阅读说明：本技术 二氢吲哚酮衍生物及其中间体的制备方法 (Process for producing indolinone derivative and intermediate thereof ) 是由 韩增影 李鹏程 欧阳广 任宇 张小春 王利春 王晶翼 于 2019-03-08 设计创作，主要内容包括：本发明提供一种如式Ⅰ所示的二氢吲哚酮衍生物及其中间体的制备方法。所述二氢吲哚衍生物中间体的制备方法包括：使2-氧化吲哚-6-甲酸甲酯与乙酸酐在甲苯中于100℃～110℃的加热条件下反应得到1-乙酰基-2-氧代二氢吲哚-6-甲酸甲基酯；所述二氢吲哚酮衍生物的制备方法包括：(1)使1-乙酰基-2-氧代二氢吲哚-6-甲酸甲基酯与原苯甲酸三甲酯或原苯甲酸三乙酯缩合反应得到式Ⅳ化合物；(2)使式Ⅳ化合物与N-(4-氨基苯基)-N-甲基-2-(4-甲基哌嗪-1-基)乙酰胺反应得到式Ⅴ化合物；(3)使式Ⅴ化合物脱保护得到式Ⅰ化合物。<Image he="574" wi="700" file="DDA0001989004010000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a preparation method of indolinone derivatives shown in formula I and intermediates thereof. The preparation method of the indoline derivative intermediate comprises the following steps: reacting 2-oxindole-6-carboxylic acid methyl ester with acetic anhydride in toluene at 100-110 ℃ to obtain 1-acetyl-2-oxoindoline-6-carboxylic acid methyl ester; the preparation method of the indolinone derivative comprises the following steps: (1) condensing 1-acetyl-2-oxoindoline-6-carboxylic acid methyl ester with trimethyl orthobenzoate or triethyl orthobenzoate to obtain a compound shown in a formula IV; (2) reacting a compound of formula IV with N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide to obtain a compound of formula V; (3) deprotection of the compound of formula V affords the compound of formula I.)

1. A preparation method of indolinone derivative intermediate shown as formula III is characterized by comprising the following steps:

reacting a compound of formula II with acetic anhydride in toluene at a temperature of 100 ℃ to 110 ℃ to obtain a compound of formula III:

2. the method for preparing indolinone derivative according to claim 1, wherein the mass ratio of the compound of formula ii to the acetic anhydride is 1:1 to 1: 10; preferably 1:2 to 1: 6.

3. The process for preparing indolinone derivative according to claim 1, further comprising a step of purifying the compound of formula iii, comprising cooling crystallization after reacting for 4-8 hours, filtering to obtain a solid, and washing the solid with an organic solution; wherein the organic solvent is selected from one or more of methanol, acetonitrile, cyclohexane, n-heptane, n-hexane and methylcyclohexane, and is preferably methanol.

4. The method for preparing indolinone derivative according to claim 3, wherein the mass volume ratio of the compound of formula II to the organic solvent is 1:3 to 1:7 (g/ml).

5. A preparation method of indolinone derivatives shown in formula I is characterized by comprising the following steps:

(1) carrying out condensation reaction on the compound shown in the formula III and trimethyl orthobenzoate or triethyl orthobenzoate to obtain a compound shown in a formula IV:

wherein R is methyl or ethyl;

a compound of formula III, when prepared as claimed in any one of claims 1 to 4;

(2) condensing the compound of formula IV with N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide to obtain a compound of formula V:

(3) deprotection of a compound of formula V affords a compound of formula I:

6. the process for preparing indolinone derivative according to claim 5, wherein the reaction solvent in step (1) is one or more selected from acetic anhydride, toluene, xylene, ethyl acetate, isopropyl acetate, preferably acetic anhydride; the reaction temperature is 90-130 ℃; the molar mass ratio of the compound of the formula III to the trimethyl orthobenzoate or the triethyl orthobenzoate is 1: 1-1: 6.

7. The process for producing an indolinone derivative according to claim 5, wherein the reaction solvent in the step (1) is acetic anhydride; the reaction temperature is 110-130 ℃; the molar mass ratio of the compound of the formula III to the trimethyl orthobenzoate or the triethyl orthobenzoate is 1: 2.4-1: 3.5.

8. The process for preparing indolinone derivative according to claim 5, wherein the solvent for condensation reaction in step (2) is one or more selected from methanol, ethanol, isopropanol, acetonitrile, toluene, N-dimethylformamide, N-dimethylacetamide; the reaction temperature is 50-130 ℃; the molar mass ratio of the IV compound to the N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide is 1: 1-1: 1.5.

9. The process for producing indolinone derivative according to claim 5, wherein the solvent for the condensation reaction in the step (2) is acetonitrile, and the reaction temperature is 60 to 80 ℃; the molar mass ratio of the IV compound to the N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide is 1: 1.0-1: 1.3.

10. The process for producing an indolinone derivative according to claim 5, wherein the reaction solvent in the step (3) is one or more selected from methanol, ethanol, isopropanol, N-dimethylformamide, N-dimethylacetamide; the reaction temperature is 20-65 ℃; the step (3) is carried out under the condition of adding an alkaline reagent, wherein the alkaline reagent is selected from one or more of alkali metal hydroxide and alkali metal alkoxide;

preferably, the reaction solvent in the step (3) is methanol; the reaction temperature is 20-45 ℃; the alkaline hydroxide is potassium hydroxide, and the alkali metal alkoxide is sodium methoxide.

Technical Field

The invention relates to a preparation method of indolinone derivatives and intermediates thereof.

Background

Indolinone derivative 3-Z-2, 3-dihydro-3- [ [ [4- [ methyl [2- (4-methyl-1-piperazinyl) acetyl ] amino ] phenyl ] amino ] phenylmethylene ] -2-oxo-1-indole-6-methoxycarbonyl-2-indolinone methyl ester, commonly known as nintedanib, has the following structural formula:

nintedanib is a combined inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), is clinically used for treating idiopathic pulmonary fibrosis, and is a potential drug for liver failure and cancer treatment, including metastatic non-small cell lung cancer, ovarian cancer, prostate cancer, colorectal cancer, renal cell carcinoma and the like.

The existing preparation method of the nintedanib has the problems of low purity of intermediate products in the preparation process and low total yield of the nintedanib.

Disclosure of Invention

In view of the above, it is necessary to provide a process for producing indolinone derivatives and intermediates thereof.

The invention provides a preparation method of an indolinone derivative intermediate shown as a formula III, which comprises the following steps:

reacting a compound of formula II with acetic anhydride in toluene at a temperature of 100 ℃ to 110 ℃ to obtain a compound of formula III:

in one embodiment, the mass ratio of the compound of formula II to the acetic anhydride is 1:1 to 1: 10; preferably 1:2 to 1: 6.

In one embodiment, the preparation method further comprises a step of purifying the compound shown in the formula III, wherein the step of cooling, crystallizing and filtering the compound after reacting for 4-8 hours to obtain a solid, and washing the solid with an organic solution; wherein the organic solvent is selected from one or more of methanol, acetonitrile, cyclohexane, n-heptane, n-hexane and methylcyclohexane, and is preferably methanol.

In one embodiment, the mass-to-volume ratio of the compound of formula II to the organic solvent is 1:3 to 1:7 (g/ml).

The invention also provides a preparation method of the indolinone derivative shown as the formula I, which comprises the following steps:

(1) carrying out condensation reaction on the compound shown in the formula III and trimethyl orthobenzoate or triethyl orthobenzoate to obtain a compound shown in a formula IV:

wherein R is methyl or ethyl;

the compound of the formula III is prepared by the method;

(2) condensing the compound of formula IV with N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide to obtain a compound of formula V:

(3) deprotection of a compound of formula V affords a compound of formula I:

in one embodiment, the reaction solvent in step (1) is one or more selected from acetic anhydride, toluene, xylene, ethyl acetate and isopropyl acetate, and is preferably acetic anhydride.

In one embodiment, the reaction temperature in the step (1) is 90-130 ℃; preferably 110 ℃ to 130 ℃.

In one embodiment, the molar mass ratio of the compound of formula III to the trimethyl orthobenzoate or the triethyl orthobenzoate in the step (1) is 1:1 to 1: 6; preferably 1:2.4 to 1: 3.5.

In one embodiment, the solvent for the condensation reaction in step (2) is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, toluene, N-dimethylformamide, N-dimethylacetamide; acetonitrile is preferred.

In one embodiment, the condensation reaction of step (2) has a reaction temperature of 50 ℃ to 130 ℃; preferably 60 ℃ to 80 ℃.

In one embodiment, the molar mass ratio of the IV compound to the N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide in the step (2) is 1: 1-1: 1.5; preferably 1:1.0 to 1: 1.3.

In one embodiment, the reaction solvent in step (3) is selected from one or more of methanol, ethanol, isopropanol, N-dimethylformamide, N-dimethylacetamide; methanol is preferred.

In one embodiment, the reaction temperature of the step (3) is 20-65 ℃; preferably 20 to 45 ℃.

In one embodiment, the step (3) is performed under the condition of adding an alkaline agent selected from one or more of alkali metal hydroxide and alkali metal alkoxide; preferably, the alkaline hydroxide is potassium hydroxide and the alkali metal alkoxide is sodium methoxide.

According to the preparation method of the indolinone derivative intermediate, acetic anhydride is selected as an acylating agent instead of chloroacetic anhydride which is high in efficiency but high in toxicity, toluene is selected as a solvent for acylation reaction, and the reaction is carried out under the heating condition of 100-110 ℃, so that the acylation reaction can still keep high acylation efficiency, the purity of an acylation reaction product is further improved, and the subsequent reaction is facilitated. The preparation method of the indolinone derivative provided by the invention has the advantages of simple steps, easiness in operation, safety, environmental friendliness and higher total yield, and is more suitable for industrial production.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below by way of examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The embodiment of the invention provides a preparation method of an indolinone derivative intermediate, which comprises the step of carrying out acetylation reaction on a compound 2-oxindole-6-methyl formate shown as a formula II serving as an initial raw material to obtain a compound shown as a formula III.

The embodiment of the invention also provides a preparation method of the indolinone derivative, which comprises the steps of taking a compound 2-oxoindole-6-methyl formate in a formula II as an initial raw material, carrying out acetylation reaction to obtain a compound in a formula III, carrying out condensation reaction on the compound in the formula III and trimethyl orthobenzoate or triethyl orthobenzoate to obtain a compound in a formula IV-a or a formula IV-b, carrying out condensation reaction on the compound in the formula IV-a or the formula IV-b and N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazine-1-yl) acetamide to obtain a compound in a formula V, and carrying out deprotection reaction on the compound in the formula V to obtain a compound in the formula (I), namely nintedanib.

The reaction equation for the preparation of compounds of formula III from compounds of formula II:

acetic anhydride is selected as an acylation reagent, 2-oxoindole-6-methyl formate is acylated to obtain a compound shown in a formula III, the reaction is carried out in a solvent toluene at 100-110 ℃, the acylation reagent is safe and environment-friendly, no toxic by-product is generated, and the acylation efficiency and the product purity under the reaction condition are very high.

In one embodiment, the mass ratio of the compound of formula II to the acetic anhydride is 1:1 to 1:10, preferably 1:2 to 1: 6.

In one embodiment, in order to further improve the purity of the compound of formula iii, after reacting for 4 to 8 hours, crystallizing by a cooling method, cooling to 0 to 5 ℃ to complete crystallization, filtering to collect a solid, washing with an organic solvent, and drying to obtain the compound of formula iii.

In one embodiment, the organic solvent is selected from one or more of methanol, acetonitrile, cyclohexane, n-heptane, n-hexane, methylcyclohexane, preferably methanol.

In one embodiment, the mass-to-volume ratio of the compound of formula II to the organic solvent is 1:3 to 1:7 (g/ml).

The reaction equation for the preparation of the compound of formula iv from the compound of formula iii:

wherein R is methyl or ethyl.

And carrying out reflux reaction on the compound shown in the formula III and trimethyl orthobenzoate or triethyl orthobenzoate in a high-boiling point and nonpolar reaction solvent at the temperature of 90-130 ℃ for 6-10 hours, and carrying out condensation reaction. And (3) cooling to room temperature (10-30 ℃) after condensation reaction, crystallizing, filtering, washing, collecting solid, and drying to obtain the compound shown in the formula IV.

In one embodiment, the washing reagent is selected from one or more of toluene, xylene and ethyl acetate.

In one embodiment, the high boiling and non-polar reaction solvent is selected from one or more of acetic anhydride, toluene, xylene, ethyl acetate, isopropyl acetate. In a preferred embodiment, the solvent is acetic anhydride.

In one embodiment, the reaction further comprises the addition of a methanol or ethanol scavenger which is acetic anhydride or propionic anhydride, preferably acetic anhydride.

In one embodiment, the condensation reaction is carried out at a reaction temperature of from 110 ℃ to 130 ℃.

In one embodiment, the mass ratio of the compound of formula iii to the trimethyl orthobenzoate or triethyl orthobenzoate is 1:1 to 1:6, preferably 1:2.4 to 1: 3.5.

During the reaction, the low-boiling, volatile fraction can be distilled off.

The reaction equation for the preparation of the compound of formula V from the compound of formula IV:

the compound of formula IV and N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide are refluxed for 4-10 hours at 50-130 ℃ in a mixed solvent of a polar solvent (such as methanol, ethanol, isopropanol and acetonitrile) or an aromatic solvent (such as toluene) and a polar solvent (such as N, N-dimethylformamide and N, N-dimethylacetamide). After condensation reaction, the product is cooled to room temperature (10-30 ℃) for crystallization, filtered, washed and collected with solid, and dried to obtain the compound of the formula V.

In one embodiment, the reaction solvent is acetonitrile.

In one embodiment, the reaction temperature in this step is 60 to 80 ℃.

In one embodiment, the mass ratio of the compound of formula IV to N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide is 1:1.0 to 1:1.5, preferably 1:1.0 to 1: 1.3.

In one embodiment, the washing solvent is acetonitrile.

Preparing a compound of formula I from a compound of formula V:

and (3) deacetylating and protecting the compound of the formula V and an alkaline reagent in an organic solvent at the temperature of 20-65 ℃ to obtain the compound of the formula I.

In one embodiment, the deprotection reaction temperature is from 20 ℃ to 45 ℃.

The alkaline agent may be an inorganic base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and the like, or an organic base; the organic base is selected from piperidine, tetrahydropyrrole, dimethylamine, diethylamine, alkali metal alkoxide (such as potassium tert-butoxide, sodium potassium alkoxide, sodium ethoxide) etc.; preferably, the alkaline agent is potassium hydroxide or sodium methoxide.

In one embodiment, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N-dimethylformamide, N-dimethylacetamide.

In one embodiment, the mass ratio of compound V to base is 1: 0.01-1: 1; preferably 1: 0.1-1: 0.6.

the structures of the compounds described in the following examples were determined by nuclear magnetic resonance (¹H-NMR) or liquid chromatography-mass spectrometry (LC-MS).

Nuclear magnetic resonance (¹H-NMR、¹³C-NMR) was conducted using Bruker AVANCE III HD 400M and the solvent was hexadeutero-dimethyl sulfoxide (DMSO-d)₆)。

The MS instrument in the liquid chromatography-mass spectrometry (LC-MS) is Agilent Technologies6120Quadrupole LC/MS. The HPLC apparatus was Agilent Technologies 1260Infinity, and the chromatographic conditions were as follows: a chromatographic column: waters Sunfire @ C185 μm 4.6 x 50mm 3.5 μm, Column; mobile phase: phase A: 0.05% formic acid water, phase B: 0.05% formic acid acetonitrile; gradient elution.

The purity of the product in the following examples was checked by HPLC, with the following specific conditions: a chromatographic column: waters CSH150 × 4.6mm 3.5 μm; mobile phase A: 10mM potassium dihydrogen phosphate, pH 2.0; mobile phase B: acetonitrile; diluent agent: pure water-acetonitrile (8:2, v/v); flow rate: 1.0 ml/min; sample introduction amount: 20 mu l of the mixture; column temperature: 25 ℃; detection wavelength: 210 nm; gradient elution.