DESC:TITLE: AN IMPROVED PROCESS FOR PREPARATION OF MARAVIROC

FIELD OF THE INVENTION
The present invention relates to the field of pharmaceuticals. More particularly the present invention relates to an improved process for preparation of Maraviroc compound of formula I which is used in the treatment of retroviral infections.

BACKGROUND OF THE INVENTION
Maraviroc chemically known as N-{(1S)-3-[3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}-4,4-difluorocyclohexanecarboxamide and has the following structure of formula I.

Maraviroc acts as modulators of the chemokine receptor CCR5 and thus useful in the treatment of retroviral diseases caused by viruses that utilize CCR5 to enter cells. In particular Maraviroc has been disclosed as being a useful therapeutic in the treatment of HIV, a retroviral infection genetically related to HIV, AIDS, or an inflammatory disease. Maraviroc is first approved in USA on November 04th, 2016 under the trade name Selzentry or Celsentri in rest of the world and marketed by Pfizer.
Maraviroc was first disclosed in US 6667314B2 (hereafter US ‘314). Various processes for preparation of Maraviroc were disclosed in the US ‘314. One such process disclosed in US ‘314 is by reacting compound of formula VII in a solvent with Sulphur trioxide pyridine complexin the presence of base followed by purification using mixture of ethyl acetate and methyl-tert-butyl ether to obtain compound of formula III. Further the compound of formula III is reacted with compound of formula II in presence of Sodium triacetoxyborohydride to obtain compound of formula I. The reaction scheme disclosed in US ‘314 is as follows (Scheme I).

Further, the US ‘314 discloses a process for the preparation of compound of formula VI comprising reacting compound of formula IV with compound of formula V in presence of base followed by isolation using mixture of ethyl acetate and heptane solvents to obtain compound of formula VI. The yield reported was 66.0%.

Organic Process Research & Development Volume: 12, Issue: 6, Pages: 1104-1113, Journal: 2008 discloses the process for preparation of Maraviroc compound of formula I comprising reacting compound of formula IV with compound of formula V in presence of base followed by isolation using mixture of solvents to obtain compound of formula VI and further reduction of compound of formula VI obtained compound of formula VII; Oxidation of compound of formula VII using TEMPO in presence of sodium bromide, base and sodium hypochlorite followed by isolation obtained compound of formula III which is further reacted with p-toluenesulfonic acid salt of compound of formula II in presence of Sodium triacetoxyborohydride to obtain compound of formula I.

The reaction scheme as disclosed in Organic Process Research & Development is as follows (Scheme III).

The process disclosed in Organic Process Research & Development has several drawbacks such as safety issues associated with the handling of Red-Al on scale (2-methoxyethanol is ateratogen) and complex workup to remove aluminium salts; oxidation of compound of formula VII generates a methylthiomethyl etherimpurity, which requires additional processing to purge, and generates DMS as a byproduct; final step reductive amination utilises dichloromethane as a solvent and is low yielding.Portion wise addition of NaBH(OAc)3 was not possible in plant scale due to the potential for hydrogen evolution.

The Indian patent application IN 201621036850 (hereafter IN ‘850) discloses a process for preparation of Maraviroc of compound of formula I comprising: converting compound of formula VIII to a compound of formula IX followed by reacting it with (S)-3-amino-3-phenylpropan-1-ol to obtain compound of formula VII; A further oxidation of compound of formula VII and its isolation obtained compound of formula III; A further reaction of formula III with phosphoric acid salt of compound of formula II obtained Maraviroc. The reaction scheme as disclosed in IN ‘850 is as follows (Scheme IV).

The Indian patent application IN 1840/MUM/2012 (hereafter IN ‘1840) discloses the process for preparation of Maraviroc compound of formula I by reductive amination comprising reacting compound of formula II with compound of formula III in presence of ammonium salt followed by isolation to obtain compound of formula I. The reaction scheme as disclosed in IN ‘1840 is as follows in the scheme V.

Overall processes for the preparation of Maraviroc described in the prior art suffer from disadvantages since the process involve tedious and cumbersome procedures such as lengthy and multiple synthesis steps, tedious work up procedures and multiple solvents are used for isolation of intermediates.

Maraviroc obtained by the processes described in the prior art does not have satisfactory purity and yield. Further, during the formation of Maraviroc intermediate unacceptable amounts of impurities are formed along with Maraviroc at various stages of the process that are difficult to purify and thus get carried forward in the subsequent steps thereby affecting the purity of final compound.

Therefore, there is need a of improved isolation process for preparation of Maraviroc intermediate and improved process for preparation of Maraviroc, which overcomes the drawbacks of prior art. The present inventors have surprisingly found an efficient process for the preparation Maraviroc and improved isolation process for preparation of Maraviroc intermediate or which offers advantages over the prior art processes in terms of High purity, less effluents, use of less amount of solvent during isolation, synthesis time is short and simple scalable procedure suitable for large scale production.

OBJECT OF THE INVENTION
The primary object of the present invention is to provide a simple, economic safe industrially viable process for preparation of Maraviroc compound of formula I.

Yet another object of the present invention is to provide improved isolation process for preparation of Maraviroc intermediate compound of formula VI with high purity.

Another one object of the present invention is to provide improved isolation process for preparation of Maraviroc intermediate compound of formula VII with high purity.

One more object of the present invention to provide to simple, economic safe industrially viable process for preparation of substantially Maraviroc compound of formula I with high purity.

One more object of the present invention is to provide polymorphic forms of the intermediate compounds of Maraviroc characterized by the X-ray diffractograms.

BRIEF DESCRIPTION OF DRAWINGS:
1. Fig 01 illustrates the X-ray diffractogram of formula VI prepared according to example 02.
2. Fig 02 illustrates the X-ray diffractogram of formula VI prepared according to example 03.

SUMMARY OF THE INVENTION
ASPECT-I:
One aspect of the present invention provides an improved process for the preparation of compound of formula VI

Comprising the steps of:
a) Reacting compound of formula IV or its acid addition salt

with a compound of formula V;
; and
b) isolating compound of formula VI from a suitable solvent.

ASPECT-Ia:
One preferred aspect of the present invention provides an improved process for the preparation of compound of formula VI

Comprising the steps of:
a) Reacting compound of formula IV or its acid addition salt

with a compound of formula V;

; and
b) isolating compound of formula VI from the solvent Toluene.

ASPECT-II:
Another aspect of the present invention provides an improved process for the preparation of compound of formula VII

comprising the steps of:
c) Reacting compound of formula VI

with a reducing agent; and
d) isolating compound of formula VII from a suitable solvent.
ASPECT-IIa:
Another preferred aspect of the present invention provides an improved process for the preparation of compound of formula VII

comprising the steps of:
c) Reacting compound of formula VI

with a reducing agent; and
d) isolating compound of formula VII from the solvent Toluene.

ASPECT-III:
One aspect of the present invention provides an improved process for the preparation of compound of formula VII

Comprising the steps of:
a) Reacting compound of formula IV or its acid addition salt

with a compound of formula V;

b) isolating compound of formula VI from a suitable solvent;
c) reacting compound of formula VI

with a reducing agent; and
d) isolating compound of formula VII from a suitable solvent;
wherein both the compounds VI and VII are isolated from the same solvent.

ASPECT-IV:
One aspect of the present invention provides an improved process for the preparation of Maraviroc comprising the steps of:
e) Reacting compound of formula VII

with an oxidizing agent to obtain compound of formula III;

f) reacting insitu the compound of formula III with compound of formula II

in presence of sodium triacetoxyborohydride to obtain Maraviroc.

ASPECT-V:
One another aspect of the present invention provides an improved process for the preparation of Maraviroc comprising the steps of:
a) Reacting compound of formula IV or its acid addition salt

with a compound of formula V;

b) isolating compound of formula VI from a suitable solvent;
c) reacting compound of formula VI

with a reducing agent;
d) isolating compound of formula VII from a suitable solvent;
e) reacting compound of formula VII

with an oxidizing agent to obtain compound of formula III; and

f) reacting the compound of formula III with compound of formula II

in presence of a reducing agent to obtain Maraviroc.

ASPECT-VI:
Some aspects of the present invention also relate to Polymorphic forms of intermediate compounds of formula VI & VII characterized by their X-ray Diffractograms.

DEFINITIONS
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.

All temperatures used herein are in degrees Celsius unless specified otherwise.

All ranges recited herein include the endpoints, including those that recite a range "between" two values.

As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.

The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.

DETAILED DESCRIPTION
The inventors of the present invention have surprisingly found that by employing the improved conditions of the present invention the present process has eliminated the potential impurities that are otherwise formed in the prior art process and helped them in achieving the Maraviroc in high purity.

The potential impurities that are formed in the prior art process are:

Further, the present inventors have developed a process wherein the intermediates VI and VII were isolated using the same solvent. Usage of single solvent in two steps for the isolation is economical, environment friendly and avoids recycling of multiple solvents.

Further, the present invention involves in-situ reaction and eliminates the isolation of intermediate compound of formula III thereby rendering the process simple and avoids unnecessary steps of isolating the intermediate compound.

The improved process of the present invention can be schematically represented as below:

Accordingly, the present invention provides a process for the preparation of compound of formula VI

Comprising the steps of:
a) Reacting compound of formula IV or its acid addition salt

with a compound of formula V;

; and

b) isolating compound of formula VI from a suitable solvent.

The starting material of formula IV of the present invention is commercially available or can be prepared by the prior art process such as the process as described in, but not limited to Bulletin des Societes Chimiques Belges, Volume: 105, Issue: 10-11, Pages: 711-719 Journal: 1996.

In one preferred embodiment, the HCl acid addition salt of compound of formula IV is used in step a).

The starting material of formula V of the present invention is commercially available or can be prepared by the prior art process such as the process as described in, but not limited to, US 6667314B2.

The Step a) process of reacting formula IV with formula V can be carried in presence of a base. The suitable base may include organic and inorganic bases. An organic base may be selected from, but not limited to, primary, secondary or tertiary amines such as methylamine, N-methyl morpholine, ethylamine, n-propylamine, isopropylamine, triethylamine, N,N-diisopropylethylamine and the like. Inorganic base may be selected from, but not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, cesium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. Preferably selected base is alkali metal carbonates, more preferably sodium carbonate.

The Step a) process of reacting formula IV with formula V can be suitably carried out at a temperature of about 20°C to about 60°C, preferably at about 30°C to 50°C for sufficient period of time to complete the reaction, preferably for 1 to 8 hours, more preferably 2 to 4 hours.

In the above process of step b), the suitable solvent for the isolation of compound of formula VI includes, but not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water. Preferably the solvent selected is hydrocarbons, more preferably Toluene.

In some embodiments, the isolated compound of formula VI has the X-ray diffractogram as shown in Figure 01.

The particle size of the compound of formula VI isolated according to the present invention has a particle size of D(10) < 15µm; D(50) < 50µm; and D(90) < 100µm.

Another aspect of the present invention provides an improved process for the preparation of compound of formula VII

Comprising the steps of:
c) Reacting compound of formula VI

with a reducing agent; and
d) isolating compound of formula VII from a suitable solvent.

The reducing agent used in the step c) of above process may be selected from, but not limited to, Lithium triethylborohydride (LiBHEt3), Lithium aluminum hydride (LiAlH4), Sodium borohydride (NaBH4), Magnesium borohydride Mg(BH4)2, Aluminum borohydride Al(BH4)2, Calcium borohydride Ca(BH4)2, Zinc borohydride Zn(BH4)2, Sodium cyanoborohydride NaBH3CN and Sodium triacetoxyborohydride NaBH(OAc)3. Preferably selected reducing agent is Sodium borohydride (NaBH4).

The reaction of step c) of above process can suitably be carried out at a temperature of about 20°C to about 60°C, preferably at about 30°C to 50°C for sufficient period of time to complete the reaction, preferably for 1 to 14 hours, more preferably 2 to 4 hours.

In the above process of step d), the suitable solvent for the isolation of compound of formula VII includes, but not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water. Preferably the solvent selected is hydrocarbons, more preferably Toluene.

In some embodiments, the isolated compound of formula VII has the X-ray diffractogram as shown in Figure 02.

The particle size of the compound of formula VI isolated according to the present invention has a particle size of D(10) < 10µm; D(50) < 200µm; and D(90) < 500µm.

One aspect of the present invention provides an improved process for the preparation of Maraviroc comprising the steps of:
e) Reacting compound of formula VII

with an oxidizing agent to obtain compound of formula III; and

f) reacting insitu the compound of formula III with compound of formula II

in presence of sodium triacetoxyborohydride to obtain Maraviroc.

In the above process of step e), the suitable oxidising agent may be selected from, but not limited to, DMSO/sulphur trioxide-pyridine complex, DMSO with (COCl)2, MnO2 or CrO3, TPAP (tetrapropylammoniumperruthenate), TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) and NMO (4-methylmorpholine N-oxide). Preferably oxidising agent is TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical).

In the above process of step e), the reaction can be carried in presence of a suitable base. The suitable base used may be selected from organic and inorganic bases. Organic base may be selected from, but not limited to, primary, secondary or tertiary amines such as methylamine, n-methyl morpholine, ethylamine, n-propylamine, isopropylamine, triethylamine, N,N-diisopropylethylamine and the like. Inorganic base may be selected from, but not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, cesium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. Preferably selected base is alkali metal bicarbonates, more preferably sodium bicarbonate.

The reaction of step e) of the above process can be suitably carried out at a temperature of about 0°C to about 50°C, preferably at about 0°C to 10°C for sufficient period of time to complete the reaction, preferably for 1 to 4 hours, more preferably 1 to 2 hours.

The suitable solvent for the in situ reaction of compound of formula III with compound of formula II is acetic acid and dichloromethane.

In the process of above step f), the product Maraviroc is obtained by isolation from a suitable solvent. The suitable solvent includes, but not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water. Preferably the solvent selected hydrocarbons, more preferably ethyl acetate.

EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example 01:
Preparation of 4, 4-Difluorocyclohexane carbonyl chloride [Formula V]
A reaction flask was charged with 4, 4-Difluorocyclohexanecarboxylic acid (250 g), toluene (625 mL) and thionyl chloride (906 g). The mixture was heated to 50-60°C and maintained at the same temperature for 3 hours and completion of the reaction was monitored by HPLC. After completion of reaction, the mixture was cooled to 40-50°C and the excess thionyl chloride was removed under reduced pressure to give title compound.
Yield: 245 gms (88.12% w/w)
HPLC Purity: 99.9%

Example 02:
Preparation of (S)-ethyl 3-(4,4-difluorocyclohexanecarboxamido)-3-phenylpropanoate [Formula VI]
A reaction flask was charged with Methylene Dichloride (here after called MDC) (750 mL), Ethyl (3S)-3-amino-3-phenylpropanoate hydrochloride (150 g), Water (750 mL) and sodium carbonate (239.5 g) at ambient temperature, and the mixture was cooled to 0-10°C. The acid chloride of example 01 in MDC (129gms dissolved in MDC) was added to the reaction mixture and maintained at the same temperature for 2 hours and completion of the reaction was monitored by HPLC. After completion of the reaction, added water (1500 mL) into reaction mass and the phases were separated. The organic layer was distilled out under vacuum. Charged toluene (1050 mL) into residue and stirred at 30-40°C for 2hrs and further cooled to 0-5°C and maintained for 2-4 hours. The solid was isolated by filtration and washed with toluene at 0-5°C.The solid isolated was subjected to drying under vacuum at 45- 55°C.
The recovered MDC and Toluene from Filtrate mother liquors were recycled and re used for preparation and isolation of (S)-ethyl 3-(4,4-difluorocyclohexanecarboxamido)-3-phenylpropanoate.
Yield: 203 gms (92 %)
HPLCPurity: 99.9 %.
XRD: Fig 01
Particle size: Dx (10): 2.71µm; Dx (50): 12.4µm; Dx (90):61.1 µm

Example 03:
Preparation of (S)-4,4-difluoro-N-(3-hydroxy-1-phenylpropyl)cyclohexanecarboxamide [Formula VII]
A reaction flask was charged with (S)-ethyl 3-(4,4-difluorocyclohexanecarboxamido)-3-phenylpropanoate (175 g) , Sodium borohydride (39 g) and Tetra Hydro Furan (875 mL). The mixture was heated to about 45-50°C.Methanol (105 ml) was slowly added to the reaction mass by maintaining at the same temperature. Heated the reaction mass to reflux and maintained and the reaction was monitored for completion by HPLC. After completion of reaction, the reaction mixture was cooled followed by addition of toluene (613ml) and Sodium hydroxide solution (5% w/w, 525ml). The mixture was stirred for 15-30 minutes and layers were separated. The organic layer was subjected to complete distillation under vacuum at below 60°C. Charged toluene (1225ml) into residue and stirred at 30-40°C for 2hrs and further cooled to 0-5°C and maintained for 4 hours. The solid was isolated by filtration. The solid isolated was subjected to drying under vacuum at 45- 55°C to afford the title compound.
The Recovered Toluene from Filtrate mother liquors were recycled by distilling off the Toluene mother liquor Under vacuum and re used in the isolation of (S)-4,4-difluoro-N-(3-hydroxy-1-phenylpropyl)cyclohexanecarboxamide.
Yield: 93.5gms (92.80%w/w)
HPLC purity: 99.8%.
XRD: Fig 02
Particle size: D(10): 2.65µm; D(50): 12.3µm; D(90): 269.0 µm.
[Particle size as analyzed by MALVERN MASTERSIZER 3000; Dry method]

Example 04:
(S)-4,4-Difluoro-N-(3-oxo-1-phenylpropyl)cyclohexanecarboxamide [Formula III]
A reaction flask was charged with (S)-4,4-difluoro-N-(3-hydroxy-1-phenylpropyl)cyclohexanecarboxamide (130 g), sodium bromide (46.8 g), sodium bicarbonate (40.4 g), TEMPO (0.65 g), water (650 ml) and MDC (1300 ml). The reaction mixture was cooled to 0-10°C. Sodium hypochlorite (336.2 gm) in water (390 ml) solution was slowly added into reaction mixture by maintain temperature below 10°C. Maintained the reaction mixture below 10°C for 2 hours and completion of the reaction was monitored by HPLC. After completion of reaction, charged 10 % Sodium thiosulphate solution (390 ml) into reaction mass and stirred for 15-30 mins. The layers were separated and organic layer was distilled out under vacuum below 45°C to give (S)-4,4-Difluoro-N-(3-oxo-1-phenylpropyl)cyclohexanecarboxamide. The residue obtained was taken to the next stage without isolating the product.

Example 05:
4,4-Difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide [Formula I]
A reaction flask containing the above residue of example 04 was dissolved in MDC (832 mL) and cooled to 10-15°C.Charged (8-Benzyl-8-azabicyclo[3.2.1]octane-3-one (83.1 g), acetic acid (21 mL) and sodiumtriacetoxy borohydride (91 g) and maintained the reaction mixture below 10°C for 2 hours and completion of the reaction was monitored by HPLC. After completion of reaction, charged water (400 mL) and acidify with dilute HCl (370 mL) and separated layers. Charged Ethyl acetate (520 mL) into aqueous layer and basify with dilute NaOH solution (423 g) and separated the layers. Organic layer was distilled out under vacuum below 50°C and charged ethyl acetate (520 mL) into residue. The slurry was stirred for 3-4 hrs at 45-50°C and further cool to 25-30°C and maintained for 2-4 hours. The solid was isolated by filtration and washed with ethyl acetate (130 mL) at 25-30°C. The wet cake (125gms) was dissolved in MDC (130 ml) at RT. Added Ethyl Acetate (1040ml) to the solution and stirred the reaction mass at RT. Distilled the reaction mixture until a volume of approximately 650 ml under vacuum at below 50° C. Maintained the reaction mass at 40-45° C for 3hrs followed by maintaining at RT for 3hrs. Filtered the material and the solid isolated was subjected to drying under vacuum at 45- 55°C for 480 minutes to afford the title compound.
Yield: 105gms (46.72% w/w)
HPLC Purity: 99.9%.

Dated this 8th day of June, 2021

Dr. Mayur Khunt,
Sr. Vice-President – R&D,
ZCL Chemicals Ltd. ,CLAIMS:We claim:
1. A process for preparation of Maraviroc comprising the steps of:
a) Reacting compound of formula IV or its acid addition salt

with a compound of formula V;

b) isolating compound of formula VI from a suitable solvent;
c) reacting compound of formula VI

with a reducing agent;
d) isolating compound of formula VII from a suitable solvent;
e) reacting compound of formula VII

with an oxidizing agent to obtain compound of formula III; and

f) reacting the compound of formula III with compound of formula II

in presence of a reducing agent to obtain Maraviroc.

2. The process according to claim 1 wherein the suitable isolation solvent of step b) is selected form alcohols, haloalkanes, ethers, esters and hydrocarbons.

3. The process according to claim 1 wherein the suitable isolation solvent of step d) is selected form alcohols, haloalkanes, ethers, esters and hydrocarbons.

4. The process according to claim 1 wherein both the compounds VI and VII are isolated from the same solvent.

5. The process according to claim 4 wherein the solvent is Toluene.

6. The process according to claim 1 wherein in step f) the compound of formula III is reacted insitu with compound of formula II.

7. A process for preparation of Maraviroc comprising the steps of:
e) reacting compound of formula VII

with an oxidizing agent to obtain compound of formula III; and

f) reacting insitu the compound of formula III with compound of formula II

in presence of a reducing agent to obtain Maraviroc.

8. The process according to claim 1 wherein the isolated compound of formula VI has an X-ray diffractogram as shown in figure 01.

9. The process according to claim 1 wherein the isolated compound of formula VII has an X-ray diffractogram as shown in figure 02.

Dated this 8th day of June, 2021

Dr. Mayur Khunt,
Sr. Vice-President – R&D,
ZCL Chemicals Ltd.