CN108164429B - Preparation method of dofetilide intermediate - Google Patents
Preparation method of dofetilide intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of a dofetilide intermediate and an analogue thereof, which comprises the following steps: dissolving the compound of formula (I) in a reaction solvent, and hydrogenating and reducing-NO of the compound of formula (I) by using palladium-carbon as a catalyst2is-NH2Separating and purifying after reaction to obtain the product; the reaction solvent is selected from one or two of ethyl acetate, isopropyl acetate, butyl acetate and methyl acetate. The method has the advantages of high yield and purity, simple operation, high production efficiency, environmental protection, safety, suitability for industrial mass production and wide market application prospect.
Description
Technical Field
The invention relates to the field of medicine preparation methods, in particular to a preparation method of a dofetilide intermediate and an analogue thereof.
Background
Dofetilide (formula I) is a new highly selective class III antiarrhythmic drug that can be administered intravenously or orally, with the chemical name N- [4- (2- {2- [4- (methanesulfonamido) phenoxy ] -N-methylethylamino } ethyl) phenyl ] -methanesulfonamide, and its molecular structure is as follows:
dofetilide is a methane sulfonamide derivative structurally similar to the antiarrhythmic drug sotalol. The pharmacological action mechanism is through inhibiting rapid potassium current (Ik)r) Increase action potential duration (QT interval) and exert the effect of III antiarrhythmic drugs. Approved by the U.S. Food and Drug Administration (FDA) in 1999 and first marketed in the united states in 5 months in 2000. Big (a)Clinical studies show that dofetilide can be used for treating and preventing atrial dysrhythmia and paroxysmal supraventricular tachycardia, and the curative effect on the repeated newly occurred atrial fibrillation and atrial flutter is better than that of other antiarrhythmic drugs. And can be used for preventing ventricular tachycardia and relieving heart failure. Has the advantages of obvious curative effect, relatively small adverse reaction and the like, and is an antiarrhythmic drug with strong effect and good selectivity.
At present, many documents disclose methods for preparing dofetilide. The existing reported synthetic route of dofetilide can be mainly divided into two routes according to different starting materials: one route is to prepare dofetilide by taking N-methyl-2- (4-nitrophenyl) ethylamine as a starting material through condensation, reduction and mesylation reactions (U.S. Pat. No. 4,989,366,CN 1019801, J.Med. chem.,1990,33(4): 1151-; the other route is to prepare the dofetilide by taking 2- (4-nitrophenyl) ethylamine as a starting material and carrying out condensation, methylation, reduction and mesylation reactions (EP0245997, CN1019801 and the like). In both routes, the reduction reaction of N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine (formula III) is involved to generate a key intermediate N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine (formula II), and the compound of the formula II is subjected to mesylation to generate the target compound dofetilide.
CN1146537, journal of the university of Jinan (Nature science edition), Jun.2005, Vol.19, No.2, Qilu Pharmaceutical affars, 2005, Vol.24, No.9 and other documents report the reduction reaction of N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine. Although the yield is high, experiments prove that the purity of the obtained product is very poor, the maximum purity is only about 84%, the obtained product continuously participates in the preparation of finished products, the purification cost of the finished products is greatly increased, the reaction time of the step is long, and the raw materials can be completely reacted within at least 16 hours.
In the method disclosed in patent CN1146537, a large amount of toluene is used for the post-treatment, which is harmful to human body and environment. If the method is used for enlarging the production scale, a large amount of material waste and production cost increase are caused, and the method is not suitable for industrial mass production.
The reduction reaction of N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine is reported in the literatures of Chinese medicine Journal of Pharmaceuticals 2003,34(4), CN1453267A, CN87103300A, J.Med.chem.,1990,33(4):1151-1155, etc., and the post-treatment in the literatures adopts recrystallization for purification. However, experiments prove that although the recrystallization mode in the literature can improve the purity of the product, the purification effect is not obvious, the highest purity can reach about 92%, and the intermediate with the purity is not beneficial to the preparation of the finished product and can increase the difficulty of the purification of the finished product. In addition, the reduction reaction time in the literature is long, at least more than 16 hours, and the time cost is undoubtedly increased for the industrial mass production.
Therefore, a preparation method of the dofetilide intermediate which has high product purity, is economical, environment-friendly and safe and is suitable for industrial mass production needs to be explored.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of a dofetilide intermediate and an analogue thereof, which comprises the following steps:
dissolving the compound of formula (I) in a reaction solvent, and hydrogenating and reducing-NO of the compound of formula (I) by using palladium-carbon as a catalyst2is-NH2Separating and purifying after reaction to obtain the product;
the reaction solvent is selected from one or two of ethyl acetate, isopropyl acetate, butyl acetate and methyl acetate;
in formula (I):
r is C1-C4An alkyl group;
x is O, S or none;
y is 1, 2-ethylene optionally substituted with methyl;
"alk" is 1, 2-ethylene, 1, 3-propylene or tetramethylene optionally substituted by methyl;
R2is H, halogen or C1-C4An alkyl group;
R1and R3Each independently is-NO2，-NHSO2-(C1-C4Alkyl) or-CONR4R5And R is1Or R3At least one of which is-NO2；
R4And R5Each independently is H or C1-C4Alkyl or together with the nitrogen atom to which it is attached forms morpholinyl.
Further, R is-CH3，R2Is H, X is an O atom, Y is a 1, 2-ethylene group, "alk" is a 1, 2-ethylene group, R1is-NO2，R3is-NHSO2CH3、-CONH2or-NO2；。
Further, R is-CH3，R2Is H, X is an O atom, Y is a 1, 2-ethylene group, "alk" is a 1, 2-ethylene group, R1is-NHSO2CH3、-CONH2or-NO2，R3is-NO2。
Further, the compound of formula (I) is represented by formula (III):
further, the volume mass ratio of the reaction solvent to the compound III is 3-10: 1mL/g, preferably 3-6: 1 mL/g.
Further, the palladium-carbon is a 10% palladium-carbon catalyst, and the weight ratio of the palladium-carbon catalyst to the compound of the formula (I) is 0.05: 1-0.15: 1.
Further, the reaction temperature of the hydrogenation reduction is 35-60 ℃.
Further, the hydrogen pressure of the hydrogenation reduction is 0.2-1.5 MPa.
Further, the purification comprises a step of recrystallization by an anti-solvent method; in the recrystallization by the anti-solvent method, the solvent A is any one of ethyl acetate, isopropyl acetate, butyl acetate and methyl acetate, and the anti-solvent B is n-hexane or cyclohexane.
Further, the volume mass ratio of the solvent A to the compound of the formula (I): 0.4-2.0: 1 mL/g; the volume mass ratio of the solvent B to the compound of the formula (I): 0.8-4.0: 1 mL/g.
Further, the volume ratio of the solvent A to the anti-solvent B is 1: 2-1: 5.
in the present invention, said C1-C4Alkyl is C1、C2、C3、C4The alkyl group of (1) is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, etc.
In the existing synthesis method, alcohol solvents are mostly adopted for reaction, the solubility of the reaction solvents to the raw material N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine is extremely poor, the solvent dosage is at least 60 times of the volume of the raw material, so that the raw material can be completely dissolved, the solvent dosage is too large, and the method is not suitable for industrial large-scale production; if the amount of the solvent is reduced, the raw materials cannot be completely dissolved, so that the reaction time is too long, impurities are increased, and the chemical purity of the obtained product is low. According to the invention, after the reaction solvent is changed into the ester solvent, the raw material solubility is greatly improved, the solvent consumption is greatly reduced, the reaction time is greatly shortened, and the purity of the obtained product is remarkably improved after the post-treatment of washing, impurity removal, concentration and refining.
Compared with the prior literature, the method has the advantages that:
1. the product obtained by the method greatly improves the chemical purity of the product, and the chemical purity can reach more than 99.85 percent (the highest chemical purity of the existing process is only about 92 percent). Therefore, the method avoids unnecessary impurity introduction, saves the cost of the subsequent purification process, and improves the quality of finished products.
2. The method has the characteristics of economy, environmental protection and safety. In the existing reaction process, alcohol solvents are mostly adopted, but the solubility of the alcohol solvents to raw materials is extremely poor, so that the use amount of the solvents is greatly increased, and the industrial production cost is greatly increased. In the reaction process, the ester solvent with good solubility to the raw materials is used instead, so that the using amount of the solvent is greatly reduced, the reaction time is shortened, the time cost is saved by at least 50%, and the reaction efficiency is greatly improved. In addition, the ester solvent used by the method is easy to recycle, and is beneficial to environmental protection.
3. The method of the invention obviously improves the appearance of the product. The product prepared by the method is white powder with uniform particles and better dispersibility, and the finished product prepared by the prior art is mostly pink blocky and is not easy to disperse.
4. The method is suitable for industrial mass production. The method is simple to operate, has no special requirements on equipment, is environment-friendly and safe, meets the requirements of large-scale industrial production, greatly saves materials, and reduces the industrial production cost.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The starting N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine may be prepared according to methods reported in the literature, for example in the literature U.S. Pat. No. 4,989,366, CN1019801, J.Med.chem.,1990,33(4): 1151-. The starting materials 1- (4-methanesulfonylaminophenoxy) -2- [ N-methyl-N- (4-nitrophenylethyl) amino ] ethane, 1- (4-nitrophenoxy) -2- [ N-methyl-N- (4-methanesulfonylaminophenylethyl) amino ] ethane, 4- {2[ N-methyl-N- (4-nitrophenylethyl) amino ] ethoxy } benzamide can be prepared according to literature reported methods, for example, in the literature CN 1019801.
The general reaction formula of the following examples is as follows:
example 1
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 330mL of ethyl acetate was added, the mixture was stirred until the starting material was completely dissolved, 16.5g of 10% palladium on charcoal catalyst was added, and the mixture was reacted under a hydrogen pressure of 1.0MPa at 35 ℃ for 8 hours, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 330mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
To the residue was added 55mL of ethyl acetate, followed by stirring, followed by addition of 110mL of cyclohexane, followed by crystallization at room temperature (20. + -. 5 ℃ C.) with stirring, followed by suction filtration, washing with cyclohexane, and drying to obtain 85g of N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine as a white powdery solid, in a yield of 93.6%, and a chemical purity by HPLC of 99.92%.
Comparative experiment 1 (see the existing literature: Chinese Journal of Pharmaceuticals 2003,34(4))
A mixture of 40g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine, 20g of 10% palladium on charcoal catalyst and 800mL of methanol was stirred under hydrogen pressure of 3.92kPa for 16 hours, at which time the pressure in the kettle did not change. The catalyst was filtered off and the solvent was removed under reduced pressure. The crude product was recrystallized from ethyl acetate-petroleum ether to give 25g of N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine as a pink solid in 75.6% yield and 91.67% chemical purity by HPLC.
Comparative experiment 2 (see the existing literature: journal of university of Jinan (Nature science edition), Jun.2005, Vol.19, No.2)
A mixture of 17g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine, 2g of 10% palladium on charcoal catalyst and 100mL of methanol was stirred under a hydrogen pressure of 4.78atm for 18 hours, at which time the pressure in the kettle did not change. The catalyst was filtered off and the solvent was removed under reduced pressure. To the residue was added 50mL of N-hexane, and the solid was precipitated by freezing, filtered and dried to obtain 12g of N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine as a pink lump solid in 85.7% yield and 79.58% chemical purity by HPLC.
Comparative experiment 3 (see prior art: CN1146537)
A mixture of 200g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine, 20g of 5% palladium on charcoal catalyst and 2000mL of methanol was stirred under a hydrogen pressure of 414kPa for 16 hours, at which time the pressure in the kettle did not change. Filtering out the catalyst, washing with methanol, reducing the pressure to a small volume, replacing the residual solvent with toluene, supplementing the toluene to 400mL, and cooling and crystallizing for 1.5 hours. Filtration, washing with 100mL of toluene and drying at 40 ℃ under reduced pressure gave 149g of N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine as a pink lumpy solid in 90.2% yield and 83.89% chemical purity by HPLC.
Example 2
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 440mL of ethyl acetate was added, the mixture was stirred until the starting material was completely dissolved, 11g of 10% palladium on carbon catalyst was added, and the mixture was reacted at 50 ℃ for 7 hours under a hydrogen pressure of 0.4MPa, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 440mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
Adding 55mL of ethyl acetate into the residue, stirring, adding 165mL of N-hexane, stirring at room temperature (20 +/-5 ℃) for crystallization, filtering, washing with the N-hexane, and drying to obtain 84g of white powdery solid N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine with the yield of 92.5% and the HPLC chemical purity of 99.90%.
Example 3
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 550mL of ethyl acetate was added, the mixture was stirred until the starting material was completely dissolved, 5.5g of 10% palladium on charcoal catalyst was added, and the mixture was reacted at 40 ℃ for 7 hours under a hydrogen pressure of 1.5MPa, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 550mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
44mL of ethyl acetate was added to the residue, followed by stirring, 176mL of cyclohexane was added, and the mixture was crystallized by stirring at room temperature (20. + -. 5 ℃ C.), filtered under suction, washed with cyclohexane, and dried to obtain 83g of N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine as a white powdery solid, with a yield of 91.4% and a chemical purity of HPLC of 99.85%.
Example 4
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 330mL of isopropyl acetate and 220mL of ethyl acetate were added, the mixture was stirred until the starting materials were completely dissolved, 5.5g of 10% palladium on charcoal catalyst was added, and the mixture was reacted under a hydrogen pressure of 1.2MPa at 40 ℃ for 8 hours, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 550mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
Adding 88mL of isopropyl acetate into the residue, stirring, adding 220mL of cyclohexane, stirring at room temperature (20 +/-5 ℃) for crystallization, filtering, washing with cyclohexane, and drying to obtain 84g of white powdery solid N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine with the yield of 92.5% and the HPLC chemical purity of 99.91%.
Example 5
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 200mL of isopropyl acetate and 350mL of butyl acetate were added, the mixture was stirred until the starting materials were completely dissolved, 5.5g of 10% palladium on charcoal catalyst was added, and the mixture was reacted at 45 ℃ for 8 hours under a hydrogen pressure of 0.8MPa, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 550mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
Adding 55mL of isopropyl acetate into the residue, stirring, adding 275mL of N-hexane, stirring at room temperature (20 +/-5 ℃) for crystallization, filtering, washing with the N-hexane, and drying to obtain 83.4g of white powdery solid N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine, wherein the yield is 91.8% and the chemical purity of HPLC is 99.89%.
Example 6
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 550mL of isopropyl acetate was added, the mixture was stirred until the starting material was completely dissolved, 11g of 10% palladium on charcoal catalyst was added, and the mixture was reacted at 50 ℃ for 7 hours under a hydrogen pressure of 0.6MPa, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 500mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
66mL of isopropyl acetate is added into the residue, stirred, 132mL of N-hexane is added, stirred and crystallized at room temperature (20 +/-5 ℃), filtered, washed by the N-hexane and dried to obtain 83.6g of white powdery solid N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine, the yield is 92.0 percent, and the chemical purity of HPLC is 99.91 percent.
Example 7
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 550mL of butyl acetate was added, the mixture was stirred until the starting material was completely dissolved, 11g of 10% palladium on carbon catalyst was added, and the mixture was reacted at 50 ℃ for 7 hours under a hydrogen pressure of 0.4MPa, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 550mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
Adding 165mL of butyl acetate into the residue, stirring, adding 330mL of N-hexane, cooling to 10 ℃, stirring, crystallizing, filtering, washing with N-hexane, and drying to obtain 84.2g of white powdery solid N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine with the yield of 92.6% and the chemical purity of HPLC of 99.92%.
Example 8
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 400mL of butyl acetate and 260mL of ethyl acetate were added, the mixture was stirred until the starting material was completely dissolved, 16.5g of 10% palladium on charcoal catalyst was added, and the mixture was reacted at 60 ℃ for 6 hours under a hydrogen pressure of 0.3MPa, at which time the pressure in the kettle did not change. The reaction solution is cooled to room temperature (20 +/-5 ℃), filtered, the filtrate is washed by 600mL of saturated sodium chloride solution, the organic phase is dried by anhydrous sodium sulfate, filtered, and concentrated to obtain a viscous residue.
And adding 220mL of butyl acetate into the residue, stirring, adding 440mL of N-hexane, cooling to 10 ℃, stirring, crystallizing, filtering, washing with N-hexane, and drying to obtain 85.2g of white powdery solid N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine, wherein the yield is 93.7% and the chemical purity of HPLC is 99.95%.
Example 9
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 550mL of methyl acetate was added, the mixture was stirred until the starting material was completely dissolved, 5.5g of 10% palladium on charcoal catalyst was added, and the mixture was reacted at 35 ℃ for 6 hours under a hydrogen pressure of 0.5MPa, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 500mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
110mL of methyl acetate was added to the residue, followed by stirring, 440mL of cyclohexane was added thereto, and the mixture was stirred at room temperature (20. + -. 5 ℃ C.) to crystallize, which was then subjected to suction filtration, washed with cyclohexane, and dried to obtain 83.2g of N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine as a white powdery solid, with a yield of 91.5% and a chemical purity of HPLC of 99.88%.
Example 10
110.00g N-methyl-N- [2- (4-nitrophenoxy) ethyl ] -4-nitrophenylethylamine was weighed, 300mL of methyl acetate and 250mL of ethyl acetate were added, the mixture was stirred until the starting materials were completely dissolved, 5.5g of 10% palladium on charcoal catalyst was added, and the mixture was reacted at 60 ℃ for 6 hours under a hydrogen pressure of 0.6MPa, at which time the pressure in the kettle did not change. The reaction solution is cooled to room temperature (20 +/-5 ℃), filtered, the filtrate is washed by 600mL of saturated sodium chloride solution, the organic phase is dried by anhydrous sodium sulfate, filtered, and concentrated to obtain a viscous residue.
Adding 110mL of methyl acetate into the residue, stirring, adding 330mL of N-hexane, stirring at room temperature (20 +/-5 ℃) for crystallization, filtering, washing with the N-hexane, and drying to obtain 83.7g of white powdery solid N-methyl-N- [2- (4-aminophenoxy) ethyl ] -4-aminophenylethylamine, wherein the yield is 92.1% and the chemical purity of HPLC is 99.91%.
Example 11
Weighing 10.0g of 1- (4-nitrophenoxy) -2- [ N-methyl-N- (4-methylsulfonylaminophenethyl) amino ] ethane, adding 55mL of butyl acetate, stirring until the raw materials are completely dissolved, adding 1.0g of 10% palladium-carbon catalyst, and reacting the mixture at 50 ℃ for 5 hours under the hydrogen pressure of 0.8MPa, wherein the pressure in the kettle does not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 55mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a viscous residue.
10mL of butyl acetate was added to the residue, followed by stirring, 40mL of cyclohexane was added, followed by crystallization with stirring at room temperature (20. + -. 5 ℃ C.), suction filtration, washing with cyclohexane, and drying to obtain 1- (4-aminophenoxy) -2- [ N-methyl-N- (4-methanesulfonylaminophenylethyl) amino ] ethane (8.31 g) as a white powdery solid, with a yield of 90% and a chemical purity of HPLC of 99.93%.
Example 12
Weighing 10.0g of 1- (4-methylsulfonylaminophenoxy) -2- [ N-methyl-N- (4-nitrophenylethyl) amino ] ethane, adding 60mL of isopropyl acetate, stirring until the raw materials are completely dissolved, adding 0.8g of 10% palladium-carbon catalyst, and reacting the mixture at 40 ℃ for 5 hours under the hydrogen pressure of 0.3MPa, wherein the pressure in the kettle does not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 60mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a yellow solid.
Adding 15mL of isopropyl acetate into the yellow solid, stirring at 40 ℃ until the raw materials are dissolved, adding 40mL of N-hexane, cooling to room temperature (20 +/-5 ℃), stirring, crystallizing, filtering, washing with N-hexane, and drying to obtain 8.43g of 1- (4-methylsulfonylaminophenoxy) -2- [ N-methyl-N- (4-aminophenylethyl) amino ] ethane as a white powdery solid, wherein the yield is 91.3% and the chemical purity of HPLC is 99.92%.
Example 13
10.0g of 4- {2[ N-methyl-N- (4-nitrophenylethyl) amino ] ethoxy } benzamide was weighed, 50mL of ethyl acetate was added, the mixture was stirred until the starting material was completely dissolved, 0.7g of 10% palladium on carbon catalyst was added, and the mixture was reacted under a hydrogen pressure of 0.2MPa at 35 ℃ for 8 hours, at which time the pressure in the kettle did not change. The reaction solution was cooled to room temperature (20. + -. 5 ℃ C.), filtered, the filtrate was washed with 50mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a yellow solid.
Adding 8mL of ethyl acetate into the yellow solid, stirring at 40 ℃ until the raw materials are dissolved, adding 40mL of N-hexane, cooling to room temperature (20 +/-5 ℃), stirring, crystallizing, filtering, washing with N-hexane, and drying to obtain 8.26g of white powdery solid 4- {2- [ N-methyl-N- (4-aminophenyl ethyl) amino ] ethoxy } benzamide, wherein the yield is 90.5%, and the chemical purity of HPLC is 99.90%.
In conclusion, the method has the advantages of high yield and purity, simple and convenient operation, high production efficiency, environmental protection, safety, suitability for industrial mass production and wide market application prospect.
Claims (6)
1. The preparation method of the dofetilide intermediate and the analogue thereof is characterized in that: the method comprises the following steps:
dissolving the compound of formula (I) in a reaction solvent, and hydrogenating and reducing-NO of the compound of formula (I) by using palladium-carbon as a catalyst2is-NH2Separating and purifying after reaction to obtain the product;
the reaction solvent is selected from one or two of ethyl acetate, isopropyl acetate, butyl acetate and methyl acetate;
the purification comprises a step of recrystallization by an anti-solvent method; in the recrystallization by the anti-solvent method, the solvent A is any one of ethyl acetate, isopropyl acetate, butyl acetate and methyl acetate, and the anti-solvent B is n-hexane or cyclohexane;
volume-to-mass ratio of solvent a to compound of formula (I): 0.4-2.0: 1 mL/g; volume to mass ratio of antisolvent B to compound of formula (I): 0.8-4.0: 1 mL/g;
the volume ratio of the solvent A to the anti-solvent B is 1: 2-1: 5;
the compound of formula (I) is represented by formula (III):
2. the method of claim 1, wherein: the volume mass ratio of the reaction solvent to the compound of the formula (I) is 3-10: 1 mL/g.
3. The method of claim 2, wherein: the volume-mass ratio of the reaction solvent to the compound of the formula (I) is 3-6: 1 mL/g.
4. The method of claim 1, wherein: the palladium-carbon is a 10% palladium-carbon catalyst, and the weight ratio of the palladium-carbon catalyst to the compound of the formula (I) is 0.05: 1-0.15: 1.
5. The method of claim 1, wherein: the reaction temperature of the hydrogenation reduction is 35-60 ℃.
6. The method of claim 1, wherein: the hydrogen pressure of the hydrogenation reduction is 0.2-1.5 MPa.
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| WO1999063932A2 (en) * | 1998-06-08 | 1999-12-16 | Advanced Medicine, Inc. | Multibinding agents that modulate the 5-ht transporter |
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| CN105017160A (en) * | 2015-06-24 | 2015-11-04 | 温州医科大学 | Pyrimidine EGFRT790M inhibitors and their synthesis method and use |
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| WO1999063932A2 (en) * | 1998-06-08 | 1999-12-16 | Advanced Medicine, Inc. | Multibinding agents that modulate the 5-ht transporter |
| CN104744272A (en) * | 2015-03-24 | 2015-07-01 | 浙江鼎龙科技有限公司 | Method for preparing 2-( methoxyl-methyl) phenyl-1,4-diamine |
| CN105017160A (en) * | 2015-06-24 | 2015-11-04 | 温州医科大学 | Pyrimidine EGFRT790M inhibitors and their synthesis method and use |
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