An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VIII. ATTEMPTED SYNTHESIS OF 3-[Β-Keto-Γ-(4-Hydroxy-2-Piperidyl)propyl]-4-Quinazolone BY THE DIKETONE APPROACH

Baker, B. R.; Schaub, Robert E.; Querry, Merle V.; Williams, James H.

doi:10.1021/jo01135a009

Cited by 29 publications

(13 citation statements)

References 8 publications

(10 reference statements)

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“…When a mixture of the monoesters of methoxymethylsuccinic acid, XXIX and XXX, were converted to a mixture of the keto malonates, XXXI and XXXII, then hydrolyzed under the identical conditions used for XXXVII, three 2,4-dinitrophenylhydrazones were obtained, namely those of -methoxymethyllevulinic acid (XXXIII), ß-methylenelevulinic acid (XXXV), and ß-aeetobutyrolactone (XXXIV). enon observed previously with other ß-methoxy ketones (7). The /3-acetobutyrolactone 2,4-dinitrophenylhydrazone was again readily separated by virtue of its insolubility in aqueous sodium bicarbonate.…”

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confidence: 52%

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. XI. SYNTHESIS OF 3-[Β-Keto-Γ-(3- AND 4-Hydroxymethyl-2-Pyrrolidyl)propyl]- 4-Quinazolones

Baker¹,

Schaub²,

Williams³

1952

J. Org. Chem.

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The two possible hydroxymethylpyrrolidine structures (XLV and XLVI) for the Hydrangea alkaloid (1) have now been synthesized via the requisite 2-pyrrolidineacetic acids, XLIII. It was found that neither of these two compounds . . BAKER, R. . SCHAUB, AND J. H. WILLIAMS tion. Cyclization to the pyrrolinone, XIa, by a one to two day treatment with 40 volumes of aqueous alcoholic ammonia was reported to give an over-all yield of 85%. Duplication of this procedure gave only a 45% yield which could be increased to 61% if the intermediate imine was not distilled.A more rapid and convenient procedure has now been devised. The imine, Xa, was prepared in 30 minutes by constant removal of water from the components in boiling benzene. Cyclization was effected by treating this benzene solution with alcoholic sodium ethoxide for ten minutes. The over-all yield was 91% of crystalline material.Treatment of the pyrrolinone, XIa, with lithium aluminum hydride caused reduction at three sites, the lactam, ester, and pseudo imine double bond with the formation of 1 -benzylpyrrolidine-2-ethanol, b.p. 115°( 0.1 mm.) in 47% yield. The N-benzyl group was readily removed by hydrogenolysis. The resultant pyrrolidine, XHIa, was oxidized with chromic acid in dilute sulfuric acid to the amino acid, XlVa, characterized as its benzoyl derivative, XVa.The same sequence of reactions proceeded smoothly from Vb to XVb with R = CH3. The pyrrolidine acid, XVb, was converted to the bromo ketone, XVI, via the acid chloride and diazoketone, then condensed with 4-quinazolone to give the crystalline carbethoxylated 4-quinazolone, XVII, in 76% over-all yield from XVb. Short 48% hydrobromic acid hydrolysis of the latter gave the desired model compound, XVIII, isolated as the dihydrochloride in 80% yield.Another method for the preparation of the pyrrolidone, XXVI, was also investigated. In this synthesis a ß-amino adipic ester was desired which could be cyclized to XXVI rather than form XXVI by the hydrogenation of the pyrrolinone, XI, which takes place with difficulty (6). In addition methanol might be added to the double bond of the ester of XX in order to obtain an intermediate of the methoxymethyl series. Reaction of methylaniline with itaconic anhydride, XIX, rapidly took place to give an 81% yield of a pure anilide, XX, which was hydrogenated to XXI in 92% yield. The structures of the monoanilides, XX and

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confidence: 52%

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. XI. SYNTHESIS OF 3-[Β-Keto-Γ-(3- AND 4-Hydroxymethyl-2-Pyrrolidyl)propyl]- 4-Quinazolones

Baker¹,

Schaub²,

Williams³

1952

J. Org. Chem.

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“…Although 18 has been prepared in several steps by two different routes from phthalimide, 23 we envisioned that it would be possible to introduce the double bond in one step from the dianion of ester 19 via successive selenation of the enolate, oxidation and selenoxide elimination. As anticipated, treatment of ester 19, which was readily prepared from 15 with diazomethane in ether-methanol (99% yield), with two equivalents of LDA at -78 °C in THF followed by the oxidative selenation protocol provided the desired enoate 18 in 74% yield.…”

Section: Resultsmentioning

confidence: 99%

Synthetic studies towards N-substituted 3-vinyl-4-piperidineacetic acid derivatives

Johnson¹,

Gribble²

2019

Arkivoc

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The synthesis and full characterization of two new (E)-2-butenyl)-5-amino-2-pentenoates, (Z)-4-[N-(3-buten-1-yl)benzamido]-2-buten-1-ol, and (Z)-1-chloro-4-[N-(3-buten-l-yl)benzamido]-2-butene are reported. These were designed as substrates for a projected thermal ene cyclization leading to the N-substituted 3-vinyl-4piperidineacetic acid scaffold. Although conditions for this ene-cyclization have not yet been uncovered, the ease of preparation of these ene-cyclization substrates gives promise for their future use.

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“…The preparation of piperidine analogues was the most expensive part, and deemed to be the real difficulty to produce halofuginone as well. So far, a lot of methods have been reported: The method illustrated in Scheme 3 was originally developed by Baker’s team [ 18 , 22 , 23 , 24 , 25 , 26 ]. Afterwards, the method was optimized a bit by Barringer et al, via changing reagents and catalyst, which successfully improved the yield by reducing the number of steps but without lowering the cost.…”

Section: Introductionmentioning

confidence: 99%

A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide

2017

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Background: Halofuginone hydrobromide (1) is recognized as an effective drug against several species of Eimeria (E.) in poultry. In this paper, we describe a convenient and low cost preparation method for the compound, as well as primary validation of its activity. Methods: First, 7-bromo-6-chloroquinazolin-4(3H)-one (2) was prepared from m-chlorotoluene by a conventional process, and then chloroacetone was creatively introduced in two steps. Finally, halofuginone hydrobromide (1) was obtained from 7-bromo-6-chloro-3-(3-cholroacetonyl) quinazolin-4(3H)-one (4) by a four-step reaction sequence including condensation, cyclization, deprotection and isomerization. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS and 1H-NMR. Besides, the protective effect of compound 1-supplemented chicken diet at doses of 6, 3 and 1.5 mg per 1 kg were evaluated on chickens infected with E. tenella, by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology, respectively. Results: Halofuginone hydrobromide (1) was prepared successfully by and improved and innovative method based on traditional research. Moreover, the synthesized halofuginone hydrobromide significantly exhibited an anti-coccidial property. Conclusions: The fruitful work described in this Communication has resulted in halofuginone hydrobromide, which has a good pharmaceutical development prospects, becoming more available for large-scale production.

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An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VIII. ATTEMPTED SYNTHESIS OF 3-[Β-Keto-Γ-(4-Hydroxy-2-Piperidyl)propyl]-4-Quinazolone BY THE DIKETONE APPROACH

Abstract: One of the approaches (1) used for the synthesis of 3-[3-keto-7-(2-piperidyl)propyl]-4-quinazolone involved diketones of type I, but without the methoxyl

Cited by 29 publications

References 8 publications

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. XI. SYNTHESIS OF 3-[Β-Keto-Γ-(3- AND 4-Hydroxymethyl-2-Pyrrolidyl)propyl]- 4-Quinazolones

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. XI. SYNTHESIS OF 3-[Β-Keto-Γ-(3- AND 4-Hydroxymethyl-2-Pyrrolidyl)propyl]- 4-Quinazolones

Synthetic studies towards N-substituted 3-vinyl-4-piperidineacetic acid derivatives

A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide

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