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Name Tiludronate disodium;Tiludronic acid disodium salt;SR-41319B;ME-3737;Cl-TMBP;Skelid
Chemical Name (4-Chlorophenylsulfanylmethylene)bisphosphonic acid disodium salt
CAS 149845-07-8
Related CAS 89987-06-4 (free acid)
Formula C7H7ClNa2O6P2S
Structure
Formula Weight 362.57444
Stage 上市-1995
Company Sanofi-synthélabo (Originator), Meiji Seika (Licensee)
Activity/Mechanism Bone Diseases, Treatment of, METABOLIC DRUGS, Treatment of Pagets Disease, Bisphosphonates
Syn. Route 2
Route 1
a synthesis for [benzene-u-14c]-tiludronate has been described:the chlorination of [u-14c]-acetanilide (i) with tetrabutylammonium iodotetrachloride gives the corresponding 4-chloro derivative (ii) (along with some of the 2-chloro isomer). the hydrolysis of (ii) with concentrated hcl at 60 c yields the chloroaniline (iii), which is converted to the corresponding diazonium salt (iv) with nano2 and hcl. the reaction of (iv) with ferric thiocyanate affords the labeled 4-chlorophenylthiocyanate (v), which is condensed with the lithium salt of methylenebis(phosphonic acid)tetraisopropyl ester (vi) in thf to yield 4-chlorophenylsulfanylmethylenebis(phosphonic acid)tetraisopropyl ester (vii). finally, this compound is hydrolyzed with concentrated hcl or aqueous naoh.
List of intermediates No.
2-[4-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)butyl]-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate (i)
2-(4-aminobutyl)-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate (ii)
trans-3-(3-indolyl)-2-propenoic acid; trans-indole-3-acrylic acid; trans-beta-indoleacrylic acid; indole-3-acrylic acid; 3-(3-indolyl)acrylic acid; (e)-3-(1h-indol-3-yl)-2-propenoic acid (iii)
2-([[(1s)-2-(benzhydryloxy)-1-methyl-2-oxoethyl]oxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid (iv)
4-methoxybenzyl (7r)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (v)
4-methoxybenzyl (7r)-7-([2-([[(1s)-2-(benzhydryloxy)-1-methyl-2-oxoethyl]oxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (vi)
4-methoxybenzyl (7r)-7-([2-([[(1s)-2-(benzhydryloxy)-1-methyl-2-oxoethyl]oxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (vii)
3-amino-4-[(2-chloro-3-pyridinyl)amino]-3-cyclobutene-1,2-dione (i)
2-amino-3,5-dichlorobenzoic acid; 3,5-dichloroanthranilic acid (ii)
1,2,3-benzotriazole; 1h-benzotriazole; azimidobenzene; benzotriazol (iii)
n-[1-(1h-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-3,5-dichlorobenzamide (iv)
3,5-dichloro-n-[1-({2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide (v)
2-bromo-3-methylpyridine; 2-bromo-3-picoline (vii)
Reference 1:
    ellames, g.j.; burgos, a.; synthesis of disodium [benzene-u-c-14]-(4-chlorophenylthio)methylenediphosphonate, [benzene-u-c-14]-tiludronate. j label compd radiopharm 1995, 36, 11, 1071.

Route 2
the reaction of di(4-chlorophenyl)disulfide (i) with tetraisopropyl methylenediphosphonate (ii) by means of nah in hot dmf gives tetraisopropyl (4-chlorophenyl)thiomethylenediphosphonate (iii), which is finally hydrolyzed with refluxing aqueous 6n hcl.
List of intermediates No.
4-methoxybenzyl (7r)-7-([2-([[(1s)-2-(benzhydryloxy)-1-methyl-2-oxoethyl]oxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iii)
chloro(triethylphosphine)gold (ii)
(2s)-2-amino-4-[[(3s)-3-amino-3-carboxypropyl]disulfanyl]butyric acid (i)
Reference 1:
    shirasaki, m. (sanofi-synthelabo); polarizing elements. de 3378140; ep 0100718 .
Reference 2:
    serradell, m.n.; castaner, j.; sr-41319. drugs fut 1985, 10, 6, 482.

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替鲁膦酸二钠;英文名Tiludronate disodium;Tiludronic acid disodium salt;SR-41319B;ME-3737;Cl-TMBP;Skelid;CAS[149845-07-8]

 
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