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药物详细合成路线

Name Silodosin;KAD-3213;KMD-3213
Chemical Name (-)-1-(3-Hydroxypropyl)-5-[2(R)-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide
CAS 160970-64-9
Related CAS 169107-04-4 (diHBr)
Formula C25H32F3N3O4
Structure
Formula Weight 495.54669
Stage 上市-2006
Company Kissei (Originator), Daiichi Pharmaceutical (Licensee), Watson (Licensee)
Activity/Mechanism Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1-Adrenoceptor Antagonists
Syn. Route 2
Route 1
the bromination of 1-acetyl-5-propionylindoline (i) with pyrrolidone hydrotribromide (ptbr) and sulfuric acid in thf gives the alpha-bromo derivative (ii), which is reduced with triethylsilane in tfa yielding the 2-bromopropyl compound (iii). nitration of (iii) with hno3 in hoac affords the 7-nitroindoline (iv), which is reduced to the corresponding amine derivative (v) with h2 over pto2 in ethanol. the reaction of amine (v) with nano2/hcl, followed by treatment with cucn, provides 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (vi), which is treated with nan3 in hot ethylene glycol monomethyl ether/water to yield the 2-azidopropyl derivative (vii). reduction of (vii) with h2 over pd/baso4 in ethanol affords the expected 2-aminopropyl compound (viii), which is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (ix) by means of nahco3 in ethanol to provide the secondary amine (x).the intermediate 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (ix) has been obtained as follows: alkylation of 2-methoxyphenol (xviii) with 2,2,2-trifluoroethyl iodide (xix) by means of k2co3 in hot dmf gives 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (xx), which is demethylated by means of bbr3 in dichloromethane to yield the corresponding phenol (xxi). finally, this compound is alkylated with 1,2-dibromoethane (xxii) and naoh in water at 120 c (1,2).
List of intermediates No.
ethyl 2-[2-([[(4-chlorophenyl)sulfonyl]amino]methyl)-2,3-dihydro-1h-inden-5-yl]-2-(methylsulfanyl)acetate (xxii)
(2s,3r)-2-amino-n-((1r)-1-[(tert-butylsulfanyl)methyl]-2-[[(4r,5r)-2-(4-[2-[(hydroperoxymethyl)amino]-2-oxoethoxy]phenyl)-4-methyl-1,3-dioxan-5-yl]amino]-2-oxoethyl)-3-hydroxybutanamide (xviii)
1,1-biphenyl (xix)
ethyl 7-((2r)-2-{(e,3s)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-butenyl}-5-oxopyrrolidinyl)heptanoate (i)
ethyl 7-((2s)-2-{(3r)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidinyl)heptanoate (ii)
2-methyl-5-neopentyl-1,5-hexadiene (iii)
p-xylene (iv)
1-methyl-4-(2-methylene-5-neopentyl-5-hexenyl)benzene (v)
1-(2-ethyl-2-propenyl)-4-methylbenzene (vi)
1-methylene-4-(2-propyl-2-propenyl)cyclohexane (vii)
1-methyl-4-(2-{2-[4-(2-propyl-2-propenyl)cyclohexyl]ethyl}-2-propenyl)benzene (viii)
1-methyl-4-(2-{2-[4-(2-propyl-2-propenyl)cyclohexyl]pentyl}-2-propenyl)benzene (ix)
(x)
ethyl 2-[4-(4-{4-[amino(imino)methyl]phenyl}-3-oxo-1-piperazinyl)-1-piperidinyl]acetate (xx)
ethyl 2,4-dioxo-4-phenylbutanoate (xxi)
Reference 1:
    sorbera, l.a.; castaner, j.; silvestre, j.s.; kmd-3213. drugs fut 2001, 26, 6, 553.
Reference 2:
    kitazawa, m.; ban, m.; okazaki, k.; ozawa, m.; yazaki, t.; yamagishi, r. (kissei pharmaceutical co., ltd.); indoline cpds. for the treatment of dysuria. ep 0600675; jp 1994220015; us 5387603 .
Reference 3:
    kitazawa, m.; ozawa, m.; okazaki, k.; yamagishi, r.; yazaki, t.; saka, m. (kissei pharmaceutical co., ltd.); indole derivs.. jp 1995330726 .

Route 2
the optical resolution of amine (x), performed by treatment with (+)-mandelic acid in ethanol, followed by crystallization of the resulting salt and then treatment with na2co3 affords the desired (r)-enantiomer (xi). compound (xi) is protected with boc2o to give the corresponding carbamate (xii), which is deacetylated with naoh in ethanol to yield the intermediate (xiii). hydrolysis of the cyano group of (xiii) with naoh and h2o2 in dmso furnishes the corresponding carboxamide (xiv), which is condensed with 3-(tert-butyldimethylsilyloxy)propyl 4-nitrobenzenesulfonate (xv) by means of k2co3 and a crown ether in dioxane to provide the indoline adduct (xvi). finally, desilylation of (xvi) with tbaf in thf yields the 3-hydroxypropyl derivative (xvii), which by removal of the boc-protecting group by means of tfa in dichloromethane gives kmd-3213.
List of intermediates No.
(x)
1-[4-(methylsulfonyl)phenyl]hydrazine; 4-hydrazinophenyl methyl sulfone (xi)
ethyl 1-[4-(methylsulfonyl)phenyl]-5-phenyl-1h-pyrazole-3-carboxylate (xii)
{1-[4-(methylsulfonyl)phenyl]-5-phenyl-1h-pyrazol-3-yl}methanol (xiii)
{1-[4-(methylsulfonyl)phenyl]-5-phenyl-1h-pyrazol-3-yl}methyl methanesulfonate (xiv)
1-(benzyloxy)-3-bromo-5-fluorobenzene; benzyl 3-bromo-5-fluorophenyl ether (xv)
4-[3-(benzyloxy)-5-fluorophenyl]tetrahydro-2h-pyran-4-ol (xvi)
4-[3-(benzyloxy)-5-fluorophenyl]-4-methoxytetrahydro-2h-pyran; benzyl 3-fluoro-5-(4-methoxytetrahydro-2h-pyran-4-yl)phenyl ether (xvii)
Reference 1:
    sorbera, l.a.; castaner, j.; silvestre, j.s.; kmd-3213. drugs fut 2001, 26, 6, 553.
Reference 2:
    kitazawa, m.; ban, m.; okazaki, k.; ozawa, m.; yazaki, t.; yamagishi, r. (kissei pharmaceutical co., ltd.); indoline cpds. for the treatment of dysuria. ep 0600675; jp 1994220015; us 5387603 .
Reference 3:
    kitazawa, m.; ozawa, m.; okazaki, k.; yamagishi, r.; yazaki, t.; saka, m. (kissei pharmaceutical co., ltd.); indole derivs.. jp 1995330726 .

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西洛多辛;英文名Silodosin;KAD-3213;KMD-3213;CAS[160970-64-9]

 
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