Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF THIAZOLIDINE-2, 4-DIONE DERIVATIVES

Abstract A process for the preparation of 5-[4-[[3-Methyl-4-oxo-3,4-dihydro-quinazolin-2- yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1) which comprises: reducing the compound of the formula (2') where R represents a (C1-C4)alky~ group using Raney Nickel or Magnesium in alcohol having 1 to 4 carbon atoms or mixtures thereof, to obtain a compound of formula (3') wherein R is as defined above, hydrolysing the compound of formula (3') wherein R is as defined above, by conventional methods to obtain the acid of the formula (4), .condensing the acid of the fonnula (4) with N-methyl anthranilamide of the fonnula (7) directly without any preactivation of the acid to produce the compound of fonnula (1) and if desired converting the compound of fonnula (I) to phannaceutically acceptable salts thereofby conventional methods.
Full Text

Field of Invention
The present invention relates to an improved process for the preparation of thiazolidine-2,4-dione derivatives. More particularly the present invention relates to an improved process for the preparation of novel 5-[4-[[3-Methyl-4-oxo-3,4-dihydroqmnazolin-2-yI]methoxy]benzyI]thiazolidine-2,4-dione of the formula (1) and pharmaceutically acceptable salts thereof which are useful as antidiabetic compounds. The thiazoIidine-2,4-dione derivative of the formula (1) is particularly useful for the treatment of diabetes type 11 (NIDDM) and related complications.

We have in our copending Indian WTO patent application number 1150/MAS/96 described the synthesis of the novel 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazoiin-2-yl]methoxy]benzyI]thiazolidine-2,4-dione of the formula {!). Compound of the formula (2) on reduction using the expensive catalyst Pd/C.in stoichiometric quantity gives the corresponding saturated compound of the formula (3). The ethyl ester of the formula (3) on hydrolysis using methanol/water/sodiumcarbonate recipe gives the acid of the formula (4) in about 80% yield after a tedious workup sequence involving removal of methanol, then dilution with water, extraction with an organic solvent to remove impurities and then adjustment of pH to precipitate the required acid of the formula (4). The acid of the formula (4) is activated by converting it either to the mixed anhydride of the formula (5) by treating with pivaloyl chloride or the acid chloride of the formula (6) by treating with thionylchloride. Condensation of formula (5) or (6) with N-methyl anthranilamide of the formula (7) gives the amide of the formula (8). Amide of the

fomiula (S) on cyclisation by refluxing in xylcne/acetic acid for -20-30 hours yields about 50% of the cyclised compound of the formula (1). Compound of the formula (I) upon treatment with potassium t-butoxide in methanol gives the corresponding potassium salt of the formula (9). The reaction steps involved in the process are shown in seheme-I


The following are the difficulties encountered during the scaleup trials employing the above said process;
• The step of preparing the compound of the formula (3) requires stoichiometric quantities of Pd/C. Nearly 70 % of the total cost of the product is due to the use of Pd/C which is very expensive. The time required for the completion of the reaction is about 40 hours, which is also very high and further escalates the cost.
• The Hydrolysis of compound of formula (3) to give the acid of the formula (4) by using mcthanol/water/sodiumcarbonate recipe makes the reaction workup more tedious because it involves removal of methanol, then dilution with water, extraction with an organic solvent to remove impurities and then adjustment of pH to precipitate the required acid of the formula (4). In addition, the reaction time is large, i.e. more than 12 hours. Further the yield is also not very good (80 %).
" The activation of the acid of the formula (4) by converting to the mixed anhydride
of the formula (5) involves lots of chemicals such as pivaloyi chloride, trielhylamine and solvents such as dichloromethane which results in messing-up of the reaction mixture. Further more the conversion of the acid of the formula (4) to the acid chloride of the formula (6) involves the use of corrosive reagents like thionyl chloride. Moreover, the reactions are moisture sensitive.
• Because of the large number of chemicals employed in the previous step, the
isolation of the intermediate amide of the formula (8) becomes very complicated
and also results in low yield (50 %) of the amide of the formula (8).

• , The cyclisation of the intermediate amide of the formula (8) results in low
yield(-50%) of the compound of the formula (1) and the reaction time is large (-40 hours).
• The preparation of potassium salt of the formula (9) employing potassium t-
butoxide is not only risky but also expensive thereby making the process non-
economical.
Keeping in view of the above difficulties in the process disclosed in our copending application mentioned above for the preparation of novel 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1), we directed our research towards developing an improved process which would be cost and time effective, as well as simple for scaling-up.
Objective of the Invention
The main objective of the present invention is, therefore, to provide an improved process for the preparation of novel 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]niethoxy]benzyl]thiazolidine-2,4-dione of the formula (I) avoiding the above mentioned difficulties.
Another objective of the present invention is to provide an improved process for the preparation of novel 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy] benzyl]thiazolidinc-2,4-dione of the formula (1) without employing expensive and hazardous chemicals thereby making the process not only economical but also safe.
Yet another objective of the present invention is to provide an improved process for the preparation of novel 5-[4-[[3-Methyl-4-oxo'3,4-dihydroquinazorm-2-yl]methoxy] bcnzyl]thiazolidine-2,4-dione of the formula (1), which involves very simple work-up procedures making the process simple.

We have developed the improved process of the present invention based on our finding that use of Raney-Nickel or magnesium/ methanol as reducing agents to reduce the compound of the formula (2') where R represents a {CrC4)alk:yl group, not only results in the reduction of cost but also affects an efficient reduction. In addition, the compound of formula (3') where R represents a {C|-C4)alkyl group and the compound of formula (4) can also be directly condensed with N-methyl anthranilamide of the formula (7) without preactivation to produce compound of formula (1) which further makes the process simple and economical.
Detailed description of the invention:
Accordingly the present invention provides an improved process for the preparation of novel 5-[4-[[3-MethyI-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]ben2yl] thiazolidine-2,4-dione of the formula (1), which comprises
a) reducing the compound of the formula (2') where R represents a (Ci-C^jalkyl group using reducing agent to obtain a compound of formula (3') in crude form wherein R is as defmed above,
b) purifying the crude compound of formula (3') to obtain pure compound of formula (3') by conventional methods.
c) hydrolysing the compound of formula (3') wherein R is as defmed above, by conventional methods to obtain the acid of the formula (4),
d) condensing the acid of the formula (4) with N-methyl anthranilamide of the formula (7) directly without any preactivation of the acid to produce the compound of formula (1),
e) converting the compound of formula (1) to pharmaceutically acceptable salts thereof by conventional methods, and
f) 'Isolating the pharmaceutically acceptable potassium salt by conventional methods.

According to an embodiment of the present invention, the compound of the formula (3') wherein R is as defined above, obtained in step (a) may also be condensed directly with N-methyl anthranilamide of the formula (7) to obtain the compound of the formula (I). The reaction is shown in Scheme-II below ;

The reduction of the compound of formula (2') wherein R is as defined above using 40-130% (w/v) preferably 100% (w/v) Raney Nickel proceeds to completion in 8 to 70 hours, preferably from 12-24 hours, at 15 °C -70 °C preferably 30 °C -60 °C and at atmospheric pressure to 600 psi, preferably from atmospheric pressure to 400 psi of hydrogen pressure. The crude material is taken in lower alcohol like methanol, ethanol, propanol etc. and precipitated by adding water thereby affording a highly pure compound of the formula (3'), in about 85-90 % overall yield and a purity of about 97-99 %. The reduction using magnesium, (4-12 eq., preferably 8-10 eq.) in alcohol having 1 to 4 carbon atoms or their mixtures at a temperature in the range of 10 °C to 60 °C, preferably at a temperature in the range of 15 °C to 30 °C for about 2-15 hours,

pre/crably from 6-8 hours results in a mixture of the acid of the formula (4) and an ester of the formula (3') where R is as defined above.
After reacting in magnesium/alcohol having I to 4 carbon atoms for 4-15 hours, preferably from 6-8 hours, either water is added and reaction continued to obtain pure compound of formula (4) or sulphuric acid is added till pH is 2 and refluxed for farther 2-15 hours, preferably for 6-8 hours to produce pure ester of the formula (3') where R is as defined above. The inorganic salts precipitate out quantitatively in the form of magnesium sulphate. Hence, no dissolved solids get into the effluent. These esters of the formula (3') upon hydrolysis with aq. sodium hydroxide give the acid of the formula (4) in 97-99 % yield and 95-99 % purity. The reaction time is drastically reduced to only -2 hours as compared to 12 hours required by the process disclosed in our above said Indian copending application. Workup is also extremely simplified involving only pH adjustment to obtain the required acid of the formula (4). The acid of the formula (4) is condensed with N-methyl anthranilamide of the fomiula (7) directly for about 6-20 hours, preferably 10-12 hours without any prc-activation of the acid of the formula (4). The yield is -70 % with a purity of-99 %.
Alternatively, the condensation can also be carried out with the esters of formula (3') where R is as defined above with N-methyl anthranilamide of the formula (7) for a period of 5-30 hours, preferably 6-20 hours albeit in low yield (20 %). However, the yield can be improved to a maximum of 60 % if the reaction time is increased to 40-50 hours. The resulting compound of formula (1) upon treating with methanolic potassium hydroxide gives the corresponding potassium salt of the formula (9) in ~90 % yield in a pharmaceutieally acceptable quality. In a similar manner, other pharmaceutical I y acceptable salts of the formula (1) can be prepared by conventional methods.
The present invention also envisages an improved process for the preparation of compound of formula (2) starting from p-hydroxybenzaldehyde of the formula (10) and alkylhaloacetate of the formula (11). This process comprises

1
a). reacting p-hydroxybenzaldehyde of the formula (10) and alkylhaloacetate of the formula (II) where Hal represents halogen atom like fluorine, chlorine, bromine, iodine and R is as defined earlier in the presence of aromatic hydrocarbon solvents, a base, alkyl or aryl sulphonic acid and iodine to obtain the compound of the formula (12) where R is as defined earlier.
b). condensing the compound of formula (12) where R is as defined earlier with thiazolidine-2,4-dione of the formula (13) using conventional methods to produce a compound of formula (2') defined earlier. The reaction is shown in Scheme-Ill below ;

The reaction may be carried out in the presence of aromatic hydrocarbon solvent such as benzene, toluene, xylene and the like or mixtures thereof. The base such as alkali and alkaline earth metal carbonates and bicarbonates like potassium carbonate, potassium bicarbonate, sodium carbonate, calcium carbonate and the like may be used. The alkyl or ary! sulphonic acid such as methane sulphonic acid, ethane sulphonic acid, propane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid, p-nitro benzene sulphonic acid and the like may be used.
We have observed that the use of iodine activates the halo group present in the compound of formula (11) where Hal represents halogen atom like fluorine, chlorine, bromine and R is as defined earlier while reflux using a Dean-Stark condenser in the presence of alkyl or aryl sulphonic acid helps in enhancing the reacfion rate. The reaction

is complete in 3-10 hours preferably 5-7 hours under these conditions as compared to -18 *hours as described in the prior art. Moreover, the reaction workup is simplified by addition of water to the reaction mixture followed by separation of solvent layer. The solvent layer is used as such for the next step of condensing the compound of formula (12) where R is as defined earlier with thiazolidine-2,4-dione of the formula (13). Since, water is being removed azeotropically, in this step, no drying of the solvent layer is required. This process not only uses a single, safe solvent but also optionally makes the two-stage process of the preparation of the compound of formula (12) where R is as defined earlier in a single pot operafion. The yield and purity of the compound of the formula (12) is also found to be good (80 % and 90 % respectively).
The process for the preparation of compound of formula (2') shown in scheme-Ill has been made the subject matter of our copending application No. 1150/MAS/99
The present invention is described in detail with examples given below which are provided by way of illustrafion only and therefore should not be construed to limit the scope of the invention.
Example-1:
Preparation of 4-frcarboethoxy)metfaoxy)benzaldefavde of formula fl2):
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toulene sulphonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05 M) was added and the reacfion refluxed for 6-S hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the-complefion of the reaction water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was washed with brine and concentrated under vacuum to give 4-((carboethoxy)methoxy)benzaldehyde as an oily material (407 g, Y^96%, P=99%)

4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethyichioroacetate (251 g, 2.05 M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was washed with brine and concentrated under vacuum to give 4-((carboethoxy)methoxy)benzaldehyde as an oily material (395 g, Y=93%, P=99%).
Example-3:
Alternative preparation of 4-«earboethoxy)methoxylbenzaldehyde of formula 02) :
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), xylene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05 M) was added and the reaction was refluxed for 6-S hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of xylene. The combined organic layer was washed with brine and concentrated under vacuum to give 4-((carboethoxy)methoxy)benzaldehyde as an oily material (408 g, Y=97%, P-99%).
Example-4:
Alternative preparation of 4-(rcarboethoxv)methoxv>benzaldehyde of formula (12) :

4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene •(2.5 L), methanesulfonic acid (20 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05 M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was washed with brine and concentrated under vacuum to give 4-((carboethoxy)methoxy)benzaldehyde as an oily material (400 g, Y=94%, P^99%).
Example-5:
Alternative preparation of 4-f(carboethoxv)methQxy)benzaldehvde of formula ^2^:
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 iM), toluene (2.5 L), ethanesulfonic acid (23 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05 M) was added and the reacdon was refluxed for 6-8-hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated v/hile the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was washed with brine and concentrated under vacuum to give 4-((carboethoxy)methoxy)ben2aldehyde as an oily material (395 g, Y=93%, P=99%).
Example-6:
Preparation of 4-f(carbQmetfaoxv)niethoxv)benzaldehvde of formula fl2):
4-Hydroxybenzaidehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toluetiesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken In a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser.

Methylbromoacetate (314 g, 2.05 M) was added and the reaction was refluxed for 6-8 'hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was washed with brine and concentrated under vacuum to give 4-((carbomethoxy)methoxy)benzaldehyde as an oily material (385 g, Y=97%, P=99%).
Exampie-7:
Alternative preparation of 4-f(carbometfaoxv>methoxv)ben2aldehvde of formula n2)
4-HydroxybenzaIdehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toiuenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser, Methyichloroacetate (223 g, 2.05 M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was washed with brine and concentrated under vacuum to give 4-((carbomethoxy)methoxy)benzaldehyde as an oily material (380 g, Y=95%, P=99%). Example-8: Preparation of 5-l4-t(carboethoxv^metboxvlbenzvHdine^thiazolidine-2.4-dione of
formula (21 :
4-((carboethoxy)methoxy)benzaldehyde obtained by following a procedure described in Example 1 (640 g, 3.08 M), thiazolidine-2,4-dione (360 g, 3.08 M), piperidine (45 ml, 0.55 M), benzoic acid (45 g, 0.37 M) and toluene (3 L) were taken in a 5 L 4'neck round bottom flask fitted with a mechanical stirrer and a Dean-Stark condenser. The reaction mixture was refluxed for 6-8 hours, while monitoring the reaction on TLC After the compledon of the reaction, the reaction mass was cooled to 10 °C and the solid thus

obtained was filtered, washed with toluene (2 X 250 ml) and dried at 80 °C for 1-2 hours,
'to afford 5-[4-[(carboethoxy)methoxy]benzylidine]thiazolidine-2,4'dione (790 g, Y=84%, P=98%).
Example-9:
Alternativepreparation of 5-t4-ffcarboetfaQxv)methoxvlbenzyndine)thiazolidine-2,4-dione of formula (2^ :
4-((carboethQxy)methoxy)benzaldehyde obtained by following a procedure described in Example 1 (640 g, 3.08 M), thiazolidine-2,4-dione (360 g, 3.08 M), piperidine (640 g, 3.08 M) (45 ml, 0.55 M), benzoic acid (45 g, 0.37 M) and xylene (3 L) were taken in a 5 L 4 neck round bottom flask fitted with a mechanical stirrer and a Dean-Stark condenser. The reaction mixture was refluxed for 6-8 hours, while monitoring the reaction on TLC. After the complefion of the reaction, the reacfion mass was cooled to 10 'C and the solid thus obtained was fdtered, washed with xylene (2 X 250 ml) and dried at 80 °C for 1-2 hours, to afford 5-[4-[(carboethoxy)methoxy]benzylidine]thiazolidine-2,4-dione (795g, Y-85%, P=98%).
Example-10 :
One pot preparation of 5-14-i(carboethoxy)methoxvlbenzvlidine]thiazolidine-2.4-
dione of formula ( 2);
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toulene sulphonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was

taken in a 5 L 4-neck round bottom flask fitted with a mechanical stirrer and a Dean-Stark condenser. Thiazolidine-2,4-dicne (239 g, 2.05 M), piperidine (30 ml, 0.30 M) and benzoic acid (30 g, 0.20 M) were added and the reaction mixture was refluxed for 6-8 hours, while monitoring the reaction on TLC. After the completion of the reaction, the reaction mass was cooled to 10 °C and the solid thus obtained was filtered, washed with toluene (2 X 250 ml) and dried at 80 °C for 1-2 hours to afford 5-[4-[(carboethoxy)niethoxy]benzylidine]thiazolidine-2,4-dione (473 g ,Y-75%, P-98%).
Example-ll:
Alternative one pot preparation of 5-[4-[fcarboethoxy)metfaoxv!benzvlidine|
thiazolidine-2.4-dione of formula f. 2);
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), xylene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was taken in a 5 L 4 neck round bottom flask fitted with a mechanical stirrer and a Dean-Stark condenser. ThiazoIidine-2,4-dione (234 g, 2.00 M), piperidine (30 ml, 0.30 M) and benzoic acid (30 g, 0.20 M) were added and the reaction mixture was refluxed for 6-8 hours, while monitoring the reaction on TLC. After the completion of the reaction, the reaction mass was cooled to 10 °C and the solid thus obtained was filtered, washed with xylene (2 X 250 ml) and dried at 80 °C for 1-2 hours, to afford 5-[4-[(carboethoxy) methoxy]benzylidine]thiazolidine-2,4-dione (474 g ,Y=75%, P-98%).
Example-12 :
Preparation of 5-[4-[fcarbomethoxv>metfaoxvIbenzvlidinelthiazolidine-2.4-dione of
formula (2):

'4-{(carbomethoxy)methoxy)benzaldehyde obtained by following a procedure described in Example 6 (500 g, 2.58 M), thia2o!idine-2,4-dione (302 g, 2.58 M), piperidine (38 ml, 0.46 M), benzoic acid (38 g, 0.31 M) and toluene (3 L) were taken in a 5 L 4-neck round bottom flask fitted with a mechanical stirrer and a Dean-Stark condenser. The reaction mixture was refluxed for 6-8 hours, while monitoring the reaction on TLC. Atter the completion of the reaction, the reaction mass was cooled to 10 °C and the solid thus obtained was filtered, washed with toluene (2 X 250 ml) and dried at 80 °C for 1-2 hours,
to afford 5-[4-[(carbomethoxy)methoxy]benzylidine]thiazolidine-2,4-dione (645g, Y=85%, P=98%).
Exaniple-13 :
Alternative preparation of 5-f4-f(carbomethoxv)methoxy|benzvlidinelthiazolidme-
2.4-dione of formula (12) :
4-((carbomelhoxy)methoxy)benzaidehyde obtained by following a procedure described in Example 6 (500 g, 2.58 M), thiazolidine-2,4-dione (302 g, 2.58 M), piperidine (38 ml, 0.46 M), benzoic acid (38 g, 0.31 M) and xylene (3 L) were.taken in a 5 L 4-neck round bottom flask fitted with a mechanical stirrer and a Dean-Stark condenser. The reaction mixture was refluxed for 6-8 hours, while monitoring the reaction on TLC. After the completion of the reaction, the reaction mass was cooled to 10 °C and the solid thus obtained was filtered, washed with xylene (2 X 250 ml) and dried at SO °C for 1-2 hours, to afford 5-[4-[(carbomethoxy)methoxy]benzylidine]thiazolidine-2,4-dione (647 g, Y=85%, P-98%).
Example-14:
One pot preparation of 5-f4-Kcarbomethoxv)methoxylbenzvlidinelthia2olidine-2.4-
dione of formula (2):

4-HydroxybenzaIdehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Methylchloroacetate (223 g, 2.05M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was taken in a 5 L 4 neck round bottom flask fitted with a mechanical stirrer and a Dean-Stark condenser. Thiazolidine-2,4-dione (234 g, 2.00 M), piperidine (30 mi, 0.30 M) and benzoic acid (30 g, 0.20 M) were added and the reaction mixture was refluxed for 6-8 hours, while monitoring the reaction on TLC. After the completion of the reaction, the reaction mass was cooled to 10 °C and the solid thus obtained was filtered, washed with toluene (2 X 250 ml) and dried at 80 °C for 1-2 hours to afford 5-[4-[(carbomethoxy)methoxy]benzyIidine]thiazolidine-2,4-dione (460 g ,Y=76%, P^98%).
Example-15 :
Alternative one pot preparation of 5-[4-[(carbQinethoxy>methoxv|benzylidine]
thiazolidine-2,4-dione of formula (2):
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4,09 M), xylene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Methylchloroacetate (223 g, 2.05M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with 2 X 500 ml of toluene. The combined organic layer was taken in a 5 L 4-neck round bottom flask fitted with a mechanical stirrer and a Dean-Stark condenser. Thiazolidine-2,4-dione (234 g, 2.00 M), piperidine (30 ml, 0.30 M) and benzoic acid (30 g, 0.20 M) were added and the reaction mixture was refluxed for 6-8

hours, while monitoring the reaction on TLC. After the completion of the reaction, the reaction mass was cooled to 10 °C and the solid thus obtained was filtered, washed with xylene (2 X 250 ml) and dried at SO °C for 1-2 hours to afford 5-[4-[(carbomelhoxy)methoxy]benzylidine]thiazolidine-2,4-dione (465 g, Y=77%, P-98%),
Example-16:
Preparation of 5-[4-frcarboetfaoxvlmethoxvlbenzvllthiazolidine-2.4-dione of the formula (3)
In an autoclave vessel (2 L), Raney Ni (60 ml) was placed along with 600 ml of ethyl acetate, after washing the Raney Ni consecutively with water (2 X 250 ml), methane! (2 X 150 ml) and ethyl acetate (2 X 100 ml). Then 5-[4-[(carboethoxy)methoxy] benzyiidine]thiazolidine-2,4-dione obtained by following a procedure described in Example 8 (100 g, 0.33 M), was charged to the vessel and 600 ml of ethyl acetate added. The mass was kept for hydrogenation at 400 psi hydrogen pressure, at room temperature for 20-30 h and the reaction was monitored on HPLC. After completion of the reaction, the catalyst was filtered and the filterate was evaporated under reduced pressure to yield an oil. This oil was kept under high vacuuin to afford the solid 5-[4-[(carboethoxy)methpxy]benzyl]thiazolidine-2,4-dione in crude form (95-97 g; Yield : 94-96%; Purity : 86-95% (HPLC)). Crude 5-[4-[(carboethoxy)methoxy]benzyl]thia2olidine-2,4-dione thus obtained was dissolved in hot methanol (200 ml) and transferred to a 2 L three neck round bottom flask fitted with a mechanical stirrer and liquid addition funnel. Deminerlised water (400 ml) was added dropwise to the reaction mixture through the addition funnel, over a period of 30 min. with vigorous stirring during which a white compound precipitated out. Stirring was continued for further 30 min. and second portion of water (200 ml) was added while stirring, over a period of 15 min. to ensure complete precipitation of the product. Stirring was continued for further I h. The product was filtered, washed with 200 ml of water and dried under vacuum to yield pure 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione (85 g, Y=85%, P=99%).

Example-17:
Preparation of 5-t4-[fcarboethoxv^methoxv]benzvlltfaiazolidine-2.4-dioneof the
formula (3):
In an autoclave vessel 5-[4-[(carboethoxy)methoxy]benzylidine]thiazolidine-2,4-dione
obtained by following a procedure described in Example 8 (100 g) and ethyl acetate (600
ml) were placed. Raney Ni (60 ml), pre washed with water (2 X 100 ml), methanol (2 X
100 ml) and ethyl acetate (1 X 100 m!) consecutively, was transferred into the vessel with
ethyl acetate (600 ml). Then the mass was kept for hydrogenation at 400 psi hydrogen
pressure and room temperature for 24 h. The catalyst was filtered and the filterate was
evaporated and dried over vacuum to obtain 5-[4-
[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione (98 g, Y=97.3 %, P= 92 %).
Example 18:
Preparation of 5-[4-[(carboethoxy)methoxylben2vl|thiazolidine-2.4-dione of the
formula (3):
In an autoclave vessel 5-[4-[(carboethoxy)methoxy]benzylidine]thiazoiidine-2,4-dione obtained by following a procedure described in Example 8 (100 g) and ethyl acetate (600 ml) were placed. Raney Ni (60 ml), pre washed with water (2 X 100 ml), methanol (2 X 100 ml) and ethyl acetate (1 X 100 ml) consecutively was trasferred into the reaction vessel with ethyl acetate (600 ml). Then the mass was kept for hydrogenation at 200 psi hydrogen pressure and room temperature for 30 h. The catalyst was filtered and the filterate was evaporated and dried over vacuum to obtain 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione (100 g, Y-97.35 %, P=31 %).
Example 19 :
Preparation of 5-l4-|fcarboethoxv)methoxvlbenzvnthiazolidine-2.4-dione of the
formula (3):
In an autoclave vessel 5-[4-[(carboethoxy)methoxy]benzylidine]thiazolidine-2,4-dione
obtained by following a procedure described in Example 8 (100 g) and ethyl acetate (600

ml) were placed. Raney Ni (60 ml) pre washed with water (2 X 100 ml), methanol (2 X -100 ml), ethyl acetate (1 X 100 ml) consecutively was transferred into the reaction vessel with ethyl acetate (600nnl).. Then the mass was kept for hydrogenation at 100 psi hydrogen pressure and room temperature for 70 h. The catalyst was filtered and the filterate was evaporated and dried over vacuum to obtain 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione (100 g, Y- 99.35 %, P=78 %).
Example 20 :
Preparation of 5-f4-lfcarboethoxv)niethoxvibenzvnthiazolidine-2.4-dione of the formula (^):
In an autoclave vessel 5-[4-[(carboethoxy)methoxy]benzylidine]thiazolidine-2,4-dione obtained by following a procedure described in Example 8 (40 g) and ethyl acetate (400 ml) were placed, then Raney Ni (32 ml) pre washed with water (2 X 100 ml), methanol (2 X 100 ml), ethyl acetate (1 X 100 ml) was transferred with 400 ml of ethyl acetate into the vessel. The mass was kept for hydrogenation at 400 psi hydrogen pressure and 50 °C - 60 °C temperature for 11 h. The catalyst was filtered and the filterate was evaporated and dried over vacuum to obtain 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-' dione (37 g, Y=92 %, P-80.17 %).
Example 21:
PreparatioD of 5-l4-ircarboethoxv)inethoxv|benzvllthiazolidine-2.4-dione of the
formula (3):
In a 3 L four necked round bottom flask with a mechanical stirrer, thermometer socket, condenser and a gas spunger, 5-[4-[(carboethoxy)methoxy]benzylidine]thia2olidine-2,4-dione obtained by following a procedure described in Example 8 (100 g)^ ethyl acetate (600 ml) were placed. Raney Ni (100 ml) pre washed with water (2 X 150 ml), methanol (2 X 150 ml), ethyl acetate (1 X 150 ml) was transferred with ethyl acetate (600 ml) into the vessel. Then hydrogen gas was bubbled into the solution at room temperature for 36h.

The catalyst was filtered and the filterate was evaporated and dried over vacuum to obtain o-[4-[{carboethoxy)methoxy]benzyl]thia2olidine-2,4-dione (100 g, Y=99.35 %, P=73 %).
Example-22 :
Alternative procedure for the preparation of 5-M-[fcarboethoxv)methoxvlbenzylI thiazolidiDe-2.4-dione of the formula (3):
5-[4-[(carboethoxy)methoxy]benzylidine]thiazolidine-2,4-dione obtained by following a procedure described in Example 8 (100 g, 0.33 M), magnesium (95 g, 3.96 M) and methanol (50 ml) were taken into a 5 L round bottom flask fitted with a mechanical stirrer and stirred for 10 minutes at room temperature during which period the magnesium starts reacting, as evinced by effervescence. Ethanol was added and the temperature of the reacdon mass was maintained at 20-25 °C for 12 hours, while monitoring the reaction by HPLC. After the complete reduction, the reaction mass was cooled to 5 °C and the pH was adjusted to 2 using cone, sulphuric acid and the reaction mixture was refluxed for a further 12 hours period, while monitoring the reaction by TLC. After complete esterification, the reaction mixture was cooled to room temperature and the magnesium salts (-500 g) were filtered. The filtrate was concentrated under vacuum and the. residue was dissolved in ethyl acetate (250 ml) and pure 5-[4-[(carboethoxy)methoxy]ben2yl] thiazolidine-2,4-dione was precipitated as a white solid by adding pet. ether (125 ml) followed by stirring at room temperattire for 1 hour (59 g ,Y=61%, P-97%).
Example-23 :
Preparation of 5-l4-[fcarbQmethoxv^niethoxvlben2vl1thiazolidine-2,4-dione of the
formula (3^:
5-[4-[(carboethoxy)m€thoxy]benzylidine]thiazolidine-2,4-dione obtained by following a procedure described in Example 8 (100 g, 0.33 M), magnesium (95 g, 3.96 M) and methanol (2 L) were taken into a 5 L round bottom flask fitted with a mechanical stirrer and stirred

for 10 minutes at room temperature during which period the magnesium starts reacting, as evinced by effervescence. The temperature of die reaction mass was maintained at 20-25 °C for 12 hours, while monitoring the reaction by HPLC. After the complete reduction and trans-esterification, the reaction mass was cooled to 5 °C and the pH was adjusted to 2 using cone, sulphuric acid and the reaction mixture was refluxed for a further 12 hours period, while monitoring the reaction by TLC. After complete esterification, the reaction mixture was cooled to room temperature and the magnesium salts (-500 g) were filtered. The filtrate was concentrated under vacuum and the residue was dissolved in ethyl acetate (250 ml) and pure 5-[4-[(carbomethoxy)methoxy]ben2yl] thiazolidine-2,4-dione was precipitated as a white solid by adding pet. ether (125 ml) followed by stirring at room temperature for 1 hour (60 g ,Y=62%, P=97%).
Example-24 :
Alternative procedure for the preparation of 5-[4-[karbomethoxv)methoxvlbenzvll
thiazQlidine-2.4-dione of the formula (3):
5-[4-[(carbomethoxy)methoxy]benzylidine]thiazolidine-2,4-dione, obtained by following a procedure described in Example 12, (100 g, 0.34 M), magnesiuni (95 g, 3.96 M) and methanol (2 L) were taken into a 5 L round bottom flask-fitted with a mechanical stirrer and stirred for 10 minutes at room temperature during which period the magnesium starts reacting, as evinced by effervescence. The temperature of the reaction mass is maintained at 20-25 °C for 12 hours, while monitoring the reaction by HPLC. After the complete reduction and trans-esterification, the reaction mass was cooled to 5 °C and the pH was adjusted to 2 using cone, sulphuric acid and the reaction mixture was refluxed for a further 12 hours period, while monitoring the reaction by TLC. After complete esterification, the reaction mixture was cooled to room temperature and the magnesium salts (-500 g) are filtered. The filtrate is concentrated under vacuum and the residue was dissolved in ethyl acetate (250 ml) and pure 5-[4-[(carbomethoxy)methoxy]

benzyI]thiazolidine-2,4-dione was precipitated as a white solid by adding pet.ether (125 ml) followed by stirring at room temperature for 1 hour (60 g, Y=60%, P=97%).
ExampIe-25 :
Preparation of 5-[4-ircarboxv^methoxvlbenzvl1thia2olidine-2.4-dione of the formula
A suspension of the 5-[4-[(carboethoxy)methoxy]benzyl]thia2oiidine-2,4-dione obtained by following a procedure described in Example 16 (135 g, 0.44 M) and water (540 ml, 4 times w/v) was taken in a round bottom flask fitted with a mechanical stirrer. Aq. sodium hydroxide solution (37 g of NaOH in 135 ml of water) was added slowly over a period of 5-10 minutes at 20-25 "C. Stirring was continued at ambient temperature for a further period of 2-3 h, while monitoring the reaction by TLC. After the completion of reaction, the pH of the reaction mixture was adjusted to 2 using cone. HC\ (Temp, raises to - 40-45 **C) and allowed to attain room temperature. The mass was cooled to ~ 10-15 °C and the solid thus obtained was filtered and dried at 60-70 °C under 1-2 mm Hg of vacuum to afford 5-[4-[(carboxy)methoxy]benzyl]thiazoIidine-2,4-dione (121 g, Y^99%, P=99.2%).
Example-26:
Alternative preparation of 5-j4-[fcarb6xy>methoxylbenzyll thiazolidine-2.4-dione
of the formula (41:
5.[4_[(carboethoxy)methoxy]benzyHdine]thiazolidine-2,4-dione, obtained by following a procedure described in Example 8 (100 g, 0.33 M), magnesium (95 g, 3.96 M) and methanol (2 L) were taken into a 5 L round bottom flask fitted with a mechanical stirrer and stirred for 10 minutes at room temperature during which period the magnesium starts reacting, as evinced by effervescence. The temperature of the reaction mass was maintained at 20-25 °C for 12 hours, while monitoring the reaction by HPLC. After the complete reduction and trans-esterification, water (2 L) was added to the reaction mass and stirred at ambient temperature for a ftirther 12 hours period, while monitoring the

reaction by TLC. After complete hydrolysis, the reaction mixture was acidified to pH 2 ,and extracted with ethyl acetate (3 X 200 ml). The combined organic extract was concentrated under vacuum. Pure 5-[4-[(carboxy)methoxyJbenzyl]thia2olidine-2,4-dione was precipitated as a white solid by adding pet.ether {125 ml) followed by stirring at room temperature for 1 hour (60 g, Y=66%, P=97%).
Example-27 :
Alternate procedure for the preparation of 5-[4-ffcarboxv)methoxvlbenzvll
thiazQlidine-2.4-dione of the formula ^4^:
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Example 23 (135 g, 0.46 M) and water (540 ml, 4 times w/v) was taken in a round bottom flask fitted with a mechanical stirrer. Aq. sodium hydroxide solution (37 g of NaOH in 135 ml of water) was added slowly over a period of 5-10 minutes at 20-25 "C- Stirring was continued at ambient temperature for a period of 2-3 h, while monitoring the reaction by TLC. After the completion of the reaction, the pH of the reaction mixture was adjusted to 2 using cone. HCl (Temp, raises to 40-45 "C) and allowed to attain room temperature. The mass was cooled to 10-15 °C and the solid thus obtained was filtered and dried at 60-70 °C under 1-2 mm Hg of vacuum to afford 5-[4-[(carboxy)methQxy]benzyl]thiazolidine-2,4-dione (121 g, Y=99%, P-99.2%).
Example-28:
Alternative Preparation of 5-[4-lfcarboxv)metfaoxvlbenzvllthiazolidine-2.4-dione of
the formula (4):
5-[4-[(carbomethoxy)methoxy]benzylidine]thiazolidme-2,4-dione obtained by following
a procedure described in Example 23 (100 g, 0.34 M), magnesium (95 g, 3.96 M) and methanol (2 L) were taken into a 5 L round bottom flask fitted with a mechanical stirrer and stirred for 10 minutes at room temperature during which period the magnesium starts reacting, as evinced by effervescence. The temperature of the reaction mass was

maintained at 20-25 °C for 12 hours, while monitoring the reaction by HPLC. After the

complete reduction and trans-esterification, water (2 L) was added to the reaction mass and stirred at ambient temperature for a further 12 hours period, while monitoring the reaction by TLC. Af^er complete hydrolysis, the reaction mixture was acidified to pH 2 and extracted with ethyl acetate (3x200 ml). The combined organic extract was concentrated under vacuum. Pure 5-[4-[(carboxy)methoxy]benzyl]thia2oUdine-2,4-dione was precipitated as a white solid by adding pet.ether (125 ml) followed by stirring at room temperature for I hour (62 g, Y-65%, P=97%).
Example-29 :
Preparation of 5-(4-||3-Methvl-4-oxo-3.4-dihydroquinazol\n-2-vHmethoxy]benzvH
thiazolidine-2.4-dione of the formula (1):
A suspension of 5-[4-[(carboxy)methoxy]benzyI]thiazolidine-2-4-dione obtained by following a procedure described in Example 25 (100 g, 0.356M), N-methyl anthranilamide (58.7 g, 0.391M), & p-toluenesulphonic acid (-200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperature 170-180 °C) for a period of 12-15 h while monitoring the reaction by TLC, After completion of the reaction, the reaction mass was cooled to 80 °C and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquina2oUn-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a
white solid (100 g ,Y-71%, P=98%).
Example-30 :
Alternative preparation of 5-t44f3-methyl-4-oxo-3.4-dihvdroquinazolin-2-
vl1methoxv]benzvllthiazolidine-2.4-diope of the formula (IV.

A suspension of 5-[4-[(carboxy)methoxy]benzyl]thia2olidine-2,4-dione obtained by .following a procedure described in Example 25 (100 g, 0.36 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (-200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperature 170-180 °C) for a period of 12-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80 °C and methanol (700 m!) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (95 g, Y=68%, P=98%).
Example-31 :
Alternative preparation of 5-[4-[[3-methvl-4-oxo-3.4-dihvdrQquinazolin-2-vl)
methoxy}benzyllthiazolidine-2.4-dione of the formuJa (1):
A suspension of 5-[4-[(carbomethoxy>methoxy]benzyl]thiazolidine-2,4-dione (100 g, 0.34 M) obtained in Example 23, N-methyl anthranilamide (58.7 g, 0.39 M) & p-toluenesulfonic acid (-200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperature 170-180 °C) for a period of 45-55 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80 °C and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroqmnazolin-2-yi]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (71 g, Y^53%, P=98%).

'ExaniDle-32 :
Alternative preparation of 5-[4-[[3-methvl-4-oxo-3.4-dihvdroquinazolin-2-vl! niethoxvlbeQzvlltfaiazolidine-2.4-dioge of tlie formula (IV.
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyi]thiazolidine-2,4-dione obtained by following a procedure described in Example 23 (100 g, 0.34 M), N-methyi anthranilamide (58.7 g, 0.39 M), xylene (100 ml) & p-toluenesulfonic acid (-200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperature 170-180 °C) for a period of 45-55 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80 °C and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (66 g, Y=49%, P=98%).
Example-33 :
Alternative preparation of 5-14-l[3-inethvl-4-oxo-3.4-dihvdroquinazolin-2-vll
metiioxvlbenzvlltliiazolidine-2,4-dione of tiie formula (1):
A suspension of 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Example 16 (100 g, 0.32 M), N-methyl anthranilamide (58.7 g, 0.39 M) & p-toluenesulfonic acid (-200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperature 170-180 ^C) for a period of 45-55 h while monitoring the reaction by TLC, After completion of the reaction, the reaction mass was cooled to 80 °C and methanol

(700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to
attain room temperature while srirring and the solid thus obtained was filtered and
washed with methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-
methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyi]thiazolidine-2,4-dione as a white solid (68 g, Y=53%, P=98%).
Example-34 :
Alternative preparation of 5-14-ll3-niethvl-4-Qxo-3.4-dihvdroquinazolin-2-vll methoxylbenzvllthiazolidine-2.4-dione of the formuia (1):
A suspension of 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Example 16 (100 g, 0.32 M), N-methylanthranilamide (58.7 g, 0.39 M), xylene (100 ml) & p-toluenesulfonic acid (^200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperature 170-180 'C) for a period of 45-55 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80 °C and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazoUdine-2,4-dione as a
white solid (62 g, Y-48%, P-98%).
Example-35 :
Alternative preparation of 5-[4-ll3-metlivl-4-oxo-3.4-dihvdroquinazolin-2-vll
methoxvlbenzvl)thiazolidine-2.4-dione of the formula (1):
A suspension of 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Example 16 (100 g, 0.32 M), N-methyl

^anthranilamide (58.7 g, 0.39 M) & p-toluenesulfonic acid (-200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperanire 150-155 °C, oil bath temperature 170-180 °C) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80 °C and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (29 g, Y=23%, P=98%).
Example-36:
Alternative preparation of 5-[4-)f3-methyl-4-oxo-3.4-dihydroquinazolin-2-
yl)methoxylbenzvllthiazolidine-2.4-dione of the formula (1):
A suspension of 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Example 16 (100 g, 0.32 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) & p-toluehesulfonic acid (-200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperature 170-180 °C) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80 °C and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed wifli methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a
white solid (29 g, Y=23%, P=98%) .

Exampte-37 •. ' Alternative preparation of 5-{4-[[3-niethvM-oxo-3.4-dihydroquinazQlio-2-vM methoxylbeazyl|thiazoUdiae-2^4-dioQe of the formula (IV.
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyl]thiazoIidine-2,4-dione obtained by following a procedure described in Example 23 (100 g, 0.34 M), N-methyl anthranilamide (58.7 g, 0.39 M) & p-toluenesulfonic acid (~200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperamre 170-180 °C) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80 °C and methanol (700 ml) was added slowly through a dropping ftinnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 m!) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazoIin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (28 g, Y=23%, P-98%).
Example-38 :
Alternative preparation of S-f4-ri3-metfavl-4-oxo-3.4-dihvdroquinazolin-2-vll
methoxylbenzvllthiazolidine-2.4-dione of the formula (1):
A suspension of 5-[4-[(carbomethoxy)methoxy]benzy!]thiazolidine-2,4-dione obtained by following a procedure described in Example 23 (100 g, 0.34 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (-200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155 °C, oil bath temperature 170-180 °C) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80 °C and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed

to attain room temperature while stirring and the solid thus obtained was filtered and .washed with methanol (150 ml) and dried at 100-120 °C for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (30 g, Y=23%, P=98%).
Example-39 :
Preparation of 5-[4-[[3-methyl-4-oxo-3.4-dihvdroquinazolin-2-vll
methoxy|benzyllthiazolidine-2.4-dione potassium salt of the formula (9):
5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazoIidine-2,4dione obtained by following a procedure described in Example 29 (100 g, 0.25 M)) was dissolved in 1 L of xylene : MeOH (1:1) mixture at 80-90 °C, treated with decolourising carbon (20 g) and filtered. To the filtrate was added potassium hydroxide solution (15.6 g of potassium hydroxide dissolved in 200 ml of methanol) slowly over a period of 5-10 min. at 60-70 °C. Stirring was continued at ambient temperature for a period of 1 h. The solid obtained was filtered, washed with methanol (300 ml) and dried at 120 °C for 1 h to yield 5-[4-[P-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione potassium salt as an off- white solid (98 g, Y-89%, P=99.5%).
Exampie-40 :
Alteroative preparation of 5-l4-[[3-Metfayl-4-oxo-3.4-dihvdro-2-auinazolinyl|methoxvj
benzvlltbiazolidiDe-2.4-dioDe potassium salt of the formula i9):
5-[4-[[3-Methyi-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzyl]thiazoIidine-2,4-dione obtained by following a procedure described in Example 29 (100 g, 0.25 M) was dissolved in 1 L of xylene ; MeOH (1 : 1) mixture at 80-90 °C, treated with decolourising carbon (20 g) and filtered. To the filtrate was added potassium t-butoxide solution (31.56 g of potassium t-butoxide dissolved in 200 ml of methanol) slowly over a

period of 5-10 min. at 60-70 "C. Stirring was continued at ambient temperature for a period of 1 h. The solid obtained was filtered, washed with methanol (300 ml) and dried at 120 °C for 1 h to yield 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]tliiazolidine-2,4-dione potassium salt as a white solid (100 g, Y=91%, P-99.6%).
Advantages of the invention:
• The process is simple and economical,
• Multisolvent systems are replaced with single solvent system.
• Use of expensive Pd/C for reduction is replaced with relatively inexpensive reagents like Raney Nickel or Magnesium /alcohol having 1 to 4 carbon atoms.
• Activation of the acid prior to condensation with N-methyl anthranilamide is avoided. Direct condensation is easier to handle as the reaction is insensitive to moisture,
• Expensive and hazardous potassium t-butoxide for potassium salt formation is replaced with potassium hydroxide.


We claim
I. A process for the preparation of pharmaceutically acceptable salt of novel 5-[4-[[3-Methyl-4-oxo-3,4-dihydro-quinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1)

wherein R is as defined above,
b) purifying the crude compound of formula (3') to obtain pure compound of formula
(3') by conventional methods
c) hydrolyzing the compound of formula {3') wherein R is as defined above, by
conventional methods to obtain the acid of the formuia (4),


directly without any preacti vation of the acid to produce the compound of formula (1)
e) converting the compound of formula (I) to its phaimaceutically acceptable potassium salt thereof by conventional methods and
f) isolating the pharmaceutically acceptable potassium salt by conventional methods.
2. The process as claimed in claim 1, wherein the reducing agent used in step (a) is
selected from Raney Nickel or magnesium in alcohol having ! to 4 carbon atoms.
3. The process as claimed in claims I and 2, wherein the reduction step (a)
employing Raney Nickel is carried out for a period ranging from S to 70 hours, preferably
ranging from 12 to 24 hours.
4. The improved process as claimed in claims 1 to 3, wherein the reduction step (a)
employing reducing agent such as Raney Nickel is carried out .at a temperature in the
range of 15 -70 °C preferably from 30 -60 °C
5. The process as claimed in claims I to 2, wherein the reduction step in (a)
employing Mg/alcohol having 1 to 4 carbon atoms is carried out using 4 to 12 equivalents
of Mg preferably 8 to 10 equivalents in alcohol having 1 to 4 carbon atoms.
6. The process as claimed in claims 1, 2 and 5, wherein the reduction step (a)
employing Mg/alcohol having I to 4 carbon atoms is carried out at a temperature in the
range of lOX to 60°C preferably from 15°C-30'^C.

7. The process as claimed in claims !, 2, 5 and 6, wherein the reduction in step (a)
employing Mg/alcohol having 1 to 4 carbon atoms is carried out for a period in the range
of 2 to 15 hours, preferably from 6 to 8 hours.
8. The process as claimed in claims 1 to 7, wherein the reduction step (a) is carried
out at a pressure ranging from atmospheric pressure to 600 psi, preferably from
atmospheric pressure to 400 psi.
9. The process as claimed in claims 1 to 8, wherein the crude reduced product
obtained in step (a) is purified in lower alcohol containing 1-4 carbon atoms & water
mixture in the ratio of 1; 1 to 1; 4 to obtain high pure material.
10. A process for the preparation of pharmaceutically acceptable salt of novel 5-{4-
[[3-Methyi-4-oxo-3,4-dihydro-quinazolin-2-yl]methoxy]benzyl]thia2olidine-2,4-dione
of the formula (1) substantially as herein described with reference to examples 39-40.


Documents:

2060-mas-1998 claims.pdf

2060-mas-1998 correspondence others.pdf

2060-mas-1998 correspondence po.pdf

2060-mas-1998 description (complete).pdf

2060-mas-1998 form-1.pdf

2060-mas-1998 form-13.pdf

2060-mas-1998 form-3.pdf

2060-mas-1998 form-6.pdf


Patent Number 187716
Indian Patent Application Number 2060/MAS/1998
PG Journal Number 30/2009
Publication Date 24-Jul-2009
Grant Date 03-Jan-2003
Date of Filing 14-Sep-1998
Name of Patentee M/S. DR. REDDY’S RESEARCH FOUNDATION
Applicant Address 7-1-27 AMEERPET, HYDERABAD 500 016
Inventors:
# Inventor's Name Inventor's Address
1 POTLAPALLY RAJENDER KUMAR DR. REDDY’S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016
2 CHEBIYYAM PRABHAKAR DR. REDDY’S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016
3 GADE CHINA BAKKI REDDY DR. REDDY’S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016
4 SATISH BALRAM MAHANTI DR. REDDY’S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016
5 MAMILLAPALLI RAMABHADRA SARMA DR. REDDY’S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016
6 GADDAM OM REDDY DR. REDDY’S RESEARCH FOUNDATION, 7-1-27 AMEERPET, HYDERABAD 500 016
PCT International Classification Number C07D 277/02
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA