CN111704559A - Method for preparing 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile - Google Patents
Method for preparing 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile Download PDFInfo
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- CN111704559A CN111704559A CN202010612481.7A CN202010612481A CN111704559A CN 111704559 A CN111704559 A CN 111704559A CN 202010612481 A CN202010612481 A CN 202010612481A CN 111704559 A CN111704559 A CN 111704559A
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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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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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- 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 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.
Description
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.
The prior art discloses several methods for the preparation of 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, et al disclose 2-bromobenzyl bromide as starting material, which is condensed with diethyl malonate under the condition of sodium ethoxide/ethanol solution reflux, then hydrolyzed with sodium hydroxide, decarboxylated at 165 ℃ and subjected to Friedel-crafts acylation reaction, and finally reacted with cuprous cyanide or zinc cyanide to obtain 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile.
The second method comprises the following steps: organic Letters,15, (23), 6022-charge 6025, 2013 discloses using 2-bromobenzyl bromide as a starting material, condensing with diethyl malonate under the conditions of ice-water bath and 60% of sodium hydrogen, then hydrolyzing with sodium hydroxide, decarboxylating at 165 ℃ and performing Friedel-crafts acylation reaction, and finally reacting with cuprous cyanide or zinc cyanide to obtain 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile.
The third method comprises the following steps: journal of Organic Chemistry,11, 884-; 2015, 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile is prepared by using 2-bromobenzyl benzaldehyde as a starting material, condensing with diethyl malonate under the conditions of PhCOOH/Piperidine/PhMe, reducing with sodium borohydride, hydrolyzing with sodium hydroxide, decarboxylating at 165 ℃ and carrying out Friedel-crafts acylation reaction, and finally reacting with cuprous cyanide or zinc cyanide.
(Chemistry-A European Journal,21(13), 4975-4-indene 4987; 2015; WO2015066515 discloses that 2-bromobenzyl benzaldehyde is used as a starting material, condensed with diethyl malonate under the condition of AcOH/Benzene reflux, reduced by sodium borohydride, hydrolyzed by sodium hydroxide, decarboxylated at 165 ℃ and subjected to Friedel-crafts acylation reaction, and finally reacted with cuprous cyanide or zinc cyanide to prepare 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile.
CN110003049A discloses a method for preparing 4-cyano-1-indanone, which comprises adding 4-bromo-1-indanone into a reaction solvent with the reaction concentration of 0.5mol/L, adding potassium ferricyanide, a catalyst, an alkaline condition, replacing with nitrogen, and completing the reaction at the reaction temperature of 100-150 ℃.
In the synthesis method, the introduction of the cyano is mainly through high-temperature reaction with cuprous cyanide, the used cuprous cyanide is highly toxic, the potential safety hazard is large, and meanwhile, a large amount of cyano-containing wastewater is generated through aftertreatment, so that the environmental pollution is serious. Meanwhile, the decarboxylation reaction is carried out at a high temperature of 165 ℃, so that the equipment requirement is strict, and the process amplification production is limited.
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.
Example 12 preparation of- ((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxo-5-yl) methyl) benzonitrile, i.e. the Compound of formula IV
140 g of potassium carbonate, 80.8 g of Meldrum's acid (compound of formula III) and DMF (500 ml) as a solvent are added into a 1000 ml four-mouth reaction bottle, the mixture is stirred at room temperature for 0.5 hour, a DMF (200 ml) solution of 2-cyanobenzyl bromide (compound of formula II) (100 g) is added, the reaction is completed within about 30 minutes, the reaction is continued for 6.0 hours, TLC is used for tracking the reaction, ethyl acetate (500 ml) is added, insoluble solids are removed by filtration, 1000 ml of water is added, extraction and layering are carried out, the pH of the lower water phase is adjusted to acidity by concentrated hydrochloric acid, a large amount of white solids are separated out, and the white solids (compound of formula IV) 129.0 g are obtained by drying, and the molar yield is 77..
LCMS-ESI(m/z)：[M+23]+＝282.0，[M+39]+＝298.0，[2M+23]+＝541.1。
EXAMPLE 22 preparation of- (2-cyanophenyl) malonic acid (i.e. compound of formula V)
Adding 2- ((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxo-5-yl) methyl) benzonitrile (60 g), trifluoroacetic acid (180 ml) and water (90 ml) into a reaction bottle, heating to 60-70 ℃, stirring for reaction for 3.0 hours, clarifying a reaction system, tracking the reaction by TLC, concentrating under reduced pressure to remove a solvent, adding water and ethyl acetate for extraction, separating an organic phase, sequentially adding water for washing, washing with salt, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 37.68g of white solid 2- (2-cyanophenyl) malonic acid, wherein the molar yield is 74.4.0%.
LCMS-ESI(m/z)：[M+1]+＝220.1，[M+23]+＝242.0。
EXAMPLE 33 preparation of- (2-cyanophenyl) propionic acid (i.e. Compound of formula VI)
The 2- (2-cyanophenyl) malonic acid (31.40 g) prepared above was added to a reaction flask, DMF (35 ml) and piperidine (0.8 ml) were added, the temperature was raised to 100 to 105 ℃ for reaction for 3.0 hours, TLC detection was completed, the temperature was lowered to room temperature, the solvent was removed by concentration under reduced pressure, 100 ml of water was added, PH was adjusted to 2 to 3 with 2M hydrochloric acid, a large amount of white solid was precipitated, and 25.01 g of 3- (2-cyanophenyl) propionic acid was obtained as an off-white solid by filtration in a molar yield of 99.6%.
1HNMR(400MHz，CDCl3)：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 42 preparation of 3, 3-dihydro-1-oxo-1H-indene-4-carbonitrile), the object product of the Compound of formula I
Adding 8.0 g of 3- (2-cyanophenyl) propionic acid which is a compound of the formula VI into a reaction bottle, adding 40 ml of dichloromethane, slowly adding 5.1 ml of oxalyl chloride dropwise at room temperature, stirring at room temperature after the dropwise addition, after the TLC tracking reaction is finished, concentrating to remove the solvent, adding 10.8 g of aluminum trichloride and 6.0 g of sodium chloride into the concentrated solution, heating to 130 ℃ and 135 ℃ for reaction for 4.0 hours, cooling to room temperature, adding ice water and dichloromethane, stirring, dissolving, extracting, separating liquid, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 5.0 g of a target product 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile, wherein the molar yield is 68.2%.
1HNMR(400MHz，CDCl3)：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 52 preparation of- ((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxo-5-yl) methyl) benzonitrile, i.e. the compound of formula IV
145 g of sodium carbonate, 80.8 g of Meldrum's acid (compound of formula III) and 500 ml of DMF (solvent) are added into a 1000 ml four-mouth reaction bottle, the mixture is stirred for 0.5 hour at room temperature, a DMF (200 ml) solution of 2-cyanobenzyl bromide (compound of formula II) (100 g) is added, the reaction is completed in about 30 minutes, the reaction is continued for 5 hours, TLC is used for tracking the reaction, ethyl acetate (500 ml) is added, insoluble solids are removed by filtration, 1000 ml of water is added, extraction and layering are carried out, the pH of the lower water phase is adjusted to acidity by concentrated hydrochloric acid, a large amount of white solids are separated out, and the white solids (compound of formula IV) 126.0 g are obtained by drying, and the molar yield is 75.6%.
EXAMPLE 62 preparation of- (2-cyanophenyl) malonic acid (i.e. compound of formula V)
Adding 2- ((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxo-5-yl) methyl) benzonitrile (60 g), acetic acid (200 ml) and water (100 ml) into a reaction bottle, heating to 60-70 ℃, stirring for reaction for 4.0 hours, clarifying a reaction system, tracking the reaction by TLC, concentrating under reduced pressure to remove a solvent, adding water and ethyl acetate for extraction, separating an organic phase, sequentially adding water for washing, washing with salt, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 36.17g of white solid 2- (2-cyanophenyl) malonic acid, wherein the molar yield is 71.40%.
EXAMPLE 73 preparation of- (2-cyanophenyl) propionic acid (i.e., compound of formula VI)
The 2- (2-cyanophenyl) malonic acid (31.50 g) prepared as described above was added to a reaction flask, N-methylpyrrolidone (35 ml) and pyridine (0.8 ml) were added, the temperature was raised to 100 to 105 ℃ to react for 3.0 hours, the TLC detection reaction was completed, the temperature was lowered to room temperature, the solvent was removed by concentration under reduced pressure, 100 ml of water was added, the PH was adjusted to 2 to 3 with 2M hydrochloric acid to precipitate a large amount of white solid, and 25.4 g of off-white solid 3- (2-cyanophenyl) propionic acid was obtained by filtration with a molar yield of 99.6%.
Example 82 preparation of 3, 3-dihydro-1-oxo-1H-indene-4-carbonitrile), the object product of the Compound of formula I
Adding 8.0 g of 3- (2-cyanophenyl) propionic acid which is a compound of the formula VI into a reaction bottle, adding 40 ml of dichloromethane, slowly adding 5.0 ml of oxalyl chloride dropwise at room temperature, stirring at room temperature after the dropwise addition, after the TLC tracking reaction is finished, concentrating to remove the solvent, adding 11.0 g of aluminum trichloride and 6.5 g of sodium chloride into a concentrated solution, heating to 130 ℃ and 135 ℃ for reaction for 4.5 hours, cooling to room temperature, adding ice water and dichloromethane, stirring, dissolving, extracting, separating liquid, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 5.2 g of a target product 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile, wherein the molar yield is 70.9%.
Claims (10)
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.
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| CN113214111A (en) * | 2021-04-30 | 2021-08-06 | 上海立科化学科技有限公司 | Preparation method of 3- (2-cyanophenyl) propionic acid and 4-cyano-1-indanone |
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