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药物详细合成路线

Name Sulprostone;ZK-57671;SH-B-286;CP-34089;Nalador
Chemical Name 16-Phenoxy-omega-17,18,19,20-tetranor-PGE2 methylsulfonamide
CAS 60325-46-4
Related CAS
Formula C23H31NO7S
Structure
Formula Weight 465.57002
Stage 上市-1981
Company Schering AG (Originator)
Activity/Mechanism ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Uterine Stimulants, Uterine Stimulants and Tocolytics
Syn. Route 2
Route 1
the condensation of methyl phenoxyacetate (i) with dimethyl methylphosphonate (ii) by means of butyllithium in thf gives dimethyl 2-oxo-3-phenoxypropylphosphanate (iii), which by a wittig condensation with 2-[3alpha-(p-phenylbenzoyloxy)-5alpha-hydroxy-2beta-formylcyclopentan-1alpha-yl]acetic acid gamma-lactone (iv) by means of butyllithium in hexane yields the keto lactone (v). this compound is reduced with zinc borohydride in dimethoxyethane affording the hydroxylactone (vi), which is hydrolyzed with k2co3 in methanol giving the dihydroxylactone (vii). the hydroxyl groups of (vii) are protected with dihydropyrane as usual giving (viii), which is reduced with diisobutylaluminitim hydride in toluene yielding the hemiacetal (ix).
List of intermediates No.
phenyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate (iv)
(2r,3e)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile (v)
ethyl (2r,3e)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate (vi)
ethyl (2r,3e)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate (vii)
(2r,3e)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal (viii)
(4r,5e)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol (ix)
(2z,4z)-n-(1-[(2z,4z)-2,4-heptadienoylamino]-3-{1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1h-2-benzoxacyclododecin-3-yl}propyl)-2,4-heptadienamide (i)
(2z,4z)-n-((e)-3-{1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1h-2-benzoxacyclododecin-3-yl}-1-propenyl)-2,4-heptadienamide (ii)
sodium (z)-2-cyano-2-(3,4-dimethoxyphenyl)-1-ethenolate (iii)
Reference 1:
    castaner, j.; wescott, a.l.; sulprostone. drugs fut 1978, 3, 1, 59.
Reference 2:
    beil, w.; hoeppener, a.; wolff, h.j.; beil, h.; substituted 16,17,18,19,20-pentanorprostaglandins. de 2355540; es 433046; es 433047; fr 2205335; gb 1456512; jp 49093342; jp 52053841 .

Route 2
a wittig condensation of [4-(methanesulfonylaminocarbonyl)butyl]triphenylphosphonium bromide (x) [the phosphonium bromide (x) is prepared bv reaction of 5-bromovaleryl chloride (xl) with methanesulfonamide (xii) at 100 c to give n-methanesulfonyl-5-bromovaleramide (xiii), which is then condensed with triphenylphosphine in refluxing acetonitrile] with hemiacetal (ix) by means of na in dmso affords n-methanesulfonyl-9alpha-hydroxy-11alpha,15alpha-bis(tetrahydropyranyloxy)-16-phenoxy-5-cis-13-trans-omega-tetranorprostadienamide (xiv), which is then oxidized with the jones reagent in acetone to the keto compound (xv). finally, this compound is deprotected with acetic acid.
List of intermediates No.
(4r,5e)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol (ix)
(z)-2-cyano-2-(3,4-dimethoxyphenyl)ethenyl benzenesulfonate (x)
methyl 3-amino-4-(3,4-dimethoxyphenyl)-2-thiophenecarboxylate (xi)
methyl 4-(3,4-dimethoxyphenyl)-3-(1h-pyrrol-1-yl)-2-thiophenecarboxylate (xii)
[4-(3,4-dimethoxyphenyl)-3-(1h-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone (xiii)
3-(3,4-dimethoxyphenyl)-8h-thieno[2,3-b]pyrrolizin-8-one (xiv)
benzyl 5-(chloromethyl)-2-methoxyphenyl ether; 2-(benzyloxy)-4-(chloromethyl)-1-methoxybenzene (xv)
Reference 1:
    castaner, j.; wescott, a.l.; sulprostone. drugs fut 1978, 3, 1, 59.
Reference 2:
    beil, w.; hoeppener, a.; wolff, h.j.; beil, h.; substituted 16,17,18,19,20-pentanorprostaglandins. de 2355540; es 433046; es 433047; fr 2205335; gb 1456512; jp 49093342; jp 52053841 .

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硫前列酮;英文名Sulprostone;ZK-57671;SH-B-286;CP-34089;Nalador;CAS[60325-46-4]

 
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