78543-08-5

Usage

Uses

Used in Pharmaceutical Industry:
Diethyl (4-amino-3-fluorophenyl)methylmalonate serves as a valuable building block in the pharmaceutical industry, utilized for the synthesis of a variety of drug candidates. Its malonate ester structure and the presence of a fluorinated aromatic ring contribute to its potential in developing new medications with unique properties.
Used in Agrochemical Development:
In the agrochemical sector, diethyl (4-amino-3-fluorophenyl)methylmalonate is employed as a key intermediate in the synthesis of various agrochemicals. Its reactivity and structural features make it suitable for creating compounds with specific pesticidal or herbicidal activities.
Used in Organic Synthesis:
As a versatile organic synthesis building block, diethyl (4-amino-3-fluorophenyl)methylmalonate is used in the preparation of a range of different products. Its ability to undergo chemical reactions such as alkylation and hydrolysis allows for the creation of diverse chemical entities with potential applications across various industries.
Used in Fluorinated Compound Development:
The incorporation of a fluorine atom in the aromatic ring of diethyl (4-amino-3-fluorophenyl)methylmalonate makes it a useful compound for the development of fluorinated compounds. Fluorination often imparts unique properties to molecules, which can be advantageous in various applications, including enhancing the pharmacokinetic and pharmacodynamic profiles of drug candidates.

InChI:InChI=1/C14H18FNO4/c1-3-19-13(17)10(14(18)20-4-2)7-9-5-6-12(16)11(15)8-9/h5-6,8,10H,3-4,7,16H2,1-2H3

Upstream product

• 609-08-5 Diethyl methylmalonate 
• 446-35-5 2,4-Difluoronitrobenzene 
• 78543-06-3 diethyl 2-(3-fluoro-4-nitrophenyl)-2-methyl-malonate 

Downstream Products

• 138568-86-2 2-(4-Cyano-3-fluoro-phenyl)-2-methyl-malonic acid diethyl ester 
• 88975-32-0 2-[3-Fluoro-4-(2,2,2-trifluoro-acetylamino)-phenyl]-2-methyl-malonic acid diethyl ester 
• 42771-81-3 diethyl 2-(2-fluorobiphenyl-4-yl)-2-methylmalonate 
• 5104-49-4 fluorobiprofen 
• 5104-49-4 (S)-(+)-flurbiprofen 
• 5104-49-4 (R)-flurbiprofen 
• 42771-82-4 2-(2-fluoro-4-biphenylyl)-2-methylmalonic acid 
• 81937-33-9 2-(4-amino-3-fluorophenyl)propionic acid 
• 138568-88-4 2-(3-Fluoro-4-thiazol-2-yl-phenyl)-2-methyl-malonic acid diethyl ester 
• 138568-87-3 2-(3-Fluoro-4-thiocarbamoyl-phenyl)-2-methyl-malonic acid diethyl ester 
• 138568-73-7 2-[4-(4-Butyl-thiazol-2-yl)-3-fluoro-phenyl]-propionic acid 
• 138568-72-6 2-[3-Fluoro-4-(4-isopropyl-thiazol-2-yl)-phenyl]-propionic acid 
• 138568-71-5 2-[4-(4-Ethyl-thiazol-2-yl)-3-fluoro-phenyl]-propionic acid 
• 138568-75-9 2-[4-(5-Ethyl-thiazol-2-yl)-3-fluoro-phenyl]-propionic acid 

Relevant academic research and scientific papers

Flurbiprofen intermediate and preparation method thereof

The invention provides a flurbiprofen intermediate and a preparation method thereof, wherein the reaction formula is defined in the specification after a compound represented by a formula III is prepared by a coupling reaction between a substituted phenylacetamide compound and a compound represented by a general formula II, R1 and R2 are the same or different halogen, ester group, alkyl-substituted ester group and cyano, X is halogen, R4 is hydrogen, hydroxyl, halogen, nitro, alkyl, alkoxy, aryloxycarbonyl, cyano and cycloalkyl, and R is lowly-substituted alkyl. According to the present invention, the flurbiprofen or the derivative thereof can be prepared by carrying out the hydrolysis and the deamination according to the any sequence; and the route is environmentally friendly, and is suitable for industrial production.

Inhibitor for AKR1C3 or pharmaceutically acceptable salt of inhibitor as well as preparation method and application of inhibitor or pharmaceutically acceptable salt

The invention discloses an inhibitor for AKR1C3 or a pharmaceutically acceptable salt of the inhibitor as well as a preparation method and application of the inhibitor or the pharmaceutically acceptable salt. Non-steroidal anti-inflammatory drug flurbiprofen is used as a lead compound for structural optimization. The invention discloses the biphenyl-based AKR1C3 inhibitor represented by a formula(I) shown in the specification and the preparation method of the inhibitor. Target activity tests prove that the compounds provided by the invention can significantly inhibit activity of AKR1C3, and can be further used for development of a drug for treating and/or preventing diseases by inhibiting the aldo-keto reductase AKR1C3; and a molecular basis is laid for drug resistance-related mechanisticstudy of tumors.

Preparation of optically pure flurbiprofen via an integrated chemo-enzymatic synthesis pathway

In the synthesis of chiral molecules, the incorporation of enantioselective enzymatic conversions within the synthetic route often presents a useful approach. For the substitution of a chemical step with an enzymatic reaction, however, the complete synthetic route leading to and from this reaction needs to be considered carefully. An integrated approach, taking the possibilities and challenges of both types of conversions into account, can give access to chemo-enzymatic processes with great potential for effective synthesis strategies. We here report on the synthesis of enantiopure flurbiprofen using arylmalonate decarboxylase (AMDase, EC 4.1.1.76) in a chemo-enzymatic approach. Interestingly, practical considerations required shifting the enzymatic step to an earlier position in the synthetic route than previously anticipated. Engineered enzyme variants made it possible to obtain both (R)- and (S)-enantiomers of the target compound in excellent optical purity (>99%ee). The presented results underline that enzymes are most useful when they fit in a synthetic route, and that the optimization of biocatalytic steps and the planning of synthetic routes should be an integrated process.

Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life

In drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug's metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti-inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4′-position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2′ or 3′ resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development. A metabolic stopper: By applying a chemical-microbiological approach to the design of drugs with enhanced metabolic stability, a series of fluorinated derivatives of the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen was synthesised that were more resistant to cytochrome P450-catalysed transformation than the original drug.

PYRIMIDINE DERIVATIVES USED AS ITK INHIBITORS

The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I): and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular ltk activity.

Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of β-amyloid1-42 secretion

Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit β-amyloid1-42 (Aβ42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Aβ42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Aβ42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Aβ42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.

Preparation and biological activity of 2-[4-(thiazol-2-yl)phenyl]propionic acid derivatives inhibiting cyclooxygenase

A series of 2-[4-(thiazol-2-yl)phenyl]propionic acids substituted at various positions were prepared by the reaction of diethyl 2-methyl-2-(4-thiocarbamoylphenyl)malonates with α-bromoaldehyde diethyl acetals or α-haloketones followed by hydrolysis of esters. The inhibition of prostaglandin H synthetase (cyclooxygenase) was assayed by use of an enzyme preparation from guinea pig polymorphonuclear leukocytes. Examination of the structure-activity relationship of these compounds indicated that the substitution pattern with halogens at position 3 (R1) of the benzene ring and a methyl group in position 4 (R2) and/or 5 (R3) of the thiazole ring were favorable for inhibitory activity. The compounds bearing bulky alkyl or polar functional groups at the R2 position were weak inhibitors. The potent inhibitors of cyclooxygenase were tested for their ability to reduce carrageenin-induced inflammation of rat paws. These derivatives had strong anti-inflammatory activity based on their strong inhibition of cyclooxygenase, with some exceptions, including those with a thiomethyl group at R1.

Processes for the preparation of hydratropic acids and esters

The invention concerns the novel compounds dialkyl 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate IIIa and dialkyl 2-(3-fluoro-4-aminophenyl)-2-methylmalonate IVa useful as intermediates in an improved process for making 2-(2-fluoro-4-biphenylyl)propionic acid, known as flurbiprofen, having the formula STR1 and ester thereof. It has anti-inflammatory activity which is about 240 times that of aspirin and analgesic activity which is about 180 times that of aspirin in standard laboratory tests. However, despite this high activity, the toxicity (LD50) is only 1.2 to 2.4 times greater than that of aspirin in standard laboratory tests. Also within the invention is a novel method of making the above intermediates and analogs thereof useful to prepare corresponding biaryl compounds which have pharmaceutical uses.