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药物详细合成路线

Name Epoxymexrenone;Eplerenone;CGP-30083;SC-66110;Inspra
Chemical Name 9alpha,11alpha-Epoxy-3,5-dioxospiro[androst-4-ene-17,2(R)-tetrahydrofuran]-7alpha-carboxylic acid methyl ester
      9alpha,11alpha-Epoxy-17beta-hydroxy-3-oxo-17alpha-pregn-4-ene-7alpha,21-dicarboxylic acid gamma-lactone 7-methyl ester
CAS 107724-20-9
Related CAS
Formula C24H30O6
Structure
Formula Weight 414.5031
Stage 上市-2002
Company Pfizer (Originator)
Activity/Mechanism Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Aldosterone Antagonists
Syn. Route 5
Route 1
eplerenone was prepared by several related ways. microbiological hydroxylation of canrenone (i) provided the 11-a hydroxy derivative (ii). this was converted to enamino compound (iv) by double addition of cyanide, followed by cyclization, on treatment with acetone cyanohydrin (iii) in the presence of triethylamine and lithium chloride in dmf or, alternatively, by treatment with sodium cyanide and sulfuric acid. hydrolysis of enamine (iv) with hcl in a methanol-water solution gave diketone (v), and further reaction with sodium methoxide in refluxing methanol gave hydroxyester (vi). after mesylation of the 11-a hydroxyl group with with mesyl chloride and triethylamine in cold dichloromethane, elimination of the resulting sulfonate (vii) to give olefin (viii) was achieved on treatment with potassium formate in a mixture of formic acid and acetic anhydride at 100 c. other conditions used for the elimination were potassium acetate in trifluoroacetic acid-trifluoroacetic anhydride, isopropenyl acetate and p-tsoh, or thermoelimination in dmso at 80 c. alternatively, hydroxyester (vi) was reacted with sulfuryl chloride at -70 c, and then treated with imidazole at room temperature to afford olefin (viii). finally, epoxidation was performed by reaction with hydrogen peroxide in the presence of trichloroacetamide or trichloroacetonitrile and po4hk2 to give eplerenone.
List of intermediates No.
4-(4-chlorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6h)-one (i)
ethyl 2-[4-(4-chlorophenyl)-3-methyl-7-oxoisoxazolo[3,4-d]pyridazin-6(7h)-yl]acetate (ii)
1,11-dichloro-12-[(2r,3r,4r,5s,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxytetrahydro-2h-pyran-2-yl]-12,13-dihydrofuro[3,4-c]indolo[2,3-a]carbazole-5,7-dione (iii)
12-[(2r,3r,4r,5s,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxytetrahydro-2h-pyran-2-yl]-12,13-dihydrofuro[3,4-c]indolo[2,3-a]carbazole-5,7-dione (iv)
3,9-dibromo-12-[(2r,3r,4r,5s,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxytetrahydro-2h-pyran-2-yl]-12,13-dihydrofuro[3,4-c]indolo[2,3-a]carbazole-5,7-dione (v)
1-nitrocyclopentane (vi)
4-[(1-nitrocyclopentyl)methyl]phenol (vii)
4-[(1-aminocyclopentyl)methyl]phenol (viii)
Reference 1:
    ng, j.s.; wang, p.t.; baez, j.a.; liu, c.; anderson, d.k.; lawson, j.p.; erb, d.; wieczorek, j.; mucciariello, g.; vanzanella, f.; kunda, s.a.; letendre, l.j.; pozzo, m.j.; sing, y.-l.l. (pharmacia corp.); process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. wo 9721720 .

Route 2
in a related way, canrenone (i) was converted to mexrenone (xi) by an analogous sequence including cyanide addition to give enamine (ix), hydrolysis to diketone (x), and ring opening with naome. the microbiological oxidation of mexrenone (xi) yielded either the 9-a (xii) or the 11-b (xiii) hydroxylated compounds, which were dehydrated to the olefin (viii), whose epoxidation, as before, afforded eplerenone.
List of intermediates No.
4-(4-chlorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6h)-one (i)
1,11-dichloro-12-[(2r,3r,4r,5s,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxytetrahydro-2h-pyran-2-yl]-12,13-dihydrofuro[3,4-c]indolo[2,3-a]carbazole-5,7-dione
4-[(1-aminocyclopentyl)methyl]phenol (viii)
tert-butyl 1-(4-hydroxybenzyl)cyclopentylcarbamate (ix)
[ethoxy(phenyl)phosphoryl]methyl 4-chlorobenzenesulfonate (x)
ethyl [4-([1-[(tert-butoxycarbonyl)amino]cyclopentyl]methyl)phenoxy]methyl(phenyl)phosphinate (xi)
ethyl [4-[(1-aminocyclopentyl)methyl]phenoxy]methyl(phenyl)phosphinate (xii)
benzyl 4-[(2s)oxiranylmethoxy]phenyl ether; (2s)-2-[[4-(benzyloxy)phenoxy]methyl]oxirane (xiii)
Reference 1:
    ng, j.s.; wang, p.t.; baez, j.a.; liu, c.; anderson, d.k.; lawson, j.p.; erb, d.; wieczorek, j.; mucciariello, g.; vanzanella, f.; kunda, s.a.; letendre, l.j.; pozzo, m.j.; sing, y.-l.l. (pharmacia corp.); process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. wo 9721720 .

Route 3
starting from enol ether (xiv), its reaction with the sulfonium ylide from trimethylsulfonium methylsulfate and koh in dmso-thf at 80 c afforded epoxide (xv). this was converted to the lactone (xvi) by treatment with diethyl malonate and sodium ethoxide in refluxing ethanol, and then decarboxylated to (xvii) on heating with nacl in moist dmf. hydrolysis of enol ether with acoh in boiling ethanol-water provided dienone (xviii), which was oxidized to trienone (xix) by means of a sequence consisting of halogenation with n-bromosuccinimide and then dehydrohalogenation with dabco and libr in dmf. using the analogous reactions as in scheme 1, (xix) was converted to enamine (xx), then hydrolyzed to diketone (xxi), treated with naome to give dienone (xxii), and finally converted to the target epoxide.
List of intermediates No.
4-[(1-aminocyclopentyl)methyl]phenol (xxii)
ethyl (4-[[1-([(2s)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino)cyclopentyl]methyl]phenoxy)methyl(phenyl)phosphinate (xiv)
ethyl [4-[(1-[[(2s)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]cyclopentyl)methyl]phenoxy]methyl(phenyl)phosphinate (xv)
1-(4-chlorobenzyl)-1h-indole (xvi)
2-[1-(4-chlorobenzyl)-1h-indol-3-yl]-2-oxoacetyl chloride (xvii)
3-chlorophenylhydrosulfide; 3-chlorobenzenethiol (xviii)
2-[(3-chlorophenyl)sulfanyl]-5-methoxybenzoic acid (xix)
1-chloro-7-methoxy-9h-thioxanthen-9-one (xx)
1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9h-thioxanthen-9-one (xxi)
Reference 1:
    ng, j.s.; wang, p.t.; baez, j.a.; liu, c.; anderson, d.k.; lawson, j.p.; erb, d.; wieczorek, j.; mucciariello, g.; vanzanella, f.; kunda, s.a.; letendre, l.j.; pozzo, m.j.; sing, y.-l.l. (pharmacia corp.); process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. wo 9721720 .

Route 4
alternatively, lactone (xviii) obtained from enol ether (xiv) as in the scheme 3, was epoxidized to give (xxiii), which was dehydrogenated using either ddq or chloranil to afford dienone (xxiv). conversion to enamine (xxv), then hydrolysis to diketone (xxvi), and ring opening with naome furnished eplerenone.
List of intermediates No.
ethyl (4-[[1-([(2s)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino)cyclopentyl]methyl]phenoxy)methyl(phenyl)phosphinate (xiv)
ethyl [4-[(1-[[(2s)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]cyclopentyl)methyl]phenoxy]methyl(phenyl)phosphinate (xv)
1-(4-chlorobenzyl)-1h-indole (xvi)
2-[1-(4-chlorobenzyl)-1h-indol-3-yl]-2-oxoacetyl chloride (xvii)
3-chlorophenylhydrosulfide; 3-chlorobenzenethiol (xviii)
1-[[2-(diethylamino)ethyl]amino]-4-(hydroxymethyl)-7-methoxy-9h-thioxanthen-9-one (xxiii)
1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxo-9h-thioxanthene-4-carbaldehyde (xxiv)
(1r)-2-[(4-aminophenethyl)[1-(tert-butoxy)vinyl]amino]-1-(3-pyridinyl)-1-ethanol (xxv)
4-[3-(3-cyclopentylpropyl)-2-oxo-1-imidazolidinyl]benzenesulfonyl chloride (xxvi)
Reference 1:
    ng, j.s.; wang, p.t.; baez, j.a.; liu, c.; anderson, d.k.; lawson, j.p.; erb, d.; wieczorek, j.; mucciariello, g.; vanzanella, f.; kunda, s.a.; letendre, l.j.; pozzo, m.j.; sing, y.-l.l. (pharmacia corp.); process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. wo 9721720 .

Route 5
microbiological oxidation of androstenedione (xxvii) produced the 11-a hydroxy compound (xxviii), which was converted to enol ether (xxix) on treatment with triethyl orthoformate and toluenesulfonic acid. reaction with trimethyl sulfonium ylide provided epoxide (xxx), and a sequence analogous to scheme 26146601c then produced lactone (xxxi), decarboxylated compound (xxxii), and enone (xxxiii). this was dehydrogenated to dienone (ii), which was converted to the title compound by the synthetic steps described in scheme 26146601a.
List of intermediates No.
tert-butyl (1r)-1-benzyl-2-(benzylamino)ethyl(methyl)carbamate (xxvii)
ethyl 2-[4-(4-chlorophenyl)-3-methyl-7-oxoisoxazolo[3,4-d]pyridazin-6(7h)-yl]acetate (ii)
tert-butyl (1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethylcarbamate (xxviii)
(2s)-2-amino-1-(4-ethyl-1-piperidinyl)-3-(4-nitrophenyl)-1-propanone (xxix)
4-chloro-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxx)
2-[[(2s)-2-amino-3-phenylpropyl]oxy]-1-ethanol (xxxi)
4-[[(1s)-1-benzyl-2-(2-hydroxyethoxy)ethyl]amino]-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxxii)
(2s)-2-(dibenzylamino)-3-phenyl-1-propanol (xxxiii)
Reference 1:
    ng, j.s.; wang, p.t.; baez, j.a.; liu, c.; anderson, d.k.; lawson, j.p.; erb, d.; wieczorek, j.; mucciariello, g.; vanzanella, f.; kunda, s.a.; letendre, l.j.; pozzo, m.j.; sing, y.-l.l. (pharmacia corp.); process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. wo 9721720 .

Route 6
2-methylimidazole (i) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in ac2o to produce 2-methyl-4-nitroimidazole (ii) . in a variant of this procedure, 2-methylimidazole (i) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. imidazole (ii) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. alternatively, the alkylation of (ii) has been reported by treatment with ethylene oxide (iii) under acidic conditions.
List of intermediates No.
tert-butyl (1r)-1-benzyl-2-(benzylamino)ethyl(methyl)carbamate (xxvii)
ethyl 2-[4-(4-chlorophenyl)-3-methyl-7-oxoisoxazolo[3,4-d]pyridazin-6(7h)-yl]acetate (ii)
tert-butyl (1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethylcarbamate (xxviii)
(2s)-2-amino-1-(4-ethyl-1-piperidinyl)-3-(4-nitrophenyl)-1-propanone (xxix)
4-chloro-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxx)
2-[[(2s)-2-amino-3-phenylpropyl]oxy]-1-ethanol (xxxi)
4-[[(1s)-1-benzyl-2-(2-hydroxyethoxy)ethyl]amino]-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxxii)
(2s)-2-(dibenzylamino)-3-phenyl-1-propanol (xxxiii)
Reference 1:
    frank, a.; karn, h.; spanig, h. (abbott gmbh & co. kg); production of 1-hydroxyalkyl-5-nitroimidazoles. de 2359625; fr 2253019; gb 1481349 .
Reference 2:
    frank, a.; dockner, t.; karn, h. (abbott gmbh & co. kg); process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. ep 0150407 .

Route 7
2-methylimidazole (i) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in ac2o to produce 2-methyl-4-nitroimidazole (ii) . in a variant of this procedure, 2-methylimidazole (i) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. imidazole (ii) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. alternatively, the alkylation of (ii) has been reported by treatment with ethylene oxide (iii) under acidic conditions.
List of intermediates No.
tert-butyl (1r)-1-benzyl-2-(benzylamino)ethyl(methyl)carbamate (xxvii)
ethyl 2-[4-(4-chlorophenyl)-3-methyl-7-oxoisoxazolo[3,4-d]pyridazin-6(7h)-yl]acetate (ii)
tert-butyl (1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethylcarbamate (xxviii)
(2s)-2-amino-1-(4-ethyl-1-piperidinyl)-3-(4-nitrophenyl)-1-propanone (xxix)
4-chloro-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxx)
2-[[(2s)-2-amino-3-phenylpropyl]oxy]-1-ethanol (xxxi)
4-[[(1s)-1-benzyl-2-(2-hydroxyethoxy)ethyl]amino]-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxxii)
(2s)-2-(dibenzylamino)-3-phenyl-1-propanol (xxxiii)
Reference 1:
    frank, a.; karn, h.; spanig, h. (abbott gmbh & co. kg); production of 1-hydroxyalkyl-5-nitroimidazoles. de 2359625; fr 2253019; gb 1481349 .
Reference 2:
    frank, a.; dockner, t.; karn, h. (abbott gmbh & co. kg); process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. ep 0150407 .

Route 8
2-methylimidazole (i) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in ac2o to produce 2-methyl-4-nitroimidazole (ii) . in a variant of this procedure, 2-methylimidazole (i) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. imidazole (ii) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. alternatively, the alkylation of (ii) has been reported by treatment with ethylene oxide (iii) under acidic conditions.
List of intermediates No.
tert-butyl (1r)-1-benzyl-2-(benzylamino)ethyl(methyl)carbamate (xxvii)
ethyl 2-[4-(4-chlorophenyl)-3-methyl-7-oxoisoxazolo[3,4-d]pyridazin-6(7h)-yl]acetate (ii)
tert-butyl (1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethylcarbamate (xxviii)
(2s)-2-amino-1-(4-ethyl-1-piperidinyl)-3-(4-nitrophenyl)-1-propanone (xxix)
4-chloro-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxx)
2-[[(2s)-2-amino-3-phenylpropyl]oxy]-1-ethanol (xxxi)
4-[[(1s)-1-benzyl-2-(2-hydroxyethoxy)ethyl]amino]-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxxii)
(2s)-2-(dibenzylamino)-3-phenyl-1-propanol (xxxiii)
Reference 1:
    frank, a.; karn, h.; spanig, h. (abbott gmbh & co. kg); production of 1-hydroxyalkyl-5-nitroimidazoles. de 2359625; fr 2253019; gb 1481349 .
Reference 2:
    frank, a.; dockner, t.; karn, h. (abbott gmbh & co. kg); process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. ep 0150407 .

Route 9
2-methylimidazole (i) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in ac2o to produce 2-methyl-4-nitroimidazole (ii) . in a variant of this procedure, 2-methylimidazole (i) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. imidazole (ii) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. alternatively, the alkylation of (ii) has been reported by treatment with ethylene oxide (iii) under acidic conditions.
List of intermediates No.
tert-butyl (1r)-1-benzyl-2-(benzylamino)ethyl(methyl)carbamate (xxvii)
ethyl 2-[4-(4-chlorophenyl)-3-methyl-7-oxoisoxazolo[3,4-d]pyridazin-6(7h)-yl]acetate (ii)
tert-butyl (1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethylcarbamate (xxviii)
(2s)-2-amino-1-(4-ethyl-1-piperidinyl)-3-(4-nitrophenyl)-1-propanone (xxix)
4-chloro-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxx)
2-[[(2s)-2-amino-3-phenylpropyl]oxy]-1-ethanol (xxxi)
4-[[(1s)-1-benzyl-2-(2-hydroxyethoxy)ethyl]amino]-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxxii)
(2s)-2-(dibenzylamino)-3-phenyl-1-propanol (xxxiii)
Reference 1:
    frank, a.; karn, h.; spanig, h. (abbott gmbh & co. kg); production of 1-hydroxyalkyl-5-nitroimidazoles. de 2359625; fr 2253019; gb 1481349 .
Reference 2:
    frank, a.; dockner, t.; karn, h. (abbott gmbh & co. kg); process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. ep 0150407 .

Route 10
2-methylimidazole (i) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in ac2o to produce 2-methyl-4-nitroimidazole (ii) . in a variant of this procedure, 2-methylimidazole (i) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. imidazole (ii) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. alternatively, the alkylation of (ii) has been reported by treatment with ethylene oxide (iii) under acidic conditions.
List of intermediates No.
tert-butyl (1r)-1-benzyl-2-(benzylamino)ethyl(methyl)carbamate (xxvii)
ethyl 2-[4-(4-chlorophenyl)-3-methyl-7-oxoisoxazolo[3,4-d]pyridazin-6(7h)-yl]acetate (ii)
tert-butyl (1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethylcarbamate (xxviii)
(2s)-2-amino-1-(4-ethyl-1-piperidinyl)-3-(4-nitrophenyl)-1-propanone (xxix)
4-chloro-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxx)
2-[[(2s)-2-amino-3-phenylpropyl]oxy]-1-ethanol (xxxi)
4-[[(1s)-1-benzyl-2-(2-hydroxyethoxy)ethyl]amino]-n-[(1s)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide (xxxii)
(2s)-2-(dibenzylamino)-3-phenyl-1-propanol (xxxiii)
Reference 1:
    frank, a.; karn, h.; spanig, h. (abbott gmbh & co. kg); production of 1-hydroxyalkyl-5-nitroimidazoles. de 2359625; fr 2253019; gb 1481349 .
Reference 2:
    frank, a.; dockner, t.; karn, h. (abbott gmbh & co. kg); process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. ep 0150407 .

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依普利酮;英文名Epoxymexrenone;Eplerenone;CGP-30083;SC-66110;Inspra;CAS[107724-20-9]

 
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