4316-33-0

Usage

Synonym

Vanoxerine

Type of compound

Organic compound

Functional groups

One methoxy group and one trimethoxymethyl group

Usage

Dopamine transporter blocker

Potential treatment for

Cocaine addiction, attention deficit hyperactivity disorder (ADHD), and depression

Status

Not approved for medical use in most countries, classified as a controlled substance in the United States.

Synthetic route

methanol (67-56-1) + p-Anisaldehyde dimethyl acetal (2186-92-7) → p-Methoxybenzoic acid methyl orthoester (4316-33-0) + methyl 4-methoxybenzoate (121-98-2)

Conditions	Yield
With sodium methylate; lithium perchlorate; Tris(2,4-dibromophenyl)amine In dichloromethane indirect electrochemical oxidation;	A 78.3% B 13.2%
With sodium methylate; potassium benzenesulfonate; Tris(2,4-dibromophenyl)amine	A 53% B 18.4%

C10H12OS2(1+)*ClO4(1-) → p-Methoxybenzoic acid methyl orthoester (4316-33-0)

Conditions	Yield
With silver nitrate; triethylamine In methanol; acetonitrile for 10h; Ambient temperature;	53%

methyl (4-methoxyphenyl)carbodithioate (5874-09-9) + dibutyldimethoxytin (1067-55-6) → p-Methoxybenzoic acid methyl orthoester (4316-33-0)

methanol (67-56-1) + Estragole (140-67-0) → p-Methoxybenzoic acid methyl orthoester (4316-33-0) + 1-(1,1-Dimethoxy-allyl)-4-methoxy-benzene (126501-50-6)

Conditions	Yield
With sodium methylate at 30℃; for 0.5h; electrolysis;	A 3 % Chromat. B 34 % Chromat.

methanol (67-56-1) + [Dimethoxy-(4-methoxy-phenyl)-methyl]-methyl-phenyl-amine (79431-14-4) → p-Methoxybenzoic acid methyl orthoester (4316-33-0) + N-methylaniline (100-61-8)

Conditions	Yield
With acetic acid for 0.166667h; Yield given;

methanol (67-56-1) + anethole (104-46-1) → p-Anisaldehyde dimethyl acetal (2186-92-7) + p-Methoxybenzoic acid methyl orthoester (4316-33-0)

Conditions	Yield
With sodium 2,2,2-trifluoroacetate electrooxidation: current 0.8 A, current density 150 mA/cm2, 5F/mole;	A 76 % Chromat. B 11 % Chromat.

methanol (67-56-1) + anethole (104-46-1) → p-Anisaldehyde dimethyl acetal (2186-92-7) + p-Methoxybenzoic acid methyl orthoester (4316-33-0) + 1-(1,2-Dimethoxy-propyl)-4-methoxy-benzene (126501-48-2, 126501-49-3, 138169-72-9) + 1-(1,2-Dimethoxy-propyl)-4-methoxy-benzene (126501-48-2, 126501-49-3, 138169-72-9)

Conditions	Yield
With sodium methylate at 30℃; for 0.75h; Product distribution; electrolysis; other time, other alkenyl phenol ethers;

methanol (67-56-1) + anethole (104-46-1) → p-Methoxybenzoic acid methyl orthoester (4316-33-0)

Conditions	Yield
With sodium methylate at 30℃; for 0.75h; electrolysis;	11 % Chromat.

4-methoxy-N-methyl-N-phenylbenzamide. (33672-81-0) → p-Methoxybenzoic acid methyl orthoester (4316-33-0)

Conditions	Yield
Multi-step reaction with 3 steps 2: 1.) sodium / 1.) - 2.) CH2Cl2, 30 min 3: glacial acetic acid / 0.17 h View Scheme

Trifluoro-methanesulfonate[1-methoxy-1-(4-methoxy-phenyl)-meth-(Z)-ylidene]-methyl-phenyl-ammonium; → p-Methoxybenzoic acid methyl orthoester (4316-33-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) sodium / 1.) - 2.) CH2Cl2, 30 min 2: glacial acetic acid / 0.17 h View Scheme

methanol (67-56-1) + p-Anisaldehyde dimethyl acetal (2186-92-7) → p-Methoxybenzoic acid methyl orthoester (4316-33-0)

Conditions	Yield
With potassium fluoride Electrochemical reaction; Continuous flow conditions;

methanol (67-56-1) + 4-methoxy-N-methyl-N-phenylbenzamide. (33672-81-0) + methyl trifluoromethanesulfonate (333-27-7) → p-Methoxybenzoic acid methyl orthoester (4316-33-0) + N-methylaniline (100-61-8)

Conditions	Yield
Stage #1: 4-methoxy-N-methyl-N-phenylbenzamide.; methyl trifluoromethanesulfonate In dichloromethane at 20℃; Stage #2: methanol With sodium In dichloromethane for 0.166667h; Overall yield = 4.35 g; Further stages;

p-Methoxybenzoic acid methyl orthoester (4316-33-0) + threothymidine (16053-52-4) → (R)-1-[2-deoxy-3,5-O-(4-methoxy-methoxybenzylidene)-β-D-threo-pentofuranosyl]thymine

Conditions	Yield
With pyridinium p-toluenesulfonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	70%

p-Methoxybenzoic acid methyl orthoester (4316-33-0) + cis,cis-1,3,5-trihydroxycyclohexane (50409-12-6) → 3-(4-methoxyphenyl)-2,4,10-trioxaadamantane

Conditions	Yield
With boron trifluoride diethyl etherate In dichloromethane at 20℃; Inert atmosphere;	58%

t-butoxycarbonylhydrazine (870-46-2) + p-Methoxybenzoic acid methyl orthoester (4316-33-0) → N'-[(tert-Butoxycarbonyl-hydrazono)-(4-methoxy-phenyl)-methyl]-hydrazinecarboxylic acid tert-butyl ester (137256-74-7)

Conditions	Yield
With toluene-4-sulfonic acid a) r.t., 16 h, b) reflux, 6 h;	54%

p-Methoxybenzoic acid methyl orthoester (4316-33-0) + 1,3,3-trimethyl-2-oxa-bicyclo[2.2.2]octane-5,6-dione 6-hydrazone 5-oxime (68430-14-8, 72121-06-3, 139628-84-5) → 3-(4-methoxy-phenyl)-6,6,8-trimethyl-5,8-dihydro-6H-5,8-ethano-pyrano[4,3-e][1,2,4]triazine (73083-57-5)

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → methyl 4-methoxybenzoate (121-98-2)

Conditions	Yield
With water In acetonitrile at 30℃; Rate constant; ionic strength 0.50 M;

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → methanol (67-56-1) + 4-methoxybenzoic acid (100-09-4)

Conditions	Yield
With hydrogenchloride; potassium chloride In acetonitrile at 30℃; Rate constant; also in biphosphate buffer solution; kinetic isotope effect;

p-Methoxybenzoic acid methyl orthoester (4316-33-0) + 2-amino-5-(3-tert-butyl-4,4-dimethyl-4,5-dihydro-furan-2-yl)-3-methoxy-phenol → 6-(3-tert-butyl-4,4-dimethyl-4,5-dihydro-furan-2-yl)-4-methoxy-2-(4-methoxy-phenyl)-benzooxazole

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → 6-(3-tert-butyl-4,4-dimethyl-4,5-dihydro-furan-2-yl)-2-(4-methoxy-phenyl)-benzooxazol-4-ol (244124-51-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: EtSNa / dimethylformamide View Scheme

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → 6-(5-tert-butyl-4,4-dimethyl-2,6,7-trioxa-bicyclo[3.2.0]hept-1-yl)-2-(4-methoxy-phenyl)-benzooxazol-4-ol

Conditions	Yield
Multi-step reaction with 3 steps 1: EtSNa / dimethylformamide 2: 93.2 percent / tetraphenylporphin; O2 / CH2Cl2 / 0.67 h / 0 °C / Irradiation View Scheme

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → 4-Amino-3-(4-methoxy-phenyl)-4H-[1,2,4]triazin-5-one (137257-07-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 54 percent / p-TsOH / a) r.t., 16 h, b) reflux, 6 h 2: 78 percent / conc. aq. HCl / methanol / 0.5 h / Ambient temperature 3: 49 percent / Et3N / methanol / 15 h / Ambient temperature View Scheme

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → 4-Amino-3-(4-methoxy-phenyl)-6-methyl-4H-[1,2,4]triazin-5-one (137257-10-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 54 percent / p-TsOH / a) r.t., 16 h, b) reflux, 6 h 2: 78 percent / conc. aq. HCl / methanol / 0.5 h / Ambient temperature 3: 55 percent / Et3N / methanol / 2 h / Heating View Scheme

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → 4-Amino-3-(4-methoxy-phenyl)-5-oxo-4,5-dihydro-[1,2,4]triazine-6-carboxylic acid methyl ester (137257-13-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 54 percent / p-TsOH / a) r.t., 16 h, b) reflux, 6 h 2: 78 percent / conc. aq. HCl / methanol / 0.5 h / Ambient temperature 3: 87 percent / Et3N / methanol / 24 h / Ambient temperature View Scheme

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → C8H12N4O*2ClH

Conditions	Yield
Multi-step reaction with 2 steps 1: 54 percent / p-TsOH / a) r.t., 16 h, b) reflux, 6 h 2: 78 percent / conc. aq. HCl / methanol / 0.5 h / Ambient temperature View Scheme

p-Methoxybenzoic acid methyl orthoester (4316-33-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridinium p-toluenesulfonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetonitrile / -40 - 0 °C / Inert atmosphere View Scheme

→ (S)-1-[2-deoxy-3,5-O-(4-methoxy-phosphonobenzylidene)-β-D-threo-pentofuranosyl]thymine disodium salt

Conditions	Yield
Multi-step reaction with 3 steps 1.1: pyridinium p-toluenesulfonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2.1: acetonitrile / -40 - 0 °C / Inert atmosphere 3.1: trimethylsilyl bromide; 2,6-dimethylpyridine / acetonitrile / 20 °C / Inert atmosphere 3.2: Dowex resin 50 Na+ form / Inert atmosphere View Scheme

p-Methoxybenzoic acid methyl orthoester (4316-33-0) → 3-(p-methoxyphenyl)-2,4-dioxabicyclo[3.3.1]nonan-7-ol

Conditions	Yield
Multi-step reaction with 2 steps 1: boron trifluoride diethyl etherate / dichloromethane / 20 °C / Inert atmosphere 2: borane-THF; N,N,N,N,N,N-hexamethylphosphoric triamide / tetrahydrofuran / 0 °C / Inert atmosphere View Scheme

Upstream product

• 5874-09-9 methyl (4-methoxyphenyl)carbodithioate 
• 1067-55-6 dibutyldimethoxytin 
• 67-56-1 methanol 
• 140-67-0 Estragole 
• 2186-92-7 p-Anisaldehyde dimethyl acetal 
• 33672-81-0 4-methoxy-N-methyl-N-phenylbenzamide. 
• 333-27-7 methyl trifluoromethanesulfonate 
• 104-46-1 anethole 
• 79431-14-4 [Dimethoxy-(4-methoxy-phenyl)-methyl]-methyl-phenyl-amine 

Downstream Products

• 73083-57-5 3-(4-methoxy-phenyl)-6,6,8-trimethyl-5,8-dihydro-6H-5,8-ethano-pyrano[4,3-e][1,2,4]triazine 
• 137256-74-7 N'-[(tert-Butoxycarbonyl-hydrazono)-(4-methoxy-phenyl)-methyl]-hydrazinecarboxylic acid tert-butyl ester 
• 67-56-1 methanol 
• 100-09-4 4-methoxybenzoic acid 
• 244124-51-4 6-(3-tert-butyl-4,4-dimethyl-4,5-dihydro-furan-2-yl)-2-(4-methoxy-phenyl)-benzooxazol-4-ol 
• 137256-70-3 C₈H₁₂N₄O*2ClH 
• 137257-13-7 4-Amino-3-(4-methoxy-phenyl)-5-oxo-4,5-dihydro-[1,2,4]triazine-6-carboxylic acid methyl ester 
• 137257-10-4 4-Amino-3-(4-methoxy-phenyl)-6-methyl-4H-[1,2,4]triazin-5-one 
• 137257-07-9 4-Amino-3-(4-methoxy-phenyl)-4H-[1,2,4]triazin-5-one 
• 121-98-2 methyl 4-methoxybenzoate 

Relevant academic research and scientific papers

Enantioselective Desymmetrization of cis-3,5- O-Arylidenecyclohexanones Catalyzed by Cinchona-Derived Quaternary Ammonium Salts

An enantioselective protocol for the desymmetrization of cis-3,5-O-arylidenecyclohexanones has been developed that proceeded under the catalysis of readily available and inexpensive Cinchona-derived quaternary ammonium salts. The synthetic relevance of the methodology was exemplified by the synthesis of a key intermediate that could be used in the preparation of the active pharmaceutical ingredient, paricalcitol (Zemplar).

Microstructured reactor for electroorganic synthesis

In the present work a brief overview of microstructured devices, the advantages and disadvantages as well as the principles of a multiscale design approach are presented. The advantages mainly comprise uniform current density distribution, local control of the process parameters, high single-pass conversion of the reactant and reduced concentration of the supporting electrolyte needed to perform the reaction. The main challenge with this type of cell is gas evolution, a typical reaction taking place at the counter-electrode. The phenomena discussed are documented using the example of anodic methoxylation of 4-methylanisole. An analysis was made of the two-phase flow hydrodynamics inside the microstructured cell. The range of operational conditions suitable for the desired reaction was identified. The results were used together with the information on the electrode reaction kinetics in the form of the Butler-Volmer-type equation for the design of a suitable bipolar microstructured cell. A bipolar cell optimized to perform the desired reaction is reported. The results are compared with the published data. An analysis was performed that proved that the performance of the existing technology is more demanding in terms of energy consumption for the separation of the final product from the reaction mixture. The process intensification was evaluated on the basis of the available data.

ELECTROCHEMICAL CLEAVAGE OF THE DOUBLE BOND OF 1-ALKENYLARENES

A study has been made of the electrochemical cleavage of the double bond of propenylbenzene (Ia) and p-propenylanisole (Ib), which takes place upon anodic oxidation of (Ia, b) in alcoholic solutions of sodium trifluoroacetate and other electrolytes and which leads to conversion of (Ia, b) to benzaldehyde dialkylacetals.Conditions are found that provide for highly selective (>80percent) conversion of (Ib) and p-propenyltoluene to p-methyl- and p-methoxybenzaldehyde dimethylacetals.

Electrochemical Methoxylation of Allyl and Propenyl Derivatives of Phenol and Phenol Ethers

Anodic oxidation of a methanolic solution of a number of phenols and phenol ethers (anethole, estragole, safrole, isosafrole, eugenol, and isoeugenol) in a single cell at constant current, with use of sodium methoxide or sodium methoxide-sodium perchlorate as the supporting electrolyte, afforded substitution and addition products, some of them not described previously in the literature.

Isolation of Dithiolanylium Salts and Their Conversion to Ketene Dithioacetals and Ortho Esters

Various 2-substituted 1,3-dithiolan-2-ylium perchlorates (1) were prepared by the reaction of 1,2-ethanedithiol with acyl chlorides in the presence of perchloric acid.Treatments of 1 with triethylamine gave 2-alkylidene-1,3-dithiolane (2) when the 2-substituent was a primary or secondary alkyl group. 2-Aryl derivatives of 1 were converted to ortho esters by the reaction with methanol in the presence of silver nitrate. 1,3-Dithian-2-ylium perchlorates and 2-alkylidene-1,3-dithianes were also prepared similarly from 1,3-propanedithiol.

INDIRECT ELECTROCHEMICAL SIDE-CHAIN OXIDATION OF ALKYL AROMATIC COMPOUNDS - SELECTIVE SYNTHESIS OF METHYL BENZOATES OR ORTHOBENZOIC ACID TRIMETHYLESTERS

The technically important side-chain oxidation of alkyl aromatic compounds to form either methyl benzoates or orthobenzoic acid trimethylesters can be performed electrochemically at low potentials in methanol solution using an undivided cell and tris(2,4-dibromophenyl)amine as redox catalyst.Under neutral or slightly acidic conditions methyl benzoates are selectively formed while under basic conditions the orthoesters are predominating.In a similar way ortho benzoic acid trimethylesters are formed selectively starting from benzaldehyde dimethylacetals.The redox catalyst is stable under the reaction conditions so that several thousand cycles can be performed without noticeable loss.