Solid phase peptide synthesis reaction vessel

Details Solid phase peptide synthesis reaction vessel Solid phase peptide synthesis reaction vessel

1999-07-29

2001-11-20

Tran, Hien (Department: 1764)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Synthesis of peptides

C422S130000, C422S131000

Reexamination Certificate

active

06320025

ABSTRACT:

FIELD OF THE INVENTION
The field of the invention is a solid phase peptide synthesis reaction vessel.
BACKGROUND OF THE INVENTION
Large scale solid phase peptide synthesis requires consideration of a number of reactor design issues. The resin used is usually a gel resin with a low degree of cross-linking which swells in certain solvents (such as DCM), and shrinks in others (such as methanol). The resin volume tends also to increase with the growth of the peptide chain length. In addition, the resins tend to be fairly soft, and sensitive to physical attrition. Furthermore, the amount of exposure time between the peptide-resin and the solvents and reactants used in the synthesis is often critical. Deprotection of the resin-bound peptide must be complete in order to obtain the highest yield, but the resulting carbocations must not remain in contact with the peptide because of undesirable side-reactions that may occur. Unfortunately, the time required to drain the solution from a resin slurry suspension increases with the depth of the resin bed formed during filtration. Consequently, exposure time of resin-bound peptide to carbocations increases as bed depth increases. As a result, the filtration times for kilogram-scale reactions are far longer than those encountered in bench-scale reactions, so the risk of damage to the peptides due to reactions with carbocations increases with batch size. Larger scale reactors must therefore be designed in such a way as to minimize the filtration time.
Several attempts have been made to overcome the constraints imposed by the resins with tube reactor designs: Verlunder, et al., U.S. Pat. No. 4,192,798 (an industrial-scale HPLC type of reactor); Baru, et al., WO88/909010.6, SU 4117080 (a zero dead volume reactor in which one end of the reactor was allowed to float with the resin); Atherton, et al., JCS Chemical Communications, p. 1151 [1981] (a rigid polymer with macropores); Lapluye and Poisson WO 92/115867 (piston-type reactor with fritted ends); Birr, German Patent No. 2,017,351 and Stepaniuk et al. WO98/34633 (“washing machine” type reactors); and Anderson and Anderson, U.S. Pat. No. 5,186,824 (a centrifugal flooded “hollow rotor” reactor).
SUMMARY OF THE INVENTION
The invention provides methods and device for containing, reacting and filtering solid phase polymer synthesis resins. We disclose reaction vessel filtration systems that avoid both long and variable drain times and exorbitant costs often associated with scaling up solid phase peptide synthesis. The two main limitations to the speed of liquid removal in solid phase polymer syntheses are the surface area of the filters and the bed height of the resin (resin bed height or RBH). By using a tubular filtration system the filter surface area can be increased up to 10 fold over a flat filter and the RBH will not change significantly throughout the peptide synthesis. Thus extremely fast and uniform filtration can be achieved at a relatively low reaction vessel cost.
The subject reaction vessels generally comprise: a housing defining a chamber for containing a resin, said housing having an operable inlet port and an operable outlet port in fluid communication with said chamber; and an elongate resin filter having an interior bore, and adapted to enable filtered fluid flow from an exterior inlet surface thereof into the filter interior bore, said filter being disposed in said chamber and having an outlet connection fluidly coupling said filter interior bore to the housing outlet port such that fluid flowing through the housing inlet port into the chamber passes through the filter inlet surface, into the filter interior bore and out the housing outlet port; wherein said reaction vessel is suitable for solid phase polymer synthesis.
In more particular embodiments, the filter is cylindrical in shape; the vessel further comprises a hollow core filter holder within the housing and the filter is sheathed over the filter holder, wherein the filter comprises a closed end opposite the outlet connection, said closed end may be closed by a cap, and/or said holder secured to the housing by a threaded connection; the vessel further comprises means for functionally securing one or more of said filters to said housing; the chamber contains a solid phase polymer synthesis resin, which may comprise one or more bound amino acids, etc.
The invention provides methods of using the subject reaction vessels in polymer syntheses generally comprising constructing polymers in such vessels and isolating resultant polymers.


REFERENCES:
patent: 4192798 (1980-03-01), Verlander et al.
patent: 4242461 (1980-12-01), Bartoli et al.
patent: 4283289 (1981-08-01), Meyst et al.

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