DESC:FIELD
The present disclosure relates to a process for preparing 6-methoxycarbonyl-2-oxindole.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Nintedanib is a therapeutic compound used for the treatment of cancer. It is synthesized from 6-methoxycarbonyl-2-oxindole (I) (CAS No. 14192-26-8).

Conventional processes for the preparation of 6-methoxycarbonyl-2-oxindole involve the steps of (i) alkylation of methyl-4-chloro-3-nitrobenzoate with dimethyl malonate to obtain dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate; (ii) reduction of dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate; and (iii) cyclization to obtain the compound of Formula (I).
The alkylation is associated with drawbacks such as low regioselectivity, need for product purification, and thereby resulting in low yield. The reduction is associated with drawbacks such as loss of catalyst due to difficulty in catalyst recovery.
As a result, conventional processes for the preparation of (I) are associated with complex purification steps, use of expensive catalyst, and catalyst loss.
There is, therefore, felt a need to provide a process of preparation of 6-methoxycarbonyl-2-oxindole (I) which obviates the drawbacks mentioned herein above. Particularly, it is desired that the process involves convenient operations, easy purification, environmentally friendly and low production costs.
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.
Another object of the present disclosure is to provide a simple process for preparing 6-methoxycarbonyl-2-oxindole.
Still another object of the present disclosure is to provide a process for preparing 6-methoxycarbonyl-2-oxindole with high purity.
Yet another object of the present disclosure is to provide a process involving convenient operations, environment friendly and low production costs.
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 relates to a process for preparing 6-methoxycarbonyl-2-oxindole (I). The process comprises esterifying 4-chloro-3-nitrobenzoic acid (II) with methanol using thionyl chloride at a first predetermined temperature for a first predetermined time to obtain methyl-4-chloro-3-nitrobenzoate (III). The methyl-4-chloro-3-nitrobenzoate (III) is alkylated with dimethyl malonate using a base in a polar fluid medium at a second predetermined temperature for a second predetermined time to obtain a reaction mixture comprising dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV). The so obtained dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) is separated from the product mixture by extracting it with dichloromethane to obtain crude dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) followed by purification by way of recrystallization to obtain dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) having a purity in the range of 95 % to 99.5%.
The dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) having a purity in the range of 95 % to 99.5% is reduced using hydrogen gas having predetermined gas pressure in the presence of Raney/Ni as a catalyst and N,N-dimethylformamide as a fluid medium at a third predetermined temperature to obtain a product mixture comprising dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V). The product mixture is filtered to obtain a residue comprising Raney/Ni catalyst and a filtrate comprising the dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V). The filtrate comprising dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V) is cyclized using an acetic acid at a fourth predetermined temperature for a third predetermined time to obtain the 6-methoxycarbonyl-2-oxindole (I).
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.
Nintedanib is a therapeutic compound used for the treatment of cancer. It is synthesized from 6-methoxycarbonyl-2-oxindole (I) (CAS No. 14192-26-8), which in turn is synthesized from dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV). The present disclosure envisages a simple and economical process for preparing 6-methoxycarbonyl-2-oxindole (I) with high purity.
The present disclosure provides a process for the preparation of 6-methoxycarbonyl-2-oxindole (I).

The schematic representation of the process of the present disclosure is provided below.
Step 1: Esterification of 4-chloro-3-nitrobenzoic acid (II)

Step 2: Alkylation of methyl-4-chloro-3-nitrobenzoate (III)

Step 3: Reduction of dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) followed by cyclization of dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V)

The process of for the preparation of 6-methoxycarbonyl-2-oxindole (I) are described in detail.
In the first step, esterification of 4-chloro-3-nitrobenzoic acid (II) with methanol using thionyl chloride is carried out at a first predetermined temperature for a first predetermined time to obtain methyl-4-chloro-3-nitrobenzoate (III).
In accordance with the present disclosure, the first predetermined temperature can be in the range of 20 oC to 70 oC and the first predetermined time can be in the range of 0.5 hour to 5 hours. In an embodiment, the esterification of II can be performed in a stepwise manner. In an exemplary embodiment the reaction mixture comprising 4-chloro-3-nitrobenzoic acid (II), methanol and thionyl chloride is stirred at a temperature in the range of 20°C to 30°C for 0.5 hour to 1 hour, followed by stirring at a temperature in the range of 60 °C to 70 °C for 1 hour to 5 hours to obtain methyl-4-chloro-3-nitrobenzoate (III).
Methyl-4-chloro-3-nitrobenzoate (III) is alkylated with dimethyl malonate using a base in a polar fluid medium at a second predetermined temperature for a second predetermined time to obtain a reaction mixture comprising dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV).

In accordance with the present disclosure, the second predetermined temperature can be in the range of 20 oC to 40 oC and the second predetermined time can be in the range of 1 hour to 8 hours. In an embodiment, the alkylation of III can be performed in a stepwise manner. In an exemplary embodiment, methyl-4-chloro-3-nitrobenzoate (III) is alkylated with dimethyl malonate using a base in a polar fluid medium under stirring at a temperature in the range of 20 °C to 30 °C for 2 hours to 4 hours, followed by heating at a temperature in the range of 30 °C to 40 °C for 1 to 4 hours.
The amount of dimethyl maleate can be in the range of 1 mole to 4 moles. In one embodiment, the amount of dimethyl maleate used in the process is 2 moles in respect of the base.
The amount of base is in the range of 1mole to 5 moles. In one embodiment, the amount of base used is 1mole in respect of dimethyl maleate.
The base used for the alkylation can be at least one selected from the group consisting of sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide. In one embodiment of the present disclosure, the base used for the alkylation is sodium methoxide.
The fluid medium used for alkylation can be at least one selected from the group consisting of N-methyl-2-pyrrolidone, N,N-dimethylformamide, Dimethylsulphoxide and Tetrahydrofuran. In one embodiment of the present disclosure, the fluid medium used for alkylation is N-methyl-2-pyrrolidone.
The so obtained dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV), is separated from the product mixture by extracting it with dichloromethane to obtain crude dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) followed by purification by way of recrystallization to obtain dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) having a purity in the range of 95 % to 99.5%.
In accordance with the present disclosure, the dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) can be separated from the product mixture by adjusting the pH of the product mixture in the range of 2 to 4 by using hydrochloric acid. After complete addition of hydrochloric acid, the resultant mixture can be stirred at 15 °C to 20 °C for 15 minutes to 45 minutes, followed by dilution with water and extraction using dichloromethane to obtain crude (IV). Crude (IV) can be recrystallized using isopropyl alcohol to obtain (IV) with a yield in the range of 70% to 80% having purity in the range of 95.0 to 99.5%.
In an exemplary embodiment pure dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) is obtained with a yield of 75% and purity of 99.5%.
Thus, the alkylation of (III) provides (IV) with high purity by a simple process involving extraction with dichloromethane and recrystallization using isopropyl alcohol. In one embodiment, dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) can be used for the next step without further purification.
Therefore, the process of the present disclosure involves convenient operations and easy purification.
Further, dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) having a purity in the range of 95 % to 99.5% is reduced using hydrogen gas having a predetermined gas pressure in the presence of Raney/Ni as a catalyst and N, N-dimethylformamide as a fluid medium at a third predetermined temperature to obtain a product mixture comprising dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V).
The weight ratio of catalyst Raney/Ni and dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) can be in the range of 1:1 to 1:10. In accordance with one embodiment of the present disclosure, the weight ratio of Raney/Ni and dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) is 1:6.6.
In accordance with the present disclosure, the third predetermined temperature can in the range of 45 °C to 50 °C. In one embodiment, the third predetermined temperature is 45 °C. The predetermined hydrogen gas pressure can be in the range of 85 psi to 215 psi. In one embodiment, the hydrogen gas pressure is 135 psi.
The product mixture is filtered to obtain a residue comprising Raney/Ni and a filtrate comprising dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V).
In one embodiment of the present disclosure, the catalyst, Raney/Ni can be separated from the product mixture by filtration. The product mixture is filtered to obtain a solid residue comprising Raney/Ni and a filtrate comprising dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V). The filtrate can be directly used in the next step without the isolation of the product dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V).
The residue comprising Raney/Ni is washed with water to obtain recovered Raney/Ni. The recovered Raney/Ni can be further reused as a catalyst for reducing dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV). Raney/Ni can be reused for at least three times without significant loss of activity. Thus, the process of the present disclosure is environmentally friendly.
The so obtained filtrate comprising dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V) is cyclized using acetic acid at a fourth predetermined temperature for a third predetermined time to obtain the 6- methoxycarbonyl-2-oxindole (I).
The fourth predetermined temperature can be in the range of 30 oC to 150 oC and the third predetermined time can be in the range of 0.5 hour to 12 hours. The ratio of the filtrate comprising dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V) to the acetic acid can be the range of 1:1 to 1:4 used during the cyclization. In one embodiment, the ratio of the filtrate to the acetic acid can be the range of 1:1 to 1:2.
In accordance with the present disclosure, cyclization of dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V) can be performed in a stepwise manner. In one embodiment, acetic acid can be added to filtrate slowly at a temperature in the range of 30 °C to 60 °C for 0.5 to 4 hours to obtain a resultant mixture. The resultant mixture can be further heated at a temperature in the range of 90 °C to 150 °C for 2 hours to 8 hours to obtain a product mixture comprising 6-methoxycarbonyl-2-oxindole (I). Further, the product mixture comprising 6-methoxycarbonyl-2-oxindole (I) can be cooled at a temperature in the range selected from -5 °C to 5 °C to obtain a suspension. The suspension can be filtered to obtain a residue. The residue can be washed with methanol and dried to obtain 6- methoxycarbonyl-2-oxindole (I).
The compound, 6-methoxycarbonyl-2-oxindole (I) is obtained with a yield of 70% to 80% having purity in the range of 90% to 99.5 %. In one embodiment of the process of the present disclosure, 6-methoxycarbonyl-2-oxindole (I) is obtained with a yield of 73% with purity of 99.5 %.
Thus, the process of the present disclosure provides 6-methoxycarbonyl-2-oxindole (I) with high purity. Thus, the cyclization provides (I) with high purity without the need for a purification step.
The process of the present disclosure uses commonly available and inexpensive reagents and fluid media. Furthermore, the process of the present disclosure has mild reaction conditions, convenient operations, easy purification, and low production costs.
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 DETAIL
Experiment 1:
Step 1: Esterification of 4-chloro-3-nitrobenzoic acid (II)
Thionyl chloride (49.6 g) was added drop-wise to a solution of 4-chloro-3-nitrobenzoic acid (160.0 g) and methanol (640 ml) for 1 hour under stirring at 20 °C, to obtain a reaction mass. The reaction mass was stirred at 60 °C for 4 hours to obtain a product mass.
The product mass was cooled to 30°C. The product mass was further cooled to 0 °C and stirred for 1 hour to get a suspension. The solid was filtered off from the suspension. The residue obtained was washed with methanol and dried under reduced pressure at 50 °C for 5 hours to obtain 130 g of methyl-4-chloro-3-nitrobenzoate (III) with yield of 76.0% and purity of 99.0 % by Gas Chromatography (GC).
Step 2: Alkylation of methyl-4-chloro-3-nitrobenzoate (III)
Dimethyl malonate (147 g) was added drop-wise to a solution of sodium methoxide (65 g) and N-methyl-2-pyrrolidone (600 ml) for 3 hours at 20 °C to obtain a resultant mass. To the resultant mass methyl-4-chloro-3-nitrobenzoate (120 g) in N-methyl-2-pyrrolidone (250 ml) was added slowly for 5 hours at 30 °C to obtain a reaction mass. The reaction mass was stirred at 30°C for 1 hour. The reaction mass was further stirred at 40 °C for 1 hour to obtain a product mass.
The product mass was cooled to 15 °C. The pH of the product mass was adjusted to 3 using dilute hydrochloric acid and the product mass was stirred at 15 °C for 30 minutes. Dichloromethane (300 ml) and water (500 ml) ware added to the product mass at 15 °C under stirring over 15 minutes. The organic layer was separated and dichloromethane was distilled at 1 atmosphere pressure at 45 °C. Further, dichloromethane was distilled at 45 °C under reduced pressure to obtain crude dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV).
Crude dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) was recrystallized from isopropyl alcohol.
Isopropyl alcohol (500 ml) was added to the crude dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) at 25 °C and mixture was heated at 45 °C for 1 hour. The mixture was cooled to 30°C and further cooled to 0 °C and stirred for 2 hours to obtain a suspension. The solid was filtered off from the suspension. The filtered solid was washed with isopropyl alcohol (100 ml) and dried under reduced pressure at 50 °C for 5 hours to obtain 130 g dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl]propanedionate (IV) with yield of 75.0% and purity of 99.5% by HPLC.
Step 3: Reduction of dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) and cyclization of dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V)
Dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (100 g) was dissolved in N,N-dimethylformamide to obtain a reaction mass. The reaction mass was hydrogenated at 45 °C in the presence of Raney/Ni catalyst (15 g) under 135 psi of hydrogen gas to obtain a product mass.
The catalyst was filtered off from the product mass to obtain a filtrate. Acetic acid (220 g) was added to the filtrate slowly below 50 °C, over 1 hour. The resultant mixture was heated to 120 °C and stirred for 3 hours.
The product mass was cooled to 25 °C. The product mass was further cooled to -2 °C and stirred for 2 hours to obtain a suspension. The suspension was filtered to obtain a residue. The residue was washed with methanol (50 ml) and dried under reduced pressure at 50 °C for 8 hours to obtain 45 g of 6-methoxycarbonyl-2-oxindole (I) with yield of 73% and purity of 99.5% by HPLC.
TECHNICAL ADVANCES AND ECONOMICAL SIGNIFICANCE
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of a process for preparation of 6-methoxycarbonyl-2-oxindole (I); that
• has convenient operations;
• easy purification steps;
• is environment friendly; and
• has low production costs.
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 6-methoxycarbonyl-2-oxindole (I) comprising the following steps:
a. esterifying 4-chloro-3-nitrobenzoic acid (II) with methanol using thionyl chloride at a first predetermined temperature for a first predetermined time to obtain methyl-4-chloro-3-nitrobenzoate (III);
b. alkylating said methyl-4-chloro-3-nitrobenzoate (III) with dimethyl malonate using a base in a polar fluid medium at a second predetermined temperature for a second predetermined time to obtain a reaction mixture comprising dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV);
c. separating said dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) from said product mixture by extracting it with dichloromethane to obtain crude (IV);
d. purifying said crude dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) by recrystallization to obtain dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) having a purity in the range of 95 % to 99.5%;
e. reducing said dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) obtained in said step d) using hydrogen gas having predetermined gas pressure in the presence of Raney/Ni as a catalyst and N,N-dimethylformamide as a fluid medium at a third predetermined temperature to obtain a product mixture comprising dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V);
f. filtering said product mixture to obtain a residue comprising said Raney/Ni and a filtrate comprising said dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V); and
g. cyclizing said filtrate comprising said dimethyl-[4-(methoxycarbonyl)-2-aminophenyl] propanedionate (V) using acetic acid at a fourth predetermined temperature for a third predetermined time to obtain said 6- methoxycarbonyl-2-oxindole (I).
2. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 20 oC to 70 oC and said first predetermined time is in the range of 0.5 hour to 5 hours.
3. The process as claimed in claim 1, wherein said base is selected from the group consisting of sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide.
4. The process as claimed in claim 1, wherein the amount of dimethyl malonate is in the range of 1mole to 4 moles and the amount of base is in the range of 1mole to 5 moles.
5. The process as claimed in claim 1, wherein said second predetermined temperature is in the range of 20 oC to 40 oC and said second predetermined time is in the range of 1 hour to 8 hours.
6. The process as claimed in claim 1, wherein said polar fluid medium in said step b) is at least one selected from the group consisting of N-methyl-2-pyrrolidone, N,N-dimethylformamide, Dimethylsulphoxide and Tetrahydrofuran.
7. The process as claimed in claim 1, wherein the weight ratio of said catalyst to said dimethyl-[4-(methoxycarbonyl)-2-nitrophenyl] propanedionate (IV) obtained in said step d) is in the range of 1:1 to 1:10.
8. The process as claimed in claim 1, wherein said predetermined gas pressure is in the range of 85 psi to 215 psi.
9. The process as claimed in claim 1, wherein said third predetermined temperature is in the range of 45 °C to 50 °C.
10. The process as claimed in claim 1, wherein the ratio of said filtrate to said acetic acid in said step g) is in the range of 1:1 to 1:4.
11. The process as claimed in claim 1, wherein said fourth predetermined temperature is in the range of 30 oC to 150 oC and third predetermined time is in the range of 0.5 hour to 12 hours.