Process for the preparation of highly pure 2-Aminobenzonitrile
APPLICANT:
HERBERT BROWN PHARMACEUTICAL
& RESEARCH LABORATORIES
W-256/257/258A, M.I.D.C. Phase II, Shivaji Udyog Nagar, Dombivli (E)-421203, District - Thane, Maharashtra, India.
Indian company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The current invention relates to a process for the preparation of highly pure 2-aminobenzonitrile of Formula I from anthranilamide of Formula II. 2-Aminobenzonitrile prepared by using the said process has GC purity more than 99.5%.

BACKGROUND OF INVENTION
2-Aminobenzonitrile is a chemical compound with molecular formula C7H6N2 and its chemical structure is shown in Formula 1

The 2-aminobenzonitrile is used in induction of nitrilase activity in anthrobactor & as a radioprotective agent. This compound is valuable as a starting material for chemical synthesis. Thus it may be hydrolyzed to 2-aminobenzamide & to an anthranilic acid, which both are important starting materials in the chemical industry. Moreover it may be catalytically reduced to the corresponding benzylamine.

Several methods are reported in the literature for the preparation of 2-aminobenzonitrile:
United State Patent 365029 discloses the production of o-aminobenzonitrile by thermal decomposition of isatin p-oximes in the presence of basic compounds. The new products are starting materials in the presence of basic compounds. The new products are starting materials for the production of dyes and pesticides which includes nanoethylene glycol, sodium methylate and isatine p- oxime are heated to 150° to 60°C. While stirring after evolution of carbon dioxide has begun, isatin B-oxime is introduced at 140-150°C. When the evolution of carbon dioxide has ceased, the o-aminobenzonitrile formed is distilled off from the reaction mixture. Pure o-aminobenzonitrile is obtained having boiling point of 135°C to 139°C and freezing pointoffrom 48° to 50°C
United State Patent 3739009 discloses the manufacture of aromatic o-aminonitrile by reaction of aromatic o-aminocarboxamide with dehydrating agents. Aromatic o-aminonitriles are intermediates in the manufacture of dyes. Which includes, 272 parts of anthranilamide reacted with 450 parts of phosphorous pentachloride in 1200 parts by volume of ethylene chloride at 25-30°, after 1 hour mixture hydrolyzed with 2000 parts of water, stirred for 2 hour at room temperature. Then adjusted pH to 7 followed by separation of organic phase and solvent distilled of. The residue is distilled in vacuo to give 193 parts of 2 ABN having % yield 81.5%
United State Patent 3783142 provides a method of preparation of o-aminobenzonitrile from o-nitrotoluene by heating the latter with ammonia at about 350-550°C, in the presence of dehydrating catalyst.


United State Patent 4178304 provides a method of producing o-aminobenzonitrile, according to which o-toluidine is reacted with ammonia at a temperature of 360-460°C. In the presence of oxygen, or a mixture thereof with inert gases, & as catalyst, namely a mixture of oxides of antimony, bismuth, vanadium, & phosphorous taken in weight ratio 5-12: 3-9: 1-9: 5-4 respectively, the catalyst being applied to support. The invention ensures an increase in the yield of o-aminobenzonitrile per unit volume of catalyst & selectivity with respect to the final product.
United State Patent 3374262A: It is known that o-aminobenzonitriles are obtained in the thermal decomposition of isatin-p- oximes at atmospheric pressure. Since in order to obtain yields which to some extent are satisfactory it is necessary to react only small amounts of isatin p-oximes, however, this method is unsuitable for operation on an industrial scale.
United States Patent 4137254: Aromatic nitriles are prepared from methylated aromatic hydrocarbons, such as toluene, xylene, tri- and tetramethylbenzenes by contacting at an elevated temperature with a nitroaromatic compound and ammonia in the presence of a catalyst composed of two or more metal oxides of the metals of Groups I B, III B, V A, VI B, VII B and VIII of the Periodic Table. A valuable coproduct of the method is an aromatic amine.
Literature processes suffers from drawbacks, which are listed below:

i) Catalyst and reagents used are expensive and commercially not available
ii) Reactions are carried out at high temperature (>300°C)
iii) Product is isolated mainly by distillation of crude oily mass at high temperature and under high vacuum
The drawbacks associated with the prior art are addressed by the present invention wherein a cost effective, operationally simple and environment friendly process for preparation of highly pure 2-aminobenzonitrile is provided.
The literature processes requires high energy and more time cycle, uses expensive catalyst and reagents and involves tedious isolation process. Therefore there is need for developing alternative process for preparation of 2-aminobenzonitrile, avoiding use of high energy, tedious unit operations and large time cycle for purification, which will allow industrial preparation of 2-aminobenzonitrile in a simplified and economic manner.
OBJECT OF INVENTION
1. An object of the invention is to provide a process for the preparation of highly pure 2-aminobenzonitrile.
2. Another object of the present invention is to provide a 2-aminobenzonitrile having GC purity more than 99.5% with single maximum impurity <0.2%.
3. Yet another object of the present invention is to provide a novel process for preparation of 2-aminobenzonitrile by using single organic solvent for the reaction and isolation of crude 2-aminobenzonitrile.
4. Another object of the present invention is to provide a novel process for preparation of 2-aminobenzonitrile, wherein the solvent used in the process is recovered and reused.

5. Another object of present invention is to provide a process for the preparation of 2-aminobenzonitrile, avoiding tedious isolation and purification process.
6. Yet another object of the present invention is to provide a simple, industrially feasible, environment safe and economical process for preparation of 2-aminobenzonitrile
SUMMARY OF THE INVENTION
According to an aspects of the present invention, there is provided a process for the preparation of highly pure 2-aminobenzonitrile of Formula I, from anthranilamide of Formula II

comprising,
a) reacting anthranilamide with phosphorous pentachloride in a polar organic solvent at 25-30°C to form 2-aminobenzonitrile of formula I
b) quenching the reaction mass in to a ice-cold water followed by separation of organic & aqueous layer at acidic pH (pH range 0 to 2)
c) extracting the aqueous layer with polar organic solvent at acidic pH (pH
range 0 to 2)
d) washing the combined organic layer with water
e) subjecting the organic layer obtained in a step (d) to charcolisation followed

by concentration to obtain a gummy mass of 2-aminobenzonitrile of Formula I having GC purity >99% f) finally purifying the gummy mass from step e) in a non polar organic solvent to obtain pure 2-aminobenzonitrile with GC purity >99.5%
DETAILED DESCRIPTION OF INVENTION
The present invention relates to a process for the preparation of highly pure 2-aminobenzonitrile of Formula I, from anthranilamide of Formula II

comprising,
a) reacting anthranilamide with phosphorous pentachloride in a polar organic solvent at 25-30°C to form 2-aminobenzonitrile of formula I
b) quenching the reaction mass in to a ice cold water followed by separation of organic & aqueous layer at acidic pH (pH range 0 to 2)
c) extracting the aqueous layer with polar organic solvent at acidic pH (pH range 0 to 2)
d) washing the combined organic layer with water
e) subjecting the organic layer obtained in a step (d) to charcolisation followed by concentration to obtain a gummy mass of 2-aminobenzonitrile of Formula I having GC purity >99%
f) finally purifying the gummy mass from step e) in a non polar organic solvent to obtain pure 2-aminobenzonitrile with GC purity >99.5%

The process for the preparation of highly pure 2-aminobenzonitrile is depicted in the Scheme I

According to an embodiment of the present invention, the amount of phosphorous pentachloride used in step a) with respect to anthranilamide is in the range of the 1.0 to 2.0 moles equivalent; preferably 1.1 mole equivalent is used.
It was observed by inventors of present invention that addition of anthranilamide in a solution of phosphorous pentachloride in organic solvent makes process easier for scale up and gives 2-aminobenzonitrile with good yield and high purity.
Phosphorous pentachloride slurry can be prepared by just adding phosphorous pentachloride in to organic solvent at room temperature.
Organic solvents used for the reaction in step a) are polar organic solvents like, dichloromethane, chloroform, etc. preferably chloroform is used.

The total amount of organic solvent used in step a) to c) for reaction & workup with respect to anthranilamide is in the range of 10-15 volumes, preferably 13 volumes are used.
Total amount of water used for quenching of reaction mixture is in the range of 8-12 volumes, preferably 10 volumes are used.
The inventors of present invention found that after quenching the reaction mass in ice cold water, when the 2-aminobenzonitrile is extracted in a polar organic solvent such as chloroform at acidic pH (pH range 0 to 2), which gives less impurities in the final product. Whereas, when the 2-aminobenzonitrile is extracted in a polar organic solvent such as chloroform at pH range 6 to 8, gives more impurities in the final product.
It was also observed that by using chloroform as a solvent gives good yield of 2-aminobenzonitrile with GC purity more than 99.5%.
The inventors of present invention have developed a process for preparing 2-aminobenzonitrile using chloroform as a solvent for the reaction and for extraction, as it gives better yield compared to other commonly known organic solvents.
Chloroform layer containing 2-aminobenzonitrile was subjected to charcolisation to improve the color and then it was concentrated under vacuum to obtain a crude 2-aminobenzonitrile with GC purity >99%.
As reported the 2-aminobenzonitrile has low melting point (45-48°C) and hence it was treated with non polar hydrocarbon solvents such as hexane or cyclohexane at 40-60°C, which after cooling gave solid 2-aminobenzonitrile product.

The GC purity of the purified 2-aminobenzonitrile is determined by using following parameters:
Column : RTX-5
Column temperature : 150°C-4minutehold
15°C to 250°-9minutehold
Flow rate : 2.0 ml
Mobile phase : N2 gas
Injection volume : l.Oμl
Run time : 19.67min
Detector : Flame Ionization Detector
Temperature of injector : 290°C
Detector : 300°C
The detail description of the invention is provided in following examples is given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1:
To the stirred solution of 336.3g phosphorous pentachloride in 1400 ml chloroform was slowly added 200gm of anthranilamide at 25-30°C. The reaction mixture was maintained at 25-30°C for 2 to 3 hours. The progress of the reaction was monitored using Gas Chromatography. After completion of reaction, it was quenched in to 2000ml ice cold water, stirred for 1 hour and then separated the layers. Aqueous layer

back extracted with 1200ml of chloroform. The combined chloroform layer washed with 500 ml of water and subjected to charcolisation followed by concentration under vacuum at 50-60°C to get oily mass (GC purity >99%). The crude gummy mass was then treated with 300ml hexane at 40-60°C for 1-2 hours and then gradually cooled to 10-15°C. Pure 2-aminobenzonitrile crystallized out was filtered, washed with hexane and dried under vacuum. (Weight: 117 gm; GC Purity: 99.96%)
1H NMR in DMSO (chemical shift in δppm): 7.37-7.33 (d, 1H, Ar-H), 7.30-7.26 (m, 1H, Ar-H), 6.78-6.76 (d, 1H, Ar-H), 6.59-6.55 (m, 1H, Ar-H), 6.02 (s, 2H, Ar-NH2)
IR (KBr): 3458.48, 3365.90, 3254.02, 3238.59, 3225.09, 3082.35, 3076.56, 3037.99, 2368.66, 2360.95, 2339.73, 2322.37, 2210.50, 2158.42,1936.60, 1626.05, 1606.76, 1568.18, 1494.88, 1456.30, 1338.64, 1315.50, 1267.27, 1203.62, 1182.40, 1157.33, 1141.90, 1030.02, 974.08, 933.58, 846.78cm"1
Example 2:
To the stirred solution of 168.17g phosphorous pentachloride in 700 ml chloroform was slowly added lOOgm of anthranilamide at 25-30°C. The reaction mixture was maintained at 25-30°C for 2 to 3 hours. The progress of the reaction was monitored using Gas Chromatography. After completion of reaction it was quenched in to 1000ml ice cold water, stirred for 1 hour and then separated the layers. Aqueous layer back extracted with 600ml of chloroform. The combined chloroform layer washed with 250 ml of water and subjected to charcolisation followed by concentration under vacuum at 50-55°C to get oily mass (GC purity >99%). The crude gummy mass was then treated with 150ml cyclohexane at 40-60°C for 1-2 hours and then gradually cooled to 10-15°C. Pure 2-aminobenzonitrile crystallized out was filtered, washed with cyclohexane and dried under vacuum. (Weight: 55 gm; GC Purity: 99.95%)

Example 3:
To the stirred solution of 16.17g phosphorous pentachloride in 70 ml dichloromethane was slowly added l0gm of anthranilamide at 25-30°C. The reaction mixture was maintained at 25-30°C for 2 to 3 hours and then it was monitored using Gas Chromatography. After completion of reaction it was quenched in to. 100ml ice cold water, stirred for 1 hour and then separated the layers. Aqueous layer back extracted with 60ml of dichloromethane. The combined dichloromethane layer washed with 25 ml of water and subjected to charcolisation followed by concentration under vacuum at 50-55°C to get oily mass (GC purity> 99%). The crude gummy mass was then treated with 150ml hexane at 40-60°C for 1-2 hours and then gradually cooled to 10-15°C. Pure 2-aminobenzonitrile crystallized out was filtered, washed with hexane and dried under vacuum. (Weight: 4.6 gm; GC Purity: 99.92%)

We claim
1. A process for the preparation of highly pure 2-aminobenzonitrile of Formula I from anthranilamide of Formula II:

Comprising,
a) reacting anthranilamide of Formula II with phosphorous pentachloride in a polar organic solvent at 25-30°C to form 2-aminobenzonitrile of formula I
b) quenching the reaction mass in to a ice cold water followed by separation of organic & aqueous layer at acidic pH (pH range 0 to 2)
c) extracting the aqueous layer with polar organic solvent at acidic pH (pH range 0 to 2)
d) washing the combined organic layer with water
e) subjecting the organic layer obtained in a step (d) to charcolisation followed by concentration to obtain a gummy mass of 2-aminobenzonitrile of Formula I having GC purity >99%
f) finally purifying the gummy mass from step e) in a non polar organic solvent to obtain pure 2-aminobenzonitrile with GC purity >99.5%
2. The process as claimed in claim 1, wherein the 2-aminobenzonitrile obtained has GC purity of more than 99.5%.

3. The process as claimed in claim 1, wherein the amount of phosphorous
pentachloride used with respect to anthranilamide in step a) is in the range of the 1.0
to 2.0 moles equivalent, preferably 1.1 mole equivalent is used.
4. The process as claimed in claim 1, wherein a polar organic solvent used in step a) to c) is selected from halogenated organic solvent like dichloromethane, chloroform, preferably chloroform is used.
5. The process as claimed in claim 1, wherein the total amount of organic solvent used for reaction & workup in step a) to c) is in the range of 10-15 volumes, preferably 13 volumes are used.
6. The process as claimed in claim 1, wherein the total amount of water used for quenching of reaction mixture is in the range of 8-12 volumes, preferably 10 volumes are used.
7. The process as claimed in claim 1, wherein the chloroform layer from quenched reaction mixture in step b) is separated at acidic pH (pH range 0 to 2) and acidic aqueous layer back extracted with chloroform.
8. The process as claimed in claim 1, wherein the organic solvent used for final isolation is selected from non polar organic solvents like hexane and cyclohexane.