55453-87-7

Basic information

• Product Name: Isoxepac
• Synonyms: isoxepac;6,11-DIHYDRO-11-OXO-DIBENZ[B,E]OXEPIN-2-ACETIC ACID;(11-OXO-6,11-DIHYDRODIBENZO[B,E]OXEPIN-2-YL)ACETIC ACID;ND4-B2;artil;e)oxepin-2-aceticacid,6,11-dihydro-11-oxo-dibenz(;hp549;DIBENZ[B,E]OXEPIN-2-ACETIC ACID, 6,11-DIOHYDRO-11-OXO
• CAS NO: 55453-87-7
• Molecular Formula: C₁₆H₁₂O₄
• Molecular Weight: 268.26
• EINECS: 1806241-263-5
• Product Categories: APIs Intermediate;Intermediates & Fine Chemicals;Pharmaceuticals;API;Pharmaceutical intermediate
• Mol File: 55453-87-7.mol

Chemical Properties

• Melting Point: 130-132°C
• Boiling Point: 528.2 °C at 760 mmHg
• Flash Point: 203.8 °C
• Appearance: Light-yellow to pale-white crystalline powder
• Density: 1.349 g/cm³
• Vapor Pressure: 5.51E-12mmHg at 25°C
• Refractive Index: 1.635
• Storage Temp.: Refrigerator
• Solubility: soluble in Methanol
• PKA: 4.24±0.10(Predicted)
• Merck: 14,5237
• CAS DataBase Reference: Isoxepac(CAS DataBase Reference)
• NIST Chemistry Reference: Isoxepac(55453-87-7)
• EPA Substance Registry System: Isoxepac(55453-87-7)

Safety Data

• Hazard Codes: T
• Statements: 25-62
• Safety Statements: 36/37-45
• RIDADR: UN 2811 6.1 / PGIII
• RTECS: HQ4110000
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 55453-87-7(Hazardous Substances Data)

Usage

Chemical Properties

Beige Solid

Uses

Isoxepac is a non-steroidal anti-inflammatory with analgesic and antipyretic activity. It is more slowly absorbed and eliminated in the rat and rabbit after oral dosing than in the dog, rhesus monkey and man.It can be used to treat allergic rhinitis, urticaria, and skin diseases with itching symptoms.

Definition

ChEBI: Isoxepac is a dibenzooxazepine.

Preparation

Isoxic acid is an important intermediate in the synthesis of the new preferred anti-allergic drug, olopatadine hydrochloride, preparation method of isoxepac:(1) condensation: prepare p-hydroxyphenylaceticacid 8-12 part, phthalide 6-12 part, sodium methylate 8-12 part by weight; Dissolve with DMAC and to add said sodium methylate behind said p-hydroxyphenylaceticacid and the phthalide; Be that 0.1-10Pa is heated to 80-170 ℃ of reaction 3-10h at pressure then; Regulate the pH value to 1-5,4-(2-carboxyl benzyloxy) toluylic acid is separated out in crystallization;(2) cyclization: with Glacial acetic acid min. 99.5 dissolving step (1) gained 4-(2-carboxyl benzyloxy) toluylic acid, adding 3-52 weight part polyphosphoric acid again, is that 0.1-10Pa is heated to 30-100 ℃ of reaction 3-12h at pressure, and crystallisation by cooling gets the Isoxepac bullion then;(3) purify: behind the said Isoxepac bullion of acetic acid ethyl dissolution, refining decolouring gets the Isoxepac product.https://patents.google.com/patent/CN102838582A/en

Brand name

Artil(Hoechst-Roussel) .

InChI:InChI=1/C16H12O4/c17-15(18)8-10-5-6-14-13(7-10)16(19)12-4-2-1-3-11(12)9-20-14/h1-7H,8-9H2,(H,17,18)

Synthetic route

4-(2-carboxybenzyloxy) phenyl acetic acid (55453-89-9) → isoxepac (55453-87-7)

Conditions	Yield
Stage #1: 4-(2-carboxybenzyloxy) phenyl acetic acid With trifluoroacetic anhydride In chlorobenzene at 20℃; for 4h; Stage #2: boron trifluoride diethyl etherate In chlorobenzene at -10 - 0℃; for 0.666667h;	96.4%
Stage #1: 4-(2-carboxybenzyloxy) phenyl acetic acid With trifluorormethanesulfonic acid; trifluoroacetic anhydride In toluene at 20 - 35℃; for 1h; Stage #2: With water In toluene	71.3%
With acetic anhydride at 80 - 90℃; for 2h; Large scale;	69.9%

4-hydroxyphenylacetate (156-38-7) + 2-(chloromethyl)benzoic acid (85888-81-9) → isoxepac (55453-87-7)

Conditions	Yield
Stage #1: 4-hydroxyphenylacetate With potassium hydroxide In methanol at 20℃; for 1h; Friedel-Crafts Acylation; Stage #2: 2-(chloromethyl)benzoic acid In methanol Reflux; Stage #3: With Eaton′s Reagent at 80℃; for 2h; Reagent/catalyst; Solvent; Concentration;	79.3%

methyl 2-bromomethylbenzoate (2417-73-4) → isoxepac (55453-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: K2CO3, KI / butan-2-one / 24 h / Heating 2: KOH / aq. ethanol / Heating 3: 1.) (CF3CO)2O, 2.) 10percent aq. HCl / 1.) CH2Cl2, reflux, 4 h, 2.) acetone, reflux, 24 h View Scheme

(4-hydroxy-phenyl)-acetic acid ethyl ester (17138-28-2) → isoxepac (55453-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: K2CO3, KI / butan-2-one / 24 h / Heating 2: KOH / aq. ethanol / Heating 3: 1.) (CF3CO)2O, 2.) 10percent aq. HCl / 1.) CH2Cl2, reflux, 4 h, 2.) acetone, reflux, 24 h View Scheme

2-(4-Ethoxycarbonylmethyl-phenoxymethyl)-benzoic acid methyl ester → isoxepac (55453-87-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: KOH / aq. ethanol / Heating 2: 1.) (CF3CO)2O, 2.) 10percent aq. HCl / 1.) CH2Cl2, reflux, 4 h, 2.) acetone, reflux, 24 h View Scheme

4-benzyloxy-3-carboxyphenylacetic acid (69031-39-6) → isoxepac (55453-87-7)

Conditions	Yield
In methylene chloride-nitromethane; 4-benzyloxy-3-chlorocarbonylphenylacetyl chloride

4-hydroxyphenylacetate (156-38-7) → isoxepac (55453-87-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium methylate / N,N-dimethyl-formamide; methanol / 120 - 135 °C 1.2: 5 - 10 °C 2.1: acetic acid / 2.5 h / 70 - 75 °C View Scheme

2-benzofuran-1(3H)-one (87-41-2) → isoxepac (55453-87-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium methylate / N,N-dimethyl-formamide; methanol / 120 - 135 °C 1.2: 5 - 10 °C 2.1: acetic acid / 2.5 h / 70 - 75 °C View Scheme

4-(2-methoxycarbonylbenzyloxy)phenyl acetic acid (1009378-92-0) → isoxepac (55453-87-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium hydroxide; N-benzyl-N,N,N-triethylammonium chloride / ethanol / 3 h / Reflux; Large scale 1.2: pH 1 - 2 / Large scale 2.1: acetic anhydride / 2 h / 80 - 90 °C / Large scale View Scheme

o-(chloromethyl)benzoic acid methyl ester (34040-62-5) → isoxepac (55453-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / ethanol / 24 h / Reflux 2.1: potassium hydroxide; N-benzyl-N,N,N-triethylammonium chloride / ethanol / 3 h / Reflux; Large scale 2.2: pH 1 - 2 / Large scale 3.1: acetic anhydride / 2 h / 80 - 90 °C / Large scale View Scheme

Methyl 4-hydroxyphenylacetate (14199-15-6) → isoxepac (55453-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / ethanol / 24 h / Reflux 2.1: potassium hydroxide; N-benzyl-N,N,N-triethylammonium chloride / ethanol / 3 h / Reflux; Large scale 2.2: pH 1 - 2 / Large scale 3.1: acetic anhydride / 2 h / 80 - 90 °C / Large scale View Scheme

isoxepac (55453-87-7) → 11-hydroxy-2-(2-hydroxyethyl)-6,11-dihydrodibenz[b,e]oxepin (56427-65-7)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran for 1h; Ambient temperature;	98%

isoxepac (55453-87-7) + benzyl alcohol (100-51-6) → (11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)-acetic acid benzyl ester (60548-16-5)

Conditions	Yield
toluene-4-sulfonic acid In toluene Reflux;	98%

isoxepac (55453-87-7) + tert-butyl alcohol (75-65-0) → tert-butyl 11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-acetate

Conditions	Yield
With 1-methyl-1H-imidazole; di-tert-butyl dicarbonate; triethylamine In toluene at 50℃; for 8.5h; Reagent/catalyst; Solvent; Temperature;	97%
Stage #1: isoxepac With trifluoroacetic anhydride In toluene at 20℃; for 1h; Stage #2: tert-butyl alcohol In toluene at 20 - 80℃; for 4h;	79.9%

isoxepac (55453-87-7) → (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydro-dibenz-[b,e]oxepine-2-acetic acid hydrobromide (951006-73-8)

Conditions	Yield
Stage #1: anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide With sodium hydride In tetrahydrofuran at 20 - 60℃; for 3.66667h; Stage #2: isoxepac In tetrahydrofuran at 10 - 25℃; for 20 - 30h; Wittig Reaction; Stage #3: With hydrogen bromide In 2-methyltetrahydrofuran; water; isopropyl alcohol pH=4.3 - 13.8; Product distribution / selectivity;	96.95%
Stage #1: (3-dimethylaminopropyl)-triphenylphosphoniumbromide With sodium hydride In tetrahydrofuran at 20 - 60℃; for 2.5h; Stage #2: isoxepac In tetrahydrofuran at 15 - 25℃; for 40h; Wittig Reaction; Stage #3: With hydrogen bromide In water; butan-1-ol at 0 - 25℃; pH=4.2 - 12.59; Product distribution / selectivity;	53.5%

isoxepac (55453-87-7) + isopropyl alcohol (67-63-0) → (11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)-acetic acid isopropyl ester (56427-76-0)

Conditions	Yield
toluene-4-sulfonic acid Reflux;	96%

methanol (67-56-1) + isoxepac (55453-87-7) → methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate (55689-64-0)

Conditions	Yield
With tert.-butylnitrite at 40℃; for 48h;	96%
With thionyl chloride at 0 - 20℃; for 24.5h;
With thionyl chloride at 0 - 25℃; for 24.5h;

isoxepac (55453-87-7) + ethanol (64-17-5) → ethyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate (55453-90-2)

Conditions	Yield
With toluene-4-sulfonic acid for 2h; Reflux;	94%
toluene-4-sulfonic acid Reflux;	93%

isoxepac (55453-87-7) + butan-1-ol (71-36-3) → (11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)-acetic acid butyl ester (60548-14-3)

Conditions	Yield
With sulfuric acid at 115℃;	93%
With sulfuric acid at 115℃; for 2h; Dean Stark apparatus;	93%

isoxepac (55453-87-7) + N-(3-chloropropyl)-N,N-dimethylamine hydrochloride → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Stage #1: N-(3-chloropropyl)-N,N-dimethylamine hydrochloride With potassium bromide for 1h; Inert atmosphere; Stage #2: With N,N,N,N,N,N-hexamethylphosphoric triamide In dimethyl sulfoxide for 2h; Reflux; Stage #3: isoxepac In dimethyl sulfoxide at 20℃; for 1h; Reagent/catalyst; Solvent;	90.5%

isoxepac (55453-87-7) + Cyclopropylamine (765-30-0) → N-cyclopropyl-2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetamide

Conditions	Yield
Stage #1: isoxepac With 1,1'-carbonyldiimidazole In dichloromethane for 1h; Stage #2: Cyclopropylamine In dichloromethane at 20℃; for 2h;	90%
Stage #1: isoxepac With 1,1'-carbonyldiimidazole In dichloromethane for 1h; Stage #2: Cyclopropylamine In dichloromethane at 20℃; for 2h;	90%

isoxepac (55453-87-7) + 1-bromo-3-propanol (627-18-9) → 3-bromopropyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; Inert atmosphere;	89%

isoxepac (55453-87-7) → 6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-carboxaldehyde (66801-46-5)

Conditions	Yield
With tris(bipyridine)ruthenium(II) dichloride hexahydrate; 1-λ3-benzo[d][1,2]iodaoxol-3(1H)-one In 2,2,2-trifluoroethanol at 40℃; for 3h; UV-irradiation;	86%
With oxygen; copper diacetate In dimethyl sulfoxide at 120℃;

isoxepac (55453-87-7) + monomethyl monopotassium malonate (38330-80-2) → C19H16O5

Conditions	Yield
Stage #1: isoxepac With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #2: monomethyl monopotassium malonate With magnesium chloride In dichloromethane at 20℃; for 24h; Inert atmosphere;	86%

isoxepac (55453-87-7) + isobutene (115-11-7) → tert-butyl 11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-acetate

Conditions	Yield
Stage #1: isoxepac With potassium carbonate; trichlorophosphate In water; chlorobenzene at 40℃; Stage #2: isobutene In water; chlorobenzene at 40℃; for 8h; Product distribution / selectivity;	85.3%

isoxepac (55453-87-7) + hex-5-en-3-yn-1-ol (28916-38-3) → hex-5-en-3-yn-1-yl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate

Conditions	Yield
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 12h; Inert atmosphere; Schlenk technique;	84%

isoxepac (55453-87-7) → 2-(chloromethyl)dibenzo[b,e]oxepin-11(6H)-one (66801-38-5)

Conditions	Yield
With tris(bipyridine)ruthenium(II) dichloride hexahydrate; dibenzenesulfonamide; 1-λ3-benzo[d][1,2]iodaoxol-3(1H)-one; tetrabutyl-ammonium chloride In dichloromethane at 40℃; for 24h; Inert atmosphere; Schlenk technique; Irradiation;	82%

isoxepac (55453-87-7) + (4-vinyl-phenyl)-methanol (1074-61-9) → 4-vinylbenzyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate

Conditions	Yield
With dmap; diisopropyl-carbodiimide In dichloromethane	82%

isoxepac (55453-87-7) + N,N-dimethyl-3-bromopropylamine (53929-74-1) → olopatadine (113806-05-6)

Conditions	Yield
Stage #1: N,N-dimethyl-3-bromopropylamine With zinc dibromide In tetrahydrofuran at 10 - 20℃; for 0.166667h; Inert atmosphere; Stage #2: With naphthalene; lithium In tetrahydrofuran at 65 - 70℃; Inert atmosphere; Stage #3: isoxepac In tetrahydrofuran at 0 - 25℃; for 16.5h; Reagent/catalyst; Temperature;	81.2%

isoxepac (55453-87-7) + 2,2,2-trifluoroethanol (75-89-8) → 2,2,2-trifluoroethyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate

Conditions	Yield
With thionyl chloride; triethylamine at 0 - 40℃; for 12.3333h; Inert atmosphere;	80%

N-hydroxyphthalimide (524-38-9) + isoxepac (55453-87-7) → 1,3-dioxoisoindolin-2-yl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	80%
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 1h;	71%
With dmap; diisopropyl-carbodiimide In dichloromethane

isoxepac (55453-87-7) + 2,2,2,-trichloroethoxycarbonyl azide → 2,2,2-trichloroethyl ((11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)methyl)carbamate

Conditions	Yield
With dmap; copper diacetate In acetonitrile at 80℃; for 3h; Schlenk technique; Sealed tube;	80%

3-(N,N-dimethylamino)propylmagnesium chloride (19070-16-7) + isoxepac (55453-87-7) → 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid

Conditions	Yield
Stage #1: 3-(N,N-dimethylamino)propylmagnesium chloride; isoxepac In tetrahydrofuran; toluene at 5 - 18℃; for 2.08333h; Stage #2: With water; acetic acid In tetrahydrofuran; toluene	79.7%

isoxepac (55453-87-7) + 4-bromo-5, 5, 5-trifluoropentan-1-ol → 4-bromo-5,5,5-trifluoropentyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 12.5h; Inert atmosphere;	79%

isoxepac (55453-87-7) + methylamine hydrochloride (593-51-1) → N-methyl-2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetamide

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane	78%

isoxepac (55453-87-7) + dibenzenesulfonamide (2618-96-4) → N-[(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)methyl]-N-phenylsulfonylbenzenesulfonamide

Conditions	Yield
With tris(bipyridine)ruthenium(II) dichloride hexahydrate; 1-λ3-benzo[d][1,2]iodaoxol-3(1H)-one In dichloromethane at 40℃; for 24h; Inert atmosphere; Schlenk technique; Irradiation;	75%

isoxepac (55453-87-7) + 1-(1-hydroxybutan-2-yl)-2,4,6-triphenylpyridin-1-ium tetrafluoroborate → 1-(1-(2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetoxy)butan-2-yl)-2,4,6-triphenylpyridin-1-ium tetrafluoroborate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	72%

isoxepac (55453-87-7) + Propargylamine (2450-71-7) → C19H15NO3

Conditions	Yield
With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 20℃; for 2h;	72%

isoxepac (55453-87-7) → 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid (66801-40-9)

Conditions	Yield
With tris(bipyridine)ruthenium(II) dichloride hexahydrate; [bis(acetoxy)iodo]benzene; oxygen In 2,2,2-trifluoroethanol for 24h; UV-irradiation;	70%

Upstream product

• 55453-89-9 4-(2-carboxybenzyloxy) phenyl acetic acid 
• 2417-73-4 methyl 2-bromomethylbenzoate 
• 17138-28-2 (4-hydroxy-phenyl)-acetic acid ethyl ester 
• 69031-39-6 4-benzyloxy-3-carboxyphenylacetic acid 
• 156-38-7 4-hydroxyphenylacetate 
• 87-41-2 2-benzofuran-1(3H)-one 
• 1009378-92-0 4-(2-methoxycarbonylbenzyloxy)phenyl acetic acid 
• 34040-62-5 o-(chloromethyl)benzoic acid methyl ester 
• 14199-15-6 Methyl 4-hydroxyphenylacetate 
• 85888-81-9 2-(chloromethyl)benzoic acid 
• 55453-90-2 ethyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate 

Downstream Products

• 173677-70-8 N-<2-(6,11-dihydro-11-oxodibenzoxepin-2-yl)ethyl>-N-(phenylmethoxy)acetamide 
• 173677-68-4 N-<2-(6,11-dihydro-11-oxodibenzoxepin-2-yl)ethyl>-N-(phenylmethoxy)-1,1-(dimethylethyl)carbamate 
• 60548-16-5 (11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)-acetic acid benzyl ester 
• 140462-76-6 olopatadine hydrochloride 
• 55689-64-0 methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate 
• 113806-05-6 olopatadine 
• 113806-06-7 11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid 

Relevant articles and documents

Preparation method of olopatadine hydrochloride

The method comprises the following steps: [3 - (dimethylamino) propyl] triphenylphosphonium bromide hydrobromide is added into tetrahydrofuran. The sodium hydride and dimethyl sulfoxide are added 11 - oxo -6, 11 - dihydrodibenzo [b, e] oxazepine -2 - acetic acid and stirred until the reaction system forms a black brown suspension reaction. The reaction solution is quenched by a mixed solution of purified water and tetrahydrofuran, and then the aqueous phase is treated with a mixed solvent of hydrochloric acid and n-butanol. The olopatadine hydrochloride is stirred and added with hydrochloric acid to form a white turbid liquid, and then is filtered through stirring after stirring, and is dried to obtain olopatadine hydrochloride, and the prepared oxalolopatadine hydrochloride is high in yield and short in reaction route.

New method for preparation of 6,11-dihydro-11-oxo dibenzo [b, e] oxepin-2-acetic acid

The present invention provides a new method for preparation of 6,11-dihydro-11-oxo dibenzo [b, e] oxepin-2-acetic acid, and the method is as follows: poly phosphoric acid, glacial acetic acid, cyclohexane and 4-(2-hydroxy benzyloxy) phenylacetic acid are mixed and heated under stirring, the temperature of the reaction liquid is controlled at 70 +/-85 DEG C for stirring for reaction for 4 + /-2 hours; a proper amount of drinking water is added under stirring and stirred; after filtering, a solid is washed with the drinking water; and the solid is dried to obtain the 6,11-dihydro-11-oxo dibenzo [b, e] oxepin-2-acetic acid.

A process for the preparation of olopatadine hydrochloride

The invention relates to a method for preparing a compound, namely, olopatadine hydrochloride. The method specifically comprises the following steps: by taking 2-chloromethyl methyl benzoate and methyl 4-hydroxyphenylacetate as initial raw materials, performing etherification, hydrolysis and cyclization, further performing wittig reaction, and salifying, thereby synthesizing olopatadine hydrochloride. The process is gentle in process reaction condition, acetic anhydride is adopted to replace polyphosphoric acid, a hydrochloric acid organic solvent is adopted to effectively split Z/E type olopatadine so as to obtain olopatadine hydrochloride, conversion of Z/E configuration is effectively achieved after an E configuration byproduct is treated by using concentrated hydrochloric acid, the yield of olopatadine hydrochloride is increased, the product purity is good, and the feasibility of industrialization production is greatly improved.

Preparation technique of olopatadine hydrochloride

The invention relates to a preparation technique of olopatadine hydrochloride. The technique comprises the following steps: carrying out reaction on 2-(chloromethyl)benzoic acid and p-hydroxyphenylacetic acid to generate Isoxepac, and carrying out reaction on the Isoxepac and a Wittig-horner agent generated by N,N-dimethylaminochloropropane hydrochloride to generate hydrochloride, thereby obtaining the olopatadine hydrochloride. The method uses the low-cost raw materials for reaction, avoids using toxic agents in the reaction process, has the advantages of short process route, mild reaction conditions, controllable operation, short production cycle, low energy consumption, high yield, high purity and safe technique, and is suitable for industrial production.

IMPROVED PROCESS FOR LL-[(Z)-3-(DIMETHYLAMINO)PROPYIIDENEL-6-LL- DIHYDRODIBENZ[B,EL OXEPIN-2-ACETICACID

The present invention relates to an improved process for the preparation of 11- [(Z)-3-(dimethylamino)propylidene]-6, 11 -dihydrodibenzo[b,e]oxepin-2-aceticacid compound of formula- 1 and its pharmaceutically acceptable salts.

TERTIARY ALKYL ESTER OF OXODIBENZOXEPIN ACETIC ACID

A tertiary alkyl ester represented by Formula (2): wherein R1 and R2 each independently represent a C1-4 alkyl group, and a method for producing the same.

Polymorphic forms of olopatadine hydrochloride and methods for producing olopatadine and salts thereof

The present invention provides a novel polymorphic form of olopatadine hydrochloride ([(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride), a selective histamine H1-receptor antagonist that is used for the treatment of ocular symptoms of seasonal allergic conjunctivitis. The present invention also provides novel methods for producing olopatadine on a large scale, and in a manner that is cost effective, provides a low level of impurities and eliminates the need to use the costly and dangerous base, butyllithium, which is used in prior art reactions for making olopatadine. The present invention further provides novel processes for carrying out a large scale production of 3-dimethylaminopropyltriphenylphosphonium bromide and its corresponding hydrobromide salt, which are employed in the production of olopatadine, and pharmaceutically acceptable salts of olopatadine.

Dibenzoxepinone hydroxylamines and hydroxamic acids: Dual inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity

Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5- lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N- methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.

6,11-Dihydro-11-oxo-dibenz[b,e]oxepin derivatives

This invention relates to 6,11-dihydro-11-oxo-dibenz[b, e]oxepin derivatives of the formula STR1 where Y is hydrogen, alkyl, alkoxy, halogen and trifluoromethyl, n is 0, 1, 2 or 3; R9 is hydrogen and alkyl; R is STR2 where Hal is a halogen; STR3 where R10 is hydrogen, alkyl and benzyl of the formula STR4 where Z is hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, nitro, and amino; where n is 0, 1, 2 or 3; p is 1 or 2; q is 0, 1 or 2; R1 to R7 are the same or different and are hydrogen and alkyl; and R8 is hydrogen, alkyl and phenyl; and R9 is hydrogen and alkyl, and where appropriate pharmaceutically acceptable acid or base addition salts thereof.

6,11-dihydrodibenz[b,e]oxepin-acetic acids and derivatives

6,11-Dihydrodibenz[b,e]oxepin-acetic acids and derivatives having the general formula STR1 are prepared by multi-step sequences. X is C=O, CHCl, CHBr, CH2 or CHOR4 ; Y is alkyl or alkoxy of 1 to 4 carbon atoms, halogen or trifluoromethyl; n is 0, 1, 2 or 3; Z is COOR5, CH2 OR5, CONR25 or CONHOR5 ; and R1 -R5 are hydrogen or alkyl of 1 to 4 carbon atoms. These compounds and the physiologically tolerable salts thereof are useful as antiinflammatory and analgesic agents.