DESC:FIELD OF INVENTION
The present invention generally relates to chemical process. In particular it pertains to a novel and commercially viable process for preparation of Diatrizoic acid and its intermediates.

BACKGROUND OF THE INVENTION
Diatrizoic acid (Diatrizoate) (1) is an organic, iodinated radiopaque X-ray contrast medium used in diagnostic radiography. It is chemically 3-5-diacetylamido-2, 4, 6-triiodobenzoic acid. It is generally formulated as sterile, aqueous solution of diatrizoate meglumine and diatrizoate sodium. It is used for gastrointestinal studies, angiography and urography. It is also used as a density gradient reagent for blood cell separation. It is generally prepared from 3, 5-diamidobenzoic acid through iodization and acetylation.

Several methods have been disclosed for the synthesis of Diatrizoic Acid. In 1896, Liitgens (Chem.Ber., 29, 2835) first prepared the intermediate 3,5-diamino-2,4,6-triiodobenzoic acid by iodinating 3,5-diaminobenzoic acid. But 3, 5-diamino-2,4,6-triiodobenzoic acid is a unstable compound and was found to be unsuitable as X-ray contrast agent.

Larsen et al (Am. Soc. 78, 1956, Norwegian Patent No. 87,963) discloses a process of acetylation of 3, 5-diamino-2,4,6-triiodobenzoic acid which yields 3,5-diacetamido-2,4,6-triiodobenzoic acid that is more stable than 3,5-diamino-2,4,6-triiodobenzoic acid. In this method for the production of 3, 5-diacetamido-2,4,6-triiodobenzoic acid in which 3,5-dinitrobenzoic acid is reduced to 3,5-diaminobenzoic acid, further iodinated to 3,5-diamino-2,4,6-triiodobenzoic acid. Iodinated compound formed is acetylated to form 3,5-diacetamido-2,4,6-triiodobenzoic acid, which on neutralization with sodium hydroxide gives the water-soluble salt, sodium 3,5-diacetamido- 2,4,6-triiodobenzoate.
Although, the both process (Litigens: 1896, Larsen et al: 1956) appears to be convenient; these process are disadvantageous because of certain inherent problems. These processes discloses that
1) Reduction of dinitrobenzoic acid can be either performed by (a) Hydrogenation in the presence of a noble metal catalyst (platinum) under pressure of an aqueous solution of the sodium salt, prepared by boiling with Raney nickel; or (b) Heating with ammonium sulphide (exothermic reaction). In the hydrogenation, hydrogenation equipment is needed, and in heating, there is requirement of large quantities of ammonium sulphide. Moreover, repeated purification operations are required to obtain the desired diamino acid with sufficient purity for the subsequent iodination to form diaminotriiodo benzoic acid.
2) The iodination of diaminobenzoic acid to the diaminotriiodo acid was carried out in 1896 by Liitgens who iodinated in alkaline solution. The unstable diaminotriiodo benzoic acid is obtained in poor yield and purity. Further, iodination in carried out in acid medium, e.g. with iodine monochloride or potassium iododichloride to overcome the difficulties but this process is difficult to control, and again afford the desired diamino triiodo benzoic acid in varying yields, purity and stability. Furthermore, the product obtained is not stable during storage.
(3) Acetylation of the sensitive diaminotriiodic acid is carried out under drastic conditions by heating with an acetyl halide (acetyl chloride) or with acetic anhydride in the presence or absence of strong acids (perchloric acid or sulphuric acid) as catalysts which leads to formation of undesired side products.

US Pat. No. 3,076,024 discloses the reduction of 3,5-dinitro benzoic acid in presence of ammonium sulphide which is generated in situ from ammonium hydroxide and hydrogen sulphide. After reduction of a nitro group, subsequent acetylation was done with acetic anhydride followed by reduction of second nitro group with Raney nickel. This reaction sequence is not commercially viable as the utilization of hydrogen sulphide gas is avoided now a days in industry due to environmental and green chemistry concerns. Moreover, ammonium sulphide is not sufficient to reduce the second nitro group in the molecule and utilization of Raney Nickel for further reduction of second nitro group (Scheme-1) is necessitated which leads to further disadvantages. However, this patent also discloses another reduction procedure in which combination of Platinum and Raney Nickel was used for complete reduction of both nitro groups. Both the reduction steps disclosed in this patent are not useful on commercial scale operations due to high cost and double operations.

US Pat. No. 3, 128,301 and US Pat. No. 3,476, 802 describes the advantages over the above mentioned processes by use of esters of substituted benzoic acids in place of the free acids and finally converting the ester group to a carboxyl group. This method has disadvantage as the final saponification reaction in the presence of alkali inevitably facilitates the deacetylation of one of or both acetamide groups and leads to impurities in the product. Furthermore, these impurities can only be removed with chromatography or fractional crystallizations.

Additional problems occur with iodination of some 3,5-diamino-benzoic acid derivatives as the first two iodine atoms may be introduced without difficulty, but introduction of third iodine atom is difficult and therefore a substantial proportion of the diiodo compounds so produced tends to remain as a contaminant impurity in the desired triiodo product. Consequently the yield and purity of triiodo product is undesirably low.

British Pat. No. 990,757 describes a process for triiodination of 3-acetamido-5-aminobenzoic acid in which the diiodo compound is prepared initially and subsequently iodinated to introduce third iodine atom under special conditions. This process has been found to be efficient and provided only 10% diiodo material as contaminant in final product but it is extremely difficult to remove the contaminants economically.

In recent times, Chinese Pat. No. CN103497120 discloses the solid phase synthesis of Diatrizoic acid in which all the synthetic steps are performed on the surface of hydroxymethyl resin. This procedure is not commercially viable as the usage of resins with hydrophobic nature of triiodo diamino molecule is very difficult and also removal of resins out of the product is a difficult task which needs repeated purifications to get desired product purity.

The above conventional diaztrizoate synthesis processes are complex and difficult to remove residual impurities in the finished product. In order to overcome the shortcomings in the prior art, there is a need of improved process for synthesis of the Diatrizoic Acid having simple process, easy purification, and low impurities content in final product.

OBJECTIVE OF THE INVENTION
An object of the present invention is to provide a novel and an industrial scale process for the preparation of Diatrizoic Acid of formula (1) and its intermediates.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of formula (I), which comprises the steps of:
i) nitration of benzoic acid (2) to obtain 3, 5-dinitro benzoic acid(2-A);
ii) reduction of 3, 5-dinitro benzoic acid (2-A) to obtain 3, 5-diamino benzoic acid (3);
iii) iodination of 3, 5-diamino benzoic acid (3) to obtain 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4);
iv) N-acetylation of 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4) to obtain 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (1);
v) Purification of 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (1).
The present invention includes within its scope, the compounds formed as part of the process, being:
1) 3, 5-diamino benzoic acid (Compound-3).
2) 3, 5-diamino-2, 4, 6-triiodobenzoic acid (Compound-4).
3) 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (compound-1), Diatrizoic Acid (1) with a very high purity of more than 99.6%.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of a Diatrizoic Acid and its intermediates thereof having formula 1.

A preferred embodiment is illustrated in Scheme-2 below.

The present invention relates to a novel process for the preparation of Diatrizoic Acid (1) and its intermediates.
The process of the present invention comprises:
i) nitration of benzoic acid (2) to obtain 3, 5-dinitro benzoic acid(2-A);
ii) reduction of 3, 5-dinitro benzoic acid (2-A) to obtain 3, 5-diamino benzoic acid (3);
iii) iodination of 3, 5-diamino benzoic acid (3) to obtain 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4);
iv) N-acetylation of 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4) to obtain 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (1);
v) Purification of 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (1).
The process of the present invention is described herein below in detail. The description is an embodiment of the present invention and may not be construed to limit the invention in any manner.

The various steps of the process of the present invention may be set out as below:
i. nitration of benzoic acid (2) to obtain 3, 5-dinitro benzoic acid(2-A);
The nitration of benzoic acid (2) may be conducted with any nitration mixtures suitably the nitration reaction may be conducted by using nitric Acid and sulphuric acid mixture. The nitration may be conducted by nitrating agent selected from the group comprising sulphuric acid and nitric acid, sulphuric acid and fuming nitric acid, only fuming nitric acid, oleum and nitric acid, or oleum and fuming nitric acid combinations. Preferably the nitrating agent is fuming nitric acid along with sulphuric acid. The addition of fuming nitric acid may be completed in a period of 80-150 minutes, preferably 90-120 min. The temperature of the reaction may be in the range of 40-100°C, preferably 60-90°C. The temperature may be held constant or may be increased in a phased manner. The reaction may be completed in a period of 20-40 hours. The 3, 5-dinitro benzoic acid of the present invention may be obtained as a solid.

ii. reduction of 3, 5-dinitro benzoic acid (2-A) to obtain 3, 5-diamino benzoic acid (3);
The reduction of the dinitro group of the 3, 5-dinitro benzoic acid (2-A) to convert the dinitro group to the diamino group may be conducted by reducing agents. The conversion may be conducted by reducing agents selected from the group comprising Iron metal and acetic acid, Iron metal and hydrochloric acid mixture, Iron metal and formic acid mixtures, preferably the reducing agent is Iron metal and acetic acid mixture. The reaction may comprise of a suitable catalyst. The catalyst may be selected from the group comprising Sulphuric acid, Oleum Trifluoro acetic acid, preferably the catalyst is Trifluoro acetic acid. The reaction may be conducted at a temperature in the range of 80-100°C, preferably in the range of 80-85°C. The reaction may be completed in a time period of 1-6 hours, preferably 2-4 hours. The pH of the reaction may be in the range of 1-3 preferably less than 2.

iii. iodination of 3, 5-diamino benzoic acid (3) to obtain 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4);
The 3, 5-diamino benzoic acid (3) is iodinated to form 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4). The iodination may be conducted by iodinating agent selected from the group comprising HICl2, NaICl2, KICl2, or ICl, preferably, the iodinating agent is NaICl2. The addition of NaICl2 may be completed in a time period of 1-4 hours, preferably 3 hours. The reaction may be conducted at a temperature range of 40-70°C, preferably in the range of 50-55°C. The reaction may be completed in 20-30 hours.

iv. N-acetylation of 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4) to obtain 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (1);
The N-acetylation of diamino group of 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4) to convert diamino to diacetamido group may be conducted by acetylating reagents. The acetylating reagent may be selected from group comprising acetic anhydride, acetic chloride, Sulphuric acid and acetic anhydride, acetic acid with oleum and trifluoro acetic acid and acetic acid most preferably acetic anhydride, acetic acid and trifluoro acetic acid mixture. The reaction may be conducted at a temperature range of 60-90°C, preferably in the range of 50-55°C. The reaction may be completed in a time period of 1-3 hours, preferably 2 hours.

v. Purification of 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (1);
The pure 3, 5-diacetamido-2, 4, 6-triiodobenzoic acid was obtained from crude 3, 5-diacetamido-2, 4, 6-triiodobenzoic acid. The purification may be performed in a combination of polar and non polar solvent selected from group comprising acetonitrile:water, ethanol:water, methanol:water, DMA:water, DMF:water, 2-ethoxyethanol:water, t-butanol:water preferably methanol:water, preferably in ratio of 4:10, 3:10, 5:10 more preferably 4:10. The purification may be conducted at a temperature range of 30-50°C, preferably in the range of 35-45°C. The purification may be completed in a time period of 2-6 hours, preferably 3-4 hours.
The present invention includes within its scope, the compounds formed as part of the process, being:
1) 3, 5-diamino benzoic acid (Compound-3).
2) 3, 5-diamino-2, 4, 6-triiodobenzoic acid (Compound-4).
3) 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (Compound-1), DiatrizoicAcid (1) with a very high purity of more than 99.6%.
Without being limited by the theory, the process of the present invention provides a novel and efficient process for the preparation of Diatrizoic Acid and its derivatives of formula 1. The process of the present invention involves the use of Iron and Acetic Acid and Catalyst TFA for reduction of both nitro groups collectively in a single step avoiding the use of metal and heterogeneous catalyst, large quantities of ammonium sulphide or mixture of both due to double operation, environmental and green chemistry which makes them unfavorable for commercial scale up. The process of the present invention also avoids the use of chromatography, fractional crystallizations and resins for purification makes process simple, user friendly and economical for commercial scale up. The process of the present invention involves purification of each intermediates synthesized and avoid the carried over impurities to get DiatrizoicAcid and its intermediates with high purity of 99.68%.

The following examples illustrate the process of the invention, without limitation. The examples are an embodiment of the present invention and may not be construed to limit the process of the present invention in my manner.

Example 1: Preparation of Diatrizoic Acid (1)

Step - I Preparation of 3, 5-dinitrobenzoic Acid (2-A):

A suitable reaction vessel was charged with 1151 gm (11.74 mol) of sulfuric acid and 250 gm of benzoic acid (2.049 mol) (2) and mixed well for 1 hr at 25-30°C. Then the reaction mass was allowed to cool to 5-10°C, at this temperature, added 189 gm (3.00 mol) of fuming nitric acid slowly over about 90-120 min. During the addition, the temperature observed to be increased to 40-45°C and held constant. Then slowly raised the temperature to 60-65°C and maintained at this temperature for 3 hrs. After that, the reaction mass temperature maintained at 80°C-85°C by gentle heating and stirred for 24h. After completion of the reaction by HPLC, (SM <1%) the reaction mass was allowed to RT and charged in to ice cold water and stirred for 60 minutes at 5-10°C. The solid resulted was isolated by filtration and washed with chilled water and dried. Yield: (391.0 gm) 90.0% HPLC purity 99.87%. (M+H) 213.23, IR (KBr): 3500 cm¯1, 1720 cm¯1, 1360-1290cm¯1, HI-NMR: (300 MHz, DMSO-d6) d 12.8 (s, 1H), 7.8 (s, 1H), 8.2 (s,2H), 13C-NMR (300 MHz-DMSO-d6): 168.1, 148.3, 135.2 133.4, 127.1.

Step -II Preparation of 3,5-diaminobenzoic acid (3):

A suitable reaction vessel was charged with 500 mL of DM Water, 250.0 gm (1.179 mol) of Compound (2-A), 1308 gm (21.8 mol) of acetic acid, 325.0 gm (5.895 mol) of iron and trifluro acetic acid (0.0001 mol) and mixed well. Slowly the reaction mass temperature was raised to 80-850C, stirred for about 3 hours and reaction vessel charged trifluro acetic acid (0.0001 mol), stirred for about 3 hours. After completion of the reaction, it was allowed to RT, filtered off, collected the liquid out and set the pH less than 2. Then it was stirred for 1 hour at 5-100C. The solid was isolated by filtration, washed with DM water and dried 3. Yield (170.0 gm) 95.0% with 97.8% of HPLC purity. (M+H) 153.5, IR (KBr): 3500 cm¯1, 3020 cm¯1, 1715cm¯1; HI-NMR: (300 MHz, DMSO-d6) d 12.8 (s, 1H), 7.8 (s, 1H), 7.56 (s, 2H), 13C-NMR (300 MHz-DMSO-d6); 167.4, 149.6. 134.3, 118.1, 117.4.

Step - III Preparation of 3,5-diamino-2,4,6-triiodobenzoic acid (4):

A suitable vessel was charged with 8250 mL of DM water, 250.0 gm (1.64 mol) of (3) and mixed well. The temperature of the reaction mass was raised to 50-55°C, and then the reaction vessel was allowed by slow addition of 1126 gm (5.0 mol) of 5.0 M NaICl2 solution about 3 hrs and stirred for about 24 h. When the reaction was completed by HPLC (SM<1%), it was allowed at RT and cooled to 0-5°C. The solid was isolated by filtration, washed with DM water and dried. Yield: (653.8 gm) 75.0% with 98.0 % of HPLC purity. (M+H) 531.84; IR (KBr): 3500 cm¯1, 3020 cm¯1; HI-NMR :( 300 MHz, DMSO-d6) d 12.8(s, 1H), 7.23 (s, 4H). 13C-NMR (300 MHz-DMSO-d6): 167.2, 139.2, 135.3, 97.3, 91.4.

Step -IV Preparation of 3,5-diacetamido-2,4,6-triiodo benzoic Acid (1):

A suitable vessel was charged with 500 mL of acetic anhydride, 262.5 gm of Acetic acid (4.375 mol) and 2.5 g of Trifluro acetic Acid at RT. The temperature of reaction mass was raised to 450C and stirred for 20 minutes at same temperature. After reaction mass temperature cool to 200C and charged 250 gm of (4), heat to 800C and maintained the reaction mass temperature at same temperature for 2 hours. Reaction mass was allowed to cool at 5-10°C and quenched by water and stirred for about 60 minutes at 5 to 10°C. Then the reaction mass was filtered to get (1), Yield: (260 g) 90 % with 99.20% of HPLC purity. (M+H) 596.9; IR (KBr): 3500 cm¯1, 3020 cm¯1, 1725cm¯1, 1705cm¯1; HI-NMR: (300 MHz, DMSO-d6) d, 12.8 (s 1H) 7.38 (s, 2H); 2.1 (s 6H); 13C-NMR (300 MHz-DMSO-d6) 172.5, 167.3, 148.3, 136.3, 95.2, 86.2, 25.3.

Purification of 3, 5-diacetamido-2,4,6-triiodo benzoic Acid:
The crude product was added to Acetonitrile: Water or Ethanol/Water or Methanol/Water or DMA/Water, DMF/Water or 2-ethoxy ethanol/Water or t-butanol/Water (3:9) and stirred about 3 to 4 h at 35-45°C, finally the reaction mass was filtered off and collected the solid of desired pure compound (1). Yield: (248.0 gm) 95.0% with 99.68%.

Example 2: Comparison of the process of the present invention again prior art processes
The process of the present invention is advantageous over other processes listed in the prior art. Comparison of the process of the present invention over other processes of prior art are listed herein below at Table 1:

Table 1: Comparison of the process of the present invention over the processes of prior art.
S.No. Prior
Art Conditions Yield
(%) Conclusion
1. US 3,476,802
US 3,128,301 This patent discloses the procedure for the preparation of Diatrizoic Acid starting with 3,5-dinitro benzoic acid esters followed by iodination of benzoic acid and reduction of nitro groups with metals. The final step of de esterification results the desired molecule. Not given The reduction conditions which mentioned in the patents end up with partial reduction of nitro groups only which leads to potential impurities in the final molecule. Moreover, the de esterifcation in the final stage with base to make free acid is not a commercially viable process because de-esterification conditions essentially remove one or both of acetyl groups attached to amine groups in the molecule which ultimately makes process not viable in commercial batches.
2. US 3,076,024 This patent disclosed only reduction of nitro group with ammonium sulphide which is in situ generated from ammonium hydroxide and hydrogen sulphide during the reaction. Further Raney nickel adds to reaction for second nitro group reduction in benzoic acid moiety to make key intermediate in the process. 45% This patent reveals the reduction conditions using ammonium sulphide but its only reduce one nitro group hence another reducing agent Raney nickel was later used. This process is not viable in two reasons i) the ammonium sulphide which generate in situ may not be in good strength as there is no quantification in the reaction but a theoretical assumption and ii) Usage of Raney nickel for reduction makes double the cost due to repeated reductions. Hence, this process is not good for commercialization.
3. CN 10,3497120 This patent describes the process for making Diatrizoic acid. The entire process carried out on hydroxymethyl resins.
56% Though the said patent process shows reasonably good procedure over the previous processes of making Diatrizoic Acid with respect to purity point of view. However, the entire process done on the surface of resins which is very difficult to apply to commercial batches. Moreover, the usage of resins on hydrophobic nature of triiodo diamino molecule is very difficult and also removal of resins out of the main product is a big task which needs repeated purifications to get desired product purity.
4. Process of Present Invention. This process starts with benzoic acid which undergoes exhaustive nitration to give 3,5-dinitrobenzoic acid and the subsequent reduction with Fe/Acetic Acid and catalytic amount of Oleum completely reduce the both the nitro functions in the molecule and give 3,5-diaminobenzoic acid. Then Compound-3 iodinated with HICl2 and converted 3,5-diamino-2,4,6-triiodo benzoic acid and further acetylation in N-methyl piperidone give the Diatrizoic Acid.

89% The process of the present invention found to be environmentally benign and commercially viable for making Diatrizoic Acid. The usage of Fe/AcOH in presence of catalytic amount of Oleum yields complete conversion of nitro groups present in the core molecule. The subsequent acetylation with acetic anhydride in NMP gives excellent yields of Diatrizoic Acid with more than 89% of yields and 99.5% of purity with simple alcohol washings.

,CLAIMS:1. A novel process for the preparation of compound of Formula(1) and its intermediates thereof;

comprising the steps of:
vi) nitration of benzoic acid (2) to obtain 3, 5-dinitro benzoic acid(2-A) in the presence of nitric mixture;

vii) reduction of 3, 5-dinitro benzoic acid (2-A) to obtain 3, 5-diamino benzoic acid (3);

viii) iodination of 3, 5-diamino benzoic acid (3) to obtain 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4);

ix) N-acetylation of 3, 5-diamino-2, 4, 6-triiodobenzoic acid (4) to obtain 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (1);

x) Purification of 3, 5-diacetamido-2, 4, 6-triiodobenzoic Acid (1).

2. The process as claimed in claim 1, wherein the compound of formula (1) is Diatrizoic Acid.

3. The process as claimed in claim 1, wherein the novel compound of formula (2A), formula (3) and formula (4) are


4. The process as claimed in claim 1(i), wherein the nitration reaction of benzoic acid (2) is conducted by addition of fuming nitric acid in a period of 80-150 minutes, preferably 90-120 min and the temperature of the reaction is in the range of 40-100°C, preferably 60-90°C and the reaction is completed in a period of 20-40 hours.

5. The process as claimed in claim 1(ii), wherein the reducing agents is selected from the group comprising Iron metal and acetic acid, Iron metal and hydrochloric acid mixture, Iron metal and formic acid mixtures, preferably Iron metal and acetic acid mixture and optionally, the reaction is conducted in presence of a catalyst selected from the group comprising Sulphuric acid, Oleum Trifluoro acetic acid, preferably the Trifluoro acetic acid.

6. The process as claimed in claim 1(ii), wherein the reaction is conducted at a temperature in the range of 80-100°C, preferably in the range of 80-85°C and reaction is completed in a time period of 1-6 hours, preferably 2-4 hours and the pH of the reaction is in the range of 1-3 preferably less than 2.

7. The process as claimed in claim 1(iii), wherein the iodination is conducted by iodinating agent selected from the group comprising HICl2, NaICl2, KICl2, or ICl, preferably, the iodinating agent is NaICl2 and the addition of NaICl2 is completed in a time period of 1-4 hours, preferably 3 hours.

8. The process as claimed in claim 1(iii), wherein the reaction is conducted at a temperature range of 40-70°C, preferably in the range of 50-55°C. and the reaction is completed in 20-30 hours.

9. The process as claimed in claim 1(iv), wherein the acetylating reagent is selected from group comprising acetic anhydride, acetic chloride, Sulphuric acid and acetic anhydride, acetic acid with oleum and trifluoro acetic acid and acetic acid, preferably acetic anhydride, acetic acid and trifluoro acetic acid mixture.

10. The process as claimed in claim 1(iv), wherein the reaction is conducted at a temperature range of 60-90°C, preferably in the range of 50-55°C. and the reaction is completed in a time period of 1-3 hours, preferably 2 hours.

11. The process as claimed in claim 1(v), wherein the reaction is performed in a combination of polar and non polar solvent selected from group comprising acetonitrile:water, ethanol:water, methanol:water, DMA:water, DMF:water, 2-ethoxyethanol:water, t-butanol:water preferably methanol:water, preferably in ratio of 4:10, 3:10, 5:10, more preferably 4:10. and the reaction is conducted at a temperature range of 30-50°C, preferably in the range of 35-45°C. and the reaction is completed in a time period of 2-6 hours, preferably 3-4 hours.