78281-72-8

Basic information

• Product Name: Nepafenac
• Synonyms: AHR 9434;AL 6515;Nevanac;Nepafenac - WS;Nepafenac;2-(2-amino-3-benzoyl-phenyl)acetamide;2-Amino-3-benzoylbenzeneacetamide;nepafenac,Nevance
• CAS NO: 78281-72-8
• Molecular Formula: C₁₅H₁₄N₂O₂
• Molecular Weight: 254.28
• Product Categories: Pharmaceuticals;Pharmaceutical intermediate;Nevanac;Other APIs;Amines;Aromatics;Intermediates & Fine Chemicals;Isotope Labelled Compounds
• Mol File: 78281-72-8.mol

Chemical Properties

• Melting Point: 177-181°C
• Boiling Point: 562.5 °C at 760 mmHg
• Flash Point: 294 °C
• Appearance: faint yellow to dark yellow/
• Density: 1.249 g/cm³
• Vapor Pressure: 1.11E-12mmHg at 25°C
• Refractive Index: 1.641
• Storage Temp.: Refrigerator
• Solubility: DMSO: ≥5mg/mL
• Water Solubility: 0.014 mg/mL in water
• Merck: 14,6469
• CAS DataBase Reference: Nepafenac(CAS DataBase Reference)
• NIST Chemistry Reference: Nepafenac(78281-72-8)
• EPA Substance Registry System: Nepafenac(78281-72-8)

Safety Data

• Hazard Codes: N
• Statements: 50/53
• Safety Statements: 60-61
• RIDADR: UN 3077 9 / PGIII
• WGK Germany: 3
• RTECS: CY1480710
• Hazardous Substances Data: 78281-72-8(Hazardous Substances Data)

Usage

Uses

Used in Ophthalmology:
Nepafenac is used as an eye drop for reducing pain and inflammation in the eyes, particularly after cataract surgery. It is effective in treating ocular pain and inflammation due to its enhanced permeability and rapid bioactivation in the ocular tissue, which translates into superior anti-inflammatory efficacy at the target sites.
Used in Pharmaceutical Industry:
Nepafenac is used as a prodrug, a cyclooxygenase 2 inhibitor, a cyclooxygenase 1 inhibitor, a non-steroidal anti-inflammatory drug, and a non-narcotic analgesic in the pharmaceutical industry. Its role as a prodrug allows for improved delivery and bioavailability, making it a valuable asset in the development of new medications for various applications.

Originator

AH Robins (US)

Biochem/physiol Actions

Nepafenac is a NSAID (nonsteroidal anti inflammatory drug) that is routinely used in opthamology to control pain following cataract surgery.

Clinical Use

Nepafenac is a novel ophthalmic non-steroidal anti-inflammatory drug (NSAID), for the treatment of eye pain and inflammation caused by cataract surgery, compared with traditional NSAIDs, chemical structure of Nepafenac is conducive to make it rapidly penetrate the cornea and distribute to its target site, which is helpful to reduce the accumulation of the drug in the corneal surface and to reduce the incidence of complications of the eye surface, it has many advantages such as infiltration, targeting strong, little toxic side effects and so on. August 19, 2005 ,the US Food and Drug Administration (FDA) approved nepafenac ophthalmic suspension for the treatment of cataract surgery-related pain and inflammation, it is the first ophthalmic NSAID prodrug formulation approved for marketing. Nepafenac after ocular administration, can rapidly pass through the cornea , and under the action of eye tissue hydrolytic enzymes,it can become into ammonia diclofenac (a kind of NSAID); and ammonia diclofenac by inhibiting prostaglandin H synthase ( cyclooxygenase), can block prostaglandin synthesis to play its role as an anti-inflammatory analgesic. As is known, prostaglandin is one of the media causing ocular inflammation it can lead to blood-aqueous barrier crash, vasodilatation, increased vascular permeability and leukocyte chemotaxis, etc. In addition, prostaglandins can also control contraction of the iris sphincter through non-cholinergic mechanism which can trigger the miosis reaction during eye surgery and after surgery. After ocular administration of NSAIDs, it can inhibit prostaglandins synthesis in the iris, ciliary body and conjunctiva, so people can prevent eye inflammation, and reduce the associated pain.The above information is edited by the lookchem of Tian Ye.

Synthesis

The synthesis of nepafenac started with commercially available 2-amino-benzophenone (89). Compound 89 was reacted with t-butyl hypochrite at – 65°C in DCM to give a mono-N-chloroaniline (90) which was subsequently treated with methylthioacetamide in THF at –65°C in the same pot to give an aza-sulfonium salt 91 as a solid. Compound 91 was slurred in DCM and triethylamine was added to give sulfer ylide 92 intermediate which under-went a Sommelet-Hauser type rearrangement to give compound 93 after re-aromatization of the intermediate cyclohexadienone imine. Compound 93 was finally reduced with Raney nickel to give nepafenac (XIV) in 73% yield as yellow needles.

Veterinary Drugs and Treatments

Nepafenac is a nonsteroidal anti-inflammatory and analgesic prodrug. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a nonsteroidal anti-inflammatory drug. Amfenac is thought to inhibit the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production. Nepafenac is indicated for the treatment of pain and inflammation associated with cataract surgery.

Clinical claims and research

In preclinical models, a single topical ocular dose of nepefenac (0.1%) inhibits prostaglandin synthesis in the iris/ciliary body by 85–95% for more than 6 h, and in the retina/choroid by 55% for up to at least 4 h. By comparison, diclofenac (0.1%) shows 100% inhibition of prostaglandin synthesis in the iris/ciliary body for only 20 min, with 75% recovery observed within 6 h. Diclofenac’s inhibition of prostaglandin synthesis in the retina/choroids is minimal. The recommended dose of nepafenac ophthalmic suspension is one drop in the affected eye(s) three times daily beginning one day prior to cataract surgery, continued on the day of surgery and through the first two weeks of the postoperative period. Although the drug is applied topically, low but quantifiable plasma concentrations of nepefenac and amfenac are observed in majority of the subjects following t.i.d. dosing of nepefenac ophthalmic solution. The clinical significance of the systemic absorption of nepefenac after ophthalmic administration is unknown. The efficacy of nepafenac was demonstrated in two placebo-controlled clinical studies involving over 680 patients. Nepafenac suspension was dosed three times daily, beginning one day prior to cataract surgery, continuing on the day of surgery, and for 14 days postoperatively.

Mode of action

Nepafenac is a non-steroidal anti-inflammatory and analgesic prodrug. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a nonsteroidal anti-inflammatory drug. Amfenac inhibits the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.

references

[1] bucolo c1, marrazzo g, platania cb, romano gl, drago f, salomone s. effects of topical indomethacin, bromfenac and nepafenac on lipopolysaccharide-induced ocular inflammation. j pharm pharmacol. 2014 jul;66(7):954-60. [2] marshall jc1, caissie al, cruess sr, cools-lartigue j, burnier mn jr. the effects of a cyclooxygenase-2 (cox-2) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production. j carcinog. 2007 nov 27;6:17.

InChI:InChI=1/C15H14N2O2/c16-13(18)9-11-7-4-8-12(14(11)17)15(19)10-5-2-1-3-6-10/h1-8H,9,17H2,(H2,16,18)

Synthetic route

2-amino-3-benzoyl-α-(methylthio)benzeneacetamide (78281-61-5) → nepafenac (78281-72-8)

Conditions	Yield
nickel In tetrahydrofuran; water at 20℃; for 0.166667h; Product distribution / selectivity;	86%
With Raney nickel In tetrahydrofuran at -5 - 5℃; for 0.5h;	78.8%
With nickel In tetrahydrofuran for 0.25h;	73%

(2-aminophenyl)(phenyl)methanone (2835-77-0) → nepafenac (78281-72-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) tert-butyl hypochlorite, 2.) triethylamine / 1.) CH2Cl2, THF, -60 deg C, 1 h, 2.) CH2Cl2, 5 min 2: 73 percent / Raney nickel / tetrahydrofuran / 0.25 h View Scheme

2-amino-3-benzoyl-α-(1-propylthio)-benzeneacetamide (173262-94-7) → nepafenac (78281-72-8)

nepafenac (78281-72-8) → 7-benzoyl-1,3-dihydroindol-2-one (51135-38-7)

Conditions	Yield
With hydrogenchloride In ethanol; water at 30℃; for 3h; Temperature; Reagent/catalyst; Solvent;	92.1%
With hydrogenchloride In ethanol Heating;

nepafenac (78281-72-8) → 2-{2-amino-3-[hydroxy(phenyl)methyl]phenyl}acetamide (1246956-18-2)

Conditions	Yield
With sodium tetrahydroborate; ethanol for 2h; Reflux;	75%

formaldehyd (50-00-0) + nepafenac (78281-72-8) → 3-Benzoyl-2-(N,N-dimethylamino)-phenylacetamide

Conditions	Yield
With sodium cyanoborohydride In acetic acid; acetonitrile

Upstream product

• 78281-61-5 2-amino-3-benzoyl-α-(methylthio)benzeneacetamide 
• 2835-77-0 (2-aminophenyl)(phenyl)methanone 
• 173262-94-7 2-amino-3-benzoyl-α-(1-propylthio)-benzeneacetamide 

Downstream Products

• 51135-38-7 7-benzoyl-1,3-dihydroindol-2-one 
• 1246956-18-2 2-{2-amino-3-[hydroxy(phenyl)methyl]phenyl}acetamide 

Relevant articles and documents

Preparation method of nepafenac

The invention discloses a preparation method of nepafenac. The method comprises the following steps: 1, synthesizing 2-(methylthio) acetamide; 2, synthesizing alpha-methylthio (2-amino-3-benzoyl) phenylacetamide; 3, synthesizing the nepafenac. Compared with the prior art, the preparation method of the nepafenac has the advantages that raw materials are easy to buy, excessive chlorinated impurities of a side reaction are easily purified, the less energy is consumed by increasing reaction temperature, and the final product does not need to be subjected to octadecyl silane (ODS) reverse phase rapid chromatography.

PROCESS FOR THE PREPARATION OF NEPAFENAC

Described herein are processes for the preparation of nepafenac and related intermediates, particularly wherein 2-aminobenzophenone is treated with a 2-(alkylthio)acetamide in the presence of sulfuryl chloride to afford a 2-(2-amino-3-benzoylphenyl)-2-(alkylthio)acetamide, which upon reduction affords nepafenac. Described herein are also processes for the purification of nepafenac, particularly for the removal of structurally similar impurities.

Development and a practical synthesis of nepafenac intermediate via modified gassman reaction

Modification of nepafenac intermediate synthesis (5A) via Gassman specific ortho-substitution is reported. According to the process, 2-aminobenzophenone (1A) and 2-(methylthio)acetamide (2) were reacted in the convenient temperature conditions, in the presence of N-chlorophthalimide (3) or 1,3-dichloro-5,5- dimethylhydantoin (4), to activate the formation of azasulfonium salt and rearrangement thereof to pure 2-amino-3-benzoyl-α-(methylthio) phenylacetamide (5A). The procedure appears to be suitable for a reaction carried out in a large scale.

Process For Preparing A Benzoylbenzeneacetamide Derivative

Disclosed is a process for preparing anti-inflammatory compound nepafenac comprising preparing a compound of formula (V) wherein a N-halosuccinimide is used as the halogenating agent, followed by desulfurization using Raney Nickel. Also disclosed is a polymorphic form B of 2-amino-3-benzoyl-α-(methylthio)-benzeneacetamide (i.e., a compound of formula (V) wherein R is methyl

FLUOROQUINOLONE DERIVATIVES FOR OPHTHALMIC APPLICATIONS

The present invention relates to fluoroquinolone derivatives having enhanced ocular penetration characteristics and/or antimicrobial activity, and to compositions comprising such derivatives. The derivatives and compositions are particularly well suited for treating ophthalmic bacterial infections. The present invention more particularly relates to the discovery that a 2-methyl substitution on a diazabicyclo group attached to a fluoroquinolone ring system produces improved permeability characteristics, and that a 5-amino substitution on a fluoroquinolone ring system results in improved anti-microbial activity.

Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders

Novel ester and amide derivatives of 3-benzoylphenylacetic acid are disclosed. The use of these novel derivatives and certain known derivatives in topically administrable compositions for the treatment of ophthalmic inflammatory disorders is also disclosed.

Antiinflammatory Agents. 4. Syntheses and Biological Evaluation of Potential Prodrugs of 2-Amino-3-benzoylbenzeneacetic Acid and 2-Amino-3-(4-chlorobenzoyl)benzeneacetic Acid

A series of potential prodrugs of 2-amino-3-benzoylbenzeneacetic acid (amfenac) and 2-amino-3-(4-chlorobenzoyl)benzeneacetic acid were synthesized and evaluated for their cyclooxygenase inhibiting properties, antiinflammatory potency, and gastrointestinal irritation liability.One compound, 2-amino-3-(4-chlorobenzoyl)benzeneacetamide, possessed a therapeutic index 1 order of magnitude greater than that of indomethacin.

Method of producing an inhibitory effect on blood platelet aggregation

Novel 2-amino-3-benzoyl-phenylacetamides are provided having the formula: STR1 wherein R represents hydrogen or lower alkyl, R1 and R2 represent hydrogen, lower alkyl, cycloalkyl, phenyl and phenyl substituted by lower alkyl, lower alkoxy, halogen, nitro and trifluoromethyl, and R1 and R2 when taken together with the adjacent nitrogen may form a heterocyclic residue; X represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; Y represents hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylthio, lower alkyloxythio or lower alkyldioxythio; Am is primary amino (--NH2), methylamino or dimethylamino, and n is 1 to 3 inclusive. The compounds exhibit anti-inflammatory, antipyretic, anti-blood platelet aggregation and analgetic pharmacological activities.