84-55-9

Usage

Uses

Used in Pharmaceutical Industry:
Viquidil is used as an intermediate in the synthesis of Quinotoxine Hydrochloride, a compound with potential pharmaceutical applications.
Used in Neurological Applications:
Viquidil is used as a vasodilator for improving blood flow in the cerebral region, which can be beneficial for various neurological conditions and treatments.

Originator

Desclidium,Spret ,France,1972

Manufacturing Process

2.70 g of N-benzoylhomomeroquinene ethyl ester (0.0086 mol) are mixed with 4.0 g of ethyl quininate (0.0173 mol = 100% excess). 1.4 g of absolutely dry pulverulent sodium ethoxide (0.0207 mol -140% excess, based on N- benzoylhomomeroquinene ethyl ester) is added, and the reaction mixture is heated to about 80°C with continuous stirring. As the ethyl quininate melts, and the materials become thoroughly mixed, the initial yellow color changes to brown and then gradually to deep red. The reaction mixture is maintained at about 82°C for fourteen hours with continuous stirring. It is then cooled, and the resulting very hard, dark red mass is decomposed with ice water and benzene. The (not entirely clear) combined aqueous layers are extracted with a small amount of ether. The clear, deep red, aqueous layer is then made just acid to litmus. The precipitated oil is taken up in ether. Evaporation of solvent, finally in vacuo, gives 2.56 g of a red glass. The combined benzene and ether extracts from above, containing largely neutral material, are extracted with 10% aqueous sodium hydroxide. The alkaline extract is made just acid to litmus, and extraction with ether followed by removal of solvent gives a further small quantity of β-ketoester, 0.16 g.Total weight of N-benzoylquinotoxine carboxylic acid ethyl ester thus obtained was 2.72 g, equivalent to 63.4% of the theoretical. 2.72 g of N-benzoylquinotoxine carboxylic acid ethyl ester are dissolved in 30 cc of 1:1 aqueous hydrochloric acid (from 15 cc concentrated hydrochloric acid and 15 cc water). The clear, reddish-orange solution is then boiled under reflux for four hours. The very dark reddish-brown solution is extracted with ether (from this extract 0.50 g of benzoic acid is obtained on evaporation). The aqueous solution is then made strongly alkaline and extracted with ether. 0.23 g of ether-insoluble interface material is dissolved in benzene and set aside. Removal of solvent from the above ether extract gives 1.39 g of crude quinotoxine as a dark red viscous oil.

Therapeutic Function

Vasodilator, Antiarrhythmic

InChI:InChI=1/C20H24N2O2/c1-3-14-13-21-10-8-15(14)4-7-20(23)17-9-11-22-19-6-5-16(24-2)12-18(17)19/h3,5-6,9,11-12,14-15,21H,1,4,7-8,10,13H2,2H3/t14-,15+/m0/s1

Upstream product

• 5345-57-3 6-methoxyquinoline-4-carboxylic acid ethyl ester 
• 26847-66-5 3-((4R)-1-benzoyl-3c-vinyl-[4r]piperidyl)-propionic acid ethyl ester 
• 6119-70-6 quinine; hydrogen sulfate dihydrate 
• 84-55-9 rac-6'-methoxy-1,8-seco-cinchonan-9-one 
• 64-19-7 acetic acid 
• 56-54-2 quinidine 
• 130-95-0 Quinine 
• 56-81-5 glycerol 
• 64-17-5 ethanol 
• 71-43-2 benzene 
• 113807-66-2 3-((3R,4R)-1-Acetyl-3-vinyl-piperidin-4-yl)-1-(6-methoxy-quinolin-4-yl)-propan-1-one 
• 113807-64-0 1-N-acetyl quinotoxine enol acetate 
• 56-54-2 9-epiquinine 
• 118-10-5 Cinchonin 

Downstream Products

• 87-69-4 L-Tartaric acid 
• 86-68-0 6-methoxyquinoline-4-carboxylic acid 
• 233746-47-9 C₂₈H₃₀N₂O₄ 
• 1422160-59-5 C₂₇H₂₈N₂O₃ 
• 1422160-60-8 C₃₄H₄₁N₃O₅ 

Relevant academic research and scientific papers

Combinatorial synthesis of novel 9R-acyloxyquinine derivatives as insecticidal agents

Background: It is one of the effective ways for pesticide innovation to develop new insecticides from natural products as lead compounds. Quinine, the main alkaloid in the bark of cinchona tree as well as in plants in the same genus, is recognized as a safe and potent botanical insecticide to many insects. The structural modification of quinine into 9R-acyloxyquinine derivatives is a potential approach for the development of novel insecticides, which showed more toxicity than quinine. However, there are no reports on the insecticidal activity of 9R-acyloxyquinine derivatives to control Mythimna separata. Methods: Endeavor to discover biorational natural products-based insecticides, 20 novel 9R-acyloxyquinine derivatives were prepared and assessed for their insecticidal activity against M. separata in vivo by the leaf-dipping method at 1 mg/mL. Results: Among all the compounds, especially derivatives 5i, 5k and 5t exhibited the best insecticidal activity with final mortality rates of 50.0%, 57.1%, and 53.6%, respectively. Conclusion: Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9-substitution is well tolerated; modification of out-ring double-bond is acceptable, and hydrogenation of double-bond enhances insecticidal activity; Quinine ring is essential and open of it is not acceptable. These preliminary results will pave the way for further modification of quinine in the development of potential new insecticides.

A novel complexity-to-diversity strategy for the diversity-oriented synthesis of structurally diverse and complex macrocycles from quinine

Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability. Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated.

COMPLEX AND STRUCTURALLY DIVERSE COMPOUNDS

The invention provides a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of sp3 carbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.

A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products

High-throughput screening is the dominant method used to identify lead compounds in drug discovery. As such, the makeup of screening libraries largely dictates the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound-screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for the modulation of many drug targets. Here we describe a novel, general and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show through the evaluation of chemical properties (which include fraction of sp 3 carbons, ClogP and the number of stereogenic centres) that these compounds are significantly more complex and diverse than those in standard screening collections, and we give guidelines for the application of this strategy to any suitable natural product.

Selenophene-containing inhibitors of type IIA bacterial topoisomerases

Figure Presented. We investigated compounds related to the previously reported antistaphyloccocal agent AVE6971 in an effort to attenuate inhibition of hERG potassium channel current that has been noted for this and related antibacterial drug classes. While most modifications of the original thiophene group compromised antibacterial activity, one selenophene analogue displayed (i) improved activity against the primary target enzyme DNA gyrase, (ii) similar activities against a panel of MRSA clinical isolates, and (iii) reduced hERG channel inhibition.

Rabe rest in peace: Confirmation of the rabe-kindler conversion of d-quinotoxine into quinine: Experimental affirmation of the woodward-doering formal total synthesis of quinine

(Chemical Equation Presented) Put to rest: The three-step conversion of d-quinotoxine into quinine, as originally reported by Rabe and Kindler in 1918, has been experimentally verified. This conversion serves to reaffirm the formal total synthesis of quin

Unification of reaction metrics for green chemistry: Applications to reaction analysis

A formalism is presented which unifies key reaction metrics associated with greenness in chemical reactions with respect to raw materials usage. The fundamental basis of this treatment begins with balanced chemical reactions in which byproducts are identified. The primary or kernel metrics are reaction yield, scale of reaction, stoichiometric factor (SF), and Trost's atom economy (AE). The stoichiometric factor is a new metric that is defined to account for reactions run under nonstoichiometric conditions, that is, with one or more reagents in excess. A general relation for reaction mass efficiency (RME) is derived which shows that this metric is a composite of the aforementioned primary metrics and takes into account solvent usage in the reaction and postreaction phases (workup and purification). The Sheldon environmental impact factor E is treated at various levels of complexity according to what is constituted as waste and is shown to be related to RME by a simple inverse expression. A flowchart is presented which shows other simple relationships connecting all metrics. Raw material costs, optimum conditions for recycling or reclaiming catalysts and reaction and postreaction solvents, and the handling of reactions giving isomeric products are also assessed. General algorithms are proposed for determining kernel reaction metrics for linear and convergent sequences that can be used to compare the intrinsic, or best-case scenario, green performances of synthetic plans to a common target structure. All key relationships can be implemented in a spreadsheet format from which reaction histograms or maps can be generated. Individual reaction RME performances can be gauged, ranked, and decomposed according to AE, SF, and reaction yield kernel metrics. This allows for the easy identification of best and worst reactions in a process or sequence. Example applications of the present methodology include the following: (a) a comparative analysis of the synthesis of quinine by the classic Woodward-Rabe and the modern greener Stork methods; (b) the analysis of the industrial synthesis of sildenafil (Viagra) by a convergent strategy; and (c) the analysis of kinetic resolution of racemic alcohols by a successive oxidation and recycling reduction cycle.

QUINOLINE DERIVATIVES AS ANTIBACTERIALS

A method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment of an effective amount of a quinoline of formula (I) or a pharmaceutically acceptable derivative thereof wherein: n is 0, 1 or 2; A is NR, O, S(O)x or CRR and B is NR, O, S(O)x or CRR where x is 0, 1 or 2 novel quinolines for use in the method.

STEREOSPECIFIC EPIMERIZATION, OXIDATION AND TOXINE REARRANGEMENT IN CINCHONA ALKALOIDS CATALYZED BY ACETIC ACID

Glacial acetic acid catalyzed a novel stereospecific epimerization of chichona alkaloids at C-9.In the presence of water, acetic acid also catalyzed the known toxine rearrangement and oxidation to the corresponding 9-keto derivatives.Addition of acetic anhydride to acetic acid diminished oxidation and epimerization at C-9, and the main products were the results of hydramine fission.Only propionic acid but no other acids, effected similar but not identical transformations.Addition of small quantities of H2O2 or exclusion of oxygen produced quantitative oxidation and rearrangement products, respectively.The catalysis by aqueous solution of acetic acid, involves C-9-OH in the formation of a three-membered ring intermediate.On the other hand, with anhydrous acetic acid, the acetoxyl at C-9 participates in construction of a five-membered ring intermediate.In both cases the reaction appears to be intramolecular.Support for the proposed mechanisms was provided by the isolation of a quarternary salt derived from quinidine, the structure of which was also characterized by X-ray diffraction analysis.Aqueous acetic acid catalyzed the rearrangement of this salt to its corresponding toxine only, and neither oxidation nor epimerization could be observed under conditions employed for the natural alkaloids.