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Name Ramelteon;TAK-375
Chemical Name (-)-(S)-N-[2-(2,6,7,8-Tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethyl]propionamide
CAS 196597-26-9
Related CAS 196597-27-0 (R-isomer), 196597-17-8 (undefined isomer)
Formula C16H21NO2
Structure
Formula Weight 259.35127
Stage 上市-2005
Company Takeda (Originator)
Activity/Mechanism PSYCHOPHARMACOLOGIC DRUGS, Sleep Disorders, Treatment of, Melatonin MT1 Agonists, Melatonin MT2 Agonists
Syn. Route 3
Route 1
the reaction of 2,3-dihydrobenzofuran (i) with dichloromethyl methyl ether (ii) by means of ticl4 in dichloromethane gives 2,3-dihydrobenzofuran-5-carbaldehyde (iii), which is condensed with the phosphonate (iv) by means of nah in thf to yield the propenoic ester (v). the reduction of (v) with h2 over pd/c in ethanol affords the saturated propionic ester (vi), which is brominated with br2 in hoac providing the 7-bromo derivative (vii). further bromination of (vii) with br2 and fe in hoac gives the 6,7-dibromo derivative (viii), which is hydrolyzed with naoh in thf/water to yield the propionic acid derivative (ix). the reaction of (ix) with hot socl2 affords the corresponding acyl chloride (x), which is cyclized by means of alcl3 in dichloroethane to provide 4,5-dibromo-2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-one (xi). the debromination of (xi) by means of h2 over pd/c in ac-oh gives 2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-one (xii), which is condensed with the phosphorane (xiii) by means of nah in thf to yield 2-(2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-ylidene)acetonitrile (xiv). the selective reduction of the cyano group of (xiv) by means of h2 over raney cobalt in ethanol/nh3 affords 2-(2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-ylidene)ethylamine (xv), which is condensed with propionyl chloride (xvi) by means of tea in thf to provide the propionamide (xvii). finally this compound is enantioselectively reduced with h2 over a chiral ru catalyst (ru(oac)2-(s)-binap) in methanol to give rise to the target (s)-enantiomer.alternatively, the reduction of 2-(2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-ylidene)acetonitrile (xiv) with h2 over rani in ethanol/nh3 gives 2-(2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-yl)ethylamine (xviii), which is acylated with propionyl chloride (xvi) and tea in dmf to yield the racemic propionamide (xix). finally this compound is submitted to optical resolution by means of chiral hplc to afford the target (s)-enantiomer.
List of intermediates No.
methyl (1r,2r)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate (iv)
n-[2-(8-bromofuro[2,3-f][1]benzofuran-4-yl)-1-methylethyl]-2,2,2-trifluoroacetamide (xiii)
4-methoxybenzyl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (i)
(2r,4r,5r,6r,8s,11s,12r,19r,20r)-5-[[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2h-pyran-2-yl]oxy]-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-13-oxa-15,18-diazatricyclo[10.6.2.0(15,20)]icos-1(18)-ene-7,9,14-trione (xvi)
1-{[(tert-butylamino)oxy]methyl}benzene; o-benzyl-n-(tert-butyl)hydroxylamine (ii)
Reference 1:
    chilman-blair, k.; castaner, j.; silvestre, j.s.; bayes, m.; tak-375. drugs fut 2003, 28, 10, 950.
Reference 2:
    ohkawa, s.; uchikawa, o.; fukatsu, k.; miyamoto, m. (takeda chemical industries, ltd.); tricyclic cpds., their production and use. ep 0885210; jp 1998287665; jp 1999152281; wo 9732871 .

Route 2
the reaction of 2,3-dihydrobenzofuran (i) with dmf (ii) and pocl3 gives 2,3-dihydrobenzofuran-5-carbaldehyde (iii), which is condensed with the phosphonate (iv) by means of t-buona in toluene to yield the acrylate (v). the reduction of (v) with h2 over pd/c in acoh affords the corresponding propionate (vi), which is brominated with br2 in acoh to provide the dibromo derivative (vii). the hydrolysis of the ester group of (vii) in acidic medium gives the expected propionic acid derivative (viii), which is treated with socl2 in dichloromethane to yield the propionyl chloride (ix). the cyclization of (ix) by means of alcl3 in dichloromethane affords the 4,5-dibromo-2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-one (x), which is submitted to an hydrogenolytic debromination with h2 over pd/c in methanol to provide the 2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-one (xi). the wittig condensation of (xi) with phosphonate (xii) by means of naome in toluene gives 2-(2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-ylidene)acetonitrile (xiii), which is reduced with h2 and raney-co in toluene/meoh to yield 2-(2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8-ylidene)ethylamine (xiv). the asymmetric reduction of (xiv) with h2 and a chiral ru catalyst in toluene/meoh affords the 2-(2,6,7,8-tetrahydro-1h-indeno[5,4-b]furan-8(s)-yl)ethylamine (xv), which is finally acylated with propionyl chloride (xvi) and naoh in aq. thf to provide the target chiral propionamide.
List of intermediates No.
methyl (1r,2r)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate (iv)
n-[2-(8-bromofuro[2,3-f][1]benzofuran-4-yl)-1-methylethyl]-2,2,2-trifluoroacetamide (xii)
4-methoxybenzyl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (i)
(2r,4r,5r,6r,8s,11s,12r,19r,20r)-5-[[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2h-pyran-2-yl]oxy]-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-13-oxa-15,18-diazatricyclo[10.6.2.0(15,20)]icos-1(18)-ene-7,9,14-trione (xvi)
7-hydroxy-4-methyl-2h-pyrano[2,3-b]pyridin-2-one (ii)
Reference 1:
    ohkawa, s.; discovery of the novel melatonin agonist tak-375. 22nd symp med chem (nov 27 2002, shizuoka) 2002, abst il 11.
Reference 2:
    chilman-blair, k.; castaner, j.; silvestre, j.s.; bayes, m.; tak-375. drugs fut 2003, 28, 10, 950.

Route 3
the condensation of 6-methoxyindan-1-one (i) with phosphonate (ii) by means of nah in thf gives 2-(6-methoxyindan-1-ylidene)acetonitrile (iii), which is hydrogenated with h2 over raney co in ethanol/nh3 to yield 2-(6-methoxyindan-1-ylidene)ethylamine (iv). the acylation of (iv) with propionyl chloride (v) and tea in thf affords the corresponding amide (vi), which is submitted to an asymmetric reduction with h2 and a chiral ru catalyst to provide n-[2-(6-methoxyindan-1(s)-yl)ethyl]propionamide (vii). the bromination of (vii) with br2 and naoac in methanol gives the 5-bromo derivative (viii), which is demethylated by means of bbr3 in dichloromethane to yield the hydroxy compound (ix). the reaction of (ix) with allyl bromide (x) by means of nah in dmf affords the allyl ether (xi), which is submitted to a claisen rearrangement in n,n-diethylaniline at 200 c to provide the 7-allyl derivative (xii).the reaction of (xii) with ozone in methanol gives the acetaldehyde derivative (xiii), which is reduced with nabh4 in methanol to yield the ethanol derivative (xiv). the hydrogenolysis of the br substituent of (xiv) by means of h2 over pd/c in methanol/tea affords the dihydroxy compound (xv), which is treated with mscl and pyridine to provide the mesylate (xvi). finally, this compound is cyclized by means of tea in refluxing ethyl acetate to furnish the target indeno[5,4-b]furan derivative.
List of intermediates No.
n-[2-(8-bromofuro[2,3-f][1]benzofuran-4-yl)-1-methylethyl]-2,2,2-trifluoroacetamide (ii)
tert-butyl (2r)-2-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylate (x)
(2r,4r,5r,6r,8s,11s,12r,19r,20r)-5-[[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2h-pyran-2-yl]oxy]-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-13-oxa-15,18-diazatricyclo[10.6.2.0(15,20)]icos-1(18)-ene-7,9,14-trione (v)
n-[(2r,6s,9s,11r,12r,14as,15s,20s,23s,25as)-20-[(1r)-3-amino-1-hydroxypropyl]-23-[(1s)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1r)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxo-12-(phenylsulfanyl)tetracosahydro-1h-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide (i)
Reference 1:
    chilman-blair, k.; castaner, j.; silvestre, j.s.; bayes, m.; tak-375. drugs fut 2003, 28, 10, 950.
Reference 2:
    uchikawa, o.; fukatsu, k.; tokunoh, r.; et al.; synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. j med chem 2002, 45, 19, 4222.

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雷美替胺;英文名Ramelteon;TAK-375;CAS[196597-26-9]

 
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