219810-59-0

Basic information

• Product Name: NERAMEXANE
• Synonyms: NERAMEXANE
• CAS NO: 219810-59-0
• Molecular Formula: C₁₁H₂₃N
• Molecular Weight: 169.31
• Mol File: 219810-59-0.mol

Chemical Properties

• Boiling Point: 195.5°Cat760mmHg
• Flash Point: 39.7°C
• Appearance: /
• Density: 0.809g/cm³
• Vapor Pressure: 0.417mmHg at 25°C
• Refractive Index: 1.433
• CAS DataBase Reference: NERAMEXANE(CAS DataBase Reference)
• NIST Chemistry Reference: NERAMEXANE(219810-59-0)
• EPA Substance Registry System: NERAMEXANE(219810-59-0)

Safety Data

• Hazardous Substances Data: 219810-59-0(Hazardous Substances Data)

Usage

Uses

Treatment of depression, Alzheimer’s disease, and pain.

InChI:InChI=1/C11H23N/c1-9(2)6-10(3,4)8-11(5,12)7-9/h6-8,12H2,1-5H3

Synthetic route

Neramexane mesylate (457068-92-7) → neramexane (219810-59-0)

Conditions	Yield
With sodium hydroxide In water at 20℃;	100%

N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine (316364-93-9) → neramexane (219810-59-0)

Conditions	Yield
Stage #1: N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine With hydrogenchloride; thiourea In water for 6h; Reflux; Stage #2: With sodium hydroxide In water pH=7;	89%
With acetic acid; thiourea In ethanol for 10h; Substitution; Heating;
Stage #1: N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine With hydrogenchloride; thiourea In water for 6h; Reflux; Stage #2: With sodium hydroxide In water pH=7;
Stage #1: N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine With hydrogenchloride; thiourea In water for 6h; Reflux; Stage #2: With sodium hydroxide In water pH=7; Product distribution / selectivity;

1-azido-1,3,3,5,5-pentamethyl-cyclohexane → neramexane (219810-59-0)

Conditions	Yield
With lithium aluminium tetrahydride In diethyl ether at 20℃; for 5h; Reduction;

1,3,3,5,5-pentamethylcyclohexanol (38490-33-4) → neramexane (219810-59-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / AcOH; H2SO4 / 5 h / 20 °C 2: thiourea; AcOH / ethanol / 10 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 67 percent / HN3; TiCl4 / CHCl3 / 24 h / 20 °C 2: LiAlH4 / diethyl ether / 5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 2.1: hydrogenchloride; thiourea / water / 6 h / Reflux 2.2: pH 7 View Scheme

3,3,5,5-tetramethylcyclohexanone (14376-79-5) → neramexane (219810-59-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / diethyl ether / 1 h / 20 °C 2: 67 percent / HN3; TiCl4 / CHCl3 / 24 h / 20 °C 3: LiAlH4 / diethyl ether / 5 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 5 - 15 °C 2.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 3.1: hydrogenchloride; thiourea / water / 6 h / Reflux 3.2: pH 7 View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 5 - 15 °C 2.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 3.1: hydrogenchloride; thiourea / water / 6 h / Reflux 3.2: pH 7 View Scheme

3,5,5-Trimethylcyclohex-2-en-1-one (78-59-1) → neramexane (219810-59-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: copper(l) iodide; lithium chloride / tetrahydrofuran / 1 h / 5 - 15 °C 2.1: tetrahydrofuran / 5 - 15 °C 3.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 4.1: hydrogenchloride; thiourea / water / 6 h / Reflux 4.2: pH 7 View Scheme
Multi-step reaction with 4 steps 1.1: copper(l) iodide; lithium chloride / tetrahydrofuran / 1 h / 5 - 15 °C 2.1: tetrahydrofuran / 1 h / 5 - 15 °C 3.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 4.1: hydrogenchloride; thiourea / water / 6 h / Reflux 4.2: pH 7 View Scheme

Neramexane mesylate (457068-92-7) → neramexane (219810-59-0)

Conditions	Yield
With sodium hydroxide In water at 20℃;	100%

N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine (316364-93-9) → neramexane (219810-59-0)

Conditions	Yield
Stage #1: N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine With hydrogenchloride; thiourea In water for 6h; Reflux; Stage #2: With sodium hydroxide In water pH=7;	89%
With acetic acid; thiourea In ethanol for 10h; Substitution; Heating;
Stage #1: N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine With hydrogenchloride; thiourea In water for 6h; Reflux; Stage #2: With sodium hydroxide In water pH=7;
Stage #1: N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine With hydrogenchloride; thiourea In water for 6h; Reflux; Stage #2: With sodium hydroxide In water pH=7; Product distribution / selectivity;

1-azido-1,3,3,5,5-pentamethyl-cyclohexane → neramexane (219810-59-0)

Conditions	Yield
With lithium aluminium tetrahydride In diethyl ether at 20℃; for 5h; Reduction;

1,3,3,5,5-pentamethylcyclohexanol (38490-33-4) → neramexane (219810-59-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / AcOH; H2SO4 / 5 h / 20 °C 2: thiourea; AcOH / ethanol / 10 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 67 percent / HN3; TiCl4 / CHCl3 / 24 h / 20 °C 2: LiAlH4 / diethyl ether / 5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 2.1: hydrogenchloride; thiourea / water / 6 h / Reflux 2.2: pH 7 View Scheme

3,3,5,5-tetramethylcyclohexanone (14376-79-5) → neramexane (219810-59-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / diethyl ether / 1 h / 20 °C 2: 67 percent / HN3; TiCl4 / CHCl3 / 24 h / 20 °C 3: LiAlH4 / diethyl ether / 5 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 5 - 15 °C 2.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 3.1: hydrogenchloride; thiourea / water / 6 h / Reflux 3.2: pH 7 View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 5 - 15 °C 2.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 3.1: hydrogenchloride; thiourea / water / 6 h / Reflux 3.2: pH 7 View Scheme

3,5,5-Trimethylcyclohex-2-en-1-one (78-59-1) → neramexane (219810-59-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: copper(l) iodide; lithium chloride / tetrahydrofuran / 1 h / 5 - 15 °C 2.1: tetrahydrofuran / 5 - 15 °C 3.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 4.1: hydrogenchloride; thiourea / water / 6 h / Reflux 4.2: pH 7 View Scheme
Multi-step reaction with 4 steps 1.1: copper(l) iodide; lithium chloride / tetrahydrofuran / 1 h / 5 - 15 °C 2.1: tetrahydrofuran / 1 h / 5 - 15 °C 3.1: sulfuric acid / acetic acid / 1 h / 5 - 10 °C 4.1: hydrogenchloride; thiourea / water / 6 h / Reflux 4.2: pH 7 View Scheme

para-dodecylbenzenesulfonic acid (121-65-3) + neramexane (219810-59-0) → neramexane 4-dodecylbenzene sulfonate

Conditions	Yield
at 20℃; Cooling;	100%

10-undecenoic acid (112-38-9) + neramexane (219810-59-0) → neramexane undecylenate

Conditions	Yield
In neat (no solvent) at 20℃; Cooling;	100%

cis-Octadecenoic acid (112-80-1) + neramexane (219810-59-0) → neramexane oleate

Conditions	Yield
In neat (no solvent) at 20℃; Cooling;	100%

ammonium tetrathiomonomolybdate + neramexane (219810-59-0) → bis(1-ammonium-1,3,3,5,5-pentamethylcyclohexane) tetrathiomolybdate

Conditions	Yield
In water; isopropyl alcohol at 20 - 25℃; for 0.5h;	95%

stearic acid (57-11-4) + neramexane (219810-59-0) → neramexane stearate

Conditions	Yield
In dichloromethane at 20℃; for 2h;	90%

Br(1-)*C18H26NO6(1+) (952431-22-0) + neramexane (219810-59-0) → {3-benzyloxycarbonyl-(R)-2-[3-(1,3,3,5,5-pentamethyl-cyclohexylcarbamoyl)-propionyloxy]-propyl}-trimethylammonium bromide

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h;	28%

L-carnitine isobutyric ester (952431-17-3) + neramexane (219810-59-0) → L-carnitine isobutyric ester

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h;	19%

methanesulfonic acid (75-75-2) + neramexane (219810-59-0) → Neramexane mesylate (457068-92-7)

Conditions	Yield
In ethyl acetate at 0 - 5℃; for 1h;
In ethyl acetate at 0 - 5℃; for 1h;
In butanone

neramexane (219810-59-0) → neramexane hydrochloride

Conditions	Yield
With hydrogenchloride In butanone Product distribution / selectivity;

Upstream product

• 457068-92-7 Neramexane mesylate 
• 78-59-1 3,5,5-Trimethylcyclohex-2-en-1-one 
• 14376-79-5 3,3,5,5-tetramethylcyclohexanone 
• 38490-33-4 1,3,3,5,5-pentamethylcyclohexanol 
• 316364-93-9 N-Chloroacetyl-1,3,3,5,5-pentamethylcyclohexanamine 

Downstream Products

• 457068-92-7 Neramexane mesylate 
• 209185-99-9 neramexane hydrochloride 

Relevant articles and documents

NERAMEXANE SALTS

This invention relates to novel salts of 1-amino-1,3,3,5,5-pentamethylcyclohexane (Neramexane).

METHOD OF PREPARING NERAMEXANE

Method of producing a salt of 1-amino-1,3,3,5,5-pentamethylcyclohexane comprising steps (i) to (v): (i) converting isophorone to 3,3,5,5-tetramethylcyclohexanone; (ii) converting 3,3,5,5-tetramethylcyclohexanone obtained in step (i) to 1- hydroxy-1,3,3,5,5-pentamethylcyclohexane; (iii) converting 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane obtained in step (ii) to 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane; (iv) converting 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane obtained in step (iii) to 1-amino-1,3,3,5,5-pentamethylcyclohexane; wherein at least one of 3,3,5,5-tetramethylcyclohexanone, 1-hydroxy-1,3,3,5,5- pentamethylcyclohexane, 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane, is not subjected to a purification step.

METHOD OF PREPARING NERAMEXANE

Method of preparing 1-amino-1,3,3,5,5-pentamethylcyclohexane or a pharmaceutically acceptable salt thereof, comprising at least two steps selected from the following steps (i) to (iv): (i) converting isophorone to 3,3,5,5-tetramethylcyclohexanone in the presence of methylmagnesium chloride; (N) converting 3,3,5,5-tetramethylcyclohexanone to 1-hydroxy-1,3,3,5,5- pentamethylcyclohexane in the presence of methylmagnesium chloride; (iii) converting 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane to 1-chloroacetamido- 1,3,3,5,5-pentamethylcyclohexane in the presence of chloroacetonitrile in acidic solution; (iv) converting 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane to 1-amino- 1,3,3,5,5-pentamethylcyclohexane in the presence of thiourea in water.

METHOD OF PREPARING 1-AMINO-1,3,3,5,5-PENTAMETHYLCYCLOHEXANE

The invention relates to a method of producing 1-amino-1,3,3,5,5-pentamethylcyclohexane (Neramexane) or a pharmaceutically acceptable salt thereof comprising the step of heating a mixture comprising 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane, thiourea and water.

Novel treatment for alzheimer's disease

The present invention concerns a new pharmaceutical composition comprising an antagonist and a co-agonist of the N-methyl-D-aspartate-type glutamate receptor (NMDAR). The inventors found that the co-administration of these two compounds effectively inhibits production of amyloide-β peptide. In patient's suffering from Alzheimer's disease, these peptides are deposited in the extracellular matrix forming neuritic "plaques". Therefore, the present inventors identified a new possibility for prophylaxis and/or treatment of Alzheimer's disease by stopping the continued formation of neuropathological extracellular deposits.

METHODS OF TREATING CNS DISORDERS

The present invention relates to methods of treating various CNS disorders, e.g., mania, bipolar disorder and schizophrenia, by administering NMDA receptor antagonists, alone or in combination with dopamine receptor antagonists.

Combination therapy using 1-aminocyclohexane derivatives and acetylcholinesterase inhibitors

The invention relates to a novel drug combination therapy useful in the treatment of dementia comprising administering an 1-aminocyclohexane derivative such as memantine or neramexane and an acetylcholinesterase inhibitor (AChEI) such as galantamine, tacrine, donepezil, or rivastigmine.

NMDA receptor antagonists and their use in inhibiting abnormal hyperphosphorylation of microtubule associated protein tau

Aminocyclohexane and aminoalkylcyclohexane compounds, which are systemic-ally-active as NMDA receptor antagonists, are effective in inhibiting abnormal hyperphosphorylation of microtubule associated protein tau, method of treating disorders resulting from or associated with abnormal hyperphosphorylation of microtubule associated protein tau, and pharmaceutical compositions comprising the same.

Synthesis and structure-affinity relationships of 1,3,5-alkylsubstituted cyclohexylamines binding at NMDA receptor PCP site

A series of 1,3,5-alkylsubstituted cyclohexylamines 2 were synthesized as ligands for the N-methyl-D-aspartate (NMDA) receptor phencyclidine (PCP) binding site. Pure diastereomers with defined configuration of amino group 2- ax and 2-eq were obtained. The optimal size of 1,3,5-substituents was determined for cyclohexylamines 2 with an equatorial amino group in the lowest energy conformation using Hansch analysis. According to the data, the lipophilic part of cyclohexylamines 2 does not discriminate between hydrophobic regions of the PCP binding site but rather recognizes this site as a whole lipophilic pocket. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

1-AMINO-ALKYLCYCLOHEXANE NMDA RECEPTOR ANTAGONISTS

Certain 1-aminoalkylcyclohexanes are systemically-active uncompetitive NMDA receptor antagonists having rapid blocking/unblocking kinetics and strong voltage-dependency and are therefore useful in the alleviation of conditions resulting from disturbances of glutamatergic transmission giving them a wide range of utility in the treatment of CNS disorders involving the same, as well as in non-NMDA indications, due to their immunomodulatory, antimalarial, anti-Borna virus, and anti-Hepatitis C activities and utilities. Pharmaceutical compositions thereof and a method-of-treating conditions which are alleviated by the employment of an NMDA receptor antagonist, as well as the aforementioned non-NMDA indications, and a method for the preparation of the active 1-aminoalkylcyclohexane compounds involved.