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【结 构 式】 
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【分子编号】48280 【品名】5-ethyl 3-methyl 4-(2-chlorophenyl)-2-methyl-6-[(2-oxoethoxy)methyl]-1,4-dihydro-3,5-pyridinedicarboxylate 【CA登记号】 |
【 分 子 式 】C20H22ClNO6 【 分 子 量 】407.85052 【元素组成】C 58.9% H 5.44% Cl 8.69% N 3.43% O 23.54% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reaction of 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (I) with ethyl 4-chloroacetoacetate (II) gives the bis adduct (III), which is cyclized with 2-chlorobenzaldehyde (IV) and methyl 3-aminocrotonate (V) in refluxing ethanol to yield the dimeric dihydropyridine (VI). The cleavage of the dioxolane ring of (VI) by means of Ts-OH in methanol affords the vicinal diol (VII), which is cleaved by means of NaIO4 in methanol to provide the acetaldehyde derivative (VIII). The reaction of (VIII) with hydroxylamine and TEA in methanol affords the corresponding oxime (IX), which is finally reduced to the target compound with Pd(OH)2/carbon and ammonium formate in refluxing methanol. Alternatively, the reductive amination of acetaldehyde (VIII) with ammonium acetate and sodium cyanoborohydride in methanol yields also the target compound.
| 【1】 Karimian, K.; Leung-Toung, R.C.S.H.; Tam, T.F. (Apotex Inc.); 1,4-Dihydropyridines, N-substd. bicyclic 4-hydropyridines, and bicyclic N-substd. 4,5-dihydropyridines. US 5723618 . |
| 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) | 48276 | (4R-trans)-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol; [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol; (-)-2,3-o-Isopropylidene-D-threitol | 73346-74-4 | C7H14O4 | 详情 | 详情 |
| (II) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (III) | 48277 | ethyl 4-([5-[(4-ethoxy-2,4-dioxobutoxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy)-3-oxobutanoate | C19H30O10 | 详情 | 详情 | |
| (IV) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
| (V) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VI) | 48278 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-([[5-([[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C43H50Cl2N2O12 | 详情 | 详情 | |
| (VII) | 48279 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[(4-[[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy]-2,3-dihydroxybutoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C40H46Cl2N2O12 | 详情 | 详情 | |
| (VIII) | 48280 | 5-ethyl 3-methyl 4-(2-chlorophenyl)-2-methyl-6-[(2-oxoethoxy)methyl]-1,4-dihydro-3,5-pyridinedicarboxylate | C20H22ClNO6 | 详情 | 详情 | |
| (IX) | 48258 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[[2-(hydroxyimino)ethoxy]methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23ClN2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The reaction of 2,2-dimethyl-1,3-dioxolane-4-methanol (X) with ethyl 4-chloroacetoacetate (II) gives the adduct (XI), which is cyclized with 2-chlorobenzaldehyde (IV) and methyl 3-aminocrotonate (V) in refluxing ethanol to yield the dihydropyridine (XII). The cleavage of the dioxolane ring of (XII) by means of Ts-OH in methanol affords the vicinal diol (XIII), which is cleaved by means of NaIO4 in methanol to provide the already reported acetaldehyde derivative (VIII).
| 【1】 Karimian, K.; Leung-Toung, R.C.S.H.; Tam, T.F. (Apotex Inc.); 1,4-Dihydropyridines, N-substd. bicyclic 4-hydropyridines, and bicyclic N-substd. 4,5-dihydropyridines. US 5723618 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (IV) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
| (V) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VIII) | 48280 | 5-ethyl 3-methyl 4-(2-chlorophenyl)-2-methyl-6-[(2-oxoethoxy)methyl]-1,4-dihydro-3,5-pyridinedicarboxylate | C20H22ClNO6 | 详情 | 详情 | |
| (IX) | 48258 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[[2-(hydroxyimino)ethoxy]methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23ClN2O6 | 详情 | 详情 | |
| (X) | 16476 | 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane; (2,2-dimethyl-1,3-dioxolan-4-yl)methanol; 2,3-o-Isopropylideneglycerol | 100-79-8 | C6H12O3 | 详情 | 详情 |
| (XI) | 48281 | ethyl 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-3-oxobutanoate | C12H20O6 | 详情 | 详情 | |
| (XII) | 48282 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C24H30ClNO7 | 详情 | 详情 | |
| (XIII) | 48283 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[(2,3-dihydroxypropoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C21H26ClNO7 | 详情 | 详情 |