3613-73-8

Basic information

• Product Name: dimebolin
• Synonyms: dimebolin;2,3,4,5-Tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]-1H-pyrido[4,3-b]indole;2,3,4,5-Tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]indole;Dimeboline;Dimebone;Preparation-84;dimebon;2,3,4,5-Tetrahydro-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-1H-pyrido[4,3-b]indole
• CAS NO: 3613-73-8
• Molecular Formula: C₂₁H₂₅N₃
• Molecular Weight: 319.44
• EINECS: 1312995-182-4
• Mol File: 3613-73-8.mol
• Article Data: 12

Chemical Properties

• Melting Point: 115-116 °C
• Boiling Point: 448.46°C (rough estimate)
• Flash Point: 259.7 °C
• Appearance: White powder
• Density: 1.13
• Vapor Pressure: 2.37E-10mmHg at 25°C
• Refractive Index: 1.6380 (estimate)
• Solubility: ≤30mg/ml in ethanol;1mg/ml in DMSO;3mg/ml in dimethyl formamide
• PKA: 9.05±0.20(Predicted)
• CAS DataBase Reference: dimebolin(CAS DataBase Reference)
• NIST Chemistry Reference: dimebolin(3613-73-8)
• EPA Substance Registry System: dimebolin(3613-73-8)

Safety Data

• Hazardous Substances Data: 3613-73-8(Hazardous Substances Data)

Usage

Uses

Non-steroidal anti-inflammatory with analgesic and antipyretic effects

Biological Activity

dimebolin is an orally-available antihistamine drug with a long history of clinical use in russia [1][2][3][4].dimebolin has been proposed to be useful for treating neurodegenerative disorders, including alzheimer's disease (ad) and huntington's disease (hd). dimebon might exhibit efficacy by blocking nmda receptors or voltage-gated ca2+ channels and by preventing mitochondrial permeability pore transition [3].dimebolin is an orally-available antihistamine drug. dimebon improved survival of cerebellar granule cells during long-term incubation with aβ25-35. dimebolin also blocked potential-dependent ca(2+) entry into neurons by about 20% by blocking l-type ca(2+) channels [4]. in the cerebellum cell culture, dimebolin protected neurons against the neurotoxic action of aβ25-35 with ec50 value of 25 μm. on isolated rat ileum intestine, dimebolin displayed ca2+-blocking properties with ic50 value of 57 μm. dimebon also exhibited anticholinesterase activity with ic50 values of 7.9 μm and 42 μm for butyryl-choline esterase and acetylcholine esterase, respectively [5].in rats treated with the neurotoxin af64a, dimebolin exhibited cognition and memory-enhancing properties. in mice, dimebolin prevented nmda-induced seizures with ec50 value of 42 ± 6 mg/kg [5].

references

[1]. lermontova nn, lukoyanov nv, serkova tp, et al. dimebon improves learning in animals with experimental alzheimer's disease. bull exp biol med. 2000 jun;129(6):544-6.[2]. doody rs, gavrilova si, sano m, et al. effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate alzheimer's disease: a randomised, double-blind, placebo-controlled study. lancet. 2008 jul 19;372(9634):207-15.[3]. wu j, li q, bezprozvanny i. evaluation of dimebon in cellular model of huntington's disease. mol neurodegener. 2008 oct 21;3:15.[4]. lermontova nn, redkozubov ae, shevtsova ef, et al. dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block l-type ca(2+) channels. bull exp biol med. 2001 nov;132(5):1079-83.[5]. bachurin s, bukatina e, lermontova n, et al. antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. ann n y acad sci. 2001 jun;939:425-35.

InChI:InChI=1/C21H25N3/c1-15-4-7-20-18(12-15)19-14-23(3)10-9-21(19)24(20)11-8-17-6-5-16(2)22-13-17/h4-7,12-13H,8-11,14H2,1-3H3

Synthetic route

2-methyl-5-vinylpyridine (140-76-1) + 2.8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (19686-05-6) → dimebon (3613-73-8)

Conditions	Yield
With potassium phosphate In ISOPROPYLAMIDE at 100℃; for 24h; Inert atmosphere;	80%
With potassium hydroxide In 1-methyl-pyrrolidin-2-one at 100℃;	55%
With potassium hydroxide In diethylene glycol dimethyl ether at 120℃; for 42h; Product distribution / selectivity;	52%
With sodium ethanolate; sodium In dimethyl sulfoxide at 90 - 95℃;
With potassium phosphate In ISOPROPYLAMIDE at 130℃;

tert-butyl 8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1227258-81-2) → dimebon (3613-73-8)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran for 2h; Reflux;	70%

1-Methyl-4-piperidone (1445-73-4) + 2-methyl-5-{2-[1-(4-methylphenyl)hydrazinyl]ethyl}pyridine (21241-08-7) → dimebon (3613-73-8)

Conditions	Yield
With acetic acid In water at 20℃; for 4h; Inert atmosphere; Reflux;
With hydrogenchloride In isopropyl alcohol for 0.25h;

N'-(1-methyl-piperidin-4-ylidene)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine (1229621-60-6) → dimebon (3613-73-8)

Conditions	Yield
With hydrogenchloride In ethanol; water at 100℃; for 0.5h;
Stage #1: N'-(1-methyl-piperidin-4-ylidene)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine With hydrogenchloride; water In ethanol at 80℃; for 1.5h; Stage #2: With sodium hydroxide In ethanol; water pH=14;
Stage #1: N'-(1-methyl-piperidin-4-ylidene)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine With hydrogenchloride In ethanol at 80℃; for 1.5h; Reflux; Stage #2: With sodium hydroxide In ethanol; water pH=14;

Latrepirdine dihydrochloride → dimebon (3613-73-8)

Conditions	Yield
With sodium hydroxide In 2-methyltetrahydrofuran; water for 1.25h;

2-methyl-5-vinylpyridine (140-76-1) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 0 °C / Reflux; Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: phosphorus tribromide / diethyl ether / 3 h / 0 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 4.1: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: potassium phosphate / ISOPROPYLAMIDE / 22 h / 100 °C 2: hydrogenchloride / isopropyl alcohol / 0.25 h View Scheme

2-(6-methylpyridin-3-yl) ethan-1-ol (100189-17-1) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphorus tribromide / diethyl ether / 3 h / 0 °C / Inert atmosphere 2: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 3: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme

Br(1-)*C21H22N3(1+) → dimebon (3613-73-8)

Conditions	Yield
With sodium tetrahydroborate In methanol; water Inert atmosphere;	0.046 g

3-(2-azido-5-methylphenyl)pyridine (1296770-62-1) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: dichloromethane / 20 °C / Inert atmosphere 2: dirhodium(II) tetrakis(perfluorobutyrate) / toluene / 15 h / 90 °C / Inert atmosphere; Molecular sieve 3: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 4: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 5: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: dichloromethane / 20 °C / Inert atmosphere 2: ruthenium trichloride hydrate / Isopropyl acetate / 15 h / 80 °C / Inert atmosphere 3: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 4: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 5: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme

1-methyl-3-(2-azido-5-methylphenyl)pyridinium triflate (1296770-72-3) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: dirhodium(II) tetrakis(perfluorobutyrate) / toluene / 15 h / 90 °C / Inert atmosphere; Molecular sieve 2: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 3: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 4: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: ruthenium trichloride hydrate / Isopropyl acetate / 15 h / 80 °C / Inert atmosphere 2: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 3: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 4: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme

CF3O3S(1-)*C13H13N2(1+) (1296770-97-2) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 2: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 3: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme

3-(2-amino-5-methylphenyl)pyridine (695185-44-5) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: acetic acid; sodium nitrite / water / 1.5 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: dichloromethane / 20 °C / Inert atmosphere 3.1: dirhodium(II) tetrakis(perfluorobutyrate) / toluene / 15 h / 90 °C / Inert atmosphere; Molecular sieve 4.1: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 6.1: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: acetic acid; sodium nitrite / water / 1.5 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: dichloromethane / 20 °C / Inert atmosphere 3.1: ruthenium trichloride hydrate / Isopropyl acetate / 15 h / 80 °C / Inert atmosphere 4.1: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 6.1: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme

2-bromo-p-toluidine (583-68-6) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 2.5 h / 80 °C / Inert atmosphere 2.1: acetic acid; sodium nitrite / water / 1.5 h / 0 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere 3.1: dichloromethane / 20 °C / Inert atmosphere 4.1: dirhodium(II) tetrakis(perfluorobutyrate) / toluene / 15 h / 90 °C / Inert atmosphere; Molecular sieve 5.1: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 7.1: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 2.5 h / 80 °C / Inert atmosphere 2.1: acetic acid; sodium nitrite / water / 1.5 h / 0 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere 3.1: dichloromethane / 20 °C / Inert atmosphere 4.1: ruthenium trichloride hydrate / Isopropyl acetate / 15 h / 80 °C / Inert atmosphere 5.1: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 7.1: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme

3-pyridylboronic acid (1692-25-7) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 2.5 h / 80 °C / Inert atmosphere 2.1: acetic acid; sodium nitrite / water / 1.5 h / 0 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere 3.1: dichloromethane / 20 °C / Inert atmosphere 4.1: dirhodium(II) tetrakis(perfluorobutyrate) / toluene / 15 h / 90 °C / Inert atmosphere; Molecular sieve 5.1: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 7.1: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 2.5 h / 80 °C / Inert atmosphere 2.1: acetic acid; sodium nitrite / water / 1.5 h / 0 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere 3.1: dichloromethane / 20 °C / Inert atmosphere 4.1: ruthenium trichloride hydrate / Isopropyl acetate / 15 h / 80 °C / Inert atmosphere 5.1: potassium hydroxide / water / 2 h / 90 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide / 15 h / 60 °C / Inert atmosphere 7.1: sodium tetrahydroborate / methanol; water / Inert atmosphere View Scheme

2-methyl-5-{2-[1-(4-methylphenyl)hydrazinyl]ethyl}pyridine (21241-08-7) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene / 24 h / 120 °C 2.1: hydrogenchloride; water / ethanol / 1.5 h / 80 °C 2.2: pH 14 View Scheme
Multi-step reaction with 2 steps 1.1: toluene / 24 h / 120 °C 2.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 2.2: pH 14 View Scheme

2-methyl-5-(2-[N-nitroso-(2-methylphenyl)amino]ethyl)pyridine → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 1.2: 12 h / 60 °C / Inert atmosphere 2.1: toluene / 24 h / 120 °C 3.1: hydrogenchloride; water / ethanol / 1.5 h / 80 °C 3.2: pH 14 View Scheme

Methyl 6-methylnicotinate (5470-70-2) → dimebon (3613-73-8)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: sodium hydride / N,N-dimethyl-formamide; toluene / 10 h / 80 °C 1.2: 2 h / 110 °C 1.3: pH 9 2.1: sulfur / 7 h / 110 °C 3.1: sodium hydroxide; water / ethanol / 17 h / 80 °C 3.2: pH 2 4.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 12 h / 20 °C 5.1: sodium tetrahydroborate; acetic acid / 1,4-dioxane / 3.5 h / 10 - 105 °C 6.1: hydrogenchloride / water / 30 °C 6.2: 1 h / 0 - 20 °C 6.3: 1 h 7.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 7.2: 12 h / 60 °C / Inert atmosphere 8.1: toluene / 24 h / 120 °C 9.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 9.2: pH 14 View Scheme

p-toluidine (106-49-0) → dimebon (3613-73-8)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 12 h / 20 °C 2.1: sodium tetrahydroborate; acetic acid / 1,4-dioxane / 3.5 h / 10 - 105 °C 3.1: hydrogenchloride / water / 30 °C 3.2: 1 h / 0 - 20 °C 3.3: 1 h 4.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 4.2: 12 h / 60 °C / Inert atmosphere 5.1: toluene / 24 h / 120 °C 6.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 6.2: pH 14 View Scheme

2-(6-methylpyridin-3-yl)acetic acid (19733-96-1) → dimebon (3613-73-8)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 12 h / 20 °C 2.1: sodium tetrahydroborate; acetic acid / 1,4-dioxane / 3.5 h / 10 - 105 °C 3.1: hydrogenchloride / water / 30 °C 3.2: 1 h / 0 - 20 °C 3.3: 1 h 4.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 4.2: 12 h / 60 °C / Inert atmosphere 5.1: toluene / 24 h / 120 °C 6.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 6.2: pH 14 View Scheme

1-(6-methyl-pyridin-3-yl)-ethanone (36357-38-7) → dimebon (3613-73-8)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: sulfur / 7 h / 110 °C 2.1: sodium hydroxide; water / ethanol / 17 h / 80 °C 2.2: pH 2 3.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 12 h / 20 °C 4.1: sodium tetrahydroborate; acetic acid / 1,4-dioxane / 3.5 h / 10 - 105 °C 5.1: hydrogenchloride / water / 30 °C 5.2: 1 h / 0 - 20 °C 5.3: 1 h 6.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 6.2: 12 h / 60 °C / Inert atmosphere 7.1: toluene / 24 h / 120 °C 8.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 8.2: pH 14 View Scheme

N-(4-methylphenyl)-2-(6-methylpyridin-3-yl)acetamide (1229621-59-3) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium tetrahydroborate; acetic acid / 1,4-dioxane / 3.5 h / 10 - 105 °C 2.1: hydrogenchloride / water / 30 °C 2.2: 1 h / 0 - 20 °C 2.3: 1 h 3.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 3.2: 12 h / 60 °C / Inert atmosphere 4.1: toluene / 24 h / 120 °C 5.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 5.2: pH 14 View Scheme

4-methyl-N-(2-(6-methylpyridin-3-yl)ethyl)aniline (21241-10-1) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 30 °C 1.2: 1 h / 0 - 20 °C 1.3: 1 h 2.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 2.2: 12 h / 60 °C / Inert atmosphere 3.1: toluene / 24 h / 120 °C 4.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 4.2: pH 14 View Scheme

4-methyl-N-[2-(6-methylpyridin-3-yl)ethyl]-N-nitrosoaniline (21241-09-8) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 1.2: 12 h / 60 °C / Inert atmosphere 2.1: toluene / 24 h / 120 °C 3.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 3.2: pH 14 View Scheme

4-[(6-methyl-pyridin-3-yl)-thioacetyl]-morpholine (19733-95-0) → dimebon (3613-73-8)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium hydroxide; water / ethanol / 17 h / 80 °C 1.2: pH 2 2.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 12 h / 20 °C 3.1: sodium tetrahydroborate; acetic acid / 1,4-dioxane / 3.5 h / 10 - 105 °C 4.1: hydrogenchloride / water / 30 °C 4.2: 1 h / 0 - 20 °C 4.3: 1 h 5.1: sodium hydroxide / ethanol; water / 0.5 h / 60 °C / Inert atmosphere 5.2: 12 h / 60 °C / Inert atmosphere 6.1: toluene / 24 h / 120 °C 7.1: hydrogenchloride / ethanol / 1.5 h / 80 °C / Reflux 7.2: pH 14 View Scheme

1-Methyl-4-piperidone (1445-73-4) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water / 20 - 55 °C / Industry scale 1.2: 2.5 h / 5 - 45 °C / pH 12.4 / Industry scale 2.1: potassium hydroxide / diethylene glycol dimethyl ether / 42 h / 120 °C View Scheme

p-tolylhydrazine hydrochloride (637-60-5) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water / 20 - 55 °C / Industry scale 1.2: 2.5 h / 5 - 45 °C / pH 12.4 / Industry scale 2.1: potassium hydroxide / diethylene glycol dimethyl ether / 42 h / 120 °C View Scheme

N-4-methylphenylhydrazine (539-44-6) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium phosphate / ISOPROPYLAMIDE / 22 h / 100 °C 2: hydrogenchloride / isopropyl alcohol / 0.25 h View Scheme

5-bromo-2-methylpyridine (3430-13-5) → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: butyl magnesium bromide; methyllithium / tetrahydrofuran / 0.5 h / -10 - 0 °C 1.2: 1 h 1.3: 1 h / 40 °C 2.1: thionyl chloride; sodium hydroxide / Isopropyl acetate 2.2: 4 h / 50 °C 3.1: potassium hydroxide / diethylene glycol dimethyl ether / 42 h / 120 °C View Scheme
Multi-step reaction with 4 steps 1.1: butyl magnesium bromide; methyllithium / tetrahydrofuran / 0.5 h / -10 - 0 °C 1.2: 1 h 1.3: 1 h / 40 °C 2.1: thionyl chloride; sodium hydroxide / Isopropyl acetate 2.2: 4 h / 50 °C 3.1: potassium phosphate / ISOPROPYLAMIDE / 22 h / 100 °C 4.1: hydrogenchloride / isopropyl alcohol / 0.25 h View Scheme

1-(6-methylpyridin-3-yl)ethanol maleate → dimebon (3613-73-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: thionyl chloride; sodium hydroxide / Isopropyl acetate 1.2: 4 h / 50 °C 2.1: potassium hydroxide / diethylene glycol dimethyl ether / 42 h / 120 °C View Scheme
Multi-step reaction with 3 steps 1.1: thionyl chloride; sodium hydroxide / Isopropyl acetate 1.2: 4 h / 50 °C 2.1: potassium phosphate / ISOPROPYLAMIDE / 22 h / 100 °C 3.1: hydrogenchloride / isopropyl alcohol / 0.25 h View Scheme

glycyrrizhin (83896-44-0, 103000-77-7, 119479-05-9, 142394-43-2, 1405-86-3) + dimebon (3613-73-8) → C42H62O16*0.25C21H25N3

Conditions	Yield
In ethanol at 45 - 50℃;	93.9%

dimebon (3613-73-8) → Latrepirdine dihydrochloride

Conditions	Yield
With hydrogenchloride In acetone at 45 - 65℃; for 0.666667h; Inert atmosphere;	84%
With hydrogenchloride In methanol; water at 0℃; for 2h; pH=2 - 3;	83%
With hydrogenchloride In methanol at 0℃; for 2h; pH=2 - 3;	83%
With hydrogenchloride In methanol; water at 20℃; for 2h;	70%

iodomethyl diisopropylcarbamate (353736-55-7) + dimebon (3613-73-8) → 2-(((diisopropylcarbamoyl)oxy)methyl)-5-(2-(1-(((diisopropylcarbamoyl)oxy)methyl)-6-methylpyridin-1-ium-3-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-2-ium diiodide

Conditions	Yield
In ethyl acetate at 20℃;	39%

iodomethyl diisopropylcarbamate (353736-55-7) + dimebon (3613-73-8) → 2-(((diisopropylcarbamoyl)oxy)methyl)-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-2-ium iodide (1402916-48-6)

Conditions	Yield
In ethyl acetate at 20℃;	15%

dimebon (3613-73-8) → 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole N,N'-dioxide (1147893-49-9)

Conditions	Yield
With dihydrogen peroxide; acetic acid In water at 65 - 70℃; for 20h;

dimebon (3613-73-8) → C21H21N3O3 (1147893-75-1)

Conditions	Yield
With selenium(IV) oxide In pyridine at 80℃; for 48h;

dimebon (3613-73-8) → 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 2-oxide (1147893-84-2)

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 25℃; for 24h;

dimebon (3613-73-8) → C21H31B2N3

Conditions	Yield
With borane-THF In tetrahydrofuran at 20℃;

dimebon (3613-73-8) → (4aRS,9bSR)-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole trihydrobromide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate; trifluoroacetic acid / 3 h / 20 °C 1.2: pH 10 - 10.5 2.1: hydrogen bromide / ethanol; water / 0.5 h View Scheme

dimebon (3613-73-8) → (4aRS,9bSR)-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

Conditions	Yield
Stage #1: dimebon With sodium tetrahydroborate; trifluoroacetic acid at 20℃; for 3h; Stage #2: With sodium hydroxide In water pH=10 - 10.5; stereoselective reaction;

dimebon (3613-73-8) → (4aRS,9bRS)-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole trihydrobromide

Conditions	Yield
Multi-step reaction with 3 steps 1.1: borane-THF / tetrahydrofuran / 20 °C 2.1: hydrogenchloride / 1,4-dioxane; water / 2 h / Reflux 2.2: pH 10 - 10.5 3.1: hydrogen bromide / ethanol; water / 0.5 h View Scheme

dimebon (3613-73-8) → (4aRS,9bRS)-2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

Conditions	Yield
Multi-step reaction with 2 steps 1.1: borane-THF / tetrahydrofuran / 20 °C 2.1: hydrogenchloride / 1,4-dioxane; water / 2 h / Reflux 2.2: pH 10 - 10.5 View Scheme

dimebon (3613-73-8) → 2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrobromide

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; trifluoroacetic acid / 3 h / 20 °C 1.2: pH 10 - 10.5 2.1: hydrogen bromide / ethanol; water / 0.5 h 3.1: oxygen / ethanol View Scheme

Upstream product

• 1227258-81-2 tert-butyl 8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate 
• 1445-73-4 1-Methyl-4-piperidone 
• 21241-08-7 2-methyl-5-{2-[1-(4-methylphenyl)hydrazinyl]ethyl}pyridine 
• 3430-13-5 5-bromo-2-methylpyridine 
• 539-44-6 N-4-methylphenylhydrazine 
• 637-60-5 p-tolylhydrazine hydrochloride 
• 19733-95-0 4-[(6-methyl-pyridin-3-yl)-thioacetyl]-morpholine 
• 21241-09-8 4-methyl-N-[2-(6-methylpyridin-3-yl)ethyl]-N-nitrosoaniline 
• 21241-10-1 4-methyl-N-(2-(6-methylpyridin-3-yl)ethyl)aniline 
• 1229621-59-3 N-(4-methylphenyl)-2-(6-methylpyridin-3-yl)acetamide 
• 36357-38-7 1-(6-methyl-pyridin-3-yl)-ethanone 
• 19733-96-1 2-(6-methylpyridin-3-yl)acetic acid 
• 106-49-0 p-toluidine 
• 5470-70-2 Methyl 6-methylnicotinate 

Relevant articles and documents

SUSTAINED RELEASE COMPOSITION CONTAINING TETRAHYDROPYRIDO Y4, 3-b¨INDOLE DERIVATIVE AND PREPARATION METHOD OF DERIVATIVE

The present invention relates to a sustained-release composition containing 2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]indole or a pharmaceutically acceptable salt thereof as an active ingredient, preparation thereof and the compound. The composition is suitable for oral administration by one time per day, and achieves the peak plasma concentration at 1.0 to 3 hours after oral administration. The composition is suitable for manufacturing a medicament for treatment of cognitive dysfunction syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, or senile dementia.

Ruthenium-catalyzed γ-carbolinium ion formation from aryl azides; Synthesis of dimebolin

A range of γ-carbolines were produced stereoselectively from ruthenium(III)-catalyzed reactions of 3-pyridyl substituted aryl azides. Other catalysts and conditions were neither as selective nor as high-yielding. This method was used to synthesize dimebolin in a concise and efficient manner.

SYNTHESIS OF 9-(ARYLALKYL)-1,2,3,4-TETRAHYDRO-Υ-CARBOLINE AND ANALOGUES AND INTERMEDIATES

The present invention pertains generally to methods of preparing certain 9-(arylalkyl)- 1,2,3,4-tetrahydro-Υ-carboline compounds and their analogues, and especially to methods of preparing dimebon. The present invention also pertains to methods of preparing certain intermediate compounds which find use in the synthesis of the 9-(arylalkyl)-1,2,3,4-tetrahydro-γ-carboline compounds.