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.
An objective of the present invention is to provide a method for preparation of ibrutinib with high purity.
SUMMARY
The invention provides an improved method for the preparation of ibrutinib and/or its salts, which is substantially pure and free from Impurities.
DETAIL DESCRIPTION
The invention relates to an improved method for the preparation of Ibrutinib of formula (I) depicted in scheme-1.
Scheme-1

The prior art US 7,514,444 discloses the use of triethyl amine as base and dichloromethane as solvent for the acylation reaction. It has been surprisingly found that the acylation reaction of compound (II) when carried out in presence of base such as potassium t-butoxide, diisopropyl ethylamine, sodium hydroxide and sodium methoxide and solvent such as dichloromethane, tetrahydrofuran provides substantially pure ibrutinib. Specifically, the acylation reaction when carried out in presence of potassium t-butoxide base, and dichloromethane solvent, provides substantially pure ibrutinib.
The substantially pure ibrutinib is at least 99% pure.
While developing the process for Ibrutinib (Scheme 1), the below mentioned process related impurities were identified.

Impurity # RRT Molecular Weight Structure
1
0.82 428.50

2 1.30 476.97

3 0.85 494.56

4 2.28 881.01

5 1.09 442.52

6 2.24 826.97

7 0.28 386.46

8 0.41 303.33

9 - 440.51

10 3.00 700.78

11 - 474.52

12 - 476.97

13 - 357.37

14 - 486.58

15 - 456.51

16 2.05 881.01

HPLC conditions:
Column X bridge C18 150 mm x 4.6 mm, 3.5 µm
Flow rate 0.9 mL/min
Column oven temperature 45 °C
Wave length 220 nm
Injection Volume 10 µL
Run time 65 minutes
Diluent Methanol
Gradient program Time (min) % Mobile Phase A % Mobile Phase B
0 70 30
25 45 55
45 5 95
58 5 95
59 70 30
65 70 30

Synthetic scheme of impurity-10:

EXAMPLES
Example 1: Preparation of Ibrutinib
10.0 g of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was taken with 200 mL of dichloromethane and 2.9 g of potassium tert-butoxide in a flask at 25-30oC and cooled to -55 to -45oC. 2.2 g of acryloyl chloride taken in 100 mL of dichloromethane was added to the above flask. After the completion of the addition, the contents of the flask were maintained at -55 to -45oC for 1-2 hours. After the completion of the reaction, the reaction mass was washed with 10 % citric acid solution followed by brine solution and the organic layer was distilled under reduced pressure to obtain the crude compound. The crude material was dissolved in acetonitrile (50 mL) and added triethyl amine (30 mL) and heated the reaction mass at 40-50°C for 10-12 h. The crude mass was distilled under vacuum and added DCM (100 mL) and 10 % citric acid solution followed by brine solution and the organic layer was distilled under reduced pressure to obtain the crude compound. The crude compound was dissolved in methanol (150 mL) and heated to 50-55oC and filtered over carbon and hyflow. To the filtrate was added distilled water (150 mL) and maintained for 1-2 to obtain the solid. To the obtained solid was added methanol (20 mL) and 5% sodium bicarbonate solution (20 mL) and heated to 50-55oC. The obtained solid was filtered to obtain substantially pure Ibrutinib (Purity: 99.73%)
Purity: Crude 95-97 %; after purification: 99.73%.
Example 2: Preparation of impurity 10
Acryloyl chloride (0.39 g) taken in dichloromethane (10 mL) was added to flask containing (R)-N-(3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,1,1-triphenyl-l5-phosphanimine hydrochloride (3.0 g), diisopropylethylamine (1.27 g) and dichloromethane (20 mL) cooled to 0-5oC. The contents were heated to 25-30 oC and maintained for 2-3 hours. The reaction mixture was quenched with 10 mL of distilled water and organic and aqueous layers were separated. Citric acid (24 mL) was added to organic layer and distilled under reduced pressure to afford the title compound.
Mass (m/z) (M+H) = 701
1H-NMR (400MHz, DMSO-d6): d (ppm) = 8.45-8.50 (d, 2H), 8.05-8.10 (s, 2H), 7.75-7.90 (m, 6H), 7.45-7.50 (m, 3H), 7.30-7.40 (m, 8H), 7.10-7.20 (m, 5H), 6.55-6.60 (m, 1H), 6.20-6.30 (m, 1H), 5.60-5.70 (m, 1H), 4.80-4.90 (m, 1H), 4.20-4.30 (m, 1H), 3.75-3.80 (m, 1H), 2.30-2.40 (m, 1H), 2.20-2.30 (m, 1H), 1.90-2.0 (m, 1H), 1.60-1.70 (m, 1H), 1.20-1.30 (m, 1H).
13C NMR (400MHz, DMSO-d6): d (ppm) = 24.0, 25.3, 29.6, 30.3, 46.2, 52.9, 105.8, 118.3, 119.0, 123.3, 127.3, 127.6, 127.8, 128.3, 129.0, 129.7, 131.4, 133.2, 133.3, 145.4, 154.4, 154.8, 157.2, 161.2, 163.9, 165.6.
31P NMR (400MHz, DMSO-d6): d (ppm) = 19.3
Example 3: Preparation of Ibrutinib
50.0 g of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was taken with 1000 mL of dichloromethane at 25-35oC in a clean and dry flask and cooled to 0-10oC. 13.8g of potassium tert-butoxide was dispensed under nitrogen atmosphere at 0-10°C and whole mixture was cooled to -60±10oC. In a separate flask 10.51 g of freshly distilled acryloyl chloride was added to 500 mL of dichloromethane, pre-cooled to -20oC, and this mixture was added to the contents of the above flask. The reaction mass was maintained at -60 ± 10 °C for 45-60 min and then heated to 20-30oC. De-mineralized water (500 mL) was added to the above reaction mass at 20-30°C and organic and aqueous phases were separated. The organic phase was washed with 10% citric acid solution (250 mL) followed by 10% sodium chloride solution (250 mL). The organic phase was concentrated under reduced pressure and methanol (250 mL) was added to the concentrated crude at 30 ± 5 °C. The contents were heated to 55 ± 5°C and treated with activated carbon. To the filtrate was added de-mineralized water (550 mL) and heated to 55 ± 5°C for 15-20 minutes. The contents were cooled to 30 ± 5 °C and stirred for 10-12 hours followed by filtration and washing with methanol and water (100 mL, 1:1). The filtered material was dried at 50± 5 °C under reduced pressure for 10-12 hours to afford the title compound.
Yield: 34.27 g
,CLAIMS:CLAIMS

We Claim:

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 presence of suitable base and in a suitable solvent or mixture of solvents at -30 to -60 oC;
b. concentrating the reaction mixture and treating the concentrated reaction mixture with a base and optionally a solvent;
c. concentrating the mixture obtained in step b) and;
d. optionally, purifying the crude obtained in step c).
2. The process of claim 1, wherein the suitable base used in step a) is potassium t-butoxide, diisopropyl ethylamine, sodium hydroxide and sodium methoxide and a suitable solvent used in step a) is dichloromethane and tetrahydrofuran.
3. The process of claim 1, wherein in step b) the base is triethyl amine and solvent is acetonitrile
4. The process of claim 1, wherein in step d) methanol and water are used for the purification.