Isolation and purification of 6-aminocaproic acid
The present invention relates to a new process for the isolation and purification of 6-aminocaproic acid, which is a known inhibitor of enzymes responsible for fibrinolysis and is used in the treatment of coagulopathies and severe post-operative bleedings.
1. A process for preparing 6-aminocaproic acid of formula (I),
comprising
mixing an addition salt of 6-aminocaproic acid of formula (Ia) with a protic acid and a solvent to produce a mixture,
wherein HX is a protic acid,
adding an organic base to said mixture to convert said addition salt of 6-aminocaproic acid into 6-aminocaproic acid of formula (I) and
recovering the 6-aminocaproic acid of formula (I) from said mixture by crystallization.
2. The process of claim 1 , wherein the addition salt of formula (Ia) is a pharmaceutically acceptable salt, in crystalline or amorphous, solvate or hydrate form.
3. The process of claim 1 , wherein the protic acid of formula HX is a mineral acid selected from the group consisting of sulfuric acid, phosphoric acid and a hydrohalic acid; or an organic acid selected from the group consisting of a sulfonic acid; an aryl carboxylic acid, and a C 1 -C 4 alkyl-carboxylic acid, wherein the C 1 -C 4 alkyl group is straight or branched, and is unsubstituted or substituted by one to three chloro or fluoro atoms.
4. The process of claim 1 , wherein the protic acid is hydrochloric acid.
5. The process of claim 1 , wherein the addition salt of 6-aminocaproic acid of formula (Ia) with a protic acid is prepared by:
1) adding a protic acid of formula HX, to a mixture of 6-aminocaproic acid of formula (I) in a solvent; or
2) reacting a precursor of the 6-aminocaproic acid in the presence of a protic acid of formula HX and a solvent.
6. The process of claim 5 , wherein the precursor of a 6-aminocaproic acid is caprolactam of formula (II)
7. The process of claim 5 , wherein the salt of formula (Ia), is further re-crystallized, optionally using a seed crystal previously obtained.
8. The process of claim 1 , wherein the organic base is a nitrogen containing organic base.
9. The process of claim 8 , wherein the base is ammonia or a primary, secondary or tertiary amine.
10. The process of claim 8 , wherein the base is triethylamine or tributylamine.
11. The process of claim 8 , wherein the base is used in about stoichiometric amounts or in excess with respect to the moles of 6-aminocaproic salt of formula (Ia) to be unblocked.
12. The process of claim 8 , wherein the base is added to the mixture of the 6-aminocaproic salt of formula (Ia) as such or dissolved (diluted) in a solvent.
13. The process of claim 1 , wherein the solvent is selected from the group consisting of a polar aprotic solvent; an ethereal solvent; a ketone; an apolar aprotic solvent; a polar protic solvent; water; and a mixture of two or three of said solvents.
14. The process of claim 13 , wherein the solvent is selected from methanol and acetonitrile.
15. The process of claim 1 , wherein the recovering of 6-aminocaproic acid of formula (I) from the mixture is performed by crystallization followed by filtration and/or centrifugation.