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Olaparib Lynparza

Taken by mouth for ovarian, breast, pancreatic and prostate cancers that carry a BRCA mutation. It blocks the enzyme a cancer cell uses to patch its own DNA, so the breaks build up until the cell dies.

  • PARP-1 / PARP-2 inhibitor
  • FDA 2014
  • C24H23FN4O3 · 434.46 g/mol
  • CAS 763113-22-0

Phosphonate-free route

4 steps · 51% overall

Four linear steps from bulk feedstock, with no metal catalyst and no phosphonate precursor. The carbon–carbon bond is made by an SRN1 α-arylation of a ketone enolate, which replaces the Horner–Wadsworth–Emmons olefination the older routes rely on.

Scale: 6.3 g of Olaparib (14.5 mmol) from 2.5 g of piperazine

Cyclopropanecarbonyl chloride
+
Piperazine
Step 1 88% isolated
AcOH
40 °C, then rt, 8 h
N-acylation, no base
Cyclopropyl(piperazin-1-yl)methanone
Cyclopropyl(piperazin-1-yl)methanone
+
5-Bromo-2-fluorobenzoic acid
Step 2 75% isolated
HBTU, DIPEA, DMF
rt (25 °C), 15 h
acid–amine coupling
(4-(5-Bromo-2-fluorobenzoyl)piperazin-1-yl)(cyclopropyl)methanone no public CAS
(4-(5-Bromo-2-fluorobenzoyl)piperazin-1-yl)(cyclopropyl)methanone no public CAS
+
2-Acetylbenzoic acid
Step 3 85% isolated
NaOtBu (5 equiv), dry DMF
120 °C, 36–40 h
enolate, then SRN1 α-arylation · Br is displaced, F is kept
2-(2-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorophenyl)acetyl)benzoic acid no public CAS
2-(2-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorophenyl)acetyl)benzoic acid no public CAS
Step 4 90% isolated
Hydrazine hydrate (0.7 mL), EtOH
reflux, 15 h
phthalazinone ring closure
Olaparib (Lynparza)
35.9% atom economy vs 26.0% 51% overall yield vs 46% 18.2 g/g PMI vs 51.8 g/g 17.2 g/g E-factor vs 50.8 g/g 12.6% reaction mass efficiency vs 7.5%

This route against the six-step medicinal chemistry route, as reported in the paper.

Chatterjee, I.; Roy, D.; Panda, G.
A scalable and eco-friendly total synthesis of poly(ADP-ribose) polymerase inhibitor Olaparib
Green Chem. 2023, 25, 9097–9102 · Scheme 4

Open the paper · DOI 10.1039/d3gc02617e

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