Preparation of ketorolac

Details Preparation of ketorolac Preparation of ketorolac

2001-01-01

2001-11-27

Solola, T. A. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S531000, C548S539000

Reexamination Certificate

active

06323344

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to the preparation of ketorolac and its pharmaceutically acceptable salts, especially the trometharnine salt.
U.S. Pat. No. 4,089,969 (to Syntex (U.S.A.) Inc.) discloses various 5-(optionally substituted benzoyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acids, including ketorolac, (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, of formula I,
the tromethamine salt of which is the active ingredient of the anti-inflammatory and analgesic drugs TORADOL® and ACULAR®.
Various methods for the preparation of ketorolac and related pyrrolizine-1-carboxylic acids are exemplified in the patent and chemical literature, and many proceed through a common intermediate, 2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, or its alkyl esters. The alkyl esters may be readily 5-aroylated by methods known to the art, e.g. by Vilsmeier-Haack or Friedel-Crafts aroylations, as described in U.S. Pat. Nos. 4,089,969 and 4,347,186 (also to Syntex (U.S.A.) Inc.), both using dialkylamides; U.S. Pat. No. 4,353,829 (also to Syntex (U.S.A.) Inc.), using morpholides; and in U.S. Pat. No. 4,496,741 (to Merck); and the resulting ester saponified by conventional methods to yield a 5-aroyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid.
U.S. Pat. No. 4,874,871 (also to Syntex (U.S.A.) Inc.) discloses a method of preparing 2,3-dihydro-1H-pyrrolizine-1-carboxylic acid and related compounds from pyrrole in the following manner:
where X and X′ are independently halogen;
Y is —OH; —OM
−
M
+
, wherein M is an alkali metal; or —NRR′ (where R is lower alkyl and R′ is lower alkyl or aryl, or —NRR′ is the residue of a saturated cyclic amine); and
Z is Li, MgCl, or MgBr.
According to U.S. Pat. No. 4,874,871, the (±)-2,3-dihydro-1H-pyrrolizine-1-carboxamides or salts may be hydrolyzed to the corresponding acid and then converted to the corresponding esters by conventional means; and the esters 5-aroylated and hydrolyzed to afford 5-aroyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acids by the methods described in U.S. Pat. Nos. 4,089,969; 4,347,186; and 4,353,829.
The disclosures of these patents, and other patents and articles referred to throughout this specification, are incorporated herein by reference.
SUMMARY OF THE INVENTION
In a first aspect, this invention includes 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxamides of Formula 6,
where R
1
is alkyl; and R
2
is optionally substituted phenyl.
In a second aspect, this invention includes a method of preparing the 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxamides of Formula 6.
In a third aspect, this invention includes a method of preparing ketorolac and its pharmaceutically acceptable salts, comprising preparing 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxamides of Formula 6, followed by hydrolysis, optionally followed by formation of a pharmaceutically acceptable salt.
In a fourth aspect, this invention includes a method of preparing the pyrrolylbutanamides of Formula 3.
In a fifth aspect, this invention includes an improved method of preparing the 2,3-dihydro-1H-pyrrolizine-1-carboxamides of Formula 4.
The preparation may be represented schematically:
where R
1
is alkyl;
R
2
is optionally substituted phenyl;
R
3
is Cl or —NR
4
R
5
(where R
4
and R
5
are independently C
3-8
alkyl, or —NR
4
R
5
is morpholino, piperidino, or pyrrolidino); and
X is Cl or Br.


REFERENCES:
patent: 4089969 (1978-05-01), Muchowski et al.
patent: 4347186 (1982-08-01), Muchowski et al.
patent: 4353829 (1982-10-01), Thurber et al.
patent: 4496741 (1985-01-01), Doherty
patent: 4874871 (1989-10-01), Fleming et al.

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