KR20060099798A - Method for preparing tolterodine l-tartrate - Google Patents

Abstract

The present invention relates to a method for preparing tolterodine tartarate, more specifically methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (4), 3- (2-methoxy- 5-Methylphenyl) -3-phenyl-propanol (5), 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (6), N, N-diisopropyl- 3- (2-methoxy-5-methylphenyl) -3-phenyl-propylamine (7) and N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine By producing tolterodine tartrate through the synthesis step of (8) relates to a method for producing tolterodine tartrate, improved yield and purity of tolterodine tartrate, easy to operate the process and reduced production cost .

Tolterodine, tartarate, incontinence

Description

Method for preparing tolterodine tartrate {Method for preparing tolterodine L-tartrate}

The present invention relates to a method for preparing tolterodine tartarate, more specifically methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (4), 3- (2-methoxy- 5-Methylphenyl) -3-phenyl-propanol (5), 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (6), N, N-diisopropyl- 3- (2-methoxy-5-methylphenyl) -3-phenyl-propylamine (7) and N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine By producing tolterodine tartrate through the synthesis step of (8) relates to a method for producing tolterodine tartrate, improved yield and purity of tolterodine tartrate, easy to operate the process and reduced production cost .

(R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine, which is commonly known as tolterodine, is known as a useful compound for treating urinary incontinence. Urinary incontinence is a urinary-related disorder and indication that a significant proportion of the adult population suffers from loss of contractile force of the bladder, obstruction of the urethra, and decline of the pelvic muscles.

Tolterodine is a type of amine that, when reacted with a sufficient concentration of acid, can itself produce acid addition salts. To prepare a pharmaceutical composition comprising tolterodine, it is preferable to prepare tolterodine as a compound that is water soluble and crystalline rather than free amine. The salts include both inorganic and organic acids. Pharmaceutically acceptable salts of tolterodine include methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, citric acid, tartaric acid, fumaric acid, maleic acid, CH _3- (CH ₂ ) n-COOH, where n is 1-4), HOOC- (CH ₂₎ -COOH (where n is known as including an acid salt, such as of 1 to 4).

In particular, (R) -tolterodine L-tartarate is known to be most effective in the treatment of urinary incontinence, and there have been many studies related to it.

U.S. Patent No. 5382600 relates to 3,3-diphenylpropylamine and pharmaceutical compositions thereof, which discloses tolterodine and its derivatives useful for the treatment of urinary incontinence and methods for their preparation.

In addition, Korean Patent No. 10-0463614 provides a method for preparing tolterodine, tolterodine hydrochloride, and tolterodine L-tartarate.

However, these conventional formulations still have a lot of room for improvement in terms of yield and purity of final products and cost of production.

Accordingly, the present inventors have conducted research and efforts to solve these conventional problems, methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (4), 3- (2-methoxy -5-methylphenyl) -3-phenyl-propanol (5), 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (6), N, N-diisopropyl -3- (2-methoxy-5-methylphenyl) -3-phenyl-propylamine (7) and N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propyl The preparation of tolterodine tartrate through the synthesis step of the amine (8), the present invention was found to be easy to operate the process as well as to reduce the production cost as well as excellent yield and purity and easy to obtain raw materials Completed.

Accordingly, an object of the present invention is to provide a novel method for preparing tolterodine tartarate.

The present invention obtains methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (4) from 6-methyl-4-phenyl-3,4-dihydrocomarin (3). Stage 1; Obtaining 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol (5) from said methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (4) Two steps; 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (6) from 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol (5); Obtaining a third step; N, N-diisopropyl-3- (2-methoxy-5-methylphenyl)-from 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (6); A fourth step of obtaining 3-phenyl-propylamine (7); N, N-diisopropyl-3- (2-hydroxy-5- from the above N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenyl-propylamine (7) A fifth step of obtaining methylphenyl) -3-phenyl-propylamine (8); A sixth step of reacting the N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine (8) with tartaric acid to obtain tolterodine tartarate; It is a method for producing tolterodine tartrate, characterized in that it comprises a.

The present invention will be described in more detail as follows.

The present invention relates to methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (4), 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol (5), 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (6), N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3 Tolterodine tartrate was prepared by a synthesis step of -phenyl-propylamine (7) and N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine (8). The present invention relates to a method for producing tolterodine tartrate, which has been improved to be excellent in yield and purity of tolterodine tartrate, to facilitate operation of the process, and to reduce production cost.

Scheme 1

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to Examples.

Example 1 Preparation of 6-Methyl-4-phenyl-3,4-dihydrocomarin (Formula 3)

115 g of p-methyl-phenol (Formula 1) were placed in a dried reactor and heated to liquid under nitrogen atmosphere. 150 g of cinnamic acid and concentrated sulfuric acid were added thereto and heated at 125 ° C. for 6 hours. The mixture was cooled to 100 ° C and the concentrated sulfuric acid was separated. Thereafter, 100 ml of water, 300 ml of toluene and potassium carbonate were added thereto, and the pH was adjusted to 8-9, and the water was separated. The remaining organic phase was extracted three times with water and after drying and evaporating, 140 ml of isopropanol was added, cooled, solidified, frozen and filtered. The filter cake was washed with cold isopropanol and dried to give 180 g of 6-methyl-4-phenyl-3,4-dihydrocomarin (Formula 3).

Example 2 Preparation of Methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (Formula 4)

180 g of 6-methyl-4-phenyl-3,4-dihydrocomarin (Formula 3), 350 ml methanol, 350 ml acetone, 230 g methyl iodide and 126 g potassium carbonate were placed in a dried reactor. The mixture was heated to reflux for 24 hours with stirring and it was cooled to room temperature. The solvent was then evaporated and filtered. The remaining filter mass was washed with ether and the filtrate was washed three times with water, dried over anhydrous sodium sulfate and evaporated. Through this process, 195 g of methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (Formula 4) was obtained as a pale yellow concentrated oil.

Example 3: Preparation of 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol (Formula 5)

26.4 g of LiAlH ₄ and 700 ml dry ether are placed in a dried reactor, 195 g of methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (Formula 4) and 350 ml of drying Dropped ether. The reaction mixture was refluxed during heat generation and stopped for 5 hours. After stirring the mixture for 24 hours, slowly stir 300 ml of water and stir again while mixing 100 ml 15% sodium hydroxide solution and continuing overnight. The mixture thus obtained was filtered. The filter mass was washed several times with ether, dried and evaporated. 163 g of 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol (Formula 5) was obtained as a concentrated yellow viscous oil.

Example 4: Preparation of 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (Formula 6)

450 ml chloroform, 163 g of 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol (Formula 5) and 205 ml of pyridine are placed in the reactor and about -10 with ice-brine. Cool to C. 232 g of p-toluene sulfonyl chloride was added thereto, followed by several exothermic reactions. After cooling with stirring for 1 hour, the ice-brine was removed, and after stirring for 1 hour at room temperature, it was maintained for one day. The resulting mixture was poured into 1000 ml ice-water, the organic phase separated and washed three times with water and twice with 2 N HCl. The remaining organic phase was washed with water until neutral. After drying, 231 g of 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (Formula 6) as a brown viscous oil was obtained.

Example 5 Preparation of N, N-Diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenyl-propylamine (Formula 7)

231 g of 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (Formula 6), 790 ml diisopropylamine and 565 ml acetonitrile were placed in an autoclave for 5 days Heated to 90 ° C. and removed and evaporated. The residue was treated with 600 ml 2 N NaOH and extracted with ether. The extract was washed twice with water and the ether was extracted with 600 ml 2 N HCl solution. The HCl solution was washed twice with ether, basified and extracted with ether. The organic phase was washed twice with water, dried and evaporated to give 126 g of oil. 300 ml of ethanol and 3 g of activated carbon were added to 126 g of the oil thus obtained, and the mixture was refluxed, filtered, evaporated and concentrated to give a viscous oil, N, N-diisopropyl-3- (2-methoxy- 121 g of 5-methylphenyl) -3-phenyl-propylamine (Formula 7) was obtained.

Example 6 Preparation of N, N-Diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine (Formula 8)

40 g, N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenyl-propylamine (Formula 7), 180 ml 40% HBr and 180 ml acetic acid were added to the reactor and stirred Heated to reflux for 6 hours. The solvent was evaporated and the residue was transferred to the beaker. 250 ml of water and 250 ml of methylene chloride were placed in a beaker and the pH was adjusted to 11 with NaOH solution. After stirring, the mixture was separated and the liquid phase was extracted once with methylene chloride. The organic phases were combined, washed twice with water, dried and evaporated to give 42 g of oil. 42 g of oil were dissolved with 300 ml ethyl acetate and heated to 55-60 ° C. and 13 ml sulfuric acid was dropped. Stirred for 1 hour, cooled to room temperature, maintained for 2 hours, then frozen for 1 hour and filtered. The filter mass was washed with ethyl acetate to give 50 g of a white solid. The solid was transferred to a beaker, 300 ml of water and 250 ml of methylene chloride were added and the pH was adjusted to 9-11 with NaOH. After dissolution the mixture was separated and the liquid phase was washed once with methylene chloride. The organic phases were combined, washed twice with water, dried and evaporated to give 35 g of concentrated oil N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine (Formula 8). Got it.

Example 7 Preparation of Tolterodine Tartarate (Formula 9)

35 g of N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine (Formula 8) were added to a dried reactor, dissolved in 100 ml ethanol, stirred, and then 16.1 g tartaric acid. The salt was dropped with 100 ml ethanol solution. Then, the mixture was refluxed for 1 hour with stirring, left overnight, and filtered. The filter cake was washed with ice-ethanol to obtain 28 g of tolterodine tartarate (Formula 9).

As described above, the method for preparing tolterodine tartrate of the present invention is methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (4), 3- (2-methoxy-5-methylphenyl ) -3-phenyl-propanol (5), 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (6), N, N-diisopropyl-3- ( 2-methoxy-5-methylphenyl) -3-phenyl-propylamine (7) and N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine (8) By producing tolterodine tartrate through the synthesis step of the yield and purity of tolterodine tartrate is excellent, easy operation of the process and there is a remarkable effect to reduce the production cost.

Claims (1)

Methyl 3- (2-methoxy-5-methylphenyl) -3- by reacting 6-methyl-4-phenyl-3,4-dihydrocoumarin (3) with methanol, acetone, methyl iodide and calcium carbonate First step of obtaining phenyl-propionate (4); 3- (2-methoxy-5-methylphenyl) -3-phenyl by reacting the methyl 3- (2-methoxy-5-methylphenyl) -3-phenyl-propionate (4) with LiAlH ₄ and dry ether A second step of obtaining propanol (5); 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol (5) and pyridine were reacted with p-toluene sulfonyl chloride to react with 3- (2-methoxy-5-methylphenyl A third step of obtaining) -3-phenyl-propanol-p-toluene sulfonate (6); By reacting 3- (2-methoxy-5-methylphenyl) -3-phenyl-propanol-p-toluene sulfonate (6) with diisopropylamine and acetonitrile, N, N-diisopropyl-3- ( A fourth step of obtaining 2-methoxy-5-methylphenyl) -3-phenyl-propylamine (7); N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenyl-propylamine (7) with 40% HBr and acetic acid to react to N, N-diisopropyl-3- A fifth step of obtaining (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine (8); A sixth step of reacting the N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenyl-propylamine (8) with tartaric acid to obtain tolterodine tartarate; Method for producing tolterodine tartrate, characterized in that it comprises a.