5693-27-6

Usage

Natural occurrence

Found in several plants, including tonka beans, sweet clover, and cassia cinnamon

Scent

Sweet, vanilla-like

Uses

Often used in perfumes and fragrances, as well as a flavoring agent in food and beverages (e.g. tobacco and some alcoholic drinks)

Health risks

High levels of consumption associated with liver toxicity and other adverse effects

Regulation

Use as a food additive is regulated in several countries.

Upstream product

• 7399-67-9 (2-(2-bromoacetyl)benzoic acid) 
• 108-31-6 maleic anhydride 
• 18435-67-1 o-methoxycarbonyl-α-diazoacetophenone 
• 624-48-6 dimethyl cis-but-2-ene-1,4-dioate 
• 4397-55-1 phthalic monoacid monomethyl ester chloride 
• 420-37-1 trimethoxonium tetrafluoroborate 
• 85-44-9 phthalic anhydride 
• 3453-63-2 3-methylidenephthalide 
• 577-56-0 2-acetyl-benzoic acid 
• 4376-18-5 Monomethyl phthalate 
• 7726-95-6 bromine 
• 208-96-8 acenaphthylene 
• 91138-31-7 o-Diazoacetyl-benzoesaeure-ethylester 

Downstream Products

• 98978-88-2 4-(4-hydroxy-1-oxo-1H-isochromen-3-ylmethylene)-2-phenyl-4H-oxazol-5-one 
• 92474-81-2 1-(o-Hydroxymethyl-phenyl)-aethandiol-(1,2) 
• 477338-28-6 3-[1-(4,5-Dimethoxy-2-nitro-phenyl)-meth-(Z)-ylidene]-isochroman-1,4-dione 
• 1681-79-4 3-(phenylmethylene)-1H-2-benzopyran-1,4(3H)-dione 
• 19193-15-8 -4-keto-3,4-dihydro-isocumarin 
• 1399839-98-5 5H,9H-bis[2]benzopyrano[3,4-e:4′,3′-b]pyridine-5,9-dione 
• 4042-30-2 parvaquone 
• 612-20-4 2-(hydroxymethyl)benzoic acid 
• 1150-59-0 2-hydroxy-3-phenyl-1,4-naphthoquinone 
• 96276-73-2 3-[2-(3-ethyl-4,5-diphenyl-3H-oxazol-2-ylidene)-ethylidene]-isochroman-1,4-dione 

Relevant academic research and scientific papers

The Reaction of Diazo Ketones in the Presence of Metal Chelates. VIII. The Stereochemistry of the 1,3-Dipolar Cycloaddition of 1-Methoxy-2-benzopyrylium-4-olates to Ethylenic Dipolarophiles

1,3-Dipolar cycloadducts were obtained in the reactions of 1-methoxy-2-benzopyrylium-4-olate (3a) with ethylenic dipolarophiles, such as dimethyl fumarate, dimethyl maleate, maleic anhydride, trans-1,2-dibenzoylethylene, N-substituted maleimides, and acenaphthylene.The configuration of the adducts was determined on the basis of the NMR coupling pattern of the methine protons of the adducts in connection with a deuterium experiment.The previously reported structure of the adduct of 3a with dimethyl fumarate was corrected according to the experimental results obtained using 3-deuterated 3a.The stereospecifity of the cycloaddition was confirmed in the reactions of dimethyl fumarate, dimethyl maleate, and trans-1,2-dibenzoylethylene; this stereospecifity was explained by the concerted (?2s + ?4s) mechanism.The exo/endo ratios of the adducts of N-substituted maleimides may be explained by the combination of the steric repulsion and ?-? interaction of the phenyl ring 3 and the substituent on the N-atom of maleimides.The cycloadditions of 1-methoxy-3-methyl-2-benzopyrylium-4-olate with N-substituted maleimides were also explained in a similar manner.

(3+3)-Annulation of Carbonyl Ylides with Donor–Acceptor Cyclopropanes: Synergistic Dirhodium(II) and Lewis Acid Catalysis

The first (3+3)-annulation process of donor–acceptor cyclopropanes using synergistic catalysis is reported. The Rh2(OAc)4-catalyzed decomposition of diazo carbonyl compounds generated carbonyl ylides in situ. These 1,3-dipoles were c

Menoctone resistance in malaria parasites is conferred by M133I mutations in cytochrome b that are transmissible through mosquitoes

Malaria-related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages of the parasite and combat the emergence of drug resistance. The diminishing arsenal of anti-liver-stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. In support of these studies, we developed a new convergent synthesis method that was facile, required fewer steps, produced better yields, and utilized less expensive reagents than the previously published method. Menoctone proved to be highly potent against liver stages of Plasmodium berghei (50 percent inhibitory concentration [IC50] = 0.41 nM) and erythrocytic stages of Plasmodium falciparum (113 nM). We selected for resistance to menoctone and found M133I mutations in cytochrome b of both P. falciparum and P. berghei. The same mutation has been observed previously in atovaquone resistance, and we confirmed cross-resistance between menoctone and atovaquone in vitro (for P. falciparum) and in vivo (for P. berghei). Finally, we assessed the transmission potential of menoctone-resistant P. berghei and found that the M133I mutant parasites were readily transmitted from mouse to mosquitoes and back to mice. In each step, the M133I mutation in cytochrome b, inducing menoctone resistance, was confirmed. In summary, this study is the first to show the mechanism of resistance to menoctone and that menoctone and atovaquone resistance is transmissible through mosquitoes.

HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME

Disclosed are chemical entities which are compounds of formula (I); or pharmaceutically acceptable salts thereof; wherein Y, Ra, Ra', Rb, Rc, X1, X2, X3, Rd, Z1, and Z2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. Chemical entities according to the disclosure can be useful as inhibitors of Sumo Activating Enzyme (SAE). Further provided are pharmaceutical compositions comprising a compound of the disclosure and methods of using the compositions in the treatment of proliferative, inflammatory, cardiovascular, and neurodegenerative diseases or disorders.

NOVEL PROCESS

Disclosed herein is novel process for preparation of atovaquone, which process includes reacting1H-2-benzopyran-1,4(3H)-dione with 4-(4-chlorophenyl)cyclohexanecarbaldehyde. The invention further discloses novel intermediates useful in the preparation of atovaquone.

Discovery and development of an efficient process to atovaquone

The discovery and development of an efficient and more sustainable manufacturing route to the antipneumocystic agent atovaquone (2-((1R,4R)-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. The existing commercial route to atovaquone delivers a poor yield of product and uses expensive reagents. The new synthesis commences with readily available phthalic anhydride, which is converted to 1,4-isochromandione 5 and then to atovaquone 1 by reaction with 4-(4-chlorophenyl)cyclohexanecarboxylic acid 3 using key bromination, Rosenmund reduction, and rearrangement chemistries. Downstream processing to atovaquone is both high yielding and robust, and the resulting process has been demonstrated on 200-kg scale. The process is simple, uses cheap raw materials, and is more sustainable in that it avoids lowyielding silver-promoted chemistry and isomerisation procedures. It includes a robust, facile, and highly efficient procedure to 1,4-isochromandione 5, and routes to 4-(4-chlorophenyl)cyclohexanecarboxaldehyde 9 have also been developed, including a Rosenmund method that was demonstrated on pilot-plant scale. Also discussed are the route-derived impurities and processing amendments to control their formation.

Synthetic methods for the preparation of ARQ 501 (β-Lapachone) human blood metabolites

ARQ 501 (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b] pyran-5,6-dione), a synthetic version of β-Lapachone, is a promising anti-cancer agent currently in multiple Phase II clinical trials. Promising anti-cancer activity was observed in Phase I and Phase II trials. Metabolism by red blood cells of drugs is an understudied area of research and the metabolites arising from oxidative ring opening (M2 and M3), decarbonylation/ring contraction (M5), and decarbonylation/oxidation (M4 and M6) of ARQ 501 offer a unique opportunity to provide insight into these metabolic processes. Since these metabolites were not detected in in vitro incubations of ARQ 501 with liver microsomes and were structurally diverse, confirmation by chemical synthesis was considered essential. In this report, we disclose the synthetic routes employed and the characterization of the reference standards for these blood metabolites as well as additional postulated structures, which were not confirmed as metabolites.

Palladium-catalyzed synthesis of o-acetylbenzoic acids: A new, efficient general route to 2-hydroxy-3-phenyl-1,4-naphthoquinones and indolo[2,3-b]naphthalene-6,11-diones

We describe here a new, efficient general synthesis of o-acetylbenzoic acids by Heck palladium-catalyzed arylation of n-butyl vinyl ether with o-bromobenzoic acid esters and the use of these compounds as starting materials for the synthesis of 3-benzylideneisochroman-1,4-diones, which readily rearrange to 2-hydroxy-3-phenyl-1,4-naphthoquinones. The application of this strategy to the synthesis of indolo[2,3-b]naphthalene-6,11-diones is also described.

USE OF HETEROCYCLIC INHIBITORS OF SERINE PROTEASES

Certain novel heterocyclic compounds, their preparation, and their use in inhibiting serine proteases with chymotrypsin-like, elastase-like, and trypsin-like specificity and in the treatment of diseases such as emphysema which involve tissue proteolysis.

THE ACID CATALYZED CYCLIZATION OF DIAZOKETONES: PREPARATION OF 2,4(3H,5H)FURANDIONES

Diazoketones derived from substituted ethyl hydrogen malonates produced by the selective hydrolysis of the corresponding malonate esters cyclize in the presence of catalytic amounts of boron trifluoride etherate in methanol to yield 2,4(3H,5H)furandiones.The cyclic keto orthoesters appear to be intermediates in the reaction.