WO2006061332A1

WO2006061332A1 - Gleevec process

Info

Publication number: WO2006061332A1
Application number: PCT/EP2005/056248
Authority: WO
Inventors: Peter Mccormack; David Cross
Original assignee: Phoenix Chemicals Limited
Priority date: 2004-12-08
Filing date: 2005-11-25
Publication date: 2006-06-15
Also published as: GB0426894D0

Abstract

The invention provides a process for the production of a pharmaceutical intermediate compound in accordance with the following scheme (formula (I)), wherein R5 is any suitable substituent group; and Z is any suitable leaving group.

Description

DESCRIPTION Gleevec Process

The present invention relates to a process for the production of certain pharmaceutical intermediate compounds, in particular to a carbonylation process for the production of certain pharmaceutical intermediate compounds, and to the use of the catalytic composition described in our co-pending P412554GB in such a carbonylation process.

The compound shown below is the active ingredient in a commercial oncology drug known by the trade names Gleevec, lmatinib and Glivec.

This material is disclosed in EP-B-0564409 and will be referred to hereinafter as Gleevec.

Gleevec is made up of the following basic core:

Compound 1

Commercially the current method for production of compound 1 occurs in which one of the aniline functions 1 is reacted with an acid chloride or

ester and the other 2 forms part of a guanidine type structure This currently is done via protection of one of the aniline groups (group 2) as a nitro compound followed by reduction of the nitro to the aniline and further reaction

As it already has selectivity built in Compound II shown above is expensive compared to Compound I

It is an object of the present invention to provide an improved synthesis of Compound III In particular, it is an object of the present invention to

- 2 - provide a synthesis of Compound III from Compound I which does not require the synthesis of compound II.

According to the present in invention there is provided a process for the production of a pharmaceutical intermediate compound in accordance with the following scheme:

Compound I

Compound wherein R^s is any suitable substituent group; and

Z is any suitable leaving group.

Preferably Z is chloride or iodide, most preferably bromide or triflate.

In one preferred process of the invention, compound III is:

This novel synthetic route involves carbonylation of a suitable substrate, for example an aryl halide/phenol derivative followed by regioselective reaction of the correct aniline to form the desired compound III.

The process of the invention may involve the use of a catalyst in the carbonylation reaction. In particular, the invention provides a process for the production of a pharmaceutical intermediate compound in accordance with the following scheme:

Compound I

Compound

wherein R' is any suitable substituent group; and

Z is any suitable leaving group;

wherein the carbonylation reaction is catalysed by a catalytic complex having the general formula (I): )

wherein:

R, R¹ and R² are, independently, selected from hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkenoxy, substituted alkenoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, alkaryl, substituted alkaryl, alkaryloxy, substituted alkaryloxy, alkenaryl, substituted alkenaryl, alkenaryloxy, substituted alkenaryloxy, aralkyl, substituted aralkyl, aralkoxy, substituted aralkoxy, aralkenyl, substituted aralkenyl, aralkenoxy, substituted aralkenoxy, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, heteroaryl, substituted heteroaryl, heteroaryioxy, substituted heteroaryloxy, heteroalkyl, substituted heteroalkyl, heteroalkyloxy and substituted heteroalkyloxy groups; and wherein each R may be the same or different;

n is from 0 to 4,

Q is a halide or pseudohalide; D is S, P₁ N or O;

X is oxygen, carbon, carbonyl, imine, benzylamine, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, alkaryl, substituted alkaryl, alkenaryl, substituted alkenaryl, aralkyl, substituted aralkyl, aralkenyl, substituted aralkenyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroalkyl or substituted heteroalkyl; or

D and X together form part of a further ring system on the palladacycle.

The invention also provides the use of the catalytic complex having formula (I) as a catalyst in the carbonylation reaction.

The palladium catalysed insertion of carbon monoxide into aryl or vinyl halides, pseudohalides or triflates, such catalytic insertion being conducted in the presence of a compound of formula (I) and an aniline- containing nucleophile is in accordance with the invention. The invention is also concerned with the subsequent transformation the resulting intermediate Pd-acyl complex with a nucleophile. A generalised reaction scheme may be presented as follows:

wherein R^s is any suitable substituent group,

Z is any suitable leaving group, and

NuH is an aniline-containing nucleophile

Suitable solvents include, by way of example, toluene, xylenes, 1 ,4 dioxane, acetonitπle and alcohols such as ethanol and butanol

In particular, NuH is preferably 2,4 diamino toluene or a derivative thereof and may also be selected from pipeπdine, N-methyl piperazine, N-benzyl piperazine and 4-toluιdιne, and derivatives thereof

Suitable leaving groups include, by way of example, halides such as chlorides, bromides and iodides and phenol derivatives such as triflates

In one preferred cataytic complex for use in the process of the invention, Q is Cl or a triflate

In another preferred cataytic complex for use in the process of the invention, D is P

In another preferred cataytic complex for use in the process of the invention, X is O n the case where D and X together form part of a further ring system on the palladacycle, one, both or neither of D and X may be heteroatoms For example, D and X together may form part of an oxazoline ring system on the pailadacycle

In still another preferred cataytic complex for use in the process of the invention, R is alkyl, preferably branched chain alkyl, preferably tertiary butyl

In yet another preferred cataytic complex for use in the process of the invention, n is 2 Preferably, both R groups are situated in meta positions with respect to the palladium substituent.

R¹ and R² are both aryloxy substituents in one preferred cataytic complex for use in the process of the invention

One particularly preferred catalytic complex for use in the process of the invention has the general formula (II):

The invention will now be more particularly described with reference to the following examples.

Example 1

To a 45 ml autoclave was added the formula Il palladacycle (3.85 x 10^~3 mM), 1 ,1 ^"-bis(diphenylphosphino)ferrocene (2.16 x 10^~2 mM), K₂CO₃ (13 O mM) and 2,4 diamino toluene (10.0 mM). The vessel was then flushed with Argon. 1 -(4-bromobenzyl)-4-methylpiperazine in 1 ,4 dioxane (14 ml of a 714 mM degassed solution) was then added. The autoclave was then flushed with Argon and then placed under CO (8 bar), the mixture was vented and then placed again under CO 8 (bar). The mixture was stirred and heated to 130 ⁰C for 6 h. The autoclave was then allowed to cool to room temperature and was carefully vented. The pale yellow mixture that resulted was then quenched into water (60 ml) and then extracted with dichloromethane (3 x 30 ml). The mixture was then dried with MgSO₄, filtered and the solvent removed under reduced pressure to give a brown oil. This crude oil was then dissolved in MeOH (10 ml) and aqueous HCI (2 equiv.) added. The solvent is removed under reduced pressure and the

_ g _ residue is triturated with hot MeOH to give a white solid (3.3 g, 80%). ¹H NMR (D₂O, 250.13 MHz): δ 2.20 (s, 3H); 2.86 (s, 3H); 3.46 (m, 8H); 4.33 (s, 2H), 7.27 (m, 2H); 7.51 (d, 2H); 7.57 (m, 1 H); 7.80 (d, 2H). Example 2 To a 45 ml autoclave was added the formulas Il palladacycle (3.85 x 10^"3 mM), 1 ,1 '-bis(diphenylphosphino)ferrocene (2.16 x 10^"2 mM), K₂CO₃ (13.0 mM) and p-toluidine (10.0 mM). The vessel was then flushed with Argon. 1 -(4-bromobenzyl)-4-methylpiperazine in 1 ,4 dioxane (14 ml of a 714 mM degassed solution) was then added. The autoclave was then flushed with Argon and then placed under a CO (8 bar), the mixture was vented and then placed again under CO 8 (bar). The mixture was stirred and heated to 120 ⁰C for 12 h. The autoclave was then allowed to cool to room temperature and was carefully vented. The pale yellow mixture that resulted was then filtered through a celite pad and the pad washed with dichloromethane (3 x 25 ml). The solvent was removed under reduce pressure and then the residue recrystallised from acetonitrile (30 ml) to give a white solid (3.0 g, 94%). ¹H NMR (CDCI₃, 250.13 MHz): δ 2.29 (s, 3H); 2.34 (s, 3H); 2.47 (m, 8H); 3.55 (s, 2H), 7.16 (d, 2H); 7.43 (d, 2H); 7.53 (d, 2H); 7.81 (d, 2H); 7.84 (br s, 1 H).

Claims

A process for the production of a pharmaceutical intermediate compound in accordance with the following scheme

Compound

Compound 111

wherein R^s is any suitable substituent group, and

Z is any suitable leaving group

A process according to claim 1 wherein compound III is

A process according to claim 1 or claim 2 wherein the carbonylation reaction is catalysed by a catalytic complex having the general formula (I) )

wherein:

R, R¹ and R² are, independently, selected from hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkenoxy, substituted alkenoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, alkaryl, substituted alkaryl, alkaryloxy, substituted alkaryloxy, alkenaryl, substituted alkenaryl, alkenaryloxy, substituted alkenaryloxy, aralkyl, substituted aralkyl, aralkoxy, substituted aralkoxy, aralkenyl, substituted aralkenyl, araikenoxy, substituted aralkenoxy, cycloalkyl, substituted cycloalkyi, cycloalkyloxy, substituted cycloalkyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroalkyl, substituted heteroalkyl, heteroalkyloxy and substituted heteroalkyloxy groups; and wherein each R may be the same or different;

n is from 0 to 4;

Q is a halide or pseudohalide; D is S, P, N or O,

X is oxygen, carbon, carbonyl, imine, benzylamine, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, alkaryl, substituted alkaryl, alkenaryl, substituted alkenaryl, aralkyl, substituted aralkyl, aralkenyl, substituted aralkenyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroalkyl or substituted heteroalkyl or

D and X together form part of a further ring system on the palladacycle

A process according to claim 3 wherein Q is Cl or a tπflate

A process according to claim 3 or claim 4 wherein D is P

A process according to any one of claims 3 to 5 wherein X is O

A process according to any one of claims 3 to 6 wherein R is alkyl

A process according any one of claims 1 to 7 wherein n is 2

A process according to any one of claims 3 to 8 wherein R¹ and R² are both aryloxy substituents 10. A process according to any one of claims 3 to 9 wherein the catalytic complex is of formula (II):

1 1. A process for the preparation of a pharmaceutical intermediate in accordance with the following reaction scheme:

wherein R^s is any suitable substituent group;

Z is any suitable leaving group; and

NuH is an aniline-containing nucleophile.