CN111704559A - A kind of method for preparing 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile - Google Patents

Abstract

The invention discloses a method for preparing 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile, which comprises reacting 2-cyanobenzyl bromide with cyclo()isopropyl malonate , and then undergo condensation, hydrolysis, decarboxylation, and finally obtain through Friedel-Crafts acylation. The method of the invention is simple, does not pollute the environment with cyanide, and has high yield.

Description

A kind of method for preparing 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile

technical field

The invention belongs to the technical field of medicinal chemistry, in particular to a preparation method of an Ozanimod intermediate 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile.

Background technique

2,3-Dihydro-1-oxo-1H-indene-4-carbonitrile (the compound of formula I below) is a key intermediate for the preparation of the drug Ozanimod, and also a raw material for the synthesis of other compounds.

The prior art discloses several methods for preparing 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile, the first method: Journal of Organic Chemistry, 52(8): 1381-96, 1987; Journal of Organic Chemistry, 49(22): 4226-37, 1984, etc. disclosed that 2-bromobenzyl bromide was used as the starting material, under the reflux condition of sodium ethoxide/ethanol solution, by condensation with diethyl malonate, Then it is hydrolyzed with sodium hydroxide, decarboxylated at a high temperature of 165 °C, acylated by Friedrich, and finally reacted with cuprous cyanide or zinc cyanide to obtain 2,3-dihydro-1-oxo-1H-indene-4- formonitrile.

The second method: Organic Letters, 15(23), 6022-6025, 2013 discloses that using 2-bromobenzyl bromide as the starting material, under ice-water bath conditions and 60% sodium hydrogen conditions, with diethyl malonate Condensed, then hydrolyzed by sodium hydroxide, decarboxylated at high temperature of 165 °C, acylated by Friedrichs, and finally reacted with cuprous cyanide or zinc cyanide to obtain 2,3-dihydro-1-oxo-1H-indene- 4-carbonitrile.

The third method: Journal of Organic Chemistry, 11, 884-892; reported in 2015, 2-bromobenzaldehyde was used as the starting material, condensed with diethyl malonate under PhCOOH/Piperidine/PhMe conditions, and then hydroborated. Sodium reduction, sodium hydroxide hydrolysis, high temperature 165 ℃ decarboxylation, Friedel-Crafts acylation reaction, and finally react with cuprous cyanide or zinc cyanide to obtain 2,3-dihydro-1-oxo-1H-indene-4- formonitrile.

(Chemistry-A European Journal, 21(13), 4975-4987; 2015; WO2015066515 discloses that using 2-bromobenzaldehyde as the starting material, under the reflux condition of AcOH/Benzene, it is condensed with diethyl malonate, and then Reduction with sodium borohydride, hydrolysis with sodium hydroxide, decarboxylation at high temperature of 165°C, acylation by Friedel-Crafts, and finally reaction with cuprous cyanide or zinc cyanide to obtain 2,3-dihydro-1-oxo-1H-indene -4-carbonitrile.

CN110003049A discloses a method for preparing 4-cyano-1-indanone, comprising adding 4-bromo-1-indanone into a reaction solvent, the reaction concentration is 0.5mol/L, adding potassium ferricyanide, catalyst, alkali Under natural conditions, nitrogen replacement, the reaction temperature is 100-150 ℃, the reaction is completed.

In the above-mentioned synthesis method, the introduction of cyano group is mainly through high temperature reaction with cuprous cyanide, and the cuprous cyanide used is highly toxic and has great potential safety hazard. At the same time, post-processing produces a large amount of waste water containing cyano groups, causing environmental pollution. serious. At the same time, the high temperature of the decarboxylation reaction is 165 °C, which requires strict equipment and has certain limitations on the scale-up of the process.

SUMMARY OF THE INVENTION

The present invention provides a new method for preparing the compound represented by formula I, namely 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile, which comprises converting formula (II) 2-cyano Benzyl bromide reacts with and formula (III) malonic acid ring (idene) isopropyl ester (to be called "Michler's acid"), then undergo condensation, hydrolysis, decarboxylation, and finally obtain the formula shown in formula I through acylation chemical compound,

In one embodiment, a kind of method for preparing compound shown in formula I of the present invention specifically comprises the following steps,

1) Condensation reaction of 2-cyanobenzyl bromide of formula (II) and cyclo(isopropylidene) malonate of formula (III) in a solvent in the presence of a base to obtain a compound of formula (IV);

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

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

4) After the compound of formula (VI) is acid-chlorinated with an acyl chloride reagent, 2,3-dihydro-1-oxo-1H-indene-4-methyl of formula (I) is obtained through Friedel-Crafts acylation reaction in the presence of a catalyst Nitrile.

In the above method of the present invention, in step 1), the molar ratio of formula II 2-cyanobenzyl bromide to formula III malonate cyclo()isopropylidene ester: 1:1.05～3.0, preferably 1:1.05; or, 2- The molar ratio of cyanobenzyl bromide and alkali: 1:1.05～3.0, preferably 1:1.10, the reaction temperature of formula II 2-cyanobenzyl bromide and formula III malonate ring (idene) isopropyl ester is -20～100 ℃, Described base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, piperidine and Any mixture of them, the solvent is selected from ethyl acetate, dichloromethane, toluene, ethanol, methanol, tetrahydrofuran, N,N,-dimethylformamide, dimethylsulfoxide and acetonitrile.

In the above method of the present invention, the reaction temperature in step 2) is 0-150°C, 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 above method of the present invention, the solvent described in step 3) is selected from N,N,-dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone, and the reaction temperature is 50-200°C, preferably, is 100-105°C.

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

In the above-mentioned method of the present invention, the acyl chloride reagent described in step 4) is oxalyl chloride, and the Friedel-Crafts acylation reaction is completed in the presence of a catalyst with or without a solvent, and the reaction temperature is 0-200 ℃ °C, preferably 100-150 °C, more preferably 130-135 °C, wherein the solvent is dichloromethane and carbon disulfide, and the catalyst is selected from sulfuric acid, polyphosphoric acid and aluminum trichloride.

In a specific embodiment, a kind of method for preparing the compound of formula I of the present invention, its reaction formula is as follows:

The method includes the following steps:

1) Condensing formula II 2-cyanobenzyl bromide and formula III malonic acid cyclo()isopropylidene in a solvent under basic conditions to obtain a compound of formula IV, namely 2-((2,2-dimethylene) -4,6-dioxo-1,3-dioxo-5-yl)methyl)benzonitrile, wherein the reaction temperature is: -20～100°C, preferably, it is carried out at room temperature, the solvent It is N,N,-dimethylformamide, the base is potassium carbonate and sodium carbonate, and the formula II compound: formula III compound: base molar ratio is: 1:1.05:1.10;

2) In the presence of a solvent and an acid or a base, the compound of formula IV is hydrolyzed at a temperature of 60 to 70°C to obtain a compound of formula V, namely 2-(2-cyanophenyl)malonic acid, preferably, the solvent is water, The acid is trifluoroacetic acid, and the molar ratio of the compound of formula IV to trifluoroacetic acid is 1:1.0-10.0;

3) The compound of formula V is heated to 100～105 ℃ in a base and solvent for decarboxylation to obtain the compound of formula VI, namely 3-(2-cyanophenyl)propionic acid, and the solvent is selected from N,N,-dimethylmethane amide, dimethyl sulfoxide and N-methylpyrrolidone, preferably, the solvent is N-methylpyrrolidone, the base is pyridine, and the molar ratio of the compound of formula V to pyridine is 1:1.0-3.0;

4) After the compound of formula VI is acyl chloride with an acyl chloride reagent, it is acylated by Friedel-Crafts in a solvent under the catalysis of Lewis acid to obtain the compound of formula (I) 2,3-dihydro-1-oxo-1H-indene-4-methyl Nitrile, wherein, preferably, the reaction temperature is 130～135℃, the acid chloride reagent is oxalyl chloride, the Lewis acid is aluminum trichloride, the molar ratio of the compound of formula VI to aluminum trichloride is 1:1.05, and the solvent is two Chloromethane.

In a preferred embodiment, a method for preparing a compound of formula I of the present invention comprises the following steps:

1) Compound of formula II (2-cyanobenzyl bromide) and compound of formula III (cyclo(isopropylidene) malonate) in solvent N,N,-dimethylformamide, in alkaline reagent potassium carbonate In the presence of a condensation reaction at room temperature, the compound of formula IV is prepared, wherein the molar ratio of the compound of formula II to the compound of formula III is 1:1.05, and the molar ratio of the compound of formula II to the base is 1:1.10;

2) Dissolve the compound of formula IV 2-((2,2-dimethyl-4,6-dioxo-1,3-dioxo-5-yl)methyl)benzonitrile in solvent water, at a temperature of 60 At ~70 ° C, hydrolysis in the presence of trifluoroacetic acid obtains the compound of formula V 2-(2-cyanophenyl)malonic acid, wherein the molar ratio of the compound of formula IV to trifluoroacetic acid is 1:(5.0～10.0 );

3) Dissolving the compound of formula V in solvent N-methylpyrrolidone, adding pyridine, and decarboxylation at 100-105° C. to obtain the compound of formula VI (3-(2-cyanophenyl)propionic acid), wherein the compound of formula V The molar ratio to pyridine is 1:1.5-3.0;

4) The compound of formula VI is subjected to oxychlorination by oxalyl chloride in a solvent dichloromethane, and then the trichloride catalyst is used to carry out a Friedel-Crafts acylation reaction to obtain the compound of formula I (2,3-dihydro-1-oxo) -1H-indene-4-carbonitrile), wherein the molar ratio of the compound of formula VI to aluminum trichloride is 1:1.05; the reaction temperature is 130-135°C.

The method of the invention overcomes the deficiencies of the prior art, and the preparation method has the advantages of easily available raw materials, short route, convenient operation, less pollution of three wastes and high yield.

Detailed ways

The following examples are only representative and are used to further understand and clarify the spirit of the present invention, but do not limit the scope of the present invention. Any variations and simple modifications within the spirit and spirit of the present invention belong to the present invention. scope of invention.

Example 1 Preparation of 2-((2,2-dimethyl-4,6-dioxo-1,3-dioxo-5-yl)methyl)benzonitrile (ie compound of formula IV)

Add 140 grams of potassium carbonate, Michaelis acid (that is, the compound of formula III) (80.8 grams) and solvent DMF (500 milliliters) to a 1000-milliliter four-necked reaction flask, stir at room temperature for 0.5 hours, add 2-cyanobenzyl bromide (that is, formula Compound II) (100 g) in DMF (200 mL), the addition was completed in about 30 minutes, and the reaction was continued for 6.0 hours. The reaction was followed by TLC, ethyl acetate (500 mL) was added, insoluble solids were removed by filtration, and 1000 mL of water was added. , extraction and layering, the lower water phase was adjusted to acidic pH with concentrated hydrochloric acid, a large amount of white solid was precipitated, and dried to obtain 129.0 g of white solid (namely the compound of formula IV), with a molar yield of 77.4%.

LCMS-ESI (m/z): [M+23] ⁺ =282.0, [M+39] ⁺ =298.0, [2M+23] ⁺ =541.1.

Example 2 Preparation of 2-(2-cyanophenyl)malonic acid (ie compound of formula V)

To the reaction flask was added 2-((2,2-dimethyl-4,6-dioxo-1,3-dioxo-5-yl)methyl)benzonitrile (60 g), trifluoroacetic acid ( 180 mL), water (90 mL), warmed up to 60～70 ℃ and stirred for 3.0 hours, the reaction system was clarified, the reaction was followed by TLC, the solvent was removed by concentration under reduced pressure, water and ethyl acetate were added for extraction, the organic phase was separated, followed by Add water, wash with salt, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 37.68 g of white solid 2-(2-cyanophenyl)malonic acid, with a molar yield of 74.4.0%.

LCMS-ESI (m/z): [M+1] ⁺ =220.1, [M+23] ⁺ =242.0.

Example 3 Preparation of 3-(2-cyanophenyl)propionic acid (ie compound of formula VI)

2-(2-cyanophenyl)malonic acid (31.40 g) prepared above was added to the reaction flask, DMF (35 mL), piperidine (0.8 mL) were added, the temperature was raised to 100～105° C. and reacted for 3.0 hours, TLC detected the completion of the reaction, cooled to room temperature, concentrated under reduced pressure to remove the solvent, added 100 ml of water, adjusted pH=2～3 with 2M hydrochloric acid, precipitated a large amount of white solid, filtered to obtain off-white solid 3-(2-cyanobenzene base) propionic acid 25.01 g, molar yield 99.6%.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.62 (d, 1H), 7.53 (d, 1H), 7.37 (d, 1H), 3.20 (t, 2H), 2.78 (t, 2H);

LCMS-ESI (m/z): [M+1] ⁺ =176.0, [M+23] ⁺ =198.1, [2M+1] ⁺ =351.0.

Example 4 Preparation of 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile) (namely the target product compound of formula I)

The compound of formula VI 3-(2-cyanophenyl)propionic acid (8.0 g) was added to the reaction flask, dichloromethane (40 mL) was added, and oxalyl chloride (5.1 mL) was slowly added dropwise at room temperature, and the dropwise addition was completed, Stir at room temperature, follow the reaction by TLC, concentrate to remove the solvent, add aluminum trichloride (10.8 g) and 6.0 g of sodium chloride to the concentrated solution, warm up to 130-135 ° C and react for 4.0 hours, cool to room temperature, add ice water and Dichloromethane was stirred to dissolve, extracted and separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile 5.0 g, with a molar yield of 5.0 g. rate 68.2%.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.96 (d, 1H), 7.88 (d, 1H), 7.52 (t, 1H), 3.34 (t, 2H), 2.81 (t, 2H);

LCMS-ESI (m/z): [M+1] ⁺ =158.1, [M+23] ⁺ =180.0.

Example 5 Preparation of 2-((2,2-dimethyl-4,6-dioxo-1,3-dioxo-5-yl)methyl)benzonitrile (ie compound of formula IV)

In a 1000-milliliter four-necked reaction flask, add 145 g of sodium carbonate, Michaelis acid (the compound of formula III) (80.8 g) and solvent DMF (500 ml), stir at room temperature for 0.5 hour, add 2-cyanobenzyl bromide (i.e. formula Compound II) (100 g) in DMF (200 mL), the addition was completed in about 30 minutes, and the reaction was continued for 5 h. The reaction was followed by TLC, ethyl acetate (500 mL) was added, insoluble solids were removed by filtration, and 1000 mL of water was added. , extracting and layering, the lower water phase was adjusted to acidic pH with concentrated hydrochloric acid, a large amount of white solid was precipitated, and dried to obtain 126.0 g of white solid (namely the compound of formula IV), with a molar yield of 75.6%.

Example 6 Preparation of 2-(2-cyanophenyl)malonic acid (ie compound of formula V)

To the reaction flask was added 2-((2,2-dimethyl-4,6-dioxo-1,3-dioxo-5-yl)methyl)benzonitrile (60 g), acetic acid (200 mL) ), water (100 ml), heated to 60～70 ℃ and stirred for 4.0 hours, the reaction system was clarified, the TLC tracking reaction was completed, the solvent was removed by concentration under reduced pressure, water and ethyl acetate were added for extraction, the organic phase was separated, and the water was washed successively. , washed with salt, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 36.17 g of white solid 2-(2-cyanophenyl)malonic acid, with a molar yield of 71.40%.

Example 7 Preparation of 3-(2-cyanophenyl)propionic acid (ie compound of formula VI)

2-(2-cyanophenyl)malonic acid (31.50 g) prepared above was added to the reaction flask, N-methylpyrrolidone (35 ml) and pyridine (0.8 ml) were added, and the temperature was raised to 100～105°C for reaction 3.0 hours, TLC detected reaction completion, cooled to room temperature, concentrated under reduced pressure to remove solvent, added 100 ml of water, adjusted pH=2～3 with 2M hydrochloric acid, separated out a large amount of white solid, filtered to obtain off-white solid 3-(2- 25.4 g of cyanophenyl) propionic acid, the molar yield is 99.6%.

Example 8 Preparation of 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile) (namely the target product formula I compound)

The compound of formula VI 3-(2-cyanophenyl)propionic acid (8.0 g) was added to the reaction flask, dichloromethane (40 mL) was added, and oxalyl chloride (5.0 mL) was slowly added dropwise at room temperature, and the dropwise addition was completed, Stir at room temperature, follow the reaction by TLC, concentrate to remove the solvent, add aluminum trichloride (11.0 g) and 6.5 g of sodium chloride to the concentrated solution, warm up to 130-135 ° C and react for 4.5 hours, cool to room temperature, add ice water and Dichloromethane was stirred to dissolve, extracted and separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5.2 g of the target product, 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile, with a molar yield of 5.2 g. rate 70.9%.

Claims (10)

1. a method for preparing a compound of formula I, comprising after the reaction of the 2-cyanobenzyl bromide of formula II and the cyclo() isopropyl malonate of formula III, condensation, hydrolysis, decarboxylation, and finally through gram acylation affords the compound of formula I,

2. method as claimed in claim 1, specifically comprises the following steps: 1) 2-cyanobenzyl bromide of formula II and cyclo()isopropyl malonate of formula III are subjected to condensation reaction in a solvent in the presence of a base to obtain a compound of formula IV;

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

3) heating and decarboxylating the compound of formula V in a solvent to obtain the compound of formula VI;

4) After the compound of formula VI is subjected to acyl chloride as an acyl chloride reagent, the 2,3-dihydro-1-oxo-1H-indene-4-carbonitrile of formula I is obtained through Friedel-Crafts acylation in the presence of a catalyst. The reaction temperature 0-200℃. 3. the method as claimed in claim 2, in step 1), the mol ratio of the 2-cyano benzyl bromide of formula II and the malonate ring (idene) isopropyl ester of formula III: 1:(1.05～3.0) ; Or, the molar ratio of 2-cyanobenzyl bromide and base: 1:(1.05～3.0). 4. The method according to claim 2, in step 1), the reaction temperature of 2-cyanobenzyl bromide of formula II and cyclo(idene) malonate of formula III is -20～100 ℃, preferably room temperature. 5. the method as claimed in claim 2 or 3, the alkali described in step 1) is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide , triethylamine, diisopropylethylamine, pyridine, piperidine and any mixture thereof, preferably potassium carbonate or sodium carbonate. 6. The method of claim 2, wherein the solvent described in step 1) is selected from ethyl acetate, dichloromethane, toluene, ethanol, methanol, tetrahydrofuran, N,N,-dimethylformamide, dimethylformamide, dimethylformamide, and dimethylformamide. sulfoxide and acetonitrile, preferably N,N,-dimethylformamide. 7. method as claimed in claim 2, the reaction temperature of step 2) is 0-150 ℃, is preferably 60-70 ℃, and described acid is selected from hydrochloric acid, acetic acid and trifluoroacetic acid, is preferably trifluoroacetic acid, The base is selected from potassium hydroxide, sodium hydroxide and lithium hydroxide. 8. The method of claim 2, wherein the solvent in step 3) is selected from N,N,-dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone, and the reaction temperature is 50-200°C , preferably 100 to 105°C. 9. The method of claim 2, in step 3), further comprising a base, and the base is pyridine. 10. method as claimed in claim 2, in step 4), described acyl chloride reagent is oxalyl chloride, and described Friedel-Crafts acylation reaction is under the condition that has solvent or does not have solvent, completes in the presence of catalyzer, temperature of reaction It is 100-150 ℃, preferably 130-135 ℃, wherein, the solvent is dichloromethane, carbon disulfide, preferably dichloromethane; the catalyst is selected from sulfuric acid, polyphosphoric acid and aluminum trichloride, preferably trichloride Aluminum chloride.