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药物详细合成路线

Name Celiprolol hydrochloride;ST-1396;Cordiax;Selectol;Celectol
Chemical Name 3-[3-Acetyl-4-(1,1-dimethylethylamino-2-hydroxypropoxy)phenyl]-1,1-diethylurea hydrochloride
CAS 57470-78-7
Related CAS 56980-93-9 (free base)
Formula C20H34ClN3O4
Structure
Formula Weight 415.96468
Stage 上市-1982
Company Aventis Pharma (Originator), Crinos (Not Determined), Nippon Shinyaku (Licensee)
Activity/Mechanism Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, beta-Adrenoceptor Antagonists
Syn. Route 6
Route 1
the condensation of 3-acetyl-4-hydroxyaniline (i) with n,n-diethylcarbamoyl chloride (ii) in pyridine gives the urea (ii), which is treated with epichlorohydrin (iv) and naoh to yield n-[3-acetyl-4-(2,3-epoxypropoxy)phenyl]-n,n-diethylurea (v). finally, the epoxy ring of (v) is opened with tert-butylamine (vi).
List of intermediates No.
(6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (iv)
(1s,5s,7r,9r,12r)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-diene-4,17-dione (vi)
(1r,3ar,4s,7ar)-1-[(1r,4s)-4,5-dihydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-1h-inden-4-yl acetate (i)
(1r,3ar,4s,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1h-inden-4-yl acetate (ii)
(1r,3ar,4s,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1h-inden-4-ol (iii)
(1r,3ar,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-4h-inden-4-one (v)
Reference 1:
    stormann-menninger-lerchenthal, h.; pittner, h.; zolss, g. (cl pharma); 4-ureido-2-acyl phenoxypropanolamine. de 2458624; us 4034009 .

Route 2
the reaction of 3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy)aniline (vii) with phenyl carbamate (viii) in pyridine gives the n-[3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenylcarbamic acid phenyl ester (ix), which is tretated with diethylamine (x) in ethanol/water.by reaction of n-[3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl]-n,n-diethylurea (xi) with tert-butylamine (vi).
List of intermediates No.
(1s,5s,7r,9r,12r)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-diene-4,17-dione (vi)
2-(2-hydroxyethoxy)-1h-isoindole-1,3(2h)-dione (x)
(6s)-6-((3r)-3-[(1r,3ar,7ar)-4-[(e)-bromomethylidene]-7a-methyloctahydro-1h-inden-1-yl]butyl)-2,2,3,3,5,5,8,8,9,9-decamethyl-4,7-dioxa-3,8-disiladecane; (2s,5r)-5-[(1r,3ar,7ar)-4-[(e)-bromomethylidene]-7a-methyloctahydro-1h-inden-1-yl]-2-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylhexyl tert-butyl(dimethyl)silyl ether (vii)
benzyl [(2r,3s)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2r,3s)-2,3-bis[(benzyloxy)methyl]oxirane (viii)
(2r,3s)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol (ix)
3-([(1s,2r)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate (xi)
Reference 1:
    stormann-menninger-lerchenthal, h.; pittner, h.; zolss, g. (cl pharma); 4-ureido-2-acyl phenoxypropanolamine. de 2458624; us 4034009 .

Route 3
there are several pathways for the preparation of the title compound according to the patent literature.
List of intermediates No.
(1s,5s,7r,9r,12r)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-diene-4,17-dione (a)
2-(2-hydroxyethoxy)-1h-isoindole-1,3(2h)-dione (d)
2-chloro-1,1-dimethoxyethyl methyl ether; 2-chloro-1,1,1-trimethoxyethane (c)
(1r,3ar,4s,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1h-inden-4-yl acetate (b)
(1r,3ar,4s,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1h-inden-4-ol (iii)
(1r,3ar,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-4h-inden-4-one (i)
(6s)-6-((3r)-3-[(1r,3ar,7ar)-4-[(e)-bromomethylidene]-7a-methyloctahydro-1h-inden-1-yl]butyl)-2,2,3,3,5,5,8,8,9,9-decamethyl-4,7-dioxa-3,8-disiladecane; (2s,5r)-5-[(1r,3ar,7ar)-4-[(e)-bromomethylidene]-7a-methyloctahydro-1h-inden-1-yl]-2-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylhexyl tert-butyl(dimethyl)silyl ether (ii)
(2r,3s)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol (v)
3-(1,4-dioxaspiro[4.5]dec-8-yl)-1h-indole-5-carbonitrile (iv)
Reference 1:
    zoelss, g.; at 335464 .
Reference 2:
    koch, h.; celiprolol hydrocloride. drugs fut 1979, 4, 3, 181.
Reference 3:
    zoelss, g.; at 335467 .
Reference 4:
    zoelss, g.; at 335465 .
Reference 5:
    zoelss, g.; et al.; at 334385 .
Reference 6:
    celiprolol - ein kardioselektiver beta-rezeptorblocker. chemie linz ag (kurzinformation), ul/2007, (nov. 1978) 1978.

Route 4
the condensation of 4-ethoxyaniline (ii) with n,n-diethylcarbamoyl chloride (ii) by means of khco3 gives the urea (iii), which is acylated with acetyl chloride and alcl3 to yield n-(3-acetyl-4-hydroxyphenyl)-n,n-diethylurea (iv). the alkylation of (iv) with epichlorohydrin (v) affords the adduct (vi), which is treated with hbr providing the bromoalcohol (vii). finally this compound is treated with tert-butylamine to furnish the target urea.
List of intermediates No.
(1s,5s,7r,9r,12r)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-diene-4,17-dione (viii)
di(tert-butyl) chloromethyl phosphate (v)
(1r,3ar,4s,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1h-inden-4-yl acetate (ii)
(1r,3ar,4s,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1h-inden-4-ol (iv)
ethyl (2s)-2-(acetylamino)-8-nonenoate (i)
(2s)-2-[acetyl(tert-butoxycarbonyl)amino]-8-nonenoic acid (iii)
(2s)-2-[(tert-butoxycarbonyl)amino]-8-nonenoic acid (vi)
8-bromo-1-octene (vii)
Reference 1:
    zolss, g.; on the synthesis of the cardioselective beta-adrenergic receptor blocking agent celiprolol. arzneim-forsch drug res 1983, 33, 1a, 2.

Route 5
the reaction of d-mannitol (i) with acetone and zncl2 gives the diacetonide (ii), which is oxidized with pb(oac)4 to yield the acetonide of (r)-glyceraldehyde (iii). the reduction of (iii) with h2 over pd/c affords the (s)-glycerin acetonide (iv), which is treated with tscl in pyridine to provide the corresponding tosylate (v). the condensation of (v) with the urea derivative (vi) by means of koh in dmso gives the adduct (vii), which is deprotected with hcl in acetone to yield the diol (viii). monotosylation of (viii) with tscl in pyridine affords the primary tosylate (ix), which is treated with na in methanol to provide the epoxide (x). finally this compound is treated with tert-butylamine to furnish the target (r)-enantiomer.
List of intermediates No.
4-[6-(benzyloxy)-1-benzothiophen-2-yl]phenyl methanesulfonate (iv)
tert-butyl (3r)-3-[3-(1,3-benzodioxol-5-ylcarbonyl)-6-butyl-2-pyridinyl]-3-[2-((2s)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate (v)
(1s,5s,7r,9r,12r)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-diene-4,17-dione (xi)
(1r,3ar,4s,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1h-inden-4-ol (vi)
(4s)-4-ethyl-4-hydroxy-6-iodo-1h-pyrano[3,4-c]pyridine-3,8(4h,7h)-dione (iii)
bromo(7-octenyl)magnesium (i)
8-nonenoic acid (ii)
(vii)
(4s)-4-benzyl-3-(8-nonenoyl)-1,3-oxazolidin-2-one (viii)
(4s)-3-[(2s)-2-azido-8-nonenoyl]-4-benzyl-1,3-oxazolidin-2-one (ix)
(4s)-3-[(2s)-2-amino-8-nonenoyl]-4-benzyl-1,3-oxazolidin-2-one (x)
Reference 1:
    hofer, o.; schlogl, k.; absolute configuration and enantiomeric purity of celiprolol. arzneim-forsch drug res 1986, 36, 8, 1157.

Route 6
the reaction of 4-nitrophenol (i) with acetic anhydride in aqueous naoh gives the corresponding acetate (ii), which is submitted to a fries migration with alcl3 in nitrobenzene at 140 c to yield the acetophenone (iii). the condensation of (iii) with epichlorohydrin (iv) by means of k2co3 affords the adduct (v), which is treated with tert-butylamine (vi) in water to obtain the aminoisopropanol derivative (vii). the reduction of the nitro group of (vii) with h2 over pd/c in methanol gives the corresponding amino derivative (viii), which is finally condensed with n,n-diethylcarbamoyl chloride (ix) by means of tea in thf to yield the target urea.
List of intermediates No.
(6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (iv)
benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-[(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)oxy]acetate (i)
(1s,5s,7r,9r,12r)-10-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-(4-methoxyphenyl)-6,8-dioxatetracyclo[10.4.1.0(1,5).0(5,9)]heptadeca-2,10-diene-4,17-dione (vi)
(1r,3ar,4s,7ar)-1-((1r,4s)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1h-inden-4-yl acetate (ix)
(6s)-6-((3r)-3-[(1r,3ar,7ar)-4-[(e)-bromomethylidene]-7a-methyloctahydro-1h-inden-1-yl]butyl)-2,2,3,3,5,5,8,8,9,9-decamethyl-4,7-dioxa-3,8-disiladecane; (2s,5r)-5-[(1r,3ar,7ar)-4-[(e)-bromomethylidene]-7a-methyloctahydro-1h-inden-1-yl]-2-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylhexyl tert-butyl(dimethyl)silyl ether (viii)
tert-butyl 4-(benzylamino)-1-piperidinecarboxylate (ii)
2-chloro-5-(trifluoromethyl)pyrimidine (iii)
tert-butyl 4-{[5-(trifluoromethyl)-2-pyrimidinyl]amino}-1-piperidinecarboxylate (v)
tert-butyl 4-{allyl[5-(trifluoromethyl)-2-pyrimidinyl]amino}-1-piperidinecarboxylate (vii)
Reference 1:
    joshi, r.a.; et al.; a new and improved process for celiprolol hydrochloride. org process res dev 2001, 5, 2, 176.

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塞利洛尔;英文名Celiprolol hydrochloride;ST-1396;Cordiax;Selectol;Celectol;CAS[57470-78-7]

 
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