A process for the preparation of isoindolinone compounds

Abstract

ABSTRACT A PROCESS FOR THE PREPARATION OF ISOINDOLINONE COMPOUNDS The present disclosure relates to a process for the preparation of Isoindolione compounds.The process of the present disclosure is simple, efficient, economical, environment friendly and provides isoindolione compounds with a comparatively high yield and high purity. The process of the present disclosure is carried out without a metal catalyst and does not employ any photocatalyst.

Description

FIELDThe present disclosure relates to a process for the preparation of isoindolinone compounds.BACKGROUND:The background information herein below relates to the present disclosure but is not necessarily prior art.1,2,3-Benzotriazinone compounds are important class of 1,2,3-triazoles which are used as a precursor for the synthesis of various azaheterocycles such as isoquinolones, isoindolinones, and ortho-functionalized benzamides. Conventionally, the synthesis of isoindolinones is carried out by using various metal catalysts or photocatalysts which thereby increases production cost. Further, the synthesis of isoindolinones is carried out by using ortho alkynylated benzaldehydes and amines which results in a low yield and purity of isoindolinones.Therefore, there is felt a need to provide a process for the preparation of isoindolinone compounds that mitigates the drawbacks mentioned hereinabove or at least provides a useful alternative.OBJECTS:Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows. An object of the present disclosure to ameliorate one or more problems of background and to provide at least a useful alternative.Another object of the present disclosure is to provide a process for the preparation of isoindolinone compounds.Still another object of the present disclosure is to provide a process for the preparation of isoindolinone compounds with a comparatively high yield and high purity.Still another object of the present disclosure is to provide a process for thepreparation of isoindolinones that is metal free.Yet another object of the present disclosure is to provide a simple and efficienteconomical process for the preparation of isoindolinone compounds.Other objects and advantages of the present disclosure will be more apparent fromthe following description, which is not intended to limit the scope of the presentdisclosure.SUMMARYThe present disclosure relates to a process for the preparation of isoindolinonecompounds. The process comprises reacting 1,2,3-benzotriazinone compound withan activated alkene by using a base in a fluid medium at a predeterminedtemperature for a first predetermined time period to obtain a reaction mixture. Thereaction mixture is photoirradiated with a light source having a predeterminedwavelength at the predetermined temperature for a second predetermined timeperiod to obtain a product mixture comprising the isoindolinone compound.In accordance with the present disclosure, the 1,2,3 benzotriazinone compound isselected from the group consisting of N-aryl benzotriazinone compounds and Nheteroarylbenzotriazinone compounds.In accordance with the present disclosure, N-aryl benzotriazinone compound is selected from the group consisting of and In accordance with the present disclosure, N-heteroaryl benzotriazinone compound is In accordance with the present disclosure, the activated alkene is an alkene with electron withdrawing groups.In accordance with the present disclosure, the activated alkene is selected from the group consisting of In accordance with the present disclosure, the first fluid medium is dimethyl sulfoxide (DMSO).In accordance with the present disclosure, the base is N,N-Di isopropyl ethylamine (DIPEA). In accordance with the present disclosure, the molar ratio of 1,2,3-benzotriazinone compound to the base is in the range of 1:1 to 1:5. In accordance with the present disclosure, the molar ratio of 1,2,3-benzotriazinone compound to the activated alkene is in the range of 1:1 to 1:5. In accordance with the present disclosure, the first predetermined temperature is in the range of 25 °C to 45 °C. In accordance with the present disclosure, the first predetermined time period is in the range of 1 minute to 10 minutes. In accordance with the present disclosure, the light source is a light-emitting diode (LED). In accordance with the present disclosure, the predetermined wavelength of irradiation is in the range of 350 nm to 500 nm. In accordance with the present disclosure, the predetermined wavelength of irradiation is in the range of 390 nm to 456 nm. In accordance with the present disclosure, the second predetermined time period is in the range of 10 hours to 15 hours.DETAILED DESCRIPTIONThe present disclosure relates to a process for the preparation of isoindolinone compounds.Embodiments, of the present disclosure, will now be described with reference to the accompanying drawing.Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilledin the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, known processes or well-known apparatus or structures, and well known techniques are not described in detail.The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a," "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," "including," and "having," are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and / or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure are not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.1,2,3-Benzotriazinone compounds are important class of 1,2,3-triazoles which are used as a precursor for the synthesis of various azaheterocycles such as isoquinolones, isoindolinones, and ortho-functionalized benzamides. Conventionally, the synthesis of isoindolinones is carried out by using various metal catalysts or photocatalysts which thereby increases production cost. Further, the synthesis of isoindolinones is carried out by using ortho alkynylated benzaldehydes and amines which results in a low yield and purity of isoindolinones.The present disclosure provides a simple and efficient process for the preparationof isoindolinone compounds.The process for the preparation of isoindolinone compounds is detailed below:In a first step, 1,2,3-benzotriazinone compound is reacted with an activated alkeneby using a base in a fluid medium at a predetermined temperature for a firstpredetermined time period to obtain a reaction mixture.In accordance with the present disclosure, the fluid medium and N, N-diisopropylethylamine is added to a 1, 2, 3 benzotriazin-4(3H)-one compound to obtain areaction mass. Activated alkene is added to the reaction mass in a dropwise mannerto obtain a reaction mixture.In accordance with the present disclosure, 1,2,3 benzotriazinone compound isselected from the group consisting of N-aryl benzotriazinone compounds and Nheteroarylbenzotriazinone compounds.In accordance with the present disclosure, N-aryl benzotriazinone compound is selected from the group consisting of and In accordance with the present disclosure, N-heteroaryl benzotriazinone compound is In accordance with the present disclosure, the activated alkene is an alkene with electron withdrawing groups.In accordance with the present disclosure, the activated alkene is selected from the group consisting of In accordance with the present disclosure, the fluid medium is dimethyl sulfoxide (DMSO).In accordance with the present disclosure, the base is N,N-Di isopropyl ethylamine(DIPEA).In accordance with the present disclosure, the molar ratio of 1,2,3-benzotriazinonecompound to the base is in the range of 1:1 to 1:5. In an exemplary embodiment,the molar ratio of 1,2,3-benzotriazinone compound to the base is 1:2.5.In accordance with the present disclosure, the molar ratio of 1,2,3-benzotriazinonecompound to the activated alkene is in the range of 1:1 to 1:5. In an exemplaryembodiment, the mass ratio of 1,2,3-benzotriazinone compound to the activatedalkene is 1:3.In accordance with the present disclosure, the first predetermined temperature is in the range of 25 °C to 45 °C. In an exemplary embodiment, the first predetermined temperature is in the range of 30 °C.In accordance with the present disclosure, the first predetermined time period is in the range of 1 minute to 10 minutes. In an exemplary embodiment, the first predetermined time period is 5 minutes.In accordance with the present disclosure, the first predetermined time period is a combined time period of the addition of base and the addition of the activated alkene.The process of the present disclosure is not suitable for N-alkyl benzotriazinones and electron rich alkenes.In a second step, the reaction mixture is photoirradiated with a light source having a predetermined wavelength at the predetermined temperature for a second predetermined time period to obtain a product mixture comprising the isoindolinone compound. In accordance with the present disclosure, the light source is a light-emitting diode (LED).In accordance with the present disclosure, the isoindolinone compounds are prepared by using visible light. In accordance with the present disclosure, the predetermined wavelength of the irradiation is in the range of 350 nm to 500 nm. In accordance with the present disclosure, the predetermined wavelength of irradiation is in the range of 390 nm to 456 nm. In an exemplary embodiment of the present disclosure, the predetermined wavelength of irradiation is 427 nm.In accordance with the present disclosure, the second predetermined time period is in the range of 10 hours to 15 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 12 hours.In accordance with an embodiment of the present disclosure, the schematic representation for the preparation of isoindolinones of the formula I is illustrated as below scheme I below: Scheme-I The process of the present disclosure, does not employ a metal complex or a photocatalyst to facilitate the reaction. The isoindolinone compounds prepared in accordance with the present disclosure are used in the preparation of sedative drugs like Pazinaclone. Analogue of Pazinaclone (3-(2-oxo-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-2-phenylisoindolin-1-one) synthesized using Isoindolinones of the present disclosure is represented by structure (I) below:(I) EXPERIMENTAL DETAILS Experiment 1: Preparation of visible light induced isoindolinone in accordance with the present disclosureExample 1: Preparation of 2-(3-oxo-2-phenylisoindolin-1-yl)acetonitrile:In an oven dried reaction tube, 0.089 g (0.4 mmol) 13-phenylbenzo[d][1,2,3]triazin-4(3H)-one 3 ml dimethyl sulfoxide, 0.129 g (2.5 eq.) N, N-Di isopropyl ethylamine were added and stirred at 30 °C for 2 minutes to obtain a reaction mass. To the obtained reaction mass 0.063 g (3.0 eq) acrylonitrile was added in a dropwise manner at 30 °C to obtain a reaction mixture. The tube was closed with screw cap and the obtained reaction mixture was irradiated with a LED blue light of wavelength 427 nm for 12 hours to obtain 2-(3-oxo-2-phenylisoindolin-1-yl)acetonitrile.Work up: After completion of reaction, the product mixture was diluted with 10 ml ethyl acetate and poured into 15 ml of water to obtain a product mass. The obtained product mass was stirred for 10 minutes. Then stirring was stopped to obtain an organic layer and an aqueous layer. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced vacuum to obtain a residue. The residue was purified by column chromatography on 100 - 200 mesh silica gel using ethylacetate / hexane as eluent to obtain 2-(3-oxo-2-phenylisoindolin-1-yl)acetonitrile in 0.085 g (86% yield).Example 2: The same procedure was followed as in example 1 for the preparation of Isoindolinone compounds using substituted N-aryl / N-heteroaryl benzotriazinone compound and activated alkenes as a reactants.Scheme 1 Table 1 below discloses the preparation of Isoindolinone compounds using the corresponding substituted N-aryl / N-heteroaryl benzotriazinones and activated alkenes as reactants.Table 1: Preparation of Isoindolinone compounds using the corresponding substituted N-aryl / N-heteroaryl benzotriazinones and activated alkenes as reactantsUsing N-aryl substituted benzotriazinones as reactantsUsing N-heteroaryl benzotriazinones as reactantsExample 3: The same procedure was followed as in example 1 for the preparationof Isoindolinone compounds using activated alkenes with different electronwithdrawing groups as one of the reactants.Table 2 below discloses the preparation of Isoindolinone compounds usingactivated alkenes with different electron withdrawing groups as one of the reactantsTable 2: Preparation of Isoindolinone compounds from the reaction ofbenzotriazinone compounds and different activated alkenesExample 4: The same procedure of Example 1 was followed for the preparation ofisoindolinone compounds using various solvents, bases, wavelengths of irradiation,temperature and time period conditions.The results are tabulated in table 3 below:Table 3: Preparation of isoindolinone compounds using various solvents,bases, wavelengths of irradiation, temperature and time period conditions1a (0.2 mmol), 2a (3.0 eq.), DIPEA (2.50 eq.), DMSO (1.5 mL), 427 nm blue LED with 50% intensity under air at room temperature for 12 h. bGC-MS yields, cIsolated yields. dDIPEA (1.0 equiv.). eDIPEA (1.5 equiv.). fDIPEA (2.0 equiv.). gDIPEA (2.50 equiv.).hwithout blue light. iin absence of 427 nm light. jin absence of DIPEA. It is observed from Table 3, that DMSO 1.5 ml, DIPEA (2.50 equiv.), Blue LED λ (% intensity)- 427 (50), at 30 °C gives better yield.Experiment 2: Synthesis of 3-(2-oxo-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-2-phenylisoindolin-1-one [Analogue of Pazinaclone]Isoindolinones 3a obtained by the procedure disclosed in above Example 1 (0.4 mmol) was heated with potassium hydroxide (KOH) (8 mmol) in ethanol (EtOH) (1 ml) and water (H2O) (1 ml) at 90 °C for 40 hours to obtain a reaction mixture. The reaction mixture was cooled to 30 °C, acidified with 1 M hydrochloric acid (HCl) (15 ml), and extracted with ethyl acetate (EtOAc) (20 ml x 3). The combined organic extracts were washed with brine (10 ml), dried over anhydrous magnesium sulphate (MgSO4), and concentrated in vacuo. The resulting carboxylic acid product was used for next step without further purification. Next, to a suspension of the above obtained carboxylic acid was added one drop of dimethyl formamide (DMF) via glass pipet, and dissolved in dichloromethane (DCM) (15 ml) stirred at 0 °C, followed by the addition of dimethyl aminopyridine (DMAP) (96 mg, 0.782mmol), EDC.HCl (300mg, 1.569 mmol) and the resultant mixture was continued stirring at 0 °C for 30 - 40 min, whereupon gas evolution ceased and a solution of 1,4-dioxa-8-azaspiro[4.5]decane (164 mg, 1.7293 mmol) was added at 0 °C. The reaction was allowed to warm to 30 °C and stirred overnight (10-12 hours). Upon completion, the reaction mixture was diluted with dichloromethane (DCM) (30 ml) and water (30 ml), dried over anhydrous MgSO4, and concentrated in vacuo. The resulting mixture was purified by column chromatography in 100 - 200 mesh silica gel (2:8 -> 4.5:5.5; Ethyl acetate:Hexane (EtOAc:Hexane)) to obtain amide 6 as a pale yellow oil (0.312 mmol, 76% yield based on 3a). Rf = 0.42 (5:5 EtOAc / Hex).TECHNICAL ADVANCEMENTSThe present disclosure described herein above has several technical advantages including, but not limited to, the realization of- a process for the preparation of isoindolinone that- provides isoindolinone compounds in a comparatively high purity and high yield;- is simple, efficient, economical and environment friendly;- is metal free; and- does not employ a photocatalyst. The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein. The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and / or adapt for various applications such specific embodimentswithout departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein. The use of the expression "at least" or "at least one" suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results. Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application. The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher / lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary. While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

Claims

1. A process for the preparation of isoindolinone compounds, said process comprising the following steps: a) reacting 1,2,3-benzotriazinone compound with an activated alkene by using a base in a fluid medium at a predetermined temperature for a first predetermined time period to obtain a reaction mixture; and b) photoirradiating said reaction mixture with a light source having a predetermined wavelength at said predetermined temperature for a second predetermined time period to obtain a product mixture comprising the isoindolinone compounds.

2. The process as claimed in claim 1, wherein 1,2,3 benzotriazinone compound is selected from N-aryl benzotriazinone compounds and Nheteroaryl benzotriazinone compounds.

3. The process as claimed in claim 2, wherein said N-aryl benzotriazinone compound is selected from the group consisting of wherein said N-heteroaryl benzotriazinone compound is .

4. The process as claimed in claim 1, wherein said activated alkene is an alkene with electron withdrawing groups.

5. The process as claimed in claim 4, wherein said activated alkene is selected from the group consisting of 6. The process as claimed in claim 1, wherein said fluid medium is dimethyl sulfoxide (DMSO).

7. The process as claimed in claim 1, wherein said base is N,N-Di isopropyl ethylamine (DIPEA).

8. The process as claimed in claim 1, wherein the molar ratio of 1,2,3- benzotriazinone compound to said base is in the range of 1:1 to 1:5.

9. The process as claimed in claim 1, wherein the molar ratio of 1,2,3- benzotriazinone compound to said activated alkene is in the range of 1:1 to 1:

5.

10. The process as claimed in claim 1, wherein said predetermined temperature is in the range of 25 °C to 45 °C.

11. The process as claimed in claim 1, wherein said first predetermined time period is in the range of 1 minutes to 10 minutes.

12. The process as claimed in claim 1, wherein said light source is a light-emitting diode (LED).

13. The process as claimed in claim 1, wherein said predetermined wavelength of irradiation is in the range of 350 nm to 500 nm.

14. The process as claimed in claim 1, wherein said predetermined wavelength of irradiation is in the range of 390 nm to 456 nm.

15. The process as claimed in claim 1, wherein said second predetermined time period is in the range of 10 hours to 15 hours.