Solution phase synthesis, 21-amino

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

In general, solid-phase synthesis, rather than solution-phase synthesis, can be the preferred method for the generation of combinatorial libraries because of the greater abihty to automate a solid-phase protocol, primarily due to the use of excess reagents in solution to effect cleaner reactions and to the ease of workup by simple filtration. The solid-phase method of peptide synthesis has had many notable successes. However, the preparation of peptides containing more than 20 amino acids in length using the solid-phase technique often causes major problems in that very extensive purification of the final product is needed. 

P-amino acids for solid-phase SwAr reactions5,6 and (ii) an efficient solution-phase synthesis to augment the number of P-amino acid esters available.7... 

Catalytic hydrogenation of peptides containing a Phe(4-N02) residue, to be subsequently converted into Phe(4-N3), that also contain cystine and/or methionine residues, requires extended reaction times. This may lead to desulfuration. Therefore, a Phe(4-NH2) residue is used as a precursor for Phe(4-N3) in the synthesis of AVP to give Phe(4-N3) residues at either position 2 or 3.1281 In this solution-phase synthesis, the 4-amino group in the 4-amino-... 

Solution-Phase Synthesis of Peptides Based on 2-Amino-2-deoxy-l-0-methyl- -D-... 

A library of di- and trisubstituted 5-amino-l 77-1-benzazepine derivatives was assembled through attachment of a preformed 1-benzazepine unit to an aminomethylated polystyrene resin. The initial solution phase synthesis of the 1-benzazepine moiety was based on an intramolecular Dieckmann cyclization (type d) followed by a ketone to primary amino group transformation via reduction ( NaBH3CN) of an imine intermediate <2007JC0487>. 

The synthesis of proline-fused heterocyclic systems by 1,3-dipolar cycloaddition has been well-established in solution-phase synthesis (Scheme 14) [42]. It is usually performed as a one-pot, three-component reaction of a dipo-larophile with an in situ prepared azomethine ylide. Perfluoroalkanesulfonyl protected hydroxybenzaldehydes [43] or fluorous alcohol protected amino esters [44] have been developed as two different fluorous components for the synthesis of proline derivatives 11 and 12. 

Chng BL, Ganesan A, Solution-phase synthesis of a beta-amino alcohol combinatorial library, Bioorg. Med. Chem. Lett., 7 511-514, 1998. 

Organ MG, Dixon CE, The preparation of amino-substituted biaryl libraries the application of solid-supported reagents to streamline solution-phase synthesis, Biotechnol. Bioeng., 71 71-77, 2000. 

The solid-phase synthesis is carried out in the direction opposite that of the solution-phase synthesis. The first step is attachment of the N-protected C-terminal amino acid (Boc-phenylalanine) to the polymer. 

The commercially available 3-amino-1,2,4-dithiazole-5-one, (3), has been attached to a hydroxyl resin via a succinic acid linker, and has been used as an efficient sulfur-transfer reagent for the solution-phase synthesis of phos-phorothioates. DNA synthesis scale-up to lOOg of a 20-mer phosphorothioate has been examined " key to this was the purification of the product, which was carried out using a high efficiency polymeric anion exchange chromatographic media. 

An efficient one-pot protocol has been developed for the solution-phase synthesis of thiohydantoins (Scheme 4) [10]. After reductive alkylation of amino acid esters 16, the isothiocyanate was added together with triethylamine, leading to thiohydantoin products 18. The work-up procedure was performed by adding gly-... 

For the parallel synthesis of ureas based on amino acids, a solid-phase synthesis as well as a solution-phase synthesis were used (Scheme 5) [11]. Solution-phase synthesis gave the desired compounds 21 in yields ranging from 80-100% and purities in the range 71-97%. The work-up involved extraction of the benzotriazole formed in the coupling steps. An aqueous borax buffer (pH 9.2) was used and the separation of the CH2CI2 layer from the aqueous phase was performed in cartridges equipped with a PTFE frit. 

Like conventional solid supports, soluble polymers may have a potential to function as scavengers in solution-phase synthesis. The approach has been applied to the synthesis of p-amino alcohols that are structurally related to propranolol. The crude products (prepared from the corresponding epoxides and amines) and an added PEG-bound borohy-dride reagent formed a complex which was precipitated and separated from unreacted starting materials and unwanted by-products. Cleavage with HC1 in MeOH/DCM and precipitation of the polymer gave a solution of pure (>92%) p-amino alcohols [75]. 

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