Miltefosine
From The Cure For The Needy
Contents |
Miltefosine (Impavido, Miltex)
Effective Against
Visceral and cutaneous Leishmaniasis. It can be administered orally or via IV. It is an orphan drug.
An antiprotozoal drug, miltefosine was originally developed as an antineoplastic (drug that inhibits and combats the growth of neoplasms, which can develop into tumors). It may also have antifungal effects as well as be useful in combating HIV infection.
The cure rate of miltefosine in phase III clinical trials is 95%; Studies in Ethiopia show that it is also effective in Africa. In HIV immunosuppressed people who are coinfected with leishmaniasis it has been shown that 2/3 of the people responded to this new treatment even in resistant cases. Clinical trials in Colombia showed a high efficacy for cutaneous leishmaniasis.
Cost
From Gold Biotechnology: 139 USD (5g) Gold Biotechnology-Miltefosine
Reported Routes of Synthesis
The synthesis of [14C]-labeled hexadecylphosphocholine has been described: By condensation of [14C]-labeled phosphocholine (I) with hexadecyl bromide (II) by means of tetrabutylammonium hydroxide in acetonitrile. The same method is used to obtain unlabeled hexadecylphosphocholine.
Wild, H.; Eilen, CC; Samson, A.; Wieder, T.; Reutter, W.; Synthesis of hexadecylphospho [methyl-14C]-choline. J Label Compd Radiopharm 1992, 31(12) 1071
Cost of Starting Materials and Selected Intermediates:
Starting Material Phosphocholine chloride calcium salt tetrahydrate from Sigma-Aldrich: 39 USD (5 g)
Starting Material 1-Bromohexadecane from Sigma-Aldrich: 10.8 USD (5 g)
Tetrabutylammonium hydroxide solution (1 M in H2O) from Sigma-Aldrich: 57.6 USD (100 mL)
In scheme 14476001a hexadecanol is reacted with phosphoroxy chloride in the presence of triethylamine in tetrahydrofuran with subsequent condensation with ethanolamine in dioxane / triethylamine. Hydrolysis with aqueous hydrochloric acid and methylation with dimethyl sulfate in the presence of potassium carbonate yields hexadecyl phosphocholine.
Engel, J.; Schumacher, W.; Hilgard, P.; Stekar, J.; Schmaehl, D.; Berger, M.R.; Eibl, H.J.; Unger, C.; Nagel, G. Hexadecylphocholine. Drugs Fut 1988, 13(11): 948
Kin, DJ; Unger, C.; Berger, MR; Fleer, EAM; Nagel, GA; Eibl, H.; Hexadecylphosphocholine, a new antineoplastic agent: cytotoxic properties in leukaemic cells. J Cancer Res Clin Oncol 1986 111(24)
Cost of Starting Materials and Selected Intermediates:
Starting Material 1-Hexadecanol from Sigma-Aldrich: 15.9 USD (5 g)
Triethylamine from Sigma-Aldrich: 12 USD (100 mL)
Hydrochloric acid from Sigma-Aldrich: 46.5 USD (100 mL)
1,3-dioxane from Sigma-Aldrich: 73.2 USD (5 g)
1,4-dioxane from Sigma-Aldrich: 40 USD (100 mL)
Potassium carbonate from Sigma-Aldrich: 35.6 USD (100 g)
Dimethyl sulfate from Sigma-Aldrich: 17.5 USD (5 mL)
Ethanol amine pricing not available from Sigma-Aldrich
The reaction of hexadecanol (I) with the cyclic chlorophosphate ester (II) and TEA in tert-butyl methyl ether gives the cyclic hexadecyl phosphate (III), which is condensed with TEA in hot acetonitrile to afford the target phosphorylcholine ester.
Lohmeyer, M.; Bittman, R. Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19(11): 1021
Cost of Starting Materials and Selected Reagents:
Starting Material 1-Hexadecanol from Sigma-Aldrich: 15.9 USD (5 g)
Triethylamine from Sigma-Aldrich: 12 USD (100 mL)
2-Chloro-1,3,2-dioxaphospholane 2-oxide from Sigma-Aldrich: 62.9 USD (5 g)
Tert-butyl methyl ether from Sigma-Aldrich: 37.6 USD (100 mL)
The reaction of hexadecanol (I) with the cyclic chlorophosphate ester (II) and DIEA in dichloromethane gives the cyclic hexadecyl phosphate (III), which is brominated with Br2 in the same solvent to yield the mixed 2-bromoethyl hexadecyl bromophosphate ester (IV) . Finally this compound is condensed with trimethylamine in acetonitrile / isopropanol / chloroform to furnish the target phosphorylcholine ester.
Lohmeyer, M.; Bittman, R. Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19(11): 1021
Reddy, KC; Byun, HS; Bittman, R.; Antitumor ether lipids: An improved synthesis of ilmofosine and an enantioselective synthesis of an ilmofosine analog. Tetrahedron Lett 1994, 35(17) 2679
Cost of Starting Materials and Selected Reagents:
Starting Material 1-Hexadecanol from Sigma-Aldrich: 15.9 USD (5 g)
2-Chloro-1,3,2-dioxaphospholane from Sigma-Aldrich: 45.5 USD (5 mL)
N,N-Diisopropylethylamine (i-Pr2NEt) from Sigma-Aldrich: 65.7 USD (100 mL)
Bromine from Sigma-Aldrich: 115 USD (50 g)
Trimethylamine from Sigma-Aldrich: 67.3 USD (100 g)
2-Propanol from Sigma-Aldrich: 19 USD (25 mL)
Chloroform from Sigma-Aldrich: 22.4 USD (25 mL)