Claims:WE CLAIM
1. A crystalline Form-P of Canrenone (A), characterized by an X-ray diffraction pattern having peaks at 10.03, 13.21, 15.82, 17.37, 18.10, 19.42, 20.10, 21.90, 26.7 and 28.10 ± 0.2 degrees 2?.

2. The compound according to claim 1, characterized by an X-ray diffraction pattern having peaks with interplanar spacings (d) of around 8.82, 6.7, 5.6, 5.1, 4.9, 4.57, 4.41, 4.06, 3.34 and 3.17 ± 0.2 angstroms (Ao).

3. The compound (A) or its salts according to claim 1 of the following formula,

which is obtained by a process comprising the steps of,
(a) reacting the compound (1) of the following formula,

with a bromination agent in the presence of a cyclic amide solvent;
(b) optionally, isolating the bromo-intermediate compound (2) of the following formula obtained from step (a),

(c) reacting the compound (2) obtained from step (b) with a base,
(d) purifying the compound (A) or its salt by treatment with charcoal.

4. The compound according to the claim 3, wherein step (a) is performed in the presence of a cyclic amide solvent which is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), caprolactam, 2-piperidinone, azetidin-2-one, N-methyl caprolactame, 1-methylpiperidin-2-one and/or 1-methylazetidin-2-one; or a mixture thereof.

5. The compound according to the claim 3, wherein step (a) is performed in the presence of a bromination agent which is selected from the group consisting of bromine, 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (DBDMH), 1-bromo-2,5-pyrrolidinedione and/or N-bromoacetamide.

6. The compound according to the claim 3, wherein step (c) is performed in the presence of a base which is selected from the group consisting of a alkali metal hydroxides and alkali-earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide (KOH), magnesium hydroxide, calcium hydroxide and/or barium hydroxide.

7. The compound according to the claim 3, wherein the step (d) provides the compound (A) free from colored impurities.

8. The compound according to the claim 7, wherein the compound (A) is a white colored crystalline in nature.

9. A crystalline Form-B of compound (2), characterized by an X-ray diffraction pattern having peaks at 13.28, 13.52, 13.99, 14.54, 15.23, 16.02, 17.9, 18.93, 20.04, 21.20, 22.46, 23.11, 23.84, 26.08, 26.73, 27.10, 28.91, 30.03 and 34.71 ± 0.2 degrees 2?.
10. The compound according to claim 9, characterized by an X-ray diffraction pattern having peaks with interplanar spacings (d) of around 6.66, 6.54, 6.32, 6.09, 5.81, 5.53, 4.95, 4.69, 4.43, 4.19, 3.96, 3.84, 3.73, 3.41, 3.33, 3.29, 3.09, 2.97 and 2.58 ± 0.2 angstroms (Ao).

Dated this day of February 2019
_________________________
SRIDEVI KRISHNAN
GENERAL MANAGER- CORPORATE PATENTS
PIRAMAL ENTERPRISES LIMITED
(APPLICANT)
To,
The Controller of Patents
The Patent Office
At Mumbai
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of (8R,9S,10R,13S,14S,17R)-10,13-dimethyl-1,3',4',8,9,10,11,12,13,14,15,16-dodecahydro-5'H-spiro[cyclopenta[a]phenanthrene-17,2'-furan]-3,5'(2H)-dione; commonly known as Canrenone (referred to as the compound (A)), pharmaceutically acceptable salts thereof and its intermediates.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Canrenone (the Compound (A)), is an anti-mineralocorticoid diuretic drug, and it is effective in the treatment of hirsutism in women. The compound is also an important active metabolite of spironolactone. The drug is marketed under the brand various names such as LUVION and PHANURANE. The compound is chemically known as (8R,9S,10R,13S,14S,17R)-10,13-dimethyl-1,3',4',8,9,10,11,12,13,14,15,16-dodecahydro-5'H-spiro[cyclopenta[a]phenanthrene-17,2'-furan]-3,5'(2H)-dione, or its salt, and is structurally represented as follows;

Canrenone being an important diuretic drug; a number of processes for its preparation as well as for its intermediates are known in the art.

US patent No. 4,155,906 refers to a process for preparing 17-hydroxy-3-oxo-17a-pregna-4,6-diene-21-carboxylic acid ?-lactone which comprises contacting 3-ethoxy-17-hydroxy-17a-pregna-3,5-diene-21-carboxylic acid ?-lactone with a brominating agent in the presence of 2-methylpyridine, 2-methylpyridine hydrobromide, and approximately 1-2 molar equivalents (relative to the lactonic starting material) of water, using cold N,N-dimethylformamide as the contact medium, and heating the resultant mixture with lithium bromide, said process being carried out in an effectively inert atmosphere.

US patent No. 4,270,994 describes an electrochemical process for dehydrogenating steroidal ?3,5 enol ethers to provide the corresponding ?4,6 dienone comprising the steps of reacting a steroidal ?3,5 enol ether in the present of a high potential catalyst, under basic conditions, with a suitable electolyte solution, at an applied voltage sufficient so that current passes, phenol is oxidized, the ?3,5 enol remains inert to the anode and the reaction proceeds to completion, and thereafter recovering the steroidal ?4,6 dienone from the reaction mixture. The patent US’994 describes a process for obtaining 17-hydroxy-3-oxo-17-a-pregna-4,6-diene-21-carboxylic acid ?-lactone by the electrochemical dehydrogenation of 3-ethoxy-17-hydroxy-17-a-pregna-3,5-diene-21-carboxylic acid-?-lactone using 2,3-dichloro-5,6-dicyanobenzoquinone as the catalyst as depicted below:

US patent No. 2,900,383 refers to a process for preparing 17a-carboxyethyl-17beta-hydroxyandrosta-4,6-dien-3-one lactone comprises reacting 17alpha-carboxyethyl-17beta-hydroxyandrost-4-en-3-one lactone with chloranil and p-toluenesulfonic acid in Xylene. The obtained product is further purified b chromatography using benzene and ethyl acetate solvent.

In addition to the afore discussed patent documents, there are a number of patent documents that describe a process for the preparation of similar compounds, its intermediates and salts thereof. For instance, the documents HU11926; PL165021B1; US 4,211,701; GB1548259 and US 3,194,803 describes a process for the preparation of the compound.

It is evident from the discussion of the processes for the preparation of Canrenone, its intermediates and its salts, described in the afore cited patent documents that the reported processes provide a product with low yield and purity, which requires repeated purification or multiple crystallization steps. Precisely, the prior art process provides the yellow colored product, which contains colored impurities. Such material requires multiple purification steps or column chromatography to obtain pure white material in order qualify the material under International Conference on Harmonization (ICH) guidelines. Also, the prior art process refers the use of critical reagent such as bromine which is hazardous for human handling and requires controlled environment; which renders the process costlier and hence are not industrially feasible. In view of these drawbacks, there is a need to develop an industrially viable commercial process for the preparation of Canrenone; which is a simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity.

Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any toxic and/or costly solvents, also does not involve use of costlier coupling agents and reagents. Moreover, the process does not require repetitive purification steps. Accordingly, the present invention provides a process for the preparation of pure white Canrenone, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to an improved process for the preparation of Canrenone (the compound (A)) or its salt, comprising the steps of:
(a) reacting the compound (1) (as described herein) with a bromination agent in the presence of a cyclic amide solvent;
(b) optionally, isolating the bromo-intermediate compound (2) (as described herein) obtained from step (a);
(c) reacting the compound (2) obtained from step (b) with a base,
(d) purifying the compound (A) or its salt by treatment with charcoal.

In another aspect, the present invention provides a novel crystalline Form-P of Canrenone; characterized by the X-ray powder diffraction graph as Figure-1 and Table-1.

In another aspect, the present invention provides a novel crystalline Form-B of (8R,9S,10R, 13S,14S,17R)-6-bromo-3-ethoxy-10,13-dimethyl-1,2,3,3',4',8,9,10, 11,12,13,14,15,16-tetradecahydro-5'H-spiro[cyclopenta[a]phenanthrene-17,2'-furan]-5'-one (the intermediate Compound (2)); characterized by the X-ray powder diffraction graph as Figure-2 and Table-2.

In another aspect, there is provided crystalline white coloured Canrenone (A) substantially free from coloured impurities.

DESCRIPTION OF THE FIGURES
Figure-1: X-ray powder diffraction (XRPD) pattern of the crystalline Form-P of Canrenone.
Figure-2: X-ray powder diffraction (XRPD) pattern of the crystalline Form-B of bromo-intermediate compound (2).

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of Canrenone (the compound (A)) or its salt represented by the following formula,

comprising the steps of;
(a) reacting (8R,9S,10R,13S,14S,17R)-3-ethoxy-10,13-dimethyl-1,2,3',4',7,8, 9,10,11,12,13,14,15,16-tetradecahydro-5'H-spiro[cyclopenta[a]phenanthrene-17,2'-furan]-5'-one (the compound (1)) represented by the following formula,

with a bromination agent in the presence of a cyclic amide solvent;
(b) optionally, isolating (8R,9S,10R,13S,14S,17R)-6-bromo-3-ethoxy-10,13-dimethyl-1,2,3,3',4',8,9,10,11,12,13,14,15,16-tetradecahydro-5'H-spiro[cyclopenta[a]phenanthrene-17,2'-furan]-5'-one (the bromo-intermediate compound (2)) represented by the following formula obtained from step (a),

(c) reacting the compound (2) obtained from step (b) with a base,
(d) purifying the compound (A) or its salt by treatment with charcoal.
In the context of the present invention, the term "optionally" when used in reference to any element; including a process step e.g. isolation of a compound; it is intended to mean that the subject element is isolated, or alternatively, is not isolated and converted to a further compound by in-situ transformation. Both alternatives are intended to be within the scope of the present invention.
In an embodiment, the cyclic amide solvent is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), caprolactam, 2-piperidinone, azetidin-2-one, N-methyl caprolactame, 1-methylpiperidin-2-one and 1-methylazetidin-2-one; or a mixture thereof.
In an embodiment, the cyclic amide solvent is N-methyl-2-pyrrolidone (NMP).
In a specific embodiment, the process for the preparation of Canrenone (A) or its salt comprises the steps of:
(i) dissolving the compound (1) in an cyclic amide solvent;
(ii) cooling the reaction mixture of the above step (i) to a temperature of about -15 oC;
(iii) adding a brominating agent to the reaction mixture of step (ii);
(iv) optionally, isolating the bromo-intermediate compound (2) obtained from step (iii);
(v) adding a base to the reaction mixture containing of compound (2);
(vi) heating the reaction mixture of the above step (v) at temperature of about 95 oC;
(vii) cooling the reaction mixture of the above step (3) at temperature of about 30 oC;
(viii) isolating the product Canrenone (A);
(ix) dissolving the compound (A) of step (viii) in a solvent;
(x) heating the reaction mixture of the above step (v) at temperature of about 80 oC;
(xi) adding charcoal to the hot solution of step (x);
(xii) isolating the white crystalline Canrenone (A) free of colored impurities.
The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme-A,

The cyclic amide solvent used in the step-(i) of the above process (as depicted in the Scheme-A) is selected from the group consisting of N-methyl-2-pyrrolidone, caprolactam, 2-piperidinone, azetidin-2-one, N-methyl caprolactame, 1-methylpiperidin-2-one and 1-methylazetidin-2-one; or a mixture thereof.

In an embodiment, the amide solvent used in step-(i) of the above process (as depicted in the Scheme-A) is N-methyl-2-pyrrolidone (NMP).

The term ‘temperature of about -15 oC’ referred to in the step (ii) of the above process (as depicted in the Scheme-A) can range from -20 oC to -5 oC.
The brominating agent used in the step-(iii) of the above process (as depicted in the Scheme-A) is selected from the group consisting of bromine (Br2), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (DBDMH), 1-bromo-2,5-pyrrolidinedione and/or N-bromoacetamide.
The term ‘isolating the product’ referred to in the step(s) (iv), (viii) and (xii) corresponds to any of the commonly used isolation methods, involving separation of organic phase, filtration, evaporation of solvent, precipitation, filtration of precipitated product, washing and drying.
The term "optionally" referred to as in the step (iv), used in context to ‘isolating’; is intended to mean that the subject element is isolated, or alternatively, is not isolated and converted to a further compound by in-situ transformation. Both alternatives are intended to be within the scope of the present invention.
The base used in the step-(v) of the above process (as depicted in the Scheme-A) is selected from the group consisting of a alkali metal hydroxides and alkali-earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide (KOH), magnesium hydroxide, calcium hydroxide and/or barium hydroxide,
The base used in the step-(v) of the above process (as depicted in the Scheme-A) is selected from the group consisting of potassium hydroxide (KOH).

The term ‘temperature of about 95 oC’ referred to in the step (vi) of the above process (as depicted in the Scheme-A) can range from 90 oC to 100 oC.
The solvent used in the step-(ix) of the above process (as depicted in the Scheme-A) is selected from the group consisting of an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane and 1,3-dioxane; an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; ketone such as acetone; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; water or a mixture thereof.

In an embodiment, the solvent used in step-(ix) of the above process (as depicted in the Scheme-A) is an alcohol solvent, such as isopropanol (IPA).
Similarly, the process of the present invention as per the specific embodiment described above is illustrated in the following Scheme-Ax,

The process of the present invention as illustrated in the above Scheme-Ax comprises suspending the compound (8R,9S,10R,13S,14S,17R)-3-ethoxy-10,13-dimethyl-1,2,3',4',7,8,9,10,11,12, 13,14,15,16-tetradecahydro-5'H-spiro[cyclopenta[a]phenanthrene-17,2'-furan]-5'-one (1) in 2-picoline and 48% hydrobromic acid (HBr) solution, followed by treatment with a brominating agent, such as 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (DBDMH). The obtained bromo-intermediate compound (2) was further treated with the lithium bromide (LiBr)/ potassium hydroxide (KOH); followed by isolating the crude Canrenone (A). The crude compound was purified by the charcoal treatment, to provide white crystalline Canrenone (A) free of colour impurities, with about overall about 60% yield and a purity of at least 99% HPLC purity.

The term “about” in reference to the yield means a range of + 5% of the specified yield.
It is evident from the processes reported in the prior art that the Canrenone was obtained with low yield and purity, precisely the prior art process provides the yellow colored product; whereas the process of the present invention provided the white crystalline Canrenone (A) free of colored impurities. It is further evident that the prior art process refers the use of column chromatography to obtain pure product; which is avoided in the currently presented improved process. This amounts to a significant advantage over the processes reported in the prior art.

According to another aspect, the present invention provides a novel crystalline Form-P of Canrenone.
Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.

In an embodiment, the crystalline Form-P of Canrenone (A) is characterized by an X-ray diffraction pattern having peaks at 10.03, 13.21, 15.82, 17.37, 18.10, 19.42, 20.10, 21.90, 26.7 and 28.10 ± 0.2 degrees 2?.

In an embodiment, the crystalline Form-P of Canrenone (A) is characterized by an X-ray diffraction pattern having peaks with interplanar spacings (d) of around 8.82, 6.7, 5.6, 5.1, 4.9, 4.57, 4.41, 4.06, 3.34 and 3.17 ± 0.2 angstroms (Ao).

In an embodiment, the crystalline Form-P of Canrenone is further characterized by the X-ray powder diffraction graph as Figure-1 and corresponding Table-1.

The X-ray powder diffraction spectrum of Canrenone was measured under the following experimental conditions:
Instrument : X-Ray Diffractometer, Bruker D8 Advance
X- Ray : Cu/40kv/40mA
Diverging : 0.3°
Counter : Lynx Eye
Scan Mode : Continuous
Scan Axes : Two Theta/Theta
Scan Range : 3° to 40°
Generator power: 40 kV, 40 mA
Scan range : 3-40° 2 ?
Step size : 0.02°
Step time : 0.25 sec
Sample rotation: 15rpm
Detector : Lynx-Eye

Table-1: summarizes the d-spacing values in Ao, and the corresponding 2? angle values of the crystalline Form-P of Canrenone.
Form-P
Canrenone
Angle
2-Theta ° d-spacing value
Angstrom Intensity %
10.03 8.82 30.30
13.21 6.7 100
15.82 5.6 42.20
17.37 5.1 33.90
18.10 4.9 34
19.42 4.57 19.10
20.10 4.41 49.80
21.90 4.06 10.40
26.7 3.34 14.80
28.10 3.17 10.90

According to another aspect, the present invention provides a novel crystalline Form-B of (8R,9S,10R,13S,14S,17R)-6-bromo-3-ethoxy-10,13-dimethyl-1,2,3,3',4',8,9,10,11,12,13,14,15, 16-tetradecahydro-5'H-spiro[cyclopenta[a]phenanthrene-17,2'-furan]-5'-one (the bromo- intermediate Compound (2)).

In an embodiment, the crystalline Form-B of the bromo-intermediate Compound (2) is characterized by the X-ray diffraction pattern having peaks at 13.28, 13.52, 13.99, 14.54, 15.23, 16.02, 17.9, 18.93, 20.04, 21.20, 22.46, 23.11, 23.84, 26.08, 26.73, 27.10, 28.91, 30.03 and 34.71 ± 0.2 degrees 2?.

In an embodiment, the crystalline Form-B of the bromo-intermediate Compound (2) is characterized by an X-ray diffraction pattern having peaks with interplanar spacings (d) of around 6.66, 6.54, 6.32, 6.09, 5.81, 5.53, 4.95, 4.69, 4.43, 4.19, 3.96, 3.84, 3.73, 3.41, 3.33, 3.29, 3.09, 2.97 and 2.58 ± 0.2 angstroms(Ao).

In an embodiment, the crystalline Form-B of the bromo-intermediate Compound (2) is further characterized by the X-ray powder diffraction graph as Figure-2 and corresponding Table-2.

The X-ray powder diffraction spectrum of the bromo-intermediate Compound (2) was measured under the following experimental conditions:
Instrument : X-Ray Diffractometer, Bruker D8 Advance
X- Ray : Cu/40kv/40mA
Diverging : 0.3°
Counter : Lynx Eye
Scan Mode : Continuous
Scan Axes : Two Theta/Theta
Scan Range : 3° to 40°
Generator power: 40 kV, 40 mA
Scan range : 3-40° 2 ?
Step size : 0.02°
Step time : 0.25 sec
Sample rotation: 15rpm
Detector : Lynx-Eye

Table-2: summarizes the d-spacing values in Ao, and the corresponding 2? angle values of the crystalline Form-B of the bromo-intermediate Compound (2).

Form- B
bromo-intermediate Compound (2)
Angle
2-Theta ° d-spacing value
Angstrom Intensity %
13.28 6.66 22.70
13.52 6.54 24.00
13.99 6.32 15.60
14.54 6.09 100
15.23 5.81 17.50
16.02 5.53 47.60
17.9 4.95 54.60
18.93 4.69 19.30
20.04 4.43 42.60
21.20 4.19 23.10
22.46 3.96 10.30
23.11 3.84 44.20
23.84 3.73 11.60
26.08 3.41 14.90
26.73 3.33 13.20
27.10 3.29 10.30
28.91 3.09 13.60
30.03 2.97 19.90
34.71 2.58 11.30

In another aspect, there is provided crystalline white coloured Canrenone (A) substantially free from coloured impurities.

In an embodiment, the crystalline Form-P of white coloured Canrenone (A) substantially free from coloured impurities is obtained by following general procedure comprises;
(s) suspending/ dissolving Canrenone in an alcoholic solvent,
(t) heating the reaction mixture of step (s) at reflux temperature,
(u) adding charcoal to the hot solution of step (t),
(v) filtering the solution of step (u) and separating the charcoal,
(w) optionally, repeating the procedure of step (s) to step (v),
(x) adding water to the filtrate of step (w),
(v) isolating the precipitated solid.

In an embodiment, the alcoholic solvent used in the step-(s) is selected from but not limited to methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol, hexanol; or a mixture thereof.

The invention is further illustrated by the following example(s) which are provided to be exemplary of the invention, and do not limit the scope of the invention. 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 intended to be included within the scope of the present invention.

EXAMPLES
Example-1: Preparation of Canrenone (the compound (A))
Charged 15 mL of N-methyl-2- pyrrolidone (NMP) in a flask followed by the addition of 5 mL 2-picoline and the reaction mixture was cooled to a temperature of about 0 to 10 °C. To the stirring solution was added 1.2 ml 48% hydrobromic acid (HBr) solution and the reaction mixture was further cooled to a temperature of about -10 to -15 °C. To the stirring solution was added 10 g of the compound (1), 3.9 g of 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (DBDMH) and 1 g of sodium metabisulfate. To the same reaction mixture was added 2.3 g of LiBr (Lithium Bromide) and heated to a temperature of about 90-95 °C for 2 hrs. The reaction mixture was cooled to 40-50 °C of temperature and to the reaction mixture was added 4.8 g of 45% aqueous potassium hydroxide (KOH) solution followed by addition of 1.5 mL of water at 40-50 °C of temperature. To the reaction mixture was added 5.8 mL of 80% aqueous acetic acid (AcOH) solution and 1.4 mL of concentrated hydrochloric acid at 40-50 °C, and was further heated to 80-85°C. The reaction mixture was cooled to 25-30 °C of temperature followed by the addition of 80 mL water. To the reaction mixture was added 6 mL of aqueous ammonia and precipitated solid was filter and wash with (50 mL X 2) water, and the wet cake was taken for purification.
Purification:
The above wet cake was charged in a flask followed by the addition of 120 mL of Isopropyl alcohol (IPA), and heated the mixture to a temperature of about 75-80 °C. To the hot reaction mixture was added 5.4 g of charcoal (Darco G60) and further stirred for 30 min. The reaction mixture was filtered through hyflo and washed with 40 mL of IPA. The filtrate was again charged in a flask followed by the addition of 5.4 g of charcoal (Darco G60) and heated the mixture to a temperature of about 75-80 °C. The reaction mixture was filtered through hyflo and washed with IPA. The filtrate was distilled under vacuum till the volume remains about 30 ml, followed by the dropwise addition of 150 mL of water at about 75-80 oC temperature. The precipitated solid was filter and wash with (50 mL X 2) water and dried to provide the pure white crystalline compound (A) with (Yield: 60%)
Example-2: Preparation of crystalline bromo intermediate (the compound (2))
Charged 7.5 mL of N-methyl-2- pyrrolidone (NMP) in a flask followed by the addition of 2.5 mL 2-picoline and the reaction mixture was cooled to a temperature of about 0 to 10 °C. To the stirring solution was added 0.6 ml 48% hydrobromic acid (HBr) solution and the reaction mixture was further cooled to a temperature of about -10 to -15 °C. To the stirring solution was added 5 g of the compound (1), 1.95 g of 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (DBDMH) was slowly added in 1.5-2 hrs at -10 °C and stirred for 1.5-2 hrs at -10 °C. Water (50 mL) was added to the stirring solution at temperature of about 0 °C and continued stirring for at room temperature for about 2 hrs. The material was filtered and cake washed by water (25 mL x 2). The material was dried under vacuum to provide the bromo-intermediate compound (2) with
Yield: 5.5 gm.