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【结 构 式】 
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【分子编号】20110 【品名】2-(triphenylphosphoranyl)acetaldehyde 【CA登记号】 |
【 分 子 式 】C20H19OP 【 分 子 量 】306.344022 【元素组成】C 78.42% H 6.25% O 5.22% P 10.11% |
合成路线1
该中间体在本合成路线中的序号：(A)The condensation of 3-(trifluoromethyl)benzaldehyde (I) with phosphonate (II) by means of NaH in THF gives the unsaturated ester (III), which is reduced with DIBAL in ethyl ether / hexane, yielding 3-[3-(trifluoromethyl)phenyl]allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) affords the epoxyalcohol (V), which is oxidized with pyridine·SO3 to the corresponding aldehyde and condensed with phosphorane (A) to provide the unsaturated epoxyaldehyde (VI). The condensation of aldehyde (VI) with the pentylphosphonium derivative (VII) by means of NaNH2 in THF gives the corresponding adduct (VIII). The addition of 4-oxo-7-sulfanyl-4H-1-benzopyran-2-carboxylic acid methyl ester (IX) to the epoxide group of (VIII) by means of Et3N in methanol yields the expected alpha-hydroxy thioether (X), which is finally hydrolyzed with NaOH in THF/water to afford the target sodium salt. The intermediate pentylphosphonium derivative (VII) has been obtained by selective alkylation of 2,4-dihydroxy-3-propylacetophenone (XI) with 1,5-dibromopentane (XII) followed by reaction of the resulting ether with triphenylphosphine in refluxing toluene.
| 【1】 Von Sprecher, A.; Beck, A.; Sallmann, A.; Breitenstein, W.; Wiestner, H.; Kimmel, S.; Anderson, G.P.; Subramanian, N.; Bray, M.A.; Peptidoleukotriene antagonists: Structural analogs of leukotriene D4 with special emphasis on CGP 45715A. Drugs Fut 1991, 16, 9, 827. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20110 | 2-(triphenylphosphoranyl)acetaldehyde | C20H19OP | 详情 | 详情 | |
| (I) | 35964 | 3-(trifluoromethyl)benzaldehyde | 454-89-7 | C8H5F3O | 详情 | 详情 |
| (II) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (III) | 42936 | ethyl (E)-3-[3-(trifluoromethyl)phenyl]-2-propenoate | 113048-68-3 | C12H11F3O2 | 详情 | 详情 |
| (IV) | 42937 | (E)-3-[3-(trifluoromethyl)phenyl]-2-propen-1-ol | C10H9F3O | 详情 | 详情 | |
| (V) | 42938 | [(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]methanol | C10H9F3O2 | 详情 | 详情 | |
| (VI) | 42939 | (E)-3-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-2-propenal | C12H9F3O2 | 详情 | 详情 | |
| (VII) | 42940 | [5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl](triphenyl)phosphonium bromide | C34H38BrO3P | 详情 | 详情 | |
| (VIII) | 42941 | 1-[2-hydroxy-3-propyl-4-[((5Z,7E)-8-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-5,7-octadienyl)oxy]phenyl]-1-ethanone | C28H31F3O4 | 详情 | 详情 | |
| (IX) | 42942 | methyl 4-oxo-7-sulfanyl-4H-chromene-2-carboxylate | C11H8O4S | 详情 | 详情 | |
| (X) | 42943 | methyl 7-[((1S,2E,4Z)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-[(R)-hydroxy[3-(trifluoromethyl)phenyl]methyl]-2,4-nonadienyl)sulfanyl]-4-oxo-4H-chromene-2-carboxylate | C39H39F3O8S | 详情 | 详情 | |
| (XI) | 13137 | 2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone | 40786-69-4 | C11H14O3 | 详情 | 详情 |
| (XII) | 30560 | 1,5-dibromopentane | 111-24-0 | C5H10Br2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)3,4-Dichlorotoluene (I) was nitrated with HNO3 in H2SO4, and the resulting nitrotoluene (II) was condensed with diethyl oxalate in the presence of KOEt to give the phenylpyruvic derivative (III). Then, reductive cyclization of (III) with Fe and AcOH produced ethyl 5,6-dichloroindole-2-carboxylate (IV). Further reduction of (IV) with LiAlH4 yielded alcohol (V), which was oxidized to aldehyde (VI) with MnO2 in Et2O. Horner-Emmons reaction of (VI) with triethyl phosphonoacetate (VII) afforded the indolylpropenoate (VIII). This was reduced to the allyl alcohol (IX) with DIBAL-H, and subsequently oxidized with MnO2 to afford the propenaldehyde (X). In a shorter procedure, Wittig reaction of (VI) with formylmethylene triphenylphosphorane (XI) yielded also propenaldehyde (X) along with the homologated pentadienaldehyde. Phosphonium bromide (XIV) was prepared by bromination of methyl methoxyacetate (XII) with NBS in the presence of dibenzoyl peroxide, followed by condensation of the resulting bromide (XIII) with PPh3. Wittig reaction of this phosphonium reagent with aldehyde (X) in the presence of DBU in boiling THF gave ester (XV). Subsequent saponification of (XV) with ethanolic KOH yielded acid (XVI). The aminopiperidine (XX) was synthesized by N-methylation of tetramethylpiperidone (XVII), followed by formation of the oxime (XIX) and catalytic reduction over Rh/C. Then, condensation of amine (XX) with acid (XVI) using 1-ethyl-3-(dimethylaminopropyl)carbodiimide-HCl (EDC) and 1-hydroxy-7-azabenzotriazole (HOAt) in DMF furnished the target compound.
| 【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568. |
| 【2】 Nadler, G.; Morvan, M.; Delimoge, I.; Belfiore, P.; Zocchetti, A.; James, I.; Zembryki, D.; Lee-Rycakzewski, E.; Parini, C.; Consolandi, E.; Gagliardi, S.; Farina, C.; (2Z,4E)-5-(5,6-Dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide, a novel, potent and selective inhibitor of the osteoclast V-ATPase. Bioorg Med Chem Lett 1998, 8, 24, 3621. |
| 【3】 Yu, M.S.; et al.; Synthesis of 2-dienylindole, SB 242784, by a three-component palladium-catalyzed coupling reaction. Tetrahedron Lett 1998, 39, 51, 9347. |
| 【4】 Farina, C.; Nadler, G.M.M.G.; Gagliardi, S. (GlaxoSmithKline SpA); Indole derivs. for the treatment of osteoporosis. US 2002173659 . |
| 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) | 20100 | 1,2-dichloro-4-methylbenzene | 95-75-0 | C7H6Cl2 | 详情 | 详情 |
| (II) | 19088 | 1,2-dichloro-4-methyl-5-nitrobenzene | C7H5Cl2NO2 | 详情 | 详情 | |
| (III) | 19089 | ethyl 3-(4,5-dichloro-2-nitrophenyl)-2-oxopropanoate | C11H9Cl2NO5 | 详情 | 详情 | |
| (IV) | 19093 | ethyl 5,6-dichloro-1H-indole-2-carboxylate | C11H9Cl2NO2 | 详情 | 详情 | |
| (V) | 19094 | (5,6-dichloro-1H-indol-2-yl)methanol | C9H7Cl2NO | 详情 | 详情 | |
| (VI) | 19095 | 5,6-dichloro-1H-indole-2-carbaldehyde | C9H5Cl2NO | 详情 | 详情 | |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 19097 | ethyl (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenoate | C13H11Cl2NO2 | 详情 | 详情 | |
| (IX) | 19098 | (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propen-1-ol | C11H9Cl2NO | 详情 | 详情 | |
| (X) | 19099 | (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal | C11H7Cl2NO | 详情 | 详情 | |
| (XI) | 20110 | 2-(triphenylphosphoranyl)acetaldehyde | C20H19OP | 详情 | 详情 | |
| (XII) | 19100 | methyl 2-methoxyacetate | 6290-49-9 | C4H8O3 | 详情 | 详情 |
| (XIII) | 19101 | methyl 2-bromo-2-methoxyacetate | C4H7BrO3 | 详情 | 详情 | |
| (XIV) | 19102 | (1,2-dimethoxy-2-oxoethyl)(triphenyl)phosphonium bromide | C22H22BrO3P | 详情 | 详情 | |
| (XV) | 19103 | methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (XVI) | 19104 | (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid | C14H11Cl2NO3 | 详情 | 详情 | |
| (XVII) | 20116 | 2,2,6,6-tetramethyl-4-piperidinone | 826-36-8 | C9H17NO | 详情 | 详情 |
| (XVIII) | 20117 | 1,2,2,6,6-pentamethyl-4-piperidinone | C10H19NO | 详情 | 详情 | |
| (XIX) | 20118 | 1,2,2,6,6-pentamethyl-4-piperidinone oxime | C10H20N2O | 详情 | 详情 | |
| (XX) | 20119 | 1,2,2,6,6-pentamethyl-4-piperidinamine; 1,2,2,6,6-pentamethyl-4-piperidinylamine | C10H22N2 | 详情 | 详情 |