# US 11,440,912 B2 · Process for the preparation of ribociclib and its salts

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- Number: US 11,440,912 B2
- Document ID: US11440912B2
- Status: Granted
- Kind: B2
- Application number: 16/758,773
- Filed: 2018-10-26
- Published: 2020-09-03
- Granted: 2022-09-13
- Earliest claimed: 2017-10-27
- Assignees: Fresenius Kabi Oncology Limited
- Applicants: Fresenius Kabi Oncology Limited
- Inventors: Sarbjot Singh Sokhi; Govind Singh; Saswata Lahiri; Maneesh Kumar Pandey; Raj Narayan Tiwari; Sonu Shukla; Sachin Musmade; Heena Dua; Walter Cabri
- Web page: https://patentgrep.com/patent/US11440912B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- B01J 23/72: Copper
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention relates to a process for the preparation of ribociclib of formula V or its salts. The invention provides novel crystalline forms of ribociclib succinate and ribociclib trifluoroacetate. The present invention also relates to pharmaceutical compositions comprising a crystalline form of ribociclib succinate and at least a pharmaceutically acceptable carrier. It further relates to the use of such compositions in the treatment of cancer.

## Claims

### Claim 1

A process for the preparation of a compound of formula V or a salt thereof,
comprising the steps of:
a) reacting a compound of formula B,
wherein X selected from bromo and chloro;
with a compound of formula C,
wherein PG is an amine protecting group;
in water in the presence of a base, which is sodium carbonate, potassium carbonate, diethylamine, N,N-diisopropylethylamine, or a combination thereof, to obtain a compound of formula A,
wherein PG is an amine protecting group;
b) converting the compound of formula A to the compound of formula V, and
c) optionally, converting the compound of formula V to a salt.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the step b) comprises the steps of:
d) reacting the compound of formula A with zinc and acetic acid to obtain a compound of formula I,
wherein PG is an amine protecting group;
e) reacting the compound of formula I with a compound of formula II,
in the presence of a base to obtain a compound of formula III,
wherein PG is an amine protecting group;
f) de-protecting the compound of formula III to obtain an acid addition salt of formula IV,
wherein X− is ion of the acid
g) converting the compound of formula IV to a compound of formula V.

### Claim 3 (depends on 2)

The process according to claim 2, wherein the step e) is carried out in presence of a metal halide catalyst.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the metal halide is copper (I) bromide, copper (I) iodide or copper (I) chloride.

### Claim 5 (depends on 3)

The process according to claim 3, wherein the base to obtain a compound of formula III is sodium hydride or potassium tertiary butoxide.

### Claim 6 (depends on 2)

The process according to claim 2, wherein the compound of formula III is a compound of formula IIIa,
wherein PG is tert-butoxycarbonyl (Boc).

### Claim 7 (depends on 6)

The process according to claim 6, wherein the compound of formula IIIa is isolated as solid by adding water, methanol, or a mixture thereof.

### Claim 8 (depends on 6)

The process according to claim 6, wherein the purity of the isolated compound of formula IIIa is greater than 99.6%, as measured by high-performance liquid chromatography (HPLC).

### Claim 9 (depends on 2)

The process according to claim 2, wherein the de-protection is carried out in the presence of trifluoroacetic acid.

### Claim 10 (depends on 2)

The process according to claim 2, wherein the acid addition salt of the compound of formula IV is a compound of formula IVa,

### Claim 11 (depends on 2)

The process according to claim 2, wherein the conversion of the compound of formula V to the salt is carried out by reacting the compound of formula V with succinic acid to obtain the compound of formula VI,