CN107365297B - Preparation method and intermediate of 2-methyl-2' -phenylpropionic acid derivative - Google Patents
Preparation method and intermediate of 2-methyl-2' -phenylpropionic acid derivative Download PDFInfo
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Abstract
The invention relates to a preparation method of a 2-methyl-2' -phenylpropionic acid derivative and an intermediate thereof, and the method is simple, efficient, less in side reaction, high in yield, low in cost and suitable for industrial production.
Description
Technical Field
The invention relates to the field of medical treatment, in particular to a preparation method of a 2-methyl-2' -phenylpropionic acid derivative and a novel intermediate compound thereof.
Background
The 2-methyl-2' -phenylpropionic acid derivative of the following formula 1 is widely used in the pharmaceutical field.
[ formula 1]
Wherein R is2Hydrogen or-CH2CH2OR3；R3C being branched or straight chain1-C10An alkyl group.
Having H, exclusively of 2-methyl-2' phenylpropionic acid derivatives1Antihistamine activity, therefore, without interaction with other drug receptors, exhibits high selectivity even at high doses, with antihistamine properties but no sedative or cardiovascular effects. Therefore, the 2-methyl-2' -phenylpropionic acid derivative can be used for patients suffering from allergic diseases, particularly patients taking other medicines simultaneously, such as those suffering from cardiovascular diseases.
CN 101952273a discloses a preparation method of 2-methyl-2' -phenylpropionic acid derivatives of formula 1. However, in this method, the elimination reaction of key intermediates inevitably occurs during the preparation process, which makes the whole process quite complicated, the requirements for reaction conditions are strict and not easy to control, a large amount of side reactions not only increase the raw material cost, but also a large amount of by-products cause purification problems, and thus, the yield of the method for preparing the 2-methyl-2' -phenylpropionic acid derivative of formula 1 on an industrial scale is low.
Therefore, there is a need to improve the yield and purity of the 2-methyl-2' -phenylpropionic acid derivatives of formula 1 and to make their preparation methods more suitable for industrial production.
Disclosure of Invention
The present invention provides a method for preparing 2-methyl-2' -phenylpropionic acid derivatives and intermediates thereof.
In one aspect, the present invention provides a method for preparing a 2-methyl-2' -phenylpropionic acid derivative of the following formula 1, comprising the step of reacting a compound of the following formula 2 with a compound of the following formula 3:
[ formula 2]
[ formula 3]
[ formula 1]
Wherein R is1Is hydrogen, branched or straight-chain C1-C10Alkyl, or C3-C6A cycloalkyl group;
R2is hydrogen or-CH2CH2OR3；
R3C being branched or straight chain1-C10An alkyl group.
Optionally, the reaction is carried out in the presence of a reducing agent.
Optionally, the reducing agent is sodium borohydride acetate, sodium cyanoborohydride, sodium borohydride, or borane tetrahydrofuran.
Optionally, the R is1C being branched or straight chain1-C6An alkyl group.
Optionally, the R is3C being branched or straight chain1-C6An alkyl group.
Optionally, R1When not hydrogen, it further comprises the step of hydrolysis of the ester in the reaction product.
Optionally, R2In the case of hydrogen, the further reaction thereof comprises the step of reacting the reaction product with a compound of the following formula 4:
[ formula 4]
XCH2CH2OR3
Wherein R is3C being branched or straight chain1-C10An alkyl group;
x is a leaving group.
Optionally, X is chloro, bromo, iodo, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy or methanesulfonyloxy.
Alternatively, the 2-methyl-2' -phenylpropionic acid derivative of formula 1 is 2- [4- (2- [4- [1- (2-ethoxy-ethyl) -1H-benzimidazol-2-yl ] -piperidin-1-yl) -ethyl ] -phenyl ] -2-methyl-propionic acid.
In another aspect, the present invention provides a compound of formula 2:
[ formula 2]
Wherein R is1Is hydrogen, branched or straight-chain C1-C10Alkyl, or C3-C6A cycloalkyl group.
Optionally, the R is1C being branched or straight chain1-C6An alkyl group.
The invention has the beneficial effects that: the preparation method of the invention has the advantages of simplicity, high efficiency, high yield, low cost and simple purification, especially when the compound of the formula 2 is carboxylic acid (when R is R)1When hydrogen) carboxylic acid can be synthesized in one step without protection and deprotectionThe 2-methyl-2' -phenylpropionic acid derivative is formed, and the industrial production is easy to realize.
Detailed Description
Currently, the method for preparing the 2-methyl-2' -phenylpropionic acid derivative of formula 1 has a low yield and is difficult to purify.
Therefore, there is a need to improve the yield and purity of the 2-methyl-2' -phenylpropionic acid derivatives of formula 1 and to make their preparation methods more suitable for industrial production.
The present invention provides a method for preparing 2-methyl-2' -phenylpropionic acid derivatives and intermediates thereof.
In one aspect, the present invention provides a method for preparing a 2-methyl-2' -phenylpropionic acid derivative of the following formula 1, comprising the step of reacting a compound of the following formula 2 with a compound of the following formula 3:
[ formula 2]
[ formula 3]
[ formula 1]
Wherein R is1Is hydrogen, branched or straight-chain C1-C10Alkyl, or C3-C6A cycloalkyl group; r2Is hydrogen or-CH2CH2OR3；R3C being branched or straight chain1-C10An alkyl group.
In the above method, the compound of formula 2 and the compound of formula 3 are reacted in the presence of a reducing agent. The reducing agent is not particularly limited as long as it is known to those skilled in the art and can achieve the above reaction. Optionally, the reducing agent is sodium borohydride acetate, sodium cyanoborohydride, sodium borohydride, or borane tetrahydrofuran. The compound of formula 2 and the compound of formula 3 can be better reacted to generate the compound of formula 1 by using the reduction reagents, and the method has the advantages of high yield, simplicity, high efficiency and low cost.
R1Is hydrogen, branched or straight-chain C1-C10Alkyl, or C3-C6A cycloalkyl group. When R is1When the compound is hydrogen, the compound of the formula 2 and the compound of the formula 3 react to obtain the 2-methyl-2 '-phenylpropionic acid derivative, carboxylic acid does not need protection and deprotection, the 2-methyl-2' -phenylpropionic acid derivative can be directly synthesized in one step, and industrial production is easier; when R is1C being branched or straight chain1-C10Alkyl, or C3-C6In the case of cycloalkyl, after the reaction of the compound of formula 2 and the compound of formula 3, if necessary, a step of hydrolyzing an ester in the reaction product to an acid may be further included, and the hydrolysis conditions of the ester are not particularly limited as long as they can be achieved. Optionally, the R is1C being branched or straight chain1-C6An alkyl group. When R is1C being branched or straight chain1-C6In the case of alkyl, the raw materials are cheap and easy to obtain, side reactions are less, and the yield is high. R2Is hydrogen or-CH2CH2OR3，R3C being branched or straight chain1-C10Alkyl, optionally, the R3C being branched or straight chain1-C6An alkyl group. When R is2In the case of hydrogen, the reaction product may be further reacted with a compound of the following formula 4, if necessary.
[ formula 4]
XCH2CH2OR3。
R3C being branched or straight chain1-C10An alkyl group. Optionally, the R is3C being branched or straight chain1-C6An alkyl group. X is a leaving group, and X is not particularly limited as long as it is a leaving group known to those skilled in the art to be capable of achieving the above reaction, and optionally, X is chlorine, bromine, iodine, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, methanesulfonyloxy, or the like.
Alternatively, the 2-methyl-2' -phenylpropionic acid derivative of formula 1 is 2- [4- (2- [4- [1- (2-ethoxy-ethyl) -1H-benzimidazol-2-yl ] -piperidin-1-yl) -ethyl ] -phenyl ] -2-methyl-propionic acid.
In another aspect, the present invention provides a compound of formula 2:
[ formula 2]
Wherein R is1Is hydrogen, branched or straight-chain C1-C10Alkyl, or C3-C6Cycloalkyl, optionally, said R1C being branched or straight chain1-C6An alkyl group. The compound of formula 2 is a new intermediate for preparing 2-methyl-2 '-phenylpropionic acid derivatives, and the method for preparing the 2-methyl-2' -phenylpropionic acid derivatives by using the compound of formula 2 is simple and efficient, has high yield and low cost, and is easy for industrial production.
The compound of formula 2 may be prepared by any method deemed feasible by one skilled in the art, and alternatively, may be prepared by a compound of formula 5 below.
[ formula 5]
Wherein R is1Is hydrogen, branched or straight-chain C1-C10Alkyl, or C3-C6Cycloalkyl, optionally, said R1C being branched or straight chain1-C6An alkyl group.
The compound of formula 5 may be used to prepare the compound of formula 2 in the presence of an oxidizing agent, which is not particularly limited as long as there is an ability to achieve the preparation of the compound of formula 2 from the compound of formula 5, and the oxidizing agent may be selected from Dess-Martin oxidizer, 2-iodoxybenzoic acid (IBX), sulfur trioxide pyridine, Tempo oxidizer, hydrogen peroxide, or the like. R1Is hydrogen, branched or straight-chain C1-C10Alkyl, or C3-C6A cycloalkyl group.
A compound of formula 5, R1Is hydrogen, branched or straight-chain C1-C10Alkyl, or C3-C6Cycloalkyl, optionally, said R1C being branched or straight chain1-C6An alkyl group. When R is1When not hydrogen, the compound of formula 5 may be substituted by R1The compound of formula 5, which is hydrogen, is prepared by esterification. The esterification reaction is not particularly limited as long as the conditions can be achieved. The reaction may be carried out under acidic conditions or basic conditions. For acidic conditions, the acid may be selected from sulfuric acid, thionyl chloride, and the like; for basic conditions, the base may be selected from potassium carbonate, sodium bicarbonate, sodium hydroxide, dimethylaminopyridine, and the like.
The experimental reagents described in the examples of the present invention are commercially available unless otherwise noted.
In order to further illustrate the present invention, the following specific examples are given to describe the present invention in detail. In the following description of the embodiments, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described herein, and thus the present invention is not limited to the specific embodiments disclosed below.
Example 1: preparation of 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid methyl ester
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid (5.0g), methanol (50mL) and concentrated sulfuric acid (0.5mL) were added, heated to 80 ℃, stirred for reaction for 20 hours, cooled to room temperature, a saturated aqueous sodium carbonate solution was added dropwise, the pH was adjusted to neutral, concentrated to no more drip, 30mL of water was added and stirred for 1 hour, 10mL of ethyl acetate was added and extracted three times, the organic phases were combined, washed with 10mL of saturated brine, the organic phase was separated, dried with 2g of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionate (5.3g, yield 100%).
1HNMR，500MHZ，CDCl3，ppm：1.56(s，6H)，2.03(t，1H)，2.82(t，2H)，3.64(s，3H)，3.82(t，2H)，7.17(d，2H)，7.27(d，2H)。MS(ESI)：[M+H]+＝222.98
Example 2: preparation of 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid methyl ester
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid (2.5g), dimethylformamide (12.5mL) and potassium carbonate (5g) were added, stirred at room temperature, iodomethane (2.0g) was added dropwise, the reaction was stirred at room temperature for 4 hours, 30mL of water was added, stirred for 30 minutes, 5mL of ethyl acetate was added and extracted three times, the organic phases were combined, washed three times with 10mL of saturated brine, the organic phases were separated, dried over 1g of anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was concentrated under reduced pressure to give methyl 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionate (2.7g, yield 100%).
1HNMR，500MHZ，CDCl3，ppm：1.56(s，6H)，2.03(t，1H)，2.82(t，2H)，3.64(s，3H)，3.82(t，2H)，7.17(d，2H)，7.27(d，2H)。MS(ESI)：[M+H]+＝222.98
Example 3: preparation of 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid ethyl ester
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid (2.5g), ethanol (25mL) and concentrated sulfuric acid (0.3mL) were added, heated to 80 ℃, stirred for reaction for 22 hours, cooled to room temperature, a saturated aqueous sodium carbonate solution was added dropwise, the pH was adjusted to neutral, concentrated to no more drip, 10mL of water was added and stirred for 1 hour, 5mL of ethyl acetate was added and extracted three times, the organic phases were combined, washed with 5mL of saturated brine, the organic phase was separated, dried with 1g of anhydrous sodium sulfate for 3 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain ethyl 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionate (2.8g, yield 100%).
MS(ESI)：[M+H]+＝237.03
Example 4: preparation of isopropyl 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionate
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid (4g), dimethylformamide (20mL) and potassium carbonate (8g) were added, stirred at room temperature, isopropyl iodide (3.9g) was added dropwise, stirred at room temperature for 6 hours, 80mL of water was added, stirred for 30 minutes, extracted three times with 15mL of ethyl acetate, the organic phases were combined, washed twice with 10mL of saturated saline, the organic phase was separated, dried over 2g of anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was concentrated under reduced pressure to give isopropyl 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionate (4.8g, yield 100%).
MS(ESI)：[M+H]+＝251.10
Example 5: preparation of n-butyl 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionate
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid (2.5g), n-butanol (25mL) and concentrated sulfuric acid (0.5mL) were added, heated to 90 ℃, stirred for reaction for 24 hours, cooled to room temperature, a saturated aqueous sodium carbonate solution was added dropwise, the pH was adjusted to neutral, concentrated to no more drip, 10mL of water was added, stirred for 1 hour, 5mL of ethyl acetate was added and extracted three times, the organic phases were combined, washed with 5mL of saturated brine, the organic phase was separated, dried with 1g of anhydrous sodium sulfate for 3 hours, filtered, and the filtrate was concentrated under reduced pressure to give n-butyl 2- (4- (2-hydroxyethyl) -phenyl) -propionate (3.1g, yield 98%).
MS(ESI)：[M+H]+＝264.74
Example 6: preparation of 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid cyclohexyl ester
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid (2.5g), cyclohexanol (25mL) and concentrated sulfuric acid (1mL) were added, heated to 100 ℃, stirred for reaction for 26 hours, cooled to room temperature, saturated aqueous sodium carbonate solution was added dropwise, the pH was adjusted to neutral, concentrated to no more drip, 10mL of water was added and stirred for 1 hour, 5mL of ethyl acetate was added and extracted three times, the organic phases were combined, washed with 5mL of saturated brine, the organic phase was separated, dried over 2g of anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was concentrated under reduced pressure to give 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid cyclohexyl ester (3.4g, yield 97%).
MS(ESI)：[M+H]+＝291.01
Example 7: preparation of 2-methyl-2- (4- (2-oxoethyl) -phenyl) propionic acid
In a reaction vessel, 2- (4- (2-hydroxyethyl) -phenyl) -2-methylpropanoic acid (2.0g), Dess-Martin oxidant (6.1g) and dichloromethane (60.0mL) were added, the reaction was stirred at room temperature for 5 hours, filtered, the filtrate was washed with 20mL of a sodium thiosulfate solution, the organic phase was separated, dried over 2g of anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to give 2-methyl-2- (4- (2-oxoethyl) -phenyl) propanoic acid (2.0g, yield 100%).
1HNMR，500MHZ，DMSO-d6，ppm：1.69(s，6H)，3.85(d，2H)，7.28(d，2H),7.32(d，2H),9.69(t，1H)。MS(ESI)：[M+H]+＝207.01
Example 8: preparation of 2-methyl-2- (4- (2-oxoethyl) -phenyl) propionic acid
In a reaction vessel, 2- (4- (2-hydroxyethyl) phenyl) -2-methylpropanoic acid (0.5g), IBX oxidant (1.0g) and ethyl acetate (20.0mL) were added, heated to 70 ℃, stirred for reaction for 16 hours, filtered, the filtrate was washed with 10mL sodium thiosulfate solution, the organic phase was separated, dried over 1g anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to give 2-methyl-2- (4- (2-oxoethyl) -phenyl) propanoic acid (0.5g, yield 100%).
1HNMR，500MHZ，DMSO-d6，ppm：1.69(s，6H)，3.85(d，2H)，7.28(d，2H),7.32(d，2H),9.69(t，1H)。MS(ESI)：[M+H]+＝207.01
Example 9: preparation of 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid methyl ester
In a reaction vessel, methyl 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionate prepared in example 1 (4.5g), Dess-Martin oxidant (12.2g) and dichloromethane (60mL) were added, the reaction was stirred at room temperature for 5 hours, filtered, the filtrate was washed with 40mL of sodium thiosulfate solution, the organic phase was separated, and dried over 4g of anhydrous sodium sulfate for 3 hours. Filtration and concentration of the filtrate under reduced pressure gave 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid methyl ester (4.5g, 100% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.50(s，6H)，3.58(s，3H)，3.73(d，2H)，7.23(d，2H),7.30(d，2H),9.68(t，1H)。MS(ESI)：[M+H]+＝220.98
Example 10: preparation of 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid methyl ester
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid methyl ester (2.2g) obtained in example 2 and methylene chloride (20mL) were added, cooled to 0 ℃ and stirred for 30 minutes, 2mL of dimethyl sulfoxide, N, N-diisopropylethylamine (DIPEA, 2.4mL) was added, stirred and reacted for 30 minutes, pyridine trioxide was added, reacted at 0 ℃ for 5 hours, 10mL of a sodium thiosulfate solution was added and stirred for 1 hour, the organic phase was separated, washed with 10mL of saturated brine, separated, and dried with 1g of anhydrous sodium sulfate for 3 hours. Filtration and concentration of the filtrate under reduced pressure gave 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid methyl ester (2.1g, 95% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.50(s，6H)，3.58(s，3H)，3.73(d，2H)，7.23(d，2H),7.30(d，2H),9.68(t，1H)。MS(ESI)：[M+H]+＝220.98
Example 11: preparation of 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid ethyl ester
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid ethyl ester (2.3g) obtained in example 3, Dess-Martin oxidant (5.0g) and dichloromethane (25mL) were added, the reaction was stirred at room temperature for 3 hours, filtered, the filtrate was washed with 10mL of sodium thiosulfate solution, and the organic phase was separated and dried over 1.5g of anhydrous sodium sulfate for 3 hours. Filtration and concentration of the filtrate under reduced pressure gave 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid ethyl ester (2.3g, 100% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.29(t，3H)，1.50(s，6H)，3.66(m，2H)，3.79(d，2H)，7.32(d，2H),7.39(d，2H),9.86(t，1H)。MS(ESI)：[M+H]+＝235.28
Example 12: preparation of isopropyl 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionate
2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -isopropyl propionate prepared in example 4 (2.5g), Dess-Martin oxidant (7.0g) and methylene chloride (40mL) were charged into a reaction vessel, stirred at room temperature for 4 hours, filtered, the filtrate was washed with 10mL of sodium thiosulfate solution, the organic phase was separated, and dried over 2g of anhydrous sodium sulfate for 4 hours. Filtration and concentration of the filtrate under reduced pressure gave isopropyl 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionate (2.4g, 96% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.21(d，6H)，1.53(s，6H)，3.59(m，1H)，3.94(d，2H)，7.31(d，2H),7.42(d，2H),9.82(t，1H)。MS(ESI)：[M+H]+＝249.34
Example 13: preparation of n-butyl 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionate
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid n-butyl ester (2.6g) obtained in example 5, Dess-Martin oxidant (8.4g) and dichloromethane (50mL) were added, the reaction was stirred at room temperature for 5 hours, filtered, the filtrate was washed with 20mL of sodium thiosulfate solution, and the organic phase was separated and dried over 1g of anhydrous sodium sulfate for 3 hours. Filtration and concentration of the filtrate under reduced pressure gave 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid n-butyl ester (2.6g, 100% yield).
1HNMR，500MHZ，DMSO-d6，ppm：0.81(m，3H)，1.17(m，2H)，1.49(m，8H)，3.48(m，2H)，3.99(m，2H)，7.12(d，2H),7.18(d，2H),9.74(t，1H)。MS(ESI)：[M+H]+＝263.99
Example 14: preparation of 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid cyclohexyl ester
In a reaction vessel, 2-methyl-2- (4- (2-hydroxyethyl) -phenyl) -propionic acid cyclohexyl ester (2.9g) obtained in example 6, Dess-Martin oxidant (8.4g) and dichloromethane (50mL) were added, the reaction was stirred at room temperature for 5 hours, filtered, the filtrate was washed with 10mL of sodium thiosulfate solution, and the organic phase was separated and dried over 2g of anhydrous sodium sulfate for 3 hours. Filtration and concentration of the filtrate under reduced pressure gave 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid cyclohexyl ester (2.8g, 96% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.04(m，2H)，1.23(m，6H)，1.52(m，8H)，3.48(m，1H)，3.84(m，2H)，7.17(d，2H),7.22(d，2H),9.70(t，1H)。MS(ESI)：[M+H]+＝288.98
Example 15: preparation of methyl 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propanoate
In a reaction vessel, 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid methyl ester (1.1g) obtained in example 9, 1- (2-ethoxyethyl) -2-piperidin-4-yl-1H-benzimidazole (1.3g) and tetrahydrofuran (20mL) were charged, reacted at room temperature for 4 hours, sodium borohydride acetate (2.1g) was added in portions, stirred and reacted for 4 hours, filtered, the filtrate was concentrated under reduced pressure, 30mL of methylene chloride and 10mL of a saturated sodium bicarbonate solution were added, the organic phase was separated, dried over 1g of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated under reduced pressure to give 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] - Ethyl } phenyl) -2-methyl-propionic acid methyl ester (2.3g, 98% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.00(t，3H)，1.49(s，6H)，1.85-1.90(m，4H)，2.09(m，2H)，2.54(t，2H)，2.74(t，2H)，3.04(m，3H)，3.34(m，2H)，3.58(s，3H)，3.65(t，2H)，4.39(t，2H)，7.15(m，2H),7.20(d，2H),7.26(d，2H)，7.51(d，1H)，7.55(d，1H)。MS(ESI)：[M+H]+＝478.52
Example 16: preparation of methyl 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propanoate
In a reaction vessel, 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid methyl ester (1.1g) prepared in example 10, 1- (2-ethoxyethyl) -2-piperidin-4-yl-1H-benzimidazole (1.3g), tetrahydrofuran (20mL) were added and reacted at room temperature for 4 hours, sodium cyanoborohydride (0.6g) was added in portions, stirred and reacted for 6 hours, filtered, the filtrate was concentrated under reduced pressure, 30mL of methylene chloride was added, 10mL of a saturated sodium bicarbonate solution was added and stirred for 1 hour, the organic phase was separated, dried with 1g of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to give 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl ] propionate Phenyl) -2-methyl-propionic acid methyl ester (2.2g, 93% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.00(t，3H)，1.49(s，6H)，1.85-1.90(m，4H)，2.09(m，2H)，2.54(t，2H)，2.74(t，2H)，3.04(m，3H)，3.34(m，2H)，3.58(s，3H)，3.65(t，2H)，4.39(t，2H)，7.15(m，2H),7.20(d，2H),7.26(d，2H)，7.51(d，1H)，7.55(d，1H)。MS(ESI)：[M+H]+＝478.52
Example 17: preparation of methyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propanoate
In a reaction vessel, 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid methyl ester (1.1g) prepared in example 9, 2- (4-piperidine) -1H-benzimidazole (1.0g), tetrahydrofuran (20mL) were added, reacted at room temperature for 2 hours, sodium borohydride acetate (3.6g) was added in portions, the reaction was completed for 6 hours, filtered, the filtrate was concentrated to dryness, 20mL of dichloromethane and 10mL of a saturated sodium bicarbonate solution were added and stirred for 1 hour, the organic phase was separated, dried over 1g of anhydrous sodium sulfate for 2 hours, filtered, the filtrate was concentrated to obtain 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionic acid methyl ester (1.9g, yield 95%).
MS(ESI)：[M+H]+＝406.12
Example 18: preparation of methyl 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propanoate
In a reaction vessel, methyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionate (1.6g) obtained in example 17, tetrahydrofuran (20mL), sodium hydrogen (0.8g) were charged, heated to 45 ℃ and a tetrahydrofuran (5mL) solution of ethyl 2-ethoxyp-toluenesulfonate (1.5g) was added dropwise, the reaction was allowed to proceed for 4 hours, cooled to room temperature, concentrated under reduced pressure, 20mL of dichloromethane and 10mL of water were added thereto and stirred for 30 minutes, the organic phase was separated, washed with 10mL of saturated saline, separated, dried over 1g of anhydrous sodium sulfate for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to give 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazole-one-type 2-Yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionic acid methyl ester (1.8g, 95% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.00(t，3H)，1.49(s，6H)，1.85-1.90(m，4H)，2.09(m，2H)，2.54(t，2H)，2.74(t，2H)，3.04(m，3H)，3.34(m，2H)，3.58(s，3H)，3.65(t，2H)，4.39(t，2H)，7.15(m，2H),7.20(d，2H),7.26(d，2H)，7.51(d，1H)，7.55(d，1H)。MS(ESI)：[M+H]+＝478.52
Example 19: preparation of ethyl 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionate
In a reaction vessel, 2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid ethyl ester (1.2g) prepared in example 11, 1- (2-ethoxyethyl) -2-piperidin-4-yl-1H-benzimidazole (1.4g), tetrahydrofuran (20mL) were added and reacted at room temperature for 4 hours, sodium borohydride acetate (2.1g) was added in portions, the reaction was completed for 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, 20mL of methylene chloride was added, 10mL of a saturated sodium bicarbonate solution was washed, the organic phase was separated, dried over 1g of anhydrous sodium sulfate for 2 hours, filtration was carried out, and the filtrate was concentrated to obtain 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl ) Ethyl-2-methyl-propionate (2.4g, 100% yield).
MS(ESI)：[M+H]+＝492.28
Example 20: preparation of 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionic acid
In a reaction vessel, 2-methyl-2- (4- (2-oxoethyl) phenyl) propionic acid (1.0g) obtained in example 7, 1- (2-ethoxyethyl) -2-piperidin-4-yl-1H-benzimidazole (1.3g) and tetrahydrofuran (15mL) were added, and the mixture was stirred at room temperature for 5 hours, then sodium borohydride acetate (4.2g) was added, and the mixture was reacted at room temperature for 16 hours, followed by filtration, then the filtrate was concentrated under reduced pressure, 10mL of methylene chloride and 5mL of a saturated sodium bicarbonate solution were added and stirred for 1 hour, the organic phase was separated, dried over 1g of anhydrous sodium sulfate for 2 hours, followed by filtration, and the filtrate was concentrated under reduced pressure to give 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl ) 2-methyl-propionic acid (2.0g, 88% yield).
1HNMR，500MHZ，DMSO-d6，ppm：1.00(t，3H)，1.46(s，6H)，1.88(m，4H)，2.13(m，2H)，2.57(t，2H)，2.75(t，2H)，3.08(m，3H)，3.34(m，2H)，3.65(t，2H)，4.39(t，2H)，7.15(m，2H),7.21(d，2H),7.26(d，2H),7.53(m，2H)。MS(ESI)：[M+H]+＝464.45
Example 21: preparation of 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionic acid
Methyl 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionate (2.0g) prepared in example 15, 0.5g of sodium hydroxide, 1mL of water and 20mL of ethanol were charged into one reaction vessel, heated under reflux for 7 hours, cooled to room temperature, concentrated under reduced pressure, added with 20mL of water, adjusted to neutral pH with a dilute hydrochloric acid solution, stirred for one hour, filtered to give 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionic acid (1.8g, yield 96%).
1HNMR，500MHZ，DMSO-d6，ppm：1.00(t，3H)，1.46(s，6H)，1.88(m，4H)，2.13(m，2H)，2.57(t，2H)，2.75(t，2H)，3.08(m，3H)，3.34(m，2H)，3.65(t，2H)，4.39(t，2H)，7.15(m，2H),7.21(d，2H),7.26(d，2H),7.53(m，2H)。MS(ESI)：[M+H]+＝464.45
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that many modifications and variations are possible in light of the above teaching. Accordingly, it is intended that all such modifications and variations be included within the scope of the invention as claimed and protected by the accompanying claims.
Claims (7)
1. A method for preparing a 2-methyl-2' -phenylpropionic acid derivative of the following formula 1, comprising the step of reacting a compound of the following formula 2 with a compound of the following formula 3:
[ formula 2]
[ formula 3]
[ formula 1]
Wherein R is1Is hydrogen;
R2is hydrogen or-CH2CH2OR3；
R3C being branched or straight chain1-C10An alkyl group, a carboxyl group,
the reaction is carried out in the presence of a reducing agent, wherein the reducing agent is sodium acetate borohydride, sodium cyanoborohydride, sodium borohydride or borane tetrahydrofuran.
2. The method of claim 1, wherein R is3C being branched or straight chain1-C6An alkyl group.
3. The method of claim 1, wherein R is2In the case of hydrogen, the further reaction thereof comprises the step of reacting the reaction product with a compound of the following formula 4:
[ formula 4]
XCH2CH2OR3
Wherein R is3C being branched or straight chain1-C10An alkyl group;
x is a leaving group.
4. The method of claim 3, wherein X is chloro, bromo, iodo, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, or methanesulfonyloxy.
5. The method of claim 3, wherein R is3C being branched or straight chain1-C6An alkyl group.
6. The method of claim 1, wherein the 2-methyl-2' -phenylpropionic acid derivative of formula 1 is 2- [4- (2- [4- [1- (2-ethoxy-ethyl) -1H-benzimidazol-2-yl ] -piperidin-1-yl) -ethyl ] -phenyl ] -2-methyl-propionic acid.
7. A compound of the following formula 2:
[ formula 2]
Wherein R is1Is hydrogen.
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Denomination of invention: A kind of preparation method of 2-methyl-2'-phenylpropionic acid derivative and intermediate thereof Effective date of registration: 20220907 Granted publication date: 20200703 Pledgee: Bank of China Limited by Share Ltd. Shanghai Development Zone Pudong branch Pledgor: LUOXIN BIOTECHNOLOGY (SHANGHAI) Co.,Ltd. Registration number: Y2022310000235 |