Committed to preserving our shared environment – further details available on request.
Can be used in processes in compliance with cGMP standards.
Manufacture of consumables is accredited by the world renowned British Standards Institute.
Flexible supply chains, back up manufacturing and warehousing ensures supply risk reduction
Can be used in processes in compliance with GLP standards.
Products which are scaleable from lab or development to process scale.
Long to indefinite product shelf life, reduced process risk.
Supports pharma guidelines for reducing elemental impurities in APIs.
Further extractable information provided on request.
Raw materials certified free of materials of human or animal origin.
Chemical substances used in our manufacturing process do not require registration.
Able to withstand mechanical stirring and heating under normal reaction conditions.
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Biotage®PS-HOBt(HL) is a sulfonamide-linked, polymer supported equivalent of 1-hydroxybenzotriazole (HOBt). PS-HOBt(HL) is used to generate bound HOBt active esters, which can either be made and used in situ, or isolated and stored as stable intermediates. Treatment of bound HOBt esters with an amine leads to amide formation in generally high purity without the need for further purification.
To date, the recommended procedure for loading PS-HOBt has required PyBroP as the coupling agent. We have developed an improved loading procedure based on the use of diisopropylcarbodiimide and DMAP. The new procedure has proven to be much more reliable, efficient, and cost effective. It requires fewer equivalents of carboxylic acid and does not require a double coupling as is the case when PyBroP is used.
Polymer-supported active esters offer some unique advantages for parallel amide synthesis. The polymer-supported active esters of PS-HOBt(HL) can be prepared using the coupling protocol and purified by solvent washes. Amide formation is accomplished by simply adding the appropriate amine to the active ester resin. By using the amine as the limiting reagent, acylation of the amine generates the amide as the sole compound in solution. Only filtration and concentration are required to isolate the product. A series of solid supported HOBt active esters can be prepared in bulk from PS-HOBt(HL) and split into individual reactors for reaction with amine (Scheme 1).
Depending on the stability of the bound active ester, long-term storage is possible and the resin can be used as required to make amides. The stability of the bound active ester is dependent on the structure of the corresponding acid. The overall transformation is shown in the scheme below
Making PS-HOBt(HL) Active Esters Using DIC/DMAP The solvents and reagents for preparing PS-HOBt(HL) active esters should be dry and care should be taken to avoid contamination by atmospheric moisture. To 150 mg of PS-HOBt(HL) resin (1.0 mmol/g, 0.15 mmol) was added 2 mL of a 0.045 M solution of DMAP in DCM (0.090 mmol) and 0.6 mL of a 0.38 M carboxylic acid solution in DMF (0.23 mmol). The mixture was shaken/ agitated briefly. This was followed by the addition of 0.4 mL of 1.65 M DIC in DCM (0.66 mmol) and the solution was mixed for 3 h at room temperature. The resin was filtered, washed with DMF (3 x 3 mL), DCM (3 x 3 mL), DMF (3 x 3 mL), and THF (3 x 3 mL) and dried to afford purified solid supported HOBt active ester.
To PS-HOBt(HL) active ester resin (0.15 mmol) was added a mixture of amine (0.07 mmol) and DIEA (0.1 mmol) in DCM or THF (2 mL) and the mixture was stirred at 25 °C for 3 h. The resin was filtered, and rinsed with DCM or THF (3 x 3 mL). The combined filtrate was concentrated to afford the desired amide. If the PS-HOBt(HL) active ester resin has been stored for an extended period, it is recommended that it be washed two to three times with DCM or THF prior to use.