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Name Indeloxazine hydrochloride;CI-974;YM-08054;Elen
Chemical Name (±)-2-[(1H-Inden-7-yloxy)methyl]morpholine hydrochloride
CAS 65043-22-3
Related CAS 60929-23-9 (free base)
Formula C14H18ClNO2
Structure
Formula Weight 267.75806
Stage 上市-1988
Company Yamanouchi (Originator)
Activity/Mechanism Cognition Disorders, Treatment of, NEUROLOGIC DRUGS
Syn. Route 4
Route 1
1) the condensation of 4-(triphenylmethyl)-2-(p-toluenesulfonyloxymethyl)morpholine (i) with 4-hydroxy-1 indanone (ii) through the corresponding potassium salt in hot dmf gives 2-(1-oxoindan-4-yloxymethyl)-4-(triphenylmethyl)morpholine (iii), which is reduced with lialh4 in thf to 2-(1-hydroxyindan-4-yloxymethyl)-4-(triphenylmethyl)morpholine (iv). finally, this compound is dehydrated and deprotected with hcl in refluxing ethanol.
List of intermediates No.
n-benzyl-6-(4-phenylbutoxy)-1-hexanamine; n-benzyl-n-[6-(4-phenylbutoxy)hexyl]amine (i)
methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate (ii)
4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol (iii)
2,2-dichloro-3-methylbutanal (iv)
Reference 1:
    arima, h.; tamazawa, k.; synthesis of 14c-labeled indeloxazine hydrochlorid. j label compd radiopharm 1985, 22, 12, 1217.
Reference 2:
    nozaki, y.; tachikawa, s.; kojima, t.; niigata, k.; fujikura, t.; takahashi, k.; kagami, s.; synthesis of (±)-2-(inden-7-yloxy)methyl]morpholin. chem pharm bull 1985, 33, 9, 3766.
Reference 3:
    tachikawa, s.; takahashi, k.; kagami, s.; kojima, t.; fujikura, t.; nozaki, y.; harada, m.; murakami, m.; usuda, s.; niigata, k. (yamanouchi pharmaceutical co., ltd.); process for the preparation of acid addition salt . ca 1103247 .
Reference 4:
    castaner, j.; prous, j.; indeloxazine hydrochloride. drugs fut 1987, 12, 6, 533.

Route 2
2) treatment of 1-[inden-7(or4)-yloxyl-2,3-epoxypropane (v) with excess 2-aminoethyl hydrogen sulfate (vi) and aqueous naoh gives (+)-2-[[inden-7(or4)-yloxylmethyl]morpholine (vii). the 4-indenyl isomer (viii) and the 7-indenyl isomer (indeloxazine) can be separated by fractional crystallization.
List of intermediates No.
benzyl (4-isopropyl-1h-imidazol-2-yl)methyl ether; 2-[(benzyloxy)methyl]-4-isopropyl-1h-imidazole (va)
2-[(benzyloxy)methyl]-5-iodo-4-isopropyl-1h-imidazole; benzyl (5-iodo-4-isopropyl-1h-imidazol-2-yl)methyl ether (vi)
bis(3,5-dichlorophenyl) disulfide; 1,3-dichloro-5-[(3,5-dichlorophenyl)disulfanyl]benzene (vii)
Reference 1:
    arima, h.; tamazawa, k.; synthesis of 14c-labeled indeloxazine hydrochlorid. j label compd radiopharm 1985, 22, 12, 1217.
Reference 2:
    nozaki, y.; tachikawa, s.; kojima, t.; niigata, k.; fujikura, t.; takahashi, k.; kagami, s.; synthesis of (±)-2-(inden-7-yloxy)methyl]morpholin. chem pharm bull 1985, 33, 9, 3766.
Reference 3:
    tachikawa, s.; takahashi, k.; kagami, s.; kojima, t.; fujikura, t.; nozaki, y.; harada, m.; murakami, m.; usuda, s.; niigata, k. (yamanouchi pharmaceutical co., ltd.); process for the preparation of acid addition salt . ca 1103247 .
Reference 4:
    castaner, j.; prous, j.; indeloxazine hydrochloride. drugs fut 1987, 12, 6, 533.

Route 3
3) the reaction of 2-(2-benzyloxyphenyl)ethanol (i) with triphenylphosphine and n-bromosuccinimide in benzene gives 2-(2-benzyloxyphenyl)ethyl bromide (ii), which upon treatment with potassium [14c]cyanide (ii) in dimethylformamide affords 3-(2-benzyloxyphenyl)-[1-14c]propionitrile (iv), which is hydrogenated with h2 over pd/c in methanol to give 3-(2-hydroxyphenyl)[1-14c]propionitrile (v). nitrile (v) is treated with hydrogen chloride in ethanol to give 3,4-dihydro[2-14c]coumarin (viii) through the acid (vi) and the ester (vii). the reaction of compound (viii) with sodium chloride- aluminum chloride complex gives 4 hydroxy-1-[1-14c]indanone (ix), which is acetylated with acetic anhydride in anhydrous 1,2-dichloromethane and triethylamine giving the acetate (x) in order to obtain pure (ix) after alkaline hydrolysis. compound (ix) is treated with 2-bromomethyl-4 triphenyl-methylmorpholine (xi) in the presence of anhydrous k2co3 to dimethylformamide to give 2-[(1-oxo[1-14c]indan-4-yloxy)methyl]-4-triphenylmethylmorpholine (xii), which is reduced with nabh4 giving 2-[(1-hydroxy[1-14c]indan-4yloxy)methyl]-4-triphenylmethylmorpholine (xiii). compound (xiii) is treated with an excess of hcl in ethanol to give (rac)-2-[[[3-14c]inden-7-yloxy]methyl]morpholine hydrochloride (indeloxazine hydrochloride) without formation of the corresponding 4-isomer.
List of intermediates No.
methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate (ix)
4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol (xii)
2,2-dichloro-3-methylbutanal (xiii)
benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1h-imidazol-2-yl]methyl ether; 2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1h-imidazole (i)
4-([2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1h-imidazol-1-yl]methyl)pyridine; benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1h-imidazol-2-yl]methyl ether (ii)
7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-carbaldehyde (iv)
1-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-2-propen-1-ol (v)
1-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-2-propen-1-one (vi)
methyl 4-[4-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-4-oxobutanoyl]benzoate (vii)
methyl 4-[5-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-1h-pyrrol-2-yl]benzoate (viii)
1-(5,8-dimethyl-2-naphthyl)-2-propen-1-ol (x)
1-(5,8-dimethyl-2-naphthyl)-2-propen-1-one (xi)
methyl 4-acryloylbenzoate (xiv)
Reference 1:
    nozaki, y.; tachikawa, s.; kojima, t.; niigata, k.; fujikura, t.; takahashi, k.; kagami, s.; synthesis of (±)-2-(inden-7-yloxy)methyl]morpholin. chem pharm bull 1985, 33, 9, 3766.
Reference 2:
    arima, h.; tamazawa, k.; synthesis of 14c-labeled indeloxazine hydrochlorid. j label compd radiopharm 1985, 22, 12, 1217.
Reference 3:
    tachikawa, s.; takahashi, k.; kagami, s.; kojima, t.; fujikura, t.; nozaki, y.; harada, m.; murakami, m.; usuda, s.; niigata, k. (yamanouchi pharmaceutical co., ltd.); process for the preparation of acid addition salt . ca 1103247 .
Reference 4:
    castaner, j.; prous, j.; indeloxazine hydrochloride. drugs fut 1987, 12, 6, 533.

Route 4
the reaction of 2-(p-toluenesulfonyloxymethyl)-4-triphenylmethylmorpholine (i) with the potassium salt of 4-hydroxy-1-indanone (ii) in dmso at 100 c gives 2-(1-oxoindan-4-yloxymethyl)-4-triphenylmethylmorpholine (iii), which is hydrolyzed with trifluoroacetic acid yielding 2-(1-oxoindan-4-yloxymethyl)morpholine (iv). the reduction of (iv) with lialh4-thf affords 2-(1-hydroxyindan-4-yloxymethyl)morpholine (v), which is finally dehydrated by treatment with p-toluenesulfonic acid in refluxing toluene.
List of intermediates No.
n-benzyl-6-(4-phenylbutoxy)-1-hexanamine; n-benzyl-n-[6-(4-phenylbutoxy)hexyl]amine (i)
4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol (iii)
(4r)-4-((1s)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazole; tert-butyl(dimethyl)silyl (1s)-2-methyl-1-[(4r)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]propyl ether (ii)
(2r,3s)-2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-1-pentanol (iv)
(5s,6r)-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; (1r,2s)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutylamine (v)
Reference 1:
    blancafort, p.; owen, r.t.; serradell, m.n.; castaner, j.; ym-08054-1. drugs fut 1979, 4, 11, 836.
Reference 2:
    niigata, k.; murakami, m.; kagami, s.; fujikura, s.; kojima, a.; tachikawa, s.; nozaki, j.; takahashi, k. (yamanouchi pharmaceutical co., ltd.); novel indene derivs. or their salts. jp 1977111580 .
Reference 3:
    takahashi, k. ; nozaki, j.; fujikura, s.; tachikawa, s.; kagami, s.; niigata, k.; kojima, a.; murakami, m. (yamanouchi pharmaceutical co., ltd.); novel indene derivs.. jp 1977083773 .
Reference 4:
    usuda, s.; fujikura, t.; kojima, t.; tachikawa, s.; kawashima, y.; kagami, s.; murakami, m.; takahashi, k.; nozaki, y.; niigata, k. (yamanouchi pharmaceutical co., ltd.); 2-(indenyloxymethyl)morpholine derivs.. de 2601703; gb 1535276 .

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鹽酸茚洛秦;英文名Indeloxazine hydrochloride;CI-974;YM-08054;Elen;CAS[65043-22-3]

 
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