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Name NSC-706995;MS-275;MS-27-275
Chemical Name N-[4-[N-(2-Aminophenyl)carbamoyl]benzyl]carbamic acid 3-pyridylmethyl ester
CAS 209783-80-2
Related CAS 209784-80-5 (monoHCl)
Formula C21H20N4O3
Structure
Formula Weight 376.41855
Stage I/II 期临床
Company Mitsui Pharmaceuticals (Originator), Schering AG (Originator)
Activity/Mechanism Colorectal Cancer Therapy, Lung Cancer Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Antimitotic Drugs, Apoptosis Inducers, Histone Deacetylase (HDAC) Inhibitors
Syn. Route 2
Route 1
the acylation of 4-(aminomethyl)benzoic acid (i) with trifluoroacetic anhydride gives the corresponding trifluoroacetamide (ii), which is condensed with the monoprotected ortho-phenylenediamine (iii) by means of oxalyl chloride in dichloromethane/dmf yielding the benzamide (iv). elimination of the trifluoacetyl group of (v) by means of k2co3 in methanol/water affords the 4-(aminomethyl)-derivative (v), which is condensed with 3-(hydroxymethyl)pyridine (vi) and carbonyldiimidazole (cdi) in thf providing the boc-protected intermediate (vii). finally, this compound is deprotected by a treatment with 4n hcl in dioxane/water.
List of intermediates No.
diammine dinitrato platinum complex (vi)
tert-butyl (2s,3r,6r)-2-methyl-6-[(1s,7s)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate (i)
tert-butyl (2s,3r,6r)-2-methyl-6-[(1r,7s)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate (ii)
(1r,7s)-1-[(2r,5r,6s)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl 3-(trifluoromethyl)benzoate (iii)
(1r,4s,6s,7r,9ar)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(e,3s)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2h-quinolizin-1-yl 3-(trifluoromethyl)benzoate (iv)
(1r,4s,6s,7r,9ar)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(e,3s)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2h-quinolizin-1-yl methanesulfonate (v)
(3r,4s,6s,9as)-4-methyl-6-[(e,3s)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2h-quinolizin-3-ol (vii)
Reference 1:
    suzuki, t.; ando, t.; tsuchiya, k.; nakanishi, o.; saito, a.; yamashita, t.; shiraishi, y.; tanaka, e. (mitsui chemicals, inc.); benzamide derivs., useful as cell differentiation inducers. ep 0847992 .

Route 2
the reaction of 4-(aminomethyl)benzoic acid (i) with 3-pyridinylmethanol (ii) and cdi by means of dbu and tea in thf gives the carbamate (iii), which is treated with oxalyl chloride in toluene to yield the corresponding acyl chloride (iv). finally, the condensation of (iv) with 1,2-phenylenediamine (v) by means of imidazole in thf affords the target compound.alternatively, the condensation of acyl chloride (iv) with 2-nitroaniline (vi) by means of pyridine gives the corresponding amide (vii), which is finally reduced with sncl2 and ammonium acetate in methanol.
List of intermediates No.
tert-butyl (3r,4s,5s)-4-[[(2s)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate (vi)
benzyl 3-(benzyloxy)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl ether (v)
diammine dinitrato platinum complex (ii)
tert-butyl (2s,3r,6r)-2-methyl-6-[(1s,7s)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate (i)
ethyl (-)-(1r,2r,5s,6s)-6-fluoro-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate (iii)
(iv)
(vii)
Reference 1:
    suzuki, t.; fukazawa, n.; ando, t.; tsuchiya, k.; synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. j med chem 1999, 42, 15, 3001.

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恩替诺特;英文名NSC-706995;MS-275;MS-27-275;CAS[209783-80-2]

 
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