阅读说明：本技术 一种制备2,3-二氢-1-氧代-1h-茚-4-甲腈的方法 (Method for preparing 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile ) 是由 张稳稳 刘小东 于 2020-06-30 设计创作，主要内容包括：本发明公开了一种制备2,3-二氢-1-氧代-1H-茚-4-甲腈的方法包括将2-氰基苄溴与丙二酸环(亚)异丙酯反应后,再过缩合、水解、脱羧,最后经付克酰基化而得到,本发明的方法简单、无氰化物污染环境、收率高。(The invention discloses a method for preparing 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile, which comprises the steps of reacting 2-cyanobenzyl bromide with malonic acid cyclo (isopropylidene), then carrying out condensation, hydrolysis and decarboxylation, and finally carrying out friedel-crafts acylation.)

1. A process for preparing the compound of formula I, which comprises reacting 2-cyanobenzyl bromide of formula II with isopropylidene malonate of formula III, then carrying out overcondensation, hydrolysis, decarboxylation, and finally carrying out Friedel-crafts acylation to obtain the compound of formula I,

2. the method according to claim 1, comprising in particular the steps of:

1) carrying out condensation reaction on 2-cyanobenzyl bromide of a formula II and isopropylidene malonate of a formula III in a solvent in the presence of alkali to obtain a compound of a formula IV;

2) hydrolyzing the compound shown in the formula IV in the presence of acid or alkali to obtain a compound shown in the formula V;

3) heating the compound of the formula V in a solvent for decarboxylation to obtain a compound of a formula VI;

4) after acyl chloride is used as an acyl chloride reagent, the compound shown in the formula VI is subjected to Friedel-crafts acylation reaction in the presence of a catalyst to obtain the 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile shown in the formula I, wherein the reaction temperature is 0-200 ℃.

3. The process of claim 2, step 1) the molar ratio of 2-cyanobenzyl bromide of formula II to cyclopropane (isopropylidene) ring of formula III: 1, (1.05-3.0); alternatively, the molar ratio of 2-cyanobenzyl bromide to base: 1, (1.05-3.0).

4. The process according to claim 2, wherein the reaction temperature of the 2-cyanobenzyl bromide of formula II and the isopropylidene malonate of formula III in step 1) is-20 to 100 ℃, preferably room temperature.

5. The process according to claim 2 or 3, wherein the base in step 1) is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, piperidine and any mixture thereof, preferably potassium carbonate or sodium carbonate.

6. The process according to claim 2, wherein the solvent in step 1) is selected from the group consisting of ethyl acetate, dichloromethane, toluene, ethanol, methanol, tetrahydrofuran, N, -dimethylformamide, dimethyl sulfoxide and acetonitrile, preferably N, -dimethylformamide.

7. The process according to claim 2, wherein the reaction temperature in step 2) is 0 to 150 ℃, preferably 60 to 70 ℃, the acid is selected from the group consisting of hydrochloric acid, acetic acid and trifluoroacetic acid, preferably trifluoroacetic acid, and the base is selected from the group consisting of potassium hydroxide, sodium hydroxide and lithium hydroxide.

8. The process according to claim 2, wherein the solvent in step 3) is selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone, and the reaction temperature is 50 to 200 ℃, preferably 100 to 105 ℃.

9. The method of claim 2, further comprising a base in step 3), wherein the base is pyridine.

10. The method according to claim 2, wherein the acid chloride reagent in step 4) is oxalyl chloride, and the Friedel-crafts acylation reaction is carried out in the presence of a catalyst in the presence or absence of a solvent, wherein the reaction temperature is 100-150 ℃, preferably 130-135 ℃, and the solvent is dichloromethane and carbon disulfide, preferably dichloromethane; the catalyst is selected from sulfuric acid, polyphosphoric acid and aluminum trichloride, and is preferably aluminum trichloride.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of an Ozanimod intermediate 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile.

Background

2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile (such as the compound of formula I) is a key intermediate for the preparation of the drug Ozanimod, and is also a synthetic starting material for other compounds.

Disclosure of Invention

The invention provides a novel method for preparing a compound shown in formula I, namely 2, 3-dihydro-1-oxo-1H-indene-4-formonitrile, which comprises the steps of reacting 2-cyanobenzyl bromide shown in formula (II) with cyclopropyl (ylidene) malonate (called 'miglitol') shown in formula (III), then carrying out condensation, hydrolysis and decarboxylation, and finally carrying out Friedel-crafts acylation to obtain a compound shown in formula I,

in one embodiment, the method for preparing the compound shown in the formula I comprises the following steps,

1) condensing 2-cyanobenzyl bromide of a formula (II) and cyclopropyl (ylidene) malonate of a formula (III) in a solvent in the presence of alkali to obtain a compound of a formula (IV);

2) hydrolyzing the compound of the formula (IV) in the presence of acid or alkali to obtain a compound of the formula (V);

3) heating the compound of the formula (V) in a solvent for decarboxylation to obtain a compound of a formula (VI);

4) after the compound of formula (VI) is chloridized by using an acyl chloride reagent, the compound of formula (I) is subjected to Friedel-crafts acylation reaction in the presence of a catalyst to obtain the 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile of formula (I).

The above process of the present invention, step 1), has a molar ratio of the cyanobenzyl bromide of formula II 2-to the cyclopropanecarboxylic acid ring (isopropylidene) of formula III: 1: 1.05-3.0, preferably 1: 1.05; alternatively, the molar ratio of 2-cyanobenzyl bromide to base: 1:1.05 to 3.0, preferably 1:1.10, reaction temperature of 2-cyanobenzyl bromide of formula II with cyclopropyl (ylidene) propionate of formula III is-20 to 100 ℃, said base is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, piperidine and any mixture thereof, said solvent is selected from the group consisting of ethyl acetate, dichloromethane, toluene, ethanol, methanol, tetrahydrofuran, N, -dimethylformamide, dimethyl sulfoxide and acetonitrile.

In the method of the present invention, the reaction temperature in step 2) is 0 to 150 ℃, the acid is selected from hydrochloric acid, acetic acid and trifluoroacetic acid, and the base is selected from potassium hydroxide, sodium hydroxide and lithium hydroxide.

In the method of the present invention, the solvent in step 3) is selected from N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone, and the reaction temperature is 50 to 200 ℃, preferably 100-105 ℃.

The above process of the present invention, step 3), is carried out under basic conditions, preferably, the base is selected from pyridine.

In the method of the present invention, the acylating and chlorinating agent in step 4) is oxalyl chloride, and the Friedel-crafts acylation reaction is carried out in the presence of a catalyst in the presence or absence of a solvent at a temperature of 0-200 ℃, preferably 100-150 ℃, more preferably 130-135 ℃, wherein the solvent is dichloromethane and carbon disulfide, and the catalyst is selected from sulfuric acid, polyphosphoric acid and aluminum trichloride.

In one embodiment, the invention is a process for preparing a compound of formula I, having the formula:

the method comprises the following steps:

1) condensing 2-cyanobenzyl bromide shown in the formula II and malonic acid cyclo (ylidene) isopropyl ester shown in the formula III in a solvent under an alkaline condition to obtain a compound shown in the formula IV, namely 2- ((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxo-5-yl) methyl) benzonitrile, wherein the reaction temperature is as follows: -20 to 100 ℃, preferably at room temperature, the solvent is N, -dimethylformamide, the base is potassium carbonate, sodium carbonate, a compound of formula II: a compound of formula III: the alkali molar ratio is: 1: 1.05: 1.10;

2) hydrolyzing a compound shown in the formula IV in the presence of a solvent and acid or alkali at the temperature of 60-70 ℃ to obtain a compound shown in the formula V, namely 2- (2-cyanophenyl) malonic acid, wherein preferably, the solvent is water, the acid is trifluoroacetic acid, and the molar ratio of the compound shown in the formula IV to the trifluoroacetic acid is 1: 1.0-10.0;

3) heating a compound shown in the formula V to 100-105 ℃ in a base and a solvent to decarboxylate to obtain a compound shown in the formula VI, namely 3- (2-cyanophenyl) propionic acid, wherein the solvent is selected from N, N, -dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone, preferably, the solvent is N-methylpyrrolidone, the base is pyridine, and the molar ratio of the compound shown in the formula V to the pyridine is 1: 1.0-3.0;

4) after acyl chloride is used for a compound shown in the formula VI, the compound is acylated with acyl chloride reagent in a solvent under catalysis of Lewis acid to obtain a compound 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile shown in the structural formula (I), wherein preferably, the reaction temperature is 130-135 ℃, the acyl chloride reagent is oxalyl chloride, the Lewis acid is aluminum trichloride, and the molar ratio of the compound shown in the formula VI to the aluminum trichloride is 1:1.05, and the solvent is dichloromethane.

In a preferred embodiment, the present invention is a process for the preparation of a compound of formula I, comprising the steps of:

1) carrying out condensation reaction on a compound (2-cyanobenzyl bromide) in a formula II and a compound (malonic acid cyclo (isopropylidene)) in a formula III in a solvent N, N-dimethylformamide in the presence of an alkaline reagent potassium carbonate at room temperature to obtain a compound in a formula IV, wherein the molar ratio of the compound in the formula II to the compound in the formula III is 1:1.05, the molar ratio of the compound of formula ii to the base is 1: 1.10;

2) dissolving a compound 2- ((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxo-5-yl) methyl) benzonitrile shown in the formula IV in solvent water, and hydrolyzing at the temperature of 60-70 ℃ in the presence of trifluoroacetic acid to obtain a compound 2- (2-cyanophenyl) malonic acid shown in the formula V, wherein the molar ratio of the compound shown in the formula IV to the trifluoroacetic acid is 1 (5.0-10.0);

3) dissolving a compound shown in a formula V in a solvent N-methylpyrrolidone, adding pyridine, and decarboxylating at 100-105 ℃ to obtain a compound shown in a formula VI (3- (2-cyanophenyl) propionic acid), wherein the molar ratio of the compound shown in the formula V to the pyridine is 1: 1.5-3.0;

4) the method comprises the following steps of (1) carrying out oxalyl chloride chlorination on a compound shown in a formula VI in a solvent dichloromethane, and then carrying out Friedel-crafts acylation reaction under the catalyst of aluminum trichloride to obtain a compound shown in a formula I (2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile), wherein the molar ratio of the compound shown in the formula VI to the aluminum trichloride is 1: 1.05; the reaction temperature is 130-135 ℃.

The preparation method of the invention overcomes the defects of the prior art, and has the advantages of easily available raw materials, short route, convenient operation, little three-waste pollution, high yield and the like.

Detailed Description

The following examples are merely representative for further understanding and illustrating the spirit of the present invention, but are not to be construed as limiting the scope of the present invention, and any variations and simple modifications made within the spirit of the present invention are included in the scope of the present invention.