81403-68-1

Basic information

• Product Name: Alfuzosin hydrochloride
• Synonyms: alfuzosinehydrochloride;SL-77,499-10;MITTOVAL;N-[3-[(4-AMINO-6,7-DIMETHOXY-2-QUINAZOLYNYL)METHYLAMINO]PROPYL]TETRAHYDRO-2-FURANCARBOXAMIDE;n-[3-[(4-amino-6,7-dimethoxy-2-quinazolynyl)methylamino]propyl]tetrahydro-2-furancarboxamide hydrochloride;XATRAL;URION;UROXANTRAL
• CAS NO: 81403-68-1
• Molecular Formula: C₁₉H₂₇N₅O₄*ClH
• Molecular Weight: 425.91
• EINECS: 1308068-626-2
• Product Categories: APIs;Antihypertensive;Antihypertensive, Treatment of BPH;Intermediates & Fine Chemicals;Pharmaceuticals;Alfuzosin;Amines;Aromatics;Heterocycles;API;Uroxatral
• Mol File: 81403-68-1.mol

Chemical Properties

• Melting Point: 225°C
• Boiling Point: 687.7 °C at 760 mmHg
• Flash Point: 369.7 °C
• Appearance: White to off-white solid
• Density: 1.272 g/cm3
• Vapor Pressure: 3.75E-19mmHg at 25°C
• Storage Temp.: Store at RT
• Solubility: DMSO: >10mg/mL
• PKA: 8.13(at 25℃)
• Merck: 14,238
• CAS DataBase Reference: Alfuzosin hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Alfuzosin hydrochloride(81403-68-1)
• EPA Substance Registry System: Alfuzosin hydrochloride(81403-68-1)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• WGK Germany: 3
• RTECS: LT9965475
• Hazardous Substances Data: 81403-68-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Alfuzosin hydrochloride is used as an antihypertensive agent for the treatment of high blood pressure. It functions as an alpha-1 adrenergic antagonist, helping to relax blood vessels and improve blood flow.
Used in Urological Applications:
Alfuzosin hydrochloride is used as a treatment for benign prostatic hyperplasia (BPH). As an α1-adrenoceptor antagonist, it helps to improve urinary symptoms and reduce prostate size, providing relief to patients suffering from this condition.
Used in Quality Control:
Alfuzosin hydrochloride serves as a pharmaceutical secondary standard, offering a convenient and cost-effective alternative for the preparation of in-house working standards in pharmaceutical laboratories and manufacturing facilities. This ensures the quality and consistency of the drug in the production process.
Chemical Properties:
Alfuzosin hydrochloride is a white to off-white solid, with the brand name Uroxatral (Sanofi Aventis). It was launched as an extended-release formulation in the US in November 2003, utilizing Skyepharma's oral controlled-release technology.

Biological Activity

Functionally uro-selective α 1 adrenoceptor antagonist that does not discriminate between α 1 subtypes. Inhibits increases in intraurethral pressure caused by phenylephrine-induced contraction by 81% with minor cardiovascular effects. Also relaxes corpus cavernosum tissue (pIC 50 = 7.64) in vitro .

Biochem/physiol Actions

Alfuzosin hydrochloride is an alpha-adrenergic blocker used to treat benign prostatic hyperplasia (BPH). It works by relaxing the muscles in the prostate and bladder neck, making it easier to urinate.

Clinical Use

Alpha-blocker: Treatment of benign prostatic hyperplasia Treatment of acute urinary retention

Synthesis

Although syntheses of alfuzosin (I) have appeared in several reports, an optimized route used for the manufacture of the compound does not appear in the literature. The synthesis reported by the Sanofi group for alfuzosin will be described and is shown in the scheme. The commercially available 4- amino-2-chloro-6,7-dimethoxyquinazoline (1) was treated with 3-methylaminopropionitrile (2) in isoamyl alcohol and refluxed for 5 hrs. Filtration of the precipitated product and washing with ethanol gave nitrile 3 in 62% yield. Hydrogenation of the nitrile was done in 15% ammonia solution in ethanol with Raney nickel as catalyst at 70°C and 1000 psi to obtain the corresponding amine free base. Conversion of the free base to the hydrochloride salt was done in ethanol to give the HCl salt 4 in 52% yield. The final acylation of amine 4 was done with the imidazolyl anhydride of furan 5. Thus, 2-carboxyfuran was treated with carbonyldiimidazole in THF at 40°C for 1 hr and then cooled to 10°C. Addition of amine 4 in THF in the presence of triethylamine at 10°C, then refluxing the reaction for 1 hr, and aqueous workup gave the alfuzosin free base. After conversion to the hydrochloride salt and recrystallization from 2-propanol alfuzosin hydrochloride (I) was obtained in 44% yield.

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Antidepressants: enhanced hypotensive effect with MAOIs. Antivirals: concentration possibly increased by ritonavir - avoid; avoid with telaprevir. Avanafil, vardenafil, sildenafil and tadalafil: enhanced hypotensive effect, separate administration by 4-6 hours. 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. Cobicistat: concentration of alfuzosin possibly increased - avoid. Diuretics: enhanced hypotensive effect; increased risk of first dose hypotensive effect. Moxisylyte: possibly severe postural hypotension.

Metabolism

Extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4, to inactive metabolites that are mainly excreted in faeces via the bile.

InChI:InChI=1/C19H27N5O4.ClH/c1-24(8-5-7-21-18(25)14-6-4-9-28-14)19-22-13-11-16(27-3)15(26-2)10-12(13)17(20)23-19;/h10-11,14H,4-9H2,1-3H3,(H,21,25)(H2,20,22,23);1H

Synthetic route

alfuzosin (81403-80-7) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
With hydrogenchloride In ethanol at 20 - 25℃;	88%
With hydrogenchloride In methanol; isopropyl alcohol at 20℃; for 0.5h; pH=3 - 4; Product distribution / selectivity;	85%
With hydrogenchloride In isopropyl alcohol at 20℃; for 0.75 - 1h; Product distribution / selectivity;	82%

N1-(4-amino-6,7-dimethoxyquinazol-2-yl)-N1-methyl-N2-(tetrahydrofuro-2-yl)propylenediamine (7,7-dimethyl-2-oxo-bicyclo[2,2,1]hept-1-yl)methanesulfonate → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
Stage #1: N1-(4-amino-6,7-dimethoxyquinazol-2-yl)-N1-methyl-N2-(tetrahydrofuro-2-yl)propylenediamine (7,7-dimethyl-2-oxo-bicyclo[2,2,1]hept-1-yl)methanesulfonate With sodium hydroxide In dichloromethane; water at 20℃; for 0.5h; Stage #2: With hydrogenchloride In ethanol; dichloromethane	87.5%

N-<3-(methylamino)propyl>tetrahydrofuran-2-carboxamide (81403-67-0) + 2-chloro-6,7-dimethoxyquinazolin-4-amine (23680-84-4) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
In i-Amyl alcohol for 12h; Heating;	66%
In i-Amyl alcohol for 10h; Solvent; Reflux;	66%
In i-Amyl alcohol for 6h; Solvent; Reflux;	65.5%

tetrahydro-2-furancarboxylic acid (16874-33-2) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: Et3N / tetrahydrofuran / 0.25 h / 5 °C 2: tetrahydrofuran / Ambient temperature 3: 68 percent / H2, 10percent ethanolic NH3 / Rh/C / 80 °C / 43440.4 Torr 4: 66 percent / 3-methyl-butan-1-ol / 12 h / Heating View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride 2: triethylamine / 1,2-dichloro-ethane / 3 h / 5 - 10 °C 3: i-Amyl alcohol / 6 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: thionyl chloride / 3 h / 35 °C 2: triethylamine / 1,2-dichloro-ethane / 3 h / 5 - 35 °C 3: palladium on activated charcoal; ammonium formate / methanol / 2 h / Reflux 4: i-Amyl alcohol / 10 h / Reflux View Scheme

tetrahydro-N-(3-cyanopropyl)-N-methylfurancarboxamide (72104-44-0) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 68 percent / H2, 10percent ethanolic NH3 / Rh/C / 80 °C / 43440.4 Torr 2: 66 percent / 3-methyl-butan-1-ol / 12 h / Heating View Scheme

C8H12O5 (167391-50-6) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrahydrofuran / Ambient temperature 2: 68 percent / H2, 10percent ethanolic NH3 / Rh/C / 80 °C / 43440.4 Torr 3: 66 percent / 3-methyl-butan-1-ol / 12 h / Heating View Scheme

N1-methyl-N1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-1,3-propanediamine (76362-29-3) + 1-(tetrahydrofuran-2-ylcarbonyl)-1H-imidazole (1005197-73-8) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
Stage #1: N1-methyl-N1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-1,3-propanediamine; 1-(tetrahydrofuran-2-ylcarbonyl)-1H-imidazole In dichloromethane at 38 - 40℃; Stage #2: With hydrogenchloride In ethanol; isopropyl alcohol

(R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide acetate (1100050-87-0) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
With hydrogenchloride In isopropyl alcohol Product distribution / selectivity; Heating / reflux;

tetrahydrofuran-2-carbonyl chloride (52449-98-6) + N1-methyl-N1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-1,3-propanediamine (76362-29-3) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
Stage #1: tetrahydrofuran-2-carbonyl chloride; N1-methyl-N1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-1,3-propanediamine In toluene at 25 - 30℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water Stage #3: With hydrogenchloride In methanol; isopropyl alcohol pH=1 - 2;

tetrahydrofuran-2-carbonyl chloride (52449-98-6) → alfuzosin hydrochloride (81403-68-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / 1,2-dichloro-ethane / 3 h / 5 - 35 °C 2: palladium on activated charcoal; ammonium formate / methanol / 2 h / Reflux 3: i-Amyl alcohol / 10 h / Reflux View Scheme

10-camphorsufonic acid (5872-08-2) + alfuzosin hydrochloride (81403-68-1) → N1-(4-amino-6,7-dimethoxyquinazol-2-yl)-N1-methyl-N2-(tetrahydrofuro-2-yl)propylenediamine (7,7-dimethyl-2-oxo-bicyclo[2,2,1]hept-1-yl)methanesulfonate

Conditions	Yield
Stage #1: alfuzosin hydrochloride With sodium hydroxide In dichloromethane; water Stage #2: 10-camphorsufonic acid In dichloromethane at 20 - 40℃; Product distribution / selectivity;	84%

alfuzosin hydrochloride (81403-68-1) → alfuzosin (81403-80-7)

Conditions	Yield
With potassium carbonate In water
With sodium hydroxide In dichloromethane; water at 20 - 25℃; for 0.25h; pH=12; Product distribution / selectivity;

Upstream product

• 81403-67-0 N-<3-(methylamino)propyl>tetrahydrofuran-2-carboxamide 
• 23680-84-4 2-chloro-6,7-dimethoxyquinazolin-4-amine 
• 52449-98-6 tetrahydrofuran-2-carbonyl chloride 
• 76362-29-3 N¹-methyl-N¹-(4-amino-6,7-dimethoxy-2-quinazolinyl)-1,3-propanediamine 
• 1100050-87-0 (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide acetate 
• 1005197-73-8 1-(tetrahydrofuran-2-ylcarbonyl)-1H-imidazole 
• 81403-80-7 alfuzosin 
• 167391-50-6 C₈H₁₂O₅ 
• 72104-44-0 tetrahydro-N-(3-cyanopropyl)-N-methylfurancarboxamide 
• 16874-33-2 tetrahydro-2-furancarboxylic acid 

Downstream Products

• 81403-80-7 alfuzosin 

Relevant articles and documents

Improved method used for preparing quinazoline drugs

The invention relates to an improved method used for preparing quinazoline drugs, and provides a synthesis route taking 2-chloro-4-amino-6,7-dimethoxyquinazoline as an intermediate. The synthesis route comprises following steps: acrylonitrile and a methylamine alcohol solution are subjected to amination reaction so as to obtain intermediate (I); triethylamine is taken as an acid binding agent, andbenzyl chloride is taken as a protective group so as to obtain an intermediate (II); a metal hydride is adopted so as to obtain an intermediate (III) through reduction; acylation with tetrahydro-2-furancarbonylchloride is carried out so as to obtain an intermediate (IV); the intermediate (IV) and ammonium formate are subjected to hydrogenolysis under catalytic effect of palladium on carbon so asto obtain an intermediate (V); and at least condensation reaction with 2-chloro-4-amino-6,7-dimethoxyquinazoline is carried out so as to obtain quinazoline drug Alfuzosin Hydrochloride (VI). Comparedwith the prior art, the improved method possesses following advantages: operation is simple and safe; reaction conditions are convenient to control; energy consumption is low; yield is stable; and industrialized application prospect is promising.

A process for the preparation of alfuzosin hydrochloride method (by machine translation)

The invention relates to a process for the preparation of alfuzosin hydrochloride method, method comprises the following steps: (1) 15 °C following, acrylonitrile into the the methylamine is mellow solution to stir, by distillation to obtain (I); (2) to (I) is dripped reducing agent in an organic solvent, heating to reflux, then slowly sequentially into the 25% sodium hydroxide solution and distilled water, by the distillation treatment to obtain the (II); (3) under dry condition, the thionyl chloride is slowly dripped into the 2 - tetrahydrofuran formic acid, a 2 - tetrahydrofuran chloride; (4) the temperature control in the 5 - 15 °C conditions, will be 2 - tetrahydrofuran formyl the chlorine drips into containing acid, organic solvent and (II) of the mixed solution, then completing the stirring 3 hours, for 25% sodium hydroxide solution to neutralize, by organic solvent extraction, (III) be; (5) to (III) with 2 - chloro - 4 - amino - 6, 7 - dimethoxy quinazoline in presence of organic solvent, reflux stirring 4 - 10 hours, cooling and filtering, and steaming and removing the organic solvent, acetone dispersed precipitate solid, then re-crystallizing mixed solvent, to get the alfuzosin hydrochloride (IV). (by machine translation)

Process for the Preparation of Alfuzosin Hydrochloride

A process for preparing alfuzosin or a salt thereof comprising: (a) condensing 4-amino-2-chloro-6,7-dimethoxyquinazoline with 3-methylaminopropionitrile in the presence of a polar aprotic solvent selected from the group consisting of diglyme, dimethyl formamide, t-butanol, hexamethylphosphoramide or mixtures thereof to form N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine (b) hydrogenating the N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine using a hydrogenating agent under a pressure of less than 10 kg/cm2 to form N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylenediamine and optionally converting the N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylenediamine to an acid addition salt thereof; and (c) converting tetrahydrofuroic acid to an intermediate form and condensing the intermediate form with the N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylenediamine or with the acid addition salt to yield alfuzosin base, and optionally converting alfuzosin base to a salt of alfuzosin.

METHOD OF PREPARING ANHYDROUS ALFUSOZIN HYDROCHLORIDE

There is described a method of preparing anhydrous alfuzosin hydrochloride by means of a condensation reaction between N1-methyl-N2-(tetrahydrodrofuroyl-2)-propylenediamine and 4-amino-2-chloro-6,7-dimethoxyquinazoline. The obtained crude product is subsequently purified by further stages that include steps of preparing novel intermediates. The described alfuzosin synthesis and purification process allow to obtain this active ingredient with a high yield and purity, and therefore suitable to be employed as an active ingredient in medicaments.

AN IMPROVED PROCESS FOR THE PREPARATION OF ALFUZOSIN AND ITS NOVEL POLYMORPH

The present invention relates to an improved process for the preparation of Alfuzosin of formula (I). The process involves utilizing intermediate of formula (Ia) wherein S represents acid residue of organic acids like acetic acid, oxalic acid, succinic acid, methane sulfonic acid, p-toluene sulfonic acid and the like. The present invention also relates to novel Amorphous form of Alfuzosin of formula (I).

AN IMPROVED PROCESS FOR THE PREPARATION OF ALFUZOSIN HYDROCHLORIDE

The present invention relates to an improved process for the preparation of Alfuzosin hydrochloride of formula (I) comprising a step of reacting compound of formula (IV) with compound of formula (V) in presence of aprotic solvent to obtain compound of formula (III) which is a useful intermediate for synthesis of Alfuzosin hydrochloride of formula (I).

A NOVEL PROCESS FOR THE PREPARATION OF 2-HALO-4-AMINOQUINAZOLINES

2-Halo-4-aminoquinazolines are produced by a one-step process involving intramolecular cyclization of appropriately substituted formamide derivatives in the presence of phosphorous oxyhalides. Exemplary of the process is the intramolecular cyclization of 3,4-dimethoxy-6-cyanoaniline-1-yl formamide in the presence of phosphorous oxychloride to 2-chloro-4-amino-6,7-dimethoxyquinazoline. These chemical compounds are utilized as intermediates in the preparation of some of the important antihypertensive agents e.g. 2-chloro-4-amino-6,7-dimethoxyquinazolines is used for the synthesis of alfuzosin hydrochloride.

AN IMPROVED PROCESS FOR THE PREPARATION OF ALFUZOSIN HYDROCHLORIDE

The present invention relates to an improved process for the preparation of Alfuzosin hydrochloride of formula (I) by reacting N-(3-aminopropyl)-6,7-dimethoxy-N-methylquinazoline-2,4-diamine of Formula (II) with 1-(tetrahydrofuran-2-ylcarbonyl)-1H-imidazole of formula (IV) using acetonitrile as an organic solvent. This invention also relates to a method for the purification of N-(3-aminopropyl)-6,7-dimethoxy-N-methylquinazoline-2,4-diamine of formula (II), which is a key starting material of Alfuzosin hydrochloride by making its corresponding salt of formula (III) using an organic di-carboxylic acid in an alcoholic solvent wherein, A is denoted as a corresponding moiety of organic di-carboxylic acid.

PROCESS FOR PREPARING ALFUZOSIN

Processes for preparing alfuzosin and pharmaceutically acceptable salts, solvates, hydrates thereof are disclosed. The present invention also discloses processes for preparation of anhydrous alfuzosin hydrochloride having substantially free from other pseudopolymorphic crystalline forms particularly dihydrate form of alfuzosin hydrochloride.

PROCESS FOR THE PREPARATION OF ALFUZOSIN

The present invention relates to a simple process for the preparation of alfuzosin, it's bases and its pharmaceutically acceptable salts thereof.