ITMI20070942A1 - PROCESS FOR THE PREPARATION OF IMATINIB AND ITS INTERMEDIATES - Google Patents

Description

DESCRIPTION

Technical field of the invention

The object of the present invention is a process for the preparation of 4-methyl-N-3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzendiamine and its analogues, useful intermediates for the synthesis of Imatinib , or 4 - [(4— methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide.

State of the art

Imatinib mesylate, molecule of formula 9, is an important drug used in the treatment of chronic myeloid leukemia.

9

Its preparation is described for the first time in Novartis EP 564409 and is summarized in the following diagram 1. This document does not report the yields of the various preparations.

Scheme 1

However WO 2006/071130 reports that, with this synthesis route, the total yield to Imatinib is not higher than 15%. Furthermore, many steps present long and difficult workups and for this reason they are not suitable for an industrial application. Moreover, some reactants, in particular 3-acetylpyridine and N, N-dimethylformamide dimethylacetal, are expensive and for this reason this synthesis route is not economically advantageous. The problems listed above are particularly relevant for the synthesis of the 4-methyl-N3 intermediate

[4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzenediamine of formula 8.

Brief description of the invention

The present invention relates to the preparation of 4-methyl-N3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzendiamine and its analogues starting from β-οχο-3-pyridinpropanal or a salt thereof, using innovative and economically advantageous synthetic steps.

Detailed description of the invention

A process for the preparation of compounds of formula 1 has surprisingly been found

where Ri represents amine, nitro, halogen, hydroxy, NH (CO) R3, NHR4,

represents 4- (halomethyl) phenyl, 4- (hydroxymethyl) phenyl, 4 - ((4-methylpiperazinyl) carbonyl) phenyl, 4 (alkoxycarbonyl) phenyl or 4 - [(4-methyl-lpiperazinyl) methyl] phenyl, wherein alkoxy means alkoxy C1-C4,

R4 represents a protecting group for the amino group,

including the steps

a) to make the β-οχο-3-pyridine propanal or one of its enolether of formula 17 react

17

where R.2 represents hydrogen, C1-C4 alkyl, benzyl, or phenyl,

with an arylguanidine of formula 3

wherein Ri has the meaning described above, to give the compound of formula 19

19

wherein Ri has the above meaning, and b) to cyclize the intermediate of formula 19 in the presence of a base.

R1 preferably represents amino, nitro, NH (CO) R3, NHR4, more preferably amino or nitro;

R2 preferably represents hydrogen, isopropyl or n-butyl;

R3 preferably represents 4- (chloromethyl) phenyl or 4 - [(4-methyl-lpiperazinyl) methyl] phenyl;

R4 preferably represents a carboxamide, a sulfonamide or a carbamate, more preferably represents a COCH3, (CO) OBn, (CO) O-t-Bu, (S02) Ph, (S02) (4-Me-Ph) group;

When Ri is an NH (CO) R3 group, where R3 represents 4- (halomethyl) phenyl, 4 (hydroxymethyl) phenyl, 4 - ((4-methylpiperazinyl) carbonyl) phenyl, 4- (alkoxycarbonyl) phenyl, wherein alkoxy means alkoxy C1-C4, the synthesis described above will lead to a more advanced intermediate in the synthesis of Imatinib than the compound 4-methyl-N3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzendiamine of formula 8 ; this intermediate can be converted into Imatinib according to the methods known in the literature (see WO 2004108699, EP 52853, WO 2005005414 or Arch. Pharmacal Res., 27 (11), 1093-1098 (2004)).

When Ri is an NH (CO) R3 group, where R3 represents 4- [(4-methyl-1-piperazinyl) methyl] phenyl, the synthesis described above will lead directly to Imatinib.

The cyclization reaction b) requires the use of a base, preferably selected from the group consisting of sodium hydroxide, sodium carbonate, sodium alcoholates C1-C4, potassium hydroxide, potassium carbonate, potassium alcoholates C1-C4, lithium hydroxide, lithium carbonate, C1-C4 lithium alcoholates, cesium hydroxide, cesium carbonate, ammonia and 4-dimethylaminopyridine, more preferably it is potassium hydroxide. The base can be absent in step a), or be present also in step a).

The process described above comprises the optional step of isolating the intermediate of formula 19, provided that step a) is not carried out in the presence of the base used in step b); in this case the intermediate 19 is obtained in high yield and purity.

The synthesis is preferably carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene and their mixtures, more preferably isopropanol. Step a) is preferably carried out at a temperature between 0 ° C and 50 ° C and for a time between 2 and 6 hours, and step b) preferably at a temperature between 80 ° C and 140 ° C and for a time between 6 and 24 hours.

A particularly preferred embodiment of the invention is a process for the preparation of 4-methyl-N3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzenediamine of formula 8

8

including the steps

a) to make the sodium salt of the β-οχο-3-pyridinpropanal of formula 20 (or one of its tautomer) react

20

with (2-methyl-5-aminophenyl) guanidine of formula 21

21

to give the compound of formula 22

22

and b) cycling the intermediate of formula 22 in the presence of a base.

In fact, (2-methyl-5-aminophenyl) guanidine reacts with β-οχο-3-pyridinpropanal faster than (2-methyl-5-nitrophenyl) guanidine.

Following the addition of the acid to the sodium salt mixture of β-οχο-3-pyridinpropanal of formula 20 and (2-methyl-5-aminophenyl) guanidine of formula 21 at room temperature the precipitation of the product of formula 22 is obtained which can be isolated by filtration.

Crude 4-methyl-N3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzenediamine is conveniently crystallized from toluene in a yield of 80% and purity higher than 99% (HPLC). This product quality is used in the synthesis of Imatinib described in EP 564409.

The β-οχο-3-pyridinpropanal or one of its enolether of formula 17 are conveniently generated by adding an acid to the salt of the β-οχο-3-pyridinpropanal 18

18

wherein Z represents an alkali or alkaline earth metal, preferably sodium or potassium. When R2 in the compounds of formula 17 is different from hydrogen, the solvent used for their preparation is alcohol of formula R2OH. The acid is preferably hydrochloric acid or acetic acid.

The sodium salt of β-οχο-3-pyridinpropanal of formula 20 and its analogues of formula 18 can be prepared according to the teachings of DE 2125310 and can be isolated or used in situ.

The (2-methyl-5-aminophenyl) guanidine of formula 21 and its analogues of formula 3 can be prepared according to the teachings of WO 2004110452.

A further object of the present invention are the compounds of formula 19

19

where Ri has the meaning described above.

Particularly preferred is the compound of formula 22.

In conclusion, the present invention provides a simple method of preparation of 4-methyl-N3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzenediamine and its analogues having the following advantages:

1) the procedures described are simple and easily transferable to a production plant;

2) it is possible to recover and recycle many of the reagents used in excess, allowing to increase yields without affecting production costs;

3) the synthesis of 4-methyl-N3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzendiamine of formula 8 starting from the salt of β-οχο-3-pyridinpropanal 21 has an overall yield equal to or greater than 80%, making this process one of the most economically advantageous among those described in the literature.

Further characteristics and advantages of the process of the invention will emerge from the following description of preferred embodiment examples, which are given by way of non-limiting example.

Examples

Example 1: 4-methyl-N3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzenediamine 8

Under an inert atmosphere, 16 g of sodium salt of β-οχο-3-pyridine propanal are suspended, with HPLC purity of 99% (A%) and salt content of 25% (residue for calcination), and 11.7 g of (2 -methyl-5-aminophenyl) guanidine in 115 ml of n-butanol. 9 ml of acetic acid are added and the mixture is stirred at room temperature for one hour. 6 g of potassium hydroxide are added in portions and the mixture is heated under reflux for 18 hours, removing the water with a Dean Stark distiller. Upon complete conversion, the suspension is cooled and the organic phase is washed with water. The organic phase is concentrated to a small volume and toluene is added. The precipitate is filtered, obtaining, after drying, 15.5 g of product with an HPLC purity of 99.2% (A%), identified by LC-MS and <1> H-NMR.

LC-MS: [M + 1] <+> = 278.

<1> H-NMR (300 MHz, DMSO-d6): δ (ppm) 2.02 (s, 3H), 4.85 (s, 2H), 6.31 (d, 1H), 6.76 ( s, 1H), 6.84 (d, 1H), 7.33 (d, 1H), 7.50 (m, 1H), 8.38 (d, 1H), 8.43 (d, 1H), 8.66 (bs, 1H), 9.22 (s, 1H).

Example 2: 1- (5-amino-2-methylphenyl) -3- [(3-oxo-3- (3-pyridinyl) -1-prop-1-enyl] guanidine 22

Under an inert atmosphere, 10 g of sodium salt of β-οχο-3-pyridinpropanal are suspended, with HPLC purity of 99% (A%) and salts content of 25% (residue for calcination), in 80 ml of isopropanol. 24 ml of a 15% solution of hydrochloric acid in isopropanol are added and the mixture is stirred at room temperature for one hour. 7 g of (2-methyl-5-aminophenyl) guanidine are added in portions and the mixture is stirred at room temperature for 12 hours. After complete conversion, the precipitate is filtered, obtaining, after drying, 13.5 g of product with HPLC purity of 98% (A%) and salts content of 30% (residue by calcination), identified by LC-MS.

LC-MS: [M + 1] <+> = 296.

Example 3: N- (2-methyl-5-nitrophenyl) -4- (3pyridinyl) -2-pyrimidinamine 1 (Ri = N02)

Under an inert atmosphere, 5 g of sodium salt of β-οχο-3-pyridine propanal are suspended, with HPLC purity of 99% (A%) and content in salts of 25% (residue for calcination), and 8 ml of hydrochloric acid in isopropanol in 50 ml of toluene. 3.7 g of (2-methyl-5-nitrophenyl) guanidine are added and the mixture is stirred at room temperature for one hour. The mixture is heated under reflux for 18 hours, removing the water with Dean Stark's still. Upon complete conversion, the suspension is cooled to 10 ° C and the precipitate is filtered; this is pulped in warm water, obtaining, after filtration and drying, 2.5 g of product with HPLC purity of 96% (A%), identified by GC-MS.

MS m / e (int. Rei.): 307 (M +) (100), 292 (76), 260 (63), 246 (38).

Claims (1)

CLAIMS 1. Process for the preparation of compounds of formula 1 wherein Ri represents amino, nitro, halogen, hydroxy, NH (CO) R3, NHR4 R3 represents 4- (halomethyl) phenyl, 4- (hydroxymethyl) phenyl, 4 - ((4-methylpiperazinyl) carbonyl) phenyl, 4- (alkoxycarbonyl) phenyl or 4 - [(4-methyl-lpiperazinyl) methyl] phenyl, in which alkoxy means C1-C4 alkoxy, R4 represents a protecting group for the amino group, including the steps a) to make the β-οχο-3-pyridine propanal or one of its enolether of formula 17 react where R2 represents hydrogen, C1-C4 alkyl r benzyl, or phenyl, with an arylguanidine of formula 3 wherein Ri has the meaning described above, to give the compound of formula 19 19 wherein Ri has the above meaning, and b) to cyclize the intermediate of formula 19 in the presence of a base. 2. Process according to claim 1 wherein Ri represents amino, nitro, NH (C0) R3, NHR4, preferably amino or nitro. 3. Process according to claims 1-2 wherein R 2 represents hydrogen, isopropyl or n-butyl. 4. Process according to claims 1-3 wherein R3 represents 4- (chloromethyl) phenyl or 4 - [(4-methyl-lpiperazinyl) methyl] phenyl. 5. Process according to claims 1-4 wherein R.4 represents a carboxamide, a sulfonamide or a carbamate, preferably represents a group COCH3, (CO) OBn, (CO) O-t-Bu, (S02) Ph, (S02) ( 4-Me-Ph). 6. Process according to claims 1-5 wherein the base used in step b) is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium alcoholates C1-C4, potassium hydroxide, potassium carbonate, potassium alcoholates C1-C4, lithium hydroxide, lithium carbonate, lithium C1-C4 alcoholates, cesium hydroxide, cesium carbonate, ammonia and 4-dimethylaminopyridine, preferably it is potassium hydroxide. 7. Process according to claims 1-6 wherein said base is also present in step a). 8. Process according to claims 1-6 wherein said base is absent in step a) and comprising the step of isolating the intermediate of formula 19. 9. Process according to claims 1-8 wherein the synthesis is carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene and their mixtures, preferably isopropanol . 10. Process for the preparation of 4-methyl-N3- [4- (3-pyridinyl) -2-pyrimidinyl] -1,3-benzenediamine of formula 8 including the steps a) to make the sodium salt of the β-οχο-3-pyridinpropanal of formula 20 (or one of its tautomer) react 20 with (2-methyl-5-aminophenyl) guanidine of formula 21 21 to give the compound of formula 22 22 and b) cycling the intermediate of formula 22 in the presence of a base. 11. Compounds of formula 19 19 where Ri represents amino, nitro, halogen, hydroxy, NH (CO) R3, NHR4, represents 4- (halomethyl) phenyl 4- (hydroxymethyl) phenyl 4 - ((4-methylpiperazinyl) carbonyl) phenyl 4- (alkoxycarbonyl) phenyl or 4 - [(4-methyl-lpiperazinyl) methyl] phenyl, wherein alkoxy means alkoxy C1-C4e R4 represents a protecting group for the amino group. 12. Compounds according to claim 11 wherein R1 represents animino, nitro, NH (C0) R3, NHR4, preferably animino or nitro, more preferably animino. 13. Compounds according to claims 11-12 wherein R3 represents 4- (chloromethyl) phenyl or 4— [Cimethyl-1-piperazinyl) methyl] phenyl. 14. Compounds according to claims 11-13 wherein R4 represents a carboxamide, a sulfonamide or a carbamate, preferably represents a COCH3, (CO) OBn, (CO) O-t-Bu, (S02) Ph, (S02) (4- Me-Ph).