酰胺键广泛存在于天然产物和药物分子中，经典的构建方法是羧酸和胺在缩合剂的作用下进行缩合，目前缩合剂的种类也是多种多样如HATU，DCC，T3P，PyBOP，HBTU，DPPA等。
1.Coupling via acid chloride
SOCl2 and (COCl)2, the two are most widely employed reagents in process chemistry. A drawback of these methods is that HCl is a byproduct of acid chloride generation, which can lead to incompatibility with acid-sensitive functional groups.
Amide Bond Formation with SOCl2:
Amide Bond Formation with POCl3:
Amide Bond Formation with POCl3:
Amidation via Vilsmeier Reagent:
2.Coupling via acid anhydride
2.1 Carboxylic/ Carbonic Acid Anhydrides
Amide bond formation via mixed anhydride is one of the oldest approaches. Carbon-based mixed anhydrides can be subdivided into two categories depending on the type of activating reagent.
Activation with Acetic Anhydride:
PivCl-Mediated Coupling:
Ethyl Chloroformate-Mediated Coupling:Amidation via IBCF:
Boc2O-Mediated Amide Coupling:
EEDQ as the Activating Agent:
2.2 Sulfonate-Based Mixed Anhydrides
Sulfonate-based mixed anhydrides derived from either reagent display excellent selectivity in which amines add preferentially to the activated carbonyl instead of the sulfonate ester.
Amide Couplings via MsCl Activation:
Amide Coupling via TsCl Activation:
2.3 Phosphorus-Based Mixed Anhydrides
T3P and EMPA have been applied by process chemistry groups for the synthesis of drug candidates. However, EMPA relatively high toxicity (LD50=7 mg/kg) and the need for its low level purging from drug substances have limited use of this reagent on industrial scale.
T3P as the Activating Agent:
Amide Forming via Ethylmethylphosphinic Anhydride:
Amide Coupling via Imidazolide:
3.Coupling via Activated Ester
3.1 Carbodiimides
A primary consideration when selecting a carbodiimide is the preferred workup since the method for removal of the urea byproduct can vary widely. 1-hydroxybenzotriazole (HOBt) is by far the most commonly used for carbodiimide-mediated reactions in either stoichiometric or catalytic fashion.
DCC-Mediated Coupling:
DIC/HOBt-Mediated Amidation:
EDC/HOBt-Mediated Amidation:
3.2 Phosphonium Salts
BOP was the first reagent of the HOBt-basedonium salts to be introduced for amide bond formation to avoid epimerization and other side reactions that can take place with carbodiimide reagents.
Amide Bond Formation with BOP:
3.3 Guanidinium and Uronium Salts
These reagents afford fast amide bond formations and can be very useful for the coupling of sterically hindered amino acids in peptide synthesis.
Amide Coupling with HBTU:
HATU-Mediated Amide Bond Formation:
Amide Bond Formation via TBTU:
Amide Bond Formation with TBTU:
TOTU as a Coupling Agent:
4.Triazine-Based Coupling Reagents
Cyanuric chloride is a highly reactive coupling reagent produced on the industrial scale by the hundreds of thousands of metric tons per year via trimerization of cyanogen chloride.
Cyanuric Chloride-Mediated Amide Bond Formation:
CDMT-Promoted Amide Formation:
DMTMM as Coupling Reagent:
5.Coupling via Boron Species
Boric acid clearly stands out as a very desirable reagent since it is inexpensive and displays excellent atom economy. In addition, after reaction completion, the water-soluble reagent can be extracted into an aqueous workup.
ABBREVIATIONS (缩写):
BOP:(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophospha -te
CDI: 1,1′-carbonyldiimidazole
CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine
DCC: N,N′-dicyclohexylcarbodiimide
DCU: N,N′-dicyclohexylurea
DIC: N,N′-diisopropylcarbodiimide
DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
ECF: ethyl chloroformate
EDAC: 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide
EDC or EDCI: 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide
EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
EMPA: ethylmethylphosphinic anhydride
HATU:N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
HBTU:N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide
HOAt: 1-hydroxy-7-azabenzotriazole
HOBt: N-hydroxybenzotriazole
HONB: N-hydroxy-5-norbornene-endo-2,3-dicarboxylic acid imide
HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-(1,2,3)-benzotriazine
IBCF: isobutyl chloroformate
MsCl: methanesulfonyl chloride
PPA: n-propanephosphonic acid anhydride
Piv: pivaloyl py: pyridine
PyBOP:(benzotriazol-1-yloxy)tris(pyrrolidine)phosphonium hexafluorophosphate
PyBrop: bromotripyrrolidinophosphonium hexafluorophosphate
T3P: n-propanephosphonic acid anhydride
TBTU:N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate Noxide
TMP: 2,2,6,6-tetramethylpiperidine
TOTU:O-[(cyano(ethoxycarbonyl)methyleneamino]N,N,N′,N′-tetramethyluronium tetrafluoroborate
TPTU: 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate
TsCl: p-toluenesulfonyl chloride
内容来源：Org. Process Res. Dev. 2016, 20, 140−177
