Miglustat
From The Cure For The Needy
Contents |
Miglustat (Zavesca)
Effective Against
Gaucher's disease (GD1)
People with type 1 Gaucher disease are missing an enzyme that breaks down a chemical in the body called glucosylceramide. Too much glucosylceramide causes liver and spleen enlargement, changes in the blood, and bone disease. Miglustat works by stopping the body from making glucosylceramide.
Cost
Cost of molecule from Tocris Bioscience: 145 USD (10mg) for hydrochloride form
Reported Routes of Synthesis
1) The reductive ring opening of 2,3,4,6-tetra-O-benzyl-a-D-glucopyranose (I) with LiAlH4 in THF gives the diol (II), which is oxidized by means of DMSO, trifluoroacetic anhydride and triethylamine in dichloromethane to yield the unstable ketoaldehyde (III), which, without isolation, is submitted to a reductocyclization with butyl-amine and NaBH3CN in methanol to afford the protected iminosugar (IV). Finally, this compound is debenzylated by means of Li and NH3 in THF (1,2). 2) The oxidation of 1,2-O-isopropylidene-5-oxo-a-D-glucofuranose (V) by means of Bu2SnO and Br2 in refluxing methanol provides the 5-oxoglucofuranose derivative (VI), which is hydrolyzed with Dowex 50W-X8 in water to yield 5-oxo-D-glucose (VII). Finally, this compound is submitted to a reductocyclization with butyl-amine and NaBH3CN in methanol (3,4).
Sorbera, L.A., Castaner, J., Bayes, M. Miglustat. Drugs of the Future 2003, 28(3) 229
Baxter, E.W.; Reitz, A.B. Expeditious synthesis of azasugars by the double reductive amination of dicarbonyl sugars. J Org Chem 1994, 59(11): 3175
Matos, C.R.R.; Lopes, R.S.C.; Lopes, C.C. Synthesis of 1-deoxynojirimycin and N-butyl-1-deoxynojirimycin. Synthesis (Stuttgart) 1999, (4): 571
Ortho-McNeil-Janssen Pharmaceutical, Inc. Process for producing polyhydroxylated piperidines and pyrrolidines and compounds thereof. WO 1992005152
A novel process for the synthesis of aza-sugars. BR 9902585
Cost of Starting Materials and Selected Reagents:
Starting Material Tetrabenzyl glucose
- Methyl α-D-glucopyranoside from Sigma-Aldrich: 32.8 USD (100g)
- Benzyl Chloride from Sigma-Aldrich: 20.7 USD (50g)
Starting Material 1,2-O-isopropylidene-D-glucofuranose from Sigma-Aldrich: 63.90 USD (25g)
Lithium aluminum hydride solution from Sigma-Aldrich: 46.1 USD (100mL, 1.0M in diethyl ether)
DMSO from Sigma-Aldrich: 29 USD (50 mL)
Trifluoroacetic Anhydride from Sigma-Aldrich: 136.5 USD (250 mL, 1.511 g/mL)
Butylamine from Sigma-Aldrich: 24.6 USD (250 mL, 0.75g/mL)
Sodium cyanoborohydride from Sigma-Aldrich: 40.1 USD (10g)
Dibutyltin (IV) oxide from Sigma-Aldrich: 83.1 USD (500g)
Bromine from Sigma-Aldrich: 115 USD (50g)
Dowex 50WX8 from Sigma-Aldrich: 171 USD (100g)
3) The reductocondensation of D-glucose (VIII) and butylamine by means of H2 over Pd/C in ethanol gives N-butylglucamine (IX), which is submitted to a biochemical oxidation by means of Gluconobacter oxidans in water to yield 6-(butylamino)-6-deoxy-a-L-sorbofuranose (X). Finally, this compound is submitted to a reductive cyclization with H2 over Pd/C in ethanol/water (5-7). 4) The selective hydrolysis of 1,2:4,6-di-O-isopropylidene-a-L-sorbofuranose (XI) (together with some of its 1,3:4,6-isomer) by means of H2SO4 in methanol gives 1,2-O-isopropylidene-a-L-sorbofuranose (XII), which is treated with tosyl chloride, triethylamine and pyridine to yield the monotosylated sugar (XIII). Reaction of the protected sugar (XIII) with butylamine in hot pyridine/triethylamine affords 6-(butylamino)-6-deoxy-1,2-O-isopropylidene-a-L-sorbofuranose (XIV), which is finally submitted to a reductive cyclization by means of H2 over Pd/C in water (8). 5) Directly by reductocondensation of 1-deoxynojirimycin (XV) with butyraldehyde (XVI) by means of H2 over Pd/C in methanol (9,10) or with NaBH3CN in methanol/ HCl (11).
Sorbera, L.A., Castaner, J., Bayes, M. Miglustat. Drugs of the Future 2003, 28(3): 229
Scaros, M.G.; Prunier, M.L.; Rutter, R.J.; Yonan, P.K.; Grabner, R.; Landis, B. A new and improved synthesis of N-butyl-1-deoxynojirimycin. Chem Ind (NY) 1994, 53: 41
Landis, B.H.; McLaughlin, J.K.; Heeren, R.; Grabner, R.W.; Wang, P.T. Bioconversion of N-butylglucamine to 6-deoxy-6-butylamino sorbose by Gluconobacter oxydans. Org Process Res Dev 2002, 6(4): 547
Bayer Healthcare AG. New 3,4,5-Trihydroxypiperidine derivatives, process for their preparation and medicaments and fodder containing them. EP 0000947, DE 2758025
Pfizer Inc. Use of 1-deoxynojirimycin and its derivatives for treating mammals infected with respiratory syncytial virus. WO 1995022975
Pfizer Inc. Process for producing N-substituted-1-deoxynojirimycin. EP 0477160
Pfizer Inc. Process for preparation of 1,5-(alkylimino)-1,5-dideoxy-D-glucitol and derivatives thereof. WO 1991017145
Pfizer Inc. Antiviral compounds. US 5310745
Cost of Starting Materials and Selected Reagents:
Starting Material 2,2,3',3'-tetramethylspiro[1,3-dioxolane-4,8'-2,4,7-trioxabicyclo[4.3.0]nonane]-9'-ol
Starting Material D-(+)-Glucose from Sigma-Aldrich: 18.9 USD (100g)
m-Toluenesulfonyl chloride from Sigma-Aldrich: 48.7 USd (5g)
Gluconobacter oxydans: bacteria that can partially oxidize carbohydrates and can be used for synthesis of Vitamin C, D-gluconis acid and ketogluconic acids. Please see MicrobeWiki
Triethanolamine from Sigma-Aldrich: 152 USD (2.5 L)
Butylamine from Sigma-Aldrich: 24.6 USD (250 mL, 0.75g/mL)
Sodium cyanoborohydride from Sigma-Aldrich: 40.1 USD (10g)
1-Deoxynojirimycin hydrochloride from Sigma-Aldrich: 139.5 USD (5mg)
Butanal from Sigma-Aldrich: 18.6 USD (100mL)