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Name Temocapril hydrochloride;CS-622;RS-5142;Acecol
Chemical Name 2-[(2S,6R)-6-[1(S)-(Ethoxycarbonyl)-3-phenylpropylamino]-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetic acid hydrochloride
CAS 110221-44-8
Related CAS 111902-57-9 (free base), 102090-90-4 (monoHCl;undefined isomer)
Formula C23H29ClN2O5S2
Structure
Formula Weight 513.07898
Stage 上市-1994
Company Sankyo (Originator), Nippon Boehringer Ingelheim (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors
Syn. Route 2
Route 1
1) the reduction of 2-thiophenecarboxaldehyde cyanohydrin (i) with lialh4 gives 2-amino-1-(2-thienyl)ethanol (ii), which is n-protected with di-tert-butyl pyrocarbonate yielding 2-(tert-butoxycarbonylamino)-1-(2-thienyl)ethanol (iii). the reaction of (iii) with pcl5 in dichloromethane affords 2-(tert-butoxycarbonylamino)-1-chloro-1-(2-thienyl)ethane (iv), which is condensed with benzhydryl n-phthaloylcysteinate (v) by means of na2co3 in hot dmf giving the s-substituted cysteinate (vi). the deprotection of (vi) with trifluoroacetic acid in anisole yields s-[2-amino-1-(2-thienyl)ethyl]-n-phthaloylcysteine (vii), which is cyclized by means of diphenylphosphoryl azide (dpa) in dmf giving 6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-5-one (viii). the condensation of (viii) with tert-butyl bromoacetate (ix) by means of nah in dmf affords tert-butyl 2-[6-phthalimido-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (x), which is treated with methylhydrazine in methanol-dichloromethane yielding the 6-amino derivative (xi). the condensation of (xi) with ethyl 2-bromo-4-phenylbutyrate (xii) by means of na2co3 in hot dmf gives the tert-butyl ester of the desired product (xiii), which is finally deprotected with trifluoroacetic acid in anisole.
List of intermediates No.
(2s)-2-azido-2-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamide (ix)
(1s,3s,3ar,4as,8ar,9as)-1-methoxy-3-methyldecahydronaphtho[2,3-c]furan-4(1h)-one (i)
(1s,3s,3as,4as,8ar,9as)-1-methoxy-3-methyl-4-methylenedodecahydronaphtho[2,3-c]furan; (1s,3s,3as,4as,8ar,9as)-3-methyl-4-methylenedodecahydronaphtho[2,3-c]furan-1-yl methyl ether (ii)
[(1s,3s,3ar,4r,4as,8ar,9as)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methanol (iii)
[(1s,3s,3ar,4r,4as,8ar,9as)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methyl methanesulfonate (iv)
3-(cyclopentyloxy)benzoyl chloride (v)
3-(cyclopentyloxy)-4-methoxybenzoic acid (vi)
barbaloin; (10r)-1,8-dihydroxy-3-(hydroxymethyl)-10-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2h-pyran-2-yl]-9(10h)-anthracenone (vii)
acetylbarbaloin; (10r)-8-(acetoxy)-3-(hydroxymethyl)-9-oxo-10-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2h-pyran-2-yl]-9,10-dihydro-1-anthracenyl acetate (viii)
(2r,4ar,6r,7r,8s,8ar)-7-(acetoxy)-6-hydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate (x)
(2r,4ar,6r,7r,8s,8ar)-6-[[(5s,5ar,8ar,9r)-9-(4-[[(benzyloxy)carbonyl]oxy]-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3,4:6,7]naphtho[2,3-d][1,3]dioxol-5-yl]oxy]-7-(acetoxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate (xi)
(6r,7r)-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)pentanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xii)
(6r,7r)-3-[(acetoacetoxy)methyl]-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)pentanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xiii)
Reference 1:
    yanagisawa, h.; ishihara, s.; ando, a.; kanazaki, t.; koike, h.; tsujita, y. (sankyo co., ltd.); perhydrothiazepine derivatives, their preparation and their therapeutical use. au 8541058; ep 0161801; es 8702388; es 8801229; jp 85215678; jp 86267579 .
Reference 2:
    prous, j.; castaner, j.; rs-5142. drugs fut 1989, 14, 4, 336.
Reference 3:
    ishihara, s.; ando, a.; miyamoto, s.; kanazaki, t.; hata, t.; oizumi, k.; matsushita, y.; koike, h.; yanagisawa, h.; iijima, y.; angiotensin-converting enzyme inhibitors: perhydro-1,4-thiazepin-5-one derivatives. j med chem 1987, 30, 11, 1984.

Route 2
2) the addition of tert-butoxycarbonyl)-l-cysteine (xiv) to 2-(2-nitroethenyl)thiophene (xv) by means of n-methylmorpholine in toluene gives s-[2-nitro-1-(2-thienyl)ethyl-n-(tert-butoxycarbonyl-l-cysteine (xvi), which is reduced with h2 over pd/c in acetic acid yielding the corresponding amine (xvii). the cyclization of (xvii) by means of diphenyl phosphorazidate (dpn) and n-methylmorpholine in dmf affords (2rs,6r)-6-(tert-butoxycarbonylamino)-2-(2-thienyl)perhydro-1,4-thiazepine (xviii), which by hydrolysis and fractional crystallization gives (2s,6r)-6-amino-2-(2-thienyl)perhydro-1,4-thiazepine (xix). the condensation of (xix) with ethyl 2(r)-(trifluoromethylsulfonyloxy)-4-phenylbutanoate (xx) by means of triethylamine in dichloromethane yields (2s,2r)-6-[1(s)-(ethoxycarbonyl)-3-phenylpropylamino]-2-(2-thienyl)- perhydro-1,4-thiazepin-5-one (xxi), which is condensed with tert-butyl bromoacetate (xxii) by means of nah in dmf to give the precursor (xxiii). finally, this compound is hydrolyzed with 4n-hcl-dioxane at room temperature.
List of intermediates No.
(2s)-2-azido-2-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamide (xxii)
(6r,7r)-3-[(acetoacetoxy)methyl]-7-[(4-chloro-3-oxobutanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xiv)
(6r,7r)-3-[(acetoacetoxy)methyl]-7-[[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xv)
1-[2-(dimethylamino)ethyl]-1h-1,2,3,4-tetraazole-5-thiol; 1-[2-(dimethylamino)ethyl]-1h-1,2,3,4-tetraazol-5-ylhydrosulfide (xvi)
(6r,7r)-7-(acetoacetamido)-3-[(acetoxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xvii)
(6r,7r)-7-amino-3-[([1-[2-(dimethylamino)ethyl]-1h-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xviii)
(6r,7r)-7-[(4-chloro-3-oxobutanoyl)amino]-3-[([1-[2-(dimethylamino)ethyl]-1h-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xix)
2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid (xx)
5-bromophthalide; 5-bromo-2-benzofuran-1(3h)-one (xxi)
4-bromo-4-fluoro-2-(hydroxymethyl)benzhydrol; [4-bromo-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanol (xxiii)
Reference 1:
    yanagisawa, h.; ishihara, s.; ando, a.; kanazaki, t.; koike, h.; tsujita, y. (sankyo co., ltd.); perhydrothiazepine derivatives, their preparation and their therapeutical use. au 8541058; ep 0161801; es 8702388; es 8801229; jp 85215678; jp 86267579 .
Reference 2:
    ishihara, s.; ando, a.; miyamoto, s.; kanazaki, t.; hata, t.; oizumi, k.; matsushita, y.; koike, h.; yanagisawa, h.; iijima, y.; angiotensin-converting enzyme inhibitors: perhydro-1,4-thiazepin-5-one derivatives. j med chem 1987, 30, 11, 1984.
Reference 3:
    prous, j.; castaner, j.; rs-5142. drugs fut 1989, 14, 4, 336.

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盐酸替莫普利;英文名Temocapril hydrochloride;CS-622;RS-5142;Acecol;CAS[110221-44-8]

 
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