79560-20-6

Basic information

• Product Name: 4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenimine
• Synonyms: N-(4-(3,4-DICHLOROPHENYL)-3,4-DIHYDRO-1(2H)-NAPHTHALENE-1-YL)-METHANAMINE;N-(4(3,4-DICHLOROPHENYL)-3,4-DIHYDRO-1(2H)NAPHTHALIDENE) METHANAMINE;SERTRALINE HCL FORM I;SERTRALINE HCL FORM II;SETRALINE HCL;(1S,4S)-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-N-METHYL-1-NAPHTHALENAMINE HYDROCHLORIDE;(1S,4S)-1-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-4-(METHYLAMINO)NAPHTHALENE HYDROCHLORIDE;4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-n-methyl-1-naphthalenimine
• CAS NO: 79560-20-6
• Molecular Formula: C₁₇H₁₅Cl₂N
• Molecular Weight: 304.22
• Mol File: 79560-20-6.mol
• Article Data: 9

Chemical Properties

• Melting Point: 243-247°C
• Boiling Point: 390.529 °C at 760 mmHg
• Flash Point: 190 °C
• Appearance: white/solid
• Density: 1.251 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.619
• Solubility: DMSO: ~26 mg/mL
• PKA: 5.41±0.40(Predicted)
• CAS DataBase Reference: 4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenimine(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenimine(79560-20-6)
• EPA Substance Registry System: 4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenimine(79560-20-6)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 3
• RTECS: QJ0352070
• Hazardous Substances Data: 79560-20-6(Hazardous Substances Data)

Usage

Chemical Properties

white to light yellow crystal powde

InChI:InChI=1/C17H15Cl2N/c1-20-17-9-7-12(13-4-2-3-5-14(13)17)11-6-8-15(18)16(19)10-11/h2-6,8,10,12H,7,9H2,1H3/b20-17+

Synthetic route

4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one (79560-19-3) + methylamine (74-89-5) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
In ethanol at 0℃; Solvent; Heating; Industrial scale; Large scale;	95%
With formic acid In methanol	95%
With thionyl chloride In tetrahydrofuran at -10 - 20℃;	93%

4-(2,3-dichlorophenyl)-3,4-dihydro-1(2H)-naphthone + 4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one (79560-19-3) + methylamine (74-89-5) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
methanesulfonic acid In ethanol at 0 - 70℃; for 4h;	88%
methanesulfonic acid In acetonitrile at 0 - 70℃; for 4h;	88%
In triethylamine at 0 - 90℃; for 10h;	87%
toluene-4-sulfonic acid In triethylamine at 0 - 50℃; for 4h;	82%

3,4-dichlorobenzophenone (6284-79-3) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium tert-butoxide / 2-methyl-propan-2-ol / 16 h / Heating 2: 50 percent / 48percent aq. HBr / acetic acid / 36 h / Heating 3: 100 percent / H2 / 5percent Pd/C / ethyl acetate / 24 h / 760 Torr / Ambient temperature 4: SOCl2 / toluene / 1.25 h 5: AlCl3 / CS2 / 16 h / Ambient temperature 6: TiCl4 / toluene / 17 h / Ambient temperature View Scheme

4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (79560-18-2) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOCl2 / toluene / 1.25 h 2: AlCl3 / CS2 / 16 h / Ambient temperature 3: TiCl4 / toluene / 17 h / Ambient temperature View Scheme

4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (79560-17-1) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 100 percent / H2 / 5percent Pd/C / ethyl acetate / 24 h / 760 Torr / Ambient temperature 2: SOCl2 / toluene / 1.25 h 3: AlCl3 / CS2 / 16 h / Ambient temperature 4: TiCl4 / toluene / 17 h / Ambient temperature View Scheme

4-(3,4-dichlorophenyl)-4-phenylbutyric acid (149620-65-5) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: AlCl3 / CS2 / 16 h / Ambient temperature 2: TiCl4 / toluene / 17 h / Ambient temperature View Scheme

3-(ethoxycarbonyl)-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (79560-16-0) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: 50 percent / 48percent aq. HBr / acetic acid / 36 h / Heating 2: 100 percent / H2 / 5percent Pd/C / ethyl acetate / 24 h / 760 Torr / Ambient temperature 3: SOCl2 / toluene / 1.25 h 4: AlCl3 / CS2 / 16 h / Ambient temperature 5: TiCl4 / toluene / 17 h / Ambient temperature View Scheme

4-(2,3-dichlorophenyl)-3,4-dihydro-1(2H)-naphthone + 4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one (79560-19-3) + methylamine (74-89-5) → 2,3-dichlorosertraline-imine (340830-05-9) + N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
methanesulfonic acid In ethanol at 0 - 70℃; for 4h;
toluene-4-sulfonic acid at 60℃; under 3750.38 - 7500.75 Torr; for 5h;

4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one (79560-19-3) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
With formic acid; methylamine In N,N-dimethyl-formamide

1,2-dichloro-benzene (95-50-1) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride 2: ethanol / 0 °C / Heating; Industrial scale; Large scale View Scheme

α-naphthol (90-15-3) → N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride 2: ethanol / 0 °C / Heating; Industrial scale; Large scale View Scheme

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → cis-1-methylamino-4-(3,4-dichlorophenyl)tetralin + trans-1-methylamino-4-(3,4-dichlorophenyl)tetralin

Conditions	Yield
With hydrogen; 5 % alumina-supported palladium In methanol at 26 - 29℃; Product distribution / selectivity; Autoclave;	A 91.52% B 6.54%

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → cis-1-methylamino-4-(3,4-dichlorophenyl)tetralin

Conditions	Yield
With hydrogen; CuCrBa oxide In ethanol at 130 - 150℃; under 9000.9 Torr; for 1h;	83%
With hydrogen; CuCrBa oxide In butan-1-ol
With hydrogen; CuCrBa oxide In isopropyl alcohol
With hydrogen; CuCrBa oxide In methanol

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → sertraline (140631-53-4)

Conditions	Yield
With tris(pentafluorophenyl)borate; 1,1'-[1-methyl-3-(2,6-dimethylpiperidinyl)-1,3-propyl]ferrocene; hydrogen In toluene at 80℃; under 15001.5 Torr;	83%
With tris(pentafluorophenyl)borate; diisopropylamine at 100℃; for 24h; Neat (no solvent);	90 %Spectr.
With 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; tert-butyl alcohol In chloroform-d1	83 %Spectr.

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthaleneamine (79617-95-1) + trans-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (79836-45-6)

Conditions	Yield
With sodium tetrahydroborate In methanol for 1.5h; Ambient temperature;
With palladium on activated charcoal; hydrogen	A n/a B n/a

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthaleneamine (79617-95-1)

Conditions	Yield
With hydrogen; 5 wt% palladium on calcium carbonate In methanol; water at 20 - 35℃; for 3.5h;
With Lindlar's catalyst; hydrogen; pyrographite In ethanol at 20 - 40℃; Solvent; Industrial scale; Large scale;	n/a

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → (1R,4R)-sertraline (79617-98-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium borohydride / methanol / 1.5 h / Ambient temperature View Scheme

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → trans-(1S,4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (91797-60-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium borohydride / methanol / 1.5 h / Ambient temperature View Scheme

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → trans-(1R,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (79951-46-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium borohydride / methanol / 1.5 h / Ambient temperature View Scheme

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → Sertraline (79617-96-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium borohydride / methanol / 1.5 h / Ambient temperature View Scheme
Stage #1: With hydrogen; G-69 (Ni/Kieselguhr) at 150℃; for 2h; Stage #2: N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine With hydrogen In tetrahydrofuran at 90℃; under 6080.41 Torr;	86 %Chromat.

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → cis-(1S,4S)-N-methyl-(3-chlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine (871838-58-3) + (1S)-cis-N-methyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (91797-63-6) + 4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one (79560-19-3) + trans-(1S,4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (91797-60-3) + Sertraline (79617-96-2)

Conditions	Yield
With hydrogen; SA-3135 support, Co(NO3)2, H2O; dried and calcined ones or twice (Co 11 - 25percent); reduction with H2 In tetrahydrofuran at 120 - 150℃; under 6000.6 Torr;	A n/a B n/a C 0.2 - 0.7 %Chromat. D 7 - 9.4 %Chromat. E 87 - 91 %Chromat.

triphenyl phosphite (101-02-0) + N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → sertraline (140631-53-4)

Conditions	Yield
palladium on graphite In N-methyl-acetamide; methanol

palladium on graphite + N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → sertraline (140631-53-4)

Conditions	Yield
With phosphorous acid trimethyl ester In methanol

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthaleneamine hydrochloride + sertraline hydrochloride (79559-97-0)

Conditions	Yield
Stage #1: N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine With hydrogen; pyridine hydrochloride; 50% Pd/C In methanol at 25 - 35℃; for 6h; Stage #2: With hydrogenchloride In methanol; water pH=1 - 2; Product distribution / selectivity;
Stage #1: N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine With hydrogen; pyridine hydrochloride; platinum on carbon In methanol at 25 - 35℃; for 0.5h; Stage #2: With hydrogenchloride In methanol; water pH=1 - 2; Product distribution / selectivity;
Stage #1: N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine With hydrogen; N,N-dimethylacetamide hydrochloride; 50% Pd/C In methanol at 25 - 35℃; for 4h; Stage #2: With hydrogenchloride In methanol; water pH=1 - 2; Product distribution / selectivity;

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → (1R,4R)-sertraline (79617-98-4) + trans-(1S,4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (91797-60-3) + trans-(1R,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (79951-46-5) + Sertraline (79617-96-2)

Conditions	Yield
With C32H12BF24(1-)*C36H44IrNOP(1+); hydrogen at 20℃; under 15201 Torr; for 12h; optical yield given as %ee; enantioselective reaction;

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → (1R,4R)-sertraline (79617-98-4) + trans-(1R,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (79951-46-5) + Sertraline (79617-96-2)

Conditions	Yield
With R,S-[Ir(1,5-cyclooctadiene)(PPh2(C9H10)(C3H3NO-i-Bu))] tetrakis(3,5-bis(trifluoromethyl)phenyl)borate; hydrogen at 20℃; under 15201 Torr; for 12h; optical yield given as %ee; enantioselective reaction;

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (79560-20-6) → (cis-1S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (R)-mandelate (244223-89-0, 79617-97-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyrographite; hydrogen; Lindlar's catalyst / ethanol / 20 - 40 °C / Industrial scale; Large scale 2: ethanol / Reflux; Industrial scale; Large scale View Scheme

Upstream product

• 90-15-3 α-naphthol 
• 95-50-1 1,2-dichloro-benzene 
• 79560-17-1 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid 
• 79560-18-2 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid 
• 79560-19-3 4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one 
• 152448-80-1 4-(2,3-dichlorophenyl)-3,4-dihydro-1(2H)-naphthone 
• 74-89-5 methylamine 
• 79560-16-0 3-(ethoxycarbonyl)-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid 
• 149620-65-5 4-(3,4-dichlorophenyl)-4-phenylbutyric acid 
• 6284-79-3 3,4-dichlorobenzophenone 

Downstream Products

• 79617-98-4 (1R,4R)-sertraline 
• 91797-60-3 trans-(1S,4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 
• 79951-46-5 trans-(1R,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 
• 79617-96-2 Sertraline 
• 244223-89-0 (cis-1S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (R)-mandelate 
• 140631-53-4 sertraline 
• 79559-97-0 sertraline hydrochloride 
• 871838-58-3 cis-(1S,4S)-N-methyl-(3-chlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine 
• 91797-63-6 cis-(1S,4S)-N-methyl-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine 
• 79560-19-3 4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one 
• 79617-95-1 cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthaleneamine 
• 79836-45-6 trans-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 

Relevant articles and documents

Development of [3]ferrocenophane-derived N/B frustrated Lewis pairs for the metal-free catalytic hydrogenation of imines

A series of novel [3]ferrocenophane-derived N/B frustrated Lewis pairs (FLPs) were synthesized and successfully applied to the catalytic hydrogenation of imines in 71–93% yields. This approach could be easily conducted on gram scale and provided versatile synthetic route for the key intermediate of sertraline hydrochloride without heavy metal residues.

PROCESS FOR THE PREPARATION OF AN IMINE INTERMEDIATE

The invention is directed to a process for the preparation of [4(S,R)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-ylidene]-methyl-amine of the Formula (I) by reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalene-l-one of the Formula (II) with monomethyl amine which comprises carrying out the reaction in the presence of thionyl chloride in an ether-type solvent. The [4(S,R)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-ylidene]-methyl-amine of the Formula I is a valuable pharmaceutical intermediate.

Process for the preparation of ketimines

Described is a process for the preparation of compounds of formula (1a) which comprises reacting an isomeric mixture consisting of from 75 to 95% of compound of formula (2a) and from 5 to 25% of a compound of formula (2b) with methylamine, in a suitable solvent, to form a sertraline-imine isomeric mixture consisting of from 75 to 95% of formula (1a) and from 5 to 25% of formula (1b)(A1), or reacting an isomeric mixture consisting of from 75 to 95% of a compound of formula (2a) and from 5 to 25% of a compound of formula (2b) with methylamine, in a suitable solvent, using suitable methods of isolation to form an enriched sertraline-imine isomeric mixture, consisting of >99% of a compound of formula (1a) and 2); and then subjecting the sertraline-imine isomeric mixture obtained according to reaction route (A1) or (A2), in a suitable solvent, to recrystallisation (B), in accordance with scheme (I) wherein in formula (1a), R1, R2and R3are each independently of the others hydrogen, halogen, trifluoromethyl or C1-C4alkoxy and formulae (1b), (2a) and (2b) are as defined in the description.