NOVEL PROCESS FOR THE PREPARATION OF 6-METHYL-PYRAZIN-2-YLAMINE.

The invention relates to processes for preparing pyrazine derivatives.

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Studies have demonstrated that the actions of chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl (for the C-C family); CXCRl, CXCR2, CXCR3 , CXCR4 and CXCR5 (for the C-X-C family) and CX ₃ CRl for the C-X ₃ - C family. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

WO 03/059893 describes a series of N-pyrazinyl-phenyl sulphonamides, their use in the treatment of chemokine-mediated diseases, and processes for their preparation. A number of the compounds described in WO 03/059893 are prepared from 6-methyl- pyrazin-2-ylamine (I), which important intermediate is itself prepared in WO 03/059893 from 6-chloro-2-pyrazinamine by reaction with dimethylzinc in the presence of a nickel(II) catalyst. However, this reaction is unsuitable for large-scale preparation as the metallic reagents employed are either pyrophoric and/or difficult to separate from the product.

Other literature methods of preparing 6-methyl-pyrazin-2-ylamine are also unsuitable for large-scale preparation. The preparation of 2,6-disubstituted pyrazines by the formation and subsequent cleavage and decarboxylation of 7-methyllumazine, as described by Sharefkin in J. Org. Chem.; 24; 1959; 345-348, involves problematic chemistry and is inefficient in terms of reagents employed. Moreover, preparations involving the use of 2- chloro-6-methyl-pyrazine as an intermediate arehindered by the lack of a convenient method of preparing this intermediate, and the material's low melting and boiling point (e.g. see Karmas et al. J. Am. Chem. Soc; 74; 1952; 1580-1582).

Therefore, it would be advantageous if there were an efficient synthesis of 6-methyl- pyrazin-2-ylamine.

The present invention provides a process of preparing 6-methyl-pyrazin-2-ylamine, which process comprises:-

(a) reacting 2,6-dichloropyrazine and dialkylmalonate in the presence of a base to form

2-(6-chloro-pyrazin-2-yl)-malonic acid dialkyl ester, (b) converting 2-(6-chloro-pyrazin-2-yl)-malonic acid dialkyl ester to 6-chloro- pyrazin-2-yl-acetic acid, and (c) reacting 6-chloro-pyrazin-2-yl-acetic acid with ammonia to yield 6-methyl-pyrazin-

2-ylamine

The process of the present invention is depicted in Scheme 1, wherein compound (I) is 6-methyl-pyrazin-2-ylamine, compound (II) is 2-(6-chloro-pyrazin-2-yl)-malonic acid dialkyl ester and compound (III) is 6-chloro-pyrazin-2-yl-acetic acid. Scheme 1

(b)

In step (a) 2,6-dichloropyrazine is reacted with dialkylmalonate to form 2-(6-chloro- pyrazin-2-yl)-malonic acid dialkyl ester (II). This reaction is conducted in the presence of a base. Examples of bases that may conveniently be employed in the reaction are sodium hydride, sodium bistrirnethylsilylamide, potassium bistrimethylsilylamide, and lithium hydride. In one embodiment of the invention the base is sodium hydride. The alkyl groups in the dialkylmalonate may conveniently be C _1-6 alkyl groups, such as methyl, ethyl, n-propyl, iso-propyl and n-butyl. In one embodiment of the invention the dialkylmalonate is diethyhnalonate.

The reaction of step (a) may be conducted in a suitable solvent. Examples of suitable solvents include hydrocarbon solvents such as toluene, and ethers such as tetrahydrofuran.

As will be understood by those skilled in the art, the optimal temperature for conducting reaction (a) will vary depending on the specific reagents used, however, in general the reaction may conveniently be conducted at temperatures ranging from O ⁰ C to the reflux temperature of the reaction solvent, e.g. from 0 ⁰ C to 100 ⁰ C, or from 20 to 7O ⁰ C. Similarly, the quantities of reagents may vary depending on the specific reagents and conditions used, however, good results are achieved when the molar ratio of dialkylmalonate and base to 2,6-dichloropyrazine is at least 2:1. On completion of the reaction the 2-(6-chloro-pyrazin- 2-yl)-malonic acid dialkyl ester (II) can either be used in situ or isolated for subsequent use using standard techniques. 2,6-Dichloropyrazine and dialkylmalonates such as diethylmalonate are commercially available.

In step (b) the 2-(6-chloro-pyrazin-2-yl)-malonic acid dialkyl ester (II) is converted into 6-chloro-pyrazin-2-yl-acetic acid (III). This conversion may be achieved using standard chemistry for saponification and decarboxylation reactions, for example by firstly treating 2-(6-chloro-pyrazin-2-yl)-malonic acid dialkyl ester (II) with a base such as sodium hydroxide to form the corresponding diacid [2-(6-chloro-pyrazin-2-yl)-malonic acid], and subsequently treating the diacid with an acid such as hydrochloric acid to facilitate decarboxylation and form 6-chloro-pyrazin-2-yl~acetic acid (III). On completion of the reaction the 6-chloro-pyrazin-2-yl-acetic acid (III) can be isolated using standard techniques. Conveniently the saponification may conducted at a temperature of from O ⁰ C to 30 ⁰ C, and the decarboxylation of from O ⁰ C to 30 ⁰ C.

In step (c) 6-chloro-pyrazin-2-yl-acetic acid is reacted with ammonia to yield 6- methyl-pyrazin-2-ylamine. The reaction may conveniently be conducted in a sealed vessel using aqueous ammonia and the reaction heated to a temperature in the range of 50 to 250 ⁰ C, and a pressure in the range of 2 to 50 bar (200 to 500OkPa). In an embodiment of the invention the temperature of the reaction is in the range of 100 to 200 ⁰ C. In another embodiment of the invention the pressure is in the range of 20 to 40 bar (2000 to 400OkPa). On completion of the reaction 6-methyl-pyrazin-2-ylamine may be isolated using standard techniques.

The present invention provides an efficient preparation of 6-methyl-pyrazin-2- ylamine. In particular, 6-chloro-pyrazin~2-yl-acetic acid (III), which is itself a novel material, is a stable and readily manipulated solid that can be converted into 6-methyl- pyrazin-2-ylamine in a single step, with the decarboxylation and substitution of chloride with amino being enacted by reaction with ammonia.

In a further aspect the present invention provides a process of preparing 6-methyl- pyrazin-2-ylamine, which comprises reacting 6-chloro-pyrazin-2-yl-acetic acid with ammonia.

In a further aspect the invention provides the novel compound 6-chloro-pyrazin-2-yl- acetic acid.

The invention will now be further explained with reference to the following illustrative examples. In the examples the NMR spectra were measured on a Varian Unity spectrometer at a proton frequency of either 300 or 400 MHz. The MS spectra were collected using Liquid chromatography mass spectrometry and were recorded by a Waters 2790 HPLC, 996 Photo Diode Array Detector and MicroMass ZMD single quadrupole mass spectrometer with Z-spray interface using electrospray ionisation with Pos/Neg switching, the HPLC method used was common to the purity method outlined below. HPLC purity determination was performed using a MetaChem Polaris Cl 8 (50mm x 2mm) column. Mobile phase A 0.03% aqueous trifluoroacetic acid; Mobile phase B 0.02% trifluoroacetic acid in acetonitrile. A gradient method of : Omins 0% B, 5mins 95% B,

7.5mins 95% B was used, with a detector wavelength of 210nm. GC/MS (EI) analysis was performed on a Hewlett Packard HP 6890 GC-system with a Hewlett Packard 5973 mass selective detector.

Preparation of 6-methyl-2-pyrazin-2-ylamine To a suspension of sodium hydride [60% dispersion in mineral oil] (11.2g,) in THF

(60ml) at O ⁰ C was added, diethylmalonate (2.1moleq) in THF (60ml) and 2,6- dichloropyrazine (2Og) in THF (40ml). The mixture was then heated to reflux for 18hrs before being allowed to cool and 2M Hydrochloric acid (100ml) added. The resulting two layers were separated and the THF layer partially concentrated under vacuum to give a solution containing 2-(6-chloro-pyrazin-2-yl)-malonic acid diethyl ester. This solution was

then cooled to 10 ⁰ C and 2M sodium hydroxide (328ml) added. After stirring for 24hrs the mixture was washed with methyl isobutyl ketone [MIBK] (200ml) and the organic layer discarded. The aqueous layer containing 2-(6-chloro-pyrazin-2-yl)-malonic acid was then added to 6M hydrochloric acid (135ml), maintaining a reaction temperature of 20-25°C to facilitate the decarboxylation.

The resulting 6-chloro-pyrazin-2-yl-acetic acid partially precipitated from the mixture, but for ease of isolation was extracted into MIBK (130ml), dried using MgSO ₄ , filtered and evaporated to give a yellow solid. The resulting crude solid 22.4g was then crystallised from methyl-t-butyl ether (MTBE) to give pure 6-chloro-pyrazin-2-yl-acetic acid , 15.4g 67% yield based on 2,6-dichlorpyrazine.

The 6-chloro-pyrazin-2-yl-acetic acid (20.Og) was then treated with aqueous ammonia (120ml) in a sealed vessel at 180°C (35 bar) for 8hrs. The mixture was then cooled to 20°C and water (40ml) added, before being concentrated under vacuum to remove the ammonia. The product was extracted into ethyl acetate and the solution treated with charcoal, before being dried using MgSO ₄ , filtered and evaporated to give 6-methyl-2-pyrazin-2-ylamine as a pale green solid 9.Og, 71% yield based on 6-chloro-pyrazin-2-yl-acetic acid. Analysis 2-(6-Chloro-pyrazin-2-yl)-malonic acid diethyl ester

MS (EI +ve) 273/275 (M+H) IH NMR (CDCl ₃ ) :δ 8.7 (IHs), 8.5 (IHs), 4.9 (IHs), 4.2(2x2Hq), 1.2 (2x3Ht).

6- Chloro-pyrazin-l-yl-acetic acid

MS (EI +ve) 173/175 (M+H)

IHNMR (CDCl ₃ ) :δ 8.55 (IH s), 8.50 (IH s); 3.9 (2Hs).

6-Methyl-2-pyrazin-2-ylamine MS (GC/MS) : 100% RT 2.0mins, M+H = 110

IHNMR (CDC13) : δ 7.8 (IHs), 7.8 (IHs), 4.4 (2H bs), 2.4 (3Hs). Mpt : 124-125 ⁰ C