The Synthesis of ARV-110

The process synthesis of ARV-10, the first PROTAC in clinical trial, was disclosed in a patent (Ref 2) by Arvinas in a detailed manner.

This larger-than-usual molecule was made in an especially elegant way. The synthesis of ARV-110 1 took 6 steps in the longest linear sequence (Scheme 1). It began with the synthesis ether 4 from dichlorobenzonitrile 2 and cyclohexanol 3 using O-SNAr reaction. After the reaction was complete, it was quenched by adding water, and the product 4 precipitated from the mixture. The Boc group in 4 was cleaved under acidic conditions (AcCl/MeOH) to give a primary amine salt 5-01. Then an amide coupling was applied to afford 7 from 5-01 and pyridazine acid 6. The piperidine alcohol 8 was annealed to intermediate chloride 7 with another SNAr reaction in this sequence to result in primary alcohol 9. Upon the exposure of 9 to TEMPO-mediated oxidation conditions with NaClO as an oxidant source, aldehyde 10 was obtained in 90.6% yield. The final PROTAC molecule was furnished under mild reductive amination conditions by reacting aldehyde 10 with E3 Cereblon type ligand piperazine salt 11-01 with NaBH(OAc)3 as a reducing agent.

The E3 ligand building block 11 was made from difluorophthalic acid 12 and amino piperidinedione 13. The condensation of 12 and 13 under acidic conditions provided phthalimide 14. A third SNAr reaction in the whole synthesis replaced one of fluorides in 14 with Boc-protected piperazine moiety to access 16. Treatment of 16 with hydrochloride in methanol afforded salt 11-01.

The process route to ARV-10 only used crystallization/recrystallization to purify intermediates and featured incredibly high yields.

Step 1. O–SNAr reaction: NaH, DMF, -10 °C, crystallization, 95%.

Step 2. Boc deprotection: AcCl, MeOH, rt, crystallization, 95%.

Step 3. Amide coupling: 6, T3P, Et3
N, EtOAc, 15 -25 °C; crystallization, 79%, recrystallization, 85%.

Step 4. N–SNAr reaction: 8, DIPEA, DMA, 90 °C, crystallization, 79.7%.

Step 5. Alcohol oxidation: NaClO,  TEMPO(cat), NaHCO3, NaBr, DCM/ H2O, 0 °C, crystallization, 90.6%

Step 6. Reductive amination: NaBH(OAc)3, Et3N, DMA, 0 – 5 °C, crystallization, recrystallization, 87%.

Step 1’. Imide synthesis: Sodium acetate, Acetic acid (5 V), 120 °C, crystallization, 88%.

Step 2’. N-SNAr reaction: 15, NaHCO3, NMP, 90 °C, crystallization, 100%.

Step 3’. Boc deprotection: HCl, MeOH, crystallization, 85%.

The unoptimized route to ARV-110 contains 5 steps (Scheme 2), a step less than the process route, but the overall yield is much lower than the optimized one.

They are several differences. First, chlorofluorobenzonitrile 17 is used for step 1 at 0 °C instead of -10 °C. Second, an advanced building block 18 is employed as the amine coupling partner with HATU as the coupling agent. The yield of this step is only 56%, which may be caused by the primary alcohol in 18. Third, the oxidation of the primary alcohol in 9 utilizes Dess-Martin periodinane and bears low yield too.

The patent only listed the synthesis route of intermediate acid 18 but did not give yields.

References

  1. Berlin, M.; Crew, A.; Dong, H.; Hornberger, K.; Snyder, L.; et al. Preparation of bifunctional compounds and methods for the targeted degradation of androgen receptor protein. WO2022087125 A1 2022.
  2. Dong, H.; Duguid, R. J.; Jager, C. K.; Kaushal, A. M.; Kennedy, S. E.; et al. Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same. WO2021231174 A1 2021.
  3. Crew, A. P.; Hornberger, K. R.; Snyder, L. B.; Zimmermann, K.; Wang, J.; Berlin, M.; Crews, C. M.; Dong, H. Preparation of bifunctional compounds for the targeted degradation of androgen receptor. US20180099940 A1 2018.