CN103554082B

CN103554082B - A kind of synthesis 3-(4-amino-1-isoindolone-2-base) method of piperidines-2,6-diketone

Info

Publication number: CN103554082B
Application number: CN201310509578.5A
Authority: CN
Inventors: 陈本顺; 周长岳; 徐秋斌
Original assignee: NANJING OCEAN PHARMACEUTICAL TECHNOLOGY Co Ltd
Current assignee: NANJING OCEAN PHARMACEUTICAL TECHNOLOGY Co Ltd
Priority date: 2013-10-25
Filing date: 2013-10-25
Publication date: 2015-12-02
Anticipated expiration: 2033-10-25
Also published as: CN103554082A

Abstract

The present invention relates to field of medicaments, particularly relate to a kind of pharmaceutical synthesis field, more specifically relate to a kind of synthesis 3-(4-amino-1-isoindolone-2-base) method of piperidines-2,6-diketone.Based on current 3-(4-amino-1-isoindolone-2-base) piperidines-2, 6-diketone suitability for industrialized production difficulty is large, subsequent treatment process is loaded down with trivial details waits deficiency, disclose a kind of synthesis 3-(4-amino-1-isoindolone-2-base newly) piperidines-2, the method of 6-diketone, creatively change traditional preparation method, traditional ring-closure reaction is instead of with halogenating reaction, avoid the use of 2-brooethyl-3-nitro-benzoic acid methyl ester (or 2-chloromethyl-3-nitro-benzoic acid methyl ester), without the need to the use of ultraviolet mercury lamp, it also avoid the use of multiple high toxicity reaction promoter, preparation method is simple, with low cost, be suitable for the requirement of suitability for industrialized production.

Description

Method for synthesizing 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-diketone

Technical Field

The invention relates to the field of medicines, in particular to the field of medicine synthesis, and more particularly relates to a method for synthesizing 3- (4-amino-1-isoindolinone-2-yl) piperidine-2, 6-diketone.

Background

Multiple myeloma is a malignant plasma cell proliferative hematological tumor. The plasma cells having the ability to secrete immunoglobulins

Functionally, but the proliferating plasma cells in most multiple myeloma patients produce only one immunoglobulin protein called accessory protein (paraprotein) or M protein that is not beneficial to the body, and normal plasma cells and other leukocytes are replaced by malignant plasma cells, resulting in reduced synthesis and secretion of normal immunoglobulins. Multiple myeloma cells also invade other tissues of the body, such as bone tissue, and cause tumorigenesis. Multiple myeloma is the second largest hematological neoplasm, with patients accounting for approximately 1% of all neoplastic patients and deaths accounting for approximately 2% of all cancer deaths.

Lenalidomide is a novel immune-regulating non-chemotherapy anti-cancer drug, the chemical components of the lenalidomide are similar to those of thalidomide (thalidomide), but the lenalidomide has a more remarkable curative effect in experimental application, and some side effects frequently caused by taking the thalidomide do not appear.

The literature reports that the route for preparing lenalidomide is generally that 3-aminopiperidine-2, 6-dione hydrochloride is condensed with 2-bromomethyl-3-nitro-methyl benzoate (or 2-chloromethyl-3-nitro-methyl benzoate) and then nitro is reduced into amino to prepare lenalidomide, and different preparation methods are different in the post-treatment process after each reaction.

For example, patent WO2010100476 discloses a process for the preparation of lenalidomide having the chemical reaction formula:

in the reaction, firstly, the raw material 2-bromomethyl-3-nitro-methyl benzoate (or 2-chloromethyl-3-nitro-methyl benzoate) needs to be irradiated under ultraviolet light (mercury lamp) to generate bromination firstly, but the catalytic reaction has long reflux time and low yield, so that the compound is taken as a starting material and industrial production is difficult. Meanwhile, the mercury lamp has harm to human body, so that the labor under ultraviolet light is not beneficial to the labor protection of staff.

Meanwhile, the solvent involved in the reaction is often a highly toxic substance, and the reaction requires a long time of reflux, which is not favorable for industrial production.

Disclosure of Invention

Based on the defects of large difficulty in industrial production, complicated subsequent treatment process and the like of the current 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-diketone, a novel method for synthesizing the 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-diketone is disclosed, and the synthetic route is as follows:

，

wherein X represents a halogen, preferably Cl or Br.

Further, we also disclose in detail, the steps are:

reacting a compound III with a compound IV in an organic solvent of inorganic base to generate a compound II, wherein the reaction temperature is 0-80 ℃;

and step two, converting the compound II into the compound I in an organic solvent environment of ammonia gas or uric acid, wherein the reaction temperature is 80-200 ℃.

Furthermore, in the first step and the second step, any one or any several of the following conditions are preferred:

in the first condition, the inorganic base in the first step is preferably one of potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate and cesium carbonate;

secondly, in the first step, the organic solvent is preferably one of N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile and acetone;

and thirdly, the organic solvent in the second step is one of water, ethanol, methanol, tetrahydrofuran, acetonitrile, dichloromethane, pyridine and triethylamine.

Meanwhile, we also disclose a method for synthesizing 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-diketone, and the synthetic route is as follows:

，

wherein R is benzyl, benzyloxycarbonyl, or tert-butoxycarbonyl.

Further, we also disclose in detail, the steps are:

reacting a compound III with a compound IX in an organic solvent of inorganic base to generate a compound VIII, wherein the reaction temperature is 0-80 ℃;

step two, converting the compound VIII into a compound I at the temperature of 20-80 ℃,

wherein,

in the first case, when R is benzyl or benzyloxycarbonyl, the compound is converted into a compound I under the reduction of hydrogen in the presence of palladium-carbon as a catalyst;

and secondly, when R is tert-butyloxycarbonyl, the tert-butyloxycarbonyl is converted into the compound I under the action of a mineral acid solution.

thirdly, in the second step, the reaction solvent is one of water, ethanol, methanol, tetrahydrofuran, acetonitrile, dichloromethane, pyridine and triethylamine;

the fourth condition is that when the first condition in the second step is adopted, the dosage of the catalyst is 5% -10% of the total reaction amount;

and fifthly, when the condition II in the step II is adopted, the inorganic acid is one of hydrochloric acid, sulfuric acid and hydrofluoric acid.

At the same time, we further disclose that the synthetic route of said compound IX is:

wherein R is one of benzyl, carbobenzoxy and tert-butyloxycarbonyl.

Furthermore, the synthesis process of the compound IX is disclosed, wherein the solvent environment of the reaction is an alkaline organic solvent, and the reaction temperature is 20-80 ℃.

Meanwhile, in the synthesis process of the compound IX, we further disclose that the basic organic solvent is an organic solvent of an inorganic base, the inorganic base is preferably one of potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate and cesium carbonate, and the organic solvent is preferably one of N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile, acetone and the like, pyridine and triethylamine.

Further, said compound III is replaced by a compound VII,

。

thus two similar synthetic routes are formed, adaptively requiring the conversion of the nitro group in an important intermediate to an amino group.

One of the synthetic routes is as follows:

wherein X also represents Cl, Br, I;

we also disclose in detail, the steps are:

step one, reacting a compound VII with a compound IV in an organic solvent of inorganic base to generate a compound VI, wherein the reaction temperature is 0-80 ℃;

and step two, converting the compound V into a compound I in an organic solvent environment of ammonia gas or uric acid, wherein the reaction temperature is 80-200 ℃.

The other synthetic route is as follows:

；

we also disclose in detail, the steps are:

reacting a compound VII with a compound IX in an organic solvent of inorganic base to generate a compound X, wherein the reaction temperature is 0-80 ℃;

step two, converting the compound X into a compound I at the temperature of 20-80 ℃,

wherein,

secondly, in the first step, the organic solvent is preferably one of N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile and acetone;

and fifthly, when the condition II in the step II is adopted, the inorganic acid is one of hydrochloric acid, sulfuric acid, hydrofluoric acid and hydrobromic acid.

The traditional preparation method is creatively changed, the traditional cyclization reaction is replaced by the halogenation reaction, the use of 2-bromomethyl-3-nitro-methyl benzoate (or 2-chloromethyl-3-nitro-methyl benzoate) is avoided, the use of an ultraviolet mercury lamp is not needed, and the use of various high-toxicity reaction aids is also avoided, so that the preparation method is simple, the cost is low, and the preparation method is suitable for the requirements of industrial production.

Meanwhile, the reaction conditions of each stage are mild, and harsh long-time reflux reaction is not needed.

Furthermore, according to the preparation process disclosed by the invention, the purity of the target product after reaction in each step is high, and complicated post-treatment steps are not needed.

The target compound can be quickly obtained only by two steps, the synthetic route is short, and the method is simple and convenient.

Meanwhile, the solvent used in the reaction of each stage is environment-friendly.

Detailed Description

Example 1

3- (4-amino-1-isoindolon-2-yl) piperidine-2, 6-dione

1) Under the protection of nitrogen, 14.8g of compound III, 50ml of N-methylpyrrolidone, 14g of potassium carbonate and 20g of bromoglutaric anhydride were added to a reaction flask, and the mixture was reacted overnight at 25 ℃ with stirring. The solid was filtered off, and the reaction solution was concentrated under reduced pressure to give 25 g. The yield thereof was found to be 96%.

2) 13g of compound II and 4g of urea were added to a reaction flask under nitrogen protection, and reacted at 180 ℃ for 3 hours with stirring. Adding 80ml of acetonitrile and 30ml of dimethyl sulfoxide into the system, stirring for 1h at 70-80 ℃, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on the solid at 100 ℃ to obtain 9g of off-white solid with the yield of 69%.

Example 2

3- (4-amino-1-isoindolon-2-yl) piperidine-2, 6-dione

1) Under nitrogen protection, 14.8g of compound III, 50ml of N, N-dimethylformamide and 14g of potassium carbonate, 30g of 1-benzyl-3-bromopiperidine-2, 6-dione were added to a reaction flask, and the mixture was reacted overnight at 80 ℃ with stirring. 75ml of water and 150ml of methylene chloride were added, the aqueous phase was discarded, and the organic phase was extracted with 2mol/L hydrochloric acid. 150ml of dichloromethane was added to the aqueous hydrochloric acid solution, sodium carbonate was added until the pH of the aqueous phase became =7, the organic phase was taken out, dried over anhydrous sodium sulfate, and the mother liquor was concentrated under reduced pressure to dryness to obtain 30g of compound VIII with a yield of 86%.

2) Adding 5g of compound VIII (wherein R is benzyl) and 100mL of methanol into a reaction bottle, stirring, adding 0.25g of 10% palladium carbon, vacuumizing the solution to obtain gray turbid solution, performing N2 replacement three times, H2 replacement three times, performing normal pressure hydrogenation, keeping the temperature at 25-30 ℃ for reaction for 41 hours, monitoring the reaction by TLC (thin layer chromatography), filtering the reaction solution, and concentrating the filtrate to dryness to obtain 3.5g of off-white solid. Adding 30ml of acetonitrile and 9ml of dimethyl sulfoxide, stirring for 1h at 70-80 ℃, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on the solid at 100 ℃ to obtain 3.2g of off-white solid with the yield of 87%.

Example 3

3- (4-amino-1-isoindolon-2-yl) piperidine-2, 6-dione

1) Under nitrogen protection, 14.8g of compound III, 50ml of N, N-dimethylformamide, 14g of potassium carbonate, and 35g of 1-benzyloxycarbonyl-3-bromopiperidine-2, 6-dione were charged into a reaction flask, and the mixture was reacted overnight at 80 ℃ with stirring. 75ml of water and 150ml of methylene chloride were added, the aqueous phase was discarded, and the organic phase was extracted with 2mol/L hydrochloric acid. 150ml of dichloromethane was added to the aqueous hydrochloric acid solution, sodium carbonate was added until the pH of the aqueous phase became =7, the organic phase was taken out, dried over anhydrous sodium sulfate, and the mother liquor was concentrated under reduced pressure to dryness to obtain 30g of compound VIII with a yield of 86%.

2) Adding 5.6g of compound VIII (wherein R is benzyloxycarbonyl) and 100mL of methanol into a reaction bottle, stirring, adding 0.25g of 10% palladium carbon, vacuumizing the solution to obtain grey turbid solution, performing N2 replacement three times, performing H2 replacement three times, hydrogenating at normal pressure, keeping the temperature at 25-30 ℃ for 41 hours, monitoring by TLC (thin layer chromatography) after the reaction is completed, filtering, and concentrating the filtrate to dryness to obtain 3.5g of an off-white solid. Adding 30ml of acetonitrile and 9ml of dimethyl sulfoxide, stirring for 1h at 70-80 ℃, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on the solid at 100 ℃ to obtain 3.0g of off-white solid with the yield of 83%.

Example 4

1) Under nitrogen protection, 14.8g of compound III, 50ml of N, N-dimethylformamide, 14g of potassium carbonate, and 32g of 1-tert-butoxycarbonyl-3-bromopiperidine-2, 6-dione were charged in a reaction flask, and the mixture was reacted overnight at 80 ℃ with stirring. 75ml of water and 150ml of methylene chloride were added, the aqueous phase was discarded, and the organic phase was extracted with 2mol/L hydrochloric acid. 150ml of dichloromethane was added to the aqueous hydrochloric acid solution, sodium carbonate was added until the pH of the aqueous phase became =7, the organic phase was taken out, dried over anhydrous sodium sulfate, and the mother liquor was concentrated under reduced pressure to dryness to obtain 30g of compound VIII with a yield of 86%.

2) 5g of compound VIII (wherein R is tert-butyloxycarbonyl), 20mL of dichloromethane and 20mL of trifluoroacetic acid were added to a reaction flask, and after completion of the reaction was monitored by TLC, the reaction solution was concentrated to dryness to obtain 3.4g of an off-white solid. Adding 30ml of acetonitrile and 9ml of dimethyl sulfoxide, stirring for 1h at 70-80 ℃, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on the solid at 100 ℃ to obtain 3.0g of off-white solid with the yield of 83%.

Example 5

Under nitrogen protection, 19g of compound XI, 50ml of N, N-dimethylformamide, 14g of potassium carbonate and 25g of benzyl bromide were added to a reaction flask, and the mixture was reacted overnight at 80 ℃ with stirring. The solid was filtered off, and the reaction solution was concentrated under reduced pressure to obtain 27 g. The yield thereof was found to be 96%.

The substituted pattern of benzyloxycarbonyl and t-butoxycarbonyl groups is the same as that of benzyl group in this reaction, and can be prepared by the methods described above, and will not be described redundantly.

Example 6

1) Under the protection of nitrogen, 17.8g of compound VII, 50ml of N, N-dimethylformamide, 14g of potassium carbonate and 20g of bromoglutaric anhydride were charged into a reaction flask, and reacted overnight at 75 ℃ with stirring. The solid was filtered off, and the reaction solution was concentrated under reduced pressure to give 26 g. The yield thereof was found to be 90%.

2) Under nitrogen protection, 14.5g of compound VI and 200mL of ammonia ethanol (containing 17g of ammonia) were added to a reaction flask, and the mixture was reacted overnight at 50 ℃ with stirring. The reaction solution was concentrated under reduced pressure to obtain 14g of Compound V, yield: 97%.

3) Adding 5g of compound V and 100mL of methanol into a reaction bottle, stirring, adding 0.25g of 10% palladium carbon, enabling the solution to be grey turbid, vacuumizing, performing N2 replacement three times, performing H2 replacement three times, hydrogenating at normal pressure, preserving the temperature at 25-30 ℃ for 41H, enabling the solution to slowly turn black from grey during the reaction, monitoring by TLC (thin layer chromatography) after the reaction is completed, filtering, and concentrating the filtrate to be dry to obtain 4.4g of off-white solid. Adding 30ml of acetonitrile and 9ml of dimethyl sulfoxide, stirring for 1h at 70-80 ℃, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on the solid at 100 ℃ to obtain 3g of off-white solid with the yield of 67%.

Example 7

1) Under nitrogen protection, 17.8g of compound VII, 50ml of N, N-dimethylformamide, 14g of potassium carbonate, 30g of 1-benzyl-3-bromopiperidine-2, 6-dione were charged in a reaction flask, and reacted overnight at 80 ℃ with stirring. 75ml of water and 150ml of methylene chloride were added, the aqueous phase was discarded, and the organic phase was extracted with 2mol/L hydrochloric acid. Further, 150ml of methylene chloride was added to the aqueous hydrochloric acid solution, sodium carbonate was added to adjust the pH of the aqueous phase to =7, the organic phase was taken out, dried over anhydrous sodium sulfate, and the mother liquor was concentrated under reduced pressure to dryness to obtain 33g of compound X with a yield of 87%.

2) Adding 5g of compound X (wherein R is benzyl) and 100mL of methanol into a reaction bottle, stirring, adding 0.25g of 10% palladium carbon, vacuumizing the solution to obtain gray turbid solution, performing N2 replacement three times, H2 replacement three times, performing normal pressure hydrogenation, keeping the temperature at 25-30 ℃ for reaction for 41 hours, monitoring the reaction by TLC (thin layer chromatography), filtering the reaction solution, and concentrating the filtrate to dryness to obtain 3.1g of an off-white solid. Adding 25ml of acetonitrile and 7ml of dimethyl sulfoxide, stirring for 1h at 70-80 ℃, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on the solid at 100 ℃ to obtain 2.8g of off-white solid with the yield of 82%.

Example 8

1) Under nitrogen protection, 17.8g of compound VII, 50ml of N, N-dimethylformamide, 14g of potassium carbonate, and 35g of 1-benzyloxycarbonyl-3-bromopiperidine-2, 6-dione were charged into a reaction flask, and the mixture was reacted overnight at 80 ℃ with stirring. 75ml of water and 150ml of methylene chloride were added, the aqueous phase was discarded, and the organic phase was extracted with 2mol/L hydrochloric acid. Further, 150ml of methylene chloride was added to the aqueous hydrochloric acid solution, sodium carbonate was added to adjust the pH of the aqueous phase to =7, the organic phase was taken out, dried over anhydrous sodium sulfate, and the mother liquor was concentrated under reduced pressure to dryness to obtain 36g of compound X with a yield of 86%.

2) Adding 5g of compound X (wherein R is benzyloxycarbonyl) and 100mL of methanol into a reaction bottle, stirring, adding 0.25g of 10% palladium carbon, vacuumizing the solution to obtain gray turbid solution, performing N2 replacement three times, performing H2 replacement three times, performing normal pressure hydrogenation, keeping the temperature at 25-30 ℃ for reaction for 41 hours, monitoring the reaction by TLC (thin layer chromatography), filtering the reaction solution after the reaction is completed, and concentrating the filtrate to dryness to obtain 3.1g of an off-white solid. Adding 25ml of acetonitrile and 7ml of dimethyl sulfoxide, stirring for 1h at 70-80 ℃, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on the solid at 100 ℃ to obtain 2.5g of off-white solid with the yield of 81%.

Example 9

1) Under nitrogen protection, 17.8g of compound VII, 50ml of N, N-dimethylformamide, 14g of potassium carbonate, and 32g of 1-tert-butoxycarbonyl-3-bromopiperidine-2, 6-dione were charged in a reaction flask, and the mixture was reacted overnight at 80 ℃ with stirring. 75ml of water and 150ml of methylene chloride were added, the aqueous phase was discarded, and the organic phase was extracted with 2mol/L hydrochloric acid. Further, 150ml of methylene chloride was added to the aqueous hydrochloric acid solution, sodium carbonate was added to adjust the pH of the aqueous phase to =7, the organic phase was taken out, dried over anhydrous sodium sulfate, and the mother liquor was concentrated under reduced pressure to dryness to obtain 33g of compound X with a yield of 85%.

2) Adding 5g of compound X (wherein R is tert-butyloxycarbonyl) into a reaction bottle, stirring 100mL of methanol, 10mL of trifluoromethanesulfonic acid, adding 0.25g of 10% palladium carbon, wherein the solution is grey turbid, vacuumizing, replacing three times with N2, replacing three times with H2, hydrogenating under normal pressure, keeping the temperature at 25-30 ℃ for 41 hours, monitoring by TLC after the reaction is completed, filtering, and concentrating the filtrate to dryness to obtain 3.1g of off-white solid. Adding 25ml of acetonitrile and 7ml of dimethyl sulfoxide, stirring for 1h at 70-80 ℃, cooling to room temperature, carrying out suction filtration, and carrying out forced air drying on the solid at 100 ℃ to obtain 2.7g of off-white solid with the yield of 82%.

Claims

1. A method for synthesizing 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-diketone, which is characterized in that the synthetic route is as follows:

wherein X represents a halogen.

2. The method for synthesizing 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-dione as claimed in claim 1, wherein the halogen is Cl or Br.

3. The process of claim 1 for the synthesis of 3- (4-amino-1-isoindolon-2-yl) piperidine-2, 6-dione, comprising the steps of:

4. The method for synthesizing 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-dione as claimed in claim 3, further comprising one or more of the following conditions:

in the first step, the inorganic base is one of potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate and cesium carbonate;

secondly, in the first step, the organic solvent is one of N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile and acetone;

5. A method for synthesizing 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-diketone, which is characterized in that the synthetic route is as follows:

wherein R is benzyl, benzyloxycarbonyl, or tert-butoxycarbonyl.

6. The process of claim 5 for the synthesis of 3- (4-amino-1-isoindolon-2-yl) piperidine-2, 6-dione, comprising the steps of:

wherein,

7. The method for synthesizing 3- (4-amino-1-isoindolone-2-yl) piperidine-2, 6-dione according to claim 6, further comprising one or more of the following conditions:

the fourth condition is that when the first condition in the second step is adopted, the dosage of the catalyst is 5-10% of the total reaction amount;

8. The process for the synthesis of 3- (4-amino-1-isoindolon-2-yl) piperidine-2, 6-dione, according to claim 5, characterized by the fact that the synthesis route of compound IX is:

wherein R is one of benzyl, carbobenzoxy and tert-butyloxycarbonyl.

9. The method for synthesizing 3- (4-amino-1-isoindolinone-2-yl) piperidine-2, 6-dione as claimed in claim 8, wherein the solvent environment for the reaction is a basic organic solvent, and the reaction temperature is 20-80 ℃.

10. The method for synthesizing 3- (4-amino-1-isoindolinone-2-yl) piperidine-2, 6-dione as claimed in claim 9, wherein the basic organic solvent is an organic solvent of an inorganic base.

11. The method according to claim 10, wherein the inorganic base is one of potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate and cesium carbonate, and the organic solvent is one of N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, acetone, etc., pyridine and triethylamine.

12. The process for the synthesis of 3- (4-amino-1-isoindolon-2-yl) piperidine-2, 6-dione as claimed in claim 1 or 5, wherein said compound III is replaced by compound VII,