Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-02
2001-08-07
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S134000
Reexamination Certificate
active
06271394
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,017,513 describes resin-mediated (i.e., Dowex 50WX8 cation-exchange resin) synthesis of optically pure amino acid amides. These resin-based methods for amino acid amide synthesis comprise (a) esterification of an amino acid with methanol and (b) reaction of the ester with ammonia to form the amide (FIG.
1
). Most amino acids are unreactive in polar solvents such as methanol because of zwitterion formation, but amino acid adsorption on a cation-exchange resin with, e.g., sulfonic acid groups, activates the amino acid molecules to esterification and subsequent amidation.
In the esterification reaction, the ion-exchange resin does not act as a catalyst because the ester remains adsorbed to the resin. Consequently, stoichiometric amounts of acid sites are required for complete amino acid esterification.
The process described in U.S. Pat. No. 4,017,513 is carried out in vessel containing an agitated slurry of resin particles with which the reactants are admixed. Ammonia is introduced as a vapor into the headspace of the reaction vessel, and is absorbed into the reaction slurry. Considerable resin attrition occurs in such a process due to the high agitation rates that are required to suspend the resin and contact it thoroughly with the reactants. Such agitation results in mechanical degradation of resin, i.e., the production of fine resin particles. The fine resin particles slow processing significantly because filtration of slurries containing fine solids is very slow. Further, fine particles are likely to increase the surface tension of the slurry and decrease the rate of ammonia absorption into the slurry, resulting in a slow amidation reaction. Thus, when practicing a process that requires filtration, either of final product or of some reaction intermediate, the production of fine particles should be avoided. Suspension of large amounts of dense resin particles with minimal attrition is particularly difficult in pilot-plant or production-scale reaction vessels. Thus, there is a need in the art for methods for the synthesis of amino acid amides using cation exchange resins which do not suffer from the problems associated with fine particle formation due to agitation of resin.
SUMMARY OF THE INVENTION
The present inventors have discovered a method for the synthesis of amino acid amides utilizing cation exchange resins that does not suffer from the problems associated with the filtration of cation exchange resin from reaction products and fine resin particle formation.
In one aspect, the invention relates to a method for the synthesis of amino acid amides which comprises providing a fixed bed of a cation exchange resin, admixing a primary alcohol and an amino acid in a reaction vessel in fluid communication with the fixed bed to form a first mixture, contacting the fixed bed of cation exchange resin with the first mixture for a period of time, thereby causing amino acid ester intermediate to be formed on the cation exchange resin, adding liquid ammonia to the reaction vessel, and contacting the fixed bed of cation exchange resin with ammonia, the fixed bed having previously been contacted with the first mixture.
In another aspect, the invention relates to a method for the synthesis of amino acid amides which comprises providing a fixed bed of a cation exchange resin, admixing a primary alcohol and an amino acid in a reaction vessel in fluid communication with the fixed bed to form a first mixture, contacting the fixed bed of cation exchange resin with the first mixture for a period of time, thereby causing amino acid ester intermediate to be formed on the cation exchange resin, adding liquid ammonia to the reaction vessel to form a second mixture, and contacting the fixed bed of cation exchange resin with second mixture, the fixed bed having previously been contacted with the first mixture, which further comprises contacting the fixed bed of cation exchange resin with the first mixture by recirculating the first mixture between the fixed bed and the reaction vessel for period of time sufficient for at least about 50% of the amino acid to be esterified. In another, preferred aspect, the method also comprises contacting the the fixed bed of cation exchange resin with the liquid ammonia-containing second mixture by recirculating the ammonia between the fixed bed and the reaction vessel for a sufficient period of time until at least about 75% of the amino acid ester intermediate is converted into amino acid amide.
In yet another, preferred, aspect of the method of the invention, the cation exchange resin employed in the method is a stirene-divinylbenzene-based sulfonic acid group-containing resin, and the ammonia to amino acid mole ratio is between about 11 and about 30.
In a particularly preferred embodiment, the invention relates to a method for the synthesis of L-prolinamide which comprises providing a fixed bed of a stirene-divinylbenzene-based sulfonic acid group-containing cation exchange resin, admixing methanol and L-proline in a reaction vessel in fluid communication with the fixed bed to form a first mixture, repeatedly contacting the fixed bed of stirene-divinylbenzene-based sulfonic acid group-containing cation exchange resin with the first mixture by recirculating the first mixture between the fixed bed and the reaction vessel for period of time sufficient for between about 60% and about 75% of the L-proline to be esterified to L-proline methyl ester intermediate on the resin, adding liquid ammonia to the reaction vessel to form a second mixture, where the ammonia to L-proline mole ratio is between about 11 and about 25, and repeatedly contacting the the fixed bed of cation exchange resin with the liquid ammonia-containing second mixture by recirculating the second mixture between the fixed bed and the reaction vessel for a sufficient period of time until at least about 95% of the L-proline methyl ester intermediate is converted into L-prolinamide.
REFERENCES:
patent: 4017513 (1977-04-01), Roteman
Girgis Michael John
Shekhar Ratna
Novartis AG
Powers Fiona T.
Wildman David E.
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