AU2016101825A4 - A method for preparation of 3-Nitrophthalic Anhydride - Google Patents

Abstract

A METHOD FOR PREPARATION OF 3-NITROPHTHALIC ANHYDRIDE The present disclosure relates to a method for preparation of 3-nitrophthalic anhydride. The method of the present disclosure does not require the use of a 'controlled substance' like acetic anhydride and uses an anhydride selected from propionic anhydride, n-butyric anhydride, isobutyric anhydride and acetic formic anhydride, in less molar quantities than the methods of the prior art. Also, the method of the present disclosure is less laborious and relies on commercially available organic fluid media for purification. The method of present disclosure is useful in preparing 3-nitrophthalic anhydride commercially in an economic and safe way. -N A0 3-Nitrophthalic Anhydride

Description

2016101825 18 Oct 2016

TITLE: A METHOD FOR PREPARATION OF 3-NITROPHTHALIC ANHYDRIDE

FIELD

The present disclosure relates to a method for preparation of 3-nitrophthalic 5 anhydride.

BACKGROUND 3-nitrophthalic anhydride (3-NPAH) is, commonly, used as an intermediate for the synthesis of pharmaceutical drugs, for example- pomalidomide - a drug used for the treatment of relapsed and refractory multiple myeloma. There are a number of 10 literature sources in the state-of-the-art teaching various methods to prepare 3-NPAH.

Conventionally, 3-NPAH is prepared by reacting 3-nitrophthalic acid (3-NPA) and acetic anhydride. The method involves using an excess of acetic anhydride (over 2 moles per mole of 3-NPA) which is a ‘controlled substance’ and is subject to 15 various restrictive laws in India and abroad. This adds to the costs of production and hence not economical. One of the major drawbacks of this method is the use of alcohol-free diethyl ether. Diethyl ether is a known hazardous chemical. Also, even slight presence of alcohol results in the formation of some mono ethyl ester which in turn reduces the purity of the final product. Moreover, the method 20 involves laborious process steps of multiple washings and grinding which renders it unprofitable on a commercial scale. A variation of this method uses isopropyl acetate as a diluent in the reaction between 3-nitrophthalic acid and acetic anhydride to reduce the exotherm.

Another reported process teaches direct nitration of phthalic anhydride (using a 25 nitrating mixture) which results in a product mixture of 4-nitrophthalic anhydride and 3-nitrophthalic anhydride. The nitrophthalic anhydrides are separated from sulphuric acid using methylene chloride. Further, 3-nitrophthalic anhydride is 1 2016101825 18 Oct 2016 separated from 4-nitro phthalic anhydride by fractional distillation. This method requires 98 - 100% cone, sulphuric acid, otherwise, water liberated during the course of reaction dilutes the nitric acid and 3-nitrophthalic acid is produced instead of 3-NPAH. This process requires the use of severe acidic conditions and 5 is economically straining to isolate 3-NPAH using fractional distillation from its isomer 4-NPAH.

These methods are clearly disadvantageous either due to laborious processes involved or the use of hazardous solvents like diethyl ether or the use of ‘controlled substances’ as reactants. 10 Hence, there is a felt need for a method for preparation of 3-NPAH that uses less laborious steps, non-hazardous solvents and non-controlled reactants. Also, an economic way to prepare 3-NPAH is sought after.

OBJECTS

Some of the objects of the present disclosure, which at least one embodiment herein 15 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 a simple method for preparation of 3-nitrophthalic anhydride. 20 Another object of the present disclosure is to provide a method for preparation of 3-nitrophthalic anhydride that is economical.

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. 2 2016101825 18 Oct 2016

SUMMARY A method for preparation of 3-nitrophthalic anhydride is disclosed. 3-Nitrophthalic acid (3-NPA) and at least one anhydride selected from the group consisting of propionic anhydride, n-butyric anhydride, isobutyric anhydride and 5 acetic formic anhydride are charged into a reactor and maintained at a temperature in the range of 20° C to 35° C to obtain a first mixture. The molar ratio of 3-nitrophthalic acid and the at least one anhydride is in the range of 1:1.2 to 1:1.8. The first mixture is then heated at a temperature in the range of 140° C to 170° C for a time period in the range of 4 hours to 10 hours to obtain a resultant. The 10 resultant is then cooled to a temperature in the range of 110° C to 135° C to obtain a cooled resultant. A first organic fluid medium is introduced into the reactor and added to the cooled resultant to obtain a second mixture. After the complete introduction of the first organic fluid medium into the reactor, the second mixture is further cooled to a temperature in the range of 20° C to 35° C to obtain a cooled 15 second mixture. 3-Nitrophthalic anhydride is then isolated from the cooled second mixture.

Typically, the isolating of 3-nitrophthalic anhydride from the cooled second mixture comprises filtering the cooled second mixture to obtain a wet cake, washing the wet cake with a second organic fluid medium to obtain a washed wet 20 cake and drying the washed wet cake.

Typically, the first organic fluid medium is at least one selected from the group consisting of toluene, xylene, benzene, cumene, and mesitylene. The second organic fluid medium is at least one selected from the group consisting of toluene, xylene, benzene, cumene, and mesitylene. 25 Typically, the yield of 3-nitrophthalic anhydride by the method of the present disclosure is in the range of 84% to 90%. 3 2016101825 18 Oct 2016

Typically, the purity of 3-nitrophthalic anhydride prepared using the method of the present disclosure is in the range of 90% to 99.99%.

DETAILED DESCRIPTION

The methods for preparation of 3-nitrophthalic anhydride (3-NPAH) involve 5 laborious preparatory steps including multiple washings with solvents like diethyl ether and further distilling the filtrate to recover fractions of washed away 3-NPAH. Other methods include direct nitration under severe acidic conditions and separation of 3-NPAH by fractional distillation. These methods require large amounts of acetic anhydride which is a “controlled substance” as a reactant and 10 hazardous chemicals like diethyl ether. Therefore, the present disclosure envisages a simpler method for preparation of 3-NPAH which results in a product of high purity, involves less laborious preparatory steps, and avoids the use of hazardous chemicals. 3-Nitrophthalic acid (3-NPA) and at least one anhydride selected from the group 15 consisting of propionic anhydride, n-butyric anhydride, isobutyric anhydride and acetic formic anhydride are charged into a reactor while maintaining the content of the reactor at a temperature in the range of 20° C to 35° C to obtain a first mixture. The molar ratio of 3-nitrophthalic anhydride and the at least one anhydride is in the range of 1:1.2 to 1:1.8. 20 In conventional methods, acetic anhydride, which is a controlled substance is used in high molar quantities (over 2 moles per mole of 3-NPA). The anhydrides used in the method of the present disclosure does not require the use of a controlled substance and also the molar quantities of the anhydride required is in the range of 1.2 moles to 1.8 moles per mole of 3-NPA. 25 The first mixture is then heated at a temperature in the range of 140° C to 170° C for a time period in the range of 4 hours to 10 hours to obtain a resultant. The temperature of the resultant is then lowered to a temperature in the range of 110° C to 135° C to obtain a cooled resultant and a first organic fluid medium is slowly 4 2016101825 18 Oct 2016 introduced into the reactor and added to the cooled resultant to obtain a second mixture. After the complete addition of the first organic fluid medium, the second mixture is then cooled to a temperature in the range of 25° C to 35° C to obtain a cooled second mixture. 3-Nitrophthalic anhydride is then isolated from the cooled 5 second mixture.

In accordance with an embodiment of the present disclosure, the isolating of 3-nitrophthalic anhydride from the cooled second mixture comprises fdtering the cooled second mixture to obtain a wet cake, washing the wet cake with a second organic fluid medium to obtain a washed wet cake and drying the washed wet cake. 10 ^COOH Propionic anhydride/n- o J! I butyric anhydride/isobutyric 7 o τ XOOH anhvdride/acetic formic ^ 1 NO, anhydride m2

140° C to 170° C 3-nitrophthalic acid 3-nitrophthalic anhydride

In a particular embodiment of the present disclosure, 3-NPA and propionic anhydride are taken in 1:1.5 molar ratio and reacted at 150° C for 6 hours to obtain 15 3-nitrophthalic anhydride.

The yield of 3-nitrophthalic anhydride by the method of the present disclosure is in the range of 84 % to 90%.

The first organic fluid medium is at least one selected from the group consisting of toluene, xylene, benzene, cumene, and mesitylene. The second organic fluid 20 medium is at least one selected from the group consisting of toluene, xylene, benzene, cumene, and mesitylene. In an exemplary embodiment, the first and the second organic fluid media are toluene.

The method of the present disclosure does not make use of diethyl ether which is a known hazardous substance. Instead, it makes use of commercially available 25 known organic fluid media like toluene, xylene, benzene, cumene, and mesitylene which are not as hazardous as diethyl ether. 5 2016101825 18 Oct 2016

The purity of 3-nitrophthalic anhydride prepared by the method of the present disclosure is in the range of 90% to 99.99%.

The present disclosure is further described in the light of the following laboratory experiments which are set forth for illustration purpose only and not to be construed 5 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.

EXPERIMENTS

Experiment 1 10 A 1 litre reactor was charged with 196 g of Propionic anhydride (1.5 mole) and 211 g of 3-Nitrophthalic acid (1.0 mole) while maintaining the content of the reactor at 30° C to obtain a first mixture. The first mixture is then heated to 150° C and heating was continued for a time period of 6 hours to obtain a resultant. The resultant was then cooled to a temperature of 130° C to obtain a cooled resultant, 15 and 200 ml of toluene was slowly added to the cooled resultant to obtain a second mixture. After the complete addition of toluene, the second mixture was further cooled to 30° C to obtain a cooled second mixture and a product comprising 3-nitrophthalic anhydride was isolated in the form of a wet cake by filtration from the cooled second mixture. The wet cake, so obtained, was washed with toluene 20 and dried to get 169.84 g of 3-nitrophthalic anhydride. The yield of 3-nitrophthalic anhydride was 88%. The purity of the 3-nitrophthalic anhydride isolated from the cooled second mixture was 99.65%.

Experiment 2 A 1 litre reactor was charged with 170 g of Propionic anhydride (1.3 mole) and 25 211 g of 3-Nitrophthalic acid (1.0 mole) while maintaining the content of the reactor at 30° C to obtain a first mixture. The first mixture is then heated to 150° C and heating was continued for a time period of 8 hours to obtain a resultant. The 6 2016101825 18 Oct 2016 resultant was then cooled to a temperature of 125° C to obtain a cooled resultant, and 200 ml of toluene was slowly added to the cooled resultant to obtain a second mixture. After the complete addition of toluene, the second mixture was further cooled to 30° C to obtain a cooled second mixture and a product comprising 3-5 nitrophthalic anhydride was isolated in the form of a wet cake by filtration from the cooled second mixture. The wet cake, so obtained, was washed with toluene and dried to get 168.87 g of 3-nitrophthalic anhydride. The yield of 3-nitrophthalic anhydride was 86.33%. The purity of the 3-nitrophthalic anhydride isolated from the cooled second mixture was 98.16%. 10 Experiment 3 A 1 litre reactor was charged with 238 g of n-butyric anhydride (1.5 mole) and 211 g of 3-Nitrophthalic acid (1.0 mole) while maintaining the content of the reactor at 32° C to obtain a first mixture. The first mixture is then heated to 150° C and heating was continued for a time period of 7 hours to obtain a resultant. The 15 resultant was then cooled to a temperature of 130° C to obtain a cooled resultant, and 200 ml of toluene was slowly added to the cooled resultant to obtain a second mixture. After the complete addition of toluene, the second mixture was further cooled to 32° C to obtain a cooled second mixture and a product comprising 3-nitrophthalic anhydride was isolated in the form of a wet cake by fdtration from 20 the cooled second mixture. The wet cake, so obtained, was washed with toluene and dried to get 165.98 g of 3-nitrophthalic anhydride. The yield of 3-nitrophthalic anhydride was 86.81%. The purity of the 3-nitrophthalic anhydride isolated from the cooled second mixture was 96.77%.

Experiment 4 25 A 1 litre reactor was charged with 238 g of isobutyric anhydride (1.5 mole) and 211 g of 3-Nitrophthalic acid (1.0 mole) while maintaining the content of the reactor at 32° C to obtain a first mixture. The first mixture is then heated to 150° C and heating was continued for a time period of 6 hours to obtain a resultant. The 7 2016101825 18 Oct 2016 resultant was then cooled to a temperature of 120° C to obtain a cooled resultant, and 200 ml of toluene was slowly added to the cooled resultant to obtain a second mixture. After the complete addition of toluene, the second mixture was further cooled to 32° C to obtain a cooled second mixture and a product comprising 35 nitrophthalic anhydride was isolated in the form of a wet cake by filtration from the cooled second mixture. The wet cake, so obtained, was washed with toluene and dried to get 164 g of 3-nitrophthalic anhydride. The yield of 3-nitrophthalic anhydride was 87.87%. The purity of the 3-nitrophthalic anhydride isolated from the cooled second mixture was 99.15%. 10 The method of the present disclosure is clearly advantageous over the methods in the state-of-the-art. Unlike acetic anhydride, other anhydrides used in the method of the present disclosure are not ‘controlled substances’ and are not required in as much molar quantities as acetic anhydride for the preparation of 3-nitrophthalic anhydride. The method uses commercially available regular organic fluid media 15 like toluene, benzene and xylene for purification which renders the process economical. Also, the method of the present disclosure involves less steps and is therefore, not laborious.

TECHNICAL ADVANCES AND ECONOMICAL SIGNIFICANCE

The present disclosure described herein above has several technical advantages 20 including, but not limited to, the realization of a method for preparation of 3-nitrophthalic anhydride that: - Provides 3-nitrohphthalic anhydride of high purity; - does not make use of a large excess of ‘controlled substances’ as reactants; and 25 - does not use hazardous organic fluid media.

The foregoing description of the specific embodiments so fully reveals the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments 8 2016101825 18 Oct 2016 without 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 5 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.

Throughout this specification the word “comprise”, or variations such as 10 “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 15 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 20 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. 25 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 9 2016101825 18 Oct 2016 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 5 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 10 be interpreted merely as illustrative of the disclosure and not as a limitation. 10

Claims (5)

1. CLAIM:

   1. A method for preparation of 3-nitrophthalic anhydride, said method comprising the following steps: (a) charging a reactor with 3-nitrophthalic acid (3-NPA) and at least one anhydride selected from the group consisting of propionic anhydride, n-butyric anhydride, isobutyric anhydride and acetic formic anhydride while maintaining the content of the reactor at a temperature in the range of 20° C to 35° C to obtain a first mixture, wherein the molar ratio of 3-nitrophthalic acid and said at least one anhydride is in the range of 1:1.2 to 1:1.8; (b) heating said first mixture at a temperature in the range of 140° C to 170° C for a time period in the range of 4 hours to 10 hours to obtain a resultant; (c) cooling said resultant to a temperature in the range of 110° C to 135° C to obtain a cooled resultant and adding a first organic fluid medium to said cooled resultant to obtain a second mixture; and (d) further cooling said second mixture to a temperature in the range of 20° C to 35° C to obtain cooled second mixture followed by isolating 3-nitrophthalic anhydride from said cooled second mixture.
2. 2. The method as claimed in claim 1, wherein the method step of isolating 3-nitrophthalic anhydride comprises filtering said cooled second mixture to obtain a wet cake, washing said wet cake with a second organic fluid medium to obtain a washed wet cake and drying said washed wet cake.
3. 3. The method as claimed in claim 1, wherein said first organic fluid medium is at least one selected from the group consisting of toluene, xylene, benzene, cumene, and mesitylene.
4. 4. The method as claimed in claim 2, wherein said second organic fluid medium is at least one selected from the group consisting of toluene, xylene, benzene, cumene, and mesitylene.
5. 5. The method as claimed in claim 1, wherein the yield of 3-nitrophthalic anhydride is in the range of 84% to 90% and purity of 3-nitrophthalic anhydride is in the range of 90% to 99.99.