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
• Article Data: 13

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

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

Downstream Products

• 60548-16-5 (11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)-acetic acid benzyl ester 
• 140462-76-6 olopatadine hydrochloride 
• 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.

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.