DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“A PROCESS FOR PURIFICATION OF POLYCYCLIC-PYRIDONE COMPOUNDS”

Laurus Labs Limited, an Indian company of DS-1, IKP Knowledge Park, Genome Valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri district, Hyderabad-500 078, Telangana, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.
FIELD OF THE INVENTION

The present invention relates to a process for purification of polycyclic-pyridone compounds, an intermediate for preparation of cabotegravir. The present invention further relates to a process for preparation of pure cabotegravir or its pharmaceutically acceptable salts thereof using the pure polycyclic-pyridone compounds.

BACKGROUND OF THE INVENTION

Cabotegravir is a class of polycyclic carbamoyl pyridone compounds and is chemically known as (3S,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide, and is approved as free acid and its sodium salt, it has the following structure:

Cabotegravir was approved as its free acid and its sodium salt and sold under the brand name Vocabria® (Cabotegravir Sodium (Tablet; Oral)) & Cabenuva® KIT (combination co-pack of Cabotegravir and Rilpivirine (Suspension, Extended Release; Intramuscular)) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. Further, on December 20, 2021, U.S. FDA approved Cabotegravir free acid under the brand name Apretude® (Cabotegravir extended-release injectable suspension) for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1.

Polycyclic-pyridone compounds represented by following structural Formula XI is one of the important intermediate in the preparation of cabotegravir.

Formula XI
wherein “Y” represents hydrogen, chloro or -OR; and “R’ ” represents hydrogen, –COOH, -COOR, –CONH2, -CHO, -CN or halogen; and “R” represents alkyl, aryl or aralkyl.

Preparation of compound of Formula XI was disclosed in different patent publications, for example specifically compound of Formula XIa (Y= -OMe and R’= -COOH) was disclosed in PCT application Number: 2011/119566 (“the ‘566 publication”) as an intermediate for preparation of cabotegravir. The ‘566 application disclosed process involves preparation of compound of Formula XIa by reaction of aldehyde compound with 3-amino cyclopentanol and followed by purification of Formula XIa from methanol and finally converting it in to cabotegravir. The ‘566 application disclosed process is as follows:

Further other known literatures for ex: Wang et al., in Organic Letters 2015, 17(3), 564-567 and CN113527332A (“the ‘332 publication”) discloses process for preparation of cabotegravir by formation of key acid intermediate of Formula XIa followed by purification of the same from methanol by following the same process disclosed in the ‘566 application.

PCT application Number: 2010/068253 (“the ‘253 publication”) discloses a process for preparation of cabotegravir by formation of key acid intermediate of Formula XIb (Y = -Obenzyl and R’ = hydrogen) and Formula XIc (Y = -Obenzyl and R’ = Br). The ‘253 application disclosed process is as follows:

Compound of Formula XI is the key intermediate in the preparation of cabotegravir, as it comprises stereomeric centers and as per the reported processes it always contaminate with the impurities, an open chain impurity having structural Formula XIA and diastereomer impurity having structural Formula XIB, which needs to be controlled at the source level itself otherwise the same may interfere with further stages of the synthesis; solvent purification to remove these impurities at final stage of the synthesis is always compromise in the final yield.

Cabotegravir/ its sodium salt is one of the important drug available in the market for the treatment of HIV infection. Hence, it’s important to develop a simple and cost effective process for preparation of pure intermediates and there by preparation of pure cabotegravir API to obviate the aforementioned problems, which is readily amenable to large scale production and free from its hydroxy and diastereomer impurities. Thus, the main objective of the present invention is to provide an effective purification process of compound of Formula XI and converting the same in to cabotegravir.
SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for purification of compound of Formula XI, and its conversion to cabotegravir or pharmaceutically acceptable salt thereof.

In accordance with one embodiment, the present invention provides process for purification of compound of Formula XI, comprising:

Formula XI
a) suspending or dissolving a compound of Formula XI in a suitable solvent at a suitable temperature; wherein the compound of Formula XI having more than 0.15% by HPLC of a compound of Formula XIA and/or Formula XIB, and wherein “Y” represents hydrogen, chloro or -OR; “R’ ” represents hydrogen, –COOH, -COOR, –CONH2, -CHO, -CN or halogen; and “R” represents alkyl, aryl or aralkyl; and

Formula XI Formula XIA Formula XIB

b) isolating the pure compound of Formula XI.

In accordance with another embodiment, the present invention provides process for purification of compound of Formula XI, comprising:
a) suspending or dissolving a compound of Formula XI in a suitable solvent at a suitable temperature; wherein the compound of Formula XI having more than 0.15% by HPLC of a compound of Formula XIA and/or Formula XIB, and wherein “Y” represents hydrogen, chloro or -OR; “R’ ” represents hydrogen, –COOH, -COOR, –CONH2, -CHO, -CN or halogen; and “R” represents alkyl, aryl or aralkyl; and
b) isolating the pure compound of Formula XI; wherein the suitable solvent is selected from the group comprising alcohols, halogenated hydrocarbons, ketones, nitriles, water or mixture thereof.

In accordance with another embodiment, the present invention provides process for purification of compound of Formula XIa, comprising:

Formula XIa

a) suspending or dissolving a compound of Formula XIa in a suitable solvent at a suitable temperature; wherein the compound of Formula XIa having more than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’, and

Formula XIa Formula XIA’ Formula XIB’

b) isolating the pure compound of Formula XIa.

In accordance with another embodiment, the present invention provides process for purification of compound of Formula XIa, comprising:
a) suspending or dissolving a compound of Formula XIa in a suitable solvent at room temperature to about reflux; wherein the compound of Formula XIa having more than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’,
b) optionally, cooling the step a) reaction mass to below 25°C, and
c) isolating the pure compound of Formula XIa; wherein the pure compound of Formula XIa having less than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’; wherein the suitable solvent is selected from the group comprising alcohols, halogenated hydrocarbons, ketones, nitriles, water or mixture thereof.

In accordance with another embodiment, the present invention provides an improved process for the preparation of cabotegravir or its pharmaceutically acceptable salts thereof, comprising purifying the compound of Formula XI as process described above, and converting the compound of Formula XI substantially free of Formula XIA and/or Formula XIB in to cabotegravir or its pharmaceutically acceptable salts thereof.

In accordance with another embodiment, the present invention provides a pharmaceutical composition, comprising cabotegravir or its pharmaceutically acceptable salts thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for purification of compound of Formula XI, which is substantially free of open chain impurity of Formula XIA and/or diastereomer impurity of Formula XIB. The present invention further relates to a process for preparation of pure cabotegravir or its pharmaceutically acceptable salts thereof using the pure compound of Formula XI.

Formula XI
wherein “Y” represents hydrogen, chloro or -OR; “R’ ” represents hydrogen, –COOH, -COOR, –CONH2, -CHO, -CN or halogen; and “R” represents alkyl, aryl or aralkyl.

The compound of Formula XI is the key intermediate in the preparation of cabotegravir, as it comprises stereomeric centers. The compound of Formula XI prepared according to the process disclosed in the art involves formation of open chain impurity of Formula XIA due to cleavage of oxazole ring and diastereomer impurity of Formula XIB.

Further, these impurities once contaminated with the compound of Formula XI the same may be involved in subsequent stages along with the compound of Formula XI and generates corresponding open chain impurity and diastereomer impurities in the final cabotegravir. Due to less polarity differences, these two impurities cannot be controlled or removed from main product by regular process parameters such as modification trials or other purification technique. Hence, the purity of the compound of Formula XI is critical parameter in the preparation of cabotegravir as it maintains the same purity level until the final API. If not controlled properly these impurities at the intermediate stage and subsequent purification of cabotegravir to remove these impurities is very difficult as the cabotegravir is a BCS-2 drug substance and having less solubility in most of the solvents.

Open chain impurity of Formula XIA
Diastereomer impurity of Formula XIB
wherein “Y” represents hydrogen, chloro or -OR; “R’ ” represents hydrogen, –COOH, -COOR, –CONH2, -CHO, -CN or halogen and “R” represents alkyl, aryl or aralkyl.

Open chain impurity of cabotegravir Diastereomer impurity of cabotegravir

Hence, it is an object of the present invention to provide a process for the purification of compound of Formula XI, free from open chain impurity of Formula XIA and/or diastereomer impurity of Formula XIB. The present inventors have surprisingly found that the open chain and diastereomer impurities can be separated from the product by solvent purification process in accordance with below embodiments.

The present invention provides a process for purification of compound of Formula XI, an intermediate for preparation of cabotegravir or its pharmaceutically acceptable salts thereof.

In accordance with one embodiment, the present invention provides process for purification of compound of Formula XI, comprising:

Formula XI
a) suspending or dissolving a compound of Formula XI in a suitable solvent at a suitable temperature; wherein the compound of Formula XI having more than 0.15% by HPLC of a compound of Formula XIA and/or Formula XIB, and wherein “Y” represents hydrogen, chloro or -OR; “R’ ” represents hydrogen, –COOH, -COOR, –CONH2, -CHO, -CN or halogen; “R” represents alkyl, aryl or aralkyl; and

Formula XI Formula XIA Formula XIB

b) isolating the pure compound of Formula XI.

Unless otherwise specified the term “alkyl” used herein is selected from but not limited to methyl, ethyl, isopropyl, butyl, tert-butyl, isoamyl and the like.

Unless otherwise specified the term “aryl” or “aralkyl” used herein is selected from but not limited to benzyl, benzoyl, para nitro benzyl and the like.

Unless otherwise specified the term “halogen” used herein is selected from fluoro, bromo, chloro and Iodo.

In accordance with a preferred embodiment, the present invention provides process for purification of compound of Formula XI,

Formula XI
wherein “Y” represents chloro, -OMe or O-benzyl; “R’ ” represents hydrogen or –COOH or halogen.

In accordance with a specific embodiment, the compound of Formula XI specifically represents as following compound of Formula XIa:

Formula XIa

In accordance with another preferred embodiment, the present invention provides process for purification of compound of Formula XIa, comprising:

Formula XIa

a) suspending or dissolving a compound of Formula XIa in a suitable solvent at a suitable temperature; wherein the compound of Formula XIa having more than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’, and

Formula XIa Formula XIA’ Formula XIB’

b) isolating the pure compound of Formula XIa.

The compound of Formula XIa, which is used herein as a starting material is known in the art and can be prepared by any known methods. For example, may be prepared as per the process disclosed in WO2011/119566.

The starting compound of Formula XIa may contain about 0.15% to about 50% of the compound of Formula XIA’ and/or Formula XIB’, as an impurity as measured by HPLC. Further the said compound of Formula XIa may be obtained directly from the reaction mass in the form of crude, or a solution comprising mixture of compound of Formula XIa and, Formula XIA’ and/or Formula XIB’ or may be in the form of semi-solid or solid.

The aforementioned step a) process of formation of suspension or solution of compound of Formula XIa with more than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’ in a suitable solvent, wherein the solvent is selected from the group comprising alcohols, halogenated hydrocarbons, ketones, nitriles, water or mixture thereof.

The suitable solvent used herein step a) is selected from the group comprising of but not limited to alcohols, such as methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol and the like; halogenated hydrocarbons, such as methylene chloride, chloroform, chlorobenzene and the like; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like; nitriles, such as acetonitrile, propionitrile and the like; water and mixtures thereof; preferably methanol, ethanol, isopropanol, n-butanol, methylene chloride, acetone, acetonitrile, water and mixtures thereof.

The step a) reaction may be carried out at a temperature of about room temperature to about reflux temperature of the solvent used; preferably at about 25°C to about 85°C.

Then the reaction mass can be optionally cooled to below 25°C and stirring for a sufficient period of time. Then isolating the compound of Formula XIa substantially free of Formula XIA’ and/or Formula XIB’ by any conventional techniques, for example filtration or decantation; preferably by filtration and by this solvent purification the unwanted impurities of compound of Formula XIA’ and/ or Formula XIB’ are separated through filtrate and pure required solid product is obtained.

The above purification process may be applied once or twice until the required purity of compound of Formula XIa is attained.

In another embodiment, the compound of Formula XIa obtained by the processes described as above, having purity of at least about 99% as measured by HPLC, preferably at least about 99.5% as measured by HPLC and having less than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’, preferably less than about 0.1% by HPLC of a compound of Formula XIA’ and/or Formula XIB’; more preferably less than about 0.05% by HPLC of a compound of a Formula XIA’ and/or Formula XIB’.

In another embodiment, compound of Formula XIa having purity of at least about 99% as measured by HPLC, preferably at least about 99.5% as measured by HPLC and substantially free of compound of Formula XIA’ and/or Formula XIB’; wherein the word "substantially free" refers to compound of Formula XIa having less than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’, preferably less than about 0.1% by HPLC of a compound of Formula XIA’ and/or Formula XIB’; more preferably less than about 0.05% by HPLC of a compound of a Formula XIA’ and/or Formula XIB’.

The reported processes in art involves formation of open chain impurity of Formula XIA’ and diastereomer impurity of Formula XIB’ around 3% and 6% respectively by HPLC along with compound of Formula XIa. Due to polarity difference, these impurities are difficult to separate from compound of Formula XIa. Further, these impurities reacted in subsequent stage and carry forward to final stage and form corresponding open chain impurity and diastereomer impurity of cabotegravir and these are not easily separable from the final product. Hence, the compound of Formula XIa purity is important for preparation of pure cabotegravir API.

In contrast, the purification process of the present invention involves purification of compound of Formula XIa by solvent purification. The present process easily separates the undesired open chain impurity of Formula XIA’ and/or diastereomer impurity of Formula XIB’ along with mother liquors as these impurities are highly soluble in solvents used for the purification and the required product is partially/insoluble in the solvents used for the purification. Hence the purification process of compound of Formula XIa is more economic and easy to scale up to commercial level.

In another embodiment, the present invention provides an improved process for the preparation of cabotegravir or its pharmaceutically acceptable salts thereof, comprising purifying the compound of Formula XIa as process described above, and converting the compound of Formula XIa having less than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’ in to cabotegravir or its pharmaceutically acceptable salts thereof.

The compound of Formula XIa substantially free of Formula XIA’ and/or Formula XIB’ may be converted in to cabotegravir or its pharmaceutically acceptable salts thereof, by the process disclosed in art for example according to the ‘566 publication process or may be using the process exemplified in the present application.

In another embodiment, cabotegravir prepared by using the purified compound of Formula XIa obtained by the processes described as above, having purity of at least about 99% as measured by HPLC, preferably at least about 99.5% as measured by HPLC and having less than 0.15% by HPLC of corresponding open chain impurity of cabotegravir and/or corresponding diastereomer impurity of cabotegravir, preferably less than about 0.1% of corresponding open chain impurity of cabotegravir and/or corresponding diastereomer impurity of cabotegravir as measured by HPLC; more preferably less than about 0.05% of corresponding open chain impurity of cabotegravir and/or corresponding diastereomer impurity of cabotegravir as measured by HPLC.

In another embodiment, the present invention provides a pharmaceutical composition, comprising cabotegravir or its pharmaceutically acceptable salts thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

The present invention provides purification of compound Formula XI, obtained by the above process, as analyzed using the high performance liquid chromatography with the conditions described below:
Column Zorbax RX C8
Mobile phase 1. Buffer and acetonitrile
2. Acetonitrile and water
Flow rate 0.8 mL/min
Elution Gradient
Detection 230 nm
Mode Gradient
Time
(min) Mobile phase-A
(% v/v) Mobile phase-B
(% v/v)
0 95 5
40 85 15
50 20 80
60 95 5
70 95 5

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

REFERENCE EXAMPLE-1:

Preparation of compound of Formula XIa according to the ‘566 publication

MDHC (22.5 gm) in acetonitrile (220 mL) and acetic acid (20 mL), methanesulfonicacid (1.4 mL) were added in to a round bottom flask at 25-30°C and was heated to 57-65°C and stirred for 19.5 hrs at same temperature. To the reaction mass was added a solution of (S)-(+)-2-amino-1-propanol (7.51 gm dissolved in 15 mL) and stirred for 18.5 hrs at 65°C. The mixture was concentrated, and the residue was dissolved in methylene chloride (170 mL) and 1N HCI (170 mL) and stirred for 10-15 min. Then the product containing organic layer was separated and concentrated under vacuum. Methanol (50 mL) was added and the resultant mixture was again concentrated to obtain title compound.
Purification A
A). To the above crude compound (Purity: 84.12% by HPLC; Formula XIA’- 0.5% by HPLC; and Formula XIB’- 2.5% by HPLC) was added methanol (80 mL) and was heated at reflux for 4 h. Reaction mass was allowed to cool to 20°C and stirred at for 15 h at same temperature. The product was collected by filtration and dried under vacuum at 60°C for 12hr. Wt: 13.1 gm.

Purification B
B). To the above crude compound (10 gm; Purity: 97.15% by HPLC; Formula XIA’: 0.3% by HPLC; and Formula XIB’: 2.5% by HPLC) was added methanol (80 mL) and was heated at reflux for 4 h. Reaction mass was allowed to cool to 20°C and stirred at for 15 h at same temperature. The product was collected by filtration and dried under vacuum at 60°C for 12hr. Wt: 5.8 gm.

REFERENCE EXAMPLE-2:

Purification of compound of Formula XIa (from methanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC) and methanol (40 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 45°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 5.9 gm

REFERENCE EXAMPLE-3:

Purification of compound of Formula XIa (from ethanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC) and ethanol (40 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 45°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 6.1 gm

Analytical data for Reference Examples 1-3 is as follows (Table – 1)
Purity
(% by HPLC) Formula XIA’
(% by HPLC) Formula XIB’
(% by HPLC)
Ref Example-1 84.12 0.5 2.5
Purification A 97.15 0.3 2.5
Purification B 97.4 0.1 2.4
Ref Example-2 95.1 1.5 2.4
Ref Example-3 94.9 1.4 2.3

EXAMPLE-2:

Preparation of crude compound of Formula XIa

MDHC (150 gm) in acetonitrile (2.8 lit) and acetic acid (150 mL) and methanesulfonicacid (5.5 gm) were added in to a round bottom flask at 25-30°C and was heated to 75-81°C and stirred for 18 hr at same temperature. Reaction mass was allowed to cool to 30°C and was added potassium acetate (7 gm) and stir for 2 hr at same temperature. To the reaction mass was added (S)-(+)-2-amino-1-propanol (72.8 gm) at 30°C and was heated to 75-81°C and stir for 12 hr at same temperature. Reaction mass was concentrated under vacuum to obtain title compound. Wt: 168 gm; HPLC analysis: Product-78%; Formula XIA’- 2.5%; and Formula XIB’- 5.9%.

EXAMPLE-3:

Purification of compound of Formula XIa (from methylene chloride and water)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), methylene chloride (20 mL) and water (60 mL) were added in to a round bottom flask at about 25°C to 35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 6.5 gm. HPLC analysis: Product-99.9%; Formula XIA’- Not detected; and Formula XIB’- 0.1%.

EXAMPLE-4:

Purification of compound of Formula XIa (from methylene chloride)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), methylene chloride (20 mL) were added in to a round bottom flask and stirred for 1-2 hr at 38°C. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 6.7 gm; HPLC analysis: Product-99.8%; Formula XIA’- 0.05%; and Formula XIB’- 0.12%.

EXAMPLE-5:

Purification of compound of Formula XIa (from acetonitrile)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), acetonitrile (40 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 45°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 6.4 gm; HPLC analysis: Product-99.7%; Formula XIA’- 0.1%; and Formula XIB’- not detected

EXAMPLE-6:

Purification of compound of Formula XIa (from acetone)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), acetone (40 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 45°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 6.5 gm; HPLC analysis: Product-99.8%, Formula XIA’- 0.1% and Formula XIB’- 0.1%

EXAMPLE-7:

Purification of compound of Formula XIa (from methylene chloride and methanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), methylene chloride (10 mL) and methanol (50 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 55°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 6.7 gm; HPLC analysis: Product- 99.9%; Formula XIA’- not detected; and Formula XIB’- 0.05%

EXAMPLE-8:

Purification of compound of Formula XIa (from methylene chloride and ethanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), methylene chloride (10 mL) and ethanol (50 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 75°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 6.8 gm; HPLC analysis: Product-99.8% Formula XIA’- 0.03% and Formula XIB’- 0.08%

EXAMPLE-9:

Purification of compound of Formula XIa (from methylene chloride and n-butanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), methylene chloride (10 mL) and n-butanol (50 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 75°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 7 gm; HPLC analysis: Product-99.7%; Formula XIA’- not detected and Formula XIB’- 0.15%.

EXAMPLE-10:

Purification of compound of Formula XIa (from acetonitrile and methanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), acetonitrile (10 mL) and methanol (50 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 75°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 7.2 gm; HPLC analysis: Product-99.9%; Formula XIA’- not detected; and Formula XIB’- 0.05%.

EXAMPLE-11:

Purification of compound of Formula XIa (from acetonitrile and ethanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), acetonitrile (10 mL) and ethanol (50 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 75°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 7.3 gm; HPLC analysis: Product-99.9%; Formula XIA’- 0.03% and Formula XIB’- 0.07%.

EXAMPLE-12:

Purification of compound of Formula XIa (from acetonitrile and n-butanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), acetonitrile (10 mL) and n-butanol (50 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 75°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 7.8 gm; HPLC analysis: Product-99.8%; Formula XIA’- not detected and Formula XIB’- 0.15%.

EXAMPLE-13:

Purification of compound of Formula XIa (from acetonitrile and Isopropanol)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), acetonitrile (10 mL) and Isopropanol (125 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 75°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 7.7 gm; HPLC analysis: Product-99.9%; Formula XIA’- 0.04% and Formula XIB’- 0.1%.

EXAMPLE-14:

Purification of compound of Formula XIa (from acetonitrile and water)

Compound of Formula XIa (10 gm; Purity: 78% by HPLC; Formula XIA’- 2.5% by HPLC; and Formula XIB’- 5.9% by HPLC), acetonitrile (10 mL) and water (150 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 40°C and stirred for 30-40 min at same temperature. Then the reaction mass was cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried the solid for 15 min and dried the wet material under vacuum at 60°C for about 12 hr to obtain the pure compound of Formula XIa. Wt: 6.5 gm; HPLC analysis: Product-99.8%; Formula XIA’- 0.05% and Formula XIB’- 0.13%.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:We Claim:

1. A process for purification of compound of Formula XI, comprising:

Formula XI
a) suspending or dissolving a compound of Formula XI in a suitable solvent at a suitable temperature; wherein the compound of Formula XI having more than 0.15% by HPLC of a compound of Formula XIA and/or Formula XIB, and wherein “Y” represents hydrogen, chloro or -OR; “R’ ” represents hydrogen, –COOH, -COOR, –CONH2, -CHO, -CN or halogen; and “R” represents alkyl, aryl or aralkyl; and

Formula XI Formula XIA Formula XIB

b) isolating the pure compound of Formula XI.

2. The process as claimed in claim 1, wherein the alkyl is selected from the group comprising methyl, ethyl, isopropyl, butyl, tert-butyl, isoamyl; aryl or aralkyl is selected from the group comprising benzyl, benzoyl and para nitro benzyl; wherein the “Y” represents –OMe and wherein the “R’” represents –COOH.

3. The process as claimed in claim 1, wherein the suitable solvent is selected from the group comprising alcohols, halogenated hydrocarbons, ketones, nitriles, water and mixture thereof.

4. The process as claimed in claim 3, wherein the suitable solvent is selected from the group comprising methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, methylene chloride, chloroform, chlorobenzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, acetonitrile, propionitrile, water and mixtures thereof.

5. The process as claimed in claim 4, wherein the suitable solvent is selected from the group comprising methanol, ethanol, isopropanol, n-butanol, methylene chloride, acetone, acetonitrile, water and mixtures thereof.

6. The process as claimed in claim 1, wherein the step a) is carried out at a temperature of about 25°C to about 85°C.

7. A process for purification of compound of Formula XIa, comprising:

Formula XIa
a) suspending or dissolving a compound of Formula XIa in a suitable solvent at a suitable temperature; wherein the compound of Formula XIa having more than 0.15% by HPLC of a compound of Formula XIA’ and/or Formula XIB’, and

Formula XIa Formula XIA’ Formula XIB’

b) isolating the pure compound of Formula XIa.

8. The process as claimed in claim 8, wherein the suitable solvent is selected from the group comprising methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, methylene chloride, chloroform, chlorobenzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, acetonitrile, propionitrile, water and mixtures thereof.

9. The process as claimed in claim 8, wherein the step a) is carried out at a temperature of about 25°C to about 85°C.

10. The process as claimed in claim 1 to 9, wherein the compound of Formula X1a obtained is having less than 0.15% by HPLC of a compound of Formula XIA and/or Formula XIB.