DESC:A PROCESS FOR THE PREPARATION OF BRIGATINIB INTERMEDIATES
FIELD OF THE INVENTION
The present invention relates to a novel process for the synthesis of Brigatinib intermediates.
BACKGROUND OF THE INVENTION
Brigatinib is a small-molecule targeted cancer therapy being developed by ARIAD Pharmaceuticals. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.
Brigatinib is chemically known as 5-chloro-N4-[2-(dimethylphosphinyl) phenyl]-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-2,4-pyrimidine diamine, having the structure below:

I
Brigatinib is marketed by Takeda Pharmaceuticals Inc under the brand name of ALUNBRIG, in US, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
U.S. Patent No. 9,012,462 discloses Brigatinib and process for its preparation, which is as shown below:

The compound of formula V is an important starting material in the preparation of Brigatinib.
PCT publication No. WO 2015/127873 A1 disclosed preparation of formula V as follows:

However, this preparation methods involve high cost, low yields, time consuming and less product purity.
Therefore, there is still a need in the art for an improved low-cost process for the preparation of compound of formula V, which will be suitable for large-scale preparation, in terms of simplicity, chemical yield and purity of the product.
SUMMARY OF THE INVENTION
In the first embodiment the present application provides a process for the preparation of compound of formula V, comprising:
reductive amination of compound of formula II with 1-methylpiperizine of formula III to give compound of formula IV and then hydrolysing compound of formula IV:

Wherein R is a C1-3 alkyl group.
In the second embodiment the present application provides a process for the preparation of compound of formula V, comprising
comprising:
reductive amination of compound of formula II’ with 1-methylpiperizine of formula III to give compound of formula IV’ and then hydrolysing compound of formula IV’:

In the third embodiment, the present application provides a compound of formula IV:

Wherein R is a C1-3 alkyl group.
DETAILED DESCRIPTION OF THE INVENTION
In the aspects, the present application provides a process for the preparation of compound of formula V, comprising:
reductive amination of compound of formula II with 1-methylpiperizine of formula III to give compound of formula IV and then hydrolysing compound of formula IV:

Wherein R is a C1-3 alkyl group.
In aspects, the reductive amination of compound of formula II is conducted using an appropriate agent such as Sodium triacetoxy borohydride, Sodium borohydride or Palladium on carbon or Raney Nickel or sodium hydrosulfite.
In aspects, the reductive amination of compound of formula II may be performed in a suitable solvent. The solvents include but not limited to water, alcohol solvents such as methanol, ethanol, propanol, iso-propanol; ether solvent such as, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof.
The reductive amination may be carried out for about 30 minutes to about 24 hours at about 0°C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 8 hour to about 12 hours at about 60 °C to about 75 °C. The resulting compound of formula IV may be isolated or it can be carried to the next step without isolation.
In aspects, the hydrolysis of compound of formula IV is carried in the presence of a base. The base includes but not limited to inorganic base such as sodium hydroxide, potassium hydroxide, Lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be potassium hydroxide.
The hydrolysis compound of formula IV may be carried out for about 30 minutes to about 24 hours at about 0°C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 3 hours to about 5 hours at about 60 °C to about 75 °C. The resulting compound of formula V may be isolated from the reaction mass by any method known in the art.
In aspects, the hydrolysis of compound of formula IV may be performed in a suitable solvent. The solvents include but not limited to water, alcohol solvents such as methanol, ethanol, propanol, iso-propanol; ether solvent such as, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof.
In aspects the present application provides a compound of formula IV:

wherein R is a C1-3 alkyl group.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, "generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.
The terms “reductive amination” refer broadly to the reactions of aldehydes or ketones (i.e., carbonyl compounds) with ammonia, primary amines, or secondary amines in the presence of reducing agents to yield primary, secondary, or tertiary amines, respectively. Carbonyl compounds are reductively aminated. There are two general types of reductive amination reactions, indirect (or stepwise) and direct. Direct reactions do not entail prior formation of the intermediate imine when the carbonyl compound and the amine are combined with an appropriate reducing agent. Conversely, indirect reactions entail the formation of the intermediate imine in a distinct step prior to the reduction [See, A. F. Abdel-Magid et al., J. Org. Chem. 61:3849-3862 (1996)]. The methods of the present invention may be employed with either direct or indirect reactions direct reactions.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours.
The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.
The isolation may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique.
Suitable temperatures for isolation may be less than about 120 °C, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 °C, less than about 20 °C, less than about 10 °C, less than about 0 °C, less than about -10 °C, less than about -40 °C or any other suitable temperatures.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
EXAMPLES
Example 1: Preparation of 1-methyl-4-(piperidin-4-yl)piperazine
Step 1: To an autoclave methanol (2280 ml), ethyl-4-oxopiperidine-1-carboxylate (600 gm), 1-methylpiperazine (354 gm) and 5 % Pd/C (12 gm) were charged at room temperature. Hydrogen gad was passed into the reaction mass at 4-5 kg/cm2 pressure. The temperature of the reaction mass was raised to 75 oC and maintained for 9 hours. Cool the reaction mass to room temperature, hydrogen gas was released and filtered. The filtrate was washed with methanol (204 ml) and the solvent was completely distilled out to give 867 gm of ethyl 4-(4-methylpiperizin-1-yl)piperidine-1-carboxylate.
Step 2: To a round bottom flask methanol (400 ml) and ethyl 4-(4-methylpiperizin-1-yl)piperidine-1-carboxylate (143 gm) were charged at room temperature. The temperature of the mass was reduced to 15 oC and potassium hydroxide (155 gm) flakes were added. Temperature of the reaction mass was raised to 80 oC and maintained for 5 hours and solvent was distilled out. Water (400 ml) was added and stirred for 20 minutes at 50 oC and then cooled to room temperature. Dichloromethane (300 ml) was added to the flask and stirred for 25 minutes. The layers were separated and aqueous layer was extracted with dichloromethane (200 ml). The organic layers were combined and dried with sodium sulphate (20 gm) and solvent was completely distilled out under vacuum to give 80.4 gm of titled product.

Dated this on 25th day of September, 2024

Signature: ___________________
Name: Dr. Phani Kumar Balusu
Vasudha Pharma Chem Limited
,CLAIMS:1) A process the preparation of compound of formula V, comprising:
reductive amination of compound of formula II with 1-methylpiperizine of formula III to give compound of formula IV and then hydrolysing compound of formula IV:

wherein R is a C1-3 alkyl group.
2) A process the preparation of compound of formula V, comprising:
reductive amination of compound of formula II’ with 1-methylpiperizine of formula III to give compound of formula IV’ and then hydrolysing compound of formula IV’:

3) The process as claimed in claims 1 or 2, wherein the reductive amination is performed using the catalyst selected from Sodium triacetoxy borohydride, Sodium borohydride, Palladium on carbon, Raney Nickel and sodium hydrosulfite.
4) The process as claimed in claim 1 or 2, wherein the hydrolysis of compounds of formula IV or IV’ conducted in the presence of a base.
5) The process as claimed in claim 4, wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and mixtures thereof.
6) A compound of formula IV:

wherein R is a C1-3 alkyl group.
7) The compound as claimed in claim 6, wherein R is ethyl.

Dated this on 25th day of September, 2024

Signature: ___________________
Name: Dr. Phani Kumar Balusu
Vasudha Pharma Chem Limited