85650-56-2

Basic information

• Product Name: Asenapine Maleate
• Synonyms: trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate;Org 5222;Asenapine maleate;Einecs 288-064-8;Unii-cu9463U2E2;Org 5222 Maleate;Org5222 Maleate;Org-5222 Maleate
• CAS NO: 85650-56-2
• Molecular Formula: C21H20ClNO5
• Molecular Weight: 401.8402
• EINECS: 288-064-8
• Product Categories: Saphris;Inhibitors
• Mol File: 85650-56-2.mol

Chemical Properties

• Melting Point: 141-145°
• Boiling Point: 357.9 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: white to off-white/
• Vapor Pressure: 2.65E-05mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: H2O: ≥10mg/mL
• PKA: pK1 <3, pK2 7.52, pK3 8.51(at 25℃)
• CAS DataBase Reference: Asenapine Maleate(CAS DataBase Reference)
• NIST Chemistry Reference: Asenapine Maleate(85650-56-2)
• EPA Substance Registry System: Asenapine Maleate(85650-56-2)

Safety Data

• Hazard Codes: Xn,N,T,F
• Statements: 22-36/37/38-50/53-39/23/24/25-23/24/25-11
• Safety Statements: 26-60-61-45-36/37-16
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 3
• Hazardous Substances Data: 85650-56-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Asenapine Maleate is used as an antipsychotic medication for the treatment of acute schizophrenia and bipolar mania. Its application is based on its antagonist activity at D2 and 5-HT2A receptors, which helps in managing the symptoms of these mental health conditions.
Used in Research and Development:
Asenapine Maleate is used as a research compound for studying the Fos expression in forebrain structures of rat models, providing insights into its mechanism of action and potential applications in neuroscience.
Used in Clinical Toxicology and Forensic Testing:
Asenapine Maleate is used as a solution standard in liquid chromatography-mass spectrometry (LC/MS) or gas chromatography-mass spectrometry (GC/MS) applications, aiding in the identification and quantification of the drug in biological samples for clinical and forensic purposes.

Originator

Organon (US)

Biochem/physiol Actions

Asenapine maleate is a 5-HT receptor antagonist (5-HT1A,1B, 5-HT2A, 2B, 2C, 5-HT5A, 5-HT6 and 5-HT7), a D2 antagonist, and an antipsychotic.

Side effects

The most common adverse effects associated with asenapine treatment include insomnia, somnolence, nausea, anxiety, agitation, headache, vomiting, constipation, and psychosis. In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Asenapine is not approved for the treatment of patients with dementia-related psychosis.

Synthesis

The chemical synthesis of asenapine can be achieved by several different methods. A concise synthesis of asenapine begins with the Horner-Emmons condensation of diethyl (5-chloro-2-fluoro)benzyl phosphonate with salicylaldehyde to produce the corresponding stilbene derivative, which undergoes a 1,3-dipolar cycloaddition reaction with trimethylamine-N-oxide in the presence of lithium diisopropylamide to furnish a trans-3,4-diarylpyrrolidine intermediate. Then, a base-catalyzed intramolecular cyclization involving the nucleophilic displacement of the fluoro group by the phenolic hydroxyl group affords asenapine, which is finally treated with maleic acid in ethanol to yield the corresponding maleate salt.

InChI:InChI=1/C17H16ClNO.C4H4O4/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17)15(14)10-19;5-3(6)1-2-4(7)8/h2-8,14-15H,9-10H2,1H3;1-2H,(H,5,6)(H,7,8)/b;2-1-/t14-,15-;/m1./s1

Upstream product

• 65576-45-6 asenapine 
• 110-16-7 maleic acid 
• 2444-36-2 2'-chloro-benzeneacetic acid 
• 106-48-9 4-chloro-phenol 
• 25563-04-6 o-(p-chlorophenoxy)phenylacetic acid 
• 934996-79-9 5-chloro-2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7]oxepino [4,5-c]pyrrole-1-one 
• 912356-09-3 trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one 
• 912356-09-3 cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one 
• 1035404-17-1 ethyl N-[2-[2-(4-chlorophenoxy)phenyl]acetyl]-N-methylglycinate 
• 129385-59-7 trans-(3a,12b)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-C]pyrrol-1-one 
• 70958-20-2 5-chloro-2-phenoxyphenylacetic acid 

Downstream Products

• 65576-45-6 asenapine 
• 129385-60-0 5-Chloro-2-methyl-2H-8-oxa-2-aza-dibenzo[e,h]azulene 
• 129385-61-1 5-Chloro-2-methyl-8-oxa-2-aza-dibenzo[e,h]azulene-1,3-dione 
• 129385-59-7 trans-(3a,12b)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-C]pyrrol-1-one 
• 128915-56-0 trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenz<2,3:6,7>oxepino<4,5-c>pyrrole 
• 128915-55-9 asenapine N-oxide 
• 128923-28-4 5-Chloro-1,3,3a,12b-tetrahydro-8-oxa-2-aza-dibenzo[e,h]azulene-2-carboxylic acid (2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl ester 

Relevant articles and documents

A PROCESS FOR THE PREPARATION OF ASENAPINE AND NOVEL SALTS THEREOF

A process for preparation of asenapine of formula (1) or its acid addition salts; The said process comprises preparation of trans racemate of asenapine by reacting trans- 1 1-chloro-2,3,3a, 12b-tetrahydro-2-methyl-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-l-one with mixture of aluminium chloride and lithium aluminium hydride in solvent followed by converting it into acid addition salt of asenapine followed by hydrolyzing the acid addition salt into trans racemate asenapine base and converting the asenapine base into acid addition salt. Asenapine sulphate of formula (Via) and asenapine maleate of formula (IVb) are also disclosed. The co-precipitate of acid addition salt of asenapine with a pharmaceutically acceptable excipient of formula (V); is also disclosed.

COMPRESSED ORAL DOSAGE FORM FOR ASENAPINE MALEATE

The present invention relates to a compressed pharmaceutical dosage form intended for sublingual or buccal administration and capable of being rapidly disintegrated, the compressed pharmaceutical dosage form containing asenapine maleate in a microcrystalline monoclinic form. It further relates to a method of preparing the same and to a container comprising the dosage form.

CRYSTAL FORM OF ASENAPINE MALEATE

The present invention relates to a form of Asenapine Maleate with XRPD peaks at about 5.5,12.5,19.0 and 25.3 and to methods for the preparation thereof. Furthermore the invention relates to a reproducible process for the preparation of pure monoclinic form of Asenapine Maleate in crystalline form and to pharmaceutical compositions comprising the pure monoclinic form of asenapine maleate.

PROCESS FOR THE PREPARATION OF (3ARS,12BRS)-5-CHLORO-2-METHYL-2,3,3A12B-TETRAHYDRO-1HDIBENZO[2,3:6,7] OXEPINO [4,5-C]PYRROLE MALEATE AND IT'S PHARMACEUTICAL COMPOSITION THEREOF

The present invention relates to an improved process for the preparation (3aRS,12bRS)-5-Chloro-2-menthyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino [4,5-c]pyrrole maleate represented by the compound of formula-1a and its pharmaceutical composition.(F)

PROCESS FOR THE PREPARATION OF TETRACYCLIC DERIVATIVES AND INTERMEDIATE PRODUCTS USED IN THE PROCESS

A process for preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, is disclosed. The process involves subjecting a compound of formula II to Ullmann-type conditions to effect an intra-molecular ring closure reaction to form the compound of formula I. The different substituents are as described in the specification. Further, the process can provide an alternate route for the synthesis of asenapine from starting materials that can be readily available.

NOVEL PROCESS FOR THE PREPARATION OF ASENAPINE

The present invention is directed to novel compounds of formula (I) as well as to the process for their preparation. Novel compounds of formula (I) can be converted into asenapine through an efficient process. The invention also relates to novel intermediates used in this process and their use in the preparation of compounds of formula (I).

Processes for the preparation of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole

This invention provides improved processes for the preparation of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole, asenapine. These processes allow the preparation of asenapine at industrial scale in good yields and high stereoselectivity.

NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID

The present invention relates to two new crystal forms of the salt of trans-5-chloro-2- methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrolewith maleic acid, processes for preparing thereof and compositions comprising thereof. These new crystal forms of the salt of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenzo[2,3:6,7]oxepino[4,5-c]pyrrolewith maleic acid are stable under micronization and show an improved water solubility when compared to other asenapine maleate crystalline forms described in the prior art, such as the orthorhombic form (form L) and the monoclinic form (form H).

CRYSTALLINE SALTS OF ASENAPINE

Disclosed is asenapine phosphate of formula (I) and its enantiomer (I) which can be used to prepare asenapine maleate. Further disclosed is a monoclinic crystalline form of asenapine maleate.

ASENAPINE MALEATE

Aspects of the present application relate to a microcrystalline monoclinic form of asenapine maleate represented by structural Formula (I); processes for its preparation; and pharmaceutically acceptable dosage forms thereof.