Automated allyl deprotection in solid-phase synthesis

• US 5,861,351 A
• Filed: 09/20/1996
• Issued: 01/19/1999
• Est. Priority Date: 04/05/1993
• Status: Expired due to Term

• Current Assignee: Perseptive Biosystems Incorporated (Ecovyst, Inc.)
• Original Assignee: Perseptive Biosystems Incorporated (Ecovyst, Inc.)
• Inventors: Albericio, Fernando, Kates, Steven A.
• Primary Examiner(s): Caldarola, Glenn
• Assistant Examiner(s): GRIFFIN, WALTER DEAN
• Application Number:
  US08/717,208
• Time in Patent Office: 851 Days
• Field of Search: 502/150, 502/152, 502/155
• US Class Current: 502/150
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00286 Reactor vessels with top and bottom openings
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00686 Automatic
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: B01J 2231/60 Reduction reactions, e.g. hydrogenation
• CPC Class Codes: B01J 23/44 Palladium
• CPC Class Codes: B01J 2531/824 Palladium
• CPC Class Codes: B01J 31/0237 Amines
• CPC Class Codes: B01J 31/04 containing carboxylic acids or their salts B01J31/0277 - B01J31/0298 take precedence; multi-metal carboxylate complexes like Pd (II) acetate, i.e. Pd3 (OAc) 6 or Cr(II)acetate, i.e. Cr2(OAc)4 B01J31/2226
• CPC Class Codes: B01J 31/2404 Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
• CPC Class Codes: C07K 1/12 by hydrolysis , i.e. solvolysis in general
• CPC Class Codes: C07K 1/122 Hydrolysis with acids different from HF
• CPC Class Codes: C40B 40/10 Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A method for removing an allyl protecting group from an allyl-protected derivative of a biologically relevant amino acid is disclosed. One relevant aspect of the method is the use of soluble organometallic catalyst, such as an organopalladium catalyst. Preferably, soluble tetrakistriphenylphosphine palladium (0) is used. The allyl deprotection method now disclosed is suitable for use on an instrument for automated peptide synthesis. Methods of preparing the soluble organometallic catalyst are also disclosed, as are soluble catalyst compositions.

Claims

1. A composition for the removal of allyl protecting groups from an allyl-protected derivative, formed by:

providing inert atmosphere; and

mixing a solvent, a carboxylic acid;

a radical scavenger, and an organopalladium compound, thereby forming a single-phase solution;

wherein said composition is suitable for the selective removal of said allyl protecting groups in the presence of other orthogonal protecting groups on said derivative.

2. The composition of claim 1 wherein the organopalladium compound is an organopalladium (0) compound.

3. The composition of claim 2 wherein the organopalladium compound is tetrakistriphenyl-phosphine palladium (0).

4. The composition of claim 1 wherein the solvent is selected from the group consisting of chloroform, methylene chloride and benzene.

5. The composition of claim 1 wherein the carboxylic acid is selected from the group consisting of formic acid, acetic acid and propionic acid.

6. The composition of claim 1 wherein the organopalladium compound is tetrakistripheinyl-phosphine palladium (0), the solvent is chloroform, the carboxylic acid is acetic acid and the radical scavenger is N-methylmorpholine.

7. The composition of claim 6 wherein said chloroform solvent contains about 5% acetic acid and about 2.5% N methylmorpholine.

8. The composition of claim 1 wherein the radical scavenger is an allyl radical scavenger.

9. The composition of claim 8 wherein the allyl radical scavenger is selected from the group consisting of dimedone, N-methylaniline, N,N'"'"'-dimethylbarituric acid, morpholine and N-methylmorpholine.