74191-85-8

Usage

Uses

Used in Pharmaceutical Industry:
[4-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)piperazin-1-yl]-(2,5-dioxabicyclo[4.4.0]deca-6,8,10-trien-4-yl)methanone is used as a pharmaceutical intermediate for the development of drugs targeting various medical conditions. Its unique structure and functional groups allow it to interact with biological targets, making it a promising candidate for drug discovery and design.
Used in Chemical Research:
[4-(4-Amino-6,7-dimethoxy-quinazolin-2yl)piperazin-1-yl]-(2,5-dioxabi cyclo[4.4.0]deca-6,8,10-trien-4-yl)methanone is also used in chemical research for studying the synthesis and properties of complex organic molecules. Its unique structure can provide insights into the development of new synthetic methods and the exploration of novel chemical reactions.

Originator

Pfizer (United Kingdom)

Clinical Use

Alpha-adrenoceptor blocker:HypertensionBenign prostatic hyperplasia (BPH)

Drug interactions

Potentially hazardous interactions with other drugsAntidepressants: enhanced hypotensive effect with MAOIs.Avanafil, vardenafil, sildenafil and tadalafil: enhanced hypotensive effect, avoid with tadalafil, start the others at the lowest possible dose.Beta-blockers: enhanced hypotensive effect; increased risk of first dose hypotensive effect.Calcium-channel blockers: enhanced hypotensive effect, increased risk of first dose hypotensive effect.Diuretics: enhanced hypotensive effect, increased risk of first dose hypotensive effect.Moxisylyte: possibly severe postural hypotension when used in combination.

Metabolism

Doxazosin is extensively metabolised in the liver, and excreted in faeces as inactive metabolites (6-hydroxydoxazosin) and a small amount of unchanged drug

InChI:InChI=1/C23H25N5O5.CH4O3S/c1-30-18-11-14-15(12-19(18)31-2)25-23(26-21(14)24)28-9-7-27(8-10-28)22(29)20-13-32-16-5-3-4-6-17(16)33-20;1-5(2,3)4/h3-6,11-12,20H,7-10,13H2,1-2H3,(H2,24,25,26);1H3,(H,2,3,4)

Synthetic route

2-chloro-6,7-dimethoxyquinazolin-4-amine (23680-84-4) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → doxazosin (74191-85-8)

Conditions	Yield
In butan-1-ol Reflux;	88%
In butan-1-ol for 5h; Heating;	83%

1,4-benzodioxane-2-carboxylic acid (3663-80-7, 34385-93-8, 70918-53-5, 70918-54-6) + 4-amino-6,7-dimethoxy-2-piperazin-1-ylquinazoline (60547-97-9) → doxazosin (74191-85-8)

Conditions	Yield
With 1,1'-carbonyldiimidazole In tetrahydrofuran at 0 - 20℃; for 5.16667h;	80%

ethyl 2,3-dihydro-1,4-benzodioxin-2-carboxylate (4739-94-0) → doxazosin (74191-85-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 65 percent / 6 h / 70 - 80 °C 2: 83 percent / butan-1-ol / 5 h / Heating View Scheme

benzene-1,2-diol (120-80-9) → doxazosin (74191-85-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 85 percent / potassium hydroxide; polyethylene glycol-400; potassium carbonate / toluene / 3.75 h / Heating 2: 65 percent / 6 h / 70 - 80 °C 3: 83 percent / butan-1-ol / 5 h / Heating View Scheme

(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1H-imidazol-1-yl)methanone (1246188-97-5) + 4-amino-6,7-dimethoxy-2-piperazin-1-ylquinazoline (60547-97-9) → doxazosin (74191-85-8)

Conditions	Yield
In tetrahydrofuran at 25 - 28℃; Product distribution / selectivity;

1,4-benzodioxane-2-carboxylic acid (3663-80-7, 34385-93-8, 70918-53-5, 70918-54-6) → doxazosin (74191-85-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / 2 h / 20 - 25 °C 2: tetrahydrofuran / 25 - 28 °C View Scheme
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C 3: butan-1-ol / Reflux View Scheme

2-hydroxymethyl-2,3-dihydrobenzo[1,4]dioxin (3663-82-9) → doxazosin (74191-85-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium hydroxide; potassium permanganate / water / 0 °C 2: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5.17 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: potassium hydroxide; potassium permanganate / water / 0 °C 2: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C 4: butan-1-ol / Reflux View Scheme

2-Iodophenol (533-58-4) → doxazosin (74191-85-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide; water; ethyl acetate / 24 h / 50 °C 2: sodium tetrahydroborate / tetrahydrofuran; methanol / 6 h / 0 °C 3: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 4: potassium hydroxide; potassium permanganate / water / 0 °C 5: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5.17 h / 0 - 20 °C View Scheme
Multi-step reaction with 7 steps 1: potassium carbonate / N,N-dimethyl-formamide; water; ethyl acetate / 24 h / 50 °C 2: sodium tetrahydroborate / tetrahydrofuran; methanol / 6 h / 0 °C 3: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 4: potassium hydroxide; potassium permanganate / water / 0 °C 5: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 6: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C 7: butan-1-ol / Reflux View Scheme

C13H15IO5 → doxazosin (74191-85-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / tetrahydrofuran; methanol / 6 h / 0 °C 2: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 3: potassium hydroxide; potassium permanganate / water / 0 °C 4: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5.17 h / 0 - 20 °C View Scheme
Multi-step reaction with 6 steps 1: sodium tetrahydroborate / tetrahydrofuran; methanol / 6 h / 0 °C 2: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 3: potassium hydroxide; potassium permanganate / water / 0 °C 4: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 5: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C 6: butan-1-ol / Reflux View Scheme

2-(2-iodophenoxy)propane-1,3-diol → doxazosin (74191-85-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 2: potassium hydroxide; potassium permanganate / water / 0 °C 3: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5.17 h / 0 - 20 °C View Scheme
Multi-step reaction with 5 steps 1: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 2: potassium hydroxide; potassium permanganate / water / 0 °C 3: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C 5: butan-1-ol / Reflux View Scheme

acetyl chloride (75-36-5) + doxazosin (74191-85-8) → N-(2-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)-6,7-dimethoxyquinazolin-4-yl)acetamide

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide	36%

methanesulfonic acid (75-75-2) + doxazosin (74191-85-8) → doxazosin mesylate

Conditions	Yield
In acetone at 25 - 38℃;

methanesulfonic acid (75-75-2) + doxazosin (74191-85-8) → doxazosin mesylate

Conditions	Yield
In acetone at 10 - 25℃;

doxazosin (74191-85-8) → doxazosin hydrochloride

Conditions	Yield
With hydrogenchloride In water; acetone at 10 - 25℃; pH=2 - 3;

doxazosin (74191-85-8) → C23H24N4O6

Conditions	Yield
With sodium dodecyl-sulfate; sodium hydrogensulfite In ethanol; water Solvent; Reagent/catalyst; Reflux;

Upstream product

• 23680-84-4 2-chloro-6,7-dimethoxyquinazolin-4-amine 
• 70918-00-2 (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone 
• 4739-94-0 ethyl 2,3-dihydro-1,4-benzodioxin-2-carboxylate 
• 533-58-4 2-Iodophenol 
• 3663-80-7 1,4-benzodioxane-2-carboxylic acid 
• 60547-97-9 4-amino-6,7-dimethoxy-2-piperazin-1-ylquinazoline 
• 3663-82-9 2-hydroxymethyl-2,3-dihydrobenzo[1,4]dioxin 
• 1246188-97-5 (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1H-imidazol-1-yl)methanone 
• 120-80-9 benzene-1,2-diol 

Downstream Products

• 156154-10-8 doxazosin mesylate 
• 156154-10-8 doxazosin mesylate 

Relevant academic research and scientific papers

Method for synthesizing doxazosin

The invention discloses a method for synthesizing doxazosin and belongs to the technical field of chemical synthesis. According to the method, the doxazosin is synthesized by adopting a synthesis route, represented by formulae shown in the description, different from the conventional technologies, and thus a novel synthesis route is provided for preparing the doxazosin; and the method has the advantages of moderate conditions, simple and convenient steps and high yield, and the doxazosin can be obtained simply and efficiently.

Process for the Preparation of Doxazosin and Salts Thereof

The present invention relates to a process for the preparation of doxazosin or salts thereof.

THERAPY FOR COMPLICATIONS OF DIABETES

A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.

ANTIHYPERTENSIVE THERAPY

A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.

Method for treating resistant hypertension

A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.

Method for obtaining polymorph a from doxazosine mesylate

The invention discloses a process for the preparation of the polymorh A of doxazosin meylate, consisting essentially of reacting doxazosin base with methanesulfonic acid in a mixture of solvents containing an alcohol and a chlorinated solvent, subsequently removing the chlorinated solvent by distillation and precipitating the desired product in an alcohol, after heating the suspension formed to the reflux temperature of the solvent.

Preparation of amides and quinazoline derivatives

The present invention relates to a process for the preparation of amides, comprising reacting amines with carboxylic acids in the presence of silicon amines. The present invention further relates to a process for the preparation of quinazoline derivatives, comprising reacting amines with carboxylic acids in the presence of silicon amines to obtain amides and contacting the resultant amides with quinazoline.

Process for preparing amides

The present invention provides a process for preparing an amide, which comprises reacting an amine with an ester in a molten form in the absence of a solvent.