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藥物詳細合成路線

Name Galanthamine hydrobromide;Galantamine hydrobromide;R-113675;GP-37267;Reminyl;Nivalin
Chemical Name (4aS,6R,8aS)-6-Hydroxy-3-methoxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f][2]benzazepine hydrobromide
CAS 1953-04-4
Related CAS 357-70-0 (free base)
Formula C17H22BrNO3
Structure
Formula Weight 368.27379
Stage 上市-1995
Company Sanochemia (Originator), Ortho-McNeil (Marketer), Janssen (Licensee), Janssen-Cilag (Licensee), Janssen-Kyowa (Licensee), Shire Laboratories (Licensee)
Activity/Mechanism Alzheimers Dementia, Treatment of , ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Neuropathic Pain, Treatment of, Vascular Dementia, Treatment of, Acetylcholinesterase Inhibitors, Butyrylcholinesterase Inhibitors
Syn. Route 12
Route 1
the salification of racemic narwedine (i) with di-p-toluoyl-d-tartaric acid (ii) produces high yields of the 1:1 (iii) or the 2:1 (iv) salts with a high enantiomeric enhancement (97% and 98% e.e., respectively), a dinamic optical enrichement being produced. in a second step, salts (iii) and (iv) are reduced to (-)-galanthamine with l-selectride, which is finally purified up to >99% e.e. by crystallization of its hydrobromide.
List of intermediates No.
tert-butyl (5s)-5-[[(2r)-2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propanoyl]amino]-6-oxo-6-[4-(4-pyridinyl)-1-piperazinyl]hexylcarbamate (i)
tert-butyl (5s)-5-([(2r)-3-(3,5-dibromo-4-hydroxyphenyl)-2-[([4-[2-oxo-1,4-dihydro-3(2h)-quinazolinyl]-1-piperidinyl]carbonyl)amino]propanoyl]amino)-6-oxo-6-[4-(4-pyridinyl)-1-piperazinyl]hexylcarbamate (ii)
2-propylpyridine (iii)
1-[2-(4-methoxyphenyl)-2-oxoethyl]-2-propylpyridinium bromide (iv)
Reference 1:
    chaplin, d.a.; et al.; dynamic diastereomeric salt resolution of narwedine and its transformation to (-)-galanthamine. tetrahedron lett 1998, 39, 37, 6777.

Route 2
the bromination of 3,4-dimethoxybenzaldehyde (i) with br2 in methanol gives the 6-bromo-3,4-dimethoxybenzaldehyde (ii), which is regioselectively demethylated with conc. h2so4 yielding 6-bromo-3-hydroxy-4-methoxybenzaldehyde (iii). the reductocondensation of (iii) with 2-(4-hydroxyphenyl)ethylamine (iv) by means of nabh4 in ethanol affords the secondary amine (v), which is formylated with ethyl formate and formic acid in dioxane furnishing the formamide (vi). the oxidative cyclization of (vi) by means of potassium ferricyanide and k2co3 in toluene/water gives the (+/-)-bromoformylnarwedine (vii), which is protected with propyleneglycol (viii) and tsoh in hot toluene yielding the ketal (ix). the reduction of the formyl group of (ix) with lialh4 in thf affords racemic narwedine (x), which is submitted to a crystallization-induced chiral transformation using a catalytic amount of seed crystals of (-)-narwedine in refluxing ethanol containing tea, an 80% of (-)-narwedine (xi) is obtained. finally, this compound is stereoselectively reduced to the target compound by means of l-selectride in thf.
List of intermediates No.
(8s,10s)-6,8,10,11-tetrahydroxy-1-methoxy-8-[(4r)-4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl]-7,8,9,10-tetrahydro-5,12-naphthacenedione (i)
3-[3-(4-benzyl-1-piperazinyl)propyl]-5-fluoro-1h-indole (iv)
tert-butyl (5s)-5-[[(2r)-2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propanoyl]amino]-6-oxo-6-[4-(4-pyridinyl)-1-piperazinyl]hexylcarbamate (x)
(2s,3r,4r,5r)-2-([(2s,3r,4r,5s)-3-(acetoxy)-2-(benzyloxy)-5-[(triethylsilyl)oxy]tetrahydro-2h-pyran-4-yl]oxy)-4,5-bis[(triethylsilyl)oxy]tetrahydro-2h-pyran-3-yl 4-methoxybenzoate (ii)
(2s,3r,4r,5r)-2-([(3r,4r,5s)-3-(acetoxy)-2-hydroxy-5-[(triethylsilyl)oxy]tetrahydro-2h-pyran-4-yl]oxy)-4,5-bis[(triethylsilyl)oxy]tetrahydro-2h-pyran-3-yl 4-methoxybenzoate (iii)
(2s,3r,4r,5r)-2-([(3r,4r,5s)-3-(acetoxy)-2-[(2,2,2-trichloroethanimidoyl)oxy]-5-[(triethylsilyl)oxy]tetrahydro-2h-pyran-4-yl]oxy)-4,5-bis[(triethylsilyl)oxy]tetrahydro-2h-pyran-3-yl 4-methoxybenzoate (v)
(3s,10r,13s)-17-[(z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17h-cyclopenta[a]phenanthren-3-ol (vi)
1-(5-fluoro-1-benzothiophen-2-yl)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propanone (vii)
tert-butyl (1s)-2,2-dimethyl-1-([[(1r)-1-phenylethyl]amino]carbonyl)propylcarbamate (ix)
(2s)-2-amino-3,3-dimethyl-n-[(1r)-1-phenylethyl]butanamide (xi)
(2r)-2-[2-(tert-butoxy)-2-oxoethyl]-4-pentenoic acid (viii)
Reference 1:
    kuenburg, b.; et al.; development of a pilot scale process for the anti-alzheimer drug (-)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion. org process res dev 1999, 3, 6, 425.
Reference 2:
    chaplin, d.a.; et al.; a concise, scaleable synthesis of narwedine. tetrahedron lett 1997, 38, 45, 7931.
Reference 3:
    czollner, l.; et al.; new kilogram-synthesis of the anti-alzheimer drug (-)-galanthamine. tetrahedron lett 1998, 39, 15, 2087.

Route 3
the enantioselective condensation of 2-bromovanillin (i) with cyclohexenecarboxylate (ii) by means of the chiral phosphine ligand (iii) gives the chiral aryl ether (iv), which is reduced with dibal to yield the diol (v). the protection of (v) with tbdms-otf affords the bis silyl ether (vi), which is cyclized by means of pd(oac)2 to furnish the tetrahydrodibenzofuran (vii). the deprotection of (vii) with tbaf gives the diol (viii), which is chemoselectively oxidized with mno2 to yield the hydroxyaldehyde (ix). the reductocondensation of (ix) with methylamine and nabh3cn affords the secondary amine (x), which is protected with boc2o, providing the carbamate (xi). the oxidation of (xi) with dmp gives the aldehyde (xii), which is condensed with the phosphonium bromide (xiii) and nahmds, yielding the vinyl ether (xiv). the deprotection and cyclization of (xiv) by means of tfa affords the seven-member ring hemiaminal (xv), which is reduced with nabh3cn to provide deoxygalanthamine (xvi). the epoxidation of (xvi) with dimethyldioxirane (dmdo) and tsoh furnishes the epoxide (xvii), which is regioselectively opened with diphenyl diselenide and nabh4 to give the alpha-hydroxy selenide (xviii). elimination of the selenide group of (xviii) by oxidation with naio4 at 80 c yielded isogalanthamine (xix), which is finally isomerized to the target compound by treatment with osborns rhenium catalyst (ph3sio-reo3).
List of intermediates No.
methyl 2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate (xiii)
2-chloro-1-phenyl-1-ethanone (i)
(6ar,6bs,8ar,12as,14ar,14bs)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-4a(2h)-picenecarboxamide (ii)
(1s,5r,13r,17s)-14-(benzylimino)-4-(cyclopropylmethyl)-12-oxa-4-azapentacyclo[9.6.1.0~1,13~.0~5,17~.0~7,18~]octadeca-7(18),8,10-triene-10,17-diol (iii)
trans-1-nitro-2-phenylethylene (iv)
2-azidobenzoyl chloride (v)
2,3-dihydropyrrolo[2,1-b]quinazolin-9(1h)-one (vi)
o-acetylsyringaldehyde; 4-acetoxy-3,5-dimethoxybenzaldehyde (vii)
3-bromopropiophenone; 3-bromophenyl ethyl ketone; 3-bromopropiophenone (viii)
tert-butyl 3-hydroxy-2-{2-oxo-3-[4-oxo-3(4h)-quinazolinyl]propyl}-1-piperidinecarboxylate (ix)
tert-butyl 3-oxo-2-{2-oxo-3-[4-oxo-3(4h)-quinazolinyl]propyl}-1-piperidinecarboxylate (x)
3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3h)-quinazolinone (xi)
2-acetamidophenol; 2-hydroxyacetanilide; o-acetamidophenol; o-hydroxyacetanilide (xii)
n-[2-(benzyloxy)phenyl]acetamide (xiv)
n-[2-(benzyloxy)phenyl]ethanethioamide (xv)
methyl n-[2-(benzyloxy)phenyl]ethanimidothioate (xvi)
4-biphenylcarboxylic acid hydrazide; 4-phenylbenzhydrazide (xvii)
benzyl 2-(3-[1,1-biphenyl]-4-yl-5-methyl-4h-1,2,4-triazol-4-yl)phenyl ether; 4-[2-(benzyloxy)phenyl]-3-[1,1-biphenyl]-4-yl-5-methyl-4h-1,2,4-triazole (xviii)
2-(3-[1,1-biphenyl]-4-yl-5-methyl-4h-1,2,4-triazol-4-yl)phenol (xix)
Reference 1:
    trost, b.m.; toste, f.d.; enantioselective total synthesis of (-)-galanthamine. j am chem soc 2000, 122, 45, 11262.

Route 4
the reaction of (-)-galanthamine hydrobromide (i) with h2o2 in formic acid at 100 c gives 8-bromo-(-)galanthamine (ii), which is then treated with liald4 and d2o to yield the target deuterated compound.
List of intermediates No.
methyl 2-methyl-6-[(5-nitro-1-benzofuran-2-yl)carbonyl]-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate (i)
methyl 8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5-nitro-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate (ii)
Reference 1:
    fels, g.; linnemann, e.; synthesis of 3h-(-)-galanthamine. j label compd radiopharm 2001, 44, 9, 661.

Route 5
the reduction of (-)-narwedine (i) with buli, d2, tris(sec-butyl)borane and n,n,n,n-tetramethylethylenediamine in hexane gives the target deuterated compound.
List of intermediates No.
(2s)-2-amino-3,3-dimethyl-n-[(1r)-1-phenylethyl]butanamide (i)
Reference 1:
    fels, g.; linnemann, e.; synthesis of 3h-(-)-galanthamine. j label compd radiopharm 2001, 44, 9, 661.

Route 6
the reduction of (-)-narwedine (i) with buli, 3h2, tris(sec-butyl)borane and n,n,n,n-tetramethylethylenediamine in hexane gives the target tritiated compound.
List of intermediates No.
(2s)-2-amino-3,3-dimethyl-n-[(1r)-1-phenylethyl]butanamide (i)
Reference 1:
    fels, g.; linnemann, e.; synthesis of 3h-(-)-galanthamine. j label compd radiopharm 2001, 44, 9, 661.

Route 7
the oxidative cyclization of the formamide derivative (i) with iodosobenzene bis(trifluoroacetate) (pifa) gives the tricyclic semiquinone (ii), which is debenzylated by means of tfa and me2s and cyclized with ms-oh to yield the tetracyclic ketone (iii). elimination of the extra oh group of (iii) by means of tf2o, pd(oac)2 and tea affords the intermediate (iv), which is reduced by means of l-selectride and lialh4 to provide racemic galanthamine (v). finally, this compound is submitted to optical resolution to furnish the target (-)-galanthamine. alternatively, the protection of the ketonic group of (iv) with ethyleneglycol and ppts gives the spiroketal (vi), which is selectively reduced with lialh4 and hydrolyzed with hcl to yield racemic narwedine (vii). finally, the reduction of (vii) with l-selectride affords the already described racemic galanthamine.
List of intermediates No.
(2s)-2-amino-3,3-dimethyl-n-[(1r)-1-phenylethyl]butanamide (vii)
[(1r,2r)-2-[(benzoyloxy)methyl]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl benzoate (v)
methyl 6-[(5-amino-1-benzofuran-2-yl)carbonyl]-8-(chloromethyl)-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate (i)
7-nitro-1h-indole-2-carboxylic acid (ii)
methyl 8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5-{[(7-nitro-1h-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate (iii)
methyl 8-(chloromethyl)-2-methyl-6-[(5-{[(7-nitro-1h-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-4-({[(4-nitrophenyl)oxy]carbonyl}oxy)-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate (iv)
methyl 8-(chloromethyl)-2-methyl-4-{[(4-methyl-1-piperazinyl)carbonyl]oxy}-6-[(5-{[(7-nitro-1h-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate (vi)
Reference 1:
    node, m.; et al.; an efficient synthesis of (±)-narwedine and (±)-galanthamine by an improved phenolic oxidative coupling. angew chem. int ed engl 2001, 40, 16, 3060.

Route 8
the esterification of the carboxylic acid (ii) with 2-iodo-6-methoxyphenol (i) by means of edc and dmap in dichloromethane gives the corresponding ester (iii), which is cyclized by means of a pd catalyst and tloac in refluxing acetonitrile to yield the spiranic 1-benzopyranone (iv). the cleavage of the ethylene ketal group of (iv) with ph3c-bf4 in dichloromethane affords the spiranic diketone (v), which is dehydrogenated with (ph-seo)2o in refluxing dichloromethane to provide the spiranic cyclohexadienone (vi). the reaction of dienone (vi) with methylamine resulted in a spontaneous michael addition to give the n-methylamide (vii), which is cyclized with paraformaldehyde and tfa yielding the tetracyclic compound (viii). the enantioselective reduction of the ketonic group of (viii) with l-selectride in thf affords the alcohol (ix), which is finally reduced with lialh4 providing the target galanthamine.
List of intermediates No.
Reference 1:
    guillou, c.; et al.; an efficient total synthesis of (±)-galanthamine. angew chem. int ed 2001, 40, 24, 4745.

Route 9
the n-demethylation of galantamine (i) by means of mcpba and feso4 in dichloromethane gives the n-demethylated compound (ii), which is then remethylated with 14c-methyl iodide and diisopropylamine (dia) in methanol to obtain the target labeled compound.
List of intermediates No.
[(1r,2r)-2-[(benzoyloxy)methyl]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl benzoate (i)
Reference 1:
    janssen, c.g.m.; et al.; synthesis of 3h-, 14c-, and stable-isotope-labelled galantamine. j label compd radiopharm 2002, 45, 10, 841.

Route 10
the o-demethylation of galantamine (i) by means of buli and butanethiol in hmpt gives the o-demethylated compound (ii), which is then remethylated with 14c-methyl iodide, koh and 1,3-dimethylimidazolidin-2-one (dmio) to obtain the target labeled compound.
List of intermediates No.
[(1r,2r)-2-[(benzoyloxy)methyl]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl benzoate (i)
{(1r,2s)-2-{[2-amino-6-(benzyloxy)-9h-purin-9-yl]methyl}-2-[(benzoyloxy)methyl]cyclopropyl}methyl benzoate (ii)
Reference 1:
    janssen, c.g.m.; et al.; synthesis of 3h-, 14c-, and stable-isotope-labelled galantamine. j label compd radiopharm 2002, 45, 10, 841.

Route 11
the o-demethylation of galantamine (i) by means of buli and butanethiol in hmpt gives the o-demethylated compound (ii), which is then remethylated with fully deuterated 13c-methanol, diad and pph3 in thf to obtain the target labeled compound.
List of intermediates No.
[(1r,2r)-2-[(benzoyloxy)methyl]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl benzoate (i)
{(1r,2s)-2-{[2-amino-6-(benzyloxy)-9h-purin-9-yl]methyl}-2-[(benzoyloxy)methyl]cyclopropyl}methyl benzoate (ii)
Reference 1:
    janssen, c.g.m.; et al.; synthesis of 3h-, 14c-, and stable-isotope-labelled galantamine. j label compd radiopharm 2002, 45, 10, 841.

Route 12
the condensation of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (i) with the cyclohexenecarboxylate (ii) by means of a pd catalyst and a chiral auxiliary gives the chiral aryl ether (iii), which is treated with methyl orthoformate and ts-oh in methanol to yield the dimethylacetal (iv). the reduction of the ester group of (iv) by means of dibal affords the methanol derivative (v), which is treated with acetone cyanohydrin, pph3 and ts-oh to provide the acetonitrile derivative (vi). the cyclization of (vi) by means of pd(oac)2 and ag2co3 in refluxing toluene leads to the tetrahydro dibenzofuran derivative (vii), which is diastereoselectively oxidized by means of seo2 in hot dioxane to give the chiral secondary alcohol (viii). the reaction of (viii) with methylamine in methanol yields the methylimine (ix), which is submitted to reductocyclization by means of dibal to afford the tetracyclic intermediate (x). this compound, without isolation, is reduced with nabh3cn to provide the target galanthamine.
List of intermediates No.
2-chloro-1-phenyl-1-ethanone (i)
(6ar,6bs,8ar,12as,14ar,14bs)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-4a(2h)-picenecarboxamide (ii)
trans-1-nitro-2-phenylethylene (iii)
Reference 1:
    trost, b.m.; tang, w.p.; an efficient enantioselective synthesis of (-)-galanthamine. angew chem. int ed 2002, 41, 15, 2795.

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氫溴酸加蘭他敏;英文名Galanthamine hydrobromide;Galantamine hydrobromide;R-113675;GP-37267;Reminyl;Nivalin;CAS[1953-04-4]

 
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