DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PURIFICATION OF IBRUTINIB AND ITS INTERMEDIATES

INTRODUCTION
The present invention provides process for the purification of Ibrutinib and its intermediates.
BACKGROUND OF THE INVENTION
The drug compound having the adopted name “Ibrutinib” has a chemical name l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one, and is structurally represented below.

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) and is approved in US for the treatment of patients with mantle cell lymphoma and chronic lymphocytic leukemia who have received at least one prior therapy.
US patent 8,697,711 discloses a process for the preparation of Ibrutinib. The process disclosed in the patent is outlined below.

In US ‘711, the compound of formula II is Boc de-protected and then reacted with acryloyl chloride to give Ibrutinib. The US ‘711 patent does not disclose the enantiomeric purity of the Ibrutinib obtained from the process.
US application 2013/0225812 discloses process for the preparation of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound of Formula I).

The compound of formula II is treated with acid followed by base to give compound of formula I. The US ‘512 application does not disclose the enantiomeric purity of the compound of formula I.
The compound of Formula I is a key intermediate in the preparation of Ibrutinib. For the preparation of pharmaceutically acceptable Ibrutinib on a large scale, it is desirable to have an enantiomerically pure compound of Formula I.
The above disclosed processes lead to the formation of the undesired S-isomer of Ibrutinib in considerable amount. The Ibrutinib is isolated by column chromatographic methods.
There remains a need for a purification process that would provide the compound of formula I in very high enantiomeric purity.
The inventors of the present invention have found a purification method for obtaining enantiomerically pure compound of formula I. The purification method eliminates expensive and time-consuming column chromatographic purification required by the prior art methods.
SUMMARY
In an first aspect, the present invention provides process for isolating enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
In a further aspect, the present invention provides diastereomeric salts of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine with chiral organic acids.
In a further aspect, the present invention provides the use of diastereomeric salts of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine in the preparation of pharmaceutically acceptable Ibrutinib.
DETAIL DESCRIPTION
In a first aspect, the present invention provides process for the isolation of enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine comprising the steps of:
a) contacting compound of formula I with a chiral organic acid in an organic solvent;

b) stirring the reaction mixture of step a) at a temperature of about 0°C to about reflux temperature;
c) isolating the diastereomeric salt of formula Ia;

d) neutralizing the salt to obtain enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
The chiral organic acids include Di-p-toluoyl-D-tartaric acid, Di-p-Toluoy-L-Tartaric Acid, D (+)-Tartaric Acid, R-Mandalic Acid, D-Camphorsulfonic acid, L- Camphorsulfonic acid, D-Dibenzoyl tartaric acid, L-Dibenzoyl tartaric acid, N-Acetyl-L-Leucine, N-Acetyl-D-Leucine L-Glucamic acid Mono Sodium salt, D-Mandalic Acid , L-Mandalic Acid.
The diastereomeric salt is represented by formula Ia,

wherein HA represents chiral organic acids.
Step a) involves combining crude (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained from the reaction with a chiral organic acid in an organic solvent.
Organic solvent used in step a) may be selected from a group comprising aliphatic ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone or diethyl ketone or the like; esters of carboxylic acids such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate or the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane or the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, or C1-C6 alcohols or the like; aromatic hydrocarbons such as toluene, xylene or the like.
The reaction mixture may be obtained at temperature ranging from about 0°C to about reflux temperature of the solvent selected. Step b) involves stirring the reaction mixture of step a) at a temperature of about 0°C to about reflux temperature.
The reaction mixture of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and the acid compound in the organic solvent obtained in step a) is stirred and maintained at a temperature of about 0°C to about reflux temperature of the solvent selected, to facilitate the formation of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine salt.
The reaction mixture of step a) is maintained at a temperature of about 10°C to about 45°C, preferably at about 25°C to about 35°C. The reaction mixture is maintained at the desired temperature for sufficient time to ensure the complete formation of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine salt.
Step c) involves isolating the (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine salt. The salt is isolated in a manner known per se, and depending on the solvent used, which include, but not limited to filtration by gravity or by suction, distillation, centrifugation, or slow evaporation or the like.
The product obtained in step c) may be dried at a temperature less than about 50°C to obtain (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine salt.
In a specific embodiment, the diastereomeric salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine with N-acetyl-L-leucine is provided. The compound is represented by formula Ib.

In an embodiment, the present invention provides isolation of enantiomerically pure N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine comprising the steps of:
a) contacting compound of formula I with N-acetyl-L-leucine in an organic solvent;
b) stirring the reaction mixture of step a) at a temperature of about 0°C to about reflux temperature;
c) isolating the N-acetyl-L-leucine salt of formula Ib;
d) neutralizing the salt.
In step a) the compound of formula I is contacted with N-acetyl-L-leucine in presence of suitable organic solvent to obtain a reaction mixture. The compound of formula I may be obtained by known process including the process disclosed in US patent 8,697,711 and US patent 7,514,444. Organic solvent used in step a) may be selected from a group comprising aliphatic ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone or diethyl ketone or the like; esters of carboxylic acids such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate or the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane or the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, C1-C6 alcohols or the like; aromatic hydrocarbons such as toluene, xylene or the like.
The reaction mixture may be obtained at temperature ranging from about 0°C to about reflux temperature of the solvent selected. Step b) involves stirring the reaction mixture of step a) at a temperature of about 0°C to about reflux temperature.
The reaction mixture of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetyl-L-leucine in the organic solvent obtained in step a) is stirred and maintained at a temperature of about 0°C to about reflux temperature of the solvent selected, to facilitate the formation N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
The reaction mixture of step a) is maintained at a temperature of about 10°C to about 45°C, preferably at about 25°C to about 35°C. The reaction mixture is maintained at the desired temperature for sufficient time to ensure the complete formation of N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
Step c) involves isolating the N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. The salt is isolated in a manner known per se, and depending on the solvent used, which include, but not limited to filtration by gravity or by suction, distillation, centrifugation, or slow evaporation or the like.
The product obtained in step c) may be dried at a temperature less than about 50°C to obtain N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
The N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine may be neutralized by a suitable method to isolate enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and the chiral organic acid. The N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine may be converted directly to Ibrutinib.
Any method may be used to break the diastereoisomerically pure salt. For example, N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine is dissolved in suitable solvent or mixture of solvents. Suitable solvent used in step b) may be selected from water; aliphatic alcohols, such as methanol or ethanol; esters of carboxylic acids, such as ethyl acetate, isopropyl acetate; ethers, such as tetrahydrofuran; aromatic hydrocarbons such as toluene; or mixtures thereof. The solution containing the diastereisomerically pure salt may be made alkaline and the enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine can be extracted with a suitable organic solvent which separates it from the aqueous layer, followed by distilling off the organic solvent, thereby allowing the isolation of the enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.
Enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained according to the present invention have an enantiomeric excess greater than 96%, more preferably greater than 98%, most preferably greater than 99%.
Certain specific aspects and embodiments of the present invention will be explained in more 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 present application in any manner.
EXAMPLES
Example 1: preparation of enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
Step (a)
To a stirred mixture of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3, 4-d]pyrimidin-4-amine (140 g) in Ethyl Acetate: MeOH (300: 100 mL) was added the N-acetyl-L-Leucine solution (62.7 gm. in EtOAc: MeOH, 200: 100 mL). The reaction mass was stirred at 25-35 oC for 10-12hr and filtered using the vacuum pump to afford N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. The salt was washed with 100 mL of acetone. The washed salt was charged into a fresh RBF with ethyl acetate: methanol (300: 100 mL) and heated to 55-60 oC for 3.5-4 hr. The solid was filtered and washed with ethyl acetate.
RS Purity: 99%
Chiral Purity: 99.5%.
1H NMR (400 MHz, CD3OD): 0.85-1.0 (6H,m), 1.5-1.75 (3H),1.8 -2.0 (5H, m), 2.25 -2.50 (2H, m), 3.25 -3.80 (2H,m),3.50 -3.70 (2 H,m), 4.60 - 4.85 (1H, m), 5.20 -5.40 (1 H, m), 7.0 -7.3 (5H, m),7.4-7.50 (2H, m), 7.70 -7.80 (2H, d), 8.30-8.34 (1H, S).

Step (b)
N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 gm.) and 300 mL of water was charged into a fresh RBF and stirred for 30-45 minutes at 20-30 oC. The contents of the flask were cooled to 10-20 oC and NaOH solution (6.7 g of NaOH dissolved in 10 mL of water) was slowly added. The reaction mass was stirred at 10-20 oC for 30-45 minutes and at 20-30 oC for 90-120 minutes. The reaction mass was filtered and washed with 50 mL of water. The material was suck dried for 30-45 minutes and dried in vacuum oven at 50-60 oC for 6-8 hours to obtain the title compound.
Chiral Purity: 99.5%,
RS Purity: 99%.
Example 2: preparation of enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
Step (a)
To a stirred mixture of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100g) in acetone (300mL) was added N-acetyl-L-Leucine suspension (44.87g suspended in 100 mL acetone). The contents of the flask were stirred at 20-30 oC for 90-120 minutes and filtered using the vacuum pump to afford N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. The salt was washed with 100 mL of acetone and dried in vacuum oven.
Step (b)
N-acetyl-L-leucine salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (130g) was charged into and 390 mL of ethyl acetate-methanol mixture (3:1) in a dry RBF and stirred for 20-30 minutes at 20-30 oC. The contents of the flask were heated to 55-60 oC and maintained for 60-90 minutes. The contents were filtered, washed with 100 mL of ethyl acetate and suck dried for 90-120 minutes. The obtained solid was charged into a fresh RBF with 300 mL of distilled water and stirred for 30-45 minutes at 20-30 oC. The contents of the flask were cooled to 10-20 oC and NaOH solution (5.9g of NaOH dissolved in 6 mL of distilled water) was added. The reaction mass was stirred at 10-20 oC for 30-45 minutes. The temperature of the reaction mass was increased to 20-30 oC and stirred for 90-120 minutes. The reaction mass was filtered and washed with 50 mL of distilled water. The material was suck dried for 30-45 minutes and dried in vacuum oven at 50-60 oC for 6-8 hours to obtain the title compound.
,CLAIMS:We Claim:
1. Diastereomeric salt of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine with chiral organic acid represented by formula Ia.

2. The diastereomeric salt of claim 1, wherein the chiral organic acid is selected from Di-p-toluoyl-D-tartaric acid, Di-p-Toluoy-L-Tartaric Acid, D (+)-Tartaric Acid, R-Mandalic Acid, D-Camphorsulfonic acid, L- Camphorsulfonic acid, D-Dibenzoyl tartaric acid, L-Dibenzoyl tartaric acid, N-Acetyl-D-Leucine L-Glucamic acid Mono Sodium salt, D-Mandalic Acid , L-Mandalic Acid.
3. The diastereomeric salt of claim 1, wherein the chiral organic acid is N-Acetyl-L-Leucine.
4. The diastereomeric salt of claim 1, wherein the compound is

5. A process for the isolation of enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine comprising the steps of:
a) contacting compound of formula I with a chiral organic acid in an organic solvent;

b) stirring the reaction mixture of step a) at a temperature of about 0°C to about reflux temperature;
c) isolating the diastereomeric salt of formula Ia; and

d) neutralizing the salt to obtain enantiomerically pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.