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【结 构 式】

【分子编号】18320

【品名】ethyl 2-[6-[4-(methoxymethoxy)phenyl]-5-methyl-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate

【CA登记号】

【 分 子 式 】C27H28N2O6S2

【 分 子 量 】540.6612

【元素组成】C 59.98% H 5.22% N 5.18% O 17.76% S 11.86%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XII)

Thiophene (III) was obtained by condensation of (4-methoxyphenyl)acetone (I) with ethyl cyanoacetate (II) in the presence of NH4OAc and AcOH, followed by treatment with sulfur and diethylamine. Subsequent reaction of (III) with ethyl isocyanato-acetate (IV) in pyridine at 45 C and further cyclization with ethanolic NaOEt provided the thienopyrimidine (V). Cleavage of the methyl ether was performed by treatment with AlCl3 and dimethyl disulfide in CH2Cl2 at r.t. to afford phenol (VI), which was then acetylated with Ac2O in pyridine to give ester (VII). N-Alkylation with 2-(methylsulfanyl)benzyl chloride (VIII) in the presence of K2CO3 in DMF yielded (IX), and then the acetate ester was hydrolyzed with K2CO3 in a mixture of H2O/MeOH/THF. The resulting phenol (X) was alkylated with chloromethyl methyl ether (XI) in the presence of NaH to provide (XII).

1 Cho, N.; Nara, Y.; Harada, M.; Sugo, T.; Masuda, Y.; Abe, A.; Kusumoto, K.; Itoh, Y.; Ohtaki, T.; Watanabe, T.; Furuya, S.; Thieno[2,3-d]pyrimidine-3-acetic acids a new class of nonpeptide endothelin receptor antagonists. Chem Pharm Bull 1998, 46, 11, 1724.
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) 10038 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone 122-84-9 C10H12O2 详情 详情
(II) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(III) 18311 ethyl 2-amino-5-(4-methoxyphenyl)-4-methyl-3-thiophenecarboxylate C15H17NO3S 详情 详情
(IV) 18312 ETHYL ISOCYANATOACETATE; ethyl 2-isocyanatoacetate 2949-22-6 C5H7NO3 详情 详情
(V) 18313 ethyl 2-[6-(4-methoxyphenyl)-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C18H18N2O5S 详情 详情
(VI) 18314 ethyl 2-[6-(4-hydroxyphenyl)-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C17H16N2O5S 详情 详情
(VII) 18315 ethyl 2-[6-[4-(acetoxy)phenyl]-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C19H18N2O6S 详情 详情
(VIII) 18316 1-(chloromethyl)-2-(methylsulfanyl)benzene; 2-(chloromethyl)phenyl methyl sulfide C8H9ClS 详情 详情
(IX) 18317 ethyl 2-[6-[4-(acetoxy)phenyl]-5-methyl-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C27H26N2O6S2 详情 详情
(X) 18318 ethyl 2-[6-(4-hydroxyphenyl)-5-methyl-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C25H24N2O5S2 详情 详情
(XI) 18319 Chloro(methoxy)methane; Chloromethyl methyl ether 107-30-2 C2H5ClO 详情 详情
(XII) 18320 ethyl 2-[6-[4-(methoxymethoxy)phenyl]-5-methyl-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C27H28N2O6S2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XII)

After bromination of the methyl group of (XII) with N-bromosuccinimide in the presence of 2,2'-azobis(isobutyro-nitrile) to give (XIII), the aminomethyl derivative (XVI) was obtained by condensation with potassium phthalimide (XIV) in DMF and subsequent hydrazinolysis of the resulting (XV). Treatment with methanesulfonyl chloride and triethylamine then provided sulfonamide (XVII), and the ester function was finally hydrolyzed to the target carboxylic acid with NaOH in a mixture of H2O/MeOH/THF.

1 Cho, N.; Nara, Y.; Harada, M.; Sugo, T.; Masuda, Y.; Abe, A.; Kusumoto, K.; Itoh, Y.; Ohtaki, T.; Watanabe, T.; Furuya, S.; Thieno[2,3-d]pyrimidine-3-acetic acids a new class of nonpeptide endothelin receptor antagonists. Chem Pharm Bull 1998, 46, 11, 1724.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 18320 ethyl 2-[6-[4-(methoxymethoxy)phenyl]-5-methyl-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C27H28N2O6S2 详情 详情
(XIII) 18321 ethyl 2-[5-(bromomethyl)-6-[4-(methoxymethoxy)phenyl]-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C27H27BrN2O6S2 详情 详情
(XIV) 10926 (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium C8H4KNO2 详情 详情
(XV) 18323 ethyl 2-[5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[4-(methoxymethoxy)phenyl]-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C35H31N3O8S2 详情 详情
(XVI) 18324 ethyl 2-[5-(aminomethyl)-6-[4-(methoxymethoxy)phenyl]-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C27H29N3O6S2 详情 详情
(XVII) 18325 ethyl 2-[6-[4-(methoxymethoxy)phenyl]-1-[2-(methylsulfanyl)benzyl]-5-[[(methylsulfonyl)amino]methyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate C28H31N3O8S3 详情 详情
Extended Information