140462-76-6

Basic information

• Product Name: Olopatadine hydrochloride
• Synonyms: OLOPATADINE HCL;OLOPATADINE HYDROCHLORIDE;OLOPATDINEHYDROCHLORIDE;OLOPATADINE HYDROCHLORIDE AND THE INTERMEDIATES;(Z)-11-[3-(Dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride;OLAPATADINE HCL;Olopatadine Hydrochloride (150 mg);Olopatadin HCL
• CAS NO: 140462-76-6
• Molecular Formula: C₂₁H₂₃NO₃*ClH
• Molecular Weight: 373.87316
• EINECS: 1308068-626-2
• Product Categories: Pharmaceutical material and intermeidates;APIs;Olopatadine;Amines;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Opatanol, Pataday, Patanase, Allelock;API
• Mol File: 140462-76-6.mol

Chemical Properties

• Melting Point: 242-245?C
• Boiling Point: 523 °C at 760 mmHg
• Flash Point: 270.1 °C
• Appearance: White Solid
• Density: ==
• Vapor Pressure: 9.65E-13mmHg at 25°C
• Storage Temp.: Refrigerator
• Solubility: H2O: ≥20mg/mL
• Merck: 14,6840
• CAS DataBase Reference: Olopatadine hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Olopatadine hydrochloride(140462-76-6)
• EPA Substance Registry System: Olopatadine hydrochloride(140462-76-6)

Safety Data

• Hazard Codes: T,N
• Statements: 25-50
• Safety Statements: 45-61
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 3
• RTECS: HQ4135060
• Hazardous Substances Data: 140462-76-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Olopatadine hydrochloride is used as an antiallergic and antihistaminic agent for the treatment of allergic rhinitis, conjunctivitis, and chronic urticaria. It is particularly effective in providing temporary relief from itching caused by allergic conjunctivitis and helps in suppressing motion sickness or for sedation due to its central properties.
Used in Ophthalmology:
Olopatadine hydrochloride is used as a mast cell stabilizer and histamine H1 antagonist in the treatment of ocular allergies and conditions involving type 1 immediate hypersensitivity reactions. Its selective action on the H1 receptor and minimal impact on cognitive functions make it a valuable asset in the symptomatic treatment of various immediate hypersensitivity reactions in the eye.

Originator

Kyowa Hakko (Japan)

Preparation

Olopatadine hydrochloride can be prepared in five steps from the sodium salt of phydroxyphenylacetic acid methyl ester with phthalide.

Pharmacokinetics

Olopatadine hydrochloride was launched in the US for use in allergic conjunctivitis. It has a fast onset of action with a long duration of action (due to slow dissociation kinetics) that combines the ability to prevent human conjunctival mast cell mediator release with selective H1-receptor antangonistic activity (greater H3:H1 selectivity than H2:H1 selectivity). In addition, Olopatadine hydrochloride had no inhibition of 5-lipoxygenase, PAF acetyltransferase and thromboxane synthase while interfering with phospholipase A2. It has a presynaptic inhibition of tachykinin release and inhibits bronchial sensory nerves through activation of small conductance calcium activated potassium channels. It was more potent than ketotifen and terfenadine and was effective at inhibition of PAF, LTC4 induced conjunctivitis and TXB2 production. It does not accumulate in the CNS, has a low affinity for H1-receptors in the brain, and significantly inhibits allergen induce sneezing. Olopatadine hydrochloride was more effective in conjuctival than in corneal or the trabecuiar meshwork cells.

Veterinary Drugs and Treatments

Olopatadine HCl is a selective H1 receptor antagonist and inhibitor of histamine release from mast cells. It is marketed for topical use to alleviate symptoms of allergic conjunctivitis in humans and is thought to be safe for use in children three years of age and older. Olopatadine, upon topical application in humans, was shown to have very limited systemic absorption. It was detectable in the milk of nursing rats, after topical application, and like most medications should be avoided in pregnant or nursing animals.

InChI:InChI=1/C21H23NO3.ClH/c1-22(2)11-5-8-18-17-7-4-3-6-16(17)14-25-20-10-9-15(12-19(18)20)13-21(23)24;/h3-4,6-10,12H,5,11,13-14H2,1-2H3,(H,23,24);1H/b18-8+;

Synthetic route

(11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)-acetic acid benzyl ester (60548-16-5) + anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (27710-82-3) → (E )-11-[ 3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride (949141-22-4) + olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Stage #1: anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide With sodium hydride In tetrahydrofuran for 3h; Wittig Reaction; Heating / reflux; Stage #2: (11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)-acetic acid benzyl ester In tetrahydrofuran at 0 - 30℃; for 3h; Stage #3: With hydrogenchloride; water In di-isopropyl ether pH=2;	A 0.5% B 99%

olopatadine (113806-05-6) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
With hydrogenchloride In water; acetone at 5 - 25℃; for 2 - 15h; Product distribution / selectivity;	95.6%
With hydrogenchloride In water; acetone at 0 - 25℃; for 16 - 22h; Product distribution / selectivity;	88.1%
With hydrogenchloride In water; acetone at 20 - 60℃; Product distribution / selectivity;	81.2%
With hydrogenchloride In water
With hydrogenchloride In tetrahydrofuran; water at 15 - 20℃; for 0.75 - 0.833333h; pH=0 - 1; Heating / reflux;

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%

(Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenzoxepin-2-acetic acid methyl ester (113806-01-2) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Stage #1: (Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenzoxepin-2-acetic acid methyl ester With water; sodium hydroxide In methanol for 2h; Reflux; Stage #2: With hydrogenchloride In water pH=2;	88.4%
Stage #1: (Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenzoxepin-2-acetic acid methyl ester With sodium hydroxide In methanol; water at 20℃; for 3h; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 0.0833333h;	66%

11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
With hydrogenchloride; acetic anhydride In toluene at 100℃; for 6h; Sealed tube;	79.5%

isoxepac (55453-87-7) + (3-dimethylaminopropyl)-triphenylphosphoniumbromide (18355-96-9) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Stage #1: (3-dimethylaminopropyl)-triphenylphosphoniumbromide With sodium hydride In tetrahydrofuran at 20 - 22℃; for 1h; Stage #2: isoxepac With methanol In tetrahydrofuran at 0℃; for 2h; Reflux;	60.6%

(Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid ethyl ester (113806-03-4) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
With hydrogenchloride; water In acetone for 10h; Product distribution / selectivity; Reflux;	50%

isoxepac (55453-87-7) + anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (27710-82-3) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Stage #1: anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide With sodium hydride In tetrahydrofuran; mineral oil at 65℃; Inert atmosphere; Stage #2: isoxepac In tetrahydrofuran; mineral oil at 20℃; for 15h; Wittig Reaction; Stage #3: With hydrogenchloride In tetrahydrofuran; water; mineral oil pH=2.27; Product distribution / selectivity;	n/a
Stage #1: anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide With n-butyllithium In tetrahydrofuran at 0 - 5℃; for 1h; Inert atmosphere; Stage #2: isoxepac In tetrahydrofuran at 0℃; Reflux; Stage #3: With hydrogenchloride; acetic acid In tetrahydrofuran; water at 25 - 30℃; for 0.25h; Product distribution / selectivity;

3-(N,N-dimethylamino)propylmagnesium chloride (19070-16-7) + isoxepac (55453-87-7) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Stage #1: 3-(N,N-dimethylamino)propylmagnesium chloride; isoxepac In tetrahydrofuran at 20℃; Grignard Reaction; Inert atmosphere; Stage #2: With ammonium chloride In tetrahydrofuran; water Stage #3: With hydrogenchloride In tetrahydrofuran; water at 20℃; for 17.75h; pH=~ 1; Reflux;	n/a

isoxepac (55453-87-7) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: thionyl chloride / dichloromethane / 5 h / Reflux 2.1: dichloromethane / 0 - 20 °C / pH 9.5 - 10 3.1: tetrahydrofuran / 1 h / 0 - 5 °C 3.2: 0 - 35 °C 3.3: 0 - 5 °C / pH 9 - 10 4.1: hydrogenchloride; water / 90 - 95 °C 4.2: 0.5 h / 10 - 15 °C / pH 6.8 - 7.2 5.1: hydrogenchloride / chlorobenzene / 5 h / 80 - 85 °C View Scheme
Multi-step reaction with 2 steps 1: toluene; tetrahydrofuran / 2.08 h / 5 - 18 °C 2: hydrogenchloride; acetic anhydride / toluene / 6 h / 100 °C / Sealed tube View Scheme

olopatadine (113805-63-3) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
With hydrogenchloride In chlorobenzene at 80 - 85℃; for 5h;
With hydrogenchloride at 90℃; for 5h;

C23H28N2O2 → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; water / 90 - 95 °C 1.2: 0.5 h / 10 - 15 °C / pH 6.8 - 7.2 2.1: hydrogenchloride / chlorobenzene / 5 h / 80 - 85 °C View Scheme

2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetyl chloride (87486-90-6) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: dichloromethane / 0 - 20 °C / pH 9.5 - 10 2.1: tetrahydrofuran / 1 h / 0 - 5 °C 2.2: 0 - 35 °C 2.3: 0 - 5 °C / pH 9 - 10 3.1: hydrogenchloride; water / 90 - 95 °C 3.2: 0.5 h / 10 - 15 °C / pH 6.8 - 7.2 4.1: hydrogenchloride / chlorobenzene / 5 h / 80 - 85 °C View Scheme

N, N-dimethyl-2-(11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-yl)acetamide → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 0 - 5 °C 1.2: 0 - 35 °C 1.3: 0 - 5 °C / pH 9 - 10 2.1: hydrogenchloride; water / 90 - 95 °C 2.2: 0.5 h / 10 - 15 °C / pH 6.8 - 7.2 3.1: hydrogenchloride / chlorobenzene / 5 h / 80 - 85 °C View Scheme

4-hydroxyphenylacetate (156-38-7) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 3 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 3.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 3.2: 0 °C / Reflux 3.3: 0.25 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 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 3.1: iodine; magnesium; ethylene dibromide / tetrahydrofuran / 1 h / Inert atmosphere; Reflux 3.2: 5 - 30 °C 3.3: 25 - 30 °C View Scheme

isoxepac (55453-87-7) + 3-(Dimethylamino)propyl chloride (109-54-6) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Stage #1: 3-(Dimethylamino)propyl chloride With iodine; magnesium; ethylene dibromide In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: isoxepac In tetrahydrofuran at 5 - 30℃; Stage #3: With hydrogenchloride; acetic acid In tetrahydrofuran; water at 25 - 30℃; Product distribution / selectivity;

2-benzofuran-1(3H)-one (87-41-2) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 3 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 3.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 3.2: 0 °C / Reflux 3.3: 0.25 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 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 3.1: iodine; magnesium; ethylene dibromide / tetrahydrofuran / 1 h / Inert atmosphere; Reflux 3.2: 5 - 30 °C 3.3: 25 - 30 °C View Scheme

4-(2-carboxybenzyloxy) phenyl acetic acid (55453-89-9) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetic acid / 2.5 h / 70 - 75 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 2.2: 0 °C / Reflux 2.3: 0.25 h / 25 - 30 °C View Scheme

11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride (203188-29-8) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Stage #1: 11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride With hydrogenchloride In water at 25 - 95℃; Stage #2: With acetic acid In water at 25 - 30℃; Purification / work up;

3-(N,N-dimethylamino)propylmagnesium chloride (19070-16-7) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene; tetrahydrofuran / 2.08 h / 5 - 18 °C 2: hydrogenchloride; acetic anhydride / toluene / 6 h / 100 °C / Sealed tube View Scheme

C15H18O5 (1354633-17-2) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: hydrogenchloride / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride; water / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride; water / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme

C15H16O5 (1354633-33-2) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme
Multi-step reaction with 6 steps 1.1: Alkaline conditions; Enzymatic reaction 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme
Multi-step reaction with 6 steps 1.1: Alkaline conditions; Enzymatic reaction 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme

C13H14O4 (1354633-20-7) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide 2.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 3.1: pyridine / 5 - 20 °C 4.1: methanol; water / 3 h / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux 5.2: pH 2 View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide 2.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 3.1: pyridine / 5 - 20 °C 4.1: methanol; water / 3 h / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux 5.2: pH 2 View Scheme

methyl 2-{4-[(2-bromobenzyl)oxy]-3-(4-hydroxybut-1-yn-1-yl)phenyl}acetate (916243-38-4) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 2.1: pyridine / 5 - 20 °C 3.1: methanol; water / 3 h / Reflux 4.1: water; sodium hydroxide / methanol / 2 h / Reflux 4.2: pH 2 View Scheme
Multi-step reaction with 4 steps 1.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 2.1: pyridine / 5 - 20 °C 3.1: methanol; water / 3 h / Reflux 4.1: water; sodium hydroxide / methanol / 2 h / Reflux 4.2: pH 2 View Scheme

methyl 2-{4-[(2-bromobenzyl)oxy]phenyl}acetate (833485-11-3) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: iodine; silver sulfate / methanol / 2 h / 18 °C 2.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme
Multi-step reaction with 6 steps 1.1: iodine; silver sulfate / methanol / 2 h / 18 °C 2.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2 View Scheme

methyl 2-{4-[(2-bromobenzyl)oxy]-3-iodophenyl}acetate (916243-37-3) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 2.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 3.1: pyridine / 5 - 20 °C 4.1: methanol; water / 3 h / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux 5.2: pH 2 View Scheme
Multi-step reaction with 5 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 2.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 3.1: pyridine / 5 - 20 °C 4.1: methanol; water / 3 h / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux 5.2: pH 2 View Scheme

(Z)-methyl 2-[11-(3-hydroxypropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-yl]acetate (916243-39-5) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: pyridine / 5 - 20 °C 2.1: methanol; water / 3 h / Reflux 3.1: water; sodium hydroxide / methanol / 2 h / Reflux 3.2: pH 2 View Scheme

methyl 2-{11-[(Z)-3-(methanesulfonyloxy)propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetate → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: methanol; water / 3 h / Reflux 2.1: water; sodium hydroxide / methanol / 2 h / Reflux 2.2: pH 2 View Scheme

Methyl 4-hydroxyphenylacetate (14199-15-6) → olopatadine hydrochloride (140462-76-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 25 °C 2.1: iodine; silver sulfate / methanol / 2 h / 18 °C 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 4.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2 View Scheme
Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 25 °C 2.1: iodine; silver sulfate / methanol / 2 h / 18 °C 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 4.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2 View Scheme
Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: hydrogenchloride / methanol 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2 View Scheme

diethyl-(2-[4]piperidyl-ethyl)-amine (64168-10-1) + olopatadine hydrochloride (140462-76-6) → 1-[4-(2-diethylamino-ethyl)-piperidin-1-yl]-2-{11-[3-dimethylamino-prop-(Z)-ylidene]-6, 11-dihydro-dibenz[b,e]oxepin-2-yl}-ethanone (872040-96-5)

Conditions	Yield
Stage #1: diethyl-(2-[4]piperidyl-ethyl)-amine; olopatadine hydrochloride With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 23℃; for 16h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water	99%

methanol (67-56-1) + olopatadine hydrochloride (140462-76-6) → (Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenzoxepin-2-acetic acid methyl ester (113806-01-2)

Conditions	Yield
Stage #1: methanol; olopatadine hydrochloride With acetyl chloride In methanol at 23℃; for 2h; Stage #2: With sodium hydrogencarbonate In methanol; water	94%

Upstream product

• 113806-05-6 olopatadine 
• 60548-16-5 (11-oxo-6,11-dihydro-dibenzo[b,e]oxepin-2-yl)-acetic acid benzyl ester 
• 27710-82-3 anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide 
• 113806-03-4 (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid ethyl ester 
• 55453-87-7 isoxepac 
• 113805-63-3 olopatadine 
• 87486-90-6 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetyl chloride 
• 19070-16-7 3-(N,N-dimethylamino)propylmagnesium chloride 
• 916243-39-5 (Z)-methyl 2-[11-(3-hydroxypropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-yl]acetate 
• 14199-15-6 Methyl 4-hydroxyphenylacetate 
• 34918-57-5 methyl 3-bromo-4-hydroxyphenylacetate 
• 100126-08-7 3-Brom-4-methoxymethyloxy-phenylessigsaeure-methylester 
• 113806-01-2 (Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenzoxepin-2-acetic acid methyl ester 
• 3433-80-5 1-Bromo-2-bromomethyl-benzene 

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.

A preparation method of olopatadine hydrochloride (by machine translation)

The invention discloses a method for preparation of olopatadine hydrochloride, comprises the following steps: preparation of olopatadine hydrochloride crude; preparation of olopatadine free alkali; of olopatadine hydrochloride. The invention key steps upgraded, has the following advantages: 1, thereby reducing the reaction steps, the loss is reduced, thereby improving the production efficiency; 2, reduces the generation of hydrogen gas, decreasing the potential safety hazard 3, reduces the processing difficulty at the same time guarantee quality and yield unchanged; 4, optimizing the reaction temperature, pick out the low-temperature harsh reaction, reducing the reliance on the equipment; 5, in addition to eliminating the original separate heterogeneous step; 6, high yield and quality. (by machine translation)

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.

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.

A PROCESS FOR THE PREPARATION OF OLOPATADINE AND SYLIL INTERMEDIATES THEREOF

The present invention refers to a new "one-pot" process for the preparation of olopatadine via intermediates of formula (III).

A PROCESS FOR THE SYNTHESIS OF OLOPATADINE

The present invention provides a process for the synthesis of olopatadine. Further, the invention discloses a process that results in improved yield of the desired Z isomer.

Stereoselective syntheses of the antihistaminic drug olopatadine and its E-isomer

Practical stereoselective synthetic routes to the antihistaminic drug olopatadine and its E-isomer have been developed, the key steps being a trans stereoselective Wittig olefination using a nonstabilized phosphorus ylide and a stereoselective Heck cyclization. The stereoselectivity of the Wittig reaction depends on both the phosphonium salt anion and the cation present in the base used to generate the ylide.

A new efficient synthetic route for the synthesis of the antiallergic drug, olopatadine hydrochloride, via stereospecific palladium-catalyzed reaction

A new practical and efficient synthetic route for the synthesis of olopatadine hydrochloride via the intramolecular stereospecific seven-membered ring cyclization from an alkyne intermediate using palladium catalyst and hydride source was established. Furthermore, the optimization of that key stereospecific reaction was examined by design of experiment (DoE), and the desired Z-isomer could be obtained with high yield.

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.

PROCESS FOR PRODUCING DIBENZOXEPIN COMPOUND

A process for producing (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid or an acid addition salt thereof, which comprises subjecting 11-hydroxy-11- (3-dimethylaminopropyl)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid or a salt thereof to a heat treatment in a solvent and a water removal treatment in a reaction system in the presence of an acid selected from a group consisting of hydrogen chloride, sulfuric acid, methanesulfonic acid and p-toluenesulfonic acid, enables the production of (Z)-11-(3-dimethylamino-oropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid or an acid addition salt thereof, which is useful as a medicinal agent, in a high yield and in an industrially advantageous manner.