Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-05-02
2002-10-22
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S284000, C544S298000, C544S183000, C544S200000
Reexamination Certificate
active
06469167
ABSTRACT:
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 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1) and pharmaceutically acceptable salts thereof which are useful as antidiabetic compounds. The thiazolidine-2,4-dione derivative of the formula (1) is particularly useful for the treatment of diabetes type II (NIDDM) and related complications.
BACKGROUND OF THE INVENTION
We have in our international publication number WO 97/41097 described the synthesis of the 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1). 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/sodium carbonate 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 formula (8) on cyclisation by refluxing in xylene/acetic acid for ~2-30 hours yields about 50% of the cyclised compound of the formula (1). Compound of the formula (1) 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 scheme-I below.
The following are the difficulties encountered during the scaleup trials employing the above said process:
The step of preparing the compound of the formula 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 methanol/water/sodium carbonate 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 use of different chemicals such as pivaloyl chloride, triethylamine 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 uneconomical.
Keeping in view of the above difficulties in the process disclosed in our copending application mentioned above for the preparation of 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 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1) avoiding the above mentioned difficulties.
Another objective of the present invention is to provide an improved process for the preparation of 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy] benzyl]thiazolidine-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 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]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 (C
1
-C
4
)alkyl group, not only results in the reduction of cost but also results in efficient reduction. In addition, the compound of formula (3′) where R represents a (C
1
-C
4
)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 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1), which comprises:
(a) reducing the compound of the formula (2′) where R represents a (C
1
-C
4
)alkyl group using Raney Nickel or Magnesium in alcohol having 1 to 4 carbon atoms or mixtures thereof, and if desired reesterifying using sulphuric acid at a temperature in the range of 0° C. to 60° C. to obtain a compound of formula (3′) wherein R is as defined above,
(b) hydrolysing the compound of formula (3′) wherein R is as defined above, by conventional methods to obtain the acid of the formula (4),
(c) 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) and if desired
(d) converting the compound of formula (1) to pharmaceutically acceptable salts thereof 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 (1). 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 and the like and precipitated big 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., prefera
Chebiyyam Prabhakar
Gaddam Om Reddy
Gade Chinna Bakki Reddy
Mamillapalli Ramabhadra Sarma
Potlapally Rajender Kumar
Dr. Reddy's Research Foundation
Higel Floyd D.
Ladas & Parry
Saeed Kamal
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