Process for the preparation of pyrazine compounds

Details Process for the preparation of pyrazine compounds Process for the preparation of pyrazine compounds

2002-11-05

2004-10-12

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C564S246000

Reexamination Certificate

active

06803464

ABSTRACT:

The present invention relates to a process for the preparation of both the phenyl pyrazine derivative 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine and an intermediate in the synthesis of 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine, 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine or a salt thereof.
International patent application no. PCT/EP98/01077, publication no. WO 98/38174, discloses a class of phenyl pyrazine derivatives including 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine and pharmaceutically acceptable derivatives thereof, their use in treatment of certain CNS disorders and processes for their preparation. In particular, WO 98/38174 describes a process for producing 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine which comprises the addition of potassium cyanide to a mixture of aminoacetamidine dihydrobromide and 2,3,5-trichlorobenzaldehyde in methanol to yield the intermediate 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine hydrobromide. The intermediate 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine hydrobromide is reacted with lithium hydroxide in methanol to yield 2,6-diamino-3-(2,3,5-trichlorophenyl) pyrazine.
The process described in WO 98/38174 has a number of disadvantages. Specifically, the reaction is characterised by poor yields, a problem which is exacerbated by the fact that the 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine hydrobromide is unstable to the basic conditions which exist towards the end of the reaction.
We have now surprisingly found that by careful control of the reaction conditions and by judicious choice of the order of addition of the reactants the above mentioned disadvantages may be alleviated. In particular, we have found that by mixing a cyanide source with an acid salt of aminoacetamidine before addition of 2,3,5-trichlorobenzaldehyde to the reaction mixture the yield of the reaction is increased.
Accordingly, the present invention provides a process for the preparation of 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamide or a salt thereof which process comprises the steps of:
(i) reaction of an acid salt of aminoacetamidine with a source of cyanide; and
(ii) reaction of the product of step (i) with 2,3,5-trichlorobenzaldehyde.
Without wishing to be bound by theory, it is thought that in the prior art process the acidity of the initial reaction mixture, caused by the presence of the acid associated with the aminoacetamidine, leads to irreversible formation of acetals and hemiacetals from 2,3,5-trichlorobenzaldehyde. However, in the process of the present invention it is believed that the cyanide source reacts with the acid salt of the aminoacetamidine to form an aminoacetamidine mono acid mono hydrocyanide salt thereby reducing the acidity of the solution and thus reducing the tendency of the 2,3,5-trichlorobenzaldehyde to form acetals and hemiacetals. Moreover, because the cyanide source exists as a hydrocyanide salt of aminoacetamidine the reaction mixture is less basic at the end of the reaction and consequently the 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine is more stable in the product mixture.
The process of the present invention leads to an increase in yield of about 35% compared with the process described in the prior art.
The reaction may be effected in any suitable solvent or mixture of solvents. Preferably the solvent is a polar solvent such as an alcohol, e.g. methanol, ethanol, isopropyl alcohol, or dimethylformamide. Methanol is most preferred.
The process may be effected at any suitable temperature. Suitably, reaction step (i) is conducted at room temperature and reaction step (ii) is conducted at elevated temperature, preferably at about 50° C.
It will be appreciated that the relative amounts of aminoacetamidine, cyanide; and 2,3,5-trichlorobenzaldehyde may be varied. Preferably the aminoacetamidine or 2,3,5-trichlorobenzaldehyde is in excess, most preferably the aminoacetamidine is in excess.
Suitable sources of cyanide include potassium cyanide, sodium cyanide, tetrabutylammonium cyanide, preferably, potassium cyanide.
It will be appreciated that any suitable acid salt of aminoacetamidine may be used in the reaction. Examples of suitable acid salts include inorganic acid salts such as hydrochloric and hydrobromic acid, and organic acid salts such as maleic and formic acid.
2,3,5-trichlorobenzaldehyde may be prepared according to the methods described in WO95/07877.
Aminoacetamidine, may be prepared according to known procedures, for example, those described in Chem. Berichte, 89, 1185 (1956).
2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine or a salt thereof is particularly useful as an intermediate in the synthesis of 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine.
Accordingly, in a further aspect, the present invention provides a process for the preparation of 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine or a pharmaceutically acceptable derivative thereof which process. comprises the steps of:
(i) reaction of an acid addition salt of aminoacetamidine with a source of cyanide;
(ii) reaction of the product of step (i) with 2,3,5-trichlorobenzaldehyde to afford 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine or a salt thereof; and
(iii) cyclisation and oxidation of 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine or a salt thereof.
Suitable conditions for the cyclisation and oxidation of 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine or a salt thereof (step(iii)) are well known in the literature. For example the reaction may be effected by neutralising a salt of a compound of 2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine, e.g. with lithium hydroxide in a suitable solvent such as an alcohol, e.g. methanol, under which conditions spontaneous oxidation to 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine occurs.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine or an active metabolite or residue thereof (e.g. a prodrug). Suitable prodrugs are well-known in the art and include N-acyl derivatives, for example at any of the nitrogen atoms in 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine, for example simple acyl derivatives such as acetyl, propionyl and the like or groups such as R—O—CH
2
-nitrogen or R—O—C(O)-nitrogen.


REFERENCES:
patent: 98/38174 (1998-09-01), None
patent: 00/12488 (2000-03-01), None
Lakhan, R. et al., “Novel Synthesis of Heterocycles from Chi-oxonitriles; Part III. 2-Amino-3-Arylpyrazines,”Sythesis, DE, Gerog Thieme Verlag, Stutgart, vol. 10. pp. 914-915 (Oct. 1, 1987).

Affiliated with

Also associated with

Rating

Process for the preparation of pyrazine compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of pyrazine compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of pyrazine compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3279791