136434-34-9

Usage

Uses

1. Used in Pharmaceutical Industry:
Duloxetine hydrochloride is used as an antidepressant for the treatment of major depressive disorder (MDD). It acts as a dual serotonin and norepinephrine reuptake inhibitor (SNRI), increasing the availability of neurotransmitters and ultimately increasing serotonergic and noradrenergic function within the central nervous system (CNS).
2. Used in Neuropathic Pain Treatment:
Duloxetine hydrochloride is used as an analgesic for the treatment of diabetic peripheral neuropathic pain (DPN). It inhibits the reuptake of serotonin and norepinephrine, thereby increasing their concentration in the CNS and providing pain relief.
3. Used in Urinary Incontinence Treatment (Europe):
Duloxetine hydrochloride is used as a treatment for stress urinary incontinence (SUI) in Europe. 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.
4. Used in Antidepressant and Analgesic Applications:
Duloxetine hydrochloride is used as an anti-depressant and analgesic for osteoarthritis and musculoskeletal pain. It inhibits the reuptake of serotonin and norepinephrine, increasing their availability in the CNS and providing relief from pain and depression.
5. Used in Quality Control:
Duloxetine hydrochloride serves as pharmaceutical secondary standards for application in quality control, providing a convenient and cost-effective alternative to the preparation of in-house working standards for pharma laboratories and manufacturers.
6. Used in Leukotriene Antagonist and Antiasthmatic Applications:
Duloxetine hydrochloride is used as a leukotriene antagonist and antiasthmatic, potentially providing relief from asthma symptoms by inhibiting the action of leukotrienes, which are inflammatory mediators.
7. Used in Solubility Testing:
Duloxetine hydrochloride is soluble in water at a concentration of 5 mg/mL (clear solution, warmed), which can be useful for solubility testing and formulation development in the pharmaceutical industry.

Pharmacological effects

Duloxetine hydrochloride is the salt form of antidepressant drug duloxetine. It was successfully developed by Eli Lilly Company. Its pharmacological effect is the same as duloxetine. Duloxetine hydrochloride is a new kind of selective dual inhibitor of 5 hydroxy trptamine (5-HT) and norepinephrine reuptake, and thus having antidepressant effect, while also having inhibitory effect on the central pain. Its pharmacological characteristic is being able to inhibit neuronal pre-synaptic membrane’s reuptake on 5-hydroxy trptamine and norepinephrine but instead have a low inhibitory effect on the reuptake of dopamine. Duloxetine hydrochloride is indicated for depression and it is effective in treating both endogenous and non-endogenous depression as well as the feeling of pain associated with depression. It has a therapeutic dose of 60mg/d~120mg/d with a good security and fewer adverse reactions with common adverse reactions such as nausea, dry mouth, constipation, poor appetite, fatigue, sleepiness, and increased sweating. Another indication is the pain caused by diabetic neuropathy. [Product Name] Cymbalta [Alias] LY-264453, LY-248686 [Efficacy] antidepressant drug for treatment of stressful urinary incontinence. [CAS]:136434-34-9 [Development Unit] Japan Shionogi Company, American company Eli-Lilly. Duloxetine is a selective inhibitor for 5-HT and NE reuptake (SSNRI). The exact mechanism of the anti-depression duloxetine and central analgesic effect is not yet clear. It is thought that it is related to its reinforcing effect on the function of 5 hydroxy trptamine (5-HT) and norepinephrine in the central nervous system. The results of the clinical studies have shown that duloxetine is a strong inhibitor of the neuronal 5-HT and NE reuptake and has a relatively weak inhibitory effect on the reuptake of dopamine. In vitro studies have showed that duloxetine has no significant affinity to dopaminergic receptors, adrenergic receptors, cholinergic receptors, histamine receptors, opiate receptors, glutamate receptors, and the GABA receptors. Duloxetine does not inhibit monoamine oxidase. Figure 1: The molecule formula of Duloxetine hydrochloride

Pharmacokinetics

Absorption and Distribution: oral administration of duloxetine hydrochloride enteric-coated capsules can yield a complete absorption with the average lag being two hours before the drug began to be absorbed (TLag). At 6 hours after oral administration, the duloxetine reaches maximum plasma concentration (Cmax) with eating causing no effects on the Cmax, but will delay the peak time to about 6 to 10 hours with slightly lower degree of absorption at about 10%. Compare the evening administration once with morning administration once, the absorption of duloxetine is delayed by 3 hours; apparent elimination increases by one thirds; the apparent volume of distribution is about 1640 L. Duloxetine has a high affinity (> 90%) to the human plasma proteins which mainly binds with albumin and α-acid glycoprotein. There has been no evaluation of whether there exist interactions between duloxetine with other high affinity protein binding drugs. Liver or renal insufficiency does not affect the binding between plasma protein and duloxetine. Metabolism and Excretion: oral administration of C14-labeled duloxetine can be used to determine their in vivo biotransformation and degradation. The plasma duloxetine only account for about 3% of the total radiolabel, suggesting that duloxetine is extensively metabolized with many kinds of metabolites. The major biotransformation pathway of duloxetine includes naphthyl epoxidization after the binding and further oxidation. Among in vitro tests, CYP2D6 and CYPIA2 can both catalyze the epoxidation of naphthyl with the plasma product including glucuronide-bound 4-hydroxy duloxetine and sulfate-bound 5-hydroxy 6-methoxy duloxetine. It has been separated of various kinds of other metabolites from urine with some appearing only in the small elimination metabolic bypass. Only a small amount (about 1% of the oral dose) of non-metabolized duloxetine prototype is detected in the urine with the majority (about 70% of the oral dose) existing in the form of duloxetine metabolic product which is excreted in urine. About 20% of them is excreted through feces. The above information is edited by the lookchem of Dai Xiongfeng.

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.

Precautions

1. Liver and kidney dysfunction can significantly reduce the metabolism and clearance of duloxetine. Thus it is not recommended for such patients to apply duloxetine. 2. The interaction between duloxetine and alcohol may cause liver damage. Thus it is not generally recommended for the treatment of patients with alcoholism. 3. In the clinical trials, when compared with placebo, duloxetine causes the mean systolic blood pressure increase by 2mmHg, and the average diastolic blood pressure increase by 0.5mmHg. We recommend regular measurement of blood pressure both before and during treatment and therapy.

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).

Medication of Special Populations

[Medication of Pregnant women and lactating women] It is not clear whether it is safe when applied this drug for pregnant women of pregnancy category. Therefore, for pregnant women, they should weigh both the advantages and disadvantages to decide whether they should administrate this drug. Only with potential benefits higher than risks can they apply it. Otherwise, they should not administrate this drug during pregnancy and lactation period. [Pediatric administration] There has been no enough clinical experience on the application on children. [Elderly people] Clinical studies have not observed a significant difference of the security and efficacy between the elderly population and young population. But it can’t be exclude that the sensitivity of some elderly patients can be increased.

Contraindications

1. It should be contraindicated in patients known to be allergic to duloxetine or any of the inactive ingredients contained in the product. 2. It should be prohibited to apply it in combination with monoamine oxidase inhibitors (MAOIs). It is also not allowed to administrate this drug within 14 days after the withdrawal of MAOIs; According to the half-life of duloxetine, only after the five days of the withdrawal of duloxetine can the patients begin to administrate MAOIs. 3. Clinical trials have shown that duloxetine can increase the risk of mydriasis and therefore the angle-closure glaucoma patients without control should avoid applying duloxetine.

Originator

Lilly (US)

Biochem/physiol Actions

Duloxetine hydrochloride is a dual serotonin/norepinephrine reuptake inhibitor (SNRI), widely used clinically as an antidepressant and anxiolytic.

Synthesis

The synthesis from Lilly’s group is depicted in Scheme 4. Friedel-Crafts acylation of thiophene (24) by 3- chloropropanoyl chloride (25) with SnCl4 as Lewis acid gave ketone 26 which was then enantioselectively reduced with (R )-1-methyl-3,3-diphenyl-tetrahydropyrrolo[1,2- c][1,3,2]oxazaborole (27) in the presence of borane in THF to give (S)-3-chloro-1-(2-thienyl)-1-propanol (28). Compound 28 was subjected to Finkelstein reaction to give (S)-3-iodio-1-(2-thienyl)-1-propanol which was reacted with methylamine in THF to give compound 29. The alcohol 29 was then used in a nucleophilic displacement reaction with 1-fluoronaphthalene (30) in the presence of sodium hydride in DMA to give duloxetine free base in 88% yield. Finally, the free base was treated with HCl to yield duloxetine hydrochloride (IV).

InChI:InChI=1/C18H19NOS.ClH/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16;/h2-10,13,17,19H,11-12H2,1H3;1H/t17-;/m1./s1

Upstream product

• 161005-84-1 (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt 
• 1885-14-9 phenyl chloroformate 
• 116539-60-7 (R)-Duloxetine 
• 959392-22-4 (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(3-thienyl)propanamine 
• 896446-94-9 duloxetine ethyl carbamate 
• 88-15-3 2-Acetylthiophene 
• 321-38-0 1-Fluoronaphthalene 
• 132335-44-5 (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol 
• 1263719-09-0 (RS)-N-methylbenzyl-3-(naphthalen-1-yloxy)-3-(2-thiophenyl)propylamine 
• 132335-48-9 3-[benzyl(methyl)amino]-1-(thiophen-2-yl)propan-1-one 
• 132335-49-0 α-[2-(dimethylamino)ethyl](thiophene-2-yl)methanol 
• 116817-13-1 duloxetine 
• 116539-55-0 (S)-3-methylamino-1-(2-thienyl)-1-propanol 
• 116817-77-7 Duloxetine oxalate 

Downstream Products

• 199191-66-7 duloxetine succinamide 
• 940291-11-2 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene 
• 116539-58-3 Duloxetine 
• 949095-98-1 (+/-)-N-methyl-3-(2-thienyl)-3-(4-hydroxy-1-naphthyl)-propylamine 
• 90-15-3 α-naphthol 
• 1309349-83-4 diclofenac (S)-duloxetine salt 
• 199191-67-8 duloxetine phthalamide 

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Duloxetine hydrochloride, a secondary amine containing pharmaceutical, currently marketed as Cymbalta™, is shown to undergo N-formylation as an artifact of sample preparation prior to HPLC analysis for impurities. The reaction was discovered as a result of an investigation into variability in th...detailed

Original articleStudy on the binding of chiral drug Duloxetine hydrochloride (cas 136434-34-9) to human serum albumin☆09/05/2019

Duloxetine holds a special promise as an antidepressant, and its effect depends on its binding to human serum albumin (HSA). For this reason, the binding mechanism of duloxetine with HSA was investigated. The specific binding site in HSA was identified and binding constants were determined. Dulo...detailed

Original Research PaperPreparation and evaluation of Duloxetine hydrochloride (cas 136434-34-9) enteric-coated pellets with different enteric polymers09/03/2019

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Relevant academic research and scientific papers

Preparation method of S-(+)duloxetine hydrochloride intermediate

The invention discloses a preparation method of a compound of a formula B (shown in the description). The preparation method comprises the steps of dissolving a compound of a formula A (shown in the description) in a solvent, and reacting under the effect of a reducing agent. Furthermore, the ee value of the compound of the formula B obtained by reducing in the presence of a complex, namely ferrocene, is over 98%. The preparation method provided by the invention is simple and feasible, the resolution or the chiral catalysis induction is not required, the product yield and the chiral purity arehigh, and the preparation method is suitable for the industrial production of S-(+)duloxetine hydrochloride intermediate.

Anti-depression of the raw material preparation method

The present invention discloses an anti-depression drug duloxetine hydrochloride - process improvement and optimization, which belongs to the field of biological medicine. Comprises the following main features: a) used in the Mannich reaction in N - methyl benzylamine hydrochloride, without the use of dimethylamine hydrochloride, so that the follow-up steps in the dealkylation reaction effect is better, yield is higher; b) without using any expensive chiral catalyst or a phase transfer catalyst, to use with high stability and high catalytic performance of metal catalyst; c) the better solvent for crystallization and to the solvent method, to avoid the harm of the residual solvent for crystallization; d) splitting the chiral compound in the dealkylation after, adopts a unique recrystallization technology, will split the mixture after separation, purity and relatively easy to assemble and disassemble the luminosity (S)- N - methyl - 3 - (1 - naphthoxy) - 3 - (2 - thienyl) propylamine/tartrate, so that the resulting duloxetine hydrochloride product can achieve a better therapeutic effect. The process of the invention clear, simple and convenient operation, mild reaction conditions, low production cost, is extremely beneficial to industrial production.

Preparation method for duloxetine salified hydrochloride

The invention discloses a preparation method for duloxetine salified hydrochloride, and particularly relates to a reaction for the duloxetine salified hydrochloride. The reaction comprises the following steps: using duloxetine as a reactant, adding organic solution of hydrogen chloride into duloxetine solution for reacting, while a pH value is adjusted to be 7-8, stopping adding the organic solution of hydrogen chloride until a solid is separated out, continuously adding the organic solution of hydrogen chloride, and reacting until the pH is 3-4. The salifying method is moderate in reaction conditions, simple in operation, high in product purity and optical purity, and good in inter-batch quality stability, and suitable for the industrialized production.

Preparation of duloxetine hydrochloride

The invention belongs to the fields of organic chemistry and pharmaceutical chemistry, and particularly relates to a synthesis technique of duloxetine hydrochloride. By converting the R configuration compound into S configuration, compared with the duloxetine hydrochloride prepared from the single S-configuration compound, the total yield is enhanced by nearly 47%, and the production cost is lowered. 1-chloroethylchloroformate is used instead of phenyl chloro-formate to directly generate the duloxetine hydrochloride during demethylation, thereby reducing the salification step, shortening the production cycle and saving the cost.

Duloxetine hydrochloride salt of basic and duloxetine (by machine translation)

[Problem] to suppress toxic byproducts, and suppressing the formation of decomposition products of high purity optical isomers as well as the method for manufacturing a basic duloxetine hydrochloride duloxetine. [Solution] a basic manufacturing method of duloxetine, [...], potassium hydroxide and toluene in the presence of alcohol in the mixing step, and, by heating the reaction mixture obtained, comprising the step of distilling off the solvent in the reaction portion, a basic manufacturing method of duloxetine. [Drawing] no (by machine translation)

Method for the synthesis of duloxetine

A synthetic method of duloxetine is as below: reacting water, tetrahydrofuran or dioxane, 1-chloro ethyl-N-methyl-((S)-3-(naphthalene-1-phenoxy)-3-(thiophene-2-yl) propyl) carbamate and alkali at a reflux temperature of 20 DEG C, preferably 50 DEG C; after the reaction, condensing a reaction liquid; and adding another organic solvent for extraction, so as to obtain a solution containing dutoxetine. Compared with the existing method for preparing duloxetine, the method overcomes the disadvantages of long reaction time or high reaction temperature, high energy consumption, long production cycle, low yield, a large amount of industrial waste water difficult to process, harm to the environment, flammable and explosive reagents and huge security hidden trouble, and has the advantages of low reaction temperature, short reaction time, a small amount of produced industrial waste liquid, greenness, environment-friendliness, high safety, and suitability for large-scale industrial production of duloxetine.

OLIGOMER-ARYLOXY-SUBSTITUTED PROPANAMINE CONJUGATES

The invention relates to (among other things) oligomer- aryloxy-substituted propanamine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated aryloxy-substituted propanamine compounds.

A method for preparing duloxetine hydrochloride

The invention provides a method for preparing duloxetine hydrochloride. The method comprises the following steps: dripping a compound III in sodium hydroxide to react to prepare a compound II; adding the compound II into solid ammonium chloride in batches to prepare duloxetine hydrochloride; washing with cold diethyl ether; crystallizing with acetone to prepare duloxetine hydrochloride with high purity and high yield. Compared with the prior art, the method has the advantages that the reaction time is greatly shortened, in the literature is shortened from 18-70 hours to 2-4 hours. Furthermore, the duloxetine hydrochloride prepared by the method is more convenient and more practical, and the yield is high; the duloxetine hydrochloride is washed with cold diethyl ether, and is crystalized with acetone, so that the duloxetine hydrochloride can be precipitated more easily, is high in purity and is not needed to be recrystallized, and loss is avoided. The synthesis method is easier and more practical, the production efficiency is greatly improved, the production cost is reduced, and the total yield of duloxetine hydrochloride synthesized from an initial raw material 2-acetylthiophene can be over 17 percent.

PROCESS FOR THE PREPARATION OF HIGHLY PURE DULOXETINE HYDROCHLORIDE

The present invention relates to an improved process for the preparation of Duloxetine and pharmaceutical acceptable salts or derivatives thereof, in particular to a process for large scale production of Duloxetine hydrochloride in high yield and high enantiomeric and chemical purity.