& Mechanism
Green Chem
& Mechanism
Reaction & Reagents info
- HBTU is Hexafluorophosphate Azaenzotriazole Tetramethyl Uronium
- Uronium salts are useful for the coupling of sterically hindered amino acids in pbeptide synthesis
- When the carboxylic acid contains epimerizable α-stereocenter, 1 eq. of HOAt or HOBt shall be used to suppress epimerization
Disadvantages of Uronium salts:
- The by-product from these uronium salts, namely N,N,N′,N′-tetramethylurea are cytotoxic
- The presence of high energy moiety (Benzotriazole) makes it less attractive for large-scale reactions – Mild reaction conditions should only be maintained
- As the molecular weight is high, quantities required would be higher, thereby higher cost per mole
Comparison of HATU, HBTU and TBTU from Scale-up perspective: Refer to the tab “Scale-up & Green Chem”
Commonly used Uronium salts:
- The counterion in the above salts has no influence on the reactivity
Side-product formation while using HBTU or HATU:
- Uronium species are also known to be guanidylation agents as well
- The side-product formation shall can be diminished by adding HOBt to the reaction (similar to HOBt in DCC)
- HOBt and HOAt have explosive character, especially in water-free form
- HOBt and HOSu are commonly used additives. HOAt is very expensive
Oxyma Pure® (Ethyl 2-cyano-2-(hydroximino)acetate)
- A recently developed additive and is trademark of Luxembourg Bio Technologies Ltd, Rechovot, Israel
- Oxyma Pure®is a non-explosive alternative to HOBt or HOAt, and allows high coupling rates at low racemization when applied in combination with carbodiimides.
Mechanism
Acid-Amine coupling by HATU – Mechanism
- The first step is the formation of carboxylate anion with bases such as Et3N or DIPEA
- The next step is the formation of activated HOBt ester by the reaction between carboxylate anion and HATU. The by-product of HATU viz., N,N,N′,N′-tetramethylurea is liberated here.
- HOBt ester gets attached by amine to give amide
Additional details
Acid-Amine Coupling by HATU;
General Procedure:
To a solution of acid (1 eq.) in CH2Cl2 (10 Vol) , amine (1 eq.), DIPEA or Et3N (1.2 eq), HATU (1.2 eq.) and HOAt (0.1 eq.) are added at RT and stirred overnight. The reaction is monitored by TLC. The organic layer is diluted with CH2Cl2 (10 Vol) and then successively washed with water (15 ml x 2) and brine solution (15 ml). The resultant organic layer is dried using sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography.
Note; HOAt is an additive. It is usually added along with HATU.
Note:
- HATU is Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium
- HOAt is 1-Hydroxy-7-azabenzotriazole
- The most preferable solvent is DCM. Other solvents are NMP
For more details on reactions and reagents,
refer to the tab "Reaction, Reagents and Mechanism"
Typical Procedure:
- A Scalable Synthesis of a Hydroxamic Acid LpxC Inhibitor (OPRD, 2012) — HATU is used; 50.8 g batch (acid derivative)
- Condensation using HATU (TCI) — refer to sub-section “Applications & Literature“
For more details on large-scale reactions and OPRD procedures,
refer to the tab "Scale-up & Green Chem"
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Green Chem
- HATU and TBTU are used for process development, though HBTU is not used widely in process chemistry,
- Both HATU and TBTU provide faster couplings, reduce epimerization and result in high yields (Ref: OPRD, 2016, 140-177)
- Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale (OPRD, 2013) – 1.08 Kg HATU is used; 705 g batch (acid derivative)
- Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals (OPRD, 2016) – Excellent review article, providing comprehensive information on large-scale reactions of coupling reagents
