768398-03-4

Usage

Uses

Impurity of Zolpidem (Z650000), a selective non-benzodiazepine GABAA receptor agonist.

InChI:InChI=1/C17H15N3/c1-12-3-6-14(7-4-12)17-15(9-10-18)20-11-13(2)5-8-16(20)19-17/h3-8,11H,9H2,1-2H3

Synthetic route

6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine (88965-00-8) + cyanomethyl bromide (590-17-0) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
With fac-tris(2-phenylpyridinato-N,C2')iridium(III); sodium hydrogencarbonate In dimethyl sulfoxide at 20℃; for 12h; Schlenk technique; Inert atmosphere; Irradiation; regioselective reaction;	85%

S-cyanomethyl O-ethyl carbonodithioate (59463-54-6) + 6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine (88965-00-8) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
With tris[2-phenylpyridinato-C2,N]iridium(III); N,N-dimethyl-formamide at 24℃; Minisci Aromatic Substitution; Inert atmosphere; UV-irradiation; regioselective reaction;	61%
With dilauryl peroxide In 1,2-dichloro-ethane at 85℃; Microwave irradiation; regioselective reaction;	51%

diazoacetonitrile (13138-21-1) + 6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine (88965-00-8) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
With iron(III) chloride In acetonitrile at 60℃; for 6h; Sealed tube; Green chemistry;	50%

6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine (88965-00-8) + acetonitrile (75-05-8) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
With ferrocene; bis(1-methyl-1-phenylethyl)peroxide at 20 - 100℃; for 20h; Inert atmosphere; Sealed tube;	48%

sodium cyanide (143-33-9) + Trimethyl-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-ammonium; iodide (106961-34-6) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
Yield given;
In water at 82 - 84℃; for 12h;

potassium cyanide (151-50-8) + dimethyl-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-ylmethyl)-amine (106961-33-5) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4) + 2-(4-methylphenyl)-6-methylimidazo[1,2-α]pyridine-3-acetamide (365213-58-7)

Conditions	Yield
Stage #1: dimethyl-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-ylmethyl)-amine With methyl iodide In ethanol at 20℃; for 24h; Stage #2: potassium cyanide In ethanol; water for 4h; Heating;

6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine (88965-00-8) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 78 percent / acetic acid / H2O / 4 h / 50 - 55 °C 2.1: MeI / ethanol / 24 h / 20 °C 2.2: H2O; ethanol / 4 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 79 percent / AcOH View Scheme

dimethyl-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-ylmethyl)-amine (106961-33-5) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

C20H24N3O2(1+)*Cl(1-) (1101863-48-2) + sodium cyanide (143-33-9) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
Stage #1: C20H24N3O2(1+)*Cl(1-) With sodium hydroxide; water pH=7.5 - 8; Stage #2: sodium cyanide In water at 50 - 55℃; for 3h; Product distribution / selectivity;

(5-methyl-pyridin-2-yl)amine (1603-41-4) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethanol / 6 h / 20 °C / Inert atmosphere 2: ferrocene; bis(1-methyl-1-phenylethyl)peroxide / 20 h / 20 - 100 °C / Inert atmosphere; Sealed tube View Scheme

4-(bromoacetyl)toluene (619-41-0) → 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethanol / 6 h / 20 °C / Inert atmosphere 2: ferrocene; bis(1-methyl-1-phenylethyl)peroxide / 20 h / 20 - 100 °C / Inert atmosphere; Sealed tube View Scheme

ethanol (64-17-5) + 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4) → ethyl 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetate (193979-47-4)

Conditions	Yield
With sulfuric acid; water at 90℃; for 12h;	95%
With sulfuric acid at 90℃; for 12h;	95%

6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4) → 6-methyl-2-(4-methylphenyl)-imidazo<1,2-a>pyridine-3-acetic acid (189005-44-5)

Conditions	Yield
With hydrogenchloride; water	91%
Stage #1: 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine With sulfuric acid; water at 110℃; for 4 - 5h; Stage #2: With sodium hydroxide; water at 0℃; pH=9; Stage #3: With water; acetic acid pH=5.5; Product distribution / selectivity;	72%
Stage #1: 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine With hydrogenchloride In water at 25 - 100℃; for 12h; Heating / reflux; Stage #2: With potassium hydroxide In water at 25 - 105℃; for 2 - 3h; Stage #3: With acetic acid In water at 30 - 40℃;
Stage #1: 6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine With sodium hydroxide; water at 55 - 98℃; for 16.5h; Heating / reflux; Stage #2: With acetic acid In water at 25℃; for 4h; pH=5.3;
With sulfuric acid at 110℃; Inert atmosphere;

6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4) → 3-((2H-tetrazol-5-yl)methyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine (1387635-23-5)

Conditions	Yield
With indium(III) chloride; sodium azide In N,N-dimethyl-formamide for 0.166667h; Microwave irradiation;	76%

6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4) → 1-Imidazol-1-yl-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-ethanone

Conditions	Yield
Multi-step reaction with 2 steps 1: 91 percent / H2O, HCl View Scheme

6-methyl-3-cyanomethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (768398-03-4) → N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide (82626-48-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / H2O, HCl View Scheme
Multi-step reaction with 2 steps 1.1: sulfuric acid / 110 °C / Inert atmosphere 2.1: phosphorus pentachloride / dichloromethane / Reflux; Inert atmosphere 2.2: 0 °C / Inert atmosphere View Scheme

Upstream product

• 143-33-9 sodium cyanide 
• 106961-34-6 Trimethyl-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-ylmethyl)-ammonium; iodide 
• 151-50-8 potassium cyanide 
• 106961-33-5 dimethyl-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-ylmethyl)-amine 
• 1101863-48-2 C₂₀H₂₄N₃O₂⁽¹⁺⁾*Cl^(1-) 
• 59463-54-6 S-cyanomethyl O-ethyl carbonodithioate 
• 88965-00-8 6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyridine 
• 75-05-8 acetonitrile 
• 1603-41-4 (5-methyl-pyridin-2-yl)amine 
• 619-41-0 4-(bromoacetyl)toluene 
• 590-17-0 cyanomethyl bromide 
• 13138-21-1 diazoacetonitrile 

Downstream Products

• 1387635-23-5 3-((2H-tetrazol-5-yl)methyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine 
• 193979-47-4 ethyl 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetate 
• 82626-48-0 N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide 
• 189005-44-5 6-methyl-2-(4-methylphenyl)-imidazo<1,2-a>pyridine-3-acetic acid 

Relevant academic research and scientific papers

FeCl3-catalyzed C-3 functionalization of imidazo[1,2-a]pyridines with diazoacetonitrile under oxidant- and ligand-free conditions

A facile synthesis of 2-(imidazo[1,2-a]pyridin-3-yl)acetonitriles via FeCl3-catalyzed site-selective C(sp2)-H alkylation of imidazo[1,2-a]pyridines with diazoacetonitrile is presented. This new method features with an environmentally benign catalyst, easily obtainable substrates, and oxidant- and ligand-free reaction conditions. Moreover, the importance of the products thus obtained is showcased by their ready transformation into some synthetically and pharmaceutically interesting products with good efficiency.

A cyanogen methylation imidazopyridine compound of preparation method (by machine translation)

The invention discloses a cyanogen methylation imidazopyridine compound of preparation method, in order to imidazo [1, 2 - a] pyridine compound as raw material, with the bromine second grade nitrile or [...] and under the action of the photocatalysis reaction, is obtained. Compared with the prior art, the method of the invention avoids the use of potassium cyanide or sodium cyanide and two connecting, iodomethane, and in the preparation of imidazo [1, 2 - a] pyridine compound of the cyanogen methylation product in the process, the chemical conversion from the original threestep shortened to step. The invention short preparation route, the preparation method is simple, the production cost is low, and the yield is high, have reduced the solvent to use and at the time of blowdown to the environment caused by pollution, easy to implement, easy to realize industrial. (by machine translation)

Visible light/Ir(III) photocatalytic initiation of xanthate-based radical-chain reactions: Xanthate group transfer and oxidative addition to aromatic systems

A photocatalyzed redox generation of radicals from O-ethyl xanthates to generate electrophilic radicals under photoredox catalysis, using Ir(ppy)3 and blue LEDs irradiation is described. The protocol can be used in classical xanthate-based inter- and intra-molecular group transfer reactions and oxidative radical addition to several heteroaromatic systems. The process does not require high temperature and reactions are cleaner compared with the traditional peroxide initiation. In the oxidative addition to aromatic systems, the oxidation process is part of the catalytic cycle and does not require a stoichiometric oxidant such as DLP which is particularly difficult to separate from the product.

Iron-Catalyzed Dehydrogenative sp3-sp2 Coupling via Direct Oxidative C-H Activation of Acetonitrile

An iron-catalyzed dehydrogenative sp3-sp2 coupling of acetonitrile and 2-arylimidazo[1,2-a]pyridine has been realized, which can serve as a novel approach toward heteroarylacetonitriles. The merit of this strategy is illustrated by the breadth of functional groups tolerated in the transformation and the fast access to pharmaceuticals (such as zolpidem) directly from the heteroarylacetonitriles.

Xanthate-based microwave-assisted C–H radical functionalization of caffeine, 1,3-dimethyluracil, and imidazo[1,2-a]pyridines

Xanthate-based radical chemistry was used for the regioselective direct alkylation of caffeine, uracil, and imidazo[1,2-a]pyridine systems, using dilauroyl peroxide as initiator and oxidant, under microwave irradiation. Under these conditions, several electrophilic radicals (located alpha to a carbonyl function such as esters, amides, ketones, malonates and cyano groups) were added to the title heterocyclic systems. The methodology allows the intermolecular regioselective construction of a sp2-sp3C–C bond via a C–H functionalization in an aromatic substitution, from readily available starting materials.

Visible-Light-Induced Regioselective Cyanomethylation of Imidazopyridines and Its Application in Drug Synthesis

3-Cyanomethylated imidazopyridines were synthesized via a visible light-promoted reaction of imidazopyridines with bromoacetonitrile or iodoacetonitrile catalyzed by fac-Ir(ppy)3 under mild conditions. For the substrates with various substituents on benzene or pyridine ring, the reaction proceeded smoothly to give the corresponding products in moderate to good yields. The synthetic utility of this visible-light-induced reaction has been illustrated in the efficient synthesis of zolpidem and alpidem.

PROCESS FOR PREPARING ZOLPIDEM AND ITS INTERMEDIATE

The present invention relates to an improved process for the preparation of 6- methyl-2-[4-methylphenyl]imidazo[l,2-a]pyridine-3-N,N-dimethyl acetamide having formula (1). The compound of formula (1) has adopted name "Zolpidem". The present invention also relates to novel intermediate of the formula (2) and a process for its preparation.Wherein R represents methyl, ethyl, propyl, butyl, isopropyl, isobutyl or tertiary butyl group. The novel intermediate of formula (2) is used in preparation of Zolpidem having formula (1). Zolpidem is useful in the treatment of anxiety, sleep disorders and convulsion.

PROCESS FOR PREPARING ZOLPIDEM

A process for preparing zolpidem.

A structure-activity relationship study of the affinity of selected imidazo[1,2-a]pyridine derivatives, congeners of zolpidem, for the ω1-subtype of the benzodiazepine receptor

A series of 6-substituted 2-aryl-N,N-dimethylimidazol [1,2-a]pyridine-3-acetamides, congeners of zolpidem and alpidem, was synthesized and tested in vitro for binding with the benzodiazepine receptor in the competition with 3H-zolpidem as an ω1-selective radioligand. Molecular electrostatic potential (MEP) and the HOMO and LUMO energies were calculated for the compounds by semi-empirical quantum chemistry methods. The lipophilicity parameter of the compounds, expressed as the logarithm of the octanol-water partition coefficient (log P), was calculated; alternatively, standard values of the Hansch hydrophobic substituent constants π were used. In agreement with earlier investigations on the benzodiazepine receptor ligands with a high preference for the ω1-subtype, a quantitative correlation of the biological data with molecular parameters has revealed a significant dependence (r=0.954) of the binding affinity (IC50) on the deepest MEP minimum, in this case associated with the amide carbonyl oxygen atom. The lipophilicity parameters were found to be of lower significance.