DESC:FIELD OF THE INVENTION
The present application relates to a novel process for the preparation of 3-bromo-4-(bromo methyl)benzoic acid of formula (I), which is an important intermdiate for Tofogliflozin.

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Formula-I

BACK GROUND OF THE INVENTION

3-bromo-4-(bromo methyl)benzoic acid is a fine chemical reagent used in organic synthesis, particularly in medicinal chemistry. It has applications as a building block for the synthesis of various pharmaceuticals and biologically active compounds.

3-bromo-4-(bromo methyl)benzoic acid is key intermediate in the synthesis of Tofogliflozin, which is an oral hypoglycemic agent with a novel mechanism of action that reduces blood glucose levels by promoting glucose excretion in urine, achieved by selectively inhibiting sodium-glucose co-transporter 2 (SGLT2).

Tofogliflozin chemically known as (1S,3'R,4'S,5'S,6'R)-6-[(4-Ethylphenyl)methyl]-6'-(hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzo-furan-1,2'-pyran]-3',4',5'-triol, shown below, is known as Anti diabetic reported in US 7,767,651 B2

N-Bromosuccinimide (NBS) is a well known synthetic organic reagent which is useful in bromination and/or oxidation of a wide variety organic moieties under a wide variety of reaction conditions. While NBS brominations of aromatic moieties have been performed, however observed the imide and multiple brominations as by products.

Dibromodimethylhydantoin (DBDMH), while not as widely employed as NBS, is a versatile organic reagent .It offers the advantage of being more stable and less costly on a bromine equivalent basis than NBS. Previous disclosed brominations of aromatic substrated using NBS were run in refluxing CCl4 or CHCl3, Where as DBDMH in nitrile solvents provided good yileld and purity.

Preparation of Formula I involves bromination of 3-bromo-4-methyl benzoic acid , which was disclosed in the following prior arts:

WO2009097992A1, WO2014019609A disclosed the Process of 4-Bromo-3-(bromo methyl)benzoic acid, as shown below:

NBS stands for N-bromosuccinimide, AIBN stands for azobisisobutyronitrile CCl4 stands for carbon tetrachloride

WO2014019609A(WO’609) disclosed that “The crude mixture thus obtained containing 3- bromo-4-bromomethyl benzoic acid and the 3-bromo-4-dibromomethyl benzoic acid”.

WO’609 process has dibrmo impurity along with the desired bromo product, as shown below:

WO2014151616A (WO’616) disclosed the Process of 4-Bromo-3-(bromo methyl)benzoic acid, as shown below:

WO’616 used trfluorotoluene as solvent , NBS (1.1 equiv.) as brominating agent, however in this process 60% yield obtained.

Bromination of commercially available 3-bromo-4-methyl benzoic acid employing NBS and CCl4 shown below.

Although NBS is a well known brominating reagent for bomination in the prepration of Formula I, but several impurities were reported along with the desired bromo compound, which were shown below, result from the further reaction of the product and bromine and/or the hydrogen bromide generated in the reaction.

Inventors of the present invention have developed an improved bromination process that addresses the problems associated with the processes reported in the prior art. Further there is always a need for an alternative process, which for example, involves use of reagents/solvents that are less expensive and easier to handle, consume smaller amounts of reagents, and provide a higher yield of product with higher purity. Hence,the main objective of the present invention is to provide cost effective and commercially viable process for the preparation of Tofogliflozin intermediate.

Advantages of DBDMH over NBS:
1,3-dibromo-5,5-dimethylhydantoin also known as DBDMH as shown below:

DBDMH is characterized by reduced bromination costs and byproduct amounts over NBS, the commonly used brominating agent, while maintaining a similar reactivity. DBDMH is not as widely known as NBS but has a strong following as a brominating agent in various fields.

The instant invention provides an improved bromination process for the preparation of brominated aromatic compounds which results in quantitatively fewer of the impurities that are associated with previous disclosed bromination processes.The instant invention also provides a novel reaction condition for bromination of aromatic compounds with dibromodimethylhydantoin wherein the solvent is nitriles.

Since DBDMH powder is easier to handle, With its ability to undergo long-term storage in cool, dark, dry places, DBDMH is also relatively inexpensive. The two bromine atoms in the DBDMH compound enable major advantages over NBS with lower bromination costs and reduced amounts of imide byproducts.

CCl4 has been the most widely used solvent in benzylic brominations. One of the major concerns is the use of carbon tetrachloride, as it is a toxic and carcinogenic substance that has also shown both ozone-depleting and greenhouse effects. Efforts to find environmentally friendlier methods for radical halogenations have led to alternative solvents, such as nonchlorinated hydrocarbons, hence present inventors used nitrile solvents.

OBJECTIVE OF THE INVENTION

An object of the present invention is to provide the process for preparation of 3-bromo-4- (brom methyl) benzoic acid of Formula-I, which is cost effective and industrially feasible.

An object of the present invention is to provide the process for preparation of 3-bromo-4- (bromo methyl) benzoic acid, having high purity and yield.

SUMMARY OF THE INVENTION:

In one aspect of the present invention provides a process for the preparation 3-bromo-4-(bromo methyl) benzoic acid of Formula I,

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Formula-I

which comprises:
(i) treating a benzoic acid of the Formula II

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Formula-II

in nitrile solvent with brominating agent 1,3-dibromo-5,5-dimethylhydantoin at a temperature and and for a length of time sufficient to optimally convert the compound of formula II to the compound of formula I;
(ii) Purifying the Formula I in nitirles, ethers or mixtures there of.

DETAILED DESCRIPTION OF THE INVENTION:
In an embodiment of the present invention provides an improved bromination process for the prepration 3-bromo-4-(bromo methyl) benzoic acid of formula I, which comprises reacting 3-bromo-4-methyl benzoic acid of formula II with the brominating agent 1,3-dibromo-5,5-dimethylhydantoin in a suitable solvent and radical initiator such as AIBN, benzoyl peroxide at a temperature and for a length of time sufficient to optimally convert the compound of formula II to the compound of formula I, and then treating the reaction mixture with an acid and purifying the compound of formula I in nitirles, ethers or mixtures there of.

In an embodiment of the present invention, compound of formula II reacted with bominating agent dibromo-5,5-dimethylhydantoin in s suitable solvent to provide the compoundof formula I, where I suitabl solvent is selected from nitrile solvents such as acetonitrile, propionotrile, isobutyrinitrile or mixture there of.

In an embodiment of the present invention , The term "temperature . . . . sufficient to optimally convert the compound of the formula II to compound of the formula I" represents a temperature sufficiently high to maintain conversion of the starting material II but also sufficiently low to avoid decomposition of the starting material and the product. The term includes temperatures between 80°C and 90°C. A preferred temperature is between 80° and 85°C. The term "length of time sufficient to optimally convert the compounds of the formula II to compound of the formula I" represents a period of time sufficiently long to convert the maximum amount of the starting material to the compound of the formula I. The term includes times of 4 to 8 hours. A preferred length of time is a time length between 6 to 7 hours.

Another embodiment of the present invention is that process wherein the brominating agent employed is dibromodimethylhydantoin in an amount selected from a value in the range between 0.5 to 0.7 molar equivalents with respect to starting aromatic compound of formula II.

Another embodiment of the present invention ,The term "acid" includes aqueous acidic solutions..The term "aqueous acidic solution" includes solutions of acid in an aqueous solvent,where in acid selected form citric acid, ascorbic acid, acetic acid A preferred aqueous solvent is water.

In an embodiment of the present invention, different solvents were initially explored to avoid the use of CCl4. Unfortunately, the reaction does not work in water, but it works well in CH3CN, which are less toxic than CCl4; however, Accordingly, CH3CN was chosen as the most suitable solvent to perform the reaction. Hence Applicant conducted number experiments to select brominating solvent while using 1,3-dibromo-5,5-dimethylhydantoin as brominating agent which were summarized below:

S.NO Solvent Temperature and hours DBDMH mole equivalents Observations
1. Dichloro methane 35°C, 10hrs 0.65 50% unreacted starting material observed.
2. CCl4 70°C, 9hrs 0.6 Yield :72% with Dibromo impurity 3%
3. MTBE 50°C, 10 hrs 06 50% unreacted starting material observed
4 Acetonitirle 80°, 6 hrs 0.55 Yield : 86% with HPLC purity >99%
5 Propionitrile 80°C,6 hrs 0.55 Yield :85% with HPLC purity >99%
6 EDC 80°C 0.6 Yield :70% with Dibromo impurity 2%

In conclusion, present inventors developed an efficient method for the benzylic radical bromination in good yields, without the use of chlorinated solvents and avoiding the formation of by-products. The applied conditions allow to obtain the desired bromoderivatives in a reproducible manner at different scale processes.

Another embodiment of the present invention is purifying the compound of formula I in nitirles, ethers or mixtures there of. Wherein nitrile solvents such as acetonitrile, propionotrile, isobutyrinitrile ; ethers such as methyl tertiarybutyl ether, tetrahydrofuran, diethyl ether, methyl isobutyl ether, isopropyl ether or mixtures thereof.

As per the comparision with the prior arts with current patent application process are summarized below:
S.no Brominating agent Required moles w. r. to Formula II Impurities Solvent /reaction conditions Yield
1. N-bromo succinimide 1.05
Impurity-A CCl4 44%

Impurity-B
2 N-bromo succinimide 1.1 Not reported Trifluorotoluene
Overnight at 90°C 60%
3 Dibromodimethyl hydantoin 0.55 Less than 0.15% Acetonitirle, 80°C 6 hrs 86%
4 Dibromodimethyl hydantoin 0.55 Less than 0.15% Isopropyl nitrile, 80°C,6 hrs 85%

Using DBDMH allows for the selective monobromination of methyl groups or methylene groups adjacent to aromatic rings and progresses as a radical chain reaction.

The expected mechanism has a series of steps. First, when the N-Br bond present in DBDMH is radically cleaved, the resulting bromine radicals extract the benzylic hydrogen atoms, forming benzyl radicals and HBr. This HBr then reacts with the bromine atoms of the DBDMH, forming Br2 in situ. The Br2 reacts with the benzyl radicals mentioned above, brominating the benzylic position. Additional bromine radicals are generated in the bromination process, resulting in a radical chain reaction.

The process details of the invention are provided in the examples given below, which
are provided by way of illustration only and therefore should not be construed to limit
the scope of the invention.

Examples:
Comparative example 1:
Synthesis of 3-bromo-4-(bromomethyl)benzoic acid.

3-Bromo-4-methylbenzoic acid (10 g), N-bromosuccinimide (8.7 g) and 2,2'-azobisisobutyronitrile (0.4 g) were suspended in carbon tetrachloride (50 ml) and then heated to reflux for 2 hours. The mixture was returned to room temperature and added a 15% aqueous solution of citric acid (20 ml), and stirred for some time. Resulting crystals were filtered and washed with the 15% aqueous solution of citric acid (20 ml), and then dried, to obtain 3-bromo-4-(bromomethyl)benzoic acid (6 g)

Comparative example 2:
Synthesis of 3-bromo-4-(bromomethyl)benzoic acid

To a solution of 3-bromo-4-methylbenzoic acid (1.0 equiv.) and AIBN (0.05 equiv.) in trfluorotoluene (0.28 M) was added NBS (1.1 equiv.). The mixture was heated at 90 °C overnight. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with NaCI(sat.), dried over MgS04, filtered, concentrated to yield 3- bromo-4-(bromomethyl)benzoic acid in 60% yield.

Example 1: Preparation of 3-bromo-4-(bromo methyl)benzoic acid ( Formula-I)
To a clean and round RBF, 3-bromo-4-methyl benzoic acid 100 g, Acetonitirle(500 ml), AIBN(11gm), Dibromodimethylhydantoin(75gm)were added and heated to 80°C.Reaction mass stirred for 6 hrs. After completion of the reaction, distilled off the solvent completely under vacuum at 50 - 60°C.To the reaction mass ethylacetate (500ml) and 5% Citricacid solution(500ml) were added. Stirred and separated the organic layer followed by distilled off the solvent under vacuum . To this crude mixture of Acetonitirle(150ml) and Methyl tert-Butyl ether(50 ml) added, stirred at 50°C for 1 hour. Cooled to 25-30°C and filtered to obtain tiltled compound.
Yield: 86%
HPLC Purity:99.52%; ImpurityA:0.04%; Impurity B:0.03%

Example 2: Preparation of 3-bromo-4-(bromo methyl)benzoic acid ( Formula-I)
To a clean and round RBF, 3-bromo-4-methyl benzoic acid 100 g, isopropylnitirle(500 ml), AIBN(11gm), Dibromodimethylhydantoin(75gm)were added and heated to 80°C. Reaction mass stirred for 6 hrs. After completion of the reaction, distilled off the solvent completely under vacuum at 50 - 60°C. To the reaction mass ethylacetate (500ml) and 5% Citricacid solution(500ml) were added. Stirred and separated the organic layer followed by distilled off the solvent under vacuum . To this crude mixture of Acetonitirle(150ml) and Methyl tert-Butyl ether(50 ml) added, stirred at 50°C for 1 hour. Cooled to 25-30°C and filtered to obtain tiltled compound.

Yield: 85%
HPLC Purity:99.58%; ImpurityA:0.03%; Impurity B:0.03%

,CLAIMS:1. A process for the preparation 3-bromo-4-(bromo methyl) benzoic acid of Formula I,

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Formula-I
which comprises:
(i) treating a benzoic acid of the Formula II

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Formula-II
in a suitable solvent solvent with brominating agent 1,3-dibromo-5,5-dimethylhydantoin to obtain compound of Formula I; wherein suitable solvent is nitrile solvent.
(ii) Purifying the Formula I in nitirles, ethers or mixtures there of.

2 The process according to claim 1, Impurity A and Impurity B are less than 0.15%.

3. The process according to claim 1, wherein the reacting compound of Formula II with brominating agent 1,3-dibromo-5,5-dimethylhydantoin is carried out at a temperature of between 60°C and 90°C, preferably 75-85°C.

4. The process according to claim 1, wherein the nitrile solvents such as acetonitrile, propionotrile, isobutyrinitrile or mixture there of and ethers such as methyl tertiarybutyl ether, tetrahydrofuran, diethyl ether, methyl isobutyl ether, isopropyl ether or mixtures thereof.

5. The process according to claim 1, 3-bromo-4-(bromo methyl) benzoic acid of Formula I can be used in the synthesis of Tofogliflozin.