KR100510788B1 - Process for preparation of the propiverine hydrochloride from O-n-propylbenzylic acid - Google Patents

Abstract

The present invention is to prepare a propiberine by reacting the on-propyl benzylic acid ester prepared from benzyl acid with 4-hydroxy-1-methylpiperidine to crystallize with hydrochloric acid gas to prepare propiberine hydrochloride Way.

Description

Process for preparation of the propiverine hydrochloride from O-n-propylbenzylic acid}

The present invention is directed to bladder stimulating conditions such as neurogenic bladder disease, neuronal urinary disease, unstable bladder disease, chronic cystitis and chronic prostatitis, as well as neurogenic bladder disease, neuronal urinary disease, unstable bladder disease, chronic cystitis and chronic prostatitis. The present invention relates to a method for preparing propiberine hydrochloride, which is useful as an agent for preventing and treating urinary incontinence and urinary incontinence caused by bladder irritant conditions.

More specifically, the present invention is prepared by reacting the on-propyl benzylic acid ester prepared from benzylic acid with 4-hydroxy-1-methylpiperidine to produce propiberine and then crystallized with hydrochloric acid gas to produce propiberine hydrochloride It relates to a method for producing propiberine hydrochloride.

Propyberine hydrochloride is a therapeutic agent for overactive bladder disease. Irritable (overactive) bladder that causes urinary incontinence (urgery incontinence) irrespective of one's will or activity if urine is frequent (urinary) or urine is urgent (urgency urinary) is the most researched in the field of urination disorder It is an ongoing and developing field. At present, etiology is active, but the exact cause is not known. Symptoms of overactive bladder disease include frequent urine, urgency and urge incontinence more than eight times a day. According to the World Urinary Incontinence Society, it can be diagnosed by urinadynamic test, especially hypotonic bladder pressure measurement, and the patient himself attempts to suppress it, but involuntary decay muscle contraction is caused by objective or causal factor. If a neurological abnormality is found, it is called "detrusor hyperreflection", otherwise it is called "detrusor root instability".

There is still considerable debate about the etiology of overactive detrusors. The main types of anaphylactic detrusors include detrusor hyperreflection, detrusor instability associated with bladder outlet obstruction, and idiopathic detrusor instability. This cannot be distinguished by bladder filling test and the pathology is different. It appears that the different forms are the result of neuronal and muscular toughness alone or in combination. The exact mechanism of overactive detrusor is currently being studied using the physiology of nerves and muscles, the microstructure of detrusor smooth muscle, and cell biochemistry.

The bladder pressure test is very important in the diagnosis of detrusor hyperactivity. Previously, urinary muscle contraction pressure of more than 15cmH2O should be required, but recently, patients have suppressed urination. If urinary muscle contraction pressure is accompanied by urinary incontinence or urinary incontinence, a diagnosis can be made. Cold water tests have been used to distinguish between detrusor overreflection and instability, but they have been used to distinguish between various forms of neurogenic lower urinary tract dysfunction.

The goal of treatment of overactive bladder is to effectively improve symptoms such as frequent urination, nocturia, urgency and urinary incontinence. There are various methods of treatment, and it can be divided into medical treatment and surgical treatment. Medical treatment includes behavioral therapy, pharmacotherapy and electro-stimulation therapy.

As behavior therapy, voluntary control of bladder function is done in early childhood, and urea medicine is a combination of normal physiological function with social behavior acquired through learning. Behavioral therapy is widely used for the treatment of lower urinary tract dysfunction, and is particularly effective for urinary incontinence and primary sensory urgency of urinary sphincter or detrusor dysfunction. A variety of behavioral therapies have been studied in the meantime, but the results of long-term follow-up on improving subjective and objective symptoms have not been reported.

Bladder training or drill is a type of biofeedback therapy that corrects poor urination habits and has three components: education, scheduled voiding, and positive reinforcement. Explain the normal urination mechanism and interval to the patient to understand the type of urination that is formed incorrectly by the patient and explain the effect of bladder training. Bladder training is a training that gradually extends the urination interval. We aim at extension to four hours. Patient education is important because the critical factor predicting success in this treatment is patient compliance with the treatment method.

As pharmacological therapy, the direct suppression of the detrusor itself and the regulation of cholinergic and adrenergic neuronal functions reflect most of the drug treatment of overactive bladder. Drugs that can inhibit or reduce physiological mechanisms associated with detrusor muscle contraction include anticholinergic drugs, smooth muscle relaxants, calcium antagonists, beta sympathetic agents, tricyclic antidepressants, and K channel openers. Can be divided.

Anticholinergic drugs (Anticholinergics), the main nerve stimulation of physiological bladder contraction is cholinergic, so anticholinergic drugs are the main treatment of overactive bladder. Anticholinergic drugs are competitive inhibitors that interfere with the muscarinic effect of acetylcholine. They inhibit normal bladder contractions and involuntary detrusor contractions. Dry mouth, decreased sweating, emotional disorders, constipation, pupil dilatation, visual field disorders, tachycardia, severe cardiac arrhythmias, angular glaucoma, gastrointestinal obstruction, severe myasthenia gravis are contraindicated. Anticholinergic medication alone is difficult to treat and can be combined with other mechanisms.

As musculotropic relaxants, there have been efforts to find other drugs due to unsafe reactions and side effects of bladder muscle to Atropine-like drugs. Smooth muscle relaxant acts directly on the distal portion of cholinergic receptors and inhibits smooth muscle activity, resulting in various anticholinergic and local anesthetic effects. Drugs include oxybutynin chloride, dicyclomine HCl, flavoxate HCl, and propiverine HCl. Side effects are similar to other anticholinergic drugs. Recently, tolterodine (Detrol) and oxybutynin ER (Ditropan XL), which have significantly reduced anticholinergic side effects, have been developed and used. Intracavitary infusions of oxybutynin were initiated due to the possibility of obtaining high concentrations of drugs in the detrusor muscle and avoiding systemic side effects and are effective when oral administration is difficult.

As calcium antagonists, calcium is a necessary element for muscle contraction. Therefore, calcium channel blockers that prevent the inflow of calcium into myocytes can be used to inhibit bladder contraction. Drugs include terodiline HCl and nifedifine. Terodiline is a representative drug with calcium antagonism and anti-muscarin action. Common side effects of calcium antagonists include hypotension, headache, constipation, tachycardia and abdominal pain.

As a beta-adrenergic agonists, there is a study to treat hyperactive bladder by stimulating the presence of beta-sympathetic receptors in the detrusor muscle, and it has been reported that terbutaline was effective in some patients.

Tricyclic antidepressants have been used for a long time to increase bladder volume and urethral resistance in children with nocturnal enuresis and urinary incontinence. Inhibition results in alpha-sympathetic nerve stimulation. The mechanism of action on the bladder is controversial, but there is a dual action that promotes urinary storage in the lower urinary tract, which reduces bladder contractility and enhances sphincter resistance. Drugs include imipramine HCl. amitriptyline HCl, doxepin.

K channel openers, as potassium channel openers, increase K excretion in smooth muscle, thereby relaxing membrane muscle hypermembrane (membrane yperpolarization). Although it does not affect the contractile force involved in normal urination, there are no objective data on clinical efficiency, proper dose, and side effects.

Alpha sympathetic blockers (alpha-adrenergic antagonists) are widely used as a drug for the treatment of prostate hyperplasia and have a good effect on urinary incontinence. In particular, when the bladder is decentralized due to nerve damage, the beta-sympathetic nerve receptor in the bladder gradually changes to the alpha-sympathetic nerve receptor, which decreases the elasticity of the bladder and increases the pressure in the bladder, resulting in an urinary incontinence. Increase the risk of kidney damage.

As other drugs, capsaicin, resiniferatoxin, and lidocaine may be used for intra- bladder administration. Capsaicin is a pungent ingredient of red pepper, which reversibly inhibits sensory nerve activity after desensitizing C-fibers that stimulate detrusor hyperactivity. It has been used topically for the treatment of skin pain disorders and increases the bladder volume and reduces bladder irritation symptoms by eliminating systemic side effects.

As electrical stimulation therapy, Caldwell reported a success rate of about 50% in 1963 by placing electrodes around the urethra and applying chronic electrical stimulation for the purpose of treating urinary incontinence, but the success rate was relatively lower than the risk of planting electrodes around the urethra. It has changed into a non-invasive way of electrical stimulation through the anus, anus and skin. Electrical stimulation has two effects: contraction of pelvic muscles and relaxation or inhibition of bladder activity. Only at low currents below 35 mA, only the pelvic muscles are affected. Pelvic muscle contractions for high currents of 65 mA or more and 40 mA or more And bladder relaxation have two effects. When the electrical stimulation is fixed at 20Hz and only the current intensity is changed, the effect of pelvic muscle contraction and bladder relaxation can be obtained, and the frequency of 20-50Hz for urinary sphincter contraction and 5-10Hz for suppressing bladder activity have. In an overactive bladder, intravaginal or intravaginal electrical stimulation strengthens the urethral muscles, increasing exit resistance and inhibiting the detrusor muscles, thereby reducing the overactive activity of the detrusor muscles. Reflexive suppression of the detrusor muscle is stimulated by the genital afferent nerves by electrical stimulation, and depressive muscle suppression is induced by pudendal-hypogastric and pudendal-pelvic spinal reflex through the shallow water. These findings indicate that bladder contractions during bladder pressure test in hypersensitive bladder patients disappear or decrease during electrostimulation treatment and the bladder volume increases by 2-5 times. However, it is reported that electrostimulation therapy is effective and long lasting for idiopathic causes, but only for a short period of time in neurogenic causes.

Intestinal cystoplasty with surgery is generally considered as a last resort before urinary tract surgery in patients with idiopathic urinary incontinence. The results are good in terms of postoperative symptoms, but cystoplasty is associated with severe complications. Bladder self-expansion using detrusor partial resection is less than cystoplasty, but there is improvement in symptoms and significant improvement in urodynamic parameters. The success rate was clearly higher in patients with idiopathic detrusor instability than in hyperreflective patients. Although less effective than using the intestine, intestinal complications can be avoided and intestinal cystoplasty may be performed later.

Prior to the present application, there is a known method for preparing propiberine hydrochloride, the synthesis process of which is as follows (see Chinese Patent No. 1285348A).

The synthesis process comprises the steps of adding sodium hydroxide to diphenyl hydroxyacetic acid to prepare a sodium salt of diphenyl hydroxyacetic acid; Adding 4-chloro-1-methylpiperidine to the sodium salt of diphenylhydroxyacetic acid to prepare hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester; Thionylchloride was added to the hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester to prepare chloro-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester hydrochloride. ; It is known to prepare propiberine hydrochloride, which comprises adding propyl alcohol to the chloro-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester hydrochloride to produce propiberine hydrochloride.

However, the main drawback in the above-described method of preparing propiberine hydrochloride is that 4-chloro-1-methylpiperidine is added to the sodium salt of diphenylhydroxyacetic acid to give 1-methyl hydroxy-diphenyl-acetic acid. In the step of preparing piperidin-4-yl ester, the reaction must be carried out under strong basic conditions, so that the ring of piperidine may be decomposed, and thus 4-chloro-1 in the sodium salt of diphenylhydroxyacetic acid. In the preparation of the hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester by addition of -methylpiperidine, the yield is actually only 30% or less. In addition, thionyl chloride was added to the conventional hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester described above to give chloro-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester. In the step of preparing hydrochloride, the reaction must be carried out using strong acid thionyl chloride, and thus the ring of piperidine may be decomposed, which causes chloro-diphenyl-acetic acid 1 from the sodium salt of diphenylhydroxyacetic acid. The yield in the preparation of -methyl-piperidin-4-yl ester hydrochloride is only 28%. Therefore, the above conventional method is inefficient in the manufacturing process and unsuitable for the industrial mass production method. In addition, the method of preparing propiberine hydrochloride by adding propyl alcohol to chloro-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester hydrochloride does not proceed well and yields poor results. A problem occurred.

The present inventors have made a lot of research and efforts to solve the above-mentioned problems in the conventional method and found a novel manufacturing method which is simpler, safer and higher in yield, and completed the present invention. The present invention relates to a method for producing propiberine hydrochloride, which has an anticholinergic action and calcium antagonistic action, and has an urinary tract disorder such as urinary insufficiency, urinary incontinence, and the like in diseases such as neuropathy, neurogenic bladder, enuresis, unstable bladder, and chronic cystitis. The present invention relates to a method for producing propiberine hydrochloride, which is a raw material of a pharmaceutical preparation for prophylaxis and treatment. Drugs that inhibit reflex bladder contraction are useful for preventing and treating urinary disorders such as anemia, neurogenic bladder, nocturnal enuresis, unstable bladder, anemia caused by chronic cystitis, and urinary incontinence. Oxyvintin hydrochloride with anticholinergic activity, propiberine hydrochloride, bamicamide, tolterodine and Japanese Patent Laid-Open No. 2-262548, Japanese Patent Laid-Open No. 6-92921, Japanese Patent Laid-Open No. 6-135958, Japanese Patent Laid-Open Compounds described in Japanese Patent Application Laid-Open No. 7-258250, Japanese Patent Application Laid-Open No. 8-291141, Japanese Patent Application Laid-Open No. 9-71563, WO93 / 16048, WO95 / 06635, WO96 / 33973, WO97 / 13766, and WO97 / 45414. This is being reported. However, these conventional compounds have insufficient effect of inhibiting reflex bladder contraction or, if sufficient, thirst (saliva secretion inhibitory effect), which is a side effect of anticholinergic action, appears as an effective amount, and the separation of main action and side effects is insufficient. It is a problem. An object of the present invention is to provide a compound that inhibits reflex bladder contraction, has a low side effect of thirst (saliva secretion inhibitory effect), has high safety, and is useful as a medicament for preventing and treating urinary tract disorders. In view of the above facts, the present inventors synthesized various compounds and studied intensively thereof, and found that they have excellent anticholinergic and calcium antagonistic effects, have little side effects such as thirst, are safe, and useful as preventive and therapeutic agents for urinary disorders. The present invention has been completed.

The present invention is to prepare a propiberine by reacting the on- propyl benzylic acid ester prepared from benzyl acid with 4-hydroxy-1-methylpiperidine to crystallize with hydrochloric acid gas to prepare propiberine hydrochloride Way. Profiberine hydrochloride preparation method of the present invention is added to 21% by weight sodium ethoxide in a nitrogen atmosphere, and then reacted by sequentially adding On-propyl benzylic acid ester, toluene, benzene and 4-hydroxy-1-methylpiperidine Profiberine is prepared and then crystallized with hydrochloric acid gas to produce propiberine hydrochloride.

O-n-propylbenzylic acid esters in the method for preparing propibel hydrochloride according to the present invention comprises the steps of preparing benzylic acid esters by reacting benzylic acid with at least one alcohol selected from the group consisting of methanol, ethanol, n-propanol and isopropanol; Tetrahydrofuran, triphenylphosphine and 1-propanol were added sequentially under a nitrogen atmosphere, and after stirring, 40% diethazodicarboxylate was added to the reaction solution, and a solution of benzylic acid ester dissolved in tetrahydrofuran was added thereto. Reaction was made to prepare an On-propylbenzylic acid ester. In addition, the O-n-propylbenzylic acid ester in the method for preparing hydrophilic hydrochloride of the present invention is prepared by reacting 1-propanol after adding phosphorus pentachloride to benzylic acid to produce O-n-propylbenzylic acid; Reacting the O-n-propylbenzylic acid with at least one alcohol selected from the group consisting of methanol, ethanol, n-propanol and isopropanol to prepare an O-n-propylbenzylic acid ester. In addition, O-n-propylbenzylic acid ester in the method for preparing propiberine hydrochloride according to the present invention comprises the step of adding benzylic acid, dioxane and anhydrous potassium carbonate in order to react the propyl chloride to the reactant to produce O-n-propylbenzylic acid; Reacting the O-n-propylbenzylic acid with at least one alcohol selected from the group consisting of methanol, ethanol, n-propanol and isopropanol to prepare an O-n-propylbenzylic acid ester.

Referring to the synthesis method for synthesizing propiberine hydrochloride according to the present invention in detail. O-n-propylbenzylic acid ester should be synthesized from benzylic acid in order to prepare propiberine hydrochloride of the present invention. In the method for preparing the intermediate product, the synthesis method of benzylic acid ester is as follows.

That is, one or more alcohols selected from the group consisting of methanol, ethanol, n-propanol and isopropanol is added to benzylic acid and sulfuric acid is carefully added. The reactant is refluxed and cooled, and the resulting crystals are filtered, washed, and dried to obtain benzylic acid ester.

The method for synthesizing O-n-propylbenzylic acid ester from the benzylic acid ester is as follows.

That is, tetrahydrofuran, triphenylphosphine and 1-propanol are sequentially added under a nitrogen atmosphere and stirred. After stirring, 40 wt% diezaazodicarboxylate was slowly added to the reaction solution at room temperature, and then a solution of benzylic acid ester dissolved in tetrahydrofuran was added, followed by reaction at room temperature. After filtering the precipitate, the filtrate is distilled, toluene is added, washed with water and treated with anhydrous sodium sulfate, and then distilled and crystallized to obtain O-n-propylbenzylic acid ester.

The method for synthesizing propiberine hydrochloride from the O-n-propylbenzylic acid ester is as follows.

21 wt% sodium ethoxide is added to the reactor under a nitrogen atmosphere, and O-n-propylbenzylic acid methyl ester, toluene, benzene, and 4-hydroxy-1-methylpiperidine are sequentially added and reacted. The reaction solution was concentrated under reduced pressure, and then toluene was added thereto and refluxed. The reaction was cooled, washed with purified water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to form propiberine base. Acetone is added thereto, hydrochloric acid gas is added to crystallize the filtrate.

In addition, another synthesis process for preparing the reaction intermediate product O-n-propylbenzylic acid ester from benzylic acid is as follows.

Benzylic acid, benzene and phosphorus pentachloride were added to the reactor and reacted, and the reaction mixture was concentrated under reduced pressure. 1-propanol was added to the concentrated reaction, refluxed and cooled. Caustic soda and purified water were added to the cooled reactant, refluxed, cooled, filtered and washed to obtain O-n-propylbenzylic acid. In order to synthesize O-n-propylbenzylic acid ester, one or more alcohols selected from the group consisting of methanol, ethanol, n-propanol and isopropanol are added to O-n-propylbenzylic acid in a reactor and sulfuric acid is carefully added. The reaction is refluxed, cooled and the resulting crystals are filtered off, washed and dried to give O-n-propylbenzylic acid ester.

In addition, another synthesis process for preparing the reaction intermediate product O-n-propylbenzylic acid ester from benzylic acid is as follows.

In order to prepare O-n-propylbenzylic acid, benzylic acid, dioxane and anhydrous potassium carbonate were sequentially added to the reactor and stirred. After stirring, slowly adding propylchloride to the reaction and refluxing. After the reaction was cooled and filtered, the filtrate was concentrated under reduced pressure and extracted with petroleum ether. Washed with purified water, dried over anhydrous sodium sulfate, filtered and the filtrate was distilled to crystallize to obtain O-n-propylbenzylic acid. In order to synthesize O-n-propylbenzylic acid ester, one or more alcohols selected from the group consisting of methanol, ethanol, n-propanol and isopropanol are added to O-n-propylbenzylic acid in a reactor and sulfuric acid is carefully added. The reaction is refluxed, cooled and the resulting crystals are filtered off, washed and dried to give O-n-propylbenzylic acid ester.

Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.

Example 1

(Step 1) Synthesis of Benzylic Acid Methyl Ester

Into a 1 L reactor, 79.88 g (0.35 mol) of benzylic acid and 58 g (1.8 mol) of methanol are carefully added 13.72 g (0.14 mol) of sulfuric acid. The reaction was refluxed for 5 hours, cooled, and the resulting crystals were filtered, washed, and dried to yield 79.94 g of benzyl acid methyl ester. (Yield 94.29%)

(Second Step) Synthesis of O-n-propylbenzylic Acid Methylester

700 ml of tetrahydrofuran, 86.56 g (0.33 mol) of triphenylphosphine and 29.75 g (0.5 mol) of 1-propanol were added to a 2 L reactor under a nitrogen atmosphere, followed by stirring. After stirring for 1 hour, 143.6 g (57.47 g 0.33 mol) of 40% by weight of diezaazodicarboxylate was slowly added to the reaction mixture at room temperature, and 79.94 g (0.33 mol) of benzyl acid methyl ester was dissolved in 700 ml of tetrahydrofuran. The solution is added at room temperature for 1 hour and then reacted at room temperature for 24 hours. After filtering the precipitate, the filtrate was distilled, 700 g of toluene was added, washed with water and anhydrous sodium sulfate, distilled and crystallized to obtain 82.43 g of O-n-propylbenzylic acid methyl ester (yield: 87.89%).

(Step 3) Synthesis of Propyberine Hydrochloride

940 g of 21% sodium ethoxide ((197.34 g, 2.9 mol) was added to a 2 L reactor under a nitrogen atmosphere. Add 36.85 g (0.32 mol) of methyl piperidine in order and react for 3 hours The reaction solution was concentrated under reduced pressure, and then 300 g of toluene was added and refluxed for 1 hour. After drying over sodium sulfate and filtration, the filtrate was concentrated under reduced pressure to form Propyverine Base, where 500 g of acetone was added and 16.06 g (0.44 mol) of hydrochloric acid was added to crystallize. 85.36%)

Example 2

(First Step) Preparation of O-n-propylbenzylic Acid

Benzylic acid 107.27g (0.47mol), benzene 500g, phosphorus pentachloride 212.4g (1.02mol) was added to the 2L reactor for 2 hours and the reaction was concentrated under reduced pressure. 306 g (5.1 mol) of 1-propanol was added to the concentrated reaction mixture, refluxed for 6 hours, and cooled. 22.56 g (0.56 mol) of caustic soda and 200 mL of purified water were added to the cooled reaction, and the mixture was refluxed for 1 hour, filtered, washed, and dried to obtain 117.91 g of O-n-propylbenzylic acid (yield: 92.84%).

(Second Step) Synthesis of O-n-propylbenzylic Acid Methylester

In a 1 L reactor, 94.58 g (0.35 mol) of O-n-propylbenzylic acid and 58 g (1.8 mol) of methanol were added carefully and 13.72 g (0.14 mol) of sulfuric acid were carefully added. The reaction was refluxed for 5 hours, cooled, and the resulting crystals were filtered, washed, and dried to yield 93.8 g of O-n-propylbenzylic acid methyl ester. (Yield 94.29%)

(Step 3) Synthesis of Propyberine Hydrochloride

940 g ((197.34 g, 2.9 mol) of 21 wt% sodium ethoxide was added to a 2 L reactor under nitrogen atmosphere, 82.43 g (0.29 mol) of on-propylbenzylic acid methyl ester, 300 g of toluene, 300 g of benzene, and 4-hydroxy- Add 36.85 g (0.32 mol) of 1-methylpiperidine in order and react for 3 hours The reaction solution was concentrated under reduced pressure, and then 300 g of toluene was added and refluxed for 1 hour.The reaction was cooled, washed three times with purified water and After drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure to form Propyverine Base, where 500 g of acetone was added and 16.06 g (0.44 mol) of hydrochloric acid was crystallized, followed by filtration to obtain 100 g of Propyberine Hydrochloride. : 85.36%)

Example 3

(First Step) Preparation of O-n-propylbenzylic Acid

107.27 g (0.47 mol) of benzylic acid, 640 g of dioxane, and 162.4 g (1.18 mol) of anhydrous potassium carbonate were sequentially added to the 2 L reactor and stirred. After stirring for 1 hour, 71.45 g (0.52 mol) of propyl chloride was slowly added to the reaction, followed by reflux for 24 hours. After the reaction was cooled and filtered, the filtrate was concentrated under reduced pressure and extracted with petroleum ether. After washing with purified water and drying over anhydrous sodium sulfate, and the filtrate was distilled and crystallized, 83.77 g of O-n-propylbenzylic acid was obtained. (Yield 92.84%)

(Second Step) Synthesis of O-n-propylbenzylic Acid Methylester

In a 1 L reactor, 94.58 g (0.35 mol) of O-n-propylbenzylic acid and 58 g (1.8 mol) of methanol were added carefully and 13.72 g (0.14 mol) of sulfuric acid were carefully added. The reaction was refluxed for 5 hours, cooled, and the resulting crystals were filtered, washed, and dried to yield 93.8 g of O-n-propylbenzylic acid methyl ester. (Yield 94.29%)

(Step 3) Synthesis of Propyberine Hydrochloride

940 g ((197.34 g, 2.9 mol) of 21 wt% sodium ethoxide was added to a 2 L reactor under nitrogen atmosphere, 82.43 g (0.29 mol) of on-propylbenzylic acid methyl ester, 300 g of toluene, 300 g of benzene, and 4-hydroxy- Add 36.85 g (0.32 mol) of 1-methylpiperidine in order and react for 3 hours The reaction solution was concentrated under reduced pressure, and then 300 g of toluene was added and refluxed for 1 hour.The reaction was cooled, washed three times with purified water and After drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure to form Propyverine Base, where 500 g of acetone was added and 16.06 g (0.44 mol) of hydrochloric acid was crystallized, followed by filtration to obtain 100 g of Propyberine Hydrochloride. : 85.36%)

Example 4

(Step 1) Synthesis of Benzylic Acid Ethyl Ester

As a result of synthesizing benzylic acid ethyl ester using the same molar number and the same reaction conditions as ethanol instead of methanol in the first step of Example 1, the same yield as the benzyl methyl ester synthesized in the first step of Example 1 And ethyl benzylic acid ester of purity was synthesized.

(Second Step) O-n-propylbenzylic acid ethyl ester synthesis

In the second step of Example 1, instead of using benzyl acid methyl ester, on-propyl benzylic acid ethyl ester was synthesized using the same number of moles and the same reaction conditions as ethyl benzylic acid ethyl ester. On-propylbenzylic acid ethyl ester having the same yield and purity as the synthesized on-propylbenzylic acid methyl ester was synthesized.

(Third step) hydrophilic hydrochloride synthesis

As a result of synthesizing On-propylbenzylic acid ethyl ester using the same number of moles and the same reaction conditions instead of using On-propylbenzylic acid methyl ester in the third step of Example 1 Propyl hydrochloride hydrochloride having the same yield and purity as that synthesized in step 2 of step 1 was synthesized.

Example 5

(First Step) Synthesis of Benzylic Acid n-propyl Ester

Benzylic acid synthesized in the first step of Example 1 as a result of synthesizing the benzylic acid n-propyl ester using the same molar number and the same reaction conditions instead of using methanol in the first step of Example 1 Benzylic acid n-propylester in the same yield and purity as the methyl ester was synthesized.

(Second Step) O-n-propylbenzylic acid n-propyl ester synthesis

As a result of synthesizing the on-propylbenzylic acid n-propyl ester using the same molar number and the same reaction conditions instead of using the benzylic acid n-propyl ester in the second step of Example 1 On-propylbenzylic acid n-propyl ester having the same yield and purity as that of On-propylbenzylic acid methyl ester synthesized in Step 2 of 1 was synthesized.

(Third step) hydrophilic hydrochloride synthesis

Instead of using On-propylbenzylic acid methyl ester in the third process of Example 1, using On-propylbenzylic acid n-propyl ester and synthesizing On-propylbenzylic acid n-propyl ester under the same molar number and same reaction conditions As a result, propibel hydrochloride having the same yield and purity as the hydropropiline hydrochloride synthesized in the second step of Example 1 was synthesized.

Test Example 1 Effect of Propyberine Hydrochloride on Acetylcholine-Induced Bladder Contraction

SD male rats weighing 230-390 g were intraperitoneally administered urethane 500 mg / kg and α-chlorarose 50 mg / kg. After rats were fixed, the rats were fixed in the abdomen and the bladder was exposed to expose the menstruation. A polyethylene tube filled with saline was inserted into the bladder government, and the bladder internal pressure was measured. An intravenous cannula for drug administration was inserted into the femoral vein, and 10 μg / kg of acetylcholine was used to cause bladder contraction, followed by acetylcholine at 10 minute intervals. After bladder contraction by acetylcholine was stabilized, the center of the test compound was dissected and administered using a needle in the duodenum, and then the action on bladder contraction reaction was observed for 120 minutes.

Bladder contraction response was measured by the difference in bladder pressure before and after the administration of acetylcholine. In addition, the bladder contraction before administration of the test compound was taken as the pre-administration value, and the 50% inhibitory dose (ID50) was calculated from the contraction response after administration of each test compound. The results are shown in the table below.

Experimental Example 2 Effect of Propyberine Hydrochloride on Carbacol-Induced Saliva Secretion Hyperactivity

The test compound was orally administered to SD male rats weighing 100 to 150 g, and carbacol 0.1 mg / kg was intraperitoneally administered 30 minutes later. Immediately after this carbacol administration, the rat was anesthetized and fixed by hand, and the saliva was wiped off with a cotton ball for 10 minutes in that state. The weight of this saliva was measured, and the saliva secretion inhibitory dose (ID50) of 50% was computed as 100% of the saliva secretion amount of the group which administered only the excipient. The results are shown in the table below.

Compound number Bladder contraction Saliva secretion Saliva secretion inhibitory bladder contraction Selectivity 3  9.4 33.9 3.6 4.0 4  9.8 56.6 5.8 6.2 12 10.0 22.5 2.3 2.4 Oxybutynin hydrochloride  3.4  3.5 1.0 1.1 Hydrochloric acid  9.9  9.2 0.9 1.0

From the above results, the compound of the present invention showed better bladder selectivity than the comparative control oxybutynin hydrochloride and the other company's commercially available propiberine hydrochloride, and showed diseases such as anemia, neurogenic bladder, enuresis, unstable bladder, and chronic cystitis. It can be confirmed that it is useful as an agent for the prevention and treatment of urinary disorders such as urinary frequency and urinary incontinence.

Profiberine hydrochloride preparation method of the present invention can be easily synthesized by using the intermediate product On-propylbenzylic acid, propiberine hydrochloride of the present invention has excellent anticholine action and calcium antagonism action and various bladder urination It has an excellent effect as an agent for preventing or treating an obstacle.

Claims (5)

A process for producing propiberine hydrochloride, characterized in that to produce propiberine by reacting O-n-propylbenzylic acid ester with 4-hydroxy-1-methylpiperidine to crystallize with hydrochloric acid gas. The method according to claim 1, wherein 21 wt% sodium ethoxide is added under a nitrogen atmosphere, and on-propylbenzylic acid ester, toluene, benzene, and 4-hydroxy-1-methylpiperidine are added sequentially, followed by reaction to prepare propibelin. And then crystallizing with hydrochloric acid gas to produce propyberine hydrochloride. The method of claim 1, wherein the O-n-propylbenzylic acid ester is reacted with benzylic acid to at least one alcohol selected from the group consisting of methanol, ethanol, n-propanol and isopropanol to prepare a benzylic acid ester; And tetrahydrofuran, triphenylphosphine and 1-propanol were added in a nitrogen atmosphere, and after stirring, 40% by weight of dimethylazodicarboxylate was added to the reaction solution, and a solution of benzylic acid ester was dissolved in tetrahydrofuran. A method for preparing propiberine hydrochloride, comprising the step of adding and reacting to produce an on-propylbenzylic acid ester. The method of claim 1, wherein the O-n-propylbenzylic acid ester is prepared by adding phosphorus pentachloride to benzylic acid and reacting 1-propanol to prepare O-n-propylbenzylic acid; And reacting the on-propylbenzylic acid with one or more alcohols selected from the group consisting of methanol, ethanol, n-propanol and isopropanol to prepare an on-propylbenzylic acid ester. Way. The method of claim 1, wherein the O-n-propylbenzylic acid ester comprises adding benzylic acid, dioxane and anhydrous potassium carbonate in order to react O-n-propylbenzylic acid by reacting propyl chloride with the reactant after stirring; And reacting the on-propylbenzylic acid with one or more alcohols selected from the group consisting of methanol, ethanol, n-propanol and isopropanol to prepare an on-propylbenzylic acid ester. Way.