• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【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%

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:(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
Extended Information