Bortezomib
From The Cure For The Needy
Contents |
Bortezomib (Velcade)
Effective Against
Relapsed multiple myeloma and Mantle cell lymphoma
Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome. This drug is thought to inhibit many proteins (known as proteasomes) that cancer cells need to survive and multiply. It has been shown to have anti-tumor activity in B cell malignancies.
Cost
From LC Laboratories: 93 USD (5mg)
Reported Route of Synthesis
Pinanediol leucine boronate (I) was coupled with N-Boc-L-phenylalanine (II) in the presence of TBTU to afford the dipeptide boronate (III). Acid cleavage of the Boc protecting group of (III), followed by acylation of the resultant amine (IV) with 2-pyrazinecarboxylic acid (V), furnished amide (VI). Finally, deprotection of the boronic acid (VI) was accomplished by two-phase transesterification with isobutylboronic acid.
Adams, J.; Behnke, M.; Chen, S.; Cruickshank, AA; Dick, LR; Grenier, L.; Klunder, JM; Ma, YT; Plamondon, L.; Stein, RL; Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids. Bioorg Med Chem Lett 1998, 8(4) 333
Boronic ester and acid compounds, synthesis and uses. Millennium Pharmaceuticals, Inc. EP 1997823, EP 1627880, WO 1996013266, JP 1998510245, CA 2496538, EP 0788360, US 6083903, EP 1312609
Cost of Starting Materials and Selected Reagents:
Starting Material Pinanediol leucine boronate pricing not available from Sigma-Aldrich
- (1S,2S,3R,5S)-(+)-Pinanediol from Sigma-Aldrich: 47.8 USD (1g)
Starting Material Trifluoroacetic acid from Sigma-Aldrich: 201.5 USD (500 mL)
O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) from Sigma-Aldrich: 56.6 USD (5g)
Boc-Phe-OH from Sigma-Aldrich: 12.9 USD (1 g)
N-ethyl-N,N-diisopropylamine (i-Pr2NEt) from Sigma-Aldrich: 65.7 USD (100 mL)
Hydrochloric Acid from Sigma-Aldrich: 46.5 USD (100 mL)
1,3-dioxane from Sigma-Aldrich: 73.2 USD (5g)
1,4-dioxane from Sigma-Aldrich: 40 USD (100 mL)
Pyrazinecarboxylic acid from Sigma-Aldrich: 27.8 USD (25g)
(2-Methylpropyl)boronic acid from Sigma-Aldrich: 19.7 USD (1g)
Hexane from Sigma-Aldrich: 38.9 USD (100 mL)
Coupling of (+)-pinanediol (I) with 2-methylpropylboronic acid (II) in Et2O yields boronic acid derivative (III), which is then treated with LDA in THF/CH2Cl2 and is subsequently chlorinated with ZnCl2 in THF to give (1S)-chloro derivative (IV). Derivative (IV) is aminated with LiHMDS in methylcyclohexane to furnish bis(trimethylsilyl)amine derivative (V), which is then deprotected by means of TFA in methylcyclohexane/(i-Pr)2O to yield TFA salt of amine derivative (VI). Amine derivative (VI) couples with sodium salt of N-(pyrazine-2-ylcarbonyl)-L-phenylalanine (VII) (which is previously treated with TBTU in CH2Cl2) in CH2Cl2 to give pyrazine derivative (VIII). Derivative (VIII) is finally treated with HCl in the presence of i-BuB(OH)2 in MeOH/hexane to afford the title compound. Intermediate (VII) can be prepared as follows: Phenylalanine derivative (IX) undergoes amidation with pyrazinoic acid (X) in the presence of TBTU and DIEA in CH2Cl2 to furnish 2(S)-(pyrazin-2-ylformamido)propionate derivative (XI), which is then hydrolyzed with NaOH in MeOH to afford sodium salt of N-(pyrazine-2-ylcarbonyl)-L-phenylalanine (VII) (1).
Methods for preparing bortezomib and intermediates used in its manufacture. Pliva Croatia Ltd. WO 2009004350