An Improved Synthesis of 7-Substituted Pyrrolo[3,2-d]pyrimidines

Elliott, Arthur J.; Morris, Phillip; Petty, Sandra L.; Williams, Carl H.

doi:10.1021/jo971062j

Cited by 38 publications

(14 citation statements)

References 10 publications

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“…A suspension of 2-amino-7-benzyl-3 H –pyrrolo[3,2- d ]pyrimidin-4(5 H )-one 14 46 (1.25 g, 5.20 mmol in 20 mL of trimethylacetic anhydride was heated at 100 °C for 2 h. The resulting mixture was cooled, diluted with hexanes and filtered. The solid obtained was resuspended in water, and an ammonia solution was added to adjust the pH to 8.…”

Section: Methodsmentioning

confidence: 99%

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Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

Pavana

Choudhary

Bastian

et al. 2017

Bioorganic & Medicinal Chemistry

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The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI50 values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin.

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Section: Methodsmentioning

confidence: 99%

“…Chlorination of the 2-amino-4-oxo-pyrrolo[3,2- d ]pyrimidine 14 46 (Scheme 2) gave poor yields (<20%). The subsequent aniline displacement reactions also did not proceed to completion, and a separation of the product from the starting materials was tedious and required extensive column chromatography.…”

Section: Chemistrymentioning

confidence: 99%

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

Pavana

Choudhary

Bastian

et al. 2017

Bioorganic & Medicinal Chemistry

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“…[1][2][3][4][5][6][7][8] The Baylis-Hillman reaction is a novel carbon-carbon bond forming reaction providing a useful class of multifunctional molecules which have been successfully employed in several different stereoselective processess. [9][10][11][12][13][14][15][16][17][18][19][20] In continuation of our interest in the Baylis-Hillman reaction, [12][13][14][15][16][17] we herein report an aqueous sulfuric acid (20%) mediated isomerization of the BaylisHillman adducts, i.e.…”

Section: Development Of Simple and Convenient Methodology For Stereo-mentioning

confidence: 99%

Applications of the Baylis-Hillman Adducts in Organic Synthesis: A Facile Synthesis of [E]-α-Cyanocinnamyl Alcohols and [E]-α-Cyanocinnamic Aldehydes

Basavaiah¹,

Kumaragurubaran²,

Padmaja³

1999

Synlett

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Aqueous sulfuric acid mediated transformation of the Baylis-Hillman adducts, i.e. 3-aryl-3-hydroxy-2-methylenepropanenitriles, into [E]-a-cyanocinnamyl alcohols and subsequent oxidation with PCC leading to the formation of stereochemically pure [E]-a-cyanocinnamic aldehydes, which represents an efficient alternative route to the Knoevenagel condensation reaction, is described.Development of simple and convenient methodology for stereo-selective synthesis of [E]-a-cyanocinnamyl alcohols and [E]-a-cyanocinnamic aldehydes has been an important endeavor in synthetic organic chemistry because these molecules constitute an important class of synthons for synthesis of various biologically active and heterocyclic molecules. 1-8 The Baylis-Hillman reaction is a novel carbon-carbon bond forming reaction providing a useful class of multifunctional molecules which have been successfully employed in several different stereoselective processess. 9-20 In continuation of our interest in the Baylis-Hillman reaction, 12-17 we herein report an aqueous sulfuric acid (20%) mediated isomerization of the BaylisHillman adducts, i.e. 3-aryl-3-hydroxy-2-methylenepropanenitriles thus providing simple and efficient methodology for synthesis of [E]-a-cyanocinnamyl alcohols, and their subsequent oxidation with pyridinium chlorochromate (PCC) leading to the formation of stereochemically pure [E]-a-cyanocinnamic aldehydes.Recently Amri and coworkers 2,3 reported an interesting three step reaction sequence "bromination-formylationhydrolysis" for conversion of the Baylis-Hillman adducts, 3-hydroxy-2-methylenealkanenitriles, obtained from acrylonitrile, into 3-substituted 2-cyano allylic alcohols in good (60-100%) [E]-stereoselectivity. In view of the importance of 3-substituted 2-cyano allylic alcohols we felt that it will be highly useful if the Baylis-Hillman adducts, 3-hydroxy-2-methylenealkanenitriles can be transformed directly into 3-substituted 2-cyano allylic alcohols in one step with 100% stereoselectivity. During our studies in this direction, we have examined the possible isomerization of 3-hydroxy-2-methylene-3-phenylpropanenitrile (1a) under a variety of conditions. The best results were obtained when this molecule 1a (5mM) was treated with aqueous sulfuric acid (20%, 10 mL) at reflux temperature for 2 hours thus providing after usual workup followed by column chromatography (silica gel, 5% ethyl acetate in hexanes), stereochemically pure [2E]-2-cyano-3-phenylprop-2-enol (2a) in 60% yield. 21,22 The [E]-stereochemistry of this molecule was confirmed by comparing the 13 C NMR spectral data with literature values. 23 This success led us to transform representative 3-aryl-3-hydroxy-2-methylenepropanenitriles (1b-1g) into stereo-chemically pure [E]-a-cyanocinnamyl alcohols (2b-2g) (Scheme 1, Table 1). However, our attempts to transform 3-hydroxy-2-methylenehexanenitrile and 3-hydroxy-2-methyleneoctanenitrile into the corresponding 3-substituted 2-cyano allylic alcohols were unsuccessful. Scheme 1The [E]-selectivity in the sulfuric acid ...

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“…3-Aminopyrroles featuring electron-withdrawing moieties have attracted some interest as building blocks for pyrrolo [2,3-d]pyrimidines [647,648]. Consequently, several synthetic approaches to such derivatives have been described.…”

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confidence: 99%

“…The a-cyanoaldehydes 414, which are derived from suitable aldehydes by base induced condensation with 3,3-dimethoxypropionitrile, followed by hydrolysis of the acetal and catalytic hydrogenation, serve as excellent substrates for the generation of enamine intermediates 415 by treatment with diethyl aminomalonate (Scheme 4.129). A final cyclization step afforded the 3-aminopyrrole derivatives 416 in moderate to good overall yields [648]. A route based on cyclization of similar enamine intermediates has been used for the synthesis of methyl 3-amino-4-arylpyrrole-2-carboxylates [649].…”

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confidence: 99%