Process for preparing a pharmaceutically active compound
View Patent ↗In particular, rizatriptan or a pharmaceutically acceptable salt thereof, which includes a) Preparation of the diazonium salt of aniline hydrochloride (II); followed by reduction and acidification to give the hydrazine (III); b) reaction in situ of the hydrazine hydrochloride (III) with α-keto-δ-valerolactone, to give the hydrazone (IV); c) Fischer indole reaction of the hydrazone (IV), to give the pyranoindolone (V), optionally followed by a hydrolysis reaction to give (VI); d) Transesterification of (V) or esterification of its hydrolysis product (VI), to give (VII), where R means straight or branched C1-C4 alkyl chain; e) Conversion of the hydroxyl group of (VII) into dimethylamino, to give the indolecarboxylate (VIII), where R has the meaning defined above; f) Saponification of the 2-carboalkoxy group of (VIII) to give indolecarboxylic acid (IX); and g) Decarboxylaton of the indolecarboxylic acid (IX) to give rizatriptan and, eventually, to obtain a pharmaceutically acceptable salt thereof. The invention also relates to synthesis intermediates to obtain rizatriptan.
1. Process for preparing a pharmaceutically active compound, rizatriptan, or a pharmaceutically acceptable salt thereof, which comprises the following steps:
a) Preparation of the diazonium salt of the aniline hydrochloride of formula (II)
followed by reduction and acidification to give the hydrazine of formula (III):
b) In situ reaction of the hydrazine hydrochloride of formula (III) with α-keto-δ-valerolactone, to give the hydrazone of formula (IV):
c) Fischer indole reaction of the hydrazone of formula (IV), to give the pyranoindolone of formula (V):
followed optionally by hydrolysis to give the product of formula (VI):
d) Transesterification of the compound of formula (V) or esterification of its hydrolysis product of formula (VI), to give a compound of formula (VII):
where R represents a straight or branched C1-C4 alkyl chain;
e) conversion of the hydroxyl group of the compound of formula (VII) into dimethylamino, to give the indolecarboxylate of formula (VIII):
where R has the same meaning as defined above;
f) Saponification of the 2-carboalkoxy group of the compound of formula (VIII), to give the indolecarboxylic acid of formula (IX):
g) Decarboxylation of the indolecarboxylic acid of formula (IX), to give rizatriptan, and
eventually, the preparation of a pharmaceutically acceptable salt thereof.
2. Process according to claim 1 , wherein in step c) the indolisation is carried out in a solution of dry hydrogen chloride in a straight or branch C1-C4 alcohol chain.
3. Process according to claim 1 , wherein steps a), b) and c) are carried out as a one pot reaction.
4. Process according to claim 1 , wherein step c) is carried out in aqueous acid medium and is followed by a hydrolysis reaction to give the product of formula (VI).
5. Process according to claim 1 , wherein step e) is carried out in two steps:
e-i) substitution of the hydroxyl group of the compound of formula (VII) by a leaving group X; and
e-ii) subsequent substitution reaction of the leaving group X with dimethylamine to give the compound of formula (VIII).
6. Process according to claim 5 , wherein the leaving group X is selected from a halogen atom, a mesylate group or a tosylate group.
7. Process according to claim 1 , wherein step d) is carried out in an alcoholic solution and in the presence of an acid.
8. Process according to claim 1 , wherein a Synthesis intermediate of formula (IV):
9. Process according to claim 1 , wherein a Synthesis intermediate of formula (V):
10. Process according to claim 1 , wherein a Synthesis intermediate of formula (VI):
11. Process according to claim 1 , wherein a Synthesis intermediate of formula (VII):
where R represents a straight or branched C1-C4 alkyl chain.
12. Process according to claim 1 , wherein a Synthesis intermediate of formula (VIII):
where R represents a straight or branched C1-C4 alkyl chain.
13. Process according to claim 1 , wherein a Synthesis intermediate of formula (IX):