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药物详细合成路线

Name Anagrelide hydrochloride;BMY-26538-01;BL-4162A;Xagrid;Agrylin;Agrelin
Chemical Name 6,7-Dichloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one hydrochloride;6,7-Dichloro-3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one hydrochloride;6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one hydrochloride
CAS 58579-51-4
Related CAS 68475-42-3 (free base)
Formula C10H8Cl3N3O
Structure
Formula Weight 292.55376
Stage 上市-1997
Company Inverni della Beffa (Orphan Drug), Kirin Brewery (Orphan Drug), Shire Pharmaceuticals (Orphan Drug), Shire BioChem (Originator), Shire Pharmaceuticals (Originator), Inverni della Beffa (Licensee), Kirin Brewery (Licensee), Yuhan (Licensee)
Activity/Mechanism Antithrombocythemic, HEMATOLOGIC DRUGS, Hematopoiesis Disorders Therapy, Phosphodiesterase III Inhibitors
Syn. Route 4
Route 1
the nitration of 1,2,3-trichlorobenzene (i) with concentrated hno3 gives 2,3,4-trichloronitrobenzene (ii), which by reaction with cuprous cyanide in hot pyridine is converted to 2,3-dichloro-6-nitrobenzonitrile (iii). the reduction of (iii) with borane in thf yields 2,3-dichloro-6-nitrobenzylamine (iv), which by reaction with ethyl bromoacetate (v) by means of triethylamine in refluxing dioxane affords ethyl n-(2,3-dichloro-6-nitrobenzyl)glycinate (vi). the reduction of (vi) with sncl2 in concentrated hcl gives ethyl n-(6-amino-2,3-dichlorobenzyl)glycinate (vii), which is cyclized with cyanogen bromide (viii) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1h)-iminoquinazoline-3-acetate (ix). finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.
List of intermediates No.
[(2r,3s,4s,5r)-5-(6-amino-2-fluoro-9h-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl diethyl phosphate (v)
potassium (9z,12z)-9,12-octadecadienoate (viii)
tert-butyl(dimethyl)[2-[(2r,3s)-3-methyl-6-methylenetetrahydro-2h-pyran-2-yl]ethoxy]silane; tert-butyl(dimethyl)silyl 2-[(2r,3s)-3-methyl-6-methylenetetrahydro-2h-pyran-2-yl]ethyl ether (i)
(z)-2-butyl-2-butenal (ii)
tert-butyl(dimethyl)silyl 2-[(2r,3s,6s)-9-butyl-3-methyl-1,7-dioxaspiro[5.5]undec-8-en-2-yl]ethyl ether; tert-butyl[2-[(2r,3s,6s)-9-butyl-3-methyl-1,7-dioxaspiro[5.5]undec-8-en-2-yl]ethoxy]dimethylsilane (iii)
(iv)
(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]decane-2-carbaldehyde (vi)
(1r)-1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-ol (vii)
1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-one (ix)
Reference 1:
    jenks, t.a.; beverung, w.n.jr.; partyka, r.a. (bristol-myers squibb co.); preparation of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3h)-one. ca 1137474 .

Route 2
the reaction of 3-chloroaniline (x) with choral hydrate (xi) and hydroxylamine gives isonitroso-3-chloroacetanilide (xii), which is cyclized by means of h2so4 to 4-chloroisatin (xiii). chlorination of (xiii) with so2cl2 affords 4,5-dichloroisatin (xiv), which is oxidized with h2o2 yielding 5,6-dichloroanthranilic acid (xv). the reduction of (xv) with borane in thf gives 6-amino-2,3-dichlorobenzyl alcohol (xvi), which by reaction with socl2 in benzene is converted to 6-amino-2,3-dichlorobenzyl chloride (xvii). this compound is condensed with ethyl glycinate (xviii) by means of triethylamine in refluxing methylene chloride to give ethyl n-(6-amino-2,3-dichlorobenzyl)glycinate (vii), which is cyclized with cyanogen bromide (viii) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1h)-iminoquinazoline-3-acetate (ix). finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.
List of intermediates No.
1-methoxy-2-naphthaldehyde (xviii)
(3r)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2h-chromene-5-carboxylic acid (xi)
(3r)-6-bromo-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2h-chromene-5-carbonyl chloride (x)
potassium (9z,12z)-9,12-octadecadienoate (viii)
(1r)-1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-ol (vii)
1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-one (ix)
(1s)-1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-ol (xii)
(1s)-1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propyn-1-ol (xiii)
(1s)-1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propynyl tert-butyl(dimethyl)silyl ether; tert-butyl([(1s)-1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-2-propynyl]oxy)dimethylsilane (xiv)
2-[(2r,5s,7r,8s)-2-butyl-2-((1s)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-1-ethanol (xv)
2-[(2r,5s,7r,8s)-2-butyl-2-((1s)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]acetaldehyde (xvi)
(e)-4-[(2r,5s,7r,8s)-2-butyl-2-((1s)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-2-methyl-2-butenal (xvii)
Reference 1:
    jenks, t.a.; beverung, w.n.jr.; partyka, r.a. (bristol-myers squibb co.); preparation of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3h)-one. ca 1137474 .

Route 3
the condensation of 2-nitro-6-chlorobenzyl chloride (i) with ethyl glycinate (ii) by means of triethylamine in refluxing ethanol gives ethyl n-(2-nitro-6-chlorobenzyl)glycinate (iii), which is reduced with h2 over pd/c in ethanol yielding ethyl n-(2-amino-6-chlorobenzyl)glycinate (iv). the cyclization of (iv) with cyanogen bromide (a) in refluxing ethanol affords 6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (v), which is finally chlorinated with cl2 and fecl3 in hot nitromethane.
List of intermediates No.
1-methoxy-2-naphthaldehyde (ii)
potassium (9z,12z)-9,12-octadecadienoate (a)
(2r,3r)-2-(2,4-difluorophenyl)-1-(1h-1,2,4-triazol-1-yl)-2,3-butanediol (i)
1-[[(2s,3s)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1h-1,2,4-triazole (iii)
(2r,3r)-2-(2,4-difluorophenyl)-3-(methylsulfanyl)-1-(1h-1,2,4-triazol-1-yl)-2-butanol (iv)
(2r,3r)-2-(2,4-difluorophenyl)-3-(methylsulfanyl)-1-(1h-1,2,4-triazol-1-yl)-2-butanol (v)
Reference 1:
    beverung, w.n.jr.; partyka, a.; optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(h)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones. us 3932407 .
Reference 2:
    castaner, j.; serradell, m.n.; hillier, k.; blancafort, p.; anagrelide hydrochloride. drugs fut 1980, 5, 3, 117.

Route 4
the nitration of 2,3-dichlorobenzaldehyde (i) with hno3/h2so4 gives 2,3-dichloro-6-nitrobenzaldehyde (ii), which is reduced with nabh4 in methanol, yielding 2,3-dichloro-6-nitrobenzyl alcohol (iii). the reaction of (iii) with socl2 and tea affords the benzyl chloride (iv), which is condensed with glycine ethyl ester (v) by means of tea to provide the adduct (vi). the reduction of the nitro group of (vi) with sncl2 in aq. hcl or h2 over pto2/c in ethanol gives the expected amino derivative (vii), which is cyclized with cn-br in toluene to yield the iminoquinazoline (viii). finally, this compound is further cyclized by means of tea in water to afford the target imidazoquinazolinone.
List of intermediates No.
1-methoxy-2-naphthaldehyde (v)
tert-butyl (1s)-1-[[(2,5-dioxo-2,5-dihydro-1h-pyrrol-1-yl)oxy]carbonyl]-2-methylpropylcarbamate (i)
(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]decane-2-carbaldehyde (vi)
(1r)-1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-ol (vii)
1-[(2r,5s,7r,8s)-2-butyl-7-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-3-(trimethylsilyl)-2-propyn-1-one (viii)
Reference 1:
    lang, p.c.; spencer, r.p.; yeh, w.-l.; roth, m.j. (shire richwood inc.); method for the manufacture of anagrelide. wo 0208228 .

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阿那格雷;英文名Anagrelide hydrochloride;BMY-26538-01;BL-4162A;Xagrid;Agrylin;Agrelin;CAS[58579-51-4]

 
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