& Mechanism
Green Chem
& Mechanism
Reaction & Reagents info
- BOP reagent is also called “Castro’s reagent”
- In order to avoid racemization and side product formation during coupling, several reagents have been developed wherein “-OBt ester” is generated in-situ. BOP is one such reagent. Othe reagents include HBTU, HATU, TBTU, PyBOP etc..
- Besides amidation, BOP is useful for selective esterification and lactonization.
- The major disadvantage in using BOP is that it generates a highly carcinogenic HMPA (hexamethylphosphoramide) as a by-product during coupling reaction
- 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 BOP and PyBOP from Scale-up perspective: Refer to the tab "Scale-up & Green Chem"
Commonly used BOP and BOP related agents:
Mechanism
Acid-Amine coupling by BOP – 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 BOP. The by-product of HMPA ((hexamethylphosphoramide) is liberated here.
- HOBt ester gets attached by amine to give amide
Additional details
Acid-Amine Coupling by BOP;
General Procedure:
To a solution of acid (1 eq.) amine (1.2 eq.), DIPEA or Et3N (1.5 eq) in DMF (10 Vol) at 0 oC is added BOP (1.2 eq.). The reaction is then brought to RT and stirred overnight. The reaction is monitored by TLC. The reaction is monitored by TLC. The organic layer is diluted with CH2Cl2 (20 Vol) and then successively washed with 10 % citric acid (10 Vol), water (10 Vol x 2), NaHCO3 solution and brine solution. The resultant organic layer is dried using sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography.
Note:
- BOP is (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
- The most preferable solvent is DMF.
- The by-product of BOP is HMPA (Hexamethylphosphoramide), which is a known carcinogen. Hence, BOP is usually avoided. However, pyBOP is considered to be a safer alternative to BOP
For more details on reactions and reagents,
refer to the tab "Reaction, Reagents and Mechanism"
Typical Procedure:
For more details on large-scale reactions and OPRD procedures,
refer to the tab "Scale-up & Green Chem"
WO2010038081, page No 477
WO2007127635, page No 248
Green Chem
- BOP reagent is not a preferable reagent for process development, as it generates carcinogenic HMPA.
Alternative to BOP reagent — PyBOP:
- PyBOP shall be considered as an alternative to BOP, as PyBOP by-product viz., tris(pyrrolidin-1-yl)phosphine oxide, is more benign.
- 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
