� N Q ' coPh
CATALYSTS closely with academic groups , pharmaceutical innovators and CDMOs to provide a library of PGM and non-PGM catalysts .
Overcoming challenges
Optimisations to some API synthesis routes have included a change to non-PGM catalysis in order to solve challenges encountered during the process .
Elbasvir , a hepatitis C treatment , was originally synthesised using an oxidative aromatisation with KMnO 4
, which resulted in hazardous MnO 2 waste . Merck & Co . developed an alternative oxidation using [ Cu ( MeCN ) 4
]
BF 4 to provide the intermediate at a 500g scale with good conversion and no by-products ( Figure 1a ).
An anticancer candidate , pictilisib , was produced at multikilo scale by Genentech using a Suzuki-Miyaura reaction catalysed by Ni ( NO 3
) 2 · 6H 2 O /
PPh 3
. This reaction was also developed using a palladium catalyst ; the Pd route was found to require more extensive workup and expensive metal scavengers , as well as a higher catalyst loading ( Figure 1b ).
Bristol Myers Squibb ( BMS ) used
NiCl 2
( DME ) to catalyse a reductive cross-coupling for a key intermediate on a kilogram scale , after Suzuki and Heck strategies were unsuccessful and reagent availability limited a Pdcatalysed Negishi coupling ( Figure 1c ). Sinocompound aims to facilitate largescale applications with nickel catalysts , such as NiCl 2
( DME ), by providing these on a commercial scale .
Efforts to use non-PGM catalysis in industrial chemical manufacturing have encountered challenges , however . These catalysts often result in more complex reactions and are less well understood than PGM catalysis . Comparatively few non-PGM catalysts are in use at scale .
This is often due to sourcing , as precursors not as readily available , especially at commercial scale , an issue that Sinocompound is working to solve by providing specialised catalyst production at a wide range of scales . While the non-precious metals themselves are usually less costly than their PGM alternatives , expensive ligands can drive up the process cost . New ligands are being developed all the time , but they often have limited substrate scope .
Non-PGM solutions in pharma
While the drawbacks to non-PGM catalysis may lead risk-averse manufacturers to avoid these synthetic routes , many pharmaceutical manufacturers have solved these issues and used non-PGM catalysts in large batches . A large number of these advances in non-PGM catalysis have been shown to work at milligram and gram scales , but some have been amenable to scale-up and commercial production ( Figure 2 ).
AbbVie and Pfizer collaborated to find a solution to the poor reactivity of nickel catalysts with arylboron nucleophiles . A phosphine / nickel catalyst screening showed that
PPh 2
Me was a highly effective ligand for this Suzuki-Miyaura reaction , and this ligand was demonstrated , for example in the synthesis of an intermediate ( 1 ), for ruxolitinib .
One use of non-PGM catalysis on a commercially viable scale ( hundreds
_ N
�
::-- I,
Meo , N -N
Et
�
, SEM
1 Precursor to ruxolitinib
Me 0�
NH
N , NMe
5
�ro
� :::,...
I
F 3 C
• HCI Me :::,...
I
9 Precursor to calcium-sensing receptor antagonist o
� N Q ' coPh
\\ N , N -Z
Me 2 Precursor to BMS-663068
O N Me tf"
1 Bu
� /;
NH
C02Et
6 Precursor to ABBV-3221
10 Precursor to MCL-509 of kilograms ) is for an intermediate ( 2 ) of the HIV prodrug BMS-663068 , which uses CuI for a C-N coupling step . The CuI loading is high ( 30 mol %), but use of the copper scavenger APDTC reduces residual metal content to acceptable levels .
An intermediate ( 3 ) for the Merck cough treatment Gefapixant uses a copper-catalysed C-O coupling , but the initial process resulted in an unwanted dimer by-product . Crystallisation with DABCO enhanced purity and inhibited dimerisation , leading to production on a 120 kg scale . BMS used Ni ( acac ) ( 2 ) to produce multi-kilo quantities of an API intermediate ( 4 ) that was subsequently used to synthesise enough of a breast cancer drug candidate for clinical trials .
A Pfizer / STA Pharmaceutical collaboration resulted in the synthesis of 50 kg of an intermediate ( 5 ) using a copper-catalysed C-N coupling . Similarly , an AbbVie intermediate ( 6 ) was synthesised on a multi-kilo scale via copper-catalysed [ 3 + 2 ] cycloaddition , requiring a very low loading of 0.25 mol % Cu ( OTf ) 2 · C 6
H 6 and 0.55 mol % of the ligand . The Pfizer / Curia antiviral Nirmatrelvir
( 7 ) was produced a using a cobalt-
Meo
Me
Me
◊ � OH
I
�
3 Precursor to gefapixant
Boc , � N o
Me
Me Me
7 Precursor to nirmatrelvir
Me )- Me
Me O Me _)(
)l_ y-0
Me O N Me
H 0
11 Precursor to carfilzomib
4 Precursor to breast cancer drug
Me N r�
�CF3
8 Precursor to NK1 / serotonin receptor antagonist
Cl
� N- <J
0
1.) N
Figure 2 - Types of structures synthesised by non-PGM catalysis in larger scale pharmaceutical settings
12
JAN / FEB 2025 SPECCHEMONLINE . COM
25