Synthesis of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one a key intermediate in the manufacture of palbociclib

Abstract

The present invention offers an environmentally friendly, expensive metal-free, cost- effective, and safe easy to handle synthetic process to synthesize a key intermediate 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (E) for the large scale synthesis of Palbociclib. Till date, numerous methods have been developed to synthesize Palbociclib. The current synthesis method of the invention has relatively simple operation, mild reaction conditions, high yield and a simple process. There are several problems in the prevailing synthetic methods for the preparation of Palbociclib, such as the requirement of an expensive Pd metal catalyst, Phosphine ligands, fancy acylating agent, necessity of silver salts to achieve acylation, toxic oxidants, multi-step operation including bromination, and elevated temperature. Notably, a significant gap exists in finding a straightforward, eco-friendly, cost-effective route for synthesizing Palbociclib with high efficacy.

Description

[0001] PT / 2026 / 11281

[0002] SYNTHESIS OF 6-ACETYL-2-CHLORO-8-CYCLOPENTYL-5- METHYLPYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE A KEY INTERMEDIATE IN THE MANUFACTURE OF PALBOCICLIB

[0003] FIELD OF THE INVENTION:

[0004] The present invention offers an environmentally friendly, cost-effective, and safe as well as easy to handle synthetic process to synthesize a key intermediate 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one for the synthesis of Palbociclib. The present invention more particularly relates to the synthesis of palbociclib through a key intermediate 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d|pyrimidin-7(8 / - / )-one.

[0005] There are several problems in the prevailing synthetic methods for the preparation of Palbociclib, such as the requirement of an expensive Pd metal catalyst, Phosphine ligands, fancy acylating agent, the necessity of silver salts to achieve acylated intermediate, toxic oxidants, multi-step operation including bromination, and elevated temperature. Notably, a significant gap exists in finding a straightforward, eco-friendly, cost-effective route for synthesizing Palbociclib with high efficacy.

[0006] The present synthesis describes an environmentally friendly ambient method that doesn't require expensive transition metals and toxic chemicals. This method is highly effective and scalable, contributing to both atom and step economy in the process. As a result, this methodology holds substantial significance. It presents an alternative avenue for synthesizing highly demanding Palbociclib from feedstock chemicals.

[0007] BACKGROUND OF THE INVENTION

[0008] Breast cancer (BC) is the second most common cancer in women. Although it is treatable, metastatic breast cancer (MBC) remains practically an incurable disease with a median overall survival (OS) of 3 years and a 5-year OS of only 25%. Palbociclib is a cyclin-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer Inc. It obtained the qualification of "breakthrough therapy” from the U. S. FDA in April 2013. Owing to its satisfactory clinical performance in Phase III trial, Pfizer Inc. inPT / 2026 / 11281

[0009] August 2014, submitted an application for going to sale it to the U. S. FDA and obtained the prioritized examination qualification, and used for the first line treatment of advanced breast cancer of estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative or metastatic breast cancer and marketed in the name of IBRANCE (Drugs Context. 2019, 8, 212579; Clin Cane. Res. 2016; 22, 4968-4972; Clin Cane Res. 2015, 21, 995-1001, Breast. 2021, 59, 321-326). Palbociclib have been approved for the treatment of endocrine-resistant MBC in combination with ET. These agents are orally available, highly selective CDK4 and CDK6 and serine-threonine kinases inhibitors inhibiting tumour cell proliferation (Genes & Dev. 1999, 13, 1501-1512).

[0010] Palbociclib was first synthesized by Pfizer in 2005 and 2006 by Pfizer Inc. (WO2019224194A1) (W02008032157). Afterwards, several processes were developed (Scheme I) to synthesize the key intermediate 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- ]pyrimidin-7(8 / - / )-one to synthesize palbociclib.

[0011]

[0012] (Bromo Int )

[0013] Scheme I

[0014] In most of the cases, existing processes the cyclic bromo intermediate 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- ]pyrimidin-7(8 / - / )-one is used to synthesize the key intermediate 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- ]pyrimidin-7(8H)-one via palladium catalyzed Heck coupling reaction. This cyclic bromo intermediate 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one is prepared via multi-step synthesis using different starting materials such as dichloro bromo pyrimidine (Org. Process Res. Dev. 2016, 20, 1191-1202), (Xuegen et al.; CN 105541832; PD: 2015-12-15), 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (J. Med. Chem. 2005, 48, 2371-2387), 1-(2,4-dichloropyrimidin-5-PT / 2026 / 11281

[0015] yl)ethan-1-one (Avra Laboratories Pvt. Ltd. Application No. 201641043500 A), (WO2012018540 A1, PD: 2007-07-21), dichloro acyl pyrimidine, 2, 4-dichloro-5-cyanopyrimidine(Xinfa Pharmaceutical Co., Ltd., CN 104610254; PD: 2015-05-13), thiouracil (Journal of Chemical Research, 2019, 43, 14-19) etc and followed by bromination.

[0016] The intermediate 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Dr. Reddy's Laboratories Limited, IN201641022857; PD: 2020-06-19) is further converted to key intermediate 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- |pyrimidin-7(8 / - / )-one via Heck coupling using an expensive palladium catalyst. This acetylated intermediate is used to produce palbociclib in a few steps. The acetylated intermediate has also been synthesized using an expensive and hazardous silver catalyst using 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (Shen etal. CN114539251).

[0017] However, it's important to note that all of these methods necessitated the presence of either an acid expensive starting materials and expensive transition metal catalysts and which generate hazardous waste as well as toxic and costly reagents, solvents, and high temperature. While these approaches offer valuable insights, these factors pose challenges in terms of safety and scalability for industrial applications. Some methods required the use of toxic Grignard reagents and bromination step with extended reaction steps (protection of carbonyl functionality). These factors collectively pose obstacles when considering the feasibility of implementing the approach on an industrial scale.

[0018] Hence, there is an urgent need for a better environmentally friendly and industrially viable methodology. In contrast, the present invention employs a mild, environmentfriendly, cost-effective, operationally simple improved synthetic process for 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- |pyrimidin-7(8 / - / )-one, a key intermediate for Palbociclib. Major merits of this synthesis are - (1) expensive Metal-free synthetic steps 2) Readily available synthons; 3) Economical; 4) Cheap Raw Materials 5) Expensive Pd catalyst, silver catalyst, Phosphine ligands and sulfur containing compounds are avoided; 6) Easy to handle chemicals 7) avoid bromination step. Furthermore, this synthesis can be comfortably conducted at ambient temperatures in a minimum no. of steps from feedstock chemicals. This method not only holdsPT / 2026 / 11281

[0019] promise for efficient synthesis but also aligns well with potential industrial production processes.

[0020] OBJECTIVES OF THE INVENTION

[0021] Main object of the present invention is to provide an improved cost-efficient process for the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d|pyrimidin-7(8H)-one, a key intermediate for Palbociclib.

[0022] Another object of the present invention is to offer a commercially viable process for synthesizing the intermediate 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8 / - / )-one (Palbociclib).

[0023] Yet another object of the present invention to provide a process for synthesizing 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-c / ]pyrimidin-7(8H)-one with a cheaper starting material under mild and ambient conditions without using the expensive Pd or Ag metal catalyst, phosphine ligands or Grignard reagents.

[0024] SUMMARY OF THE INVENTION

[0025] Accordingly, the current invention provides an improved, more efficient synthetic process for synthesizing the key intermediate 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8 / - / )-one, especially from easy-to-prepare starting material 5-acetyl uracil (A) derived intermediate 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d|pyrimidin-7(8 / - / )-one (D). There are several problems in the existing synthetic methods for the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8 / - / )-one (E), such as the requirement of an expensive Pd and Ag catalyst, toxic reagents, toxic oxidants, multi-step operations, and elevated temperature. Notably, a significant gap exists in finding a straightforward, eco-friendly, cost-effective route for synthesizing Palbociclib by applying eco-friendly and expensive metal-free conditions.

[0026] The present invention provides a process for the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8 / - / )-one a key intermediate in the synthesis of palbociclib comprising:PT / 2026 / 11281

[0027] C-6 acylation of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )- one (D) in presence of a catalyst, a solvent, an oxidant and pyruvic acid as the acetyl source to obtain 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- d]pyrimidin-7(8 / - / )-one (E),

[0028]

[0029] wherein the catalyst is 0.1 to 1 eq. of iron catalyst selected from the group consisting of Iron (II) chloride, Iron(ll) bromide, Iron(ll) acetate, Iron(ll) oxalate dihydrate, Iron(ll) perchlorate hydrate, ferrocene, iron(lll) chloride, iron(ll) triflate, iron(ll) acetylacetonate, Iron(lll) acetylacetonate, Iron(lll) sulfate hydrate, ammonium ferrous sulfate, preferably iron(II) sulfate heptahydrate.

[0030] In an embodiment of the present invention, the molar ratio of intermediate D and pyruvic acid is 1: 1 to 1: 3, preferably 1: 2.

[0031] In an embodiment of the present invention, the solvent is selected from a group consisting of dimethylsulfoxide (DMSO), acetonitrile (ACN), dichloromethane (DCM), ethanol, ethyl acetate, water, acetone or a mixture thereof.

[0032] In an embodiment of the present invention, the oxidant is selected from a group consisting of ammonium persulfate, potassium persulphate, sodium persulfate, sodium bromate, sodium periodate, benzoquinone, benzoyl peroxide and hydrogen peroxide, preferably ammonium persulfate.

[0033] In an embodiment of the present invention, the reaction is carried out at a temperature in the range of 0 °C to 100 °C preferably in the range 55-60 °C.

[0034] In a preferred embodiment of the present invention, the process for the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8 / - / )-one comprises the steps of:PT / 2026 / 11281

[0035] i. chlorination reaction of 5-acetyl uracil (A) with POCl3in presence of diethylamine base and an organic solvent at 115-120 °C under inert condition to produce (2,4-dichloropyrimidin-5-yl)ethan-1-one (B);

[0036]

[0037] ii. selective C-4 amination of 1-(2,4-dichloropyrimidin-5-yl)ethan-1-one (B) using triethylamine base in presence of an organic solvent to produce 1 -(2-chloro-4- (cyclopentylamino)pyrimidin-5-yl)ethan-1-one from (C);

[0038]

[0039] iii. LiHMDS mediated cyclization of 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5- yl)ethan-1-one (C) to produce 2-chloro-8-cyclopentyl-5-methylpyrido[2,3- d]pyrimidin-7(8 / - / )-one (D); and

[0040]

[0041] iv. Fe(II) / S2O82--catalyzed C-6 acylation of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (D) using pyruvic acid as the acetyl source to obtain 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (E).PT / 2026 / 11281

[0042]

[0043] In an embodiment of the present invention, the organic solvent of step (i) is selected from the group consisting of acetic acid, tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate and acetone and the organic solvent of step (ii) is selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate or acetone.

[0044] In an embodiment of the present invention, the the LiHMDS mediated cyclization reaction of 1-(2-chloro-4-(cyclopentyl amino)pyrimidin-5-yl)ethan-1-one (C) is carried out in the presence of ethyl acetate.

[0045] In an embodiment of the present invention, the invention further comprising LiHMDS mediated SNAr coupling of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (E) with Tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate to produce tert-butyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1 -carboxylate (F) followed by hydrolysis of (F) to obtain palbociclib G.

[0046]

[0047] (Palbociclib)

[0048] In an embodiment of the present invention, the yield of 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8H)-one is 52-65% with more than 99%PT / 2026 / 11281

[0049] purity. The overall, the purity of the API using the process of the invention is more than 99%.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] The present invention provides a cost-effective and efficient method for the synthesis 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d]pyrirnidin-7(8 / - / )-one (E), the key intermediate towards the synthesis of Palbociclib starting from 5-acetyl-2,4-dichloropyrimidine (A). Scheme II provides the synthesis of the key intermediate (E) and the synthesis of Palbociclib from the key intermediate (E).

[0052]

[0053] The technical details of the present invention are further specifically described below:

[0054] 5-acetyl uracil (A) furnishes the (2,4-dichloropyrimidin-5-yl)ethan-1-one (B) through chlorination reaction between the 5-acetyl uracil (A) and POCl3in presence of diethylamine base under inert condition at 115-120 °C.

[0055] Selective C-4 amination of 1-(2,4-dichloropyrimidin-5-yl)ethan-1-one (B) using triethylamine base under ambient condition provides 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethan-1-one from (C).

[0056] LiHMDS mediated cyclization of 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethan-1-one (C) with ethyl acetate to delivers 2-chloro-8-cyclopentyl-5-methylpyrido[2,3- |pyrimidin-7(8 / - / )-one (D).PT / 2026 / 11281

[0057] Fe(II) / S2O82--catalyzed C-6 acylation of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (D) using pyruvic acid as the acetyl source furnishes 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (E), the key intermediate for the synthesis of palbociclib.

[0058] In a vacuum dried Schlenk tube, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (D), (2.64 g, 1.0 equiv., 10 mmol), FeSO4·7H2O (0.278 g; 1.0 mmol, 0.1 equiv.), oxidant (NH4)2S2O8(4.56 g; 20 mmol, 2.0 equiv.) were taken and pyruvic acid (1.4 ml, 20 mmol; 2.0 equiv.) was added dropwise to the above mixture. The tube was then sealed and purged with argon for three times. Then water and DMSO mixture (20:1 v / v) (40 ml) was added via a syringe under inert condition. The reaction mixture was heated to 55 to 60 °C and stirred for 12 h. After completion of the reaction, the crude reaction mixture was quenched using satd. NaHCO3water (30 ml) and extracted using ethyl acetate. Then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulphate and purified using silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid; yield: 52%.

[0059] LiHMDS mediated SNAr coupling of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d|pyrimidin-7(8 / - / )-one (E) with Tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1 -carboxylate provides tert-butyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (F).

[0060] The intermediate F can now easily deliver the targeted Palbociclib in a single hydrolysis step after coupling with Tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate.

[0061] EXAMPLES

[0062] The following examples are given by way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention.

[0063] Example 1: Step I: Chlorination of 5-acetylpyrimidine-2,4(1H, 3H)-dione to

[0064]

[0065] produce 1-(2,4-dichloropyrimidin-5-yl)ethan-1-one (B):PT / 2026 / 11281

[0066]

[0067] The 5-acetyl uracil ((5-acetylpyrimidine-2,4(1 / - / ,3 / - / )-dione); A) (1.54 g, 10 mmol) and diethylamine (Et2NH) (1.28 g, 50 mmol) were added into the reaction flask under nitrogen atmosphere and then POCl3(30 ml) was added to the above reaction mixture dropwise and the resulting reaction mixture was stirred at 118-120 °C for 2h. After the stipulated period of time, reaction mixture was cooled down to room temperature and excess POCl3was removed under reduced pressure. The crude reaction mixture then directly loaded on silica-gel column chromatography and purified using silica gel chromatography with EA and pet ether as eluent (15% EA / PE). The pure product (1 -(2,4-dichloropyrimidin-5-yl)ethan-1-one; B) obtained were obtained as light yellow oil; yield: 52%;1H NMR (400 MHz, chloroform-d) 58.80 (s, 1 H), 2.70 (s, 3H).13C NMR (100 MHz, chloroform-d) 5 194.9, 162.2, 160.9, 159.7, 130.4, 30.64.

[0068] Example 2: Step II: Preparation of 1-(2-chloro-4-(cvclopentylamino)pyrimidin-5-yl)ethan-1-one (C):

[0069]

[0070] To the mixture of (1-(2,4-dichloropyrimidin-5-yl)ethan-1-one; (B) (1.9 g, 10 mmol) and cyclopentyl amine ( 9.35 g, 11 mmol ) in 15 mL ethyl acetate, triethylamine (2.2 g, 20 mmol) was added dropwise at room temperature and the resulting mixture was stirred for 15 min at room temperature under air. After the stipulated period of time,PT / 2026 / 11281

[0071] the reaction mixture was quenched using satd. NH4CI solution (10 ml) and then stirred for 10 min at room temperature and finally extracted using ethyl acetate and water. The combined organic portion was then concentrated under reduced pressure, dried over anhydrous sodium sulphate and purified using silica gel column chromatography using EA and pet ether as eluent (20% EA / PE). The pure product 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethan-1-one (C) were obtained as white solid; yield: 86%.1H NMR (400 MHz, chloroform-d) 5 9.31 (brs, 1H), 8.58 (s, 1H), 4.53-4.44 (m, 1H), 2.53 (s, 3H), 2.09-2.05 (m, 2H), 1.75-1.67 (m, 2H), 1.53-1.48 (m, 2H).13C NMR (100 MHz, chloroform-d) 5 202.3, 169.5, 162.2, 160.9, 159.7, 113.4, 58.6, 31.6, 28.9, 28.2, 21.9, 14.3.

[0072] Example 3: Step III: Preparation of 2-chloro-8-cvclopentyl-5-methylpyrido[2,3-

[0073]

[0074] i-one

[0075]

[0076] In the cool reaction bath under argon atmosphere, the mixture of 1 -(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethan-1-one (C) ( 1.2 g, 5 mmol, 1.0 equiv.) and LiHMDS 1 M in hexane (15.0 mL, 1.0 mol / L, 15 mmol) was stirred in dry THF (15 mL) at -78 °C for 20 min and then freshly distilled ethyl acetate (4.9 ml, 30 mmol, 6.0 equiv.) was added dropwise into the above reaction mixture under inert condition. Then the temperature of the resulting solution was gradually increased to room temperature and stirred to react for about 15 h, and after the stipulated period of time, the resulting solution was quenched using saturated NH4CI solution (20 mL) and stirred for 10 min at room temperature. The reaction mixture then extracted using ethyl acetate and water, dried over anhydrous sodium sulphate and concentrated under reduced pressure and finally purified using silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid (D); yield: 50%.1H NMR (400 MHz, chloroform-d) 5PT / 2026 / 11281

[0077] 8.73 (s, 1 H), 6.53 (s, 1 H), 5.89-5.78 (m, 1 H), 2.43 (s, 3H), 2.22-2.21 (m, 2H), 2.11-2.08 (m, 2H), 1.90-1.88 (m, 2H), 1.67-1.65 (m, 2H);13C NMR (100 MHz, chloroform-d) δ 162.5, 159.3, 156.3, 155.7, 142.6, 123.4, 113.9, 55.3, 28.9, 26.2, 17.3.

[0078] Example 4a: Step IV: Fe(ll) / Fe(lll)-catalyzed acylation of 6-acetyl-2-chloro-8-cvclopentvl-5-methvlpvridof2,3-cflpvrimidin-7(8H) i-one (D) to synthesize intermediate (E):

[0079]

[0080] In a vacuum dried Schlenk tube, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (D), (2.64 g, 1.0 equiv., 10 mmol), FeSO4·7H2O (0.278 g; 1.0 mmol, 0.1 equiv.), oxidant (NH4)2S2O8(4.56 g; 20 mmol, 2.0 equiv.) were taken and pyruvic acid (1.4 ml, 20 mmol; 2.0 equiv.) was added dropwise to the above mixture. The tube was then sealed and purged with argon for three times. Then water and DMSO mixture (20:1 v / v) (40 ml) was added via a syringe under inert condition. The reaction mixture was heated to 55 to 60 °C and stirred for 12 h. After completion of the reaction, the crude reaction mixture was quenched using satd. NaHCO3water (30 ml) and extracted using ethyl acetate. Then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulphate and purified using silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid; yield: 52%.1H NMR (400 MHz, chloroform-d) δ 7.25 (s, 1H), 6.53 (s, 1H), 5.87-5.81 (m, 1 H), 2.54 (s, 3H), 2.24 (s, 3H), 2.21 -2.20 (m, 2H), 2.18-2.11 (m, 2H), 1.92 (m, 2H), 1.68-1.66 (m, 2H);13C NMR (100 MHz, chloroform-d) 5 201.5, 160.6, 157.2, 155.4, 140.0, 135.2, 113.08, 54.3, 31.3, 28.8, 26.1, 14.2.

[0081] Example 4b: Iron(lll) sulfate hydrate [Fe2(SO4)s.xH2O] as Fe-catalystPT / 2026 / 11281

[0082]

[0083] In a vacuum dried Schlenk tube, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (D), (2.64 g, 1.0 equiv., 10 mmol), Iron(III) sulfate hydrate [Fe2(SO4)3.xH2O] (0.4 g; 1.0 mmol, 0.1 equiv.), oxidant (NH4)2S2O8(4.56 g; 20 mmol, 2.0 equiv.) were taken and pyruvic acid (1.4 ml, 20 mmol; 2.0 equiv.) was added dropwise to the above mixture. The tube was then sealed and purged with argon for three times. Then water and DMSO mixture (20:1 v / v) (40 ml) was added via a syringe under inert condition. The reaction mixture was heated to 55 to 60 °C and stirred for 12 h. After completion of the reaction, the crude reaction mixture was quenched using satd. NaHCO3water (30 ml) and extracted using ethyl acetate. Then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulphate and purified using silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid; yield: 52% with morethan 99% purity.

[0084] Example 4c: Use of Iron(II) sulfate heptahydrate (FeSO4.7H2O) in stoichiometric amount

[0085]

[0086] In a vacuum dried Schlenk tube, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3- ]pyrimidin-7(8 / - / )-one (D), (2.64 g, 1.0 equiv., 10 mmol), Iron(II) sulfate heptahydrate (FeSO4.7H2O) (2.78 g; 10.0 mmol, 1.0 equiv.), oxidant (NH4)2S2O8(4.56 g; 20 mmol,PT / 2026 / 11281

[0087] 2.0 equiv.) were taken and pyruvic acid (1.4 ml, 20 mmol; 2.0 equiv.) was added dropwise to the above mixture. The tube was then sealed and purged with argon for three times. Then water and DMSO mixture (20:1 v / v) (40 ml) was added via a syringe under inert condition. The reaction mixture was heated to 55 to 60 °C and stirred for 12 h. After completion of the reaction, the crude reaction mixture was quenched using satd. (aq) NaHCO3(30 ml) and extracted using ethyl acetate. Then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulphate and purified over silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid; yield: 65% with morethan 99% purity.

[0088] Example 4d: Iron(II) perchlorate hydrate, Fe(ClO4)2.xH2O as Fe-catalyst

[0089]

[0090] In a vacuum dried Schlenk tube, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3- ]pyrimidin-7(8 / - / )-one (D), (2.64 g, 1.0 equiv., 10 mmol), Iron(III) acetylacetonate [Fe(acac)3] (0.353 g; 1.0 mmol, 0.1 equiv.), oxidant (NH4)2S2O8(4.56 g; 20 mmol, 2.0 equiv.) were taken and pyruvic acid (1.4 ml, 20 mmol; 2.0 equiv.) was added dropwise to the above mixture. The tube was then sealed and purged with argon for three times. Then water and DMSO mixture (20:1 v / v) (40 ml) was added via a syringe under inert condition. The reaction mixture was heated to 55 to 60 °C and stirred for 12 h. After completion of the reaction, the crude reaction mixture was quenched using satd. NaHCO3water (30 ml) and extracted using ethyl acetate. Then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulphate and purified using silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid; yield: 48%.

[0091] Example 4e: Iron(II) perchlorate hydrate, Fe(ClO4)2.xH2O as Fe-catalystPT / 2026 / 11281

[0092]

[0093] In a vacuum dried Schlenk tube, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3- ]pyrimidin-7(8 / - / )-one (D), (2.64 g, 1.0 equiv., 10 mmol), Iron(II) perchlorate hydrate [Fe(ClO4)2.xH2O] (0.255 g; 1.0 mmol, 0.1 equiv.), oxidant (NH4)2S2O8(4.56 g; 20 mmol, 2.0 equiv.) were taken and pyruvic acid (1.4 ml, 20 mmol; 2.0 equiv.) was added dropwise to the above mixture. The tube was then sealed and purged with argon for three times. Then water and DMSO mixture (20:1 v / v) (40 ml) was added via a syringe under inert condition. The reaction mixture was heated to 55 to 60 °C and stirred for 12 h. After completion of the reaction, the crude reaction mixture was quenched using satd. NaHCO3water (30 ml) and extracted using ethyl acetate. Then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulphate and purified using silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid; yield: 42%.

[0094] Example 4f: Ammonium iron(lll) sulfate dodecahydrate, NH4Fe(SO4)2.12H2O as Fe-catalyst

[0095]

[0096] In a vacuum dried Schlenk tube, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (D), (2.64 g, 1.0 equiv., 10 mmol), Ammonium iron(III) sulfate dodecahydrate [NH4Fe(SO4)2.12H2O] (0.482 g; 1.0 mmol, 0.1 equiv.), oxidant (NH4)2S2O8(4.56 g; 20 mmol, 2.0 equiv.) were taken and pyruvic acid (1.4 ml, 20 mmol; 2.0 equiv.) was added dropwise to the above mixture. The tube was thenPT / 2026 / 11281

[0097] sealed and purged with argon for three times. Then water and DMSO mixture (20:1 v / v) (40 ml) was added via a syringe under inert condition. The reaction mixture was heated to 55 to 60 °C and stirred for 12 h. After completion of the reaction, the crude reaction mixture was quenched using satd. NaHCO3water (30 ml) and extracted using ethyl acetate. Then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulphate and purified using silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid; yield: 42%.

[0098] Example 4g: Iron(ll) acetylacetonate, Fe(acac)2 as Fe-catalyst

[0099]

[0100] In a vacuum dried Schlenk tube, 2-chloro-8-cyclopentyl-5-methylpyrido[2,3- ]pyrimidin-7(8 / - / )-one (D), (2.64 g, 1.0 equiv., 10 mmol), Iron(II) acetylacetonate [Fe(acac)2] (0.254 g; 1.0 mmol, 0.1 equiv.), oxidant (NH4)2S2O8(4.56 g; 20 mmol, 2.0 equiv.) were taken and pyruvic acid (1.4 ml, 20 mmol; 2.0 equiv.) was added dropwise to the above mixture. The tube was then sealed and purged with argon for three times. Then water and DMSO mixture (20:1 v / v) (40 ml) was added via a syringe under inert condition. The reaction mixture was heated to 55 to 60 °C and stirred for 12 h. After completion of the reaction, the crude reaction mixture was quenched using satd. NaHCO3water (30 ml) and extracted using ethyl acetate. Then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulphate and purified using silica gel column chromatography using EA and pet ether as eluent (30% EA / PE). The final product was obtained as off-white solid; yield: 44%.

[0101] Example 5: Step V: Preparation of tert-butyl 4-(6-((6-acetyl-8-cvclopentyl-5-methyl-7-oxo-7,8-dihvdropyrido[2,3-cflpyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1 -carboxylate (F):PT / 2026 / 11281

[0102]

[0103] In a 100 ml long two-neck Rb first amine (2.92 g, 10.5 mmol, 2.1 equiv.) were taken and the reaction flask was purged with argon for three times. Then dry toluene (15 ml) was added via a syringe under inert condition. The mixture was set to cool at 0 °C using a cool reaction bath. Then LiHMDS (1 M in hexane) (10.0 mL, 1.0 mol / L, 10 mmol) was added to the above mixture dropwise via a syringe under argon atmosphere. After addition of base, the temperature of the reaction mixture in round bottom flask was maintained between 0 °C to 5 °C for at least 30 min. Then after 30 min, compound E (1.53g, 1.0 equiv., 5 mmol) in 15 ml dry toluene was added dropwise to activated amine solution dropwise via a syringe. Then after stirring the above reaction solution at 0 °C to 5 °C for 15 min, the temperature was increased to 20 °C and then the reaction was continued for the next 2 h at room temperature. After 2 h, the saturated bicarbonate solution (2 ml) was added to the reaction mixture and stirred at RT for 30 min. Then the crude reaction mixture was extracted using ethyl acetate and water and then the combined ethyl acetate part was concentrated, dried over anhydrous sodium sulfate and purified using silica gel column chromatography using EA and pet ether as eluent (50% EA / PE). The final product was obtained as brown solid; yield: 70%.1H NMR (400 MHz, chloroform-d) δ 8.81 (s, 1H), 8.35 (d, J = 9.2 Hz, 1H), 7.91 (s, 1H), 7.48-7.44 (m, 1H), 5.88-5.81 (m, 1H), 3.62-3.59 (m, 4H), 3.13 (s, 4H), 2.53 (s, 3H), 2.34 (s, 3H), 2.29 (m, 2H), 2.16-2.09 (m, 2H), 1.89-1.86 (m, 2H), 1.68-1.66 (m, 2H), 1.48 (s, 9H);13C NMR (100 MHz, chloroform-d) 5 206.9, 155.5, 144.0, 119.5, 80.0, 58.4, 53.8, 48.9, 31.0, 28.5, 25.5, 18.4, 16.9.

[0104] Example 6: Step VI: Preparation of 6-acetyl-8-cvclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d|pyrimidin-7(8H)-one

[0105]

[0106] (Palbociclib):PT / 2026 / 11281

[0107]

[0108] In an oven dried two-neck round bottom flask, Boc-protected palbociclib (F) (1.0 g, 1.0 equiv., 1.82 mmol) was taken into n-butanol (12 ml; 12 v) and water (10 ml; 10 v) mixture and heated at 70 °C. Then concentrated HCI (0.2 ml; 4.55 mmol; 2.5 equiv.) was added dropwise to the above solution and stirring was continued for 2 h. After complete disappearance of reactants, benzyl ether (18 ml; 18 v) was added to the resulting solution. Then 30% NaOH solution was added dropwise to the above solution to make the pH>9, stirred well at room temperature for at least 4 h to separate out a solid precipitate. After complete precipitation, the solid was filtered, washed with water for several times until became neutral and recrystallized with n-BuOH and anisole. Finally, the crystal was dried to obtain a bright yellow solid (palbociclib) with more than 99% purity; yield: 80%.1H NMR (400 MHz, chloroform-d) δ 10.63 (s, 1H), 10.03 (s, 1H), 8.91 (s, 1H), 7.99 (s, 1H), 7.79 (d, J= 8.8 Hz, 1H), 7.42-7.39 (m, 1H), 5.80-5.76 (m, 1H), 3.03-3.00 (m, 4H), 2.82-2.79 (s, 4H), 2.46 (s, 3H), 2.38 (s, 3H), 2.35-2.27 (m, 2H), 1.84 (m, 2H), 1.70 (m, 2H), 1.53 (m, 2H);13C NMR (100 MHz, chloroform-d) 5 206.9, 155.5, 144.0, 119.5, 80.0, 58.4, 53.8, 48.9, 31.0, 28.5, 25.5, 18.4, 16.9.

[0109] Advantages of the invention

[0110] 1. There is an urgent need for a better environmentally friendly and industrially viable process. Our established method provides a simple green, hazardous reagent-free protocol for synthesizing 6-acetyl-2-chloro-8-cyclopentyl-5- methylpyrido[2,3- |pyrimidin-7(8 / - / )-one (E), a key intermediate for synthesizing Palbociclib with good yield. In our quest to enhance the efficiency and practicality of this reaction, we've uncovered a valuable synthetic method starting from 5-acetyl uracil derived intermediate. This newly devised method offers a straightforward and achievable alternative, boastingPT / 2026 / 11281

[0111] advantages such as poor cost, satisfactory yield, and suitability for large-scale production.

[0112] 2. Notably, the innovation lies in the fact that none of the traditional reagents such as oxidants (e.g., Mn02 or reducing agents LAH), expensive transition metal catalysts, expensive silver and palladium catalyst, Sulphur compounds and Grignard reagents, phosphine ligands or Bromine sources are utilized in this present invention.

[0113] 3. In our developed reaction strategy, most of the steps carried out under atmospheric pressure and at room temperature highlighting its high practicality and simplicity. This method stands out for being both operationally straightforward and economically feasible, rendering it a valuable tool for large-scale industrial preparation.

[0114] 4. The key step of synthesis of 6-acetyl-2-chloro-8-cyclopentyl-5- methylpyrido[2,3- |pyrimidin-7(8 / - / )-one (E) using cheap iron(II) sulfate heptahydrate catalyst and persulfate oxidant in water solvent in presence of catalytic amount of DMSO under low heating condition circumvents the need for expensive Ag or Pd catalysts, costly phosphine ligands, high reaction temperature and hazardous solvent mixture and thus presents a novel catalytic combination for the synthesis of the key intermediate E of Palbociclib.

[0115] 5. The solvents used for the preparation of Palbociclib are also a key factor.

[0116] Bottle-grade solvents (such as ethyl acetate, water, and DMSO) used for the synthesis performed well under the applied reaction conditions.

[0117] 6. The key acylation step of (D) using commercially available pyruvic acid was carried out in water solvent in the presence of the catalytic amount of DMSO. Water and DMSO are also considered safer and more environmentally friendly as compared to acetonitrile (hazardous waste that requires careful disposal). Acetonitrile is easily ignited by heat, gives off highly toxic hydrogen cyanide fumes on heating and thus is a potentially toxic and highly volatile pollutant of many industrial wastewaters.PT / 2026 / 11281

[0118] 7. It is a relatively straightforward, economically viable and operationally simple synthetic route of Palbociclib; hence this process is highly effective for large scale production.

[0119] 8. Existing synthetic methods for preparing Palbociclib often involve drawbacks such as the use of expensive palladium metal catalysts, phosphine ligands, specialized acylating agents, silver salts for acylation, oxidants, multi-step procedures including bromination, and high reaction temperatures. In contrast, the invention described herein presents a cost-effective approach that avoids the need for expensive palladium and silver catalysts, Grignard reagents, and toxic chemicals. Consequently, this methodology offers significant advantages in terms of the overall cost of the active pharmaceutical ingredient (API) and its intermediate E. The present invention provides a toxic silver salt-free, environmentally friendly, and safe synthetic process that is easy to handle for synthesizing the key intermediate, 6-acetyl-2-chloro-8- cyclopentyl-5-methylpyrido[2,3- |pyrimidin-7(8H)-one (E), for the synthesis of Palbociclib.

[0120] 9. The cost of the catalyst required to synthesize the key intermediate (E) from starting material D using the present invention, which employs iron(II) sulfate heptahydrate, is 2 to 2.3 times cheaper than the existing process that requires a silver catalyst. This is primarily because the cost of FeSO4·7H2O is 20 times less than that of silver catalysts. In the present invention, the loading of the iron catalyst ranges from 10 mol%, whereas existing methods require a higher loading of silver catalysts (24-40 mol%). These two factors — the cost of the catalyst and the catalyst loading — make the present invention a more efficient and cost-effective process for the synthesis of intermediate E.

[0121] 10. The formation of large amounts of toxic silver waste after the reaction can be avoided by employing an iron catalyst. Besides the environmental benefits, avoiding Ag-salt in the acylation step offers the advantage of preventing difficulties related to removing silver waste contamination in subsequent steps and from the reaction vessel.PT / 2026 / 11281

[0122] 11. The cost of the step involving the synthesis of a key intermediate 6-acetyl-2- chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (E) is effectively reduced by employed ammonium persulfate instead of potassium persulfate. The cost of potassium persulfate is almost 1.5 times higher than that of employed ammonium persulfate. Cost of ammonium persulfate (Sigma Aldrich) is Rs. 22 / g while the cost of potassium persulfate (Sigma Aldrich) is Rs. 24 / g. Additionally, using NH4S2O8as an oxidant promotes the generation of safer, eco-friendly, soft-metal-free waste compared to other oxidants like K2S2O8.

[0123] 12. The chemicals, reagents, and solvents used throughout the process improved the overall purity of the API and the intermediate E by more than 99%.

Claims

1. PT / 2026 / 11281WE CLAIM:

1. A process for the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-substituent- pyrido[2,3-d]pyrimidin-7(8 / - / )-one a key intermediate in the synthesis of palbociclib comprising:C-6 acylation of 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (D) in presence of a catalyst, a solvent, an oxidant and pyruvic acid as the acetyl source to obtain 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (E),wherein the catalyst is 0.1 to 1 eq. of iron catalyst selected from the group consisting of Iron (II) chloride, Iron(II) bromide, Iron(II) acetate, Iron(II) oxalate dihydrate, Iron(II) perchlorate hydrate, ferrocene, iron(III) chloride, iron(II) triflate, iron(II) acetyl acetonate, Iron(III) acetylacetonate, Iron(III) sulfate hydrate, ammonium ferrous sulfate, preferably iron(II) sulfate heptahydrate.

2. The process as claimed in claim 1, wherein the molar ratio of intermediate D and pyruvic acid is 1: 1 to 1: 3, preferably 1: 2.

3. The process as claimed in claim 1, wherein the solvent is selected from a group consisting of dimethylsulfoxide (DMSO), acetonitrile (ACN), dichloromethane (DCM), ethanol, ethyl acetate, water, acetone or a mixture thereof.

4. The process as claimed in claim 1, wherein the oxidant is selected from a group consisting of ammonium persulfate, potassium persulphate, sodium persulfate, sodium bromate, sodium periodate, benzoquinone, benzoyl peroxide and hydrogen peroxide, preferably ammonium persulfate.

5. The process, as claimed in claim 1, wherein the reaction is carried out at a temperature in the range of 0 °C to 100 °C, preferably in the range 55-60 °C.PT / 2026 / 112816. The process as claimed in claim 1, wherein the process for the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8 / - / )-one comprises the steps of:i. chlorination reaction of 5-acetyl uracil (A) with POCl3in presence of diethylamine base and an organic solvent at 115-120 °C under inert condition to produce (2,4-dichloropyrimidin-5-yl)ethan-1-one (B);A Bii. selective C-4 amination of 1-(2,4-dichloropyrimidin-5-yl)ethan-1-one (B) using triethylamine base in presence of an organic solvent to produce 1 -(2- chloro-4-(cyclopentylamino)pyrimidin-5-yl)ethan-1-one from (C);iii. LiHMDS mediated cyclization of 1-(2-chloro-4-(cyclopentylamino)pyrimidin-5- yl)ethan-1-one (C) to produce 2-chloro-8-cyclopentyl-5-methylpyrido[2,3- d]pyrimidin-7(8 / - / )-one (D); andiv. Fe(ll) / S2O82--catalyzed C-6 acylation of 2-chloro-8-cyclopentyl-5- methylpyrido[2,3-d]pyrimidin-7(8 / - / )-one (D) using pyruvic acid as the acetylPT / 2026 / 11281source to obtain 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (E).

7. The process as claimed in claim 6, wherein the organic solvent of step (i) is selected from the group consisting of acetic acid, tetrahydrofuran (THF), 1,4- dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate and acetone and the organic solvent of step (ii) is selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, toluene, benzene, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide, ethyl acetate or acetone.

8. The process as claimed in claim 6, wherein the LiHMDS mediated cyclization reaction of 1-(2-chloro-4-(cyclopentyl amino)pyrimidin-5-yl)ethan-1-one (C) is carried out in the presence of ethyl acetate.

9. The process as claimed in claim 1, further comprising LiHMDS mediated SNAr coupling of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (E) with Tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1 -carboxylate to produce tert-butyl 4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1 -carboxylate (F) followed by hydrolysis of (F) to obtain palbociclib G.(Palbociclib)PT / 2026 / 1128110. The process as claimed in claim 1, wherein the yield of 6-acetyl-8-cyclopentyl- 5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8 / - / )-one is 52% with more than 99% purity.

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