70958-20-2

Basic information

• Product Name: 5-Chloro-2-phenoxyphenylacetic acid
• Synonyms: 5-Chloro-2-phenoxyphenylacetic acid;2-(5-chloro-2-phenoxyphenyl)acetic acid;2-(5-chloro-2-phenoxyphenyl)acetic acid (en);Benzeneacetic acid, 5-chloro-2-phenoxy-;2-(5-Chloro-2-phenoxyphenyl)
• CAS NO: 70958-20-2
• Molecular Formula: C₁₄H₁₁ClO₃
• Molecular Weight: 262.69
• Mol File: 70958-20-2.mol
• Article Data: 4

Chemical Properties

• Melting Point: 123-125°C
• Boiling Point: 395.1 °C at 760 mmHg
• Flash Point: 192.7 °C
• Appearance: /
• Density: 1.317 g/cm³
• Vapor Pressure: 5.96E-07mmHg at 25°C
• Refractive Index: 1.605
• Storage Temp.: Sealed in dry,Room Temperature
• CAS DataBase Reference: 5-Chloro-2-phenoxyphenylacetic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 5-Chloro-2-phenoxyphenylacetic acid(70958-20-2)
• EPA Substance Registry System: 5-Chloro-2-phenoxyphenylacetic acid(70958-20-2)

Safety Data

• Hazard Codes: Xi
• HazardClass: IRRITANT
• Hazardous Substances Data: 70958-20-2(Hazardous Substances Data)

Usage

Synthesis Reference(s)

Journal of Medicinal Chemistry, 25, p. 855, 1982 DOI: 10.1021/jm00349a018

InChI:InChI=1/C14H11ClO3/c15-11-6-7-13(10(8-11)9-14(16)17)18-12-4-2-1-3-5-12/h1-8H,9H2,(H,16,17)

Synthetic route

5-chloro-2-phenoxyacetophenone (70958-18-8) → 5-chloro-2-phenoxyphenylacetic acid (70958-20-2)

Conditions	Yield
Stage #1: 5-chloro-2-phenoxyacetophenone With morpholine; sulfur at 110℃; for 12h; Stage #2: With hydrogenchloride; acetic acid In water for 8h; Reflux;	67.1%
With morpholine; hydrogenchloride; sulfur; acetic acid 1.) reflux, 12 h, 2.) reflux, 8 h; Yield given. Multistep reaction;
Multi-step reaction with 2 steps 1: sulfur / 24 h / Heating 2: KOH / methanol / 72 h / Heating View Scheme

4-[2-(5-chloro-2-phenoxyphenyl)-1-thioxoethyl]morpholine (70958-19-9) → 5-chloro-2-phenoxyphenylacetic acid (70958-20-2)

Conditions	Yield
With potassium hydroxide In methanol for 72h; Heating;

2,5-dichloroacetophenone (2476-37-1) → 5-chloro-2-phenoxyphenylacetic acid (70958-20-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 63 percent / K2CO3, Cu / 10 h / Heating 2: 1.) morpholine, sulfur, 2.) glacial acetic acid, conc. aq. HCl / 1.) reflux, 12 h, 2.) reflux, 8 h View Scheme
Multi-step reaction with 3 steps 1: phenol, copper / 24 h / 120 - 125 °C 2: sulfur / 24 h / Heating 3: KOH / methanol / 72 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate / copper / 10 h / 130 °C 2.1: morpholine; sulfur / 12 h / 110 °C 2.2: 8 h / Reflux View Scheme

phenol (108-95-2) + (+-)-1-<1-chloro-cyclohexyl>-cyclohexanone-(2) → 5-chloro-2-phenoxyphenylacetic acid (70958-20-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 63 percent / K2CO3, Cu / 10 h / Heating 2: 1.) morpholine, sulfur, 2.) glacial acetic acid, conc. aq. HCl / 1.) reflux, 12 h, 2.) reflux, 8 h View Scheme

sodium phenoxide (139-02-6) + 2-methoxy-m-phenylene disodium → 5-chloro-2-phenoxyphenylacetic acid (70958-20-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: phenol, copper / 24 h / 120 - 125 °C 2: sulfur / 24 h / Heating 3: KOH / methanol / 72 h / Heating View Scheme

phenol (108-95-2) → 5-chloro-2-phenoxyphenylacetic acid (70958-20-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / copper / 10 h / 130 °C 2.1: morpholine; sulfur / 12 h / 110 °C 2.2: 8 h / Reflux View Scheme

methanol (67-56-1) + 5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → (5-chloro-2-phenoxy-phenyl)-acetic acid methyl ester (1141493-78-8)

Conditions	Yield
With sulfuric acid at 50℃; for 2h;	98%

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → 2-chloro-10,11-dihydrodibenzoxepin-10-one (55595-54-5)

Conditions	Yield
With PPA at 100 - 105℃;	61%
With sodium hydroxide; PPA

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → (5-Chloro-2-phenoxy-phenyl)-acetyl chloride

Conditions	Yield
With thionyl chloride In toluene Heating;
With thionyl chloride In toluene

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → 1-[2-chloro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine (57389-06-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 61 percent / polyphosphoric acid / 100 - 105 °C 2: 60 percent / TiCl4 / benzene / 4 h / Heating View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → 8-chloro-dibenz[b,f]oxepin-10-carboxylic acid methyl ester (912356-02-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / 2 h / 50 °C 2: sodium t-butanolate / tert-butyl methyl ether / 2 h / 5 - 20 °C 3: pyrophosphoric acid / water / 2 h / 0 - 60 °C View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → (E and Z)-2-(5-chloro-2-phenoxy-phenyl)-3-hydroxy-acrylic acid methyl ester (912356-01-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid / 2 h / 50 °C 2: sodium t-butanolate / tert-butyl methyl ether / 2 h / 5 - 20 °C View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz<2,3:6,7>oxepino<4,5-c>pyrrolidine maleate (85650-56-2)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: sulfuric acid / 2 h / 50 °C 2.1: sodium t-butanolate / tert-butyl methyl ether / 2 h / 5 - 20 °C 3.1: pyrophosphoric acid / water / 2 h / 0 - 60 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 20 - 35 °C 5.1: hydrogen / Ni-Raney / tetrahydrofuran / 48 h / 20 °C / 2585.81 - 3102.97 Torr 6.1: ethyl acetate / 96 h / 25 °C 7.1: boron trifluoride diethyl etherate; triethylsilane / 24 h / 105 °C 8.1: sodium hydroxide / dichloromethane; water / pH > 10 8.2: 2 h / 60 °C View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → trans-8-chloro-11-nitromethyl-10,11-dihydro-dibenzo[b,f]oxepine-10-carboxylic acid methyl ester

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / 2 h / 50 °C 2: sodium t-butanolate / tert-butyl methyl ether / 2 h / 5 - 20 °C 3: pyrophosphoric acid / water / 2 h / 0 - 60 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / 20 - 35 °C View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → 11-aminomethyl-8-chloro-10,11-dihydro-dibenzo[b,f]oxepine-10-carboxylic acid methyl ester

Conditions	Yield
Multi-step reaction with 5 steps 1: sulfuric acid / 2 h / 50 °C 2: sodium t-butanolate / tert-butyl methyl ether / 2 h / 5 - 20 °C 3: pyrophosphoric acid / water / 2 h / 0 - 60 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / 20 - 35 °C 5: hydrogen / Ni-Raney / tetrahydrofuran / 48 h / 20 °C / 2585.81 - 3102.97 Torr View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → trans-11-chloro-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one

Conditions	Yield
Multi-step reaction with 6 steps 1: sulfuric acid / 2 h / 50 °C 2: sodium t-butanolate / tert-butyl methyl ether / 2 h / 5 - 20 °C 3: pyrophosphoric acid / water / 2 h / 0 - 60 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / 20 - 35 °C 5: hydrogen / Ni-Raney / tetrahydrofuran / 48 h / 20 °C / 2585.81 - 3102.97 Torr 6: ethyl acetate / 96 h / 25 °C View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole hydrochloride

Conditions

Yield

Multi-step reaction with 7 steps 1: sulfuric acid / 2 h / 50 °C 2: sodium t-butanolate / tert-butyl methyl ether / 2 h / 5 - 20 °C 3: pyrophosphoric acid / water / 2 h / 0 - 60 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / 20 - 35 °C 5: hydrogen / Ni-Raney / tetrahydrofuran / 48 h / 20 °C / 2585.81 - 3102.97 Torr 6: ethyl acetate / 96 h / 25 °C 7: boron trifluoride diethyl etherate; triethylsilane / 24 h / 105 °C View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenz<2,3:6,7>oxepino<4,5-c>pyrrole (128915-56-0, 136085-14-8, 136085-16-0, 136085-18-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sulfuric acid / 2 h / 50 °C 2.1: sodium t-butanolate / tert-butyl methyl ether / 2 h / 5 - 20 °C 3.1: pyrophosphoric acid / water / 2 h / 0 - 60 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 20 - 35 °C 5.1: hydrogen / Ni-Raney / tetrahydrofuran / 48 h / 20 °C / 2585.81 - 3102.97 Torr 6.1: ethyl acetate / 96 h / 25 °C 7.1: lithium aluminium tetrahydride; aluminum (III) chloride / tetrahydrofuran / 0 - 20 °C 7.2: 0.33 h / 2 °C View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → C18H18ClNO4

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / toluene 2: triethylamine / N,N-dimethyl-formamide View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → 3-(5-chloro-2-phenoxyphenyl)-1-methylpyrrolidine-2,4-dione (1162120-35-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: thionyl chloride / toluene 2: triethylamine / N,N-dimethyl-formamide 3: potassium tert-butylate / toluene View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (1012884-46-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / toluene 2: triethylamine / N,N-dimethyl-formamide 3: potassium tert-butylate / toluene 4: phosphoric acid; phosphorus pentoxide / toluene View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one

Conditions	Yield
Multi-step reaction with 5 steps 1: thionyl chloride / toluene 2: triethylamine / N,N-dimethyl-formamide 3: potassium tert-butylate / toluene 4: phosphoric acid; phosphorus pentoxide / toluene 5: magnesium / methanol; toluene; dichloromethane / 5 h / 40 °C / Inert atmosphere; Large scale View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → cis-11-chloro-2,3,3a,12btetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one

Conditions	Yield
Multi-step reaction with 5 steps 1: thionyl chloride / toluene 2: triethylamine / N,N-dimethyl-formamide 3: potassium tert-butylate / toluene 4: phosphoric acid; phosphorus pentoxide / toluene 5: magnesium / methanol; toluene; dichloromethane / 5 h / 40 °C / Inert atmosphere; Large scale View Scheme

5-chloro-2-phenoxyphenylacetic acid (70958-20-2) → trans-8-chloro-10,11-dihydro-11-[(methylamino)methyl]-dibenz[b,f]oxepin-10-carboxylic acid

Conditions	Yield
Multi-step reaction with 6 steps 1: thionyl chloride / toluene 2: triethylamine / N,N-dimethyl-formamide 3: potassium tert-butylate / toluene 4: phosphoric acid; phosphorus pentoxide / toluene 5: magnesium / methanol; toluene; dichloromethane / 5 h / 40 °C / Inert atmosphere; Large scale 6: potassium hydroxide / ethanol / 5 h / 106 °C / Reflux View Scheme

Upstream product

• 108-95-2 phenol 
• 139-02-6 sodium phenoxide 
• 2476-37-1 2,5-dichloroacetophenone 
• 70958-19-9 4-[2-(5-chloro-2-phenoxyphenyl)-1-thioxoethyl]morpholine 
• 70958-18-8 5-chloro-2-phenoxyacetophenone 

Downstream Products

• 912355-99-8 trans-8-chloro-10,11-dihydro-11-[(methylamino)methyl]-dibenz[b,f]oxepin-10-carboxylic acid 
• 1180843-77-9 cis-11-chloro-2,3,3a,12btetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one 
• 1180843-77-9 trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one 
• 1012884-46-6 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one 
• 1162120-35-5 3-(5-chloro-2-phenoxyphenyl)-1-methylpyrrolidine-2,4-dione 
• 1180843-76-8 C₁₈H₁₈ClNO₄ 
• 1141493-78-8 (5-chloro-2-phenoxy-phenyl)-acetic acid methyl ester 
• 128915-56-0 trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenz<2,3:6,7>oxepino<4,5-c>pyrrole 
• 1170701-78-6 trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole hydrochloride 
• 85650-56-2 trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz<2,3:6,7>oxepino<4,5-c>pyrrolidine maleate 
• 912356-01-5 (E and Z)-2-(5-chloro-2-phenoxy-phenyl)-3-hydroxy-acrylic acid methyl ester 
• 55595-54-5 2-chloro-10,11-dihydrodibenzoxepin-10-one 

Relevant articles and documents

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.

Affinity of 10-(4-Methylpiperazino)dibenzoxepins for Clozapine and Spiroperidol Binding Sites in Rat Brain

10-(4-Methylpiperazino)dibenzoxepins were prepared and evaluated as potential antipsychotic agents using specific clozapine diazepine> binding sites in rat forebrain that are noncholinergic and nondopaminergic in nature and from which clozapine is displaced by known antipsychotic agents. Clozapine binding in the presence of atropine represents nonmuscarinic binding, while binding in the absence of atropine represents muscarinic (cholinergic) plus nonmuscarinic binding.The relative affinity for dopamine binding sites was determined by displacement of spiroperidol from binding sites in rat caudate nuclei.Thus, clozapine, its 2-chloro isomer, its dechloro analogue, and their 5H-dibenzocycloheptene and dibenzoxepin analogues have about the same relative affinity for the nonmuscarinic clozapine binding sites.At the spiroperidol (dopaminergic) sites, both the nature of the tricyclic system and the presence of chlorine atom on the tricyclic system have a substantial effect on the binding affinity.Within each series, shift of a chlorine atom from the position distal to the piperazino group to the proximal position increases the binding affinity by a factor of about nine, but removal of the chlorine atom substantially decreases the binding affinity.Nevertheless, 10-(4-methylpiperazino)dibenzoxepin has a threefold greater affinity for the dopaminergic binding sites than does clozapine itself.