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藥物詳細合成路線

Name Bosentan;Ro-47-0203/039;Ro-47-0203/029(monohydrate);Ro-47-0203;Tracleer
Chemical Name 4-tert-Butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-yl]benzenesulfonamide
CAS 147536-97-8
Related CAS 174227-18-0 (deleted CAS), 157212-55-0 (monoH2O)
Formula C27H29N5O6S
Structure
Formula Weight 551.62608
Stage 上市-2001
Company Actelion (Orphan Drug), Genentech (Orphan Drug), Roche (Originator), Actelion (Licensee), Genentech (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Interstitial Lung Diseases, Treatment of, Melanoma Therapy, Oncolytic Drugs, Pulmonary Hypertension, Treatment of, RESPIRATORY DRUGS, Scleroderma, Agents for, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Other Autoimmune Disorders, Endothelin ETA Receptor Antagonists, Endothelin ETB Receptor Antagonists
Syn. Route 2
Route 1
the condensation of diethyl (2-methoxyphenoxy)malonate (i) with pyrimidine-2-carboxamidine (ii) by means of naome (na in meoh), followed by treatment with naoh, provides the dihydroxy pyrimidine derivative (iii), which is converted into the dichloro derivative (iv) by treatment with refluxing pcl5 and diea. compound (iv) can also be obtained from the pyrimidinedione (v) by reaction with phosphorus oxychloride at 90 c. reaction of compound (iv) with 4-tert-butylbenzenesulfonamide (vi), performed either directly in dmso or by means of benzyltriethylammonium chloride (bteac) or tetrabutylammonium bromide (tbab) and k2co3 in refluxing toluene, gives compound (vii). finally, this compound is converted into bosentan by reaction with sodium and ethylene glycol (viii).
List of intermediates No.
(1r,4as,10ar)-7-isopropyl-1,4a-dimethyl-6-sulfo-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylic acid (viii)
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (iv)
ethyl (e)-4-chloro-4-oxo-2-butenoate (i)
11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carbonitrile (ii)
11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylic acid (iii)
methyl 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (v)
[4-(methyloxy)phenyl]methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (vi)
methyl 11-{[4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (vii)
methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (ix)
11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylic acid (x)
[4-(methyloxy)phenyl]methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (xi)
Reference 1:
    mealy, n.e.; del fresno, m.; bayes, m.; bosentan. drugs fut 2001, 26, 12, 1149.
Reference 2:
    burri, k.; clozel, m.; fischli, w.; hirth, g.; loffler, b.-m.; ramuz, h.; neidhart, w. (f. hoffmann-la roche ag); sulfonamide, preparation and use thereof as medicine and intermediate. ep 0526708; jp 1993222003; us 4292740 .
Reference 3:
    dehoff, b.s.; harrington, p.j.; khatri, h.n. (roche colorado corp.); preparation of sulfonamides. us 6136971 .
Reference 4:
    harrington, p.j.; dehoff, b.s.; khatri, h.n. (f. hoffmann-la roche ag); preparation of sulfonamides. wo 0155120 .

Route 2
the conversion of 2-chloropyrimidine (i) to pyrimidine-2-carboxamidine (iii) is performed by known methods through the intermediate pyrimidine-2-carbonitrile (ii). the cyclization of (iii) with 2-(2-methoxyphenoxy)malonic acid diethyl ester (iv) -prepared by condensation of 2-chloromalonic acid diethyl ester (v) with guaiacol (vi)- yields the bipyrimidinedione (vii). this compound is treated with refluxing pocl3 to afford the dichlorobipyrimidine (viii). the chlorine monosubstitution in (viii) with 4-tert-butylphenylsulfonamide (ix), k2co3 and tetrabutylammonium bromide (tbab) in toluene provides the substituted sulfonamide (x), which is submitted to a second chlorine substitution with ethyleneglycol mono-tert-butyl ether (xi) by means of naoh in hot toluene to give the tert-butyl-intermediate (xii). finally, this compound is deprotected by reaction with formic acid yielding the formate ester (xiii), which is hydrolyzed with naoh in ethanol/water, and submitted to crystallization in refluxing ethanol/water to afford the target bosentan.
List of intermediates No.
diethyl 2-(2-cyanoethyl)-2-(3-nitro-2-pyridinyl)malonate (i)
(2s,3r)-2-amino-n-((1r)-1-[(tert-butylsulfanyl)methyl]-2-[[(4r,5r)-2-(4-[2-[(hydroperoxymethyl)amino]-2-oxoethoxy]phenyl)-4-methyl-1,3-dioxan-5-yl]amino]-2-oxoethyl)-3-hydroxybutanamide (vi)
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (viii)
11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carbonitrile (iii)
methyl 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (vii)
[4-(methyloxy)phenyl]methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (ix)
methyl 11-{[4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (x)
methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (xi)
11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylic acid (xii)
[4-(methyloxy)phenyl]methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate (xiii)
Reference 1:
    harrington, p.j.; khatri, h.n.; dehoff, b.s.; guinn, m.r.; boehler, m.a.; glaser, k.a.; research and development of a second-generation process for bosentan, and endothelin receptor antagonist. org. proc. res. & develop. 2002, 6, 2, 120.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名伯森坦;英文名Bosentan;Ro-47-0203/039;Ro-47-0203/029(monohydrate);Ro-47-0203;Tracleer;CAS[147536-97-8]

 
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