Plerixafor
From The Cure For The Needy
Contents |
Plerixafor (MOZOBIl, JM 3100, AMD3100)
Effective Against
Mozobil is a hematopoietic stem cell mobilizer and inhibitor of the CXCR4 chemokine receptor. CXXR4 is specific for stromal-derived-factor-1 (SDF-1), a molecule endowed with potent chemotactic activity for lymphocytes. Because the interaction between SDF-1 and CXCR4 plays an important role in holding hematopoietic stem cells in the bone marrow, drugs that block the CXCR4 receptor appear to be capable of "mobilizing" hematopoietic stem cells into the bloodstream. (Hematopoietic stem cells are multipotent stem cells that give rise to all blood cell types and are found in the bone marrow of adults.)
Cost
From Sigma-Aldrich: 69.70 USD (5mg) for octahydrochloride hydrate form
From Tocris Bioscience: 99 USD (10mg) for octahydrochloride form
Reported Routes of Synthesis
Plerixafor can be prepared by several related procedures. 1) The macrocyclic tetraamine cyclam (I) is protected with p-toluenesulfonyl chloride at a 1:2 molar ratio, yielding the target tritosyl derivative (II) along with di- and monotosylated derivatives, which can be separated by fractional crystallization from MeOH (1). Subsequent condensation of (II) with α,α’-p-dibromoxylene (IIIa) gives the hexatosyl bis-cyclam (IV), which is finally deprotected by treatment with hot concentrated H2SO4 or with HBr in AcOH (1,2). Alternatively, protection of (I) with di-tert-butyl dicarbonate provides the tri-Boc derivative (V), which is dimerized to (VI) by treatment with p-dibromoxylene (IIIa) and Na2CO3. Deprotection of (VI) is then effected by heating with aqueous HCl (3,4). Similarly, treatment of the macrocyclic amine (I) with an excess of ethyl trifluoroacetate in the presence of Et3N affords the tris-trifluoroacetyl cyclam (VII) as the major product. Subsequent condensation of (VII) with either p-dibromoxylene (IIIa) or p-dichloroxylene (IIIb) in the presence of KI gives the trifluoroacetyl-protected compound (VIII), which is finally deprotected by treatment with NaOH or K2CO3 in MeOH (5,6).
Bridger, G.J.; Skerlj, R.T.; Thornton, D.; et al. Synthesis and structure-activity relationships of phenylenebis(methylene)linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker. J Med Chem 1995, 38(2): 366
Dessolin, J.; Galea, P.; Vlieghe, P.; Chermann, J.-C.; Kraus, J.-L. New bicyclam-AZT conjugates: Design, synthesis, anti-HIV evaluation, and their interaction with CXCR-4 coreceptor. J Med Chem 1999, 42(2): 229
Ciampolini, M.; Fabbrizzi, L.; Perotti, A.; Poggi, A.; Seghi, B.; Zanobini, F. Dinickel and dicopper complexes with N,N-linked bis(cyclam) ligands. An ideal system for the investigation of electrostatic effects on the redox behavior of pairs of metal ions. Inorg Chem 1987, 26(21): 3527
Davies, S.L.; Serradell, N.; Bolos, J.; Bayes, M. Plerixafor Hydrochloride. Drugs Fut 2007, 32(2): 123
2) In a different procedure, the acyclic tetraamine (IX) is protected with p-toluenesulfonyl chloride to afford a separable mixture of ditosyl (X) and tritosyl compounds (XI). Condensation of (X) with p-dibromoxylene (IIIa) provides the tetratosyl dimer (XII), which is further tosylated to (XIII) by means of p-toluenesulfonyl chloride and K2CO3. Alternatively, the hexatosyl dimer (XIII) can be obtained by condensation of the trisulfonylated tetraamine (XI) with p-dibromoxylene (IIIa) in the presence of N,N-diisopropylethylamine. Ring closure of (XIII) to furnish the bis-macrocycle (IV) is then accomplished by reaction with ethylene glycol ditosylate (XIV) in the presence of Cs2CO3 or under phase-transfer conditions. Subsequent acidic deprotection of (IV) gives the target compound (7). In a related approach, the open-chain tetraamine (IX) is protected with ethyl trifluoroacetate and N,N-diisopropylethylamine to afford the triacyl derivative (XV) as the main product, which is further condensed with dibromide (IIIa), yielding the trifluoroacetyl-protected dimer (XVI). The hexatrifluoroacetyl compound (XVI) is then converted to the hexatosyl analogue (XIII) by alkaline amide hydrolysis, followed by treatment with p-toluenesulfonyl chloride. Ring closure of (XIII) with ethylene glycol ditosylate (XIV) and subsequent acidic deprotection as above gives plerixafor (8,9).
Davies, S.L., Serradell, N., Bolos, J., Bayes, M. Plerixafor Hydrochloride. Drugs of the Future 2007, 32(2): 123
Cost of Starting Materials and Selected Reagents:
Starting Material 1,2-Bis(3-aminopropylamino)ethane from Sigma-Aldrich: 21.8 USD (100 mL)
m-Toluenesulfonyl chloride (TsCl) from Sigma-Aldrich: 48.7 USD (5 g)
Sodium hydroxide (10M in H2O) from Sigma-Aldrich: 61.6 USD (100 mL)
Potassium carbonate from Sigma-Aldrich: 35.6 USD (100 g)
N,N-Diisopropylethylamine (i-Pr2NEt) from Sigma-Aldrich: 65.7 USD (100 mL)
Ethyl trifluoroacetate from Sigma-Aldrich: 23.2 USD (25 g)
Calcium carbonate from Sigma-Aldrich: 32.7 USD (100 g)
Sulfuric acid from Sigma-Aldrich: 67.2 USD (100 mL)
Hydrobromic acid from Sigma-Aldrich: 154.5 USD (1 L)
Acetic Acid from Sigma-Aldrich: 28.8 USD (100 g)
- [(Bu4N)2SO4] from Sigma-Aldrich: USD ()
α,α′-Dibromo-p-xylene from Sigma-Aldrich: 80.4 USD (25 g)
3) A different protection strategy involves masking the ring nitrogens as amide groups. Methyl acrylate (XVII) is reacted with neat ethylenediamine (XVIII) to yield the aminopropionamide derivative (XIX), which is then cyclized with dimethyl malonate (XX), producing the trioxocyclam (XXI). After condensation of (XXI) with p-dibromoxylene (IIIa), the resulting hexaoxo bis-cyclam (XXII) is reduced to the title compound employing borane-dimethyl sulfide complex in refluxing THF (10). Alternatively, protection of the linear tetraamine (XXIII) with pyruvic aldehyde (XXIV) generates the tricyclic bis-aminal (XXV) along with its minor isomer (XXVI). The crude mixture of bis-aminals (XXV) and (XXVI) is then cyclized to (XXVIII) with 1,3-dibromopropane (XXVII) and K2CO3. After condensation of (XXVIII) with dibromide (IIIa), the resulting bis-ammonium dimer (XXIX) is hydrolyzed to the title compound upon heating with 3M NaOH (11).
Davies, S.L., Serradell, N., Bolos, J., Bayes, M. Plerixafor Hydrochloride. Drugs of the Future 2007, 32(2): 123
4) The tetraazacyclotetradecane (I) is protected as the chromium tridentate complex (XXX) upon heating with chromium hexacarbonyl in deaerated dibutyl ether. Subsequent condensation of the cyclam-Cr(CO)3 complex (XXX) with p-dibromoxylene (IIIa) produces the chromium-protected bis-cyclam (XXXI), which is deprotected to plerixafor by oxidation with air in aqueous HCl (12,13). Alternatively, protection of (I) as the phosphorotriamide (XXXII) can be accomplished by reaction with tris(dimethylamino)phosphine, followed by oxidation with CCl4 and NaOH (12) or by treatment with POCl3 and Et3N (14). After condensation of (XXXII) with dibromide (IIIa), the dimeric bis-phosphoramide obtained (XXXIII) is hydrolyzed to the title compound by treatment with diluted HCl (12,14).
Davies, S.L., Serradell, N., Bolos, J., Bayes, M. Plerixafor Hydrochloride. Drugs of the Future 2007, 32(2): 123
Cost of Starting Materials and Selected Reagents:
Starting Material 1,4,8,11-Tetraazacyclotetradecane from Sigma-Aldrich: 59.2 USD (1 g)
Chromium(0) hexacarbonyl [Cr(CO)6] from Sigma-Aldrich: 26.6 USD (1 g)
Tris(dimethylamino)phosphine from Sigma-Aldrich: 39.6 USD (5 mL)
Triethylamine from Sigma-Aldrich: 12 USD (100 mL)
Phosphorus Oxychloride from Sigma-Aldrich: 34.6 USD (25 mL)
Carbon tetrachloride from Sigma-Aldrich: 78.8 USD (100 mL)
Sodium hydroxide (10M in H2O) from Sigma-Aldrich: 61.6 USD (100 mL)
α,α′-Dibromo-p-xylene from Sigma-Aldrich: 80.4 USD (25 g)
Sodium carbonate from Sigma-Aldrich: 52.1 USD (500 g)
Hydrochloric acid from Sigma-Aldrich: 46.5 USD (100 mL)
Tetrabutylammonium sulfate solution from Sigma-Aldrich: 32.6 USD (100 mL)