37115-32-5

Basic information

• Product Name: ADINAZOLAM
• Synonyms: ADINAZOLAM;8-Chloro-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-methanamine;U-41123
• CAS NO: 37115-32-5
• Molecular Formula: C₁₉H₁₈ClN₅
• Molecular Weight: 351.83
• Mol File: 37115-32-5.mol
• Article Data: 8

Chemical Properties

• Melting Point: 171-172.5° (US 4250094); mp 165-166° (DE 2201210)
• Boiling Point: 527°Cat760mmHg
• Flash Point: 272.5°C
• Appearance: /
• Density: 1.31g/cm³
• Vapor Pressure: 3.39E-11mmHg at 25°C
• Refractive Index: 1.68
• PKA: pKa 6.2 (D2O/DClor D2O/NaOD ) (Uncertain);5.8±0.1(D2O/DClor D2O/NaOD ) (Uncertain)
• CAS DataBase Reference: ADINAZOLAM(CAS DataBase Reference)
• NIST Chemistry Reference: ADINAZOLAM(37115-32-5)
• EPA Substance Registry System: ADINAZOLAM(37115-32-5)

Safety Data

• RIDADR: 3249
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 37115-32-5(Hazardous Substances Data)

Usage

Uses

Antidepressant; sedative-hypnotic.

Definition

ChEBI: A triazolo[4,3-a][1,4]benzodiazepine having a dimethylaminomethyl group at the 1-position, a phenyl group at the 6-position and a chloro substituent at the 8-position.

InChI:InChI=1/C19H18ClN5/c1-24(2)12-18-23-22-17-11-21-19(13-6-4-3-5-7-13)15-10-14(20)8-9-16(15)25(17)18/h3-10H,11-12H2,1-2H3

Synthetic route

8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo<4,3-a><1,4>benzodiazepine (39479-72-6) + dimethyl amine (124-40-3) → adinazolam (37115-32-5)

Conditions	Yield
With potassium iodide In tetrahydrofuran; methanol for 18h; Ambient temperature;	88.9%

N-[4-(2-benzoyl-4-chloro-phenyl)-5-(dimethylamino-methyl)-4H-[1,2,4]triazol-3-ylmethyl]-phthalimide (54042-46-5) → adinazolam (37115-32-5)

Conditions	Yield
With methylamine In ethanol; dichloromethane for 18h; Ambient temperature;	70.2%
With hydrazine hydrate In ethanol 1) room temp. 2.5 h.,2) 63 deg C, 3 h.;	63.1%

estazolam (29975-16-4) → adinazolam (37115-32-5)

Conditions	Yield
In methanol	68.7%

N,N-Didemethyladinazolam (37115-34-7) + formaldehyd (50-00-0) → adinazolam (37115-32-5)

Conditions	Yield
With sodium cyanoborohydride; acetic acid In water; acetonitrile for 1.75h;	64.3%

estazolam (29975-16-4) + N,N-dimethyl(methylene)ammonium chloride (30354-18-8) → adinazolam (37115-32-5)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 3h;	62%

N,N-Didemethyladinazolam (37115-34-7) + formaldehyd (50-00-0) + aqueous ethylenediamine → adinazolam (37115-32-5)

Conditions	Yield
With sodium cyanoborohydride; acetic acid In methanol; acetonitrile	37.6%

estazolam (29975-16-4) + bis-(dimethylamino)methane (51-80-9) → 8-chloro-1,4-bis-(dimethylamino-methyl)-6-phenyl-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (71616-85-8) + adinazolam (37115-32-5)

Conditions	Yield
With potassium carbonate; benzoyl chloride 1) DMF, 0 deg C, 2) DMF, 60 deg C, 3 h; Yield given. Multistep reaction;
With potassium carbonate; benzoyl chloride 1) DMF, 0 deg C, 2) DMF, 60 deg C, 3 h; Multistep reaction;

Chloro-acetic acid N'-(7-chloro-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl)-hydrazide → adinazolam (37115-32-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid / 0.33 h / Heating 2: 88.9 percent / KI / tetrahydrofuran; methanol / 18 h / Ambient temperature View Scheme

7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine (18091-89-9, 112393-62-1) → adinazolam (37115-32-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrahydrofuran / 1.58 h / 0 - 20 °C 2: acetic acid / 0.33 h / Heating 3: 88.9 percent / KI / tetrahydrofuran; methanol / 18 h / Ambient temperature View Scheme

1,3-Dioxo-2-isoindolineacetic Acid, hydrazine (59010-35-4) → adinazolam (37115-32-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 53 percent / trifluoroacetic acid / toluene / 1.5 h / 100 - 110 °C 2: 84.9 percent / acetyl chloride / dimethylformamide / 25 h / 50 - 54 °C 3: 63.1 percent / hydrazin hydrate / ethanol / 1) room temp. 2.5 h.,2) 63 deg C, 3 h. View Scheme

N-[4-(2-benzoyl-4-chloro-phenyl)-4H-[1,2,4]triazol-3-ylmethyl]-phthalimide (54485-85-7) → adinazolam (37115-32-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84.9 percent / acetyl chloride / dimethylformamide / 25 h / 50 - 54 °C 2: 63.1 percent / hydrazin hydrate / ethanol / 1) room temp. 2.5 h.,2) 63 deg C, 3 h. View Scheme

3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline (27610-14-6) → adinazolam (37115-32-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 90.7 percent / pyridine / tetrahydrofuran / 6 h / 0 - 25 °C 2: 53 percent / trifluoroacetic acid / toluene / 1.5 h / 100 - 110 °C 3: 84.9 percent / acetyl chloride / dimethylformamide / 25 h / 50 - 54 °C 4: 63.1 percent / hydrazin hydrate / ethanol / 1) room temp. 2.5 h.,2) 63 deg C, 3 h. View Scheme

alprazolam (28981-97-7) + aqueous dimethylamine → adinazolam (37115-32-5)

Conditions	Yield
With sodium hydroxide; sulfuryl dichloride In 2,2,4-trimethylpentane; dichloromethane; water; N,N-dimethyl-formamide; toluene

adinazolam (37115-32-5) → 8-chloro-1-[(dimethylamino)methyl]-5,6-dihydro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (72874-31-8)

Conditions	Yield
With hydrogen; platinum(IV) oxide In acetic acid under 1323.9 Torr; for 3.66667h; Yield given;

adinazolam (37115-32-5) → N-Demethyladinazolam (37115-33-6)

Conditions	Yield
With humal liver microsomes In methanol; phosphate buffer at 37℃; pH=7.5; Enzyme kinetics; N-demethylation; Enzymatic reaction;

methane sulfonic acid + adinazolam (37115-32-5) → adinazolam methanesulfonate

Conditions	Yield
In methanol; acetic acid butyl ester

dimethylmethyleneammonium chloride + 8-chloro-6-(2-chlorophenyl)-4H-s-triazolo<4,3-a>-1,4-benzodiazepine (42292-42-2) + adinazolam (37115-32-5) → [8-chloro-6-(2-chloro-phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-1-ylmethyl]-dimethyl-amine (37115-38-1)

Conditions	Yield
In methanol; chloroform

Upstream product

• 37115-34-7 N,N-Didemethyladinazolam 
• 50-00-0 formaldehyd 
• 29975-16-4 estazolam 
• 27610-14-6 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline 
• 54485-85-7 N-[4-(2-benzoyl-4-chloro-phenyl)-4H-[1,2,4]triazol-3-ylmethyl]-phthalimide 
• 59010-35-4 1,3-Dioxo-2-isoindolineacetic Acid, <methylene>hydrazine 
• 18091-89-9 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 
• 39479-72-6 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo<4,3-a><1,4>benzodiazepine 
• 124-40-3 dimethyl amine 
• 54042-46-5 N-[4-(2-benzoyl-4-chloro-phenyl)-5-(dimethylamino-methyl)-4H-[1,2,4]triazol-3-ylmethyl]-phthalimide 
• 30354-18-8 N,N-dimethyl(methylene)ammonium chloride 
• 51-80-9 bis-(dimethylamino)methane 
• 28981-97-7 alprazolam 

Downstream Products

• 37115-38-1 [8-chloro-6-(2-chloro-phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-1-ylmethyl]-dimethyl-amine 
• 57938-82-6 adinazolam methanesulfonate 
• 37115-33-6 N-Demethyladinazolam 
• 72874-31-8 8-chloro-1-[(dimethylamino)methyl]-5,6-dihydro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 

Relevant articles and documents

Mannich Reactions of Heterocycles with Dimethyl(methylene) Ammonium Chloride: A High Yield, One-step Conversion of Estazolam to Adinazolam

The readily prepared ammonium salt, (CH3)2N=CH2(1+)*Cl(1-), 4, functionalized heterocycles differently, but in a predictable fashion, under neutral, basic or acidic conditions.Triazolo- and imidazobenzophenones 1b' and 5, which primarily underwent intramolecular isomerization to indolols 2a' and 6a rather than intermolecular electrophilic substitution under conditions of the normal aqueous Mannich reaction, were converted with 4 to the desired benzophenone derivatives, 1c' and 7, respectively, in moderate yields.The 1-unsubstituted triazolo- or imidazobenzodiazepines, 10a estazolam and 10b, were transformed to the corresponding 1-(dimethylamino)methyl derivatives, 11a (adinazolam) and 11b, in good to moderate yields (61percent and 32percent, respectively.) Under acidic reaction conditions, 1-methyl triazolobenzodiazepine, 10d (alprazolam), afforded 12e, the product of attack at C-4 of the triazolobenzodiazepine ring system.Under strongly basic conditions in which the anion of 10d was generated prior to reaction with 4, both 12e and its isomer, 15, were formed.These results complement the report that 4 may be used to functionalize the 1-methyl position of triazolobenzodiazepines, and further demonstrate the versatility of reagent 4 in heterocyclic synthesis.

Novel synthesis of the pharmacologically important 1-substituted-6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepines

Several 6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepines have useful biological activity both in experimental animals and in man. This manuscript describes a novel synthesis of these compounds from intermediates that do not have a pre-formed benzodiazepine ring system.

Process for the production of 1-[(dimethylamino)methyl]-6-phenyl-4H-triazolo[4,3-a][1,4]-benzodiazepine

A process for the preparation of 1-[(dimethylamino)methyl]-6-substituted-4H-s-triazolo[4,3-a][1,4]benzodiazepine which comprises the reaction of a 4H-s-triazolo[4,3-a][1,4]benzodiazepine with the reagent STR1 wherein X- signifies the anion of a monovalent acid.