DESC:FIELD OF INVENTION
The present invention relates to the process for preparation of metolazone intermediate and its conversion to metolazone.

BACKGROUND OF THE INVENTION
Metolazone is chemically know as 7-chloro-2-methyl-4-oxo-3-o-tolyl-1,2,3,4-tetrahydroquinazoline-6-sulfonamide, and is structurally represented by Formula I.
(I)
Metolazone is a potent antihypertensive and diuretic drug approved for use in an oral tablet form (MYKROX) for the treatment of hypertension alone or in combination with other anti-hypertensive drugs of a different class.
U.S. Pat. Nos. 3,360,518 and 3,557,111 described methods for preparing metolazone (I).
U.S. Pat. Nos. 3,360,518 described preparation of metolazone (I) by condensing 2-acetamido-4-chloro-5-sulfamoylbenzoic acid (II) with 2-methyl aniline (III) in presence of phosphorus trichloride to give 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) as an intermediate, which on reduction with sodium borohydride and aluminum chloride gives metolazone (I) as shown in scheme 1.

Scheme 1
The process described in US’518 uses phosphorus trichloride which is a colorless or slightly yellow fuming liquid with a pungent and irritating odor. It is a very toxic reagent; causes severe burns to skin, eyes and mucous membranes and reacts violently with water. Hence, the use of phosphorus trichloride on plant scale is highly laborious. Also, the process described in US’518 produces metolazone intermediate 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) in a very low yield further resulting in a very low yield of metolazone (I).
U.S. Pat. Nos. 3,557,111 described preparation of metolazone (I) by hydrolyzing 2-acetamido-4-chloro-5-sulfamoylbenzoic acid (II) with sodium hydroxide to give 2-amino-4-chloro-5-sulfamoylbenzoic acid (V), which was converted to its anhydride (VI) by treatment with phosgene and acetic acid. Anhydride (VI) obtained was reacted with 2-methyl aniline (III) to give 2-amino-4-chloro-5-sulfamoyl-N-(o-tolyl)benzamide (VII), which was converted to metolazone (I) by reaction with dimethyl acetal in concentrated sulphuric acid and acetic acid.

Scheme 2
The process described in US’111 required multiple steps which results in lower yield of the final product. Also, phosgene or phosgene equivalents used for the reaction are hazardous and dangerous reagents to handle on a large scale.
Hence, there is a need to develop simple and less hazardous process for large scale production. There is also a need to avoid the use of hazardous chemicals such as phosphorus trichloride and phosgene. Further, there is a need to use reagents which provides better yields.
Thus the present invention provides an improved, simple, efficient, more economical, less hazardous and eco-friendly process for the preparation of metolazone intermediate 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) and conversion of this intermediate to metolazone (I).

SUMMARY OF THE INVENTION
The present invention provides process for preparing metolazone intermediate 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV), which comprises coupling 2-acetamido-4-chloro-5-sulfamoylbenzoic acid (II) with 2-methyl aniline (III) in the presence of a carboxylic acid coupling reagent. The process of the present invention further provides conversion of the metolazone intermediate 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) to metolazone (I).

DETAILED DESCRIPTION OF THE INVENTION
Thus one embodiment of the present invention provides a process for preparing metolazone intermediate 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV),
(IV)
comprising coupling 2-acetamido-4-chloro-5-sulfamoylbenzoic acid (II)
(II)
with 2-methyl aniline (III)
(III)
in the presence of a carboxylic acid coupling reagent and a suitable solvent.
Another embodiment of the present invention provides a process for preparing metolazone (I)
(I)
comprising
i) coupling 2-acetamido-4-chloro-5-sulfamoylbenzoic acid (II)
(II)
with 2-methyl aniline (III)
(III)
in the presence of a carboxylic acid coupling reagent and a suitable solvent, to produce 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) intermediate;
(IV)
ii) reducing the 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) to give metolazone (I).
The process of the present invention is as shown in Scheme 3:

Scheme 3
The carboxylic acid coupling reagents are selected from the group comprising of carbodiimide reagents that include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide (EDC) and salts thereof. The preferred carbodiimide reagent is N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide (EDC) and its hydrochloride salt (EDC.HCl).
The suitable solvent for coupling is selected from the group comprising of C1-C6 alcohols; hydrocarbons selected from benzene, toluene and xylene; halogenated solvents selected from mono or di halogenated C1-C4 alkyls; nitrogen containing solvents selected from dimethyl formamide, dimethyl acetamide, N-ethylpyrrolidinone, N-methyl pyrrolidinone; acetonitrile, dioxane dimethyl sulfoxide; and mixtures thereof. The preferred solvent is dimethyl formamide.
Reduction of the 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) intermediate can be carried out by using any of the methods known in the prior art. One of the method includes reaction of 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) with reducing agent such as sodium borohydride in presence of a base such as sodium, lithium or potassium hydroxide, sodium or potassium methoxide, or a combination thereof; and solvent such as alcohol selected from methanol, ethanol, propanol, isopropanol or mixture thereof to give metolazone (I). The preferred base is sodium hydroxide and the preferred solvent is methanol.
The metolazone (I) obtained by the process of the present invention can be optionally purified by crystallization. The solvent for crystallization can be methanol, ethanol, dimethyl formamide or mixture thereof. The preferred solvent for crystallization is mixture of methanol-dimethyl formamide.
The 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) intermediate and metolazone (I) obtained by the process of the present invention has purity greater than 99% by HPLC.
The 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) intermediate and metolazone (I) obtained by the process of the present invention has yield greater than 75%.
The metolazone (I) obtained by the process of the present invention is optionally converted into its salt.
The metolazone (I) obtained by the process of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers, excipients, or diluents.
To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLES
Example 1: Preparation of 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV)
To 200 gm (0.68 moles) of 2-acetamido-4-chloro-5-sulfamoylbenzoic acid was added 800 ml dimethyl formamide, followed by 87.8 (0.816 moles) gm of 2-methyl aniline and reaction mixture was stirred for 10-20 minutes. To this mixture 262 gm (1.36 moles) of N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (EDC.HCl) was added in four equal lots and reaction was maintained at 25-35 °C for 3 hrs. The reaction mixture was then heated to 60-65 °C for 2 hrs and then cooled to 25-30 °C. 1000 ml of water was then added to the reaction mixture, stirred for 1 hr, filtered and then washed with 400 ml water to give wet cake (512 gm). 1600 ml of methanol was added to wet cake and mixture was heated to 60-70 °C for 30 minutes. The mixture was then cooled to 0-5 °C and maintained for 30 minutes, filtered, washed with 200 ml methanol and dried under vacuum to give 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide 240 gm (Yield: 96.7 %, HPLC purity: 99.72%).

Example 2: Preparation of metolazone (I)
1500 ml of methanol was added to 100 gm (0.27 moles) of 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide. A solution of sodium borohydride (prepared from 41.6 gm (1.09 moles) of sodium borohydride in 104 ml of 2% sodium hydroxide) was added dropwise to the above reaction mixture at 0-5 °C. The reaction was maintained for 15-16 hrs. 230 ml water was added to the reaction mixture followed by 230 ml of concentrated HCl at 10-25 °C. The reaction was stirred and maintained at 25-30 °C for 60 minutes, filtered and washed with water. The wet cake obtained was dried under vacuum to give crude metolazone 89.9 gm (Yield: 89.41%, HPLC purity: 99.12). Crude metolazone 89.9 gm obtained was purified by heating in 89 ml dimethyl formamide and then addition of 445 ml methanol to give pure metolazone 80 gm (Yield: 79.56%, HPLC purity 99.83%).
,CLAIMS:1) A process for preparation of 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV),
(IV)
an intermediate for metolazone comprising:
i) coupling 2-acetamido-4-chloro-5-sulfamoylbenzoic acid (II)
(II)
with 2-methyl aniline (III)
(III)
in the presence of a coupling agent and a suitable solvent.
2) A process for preparation of Metolazone (I)
(I)
comprising:
i) coupling 2-acetamido-4-chloro-5-sulfamoylbenzoic acid (II)
(II)
with 2-methyl aniline (III)
(III)
in the presence of a coupling agent and a suitable solvent to produce 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV);
(IV)
ii) reducing 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) to give metolazone (I).
3) The process according to claim 1 and claim 2, wherein the coupling agent is carbodiimide.
4) The process according to claim 3, wherein the carbodiimide is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide (EDC) and salts thereof.
5) The process according to claim 4, wherein the carbodiimide is N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide (EDC) and salts thereof.
6) The process according to claim 1 and claim 2, wherein the suitable solvent is selected from dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-ethylpyrrolidinone, N-methyl pyrrolidinone, acetonitrile, dioxane and mixtures thereof.
7) The process according to claim 6, wherein the suitable solvent is dimethyl formamide.
8) The process according to claim 2, wherein the 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) is reduced with sodium borohydride.
9) The process according to claim 2, wherein the metolazone with purity greater than 99% obtained, is optionally purified in dimethyl formamide and methanol.
10) The process according to claim 1, wherein 7-chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide (IV) is converted to Metolazone (I) or its salt.