74191-85-8

Basic information

• Product Name: [4-(4-Amino-6,7-dimethoxy-quinazolin-2- yl)piperazin-1-yl]-(2,5-dioxabi cyclo[4.4.0]deca-6,8,10-trien-4-yl)methanone
• Synonyms: DOXAZOSIN;[4-(4-amino-6,7-dimethoxy-quinazolin-2- yl)piperazin-1-yl]-(2,5-dioxabi cyclo[4.4.0]deca-6,8,10-trien-4-yl)methanone;DoxazosinMesylate77883-43-3/Base;DOXAZOSIN(SUBJECTTOPATENTFREE);Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]-;UK 33,274;UK 33274;DOXAZOSINMESYTL
• CAS NO: 74191-85-8
• Molecular Formula: C₂₃H₂₅N₅O₅
• Molecular Weight: 451.48
• Product Categories: Pharmaceutical;Doxazosin;API, Trade Name: Cardura & Carduran;API
• Mol File: 74191-85-8.mol
• Article Data: 9

Chemical Properties

• Melting Point: 289-290°C
• Boiling Point: 718 °C at 760 mmHg
• Flash Point: 388 °C
• Appearance: /
• Density: 1.371 g/cm³
• Vapor Pressure: 1.83E-20mmHg at 25°C
• PKA: 6.52±0.50(Predicted)
• CAS DataBase Reference: [4-(4-Amino-6,7-dimethoxy-quinazolin-2- yl)piperazin-1-yl]-(2,5-dioxabi cyclo[4.4.0]deca-6,8,10-trien-4-yl)methanone(CAS DataBase Reference)
• NIST Chemistry Reference: [4-(4-Amino-6,7-dimethoxy-quinazolin-2- yl)piperazin-1-yl]-(2,5-dioxabi cyclo[4.4.0]deca-6,8,10-trien-4-yl)methanone(74191-85-8)
• EPA Substance Registry System: [4-(4-Amino-6,7-dimethoxy-quinazolin-2- yl)piperazin-1-yl]-(2,5-dioxabi cyclo[4.4.0]deca-6,8,10-trien-4-yl)methanone(74191-85-8)

Safety Data

• Hazardous Substances Data: 74191-85-8(Hazardous Substances Data)

Usage

Description

Doxazosin mesylate is a selective alpha, blocker indicated for the treatment of hypertension, reportedly of special benefit as a first-line agent in the most hypertonic patient population. Another advantage of doxazosin is its favorable effect on blood lipids; it significantly increases the HDL/total cholesterol ratio and decreases the total cholesterol as well as triglycerides levels.

Originator

Pfizer (United Kingdom)

Uses

ACIPHEX therapeutic Erosive or Ulcerative Gastroesophageal Reflux Disease

Definition

ChEBI: A member of the class of quinazolines that is quinazoline substituted by an amino group at position 4, methoxy groups at positions 6 and 7 and a piperazin-1-yl group at position 2 which in turn is substituted by a 2,3-dihydro-1,4-benzodioxin-2-ylcarbonyl roup at position 4. An antihypertensive agent, it is used in the treatment of high blood pressure.

Brand name

Cardura (Pfizer);Carduran.

General Description

Doxazosin, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl)piperazine(Cardura), is a quinazoline compound that selectively inhibitsthe α1-subtype of α-adrenergic receptors. This agentis very useful in the management of hypertension associatedwith pheochromocytoma.

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 
• 120-80-9 benzene-1,2-diol 
• 1246188-97-5 (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(1H-imidazol-1-yl)methanone 
• 60547-97-9 4-amino-6,7-dimethoxy-2-piperazin-1-ylquinazoline 
• 3663-80-7 1,4-benzodioxane-2-carboxylic acid 
• 3663-82-9 2-hydroxymethyl-2,3-dihydrobenzo[1,4]dioxin 
• 533-58-4 2-Iodophenol 

Downstream Products

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

Relevant articles and documents

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.

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.

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.