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【结 构 式】

【药物名称】Bosentan, Ro-47-0203/039, Ro-47-0203/029(monohydrate), Ro-47-0203, Tracleer

【化学名称】4-tert-Butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-yl]benzenesulfonamide

【CA登记号】147536-97-8, 174227-18-0 (deleted CAS), 157212-55-0 (monoH2O)

【 分 子 式 】C27H29N5O6S

【 分 子 量 】551.62608

【开发单位】Actelion (Orphan Drug), Genentech (Orphan Drug), Roche (Originator), Actelion (Licensee), Genentech (Licensee)

【药理作用】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

合成路线1

 

1 Yang N, DOng JJ, Liu KI,et a1.2005.Synthe^18 0f bosentan as an end.thelin receptor antngonisL中国药物化学杂志,15 (4): 230~233
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情
(II) 61569 dimethyl 2-(2-methoxyphenoxy)malonate C12H14O6 详情 详情
(III) 66160 pyrimidine-2-carboximidamide hydrochloride   C5H7ClBN4 详情 详情
(IV) 50370 5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4,6(1H,5H)-pyrimidinedione C15H12N4O4 详情 详情
(V) 41585   C15H10Cl2N4O2 详情 详情
(VI) 50371 4-(tert-Butyl)benzenesulphonamide C10H15NO2S 详情 详情
(VII) 50372   C25H24ClN5O4S 详情 详情
(VIII) 50374   C31H37N5O6S 详情 详情
(IX) 50375   C28H29N5O7S 详情 详情

合成路线2

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).

1 Mealy, N.E.; del Fresno, M.; Bayes, M.; Bosentan. Drugs Fut 2001, 26, 12, 1149.
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 .
3 Dehoff, B.S.; Harrington, P.J.; Khatri, H.N. (Roche Colorado Corp.); Preparation of sulfonamides. US 6136971 .
4 Harrington, P.J.; Dehoff, B.S.; Khatri, H.N. (F. Hoffmann-La Roche AG); Preparation of sulfonamides. WO 0155120 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 50138 diethyl 2-(2-methoxyphenoxy)malonate C14H18O6 详情 详情
(II) 50368 2-pyrimidinecarboximidamide C5H6N4 详情 详情
(III) 50369   C15H12N4O4 详情 详情
(IV) 41585   C15H10Cl2N4O2 详情 详情
(V) 50370 5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4,6(1H,5H)-pyrimidinedione C15H12N4O4 详情 详情
(VI) 50371 4-(tert-Butyl)benzenesulphonamide C10H15NO2S 详情 详情
(VII) 50372   C25H24ClN5O4S 详情 详情
(VIII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IX) 50373 2-tert-Butoxyethanol; Ethylene glycol mono-tert-butyl ester 7580-85-0 C6H14O2 详情 详情
(X) 50374   C31H37N5O6S 详情 详情
(XI) 50375   C28H29N5O7S 详情 详情

合成路线3

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.

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.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11191 2-Chloropyrimidine 1722-12-9 C4H3ClN2 详情 详情
(II) 61568 2-Pyrimidinecarbonitrile; 2-Cyanopyrimidine 14080-23-0 C5H3N3 详情 详情
(III) 50368 2-pyrimidinecarboximidamide C5H6N4 详情 详情
(IV) 61569 dimethyl 2-(2-methoxyphenoxy)malonate C12H14O6 详情 详情
(V) 59503 dimethyl chloromalonate 28868-76-0 C5H7ClO4 详情 详情
(VI) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情
(VII) 50370 5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4,6(1H,5H)-pyrimidinedione C15H12N4O4 详情 详情
(VIII) 41585   C15H10Cl2N4O2 详情 详情
(IX) 50371 4-(tert-Butyl)benzenesulphonamide C10H15NO2S 详情 详情
(X) 50372   C25H24ClN5O4S 详情 详情
(XI) 50373 2-tert-Butoxyethanol; Ethylene glycol mono-tert-butyl ester 7580-85-0 C6H14O2 详情 详情
(XII) 50374   C31H37N5O6S 详情 详情
(XIII) 50375   C28H29N5O7S 详情 详情
Extended Information