CN109020912B

CN109020912B - Synthesis process of C-Fos/AP-1 inhibitor

Info

Publication number: CN109020912B
Application number: CN201810835780.XA
Authority: CN
Inventors: 贲昊玺; 于海涛; 孙爱学; 唐小航
Original assignee: Nanjing Haolv Biotechnology Co ltd
Current assignee: Nanjing Haolv Biotechnology Co ltd
Priority date: 2018-07-26
Filing date: 2018-07-26
Publication date: 2020-08-18
Anticipated expiration: 2038-07-26
Also published as: CN109020912A

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis process of a C-Fos/AP-1 inhibitor, which starts from cheaper raw materials of 2, 4-dimethoxybenzoic acid and 2-methoxypropionic acid, prepares acyl chloride by thionyl chloride, catalyzes a Friedel-crafts acylation reaction by aluminum trichloride to obtain a coupled product, then reacts for 30 minutes at 160 ℃ by using pyridine hydrobromide and sodium chloride to complete the reaction of demethylation and lactone ring formation in one step, the obtained product can be directly used for the next reaction without purification, introduces cyclopentyl through nucleophilic substitution, prepares methyl ester after opening the lactone ring, introduces benzisoxazole groups through nucleophilic substitution after purification, and removes protective groups to obtain a final product T5224; the method has the advantages of short route, purification only requiring three steps of Friedel-crafts acylation, lactone ring opening and introduction of benzisoxazolyl in the middle, low cost of raw materials, short reaction time of the process route and suitability for industrial production.

Description

Synthesis process of C-Fos/AP-1 inhibitor

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis process of a C-Fos/AP-1 inhibitor.

Background

T5224 is a selective c-Fos/AP-1 inhibitor, and c-Fos/AP-1 regulates the expression of inflammatory cytokines and matrix metalloproteinases, which are important in the pathogenesis of rheumatoid arthritis.

The structural formula of T5224 is as follows:

t5224 refers to 3- { [2- [ 3-oxo- (1, 2-benzisoxazol-6-yl) methoxy-5- (2-hydroxy-4-cyclopentyloxybenzoyl) ] phenyl } propanoic acid; in the prior art, the synthesis route of T5224 mainly comprises four routes: 1) U.S. Pat. No. 4, 2009099369, 1 describes that 6-methylcoumarin is used as a raw material, and is oxidized to generate coumarin-6-carboxylic acid, then acyl chloride and m-phenyl dimethyl ether are prepared, and are coupled through Friedel-crafts acylation, methyl protecting groups on phenolic hydroxyl groups are removed, bromo-cyclopentyl groups are nucleophilic substituted, lactone rings of coumarin are opened under alkaline conditions, double bonds are reduced through hydrogenation, carboxyl methyl is esterified, and methyl ester is hydrolyzed after reaction with benzyl bromide to obtain a final product. 2) In Chinese patent CN106565529A, coumarin-6-carboxylic acid is used as a starting material, coupling is carried out with m-phenyl dimethyl ether through acylation reaction catalyzed by phosphorus pentoxide and methanesulfonic acid, and the methyl protecting group is removed by pyridine hydrochloride, and the subsequent steps are basically similar to those of U.S. Pat. No. 3, 2009099369, 1. 3) In chinese patent CN103183647A, 3-bromo-4-fluorobenzoic acid is used as an initial raw material, coupled with m-xylene through an acylation reaction catalyzed by phosphorus pentoxide and methanesulfonic acid, then pyridine hydrochloride is used to remove a methyl protecting group at 200 ℃, bromo-cyclopentyl is introduced by nucleophilic substitution, and then subjected to SnAr aromatic nucleophilic substitution with 2-trityl-6- (hydroxymethyl) -1, 2-benzisoxazole-3- (2H) -one, michael addition is performed with methyl acrylate through a grignard reaction, and finally a protecting group is removed to obtain a final product. 4) Nature Biotechnology,2008, volume 26, 817-823, described that 2, 4-dimethoxybenzoic acid as an initial raw material was coupled with 2-methoxy phenylpropionic acid methyl ester through Friedel-crafts acylation reaction, aluminum trichloride was refluxed in ethyl acetate to remove methyl protecting group, cyclopentyl was introduced by mitsunobu reaction, benzisoxazolyl group was introduced by nucleophilic substitution, and finally protecting group was removed to obtain T5224.

The starting materials of the route 1-3 in the four routes are relatively expensive, the route is long, and particularly, the route 3 also uses the Grignard reaction, so that the anhydrous and anaerobic operation is difficult. The raw materials used in the route 4 are low in price and moderate in route, but the yield of aluminum trichloride and ethyl acetate adopted in the step of removing the methyl protecting group on the methyl ether is 53%, and the total yield of 17% in the first three steps is obviously low. And before introducing the cyclopentyl group, a lactone ring needs to be formed by p-toluenesulfonic acid catalysis, and then the cyclopentyl group is introduced by a mitsunobu reaction, so that the number of steps is increased, and the cost of raw materials is increased.

Disclosure of Invention

The invention solves the technical problems in the prior art and provides a synthesis process of a C-Fos/AP-1 inhibitor.

In order to solve the problems, the technical scheme of the invention is as follows:

the synthesis process of the C-Fos/AP-1 inhibitor comprises the following steps:

the C-Fos/AP-1 inhibitor has the following synthetic route:

step 1, dissolving a compound 1 in methanol, dropwise adding concentrated sulfuric acid, keeping a reaction bottle at room temperature basically in the dropwise adding process, heating to reflux at 90 ℃ after dropwise adding, reacting overnight, washing and purifying to obtain a compound 2;

step 2, adding thionyl chloride into the compound 3, heating in an oil bath until reflux, reacting for 2 hours, separating and purifying to obtain a compound 4; standing overnight under the protection of nitrogen;

step 3, dissolving the compound 2 prepared in the step 1 in dichloromethane, adding anhydrous aluminum chloride under the nitrogen atmosphere and under the conditions of ice-water bath and stirring, continuously stirring until most of the anhydrous aluminum chloride is dissolved, dropwise adding the dichloromethane solution of the compound 4 prepared in the step 2, changing the ice-water bath into a cold water bath after dropwise adding, and continuously reacting for 3 hours under the conditions; under the ice-water bath, dripping dilute hydrochloric acid into the reaction solution in a stirring state, separating, washing and purifying to obtain a compound 5;

step 4, adding pyridine hydrogen bromide salt and sodium chloride into the compound 5 prepared in the step 3, heating reactants to be molten into a liquid state under the conditions of nitrogen atmosphere and stirring, keeping the heating voltage unchanged, continuing stirring for 1.1h, stopping heating and stirring, naturally cooling to room temperature, adding a mixed solvent of ethyl acetate and water until all solids in a reaction system are dissolved, and purifying to obtain a compound 6;

step 5, adding potassium carbonate and N, N-dimethylformamide into the compound 6 in a nitrogen atmosphere, adding an N, N-dimethylformamide solution of bromocyclopentane for the first time, heating and stirring in an oil bath at 85 ℃, stopping heating after reacting for about 3 hours, naturally cooling to an internal temperature lower than 60 ℃, adding an N, N-dimethylformamide solution of bromocyclopentane for the second time, heating and stirring in an oil bath at 85 ℃, stopping heating after reacting for about 3 hours, naturally cooling to an internal temperature lower than 60 ℃, adding an N, N-dimethylformamide solution of bromocyclopentane for the third time, heating and stirring in an oil bath at 85 ℃, stopping heating after reacting for about 4 hours, then continuing stirring overnight, and purifying to obtain a compound 7;

step 6, dissolving the compound 7 prepared in the step 5 in an ethanol solution, stirring at room temperature, dropwise adding a sodium hydroxide solution, reacting at 60 ℃ for 1.5h, continuing to react for 1.5h after the temperature is raised to 70 ℃, and purifying to obtain a compound 8;

step 7, dissolving the compound 8 prepared in the step 6 in methanol, stirring in an ice-water bath, dropwise adding thionyl chloride, and supplementing the thionyl chloride after 1.5 hours; continuing to react for 1h, and then replenishing thionyl chloride again; after reacting for 1 hour again, stopping the reaction, and purifying to obtain a compound 9;

step 8, dissolving the compound 9 prepared in the step 7 in acetone, sequentially adding the compound 10 and potassium carbonate into the acetone, stirring, heating in an oil bath at 68 ℃ in a nitrogen atmosphere until refluxing is carried out, stopping the reaction after refluxing for 5.5 hours, and purifying to obtain a compound 11;

step 9, adding an ethanol solution into the compound 11 prepared in the step 8, adding a NaOH solution, heating to an external temperature of 60 ℃ until all reactant solids are dissolved, reacting for 10min, and purifying to obtain a compound 12;

and step 10, adding glacial acetic acid and water into the compound 12 prepared in the step 8, stirring and reacting at room temperature, stopping the reaction after 46 hours, and purifying to obtain a final product.

Preferably, in step 1, 1g of compound 1 is added corresponding to 5mL of concentrated sulfuric acid.

Preferably, in step 2, 1g of compound 3 is added corresponding to 1.5mL of thionyl chloride.

Preferably, in the step 3, the molar ratio of the compound 2 to the anhydrous aluminum chloride is: 1:1.44, addition of 1g of Compound 2 corresponds to the addition of 3.24mL of Compound 4.

Preferably, in the step 4, the mole ratio of the compound 5, the pyridine hydrogen bromide salt and the sodium chloride is as follows: 1:4.18:7.45.

Preferably, in the step 5, the molar ratio of the compound 6, potassium carbonate and bromocyclopentane is: 1:3:2.

Preferably, in the step 6, the molar ratio of the compound 7 to the sodium hydroxide is: 1:6.

Preferably, in step 7, 1g of compound 8 is added corresponding to 0.85mL of thionyl chloride.

Preferably, in the step 8, the molar ratio of the compound 9 to the compound 10 to the potassium carbonate is: 1:1.54:1.13.

Preferably, in the step 9, the molar ratio of the compound 11 to the NaOH is: 1:5.12.

Preferably, in step 10, 1g of compound 12 is added corresponding to 5.62mL of glacial acetic acid and 0.15mL of water.

Compared with the prior art, the invention has the advantages that 1, the raw materials of 2, 4-dimethoxybenzoic acid and 2-methoxyphenylpropionic acid are relatively cheaper; 2. pyridine hydrobromide and sodium chloride are used for reacting for 30 minutes at 160 ℃, the reaction of demethylation and lactone ring formation can be completed in one step with high yield, the obtained product can be directly used for the next step without purification, the yield is greatly improved, and the reaction and post-treatment time is shortened; 3. the general route is shorter, purification is needed only in three steps of Friedel-crafts acylation, lactone ring opening and introduction of benzisoxazolyl, the cost of raw materials is lower, the reaction time of the process route is shorter, and the method is suitable for industrial production.

Drawings

Fig. 1 is a T5224 synthetic route map provided by the present invention.

FIG. 2 preparation of crude T5224 intermediate 8 from example 6¹H-NMR chart.

FIG. 3 preparation of crude T5224 intermediate 9 from example 7¹H-NMR chart.

FIG. 4 preparation of T5224 from example 10¹H-NMR chart.

Detailed Description

Example 1:

(1)

dissolving the compound 1(50g,0.28mol) in 600mL of methanol to form a light yellow clear solution, isolating moisture in the air of the reaction system by using a calcium chloride drying tube, dropwise adding 30mL of concentrated sulfuric acid into a reaction bottle, and keeping the reaction solution at the room temperature basically; after the addition was completed, the mixture was heated to reflux, after 8 hours of reaction, heating was stopped, the solvent was removed by concentration, the residue was poured into an appropriate amount of ice-water mixture, extracted 2 times with 200mL of DCM, the organic phases were combined, washed once with an appropriate amount of water, a saturated sodium bicarbonate solution, and a brine in this order, and the organic phase was dried over anhydrous sodium sulfate to obtain 52g of a yellow liquid after concentration (HPLC purity: 95%, crude yield 96%) which was used in the next step without purification.

(2)

Adding 50mL of thionyl chloride into the compound 3(55g,0.3mol) in batches under stirring, generating a large amount of gas (a reaction system needs to be connected with an acid gas absorption device), and enabling the reaction liquid to be yellow initially and to change into purple black rapidly; and after the thionyl chloride is added, heating in an oil bath to reflux for 2 hours, cooling, removing most of thionyl chloride through common distillation, cooling to room temperature, adding a proper amount of DCM to dissolve residues in the reaction bottle, and concentrating again to obtain a purple black solid-liquid mixture, namely the compound 4 which is directly used in the next step without purification.

(3)

52g of the crude product of Compound 2 was dissolved in 400mL of a molecular sieve-soaked solutionIn methylene chloride, N₂Under the protection, cooling in an ice-water bath, adding anhydrous aluminum chloride (31g,0.23mol), changing the reaction liquid from light yellow to dark red, continuously stirring until most of the anhydrous aluminum chloride is dissolved, slowly dropwise adding 100mL of dichloromethane solution of a compound 4 (prepared in the previous step) (dichloromethane is soaked by a molecular sieve), changing the reaction liquid from dark red to black brown, returning to room temperature after dropwise adding, continuing to react for 3 hours, cooling in the ice-water bath, slowly dropwise adding 1mol/L of dilute hydrochloric acid under stirring, generating gas, generating white precipitate, not generating gas, slowly dissolving the white precipitate, stopping dropwise adding the dilute hydrochloric acid, separating an organic phase, extracting the aqueous phase with 2 × 100mL of dichloromethane twice, combining the organic phases, sequentially washing with 100mL of water, 100mL of saturated sodium bicarbonate solution and 100mL of saturated common salt water, drying with anhydrous sodium sulfate, concentrating, and carrying out gradient elution by a petroleum ether-ethyl acetate system to obtain 93.7g of a white solid compound 5 (purity of HPLC 98%, and yield of the compound 1 is calculated by two steps).

(4)

Under the protection of nitrogen and rapid mechanical stirring, a mixture of compound 5(40.76g, 0.11mol), pyridinium bromide (73.5g, 0.46mol) and sodium chloride (48g, 0.82mol) was heated to a molten state with a 2000w electric heating mantle, the reaction liquid turned brown, after heating for one hour, heating was stopped, stirring was continued until the temperature was cooled to nearly room temperature, and the reaction system coagulated into a solid state. The mixture of 50mL ethyl acetate and 20mL water was added to the reaction flask, shaken ultrasonically to dissolve the solid in the flask, and after a few minutes the solution was decanted, and the process was repeated until the solid in the reaction flask was completely dissolved. The resulting solutions were combined, the organic layer was separated by a separatory funnel, the aqueous layer was extracted with 2X 150mL of ethyl acetate, the organic phases were combined and washed with 3X 200mL of water and 1X 200mL of saturated brine, respectively, dried over anhydrous sodium sulfate and concentrated to give 31.2g of Compound 6 as a tan slightly viscous foamy solid (HPLC purity 95%, crude yield 95%) which was used directly in the next reaction without purification.

(5)

Placing a compound 6(15.13g, 0.053mol) and potassium carbonate (22.12g, 0.16mol) in a three-necked bottle, adding 100ml of mixed solution of palladium, lithium (dimethyl formamide) and bromocyclopentane (7.88g, 0.053mol) into a reaction system, heating in an oil bath, and stirring to keep the internal temperature at 82 ℃ and obtain a reddish brown reaction solution. After reacting for about 3 hours, stopping heating, naturally cooling to the internal temperature of less than 60 ℃, dissolving bromocyclopentane (3.94g, 0.026mol) in 5mL of DMF, adding the reaction system, then reheating to 82 ℃, reacting for about 3 hours at the temperature, stopping heating, naturally cooling to the internal temperature of less than 60 ℃, dissolving bromocyclopentane (4.00g, 0.027mol) in 5mL of DMF, adding the reaction system, reheating to 82 ℃, stopping heating after reacting for 4 hours, and then continuously stirring at room temperature overnight. Pouring the reaction solution into a beaker, washing the solid precipitate left at the bottom of the reaction bottle with ethyl acetate, and performing suction filtration in a suction filtration funnel; adding 300mL of water into the reaction solution, adjusting the pH value to be about 3 by using 3mol/L hydrochloric acid, dissolving the precipitate obtained by suction filtration by using 100mL of water, adjusting the pH value to be about 3 by using 3mol/L hydrochloric acid, combining water phases, combining the water phases with the filtrate obtained by suction filtration, transferring the mixture to a separating funnel, extracting the mixture for three times by using ethyl acetate, combining organic phases, washing the organic phases by using 3X 150mL of water and 1X 200mL of saturated saline solution in sequence, drying the organic phases by using anhydrous sodium sulfate, and concentrating the organic phases to obtain 13.7g of a crude product of the compound 7 (the purity of HPLC is 95 percent, the crude yield is 70 percent), wherein the crude product.

(6)

Dissolving the compound 7 (crude product obtained in the previous step) in 70mL of 95% ethanol, and stirring at room temperature; dissolving sodium hydroxide (14.88g, 0.37mol) in 20mL of water, cooling to room temperature, slowly dripping into the reaction system, after dripping, washing the container with 10mL of water, transferring into the reaction solution, washing the wall of the reaction bottle with 10mL of 95% ethanol, reacting for 3h at 70 ℃, completing hydrolysis, and stopping reaction. Ethanol was concentrated, about 150mL of water was added to the reaction flask, the pH was adjusted to about 3 with 3mol/L hydrochloric acid, extracted three times with about 200mL, 150mL, 100mL ethyl acetate, the organic phases were combined and washed with about 2 × 100mL water, 100mL saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 14.8g of crude compound 8 (HPLC purity 88%, yield 95%, 1H-NMR see fig. 2), properties: a reddish brown oil, which was used directly in the next reaction.

(7)

Dissolving 14.8g of a crude product of the compound 8 in 120mL of methanol, stirring in an ice-water bath, slowly dropwise adding 14mL of thionyl chloride through a dropping funnel, wherein reaction liquid is reddish brown clear liquid before and after dropwise adding; continuously stirring and reacting for 90 minutes in an ice-water bath, and slowly adding 5mL of thionyl chloride; after continuing the reaction for 60 minutes, 2.5mL of thionyl chloride was added again, most of the solvent was removed by concentration under reduced pressure after one hour, about 200mL of dichloromethane was added to the residue, washed once with 150mL of water and 100mL of saturated sodium bicarbonate solution in this order, the separated aqueous phases were combined and extracted with 2X 100mL of dichloromethane, all the organic phases were combined and washed once with brine, dried over anhydrous sodium sulfate, concentrated to give a dark brown liquid crude product, and separated and purified by flash column chromatography to give 12.1g of compound 9 (yield 90%), for properties: an orange oil.

(8)

Compound 9(9.44g, 0.024mol) was dissolved in 100mL of acetone, and Compound 10 (17.39g, 0.037mol) and potassium carbonate (3.76g, 0.027mol) were added in this order under nitrogen protection to give a yellow cloud under stirring, which was heated to reflux at an external temperature of about 68 ℃. As the reaction proceeded, the reaction solution gradually changed to a reddish-brown turbid solution. After refluxing for 5.5 hours, 100mL of water was added to the reaction solution and pH was adjusted to 6 with 1mol/L hydrochloric acid, extracted three times with about 150mL of ethyl acetate, the organic phases were combined, washed with 100mL of water and 100mL of saturated brine in this order, left overnight to completely separate the two phases, the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by flash column chromatography: elution with an ethyl acetate-petroleum ether gradient gave 14.99g of compound 11 (yield 80%) as a yellow-green waxy solid.

(9)

To compound 11(14.99g, 0.019mol), 200mL of 95% ethanol was added, and 20mL of NaOH aq (3.3g, 0.08mol) was slowly added to the reaction system with stirring to turn the reaction solution yellow; the reaction was stopped after the temperature was raised to 60 ℃ and TLC (PE: EA: 3:1) monitored the disappearance of the starting material. The solvent was removed by concentration, 300mL of water was added to the residue, the pH was adjusted to less than 3 with 3mol/L hydrochloric acid, the mixture was emulsified, extracted three times with ethyl acetate, the organic phases were combined and washed once with the appropriate amount of water and brine, and 14g of compound 12 was obtained after concentration as a pale yellow solid (yield 97%).

(10)

To compound 12(14g, 0.018mol), 100mL of glacial acetic acid and 4mL of water were added, and after stirring at room temperature for 46 hours, the reaction was stopped, and a large amount of precipitate was precipitated. Suction filtration, filter cake washed with proper amount of acetic acid and distilled water in turn, vacuum dried at 45 ℃ to obtain 8.3g of yellowish solid, recrystallized with absolute ethanol to obtain 7.9g of compound 13 (yield 84%) as a white-like slightly yellow fluffy solid.

Example 2:

synthesis method of compound 10

(1)

Experimental procedure

In a 1L four-neck flask, under the protection of nitrogen, adding 2-hydroxy-4-methylbenzoic acid (100g, 0.657mol) into a reaction bottle, adding 800mL of methanol, stirring to dissolve materials, and slowly dropwise adding concentrated sulfuric acid into the reaction bottle for about 20 min. After completion of the dropwise addition, the mixture was heated using an oil bath to start refluxing methanol, the oil bath was removed after 24 hours, cooled to room temperature, and the solution was transferred to a 2L single-neck bottle, and the flask was rinsed with a small amount of methanol and incorporated into the single-neck bottle. After removing 400-500ml of methanol by concentration under reduced pressure, water and ethyl acetate were added to the flask, followed by extraction, washing the organic phase with water, saturated sodium bicarbonate and saturated sodium chloride in this order, drying over anhydrous sodium sulfate, concentration to remove the solvent, and vacuum drying for 2 hours using an oil pump to obtain 90g of a yellow liquid. The yield is 82 percent

(2)

Experimental procedure

Sodium hydroxide (105.75g, 2.64mol) was dissolved in 800mL of ice water, and hydroxylamine hydrochloride (71.1g, 1.02mol) was added with stirring. Compound 2' (90g, 0.54mol) was dissolved in 450mL1, 4-dioxane, and slowly added dropwise to the reaction flask, insoluble material was generated, and the solution was completely dissolved after a certain period of reaction time. After stirring overnight at room temperature, the solution was yellow and concentrated to about 600mL, and then pH was adjusted to 1 with 1N hydrochloric acid, and a large amount of solid was precipitated. Filtration, washing with distilled water 4 times, and vacuum drying gave 87g of a pale pink solid with a yield of 96%.

(3)

Experimental procedure

Compound 3' (87g, 0.52mol) was added to 700mL of tetrahydrofuran with stirring and heated to reflux with tetrahydrofuran, leaving a small amount of solid undissolved. After cooling slightly, after the tetrahydrofuran had no longer boiled, the CDI (127.7g, 0.78mol) was added in portions, with vigorous gassing, at a rate to ensure that flushing did not occur. After the addition was completed, the reaction was continued under reflux for 4 hours. Cooling to room temperature, concentrating to remove tetrahydrofuran, adding ethyl acetate, washing with 1mol/L hydrochloric acid for 2 times, extracting water layer with ethyl acetate for 3 times, mixing organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, and separating by flash column chromatography. 40.6g of 4' pale yellow solid was obtained in 52% yield.

(4)

Experimental procedure

Ph is₃CCl (58.8g, 0.212mol) was dissolved in 550mL of dichloromethane, 16.8mL of pyridine was added, compound 4' (40g, 0.268mol) was added under rapid stirring, the mixture was heated to 40 ℃, after reaction for about 1.5 hours, 20% (wt%) aqueous sodium hydroxide solution was added to the reaction flask, the mixture was transferred to a separatory funnel after stirring, the aqueous phase was extracted once with DCM, the organic phases were combined, the solvent was concentrated to remove the solvent until a large amount of solid was precipitated, and washing was carried out by adding 4 to 5 times the total volume of isopropanol and water (isopropanol: water ═ 1: 2). Filtration followed by vacuum drying gave 72.5g (69% yield) of a white solid.

(5)

Experimental procedure

Compound 5' (72.5g, 0.186mol), N-bromosuccinimide (59.8g, 0.336mol) and 150mL of chlorobenzene were mixed, and then heated to 80 ℃ with stirring. 0.4mL of azobisisoheptonitrile was dissolved in 20mL of methylene chloride, and slowly added dropwise to the flask in 5 portions, and after completion of each dropwise addition, the mixture was stirred for 1 hour. The reaction was monitored by TLC and stopped in time when dibromo was produced. The chlorobenzene was evaporated under reduced pressure and the residue was taken up in dichloromethane and saturated with Na₂SO₃Washing for 2 times, extracting the water phase for 2 times with DCM, combining the organic phases, drying with anhydrous sodium sulfate, concentrating to remove DCM, and performing flash column chromatography with petroleum ether-ethyl acetate system. 87.5g of a brown-yellow solid was obtained (containing a small amount of incompletely reacted compound 5' without affecting the subsequent reaction).

It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and all equivalent substitutions or substitutions made on the above-mentioned embodiments are included in the scope of the present invention.

Claims

A process for the synthesis of a C-Fos/AP-1 inhibitor, wherein the C-Fos/AP-1 inhibitor has the following structural formula:

the C-Fos/AP-1 inhibitor has the following synthetic route:

the synthesis process comprises the following steps:

step 1, dissolving a compound 1 in methanol, dropwise adding concentrated sulfuric acid, keeping a reaction bottle at room temperature in the dropwise adding process, heating to reflux at 90 ℃ after dropwise adding, reacting overnight, washing and purifying to obtain a compound 2;

step 2, adding thionyl chloride into the compound 3, heating in an oil bath until reflux, reacting for 2 hours, separating and purifying to obtain a compound 4; standing overnight under the protection of nitrogen;

step 3, dissolving the compound 2 prepared in the step 1 in dichloromethane, adding anhydrous aluminum chloride under the nitrogen atmosphere, under the ice-water bath and stirring conditions, continuously stirring until the anhydrous aluminum chloride is dissolved, dropwise adding the dichloromethane solution of the compound 4 prepared in the step 2, changing the ice-water bath into a cold water bath after dropwise adding is finished, and continuously reacting for 3 hours under the conditions; under the ice-water bath, dripping dilute hydrochloric acid into the reaction solution in a stirring state, separating, washing and purifying to obtain a compound 5;

step 4, adding pyridine hydrogen bromide salt and sodium chloride into the compound 5 prepared in the step 3, heating reactants to be molten into a liquid state under the conditions of nitrogen atmosphere and stirring, keeping the heating voltage unchanged, continuing stirring for 1.1h, stopping heating and stirring, naturally cooling to room temperature, adding a mixed solvent of ethyl acetate and water until all solids in a reaction system are dissolved, and purifying to obtain a compound 6;

step 5, adding potassium carbonate and N, N-dimethylformamide into the compound 6 under the nitrogen atmosphere, adding N, N-dimethylformamide solution of bromocyclopentane for the first time, heating and stirring in an oil bath at 85 ℃, stopping heating after reacting for 3 hours, naturally cooling to a temperature lower than 60 ℃, adding N, N-dimethylformamide solution of bromocyclopentane for the second time, heating and stirring in an oil bath at 85 ℃, stopping heating after reacting for 3 hours, naturally cooling to a temperature lower than 60 ℃, adding N, N-dimethylformamide solution of bromocyclopentane for the third time, heating and stirring in an oil bath at 85 ℃, stopping heating after reacting for 4 hours, then continuously stirring overnight, and purifying to obtain a compound 7;

step 6, dissolving the compound 7 prepared in the step 5 in an ethanol solution, stirring at room temperature, dropwise adding a sodium hydroxide solution, reacting at 60 ℃ for 1.5h, continuing to react for 1.5h after the temperature is raised to 70 ℃, and purifying to obtain a compound 8;

step 7, dissolving the compound 8 prepared in the step 6 in methanol, stirring in an ice-water bath, dropwise adding thionyl chloride, and supplementing the thionyl chloride after 1.5 hours; continuing to react for 1h, and then replenishing thionyl chloride again; after reacting for 1 hour again, stopping the reaction, and purifying to obtain a compound 9;

step 8, dissolving the compound 9 prepared in the step 7 in acetone, sequentially adding the compound 10 and potassium carbonate into the acetone, stirring, heating in an oil bath at 68 ℃ in a nitrogen atmosphere until refluxing is carried out, stopping the reaction after refluxing for 5.5 hours, and purifying to obtain a compound 11;

step 9, adding an ethanol solution into the compound 11 prepared in the step 8, adding a NaOH solution, heating to 60 ℃ until all reactant solids are dissolved, reacting for 10min, and purifying to obtain a compound 12;

and step 10, adding glacial acetic acid and water into the compound 12 prepared in the step 8, stirring and reacting at room temperature, stopping the reaction after 46 hours, and purifying to obtain a final product.
2. The process for synthesizing a C-Fos/AP-1 inhibitor as claimed in claim 1, wherein in step 3, the molar ratio of compound 2 to anhydrous aluminum chloride is: 1:1.44, addition of 1g of Compound 2 corresponds to the addition of 3.24mL of Compound 4.
3. The process for the synthesis of a C-Fos/AP-1 inhibitor as claimed in claim 1, wherein in step 4, the molar ratio of compound 5, pyridinium bromide and sodium chloride is: 1:4.18:7.45.
4. The process for synthesizing the C-Fos/AP-1 inhibitor according to claim 1, wherein in the step 5, the molar ratio of the compound 6, the potassium carbonate and the bromocyclopentane is as follows: 1:3:2.
5. The process for synthesizing the C-Fos/AP-1 inhibitor according to claim 1, wherein in step 6, the molar ratio of compound 7 to sodium hydroxide is: 1:6.
6. The process for the synthesis of a C-Fos/AP-1 inhibitor as claimed in claim 1, wherein in step 7, 1g of compound 8 is added corresponding to 0.85mL of thionyl chloride.
7. The process for the synthesis of a C-Fos/AP-1 inhibitor as claimed in claim 1, wherein in step 8, the molar ratio of compound 9, compound 10, potassium carbonate is: 1:1.54:1.13.
8. The process for the synthesis of a C-Fos/AP-1 inhibitor as claimed in claim 1, wherein in step 9, the molar ratio of compound 11 to NaOH is: 1:5.12.
9. The process for the synthesis of a C-Fos/AP-1 inhibitor as claimed in claim 1, wherein in step 10, 1g of compound 12 is added corresponding to 5.62mL of glacial acetic acid and 0.15mL of water.