Field of the invention

The present invention provides an improved process for the preparation of 4-halomethyl-5-methyl-l,3-dioxolene-2-one of formula (I) which is a key intermediate for the preparation of many active pharmaceutical ingredients. Particularly the present invention provides an improved process for the preparation of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV).
wherein X represents as halogens.

Background of the Invention

A compound of 4-halomethyl-5-methyl-l,3-dioxolene-2-one (I) is a key intermediate for preparation of many active pharmaceutical ingredients like olmesartan medoxomil, azilsartan medoxomil and faropenam medoxomil etc. 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) is the precursor of 4-halomethyl-5-methyl-l,3-dioxolene-2-one of formula (I). Considering the importance of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) several literatures discloses various process for preparing the same which are summarized below:

Tetrahedron Letters, 1701-1704 (1972) discloses the preparation of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) by reacting 3-hydroxy-butan-2-one with phosgene in dichloromethane and in the presence of N,N-dimethylaniline followed by evaporation. The intermediate obtained was further heated to 160 °C to get 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) with 72 % yield. This literature fails to disclose the purity of isolated compound.

U.S. Pat. Nos. 5,466,811 (hereafter refer US '811) describes the preparation of 4-bromomethyl-5-methyl-l,3-dioxolene-2-one of formula (I) via 4,5-dimethyl-l,3-dioxolene-2-one compound of formula (IV) by reaction of 3-hydroxy-butan-2-one with triphosgene and N,N-dimethylaniline in dichloroethane followed by concentration, the obtained residue was heated to 170 °C for 2 hours and isolated as colorless solid of 4,5-dimethyl-l,3-dioxolene-2-one formula (IV) from benzene and hexane solvent mixture and then recrystallized from hexane solvent with 70% yield. The said process associated uses benzene for isolation which is highly carcinogenic also the reaction is carried out at a higher temperature without using solvent which is difficult to handle in commercial scale.

U.S. Pat. Nos. 4,554,358 describes the preparation of 4-chloromethyl-5-methyl-l,3-dioxolene-2-one of formula (I) by reacting 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) in methylene chloride with sulfuryl chloride. The resulting residue was distilled in vacuum and obtained as 42.1 g (65% of theory) of colorless oil of 4-chloro-4-methyl-5-methylene-l,3-dioxolane-2-one of formula (V) and then converted into 4-chloromethyl-5-methyl-l,3-dioxolene-2-one of formula (I) by following conventional methods.
U.S. Pat. Nos. 4,428,806 describes the preparation of 4-bromomethyl-5-methyl-l,3-dioxolene-2-one of formula (I) by reacting 4,5-dimethyl-l,3-

dioxolene-2-one (IV) with bromine in benzene or carbon tetrachloride in the presence of a, ct'-azobisisobutyronitrile as a catalyst. After reaction completion, reaction mass concentrated into syrupy liquid mass of 4-bromomethyl-5-methyl-l,3-dioxolene-2-one of formula (I).

JP 2003-064076 describes the preparation of 4-chloromethyl-5-methyl-1,3-
; dioxolene-2-one of formula (I) by reacting 4,5-dimethyl-l,3-dioxolene-2-one of
formula (IV) with trichloroisocyanuric acid in an inert solvent, filtered and
concentrated. The obtained residue was further heated at 90 °C for 2 hours and
obtained as 4-chloromethyl-5-methyl-l,3-dioxolene-2-one of formula (I).
CN 101250178A describes the preparation of 4-chloromethyl-5-methyl-l,3-dioxolene-2-one of formula (I) by reacting 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) with sulfuryl chloride as a chlorinating agent in the presence of methylene dichloride at reflux condition, followed by rearrangement at 70-100 °C for 1-4 hours to obtain 4-chloromethyl-5-methyl-l,3-dioxolene-2-one.

As the prior art process has some limitation like use of benzene as a solvent for isolation and use of very high reaction temperature (more than 160° C), our applicant focused to develop a new process for preparation of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) and surprisingly found that the process wherein such dehydrohalogenation can be carried out at moderate temperature in the range of 90 to 110 °C in the presence of polar organic solvent and the said process does not require any purification as like the reported processes. So far as none of the patents/literatures teaches or motivates this conversion in the presence of solvent. The present invention process has several advantages like handling, isolation of compound, stability and storage in commercial scales. Further the presentinvention provides the pure compound of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) and it can be utilized to next step without any purification.

Objectives of the invention
The main objective of the present invention is to provide an improved process for preparation of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) having good yield and purity.

: w; Another objective of the present invention is to provide an improved process for preparation of 4-halomethyl-5-methyl-l,3-dioxolene-2-one of formula (I), wherein halo represents fiuoro, chloro, and bromo, which is a key intermediate for the preparation of many active pharmaceutical ingredients.

Brief description of drawings

Fig. 1 shows X-ray powder diffraction pattern of crystalline form of 4,5-dimethyl-l,3-dioxolene-2-one (IV) according to the present invention.

The PXRD of said salt analyzed using following condition:

Summary of the invention

Accordingly, the aspect of the present invention provides an improved
process for the preparation of 4-halomethyl-5-methyl-l,3-dioxolene-2-one of
formula (I): wherein halo represents fluoro, chloro and bromo, the process
comprising the steps of;
i) dehydrohalogenation of 4-halo-4,5-dimethyl-l,3-dioxolan-2-one of
formula (III) into 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) in the
presence of polar solvent at a temperature in the range of 90-110 °C; and ii) converting 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) to 4-
halomethyl-5-methyl-l,3-dioxolene-2-one of formula (I); wherein the
improvement consists of use of polar solvent in step (i).
The following scheme illustrates the present invention:

Detailed description of the invention
In first embodiment of the present invention, the polar solvent used in step (i) is selected from group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane, n-butanol, anisole or mixture thereof.
In second embodiment of the present invention, converting the 4-halo-4,5-dimethyl-l,3-dioxolan-2-one of formula (III) to 4,5-dimethyl-l,3-dioxolene-2-one

of formula (IV) in the presence of polar solvent by heating the solution at a temperature in the range of 90-110 °C, preferably 90-100 °C. The present invention process has several advantages over prior arts such as moderate temperature condition, reaction in presence of solvent which avoids decomposition and formation of impurities whereas prior arts involves this reaction without solvent which is not suitable for plant scale or commercial purpose, main advantage of present invention is isolation of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) by ease filtration and increase in shelf life and also stability of compound is more. The prior art of US '811 describes the process which is involving the same reaction at higher temperature like 160 °C and above, and using benzene and hexane solvent mixture for purification purpose, the solvents disclosed in this patent is not suitable for commercial purpose. In view of prior arts, inventor has performed several experiments with different conditions i.e.) solvent, temperature etc and found that polar solvent is highly suitable for this I reaction at lower temperature with good yield and purity. The present inventor also found that isolation of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) from combination of polar solvent and water mixture enhance the purity of compound which means further purification does not required and as such can be utilized for next step. The isolation of precipitated product of formula (IV) can be done by well known techniques such as filteration, decantation and centrifugation. So far none of the patents/literature teaches or motivates this isolation technique including solvent system of the present invention.
In third embodiment of the present invention describes the preparation of 4-halomethyl-5-methyl-l,3-dioxolene-2-one of formula (I) from 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV): wherein halo represents fluoro, chloro and bromo, the process comprising the steps of converting the 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) to compound of formula (V) using halogenating

reagent and in the presence of solvent at room temperature followed by conversion into 4-halomethyl-5-methyl-l,3-dioxolene-2-one of formula (I) by heating at 90-95 °C as prepared by conventional method of prior art process. The halogenating reagent used is selected from group consisting of sulphuryl chloride, sulphuryl bromide, Sulfuryl fluoride, trichloroisocyanuric acid, bromine and chlorine; preferably sulphuryl chloride and solvents used is selected from group consisting of dichloromethane, dichloroethane, chloroform, toluene or mixture thereof.
In fourth embodiment of the present invention describes the preparation of 4-halo-4,5-dimethyl-l,3-dioxolan-2-one of formula (III); wherein halo represents fluoro, chloro, and bromo, the process comprising the steps of; reacting 3-
! hydrbxybutan-2-one with halocarbonylating agent in solvent gives compound of formula (Ha) followed by converting into 4-halo-4,5-dimethyl-l,3-dioxolan-2-one of formula (III) at 55-60°C as prepared by conventional method of prior art process. The halocarbonylating agent selected from group consisting of phosgene, brorhophosgene, fluorophosgene, fluorochlorophosgene, bromochlorophosgene,
• trichloromethylchloroformate, tribromomethylbromoformate, phosgene dimer, and bis(trichloromethyl)carbonate; preferably bis(trichloromethyl)carbonate and solvents selected from group consisting of dichloromethane, dichloroethane, chloroform, toluene or mixture thereof. The following scheme illustrates the present invention:
The other starting material used for preparation of active pharmaceutical ingredients as prepared by conventional method of prior art process.

Further active pharmaceutical ingredients obtained as per the present invention can be further micronized, milled or sieved to get the desired particle size required for pharmaceutical composition to achieve the desired dissolution : profile.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.
EXAMPLE 1
Preparation of 4,5-dimethyl-l,3-dioxolene-2-one (IV)
To the solution of 3-hydroxybutan-2-one (lOOg) in dichloromethane, N,N'-dimethyl aniline (165g) was added followed by triphosgene solution (161.67g dissolved in MDC) was added at -5 to 5° C and maintained at 0-5° C till reaction completion. After completion of the reaction, DM water was added to the reaction mixture at chilled condition, stirred and layer separated. The obtained organic layer, after washing, was distilled to residue at 40-45° C. The residue containing formula (Ha) was further heated at 55-60° C to obtain 4-chloro-4,5-dimethyl-l,3-dioxolan-2-one intermediate (III). To the obtained oily liquid, DMAc was added and temperature gradually increased to 90-100° C and maintained till reaction completion. After completion of reaction, reaction mass was cooled to room temperature and DM water was added over it till the solid formation and maintained for 1 hour. The obtained product was filtered, washed with water and dried under vacuum at room temperature. Yield: 40 g; HPLC purity: > 99.0%.

EXAMPLE 2
Preparation of 4-haIomethyI-5-methyl-l,3-dioxoIene-2-one (I)
To the solution of 4,5-dimethyl-l,3-dioxoiene-2-one (100 g) in dichloromethane, sulphuryl chloride (49.6 g) was added slowly to the reaction mixture at room temperature. After reaction completion, the reaction mass was concentrated to residue and further the reaction mass temperature gradually increased to 90-100°C till the reaction completion. To the residue, DM water and dichloromethane was added, stirred and layer separated. Organic layer washed with water, dried and concentrated under vacuum. The obtained oily liquid was I fractionally distilled at 90-100 °C under vacuum. Yield: 18 g.

Table 1
From the above table it is evident that the use of polar solvent like DMAc helps to carry out the reaction at moderate temperature and hence makes the process industrial viable. Further the reaction avoids purification steps and provides the compound of formula (IV) with purity more than 98.5%.

We claims:

1. An improved process for the preparation of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) which comprises dehydrohalogenating 4-halo-4,5-dimethyl-l,3-dioxolan-2-one of formula (III) in the presence of polar solvent, wherein the improvement consists of use of polar solvent.

wherein halo represents fiuoro, chloro and bromo,

2. The process of claim 1, wherein the polar solvent is selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane, n-butanol, anisole or mixture thereof.

3. The process of claim 1, wherein the polar solvent preferably is dimethylacetamide.

4. The process of claim 1, wherein the reaction temperature is in range of 90-110 °C, preferably 90-100 °C.

5. A process as claimed in claim 1, further comprises converting 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) to 4-halomethyl-5-methyl-l,3-dioxolene-2-one of formula (I) by conventional methods.

6. Use of 4,5-dimethyl-l,3-dioxolene-2-one of formula (IV) and 4-halomethyl-5-methyl-l,3-dioxolene-2-one of formula (I) prepared according to any one of preceding claims 1 - 5, in the preparation of olmesartan medoxomil, azilsartan medoxomil and faropenam medoxomil.