82-54-2

Usage

Uses

Used in Pharmaceutical Industry:
Cotarnine is used as an intermediate in the synthesis of Cotarnine Chloride for its potential applications in the pharmaceutical industry. Cotarnine Chloride, being an oxidative degradation product of Noscapine, may have potential therapeutic uses and contribute to the development of new drugs or drug formulations.

InChI:InChI=1/C12H15NO4/c1-13-4-3-7-5-8-10(17-6-16-8)11(15-2)9(7)12(13)14/h5,12,14H,3-4,6H2,1-2H3

Upstream product

• 550-10-7 hydrocotarnine 
• 128-62-1 (±)-α-noscapine 
• 64-19-7 acetic acid 
• 23942-99-6 (-)-α-narcotinediol 
• 10421-76-8 noscapine 
• 3860-46-6 1R,9R-(-)-β-narcotine 
• 33699-31-9 N-[2-(7-methoxy-benzo[1,3]dioxol-5-yl)-ethyl]-N-methyl-formamide 
• 10018-19-6 cotarnine chloride 
• 128-62-1 noscapine 
• 7697-37-2 nitric acid 
• 128-62-1 (±)-β-noscapine 
• 7664-93-9 sulfuric acid 
• 106424-06-0 C-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-C,C'-(3,4-dimethoxy-o-phenylene)-bis-methanol 
• 108261-03-6 N-(2-methoxy-3,4-methylenedioxybenzyl)-N-(p-toluene-sulfonyl)aminoacetaldehyde diethylacetal 

Downstream Products

• 100719-12-8 Hydrocotarnyl-essigsaeure 
• 93-89-0 benzoic acid ethyl ester 
• 120-51-4 benzoic acid benzyl ester 
• 1459-20-7 1,2-diphenyl-2-oxoethyl benzoate 
• 51254-35-4 1-Acetonylhydrocotarnin 
• 2181-83-1 4-methoxy-6-methyl-5-(4-nitro-benzyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 
• 2283-00-3 4-methoxy-6-methyl-5-(2-nitro-benzyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline 
• 51179-79-4 2-((Z)-4-methoxy-6-methyl-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquinolin-5-ylidene)-1-phenyl-ethanone 

Relevant academic research and scientific papers

Biomimetic photooxidation of noscapine sensitized by a riboflavin derivative in water: The combined role of natural dyes and solar light in environmental remediation

Noscapine (NSC) is a benzyl-isoquinoline alkaloid discovered in 1930 as an antitussive agent. Recently, NSC has also been reported to exhibit antitumor activity and, according to computational studies, it is able to attack the protease enzyme of Coronavirus (COVID-19) and thus could be used as antiviral for COVID-19 pandemic. Therefore, an increasing use of this drug could be envisaged in the coming years. NSC is readily metabolized with a half-life of 4.5 h giving rise to cotarnine, hydrocotarnine, and meconine, arising from the oxidative breaking of the C–C bond between isoquinoline and phthalide moieties. Because of its potentially increasing use, high concentrations of NSC but also its metabolites will be delivered in the environment and potentially affect natural ecosystems. Thus, the aim of this work is to investigate the degradation of NSC in the presence of naturally occurring photocatalysts. As a matter of fact, the present contribution has demonstrated that NSC can be efficiently degraded in the presence of a derivative of the natural organic dye Riboflavin (RFTA) upon exposure to visible light. Indeed, a detailed study of the mechanism involved in the photodegradation revealed the similarities between the biomimetic and the photocatalyzed processes. In fact, the main photoproducts of NSC were identified as cotarnine and opianic acid based on a careful UPLC-MS2 analysis compared to the independently synthesized standards. The former is coincident with one of the main metabolites obtained in humans, whereas the latter is related to meconine, a second major metabolite of NSC. Photophysical experiments demonstrated that the observed oxidative cleavage is mediated mainly by singlet oxygen in a medium in which the lifetime of 1O2 is long enough, or by electron transfer to the triplet excited state of RFTA if the photodegradation occurs in aqueous media, where the 1O2 lifetime is very short.

Metal-Free Activation of C(sp3)–H Bond, and a Practical and Rapid Synthesis of Privileged 1-Substituted 1,2,3,4-Tetrahydroisoquinolines

The reaction of cotarnine and acyl/aryl ketones in “green” solvents provides an efficient approach to an array of privileged 1,2,3,4-tetrahydroisoquinolines in excellent yields by metal-free activation of C(sp3)–H bonds. This one-pot procedure takes place under base-free conditions at room temperature, and tolerates a wide range of functionalities. The reaction is highly chemoselective, can be performed on a multi-gram scale, and pure products are isolated by simple filtration without workup. Interestingly, the complementary two-step procedure from cotarnine halide salts gives the Mannich products in good yields. The scope was elaborated to 9-bromocotarnine salts to access a range of 9-bromonoscapine-derived analogues. The methodology has been developed considering the structural similarity of cotarnine derivatives to noscapinoids, which represent an emerging class of microtubule-modulating anticancer agents.

Metal-Free Activation of a C(sp)?H Bond of Aryl Acetylenes

C(sp)?H Bond activation of acetylene molecule still remains a challenge for synthetic organic chemists. In practice, acetylenes are activated by strong bases and metals. The first example for activating acetylenic protons under base and metal-free conditions is reported here. It involves a general method for synthesizing propargylic derivatives of cotarnine. An array of tetrahydroisoquinolines alkaloids was synthesized by C(sp)?H bond activation of aromatic acetylenes with cotarnine at room temperature. A DFT-based mechanism is proposed for the reaction.

Copper(I) mediated facile synthesis of potent tubulin polymerization inhibitor, 9-amino-α-noscapine from natural α-noscapine

Facile synthesis of natural α-noscapine analogue, 9-amino-α-noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo-α-noscapine (obtained by bromination of natural α-noscapine) with NaN3 in DMSO at 130 °C in the presence of l-proline as an amino acid promoter. The protocol developed here avoided isolation of 9-azido-α-noscapine and did not cleave the sensitive C-C bond between two heterocyclic phthalide and isoquinoline units.

Practical Synthesis of 5,6,7,8-Tetrahydro-4-methoxy-6-methyl-1,3-dioxoloisoquinolin-5-ol (Cotarnine)

5,6,7,8-Tetrahydro-4-methoxy-6-methyl-1,3-dioxoloisoquinolin-5-ol (cotarnine, 1), an oxidative degradation product of (3S)-6,7-dimethoxy-3-isoquinolin-5-yl>phthalide (noscapine), has efficiently been synthesized from 2-methoxy-3,4-(methylenedioxy)benzaldehyde (7) in 66percent overall yield. -N-methylamino>acetaldehyde dimethyl acetal, obtained by reductive amination of 7 with aminoacetaldehyde dimethyl acetal followed by N-methylation, was cylized in acid to 5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxoloisoquinolin-8-ol (12).The major byproduct of the cyclization was C-8 methoxy derivative of 12, and the amount of this byproduct was decreased by removal of MeOH formed in the reaction mixture.Acetylation of the hydroxyl group in 12 and hydrogenolysis gave 5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxoloisoquinoline (hydrocotarnine), which was oxidized with I2 followed by basification to afford 1.

Process for preparing cotarnine

A process for preparing cotarnine is provided which comprises oxidizing the amino group of a tetrahydroisoquinoline compound represented by the following formula (I): STR1 to convert said compound into a dihydroisoquinolinium salt represented by the following formula (II): STR2 wherein A- represents an anion, and then hydrolyzing said dihydroisoquinolinium salt.

Benzylamine derivative

There is provided a novel benzylamine derivative of the formula I: STR1 wherein R1 represents a hydrogen atom or a methyl group, X represents a hydrogen atom, a methyl group or a tosyl group, and Y represents a hydrogen atom, a methyl group or STR2 in which R2 and R3 being identical or different from each other represent independently a lower alkyl group.

Anisole derivatives

There is provided a novel anisole derivative represented by the following formula (I): STR1 wherein A to D are defined as follows: (1) A, B and C are each a hydrogen atom, and D represents --OH, a halogen atom, --CO2 R1 of which R1 represents a lower alkyl group, --SO2 R2 of which R2 represents a lower alkyl group, or STR2 or (2) A and C are each a hydrogen atom, B is --OH, and D represents --CO2 R3 of which R3 represents a lower alkyl group; or (3) A is a hydrogen atom, B and C form an oxo group =O together, and D represents --CO2 R4 of which R4 represents a lower alkyl group; or (4) B and C are each a hydrogen atom, D is a halogen atom, and A represents --CHO.

Certain 6,7-methylene dioxydihydro or tetrahydro-isoquinoline derivatives

A tetrahydroisoquinoline derivative represented by formula: STR1 wherein R1 represents hydrogen or methyl and X1, X2, Y1 and Y2 are defined as follows: (1) X1 represents --OH, STR2 or OR2 wherein R2 represents lower alkyl when X2, Y1 and Y2 represent hydrogen (2) X1 and X2 together form oxo (=O), when Y1 and Y2 represent hydrogen or (3) Y1 and Y2 together form oxo (=O), when X1 and X2 represent hydrogen which is useful as an intermediate in preparation of Cotarnine.