80012-43-7

Basic information

• Product Name: Epinastine
• Synonyms: 3-amino-9,13b-dihydro-1h-dibenz[c,f]imidazo[1,5-a]azepine;EPINASTINE;EPINASTINE BASE;9,13b-Dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepin-3- amine;3-Amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine;Apinastine Base
• CAS NO: 80012-43-7
• Molecular Formula: C₁₆H₁₅N₃
• Molecular Weight: 249.31
• EINECS: 1312995-182-4
• Mol File: 80012-43-7.mol
• Article Data: 8

Chemical Properties

• Melting Point: 205-208°
• Boiling Point: 428 °C at 760 mmHg
• Flash Point: 212.7 °C
• Appearance: white to yellow crystalline powder
• Density: 1.32 g/cm³
• Vapor Pressure: 1.56E-07mmHg at 25°C
• Refractive Index: 1.727
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• PKA: 11.2(at 25℃)
• CAS DataBase Reference: Epinastine(CAS DataBase Reference)
• NIST Chemistry Reference: Epinastine(80012-43-7)
• EPA Substance Registry System: Epinastine(80012-43-7)

Safety Data

• Hazardous Substances Data: 80012-43-7(Hazardous Substances Data)

Usage

Description

Epinastine hydrochloride, an orally active antihistaminic agent, was marketed in Japan for the treatment of bronchial asthma, allergic rhinitis, urticaria, eczema, dermatitis, and psoriasis vulgaris.Epinastine is one of the most effective peripherally acting histamine H1-receptor antagonists without sedative effects.In addition, it exhibits potent anti-PAF and anti-LT activity which may also contribute significantly to its antiallergic activity. Chronic epinastine has been reported to effectively inhibit airway hyper-responsiveness in rats. Potent inhibitory effects of epinastine on bronchoconstriction induced by histamine and bradykinin, but not by other chemical mediators, has also been reported. Studies have indicated that there are no significant differences in pharmacological properties among D-, L-, and racemic epinastine.

Originator

Boehringer lngelheim (Germany)

Uses

Epinastine is antihistamine and mast cell stabilize that is used in eye drops for the treatment of allergic conjunctivitis.

Definition

ChEBI: A benzazepine that is 6,11-dihydro-5H-dibenzo[b,e]azepine in which the azepine ring is fused to the e side of 4,5-dihydro-1H-imidazol-2-amine.

Brand name

Aleslon

Clinical Use

Epinastine is a potent, long-acting H1 antihistamine and an inhibitor of the release of histamine and other transmitters from mast cells. It has some affinity for H2 receptors as well. It is used as an eye drop for allergic conjunctivitis. It does not penetrate into the CNS and is classified as a nonsedating antihistamine.

Synthesis

Several patents on the synthesis of epinastin (VIII) have appeared in Europe and Japan. The synthesis described below is taken partly from the US patent and a Japanese patent. All the syntheses utilized 6-aminomethyl-6,11-dihydro-5H-dibenzo[b.e]azepine (80) as the key intermediate which was converted to the final guanidine epinastine by reacting with cyanogen bromide. The solution of 80 in ethanol was treated with a solution of cyanogen bromide in THF at room temperature and stirred overnight. The hydrobromide salt was collected in 79% yield after adding ether to the reaction mixture. The salt was free based with a solution of sodium hydroxide and then treated with an ethereal solution of HCl to obtain the epinastine hydrochloride salt VIII. For the preparation of the key intermediate, chloroimine 78, presumably obtained from ketone 77 via Beckmann rearrangement, was reacted with sodium cyanide in DMSO to give the nitrile 79 in 70% yield. Reduction of the imino nitrile was carried out in THF in the presence of an acid with LAH to give the key intermediate 80 in 67% yield. An alternate approach to preparation of 80 is shown in Scheme 8 as well. Reaction of the commercially available chloride 81 with phthalimide in the presence of a base gave the phthalimide 82. Reduction of the imine with sodium borohydride gave 83, which was then reacted with hydrazine hydrate to free up the amine in 90% yield. The amine intermediate was isolated as the fumarate salt.

InChI:InChI=1/C16H15N3/c17-16-18-10-15-13-7-3-1-5-11(13)9-12-6-2-4-8-14(12)19(15)16/h1-8,15H,9-10H2,(H2,17,18)

Synthetic route

3-methoxycarbonylamino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine → epinastine (80012-43-7)

Conditions	Yield
With sodium hydroxide at 20℃; for 2h;	98%
With hydrogenchloride at 95℃; for 31h;	73%

3-amino-9,13b-dihydro-1H-dibenzimidazo<1,5-a>azepine hydrobromide (127786-29-2) → epinastine (80012-43-7)

Conditions	Yield
With sodium hydroxide In water at 20℃; for 3h; pH=> 10;	92%

bromocyane (506-68-3) + 6-aminomethyldibenzo[b,e]azepine → epinastine (80012-43-7)

Conditions	Yield
In ethanol at 30℃; for 10h; Temperature;	88.6%

N-(9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepin-3-yl)benzamide → epinastine (80012-43-7)

Conditions	Yield
With hydrogenchloride In water at 100℃; for 2h; Temperature;	70.1%

6,11-dihydro-5H-dibenzazepine-6-methanamine fumarate (127785-96-0) → epinastine (80012-43-7)

Conditions	Yield
With sodium hydroxide In water at 25 - 30℃; for 0.5h;

6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine (41218-84-2) → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid / toluene / 15 h / 70 °C 2: hydrogenchloride / 31 h / 95 °C View Scheme
Multi-step reaction with 3 steps 1: acetone / 3 h / 0 °C 2: 2-chloro-1-methyl-pyridinium iodide; triethylamine / N,N-dimethyl-formamide / 10 h / 25 °C 3: hydrogenchloride / water / 2 h / 100 °C View Scheme

2-(6,11-dihydro-5H-dibenzo[b,e]azepin-6-ylmethyl)isoindole-1,3-dione (143878-20-0) → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / methanol / 4 h / Reflux 2: dichloromethane / 4 h / 20 °C View Scheme

bromocyane (506-68-3) + 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine (41218-84-2) → epinastine (80012-43-7)

Conditions	Yield
In dichloromethane at 20℃; for 4h;
In methanol; ethyl acetate at 10 - 20℃; for 6h; Temperature; Solvent;

C21H20N2O → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: polyphosphoric acid / dichloromethane / 0.5 h / 160 °C 2: 5%-palladium/activated carbon / methanol / 1 h / 80 °C 3: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme

C21H18N2 → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 5%-palladium/activated carbon / methanol / 1 h / 80 °C 2: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme

C23H20N2O2 → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 5%-palladium/activated carbon / 3 h / 40 °C 2: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme

(2-aminophenyl)(phenyl)methanone (2835-77-0) → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; ethyl acetate / 10 h / 5 °C 2.1: dicyclohexyl-carbodiimide / dichloromethane / 0.5 h / 15 °C 2.2: 12 h 3.1: polyphosphoric acid / dichloromethane / 2 h / 120 °C 4.1: hydrogenchloride / ethyl acetate; water / 4 h / 20 °C 5.1: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; ethyl acetate / 10 h / 5 °C 2.1: dicyclohexyl-carbodiimide / dichloromethane / 0.5 h / 15 °C 2.2: 12 h 3.1: polyphosphoric acid / dichloromethane / 1.5 h / 130 °C 4.1: 5%-palladium/activated carbon / 3 h / 40 °C 5.1: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; ethyl acetate / 10 h / 5 °C 2.1: 4,5-dicyano-1H-imidazole / ethyl acetate / 1 h / 35 °C 2.2: 2 h 3.1: polyphosphoric acid / dichloromethane / 0.5 h / 160 °C 4.1: 5%-palladium/activated carbon / methanol / 1 h / 80 °C 5.1: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme

C30H24N2O2 → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / ethyl acetate / 2 h / 60 °C 2: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme

2-benzylaniline (28059-64-5) → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 4,5-dicyano-1H-imidazole / ethyl acetate / 1 h / 35 °C 1.2: 2 h 2.1: polyphosphoric acid / dichloromethane / 0.5 h / 160 °C 3.1: 5%-palladium/activated carbon / methanol / 1 h / 80 °C 4.1: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: dicyclohexyl-carbodiimide / dichloromethane / 0.5 h / 15 °C 1.2: 12 h 2.1: polyphosphoric acid / dichloromethane / 2 h / 120 °C 3.1: hydrogenchloride / ethyl acetate; water / 4 h / 20 °C 4.1: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: dicyclohexyl-carbodiimide / dichloromethane / 0.5 h / 15 °C 1.2: 12 h 2.1: polyphosphoric acid / dichloromethane / 1.5 h / 130 °C 3.1: 5%-palladium/activated carbon / 3 h / 40 °C 4.1: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme

C20H24N2O3 → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: polyphosphoric acid / dichloromethane / 2 h / 120 °C 2: hydrogenchloride / ethyl acetate; water / 4 h / 20 °C 3: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: polyphosphoric acid / dichloromethane / 1.5 h / 130 °C 2: 5%-palladium/activated carbon / 3 h / 40 °C 3: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme

C20H22N2O2 → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate; water / 4 h / 20 °C 2: ethyl acetate; methanol / 6 h / 10 - 20 °C View Scheme

6-(chloromethyl)-11H-dibenzazepine (21535-44-4) → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: dichloromethane / 3 h / Reflux 2: hydrogenchloride / methanol; water / 2 h / Reflux 3: palladium 10% on activated carbon; hydrogen / water; ethanol / 5 h / 20 °C 4: ethanol / 10 h / 30 °C View Scheme

6-bromomethyldibenzo[b,e]azepine → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: dichloromethane / 3 h / Reflux 2: hydrogenchloride / water; ethanol / 2 h / Reflux 3: palladium 10% on activated carbon; hydrogen / water; ethanol / 5 h / 20 °C 4: ethanol / 10 h / 30 °C View Scheme

C21H24N5(1+)*Cl(1-) → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / methanol; water / 2 h / Reflux 2: palladium 10% on activated carbon; hydrogen / water; ethanol / 5 h / 20 °C 3: ethanol / 10 h / 30 °C View Scheme

C21H24N5(1+)*Br(1-) → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / water; ethanol / 2 h / Reflux 2: palladium 10% on activated carbon; hydrogen / water; ethanol / 5 h / 20 °C 3: ethanol / 10 h / 30 °C View Scheme

6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine maleate → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / tert-butyl methyl ether; water / 2 h / 20 °C / Large scale 2: acetone / 3 h / 0 °C 3: 2-chloro-1-methyl-pyridinium iodide; triethylamine / N,N-dimethyl-formamide / 10 h / 25 °C 4: hydrogenchloride / water / 2 h / 100 °C View Scheme

C23H21N3OS → epinastine (80012-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2-chloro-1-methyl-pyridinium iodide; triethylamine / N,N-dimethyl-formamide / 10 h / 25 °C 2: hydrogenchloride / water / 2 h / 100 °C View Scheme

epinastine (80012-43-7) → epinastine hydrochloride (108929-04-0)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; water; ethyl acetate for 0.5h; Product distribution / selectivity;	92%
With hydrogenchloride In tetrahydrofuran; water at 40℃; for 4h; pH=3.6; Temperature; Solvent; pH-value;	89.7%
With hydrogenchloride In water at 0 - 60℃; for 0.5h; Product distribution / selectivity;
With hydrogenchloride In methanol; water at -10 - 20℃; for 10h; Temperature; Solvent;

mefenamic Acid (61-68-7) + epinastine (80012-43-7) → N-(9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepin-3-yl)-2-((2,3-dimethylphenyl)amino)benzamide

Conditions	Yield
Stage #1: mefenamic Acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran for 0.333333h; Inert atmosphere; Stage #2: epinastine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h;	57%

epinastine (80012-43-7) + salicylic acid (69-72-7) → N-(9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepin-3-yl)-2-hydroxybenzamide

Conditions	Yield
With triethylamine In chloroform at 20℃; for 12h;	48%

epinastine (80012-43-7) → 3-amino-7-bromo-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine

Conditions	Yield
With bromine In chloroform at 20℃; for 10h;	46%

(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (22204-53-1) + epinastine (80012-43-7) → (2S)-N-(9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepin-3-yl)-2-(6-methoxynaphthalen-2-yl)propaamide

Conditions	Yield
Stage #1: epinastine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.333333h; Inert atmosphere; Stage #2: (2S)-2-(6-methoxy(2-naphthyl))propanoic acid With HATU In tetrahydrofuran for 2h; Inert atmosphere;	37%

epinastine (80012-43-7) + [1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid (53-86-1) → 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepin-3-yl)acetamide

Conditions	Yield
Stage #1: epinastine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: [1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 2h; Inert atmosphere;	16%

Upstream product

• 143878-20-0 2-(6,11-dihydro-5H-dibenzo[b,e]azepin-6-ylmethyl)isoindole-1,3-dione 
• 506-68-3 bromocyane 
• 41218-84-2 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine 
• 80012-79-9 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine maleate 
• 21535-44-4 6-(chloromethyl)-11H-dibenzazepine 
• 127785-96-0 6,11-dihydro-5H-dibenzazepine-6-methanamine fumarate 
• 127786-29-2 3-amino-9,13b-dihydro-1H-dibenzimidazo<1,5-a>azepine hydrobromide 
• 28059-64-5 2-benzylaniline 
• 2835-77-0 (2-aminophenyl)(phenyl)methanone 

Downstream Products

• 108929-04-0 epinastine hydrochloride 
• 1217052-16-8 3-amino-7-bromo-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine 
• 706753-75-5 9H-dibenzo[c,f]imidazo[1,5-a]azepin-3-amine 

Relevant articles and documents

Epinastine hydrochloride intermediate and synthesis method thereof

The invention provides a compound shown in the formula II; the compound is used as a raw material or an intermediate for synthesizing epinastine hydrochloride, cyanogen bromide is not needed in the synthesis process, hydrogen sulfide or/and methyl mercaptan is/are not generated in the synthesis process, the operation safety is improved, the environmental protection pressure is reduced, and safetyproduction and environmental protection requirements are met. The synthetic method disclosed by the invention is short in time, the reaction can be completed within 10 hours in total in two steps, andthe synthetic method has obvious advantages in industrial production, is high in yield and is suitable for industrial production.

Synthetic method of epinastine hydrochloride impurity B

The invention relates to the field of pharmaceutical technology and, and particularly relates to a preparation process of an epinastine hydrochloride impurity. The method comprises: firstly, using 6-(phthalimidomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine (shown in the description) as a starting material, removing a protective group with hydrazine hydrate and then performing ring closure with cyanogen bromide to obtain 3- amino-9,13-dihydro-1H-dibenzo [c,f ]-imidazo [1,5-a] heterocyclic nitrogen (shown in the description) (epinastine), and finally reacting with a simple substance bromine to obtain the epinastine hydrochloride impurity B. The synthetic method of the epinastine hydrochloride impurity B has the advantages of being simple in process route, convenient to operate, good in selectivity and high in yield. The synthetic epinastine hydrochloride impurity B can be used as a control substance for testing a related substance of epinastine hydrochloride, can be applied in quality control of epinastine hydrochloride and related preparations thereof, and can be used for controlling the purity of the epinastine hydrochloride active pharmaceutical ingredients or preparations thereof.

Epinastine synthetic method

The invention discloses a method for synthesizing epinastine. The method comprises the following steps: (1) reacting 6-halomethylmorphanthridine with hexamine in an organic solvent, thereby obtaining a 6-halomethylmorphanthridine quaternary ammonium salt; (2) dissolving the 6-halomethylmorphanthridine quaternary ammonium salt in the organic solvent to carry out an acid hydrolysis reaction, thereby obtaining 6-halomethylmorphanthridine hydrochloride; (3) reducing the product 6-halomethylmorphanthridine hydrochloride obtained in the step (2) by using a reducing agent, thereby obtaining 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]aza-cycloheptatrien; and (4) adding cyanogen bromide to carry out a ring-closure reaction, thereby obtaining the epinastine. According to the synthetic method disclosed by the invention, use of high-price and flammable lithium aluminum hydride or aluminum hydride is avoided, use of virulent sodium cyanide is avoided, and the security risk and production cost are effectively reduced. The method disclosed by the invention is simple in synthetic process, the reaction conditions are mild, the product is high in yield and high in purity, and industrial production is facilitated.