CN108658834B - Preparation method of indolone derivative - Google Patents

Abstract

The invention discloses a preparation method of an indolone derivative. The method takes phenylpropargyl acid and aniline as starting raw materials, and the indolone derivative is obtained by sequentially carrying out four steps of condensation, nucleophilic substitution, palladium catalytic coupling and hydrolysis. The method has the advantages of easily obtained raw materials, simple and convenient operation, high production efficiency, easy scale-up production, high total product yield and easy purification.

Description

Preparation method of indolone derivative

Technical Field

The invention belongs to the field of chemical synthesis of medicines, and relates to a preparation method of 3- {3- [1- (4-chloro-phenyl) -1-phenyl-methyl- (E) -fork ] -2-oxo-2, 3-dihydro-indol-1-yl-methyl } -benzoic acid.

Background

In recent years, the incidence of ischemic heart disease has been increasing, seriously threatening human health. The reduction of coronary blood flow, which leads to myocardial cell injury and death, is the main cause of ischemic heart disease. The current treatment measures mainly comprise the modern technologies of artery bypass surgery, thrombolysis, percutaneous transluminal coronary angioplasty and the like to realize the blood reperfusion of the heart. However, myocardial ischemia-reperfusion may also cause myocardial damage itself, and even after vascular patency, may cause more severe acute myocardial damage than when the blood vessel is occluded, resulting in severe arrhythmia, enlargement of necrotic area of the myocardium, and heart rupture or even death. This phenomenon, in which tissue damage is rather aggravated after blood flow is restored on the basis of ischemia, and even irreversible damage occurs, is called Myocardial ischemia-reperfusion injury (MIRI). With the establishment and popularization of methods such as arterial bypass, thrombolytic therapy, percutaneous transluminal coronary angioplasty, cardiac surgery extracorporeal circulation, cardiopulmonary resuscitation, organ transplantation and the like, MIRI has become a major problem that hinders the myocardium from obtaining the best curative effect from reperfusion therapy, and thus has become an urgent major clinical problem to be solved at the present stage (fakun and the like, the research progress of vascular dysfunction caused by myocardial ischemia reperfusion injury, and chinese practical medicine 2014,9, 259-260).

The compound 3- {3- [1- (4-chloro-phenyl) -1-phenyl-methyl- (E) -ylidene ] -2-oxo-2, 3-dihydro-indol-1-yl-methyl } -benzoic acid (YLF 466D for short), a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a crystalline hydrate, a solvate or a mixture of a plurality thereof can be used for preparing a medicament for treating myocardial ischemia reperfusion injury (CN 201510740650.4).

Several synthetic methods of this series of compounds are disclosed in CN102666485, one of which is shown below:

the method has low yield in each step (for example, 62% in the first step, 65% in the second step, 62% in the third step and 70% in the fourth step), and purification in each step requires column chromatography purification, which is not suitable for scale-up production and greatly reduces production efficiency.

Therefore, there is still a need in the art to develop a new method for preparing and purifying YLF466D on a large scale.

Disclosure of Invention

The object of the present invention is to provide an efficient process for large scale preparation and purification of indolone derivatives such as YLF 466D.

In a first aspect of the present invention, there is provided a method for preparing an indolone derivative, comprising the steps of:

nucleophilic substitution reaction is carried out on a compound of a formula I and bromomethylbenzoic acid or ester thereof under the action of alkali to prepare a compound of a formula II, wherein the alkali is inorganic alkali or organic alkali, and is sodium hydride or K₂CO₃、Na₂CO₃、Li₂CO₃NaOH, KOH, LiOH, triethylamine, diisopropylethylamine, pyridine, picoline, n-butyllithium, sec-butyllithium, diisopropylaminolithium, lithium hexamethyl-silazane, sodium hexamethyl-silazane, and potassium hexamethyl-silazane (preferably, the base is K₂CO₃Or Na₂CO₃Or a mixture of both);

wherein the particle size of the inorganic base in solid form is more than 50 meshes, preferably 50-400 meshes or 100-400 meshes, 150-350 meshes or 200-400 meshes;

y is H or C1-C6 alkyl, preferably C1-C4 alkyl.

In another preferred embodiment, the bromomethylbenzoate is methyl 3-bromomethylbenzoate.

In another preferred embodiment, the reaction temperature of the nucleophilic substitution reaction is 30 ℃ to 120 ℃ (preferably 40 ℃ to 60 ℃).

In another preferred example, the nucleophilic substitution reaction is performed in an organic solution, which is one or a combination of two or more of formamide, DMF, DMA, sulfolane, DMSO, NMP, HMPA (hexamethylphosphoric triamide), acetone, butanone, benzene, toluene, ethyl acetate, butyl acetate, dichloromethane, trichloromethane, dichloroethane, isopropyl ether, tetrahydrofuran, dioxane; preferably, the organic solution is acetone, butanone or a mixed solvent of the acetone and the butanone.

In another preferred embodiment, the preparation method further comprises the following steps:

i) reacting the compound of the formula II with iodobenzene or a derivative thereof to obtain a compound of a formula III, wherein R is F, Cl, Br or H, and Y is as defined above;

ii) hydrolyzing the compound shown in the formula III to obtain the indolone derivative shown in the formula VI.

In another preferred embodiment, the reaction of step i) is carried out under catalysis of a palladium catalyst or a nickel catalyst, wherein the palladium catalyst is PdCl₂、Pd(OAc)₂、Pd(PPh₃)₂Cl₂、Pd(PPh₃)₄、Pd(dppf)Cl₂、[PdCl₂(dppf)]CH₂Cl₂One or a combination of more than two of the nickel catalysts, wherein the nickel catalyst is NiCl₂、Ni(OAc)₂、Ni(dppp)Cl₂One or a combination of two or more of them.

In another preferred embodiment, the palladium catalyst is Pd (dppf) Cl₂。

In another preferred embodiment, the preparation method further comprises the step of recrystallizing the compound of formula III obtained in step i). In another preferred example, the solvent used for recrystallization is dichloromethane-ethanol, dichloromethane-methanol, dichloromethane-ethanol-methanol; dichloromethane-ethanol is preferred. In the prior art, a column chromatography method is adopted, so that the scale-up production cannot be carried out, and the compound of the formula III with higher purity can be obtained by a recrystallization method, so that the step of column chromatography purification is avoided.

In another preferred embodiment, step ii) is carried out under a hydrochloric acid/dioxane or sodium hydroxide/dioxane system.

In another preferred embodiment, the preparation method further comprises a step of recrystallizing and purifying the indolone derivative obtained in the step ii). In the prior art, preparative HPLC purification is adopted, so that the method is not suitable for hectogram production or even kilogram production; the invention adopts a recrystallization mode, and can quickly and efficiently obtain kilogram-level indolone derivatives with the purity of more than 98.5 percent.

In another preferred example, the solvent for recrystallization is acetone-water, ethanol-water, acetone-ethanol-water; acetone-ethanol-water is preferred.

In another preferred embodiment, the compound of formula I is prepared by condensation of phenylpropanoic acid with aniline.

In another preferred embodiment, the reaction temperature of the condensation reaction is 10 to 30 ℃.

In another preferred example, the condensation reaction is carried out in an organic solution, which is a mixed solvent (preferably dichloromethane, chloroform or a mixed solvent of two or more) of dichloromethane, formamide, DMF, DMA, sulfolane, DMSO, NMP, HMPA (hexamethylphosphoric triamide), acetone, butanone, benzene, toluene, ethyl acetate, butyl acetate, trichloromethane, dichloroethane, isopropyl ether, tetrahydrofuran, and dioxane.

In another preferred example, the condensation reaction is carried out by the action of a condensing agent which is one or a combination of two or more of DCC (1, 3-dicyclohexylcarbodiimide), EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), DIC (1, 3-diisopropylcarbodiimide), BDDC (1, 3-bis (2, 2-dimethyl-1, 3-dioxolan-4-ylmethyl) carbodiimide).

The method of the invention takes the phenylpropanoic acid and the aniline as the initial raw materials, the toxicity of the reagent and the raw materials required by the reaction is low, the raw materials are easy to obtain, the cost is low, and the cost is greatly reduced. The method has the advantages of mild conditions, simple and convenient operation, high production efficiency and easy amplification. The purity and yield of the product are greatly improved, the total yield of the product is high, the purification is easy, and the method is suitable for large-scale preparation of indolone derivatives such as YLF 466D.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The inventor of the application researches extensively and deeply, develops a method suitable for large-scale preparation of indolone derivatives such as YLF466D with low cost for the first time, takes aniline and phenylpropanoic acid as raw materials, and sequentially carries out condensation, nucleophilic substitution, palladium catalytic coupling and hydrolysis reaction to obtain the indolone derivatives such as YLF 466D. The method has the advantages of easily obtained raw materials, mild conditions, simple and convenient operation, high production efficiency and easy amplification. On the basis of this, the present invention has been completed.

Indolone derivatives

In the present invention, the indolone derivative and the compound of formula VI are compounds having the following formula VI.

Wherein R, Y is as defined above.

YLF466D

In the present invention, YLF466D, (E) -3- ((3- ((4-chlorophenyl) (phenyl) methylene) -2-oxo-2, 3-dihydro-indol-1-yl) methyl) benzoic acid, 3- {3- [1- (4-chloro-phenyl) -1-phenyl-m- (E) -ylidene ] -2-oxo-2, 3-dihydro-indol-1-yl-methyl } -benzoic acid all refer to compounds having the following structure:

preparation method

In a preferred embodiment, the preparation method of YLF466D provided by the present invention comprises the following steps:

(1) the phenylpropargyl acid and aniline are subjected to condensation reaction under the action of a condensing agent to obtain an amide intermediate I (a compound shown in a formula I). The amide intermediate I can be conveniently obtained by reacting phenylpropanoic acid and aniline in a suitable solvent under the action of a condensing agent, wherein the condensing agent used is DCC, EDC, DIC, BDDC or other condensing agents.

(2) And (2) carrying out nucleophilic substitution reaction on the intermediate I obtained in the step (1) and methyl 3-bromomethylbenzoate in a proper solvent under the action of alkali at a proper temperature to obtain an intermediate II (a compound shown in a formula II).

Specifically, the temperature of the substitution reaction is 30 to 120 ℃, preferably 40The temperature is between 60 and C; the base can be sodium hydride, K₂CO₃、Na₂CO₃、Li₂CO₃Various inorganic bases such as NaOH, KOH and LiOH, organic bases such as triethylamine, diisopropylethylamine, pyridine, picoline, n-butyllithium, sec-butyllithium, diisopropylaminolithium, lithium hexamethyl-silazane, sodium hexamethyl-silazane and potassium hexamethyl-silazane, and sodium hydride and K are preferable₂CO₃Or Na₂CO₃(ii) a The solvent may be a strongly polar aprotic solvent such as formamide, DMF, DMA, sulfolane, DMSO, NMP, HMPA (hexamethylphosphoric triamide), a ketone solvent such as acetone or butanone, an aromatic solvent such as benzene or toluene, an ester solvent such as ethyl acetate or butyl acetate, a chlorinated hydrocarbon solvent such as dichloromethane or dichloroethane, an ether solvent such as isopropyl ether, tetrahydrofuran, or dioxane, and preferably a ketone solvent such as acetone or butanone.

(3) And (3) reacting the intermediate II obtained in the step (2) with p-chloroiodobenzene under the action of a palladium catalyst under an alkaline condition to obtain an intermediate III (a compound in a formula III). Wherein the base may be K₂CO₃、Na₂CO₃、Li₂CO₃、Cs₂CO₃Various inorganic bases such as NaOH, KOH and LiOH, organic bases such as triethylamine, diisopropylethylamine, pyridine and picoline, and K is preferred₂CO₃Or Na₂CO₃(ii) a The catalyst is PdCl₂、Pd(OAc)₂、Pd(PPh₃)₂Cl₂、Pd(PPh₃)₄、Pd(dppf)Cl₂Or [ PdCl₂(dppf)]CH₂Cl₂Pd (dppf) Cl is preferred₂。

(4) Heating and hydrolyzing the intermediate III obtained in the step (3) under the action of acid or alkali to obtain crude YLF 466D.

The conversion is carried out in the presence of hydrochloric acid/dioxane or sodium hydroxide/dioxane system, preferably under sodium hydroxide/dioxane conditions.

The crude YLF466D obtained by the above method can be purified by recrystallization. The solvent for recrystallization may be acetone-water, ethanol-water, preferably acetone-ethanol-water as the recrystallization solvent.

The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.

The invention has the advantages that:

(1) the yield of the prior art method steps is generally too low, each step is purified by adopting a column chromatography method, the prior art method steps are not suitable for scale-up production, and the YLF466D with the purity of more than 98 percent is difficult to obtain finally. According to the invention, the amide intermediate is obtained by directly condensing phenylpropanoic acid and aniline through EDC, the raw materials are stable and easy to obtain, the reaction is easy to operate, excessive harmful reagents are not used, the yield is extremely high (the yield of the application is 95%, and the yield reported in CN102666485 is 62%), and the scale-up production is easy;

(2) in the preparation method, the cheap and easily-obtained anhydrous potassium carbonate is adopted in the preparation process of the compound shown in the formula II, and the preparation method is characterized in that the granularity is more than 50 meshes (such as 200 meshes), the compound shown in the formula I as a raw material can be completely converted into the compound shown in the formula II, the reaction efficiency is high, the yield is greatly improved (the yield of the application is 96 percent, and the yield reported in a comparison document CN102666485 is 65 percent), and the post-treatment and purification are simpler;

(3) in the preparation method, dioxane and water are used as a mixed solvent for hydrolysis of the compound shown in the formula III, and cheap sodium hydroxide is used as alkali, so that the yield (the yield is a quantitative reaction, and the yield reported by a comparison document CN102666485 is 70%) and the purity of the step are greatly improved. The YLF466D crude product can be purified by a recrystallization method, has high production efficiency and is easy for scale-up production.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

Example 1.1

Preparation of Compounds of formula I

Phenylpropiolic acid (2000g,13.7mol) and aniline (1911g, 20.5mol) were dissolved together in dichloromethane (15L), and EDCI (5252.6g, 27.4mol) was added in portions, with the reaction temperature being controlled below 30 ℃. After the addition, the reaction was carried out at room temperature for about 20 hours.

The reaction solution was washed with 8L of 2.5mol/L dilute hydrochloric acid and 5L of 1mol/L dilute hydrochloric acid, respectively. The organic phase was washed once with 8L of saturated sodium bicarbonate and once with 8L of saturated brine, methylene chloride was recovered to give a yellowish white solid powder, which was hot-dissolved in 6600mL of anhydrous methanol, precipitated by dropping 1-fold volume (10000mL) of purified water, filtered, washed with purified water, and dried by forced air at 40 ℃ to give 2885.4g of the compound of formula I as an off-white solid powder. Yield: 95.3 percent.

¹H NMR(400M Hz,CDCl₃):7.15(t,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),7.36(t,J＝8.0Hz,1H),7.44(t,J＝8.0Hz,1H),7.57(t,J＝8.0Hz,1H),7.76(brs,1H).ESI-MS(m/z):222(M+H)⁺。

Example 1.2

Preparation of Compounds of formula I

Phenylpropiolic acid (20.0g,0.14mol) and aniline (19.11g, 0.21mol) were dissolved together in dichloromethane (150mL), and DIC (1, 3-diisopropylcarbodiimide, 34.0g, 0.27mol) was added in portions, with the reaction temperature being controlled below 30 ℃. After the addition, the reaction was carried out at room temperature for about 20 hours. The reaction mixture was washed with 80mL of 2.5mol/L dilute hydrochloric acid and 50mL of 1mol/L dilute hydrochloric acid, respectively. The organic phase was washed once with 80mL of saturated sodium bicarbonate and once with 80mL of saturated brine, methylene chloride was recovered to give a yellowish white solid powder, which was hot-dissolved in 67mL of anhydrous methanol, crystallized by dropping 100mL of purified water, filtered, washed with purified water, and then dried by forced air at 40 ℃ to give 26.6g of the compound of formula I as an off-white solid powder. Yield: 86.0 percent.

Example 1.3

Preparation of Compounds of formula I

Phenylpropiolic acid (20.0g,0.14mol) and aniline (19.11g, 0.21mol) were dissolved together in methylene chloride (150mL), and DCC (1, 3-dicyclohexylcarbodiimide, 55.62g, 0.27mol) was added in portions, with the reaction temperature being controlled to 30 ℃ or lower. After the addition, the reaction was carried out at room temperature for about 20 hours. The reaction mixture was washed with 80mL of 2.5mol/L dilute hydrochloric acid and 50mL of 1mol/L dilute hydrochloric acid, respectively. The organic phase was washed once with 80mL of saturated sodium bicarbonate and once with 80mL of saturated brine, the methylene chloride was recovered to give a yellowish white solid powder, which was hot-dissolved in 67mL of anhydrous methanol, crystallized by dropping 100mL of purified water, filtered, washed with purified water, and then dried by forced air at 40 ℃ to give 21.9g of the compound of formula I as an off-white solid powder. Yield: 70.8 percent.

Example 2.1

Preparation of Compounds of formula II

The compound of formula I (2880g, 13.0mol) was dissolved in acetone (20L), methyl 3-bromomethylbenzoate (3280g, 14.3mol) was added, 200 mesh anhydrous potassium carbonate (5390.0g, 39.1mol) was added, and the reaction was refluxed with mechanical stirring at 60 ℃ for about 20 hours. The potassium carbonate was removed by filtration, washed with a small amount of acetone, the filtrate was crystallized by dropping 3L of purified water, filtered, and the solid was washed with purified water and dried by forced air at 40 ℃ to give 4600g of the compound of formula II as a white solid powder. Purity 97.1%, yield: 96 percent.

¹H NMR(400M Hz,CDCl₃):3.89(s,3H),5.05(s,2H),7.10(d,J＝1.6Hz,2H),7.16(d,J＝3.6Hz,1H),7.17(d,J＝1.6Hz,1H),7.22(t,J＝4.0Hz,2H),7.32(t,J＝6.0Hz,1H),7.35-7.40(m,4H),7.51(d,J＝6.0Hz,1H),7.89(brs,1H),7.94(d,J＝7.2Hz,1H).ESI-MS(m/z):370(M+H)⁺。

Example 2.2

Preparation of Compounds of formula I

The compound of formula I (50g, 0.226mol) was dissolved in acetone (400mL), methyl 3-bromomethylbenzoate (56.8g, 0.249mol) was added, ordinary anhydrous potassium carbonate (93.6g, 0.678mol) powder was added, and the reaction was refluxed with mechanical stirring at 60 ℃ for about 20 h. Filtering to remove potassium carbonate, washing with a small amount of acetone, dropwise adding 50mL of purified water into the filtrate for crystallization, filtering, washing the solid with purified water, drying by air blowing at 40 ℃ to obtain 69.4g of a compound shown in the formula II, and performing recrystallization purification once again to obtain 66.1g of a white solid powder compound shown in the formula II with the purity of more than 97%. Yield: 79 percent.

Example 2.3

Preparation of Compounds of formula I

The compound of formula I (50g, 0.226mol) was dissolved in acetone (400mL), methyl 3-bromomethylbenzoate (56.8g, 0.249mol) was added, and 200 mesh sodium carbonate (93.6g, 0.678mol) powder was added, and the reaction was refluxed with mechanical stirring at 60 ℃ for about 20 hours. Filtering to remove potassium carbonate, washing with a small amount of acetone, dropwise adding 50mL of purified water into the filtrate for crystallization, filtering, washing the solid with purified water, and drying by air blowing at 40 ℃ to obtain 77.5g of a compound shown in the formula II, wherein the purity is 97%, and the yield is as follows: 93 percent.

Example 2.4

Preparation of Compounds of formula I

This example is essentially the same as example 2.1, except that the reaction temperature was controlled at room temperature (about 20 ℃ C.), and the same work-up was carried out to finally obtain a white solid powder with a yield of 91.2%.

Example 3.1

Preparation of Compounds of formula III

The compound of formula II (3480g, 9.4mol) was dissolved in acetonitrile (15L) and addedp-Chlorodiobenzene (2900g, 12.3mol), anhydrous potassium carbonate (1690g, 12.3mol), [ Pd (dppf) Cl₂]CH₂Cl₂(384.6g, 0.47mol), nitrogen protection, 85 ℃ reflux reaction for about 20 h. Filtering to remove potassium carbonate, decompressing the filtrate to recover the solvent, dissolving the obtained residue with dichloromethane (10L), washing with 5L of 5% tetrasodium EDTA and 5L of saturated saline solution, purifying the organic phase by fast silica gel column chromatography (dichloromethane elution), recovering the solvent to ensure that the residual amount of dichloromethane is 4.5L, dropwise adding 45L of absolute ethyl alcohol, stirring, crystallizing, filtering, washing the solid with absolute ethyl alcohol, and drying by air blow at 40 ℃ to obtain a crude product of an intermediate II. Dissolving the crude product with 8L of dichloromethane, decolorizing with 200g of activated carbon for 2h, purifying by flash silica gel column chromatography (eluting with dichloromethane), recovering the solvent until the residual amount of dichloromethane is 3L, dropwise adding 30L of absolute ethyl alcohol, stirring at room temperature for crystallization, filtering, washing the solid with absolute ethyl alcohol, and drying by air blow at 40 ℃ to obtain 1960g of compound of formula III as a reddish brown solid powder. Yield: 43.4 percent.

¹H NMR(400M Hz,CDCl₃):3.91(s,3H),4.96(s,2H),6.54(d,J＝6.0Hz,1H),6.65(d,J＝6.4Hz,1H),6.71(t,J＝6.4Hz,1H),7.08(dt,J₁＝0.8Hz,J₂＝6.0Hz,1H),7.29-7.32(m,2H),7.34-7.44(m,8H),7.50(d,J＝6.4Hz,1H).7.93(d,J＝6.0Hz,1H),8.01(s,1H),ESI-MS(m/z):480(M+H)⁺。

Example 3.2

Preparation of Compounds of formula III

The compound of formula II (21g, 56.9mmol) was dissolved in acetonitrile (100mL) and p-chloroiodobenzene (17.6g, 74.0mmol), anhydrous potassium carbonate (10.2g, 74.0mol), Pd (dppf) Cl was added₂(2.09g, 2.85mmol) under nitrogen, and the reaction is refluxed at 85 ℃ for about 24 hours. Filtering to remove potassium carbonate, decompressing the filtrate to recover the solvent, dissolving the obtained residue with dichloromethane, washing with 5% EDTA tetrasodium and saturated salt water, purifying the organic phase by fast silica gel column chromatography (dichloromethane elution), recovering the solvent to ensure that the residual amount of dichloromethane is about 30mL, dropwise adding 300mL of absolute ethyl alcohol, stirring, crystallizing, filtering, washing the solid with absolute ethyl alcohol, and drying by air blast at 40 ℃ to obtain a crude product of an intermediate II. Dissolving the crude product with dichloromethane, decolorizing with 2g active carbon for 2h, and purifying by flash silica gel column chromatography (dichloro-silica gel column chromatography)Methane elution), recovering solvent to make the residual amount of dichloromethane 20mL, dropwise adding 200mL absolute ethyl alcohol, stirring at room temperature for crystallization, filtering, washing the solid with absolute ethyl alcohol, and drying by air blast at 40 ℃ to obtain 12.05g of the compound of formula III as a reddish brown solid powder. Yield: 44.2 percent.

Example 3.3

Preparation of Compounds of formula III

The compound of formula II (20.0g, 54.2mmol) was dissolved in acetonitrile (100mL) and p-chloroiodobenzene (16.8g, 70.5mmol), anhydrous potassium carbonate (9.7g, 70.5mol), Pd (PPh) were added₃)₄(3.13g, 2.71mmol), under nitrogen, and reflux at 85 ℃ for about 24 h. Filtering to remove potassium carbonate, decompressing the filtrate to recover the solvent, dissolving the obtained residue with dichloromethane, washing with 5% EDTA tetrasodium and saturated salt water, purifying the organic phase by fast silica gel column chromatography (dichloromethane elution), recovering the solvent to ensure that the residual amount of dichloromethane is about 30mL, dropwise adding 300mL of absolute ethyl alcohol, stirring, crystallizing, filtering, washing the solid with absolute ethyl alcohol, and drying by air blast at 40 ℃ to obtain a crude product of an intermediate II. Dissolving the crude product with dichloromethane, decolorizing with 2g of activated carbon for 2h, purifying by flash silica gel column chromatography (eluting with dichloromethane), recovering solvent to make the residual amount of dichloromethane 20mL, dropwise adding 200mL of absolute ethanol, stirring at room temperature for crystallization, filtering, washing the solid with absolute ethanol, and drying by air blast at 40 ℃ to obtain 8.6g of compound of formula III as a reddish brown solid powder. Yield: 33 percent.

Example 3.4

Preparation of Compounds of formula III

This example is essentially the same as example 3.1, except that the solvent is tetrahydrofuran and the internal temperature of the reaction is 66 ℃ and the time is approximately 30h, and finally 42% of the compound of the formula III is still obtained.

Example 4.1

Preparation of YLF466D

The compound of formula III (1940g, 4.04mol) is dissolved in 8L dioxane, 8L 1.0mol/L sodium hydroxide solution is added dropwise, and the mixture is heated at 50 ℃ for reaction for about 20 h. Recovering part (about 4L) of dioxane under reduced pressure, dropwise adding 8L of 1.0mol/L dilute hydrochloric acid under cooling, stirring at room temperature for crystallization, filtering, washing the solid with anhydrous ethanol, and drying by air blow at 40 ℃ to obtain crude YLF466D of 1900g and gray yellow solid powder. Yield: 100 percent.

Example 4.2

Preparation of YLF466D

This example is essentially the same as example 4.1, except that the solvent is tetrahydrofuran, and finally YLF466D can still be obtained in a yield of approximately 100%.

Example 4.3

Preparation of YLF466D

The compound of formula III (50g, 104.4mmol) was dissolved in 350mL of dichloro-hexacyclic ring, and after complete dissolution, 350mL of 2.5mol/L sodium hydroxide solution was added and stirred overnight at room temperature (about 20 ℃). The raw materials are reacted completely. Cooling, adding hydrochloric acid until solid is separated out, filtering and washing. The crude product is slurried with 600mL of ethanol and dried in vacuo. After drying, crude YLF466D was obtained in about 41.5g, yield: 85.2 percent.

The total yield of the process of the prior art reference CN102666485 is 17.5%. By combining the four-step reactions of examples 1-4 of the present application, the total yield is 38.3%, which is about 2.2 times of the prior art, and the process is simpler.

Example 5.1

Purification of YLF466D

The crude YLF466D (1810g) prepared in example 4.1 was suspended in acetone (10800ml) and absolute ethanol (5400ml), and after complete dissolution by heating, activated carbon (180g) was added, followed by further heating and stirring for 2 hours, filtration was carried out while hot, the solid was washed with ethanol, and a portion of the acetone was recovered from the filtrate under reduced pressure. Adding anhydrous ethanol (32000ml) into the concentrated solution, stirring at room temperature for crystallization, filtering, washing the solid with anhydrous ethanol, and air drying at 40 deg.C to obtain yellow solid powder (1700 g). The purity of the liquid phase is not less than 99.3 percent, the single impurity is not more than 0.5 percent, and the yield is 96.5 percent.

¹H NMR(400M Hz,CDCl₃):4.99(s,2H),6.56(d,J＝6.0Hz,1H),6.67(d,J＝6.4Hz,1H),6.72(t,J＝6.8Hz,1H),7.10(t,J＝6.4Hz,1H),7.30-7.47(m,10H),7.57(d,J＝6.0Hz,1H),8.01(d,J＝6.4Hz,1H),8.07(s,1H)；¹³C NMR(100M Hz,CDCl₃):43.20,108.64,121.76,123.08,123.16,124.10,127.95,128.14,128.99,129.05,129.26,129.39,129.43,129.48,129.70,130.25,131.01,131.70,132.80,135.48,136.92,139.46,139.57,142.15,153.78,166.72,171.45.ESI-MS(m/z):464(M-H)⁺。

Example 5.2

Purification of YLF466D

41.5g of crude YLF466D prepared in example 4.1 was suspended in acetone (150ml) and absolute ethanol (600ml), and after complete dissolution by heating, activated carbon (5.0g) was added, followed by further heating and stirring for 2 hours, filtration was carried out while hot, the solid was washed with ethanol, and 800ml of pure water was added dropwise to the filtrate. Stirring at room temperature for crystallization, filtering, washing the solid with absolute ethyl alcohol, and drying at 40 ℃ to obtain 38.5g of yellow powder. The purity of the liquid phase is 98.8 percent, the single impurity is not more than 0.5 percent, and the yield is 80.0 percent.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (12)

1. A process for producing an indolone derivative characterized by comprising,

the indolone derivative is

Wherein R is F, Cl, Br or H;

the preparation method comprises the following steps:

prepared by nucleophilic substitution reaction of a compound of formula I and bromomethylbenzoic acid or ester thereof under the action of alkaliA compound of formula II, said base being K₂CO₃Or Na₂CO₃Or a mixture of the two;

wherein the particle size of the inorganic base in the solid form is 200-400 meshes;

y is H or C1-C6 alkyl.

2. The method of claim 1, wherein the nucleophilic substitution reaction has one or more of the following characteristics:

(1) the reaction temperature is 30-120 ℃;

(2) the reaction is carried out in an organic solution, wherein the organic solution is one or a combination of more than two of formamide, DMF, DMA, sulfolane, DMSO, NMP, HMPA, acetone, butanone, benzene, toluene, ethyl acetate, butyl acetate, dichloromethane, trichloromethane, dichloroethane, isopropyl ether, tetrahydrofuran and dioxane.

3. The method of claim 1, wherein when Y is H, the method further comprises the steps of:

reacting the compound of the formula II with iodobenzene or a derivative thereof to obtain the indolone derivative shown in the formula IV, wherein R is F, Cl, Br or H.

4. The method of claim 1, wherein when Y is a C1-C6 alkyl group, the method further comprises the steps of:

i) reacting the compound of the formula II with iodobenzene or a derivative thereof to obtain a compound of a formula III, wherein R is F, Cl, Br or H;

ii) hydrolyzing the compound shown in the formula III to obtain the indolone derivative shown in the formula VI.

5. The process according to claim 3 or 4, wherein the reaction of step i) is carried out with a palladium catalyst which is PdCl or a nickel catalyst which is PdCl₂、Pd(OAc)₂、Pd(PPh₃)₂Cl₂、Pd(PPh₃)₄、Pd(dppf)Cl₂、[PdCl₂(dppf)]CH₂Cl₂One or a combination of more than two of the nickel catalysts, wherein the nickel catalyst is NiCl₂、Ni(OAc)₂、Ni(dppp)Cl₂One or a combination of two or more of them.

6. The process according to claim 4, wherein step ii) is carried out in a hydrochloric acid/dioxane or sodium hydroxide/dioxane system.

7. The process according to claim 3 or 4, further comprising the step of purifying the indolone derivative of formula VI by recrystallization.

8. The method according to claim 7, wherein the solvent for recrystallization is acetone-water, acetone-ethanol, ethanol-water, or acetone-ethanol-water.

9. The process of claim 1, wherein the compound of formula I is prepared by condensation of phenylpropanoic acid with aniline.

10. The method of claim 9, wherein the condensation reaction is carried out at a reaction temperature of 10 to 30 ℃; and/or

The condensation reaction is carried out in an organic solution, and the organic solution is one or a mixed solvent of more than two of dichloromethane, formamide, DMF, DMA, sulfolane, DMSO, NMP, HMPA, acetone, butanone, benzene, toluene, ethyl acetate, butyl acetate, trichloromethane, dichloroethane, isopropyl ether, tetrahydrofuran and dioxane.

11. The method according to claim 10, wherein the condensation reaction is carried out by the action of a condensing agent which is one or a combination of two or more of 1, 3-dicyclohexylcarbodiimide DCC, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDC, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDCI, 1, 3-diisopropylcarbodiimide DIC, and 1, 3-bis (2, 2-dimethyl-1, 3-dioxolan-4-ylmethyl) carbodiimide BDDC.

12. The method according to claim 1, wherein the bromomethylbenzoate is methyl 3-bromomethylbenzoate.