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藥物詳細合成路線

Name Ono-4007
Chemical Name 2-Deoxy-3-O-(9-phenylnonanoyl)-2-[3(S)-(9-phenylnonanoyloxy)tetradecanamido]-4-O-sulfo-D-glucopyranose monosodium salt
CAS 152646-95-2
Related CAS 111250-67-0 (free acid)
Formula C50H78NNaO12S
Structure
Formula Weight 940.23246
Stage II 期臨床
Company Ono (Originator)
Activity/Mechanism IMMUNOMODULATING AGENTS, Immunomodulators, Oncolytic Drugs
Syn. Route 2
Route 1
1) the reaction of benzyl 2-amino-4,6-o-benzylidene-2-deoxy-alpha-d-glucopyranoside (i) with 3(s)-hydroxytetradecanoic acid (ii) by means of pivaloyl chloride in thf gives the corresponding amide (iii), which is acylated with 9-phenylnonanoic acid (iv), dimethylaminopyridine (dmap) and triethylamine (or tetramethylurea and oxalyl chloride) yielding the fully esterified compound (v). elimination of the benzylidene group of (v) with hbf4/nabf4 and the benzyl group by hydrogenolysis with h2 over pd/c affords the trihydroxy compound (vi), which is treated with tert-butyldimethylsilyl chloride (tbdms-cl) and pyridine to give (vii) with the primary oh-group protected with a tbdms group. the sulfonation of (vii) with so3/pyridine complex affords the sulfonated compound (viii), which is finally desilylated with acetic acid in ethanol.
List of intermediates No.
(2r)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid (i)
(4r)-1-[tert-butyl(dimethyl)silyl]-4-(hydroxymethyl)-2-azetidinone (ii)
5-mercapto-1-methyl-1h-tetrazole; 1-methyl-1h-1,2,3,4-tetraazol-5-ylhydrosulfide (iii)
(4r)-1-[tert-butyl(dimethyl)silyl]-4-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone (iv)
(4r)-4-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone (v)
1-(chloromethyl)-4-(trifluoromethyl)benzene (vi)
n-methyl-n-[4-(trifluoromethyl)benzyl]amine (vii)
3-bromoquinoline (viii)
Reference 1:
    graul, a.; martel, a.m.; castaner, j.; ono-4007. drugs fut 1997, 22, 8, 841.
Reference 2:
    imaki, k.; hashimoto, s.; wakatsuka, h. (ono pharmaceutical co., ltd.); salts of glucopyranose deriv. and its intermediate. ep 0553786; jp 1994041175; us 5733927 .

Route 2
2) the acylation of the amine group of benzyl 2-amino-2-deoxy-4,6-o-isopropylidene-beta-d-glucopyranoside (ix) with 3(s)-hydroxytetradecanoic acid (ii) by means of pivaloyl chloride in thf gives the corresponding amide (x), which is acylated with 9-phenylnonanoic acid (iv), 2-chloro-1-methylpyridinium iodide (cmpi) and dimethylaminopyridine to yield the fully esterified compound (xi). elimination of the isopropylidene group of (xi) with acetic acid/water affords the dihydroxy compound (xii), which is treated with tert-butyldimethylsilyl chloride and dmap to give (xiii) with the primary oh-group protected with a tbdms group. elimination of the benzyl protecting group of (xiii) by hydrogenation as before gives 2-deoxy-6-o-(tert-butyldimethylsilyl)-3-o-(9-phenylnonanoyl)-2-[3(s)-(9-phenylnonanoyloxy)tetradecanamido]-d-glucopyranose (xiv), which is sulfonated with so3/pyridine complex in pyridine yielding the 4-o-sulfonated compound (xv). finally, this compound is desilylated by means of acetic acid in methanol.
List of intermediates No.
(4r)-1-[tert-butyl(dimethyl)silyl]-4-(hydroxymethyl)-2-azetidinone (ii)
(4r)-1-[tert-butyl(dimethyl)silyl]-4-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone (iv)
n-methyl-n-[4-(trifluoromethyl)benzyl]amine (xiv)
n-methyl(4-nitrophenyl)methanamine (ix)
1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-nitrobenzene (x)
diethyl 1-(diethoxyphosphoryl)vinylphosphonate (xi)
(3r,4s,5s,6r,7s,9r,11r,12r,13s,14r)-7-(allyloxy)-6-[[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2h-pyran-2-yl]oxy]-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione (xii)
(2s,3r,4s,6r)-2-[[(3r,4s,5s,6r,7s,9r,11r,12r,13s,14r)-7-(allyloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2h-pyran-3-yl benzoate (xiii)
3-bromoquinoline (xv)
Reference 1:
    toda, m.; shimoji, k.; sasaki, y. (ono pharmaceutical co., ltd.); novel glucopyranose derivs. ep 0226381; jp 1988179885 .

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名Ono-4007 單鈉鹽;英文名Ono-4007;CAS[152646-95-2]

 
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