79559-97-0

Basic information

• Product Name: Sertraline HCL
• Synonyms: sertraline hydrochloride; (1s,4s)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-n-methyl-1-napthalenamine hydrochloride; 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine; (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride (1:1)
• CAS NO: 79559-97-0
• Molecular Formula: C₁₇H₁₇Cl₂N*ClH
• Molecular Weight: 342.6905
• EINECS: 616-702-0
• Product Categories: KETEK;Active Pharmaceutical Ingredients;Pharmaceutical Intermediates;APIs;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Serotonin receptor;API
• Mol File: 79559-97-0.mol
• Article Data: 33

Chemical Properties

• Melting Point: 246-249℃
• Boiling Point: 416.3°C at 760 mmHg
• Flash Point: 205.6°C
• Density: 1.37
• Vapor Pressure: 3.85E-07mmHg at 25°C
• Storage Temp.: Desiccate at RT
• Solubility: DMSO: ~26?mg/mL
• PKA: pKa (water): 9.48 ± 0.04; pKa (methanol:water, 40:60 v/v): 8.6; pKa (ethanol:water, 1:1 v/v): 8.5(at 25℃)
• Stability: Store in Freezer
• Merck: 14,8467
• CAS DataBase Reference: Sertraline HCL(CAS DataBase Reference)
• NIST Chemistry Reference: Sertraline HCL(79559-97-0)
• EPA Substance Registry System: Sertraline HCL(79559-97-0)

Safety Data

• Hazard Codes: Xi,T,F
• Statements: 36/37/38-39/23/24/25-23/24/25-11
• Safety Statements: S22:; S24/25:
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 3
• RTECS: QJ0352070
• HazardClass: IRRITANT
• Hazardous Substances Data: 79559-97-0(Hazardous Substances Data)

Usage

Description

Sertraline HCL, also known as Zoloft, is a selective serotonin reuptake inhibitor (SSRI) antidepressant used in the treatment of major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder in both adults and children. It selectively inhibits the reuptake of serotonin at the presynaptic membrane, increasing serotonin levels in the synapses and enhancing serotonergic neurotransmission, which is related to its antidepressant effect.

Uses

Used in Pharmaceutical Industry:
Sertraline HCL is used as an antidepressant for the treatment of major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder.
Used in Clinical Toxicology and Forensic Analysis:
Sertraline HCL is used as a selective serotonin reuptake inhibitor (SSRI) in LC/MS or GC/MS applications for urine drug testing, clinical toxicology, and forensic analysis.
Used in Antimicrobial Applications:
Sertraline HCL is used as an antibacterial agent, exhibiting potential antimicrobial properties.
Used in Selective Serotonin Transporter Inhibition:
Sertraline HCL is used as a selective serotonin transporter (SERT) inhibitor, with an IC50 value of 70 nM, selectively inhibiting monoamine uptake by the serotonin transporter.
Used in Glucocorticoid Function Assay:
Sertraline HCL is used in glucocorticoid function assays to study the effect of antidepressants on glucocorticoid receptor function in humans.
Used in Research on Antidepressant Effects:
The effect of exposure to sertraline hydrochloride has been studied in chronically prepared ovine fetus, providing insights into the effects of antidepressants on fetal development.
Used in Treatment of Anxiety Disorders:
Formulations containing sertraline have been used in the treatment of various anxiety disorders, including panic disorder and social anxiety disorder.
Used in Investigational Treatment of Obesity:
Sertraline hydrochloride is currently undergoing investigation for the treatment of obesity, in addition to its established use in treating obsessive-compulsive disorders.

References

https://en.wikipedia.org/wiki/Sertraline https://www.drugbank.ca/drugs/DB01104

Manufacturing Process

Manufacturing process for Sertraline hydrochloride includes these steps as follows: Preparation of hot ethyl acetate-pentane, Preparation of an analytical sample of 3-ethoxycarbonyl-4-(3,4- dichlorophenyl)-4-phenylbut-3-enoic acid; Preparation of 4-(3,4- dichlorophenyl)-4-phenylbut-3-enoic acid; Preparation of an analytical sample of the 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid, 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)- naphthalenone; Preparation of a white precipitate, containing about 70% cis-racemate and 30% tras-racemate of N-methyl-4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride; Preparation of cis-(1S)(1R)-N-methyl-4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride; Preparation of cis-(1S)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine mandelate. The mandelate salt were suspended in ethyl acetate (about 2 L). The ethyl acetate suspension was treated with 10% aqueous NaOH solution, thereby converting the amine to the free base. The resulting ethyl acetate solution was then dried, diluted with ether (2 L) and then treated with excess gaseous hydrogen chloride to give a gelatinous suspension which crystallized overnight. The crystalline HCl salt product was separated by filtration, washed with ether and air dried. The cis-(1S)-N-methyl-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride 25.96 g, 39% yield, with melting point 243°-245°C.

Therapeutic Function

Antidepressant

Biological Activity

Potent, orally active selective serotonin re-uptake inhibitor (SSRI) used clinically to treat depression.

Biochem/physiol Actions

Selective serotonin reuptake inhibitor, antidepressant.

Synthetic route

sertraline 4-methoxybenzoate → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In diethyl ether; nitromethane at 25 - 30℃; for 1h; Product distribution / selectivity;	97%

Sertraline (79617-96-2) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In propan-1-ol at 30℃; for 1h; Product distribution / selectivity;	96%
With hydrogenchloride In acetonitrile for 1h; Product distribution / selectivity;	95%
With hydrogenchloride In octanol for 1h; Product distribution / selectivity;	95%

(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphtalenamine citrate (836597-67-2) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In acetonitrile at 20℃; for 1h; Product distribution / selectivity;	95%
With hydrogenchloride In propan-1-ol; water at 20 - 70℃; for 1h; pH=0; Product distribution / selectivity;	90%

(1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine mandelate → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In methoxypropyl acetate at 20 - 70℃; for 3h; Product distribution / selectivity;	95%
With N,N-dimethylacetamide hydrochloride In 4-methyl-2-pentanone at 20 - 80℃; for 1.5h; Product distribution / selectivity;	94%
With N,N-dimethylacetamide hydrochloride In acetonitrile at 20℃; for 1h; Product distribution / selectivity;	90%

sertraline adipate (928057-23-2) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In diethyl ether; nitromethane at 25 - 30℃; for 1h; Product distribution / selectivity;	86%

(cis-1S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (R)-mandelate (244223-89-0, 79617-97-3) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With sodium hydroxide In dichloromethane; water Industrial scale;	85%
With hydrogenchloride In acetonitrile at 0 - 15℃; for 0.5 - 1h; Product distribution / selectivity;	82.6%
With hydrogenchloride In tert-Amyl alcohol at 25 - 30℃; for 8h; pH=2.0; Product distribution / selectivity;

C17H17Cl2N*C5H9NO4 → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Stage #1: C17H17Cl2N*C5H9NO4 With sodium hydroxide In water; toluene at 80℃; for 3h; Stage #2: With hydrogenchloride In ethanol pH=1.0; Heating;	83.68%

sertraline phthalate (928057-20-9) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In diethyl ether; 4-methyl-2-pentanone at 25 - 70℃; for 3h; Product distribution / selectivity;	79%

sertraline 4-methylbenzoate (928057-24-3) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In diethyl ether; nitromethane at 25 - 30℃; for 1h; Product distribution / selectivity;	79%

sertraline salicylate (928057-22-1) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In diethyl ether; nitromethane at 25 - 30℃; for 1h; Product distribution / selectivity;	73%

(+/-)-N-methyl-[(cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amine hydrochloride → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Purification / work up;	46%

hydrogenchloride (7647-01-0) + (1S,4S)-sertraline*(S)-mandelic acid (1357380-69-8) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
In water; isopropyl alcohol at 20℃; pH=1 - 2; Heating / reflux;

1S-cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthaleneamine-mandelate (254731-40-3) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Stage #1: 1S-cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthaleneamine-mandelate With sodium hydroxide In water; ethyl acetate pH=2; Stage #2: With hydrogenchloride In isopropyl alcohol pH=2;

sertraline acetate → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In isopropyl alcohol; toluene at 20 - 60℃; pH=1 - 2; Conversion of starting material;
With hydrogenchloride In water at 20 - 25℃; for 1h; pH=1 - 2;
With hydrogenchloride In isopropyl alcohol; toluene at 0 - 60℃; for 0.25 - 0.333333h; pH=1 - 2; Conversion of starting material;
With hydrogenchloride In isopropyl alcohol at 15 - 50℃; for 0.5h; pH=1 - 2; Conversion of starting material;

acetic acid (64-19-7) + Sertraline (79617-96-2) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Stage #1: acetic acid; Sertraline In water at 5 - 25℃; for 1.33333h; Stage #2: With hydrogenchloride In water at 5 - 15℃; for 1.25h;

(1S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine → trans-(1S,4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride (79896-31-4) + sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In methanol; water Product distribution / selectivity;
With hydrogenchloride In water; ethyl acetate Product distribution / selectivity;
With hydrogenchloride In water; isopropyl alcohol Product distribution / selectivity;

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;

(S)-N-(4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-ylidene)methanamine (312620-93-2) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere 2: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere; Autoclave 2: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme

α-naphthol (90-15-3) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: aluminum (III) chloride / 4 h / 100 °C / Inert atmosphere 2: chiral HPLC / Resolution of racemate 3: methanol; dichloromethane / 96 h / 20 °C / Inert atmosphere; Molecular sieve 4: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere 5: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: aluminum (III) chloride / 4 h / 100 °C / Inert atmosphere 2: chiral HPLC / Resolution of racemate 3: methanol; dichloromethane / 96 h / 20 °C / Inert atmosphere; Molecular sieve 4: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere; Autoclave 5: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 8 steps 1.1: aluminum (III) chloride / 1.5 h / 100 °C / Inert atmosphere 2.1: borane N,N-diethylaniline complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 6 h / 25 °C / Inert atmosphere 3.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 3.2: 0 - 20 °C / Inert atmosphere 4.1: sodium carbonate / hexane / 0.33 h / -40 °C / Inert atmosphere 4.2: 40 h / -40 °C / Inert atmosphere 5.1: water; sodium sulfite / hexane; ethyl acetate / 12 h / 20 °C / Inert atmosphere 6.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 6.2: 0 - 20 °C / Inert atmosphere 7.1: hydrogen / methanol; dichloromethane; water / 5 h / 20 °C / Inert atmosphere 8.1: hydrogenchloride / diethyl ether / 20 °C / Inert atmosphere View Scheme

4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one (79560-19-3) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: chiral HPLC / Resolution of racemate 2: methanol; dichloromethane / 96 h / 20 °C / Inert atmosphere; Molecular sieve 3: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere 4: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: chiral HPLC / Resolution of racemate 2: methanol; dichloromethane / 96 h / 20 °C / Inert atmosphere; Molecular sieve 3: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere; Autoclave 4: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1.1: borane N,N-diethylaniline complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 6 h / 25 °C / Inert atmosphere 2.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere 3.1: sodium carbonate / hexane / 0.33 h / -40 °C / Inert atmosphere 3.2: 40 h / -40 °C / Inert atmosphere 4.1: water; sodium sulfite / hexane; ethyl acetate / 12 h / 20 °C / Inert atmosphere 5.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 5.2: 0 - 20 °C / Inert atmosphere 6.1: hydrogen / methanol; dichloromethane; water / 5 h / 20 °C / Inert atmosphere 7.1: hydrogenchloride / diethyl ether / 20 °C / Inert atmosphere View Scheme

(4S)-4-(3,4-dichlorophenyl)-1-tetralone (79560-19-3, 79836-44-5, 124379-29-9) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: methanol; dichloromethane / 96 h / 20 °C / Inert atmosphere; Molecular sieve 2: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere 3: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: methanol; dichloromethane / 96 h / 20 °C / Inert atmosphere; Molecular sieve 2: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere; Autoclave 3: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: methanol; dichloromethane / 4 h / 20 °C / Molecular sieve; Inert atmosphere 2: C43H30BF15N2O2RuS; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Autoclave 3: hydrogenchloride / acetic acid methyl ester / 6 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: methanol; dichloromethane / 4 h / 20 °C / Molecular sieve; Inert atmosphere 2: C43H30BF15N2O2RuS; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Autoclave 3: hydrogenchloride / acetic acid methyl ester / 6 h / 20 °C View Scheme

1,2-dichloro-benzene (95-50-1) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: aluminum (III) chloride / 4 h / 100 °C / Inert atmosphere 2: chiral HPLC / Resolution of racemate 3: methanol; dichloromethane / 96 h / 20 °C / Inert atmosphere; Molecular sieve 4: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere 5: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: aluminum (III) chloride / 4 h / 100 °C / Inert atmosphere 2: chiral HPLC / Resolution of racemate 3: methanol; dichloromethane / 96 h / 20 °C / Inert atmosphere; Molecular sieve 4: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere; Autoclave 5: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 8 steps 1.1: aluminum (III) chloride / 1.5 h / 100 °C / Inert atmosphere 2.1: borane N,N-diethylaniline complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 6 h / 25 °C / Inert atmosphere 3.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 3.2: 0 - 20 °C / Inert atmosphere 4.1: sodium carbonate / hexane / 0.33 h / -40 °C / Inert atmosphere 4.2: 40 h / -40 °C / Inert atmosphere 5.1: water; sodium sulfite / hexane; ethyl acetate / 12 h / 20 °C / Inert atmosphere 6.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 6.2: 0 - 20 °C / Inert atmosphere 7.1: hydrogen / methanol; dichloromethane; water / 5 h / 20 °C / Inert atmosphere 8.1: hydrogenchloride / diethyl ether / 20 °C / Inert atmosphere View Scheme

(4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-ylidene)methylamine (261776-41-4) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: RuBArF(p-cymene)(R,R)-MsDPEN; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere 2: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: [RuBArF(p-cymene)(S,S)-MsDPEN]; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Inert atmosphere 2: hydrogenchloride / ethyl acetate / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: C43H30BF15N2O2RuS; hydrogen / 1,2-dichloro-ethane / 10 h / 40 °C / 38002.6 Torr / Autoclave 2: hydrogenchloride / acetic acid methyl ester / 6 h / 20 °C View Scheme

cis-(1S,4S)-N-(tert-butoxycarbonyl)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (267884-85-5) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
With hydrogenchloride In ethyl acetate at 20℃; for 6h; Inert atmosphere; optical yield given as %ee;	500 mg
With hydrogenchloride In acetic acid methyl ester at 20℃; for 6h;	500 mg

(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (167026-37-1) → sertraline hydrochloride (79559-97-0)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: sodium carbonate / hexane / 0.33 h / -40 °C / Inert atmosphere 2.2: 40 h / -40 °C / Inert atmosphere 3.1: water; sodium sulfite / hexane; ethyl acetate / 12 h / 20 °C / Inert atmosphere 4.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 4.2: 0 - 20 °C / Inert atmosphere 5.1: hydrogen / methanol; dichloromethane; water / 5 h / 20 °C / Inert atmosphere 6.1: hydrogenchloride / diethyl ether / 20 °C / Inert atmosphere View Scheme

(1S,4S)-1-(benzyloxy)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalene (1346228-87-2) → sertraline hydrochloride (79559-97-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: sodium carbonate / hexane / 0.33 h / -40 °C / Inert atmosphere 1.2: 40 h / -40 °C / Inert atmosphere 2.1: water; sodium sulfite / hexane; ethyl acetate / 12 h / 20 °C / Inert atmosphere 3.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 3.2: 0 - 20 °C / Inert atmosphere 4.1: hydrogen / methanol; dichloromethane; water / 5 h / 20 °C / Inert atmosphere 5.1: hydrogenchloride / diethyl ether / 20 °C / Inert atmosphere View Scheme

benzyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (1346228-88-3) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: hydrogen / methanol; dichloromethane; water / 5 h / 20 °C / Inert atmosphere 3.1: hydrogenchloride / diethyl ether / 20 °C / Inert atmosphere View Scheme

benzyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate (1346228-89-4) → sertraline hydrochloride (79559-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / methanol; dichloromethane; water / 5 h / 20 °C / Inert atmosphere 2: hydrogenchloride / diethyl ether / 20 °C / Inert atmosphere View Scheme

sertraline hydrochloride (79559-97-0) → Sertraline (79617-96-2)

Conditions	Yield
With sodium hydroxide In water; toluene for 0.25h; pH=> 10;	93%
With sodium hydroxide In water; ethyl acetate	77%
With ammonium hydroxide In water pH=10;
With sodium hydroxide In water
With potassium carbonate In water at 20℃;	10.9 g

carbonochloridic acid, chloromethyl ester (22128-62-7) + sertraline hydrochloride (79559-97-0) → chloromethyl ((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃; for 4.5h;	88%

di-tert-butyl dicarbonate (24424-99-5) + sertraline hydrochloride (79559-97-0) → cis-(1S,4S)-N-(tert-butoxycarbonyl)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (267884-85-5)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; for 2.33333h; Inert atmosphere;	86%

sertraline hydrochloride (79559-97-0) → Cis-(1S)-N-methyl-7-chlorosulphonyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrogen sulphate

Conditions	Yield
With chlorosulfonic acid; trifluoroacetic acid at 20℃; for 16h;	72%

1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-(4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl) decanedioate + sertraline hydrochloride (79559-97-0) → 1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-(4-(((((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamoyl)oxy)methyl)phenyl) decanedioate

Conditions	Yield
With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	65%

3-(2-((6-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-6-oxohexanoyl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid + sertraline hydrochloride (79559-97-0) → 1,3-bis(palmitoyloxy)propan-2-yl (2-(4-(((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)amino)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl) adipate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h;	61%

sertraline hydrochloride (79559-97-0) → UK-373911

Conditions	Yield
Stage #1: sertraline hydrochloride With chlorosulfonic acid In dichloromethane at 20℃; for 0.5h; Stage #2: With thionyl chloride In dichloromethane at 20℃; for 16h; Stage #3: With ammonia; trifluoroacetic acid more than 3 stages;	58%

sertraline hydrochloride (79559-97-0) → (1S-cis )-4-(3,4-dichlorophenyl)-7-iodo-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (291306-20-2)

Conditions	Yield
Stage #1: sertraline hydrochloride With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane at 0℃; for 41h; Stage #2: With sodium hydroxide In dichloromethane; water	35%
Stage #1: sertraline hydrochloride With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane at 0℃; for 41h; Stage #2: With sodium hydroxide In dichloromethane; water	35%

sertraline hydrochloride (79559-97-0) → C17H16Cl2IN*HI

Conditions	Yield
With iodine In ethanol

acetic acid (64-19-7) + sertraline hydrochloride (79559-97-0) → sertraline hydrochloride acetic acid solvate (620168-87-8, 820211-78-7)

Conditions	Yield
at 20 - 60℃; for 16h;

sertraline hydrochloride (79559-97-0) → Cis-(1S)-N-methyl-7-(nitro)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine + C17H16Cl2N2O2

Conditions	Yield
With trifluorormethanesulfonic acid; potassium nitrate; trifluoroacetic acid at 0℃; for 1.5h;

Upstream product

• 7647-01-0 hydrogenchloride 
• 1357380-69-8 (1S,4S)-sertraline*(S)-mandelic acid 
• 254731-40-3 1S-cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthaleneamine-mandelate 
• 79617-96-2 Sertraline 
• 836597-67-2 (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphtalenamine citrate 
• 64-19-7 acetic acid 
• 244223-89-0 (cis-1S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (R)-mandelate 
• 928057-20-9 sertraline phthalate 
• 928057-22-1 sertraline salicylate 
• 928057-23-2 sertraline adipate 
• 928057-24-3 sertraline 4-methylbenzoate 
• 79560-20-6 N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine 
• 312620-93-2 (S)-N-(4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-ylidene)methanamine 
• 90-15-3 α-naphthol 

Downstream Products

• 291306-20-2 (1S-cis )-4-(3,4-dichlorophenyl)-7-iodo-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine 
• 620168-87-8 sertraline hydrochloride acetic acid solvate 
• 79617-96-2 Sertraline 
• 267884-85-5 cis-(1S,4S)-N-(tert-butoxycarbonyl)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 
• 960287-40-5 (1S-cis)-4-(3,4-dichlorophenyl)-7-iodo-1,2,3,4-tetrahydro-N-tert-butoxycarbonyl-N-methyl-1-naphthalenamine 
• 960287-42-7 (1S-cis)-4-(3,4-dichlorophenyl)-7-(5-hydroxy-1-pentyn-1-yl)-1,2,3,4-tetrahydro-N-tert-butoxycarbonyl-N-methyl-1-naphthalenamine 

Relevant articles and documents

Preparation method of chiral sertraline hydrochloride

The invention relates to a preparation method of chiral sertraline hydrochloride, which comprises: 1) carrying out a reaction on cis-sertraline hydrochloride and an inorganic alkali in a toluene and water mixed solution, carrying out oil layer concentration to remove a solvent, adding an alcohol and water mixed solvent to dissolve the residue, and adding L-glutamic acid to carry out resolution toobtain a crude product sertraline glutamate; 2) recrystallizing the crude sertraline glutamate to obtain refined sertraline glutamate; and 3) reacting the refined glutamic acid sertraline with inorganic alkali in a mixed solution of water and toluene, concentrating an oil layer to remove the solvent, adding ethanol into residues for dissolving, and then adding a hydrogen chloride ethanol solutionfor crystallization to obtain the cis-(1S, 4S)-sertraline hydrochloride. The method is high in yield; the cis-(1S, 4S)-sertraline hydrochloride is high in purity, low in cost and suitable for industrial production.

Concise enantioselective synthesis of (+)-sertraline and (-)-CP-52002 using proline catalysis

A short enantioselective synthesis of (+)-sertraline and its C4 epimer (-)-CP-52002 with an overall yield of 30%, respectively, as its hydrochloride has been described. The key steps are the proline catalyzed Mannich reaction of acetaldehyde and acid catalyzed intramolecular Friedel-Crafts' alkylation reaction of olefin proceeding with high optical purities.

Stereoselective amination of chiral benzylic ethers using chlorosulfonyl isocyanate: Total synthesis of (+)-Sertraline

The stereoselective amination of various chiral benzylic ethers using chlorosulfonyl isocyanate is developed, and the application of this method to the total synthesis of a potent antidepressant, (+)-sertraline, from readily available 1-naphthol is also described (Figure presented).