RU2585623C1 - METHOD FOR SYNTHESIS OF 7-METHOXY-4-NITRO-3-(p-METHOXYPHENYL) ISOQUINOLINONE DERIVATIVES - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to method for synthesis of 7-methoxy-4-nitro-3-(p-methoxyphenyl)isoquinolinone derivatives, containing: first stage of producing amide, involving preparation of mixture with thionyl chloride 5-methoxy-2-toluic acid under nitrogen, which is mixed and dephlegmated for 3 hours, then excess thionyl chloride is removed at pressure of 20 mBar, residue is dissolved in methylene chloride, and then 40 % aqueous solution is added in droplets while cooling on ice, produced mixture is stirred at 0 °C for 24 hours, then reaction solution is extracted with ethyl acetate, washed with saturated solution of NaCl, dried over Na₂SO₄ and evaporated at pressure of 100 mBar, obtained residue is purified by column chromatography with silica gel to obtain 5-methoxy-2,N-dimethyl benzamide; second condensation step, involving addition to solution of 1,8M of lithium diisopropylamide, in tetrahydrofuran (THF) at -78 °C under nitrogen solution 5-methoxy-2,N-dimethyl benzamide in tetrahydrofolic acid in droplets and then solution of 4-methoxy benzonitrile in tetrahydrofuran, obtained mixture is stirred at -78 °C for 3 hours, then reaction mixture is allowed to be heated at room temperature, adding NH₄Cl saturated with water, tetrahydrofuran is removed at pressure of 20 mBar, obtained mixture is extracted in ethyl acetate and washed with saturated solution NaCl, organic layer is dried over Na₂SO₄ and evaporated at 20 mBar, obtained residue undergoes purification by column chromatography with silica gel to obtain 7-methoxy-3-(p-methoxyphenyl)isoquinolinone derivatives; third stage of nitration including cooling to 10 °C while stirring solution of 7-methoxy-3-(p-methoxyphenyl)isoquinolinone derivatives in ethyl acetate and acetic acid, then mixture is added in droplets at temperature below 15 °C with nitric acid solution in ethyl acetate, mixture is stirred at room temperature for 2 hours, then water is added, and produced solid substance is collected, dried in air and recrystallised from toluene or ethyl acetate to produce 7-methoxy-4-nitro-3-(p-methoxyphenyl)isoquinolinone derivatives.

EFFECT: novel method for synthesis of 7-methoxy-4-nitro-3-(p-methoxyphenyl)isoquinolinone derivatives on industrial scale, characterised by reduced explosion hazard of synthesis and fewer harmful emissions.

1 cl, 3 dwg

Description

The claimed invention relates to the field of development of a new method for the synthesis of 7-methoxy-4-nitro (p-methoxyphenyl) isoquinolinone.

Recent studies have shown that 7-methoxy-4-nitro-3- (p-methoxyphenyl) isoquinolinone (hereinafter, MNI) is a low molecular weight compound that disrupts cell division (synonymous with tumor progression). This compound also destroys the blood vessels of the tumor, causing massive necrosis in the tumor. Both mechanisms of action contribute to the anticancer activity of the INR. In addition, the IIR has an original molecular target, interesting pharmacological properties, a good toxicity profile and is active when administered orally.

The structure of the MINR

These properties have recently attracted increased interest in this compound from pharmaceutical companies that are actively developing new drugs based on it. And in the coming years, mass production of these drugs may begin.

However, a reliable method for the synthesis of this substance, suitable for industrial use, has not yet been developed.

The published protocol known Bisagni E., Landras C, Thirot S., Huel C, Tetrahedron, 1996, 52, 31, 10427-10440, which describes the synthesis route of 7-methoxy-4-nitro-3- (p-methoxyphenyl ) isoquinolinone.

Known Synthesis Method

However, the known method is not acceptable for obtaining substances in the amount of several kilograms. The second stage of the known synthesis is the Curtius reaction, which may be accompanied by the release of a significant amount of nitrogen. Another disadvantage of this reaction is that low molar mass acyl azides are explosive. Thus, the industrial use of this reaction is limited for safety reasons.

The aim of the claimed invention is to develop a new method for the synthesis of MNRI, which can be used for the safe production of MNRI on an industrial scale - in the amount of several kilograms.

This goal of the claimed invention is achieved by a method for the synthesis of 7-methoxy-4-nitro-3- (p-methoxyphenyl) isoquinolinone, which consists of three stages.

The first stage of the amide preparation involves the preparation of a mixture of thionyl chloride with 5-methoxy-2-toluic acid under nitrogen, which is stirred and refluxed for 3 hours, after which the excess thionyl chloride is removed at a pressure below atmospheric, the residue is dissolved in methylene chloride, and then dropwise a 40% aqueous solution of methylamine was added under ice-cooling, the resulting mixture was stirred at 0 ° C for 24 hours, then the reaction solution was extracted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ and evaporated in vac Uuma, the residue obtained is purified by silica gel column chromatography to obtain 5-methoxy-2, N-dimethylbenzamide.

The second condensation step involves adding to a solution of 1.8 M lithium diisopropylamide in tetrahydrofoleic acid (THF) at -78 ° C under nitrogen, dropwise a solution of 5-methoxy-2, N-dimethylbenzamide in tetrahydrofolic acid, and then a solution of 4-methoxybenzonitrile in tetrahydrofolic acid and the resulting mixture was stirred at -78 ° C for 3 hours, then the reaction mixture was allowed to warm at room temperature, after which water was added saturated NH ₄ Cl, tetragidrofolevuyu acid is removed under subatmospheric pressure, the resulting mixture was extracted in ethyl acetate and washed with brine, the organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo, the resulting residue was subjected to purification by silica gel column chromatography to obtain 7-methoxy-3- (p-methoxyphenyl) izohinolinona.

The third nitration step involves cooling to 10 ° C while stirring a solution of 7-methoxy-3- (p-methoxyphenyl) isoquinolinone in ethyl acetate and acetic acid, then a solution of nitric acid in ethyl acetate is added dropwise at a temperature below 15 ° C, the mixture is stirred at room temperature temperature for 2 hours, then water is added, and the resulting solid is collected, dried in air and recrystallized from toluene to give 7-methoxy-4-nitro-3- (p-methoxyphenyl) isoquinolinone.

In addition, the solid obtained in the third step can be recrystallized from ethyl acetate.

The technical result of the proposed method is to reduce the amount of harmful emissions and reduce the explosion hazard of the synthesis.

Several strategies for the preparation of isoquinolinones are known, for example, their synthesis using isocoumarin by reaction with an amine:

Another promising approach is described in patent applications US 2008/188467 A1, 08/07/2008, WO 2011/045258 A1, 04/21/2011, and WO2005 / 075431 A1, 08/18/2005. So the synthesis of isoquinolinone, known from the application WO 2005/075431 A1 represents the following reaction:

Yield: 65%.

This approach also allows us to get the ET-D5 in just three stages, and all stages are compatible with the safe scale-up of production to an industrial scale. A new way to synthesize the ISM will be considered below.

Taking into account the data obtained as a result of the research, a synthesis method was developed for the production of INR on an industrial scale, consisting of three stages:

The individual steps of the proposed new method for the synthesis of the INR will be discussed in more detail below.

Stage 1.

Amide production:

Yield 80%.

Amide is formed due to the reaction of methylamine and acid chloride. The acid chloride is formed due to the reaction of excess thionyl chloride with an acid and is used without further purification. The amide yield is 80%.

The following procedure was used to carry out this reaction.

Thionyl chloride (1.7 ml, 24 mmol) was added to 5-methoxy-2-toluic acid (2 g, 12 mmol) under nitrogen. The mixture is stirred and refluxed for 3 hours. After that, the excess thionyl chloride is removed under reduced pressure of 20 mbar and the temperature of the bath of the rotary evaporator 45 ° C. The residue was dissolved in methylene chloride (10 ml), and then a 40% aqueous solution of methylamine (4.1 ml, 48 mmol) was added dropwise under ice-cooling.

The resulting mixture was stirred at 0 ° C for 24 hours. Then the reaction solution was extracted with ethyl acetate, washed with saturated NaCl solution, dried over Na ₂ SO ₄ and evaporated under reduced pressure of 100 mbar and a temperature of a rotary evaporator bath of 45 ° C. The resulting residue was purified by silica gel column chromatography (ethyl acetate / cyclohexane in a ratio of 7/3 by volume) to obtain 5-methoxy-2, N-dimethylbenzamide (1.7 g, 80% yield).

Stage 2.

Condensation:

The second stage is the key in this method and consists in the condensation of the amide, previously obtained using 4-methoxy-benzonitrile. The condensation process was tested in the presence of low density amorphous ice (LDA) and butyl lithium (BuLi). Moreover, the best result was obtained in the case of the LDA. Condensation was carried out with a high yield of 67%.

The following procedure was used to carry out this reaction.

To a solution of 1.8 M lithium diisopropylamide (9.3 ml, 16.8 mmol) in tetrahydrofuran (THF) (15 ml) at -78 ° C under nitrogen, a solution of 5-methoxy-2, N-dimethylbenzamide (1 g 5.6 mmol) in tetrahydrofolic acid (10 ml) and then a solution of 4-methoxybenzonitrile (0.74 g, 5.6 mmol) in tetrahydrofuran (6 ml). The mixture was stirred at -78 ° C for 3 hours, then the reaction mixture was allowed to warm at room temperature, after which NH ₄ Cl saturated with water was added. Tetrahydrofuran was removed at a low pressure of 20 mbar and a bath temperature of a rotary evaporator of 45 ° C, the resulting mixture was extracted into ethyl acetate and washed with a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ and evaporated at a pressure of 20 mbar and a bath temperature of the rotary evaporator of 45 ° C. The resulting residue was purified by silica gel column chromatography (ethyl acetate / cyclohexane 8/2; v / v) to obtain 7-methoxy-3- (p-methoxyphenyl) isoquinolinone (1.05 g, 67% yield).

Stage 3.

Nitration:

Yield: 90%.

The last step is nitration. This reaction is fast and highly productive and is used in various industrial processes.

The following procedure was used to carry out this reaction.

A solution of 7-methoxy-3- (p-methoxyphenyl) isoquinolinone (1 g, 3.55 mmol) in ethyl acetate (EtOAc) (3 ml) and acetic acid (7 ml) was cooled to 10 ° C with stirring. Then, a solution of nitric acid (1.2 ml, 14.2 mmol) in EtOAc (3 ml) was added dropwise at a temperature below 15 ° C. The mixture was stirred at room temperature for 2 hours. Water (20 ml) was then added, and the resulting solid was collected, dried in air and recrystallized from toluene (or EtOAc) to give 7-methoxy-4-nitro-3- (p-methoxyphenyl) isoquinolinone (1.04 g, yield 90%).

The resulting substance was analyzed using various methods, which confirmed that the obtained substance was 7-methoxy-4-nitro-3- (p-methoxyphenyl) isoquinolinone (Fig. 1, 2, 3).

As a result of the research, a new three-stage method for the synthesis of MNRI was developed, which is suitable for the production of MNRI on an industrial scale - in the amount of several kilograms.

Claims (1)

A method for the synthesis of 7-methoxy-4-nitro-3- (p-methoxyphenyl) isoquinolinone, comprising:
- the first stage of the amide preparation, including the preparation of a mixture of thionyl chloride with 5-methoxy-2-toluic acid under nitrogen, which is stirred and refluxed for 3 hours, after which the excess thionyl chloride is removed at a pressure of 20 mbar, the residue is dissolved in methylene chloride, and then 40% aqueous methylamine solution was added dropwise under ice-cooling, the resulting mixture was stirred at 0 ° C for 24 hours, then the reaction solution was extracted with ethyl acetate, washed with saturated NaCl solution, dried over Na ₂ SO ₄ and evaporated under pressure at 100 mbar, the residue obtained is purified by silica gel column chromatography to obtain 5-methoxy-2, N-dimethylbenzamide;
- the second stage of condensation, including adding to a solution of 1.8 M lithium diisopropylamide in tetrahydrofuran (THF) at -78 ° C under nitrogen, dropwise a solution of 5-methoxy-2, N-dimethylbenzamide in tetrahydrofolic acid, and then a solution of 4-methoxybenzonitrile in tetrahydrofuran , the resulting mixture was stirred at -78 ° C for 3 hours, then the reaction mixture was allowed to warm at room temperature, then NH ₄ Cl saturated with water was added, tetrahydrofuran was removed at a pressure of 20 mbar, the resulting mixture was extracted into ethyl acetate and washed with saturated NaCl solution, the organic layer is dried over Na ₂ SO ₄ and evaporated at a pressure of 20 mbar, the obtained residue is purified by silica gel column chromatography to obtain 7-methoxy-3- (p-methoxyphenyl) isoquinolinone;
- the third nitration step, including cooling to 10 ° C while stirring a solution of 7-methoxy-3- (p-methoxyphenyl) isoquinolinone in ethyl acetate and acetic acid, then a solution of nitric acid in ethyl acetate is added dropwise at a temperature below 15 ° C, the mixture was stirred at room temperature for 2 hours, then water was added, and the resulting solid was collected, dried in air and recrystallized from toluene or ethyl acetate to give 7-methoxy-4-nitro-3- (p-methoxyphenyl) isoquinolinone.

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