DESC:FIELD
The present disclosure relates to isatin derivatives and a process for preparation thereof.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Chlorantraniliprole is an insecticide of the ryanoid class. Ryanodine is a naturally occurring insecticide isolated from Ryania speciosa.

Chlorantraniliprole
Chlorantraniliprole can be prepared by using isatin derivatives as an intermediate. Isatin derivatives are also useful in the synthesis of oxindoles, 4-carboxyquinolines, and other biologically active substances. Isatin derivatives can be prepared by cyclizing 2-hydroxyimino-N-(2-methylphenyl) acetamide in sulphuric acid. The use of sulphuric acid is toxic and hazardous to environment. Further, isatin derivatives can also be prepared by using sandmeyer method. In sandmeyer method, aniline is converted to anilide of glyoxylic acid oxime, which is subsequently treated with a strong acid to close the ring to an isatin. Usually, the isatin product is accompanied by undesired isatin oxime side-product. The formation of oxime side-product therefore decreases both, yield and purity of the isatin product.
There is, therefore, felt a need to provide isatin derivatives and a simple, efficient, environment friendly and economical process for preparation thereof.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows.
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
An object of the present disclosure is to provide isatin derivatives and a simple and efficient process for preparation thereof.
Another object of the present disclosure is to provide an environment friendly and economic process for preparing isatin derivatives with comparatively high yield and high purity.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure provides isatin derivatives and a process for preparation thereof. The process comprises charging organic acid in a reaction vessel and heating the reaction vessel at a first predetermined temperature to obtain a heated organic acid. Acetamide derivative is added to the heated organic acid for a predetermined time period by maintaining the reaction at the first predetermined temperature under continuous stirring to obtain a reaction mixture. The reaction mixture is cooled to a second predetermined temperature to obtain a resultant mixture. The resultant mixture is quenched by using water to obtain a precipitate, comprising a product mixture. The so obtained precipitate is filtered to obtain a residue. The residue is washed with water to obtain a wet cake. The wet cake is dried to obtain the isatin derivatives.
DETAILED DESCRIPTION
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 skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus 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 is 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.
Isatin derivatives are useful in the synthesis of chlorantraniliprole, oxindoles, 4-carboxyquinolines, and biologically active substances. Isatin derivatives can be prepared by cyclizing 2-hydroxyimino-N-(2-methylphenyl) acetamide, in sulphuric acid and by using sandmeyer method. However, sulphuric acid used is toxic and hazardous to environment, whereas sandmeyer method provides lower yield of isatin and isatin derivatives.
Therefore, the present disclosure provides isatin derivatives and a process for preparation thereof.
The process of the present disclosure is described in detail herein below:
In the first step, organic acid is charged in a reaction vessel and the reaction vessel is heated at a first predetermined temperature to obtain a heated organic acid. Acetamide derivative is added to the heated organic acid for a predetermined time period and the reaction of acetamide derivative and the organic acid takes place by maintaining a first predetermined temperature under continuous stirring to obtain a reaction mixture.
In an embodiment of the present disclosure, the acetamide derivative is added to the organic acid over a period of 10 minutes to 120 minutes.
In accordance with the present disclosure, acetamide derivative is selected from the group consisting of 2-hydroxyimino-N-(2-methylphenyl) acetamide, 2-hydroxyimino-N-(2-ethylphenyl) acetamide, 2-hydroxyimino-N-(4-methylphenyl) acetamide, and 2-hydroxyimino-N-(4-ethylphenyl) acetamide.
The organic acid is selected from the group consisting of methanesulfonic acid, triflic acid, trifluoroacetic acid, and benzenesulfonic acid. The first predetermined temperature is in the range of 50 °C to 100 °C. In an embodiment, the first predetermined temperature is 70 oC. In another embodiment, the first predetermined temperature is 75 oC.
In the second step, the reaction mixture is cooled to a second predetermined temperature to obtain a resultant mixture.
The second predetermined temperature is in the range of 25 °C to 40 °C.
The resultant mixture is quenched in water to obtain a precipitate.
The so obtained precipitate comprising the product mixture is filtered to obtain a residue. The residue is washed with water twice to obtain a wet cake.
The so obtained wet cake is dried to obtain the isatin derivatives. The process of the present disclosure for the preparation of isatin derivatives uses methanesulfonic acid, and triflic acid, which are less toxic and less hazardous to the environment as compared to the sulphuric acid. Since, the conversion of the reactant to the final product is 100%, the final product (isatin derivatives) does not contain by-products that results in high yield and purity of the isatin derivatives.
Therefore, the process of the present disclosure to prepare isatin derivatives is simple, efficient, economic and environment friendly.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments, which are set forth for illustration purpose only, and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial scale.
EXPERIMENTAL DETAILS
Example 1: Process for preparation of 7-methylisatin in accordance with the process of the present disclosure

Experiment-1:
42 ml of methanesulfonic acid (4.2 ml/gm) was charged in a flask and heated to 70°C under stirring. 10 gms of 2-hydroxyimino-N-(2-methylphenyl) acetamide were added to the preheated methanesulfonic acid over a period of 15 minutes to obtain a reaction mixture. The reaction mixture was maintained at 70-75°C for 15 minutes to obtain a resultant mixture. The progress of the reaction was checked using HPLC. HPLC analysis showed 100% conversion with 97% selectivity. After completion of the reaction (checked by HPLC), the resultant mixture was cooled to 30 oC and quenched in water to obtain a precipitate. The so obtained precipitate was filtered to obtain a cake. The cake was dried until a constant weight of 7-methylisatin was achieved. Cake = 6 gms; HPLC purity =95.45%. MP = 260-72°C (Reported = 270-272°C).
Experiment-2:
50 ml of methanesulfonic acid (2 ml/gm) was charged in a flask and heated to 75°C under stirring. 25 gms of 2-hydroxyimino-N-(2-methylphenyl) acetamide were added to the preheated methanesulfonic acid over a period of 25 minutes to obtain a reaction mixture. The reaction mixture was maintained at 70-75°C for 45 minutes to obtain a resultant mixture. The progress of the reaction was checked using HPLC. HPLC analysis showed 74% conversion with 85% selectivity. After completion of the reaction (checked by HPLC), the resultant mixture was cooled to 30 oC and quenched in water to obtain a precipitate. The so obtained precipitate was filtered to obtain a cake. The cake was dried until a constant weight of 7-methylisatin was achieved.
Experiment-3:
40 ml of methanesulfonic acid (2 ml/gm) was charged in a flask and heated to 85°C under stirring. 20 gms of 2-hydroxyimino-N-(2-methylphenyl) acetamide were added to the preheated methanesulfonic acid over a period of 30 minutes to obtain a reaction mixture. The reaction mixture was maintained at 85-90°C for 30 minutes to obtain a resultant mixture. The progress of the reaction was checked using HPLC. HPLC analysis showed 100% conversion with 76% selectivity. After completion of the reaction (checked by HPLC), the resultant mixture was cooled to 30 oC and quenched in water to obtain a precipitate. The so obtained precipitate was filtered to obtain a cake. The cake was dried until a constant weight of 7-methylisatin was achieved.
Experiment-4:
50 ml of Triflic acid (4.2 ml/gm) was charged in a flask and heated to 80°C under stirring. 12 gms of 2-hydroxyimino-N-(2-methylphenyl) acetamide were added to the preheated triflic acid over a period of 30 minutes to obtain a reaction mixture. The reaction mixture was maintained at 85-90°C for 30 minutes to obtain a resultant mixture. The progress of the reaction was checked using HPLC. HPLC analysis showed 100% conversion with 97% selectivity. After completion of the reaction (checked by HPLC), the resultant mixture was cooled to 30 oC and quenched in water to obtain a precipitate. The so obtained precipitate was filtered to obtain a cake. The cake was dried until a constant weight of 7-methylisatin was achieved. Cake = 9 gms; HPLC purity = 93.95%.
Experiment-5:
43 ml of Trifluoroacetic acid (4.2 ml/gm) was charged in a flask and heated to 60°C under stirring. 10 gms of 2-hydroxyimino-N-(2-methylphenyl) acetamide were added to the preheated trifluoroacetic acid over a period of 30 minutes to obtain a reaction mixture. The reaction mixture was maintained at reflux (73°C) for 30 minutes to obtain a resultant mixture. The progress of the reaction was checked using HPLC. HPLC analysis showed 100% conversion with 4% selectivity.
Experiment-6:
42 ml of benzenesulfonic acid (4.2 ml/gm) was charged in a flask and heated to 70°C under stirring. 10 gms of 2-hydroxyimino-N-(2-methylphenyl) acetamide were added to the preheated benzenesulfonic acid over a period of 90 minutes to obtain a reaction mixture. The reaction mixture was maintained at 70-75°C for 120 minutes to obtain a resultant mixture. The progress of the reaction was checked using HPLC. HPLC analysis showed 100% conversion with 5% selectivity.
Example 2: Process for preparation of 5-methylisatin in accordance with the process of the present disclosure

Experiment-1:
57 ml of methanesulfonic acid (4.2 ml/gm) was charged in a flask and heated to73°C under stirring. 14 gms of 2-hydroxyimino-N-(4-methylphenyl) acetamide were added to the preheated methanesulfonic acid over a period of 60 minutes to obtain a reaction mixture. The reaction mixture was maintained at 70-75°C for 145 minutes to obtain a resultant mixture. The progress of the reaction was checked using HPLC. HPLC analysis showed 100% conversion with 94% selectivity. After completion of the reaction (checked by HPLC), the resultant mixture was cooled to 30 oC and quenched in water to obtain a precipitate. The so obtained precipitate was filtered to obtain a cake. The cake was dried until a constant weight of 5-methylisatin was achieved. Cake = 8.6 gms; HPLC purity =93.2%.

Experiment-2:
42 ml of Triflic acid (4.2 ml/gm) was charged in a flask and heated to 70°C under stirring. 10 gms of 2-hydroxyimino-N-(4-methylphenyl) acetamide were added to the preheated methanesulfonic acid over a period of 90 minutes to obtain a reaction mixture. The reaction mixture was maintained at 70-75°C for 120 minutes to obtain a resultant mixture. The progress of the reaction was checked using HPLC. HPLC analysis showed 100% conversion with 97% selectivity. After completion of the reaction (checked by HPLC), the resultant mixture was cooled to 30 oC and quenched in water to obtain a precipitate. The so obtained precipitate was filtered to obtain a cake. The cake was dried until a constant weight of 5-methylisatin was achieved. Cake = 5.6 gms; HPLC purity =98.57%.
From examples 1 and 2, it is evident that the conversion of 2-hydroxyimino-N-(4-methylphenyl) acetamide to isatin derivatives (5 methyl isatin) in methanesulfonic acid and triflic acid is 100% with selectivity greater than 70%, whereas, the conversion of 2-hydroxyimino-N-(4-methylphenyl) acetamide to isatin derivatives (7 methyl isatin) in trifluoroacetic acid and benzenesulfonic acid is 100% with selectivity of 4% and 5%, respectively. Therefore, experiments 1 to 4 of example 1, and experiments 1 to 2 of example 2 produces high yield and high purity of isatin derivatives and higher selectivity.
Further, since the process of the present disclosure uses methanesulfonic acid and triflic acid for the preparation of isatin derivatives, the process is less toxic and less hazardous to the environment as compared to the process using sulphuric acid.
Hence, the process of the present disclosure to prepare isatin derivative is simple, efficient, economic and environment friendly.
TECHNICAL ADVANCES AND ECONOMICAL SIGNIFICANCE
The present disclosure, described herein above has several technical advantages including, but not limited to, the realization of isatin derivatives and a process for preparation of isatin derivatives, wherein the process:
- is simple and efficient;
- is economic; and
- is environment friendly.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
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:WE CLAIM:
1. A process for preparing isatin derivatives, said process comprising the following steps:
i. charging an organic acid in a reaction vessel and heating the reaction vessel at a first predetermined temperature to obtain a heated organic acid;
ii. adding an acetamide derivative to the heated organic acid over a predetermined time period by maintaining said first predetermined temperature, under continuous stirring to obtain a reaction mixture;
iii. cooling said reaction mixture to a second predetermined temperature to obtain a resultant mixture;
iv. quenching said resultant mixture by using water to obtain a precipitate comprising a product mixture;
v. filtering the precipitate to obtain a residue;
vi. washing the residue cake with water to obtain a wet cake; and
vii. drying the wet cake to obtain the isatin derivatives.
2. The process as claimed in claim 1, wherein said organic acid is at least one selected from methanesulfonic acid, triflic acid, trifluoroacetic acid, and benzenesulfonic acid.
3. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 50 °C to 100 °C.
4. The process as claimed in claim 1, wherein said predetermined time period is in the range of 10 to 120 minutes.
5. The process as claimed in claim 1, wherein the acetamide derivative is selected from 2-hydroxyimino-N-(2-methylphenyl) acetamide, 2-hydroxyimino-N-(2-ethylphenyl) acetamide, 2-hydroxyimino-N-(4-methylphenyl) acetamide, and 2-hydroxyimino-N-(4-ethylphenyl) acetamide.
6. The process as claimed in claim 1, wherein said second predetermined temperature is in the range of 25 °C to 40 °C.