KR100717361B1 - Method of preparing racemic tolterodine and its intermediate - Google Patents

Abstract

The present invention provides N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine (also referred to as 'tolterodine racemate') represented by the following general formula (I) It relates to a method of reducing, 6-methyl-4-phenyl-3,4-dihydrocoumarin is reduced by ring opening, the obtained compound is methanesulfonyl, and the iodide salt and N, N-diisopropylamine are continuously reacted. It is a method for producing tolterodine racemate easily and with high purity by hydrolyzing the obtained compound.

Tolterodine, tolterodine racemate, N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine, (R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine, 6-methyl-4-phenyl-3,4-dihydrocoumarin, methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl ) -4-methylphenyl ester

Description

Method for preparing tolterodine racemates and intermediates thereof Method of Preparing Racemic Tolterodine and Its Intermediate

The present invention relates to a process for preparing tolterodine racemates and intermediates thereof. More specifically, the present invention relates to (R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine, which is a muscarinic receptor antagonist represented by the formula (II) ( New preparation method of tolterodine racemate represented by formula (I) which is a core intermediate of tolterodine) and methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester thereof It is about.

Urinary incontinence is a condition in which urine flows out of the urethra regardless of one's intention. In particular, urge urinary incontinence is thought to be caused by uncontrolled smooth muscle fiber bundle contraction, which forms the muscle membrane of the bladder while the bladder is excessively activated to fill the bladder with urine. The recent development of tolterodine has attracted attention as a therapeutic agent for it, with clinical results showing that there is an excellent therapeutic effect on overactive bladder such as urinary, urgency, or urinary incontinence.

Methods for preparing tolterodine or analogs thereof are disclosed in US Pat. No. 5,538,600 (Pharmacia Aktiebolag), Korean Patent No. 0463614 (Pharmacia & Upjohn Company), and US Patent Application 2001/0016669 (Pher G. Andersson).

The method for preparing tolterodine disclosed in the above document is summarized as follows.

U.S. Pat.No. 5,526,600 is an initial method for preparing tolterodine, which ring-opens and reacts 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by the formula (III) with a lithium aluminum hydride. Is tosylated, reacted with diisopropylamine, and dimethylated to prepare tolterodine racemate. The tolterodine racemate obtained at this time is isolated by L (+)-tatariic acid to prepare pure tolterodine represented by the formula (II) (see Scheme 1 below). This method has a problem in that there are many reaction steps and a high pressure reaction process, as well as a number of reagents (eg, lithium aluminum hydride, tribromoborane, etc.) which are difficult to use in a mass synthesis process.

Scheme 1

The method of preparing Korean Patent No. 0463614 is an improved method of US Pat. No. 5,538,600 to reduce 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by Formula (III) as shown in Scheme 2 below. A corresponding alcohol, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopylin-2-ol, was prepared, the alcohol was reacted with isopropylamine, and the racemates formed were separated Tolterodine represented by II) is prepared (see Scheme 2 below). This method is an improvement over the process of Scheme 1, but the reaction process is greatly shortened, but there is a problem in that a reagent such as diisobutyl aluminum hydride or hydrogen reaction, which is difficult to use in a mass synthesis process, must be used.

Scheme 2

U.S. Patent No. 2001/0016669 discloses that 5-methyl-3-phenyl-in-1-one is asymmetrically reduced to a carbonyl group using (R) -MeCBS catalyst, and 5-methyl-3- (using DABCO). S) -phenyl-indan-1-one was prepared, and 6-methyl-4- (S) -phenyl-3,4-dihydrocoumarin was prepared using mCPBA, and the obtained alcohol was reduced to diiso. Reacting with propylamine to prepare tolterodine represented by the formula (II) (see Scheme 3 below). This reaction is advantageous in that it can produce only the desired isomer by asymmetric reduction instead of separating the isomer in the last step like the reaction described in Scheme 1 or Scheme 2, but the synthesis process is increased and it is difficult to use in the mass synthesis process. There are problems that many reagents or reactions must be used.

Scheme 3

Accordingly, the present inventors have continued to research to produce tolterodine in a simpler and easier process by solving the problems of the known technology as described above, 6-methyl-4-phenyl-3, represented by the formula (III), 4-dihydrocoumarin is reacted with lithium borohydride to prepare 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol represented by formula (IV), which is methanesulfonyl chloride and tri Ethylamine was reacted to prepare methanesulphonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester represented by the formula (V), and the compound (V) was reacted with an iodide salt and N, N -Diisopropylamine was reacted sequentially to prepare methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester represented by the formula (VI), and the compound (VI) Reaction of the hydroxide salt in a mixed solvent of water-soluble solvent and water to formula (I) Found out the fact that the display N, N- diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropan amine in a high yield can readily be synthesized.

That is, the inventors of the present invention are the same as the starting material described in US Pat. No. 5,538,600, but do not separately perform the protecting group introduction reaction of the phenol group, and do not use a high-pressure reaction process that is difficult to use in a mass synthesis process, N, By using a process for effectively introducing N-diisopropylamine, the existing tolterodine racemate synthesis process has been drastically improved.

According to the present invention, a reagent which causes a fire when contacted with moisture, a reagent that generates a toxic gas, or a high-pressure hydrogen is not used, and the reaction process is shortened without using a high-pressure reaction process. Tolterodine racemate represented by general formula (I) can be manufactured.

An object of the present invention is (R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine (tolte), which is a muscarinic receptor antagonist with excellent effect in the treatment of urinary incontinence. It is to provide a new method for preparing tolterodine racemate, a core intermediate of Rodin).

Another object of the present invention is simply methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl which is an intermediate of tolterodine racemate using a process for preparing tolterodine racemate. To prepare an ester.

Another object of the present invention is to provide a method for preparing a safe tolterodine racemate without using a reagent that causes a fire when contacted with moisture, a toxic gas generating reagent, or high-pressure hydrogen, unlike the known art. .

Another object of the present invention, unlike the known technology, without using a high-pressure reaction process from the 6-methyl-4-phenyl-3,4-dihydrocoumarin through a four-step reaction process to the tolterodine racemate It is to provide a method of manufacturing.

Still another object of the present invention is to provide a method for producing tolterodine racemate in high purity and high yield more simply and economically.

Another object of the present invention is to provide a method suitable for the preparation of tolterodine racemates in bulk.

The above and other objects of the present invention can be achieved by the present invention described below.

The present invention provides a method for preparing tolterodine racemates and intermediates thereof.

The present invention provides N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine represented by the following formula (I) by the following process (tolerodine racemate) A method of preparing a compound of the present invention relates to a method of preparing: 2- (3) represented by formula (IV) by reacting 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by formula (III) with lithium borohydride. Preparing hydroxy-1-phenylpropyl) -4-methylphenol, reacting a compound of formula (IV) with methanesulfonyl chloride and triethylamine to give methanesulphonic acid 3- ( Preparing 2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester, the compound of formula (V) is sequentially reacted with an iodide salt and N, N-diisopropylamine, represented by formula (VI) Preparing methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenylester, the compound of formula (VI) Reacting the compound with a hydroxide of an alkali metal in a mixed solvent of an aqueous solvent and water to prepare tolterodine racemate.

Preferred embodiments of the invention are shown in Scheme 4 below.

Scheme 4

Wherein M is an alkali metal such as lithium, sodium, potassium, rubidium, cesium or ammonium such as ammonium, tetraethylammonium or tetrabutylammonium, and M 'is an alkali metal such as lithium, sodium or potassium.

The present invention also provides a method for preparing methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenylester represented by the formula (VI) which is an intermediate compound for preparing tolterodine. .

According to the present invention, it is possible to obtain methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester as an intermediate thereof in the process of preparing tolterodine racemate. Reaction of 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol represented by formula (IV) with methanesulfonyl chloride and triethylamine to give methanesulphonic acid 3- ( 2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester was prepared, and methanesulfonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester (V) was treated with iodide and N By sequentially reacting with N-diisopropylamine, methanesulfonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester represented by the general formula (VI) can be obtained.

In the following, the present invention is described in more detail.

First step: 2- (3-hydroxy-1- Phenylpropyl )-4- Of methylphenol (IV)  Produce

2- (3-hydroxy-1) represented by formula (IV) by reacting 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by formula (III) with lithium borohydride under a reaction solvent -Phenylpropyl) -4-methylphenol is prepared.

The reaction solvent is preferably ether such as tetrahydrofuran, diisopropyl ether or dioxane, and tetrahydrofuran is most preferred. Reaction temperature is the boiling point of 0 degreeC-a reaction solvent, Preferably it is 25-35 degreeC. The reaction time is between 12 hours and 36 hours, more preferably 18 hours to 30 hours.

Lithium borohydride is used in the amount of 1 to 1.5 equivalents, more preferably 1 to 1.05 equivalents based on 6-methyl-4-phenyl-3,4-dihydrocoumarin (III).

2- (3-hydroxy-1-phenylpropyl) -4-methylphenol (IV) obtained through the reaction as described above was concentrated under reduced pressure of a solvent, water and hydrochloric acid were added to make the aqueous layer acidic. Extract with acetate and concentrate to recover.

Second step: Methanesulfonic acid  3- (2- Methane Sulfoxy -5- Methylphenyl ) -3- Phenylpropyl Ester  (V) Preparation

Methanesulfonyl chloride and triethylamine were added to 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol represented by the formula (IV) obtained in the first step under a reaction solvent to react with the formula (V). Methanesulfonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester represented by is prepared.

Reaction solvents include ethers such as tetrahydrofuran, diisopropyl ether and dioxane, nitriles such as acetonitrile, chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, dimethylacetamide and dimethylformamide. It can select from amides, such as these, and can use. Reaction temperature is 0 degreeC-35 degreeC, Preferably it is 25-30 degreeC. The reaction time is between 2 hours immediately after the start of the reaction, more preferably 40 minutes to 1 hour.

Methanesulfonyl chloride is used in the amount of 2 to 3 equivalents, preferably 2.2 equivalents, relative to 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol (IV).

Triethylamine is used in the amount of 1 to 1.2 equivalents based on methanesulfonyl chloride, preferably 1.1 equivalents.

The compound represented by the formula (V) obtained through the reaction as described above can be recovered by concentrating the solvent under reduced pressure, extracting by adding ethyl acetate and water, washing and concentrating.

Step 3: Methanesulfonic acid  2- (3- Diisopropylamino -One- Phenylpropyl )-4- Methylphenyl ester  ( VI Manufacturing

Iodine salt and N, N-diisopropylamine were added to methanesulphonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester represented by the formula (V) obtained in the second step under a reaction solvent. By sequentially reacting, methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester represented by the formula (VI) is prepared.

Reaction solvents include ethers such as tetrahydrofuran, diisopropyl ether and dioxane, nitriles such as acetonitrile, chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, dimethylacetamide and dimethylformamide. It can select from amides, such as these, and can use acetonitrile among them. The amount of the reaction solvent is used in a ratio of 5 ml to 20 ml with respect to 1 g of methanesulphonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester (V), preferably in a ratio of 7 ml to 10 ml. Used.

The reaction time with the iodide flame is 3 hours to 10 hours, more preferably 5 hours to 7 hours. The reaction time with N, N-diisopropylamine is 12 hours to 36 hours, more preferably 20 hours to 26 hours. The reaction temperature is from 60 ° C. to the boiling point of the reaction solvent.

As the iodide, iodide of an alkali metal such as lithium iodide, sodium iodide, potassium iodide, rubidium iodide, cesium iodide or the like or an iodide of ammonium such as ammonium iodide, tetraethylammonium iodide, tetrabutylammonium iodide and the like is used. Iodide is used in the amount of 1.1 to 2 equivalents, preferably 1.5 equivalents, to methanesulphonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropylester (V).

The content of N, N-diisopropylamine is 0.5 to 1 times the volume of the reaction solvent used, preferably 0.7 times.

The compound represented by the formula (VI) obtained through the reaction as described above can be recovered by concentrating the solvent under reduced pressure, extracting by adding ethyl acetate and water, washing and concentrating.

Fourth Step: N, N- Diisopropyl -3- (2- Hydroxy -5- Methylphenyl ) -3- Of phenylpropanamine (I)  Produce

N represented by the formula (I) by reacting with methanesulfonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester represented by the formula (VI) under a reaction solvent by adding a hydroxide salt, Prepare N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine.

As the reaction solvent, a mixed solvent of an aqueous solvent and water is used. The water-soluble solvent can be selected from tetrahydrofuran, acetonitrile, ethanol and methanol, of which methanol is most preferred. The volume ratio of the water-soluble solvent and water used is 10: 1 to 1: 2 and preferably 3: 1 to 1: 1.

As the hydroxide, an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide and potassium hydroxide is used. The amount of hydroxide is used in the amount of 2 to 10 equivalents based on methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester represented by the formula (VI) used in the reaction, preferably 3 to 5 equivalents are used.

Preferred reaction temperatures are the boiling points of the mixed solvents. The reaction time is 3 hours to 20 hours, more preferably 6 hours to 10 hours.

N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine represented by the formula (I) obtained through the reaction as described above was removed under reduced pressure to remove the organic solvent. After adjusting the pH of the aqueous layer to 8 with hydrochloric acid it can be recovered by extraction with ethyl acetate.

The production method according to the present invention consisting of a four-step reaction process as described above facilitates the synthesis process by not using a reagent or a high pressure process that is difficult to use in a mass synthesis process, and separates the reaction of introducing a protecting group into a phenol group. The synthesis process can be shortened by performing the process without including the process.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection defined by the appended claims.

Example

Example  1: 2- (3-hydroxy-1- Phenylpropyl )-4- Of methylphenol (IV)  Produce

After dissolving 136.2 g (571 mmol) of 6-methyl-4-phenyl-3,4-dihydrocoumarin in 400 ml of tetrahydrofuran, 13.1 g (571 mmol) of lithium borohydride was slowly added under ice-cooling, and the reaction solution was allowed to stand at room temperature. Raised to After stirring the reaction solution for 24 hours, distilled water was added little by little under ice-cooling, and the solvent was removed under reduced pressure. To the obtained residue was added 200 ml of distilled water and 20 ml of concentrated hydrochloric acid, extracted with ethyl acetate, washed with 400 ml of distilled water and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain 122.13 g (yield 88%) of solid 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol.

¹ H NMR (CDCl ₃ ) δ = 2.18 (s, 3H), 2.19 (m, 1H), 2.32 (m, 1H), 3.53 (m, 1H), 3.72 (m, 1H), 4.52 (q, 1H) , 6.68 (d, 1H), 6.85 (m, 2H), 7.17 (m, 1H), 7.27 (m, 4H)

Example  2 : Methanesulfonic acid  3- (2- Methane Sulfoxy -5- Methylphenyl ) -3- Of phenylpropyl ester (V)  Produce

115.6 g (477 mmol) of 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol obtained in Example 1 was dissolved in 500 ml of dichloromethane, and then 115.86 g (1145 mmol) of triethylamine and methanesulfonyl under ice-cooling. 120.17 g (1049 mmol) of chloride were added sequentially. After raising the temperature of the reaction solution to room temperature, the mixture was stirred for 1 hour, washed with 1500 ml of distilled water, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to give 190.08 g (yield 100%) of oily methanesulphonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester.

¹ H NMR (CDCl ₃ ) δ = 2.27 (s, 3H), 2.47 (q, 2H), 2.97 (s, 3H), 3.01 (s, 3H), 4.18 (m, 2H), 4.56 (t, 1H) , 7.04 (dd, 1H), 7.12 (d, 1H), 7.28 (m, 6H)

Example  3: Methanesulfonic acid  2- (3- Diisopropylamino -One- Phenylpropyl ) -4-methylphenyl ester ( VI)  Produce

Methanesulphonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester 190.08 g (477 mmol) and 118.78 g (715 mmol) of potassium iodide obtained in Example 2 were dissolved in 1000 ml of acetonitrile for 6 hours. It was refluxed. After the reaction solution was cooled to room temperature, 700 ml of N, N-diisopropylamine was added thereto, and the mixture was refluxed for 24 hours. After the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and 600 ml of ethyl acetate was added thereto, followed by washing with 1500 ml of distilled water. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 190.29 g (yield 99%) of oily methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester.

¹ H NMR (CDCl ₃ ) δ = 0.91 (m, 12H), 2.11 (m, 2H), 2.29 (m, 5H), 2.86 (s, 3H), 2.96 (m, 2H), 4.33 (t, 1H) , 7.00 (dd, 1H), 7.16 (m, 1H), 7.27 (m, 6H)

Example  4: N, N- Diisopropyl -3- (2- Hydroxy -5- Methylphenyl ) -3- Of phenylpropanamine  Produce

190.2 g (471 mmol) of methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester obtained in Example 3 were dissolved in 1000 ml of a 2: 1 mixed solvent of methanol and water, and sodium hydroxide 94.2 g (2350 mmol) was added. The reaction solution was refluxed for 10 hours, the temperature of the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and the volume of the reaction solution was concentrated to 1/3. The pH of the aqueous layer was adjusted to 8 with concentrated hydrochloric acid, and extracted with 600 mL of ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 152.95 g (yield 99%) of oily N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine. .

¹ H NMR (CDCl ₃ ) δ = 1.08 (dd, 12H), 2.11 (m, 3H), 2.11 (m, 1H), 2.36 (m, 2H), 2.73 (m, 1H), 3.24 (m, 2H) , 4.47 (d, 1H), 6.55 (s, 1H), 6.82 (m, 2H), 7.22 (m, 2H), 7.31 (m, 4H)

The present invention relates to 2- (3-hydroxy-1) represented by formula (IV) by reacting 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by formula (III) with lithium borohydride. -Phenylpropyl) -4-methylphenol, which is reacted with methanesulfonyl chloride and triethylamine to give methanesulphonic acid 3- (2-methanesuloxy-5-methylphenyl) -3 represented by the formula (V). -Phenylpropylester, which is reacted sequentially with an iodide salt and N, N-diisopropylamine to form methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) represented by the formula (VI) N-N-diisopropyl-3- (2-hydroxy-5-methylphenyl)-represented by the formula (I) is prepared by reacting a 4-hydroxyphenyl salt with a water-soluble solvent and a mixed solvent of water. It has the effect of providing a method for easily preparing 3-phenylpropanamine in high yield.

The prior art related to the process for preparing tolterodine racemate represented by the formula (I) has a long reaction process using a reagent which causes a fire upon contact with moisture, a reagent which generates toxic gases, or high pressure hydrogen. There was a problem that it was difficult to apply to the actual bulk process. However, the present invention does not use dangerous or toxic reagents as described above, and can produce tolterodine racemate with high quality and high yield with a new process with a shortened reaction process without using a high pressure reaction process. Has an advantage.

Simple modifications and variations of the present invention can be readily understood by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.

Claims (7)

6-methyl-4-phenyl-3,4-dihydrocoumarin represented by the following formula (III) is reacted with lithium borohydride to form 2- (3-hydroxy-1- represented by the following formula (IV) First step of preparing phenylpropyl) -4-methylphenol, Methanesulfonic acid 3- (2-methane represented by the following general formula (V) by reacting 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol (IV) with methanesulfonyl chloride and triethylamine A second step of preparing sulfoxy-5-methylphenyl) -3-phenylpropyl ester, Methanesulfonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester (V) is reacted sequentially with an iodide salt and N, N-diisopropylamine, and is represented by the following general formula (VI) A third step of preparing methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenylester, and Fourth step of reacting methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenylester (VI) with a hydroxide of an alkali metal: A process for producing (N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine (tolerodine racemate) represented by the following general formula (I).

Reaction of 2- (3-hydroxy-1-phenylpropyl) -4-methylphenol represented by the formula (IV) with methanesulfonyl chloride and triethylamine to give the methanesulphonic acid 3- ( Preparing 2-methanesulfoxy-5-methylphenyl) -3-phenylpropyl ester, and Methane represented by the formula (VI) by sequentially reacting methanesulphonic acid 3- (2-methanesulfoxy-5-methylphenyl) -3-phenylpropylester (V) with an iodide salt and N, N-diisopropylamine Preparation of sulfonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenylester: The manufacturing method of the tolterodine intermediate which consists of methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester (VI).

The method for producing tolterodine racemate according to claim 1, wherein the alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide. The method of claim 1, wherein the fourth step is performed under a mixed solvent of water-soluble solvent and water selected from the group consisting of tetrahydrofuran, acetonitrile, ethanol, and methanol. 3. An iodide of an alkali metal as claimed in claim 1 or 2, wherein the salt of iodide is lithium iodide, sodium iodide, potassium iodide, rubidium iodide, cesium iodide; Or ammonium iodide such as ammonium iodide, tetraethylammonium iodide, tetrabutylammonium iodide, or a method for producing tolterodine racemate or intermediate thereof. The method of claim 1 or 2, wherein the methanesulphonic acid 2- (3-diisopropylamino-1-phenylpropyl) -4-methylphenyl ester (VI) is prepared by using tetrahydrofuran, diisopropyl ether. , A solvent such as dioxane, nitriles such as acetonitrile, dichloromethane, chloroform, chlorinated hydrocarbons such as 1,2-dichloroethane, amides such as dimethylacetamide, and dimethylformamide. Method for producing tolterodine racemates or intermediates thereof, characterized in that. 7. The method for producing tolterodine racemate or intermediate thereof according to claim 6, wherein the reaction solvent is acetonitrile.