Abstract: ABSTRACT The present invention relates to a novel process for the preparation of Acalabrutinib (1) with purity greater than 99% and its intermediate compounds thereof.
We claim:
1. A process for the preparation of Acalabrutinib of formula (1), comprising the steps of:
a) reacting compound of formula (9) with compound of formula (8) to form compound of formula (7);
b) reacting compound of formula (7) with compound of formula (6) to form compound of formula (5);
c) alkylating compound of formula (5) with compound of formula (4) to form compound of formula (3);
d) hydrolysis of compound of formula (3) to obtain compound of formula (2); and
e) conversion of compound of formula (3) to Acalabrutinib of formula (1)
Wherein, X is halogen, selected from chloro or bromo; R is an alkyl group selected from methyl or ethyl.
Wherein Acalabrutinib (1) obtained is purified from a suitable solvent selected from protic, aprotic and mixtures thereof.
I. providing Acalabrutinib (1) in a suitable aprotic or protic or mixture of solvents.
II. stirring the reaction mixture and filtering;
III. heating the reaction mixture to a suitable temperature; and
IV. isolating pure Acalabrutinib (1).
2. The process of claim 1, wherein suitable bases used in the present invention is selected from a group comprising of n-butyl lithium, lithium diisopropyl amide (LDA), lithiumbis(trimethylsilyl)amide (LiHMDS), sodium carbonate and potassium carbonate.
3. The process of claim 1, wherein suitable solvents used is selected from the group consisting of selected from water, methanol, ethanol, ethylene glycol, isopropyl alcohol, benzyl alcohol, acetone, methyl ethyl ketone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, N, N-dimethylformamide, N,N-dimethyl
acetamide, methyl tertiary butyl ether, hexane, cyclohexane, n-heptane, toulene, xylene, tetrahydrofuran or mixtures thereof. 4. A process for the preparation of Acalabrutinib of formula (1), comprising the steps of:
a) reacting compound of formula (15) with compound of formula (14) to form compound of formula (13);
b) reacting compound of formula (13) with compound of formula (12) to form compound of formula (11);
c) conversion of compound of formula (11) to compound of formula (10); and
d) ammonolysis of compound of formula (10) to form compound of formula (1).
5. The process of claim 4, wherein step a) is earned out in presence of sodium bis(trimethylsilyl)amide.
6. A process for the preparation (S)-l-but-2-ynoylpyrrolidine-2-carboximidamide (6), comprising the steps of:
7. The process of claim 6, wherein the formula (16) is treated with but-2-ynoyl chloride in pyridine.
8. The process of claim 6, wherein formula (17) is treated with sodium methoxide (NaOMe) and ammonium chloride (NH4CI).
9. The process of claim 1 and 4, wherein Acalabrutinib (1) is having impurities less than 0.5% (w/w) by High performance liquid chromatography.
10. A process for the preparation of compound of formula (15), comprising the steps of:
i. reacting compound (18) with oxalyl chloride ((COCl)2) to obtain
compound (19); ii. treating compound (19) with 2-aminopyridine in pyridine to yield
compound (20); iii. treating compound (20) with hydrochloric acid (HC1) in dioxane to
obtain compound (21); and iv. coupling compound (21) with compound (22) to obtain 4-
((diphenylmethyleneamino)methyl)-N-(pyridin-2-yl)benzamide (1 5).
| # | Name | Date |
|---|---|---|
| 1 | 201941016828-PROVISIONAL SPECIFICATION [27-04-2019(online)].pdf | 2019-04-27 |
| 2 | 201941016828-FORM 1 [27-04-2019(online)].pdf | 2019-04-27 |
| 3 | Correspondence by Applicant_Form1_06-05-2019.pdf | 2019-05-06 |
| 4 | 201941016828-FORM 3 [27-04-2020(online)].pdf | 2020-04-27 |
| 5 | 201941016828-ENDORSEMENT BY INVENTORS [27-04-2020(online)].pdf | 2020-04-27 |
| 6 | 201941016828-COMPLETE SPECIFICATION [27-04-2020(online)].pdf | 2020-04-27 |
| 7 | 201941016828-Specification_After Filing_21-07-2020.pdf | 2020-07-21 |
| 8 | 201941016828-Form5_After Filing_21-07-2020.pdf | 2020-07-21 |
| 9 | 201941016828-Form3_After Filing_21-07-2020.pdf | 2020-07-21 |
| 10 | 201941016828-Correspondence_21-07-2020.pdf | 2020-07-21 |