Isoindolone derivative and preparation method thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to an isoindolone derivative and a preparation method thereof, the structure of the isoindolone derivative is as follows: # imgabs0 #, R1 and R2 are any one of hydrogen atoms, halogen atoms, vinyl, phenyl, benzyl, methoxyl, trifluoromethyl, sulfo groups, cyano groups or C1-C8 alkyl groups, and R1 and R2 are hydrogen atoms, halogen atoms, vinyl, phenyl, benzyl, methoxyl, trifluoromethyl, sulfo groups, cyano groups or C1-C8 alkyl groups. The preparation method comprises the following steps: reacting 2-methyl-5-nitrobenzoic acid with methanol, reacting with N-bromosuccinimide after the reaction is finished, reacting with primary amine, and reacting with acyl chloride through reduction. The method does not need to use a heavy metal catalyst, is environment-friendly, easy to modify the product and wide in application range.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to an isoindolinone derivative and a preparation method thereof. Background Art

[0002] Isoindolone compounds, as an important system of nitrogen-containing heterocyclic compounds, have important application value due to their unique benzodihydropyridone ring skeleton structure, showing a variety of pharmacological activities. Isoindolone is the core structure of natural products and drugs, and has multiple biological activities such as antibacterial, antiviral, anti-inflammatory, anti-tumor, anti-diabetic, and anti-cardiovascular disease. These compounds play a key role as highly active drug intermediates in the development of new drugs. Some drugs containing isoindolinone structures, such as faripamil, lenalidomide, indoprofen, etc., have been successfully marketed and widely used in the medical field; for example, the patent document number CN201380032233 discloses an isoindolinone composition that can treat inflammatory diseases, diabetes, obesity, cancer and AIDS.

[0003] The synthesis methods of isoindolinone derivatives mainly include CH bond activation method, amine ring closure method, metal-catalyzed coupling cyclization method and multi-component one-pot method. These methods have their own advantages, but there are also some shortcomings, such as difficulty in raw material preparation, low yield, poor environmental protection, dependence on expensive heavy metal catalysts and limited scope of application. These problems limit the potential of isoindolinone compounds in production and application. Summary of the invention

[0004] In order to solve the deficiencies of the prior art described in the background technology, the present invention provides an isoindolinone derivative and a preparation method thereof. The raw materials in the preparation method are cheap and readily available, and no heavy metal catalyst is required, the yield is high, the method is environmentally friendly, and the R 1 and R 2 In addition, the method is simple to operate, convenient for post-processing, and the product is easy to modify, and has a wide range of applications.

[0005] To solve the above technical problems, the present invention is achieved as follows:

[0006] An isoindolinone derivative, the structure of which is as follows:

[0007]

[0008] Among them, the R 1 With R 2 Each of them is any one of a hydrogen atom, a halogen atom, a vinyl group, a phenyl group, a benzyl group, a methoxy group, a trifluoromethyl group, a sulfonic acid group, a cyano group or a C1-C8 alkyl group.

[0009] The preparation method of the above-mentioned isoindolinone derivatives can be implemented according to the following steps:

[0010] (1) adding thionyl chloride dropwise to the compound 2-methyl-5-nitrobenzoic acid and a solvent under an ice bath, heating under reflux for reaction, and purifying by silica gel column chromatography after the reaction to obtain compound Ia;

[0011] (2) heating the compound Ia obtained in step (1), N-bromosuccinimide and an initiator under reflux in a solvent, and purifying by silica gel column chromatography after the reaction to obtain compound Ib;

[0012] (3) Compound Ib obtained in step (2) and primary amine NH2R 1 and a base in a solvent and heated under reflux, and after the reaction is completed, the compound is purified by silica gel column chromatography to obtain compound Ic;

[0013] (4) heating the compound Ic obtained in step (3) and a reducing agent under reflux in a solvent, and purifying the mixture by silica gel column chromatography after the reaction to obtain compound Id;

[0014] (5) Adding an acyl chloride and a solvent dropwise to a product formed by dissolving the compound Id obtained in step (4), a base and a solvent in an ice bath to carry out a reaction. After the reaction is completed, the product is purified by silica gel column chromatography to obtain the desired product.

[0015] Furthermore, in step (3), the primary amine NH2R 1 Medium R 1 It is any one of a hydrogen atom, a halogen atom, a vinyl group, a phenyl group, a benzyl group, a methoxy group, a trifluoromethyl group, a sulfonic acid group, a cyano group, or a C1-C8 alkyl group.

[0016] Furthermore, in step (5), the acyl chloride R 2 COCl 2 It is any one of a hydrogen atom, a vinyl group, a phenyl group, a benzyl group, a trifluoromethyl group, or a C1-C8 alkyl group.

[0017] Furthermore, in the step (1), the solvent is methanol, the molar ratio of the compound 2-methyl-5-nitrobenzoic acid to dithionyl chloride is 1:2-4, and the reaction temperature is 65-75°C.

[0018] Furthermore, in the step (2), the solvent is carbon tetrachloride or chloroform, the initiator is benzoyl peroxide or azobisisobutyronitrile, the molar ratio of compound Ia to N-bromosuccinimide is 1:1-1.2, and the reaction temperature is 55-75°C.

[0019] Furthermore, in step (3), the solvent is toluene, the base is N,N-diisopropylethylamine, the molar ratio of compound Ib, primary amine and base is 1:1-1.4:1-1.4 respectively, and the reaction temperature is 110-120°C.

[0020] Furthermore, in step (4), the solvent is ethanol and water, the reducing agent is iron powder or hydrogen, the molar ratio of the compound Ic solvent to the reducing agent is 1:4-6, and the reaction temperature is 70-75°C.

[0021] Furthermore, in the step (5), the solvent is dichloromethane, the base is triethylamine, the molar ratio of compound Id to the acyl chloride is 1:1-1.2, and the reaction temperature is 0-25°C.

[0022] The specific synthetic route of the present invention is:

[0023]

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The raw materials are cheap and the reaction is suitable for large-scale production;

[0026] (2) High yield;

[0027] (3) Green and free of heavy metal pollution;

[0028] (4) The product is easy to modify and has a wide range of applications.

[0029] The present invention provides a method for preparing isoindolinone derivatives with high yield from cheap 2-methyl-5-nitrobenzoic acid. The method has the characteristics of simple synthesis process and environmental protection, and can flexibly combine R 1 and R 2 Substituents are suitable for new drug research and development, polymer monomers and other fields. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The H NMR spectrum of compound Ia (methyl 2-methyl-5-nitrobenzoate) prepared in Example;

[0031] Figure 2 is the hydrogen nuclear magnetic resonance spectrum of compound Ic (2-(4-methoxybenzyl)-6-nitroisoindolone) prepared in Example;

[0032] Figure 3 is the H NMR spectrum of compound Id (6-amino-2-(4-methoxybenzyl)isoindolone) prepared in Example;

[0033] Figure 4 The H NMR spectrum of Compound I (6-p-fluorobenzamido-2-(4-methoxybenzyl)isoindolone) prepared in Example 1;

[0034] Figure 5The carbon NMR spectrum of compound Ic (2-(4-methoxybenzyl)-6-nitroisoindolone) prepared in Example;

[0035] Figure 6 The carbon NMR spectrum of compound I (6-p-fluorobenzamido-2-(4-methoxybenzyl)isoindolone) prepared in Example 1;

[0036] Figure 7 The infrared spectrum of compound Ic (2-(4-methoxybenzyl)-6-nitroisoindolone) prepared in Example;

[0037] Figure 8 is the infrared spectrum of compound Id (6-amino-2-(4-methoxybenzyl)isoindolone) prepared in Example;

[0038] Fig. 9 The infrared spectrum of compound I (6-p-fluorobenzamido-2-(4-methoxybenzyl)isoindolone) prepared in Example 1;

[0039] Fig.10 is the mass spectrum of compound Ic (2-(4-methoxybenzyl)-6-nitroisoindolone) prepared in Example;

[0040] Fig.11 is the mass spectrum of compound Id (6-amino-2-(4-methoxybenzyl)isoindolone) prepared in Example;

[0041] Fig.12 is the mass spectrum of compound I (6-p-fluorobenzamido-2-(4-methoxybenzyl)isoindolone) prepared in Example 1;

[0042] Fig.13 This is the mass spectrum of Compound I (6-acrylamido-2-(4-methoxybenzyl)isoindolone) prepared in Example 2. DETAILED DESCRIPTION

[0043] To make the purpose, features and advantages of the present invention clearer, the following will be further described in conjunction with specific embodiments. It should be clear that the embodiments are only part of the present invention, not all. Based on these embodiments, other embodiments obtained by ordinary technicians in the field without creative work all belong to the protection scope of the present invention. The raw materials used in the embodiments of the present invention can be obtained from commercial sources.

[0044] Example 1: Preparation of Compound I—6-p-fluorobenzamido-2-(4-methoxybenzyl)isoindolone

[0045]

[0046] In a 250mL single-mouth flask, weighed 2-methyl-5-nitrobenzoic acid (1.812g, 10mmol) and 100mL of anhydrous methanol were added and placed in an ice bath and stirred until completely dissolved. Subsequently, dichlorothionyl (3mL, 40mmol) was slowly added dropwise. After the addition was completed, stirring was continued for 10 minutes, then heated to about 70°C and refluxed for 4 hours. After the reaction was completed, methanol was evaporated using a rotary evaporator. Then, the reaction mixture was washed with a saturated sodium bicarbonate solution and a dichloromethane solution, the organic phase was separated, and the organic solvent was evaporated under vacuum to obtain a crude product. Purified by silica gel column chromatography, using petroleum ether / ethyl acetate (10:1) as an eluent, compound Ia (methyl 2-methyl-5-nitrobenzoate) was finally obtained, with an output of 1.7696g and a yield of 90.7%.

[0047] H NMR spectra Figure 1 As shown, 1 H NMR (400MHz, CDCl3) δ8.78 (s, 1H), 8.24 (d, J = 10.9Hz, 1H), 7.44 (d, J = 8.4Hz, 1H), 3.96 (s, 3H), 2.72 (s, 3H).

[0048] Melting point: 66-67℃.

[0049] In a 250mL three-necked flask, pre-weighed Ia (390.3mg, 2mmol), N-bromosuccinimide (427.2mg, 2.4mmol), azobisisobutyronitrile (16.4mg, 0.1mmol) and 100mL chloroform were added and stirred for 10 minutes under nitrogen protection. Subsequently, under 100W illumination, it was heated to about 60 ° C and refluxed for 6 hours. After the reaction was completed, chloroform was removed using a rotary evaporator. Then, the reaction mixture was washed with saturated sodium bicarbonate solution and dichloromethane, the organic phase was separated, and the organic solvent was evaporated under vacuum to obtain a crude product. Purified by silica gel column chromatography, using petroleum ether / ethyl acetate (15: 1) as eluent, finally obtaining compound Ib (2- (bromomethyl) -5- nitrobenzoic acid methyl ester), the output was 401.3mg, and the yield was 73.2%.

[0050] Melting point: 76-77℃.

[0051] In a 250mL single-necked flask, pre-weighed Ib (457.0mg, 1.67mmol), 4-methoxybenzylamine (0.304mL, 2.33mmol), N,N-diisopropylethylamine (406mg, 2.33mmol) and 100mL toluene were added and stirred at room temperature for half an hour. Subsequently, it was heated to about 110°C and refluxed for 4 hours. After the reaction was completed, toluene was removed using a rotary evaporator. Then, the reaction mixture was washed with saturated sodium bicarbonate solution and dichloromethane, the organic phase was separated, and the organic solvent was evaporated under vacuum to obtain a crude product. Purification by silica gel column chromatography using petroleum ether / ethyl acetate (5:1) as eluent ultimately gave compound Ic (2-(4-methoxybenzyl)-6-nitroisoindolone) with a yield of 430.0mg and a yield of 86.3%.

[0052] H NMR spectra Figure 2 As shown, 1 H NMR(400MHz, CDCl3)δ8.71(d,J=2.2Hz,1H),8.39(dd,J=8.3,2.2Hz,1H),7.59–7.52(m ,1H),7.26(d,J=2.0Hz,2H),6.92–6.84(m,2H),4.76(s,2H),4.36(s,2H),3.80(s,3H).

[0053] C NMR spectra Figure 5 As shown, 13 C NMR (101MHz, CDCl3) δ165.90,159.22,148.31,146.88,134.27,129.46,128.08,126.07,123.68,119.20,114.13,55.11,49.10,45.90.

[0054] Infrared spectra such as Figure 7 As shown, 1678.5cm -1 Nearby is the C=O stretching vibration of amide, 1533.6 cm -1 and 1348.3cm -1 Nearby is the stretching vibration of the -NO2 bond.

[0055] Mass spectrometry Fig.10 As shown, HRMS (ESI-TOF): m / z Calcd for C 16 H 14 N2O4Na:321.0851,found:321.0852.

[0056] Melting point: 142-143℃.

[0057] In a 250mL single-mouth flask, pre-weighed Ic (429.0mg, 1.44mmol), iron powder (403.0mg, 7.2mmol), ammonium chloride (231.0mg, 4.32mmol), 40mL ethanol and 10mL distilled water were added, stirred and heated to about 70°C and refluxed for 2 hours. After the reaction was completed, ethanol and water were removed using a rotary evaporator. Then, the reaction mixture was washed with saturated sodium bicarbonate solution and dichloromethane, the organic phase was separated, and the organic solvent was evaporated under vacuum to obtain a crude product. Purified by silica gel column chromatography, using petroleum ether / ethyl acetate (2: 1) as eluent, compound Id (6-amino-2-(4-methoxybenzyl) isoindolinone) was finally obtained, with an output of 364.2mg and a yield of 94.3%.

[0058] H NMR spectra Figure 3 As shown, 1 H NMR (400MHz, CDCl3) δ7.18–7.11(m,2H),7.10–7.02(m,2H),6.81–6.76(m,2H),6.7 4(dd,J=8.0,2.3Hz,1H),4.63(s,2H),4.06(s,2H),3.83–3.72(m,2H),3.71(s,3H).

[0059] Infrared spectra such as Figure 8 As shown, 3439.2cm -1 and 3348.9cm -1 Nearby is the stretching vibration of -NH2 bond, 1666.7cm -1 Nearby is the C=O stretching vibration of the amide.

[0060] Mass spectrometry Fig.11 As shown, HRMS (ESI-TOF): m / z Calcd for C 16 H 16 N2O2Na:291.1109,found:291.1113.

[0061] In a 250 mL single-necked flask, pre-weighed Id (134.2 mg, 0.5 mmol), triethylamine (83.4 μL, 0.6 mmol) and 50 mL of anhydrous dichloromethane were added and stirred in an ice bath until completely dissolved.

[0062] In a 250 mL conical flask, weighed p-fluorobenzoyl chloride (71 μL, 0.6 mmol) and 50 mL of anhydrous dichloromethane were added. Then, the solution in the conical flask was slowly dripped into the single-necked flask, and the reaction was continued by stirring at 0-25°C for 1 hour.

[0063] After the reaction is completed, the reaction mixture is washed with a saturated sodium bicarbonate solution and dichloromethane, the organic phase is separated, and the organic solvent is evaporated under vacuum to obtain a crude product. Purification by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) as an eluent ultimately yields compound I (6-p-fluorobenzamido-2-(4-methoxybenzyl)isoindolone) in an amount of 186.8 mg and a yield of 95.1%.

[0064] H NMR spectra Figure 4 As shown, 1 H NMR (400MHz, DMSO) δ10.46(s,1H),8.22(d,J=2.0Hz,1H),8.12–8.02(m,2H),7.92(dd,J=8.2,2.0Hz,1H),7.52(d, J=8.2Hz,1H),7.39(t,J=8.8Hz,2H),7.30–7.19(m,2H),6.96–6.88(m,2H),4.66(s,2H),4.31(s,2H),3.73(s,3H).

[0065] C NMR spectra Figure 6 As shown, 13 C NMR (101MHz, CDCl3) δ172.38,170.62,169.82,163.82,144.21,141.94,137.87,136.36,135 .64,134.60,134.40,128.85,128.78,120.72,120.50,119.65,119.30,60.28,54.05,50.10.

[0066] Infrared spectra such as Fig. 9 As shown, 3289.6cm -1 Nearby is the stretching vibration of -NH bond, 1680.9cm -1 and 1650.0cm -1 Nearby is the stretching vibration of C=O of amide, 1305.5 cm -1 Nearby is the stretching vibration of the -CF bond.

[0067] Mass spectrometry Fig.12 As shown, HRMS (ESI-TOF): m / z Calcd for C 23 H 19 N2O3NaF:413.1279,found:413.1277.

[0068] Melting point: 214-216℃.

[0069] The potential drug active sites of this compound are concentrated on the fluorophenyl and benzodihydropyridone ring skeletons. The introduction of fluorine atoms can effectively improve the pharmacokinetic properties of drugs, enhance bioavailability and metabolic stability. The high electronegativity and special volume of fluorine atoms enhance the binding ability of ligands to target proteins, block metabolically unstable sites, and further improve metabolic stability. This compound can be used in the research and development of new drugs such as anti-cancer, anti-inflammatory, anti-fungal and anti-viral drugs.

[0070] Example 2: Preparation of Compound I—6-acrylamido-2-(4-methoxybenzyl)isoindolone

[0071]

[0072] In a 250 mL single-necked flask, add pre-weighed Id (6-amino-2-(4-methoxybenzyl)isoindolone, 134.2 mg, 0.5 mmol), triethylamine (83.4 μL, 0.6 mmol) and 50 mL of anhydrous dichloromethane, place in an ice bath and stir until completely dissolved.

[0073] In a 250 mL conical flask, weighed acryloyl chloride (48.8 μL, 0.6 mmol) and 50 mL of anhydrous dichloromethane were added. Then, the solution in the conical flask was slowly dripped into the single-necked flask, and the reaction was continued at 0-15°C with stirring for 1 hour.

[0074] After the reaction was completed, the reaction mixture was washed with a saturated sodium bicarbonate solution and dichloromethane, the organic phase was separated, and the organic solvent was evaporated under vacuum to obtain a crude product. Purification by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) as an eluent ultimately gave Compound I (6-acrylamido-2-(4-methoxybenzyl)isoindolone) with an output of 161.1 mg and a yield of 99.9%.

[0075] The H NMR spectrum was characterized by 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.30(d,J=8.3Hz,1H),7.88(d,J=2.0Hz,1H),7.30(d, J=8.3Hz,1H),7.20–7.12(m,3H),5.66(dd,J=7.7,3.9Hz,1H),4.69(s,3H),4.18(s,3H).

[0076] Mass spectrometry Fig.13 As shown, HRMS (ESI-TOF): m / z Calcd for C 19 H 18 N2O3Na:345.1215,found:345.1217.

[0077] The compound has a double bond terminal and can be used as a monomer to further polymerize to form a polymer material. Due to its unique structure, the polymerized material has pharmaceutical activity and can be further applied to the fields of medical polymers.

[0078] The basic principles, main features and advantages of the present invention are shown and described above. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments, and these embodiments and descriptions are only used to illustrate the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which all belong to the protection scope of the present invention. The protection scope of the present invention is defined by the attached claims and their equivalents.

Claims

1. An isoindolinone derivative, characterized in that: Its structure is as follows: Among them, the R 1 With R 2 Each of them is any one of a hydrogen atom, a halogen atom, a vinyl group, a phenyl group, a benzyl group, a methoxy group, a trifluoromethyl group, a sulfonic acid group, a cyano group or a C1-C8 alkyl group.

2. A method for preparing the isoindolinone derivatives according to claim 1, characterized in that: Follow these steps to implement: (1) adding thionyl chloride dropwise to the compound 2-methyl-5-nitrobenzoic acid and a solvent under an ice bath, heating to reflux for reaction, and purifying by silica gel column chromatography after the reaction to obtain compound Ia; (2) heating the compound Ia obtained in step (1), N-bromosuccinimide and an initiator under reflux in a solvent, and after the reaction is completed, purifying by silica gel column chromatography to obtain compound Ib; (3) Compound Ib obtained in step (2) and primary amine NH2R 1 and a base in a solvent and heated under reflux, and after the reaction is completed, the compound is purified by silica gel column chromatography to obtain compound Ic; (4) heating the compound Ic obtained in step (3) and a reducing agent under reflux in a solvent, and after the reaction is completed, purifying by silica gel column chromatography to obtain a compound Id; (5) Adding an acyl chloride and a solvent dropwise to a product formed by dissolving the compound Id obtained in step (4), a base and a solvent in an ice bath to carry out a reaction. After the reaction is completed, the product is purified by silica gel column chromatography to obtain the target product.

3. The method for preparing isoindolinone derivatives according to claim 2, characterized in that: The step (3) primary amine NH2R 1 Medium R 1 It is any one of a hydrogen atom, a halogen atom, a vinyl group, a phenyl group, a benzyl group, a methoxy group, a trifluoromethyl group, a sulfonic acid group, a cyano group, or a C1-C8 alkyl group.

4. The method for preparing isoindolinone derivatives according to claim 2, characterized in that: The step (5) of 2 COCl 2 It is any one of a hydrogen atom, a vinyl group, a phenyl group, a benzyl group, a trifluoromethyl group, or a C1-C8 alkyl group.

5. The method for preparing isoindolinone derivatives according to claim 2, characterized in that: In the step (1), the solvent is methanol, the molar ratio of the compound 2-methyl-5-nitrobenzoic acid to dithionyl chloride is 1:2-4, and the reaction temperature is 65-75°C.

6. The method for preparing isoindolinone derivatives according to claim 2, characterized in that: In the step (2), the solvent is carbon tetrachloride or chloroform, the initiator is benzoyl peroxide or azobisisobutyronitrile, the molar ratio of compound Ia to N-bromosuccinimide is 1:1-1.2, and the reaction temperature is 55-75°C.

7. The method for preparing an isoindolinone derivative according to claim 2, characterized in that: In the step (3), the solvent is toluene, the base is N,N-diisopropylethylamine, the molar ratio of compound Ib, primary amine and base is 1:1-1.4:1-1.4, and the reaction temperature is 110-120°C.

8. The method for preparing isoindolinone derivatives according to claim 2, characterized in that: In the step (4), the solvent is ethanol and water, the reducing agent is iron powder or hydrogen, the molar ratio of the compound Ic solvent to the reducing agent is 1:4-6, and the reaction temperature is 70-75°C.

9. The method for preparing isoindolinone derivatives according to claim 2, characterized in that: In the step (5), the solvent is dichloromethane, the base is triethylamine, the molar ratio of compound Id to the acyl chloride is 1:1-1.2, and the reaction temperature is 0-25°C.

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