FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
Process for the preparation of highly pure benzoic anhydride
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 present invention relates to an improved process for the preparation of highly pure benzoic anhydride of Formula 1.

Formula I
More particularly, it relates to an improved process for the preparation of benzoic anhydride of Formula I having HPLC purity of more than 99%.
BACKGROUND OF THE INVENTION
Nucleoside analogues are important class of therapeutic agents. The organic synthesis of nucleoside analogues demands large quantity of highly pure benzoic anhydride of Formula I

Formula I
Several methods are known for preparation of benzoic anhydride of Formula I.
US 1948342 discloses a process for the preparation of benzoic anhydride by reacting benzoic acid with benzoyl chloride at 210-230°C for 2-3 hours.' The residue thus formed is purified by distillation under vacuum to obtain benzoic anhydride.

US4470932 discloses a process for the preparation of benzoic anhydride by reacting trimethylsilyl benzoate with benzoyl fhloride at 120-140°C. The trimethylsilyl chloride formed as a by-product during reaction is simultaneously distilled off to obtain residue of benzoic anhydride.
US4559183 discloses a process for the preparation of benzoic anhydride by reacting phenyl benzoate with iodobenzene in presence of sodium powder in benzene at 175°C under carbon monoxide atmosphere for 10 hours to obtain 36% yield of benzoic anhydride.
Bulletin of Chemical Society of Japan, 6l(l),pg- 247-253, (1988) describes a process for the preparation of benzoic anhydride by treating benzoyl chloride with 1-methyl-2H-pyridiethione in chloroform in presence of water at room temperature followed by addition of 1M sodium hydroxide. The mixture is then extracted with chloroform and the extracts are evaporated. The residue thus formed is chromatographed with chloroform to obtain benzoic anhydride wiith 79% yield.
US5292949 discloses a process for the preparation of benzoic anhydride by reacting benzoyl chloride with acetic anhydride at 110-120°C and simultaneously distilling out acetyl chloride under reduced pressure. After completion of reaction, excessive benzoyl chloride was removed by distillation at about 7 mbar pressure to obtain benzoic anhydride. The purity of benzoic anhydride obtained is not mentioned in the patent. Furthermore, removal of benzoic acid formed as a by-product during the process is not mentioned in the patent.
Furthermore, apart from above discussed references some of the other references related to process for the preparation of benzoic anhydride are WO2001028969, US4874558, US4562010, US2476859, GB280373, DE1932303, DE1067815,

DE520153, DE3037301, JP4553077, JP001149748, JP60052742, CN1178139, Tetrahedron 44(9), Pg. 2471-2476, (1988), Journal of Organic Chemistry 57(7), Pg. 1991-1995, (1992), Tetrahedron Letters 33(5), Pg. 593-594, (1992), Synthetic Communications 24(22), 3261-3268, (1994), Synthetic Communications 32(1), Pg. 23-30, (2002), Synthetic Communications 34(18), Pg. 3349-3358, (2004), Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 44B(2), Pg. 420-421, (2005), Synthetic Communications 37(18), Pg. 3219-3223, (2007), Tetrahedron Letters 49(36), Pg. 5322-5323, (2008), Bulletin of Korean Chemical Society, 30(1), Pg. 27-28, (2009) and Organic & Biomolecular Chemistry 10(23), Pg. 4509-4511, (2012).
The benzoic anhydride obtained by all the processes discussed above is required to be purified and refined to meet the purity requirement of users thereof. While the amount of impurity remaining is small, yet the benzoic anhydride obtained is contaminated to an extend that is undesirable in many cases and frequently interferes with its utilization. The benzoic anhydride used in synthesis of nucleoside requires being pure to greater extent and most of the above discussed processes have not mentioned purity of the benzoic anhydride obtained.
The other disadvantages that makes above mentioned process less feasible on commercial scale are as listed below
1. requirement of high temperature for the process
2. use of expensive reagent like trimethylsilyl benzoate, iodobenzene, rhodium
3. tedious reaction conditions
4. low yields
5. use of benzene and chloroform as solvent
6. purification by chromatography

Hence to overcome the above discussed drawbacks and to obtain pure benzoic anhydride, inventors of present invention have developed a simple, industrially feasible and environment friendly process for the preparation of highly pure benzoic anhydride.
OBJECT OF THE INVENTION
1. An object of present invention is to provide an improved process for the preparation of highly pure benzoic anhydride.
2. Another object of the present invention is to provide benzoic anhydride having HPLC purity of more than 99% in high yield.
3. Another object of the present invention is to provide benzoic anhydride substantially free from impurities.
4. Another object of the present invention is to provide an improved process for the preparation of highly pure benzoic anhydride by using single solvent for purification thereby making recovery and reuse of solvent feasible.
5. Yet another object of the present invention is to provide environment friendly, simple, economic and industrially feasible process for the preparation of highly pure benzoic anhydride.

SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided an improved process for preparation of highly pure benzoic anhydride of Formula I

comprising,
a) reacting benzoyl chloride with acetic anhydride at 90-120°C with removal by distillation of acetyl chloride and unreacted benzoyl chloride
b) cooling the reaction mixture to 40-60°C and adding a C6-C9 hydrocarbon
c) cooling the mixture to 0-15°C to crystallize out benzoic anhydride of Formula I having HPLC purity equal to or more than 98%
d) recrystallizing the benzoic anhydride obtained in step c)by using a C6-C9 hydrocarbon as a solvent to obtain benzoic anhydride of Formula 1 having HPLC purity of more than 99%.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of highly pure benzoic anhydride of Formula I

comprising,

a) reacting benzoyl chloride with acetic anhydride at 90-120°C with removal by distillation of acetyl chloride and unreacted benzoyl chloride
b) cooling the reaction mixture to 40-60°C and adding a C6-C9 hydrocarbon
c) cooling the mixture to 0-15°C to crystallize out benzoic anhydride of Formula I having HPLC purity equal to or more than 98%
d) recrystallizing the benzoic anhydride obtained in step c) by using a C6-C9 hydrocarbon as a solvent to obtain benzoic anhydride of Formula I having HPLC purity of more than 99%.
The improved process for the preparation of highly pure benzoic anhydride of Formula I can be depicted in Scheme 1

According to an embodiment of the present invention the molar ratio of acetic anhydride used with respect to benzoyl chloride is in the range of 0.4 to 0.7.
According to an embodiment of present invention, in step a) the acetyl chloride formed as a by-product and unreacted benzoyl chloride is removed by distillation, preferably under reduced pressure.
According to an embodiment of the present invention, the C6-C9 hydrocarbon used in step b) and step d) is selected from cyclic hydrocarbons like cyclohexane or aliphatic

hydrocarbons like hexane, heptane, octane and nonane, preferably n-hexane or n-heptane is used.
It was observed by the inventors of present invention that use of n-hexane or n-heptane in step b) and step d) have advantages listed below
i) it ensures removal of impurities present in traces and improves impurity profile
ii) it can be safely used on industrial scale
iii) it can be recovered with great ease
The amount of C6-C9 hydrocarbon with respect to benzoyl chloride used in step b) or step d) is in the range of 1 to 5 volumes.
According to another embodiment of the present invention, the C6-C9 hydrocarbon used in step b) and step d) can be same or different.
According to yet another embodiment of the present invention, use of single solvent in step b) and step d) makes the process environment friendly and the solvent is recovered and reused.
The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.

EXAMPLES
Example 1: Preparation of benzoic anhydride
To 50gm of benzoyl chloride was added 18.15gm of acetic anhydride and the reaction mixture was heated to 110-120°C for 3 hours. After 3 hours of heating, a mild vacuum was applied to the reaction mass for 2 hours. The temperature of reaction mixture was then reduced to 95-97°C and high vacuum of ~3 mbar was applied to reaction mixture for another 2 hours. As the reaction progresses acetyl chloride formed as by-product and excessive unreacted benzoyl chloride were distilled out. The reaction mixture was cooled to 55-60°C, the vacuum was released and at this temperature 200ml of n-hexane was added. The mixture was then cooled to 0-5°C to crystallize benzoic anhydride; the crystallized benzoic anhydride was filtered, washed with n-hexane and dried at 25-30cC to obtain 31 .Ogm of benzoic anhydride i.e. 77.5% yield with HPLC purity of 99.6%.
Example 2: Preparation of benzoic anhydride
To 50gm of benzoyl chloride was added 19.97gm of acetic anhydride and the reaction mixture was heated to 110-120°C for 3 hours. After 3 hours of heating, a mild vacuum was applied to the reaction mass for 2 hours. The temperature of reaction mixture was then reduced to 95-97°C and high vacuum of ~3 mbar was applied to reaction mixture for another 2 hours. As the reaction progresses acetyl chloride formed as by-product and excessive unreacted benzoyl chloride were distilled out. The reaction mixture was cooled to 55-60°C, the vacuum was released and at this temperature 100ml of n-hexane was added. The mixture was then cooled to 0-5°C to crystallize benzoic anhydride; the crystallized benzoic anhydride was filtered, washed with n-hexane and dried at 25-30°C to obtain 32.2gm of benzoic anhydride i.e. 80.5% yield with HPLC purity of 99.49%.

Example 3: Preparation of benzoic anhydride
To 200gm of benzoyl chloride was added 80gm of acetic anhydride and the reaction mixture was heated to 110-120°C for 5 hours. After 5 hours of heating, a mild vacuum of was applied to the reaction mass for 2 hours. The temperature of reaction mixture was then reduced to 95-97°C and high vacuum of ~3 mbar was applied to reaction mixture for another 2 hours. As the reaction progresses acetyl chloride formed as by-product and excessive unreacted benzoyl chloride were distilled out. The reaction mixture was cooled to 55-60°C, the vacuum was released and at this temperature 600ml of n-heptane was added. The mixture was then cooled to 10-15°C to crystallize benzoic anhydride; the crystallized benzoic anhydride was filtered, washed with n-heptane and dried at 25-30°C to obtain 127gm of benzoic anhydride i.e. 79.37% yield with HPLC purity of 99.55%.
Example 4: Preparation of benzoic anhydride
To lOOgm of benzoyl chloride was added 40gm of acetic anhydride and the reaction mixture was heated to 110-120°C for 7 hours. After 7 hours of heating, a mild vacuum was applied to the reaction mass for 2 hours. The temperature of reaction mixture was then reduced to 95-97°C and high vacuum of ~3 mbar was applied to reaction mixture for another 2 hours. As the reaction progresses acetyl chloride formed as by-product and excessive unreacted benzoyl chloride were distilled out. The reaction mixture was cooled to 45-50°C, the vacuum was released and at this temperature 200ml of n-heptane was added. The mixture was then cooled to 10-15°C to crystallize benzoic anhydride; the crystallized benzoic anhydride was filtered, washed with n-heptane and dried at 25-30°C to obtain 68gm of benzoic anhydride i.e. 85% yield having HPLC purity of 98.81%.

Example 5: Recrystallization of benzoic anhydride obtained in example 2 using n-hexane as solvent
To lOgm of benzoic anhydride obtained by process given in example 2, was added 30ml of n-hexane and the slurry formed was heated to 40-45°C to get clear solution. The clear solution was then cooled to 0-10°C to obtain white crystalline benzoic anhydride which was filtered and dried at 25-30°C to obtain 8.8gm of benzoic anhydride i.e. yield 88% having HPLC purity of 99.55%
Example 6: Recrystallization of benzoic anhydride obtained in example 1 or 2 using n-heptane as solvent
To 62gm of benzoic anhydride obtained by process given in example 1 or 2, was added 124ml of n-heptane and the slurry formed was heated to 40-45°C to get clear solution. The clear solution was then cooled to 10-15°C to obtain white crystalline benzoic anhydride which was filtered and dried at 25-30°C to obtain 58.38gm of benzoic anhydride i.e. yield 94.16% with HPLC purity of 99.76%.
Example 7: Recrystallization of benzoic anhydride obtained in example 3 or 4 using n-heptane as solvent
To 126gm of benzoic anhydride obtained by process given in example 3 or 4, was added 252ml of n-heptane and the slurry formed was heated to 40-45°C to get clear solution. The clear solution was then cooled to 10-15°C to obtain white crystalline benzoic anhydride which was filtered and dried at 25-30°C to obtain 120.5gm of benzoic anhydride i.e. 95.63% yield with HPLC purity of 99.66%.

We claim,
1. An improved process for the preparation of highly pure benzoic anhydride of
Formula I

comprising
a) reacting benzoyl chloride with acetic anhydride at 90-120°C with removal by distillation of acetyl chloride and unreacted benzoyl chloride
b) cooling the reaction mixture to 40-60°C and adding a C6-C9 hydrocarbon
c) cooling the mixture to 0-15°C to crystallize out benzoic anhydride of Formula I having HPLC purity equal to or more than 98%
d) recrystallizing the benzoic anhydride obtained in step c) by using a C6-C9 hydrocarbon as a solvent to obtain benzoic anhydride of Formula I having HPLC purity of more than 99%

2. The process as claimed in claim 1, wherein the molar ratio of acetic anhydride used with respect to benzoyl chloride is in range of 0.4 to 0.7
3. The process as claimed in claim 1, wherein in step a) the acetyl chloride formed as a by-product and excessive unreacted benzoyl chloride is removed by distillation, preferably under reduced pressure
4. The process as claimed in claim 1, wherein the C6-C9 hydrocarbon used in step b) and step d) is selected from cyclic hydrocarbons like cyclohexane or aliphatic hydrocarbons like hexane, heptane, octane and nonane, preferably n-hexane or n-heptane is used

5. The process as claimed in claim 1, wherein amount of C6-C9 hydrocarbon with respect to benzoyl chloride used in step b) or step d) is in the range of 1 to 5 volumes
6. The process as claimed in claim 1, wherein the C6-C9 hydrocarbon used in step b) and step d) can be same or different
7. The process as claimed in claim 1, wherein the use of single solvent in step b) and step d) makes the process environment friendly and the solvent is recovered and reused