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药物详细合成路线

Name Miltefosine;Hexadecylphosphocholine;HDPC;D-18506;Impavido;Miltex
Chemical Name 2-[Hexadecyloxy(hydroxy)phosphoryloxy]-N,N,N-trimethylethanaminium hydroxide inner salt
      Choline hydroxide,hexadecyl hydrogen phosphate,inner salt
CAS 58066-85-6
Related CAS
Formula C21H46NO4P
Structure
Formula Weight 407.57887
Stage 上市-1993
Company Zentaris (Orphan Drug), Zentaris (Originator), Baxter Oncology (Licensee), Roche (Licensee)
Activity/Mechanism ANTIINFECTIVE THERAPY, Antileishmanials, Oncolytic Drugs, Treatment of Protozoal Diseases
Syn. Route 4
Route 1
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.
List of intermediates No.
7-chloro-4a,8a-dihydro-1-quinoliniumolate (i)
2-amino-6-chloro-3-cyano-1,4-quinoxalinediiumdiolate (ii)
(2r,4ar,6r,7r,8r,8as)-6-{[(2r,3s,4r,5r,6s)-6-{[(2r,3s,4r,5r,6r)-6-{[(2r,3s,4r,5r,6r)-6-{[(1r,2s,3r,4r,5r)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-7,8-dimethoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine; (2r,4ar,6r,7r,8r,8as)-6-{[(2r,3s,4r,5r,6s)-6-{[(2r,3s,4r,5r,6r)-6-{[(2r,3s,4r,5r,6r)-6-{[(1r,2s,3r,4r, (i)
Reference 1:
    wild, h.; eilen, c.c.; samson, a.; wieder, t.; reutter, w.; synthesis of hexadecylphospho[methyl-14c]-choline. j label compd radiopharm 1992, 31, 12, 1071.

Route 2
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.
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate
(i)
(ii)
quinoline (iii)
(iv)
Reference 1:
    schumacher, w.; unger, c.; berger, m.r.; hilgard, p.; eibl, h.j.; schmahl, d.; stekar, j.; engel, j.; nagel, g.; hexadecylphocholine. drugs fut 1988, 13, 11, 948.
Reference 2:
    kin, d.j.; unger, c.; berger, m.r.; fleer, e.a.m.; nagel, g.a.; eibl, h.; hexadecylphosphocholine, a new antineoplastic agent: cytotoxic properties in leukaemic cells. j cancer res clin oncol 1986, 111, 24.

Route 3
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.
List of intermediates No.
(i)
tert-butyl 4-[[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]amino]benzoate (ii)
(1s)-2-bromo-1-(2,4-dichlorophenyl)ethyl methanesulfonate (iii)
Reference 1:
    bittman, r.; lohmeyer, m.; antitumor ether lipids and alkylphosphocholines. drugs fut 1994, 19, 11, 1021.
Reference 2:
    nossner, g.; stekar, j.; hilgard, p.; et al.; d-21266, ein neues alkylphospholipid mit hoder antineoplasticher wirkung und verbessertem therapeutischen index. asta medica 1993.

Route 4
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.
List of intermediates No.
(i)
2-(1h-imidazol-1-yl)-3,3-disulfanylacrylonitrile (ii)
(1s)-1-(2,4-dichlorophenyl)-1,2-ethanediol (iii)
(1s)-1-(2,4-dichlorophenyl)-2-[(methylsulfonyl)oxy]ethyl methanesulfonate (iv)
Reference 1:
    bittman, r.; lohmeyer, m.; antitumor ether lipids and alkylphosphocholines. drugs fut 1994, 19, 11, 1021.
Reference 2:
    reddy, k.c.; byun, h.s.; bittman, r.; antitumor ether lipids: an improved synthesis of ilmofosine and an enantioselective synthesis of an ilmofosine analog. tetrahedron lett 1994, 35, 17, 2679.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名米替福新;英文名Miltefosine;Hexadecylphosphocholine;HDPC;D-18506;Impavido;Miltex;CAS[58066-85-6]

 
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