Process for preparing idelalisib

Patent metadata

Field	Value
Publication number	US-9981965-B2
Application number	US-201615563254-A
Country	US
Kind code	B2
Filing date	Mar 24, 2016
Priority date	Mar 31, 2015
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The present invention relates to an improved process for preparing Idelalisib (1). In this process, acid addition salts of idelalisamine (2) are useful intermediates for purification purposes.

First claim

The invention claimed is:

1. In a process for synthesizing idelalisib of formula (1) from idelalisamine of formula (2),

the improvement for which comprises isolating an acid addition salt of idelalisamine before its chemical conversion to idelalisib.

2. The process of claim 1 , wherein the acid in the acid addition salt of idelalisamine (2) is hydrochloric acid, benzoic acid, fumaric acid, malonic acid, tartaric acid, ethanesulphonic acid, p-toluenesulphonic acid or oxalic acid.

3. The process of claim 1 , wherein the acid in the addition salt of idelalisamine is hydrochloric acid.

4. A process which comprises:
(a) mixing idelalisamine free base of formula 2

with an acid selected from hydrochloric acid, benzoic acid, fumaric acid, malonic acid, tartaric acid, ethanesulphonic acid, p-toluenesulphonic acid or oxalic acid, in a solvent or solvent mixture and
(b) isolating the idelalisamine acid addition salt.

5. A process of claim 4 , wherein the mixing of idelalisamine free base with an appropriate acid of step (a) is performed in a crude reaction mixture.

6. A process according to claim 5 , wherein step (a) is performed in a solvent or solvent mixture comprising at least one of: 1,4-dioxane, EtOAc, THF, 2-Me-THF, CHCl 3 , CH 2 Cl 2 , Toluene and t-BuOH.

7. A process according to claim 4 , wherein step (a) is performed in 2-Me-THF or a solvent mixture comprising 2-Me-THF.

8. A process according to claim 4 , wherein step (b) is performed by crystallising the idelalisamine acid addition salt.

9. A process according to claim 4 , which further comprises purifying said isolated idelalisamine acid addition salt which comprises the steps of:
(i) dissolving the salt in a solvent, and
(ii) inducing crystallisation of the idelalisamine acid addition salt.

10. The process of claim 9 wherein the solvent in step (i) is chosen from 1,4-dioxane, EtOAc, THF, 2-Me-THF, CHCl 3 , CH 2 Cl 2 , Toluene and t-BuOH.

11. The process of claim 9 wherein the solvent in step (i) is 2-Me-THF.

12. An acid addition salt of idelalisamine of formula (2)

13. The acid addition salt of claim 12 , wherein the acid in the acid addition salt is hydrochloric acid, benzoic acid, fumaric acid, malonic acid, tartaric acid, ethanesulphonic acid, p-toluenesulphonic acid or oxalic acid.

14. An acid addition salt of claim 12 , wherein the acid in the acid addition salt is hydrochloric acid.

15. The process according to claim 1 in which the improvement further comprises purifying said isolated idelalisamine acid addition salt which comprises the steps of:
(i) dissolving the salt in a solvent, and
(ii) inducing crystallisation of the idelalisamine acid addition salt.

16. The process according to claim 15 , wherein the acid in the addition salt of idelalisamine is hydrochloric acid.

17. The process according to claim 16 , wherein said solvent in step (i) is 2-Me-THF.

Assignees

• Synthon Bv

Inventors

• Vyklicky Libor
• Zabadal Miroslav

Classifications

• B01D9/005

  Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof · CPC title

• C07D239/91

  with aryl or aralkyl radicals attached in position 2 or 3 · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• C07B63/02

  by treatment giving rise to a chemical modification · CPC title