242478-38-2

Basic information

• Product Name: Solifenacin succinate
• Synonyms: 1-azabicyclo[2.2.2]octan-8-yl (1s)-1-phenyl-3,4-dihydro-1h-isoquinoline-2-carboxylate butanedioic acid;vesicare;solifenacin succinate;IsoprenalinoeSulfate;Butanedioic acid, compd. with (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (1:1);(1R,3R)-1-azabicyclo[2.2.2]octan-3-yl (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;(1S)-(3R)-1-Azabicyclo[2.2.2]oct-3-yl 3,4-Dihydro-1-phenyl-2(1H)- isoquinolinecarboxylate Butanedioic Acid;Vesikur
• CAS NO: 242478-38-2
• Molecular Formula: C11H19NO7S
• Molecular Weight: 480.56
• EINECS: 1592732-453-0
• Product Categories: API;Solifenacin
• Mol File: 242478-38-2.mol

Chemical Properties

• Melting Point: ~145°
• Boiling Point: 505.5 °C at 760 mmHg
• Flash Point: 259.5 °C
• Appearance: /
• Density: 1.24g/cm3
• Vapor Pressure: 2.41E-10mmHg at 25°C
• Refractive Index: 1.648
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Methanol (Slightly, Heated, Sonicated), Water (Slightly, Sonicated)
• Stability: Hygroscopic
• Merck: 14,8712
• CAS DataBase Reference: Solifenacin succinate(CAS DataBase Reference)
• NIST Chemistry Reference: Solifenacin succinate(242478-38-2)
• EPA Substance Registry System: Solifenacin succinate(242478-38-2)

Safety Data

• RTECS: NW7136000
• Hazardous Substances Data: 242478-38-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Solifenacin succinate is used as a muscarinic M3 receptor antagonist for the treatment of overactive bladder (pollakiuria). It helps in managing symptoms like urinary incontinence by reducing the frequency of urination and the urgency to urinate.
Used in Urology:
Solifenacin succinate is used as a urinary antispasmodic of the antimuscarinic class, providing relief from the discomfort and inconvenience caused by an overactive bladder.
Used in Clinical Trials:
In phase III trials, solifenacin succinate has demonstrated effectiveness in reducing urgency episodes in women, with a significant percentage reporting a 50% or more reduction in such episodes compared to those taking a placebo.
Used in Drug Development:
The synthesis and pharmacokinetic properties of solifenacin succinate make it a suitable candidate for once-daily dosing, with a long elimination half-life and oral bioavailability of 90%. It is predominantly excreted in the feces, with only a small percentage found in urine.
Precautions:
Solifenacin succinate is contraindicated in patients with hepatic impairment, gastric retention, urinary retention, or uncontrolled narrow-angle glaucoma. Dose adjustments may be necessary for patients using potent CYP3A4 inhibitors or those with a history of QT prolongation or on medications known to prolong the QT interval.

Proper Usage

This medication should be taken with liquids and swallowed whole. It may be taken with or without food. Take only the amount of this medication that has been prescribed for you by your doctor; taking more than the prescribed amount can cause adverse effects. If you miss a dose of this medication, begin taking it again the next day. Do not take two doses of solifenacin succinate in the same day.

Precautions

Individuals with any of the following medical problems should not take this medication: urinary retention, gastric retention, narrow angle or uncontrolled glaucoma, or severe kidney problems. Solifenacin succinate can aggravate each of these conditions. Solifenacin succinate may cause blurred vision; do not engage in potentially dangerous activities such as driving until you know the effect of the medication on your vision. This medication, like all anticholinergic medications, may cause drying of the mouth. Since continued dryness of the mouth can increase the risk of dental disease, alert your dentist if you are taking this medication. Like all anticholinergic medications, solifenacin succinate can cause or worsen constipation. Because of decreased sweating, this medication can cause heat prostration when used in a very hot environment. This medication has not been studied in pregnant women. However, it has been shown in animal studies to impact preand postnatal development. If you are pregnant, or planning to become pregnant, do not start this medication before you have discussed it with your physician. It is not known whether solifenacin succinate passes into breast milk. Women who taking this medication and wish to breastfeed should discuss it with their physician.

Possible Side effects

Side effects that are expected with this type of medication and do not require medical attention unless they continue or are bothersome: dry mouth; dry eyes; constipation, blurred vision, difficult urination. Less common side effect that should be reported to your physician: severe abdominal pain. Symptoms of overdose: severe central anticholinergic effects, including blurred vision; clumsiness or unsteadiness; confusion; seizures; severe diarrhea; excessive watering of the mouth; increasing 240 Multiple Sclerosis: A Self-Care Guide to Wellness muscle weakness (especially in the arms, neck, shoulders, and tongue); muscle cramps or twitching; severe nausea or vomiting; shortness of breath; slow heartbeat; slurred speech; unusual irritability, nervousness, or restlessness; unusual tiredness or weakness.

Originator

Yamanouchi (Japan)

Clinical Use

Selective M3 antimuscarinic Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency

in vitro

in radioligand receptor binding assay, the kivalues of solifenacin for human muscarinic m1, m2, m3, m4and m5receptors were 26, 170, 12, 110 and 31 nm, respectively. in isolated rat urinary bladder, solifenacin competitively antagonized carbachol-induced contractions, with a pa2value of 7.44±0.09[3].in bladder smooth muscle cells and salivary gland cells isolated from rats, solifenacin and the other antimuscarinic drugs inhibited carbachol-induced increases in intracellular ca2+levels in a concentration-dependent manner. thepki was 8.12for bladder smooth muscle cells, 3.6-fold more potent than that for salivary gland cells (pki=7.57) [1].

in vivo

in anesthetized rats, solifenacin dose-dependently inhibited carbachol-induced intravesical pressure elevation and salivary secretion, and exhibited selectivity (3.7- to 6.5-fold) for urinary bladder over salivary gland [1]. in anesthetized rats, solifenacin and oxybutynin increased the maximum bladder capacity in a dose-dependent manner and also decreased the maximum intravesical pressure [3].in healthy young men, multidose study evaluated doses. in the single-dose of solifenacin succinate (5-, 10-, 20-, and 30-mg), mean time to maximal concentration and elimination half-life ranged from 3.3 to 4.8 and from 40.2 to 57.6 hours, respectively.in the multidose study, the ranges were 2.9 to 5.8 and 45.0 to 64.8, respectively. the single-dose administration was well tolerated. the common adverse events were dry mouth, blurred vision, and headache [4].

Drug interactions

Potentially hazardous interactions with other drugs Avoid if GFR<30 mL/min if also taking itraconazole, ketoconazole or ritonavir. Anti-arrhythmics: increased risk of antimuscarinic side effects with disopyramide.

Metabolism

Extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4 and is excreted mainly as metabolites in urine and faeces.

references

[1]. ohtake a, ukai m, hatanaka t, et al. in vitro and in vivo tissue selectivity profile of solifenacin succinate (ym905) for urinary bladder over salivary gland in rats[j]. european journal of pharmacology, 2004, 492(2): 243-250.[2]. yang j, williams j a, yule d i, et al. mutation of carboxyl-terminal threonine residues in human m3 muscarinic acetylcholine receptor modulates the extent of sequestration and desensitization[j]. molecular pharmacology, 1995, 48(3): 477-485.[3]. ohtake a, saitoh c, yuyama h, et al. pharmacological characterization of a new antimuscarinic agent, solifenacin succinate, in comparison with other antimuscarinic agents[j]. biological and pharmaceutical bulletin, 2007, 30(1): 54-58.[4]. smulders r a, krauwinkel w j, swart p j, et al. pharmacokinetics and safety of solifenacin succinate in healthy young men[j]. the journal of clinical pharmacology, 2004, 44(9): 1023-1033.[5]. cardozo l, lisec m, millard r, et al. randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder[j]. the journal of urology, 2004, 172(5): 1919-1924.

InChI:InChI=1/C23H26N2O2/c26-23(27-21-16-24-13-10-18(21)11-14-24)25-15-12-17-6-4-5-9-20(17)22(25)19-7-2-1-3-8-19/h1-9,18,21-22H,10-16H2/t21?,22-/m0/s1

Upstream product

• 110-15-6 succinic acid 
• 242478-37-1 solifenacin 
• 1029430-94-1 2-(1H-imidazole-2-ylcarbonyl)-(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 25333-42-0 (R)-quinuclidin-3-ol 
• 541-41-3 chloroformic acid ethyl ester 
• 22990-19-8 (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 59483-84-0 bis(pentafluorophenyl)carbonate 
• 78816-91-8 bis(1,3-dioxoisoindolin-2-yl)carbonate 
• 74124-79-1 di(succinimido) carbonate 
• 180468-42-2 (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 1619-34-7 3-quinuclidinol 
• 1354548-49-4 1-azabicyclo[2.2.2]oct-8-yl (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate fumarate 
• 732228-02-3 (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3S)-1-azabicyclo[2.2.2]oct-3-yl ester 
• 740780-79-4 (3R)-1-azabicyclo[2.2.2]oct-3-yl (1R)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate 

Relevant articles and documents

Solifenacin succinate new preparation method

The present invention relates to a solifenacin succinate new preparation method which mainly comprises the following steps: 1) formula III compound (R)-(-)-quinuclidin-3-ol and formula IV compound N,N,-N,N-carbonyldiimidazole are reacted to obtain formula V compound (R)-imidazole-1-carboxylic acid-1-azabicyclo[2,2,2] octyl ester; 2) the formula V compound (R)-imidazole-1-carboxylic acid-1-azabicyclo[2,2,2] octyl ester is reacted with formula VI compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline to obtain a formula II solifenacin alkaline body; 3) the formula II solifenacin alkaline body isreacted with succinic acid, refined and purified to obtain formula I solifenacin succinate. The preparation method has the advantages that the yield of the solifenacin succinate is high and the purityis high, and the process is simple and suitable for industrial production.

A succinic acid thorley that new preparation method

The invention relates to a preparation method of succinic acid solifenacin, and belongs to the technical field of medicinal raw material preparation. According to the technical scheme, the preparation method of the novel succinic acid solifenacin is characterized in that R-3-quinuclidinol, S-1-phenyl-1, 2, 3, 4-tetrahydro naphthalene are used as raw materials, a reaction product of triphosgene and substituted phosphine oxide is used as a condensing agent, the solifenacin is prepared through a one-pot method, and then the succinic acid solifenacin is obtained through salifying. The preparation method of the succinic acid solifenacin has the beneficial effects that the operation is simple, reaction conditions are mild, and the preparation method is suitable for industrial amplification production.

A process for the preparation of new thorley that succinic acid

The invention relates to a method for preparing a solifenacin succinate ((3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinate). The method comprises the following steps: 1) preparing a compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester of formula III from a compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, serving as a raw material, of formula IV; 2) synthesizing a compound (3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate of formula II in an ionic liquid by using the compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester of formula III; and 3) salifying the compound (3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate of formula II in an organic solvent to obtain the compound solifenacin succinate ((3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinate) of formula I. The preparation method has the advantages that the process is simple, the method is suitable for industrialized production, the yield of the product is high and the purity of the product is high.

After-treatment for solifenacin and method for preparing succinic acid solifenacin

The invention discloses an after-treatment method for solifenacin. The method comprises the steps that strong acid is slowly dripped into total synthesis liquid of solifenacin, after a pH value is adjusted to be 1.0-2.0, temperature is raised, water is added, and an extracting agent is used for extraction; after a water phase is cooled, a saturated sodium carbonate solution is added to alkalinity, dichloromethane is added to carry out graded extraction, extract liquor is washed with water, and a drying agent is added for drying, so that a dry product is obtained; the dry product is steamed at low temperature to be dry to obtain an oily substance solifenacin. By optimizing the after-treatment technology, isopropyl ether and dichloromethane are only used in the after-treatment technology of solifenacin, types of solvent are reduced, operation and recycle are facilitated, and cost is saved greatly. Strong base or strong acid is not used in the alkali efflorescence process of hydrochloric acid solifenacin, a saturated NaCO3 solution is used, the reaction is mild, temperature can be controlled easily, most importantly, generation of isomers is greatly reduced, and the content of the isomers of a non-structure type (1S and 3R) is reduced.

PROCESS OF PREPARING SOLIFENACIN OR SALT THEREOF, AND NOVEL INTERMEDIATE USED IN THE PROCESS

Disclosed herein is a method of preparing solifenacin or a salt thereof, including the steps of: (a) reacting (R)-quinuclidinol with bis(pentafluorophenyl)carbonate in an organic solvent to prepare a solifenacin intermediate, (3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate, and (b) reacting the solifenacin intermediate with (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in an organic solvent to prepare solifenacin. The method is advantageous in that high-purity solifenacin or a salt thereof can be simply and efficiently prepared with high yield using a novel intermediate.

A PROCESS FOR THE PREPARATION OF SOLIFENACIN OR A SALT THEREOF

The present invention relates to an improved process for the preparation of Solifenacin or its salt of formula I, more particularly the present invention relates to an economically viable and industrially advantageous process for the preparation of highly pure Solifenacin or its salt of formula I.

Process for the Preparation of Solifenacin and Salts Thereof

The invention provides a new process for the preparation of solifenacin or a pharmaceutically acceptable acid addition salt thereof, comprising reacting (R)-quinuclidin-3-yl phenethylcarbamate with benzaldehyde in the presence of an acid to obtain a diast

An improved process for the preparation of highly pure solifenacin succinate via resolution through diastereomeric crystallisation

An improved process for the preparation of solifenacin succinate (1) involving resolution through diastereomeric crystallization is described. (1S)-IQL derivative (5) is esterified to form (1S)-ethoxycarbonyl IQL derivative (6) which is condensed with (RS)-3-quinuclidinol (7) to form a solifenacin diastereomeric mixture (8); this is subjected to resolution through diastereomeric crystallization to produce solifenacin succinate (1), which is used for the treatment of an overactive bladder.

NOVEL PROCESS FOR THE PREPARATION OF SOLIFENACIN SUCCINATE

The present invention relates to a process for the preparation of Solifenacin succinate by condensing a compound of formula (IVb) with (RS)-3-quinuclidinol, wherein, R represents methyl, ethyl, isopropyl; to produce a diastereomeric mixture of (1S)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylic acid (3RS)-1-azabicyclo[2.2.2]oct-3-yl ester, which is treated with succinic acid in a solvent or mixture of solvents to produce optically pure Solifenacin succinate, Formula (X).

PROCESS OF PREPARING SOLIFENACIN OR SALT THEREOF, AND NOVEL INTERMEDIATE USED IN THE PROCESS

Disclosed herein is a method of preparing solifenacin or a salt thereof, including the steps of: (a) reacting (R)-quinuclidinol with bis(pentafluorophenyl)carbonate in an organic solvent to prepare a solifenacin intermediate,(3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate, and (b) reacting the solifenacin intermediate with (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in an organic solvent to prepare solifenacin. The method is advantageous in that high-purity solifenacin or a salt thereof can be simply and efficiently prepared with high yield using a novel intermediate.