Process for preparing ibrutinib

Patent metadata

Field	Value
Publication number	US-10214532-B2
Application number	US-201615549631-A
Country	US
Kind code	B2
Filing date	Feb 4, 2016
Priority date	Feb 12, 2015
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

The present application relates to a method for preparing Ibutinib as shown by the following synthetic route and the intermediate compounds involved therein.

First claim

What is claimed is:

1. A process for preparing ibrutinib, comprising
Step 1: reacting a compound of Formula 1 with a compound of Formula 4 in the presence of a base and a catalyst to produce a compound of Formula 8,

Step 2: reacting the compound of Formula 8 with a compound of Formula 2-1 in the presence of a base to produce ibrutinib,

wherein X 1 is independently selected from the group consisting of Cl, Br and I; X 2 is independently selected from the group consisting of Cl and Br.

2. The process for preparing ibrutinib according to claim 1 , wherein the catalyst in step 1 is selected from the group consisting of Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (PhCN) 2 , Pd(OAc) 2 , Pd/C and PdCl 2 (dppf) 2 , preferably Pd(PPh 3 ) 4 ; and/or
wherein the base in step 1 is potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride; and/or
wherein a reaction solvent in step 1 is a mixed solvent of tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or ethylene glycol dimethyl ether and water; and/or
wherein the base in step 2 is potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, potassium hydride, sodium hydride, triethylamine, dimethylpyridine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; and/or
wherein a reaction solvent in step 2 is tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, acetonitrile or acetone.

3. The process for preparing ibrutinib according to claim 1 , further comprising
reacting a compound of Formula 5 with a compound of Formula 6 in the presence of a Mitsunobu reaction reagent to produce a compound of Formula 7, and deprotecting the compound of Formula 7 in the presence of an acid to produce the compound of Formula 1:

wherein R is an amino protecting group, preferably tert-butoxycarbonyl; and X 1 is independently selected from the group consisting of Cl, Br and I.

4. The process for preparing ibrutinib according to claim 3 , wherein the Mitsunobu reaction reagent is composed of a first reagent selected from the group consisting of triphenylphosphine, tributylphosphine and trimethylphosphine, and a second reagent selected from the group consisting of diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, diethyl azodicarboxylate, di-p-chlorobenzyl azodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine, N,N,N′,N′-tetraisopropylazodicarboxamide, N,N,N′,N′-tetramethylazodicarboxamide and 4,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetrazocin-3,8-dione.

5. The process for preparing ibrutinib according to claim 3 , wherein a solvent used for preparing the compound of Formula 7 is selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile and 1,4-dioxane.

6. The process for preparing ibrutinib according to claim 3 , wherein the acid used when deprotecting the compound of Formula 7 is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid and trifluoroacetic acid.

7. The process of claim 1 , wherein X 1 is Cl or Br.

8. The process of claim 2 , wherein the base in step 1 is potassium phosphate or potassium carbonate.

9. The process of claim 2 , wherein the reaction solvent in step 1 is a mixed solvent of 1,4-dioxane and water or a mixed solvent of ethylene glycol dimethyl ether and water.

10. The process of claim 2 , wherein the base in step 2 is sodium bicarbonate and potassium bicarbonate.

11. The process of claim 2 , wherein the reaction solvent in step 2 is 2-methyltetrahydrofuran.

12. The process of claim 3 , wherein X 1 is Cl and Br.

13. The process of claim 4 , wherein the Mitsunobu reaction reagent is composed of triphenylphosphine and diisopropyl azodicarboxylate.

14. The process of claim 5 , wherein the solvent used for preparing the compound of Formula 7 is tetrahydrofuran.

15. The process of claim 6 , wherein the acid used when deprotecting the compound of Formula 7 is hydrochloric acid.

Assignees

• Shanghai Dude Medical Science And Tech Co Ltd
• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Lianyungang Runzhong Pharmaceutical Co Ltd

Inventors

• Zhang Xiquan
• Kong Rui
• Liu Xin
• Chen Shan
• Chen Xiaoping
• Yang Leilei
• Zhang Aiming
• Cheng Xingdong

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title