N-methoxy-N, 2-dimethylpropionamide (IV) is hydrolyzed to 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid (V);
step 6: reacting 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid (V) with methanol to produce methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI);
and 7: condensation of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) with diphenyl-4-piperidinemethanol produced methyl 2- [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -butyryl ] phenyl ] -2-methylpropionate (VII).
2. The synthesis method according to claim 1, wherein the base used in the step 1 is sodium hydroxide and potassium hydroxide, and the molar weight ratio of the phenylacetonitrile to the dimethyl sulfate to the base is 1: 2.1-3: 4-6.
3. The method according to claim 1, wherein the base used in the hydrolysis in step 2 is sodium hydroxide or potassium hydroxide.
4. The method of claim 1, wherein step 3 comprises: the 2-methyl-2-phenylpropionic acid (II) and thionyl chloride generate acyl chloride, and then the acyl chloride and N, O-dimethylhydroxylamine hydrochloride are synthesized into N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) under the alkaline condition, and the specific synthetic route is as follows:
5. the method according to claim 4, wherein the base used in step 3 is potassium carbonate, cesium carbonate, sodium carbonate, 2-methyl-2-phenylpropionic acid (II), N, O-dimethylhydroxylamine hydrochloride, and a base in a molar weight ratio of 1:1.1 to 1.5:2 to 3.
6. The preparation method according to claim 1, wherein the molar weight ratio of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III), 4-chlorobutyryl chloride and aluminum trichloride in step 4 is 1:1.1 to 1.5:2 to 2.5.
7. The method according to claim 1, wherein the step 5 is performed by hydrolysis with 6N hydrochloric acid, the 6N hydrochloric acid is prepared by adding water to industrial grade 31% hydrochloric acid, and the hydrolysis temperature is 90-100 ℃.
8. The preparation method according to claim 1, wherein the 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoic acid (V) in the step 6 is heated with thionyl chloride in a methanol solution for 2h, then the methanol is evaporated, and hydrochloric acid gas is introduced to prepare the methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI), wherein the heating temperature is 55-65 ℃, and the specific synthetic route is as follows:
9. the method according to claim 1, wherein the catalyst and the base are used in step 7, the catalyst is potassium iodide, the base is potassium bicarbonate or sodium bicarbonate, the molar ratio of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropionate (VI) to potassium iodide to base is 1: 0.05-0.15: 2-2.5, and the reaction temperature is 80-95 ℃.
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| US20010031895A1 (en) * | 1993-06-25 | 2001-10-18 | Merrell Dow Pharmaceuticals Inc. | Novel intermediates useful for the preparation of antihistaminic piperidine derivatives |
| WO2005019175A1 (en) * | 2003-08-26 | 2005-03-03 | Cipla Limited | Fexofenadine polymorphs and processes of preparing the same |
| CN101585768A (en) * | 2009-06-06 | 2009-11-25 | 浙江大学宁波理工学院 | Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate |
| CN101585805A (en) * | 2009-06-06 | 2009-11-25 | 浙江大学宁波理工学院 | Preparation method of an antiallergic agent fexofenadine hydrochloride |
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| US20010031895A1 (en) * | 1993-06-25 | 2001-10-18 | Merrell Dow Pharmaceuticals Inc. | Novel intermediates useful for the preparation of antihistaminic piperidine derivatives |
| WO2005019175A1 (en) * | 2003-08-26 | 2005-03-03 | Cipla Limited | Fexofenadine polymorphs and processes of preparing the same |
| CN101585768A (en) * | 2009-06-06 | 2009-11-25 | 浙江大学宁波理工学院 | Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate |
| CN101585805A (en) * | 2009-06-06 | 2009-11-25 | 浙江大学宁波理工学院 | Preparation method of an antiallergic agent fexofenadine hydrochloride |
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