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

PROCESS FOR THE PREPARATION OF IBRUTINIB AND IMPURITIES THEREOF
INTRODUCTION
The present invention relates to an improved process for the preparation of Ibrutinib. The invention also relates to two novel impurities, their identification, isolation, and characterization, formed during the synthesis and preparation of Ibrutinib.
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.
Ibrutinib prepared by the methods known in the art contain related substances or impurities. These impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products.
Generally, impurities are identified spectroscopically and/or with another physical method, and then are associated with peak position, such as that in a chromatogram, or spot on a TLC plate. Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is measure in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time.”
Retention time can vary about a mean value based upon the condition of the instrumentation as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, those skilled in the art use the “relative retention time” (RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
The management of process related impurities is enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
It is desirable that there is a method for identifying, quantifying and separating the impurities formed as a result of the synthesis of Ibrutinib.
SUMMARY
An object of the present invention is to provide an improved method for the preparation of ibrutinib and/or its salts, wherein the process is simple, efficient, cost-effective, and easy to carry out. Another object of the invention is to provide a new method for the preparation of ibrutinib and/or its salts, which is substantially pure and free from Impurities.
This invention also relates to two novel Impurities (Impurities 3 and 4), their identification, isolation, and characterization, formed during the synthesis and preparation of Ibrutinib.
Yet another object of the invention is directed toward ibrutinib and/or its salts that is substantially free of Impurities, in particular Impurities 1, 2, 3, 4, 5, and 6.
Yet another object of the invention is directed toward a pharmaceutical preparation of ibrutinib and/or its salts that is substantially free of Impurities, in particular impurities 1, 2, 3, 4, 5, and 6.
DETAIL DESCRIPTION
The invention relates to an improved method for the preparation of Ibrutinib of formula (I) depicted in scheme-1.
Scheme-1

While developing the process for Ibrutinib (Scheme 1), six process related impurities listed in Table 1 were identified. Of these six impurities, two novel impurities (impurity-3 and impurity-4) are herein described.

Table-1
Impurity # RRT Molecular weight Structure
1 0.82 428.50

2 1.35 476.97

3 1.08 494.56

4 2.3 881.01

5 1.07 442.52

6 1.21 826.97

Identification, characterization, and synthesis of impurities formed during the reaction and control of the impurities in the final product to meet the regulatory norms is a critical objective during process development. As per the requirements of various regulatory authorities, the impurity profile study of drug substances and drug products has to be carried out using a suitable analytical method in the final product.
The separation of all the impurities, including degradation impurities, in a single analytical reverse phase HPLC was conducted. Analysis of crude Ibrutinib by HPLC helped to identify the impurity peaks, which were subsequently identified by LC/MS. The impurities were synthesized, characterized, and confirmed by spiking studies using HPLC.
Synthetic scheme of impurity-3:

Synthetic scheme of impurity-4:

Synthetic scheme of Ibrutinib:

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 Ibrutinib
25.0 g of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 375 mL of THF was charged into an clean and dry RBF. The contents were cooled to -25 ± 5 °C and 8.36 g of diisopropyl ethyl amine was added. 5.56 g of freshly distilled acryloyl chloride is added to the above flask by dissolving in 250 mL of THF at -45 ± 5 °C for 1-2hrs. The reaction was maintained at -30 ± 5 °C for 45-60 minutes. After the reaction was completed, the reaction mass was distilled at 45-50 oC under reduced pressure. The distilled mass was cooled to 25± 5 °C and 125 mL of 10% Citric Acid solution and 250 mL of ethyl acetate were added. The product was extracted into organic layer and washed with 10% Citric Acid solution (2x125 mL). The organic layer was washed with brine solution and distilled under reduced pressure at 45-50°C. To the distilled mass was added 125 mL of acetone and stirred for 10-15 minutes. 150 mL of demineralized water was slowly added to the above mass at 30 ± 5 °C and stirred for 7-8 hours. The reaction mass filtered and washed with 12.5 mL of acetone and 0.5 mL of water. The obtained material was dried under reduced pressure at 50-55 oC to afford the title compound. The ibrutinib obtained was analyzed by HPLC.
Purity Profile:
Ibrutinib: 99.73%, Impurity-1: 0.02%, Impurity-2: 0.04%, Impurity-3: 0.04%, Impurity-4: Not detected, Impurity-5: Not detected, Impurity-6: Not detected.
HPLC conditions:
Column: X-Bridge C18;
Flow rate: 0.8 mL/min;
Column oven temp: 25 oC;
Run time: 55 minutes;
Mobile Phase-A: Buffer (KH2PO4): CH3CN 80:20;
Mobile Phase-B: Buffer (KH2PO4): CH3CN 20:80.
Example 2: Preparation of Impurity-3:
3.0 g of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one and 30 mL of THF were charged in a clean and dry RBF. The contents were cooled to 0-5 oC and 1.2 mL of diisopropyl ethyl amine was added. 1.1 mL of acrolyl chloride (dissolved in 40 mL of THF) was added to the above flask. The contents were maintained at -5 oC to 0 oC for 2 hours. After the completion of the reaction, 60 mL of chloroform and 100 mL of demineralized water was added to the above flask and the product was extracted into organic layer. The organic layer was concentrated under reduced pressure and purified using column chromatography (Mobile Phase - Chloroform: Methanol: 9.5:0.5 v/v) to isolate impurity-3.
Mass (m/z) = 495 (M+1)
IR (cm-1): 3789, 3662, 3473, 3059, 2943, 2865, 2328, 1938, 1732, 1645, 1603, 1517, 1489, 1445, 1380, 1330, 1311, 1236, 1196, 1168.
1H-NMR (400MHz, CDCl3): d (ppm) = 8.62-8.21(m, 3H), 7.62-7.36 (m, 2H), 7.35-6.61 (m, 6H), 6.32-6.00 (m, 1H), 5.90-5.52 (m, 1H), 4.89-3.95 (m, 5H), 3.32-2.98 (m, 2H), 2.80-2.60 (m, 2H), 2.41-2.08 (m, 2H), 2.07-1.83 (m, 1H), 1.78-1.48 (m, 1H).
Example 3: Preparation of Impurity-4:
4.16 g of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one and 35 mL of dimethylacetamide were charged in a clean and dry RBF. The contents were cooled to 0-5 oC and 1.2 g of sodium hydride was added. 5.0 g of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-chloropropan-1-one dissolved in dimethylacetamide was added drop wise to the above flask. The contents were heated to 25-30 oC and maintained for 2-3 hours. After the completion of the reaction, 100 mL of ethyl acetate and 90 mL of demineralized water was added to the above flask and the product was extracted into organic layer. The organic layer was concentrated under reduced pressure and purified using column chromatography (Mobile Phase - Chloroform: Methanol: 9:1 v/v) to isolate impurity-4.
Mass (m/z) = 880 (M-1).
IR (cm-1): 3400, 2941, 2860, 1643, 1519, 1488, 1440, 1357, 1308, 1281, 1235, 1166.
1H-NMR (400MHz, CDCl3): d (ppm) = 8.48-8.21 (m, 2H), 7.73-7.49 (m, 4H), 7.47-7.32 (m, 3H), 7.24-7.02 (m, 10H), 7.01-6.87 (m, 1H), 6.71-6.20 (m, 3H), 5.96-5.42 (m, 3H), 4.99-4.71 (m, 3H), 4.70-4.31 (m, 1H), 4.30-3.58 (m, 5H), 3.49-2.93 (m, 2H), 2.92-2.49 (m, 3H), 2.48-2.13 (m, 4H), 2.12-1.82 (m, 2H), 1.81-1.49 (m, 2H).
,CLAIMS:1. A process for the preparation of Ibrutinib (I), comprising the steps of:
a. reacting (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine of formula (II) with acryloyl chloride in a suitable solvent or mixtures of solvent;
b. maintaining the reaction mixture at -20 to -40 oC;
c. distilling the reaction mixture;
d. optionally purifying the crude obtained in step c.
2. The process of claim 1, wherein freshly distilled acryloyl chloride is use in the reaction.
3. The process of claim 1, wherein the solvent used in tetrahydrofuran.
4. The process of claim 1, wherein acetone and water are used for the purification.