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【结 构 式】 
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【分子编号】10004 【品名】Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester 【CA登记号】94-02-0 |
【 分 子 式 】C11H12O3 【 分 子 量 】192.21448 【元素组成】C 68.74% H 6.29% O 24.97% |
合成路线1
该中间体在本合成路线中的序号：(I)A new synthesis for tomoxetine hydrochloride has been reported: The reduction of benzoylacetic acid ethyl ester (I) with Baker's yeast and glucose in water, or the enzymatic hydrolysis of 3-acetoxy-3-phenylpropionic acid ethyl ester (II), gives (-)-3-hydroxy-3-phenylpropionic acid ethyl ester (III), which by reaction with methylamine yields the corresponding amide (IV). The reduction of (IV) with LiAlH4 in ether affords (-)-3-hydroxy-N-methyl-3-phenylpropylamine (V), which is protected with di-tert-butyldicarbonate to the amide (VI). The condensation of (VI) with o-cresol (VII) by means of triphenylphosphine and diethylazodicarboxylate (DEAD) in ether yields the protected final product (VIII), which is finally deprotected with dry HCl in methanol.
| 【1】 Dike, S.Y.; Kumar, A.; Ner, D.H.; A new chemoenzymatic enantioselective synthesis of R-(-)-tomoxetine, (R)-fluoxetine and (S)-fluoxetine. Tetrahedron Lett 1991, 32, 16, 1901. |
| 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) | 10004 | Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester | 94-02-0 | C11H12O3 | 详情 | 详情 |
| (II) | 10005 | Ethyl 3-(acetoxy)-3-phenylpropanoate | C13H16O4 | 详情 | 详情 | |
| (III) | 10006 | Ethyl (3S)-3-hydroxy-3-phenylpropanoate; (-)-Ethyl (S)-3-hydroxy-3-phenylpropionate | 33401-74-0 | C11H14O3 | 详情 | 详情 |
| (IV) | 10007 | (3S)-3-Hydroxy-N-methyl-3-phenylpropanamide | C10H13NO2 | 详情 | 详情 | |
| (V) | 10008 | (1S)-3-(Methylamino)-1-phenyl-1-propanol | 114133-37-8 | C10H15NO | 详情 | 详情 |
| (VI) | 10009 | tert-Butyl N-[(3S)-3-hydroxy-3-phenylpropyl]-N-methylcarbamate | C15H23NO3 | 详情 | 详情 | |
| (VII) | 10010 | o-Cresol | 95-48-7 | C7H8O | 详情 | 详情 |
| (VIII) | 10011 | tert-Butyl N-methyl-N-[(3R,4E,6Z)-3-(2-methylphenoxy)-4-vinyl-4,6-octadienyl]carbamate | C22H29NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)ABPP is a phenylpyrimidinone and as such is prepared in high yield by condensation of guanidine with ethyl benzoylacetate. Ethyl benzoylacetate is commercially available and can also be prepared in high yield by condensation of dilithiomonoethylmalonate at 78 C with benzoyl chloride. Reaction of the resultant beta-ketoester with guanidine in refluxing ethanol affords its pyrimidinone in high yield. ABPP can be prepared from this pyrimidinone by bromination in acetic acid at room temperature. Similarly, iodine can be introduced at this step to afford the iodo analogue, AIPP. The overall yield of these pyrimidinones from monoethylmalonate is generally) 50%.
| 【1】 Fitzpatrick, F.A.; Wynalda, M.A.; High-perfomance liquid chromatographic determination of 5-halopyrimidinone interferon inducers. Anal Chem 1982, 17, 151. |
| 【2】 Skulnick, H.I.; Stringfellow, D.A.; Wierenga, W.; Weed, S.D.; Antiviral and interferon induction stucture-activity relationship profile of 6-aryl-pyrimidines. Am Soc Microbiol 1980, 2, 1402-1404. |
| 【3】 Brown, T.B.; Stevens, M.F.G.; Triazines and related products. XV. 2,4-Diaminopyrimidines and 2-aminopyrimidin-4(3H)-ones bearing 1,2,3-benzotriazinyl groups as potential dihydrofolic reductase inhibitors. J Chem Soc - Perkins Trans I 1975, 11, 1023-1028. |
| 【4】 Wierenga, W.; Skulnick, H.I.; J Org Chem 1979, 44, 310. |
| 【5】 Stringfellow, D.A.; Eidson, E.E.; Wierenga, W.; Skulnick, H.I.; Renis, H.E.; Weed, S.D.; 5-Substituted 2-amino-6-phenyl-4(3H)-pyrimidinones. Antiviral- and interferon-inducing agents. J Med Chem 1980, 23, 3, 237-239. |
| 【6】 Wierenga, W.; ABPP. Drugs Fut 1984, 9, 8, 567. |
合成路线3
该中间体在本合成路线中的序号：(A)The alkylation of ethyl benzoylacetate (A) with beta-ethoxyethyl bromide (B) using potassium carbonate in dimethyl formamide at 80 C gives the beta-3-keto ester (I). Condensation of (I) with guanidine hydrochloride (C) using sodium methoxide in tert-butanol at 80 C gives the pyrimidine (II). Protection of the amino group is achieved by tormylation at room temperature with the mixed anhydride (III) from formic and acetic acids. Chlorination with an excess of phosphorus oxychloride at 100 C gives a mixture of (V) and (VIII). The mixture of chloropyrimidines (V, VIII) is stirred at room temperature with excess hydrazi-ne hydrate to give the aminohydrazinopyrimidine (VI). This is heated with ethyl orthoformate in triglyme at 135 C to give the bicyclic compound (VII). This triglyme solution is then heated to 20 C to effect a Dimroth type rearrangement to give SC-33643.
| 【1】 Rorig, K.L.; Heilman, R.D.; SC-33643. Drugs Fut 1985, 10, 4, 298. |
| 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) | 10004 | Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester | 94-02-0 | C11H12O3 | 详情 | 详情 |
| (D) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (B) | 29132 | ethyl 3-bromopropanoate | 539-74-2 | C5H9BrO2 | 详情 | 详情 |
| (I) | 29133 | diethyl 2-benzoylpentanedioate | C16H20O5 | 详情 | 详情 | |
| (II) | 29134 | 2-amino-5-(2-ethoxyethyl)-6-phenyl-4-pyrimidinol | C14H17N3O2 | 详情 | 详情 | |
| (III) | 29135 | Acetyl formyl mixed anhydride | C3H4O3 | 详情 | 详情 | |
| (IV) | 29136 | 5-(2-ethoxyethyl)-4-hydroxy-6-phenyl-2-pyrimidinylformamide | C15H17N3O3 | 详情 | 详情 | |
| (V) | 29137 | 4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylformamide | C15H16ClN3O2 | 详情 | 详情 | |
| (VI) | 29138 | 5-(2-ethoxyethyl)-4-hydrazino-6-phenyl-2-pyrimidinamine | C14H19N5O | 详情 | 详情 | |
| (VII) | 29139 | 8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-5-amine | C15H17N5O | 详情 | 详情 | |
| (VIII) | 29140 | 4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylamine | C14H16ClN3O | 详情 | 详情 | |
| (C) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Acylation of Meldrum's acid (I) with butyryl chloride (II) in the presence of pyridine gave butyryl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiocaproate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), b-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
| 【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186. |
| 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) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 23711 | 5-butyryl-2,2-dimethyl-1,3-dioxane-4,6-dione | C10H14O5 | 详情 | 详情 | |
| (IV) | 23712 | 1-ethanethiol; ethylhydrosulfide | 75-08-1 | C2H6S | 详情 | 详情 |
| (V) | 23713 | S-ethyl 3-oxohexanethioate | C8H14O2S | 详情 | 详情 | |
| (VI) | 10004 | Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester | 94-02-0 | C11H12O3 | 详情 | 详情 |
| (VII) | 23715 | ethyl (E)-3-amino-3-phenyl-2-propenoate | C11H13NO2 | 详情 | 详情 | |
| (VIII) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (IX) | 23716 | ethyl 4-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-6-propyl-1,4-dihydro-3-pyridinecarboxylate | C22H29NO3S | 详情 | 详情 | |
| (X) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |