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【结 构 式】 
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【分子编号】50373 【品名】2-tert-Butoxyethanol; Ethylene glycol mono-tert-butyl ester 【CA登记号】7580-85-0 |
【 分 子 式 】C6H14O2 【 分 子 量 】118.17596 【元素组成】C 60.98% H 11.94% O 27.08% |
合成路线1
该中间体在本合成路线中的序号：(IX)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2
该中间体在本合成路线中的序号：(XI)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 |