DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian provisional patent application no IN 201841049695 filed on Dec 28, 2018.

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Ribociclib Succinate.

BACKGROUND OF THE INVENTION:
Ribociclib Succinate, chemically known as Butanedioic acid—7-cyclopentyl-N,N
dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-
carboxamide (1/1) and represented by Formula-I is approved for the inhibitor of cyclin D1/CDK4 and CDK6. It is similar to Palbociclib both structurally and pharmacologically,
acting as a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.

Formula I

Ribociclib and it’s pharmaceutically acceptable salts thereof was first claimed in US 8415355B2 patent. This patent also disclosed a process for the preparation of ribociclib as below.

US 20120115878A discloses a method for preparing the intermediate-I. Although the route selected propargylalcohol as a side chain coupling, but the yield of this step is still relatively low, and also the noble metal catalyst used higher doses, higher process cost; cyclization process, since the hydroxyl group electrically negative effect, there may be six membered ring by-product formation; use of additional oxidation of alcohol during the preparation of amides of a number of solid manganese dioxide as an oxidizing agent inconvenient. Further the process involves sodium cyanide which is highly toxic and need special handling conditions.

CN 105037236 A discloses a method for preparing Ribociclib, however the yields are low and is not suitable for industrial production.

US 20150099760A claimed process for the preparation Ribociclib Succinate and their intermediates.
WO 2018051280 claimed process for the preparation Ribociclib, acceptable salts and their intermediates.
The inventors of the present invention have developed improved process for the preparation Ribociclib Succinate with good yield using pure intermediates.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide an improved process for the preparation Ribociclib Succinate.

In one aspect, the present invention provides process for the preparation of compound of formula VIII by condensing compound of formula VI with compound of formula VII in presence of suitable metal alkoxides.

In another aspect, the present invention provides purification of compound of formula VIII.

In yet another aspect, the purified compound of formula VIII has an individual impurity less than 0.1%.

In another aspect, the present invention provides process of making compound of formula VI comprising the steps of:

(a) converting cyclized alcohol (Compound IV) to cyclized aldehyde (Compound V).

(b) converting cyclized aldehyde (Compound V) to compound of formula VI.

In yet another aspect, the present invention provides purification of compound of formula VI.

In yet another aspect, the compound of formula VIII is converted to Ribociclib or its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION.

The present invention relates to an improved process for the preparation Ribociclib Succinate.

In embodiment, the present invention relates to process for the preparation of compound of formula VIII by condensing compound of formula VI with compound of formula VII in presence of suitable metal alkoxide:

According to the present invention, condensing compound of formula VI with compound of formula VII in presence of suitable metal alkoxides such as sodium tertiary butoxide, potassium tertiary butoxide, Lithium tert-butoxide preferably sodium tertiary butoxide using suitable organic solvent such as tetrahydrofuran or dimethylformamide obtains compound of formula VIII.

Although the process of making the compound of formula VIII using combination of ligands, bases and palladium derivatives were known in the literature, the present inventors developed a method using only a base which is easy to handle and feasible for Industrial practice.

In another embodiment, the present invention relates to purification of compound of formula VIII comprising the steps of:
a) dissolving compound of formula VIII in a suitable solvent
b) isolating pure compound of formula VIII.

According to the present invention, the compound of formula VIII [prepared by the method disclosed in this disclosure] may be purified by dissolving it in a suitable organic solvent like alcohols such as methanol, ethanol, isopropanol or dimethylformamide preferably methanol or dimethylformamide and isolating the pure compound by filteration, distillation etc.

In yet another embodiment, the purified compound of formula VIII has an individual impurity less than 0.1%.

In yet another embodiment, the present invention relates process of making compound of formula VI comprising the steps of:

(a) converting cyclized alcohol (Compound IV) to cyclized aldehyde (Compound V).

(d) converting cyclized aldehyde (Compound V) to compound of formula VI.

Accoding to the present invention, compound of formula IV may be converted to compound of formula V using suitable oxidizing agents like chromium oxide, manganese dioxide, lead dioxide, nitric acid, ruthenium tetroxide or preferably manganese oxide in presence of suitable organic solvent like dichloromethane.

Literature methods involve coversion of compound of formula IV to a cyano intermediate using toxic chemicals like sodium cyanide which is then converted to compound of formula VI. Sodium cyanide, being highly toxic is not recommended for use. It also has restrictions while handling and needs special care.

The present invention does not involve cyano intermediate and hence easy for practice. The present invention involves preparation of compound of formula VI through a aldehyde intermediate obtained by oxidation of the corresponding alcohol intermediate. The oxidizing agent used does not require any special precautions for handling and is safe to use. The compound of formula V may be converted to compound of formula VI by using dimethyl amine in presence Iodine and suitable organic solvent like dichloromethane.

In yet another embodiment, the present invention relates to purification compound of formula VI compirising the steps of:
a) suspending compound of formula VI in an organic solvent of mixture fo solvents
b) isolating pure compound of formula VI.

According to the present invention, the compound of formula VI may be purified by suspending compound of formula VI in an organic solvent such as esters selected from methyl ester, ethyl ester or isopropyl ester, hexane, tetrahydrofuran or their mixtures thereof. Preferable solvent is mixture of ethyl ester and hexane.

In yet another embodiment, the compound of formula VIII prepared according to the present invention, may be converted to Ribociclib or its pharmaceutically acceptable salts by the methods shown below:

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

Examples:
Example-1: Preparation of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine
(Compound formula-III):
To a mixture of 5-Bromo-2,4-dichloro pyrimidine (100 g) in Ethyl acetate (500 ml) was added N,N-Diisoprpyl ethyl amine ( 113.6 g) and stirred for 15 min at 20-25°C. A solution of cylco pentyl amine (41.1 g) in Ethyl acetate (500 ml) was added slowly at 20-25°C, then heated to 40-45°C and stirred for 6-8hrs at 40-45°C. after completion of reaction, cooled the reaction mass to room temperature and water (500 ml) was added and separated the layers and washed the organic layer with water (500 ml). The organic layer was concentrated under vacuum then heptane (200 ml) and co-distilled off solvent completely under vacuum. To the crude added heptane (400 ml) and heated to 80-85°C and stirred for 30 min then cooled to 10-15°C slowly and stirred for 2-3 hrs, filtered the solid and washed with chilled heptane, suck dried thoroughly and dried at 50-55°C for 10-12 hrs to get 100 g of Cylco pentyl coupled compound.

Example-2: Preparation of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (Compound formula-IV):
To a mixture of cyclo pentyl coupled compound (100 g) in DMSO (700 ml) was added Copper (I) chloride (4.86 g), Sodium Iodide (108.4 g), Potassium carbonate (150 g) and 6-Methyl-2-picolinic acid (14.9 g) under argon atmosphere and degassed the reaction mass for 30-45 min , Propargyl alcohol (81.1 g) was added and heated the reaction mass to 100°C and stirred for 20-24 hrs at 100°C, after completion of reaction ,cooled the reaction mass and filtered the salt washed with DMSO (200 ml). The filtered reaction mass is quenched in water (3500 ml) at 25-30°C and stirred for 2-3 hrs, filtered the solid and dried under vacuum at 50-55°C for 12 hrs. The crude product is taken into ethyl acetate (2500 ml) and heated to 75-80°C and stirred for 30 min, filtered the insoluble, distilled of filtrate under vacuum to a minimum volume (~400 ml), cooled the reaction mass to 5-10°C, stirred for 60-90 min, filtered the product and washed with ethyl acetate (50 ml), suck dried thoroughly and dried at 50-55°C under vacuum to get 50g of Cyclized alcohol.

Example-3: Preparation of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (Compound formula-V):
To a mixture of cyclized alcohol (100 g) in Dichloromethane (2000 ml) was added MnO2 ( 345.3 g) and stirred for 15 hrs at 25-30°C. after completion of reaction, filter reaction mass through hyflo bed and washed with Dichlormethane (1000 mL), and concentrated the filtrate under vacuum at below 40°C then hexane (200 ml) was added and co-distilled off solvent completely under vacuum. To the crude added hexane (400 ml) and stirred for 60 min, filtered the solid and washed with hexane (200 mL), suck dried thoroughly and dried at 50-55°C for 10-12 hrs to get 90 g of Cyclized aldehyde.

Example-4: Preparation of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound formula-VI):
To a mixture of cyclized aldehyde (100 g) in Dichloromethane (2000 ml) was added 50% w/w aqueous N,N-Dimethyl amine (150 mL) , sodium carbonate (106.1 g), Iodine (203.2 g) at 5-10°C. stirred the reaction mass for 60 mins at 5-15°C and then raised reaction mass temperature to 25-30°C and stirred for 6-8 hrs at 25-30°C. after completion of reaction, charged 10% Aq sodium thio sulphte solution and stirred the reaction mixture for 30min. settled and separate the both layers. The aq layer was back extracted with Dichloromethane (300 mL) then combined both the organic layers and washed with water (2x 500 mL). The organic layer was concentrated under vacuum at below 40°C then hexane (200 ml) was added and co-distilled off solvent completely under vacuum. To the crude added mixture of (1:1) Ethyl acetate/hexane (500 ml) and heated to 40-50°C and stirred for 30 min then cooled to 25-30°C slowly and stirred for 16 hrs, filtered the solid and washed with mixture of (1:1)Ethyl acetate/hexane, suck dried thoroughly and dried at 50-55°C for 12 hrs to get 90 g of Compound formula-VI.

Example-5: Preparation of tert-butyl 4-(6-{[7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate (Compound formula-VIII ):
To a mixture of Compound formula-VI (100 g) and Compound formula-VII (95 g) in THF (1000 ml) was added sodium tertiary butoxide (130 g) lot wise (5 equal lots) at 15-25°C, stirred the reaction mass for 2-3 hrs at 25-30°C. after completion of reaction, added water(1000 mL) slowly and stirred the reaction mixture for 30min. settled and separate the both layers. The aq layer was back extracted with THF (500 mL), then combined both the organic layers and washed with 10% Aquoes Sodium chloride solution (500 mL). The organic layer was concentrated under vacuum at 50-55°C then Water (1000 ml) was added and stirred for 30 min then filtered the solid and washed with water (500 mL), suck dried thoroughly and Wet compound taken into RBF and added Methanol / dimethylformamide (1500 ml), heated the reaction mass to 60-650C, cooled to 25-35°C, stirred for 60 min then filtered the solid and washed with Methanol (500 mL), suck dried thoroughly dried at 50-55°C for 12 hrs to get 130 g of Boc Ribociclib compound.

Example-6: Preparation of tert-butyl 4-(6-{[7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate (Compound formula-VIII ): (Alternate Process)
To a mixture of Compound formula-VI (100 g) and Compound formula-VII (95 g) in DMF (1000 ml) was added sodium tertiary butoxide (130 g) lot wise (5 equal lots) at 15-25°C, stirred the reaction mass for 2-3 hrs at 25-30°C. after completion of reaction, added water (1000 mL), then reaction mass pH is adjusted to 7.5-8.5 using 1N HCl (500 ml), stirred for 60 min and washed with water (500 mL), suck dried thoroughly and Wet compound taken into RBF and added Methanol (1500 ml), heated the reaction mass to reflux temperature, cooled to 25-35°C, stirred for 60 min then filtered the solid and washed with Methanol (500 mL), suck dried thoroughly dried at 50-55°C for 12 hrs to get 130 g of Boc Ribociclib compound.

Example-7: Preparation of 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Ribociclib free base):
To a mixture of Boc-ribociclib (100 g) in Toluene (1000 ml) was added 6N Aqueous HCl Solution ( 500 ml) and heated the reaction mass to 50-55°C and stirred for 60 min, after completion of reaction, cooled the reaction mass, separated the layers and aqueous layer washed with dichloromethane (500 ml), then pH of aqueous layer adjusted to ~12.0 using 50% aqueous sodium hydroxide solution (~300 ml) at 5-10°C, stirred for 60 min, filtered the product and washed with water (200 ml) , suck dried thoroughly and dried at 55-60°C to get 65 g of Ribociclib free base.

Example-8: Preparation of butanedioic acid—7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1/1) (Ribociclib Succinate):

Ribociclib free base (100 g) taken into three neck RBF and isopropyl alcohol (3500 ml) was added, heated to 80-85°C, stirred for 30-60 min, filtered the insoluble. Charged clear filtrate into four neck RBF and heated to 60-65°C, succinic acid (28.5 g) in isopropyl alcohol (700 ml) was added slowly at 60-65°C, stirred for 60-90 min , cooled the mass to 25-30°C, stirred for 2-3 hrs, filtered the product and washed with isopropyl alcohol (200 ml), suck dried thoroughly and dried at 60-65°C under vacuum for 12 hrs to get 100 g of Ribociclib Succinate.

,CLAIMS:1. A process for the preparation of compound of formula VIII by condensing compound of formula VI with compound of formula VII in presence of a metal alkoxide:

2. The process as claimed in claim 1, wherein the metal alkoxide is selected from sodium tertiary butoxide, potassium tertiary butoxide or Lithium tert-butoxide.
3. The process as claimed in claim 2, wherein the metal alkoxide is sodium tertiary butoxide.
4. The process as claimed in claim 1, wherein the compound of formula VI is prepared by a process comprising the steps of:
(a) converting the compound of formula IV to compound of formula V

(b) converting the compound of formula V to compound of formula VI.

5. The process as claimed in claim 4, wherein the compound of formula IV is converted to compound of formula V using an oxidizing agent selected from chromium oxide, manganese dioxide, lead dioxide, nitric acid, ruthenium tetroxide in presence of dichloromethane.
6. The process as claimed in claim 4, wherein the compound of formula V is converted to compound of formula VI by treating with dimethyl amine in presence Iodine and an organic solvent like dichloromethane.
7. The process as claimed in claim 4, wherein the compound of formula VI is purified comprising the steps of:
c) suspending compound of formula VI in an organic solvent or mixture of solvents, and
d) isolating pure compound of formula VI.
8. The process as claimed in claim 7, wherein the organic solvent is selected from methyl ester, ethyl ester or isopropyl ester, hexane, tetrahydrofuran or their mixtures thereof.
9. The process as claimed in claim 8, wherein the organic solvent is a mixture of mixture of ethyl ester and hexane.
10. The process as claimed in claim 1, wherein the compound of formula VIII is purified comprising the steps of
a. dissolving compound of formula VIII in a solvent, and
b. isolating pure compound of formula VIII.
11. The process as claimed in claim 10, wherein the solvent is selected from alcohols such as methanol, ethanol, isopropanol or dimethylformamide or mixtures thereof.
12. The process as claimed in claim 1, wherein the purified compound of formula VIII is converted to Ribociclib or its pharmaceutically acceptable salts comprising the steps of


13. The process as claimed in claim 10, wherein the purified compound of formula VIII has an individual impurity less than 0.1%.