52606-01-6

Basic information

• Product Name: 2,6-DIMETHOXYISONICOTINALDEHYDE
• Synonyms: 2,6-DIMETHOXYISONICOTINALDEHYDE;2,6-DIMETHOXYPYRIDINE-4-CARBOXALDEHYDE;2,6-DIMETHOXYISONICO;2,6-diMethoxypyridine-4-carbaldehyde
• CAS NO: 52606-01-6
• Molecular Formula: C₈H₉NO₃
• Molecular Weight: 167.16
• Product Categories: Pyridines
• Mol File: 52606-01-6.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 268.1 °C at 760 mmHg
• Flash Point: 115.9 °C
• Appearance: /
• Density: 1.174
• Vapor Pressure: 0.00786mmHg at 25°C
• Refractive Index: 1.537
• Storage Temp.: 2-8°C
• CAS DataBase Reference: 2,6-DIMETHOXYISONICOTINALDEHYDE(CAS DataBase Reference)
• NIST Chemistry Reference: 2,6-DIMETHOXYISONICOTINALDEHYDE(52606-01-6)
• EPA Substance Registry System: 2,6-DIMETHOXYISONICOTINALDEHYDE(52606-01-6)

Safety Data

• Hazardous Substances Data: 52606-01-6(Hazardous Substances Data)

Usage

General Description

2,6-DIMETHOXYISONICOTINALDEHYDE is a chemical compound with the molecular formula C11H13NO4. It is an aldehyde derivative of isonicotinic acid and contains two methoxy groups on the 2 and 6 positions of the aromatic ring. 2,6-DIMETHOXYISONICOTINALDEHYDE is commonly used in the synthesis of pharmaceutical and agrochemical products. It is also known for its potential as a building block in organic synthesis, particularly in the development of new drug candidates. Additionally, 2,6-DIMETHOXYISONICOTINALDEHYDE has exhibited antioxidant and anti-inflammatory properties, making it a subject of research for potential therapeutic applications.

InChI:InChI=1/C8H9NO3/c1-11-7-3-6(5-10)4-8(9-7)12-2/h3-5H,1-2H3

Synthetic route

(2,6-dimethoxypyridine-4-yl)-methanol (52606-06-1) → 2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6)

Conditions	Yield
With manganese(IV) oxide In chloroform at 20℃; for 12h;	68%
With manganese(IV) oxide In methanol at 20℃; for 72h;	28.8%

citrazinic acid (99-11-6) → 2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6)

2,6-dichloropyridine-4-carboxylic acid (5398-44-7) → 2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / 1 h / Reflux 2: N,N-dimethyl-formamide / 12 h / Reflux 3: sodium tetrahydroborate / 1,4-dioxane / 1 h / Reflux 4: manganese(IV) oxide / chloroform / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: diethylene glycol dimethyl ether / 24 h / Reflux; Dean-Stark 2: lithium aluminium tetrahydride / tetrahydrofuran / 25 h / 0 - 20 °C 3: manganese(IV) oxide / methanol / 72 h / 20 °C View Scheme

methyl 2,6-dichloroisonicotinate (42521-09-5) → 2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 12 h / Reflux 2: sodium tetrahydroborate / 1,4-dioxane / 1 h / Reflux 3: manganese(IV) oxide / chloroform / 12 h / 20 °C View Scheme

2,6-dimethoxypyridine-4-carboxylic acid (6274-82-4) → 2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 25 h / 0 - 20 °C 2: manganese(IV) oxide / methanol / 72 h / 20 °C View Scheme

citrazinic acid (99-11-6) → 2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: trichlorophosphate; tetramethlyammonium chloride / 24 h / 140 °C 2: diethylene glycol dimethyl ether / 24 h / Reflux; Dean-Stark 3: lithium aluminium tetrahydride / tetrahydrofuran / 25 h / 0 - 20 °C 4: manganese(IV) oxide / methanol / 72 h / 20 °C View Scheme

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + C11H9BrClNOZn → C19H19BrN2O4

Conditions	Yield
In tetrahydrofuran at 20℃;	93%

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + ethyl (triphenylphosphoranylidene)acetate (1099-45-2) → (E)-methyl 3-(2,6-dimethoxypyridin-4-yl)acrylate (1000895-93-1)

Conditions	Yield
In dichloromethane at 18 - 25℃;	60%

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + C37H38BF2I2N5O3 → C53H52BF2I2N7O7

Conditions	Yield
With piperidine; acetic acid In benzene Reflux; Dean-Stark;	58%

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + ((4-methoxyphenyl)methyl)triphenylphosphonium bromide (1530-38-7) → (E)-2,6-dimethoxy-4-(4-methoxystyryl)-pyridine + (Z)-2,6-dimethoxy-4-(4-methoxystyryl)-pyridine

Conditions	Yield
Stage #1: ((4-methoxyphenyl)methyl)triphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at -40℃; for 1h; Stage #2: 2,6-dimethoxy-4-pyridinecarboxaldehyde In tetrahydrofuran at 20℃; for 24h; Wittig Olefination;	A 12.2% B 29.2%

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + (2-naphthalenylmethyl)triphenylphosphonium bromide (35160-95-3) → (E)-2,6-dimethoxy-4-(2-naphth-2-ylvinyl)-pyridine + (Z)-2,6-dimethoxy-4-(2-naphth-2-ylvinyl)-pyridine

Conditions	Yield
Stage #1: (2-naphthalenylmethyl)triphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at -40℃; for 1h; Stage #2: 2,6-dimethoxy-4-pyridinecarboxaldehyde In tetrahydrofuran at 20℃; for 24h; Wittig Olefination;	A 13.3% B 7.5%

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + triphenyl-(3,4,5-trimethoxybenzyl)phosphonium bromide (61240-20-8) → (E)-2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)-pyridine + (Z)-2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)-pyridine

Conditions	Yield
Stage #1: triphenyl-(3,4,5-trimethoxybenzyl)phosphonium bromide With n-butyllithium In tetrahydrofuran at -40℃; for 1h; Stage #2: 2,6-dimethoxy-4-pyridinecarboxaldehyde In tetrahydrofuran at 20℃; for 24h; Wittig Olefination;	A 1.9% B 2.9%

3-Morpholin-4-yl-propionitrile (4542-47-6) + 2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) → 2-(2,6-dimethoxy-pyridin-4-ylmethyl)-3-morpholin-4-yl-acrylonitrile (65873-52-1)

Conditions	Yield
(i) NaOMe, DMSO, (ii) /BRN= 1448374/; Multistep reaction;

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + 4-aminobenzamidine ditoluenesulphonate + Benzyl isocyanide (88333-03-3, 10340-91-7) → (RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2,6-dimethoxypyridin-4-yl)acetamide

Conditions	Yield
In tetrahydrofuran; diethyl ether; water	2.02 g (28%)

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide (54016-70-5) + 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (106331-50-4) → 1-(2,6-dimethoxypyrid-4-yl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione (106331-64-0)

Conditions	Yield
With triethylamine In ethanol

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) → N'-[5-[2-(2,6-dimethoxypyridin-4-yl)ethyl]-1H-pyrazol-3-yl]-N-[(3-methyl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine

Conditions	Yield
Multi-step reaction with 5 steps 1.1: dichloromethane / 18 - 25 °C 2.1: hydrogen / palladium 10% on activated carbon / ethanol / 18 h / 18 - 25 °C 3.1: lithium diisopropyl amide / tetrahydrofuran / 0.17 h / -78 °C 3.2: -78 - 25 °C 4.1: hydrazine hydrochloride / ethanol / 18 h / Heating / reflux 5.1: ethanol / 45 h / 18 - 80 °C View Scheme

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) → methyl 3-(2,6-dimethoxypyridin-4-yl)propanoate (1000895-92-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 18 - 25 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 18 h / 18 - 25 °C View Scheme

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) → 5-(2-(2,6-dimethoxypyridin-4-yl)ethyl)-1H-pyrazol-3-amine (1000895-91-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: dichloromethane / 18 - 25 °C 2.1: hydrogen / palladium 10% on activated carbon / ethanol / 18 h / 18 - 25 °C 3.1: lithium diisopropyl amide / tetrahydrofuran / 0.17 h / -78 °C 3.2: -78 - 25 °C 4.1: hydrazine hydrochloride / ethanol / 18 h / Heating / reflux View Scheme

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) → C12H14N2O3

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dichloromethane / 18 - 25 °C 2.1: hydrogen / palladium 10% on activated carbon / ethanol / 18 h / 18 - 25 °C 3.1: lithium diisopropyl amide / tetrahydrofuran / 0.17 h / -78 °C 3.2: -78 - 25 °C View Scheme

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) + 2-methoxy-6-bromoquinoline (99455-05-7) → C18H17BrN2O4

Conditions	Yield
With 2,2,6,6-tetramethylpiperidinyl-lithium In tetrahydrofuran at -75℃; for 4h;

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) → 6-bromo-3-((2,6-dimethoxypyridin-4-yl)methyl)-2-methoxyquinoline

Conditions	Yield
Multi-step reaction with 2 steps 1: 2,2,6,6-tetramethylpiperidinyl-lithium / tetrahydrofuran / 4 h / -75 °C 2: triethylsilane; trifluoroacetic acid / dichloromethane View Scheme

2,6-dimethoxy-4-pyridinecarboxaldehyde (52606-01-6) → 1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 2,2,6,6-tetramethylpiperidinyl-lithium / tetrahydrofuran / 4 h / -75 °C 2.1: triethylsilane; trifluoroacetic acid / dichloromethane 3.1: diisopropylamine; n-butyllithium / tetrahydrofuran; cyclohexane / 1.5 h / -78 - -70 °C / Inert atmosphere 3.2: 5 h / -78 - -70 °C / Inert atmosphere View Scheme

Upstream product

• 99-11-6 citrazinic acid 
• 6274-82-4 2,6-dimethoxypyridine-4-carboxylic acid 
• 52606-06-1 (2,6-dimethoxypyridine-4-yl)-methanol 
• 42521-09-5 methyl 2,6-dichloroisonicotinate 
• 5398-44-7 2,6-dichloropyridine-4-carboxylic acid 
• 99-11-6 citrazinic acid 

Downstream Products

• 106331-64-0 1-(2,6-dimethoxypyrid-4-yl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione 

Relevant articles and documents

Potent colchicine-site ligands with improved intrinsic solubility by replacement of the 3,4,5-trimethoxyphenyl ring with a 2-methylsulfanyl-6-methoxypyridine ring

Colchicine site antimitotic agents typically suffer from low aqueous solubilities and are formulated as phosphate prodrugs of phenolic groups. These hydroxyl groups are the aim of metabolic transformations leading to resistance. There is an urgent need for more intrinsically soluble analogues lacking these hydroxyl groups. The 3,4,5-trimethoxyphenyl ring of combretastatin A-4 is a liability in terms of solubility but it is considered essential for high cytotoxic and tubulin polymerization inhibitory (TPI) activity. We have synthesized 36 new analogues of combretastatin A-4 replacing the trimethoxyphenyl moiety with more polar pyridine based moieties, measured their aqueous solubility, and studied their anti-proliferative effects against 3 human cancer cell lines. We show here that pyridine rings can be successful replacements for the trimethoxyphenyl ring, resulting in potent and more soluble analogues. The more straightforward replacement, a 2,6-dimethoxypyridine ring led to inactive analogues, but a 2-methoxy-6-methylsulfanylpyridine moiety led to active analogues when combined with different B rings. This replacement led to potent cytotoxic activity against sensitive human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies. Cell cycle analysis also showed apoptotic responses following treatment. Docking studies suggested binding at the colchicine site of tubulin and provided a good agreement with the observed SAR. A 2-methoxy-6-methylsulfanylpyridine moiety is a good trimethoxyphenyl ring replacement for the development of new colchicine site ligands.

New 2,5-diaryl tetryhydrofurans and analogs thereof as paf antagonists

Compounds of formula: are disclosed wherein R and R1 are (a) hydrogen;(b) haloloweralkyl;(c) halo;(d) CONR2R3 wherein R2 and R3 independently represent hydrogen, C1-8 alkyl, or C3-8 cycloalkyl;(e) loweralkenyl;(f)-COR2;(g)-CH?OR2;(h) loweralkynyl;(i)-CH?NR2R3;(j)-CH?SR2;(k) =O; or(l)-OR2;(m)-R2; Ar and Ar1 are (a) phenyl or substituted phenyl of formula where R?-R? independently represent H; R2; YO-wherein Y is loweralkenyl, loweralkynyl,-CH? ,-CH?C(O) OR2,-CH?OR2,-CH?C3-8cycloalkyl,-CH? Ar2 wherein Ar2 is phenyl or substituted phenyl,-CH?-CH(OH)-CH? OH; R2S-(O)n wherein R2 can only be C3-8 cycloalkyl and n is 0 to 2; CF?SO, CF?SO?;-CONR2R3;-NR2COR3;-OCONH?-CR2R3R? wherein R? is the same as or different from R2;-CH?OR2;-CH?CO?R2;-CH?OCOR3;-CH?O-CO-OR2;-NHCH?COOR2; halo; or N?R2R3R?X? wherein X? is an anion;(b) monoheteroaryl, di-or polyheteroaryl or fused heteroaryl containing 1 to 3 of any one or more of the heteroatoms N, S or O;(c) heteroarylalkyl;(d) heterocycloalkyl; or(e) heterocycloalkenyl. These compounds are found to have potent and specific PAF (Platelet Activating Factor) antagonistic activities.