WO2010060074A1

WO2010060074A1 - Preparation of nilotinib and intermediates thereof

Info

Publication number: WO2010060074A1
Application number: PCT/US2009/065676
Authority: WO
Inventors: Adi Yeori; Yanling Wang; Jie Li; Jirang Zhu; Revital Lifshitz-Liron; Xungui He
Original assignee: Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals Usa, Inc
Priority date: 2008-11-24
Filing date: 2009-11-24
Publication date: 2010-05-27

Abstract

N-(3-Bromo-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]benzamide is an intermediate of Nilotinib. Processes for preparing this intermediate from a compound of formula (X) is described.

Description

PREPARATION OF NILOTINIB AND INTERMEDIATES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application

Serial. Nos. 61/117,478, filed November 24, 2008; 61/161,670, filed March 19, 2009; 61/171,706, filed April 22, 2009; 61/168,822, filed April 13, 2009; and PCT/US2009/051001, filed July 17, 2009, which are incorporated herein by reference.

FIELD OF INVENTION

[0002] The present invention is directed to preparation of Nilotinib and intermediates thereof.

BACKGROUND OF THE INVENTION

[0003] Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-

(trifluoromethyl)phenyl] -3 - [ [4-(3 -pyridinyl)-2-pyrimidinyl] amino] -benzamide, having the following formula

is a tyrosine kinase inhibitor used for the treatment of drug-resistant chronic myelogenous leukemia (CML), and in particular, for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (CML) in adult patients whose disease has progressed on or who cannot tolerate other therapies that included imatinib.

[0004] Nilotinib is administered as a hydrochloride salt in forms of capsules that are marketed in the USA and the EU under the name Tasigna®.

[0005] US patent no. 7,169,791 ("US 791") and its parallel PCT publication WO

2004/005281, the journal article in Synthesis, 2007, vol 14, pp 2121-2124, as well as PCT publication nos.: WO 2006/135640, WO 2006/135641 ("WO "641"), WO 2007/018325 and WO 2007/017734, report processes for preparing Nilotinib intermediate, 3- (trifluoromethyl)-5 -(4-methyl- 1 H-imidazole- 1 -yl)-benzeneamine of formula I

I by reacting 3-bromo-5-trifluoromethylaniline of formula II and 4-methylimidazole of formula III in the presence of a non-alkaline hydroxide inorganic base, such as potassium carbonate, cesium carbonate and sodium hydride, a copper (I) salt, such as copper iodide and a complexing amine ligand, such as ethylene diamine. The process can be illustrated by the following scheme:

Il '

Scheme 1

[0006] US 791 describes processes for preparing Nilotinib and its different intermediates, using di-ethyl cyano phosphate, as described in the following scheme:

Scheme 2

[0007] WO '641 further describes a process for preparing Nilotinib according to the following scheme:

[0008] There is a need in the art for improved processes for preparing Nilotinib and its intermediates. The present invention provides improved processes for preparing Nilotinib and its intermediate, N-(3-Bromo-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3- pyridinyl)-2-pyrimidinyl]amino]benzamide.

SUMMARY OF THE INVENTION

[0009] In one embodiment, the present invention provides a process for preparing

N-(3 -Bromo-5 -trifluoromethylphenyl)-4-methy 1-3 - [ [4-(3 -pyridinyl)-2- pyrimidinyl]amino]benzamide, a Nilotinib intermediate of formula IV, having the following structure:

IV comprising: combining a compound of formula X having the following structure:

X with a solvent selected from the group consisting of: an aromatic hydrocarbon, a C₄-C₆ cyclic or aliphatic ether, a chlorinated solvent, DMA, DMF, DMSO and N-methyl- pyrrolidone ("NMP"); a compound selected from the group consisting of: thionyl chloride ("SOCl₂"), thionyl bromide, oxalyl chloride, oxalyl bromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorous pentabromide, C1-C5 carboxylic acid and activated reagent such as Ci-Cs chloro formate and weinreb amide; and a compound of formula II having the following structure:

and heating the combination to obtain the compound of formula IV.

[0010] In another embodiment, the present invention provides processes for preparing Nilotinib or a salt thereof of the following formula

wherein, n is either 0 or 1, and HA is an acid, preferably, HCl, from a Nilotinib intermediate of formula IV prepared according to the above process. [0011] In yet another embodiment, the present invention provides a process for preparing Nilotinib comprising: combining compound of formula IV, a solvent selected from the group consisting of: NMP, DMSO and DMF, an iodine salt selected from the group consisting of CuI, NaI, KI and combination thereof, and N,N-dimethyl ethylene diamine to obtain a reaction mixture; heating the reaction mixture; adding 8- hydroxyquinoline, an iodine salt selected from the group consisting of CuI, NaI, KI and combination thereof, a compound of formula III, having the following structure:

and a base selected from the group consisting of: DMAP, DBU, K₂CO₃, Cs₂COs₁ Na₂COs₁ KHCO₃, and NaHCO₃; and heating to obtain Nilotinib.

DETAILED DESCRIPTION OF THE INVENTION [0012] As used herein, the term "room temperature" refers to a temperature of about 15⁰C to about 3O⁰C, more preferably, to a temperature of about 20⁰C to about 25°C.

[0013] As used herein, the term "reduced pressure" refers to a pressure of about

10 mbar to about 50 mbar.

[0014] As used herein, the term "aromatic hydrocarbon" refers to a compound containing a six-carbon ring containing three double bonds that is normally liquid at about 25°C. Toluene is a preferred aromatic hydrocarbon solvent of the present invention.

Other aromatic hydrocarbons useful in the practice of the present invention include benzene and the xylenes.

[0015] As used herein, the term "chlorinated solvent" refers to Ci-C₆ chlorinated hydrocarbon. Preferred chlorinated solvents are selected from the group consisting of: carbon tetrachloride, dichloromethane (CH₂Cl₂), dichloroethane, chlorobenzene and chloroform.

[0016] As used herein, the term "weinreb amide" has the same meaning as the term is used by those of ordinary skill in the art, and refers to a compound having the following structure:

Typically, a weinreb amide is formed using Λf,0-Dimethylhydroxylamine in amide coupling reactions, according to the following scheme:

[0017] As used herein, the term "quantitative yield" refers to yield of about 90% to about 100%, preferably, to yield of about 95% to about 100%. [0018] The present invention provides a process for preparing the Nilotinib intermediate of formula IV comprising: combining a compound of formula X having the following structure:

X with a solvent selected from the group consisting of: an aromatic hydrocarbon, a C₄-C₆ cyclic or aliphatic ether, a chlorinated solvent, dimethylacetamide ("DMA"), dimethyl formamide ("DMF"), dimethylsulfoxide ("DMSO") and N-methyl-pyrrolidone ("NMP"); a compound selected from the group consisting of: thionyl chloride ("SOCl₂"), thionyl bromide, oxalyl chloride, oxalyl bromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorous pentabromide, C1-C5 carboxylic acid and activated reagent such as Ci-Cg chloroformate or weinreb amide; and a compound of formula II having the following structure:

and heating the combination to obtain the compound of formula IV.

[0019] The process can be illustrated, for example, by the following scheme:

-C8), N(CH₃)O(CH₃)

Scheme 4

[0020] Typically, the process is done in the absence of a base.

[0021] Preferably, the aromatic hydrocarbon is toluene.

[0022] Preferably, the C₄-C₆ cyclic or aliphatic ether is selected from the group consisting of: tetrahydrofuran ("THF"), methyl tert-butyl ether ("MTBE") and methyl-

THF, more preferably, the C₄-C₆ cyclic ether is THF.

[0023] Preferably, the chlorinated solvent is selected from the group consisting of: dichloromethane, dichloroethane, chlorobenzene and chloroform, more preferably, the chlorinated solvent is dichloromethane. [0024] Preferably, the solvent is NMP.

[0025] Preferably, the compound selected from the group consisting of: thionyl chloride ("SOCl₂"), thionyl bromide, oxalyl chloride, oxalyl bromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorous pentabromide C1-C5 carboxylic acid and activated reagent such as Ci-Cs chloroformate or weinreb amide, is SOCl₂.

[0026] Preferably, the compound selected from the group consisting of: thionyl chloride ("SOCl₂"), thionyl bromide, oxalyl chloride, oxalyl bromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorous pentabromide, C1-C5 carboxylic acid and activated reagent such as Ci-Cs chloroformate or weinreb amide is added dropwise.

[0027] Preferably, the process for preparing the Nilotinib intermediate of formula

IV comprises: combining a compound of formula X with a solvent selected from the group consisting of: an aromatic hydrocarbon, a C₄-C₆ cyclic or aliphatic ether, a chlorinated solvent, DMA, DMF, DMSO and NMP; adding a compound selected from the group consisting of: SOCl₂, thionyl bromide, oxalyl chloride, oxalyl bromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorous pentabromide, C1-C5 carboxylic acid and activated reagent such as Ci-Cs chloroformate or weinreb amide; adding a compound of formula II; and heating to obtain the compound of formula IV.

[0028] Preferably, prior to the addition of the compound of formula II, a heating step is performed. Preferably, the heating is to a temperature of about 55⁰C to about 65⁰C, more preferably, to about 6O⁰C. Typically, the heating is done while stirring. The stirring may be done for about 1 hour to about 3 hours. Preferably, the stirring is done for about

2.5 hours.

[0029] Preferably, the heating is done at a temperature of about 6O⁰C to about

120°C, more preferably, at about 9O⁰C. Preferably, the heating is done for about 2 hours to about 16 hours, more preferably, for about 3 hours.

[0030] Preferably, the compound of formula IV is obtained in a quantitative yield.

[0031 ] The obtained compound of formula IV may be further recovered. The recovery can be done, for example by adding water; heating; adding a base selected from the group consisting of inorganic bases, organic C₂-Cs secondary and tertiary amines, pyridine, 4-dimethylaminopyridine ("DMAP"), 2,3,4,6,7,8,9,10-Octahydropyrimidol[l,2- α]azepine ("DBU") and (l,4-diazabicyclo(2.2.2)octane) ("DABCO"); cooling; filtering; washing; and drying.

[0032] Preferably, the heating is done to a temperature of about 6O⁰C to about

12O⁰C, more preferably, to about 80°C. Preferably, the base is inorganic base selected from the group consisting of: alkali metal hydroxide, alkali metal hydride, alkali metal carbonate, alkali metal bicarbonate and alkali metal alkoxide, more preferably, the base is selected from the group consisting of NaOH, KOH, LiOH, K₂CO₃, Na₂CO₃, NaHCO₃ NaH and Cs₂CO₃, most preferably the base is NaOH.

[0033] Preferably, the base is added until obtaining a pH of about 8 to about 12, more preferably, of about 12. Preferably, the cooling is to about O⁰C to about 4O⁰C, more preferably, to about 25⁰C. Preferably, the cooling is done for about 1 hour to about 8 hours, more preferably, for about 2 hours. After the cooling and prior to the filtering, a maintaining step may be done.

[0034] Preferably, the maintaining is done at a temperature of about O⁰C to about

40°C, more preferably, at about 25⁰C. Preferably, the maintaining step is done for about 30 minutes to about 3 hours, more preferably, for about 45 minutes. Typically, the maintaining is done while stirring. Preferably, the filtering is done under reduced pressure.

[0035] Preferably, the washing is done with water. The drying may be done under vacuum. Preferably, the drying is done at a temperature of about 50°C to about HO⁰C, more preferably, at about 70°C. Optionally, slurrying with a solvent selected from the group consisting of: aromatic hydrocarbon, a C₄-C₆ cyclic or aliphatic ether, a chlorinated solvent, DMA, DMF, DMSO and NMP, is done prior to the drying step. [0036] Preferably, the slurrying step is done with a solvent selected from the group consisting of: C₄-C₆ cyclic or aliphatic ether selected from the group consisting of: THF, MTBE and methyl-THF, more preferably, with MTBE. Typically, the slurrying step is done at about room temperature. Preferably, the slurrying is done for about 1 hour to about 5 hours, more preferably, for about 3 hours. The slurrying is followed by additional filtering and washing steps. Preferably, the additional washing is done with a solvent selected from the group consisting of: aromatic hydrocarbon, a C₄-C₆ cyclic or aliphatic ether, a chlorinated solvent, chlorobenzene and chloroform, DMA, DMF, DMSO and NMP, more preferably, with C₄-C₆ cyclic or aliphatic ether selected from the group consisting of: THF, MTBE and methyl-THF, most preferably, with MTBE. [0037] The present invention provides a process for preparing Nilotinib or a salt thereof of the following formula

wherein, n is either 0 or 1 , and HA is an acid, preferably, HCl, from a Nilotinib intermediate of formula IV prepared according to the above process. This process can be done according to the process described below.

[0038] The present invention provides a process for preparing Nilotinib comprising: combining a compound of formula IV, a solvent selected from the group consisting of: NMP, DMSO and DMF an iodine salt selected from the group consisting of CuI, NaI, KI and combination thereof, and N,N-dimethyl ethylene diamine to obtain a reaction mixture; heating the reaction mixture; adding 8-hydroxyquinoline, an iodine salt selected from the group consisting of CuI, NaI, KI and combination thereof, a compound of formula III, having the following structure:

III and a base selected from the group consisting of: DMAP, DBU, K2CO3, CS2CO3, Na₂CCh, KHCO₃, and NaHCO₃; and heating to obtain Nilotinib. [0039] Preferably, the solvent is NMP.

[0040] Preferably, the base is DBU.

[0041] Preferably, the heating is to a temperature of about 9O⁰C to about 125⁰C, more preferably, to a temperature of about 12O⁰C. Preferably, the heating, prior to the addition of 8-hydroxyquinoline, is done for about 6 hours to about 24 hours, more preferably, for about 24 hours.

[0042] Typically, following the reaction mixture heating and prior to the addition of 8-hydroxyquinoline, a cooling step is performed. Preferably, the cooling is to a temperature of about 5O⁰C to about 6O⁰C, more preferably, to a temperature of about 6O⁰C. [0043] Preferably, the heating done after the base addition, is for a period of about 16 hours to about 72 hours, more preferably, for about 22.5 hours, to obtain a reaction mixture containing Nilotinib. Typically, while heating, the reaction is monitored by HPLC. The monitoring may be done by measuring the decrease in the amount of the compound of formula IV.

[0044] Typically, the reaction is done under nitrogen environment.

[0045] Preferably, the process for preparing Nilotinib comprises: combining compound of formula IV, CuI, NaI, NMP and N,N-dimethyl ethylene diamine to obtain a reaction mixture; heating the reaction mixture; cooling; adding 8-hydroxyquinoline, CuI, a compound of formula III and DBU; and heating to obtain Nilotinib.

[0046] The obtained Nilotinib may be recovered from the reaction mixture. The recovery may be done by treating the reaction mixture with an aqueous solution of

NaHCO₃ and water to obtain a second reaction mixture; filtering; washing and drying to obtain crude Nilotinib. Preferably, the addition OfNaHCO₃ and water is done at a temperature of about 2O⁰C to about 3O⁰C, more preferably, at about 25⁰C. Preferably, the washing is done with water. Preferably, the drying is under vacuum. The obtained crude

Nilotinib may be further purified.

[0047] Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way.

EXAMPLES Example 1: Preparation of compound of formula IV

[0048] To 50OmL glass reactor was added the compound of formula 4-methyl-3-

{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid of formula X (20.0 g, 0.06 mol), and N-Methyl-pyrrolidone (100 mL). SOCl₂ (6.5 mL, 0.09 mol) was then added dropwise over 10 minutes. The resulted mixture was heated to 60⁰C, and was stirred at 60⁰C for 2.5 h. A compound of formula II (17.3 g, 0.07 mol) was added and the reaction mixture was stirred and heated to 90⁰C for 3 h. After completion of the reaction, water (100 mL) was added and the solution was heated to 80⁰C. NaOH 47% solution (16 mL) was added until pH 12. Then, the suspension was cooled to 25°C in 2 h and stirred at this temperature for 45minutes, filtered under reduced pressure at 25°C, and washed with 120 rnL H₂O in portions to yield a beige solid. This material was slurried in MTBE (164 rnL) at RT for 3 h, filtered, washed with MTBE (3x33 mL), and dried under vacuum at 70⁰C to obtain 32 g of compound IV with quantitative yield. Example 2: Preparation of Nilotinib

[0049] The compound of formula IV (29.96 g, 57 mmol), NaI (17.2 g, 11.4 mmol), CuI (1.6 g, 8 mmol) and N,N-Dimethylethylenediamine (1.9 mL, 17 mmol) and NMP (15OmL) were mixed under N₂ atmosphere. The formed mixture was heated to 120⁰C for 24h. The temperature of the above mixture was decreased to 60⁰C. 8- Hydroxyquinoline (2.5 g, 17 mmol), CuI (1.6 g, 8 mmol), the compound of formula III (6.6 g, 80 mmol) and DBU (13.0 g, 85 mmol) were added to the above mixture under N₂ atmosphere. The formed mixture was heated to 120⁰C for 22.5h. After the reaction was completed (detected by the consumption of the compound of formula IV, HPLC), the reaction solution was dropped to a solution of saturated NaHCO₃ (21.5 mL) and water (430 mL) at 25±5°C. The mixture was then filtered, and the filter cake was washed with water. 39.4 g of crude Nilotinib was obtained after drying in vacuum oven at 70⁰C.

Claims

What is claimed is:

1. A process for preparing the N-(3-Bromo-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3- pyridinyl)-2-pyrimidinyl]amino]benzamide having the following structure:

comprising: combining a compound of formula X

X with a solvent selected from the group consisting of: an aromatic hydrocarbon, a C₄-C₆ cyclic or aliphatic ether, a chlorinated solvent, DMA, DMF, DMSO and N-methyl- pyrrolidone ("NMP"); a compound selected from the group consisting of thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorous pentabromide, C1-C5 carboxylic acid, Ci-Cg chloroformate and weinreb amide; and 3-bromo-5- trifluoromethylaniline; and heating the combination to form N-(3-Bromo-5-trifluoromethylphenyl)-4-methyl-3- [ [4-(3 -pyridinyl)-2-pyrimidinyl] amino]benzamide .

2. The process of claim 1 , wherein the process is done in the absence of a base.

3. The process of claim 1 , wherein the solvent is toluene.

4. The process of claim 1 , wherein the solvent is selected from the group consisting of: tetrahydrofuran, methyl tert-butyl ether and methyl-THF.

5. The process of claim 1, wherein the solvent is selected from the group consisting of: dichloromethane chlorobenzene and chloroform.

6. The process of claim 1 , wherein the solvent is NMP.

7. The process of claim 1, wherein the compound is SOCl₂.

8. The process of claim 1 , wherein the compound is added dropwise.

9. The process of claim 1 , wherein the process comprises: combining a compound of formula X

X with a solvent selected from the group consisting of: an aromatic hydrocarbon, a C₄-C₆ cyclic or aliphatic ether, a chlorinated solvent selected from the group consisting of dichloromethane, dichloroethane, chlorobenzene and chloroform, DMA, DMF, DMSO and N-methyl-pyrrolidone ("NMP"); adding a compound selected from the group consisting of thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, phosphorous pentabromide, C1-C5 carboxylic acid, C₁-C₈ chloro formate and weinreb amide; adding 3-bromo-5- trifluoromethylaniline; and heating to form N-(3-Bromo-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3- pyridinyl)-2-pyrimidinyl]amino]benzamide.

10. The process of claim 9, wherein prior to the addition of 3-bromo-5- trifluoromethylaniline, a heating step is performed.

11. The process of claim 10, wherein the heating is to a temperature of about 55⁰C to about 65⁰C.

12. The process of claim 1, wherein the heating is to a temperature of about 6O⁰C to about 12O⁰C.

13. The process of claim 12, wherein the heating is to a temperature of about 90°C.

14. The process of claim 1, wherein the obtained N-(3-Bromo-5-trifluoromethylphenyl)- 4-methyl-3 - [[4-(3 -pyridinyl)-2-pyrimidinyl] amino]benzamide is recovered.

15. A process for preparing Nilotinib or salt thereof comprising converting N-(3-Bromo- 5 -trifluoromethylphenyl)-4-methyl-3 - [[4-(3 -pyridinyl)-2- pyrimidinyl]amino]benzamide of claim 1 to Nilotinib or a salt thereof.

16. A process for preparing Nilotinib comprising: combining N-(3 -Bromo-5 -trifluoromethylphenyl)-4-methyl-3 - [ [4-(3 -pyridinyl)-2- pyrimidinyl]amino]benzamide; a solvent selected from the group consisting of: NMP, DMSO and DMF; an iodine salt selected from the group consisting of CuI, NaI, KI and combination thereof; and N,N-dimethyl ethylene diamine to obtain a reaction mixture; heating the reaction mixture; adding 8-hydroxyquinoline; an iodine salt selected from the group consisting of CuI, NaI, KI and combinations thereof; a compound of formula III having the following structure:

III and a base selected from the group consisting of: DMAP, DBU, K2CO3, CS2CO3, Na₂COs, KHCO₃, and NaHCO₃; and heating to obtain Nilotinib.

17. The process of claim 16, wherein the solvent is NMP.

18. The process of claim 16, wherein the base is DBU.

19. The process of claim 16, wherein the heating is to a temperature of about 9O⁰C to about 125⁰C.

20. The process of claim 19, wherein the heating is to a temperature of about 12O⁰C.

21. The process of claim 16, wherein following the reaction mixture heating and prior to the addition of 8-hydroxyquinoline, a cooling step is done.

22. The process of claim 21, wherein the cooling is to a temperature of about 5O⁰C to about 6O⁰C.

23. The process of claim 16, wherein the process comprises: combining N-(3-Bromo-5- trifluoromethy lphenyl)-4-methyl-3 - [[4-(3 -pyridinyl)-2-pyrimidinyl] amino]benzamide, CuI, NaI, NMP and N,N-dimethyl ethylene diamine to obtain a reaction mixture; heating the reaction mixture; cooling; adding 8-hydroxyquinoline, CuI, a compound of formula III and DBU; and heating to obtain Nilotinib.

24. The process of claim 16, wherein the Nilotinib is recovered from the reaction mixture.