diethyl 2-(2-methoxyphenoxy)malonate -Drug Synthesis Database

【结构式】

【分子编号】50138

【品名】diethyl 2-(2-methoxyphenoxy)malonate

【CA登记号】

【分子式】C₁₄H₁₈O₆

【分子量】282.29332

【元素组成】C 59.57% H 6.43% O 34.01%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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).

参考文献中间体

合成目标

【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：(III)

Reaction of 4-cyano-pyridine (I) with Na in methanol followed by treatment with ammonium chloride provides 4-amidino-pyridine hydrochloride (II), which is then converted into 5-(2-methoxyphenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (IV) by condensation with diethyl malonate derivative (III) by means of Na in MeOH. By heating compound (IV) with phosphorus oxychloride (POCl3), 4,6-dichloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl)pyrimidine (V) is obtained, which in turn is oxidized with peracetic acid in refluxing acetonitrile to afford N-oxide derivative (VI). Condensation of (VI) with 5-isopropylpyridine-2-sulfonamide potassium (VII) furnishes 5-isopropylpyridine-2-sulfonic acid 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide (VIII), which is then dissolved in dimethoxyethane and subjected to reaction with Na in hot ethylene glycol (IX) to provide N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-5-isopropylpyridine-2-sulfonamide (X). Refluxing of (X) with trimethylsilylcyanide and Et3N in acetonitrile yields cyano derivative (XI), which is then converted into the tetrazole derivative (XII) by reaction with sodium azide and NH4Cl in DMF at 70 C. Finally, the disodium salt of tezosentan is obtained by treatment of (XII) with Na/MeOH in THF.

参考文献中间体

合成目标

【1】 Chilman-Blair, K.; Castaner, J.; Leeson, P.A.; Bayes, M.; Tezosentan Disodium. Drugs Fut 2003, 28, 8, 754.
【2】 Breu, V.; Burri, K.; Cassal, J.-M.; Clozel, M.; Hirth, G.; Loffler, B.-M.; Muller, M.; Neidhart, W.; Ramuz, H. (F. Hoffmann-La Roche AG); Novel sulfonamides. EP 0799209; JP 1998509182; WO 9619459 .
【3】 Spurr, P. (F. Hoffmann-La Roche AG); Process for the preparation of 2,5-disubstd. pyridines. EP 0897914 .

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)	50136	4-Cyanopyridine; Pyridine-4-carbonitrile; Isonicotinic acid nitrile; Isonicotinonitrile; iso-Nicotinonitrile	100-48-1	C₆H₄N₂	详情	详情
(II)	50137	4-pyridinecarboximidamide		C₆H₇N₃	详情	详情
(III)	50138	diethyl 2-(2-methoxyphenoxy)malonate		C₁₄H₁₈O₆	详情	详情
(IV)	50139	5-(2-methoxyphenoxy)-2-(4-pyridinyl)-4,6-pyrimidinediol		C₁₆H₁₃N₃O₄	详情	详情
(V)	50140	4,6-dichloro-2-(4-pyridinyl)-5-pyrimidinyl 2-methoxyphenyl ether; 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridinyl)pyrimidine		C₁₆H₁₁Cl₂N₃O₂	详情	详情
(VI)	50141	4-[4,6-dichloro-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate		C₁₆H₁₁Cl₂N₃O₃	详情	详情
(VII)	50142			C₈H₁₁KN₂O₂S	详情	详情
(VIII)	50143	4-[4-chloro-6-[[(5-isopropyl-2-pyridinyl)sulfonyl]amino]-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate		C₂₄H₂₂ClN₅O₅S	详情	详情
(IX)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(X)	50144	4-[4-(2-hydroxyethoxy)-6-[[(5-isopropyl-2-pyridinyl)sulfonyl]amino]-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate		C₂₆H₂₇N₅O₇S	详情	详情
(XI)	50145	N-[2-(2-cyano-4-pyridinyl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-5-isopropyl-2-pyridinesulfonamide		C₂₇H₂₆N₆O₆S	详情	详情
(XII)	50146	N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-1,2,3,4-tetraazol-5-yl)-4-pyridinyl]-4-pyrimidinyl]-5-isopropyl-2-pyridinesulfonamide		C₂₇H₂₇N₉O₆S	详情	详情

Extended Information