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【结 构 式】 
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【药物名称】CGS-34043 【化学名称】N-[2-(Dibenzo[b,d]furan-3-yl)-1(S)-(1H-tetrazol-5-yl)ethyl]aminomethylphosphonic acid 【CA登记号】 【 分 子 式 】C16H16N5O4P 【 分 子 量 】373.31082 |
【开发单位】Novartis (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Endothelin-Converting Enzyme Inhibitors, Neprilysin Inhibitors |
合成路线1
The chiral amino acid (V) was prepared by two alternative procedures. Heck coupling between 3-iododibenzofuran (I) and methyl 2-acetamidoacrylate (II) in the presence of palladium diacetate afforded the alpha,beta-unsaturated alpha-amido ester (III), which was hydrogenated over Pd/C to yield the racemic saturated ester (IV). Incubation of (IV) with alcalase led to the enantiospecific hydrolysis of the S-enantiomer to give the required S-carboxylic acid (V). The unreacted R-enantiomer (VI) was recycled by epimerization in the presence of DBU.
| 【1】 Blanchard, L.; De Lombaert, S.; Stamford, L.B.; et al.; Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. J Med Chem 2000, 43, 3, 488. |
| 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) | 38080 | 3-iododibenzo[b,d]furan | C12H7IO | 详情 | 详情 | |
| (II) | 38081 | methyl 2-(acetamido)acrylate | 35356-70-8 | C6H9NO3 | 详情 | 详情 |
| (III) | 38082 | methyl (E)-2-(acetamido)-3-dibenzo[b,d]furan-3-yl-2-propenoate | C18H15NO4 | 详情 | 详情 | |
| (IV) | 38083 | methyl 2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate | C18H17NO4 | 详情 | 详情 | |
| (V) | 38084 | (2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid | C17H15NO4 | 详情 | 详情 | |
| (VI) | 38085 | methyl (2R)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate | C18H17NO4 | 详情 | 详情 |
合成路线2
In a different procedure, biaryl formation via ortho palladation of diaryl ether (VII) provided the desired dibenzofuran (VIII) along with a small amount of regioisomer (IX). Kinetic resolution with alcalase produced the S-carboxylic acid (V), whereas the R-ester (X) was recycled by base-catalyzed epimerization.
| 【1】 Blanchard, L.; De Lombaert, S.; Stamford, L.B.; et al.; Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. J Med Chem 2000, 43, 3, 488. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 38084 | (2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid | C17H15NO4 | 详情 | 详情 | |
| (VII) | 38086 | ethyl 2-(acetamido)-3-(3-phenoxyphenyl)propanoate | C19H21NO4 | 详情 | 详情 | |
| (VIII) | 38087 | ethyl 2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate | C19H19NO4 | 详情 | 详情 | |
| (IX) | 38088 | ethyl 2-(acetamido)-3-dibenzo[b,d]furan-2-ylpropanoate | C19H19NO4 | 详情 | 详情 | |
| (X) | 38089 | ethyl (2R)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropanoate | C19H19NO4 | 详情 | 详情 |
合成路线3
Acid hydrolysis of the acetamido group of (V) gave amino acid (XI), which was further esterified with HCl in MeOH. The resulting amino ester (XII) was then protected as the tert-butyl carbamate (XIII) and the methyl ester was hydrolyzed to carboxylic acid (XIV) by means of LiOH. Coupling of (XIV) with 3-aminopropionitrile (XV) using BOP reagent provided the N-cyanoethyl amide (XVI). Elaboration of the tetrazole ring (XVII) was carried out by treatment of (XVI) with trimethylsilyl azide, diisopropyl azodicarboxylate and triphenyl phosphine. The Boc group of (XVII) was then deprotected by treatment with formic acid. The resulting amine (XVIII) was condensed with formaldehyde, followed by reaction of the intermediate trimeric hexahydrotriazine with diphenyl phosphite to furnish alpha-aminophosphonate (XIX). Basic cleavage of the cyanoethyl group of (XIX) produced the N-dealkylated tetrazole (XX). Finally, basic hydrolysis of phosphonate ester groups of (XX) gave rise to the title compound.
| 【1】 Blanchard, L.; De Lombaert, S.; Stamford, L.B.; et al.; Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. J Med Chem 2000, 43, 3, 488. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 38084 | (2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid | C17H15NO4 | 详情 | 详情 | |
| (XI) | 38090 | (2S)-2-amino-3-dibenzo[b,d]furan-3-ylpropionic acid | C15H13NO3 | 详情 | 详情 | |
| (XII) | 38091 | methyl (2S)-2-amino-3-dibenzo[b,d]furan-3-ylpropanoate | C16H15NO3 | 详情 | 详情 | |
| (XIII) | 38092 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-dibenzo[b,d]furan-3-ylpropanoate | C21H23NO5 | 详情 | 详情 | |
| (XIV) | 38093 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-dibenzo[b,d]furan-3-ylpropionic acid | C20H21NO5 | 详情 | 详情 | |
| (XV) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (XVI) | 38095 | tert-butyl (1S)-2-[(2-cyanoethyl)amino]-1-(dibenzo[b,d]furan-3-ylmethyl)-2-oxoethylcarbamate | C23H25N3O4 | 详情 | 详情 | |
| (XVII) | 38096 | tert-butyl (1S)-1-[1-(2-cyanoethyl)-1H-1,2,3,4-tetraazol-5-yl]-2-dibenzo[b,d]furan-3-ylethylcarbamate | C23H24N6O3 | 详情 | 详情 | |
| (XVIII) | 38097 | 3-[5-[(1S)-1-amino-2-dibenzo[b,d]furan-3-ylethyl]-1H-1,2,3,4-tetraazol-1-yl]propanenitrile | C18H16N6O | 详情 | 详情 | |
| (XIX) | 38098 | diphenyl ([(1S)-1-[1-(2-cyanoethyl)-1H-1,2,3,4-tetraazol-5-yl]-2-dibenzo[b,d]furan-3-ylethyl]amino)methylphosphonate | C31H27N6O4P | 详情 | 详情 | |
| (XX) | 38099 | diphenyl [[(1S)-2-dibenzo[b,d]furan-3-yl-1-(1H-1,2,3,4-tetraazol-5-yl)ethyl]amino]methylphosphonate | C28H24N5O4P | 详情 | 详情 |