A process for the preparation of palbociclib intermediate

Abstract

The present disclosure relates to a process for the preparation of Palbociclib intermediate. Particularly, the present disclosure relates to a process for the preparation of 6-bromo-2-chloro- 8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one. The process of the present 5 disclosure is simple, cost effective and environment friendly; and provides 6-bromo- 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one with a comparatively better purity and better yield.

Description

[0001] A PROCESS FOR THE PREPARATION OF PALBOCICLIB INTERMEDIATE

[0002] FIELD

[0003] The present disclosure relates to a process for the preparation of palbociclib intermediate. Particularly, the present disclosure relates to a process for the preparation of 6-bromo-2-chloro- 8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one.

[0004] BACKGROUND

[0005] The background information herein below relates to the present disclosure but is not necessarily prior art.

[0006] Palbociclib is a kinase inhibitor and is used for treating certain type of advanced breast cancer that spreads to other parts of the body. It works by blocking the action of the abnormal protein thereby helping to stop or slow down the spread of cancer cells.

[0007] 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one is a key intermediate forthe synthesis of Palbociclib. The structure of 6-bromo-2-chloro-8-cyclopentyl- 5-methylpyrido[2,3-d] pyrimidin-7(8H)-one is:

[0008] Conventional methods for the preparation of 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d]pyrimidin-7(8H)-one are associated with drawbacks such as formation of dibromo impurities which results in low yield and low purity of the aforesaid intermediate. The dibromo impurities are difficult to remove and require tedious work up steps, thereby making the process time-consuming and uneconomical. Further, such dibromo impurities generated during the process are carried to the next step resulting in reduced yield and poor quality of the final product, thereby decreasing the efficacy of the final product. Therefore, there is felt a need to provide a process for the preparation of 6-bromo-2-chloro-8- cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one that mitigates the aforestated drawbacks or at least provides a useful alternative.

[0009] OBJECTS

[0010] Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:

[0011] It is an object of the present disclosure to ameliorate one or more problems of the background or to at least provide a useful alternative.

[0012] Another object of the present disclosure is to provide a process for the preparation of palbociclib intermediate.

[0013] Yet another object of the present disclosure is to provide a process for the preparation of 6- bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one.

[0014] Still another object of the present disclosure is to provide a process for the preparation of 6- bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one with a comparatively better purity and yield.

[0015] Still another object of the present disclosure is to provide a simple and cost-effective process for the preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin- 7(8H)-one.

[0016] Yet another object of the present disclosure is to provide an environment-friendly and commercially scalable process for the preparation of 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3 -d] pyrimidin-7(8H)-one .

[0017] Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.

[0018] SUMMARY

[0019] The present disclosure relates to a process for the preparation of 6-bromo-2-chloro-8- cyclopentyl-5 -methylpyrido [2,3 -d] pyrimidin-7(8H)-one. The process comprises the following steps: a) mixing a fluid medium, a brominating agent, a base and a catalyst under stirring at a first predetermined temperature to obtain a mixture; and b) heating the mixture to a second predetermined temperature followed by adding 2- chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one solution and continuing stirring at the second predetermined temperature for a predetermined time period to obtain a product mixture comprising 6-bromo-2-chloro-8- cyclopentyl-5-methylpyrido[2,3-d]pyramidin-7(8H)-one.

[0020] A mole ratio of the brominating agent to 2-chloro-8-cyclopentyl-5-methylpyrido [2,3- d]pyrimidin-7(8H)-one solution is in the range of 2: 1 to 6: 1.

[0021] A mole ratio of the brominating agent to 2-chloro-8-cyclopentyl-5-methylpyrido [2,3- d]pyrimidin-7(8H)-one solution is 4.4: 1.

[0022] The fluid medium is selected from the methylene dichloride, ethylene dichloride and a combination thereof.

[0023] The fluid medium is methylene dichloride.

[0024] The brominating agent is selected from the group consisting of bromine, N- bromosuccinimide, 1, 3 -dibromo-5, 5 -dimethylhydantoin, dibromoisocyanuric acid, 5,5- dibromomeldrum's acid, bromotrichloromethane, phosphorous tribromide and pyridinium bromide perbromide.

[0025] The brominating agent is bromine.

[0026] The base is selected from the group consisting of sodium acetate, potassium acetate, lithium acetate, cesium acetate and calcium acetate.

[0027] The base is sodium acetate.

[0028] The catalyst is acetic acid.

[0029] The first predetermined temperature is in the range of 20 °C to 30 °C.

[0030] The second predetermined temperature is in the range of 32 °C to 90 °C. The second predetermined temperature is in the range of 35 °C to 45 °C.

[0031] The predetermined time period is in the range of 15 minutes to 90 minutes.

[0032] The predetermined time period is 60 minutes.

[0033] The product mixture is quenched in an aqueous solution of a quenching agent to obtain a biphasic mixture comprising an organic layer and an aqueous layer.

[0034] The organic layer is separated from the biphasic mixture and distilled to obtain solids comprising 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

[0035] The quenching agent is selected from the group consisting of sodium bisulphite, sodium thiosulfate, sodium metabisulfite, sodium dithionite and sodium hydrosulfite.

[0036] The purity of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one is in the range of 99.5% to 99.9% with a maximum single impurity less than 0. 10%.

[0037] The yield of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one is in the range of 85% to 95%.

[0038] DETAILED DESCRIPTION

[0039] The present disclosure relates to a process for the preparation of palbociclib intermediate. Particularly, the present disclosure relates to a process for the preparation of 6-bromo-2-chloro- 8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one.

[0040] Embodiments, of the present disclosure, will now be described herein. Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.

[0041] The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and / or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.

[0042] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed elements.

[0043] The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.

[0044] Conventional methods for the preparation of 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d] pyrimidin-7(8H)-one are associated with drawbacks such as formation of dibromo impurities which results in low yield and low purity of the aforesaid intermediate. The dibromo impurities are difficult to remove and require tedious work up steps, thereby making the process time-consuming and uneconomical. Further, such dibromo impurities generated during the process are carried to the next step thereby resulting in reduced yield and poor quality of the final product.

[0045] The present disclosure provides a process for the preparation of palbociclib intermediate. Particularly, the present disclosure provides an improved process for the preparation of 6- bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one.

[0046] The process of the present disclosure is simple, environment friendly, economical, and results in improved yield and higher purity of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one . In accordance with the present disclosure, the process for the preparation of 6-bromo-2-chloro- 8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one comprises the following steps: i. mixing a fluid medium, a brominating agent, a base and a catalyst under stirring at a first predetermined temperature to obtain a mixture; and ii. heating the mixture to a second predetermined temperature followed by adding 2- chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one solution and continuing stirring at the second predetermined temperature for a predetermined time period to obtain a product mixture comprising 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3 -d] pyrimidin-7(8H)-one .

[0047] The process for the preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one is described in detail herein below:

[0048] In a first step, a fluid medium, a brominating agent, a base and a catalyst are mixed under stirring at a first predetermined temperature to obtain a mixture.

[0049] In an embodiment of the present disclosure, the first predetermined temperature is in the range of 20 °C to 30 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is 27 °C.

[0050] In an embodiment of the present disclosure, the fluid medium is selected from methylene dichloride, ethylene dichloride and a combination thereof. In an exemplary embodiment of the present disclosure, the fluid medium is methylene dichloride.

[0051] In an embodiment of the present disclosure, the brominating agent is selected from the group consisting of bromine, N-bromosuccinimide, 1, 3 -dibromo-5, 5 -dimethylhydantoin, dibromoisocyanuric acid, 5,5-dibromomeldrum's acid, bromotrichloromethane, phosphorous tribromide and pyridinium bromide perbromide. In an exemplary embodiment of the present disclosure, the brominating agent is bromine.

[0052] In an embodiment of the present disclosure, the base is selected from the group consisting of sodium acetate, potassium acetate, lithium acetate, cesium acetate and calcium acetate. In an exemplary embodiment of the present disclosure, the base is sodium acetate.

[0053] In an embodiment of the present disclosure, the catalyst is acetic acid. In a second step, the mixture is heated to a second predetermined temperature followed by adding 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one solution and continuing stirring at the second predetermined temperature for a predetermined time period to obtain a product mixture comprising 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- d]pyrimidin-7(8H)-one .

[0054] In an embodiment of the present disclosure, the second predetermined temperature is in the range of 32 °C to 90 °C. In another embodiment of the present disclosure, the second predetermined temperature is in the range of 35 °C to 45 °C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is 40 °C.

[0055] In an embodiment of the present disclosure, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one is mixed in the fluid medium selected from methylene dichloride, ethylene dichloride and a combination thereof to obtain a 2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d] pyrimidin-7(8H)-one solution. In an exemplary embodiment of the present disclosure, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one solution is prepared by using methylene dichloride.

[0056] In an embodiment of the present disclosure, a mole ratio of the brominating agent to 2-chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one solution is in the range of 2: 1 to 6: 1. In an exemplary embodiment of the present disclosure, the mole ratio of the brominating agent to 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one solution is 4.4: 1.

[0057] In an embodiment of the present disclosure, the predetermined time period is in the range of 15 minutes to 90 minutes. In an exemplary embodiment of the present disclosure, the predetermined time period is 60 minutes.

[0058] In an embodiment of the present disclosure, the addition of solution of 2-chloro-8-cyclopentyl- 5-methylpyrido[2,3-d]pyrimidin-7(8H)-one in chlorinated solvents to the mixture of bromine, sodium acetate and acetic acid reduces the formation of dibromo impurity to less than 0.10% which in turn results in enhanced yield of 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3 -d] pyrimidin-7(8H)-one .

[0059] In an embodiment of the present disclosure, the product mixture is quenched in an aqueous solution of a quenching agent to obtain a biphasic mixture comprising an organic layer and an aqueous layer. The organic layer is separated from the biphasic mixture and distilled to obtain solids comprising 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)- one. The solids are purified using fluid medium such as acetone, methyl isobutyl ketone (MIBK) and diethylketone to obtain 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- d]pyrimidin-7(8H)-one .

[0060] In an embodiment of the present disclosure, the quenching agent is selected from the group consisting of sodium bisulphite, sodium thiosulfate, sodium metabisulfite, sodium dithionite and sodium hydrosulfite. In an exemplary embodiment of the present disclosure, the quenching agent is sodium bisulphite.

[0061] In an embodiment of the present disclosure, the purity of 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d] pyrimidin-7(8H)-one is in the range of 99.5% to 99.9% with a maximum single impurity less than 0.10%. In an exemplary embodiment of the present disclosure, the purity of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one is 99.9% with a maximum single impurity less than 0.10%.

[0062] In an embodiment of the present disclosure, the yield of 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d] pyrimidin-7(8H)-one is in the range of 85% to 95%. In an exemplary embodiment of the present disclosure, the yield of 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d] pyrimidin-7(8H)-one is 92.5%.

[0063] In the conventional process, during bromination the dibromo impurity is formed in an amount in the range of 0.5 % to 0.7 %. The dibromo impurity generated during bromination will be carried forward to the next stage. If the impurities are present in the final product, then purification of the product is time consuming as well as leads to yield loss.

[0064] In accordance with an embodiment of the present disclosure, the schematic representation for the preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)- one is illustrated as Scheme-A below:

[0065]

[0066] Scheme-A

[0067] The present disclosure provides a simple, environment friendly and economic process for the preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one with a comparatively better yield and better purity.

[0068] The foregoing description of the embodiments has been provided for purposes of illustration and is not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.

[0069] The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial / commercial scale and the results obtained can be extrapolated to the industrial scale.

[0070] EXPERIMENTAL DETAILS

[0071] Experiment 1: Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one in accordance with the present disclosure

[0072] 500 mL of methylene dichloride was charged to the reactor followed by adding 270 g of bromine, 150 g of sodium acetate and 10 mL of acetic acid under stirring at 27 °C to obtain a mixture. The mixture was heated to 40 °C (reflux temperature of methylene dichloride) followed by adding 500 mL (100g of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin- 7(8H)-one dissolved in 500 mL of methylene dichloride) of 2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d]pyrimidin-7(8H)-one solution and continuing stirring at 40°C for 1 hour to obtain a product mixture comprising 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- d]pyrimidin-7(8H)-one .

[0073] The product mixture was quenched using 700 mb of aqueous sodium bisulphite solution to obtain a biphasic mixture comprising a methylene dichloride layer and an aqueous layer. The methylene dichloride layer was separated from the biphasic mixture followed by distillation of methylene dichloride to obtain solids comprising 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d] pyrimidin-7(8H)-one. The solids were purified using acetone to obtain 6- bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one with 92.5% yield and HPLC purity of 99.9% with maximum single impurity less than 0.10% with dibromo impurity 0.07%.

[0074] Experiment 2: Comparative Examples

[0075] Example 1: Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one using conventional method

[0076] 1000 m of Methylene dichloride was charged to the reactor followed by adding 100 g of 2- chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one, 150 g of sodium acetate and 10 mb of acetic acid to obtain a mixture. The mixture was heated to 40 °C followed by slowly adding 270 g of bromine under stirring and maintaining at a temperature of 40 °C for 1 hour to obtain a product mixture comprising 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3 -d] pyrimidin-7(8H)-one .

[0077] The product mixture was quenched by using 700 mb of aqueous sodium bisulphite solution to obtain a biphasic mixture comprising a methylene dichloride layer and an aqueous layer. The methylene dichloride layer was separated from the biphasic mixture followed by distillation of methylene dichloride to obtain solids comprising 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d]pyrimidin-7(8H)-one. The solids were purified using acetone to obtain 6- bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one with 88% yield and 98.7% HPLC purity (0.67% of dibromo impurity observed).

[0078] Example 2: Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one using NBS as brominating agent 600 mL of N,N -Dimethylformamide was charged to the reactor followed by addition of 100 g of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one at 30°C to obtain a first mixture. The mixture was cooled to 10 °C to 15 °C and 168 g of N-Bromosuccinimide in 350 mL DMF was added at 10 °C to 15 °C to obtain a second mixture. The second mixture was heated to 45 °C to 50 °C and maintained for 5 hours to 6 hours to obtain a product mixture comprising 6-bromo-2-chloro-8-cyclopentyl-5 -methylpyrido [2,3 -d] pyrimidin-7(8H)-one .

[0079] 10 g of sodium bisulphite was dissolved in 100 mL water to obtain sodium bisulphite solution. Sodium bisulphite solution was added to the product mixture to obtain a biphasic mixture comprising a methylene dichloride layer and an aqueous layer. The methylene dichloride layer was separated from the biphasic mixture followed by distillation of methylene dichloride to obtain solids comprising 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d] pyrimidin- 7(8H)-one. The solids were purified using acetone to obtain 6-bromo-2-chloro-8-cyclopentyl- 5 -methylpyrido [2,3 -d]pyrimidin-7(8H)-one with 70 % yield and 95 % HPLC purity (2.30 % of dibromo impurity).

[0080] From Experiment 1, it is observed that the process for the preparation of 6-bromo-2-chloro-8- cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one of the present disclosure provides higher yield and higher purity i.e. 92.5% yield with HPLC purity of 99.9 % as compared to Experiment 2 (comparative Examples 1 and 2) wherein 6-bromo-2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d]pyrimidin-7(8H)-one is obtained with lower yield and lower purity i.e. 88% yield with 98.7% HPLC purity and 70% yield with 95 % HPLC purity respectively.

[0081] TECHNICAL ADVANCEMENT

[0082] The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of 6-bromo-2-chloro-8- cyclopentyl-5 -methylpyrido [2,3 -d] pyrimidin-7(8H)-one, that;

[0083] • is simple, cost effective and environment friendly; and

[0084] • provides 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 H)- one having a comparatively better purity and better yield.

[0085] The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0086] The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and / or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

[0087] The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.

[0088] Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.

[0089] The numerical values given for various physical parameters, dimensions, and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions, and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.

[0090] While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

Claims

CLAIMS:

1. A process for the preparation of 6-bromo-2-chloro-8-cyclopentyl- 5- methylpyrido[2,3-d]pyrimidin-7(8H)-one, said process comprising the following steps: a) mixing a fluid medium, a brominating agent, a base and a catalyst under stirring at a first predetermined temperature to obtain a mixture; and b) heating said mixture to a second predetermined temperature followed by adding2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one solution and continuing stirring at said second predetermined temperature for a predetermined time period to obtain a product mixture comprising 6-bromo-2-chloro-8-cyclopentyl-5 -methylpyrido [2,3 -d]pyrimidin-7(8H)-one .

2. The process as claimed in claim 1 , wherein a mole ratio of said brominating agent to 2- chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one is in the range of 2: 1 to 6: 1.

3. The process as claimed in claim 1 , wherein a mole ratio of said brominating agent to 2- chloro-8-cyclopentyl-5-methylpyrido [2,3-d]pyrimidin-7(8H)-one is 4.4: 1.

4. The process as claimed in claim 1, wherein said fluid medium is selected from methylene dichloride, ethylene dichloride and a combination thereof.

5. The process as claimed in claim 1, wherein said fluid medium is methylene di chloride.

6. The process as claimed in claim 1, wherein said brominating agent is selected from the group consisting of bromine, N- bromosuccinimide, l,3-dibromo-5,5- dimethylhydantoin, dibromoisocyanuric acid, 5, 5 -dibromomeldrum's acid, bromotrichloromethane, phosphorous tribromide and pyridinium bromide perbromide.

7. The process as claimed in claim 1, wherein said brominating agent is bromine.

8. The process as claimed in claim 1, wherein said base is selected from the group consisting of sodium acetate, potassium acetate, lithium acetate, cesium acetate and calcium acetate.

9. The process as claimed in claim 1, wherein said base is sodium acetate.

10. The process as claimed in claim 1, wherein said catalyst is acetic acid.

11. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 20 °C to 30 °C.

12. The process as claimed in claim 1, wherein said second predetermined temperature is in the range of 32 °C to 90 °C.

13. The process as claimed in claim 1, wherein said second predetermined temperature is in the range of 35 °C to 45 °C.

14. The process as claimed in claim 1, wherein said predetermined time period is in the range of 15 minutes to 90 minutes.

15. The process as claimed in claim 1, wherein said predetermined time period is 60 minutes.

16. The process as claimed in claim 1, wherein said product mixture is quenched in an aqueous solution of a quenching agent to obtain a biphasic mixture comprising an organic layer and an aqueous layer.

17. The process as claimed in claim 16, wherein said organic layer is separated from said biphasic mixture and distilled to obtain solids comprising 6-bromo-2-chloro-8- cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one.

18. The process as claimed in claim 16, wherein said quenching agent is selected from the group consisting of sodium bisulphite, sodium thiosulfate, sodium metabisulfite, sodium dithionite and sodium hydrosulfite.

19. The process as claimed in claim 17, wherein the purity of 6-bromo-2-chloro-8- cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one is in the range of 99.5% to 99.9% with a maximum single impurity less than 0.10%.

20. The process as claimed in claim 17, wherein the yield of 6-bromo-2-chloro-8- cyclopentyl-5-methylpyrido[2,3-d] pyrimidin-7(8H)-one is in the range of 85% to 95%.

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