Preparation of ketorolac

Details Preparation of ketorolac Preparation of ketorolac

1999-12-13

2001-03-06

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S537000, C548S539000

Reexamination Certificate

active

06197976

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to the preparation of ketorolac and its pharmaceutically acceptable salts, especially the tromethamine 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
+
, 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.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
“Alkanol” means C
1-4
alcohols such as methanol, ethanol, propanol, isopropanol or butanol. A preferred alkanol is methanol.
“Alkyl” means a straight, branched, or cyclic saturated monovalent hydrocarbon radical having from one to eight carbon atoms, e.g. methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, and the like. “Lower alkyl” means C
1-4
alkyl. “Lower alkoxy” means—OR where R is lower alkyl.
“Grignard solvent” means a solvent suitable for the formation of Grignard reagents or their reaction with other reagents. “Grignard solvent” includes ethers such as tetrahydrofuran and diethylene glycol dibutyl ether (butyl diglyme), which may be used as sole solvents, especially in the formation of the pyrrole Grignard reagent of formula 1, and mixtures of such suitable sole solvents, especially tetrahydrofuran, with aprotic cosolvents such as hydrocarbon solvents, e.g. toluene, or polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidinone (NMP), tetramethylethylenediamine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMEU), or ethylene glycol diethers, e.g. 1,2-dimethoxyethane (glyme), diethylene glycol dimethyl ether (diglyme), diethylene glycol diethyl ether, triethylene glycol dimethyl ether (triglyme), tetraethylene glycol dimethyl ether (tetraglyme), which may be used either in the formation of the pyrrole Grignard reagent of formula 1 or, especially, in the formation of the pyrrolylbutanamide of formula 2. Butyl diglyme may be used as a sole solvent in the formation of the pyrrole Grignard reagent and used without addition of aprotic polar cosolvents in the formation of the pyrrolylbutanamide. A preferred cosolvent for tetrahydrofuran is diglyme.
“Hydrocarbon solvent” means aliphatic or aromatic hydrocarbon solvents such as hexane, cyclohexane, toluene, and the like.
“Optionally substituted phenyl” means phenyl optionally substituted with one to three lower alkyl, lower alkoxy, nitro, fluoro, chloro, bromo, or trifluoromethyl substituents.
“Organic solvent” includes the hydrocarbon solvents mentioned above and also includes esters such as ethyl acetate and the like, chlorinated hydrocarbons such as dichloromethane and the like, and the polar aprotic solvents mentioned above.
“Strong base” refers to bases such as alkali metal hydroxides, lower alkoxides, and the like, especially the alkali metal hydroxides.
When a solvent is described as being of a particular type, such as a “Grignard solvent”, the term includes not only a “Grignard solvent” as defined, but in addition solvent mixtures containing a Grignard solvent and minor proportions of other solvents (e.g. hydrocarbon solvents), provided that the solvent properties are primarily determined by the type of solvent named.
Starting Materials and Purification
The starting pyrrole and the compounds of formula 2, 3, 4, and 6 may be isolated and purified, if desired, or may be carried into the next reaction step by removing the solvent, using conventional techniques including but not limited to filtration, distillation, crystallization, chromatography, and the like. The compounds may be characterized using conventional means, including physical constants and spectral characteristics. The product ketorolac and its pharmaceutically acceptable salts may be isolated, purified, and characterized similarly. Compounds 2. The N-alkyl-N-aryl-2-bromo-4-chlorobutanamides of formula 2 may be prepared by methods known to the art. See, for example, West German Patent No. 804 567 (BASF), for the preparation of 2-bromo-4-chlorobutanoyl chloride from &agr;-bromo-&ggr;-butyrolactone. 2-Bromo-4-chlorobutanoyl bromide may be prepared by the bromination of 4-chlorobutanoyl chloride with bromine, as shown in the Example. See also U.S. Pat. No. 4,874,871, referred to previously, for the preparation of the butanamides from the butanoyl halides.
An N-alkyl-arylamine is treated with a 2-bromo-4-chlorobutanoyl halide in the presence of a tertiary amine base such as a trialkylamine and an organic solvent such as toluene. The reaction temperature is maintained at about 10° C. to 80° C. while the addition is allowed to proceed to completion in about 10 minutes to 10 hours. The resulting dihalobutanamide (2) may be isolated by conventional techniques, such as addition of water and acidification of the solution with mineral acid, e.g. hydrochloric acid, separation of the organic and aqueous layers, and evaporation of the solvent; and is used either w

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