58581-89-8

Basic information

• Product Name: Azelastine
• Synonyms: 1(2h)-phthalazinone,4-((4-chlorophenyl)methyl)-2-(hexahydro-1-methyl-1h-azepin;4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1h-azepin-4-yl)-1-(2h)-phthalazinon;-4-yl)-;AZELASTINE;1(2H)-Phthalazinone, 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-;4-[(4-chlorophenyl)methyl]-2-(1-methylazepan-4-yl)-phthalazin-1-one;CAS 790307-93-0;4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-y1)-1(2H)-phthalazinone
• CAS NO: 58581-89-8
• Molecular Formula: C₂₂H₂₄ClN₃O
• Molecular Weight: 381.9
• EINECS: 253-720-4
• Product Categories: API;TELAZOL
• Mol File: 58581-89-8.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 533.9 °C at 760 mmHg
• Flash Point: 276.7 °C
• Appearance: /
• Density: 1.1505 (rough estimate)
• Refractive Index: 1.5790 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly, Heated), Methanol (Slightly)
• PKA: pKa 9.82(H2O t=25 I=0.025) (Uncertain)
• CAS DataBase Reference: Azelastine(CAS DataBase Reference)
• NIST Chemistry Reference: Azelastine(58581-89-8)
• EPA Substance Registry System: Azelastine(58581-89-8)

Safety Data

• Hazardous Substances Data: 58581-89-8(Hazardous Substances Data)

Usage

Uses

anesthetic, anticonvulsant

Definition

ChEBI: A phthalazine compound having an oxo substituent at the 1-position, a 1-methylazepan-4-yl group at the 2-position and a 4-chlorobenzyl substituent at the 4-position.

Brand name

Astelin (Medpointe); Optivar (Medpointe).

Clinical Use

Azelastine, although not a close structural analogue to the benzimidazoles, has some structural similarities to them. It is used as a nasal spray for allergic rhinitis and as eye drops for allergic conjunctivitis.Like olopatadine, azelastine also stabilizes mast cells, preventing degranulation and subsequent release of histamine, leukotrienes, and PGD2. It is available in Europe for systemic use in the treatment of asthma and seasonal allergies. Besides antihistaminic effects, it also may block release of histamine and other inflammatory mediators from mast cells. When administered orally, the N-dealkylated metabolite appears to contribute significantly to its pharmacological effects.

Safety Profile

Poison by ingestion,subcutaneous, intravenous, and intraperitoneal routes.Experimental reproductive effects. When heated todecomposition it emits toxic fumes of NOx and Cl- .

InChI:InChI=1/C22H25ClN3O/c1-25-13-4-5-18(12-14-25)26-22(27)20-7-3-2-6-19(20)21(24-26)15-16-8-10-17(23)11-9-16/h2-3,6-11,18,21H,4-5,12-15H2,1H3/q+1

Synthetic route

4-[(4-chlorophenyl)methyl]-1(2H)-phthalazinone (53242-88-9) + 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride → 4-(p-Chlorbenzyl)-2-<2-(N-methylpyrrolidin-2-yl)-ethyl>-1(2H)-phthalazinon + azelastine (58581-89-8)

Conditions	Yield
With sodium hydroxide at 70℃; for 1h; Yield given;

2‐(4-chlorophenylacetyl)benzoic acid (53242-76-5) + 2-Benzoyl-1-(hexahydro-1-methyl-1H-azepin-4-yl)hydrazin-hydrochlorid → azelastine (58581-89-8)

Conditions	Yield
With hydrogenchloride; potassium hydroxide 1.) reflux, 3 h, 2.) methanol, reflux, 2 h; Yield given. Multistep reaction;

4-chlorophenylacetic Acid (1878-66-6) → azelastine (58581-89-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: CH3COONa / 3 h / 245 - 250 °C 2: aq. NaOH / 2 h / Heating 3: 1.) 23percent aq. HCl, 2.) KOH / 1.) reflux, 3 h, 2.) methanol, reflux, 2 h View Scheme
Multi-step reaction with 4 steps 1: CH3COONa / 3 h / 245 - 250 °C 2: aq. NaOH / 2 h / Heating 3: 90 percent / hydrazine sulfate, aq. NaOH / 2 h / Heating 4: aq. NaOH / 1 h / 70 °C View Scheme

1-methyl-1,2,3,5,6,7-hexahydroazepin-4-one (1859-33-2) → azelastine (58581-89-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2.) NaBH4 / 1.) CH3OH, room temp. 2: 1.) 23percent aq. HCl, 2.) KOH / 1.) reflux, 3 h, 2.) methanol, reflux, 2 h View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: acetonitrile / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux View Scheme

phthalic anhydride (85-44-9) + 3-<2-carboxy-phenyl>-pyridine-carboxylic acid-(2) → azelastine (58581-89-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: CH3COONa / 3 h / 245 - 250 °C 2: aq. NaOH / 2 h / Heating 3: 1.) 23percent aq. HCl, 2.) KOH / 1.) reflux, 3 h, 2.) methanol, reflux, 2 h View Scheme
Multi-step reaction with 4 steps 1: CH3COONa / 3 h / 245 - 250 °C 2: aq. NaOH / 2 h / Heating 3: 90 percent / hydrazine sulfate, aq. NaOH / 2 h / Heating 4: aq. NaOH / 1 h / 70 °C View Scheme

(Z)-3-(4-chlorophenyl)methylidenephthalide (105279-16-1) → azelastine (58581-89-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. NaOH / 2 h / Heating 2: 1.) 23percent aq. HCl, 2.) KOH / 1.) reflux, 3 h, 2.) methanol, reflux, 2 h View Scheme
Multi-step reaction with 3 steps 1: aq. NaOH / 2 h / Heating 2: 90 percent / hydrazine sulfate, aq. NaOH / 2 h / Heating 3: aq. NaOH / 1 h / 70 °C View Scheme

2‐(4-chlorophenylacetyl)benzoic acid (53242-76-5) → azelastine (58581-89-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / hydrazine sulfate, aq. NaOH / 2 h / Heating 2: aq. NaOH / 1 h / 70 °C View Scheme

1H-azepine, 4-hydrazinohexahydro-1-methyl, dihydrochloride + 2‐(4-chlorophenylacetyl)benzoic acid (53242-76-5) → azelastine (58581-89-8)

Conditions	Yield
Stage #1: 1H-azepine, 4-hydrazinohexahydro-1-methyl, dihydrochloride; 2‐(4-chlorophenylacetyl)benzoic acid With sodium hydroxide In methanol; water for 4h; Heating / reflux; Stage #2: With hydrogenchloride In methanol; 2,8-dimethylnonan-5-one; water

azelastine hydrochloride (79307-93-0) → azelastine (58581-89-8)

Conditions	Yield
With sodium hydroxide In water pH=10; Inert atmosphere;

C14H23N3O(2+)*C4H2O4(2-) + 2‐(4-chlorophenylacetyl)benzoic acid (53242-76-5) → azelastine (58581-89-8)

Conditions	Yield
Stage #1: C14H23N3O(2+)*C4H2O4(2-) With hydrogenchloride at 20℃; for 2h; Reflux; Stage #2: 2‐(4-chlorophenylacetyl)benzoic acid for 2h; Reflux;	8.1 g

C14H23N3O(2+)*C4H2O4(2-) + 2‐(4-chlorophenylacetyl)benzoic acid (53242-76-5) → azelastine (58581-89-8)

Conditions	Yield
Stage #1: C14H23N3O(2+)*C4H2O4(2-) With hydrogenchloride at 20℃; for 2h; Reflux; Stage #2: 2‐(4-chlorophenylacetyl)benzoic acid for 2h; Reflux;	7.5 g

C14H21N3O → azelastine (58581-89-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 2.1: hydrogenchloride / 2 h / 20 °C / Reflux 2.2: 2 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 2.1: hydrogenchloride / 2 h / 20 °C / Reflux 2.2: 2 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: acetonitrile / 1 h / 0 - 10 °C / Reflux 2.1: hydrogenchloride / 2 h / 20 °C / Reflux 2.2: 2 h / Reflux View Scheme

C14H23N3O(2+)*C4H4O4(2-) + 2‐(4-chlorophenylacetyl)benzoic acid (53242-76-5) → azelastine (58581-89-8)

Conditions	Yield
Stage #1: C14H23N3O(2+)*C4H4O4(2-) With hydrogenchloride at 20℃; for 2h; Reflux; Stage #2: 2‐(4-chlorophenylacetyl)benzoic acid for 2h; Reflux;	8 g

benzoic acid hydrazide (613-94-5) → azelastine (58581-89-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrahydrofuran / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water / 1 h / 25 - 35 °C 1.2: 2 h / 0 - 10 °C 2.1: acetonitrile / 1 h / 0 - 10 °C / Reflux 3.1: hydrogenchloride / 2 h / 20 °C / Reflux 3.2: 2 h / Reflux View Scheme

2-(2-methylphenyl)pyridine (10273-89-9) + azelastine (58581-89-8) → C34H34N4O

Conditions	Yield
With C17H24N5Ru(1+)*F6P(1-); potassium acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 35℃; for 72h; Inert atmosphere;	91%

azelastine (58581-89-8) → azelastine hydrochloride (79307-93-0)

Conditions	Yield
With hydrogenchloride In toluene Reflux;	87%

3-methoxyphenylboronic acid (10365-98-7) + azelastine (58581-89-8) → 4-((3'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-(1-methylazepan-4-yl)phthalazin-1(2H)-one

Conditions	Yield
With 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; 1,8-diazabicyclo[5.4.0]undec-7-ene In methanol; N,N-dimethyl acetamide at 80℃; for 21h; Reagent/catalyst; Solvent; Inert atmosphere; Glovebox;	51%

phenylmagnesium bromide (100-58-3) + azelastine (58581-89-8) → 2-(1-benzylazepan-4-yl)-4-(4-chlorobenzyl)phthalazin-1(2H)-one (103541-65-7)

Conditions	Yield
Stage #1: azelastine With 1,4-diaza-bicyclo[2.2.2]octane; tri(4-tolyl)aminium hexafluorophosphate In acetonitrile at -5℃; Inert atmosphere; Stage #2: phenylmagnesium bromide In tetrahydrofuran; acetonitrile at 0℃; Inert atmosphere; regioselective reaction;	25%

Trimethylboroxine (823-96-1) + azelastine (58581-89-8) → C23H26ClN3O

Conditions	Yield
With pentamethylcyclopentadienyl(benzene)cobalt(III) hexafluorophosphate; potassium carbonate; silver carbonate In 2-methyltetrahydrofuran at 100℃; for 16h; Inert atmosphere; Sealed tube;	25%

azelastine (58581-89-8) → Azelastine monohydrate

Conditions	Yield
With water In ethanol Heating / reflux;

azelastine (58581-89-8) → C22H24ClN3O + C22H24ClN3O

Conditions	Yield
With mixed selector chiral stationary phase prepared with co-immobilized human serum albumin and cellulase on a poly(glycidylmethacrylate-co-ethylene glycol dimethacrylate) monolith In aq. phosphate buffer; isopropyl alcohol at 20℃; pH=7; Resolution of racemate;

Upstream product

• 53242-76-5 2‐(4-chlorophenylacetyl)benzoic acid 
• 117078-69-0 2-Benzoyl-1-(hexahydro-1-methyl-1H-azepin-4-yl)hydrazin-hydrochlorid 
• 79307-93-0 azelastine hydrochloride 
• 613-94-5 benzoic acid hydrazide 
• 110406-94-5 C₁₄H₂₁N₃O 
• 53242-88-9 4-[(4-chlorophenyl)methyl]-1(2H)-phthalazinone 
• 56824-22-7 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride 
• 105279-16-1 (Z)-3-(4-chlorophenyl)methylidenephthalide 
• 85-44-9 phthalic anhydride 
• 1859-33-2 1-methyl-1,2,3,5,6,7-hexahydroazepin-4-one 
• 1878-66-6 4-chlorophenylacetic Acid 

Downstream Products

• 103541-65-7 2-(1-benzylazepan-4-yl)-4-(4-chlorobenzyl)phthalazin-1(2H)-one 
• 143228-85-7 (R)-azelastine 
• 143228-85-7 (S)-azelastine 
• 79307-93-0 azelastine hydrochloride 
• 1346617-06-8 C₂₂H₂₄ClN₃O₂ 
• 1346617-06-8 C₂₂H₂₄ClN₃O₂ 

Relevant articles and documents

Synthesis and structure of azelastine-N-oxides

Azelastine is among the most frequently used drugs; however, knowledge and solid data about its metabolites are scarcely found in literature. Thus, microsomal oxidation of azelastine is thought to produce the corresponding N-oxides, However, until now these products had never been produced in significant amounts. By oxidation of azelastine with H2O2, these N-oxides were now prepared in racemic form for the first time and were fully characterized. Their structure was additionally confirmed by a single crystal X-ray analysis. Both N-oxides were found to be non-cytotoxic in SRB assays.

Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C-H Functionalization of Trialkylamine N-CH3 Groups

We report a simple one-pot protocol that affords functionalization of N-CH3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+?, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C-H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure-activity relationships.

Synthesis and X-ray-structure analysis of azelastine

-