N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-aminium chloride

Base Information

• Chemical Name: N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-aminium chloride
• CAS No.: 136434-34-9
• Molecular Formula: C18H19NOS.HCl
• Molecular Weight: 333.882
• Hs Code.: 29349990
• Mol file: 136434-34-9.mol

Synonyms:SCHEMBL119403;N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-aminium chloride

Chemical Property of N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-aminium chloride

Chemical Property:

• Appearance/Colour: White or white crystalline powder
• Vapor Pressure: 7.23E-09mmHg at 25°C
• Melting Point: 118-122 °C
• Boiling Point: 466.2 °C at 760 mmHg
• PKA: pKa in DMF-water (66:34): 9.6(at 25℃)
• Flash Point: 235.7 °C
• PSA: 49.50000
• LogP: 5.82380
• Storage Temp.: -20°C Freezer
• Solubility.: H2O: soluble5mg/mL (clear solution, warmed)
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 3
• Rotatable Bond Count: 6
• Exact Mass: 333.0954131
• Heavy Atom Count: 22
• Complexity: 312

Purity/Quality:

99%MIN ^*data from raw suppliers

Duloxetine Hydrochloride ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xi
• Hazard Codes: Xi,Xn,T,F
• Statements: 36/37/38-22-39/23/24/25-23/24/25-11
• Safety Statements: 26-36/37-45-16-7

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: C[NH2+]CCC(C1=CC=CS1)OC2=CC=CC3=CC=CC=C32.[Cl-]
• Isomeric SMILES: C[NH2+]CC[C@@H](C1=CC=CS1)OC2=CC=CC3=CC=CC=C32.[Cl-]
• Indications: It is used for the treatment of depression and the treatment of stress urinary incontinence. In 2004, Japan Shionogi Pharmaceutical Co., Ltd. had obtained the authorization of Eli Lilly Company of US to perform further development on the duloxetine which has dual inhibitory effect on the reuptake of both 5 hydroxy trptamine (5-HT) and norepinephrine (NE). Existing studies have shown that this drug has certain efficacy in treating tension urinary incontinence, depression, and obesity. Currently, clinical trials of the drug for treatment of tension urinary incontinence and depression have all been completed.
• Drug Interactions: Duloxetine is metabolized through CYP2D6 and CYP1A2 metabolism with moderate inhibition of CYP2D6 but no inhibition and induction effects on CYP1A2 and CYP3A4. We should be cautious when apply it together with other drugs which are also metabolized through CYP2D6 and of narrow therapeutic window (such as: TCAs, Ic antiarrhythmic drugs, and phenothiazines).
• Description: Duloxetine is a selective serotonin (5-HT) and norepinephrine reuptake inhibitor (SSNRI) for oral administration, and it is currently approved in the US and in Europe for the treatment of major depressive disorder (MDD) and diabetic peripheral neuropathic pain (DPN). Additionally, it is indicated for the treatment of stress urinary incontinence (SUI) in Europe. However, the US approval for SUI is still pending, and Lilly recently withdrew the NDA for this indication. It is expected that additional clinical trials may be required to secure FDA approval for SUI treatment due to concern over the potential of duloxetine to prolong the QT interval in patients taking concomitant CYP2D6 or CYP1A2 inhibitors such as tricyclic antidepressants, type 1C antiarrhythmics and phenothiazines. Duloxetine is the second SSNRI to enter the market. Its predecessor, venlafaxine, has been available since 1994 for the treatment of depression. Duloxetine has a higher affinity for human norepinephrine (Ki=7.5 nM) and 5-HT transporters (Ki=0.8 nM) than venlafaxine (Ki=2480nM and 82nM, respectively). Additionally, it shows a more balanced ratio of 5-HT to norepinephrine uptake inhibition than venlafaxine. Duloxetine is a moderate inhibitor of dopamine reuptake (Ki=300nM in rat brain preparations) and shows only weak affinity for muscarinic, α1-and α2 adrenergic and histamine H1 receptors （Ki=＞2.3μ）. It is devoid of any activity against monoamine oxidase. In vivo, duloxetine inhibits 5-HT and norepinephrine uptake in rats, with ED50 values of 12 mg/kg and 22 mg/kg p.o., respectively, and has no effect on dopamine uptake at doses up to 30 mg/kg. The antidepressant and central paininhibitory action of SSNRIs are derived from the inhibition of both 5-HT and norepinephrine uptake, which increases the availability of neurotransmitters and ultimately increases serotonergic and noradrenergic function within the CNS. In the treatment of SUI with duloxetine, the increased neurotransmitter concentration is believed to increase the tone and contractions of the urethral sphincter at the opening of the bladder, helping to prevent accidental urine leakage. The absolute stereochemistry of duloxetine is shown to be S(+). It is prepared in four steps starting from 2-acetylthiophene. A key intermediate in the synthesis of duloxetine is (S)-3-dimethylamino-1-(2-thienyl)-1-propanol, which is obtained from the corresponding ketone, either by reduction with sodium borohydride and subsequent chiral resolution of the alcohol product with S-mandelic acid, or by enantioselective reduction with a chiral amine complex of lithium aluminum hydride. Etherification of this intermediate with 1-fluoronaphthalene, followed by N-demethylation with trichloroethylchloroformate affords duloxetine. Orally administered duloxetine is well absorbed, with Cmax achieved in 6 hours post dose. It exhibits dose-proportional pharmacokinetics at doses of 20–40 mg twice daily, with an average bioavailability of about 50% and an elimination half-life of about 12 hours. The volume of distribution is high (1943 L) and steady-state plasma levels are achieved after 3 days of dosing. Duloxetine is extensively metabolized, mainly by CYP2D6 and CYP1A2. The primary routes of elimination are in the urine (70%) and in the feces (20%). The recommended dosages of duloxetine are 20 mg to 30 mg twice daily for treating MDD, 60 mg once daily for treating DPN, and 40 mg twice daily for treating SUI. In clinical trials with adult MDD outpatients (n =1059), duloxetine at doses of 40–120 mg daily for 8 to 9 weeks demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale total score. In trials involving 791 DPN patients, 60 and 120 mg once daily dose of duloxetine statistically significantly improved the endpoint mean pain scores from baseline, and increased the proportion of patients with at least 50% reduction in pain score from baseline. All doses of duloxetine resulted in superior results than placebo. In phase III studies of adult women with predominant symptoms of SUI (n=1635), duloxetine 40 mg twice daily reduced the median incontinence episode frequency from baseline to a significantly greater extent than placebo (50.0–53.6% versus 27.5–40.0%). In addition, duloxetine recipients experienced significantly greater increases in their average voiding interval than placebo recipients (15.0–20.4 versus 1.7–8.5 minutes). The most commonly observed adverse events associated with duloxetine therapy are nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating. As with other 5-HT reuptake inhibitors, duloxetine is contraindicated in patients taking MAO inhibitors. Additionally, it is contraindicated in patients with uncontrolled narrowangle glaucoma.
• Uses: Duloxetine Hydrochloride acts as an antidepressant and a dual serotonin and norepinephrine reuptake inhibitor (SNRI) (1,2). Exhibits linear pharmacokinetics in mice and is not associated in any drastic changes of blood pressure or heart rate (3). Labelled Duloxetine, which is used as an antidepressant. A dual serotonin and norepinephrine reuptake inhibitor (SNRI). Current lot is 97% d7 with no d0, d1 or d2 An antidepressant. A dual serotonin and norepinephrine reuptake inhibitor (SNRI). Used in treatment of stress urinary incontinence. leucotriene antagonist, antiasthmatic anti-depressant, analgesic for osteoarthiritis and musculoskeletal pain solubility H2O: soluble5 mg/mL (clear solution, warmed)

Technology Process of N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-aminium chloride

There total 37 articles about N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-aminium chloride which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 95.0%

Duloxetine (116539-58-3,116539-59-4,116539-60-7,116817-13-1) → duloxetine hydrochloride (136434-34-9)

Guidance literature:

With hydrogenchloride; In ethyl acetate; acetone; at 25 - 35 ℃; pH=~ 1;

Reference yield: 93.0%

1-Fluoronaphthalene (321-38-0) + (S)-3-methylamino-1-(2-thienyl)-1-propanol (116539-55-0) → duloxetine hydrochloride (136434-34-9)

Guidance literature:

1-Fluoronaphthalene; (S)-3-methylamino-1-(2-thienyl)-1-propanol; With sodium hydride; In paraffin oil (nujol); dimethyl sulfoxide; at 20 - 50 ℃;

With hydrogenchloride; acetic acid; In Isopropyl acetate; at 0 - 15 ℃; for 5h;

Reference yield: 93.0%

C18H19NOS*ClH (1104890-90-5) + (R)-(-)-N-methyl-3-(1-napthalenyloxy)-3-(2-thienyl)propanamine hydrochloride (910138-96-4) → duloxetine hydrochloride (136434-34-9)

Guidance literature:

In methanol; tert-butyl methyl ether; at 0 - 25 ℃; Purification / work up;

upstream raw materials:

Duloxetine

(S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt

phenyl chloroformate

N-methyl-(S)-duloxetine

Downstream raw materials:

duloxetine succinamide

duloxetine phthalamide

2-(N-methyl-propanamine)-3-(2-naphthol)thiophene

Duloxetine

Refernces

• 1、 -. "Preparation method of S-(+)duloxetine hydrochloride intermediate". Paragraph 0100-0102. . Retrieved 2019/04/09.
• 2、 -. "Anti-depression of the raw material preparation method". Paragraph 0028; 0029. . Retrieved 2018/07/15.