CN110627683A - Preparation method of indanone intermediate - Google Patents
Preparation method of indanone intermediate Download PDFInfo
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- CN110627683A CN110627683A CN201910548123.1A CN201910548123A CN110627683A CN 110627683 A CN110627683 A CN 110627683A CN 201910548123 A CN201910548123 A CN 201910548123A CN 110627683 A CN110627683 A CN 110627683A
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- cyanobenzyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
The invention provides a preparation method of an indanone intermediate, belonging to the field of pharmaceutical chemicals. The method may comprise: 2-cyanobenzyl bromide or 2-cyanobenzyl chloride and dimethyl malonate undergo condensation reaction, hydrolysis and decarboxylation in an organic solvent to obtain 2-cyanophenylpropionic acid; and reacting the obtained 2-cyanophenylpropionic acid with aluminum trichloride and an auxiliary agent to obtain 4-cyano-1-indanone. The method does not need a virulent cyaniding reagent, and has the advantages of high product purity, good safety, high yield, simple operation and the like. The method provided by the invention can effectively prepare the indanone intermediate and provides favorable conditions for further preparing the ozapimod.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an indanone intermediate.
Background
Ozazamod (Ozanimod), CAS No.: 1306760-87-01, a novel oral, selective sphingosine 1 phosphate receptor (S1P1R) modulator, developed for the treatment of autoimmune diseases. Currently, the phase iii clinical trial has been completed on the Multiple Sclerosis (MS) program of the drug.
The chemical structural formula of the ozapimod is shown as follows:
the compound 4-cyano-1-indanone is an important intermediate for preparing the ozapimod. In the prior art, the method for preparing the intermediate 4-cyano-1-indanone has the following problems:
1. the use of highly toxic cyaniding reagents, the toxicity of which is lethal to humans;
2. 4-bromo-1-indanone which is an easily available starting material is used, so that the material cost is high.
These limit the possibility of large-scale production and are not conducive to further production development.
Disclosure of Invention
Definition of terms
The term "about" in the present invention means within ± 10% of the stated numerical value.
In the present invention, the reaction is considered complete or complete when the remaining amount of the raw materials is less than 0.5% of the charged amount.
In the invention, the room temperature is 15-35 ℃, or 20-30 ℃ or 25-28 ℃.
In the present invention, when the main raw material of the reaction is 1% or 0.5% or 0.1% less than the charged amount, the reaction is considered to be complete or complete.
Detailed Description
The present invention is directed to solving, at least to some extent, the technical problems in the related art. Therefore, the invention aims to improve the synthesis method to obtain the intermediate ozagrimod more safely and simply.
The method provided by the invention does not need a virulent cyaniding reagent, has good safety, adopts cheap and easily-obtained raw materials, has mild reaction conditions, and is beneficial to large-scale production.
According to one aspect of the invention, the invention provides a preparation method of an intermediate dimethyl 2- (2-cyanobenzyl) malonate, which comprises the following steps:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in an organic solvent under the action of alkali and a catalyst at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain the dimethyl 2- (2-cyanobenzyl) malonate.
According to one aspect of the invention, the invention provides a preparation method of an intermediate 2- (2-cyanobenzyl) malonic acid, which comprises the following steps:
(2) reacting 2- (2-cyanobenzyl) malonic acid dimethyl ester in an organic solvent under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonic acid.
In some embodiments, according to one aspect of the present invention, a method for preparing an intermediate 2- (2-cyanobenzyl) malonic acid comprises the steps of:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in an organic solvent under the action of alkali and a catalyst at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2- (2-cyanobenzyl) dimethyl malonate; and/or
(2) Reacting 2- (2-cyanobenzyl) malonic acid dimethyl ester in an organic solvent under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonic acid.
According to one aspect of the present invention, there is provided a process for the preparation of an intermediate 2-cyanophenylpropionic acid comprising at least one of the following steps:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in an organic solvent under the action of alkali and a catalyst at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2- (2-cyanobenzyl) dimethyl malonate;
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate; and
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2-cyanophenylpropionic acid.
In some embodiments, according to one aspect of the present invention, a process for preparing an intermediate 2-cyanophenylpropionic acid, comprises the steps of:
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2-cyanophenylpropionic acid.
In some embodiments, according to one aspect of the present invention, a process for preparing an intermediate 2-cyanophenylpropionic acid, comprises the steps of:
(2) adding 2- (2-cyanobenzyl) dimethyl malonate into an organic solvent, reacting under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonic acid; and
(3) dissolving 2- (2-cyanobenzyl) malonic acid in an organic solvent, reacting at a certain temperature, and performing post-treatment after the reaction to obtain 2-cyanophenylpropionic acid.
In some embodiments, according to one aspect of the present invention, a process for preparing an intermediate 2-cyanophenylpropionic acid, comprises the steps of:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in an organic solvent under the action of alkali and a catalyst at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2- (2-cyanobenzyl) dimethyl malonate;
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate; and
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2-cyanophenylpropionic acid.
According to one aspect of the invention, the invention provides a preparation method of indane intermediate 4-cyano-1-indanone, which comprises at least one of the following steps:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in an organic solvent under the action of alkali and a catalyst at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2- (2-cyanobenzyl) dimethyl malonate;
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate;
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2-cyanophenylpropionic acid; and
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and a promoter at a certain temperature, and performing post-treatment after the reaction to obtain 4-cyano-1-indanone.
In some embodiments, according to one aspect of the invention, a process for preparing indane intermediate 4-cyano-1-indanone comprises the steps of:
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and a promoter at a certain temperature, and performing post-treatment after the reaction to obtain 4-cyano-1-indanone.
In some embodiments, according to one aspect of the invention, a process for preparing indane intermediate 4-cyano-1-indanone comprises the steps of:
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2-cyanophenylpropionic acid; and
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and a promoter at a certain temperature, and performing post-treatment after the reaction to obtain 4-cyano-1-indanone.
In some embodiments, according to one aspect of the invention, a process for preparing indane intermediate 4-cyano-1-indanone comprises the steps of:
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate; and
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2-cyanophenylpropionic acid.
In some embodiments, according to one aspect of the invention, a process for preparing indane intermediate 4-cyano-1-indanone comprises the steps of:
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate;
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2-cyanophenylpropionic acid; and
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and a promoter at a certain temperature, and performing post-treatment after the reaction to obtain 4-cyano-1-indanone.
In some embodiments, according to one aspect of the invention, a process for preparing indane intermediate 4-cyano-1-indanone comprises the steps of:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in an organic solvent under the action of alkali and a catalyst at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2- (2-cyanobenzyl) dimethyl malonate;
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate;
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2-cyanophenylpropionic acid; and
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and a promoter at a certain temperature, and performing post-treatment after the reaction to obtain 4-cyano-1-indanone.
In the above method, the base in step (1) is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or a combination thereof; the catalyst in the step (1) is sodium iodide, potassium iodide or a combination thereof.
According to some embodiments of the invention, the organic solvent in step (1) is acetonitrile, N-dimethylformamide, dimethylsulfoxide, acetone, tetrahydrofuran, or a mixture thereof. In some embodiments, the organic solvent in step (1) is acetonitrile.
According to some embodiments of the invention, the temperature in step (1) is about 30 ℃ to about 80 ℃. In some embodiments, the temperature in step (1) is about 40 ℃ to about 80 ℃. In some embodiments, the temperature in step (1) is about 50 ℃ to about 80 ℃. In some embodiments, the temperature in step (1) is about 60 ℃ to about 80 ℃. In some embodiments, the temperature in step (1) is about 65 ℃ to about 75 ℃. In some embodiments, according to some embodiments of the invention, the temperature in step (1) is about 60 ℃ or about 70 ℃.
According to some embodiments of the invention, the base in step (1) is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide. In some embodiments, the base in step (1) is potassium carbonate.
According to some embodiments of the invention, the catalyst in step (1) is sodium iodide or potassium iodide.
According to some embodiments of the invention, the molar ratio of 2-cyanobenzyl bromide or 2-cyanobenzyl chloride charged in step (1) to the base charged in step (1) is 1:1 to 1: 5. In some embodiments, the molar ratio of 2-cyanobenzyl bromide or 2-cyanobenzyl chloride fed in step (1) to the base fed in step (1) is 1:1.5 to 1:3. In some embodiments, the molar ratio of 2-cyanobenzyl bromide or 2-cyanobenzyl chloride fed in step (1) to the base fed in step (1) is 1:2 to 1: 4.
According to some embodiments of the invention, the molar ratio of 2-cyanobenzyl bromide or 2-cyanobenzyl chloride to dimethyl malonate in step (1) is 1:2 to 1: 4. In some embodiments, the molar ratio of 2-cyanobenzyl bromide or 2-cyanobenzyl chloride to dimethyl malonate in step (1) is 1:2.5 to 1: 3.5.
According to some embodiments of the invention, the molar ratio of the catalyst to 2-cyanobenzyl bromide or 2-cyanobenzyl chloride in step (1) is 1:3 to 1: 7. In some embodiments, the molar ratio of the catalyst to 2-cyanobenzyl bromide or 2-cyanobenzyl chloride in step (1) is 1:4 to 1: 6.
According to some embodiments of the invention, the organic solvent in step (2) is C1-C8The alcohol of (1). In some embodiments, the organic solvent in step (2) is methanol or ethanol. According to some embodiments of the invention, the organic solvent in step (2) is dichloromethane, ethyl acetate or toluene. In some embodiments, the organic solvent in step (2) is dichloromethane.
According to some embodiments of the invention, the base in step (2) is sodium hydroxide, potassium hydroxide or potassium tert-butoxide. In some embodiments, the base in step (2) is sodium hydroxide.
According to some embodiments of the invention, in some embodiments, the molar ratio of dimethyl 2- (2-cyanobenzyl) malonate to base in step (2) is 1:3 to 1: 5. In some embodiments, the molar ratio of dimethyl 2- (2-cyanobenzyl) malonate to base in step (2) is 1: 4.
According to some embodiments of the invention, in some embodiments, the alkali in the aqueous solution of alkali in the step (2) is 5% to 15% by mass. In some embodiments, the mass percentage of the base in the aqueous solution of the base in the step (2) is 5% to 10%.
According to some embodiments of the invention, the reaction temperature in step (2) may be from 0 ℃ to 60 ℃ in some embodiments. According to some embodiments of the invention, in some embodiments, the reaction temperature in step (2) is from 20 ℃ to 40 ℃.
According to some embodiments of the present invention, in the step (2), after the reaction is completed, the 2- (2-cyanobenzyl) malonic acid is obtained through post-treatment. In some embodiments, the post-processing comprises: adding dichloromethane, ethyl acetate or toluene into the reaction system, stirring at room temperature, then layering, collecting a water layer, adjusting the pH value to acidity by using acid, extracting by using dichloromethane, ethyl acetate or toluene, combining organic layers, and concentrating under reduced pressure to obtain the 2- (2-cyanobenzyl) malonic acid.
According to some embodiments of the invention, the organic solvent in step (3) is xylene, toluene, N-dimethylformamide, dimethylsulfoxide, N-butanol, sulfolane, N-methylpyrrolidone, or a combination thereof. In some embodiments, the organic solvent in step (3) is xylene or toluene. In some embodiments, the organic solvent in step (3) is xylene.
According to some embodiments of the present invention, in the step (3), the organic solvent may be used in an amount of 5mL to 50mL per gram of 2- (2-cyanobenzyl) malonic acid. In some embodiments, in step (3) above, the amount of organic solvent used may be 5mL to 30mL per gram of 2- (2-cyanobenzyl) malonic acid. In some embodiments, in step (3) above, the amount of organic solvent used may be 8mL to 20mL per gram of 2- (2-cyanobenzyl) malonic acid. In some embodiments, in step (3) above, the amount of organic solvent used may be 8mL to 16mL per gram of 2- (2-cyanobenzyl) malonic acid. In some embodiments, in step (3) above, the amount of organic solvent used may be 10mL to 15mL per gram of 2- (2-cyanobenzyl) malonic acid.
In some embodiments, in step (3), the reaction temperature is from 105 ℃ to 150 ℃. In some embodiments, in the step (3), the reaction temperature is 130 ℃ to 150 ℃, so that the reaction product is obtained.
According to some embodiments of the invention, in the step (3), after the reaction is completed, the 2-cyanophenylpropionic acid is obtained through post-treatment; the post-processing comprises: stopping stirring, cooling the reaction system to room temperature (20-40 ℃), and concentrating under reduced pressure to obtain the 2-cyanophenylpropionic acid.
According to some embodiments of the invention, the auxiliary agent in step (4) is sodium chloride, magnesium chloride or ferric chloride. In some embodiments, the auxiliary agent in step (4) is sodium chloride.
According to some embodiments of the invention, the base in step (4) is sodium hydroxide, potassium hydroxide or potassium tert-butoxide. In some embodiments, the base in step (4) is sodium hydroxide.
In some embodiments, in step (4), the reaction is carried out in the molten state. In some embodiments, in step (4), the reaction is carried out at 130 ℃ to 150 ℃.
According to some embodiments of the invention, the reaction time in the step (4) is 5 to 20 hours. In some embodiments, the reaction time in step (4) is 10 to 15 hours.
According to some embodiments of the invention, the molar ratio of the 2-cyanophenylpropionic acid to the auxiliary agent in the step (4) is 1:5 to 1: 20. In some embodiments, the molar ratio of 2-cyanophenylpropionic acid to the co-agent in step (4) is from 1:8 to 1: 15. In some embodiments, the molar ratio of 2-cyanophenylpropionic acid to the co-agent in step (4) is 1: 10.
According to some embodiments of the invention, the molar ratio of the 2-cyanophenylpropionic acid to the aluminum trichloride in the step (4) is 1:20 to 1: 80. In some embodiments, the molar ratio of 2-cyanophenylpropionic acid to aluminum trichloride in step (4) is from 1:30 to 1: 60. In some embodiments, the molar ratio of 2-cyanophenylpropionic acid to aluminum trichloride in step (4) is from 1:30 to 1: 50. In some embodiments, the molar ratio of 2-cyanophenylpropionic acid to aluminum trichloride in step (4) is 1:40 or 1: 50.
In some embodiments, in step (4), the post-processing comprises: after the reaction is finished, cooling, adding ice water and ethyl acetate, stirring at the temperature of minus 5-5 ℃, filtering, separating filtrate, mixing an organic layer and a sodium hydroxide aqueous solution, stirring, then layering, collecting the organic layer, and concentrating to obtain the 4-cyano-1-indanone.
In some embodiments, according to one aspect of the invention, a process for preparing indane intermediate 4-cyano-1-indanone comprises the steps of:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in an organic solvent under the action of alkali and a catalyst at a certain temperature, and after the reaction is finished, carrying out post-treatment to obtain 2- (2-cyanobenzyl) dimethyl malonate;
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent at 20-40 ℃ under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate;
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at 105-150 ℃, and performing post-treatment to obtain 2-cyanophenylpropionic acid;
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and a promoter at 130-150 ℃, and after the reaction is finished, carrying out post-treatment to obtain 4-cyano-1-indanone;
the above reaction can be represented by the following reaction formula:
according to some embodiments of the present invention, in some embodiments, a process for preparing indan intermediate 4-cyano-1-indanone comprises the steps of:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in acetonitrile at 60-80 ℃ under the action of alkali and sodium iodide, and performing post-treatment after the reaction to obtain 2- (2-cyanobenzyl) dimethyl malonate;
(2) adding 2- (2-cyanobenzyl) malonic acid dimethyl ester into methanol, reacting at 20-40 ℃ under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonic acid;
(3) dissolving 2- (2-cyanobenzyl) malonic acid in an organic solvent, reacting at 130-150 ℃, and performing post-treatment to obtain 2-cyanophenylpropionic acid;
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and sodium chloride at 130-150 ℃, and after the reaction is finished, carrying out post-treatment to obtain 4-cyano-1-indanone.
Wherein the alkali in the step (1) is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide; the alkali in the step (2) is sodium hydroxide, potassium hydroxide or potassium tert-butoxide; the organic solvent in the step (3) is xylene, toluene, N, N-dimethylformamide, dimethyl sulfoxide, N-butanol, sulfolane, N-methylpyrrolidone or a combination thereof; in the step (1), the molar ratio of 2-cyanobenzyl bromide or 2-cyanobenzyl chloride to dimethyl malonate is 1: 2-1: 4; the molar ratio of the potassium carbonate to the 2-cyanobenzyl bromide or the 2-cyanobenzyl chloride is 1: 3-1: 7; in the step (2), the molar ratio of the dimethyl 2- (2-cyanobenzyl) malonate to the alkali is 1: 3-1: 5, and the mass percent of the alkali in the alkali aqueous solution is 5% -15%; in the step (4), the molar ratio of the 2-cyanophenylpropionic acid to the auxiliary agent is 1: 5-1: 20; the molar ratio of the 2-cyanophenylpropionic acid to the aluminum trichloride is 1: 30-1: 80; is beneficial to obtaining the target product.
According to some embodiments of the present invention, in some embodiments, a process for preparing indan intermediate 4-cyano-1-indanone comprises the steps of:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate in an organic solvent such as acetonitrile, N, N-dimethylformamide or dimethyl sulfoxide under the action of potassium carbonate and sodium iodide at the temperature of 60-80 ℃, and after the reaction is finished, carrying out post-treatment to obtain 2- (2-cyanobenzyl) dimethyl malonate; wherein the molar ratio of 2-cyanobenzyl bromide or 2-cyanobenzyl chloride to dimethyl malonate is 1: 2-1: 4, and the molar ratio of potassium carbonate to 2-cyanobenzyl bromide or 2-cyanobenzyl chloride is 1: 3-1: 7;
(2) adding 2- (2-cyanobenzyl) malonic acid dimethyl ester into methanol or ethanol, reacting at 20-40 ℃ under the action of an aqueous solution of sodium hydroxide, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonic acid; wherein the molar ratio of the 2- (2-cyanobenzyl) malonic acid dimethyl ester to the sodium hydroxide is 1: 3-1: 5; the mass percent of the sodium hydroxide in the aqueous solution of the sodium hydroxide is 5 to 15 percent;
(3) dissolving 2- (2-cyanobenzyl) malonic acid in xylene, reacting at 130-150 ℃, and performing post-treatment to obtain 2-cyanophenylpropionic acid; wherein the post-processing comprises: stopping stirring, cooling the reaction system to room temperature (20-40 ℃), and concentrating under reduced pressure to obtain 2-cyanophenylpropionic acid;
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and sodium chloride at 130-150 ℃, and after the reaction is finished, carrying out post-treatment to obtain 4-cyano-1-indanone; wherein the molar ratio of the 2-cyanophenylpropionic acid to the sodium chloride is 1: 5-1: 20; the molar ratio of the 2-cyanophenylpropionic acid to the aluminum trichloride is 1: 30-1: 60.
The method provided by the invention does not need a virulent cyaniding reagent, is convenient to operate, has good safety, has higher yield and purity of reactions such as decarboxylation and the like, has mild reaction conditions, and is beneficial to large-scale production.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Unless otherwise stated, reagents and solvents used were commercially available and all experimental solvents were of technical grade. Unless otherwise noted, yields are by weight and are uncorrected.
Example 1: preparation of 2- (2-cyanobenzyl) malonic acid dimethyl ester
The reaction formula is shown as follows:
2-cyanobenzyl bromide (20.0g), acetonitrile (200mL), potassium carbonate (28.20g), sodium iodide (3.06g), dimethyl malonate (26.96g) were added in this order to a single-necked flask; heating to 60 ℃ and stirring; after the reaction is finished, cooling the system to 30 ℃, distilling under reduced pressure, adding 200mL of water and 200mL of dichloromethane, collecting a dichloromethane layer, washing with water once, collecting the dichloromethane layer, and concentrating to obtain 32.62g of 2- (2-cyanobenzyl) malonic acid dimethyl ester with the purity of 80% and the yield of 100%.
LC-MS:m/z(ESI):248.20(M+H)+。
Example 2: preparation of 2- (2-cyanobenzyl) malonic acid
The reaction formula is shown as follows:
the product dimethyl 2- (2-cyanobenzyl) malonate, methanol (25mL), and sodium hydroxide (aqueous solution containing 227mL of water and 16.32g of sodium hydroxide) obtained in example 1 were weighed in a single-neck flask, stirred at 30 ℃, after the reaction was completed, 200mL of dichloromethane was added, stirred at 30 ℃, the aqueous layer was collected, the pH of the aqueous layer was adjusted with hydrochloric acid, extracted with ethyl acetate, and concentrated to obtain 15.7g of 2- (2-cyanobenzyl) malonate with purity of 92% and yield of 70.02%.
LC-MS:m/z(ESI):218.10(M-H)-。
Example 3: preparation of 2-cyanophenylpropionic acid
The reaction formula is shown as follows:
the product of example 2, 2- (2-cyanobenzyl) malonic acid (3.16g) and xylene (32mL) were weighed into a single-neck flask, and stirred at 140 ℃. Stirring for 1 hour under heat preservation; after the reaction is finished; reducing the temperature to 30 ℃, and concentrating to obtain 2.34g of 2-cyanophenylpropionic acid solid with the purity of 94 percent and the yield of 92.2 percent.
LC-MS:m/z(ESI):174.10(M-H)-，
1H NMR(400MHz,CDCl3)δ＝10.05(s,1H),7.62(d,J＝7.6Hz,1H),7.53(t,J＝7.6Hz,1H),7.41–7.28(m,2H),3.17(t,J＝7.6Hz,2H),2.76(t,J＝7.6Hz,2H)；13C NMR(101MHz,CDCl3)δ177.83(s),143.97(s),133.01(s),129.57(s),127.13(s),117.68(s),112.46(s),34.35(s),29.13(s)。
Example 4: preparation of 4-cyano-1-indanone
The reaction formula is shown as follows:
the product 2-cyanophenylpropionic acid (500mg) obtained in example 3, aluminum trichloride (15.22g) and sodium chloride (1.67g) were weighed into a single-neck flask and stirred at 140 ℃; stirring for about 11 hours under the condition of heat preservation, and after the reaction is finished; adding 20mL of water and 20mL of ethyl acetate, stirring and filtering, collecting an ethyl acetate layer, adding 20mL of an aqueous sodium hydroxide solution (1mol/L), stirring, collecting an ethyl acetate layer, and concentrating to obtain 330mg of 4-cyano-1-indanone solid. Purity 99%, yield 73.56%.
LC-MS:m/z(ESI):158.20(M+H)+，
1H NMR(400MHz,CDCl3)δ＝7.97(d,J＝7.7,1H),7.89(d,J＝7.5,1H),7.52(t,J＝7.6,1H),3.37–3.30(m,2H),2.83–2.77(m,2H)。
In the description herein, references to the description of the term "one embodiment," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A preparation method of an intermediate 4-cyano-1-indanone is characterized by comprising the following steps:
(4) reacting 2-cyanophenylpropionic acid, aluminum trichloride and a promoter at a certain temperature, and performing post-treatment after the reaction to obtain 4-cyano-1-indanone; wherein the auxiliary agent is selected from sodium chloride, magnesium chloride or ferric chloride.
2. A preparation method of an intermediate 2-cyanophenylpropionic acid is characterized by comprising the following steps:
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at 105-150 ℃, and performing post-treatment to obtain 2-cyanophenylpropionic acid; wherein the organic solvent is selected from xylene, toluene, N-dimethylformamide, dimethyl sulfoxide, N-butanol, sulfolane, N-methylpyrrolidone or a combination thereof; the dosage of the organic solvent is 5 mL-50 mL per gram of 2- (2-cyanobenzyl) malonic acid.
3. A preparation method of an intermediate 2- (2-cyanobenzyl) malonic acid is characterized by comprising the following steps:
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent at 0-60 ℃ under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate; wherein the base is selected from sodium hydroxide, potassium tert-butoxide or a combination thereof; the organic solvent is at least one selected from C1-C8 alcohol, dichloromethane, ethyl acetate and toluene.
4. The method of claim 1, further comprising the steps of:
(3) reacting 2- (2-cyanobenzyl) malonic acid in an organic solvent at 105-150 ℃, and performing post-treatment to obtain 2-cyanophenylpropionic acid; wherein the organic solvent in the step (3) is selected from xylene, toluene, N-dimethylformamide, dimethyl sulfoxide, N-butanol, sulfolane, N-methylpyrrolidone or a combination thereof, each gram of 2- (2-cyanobenzyl) malonic acid is prepared, and the dosage of the organic solvent in the step (3) is 5-50 mL.
5. The method of claim 1 or 2 or 4, further comprising the steps of:
(2) reacting dimethyl 2- (2-cyanobenzyl) malonate in an organic solvent at 0-60 ℃ under the action of an aqueous solution of alkali, and performing post-treatment to obtain 2- (2-cyanobenzyl) malonate; wherein, the alkali in the step (2) is sodium hydroxide, potassium tert-butoxide or the combination thereof; the organic solvent in the step (2) is at least one selected from C1-C8 alcohol, dichloromethane, ethyl acetate and toluene.
6. The method of any one of claims 1-5, further comprising the steps of:
(1) reacting 2-cyanobenzyl bromide or 2-cyanobenzyl chloride with dimethyl malonate at 30-80 ℃ in an organic solvent under the action of alkali and a catalyst, and performing post-treatment after the reaction to obtain 2- (2-cyanobenzyl) dimethyl malonate; wherein the base in step (1) is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or a combination thereof; the catalyst in the step (1) is sodium iodide, potassium iodide or a combination thereof; the organic solvent in the step (1) is at least one selected from acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, acetone and tetrahydrofuran.
7. The preparation method of claim 1 or 4, wherein the molar ratio of the 2-cyanophenylpropionic acid to the auxiliary agent in the step (4) is 1:5 to 1: 20; the molar ratio of the 2-cyanophenylpropionic acid to the aluminum trichloride is 1: 30-1: 80.
8. The process according to claim 1 or 4, wherein in the step (4), the reaction is carried out in a molten state or at a temperature of 130 to 150 ℃.
9. The method according to claim 3 or 5, wherein the molar ratio of dimethyl 2- (2-cyanobenzyl) malonate to base in step (2) is 1:3 to 1: 5.
10. The preparation method of claim 6, wherein the molar ratio of the catalyst to the 2-cyanobenzyl bromide or the 2-cyanobenzyl chloride in the step (1) is 1:3 to 1: 7.
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| CN111704559A (en) * | 2020-06-30 | 2020-09-25 | 重庆医药高等专科学校 | Method for preparing 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile |
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