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Enzalutamide Xtandi

Taken by mouth for prostate cancer. It blocks the androgen receptor at several points at once, so testosterone can no longer drive the tumour to grow. Enzalutamide is achiral, so there is no enantiomer to separate.

  • Androgen receptor inhibitor
  • FDA 2012
  • C21H16F4N4O2S · 464.44 g/mol
  • CAS 915087-33-1

Three-step process route

3 steps · purity above 99.5%

A generic manufacturer's route, written to avoid what makes the earlier published processes hard to run at scale. Thiophosgene is gone, the microwave step is gone, and the acid chloride is made with oxalyl chloride at 25–30 °C instead of refluxing thionyl chloride at 60–110 °C. The copper-catalysed coupling uses L-proline as the ligand, which the inventors found cleaner than 2-acetylcyclohexanone, and the amide and the thiohydantoin ring both close at room temperature. The point of the route is purity and handling rather than yield: the isolated material runs above 99.5% by HPLC after a solvent wash, with no column.

Scale: kilogram-scale examples: 175 g of the acid through step 1, 143 g through step 2, 83 g through step 3. The patent reports its yields as masses, so the percentages below are worked out from those masses.

4-Bromo-2-fluorobenzoic acid (II) no public CAS
+
Methylamine (40% in water) no public CAS
Step 1 85% isolated
Oxalyl chloride, cat. DMF, CH2Cl2, 25–30 °C
then 40% aq. methylamine, MTBE, 10–15 °C
the acid chloride forms at room temperature · the prior art refluxes thionyl chloride at 60–110 °C to do the same thing · 158 g, 99.74% by HPLC
4-Bromo-2-fluoro-N-methylbenzamide (III) no public CAS
4-Bromo-2-fluoro-N-methylbenzamide (III) no public CAS
+
2-Aminoisobutyric acid no public CAS
Step 2 63% isolated
2-Aminoisobutyric acid, CuCl, L-proline, K2CO3
DMF / 1,4-dioxane / water, reflux 22–24 h
copper-catalysed C–N coupling · L-proline as the ligand gives cleaner material than 2-acetylcyclohexanone, and dissolves in water so it washes out · 85–95% by HPLC depending on the batch
2-(3-Fluoro-4-methylcarbamoylphenylamino)-2-methylpropionic acid (IV) no public CAS
2-(3-Fluoro-4-methylcarbamoylphenylamino)-2-methylpropionic acid (IV) no public CAS
+
4-Isothiocyanato-2-(trifluoromethyl)benzonitrile (V) no public CAS
Step 3 30% isolated
Et3N, CH2Cl2, 23–28 °C, 16–20 h
then MeOH / water, and a wash with IPA or EtOAc
the isothiocyanate closes the thiohydantoin ring at room temperature · no thiophosgene and no microwave · 99.68% by HPLC, and above 99.5% after the solvent wash, without a column
Enzalutamide (Xtandi)
Hirpara, S.; Shrawat, V. K.; Pothuraju, R.; Tripathi, C. K.; Akshaykant, C. — Shilpa Medicare Limited
An improved process for the preparation of enzalutamide
WO 2016/005875 A1, published 14 January 2016 · Scheme-I and Examples 9 to 11

Open the patent on PATENTSCOPE Read the PDF

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