- 【化学名】Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester
- 【CAS登记号】94-02-0
- 【结构式】
- 【分子式】C11H12O3
- 【分子量】192.2165
- 【来源】Acros Organics; Aldrich; Aldrich Flavors and Fragrances; Alfa Aesar; Fluka; FujiHunt; ICN Biomedical Research Products; Keyuan Co., Ltd.; Lancaster Synthesis Inc.; Pfaltz & Bauer, Inc.; PolyCarbon Inds., Inc.; Spectrum Quality Products, Inc.; TCI; Wujian Shuguang Chemical Factory
- 【合成情况】
- 〖目标产物〗Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera
- 〖合成路线〗
- 〖合成方法〗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.
- 〖参考〗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
- 〖目标产物〗Bropirimine, PNU-54461, U-54461, ABPP, Remisar
- 〖合成路线〗
- 〖合成方法〗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%.
- 〖参考〗Wierenga, W.; ABPP. Drugs Fut 1984, 9, 8, 567
- 〖目标产物〗Bropirimine, PNU-54461, U-54461, ABPP, Remisar
- 〖合成路线〗
- 〖合成方法〗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%.
- 〖参考〗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
- 〖目标产物〗Bropirimine, PNU-54461, U-54461, ABPP, Remisar
- 〖合成路线〗
- 〖合成方法〗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%.
- 〖参考〗Wierenga, W.; Skulnick, H.I.; . J Org Chem 1979, 44, 310
- 〖目标产物〗Bropirimine, PNU-54461, U-54461, ABPP, Remisar
- 〖合成路线〗
- 〖合成方法〗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%.
- 〖参考〗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
- 〖目标产物〗Bropirimine, PNU-54461, U-54461, ABPP, Remisar
- 〖合成路线〗
- 〖合成方法〗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%.
- 〖参考〗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
- 〖目标产物〗Bropirimine, PNU-54461, U-54461, ABPP, Remisar
- 〖合成路线〗
- 〖合成方法〗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%.
- 〖参考〗Fitzpatrick, F.A.; Wynalda, M.A.; High-perfomance liquid chromatographic determination of 5-halopyrimidinone interferon inducers. Anal Chem 1982, 17, 151
- 〖目标产物〗Bemitradine, SC-33643
- 〖合成路线〗
- 〖合成方法〗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.
- 〖参考〗Rorig, K.L.; Heilman, R.D.; SC-33643. Drugs Fut 1985, 10, 4, 298
- 〖目标产物〗MRS-1486
- 〖合成路线〗
- 〖合成方法〗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.
- 〖参考〗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
新药研发行业门户网站
制药行业专业信息平台
