“IMPROVED PROCESS FOR THE PREPARATION OF 7- CYCLOPENTYL-N, N-DIMETHYL-2-(5-(PIPERAZIN-l-YL) PYRIDIN-2- YLAMINUTESO)-7H-PYRROLO[2,3-D] PYRIMIDINE-6- CARBOXAMIDE SUCCINATE (RIBOCICLIB SUCCINATE) AND IT’S

CRYSTALLINE FORMS THEREOF”

CROSS REFERENCE

This application claims priority from Indian Patent Application No.

201841004284 filed Indian Patent Office on Feb 05, 2018.

BACKGROUND OF INVENTION

Ribociclib succinate (1) is a selective cyclin-dependent kinase inhibitor that help to slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). It is used for the treatment of certain kinds of breast cancer and is being studied for the treatment for other drug-resistant cancers. Chemically, it is 7-cyclopentyl-N, N-dimethyl-2-(5-(piperazin-l-yl) pyridin-2- ylaminuteso)-7H-pyrrolo[2,3-D] pyrimidine-6-carboxamide succinate (1).

The following patents and applications describes the synthesis of Ribociclib succinate (1) and its different salts and polymorphs.

US2012115878 discloses the synthesis of intermediates 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide and 4-(6-nitro-pyridin-3- yl)-piperazine-l -carboxylic acid tert-butyl ester used for the preparation of Ribociclib free base (1). 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamide was coupled with 4-(6-nitro-pyridin-3-yl)- piperazine-l -carboxylic acid tert-butyl ester using palladium (II) acetate, (2,2'- bis(diphenylphosphino)- 1, G-binaphthyl) (BINAP) and cesium carbonate to form the protected intermediate tert-butyl 4-(6-(7-cyclopentyl-6-(dimethyl carbamoyl)-7H- rnitoΐo 12.3-d |pyrimidin-2-ylaminuteso)pyridiii-3-yl)piperaziiic-l -carboxyl ate which on deprotection with aqueous hydrochloric acid formed Ribociclib free base. Ribociclib free base was further treated with succinic acid to form Ribociclib succinate (1). It further discloses different forms of succinate salt of Ribociclib including non-hydrate, hydrate forms, or mixtures thereof.

US2017342075 discloses form A of hemi-succinate, adipate, maleate and glycolate salts of Ribociclib. It further discloses the mono-succinate crystalline form-I of Ribociclib along with the XRD and DSC data.

Thus, based on prior art and literatures, very less information is available regarding stable forms of Ribociclib succinate. Hence, the present inventors hereby report an improved process for the preparation of Ribociclib succinate (1) and its novel polymorphs which are stable by using safe and commercially viable reagents under mild reaction conditions which can be industrially feasible.

OBJECTIVE OF THE INVENTION

Accordingly, one objective of the invention is to provide an improved process for the preparation of Ribociclib succinate (1) with purity greater than 99.5% by HPLC. Another objective of the invention is to provide novel crystalline forms of Ribociclib succinate (1)

Yet, another objective of the invention is to provide a process for the preparation of novel crystalline forms of Ribociclib succinate (1)

SUMMARY OF THE INVENTION

Accordingly, in one embodiment the present invention relates to an improved process for the preparation of Ribociclib succinate (1), which comprises of the following steps:

a) coupling of 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide (5) with tert-butyl 4-(6-aminutesopyridin-3-yl) piperazine- l-carboxylate (4) in presence of a suitable base and isolated from a suitable protic solvent to form tert-butyl 4-(6-(7-cyclopentyl-6-(dimethyl carbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2-ylaminuteso) pyridin-3-yl) piperazine- l-carboxylate (3)

b) deprotecting the amine protecting group of the intermediate (3) in presence of suitable acid to form Ribociclib free base (2)

c) converting Ribociclib free base (2) to succinate salt of Ribociclib (1) using succinic acid in a suitable protic solvent.

Accordingly, the present invention provides novel crystalline forms of Ribociclib succinate (1).

In another aspect, the invention provides a process for preparation of crystalline forms of Ribociclib succinate (1) comprising the steps of:

I. contacting Ribociclib succinate (1) with a solvent or mixture of solvents;

II. optionally, heating the solvent or solvents mixture with Ribociclib succinate (1)

III. stirring the reaction mixture at 25-30°C and

IV. precipitating Ribociclib succinate (1) from solvent or solvents mixture by using conventional techniques viz. slow or fast cooling, addition of crystallization solvent, distillation under reduced pressure, drying at atmospheric or reduced pressure, to obtain the desired crystalline form of Ribociclib succinate (1);

wherein the crystalline forms of Ribociclib succinate (I) produced by the process is any of polymorphic forms form I, form II, form II and form IV, each crystalline form is characterized by XRPD peaks patterns as depicted in figure- 1, figure-2, figure-3 and figure-4 respectively.

wherein the solvent or solvents mixture can be selected from the protic solvents selected from the group comprising water, methanol, ethanol, propanol, isopropyl alcohol, butanol, benzyl alcohol or the like, preferably methanol, benzyl alcohol and water were used in the present invention.

In another embodiment the aprotic solvents used for the preparation of crystalline forms of Ribociclib succinate (1), was selected from the group comprising acetone, acetonitrile, nitromethane, l,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, 3-butyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like, preferably acetonitrile, nitromethane, butyl acetate and dichloromethane were used in the present invention.

Yet another embodiment, the crystalline forms of Ribociclib succinate obtained in the present invention is having purity greater than 99.5% by High-performance liquid chromatography, (HPLC).

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 : X-Ray powder diffraction (XPRD) pattern of crystalline form I of Ribociclib succinate (1) as prepared in example-4a

Figure 2: X-Ray powder diffraction (XPRD) pattern of crystalline form II of Ribociclib succinate (1) as prepared in example-4b

Figure 3: X-Ray powder diffraction (XPRD) pattern of crystalline form III of Ribociclib succinate (1) as prepared in example-4c

Figure 4: X-Ray powder diffraction (XPRD) pattern of crystalline form IV of Ribociclib succinate (1) as prepared in example-4d

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, in one embodiment the present invention provides an improved process for the preparation of Ribociclib succinate (1) with purity greater than or equal to 99.5% by HPLC.

In another embodiment of the invention provides the novel crystalline forms of Ribociclib succinate (1)

Ribociclib succinate (1) prepared in the present invention is as represented in Scheme- 1 below:

Scheme-1

Step a) proceeds with the coupling of 2-chloro-7-cyclopentyl-N, N-dimethyl-7H- pyrrolo[2,3-d] pyrimidine-6-carboxamide (5) with tert-butyl 4-(6- aminutesopyridin-3-yl) piperazine- l-carboxylate (4). Intermediate (5) was added to the reaction mass containing intermediate (4) dissolved in an aprotic solvent and a suitable base at a temperature range of 10-30 °C. Reaction completion time ranges from 10-14 hrs. On completion of reaction, reaction mass was cooled to 10-15 °C and suitable protic solvent was added. The aqueous layer was extracted with a suitable aprotic solvent. The residue was then treated with a protic solvent at 60-65 °C to obtain tert-butyl 4-(6-(7-cyclopentyl-6-(dimethyl carbamoyl)-7H-pyrrolo[2,3- d] pyrimidin-2-ylaminuteso) pyridin-3-yl) piperazine- l-carboxylate (3)

The suitable base used in step a) was selected from a group comprising lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS) and sodium bis(trimethylsilyl)amide (NaHDMS) or the like; preferably lithium bis (trimethylsilyl)amide (LiHMDS) was used in the present invention.

Step b) proceeds with the deprotection of amine protecting group of tert-butyl 4-(6- (7-cyclopentyl-6-(dimethyl carbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2- ylaminuteso) pyridin-3-yl) piperazine- l-carboxylate (3). Intermediate (3) was treated with a suitable deprotecting agent in a protic solvent. Preferably the deprotecting agent is an acid, more preferably an organic acid. The reaction temperature ranges from 25 to 65 °C, preferably 60 to 65°C. On completion of the reaction, the reaction mass was cooled to 10-15 °C and pH was adjusted to an optimum range in between 10 to 11 using a suitable base. The solid so formed was then filtered and optionally treated with a protic solvent to obtain Ribociclib free base (2).

The acid used for deprotection in step b) was selected from a group comprising of organic or inorganic acids. The organic acid may be selected form the group consisting of carboxylic acid or sulphonic acid such as trifluoro acetic acid, trifluoromethanesulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-touenesulphonic acid or the like. The inorganic acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or the like. More preferably p-touenesulphonic acid was used in the present invention.

The base used in step b) was selected from a group comprising sodium hydroxide, potassium hydroxide, sodium carbonate potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate cesium bicarbonate, sodium methoxide, sodium ethoxide; potassium methoxide, potassium ethoxide or the like. Preferably sodium hydroxide was used in the present invention.

Step c) involves the conversion of Ribociclib free base (2) to succinate salt of Ribociclib (1). Ribociclib free base (2) was added to a suitable protic solvent and heated to 60 to70 °C. Succinic acid was added to the reaction mass. The temperature of the reaction may range from 15-85 °C. The reaction completion time range from lhr to 3 hr., preferably lhr to 2 hr. The final compound was isolated from a protic solvent to obtain pure Ribociclib succinate (1).

The suitable protic solvent used in step a), step b) and step c) were selected from a group comprising of methanol, ethanol, isopropyl alcohol (IP A), n-propanol, n- butanol, water or the like, preferably methanol, water and isopropyl alcohol were used in the present invention.

The suitable aprotic solvents used in step a) were selected from a group comprising of acetone, acetonitrile, l,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like; preferably tetrahydrofuran, toulene and ethyl acetate were used in the present invention.

Ribociclib succinate (1) obtained by the above process was having purity greater than equal to 99.5% by HPLC.

In another aspect, the invention provides a process for preparation of crystalline forms of Ribociclib succinate (1) comprising the steps of:

I. contacting Ribociclib succinate (1) with a solvent or mixture of solvents;

II. optionally, heating the solvent or solvents mixture with Ribociclib succinate

(1)

III. stirring the reaction mixture at 25-30°C and

IV. precipitating Ribociclib succinate (1) from solvent or solvents mixture by using conventional techniques namely slow or fast cooling, addition of crystallization solvent, distillation under reduced pressure, drying at atmospheric or reduced pressure, to obtain the desired crystalline form of Ribociclib succinate (1);

In another embodiment the protic solvents used for the preparation of crystalline forms of Ribociclib succinate (1) was selected from a group comprising of water, methanol, ethanol, propanol, isopropyl alcohol, butanol, benzyl alcohol or the like, preferably methanol, benzyl alcohol and water were used in the present invention. In another embodiment the aprotic solvents used for the preparation of crystalline forms of Ribociclib succinate (1), was selected from a group comprising of acetone, acetonitrile, nitromethane, l.4-dioxane. diethyl ether, dichloromethane, ethyl acetate, 3-butyl acetate, N, N-dimcthylfonn amide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like, preferably acetonitrile, nitromethane, 3-butyl acetate and dichloromethane were used in the present invention.

In another aspect, the crystalline forms of Ribociclib succinate (1) obtained in the present invention was having purity greater than equal to 99.5% by HPLC.

In another aspect, the crystalline forms I, II, III and IV of Ribociclib succinate (1) may produce an X-ray diffraction (XRD) pattern as illustrated in figure 1, figure 2, figure 3 and figure 4 and whose 2 theta values are tabulated in table 1, table 2, table 3 and table 4 below.

The crystalline form I of Ribociclib succinate (1) may produce an X-Ray diffraction (XRD) pattern comprising one or more of the following characteristic reflections: 4.51 ,10.57, 13.00, 13.82, 16.13, 16.44, 18.18, 19.95, 21.41, 21.93, 23.42, 25.18 and 26.23±20 or that produces an X-ray powder diffraction pattern further comprising one or more of the following additional reflections at 8.40, 8.84, 9.23, 11.91, 24.39, 25.18, 27.88, 28.65, 29.83, 30.52 and 34.06±20 or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table- 1

The crystalline form II of Ribociclib succinate (1) may produce an X-Ray diffraction (XRD) pattern comprising one or more of the following characteristic reflections at 6.45, 7.60, 11.19, 12.62, 13.92, 14.68, 15.13, 16.54, 17.52, 18.46, 18.95, 19.30, 19.78, 20.58, 21.24, 21.79, 22.19, 23.72, 25.16, 25.34, 25.58, 26.26, 26.62, 28.05, 28.59, 30.05 aid 30.6l±20 or that produces an X-ray powder diffraction pattern further comprising one or more of the following additional reflections at 10.09, 24.83, 29.37, 31.18, 32.04, 34.21 and 35.06 ±20 or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table-2

The crystalline form III of Ribociclib succinate (1) may produce an X-Ray diffraction (XRD) pattern comprising one or more of the following characteristic reflections at 4.41, 6.91, 11.16, 12.37, 12.76, 14.86, 15.79, 17.55, 18.13, 19.22, 19.68, 21.16, 21.43, 21.81, 22.51 and 23.79 ±20 or that produces an X-ray powder diffraction pattern further comprising one or more of the following additional reflections at 4.73, 6.15, 8.85, 9.26, 9.63, 10.11, 10.59, 13.49, 24.65, 25.86, 29.41, 30.18, 30.76, 31.60 and 36.02 ±20 or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table-3

The crystalline form IV of Ribociclib succinate (1) may produce an X-Ray diffraction (XRD) pattern comprising one or more of the following characteristic reflections at 5.22,9.18, 9.60, 10.20, 10.44, 13.81, 16.88, 17.30, 17.83, 18.08, 20.32, 20.79, 21.41, 22.70, 23.05, 23.79 and 25.15 ±20 or that produces an X-ray powder diffraction pattern further comprising one or more of the following additional reflections at 4 .83, 8.25, 11.85, 12.48, 12.96, 14.31, 15.44, 15.75, 16.620, 18.37, 19.33, 24.97, 26.02, 26.88, 27.39, 28.10, 28.40, 29.86, 32.30, 33.48, 37.48 and 39.67 ±20 or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table-4

In another embodiment,

-the crystalline form I of Ribociclib succinate (1) is obtained by heating Ribociclib succinate in methanol and isolating by cooling to 25-30°C -The crystalline form II of Ribociclib succinate (1) is obtained by stirring in benzyl alcohol at 25-30°C for lOhrs to l2hrs

-The crystalline form III of Ribociclib succinate (1) is obtained by 3-butyl acetate at 25-30°C for lOhrs to l2hrs - the crystalline form IV of Ribociclib succinate (1) is obtained by heating Ribociclib succinate in methanol and isolating by distilling off the solvent under vacuum

The X-Ray diffraction data of the Ribociclib succinate forms obtained are tabulated below

Table 1: X-Ray diffraction data of Ribociclib succinate (1) form I

Table 2: X-Ray diffraction data of Ribociclib succinate (1) form II

Table 3: X-Ray diffraction data of Ribociclib succinate (1) form III

Table 4: X-Ray diffraction data of Ribociclib succinate (1) form IV

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.

EXAMPLE -1 Preparation of tert-butyl 4-(6-(7-c clopentyl-6-(dimethyl carbamoyl)-7H- pyrrolo[2,3-d] pyiiniidin-2-ylaminuteso) pyridin-3-yl) piperazine-1- carboxylate (3)

209.5g of tert-butyl 4-(6-aminutesopyridin-3-yl) piperazine- l-carboxylate (4) was added to lOOOmL of toulene and stirred for 10-15 mins. The reaction mixture was then cooled to 10- 15 °C and a solution of 1.0M lithium bis(trimethylsilyl)amide in tetrahydrofuran was added to the reaction mass. The temperature of the reaction mixture was raised to 20-35 °C and stirred for lhr. lOOg of 2-chloro-7-cyclopentyl- N, N-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide (5) was added to the reaction mass and stirred for 22-24hrs at 25-30 °C. On completion of reaction, the reaction mass was cooled to 10-15 °C and water was added. The temperature of the reaction mixture was again raised to 25-30 °C and the layers were separated. The aqueous layer was extracted with ethyl acetate and the total organic layer was distilled under vacuum below 50 °C. The residue was then treated with methanol and heated for lhr at 60-65 °C. The reaction mixture was cooled to 5-10 °C and filtered. The solid so obtained was washed with methanol and dried below 65°C to obtain tert-butyl 4-(6-(7-cyclopentyl-6-(dimethyl carbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2-ylaminuteso) pyridin-3-yl) piperazine- l-carboxylate (3)

Yield: 60%

Purity: 97.0%

EXAMPLE-2

Preparation of Ribociclib free base (2)

lOOg of tert-butyl 4-(6-(7-cyclopentyl-6-(dimethyl carbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2-ylamino) pyridin-3-yl) piperazine- l-carboxylate (3) was added to lOOOmL of isopropyl alcohol and acidified with i-toluenesulfonic acid at 25-30 °C. The reaction mixture was heated at 60-65 °C for 8-10 hrs. On completion of reaction, the reaction mixture was cooled tol0-l5 °C and the pH was adjusted to 10-11 using 20% sodium hydroxide solution. The reaction mixture was stirred for lhr at 25-30 °C and filtered to obtain the solid. The solid so obtained was washed with water and dried below 65 °C to obtain Ribociclib free base (2) Yield: 86%

Purity: 98.0%

EXAMPLE S

Preparation of Ribociclib succinate (1)

lOOg of Ribociclib free base (2) was dissolved in 2500mL of methanol, stirred for 10 minutes and heated to 60-65 °C. 28.5g of succinic acid was added to the reaction mass and the reaction mass heated to 75-80 °C for 2hrs. The reaction mixture was cooled to 15-20 °C, stirred for 2hrs and filtered. The solid so obtained was then washed with 100 mL of cold methanol (0-5°C) and dried below 65 °C to obtain Ribociclib succinate (1)

Yield: 90%

Purity: 99.85%

XRD: figure 1; table 1

EXAMPLE-4

a) Preparation of crystalline form of Ribociclib succinate (1)

5.0g of Ribociclib succinate (1) was suspended in l25mL of methanol at 25-30 °C, heated to 60-65 °C and stirred for 10-15 mins. 2.0mL of water was added to the reaction mixture and stirred to form a clear solution. The clear solution was then cooled to 25-30 °C and stirred for 30 mins to form a solid mass. The solid so formed was filtered, washed with lOmL of methanol and dried under vacuum for 15 mins to obtain crystalline of Ribociclib succinate (1)

Yield: 71%

XRD: figure 1; table 1 b) Preparation of crystalline form of Ribociclib succinate (1)

l.Og of Ribociclib succinate (1) was charged with 20mL of benzyl alcohol at 25-30 °C and stirred for l0-l5mins to form a clear solution. The reaction mixture was maintained for l2hrs at 25-30 °C. The slurry so formed was then filtered and the residue was washed with 2mL of benzyl alcohol. The wet cake so obtained was dried under vacuum for 10-15 mins to obtain crystalline Ribociclib succinate (1) Yield: 73%

XRD: figure 2; table 2 c) Preparation of crystalline form of Ribociclib succinate (1)

l.Og of Ribociclib succinate (1) was charged 25mL of 3-butyl acetate and stirred for 10 mins at 25-30 °C. The reaction mixture was maintained for l2hrs at 25-30 °C. The slurry so formed was then filtered and the residue so obtained was dried under vacuum for 15 mins to obtain crystalline form of Ribociclib succinate (1) Yield: 78%

XRD: figure 3; table 3

d) Preparation of crystalline form of Ribociclib succinate (1)

3.0g of Ribociclib succinate (1) was charged in 300mL of methanol and stirred for 30 mins at 25-30 °C. The reaction mixture was then heated to 60-65 °C for 30mins to form a clear solution. The clear solution was then distilled off under vacuum to obtain crystalline form of Ribociclib succinate (1)

Yield: 75%

XRD: figure 4; table 4