KR100686351B1 - Method of preparing racemic tolterodine - Google Patents

Abstract

Provided is a method for preparing tolterodine racemate, which mass-produces high-purity tolterodine racemate in a simple and economical manner without using toxic reagents or high-pressure hydrogen. The method for preparing N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropaneamine(tolterodine racemate) represented by the following formula (I) comprises the steps of: (1) reacting 6-methyl-4-phenyl-3,4-dihydrocoumarin with sodium borohydride to prepare 2-(3-hydroxy-1-phenyl-propyl)-4-methylphenol; (2) reacting the prepared 2-(3-hydroxy-1-phenyl-propyl)-4-methylphenol with alkyl or aryl sulfonyl chloride and triethylamine, and N,N-diisopropylamine in order to prepare a compound represented by the following formula (V), in the alkyl or aryl sulfonyl chloride in which an alkyl group is a C1-4 alkyl group and an aryl group is a phenyl group or a C1-3 alkyl-substituted phenyl group; and (3) reacting the compound represented by the formula (V) with hydroxide of alkali metal.

Description

Method for preparing tolterodine racemate {Method of Preparing Racemic Tolterodine}

The present invention relates to a process for the preparation of tolterodine racemates. 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) ( It relates to a novel method for preparing tolterodine racemate represented by formula (I) which is a key intermediate of tolterodine).

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 U.S. Pat.

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

US Pat. No. 5,532,600 introduces an initial method for preparing tolterodine as follows: ring-opening reaction of 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by formula (III) and lithium aluminum hydroxide It is a method of producing the tolterodine racemate obtained by reducing with lead, tosylating alcohol, reacting with diisopropylamine, and dimethylating. 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 that there are many reaction processes and many reagents (eg, lithium aluminum hydride, tribromoborane, etc.) which are difficult to use in the mass synthesis process are used.

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. Prepare the corresponding alcohol, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopylin-2-ol, react the alcohol with isopropylamine, separate the racemates formed, and It is prepared by isolating tolterodine represented by (II). This method is an improved method than the process of Scheme 1, but the reaction process is greatly shortened, but there is a problem that a reagent or hydrogen reaction, such as diisobutyl aluminum hydride, 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. By reacting with propylamine, tolterodine represented by the formula (II) is prepared. This reaction is advantageous in that it can produce only the desired isomer by asymmetric reduction reaction instead of separating the isomer in the last step as in Scheme 1 or Scheme 2, but the synthesis process is increased and the reagent or reaction that is difficult to use in mass synthesis process This has a number of problems that must be used.

Scheme 3

Accordingly, the present inventors have continued the research to solve the problems of the known technology as described above to obtain tolterodine in a simpler and easier process, 6-methyl- represented by the formula (III) as shown in Scheme 4 below 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol represented by the formula (IV) by reacting 4-phenyl-3,4-dihydrocoumarin with sodium borohydride (NaBH ₄ ) To prepare a compound represented by the formula (V) by sequentially reacting alkyl or arylsulfonyl chloride and triethylamine and N, N-diisopropylamine, and the hydroxide salt in a mixed solvent of water-soluble solvent and water It was found that N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine represented by the formula (I) can be easily synthesized by high yield.

That is, the present inventors use the process of preparing the N-N-diisopropylamine effectively without performing the protecting group introduction reaction of the phenol group, while using the same process and the starting material of the reaction formula 1 of the known methods This drastically improved the synthesis process. The present inventors focused on finding a method for synthesizing tolterodine racemate by omitting the protecting group introduction reaction of the phenol group or by including it in an existing process without a separate process.

As a result, the inventors reacted 6-methyl-4-phenyl-3,4-dihydrocoumarin with sodium borohydride (III) to give 2- (3-hydroxy-1-phenyl-propyl) -4-methyl Phenol (IV) was prepared, and alkyl or arylsulfonyl chloride and triethylamine were sequentially reacted with N, N-diisopropylamine to prepare a compound represented by the formula (V), and a mixed solvent of an aqueous solvent and water. A method of preparing N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine (I) in high yield by reacting a hydroxide with

Therefore, according to the present invention, the reaction process is shortened without using a reagent that causes a fire when contacted with water used in the prior art, a reagent that generates a toxic gas, or using high pressure hydrogen. High quality tolterodine racemates represented by formula (I) could be prepared.

The present invention relates to tolterodine racemic, a key intermediate of the muscarinic receptor antagonist (R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine (tolerodine). It relates to a new method for producing a sieve.

It is an object of the present invention to provide a novel method for preparing tolterodine racemate, which is a key intermediate of tolterodine, which has an excellent effect on the treatment of urinary incontinence.

Another object of the present invention is that, unlike the known art, 6-methyl-4-phenyl-3 does not use a reagent that causes a fire or a toxic gas upon contact with moisture, and does not use high pressure hydrogen. It is to provide a method for preparing tolterodine racemate from a, 4-dihydrocoumarin through a three-step reaction step.

Still another object of the present invention is to provide a method for producing high purity tolterodine racemates in 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 relates to a method for producing N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine (tolerodine racemate) represented by the following general formula (I) will be. The tolterodine racemate is 2- (3-) represented by formula (IV) by reacting 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by formula (III) with sodium borohydride. Hydroxy-1-phenyl-propyl) -4-methylphenol is prepared, which is sequentially reacted with alkyl or arylsulfonyl chloride and triethylamine with N, N-diisopropylamine, represented by the formula (V). Compounds are prepared and reacted with hydroxides of alkali metals in a mixed solvent of water-soluble solvents and water.

In the above manufacturing process, the reaction completion rate is increased without using a reagent that causes a fire or a toxic gas that is in contact with water, and a high-pressure hydrogen is used, and the reaction process is shortened.

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

Scheme 4

Wherein R is a C ₁ to C ₄ alkyl group, an unsubstituted phenyl group, or a C ₁ to C ₃ alkyl group substituted, preferably methyl or p-methylbenzene, M is lithium, sodium, or Alkali metals such as potassium.

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

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

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

The solvent used for the reaction is preferably a lower alcohol such as methanol or ethanol, of which methanol is most preferred. The reaction temperature is a boiling point of 40 ° C. to the reaction solvent, and preferably 60 to 65 ° C. The reaction time is between 6 hours and 36 hours, more preferably 12 hours to 24 hours.

Sodium borohydride is used in the amount of 2 to 5 equivalents, more preferably 2.5 to 3.0 equivalents, relative to 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by the formula (III).

2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol (IV) obtained through the reaction as described above was concentrated by reducing the solvent under reduced pressure, ethyl acetate and water were added, and the aqueous layer was made acidic and extracted. And concentrated to recover.

Second Step: Preparation of Compound of Formula (V)

Alkyl or arylsulfonyl chloride and triethylamine, and N, N-diisopropylamine to 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol represented by the formula (IV) under the reaction solvent To react sequentially to prepare a compound represented by the formula (V). Specifically, alkyl or arylsulfonyl chloride and triethylamine are added to 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol represented by the formula (IV) under a reaction solvent. Thereafter, after adding N, N-diisopropylamine, the reaction vessel is sealed and the reactor is heated to react while maintaining the internal pressure of the reactor at a high pressure to prepare a compound represented by the formula (V).

The solvent used for the reaction includes ethers such as tetrahydrofuran, diisopropyl ether and dioxane, nitriles such as acetonitrile, chloride hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, dimethylacetamide, It can select from amides, such as dimethylformamide, and can use, and acetonitrile is the most preferable among these. The amount of the solvent used is used in a ratio of 5 ml to 20 ml with respect to 1 g of 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol (IV) used in the reaction, and preferably 7 ml to 10 ml. Used as a ratio.

In alkyl or arylsulfonyl chloride, the alkyl group is a C ₁ to C ₄ alkyl group and the aryl group is an unsubstituted phenyl group or a phenyl group substituted with a C ₁ to C ₃ alkyl group. Preferably the compound is methanesulfonyl chloride or p-toluenesulfonyl chloride. The temperature at the time of reacting the compound represented by general formula (IV) with alkyl or arylsulfonyl chloride is -20 degreeC-60 degreeC, Preferably it is 0-30 degreeC. The outer temperature of the reactor after sealing the reactor is 60 to 120 ℃, preferably 70 to 90 ℃. The reaction time when reacting with alkyl or arylsulfonyl chloride is between 3 hours immediately after the start of the reaction, more preferably 30 minutes to 1 hour. The reaction time after the reactor sealing is between 12 hours and 96 hours, more preferably between 24 hours and 36 hours.

Alkyl or arylsulfonyl chloride is used in the amount of 2 to 3 equivalents, preferably 2.4 equivalents, relative to 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol (IV).

Triethylamine is used in the amount of 1 to 1.5 equivalents based on alkyl or arylsulfonyl chloride, preferably 1.2 equivalents.

N, N-diisopropylamine is used in the volume ratio of 1/3 to 3 times the reaction solvent used, preferably in the same volume.

The compound represented by the formula (V) obtained through the reaction as described above may be recovered by concentrating the solvent under reduced pressure, adding methylene chloride and water, making the aqueous layer acidic, washing and concentrating.

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

N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine represented by formula (I) by reacting a hydroxide with a compound represented by formula (V) under a reaction solvent To prepare.

As a solvent used in the reaction, a mixed solvent of a water-soluble solvent and water is used, and the water-soluble solvent can be selected from tetrahydrofuran, acetonitrile, ethanol, methanol, and the like, 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 salt used is used in the amount of 2 to 10 equivalents, preferably 3 to 5 equivalents, based on the compound represented by the formula (V) used in the reaction.

Preferred reaction temperatures are the boiling points of the mixed solvents. The reaction time is between 1 hour and 10 hours, more preferably 3 hours to 6 hours.

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

As described above, according to the present invention, 6-methyl-4-phenyl-3,4-dihydrocoumarin represented by formula (III) is reacted with sodium borohydride to form 2- ( 3-hydroxy-1-phenyl-propyl) -4-methylphenol is prepared, and a compound represented by the formula (V) is prepared by sequentially reacting alkyl or arylsulfonyl chloride with N, N-diisopropylamine. And reacting the hydroxide salt in a mixed solvent of a water-soluble organic solvent and water to increase the N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine represented by the formula (I). Easily synthesized in yield.

As described above, the production method according to the present invention could easily proceed with the synthesis process by not using reagents or processes that are difficult to use in the mass synthesis process, and include the protection group introduction reaction of the phenol group in the existing process without a separate process. By performing the synthesis process can be shortened.

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- Phenyl -Propyl) -4- Of methylphenol (IV)  Produce

50 g (209.83 mmol) of 6-methyl-4-phenyl-3,4-dihydrocoumarin was dissolved in 800 ml of methanol, followed by the slow addition of 23.8 g (629.49 mmol) of sodium borohydride at room temperature. After stirring at room temperature for 30 minutes, the temperature of the reaction solution was gradually raised to reflux for 24 hours. The reaction solution was cooled down and removed under reduced pressure. 400 ml of water and 10 ml of concentrated hydrochloric acid were added to the obtained residue, followed by extraction with ethyl acetate. The obtained organic layer was washed with 300 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 49 g of 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol as an oily solid (yield 96.4%). .

¹ H NMR (CDCl ₃ ) δ = 2.04 (m, 1H), 2.14 (s, 3H), 3.53 (m, 1H), 3.76 (m, 1H), 4.56 (q, 1H), 6.73 (d, 1H) , 6.76 (d, 1H), 6.84 (dd, 1H), 7.18 (m, 1H), 7.26 (m, 4H)

Example  2: 2- (3- Methanesulfonyloxy -One- Phenyl -Propyl) -4- Of methylphenol (V)  Manufacture 1

40 g (165.07 mmol) of 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol obtained in Example 1 were dissolved in 300 ml of acetonitrile in a high-pressure reactor, and then 40.09 g (396.17) of triethylamine under ice-cooling. mmol) and 41.60 g (363.15 mmol) of methanesulfonyl chloride were added sequentially. After stirring for 1 hour while gradually raising the temperature of the reaction solution to room temperature, 300 ml of N, N-diisopropylamine was added and the reaction vessel was sealed. After raising the external temperature of the high-pressure reactor to 80 ° C and stirring for 60 hours, the temperature of the reactor was cooled to room temperature again. After the solvent was removed under reduced pressure, 600 ml of dichloromethane was added, and the mixture was washed sequentially using 300 ml of diluted aqueous sodium hydroxide solution and 300 ml of diluted hydrochloric acid solution. The solvent was removed under reduced pressure, dissolved in 500 ml of dilute hydrochloric acid solution, washed with 300 ml of diisopropyl ether, and sodium hydroxide was added to convert the aqueous solution to basic. The aqueous solution was extracted with 600 ml of dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 50.0 g (yield 75.0%) of 2- (3-methanesulfonyloxy-1-phenyl-propyl) -4-methylphenol as an oil. .

¹ H NMR (CDCl ₃ ) δ = 0.93 (d, 12H), 2.11 (s, 3H), 2.13 (m, 2H), 2.33 (m, 2H), 2.78 (s, 3H), 2.97 (m, 2H) , 4.32 (t, 1H), 6.80 (m, 1H), 7.03 (d, 1H), 7.17 (m, 1H), 7.26 (m, 4H)

Example  3: N, N- Diisopropyl -3- (2- Hydroxy -5- Methylphenyl ) -3- Of phenylpropanamine (I)  Manufacture 1

40 g (99.11 mmol) of 2- (3-methanesulfonyloxy-1-phenyl-propyl) -4-methylphenol obtained in Example 2 were dissolved in 450 ml of a 2: 1 mixed solvent of methanol and water, and 19.82 g (495.55 mmol) of sodium hydroxide were dissolved. ) Was added. The reaction solution was refluxed for 6 hours, cooled to room temperature, the solvent was removed under reduced pressure, and the reaction solution was concentrated to 1/3. 600 ml of dichloromethane and 300 ml of water were added to extract the organic layer and washed again with 300 ml of water. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 30.0 g (yield 93.0%) of N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine as a solid. .

¹ H NMR (CDCl ₃ ) δ = 1.10 (dd, 12H), 2.11 (s, 3H), 2.11 (m, 1H), 2.37 (m, 2H), 2.73 (m, 1H), 3.22 (m, 2H) , 4.48 (dd, 1H), 6.54 (s, 1H), 6.82 (m, 2H), 7.22 (m, 2H), 7.32 (d, 4H)

Example  4: 2- (3-p- Toluenesulfonyloxy -One- Phenyl -Propyl) -4- Of methylphenol (V)  Manufacture 2

40 g (165.07 mmol) of 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol obtained in Example 1 were dissolved in 300 ml of acetonitrile in a high-pressure reactor, and then 40.09 g (396.17) of triethylamine under ice-cooling. mmol) and 69.24 g (363.15 mmol) of p-toluenesulfonyl chloride were added sequentially. After stirring for 1 hour while gradually raising the temperature of the reaction solution to room temperature, 300 ml of N, N-diisopropylamine was added and the reaction vessel was sealed. After raising the external temperature of the high-pressure reactor to 80 ° C and stirring for 60 hours, the temperature of the reactor was cooled to room temperature again. After the solvent was removed under reduced pressure, 600 ml of dichloromethane was added, and the mixture was washed sequentially using 300 ml of diluted aqueous sodium hydroxide solution and 300 ml of diluted hydrochloric acid solution. The solvent was removed under reduced pressure, dissolved in 500 ml of dilute hydrochloric acid solution, washed with 300 ml of diisopropyl ether, and sodium hydroxide was added to convert the aqueous solution to basic. The aqueous solution was extracted with 600 ml of dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 60.57 g of 2- (3-p-toluenesulfonyloxy-1-phenyl-propyl) -4-methylphenol as an oil (yield 76.5%). Got.

¹ H NMR (CDCl ₃ ) δ = 0.83 (d, 12H), 2.11 (s, 3H), 2.19 (m, 2H), 2.28 (s, 3H), 2.88 (m, 2H), 4.06 (t, 1H) , 6.74 (s, 2H), 6.98 (s, 2H), 7.08 (m, 4H), 7.13 (d, 2H), 7.63 (d, 2H)

Example  5: N, N- Diisopropyl -3- (2- Hydroxy -5- Methylphenyl ) -3- Of phenylpropanamine (I)  Manufacture 2

50 g (104.23 mmol) of 2- (3-p-toluenesulfonyloxy-1-phenyl-propyl) -4-methylphenol obtained in Example 4 were dissolved in 450 ml of a 2: 1 mixed solvent of methanol and water, and 20.85 g of sodium hydroxide ( 521.17 mmol) was added. The reaction solution was refluxed for 6 hours, cooled to room temperature, the solvent was removed under reduced pressure, and the reaction solution was concentrated to 1/3. 600 ml of dichloromethane and 300 ml of water were added to extract the organic layer and washed again with 300 ml of water. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 31.31 g (yield 92.3%) of N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine as a solid. .

¹ H NMR (CDCl ₃ ) δ = 1.10 (dd, 12H), 2.11 (s, 3H), 2.11 (m, 1H), 2.37 (m, 2H), 2.73 (m, 1H), 3.22 (m, 2H) , 4.48 (dd, 1H), 6.54 (s, 1H), 6.82 (m, 2H), 7.22 (m, 2H), 7.32 (d, 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 sodium borohydride. -Phenyl-propyl) -4-methylphenol was prepared, and a compound represented by the formula (V) was prepared by sequentially reacting alkyl or arylsulfonyl chloride with N, N-diisopropylamine, and in aqueous methanol solution. Providing a method for easily producing (N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine represented by formula (I) by reacting a flame with high yield Has an effect.

Prior art related to the method for preparing tolterodine racemate represented by formula (I) uses a reagent that causes a fire or a toxic gas when contacted with water, or a reaction process using hydrogen at high pressure There is a problem that this is long or difficult, so it is difficult to apply to a real bulk process. However, the present invention does not use these undesirable reagents and can produce a high quality tolterodine racemate represented by the formula (I) in a new process with a shortened reaction process without using high pressure hydrogen. 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 (6)

6-methyl-4-phenyl-3,4-dihydrocoumarin represented by the following formula (III) is reacted with sodium borohydride to form 2- (3-hydroxy-1- represented by the following formula (IV) First step of preparing phenyl-propyl) -4-methylphenol, The 2- (3-hydroxy-1-phenyl-propyl) -4-methylphenol is sequentially reacted with alkyl or aryl sulfonyl chloride and triethylamine, and N, N-diisopropylamine to give formula (V) In the second step of preparing a compound represented by, in the alkyl or aryl sulfonyl chloride, alkyl is C ₁ to C ₄ alkyl, aryl is phenyl or phenyl group substituted with C ₁ to C ₃ alkyl, and The third step of reacting a compound represented by the formula (V) with a hydroxide of an alkali metal: A method for producing N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine (tolerodine racemate) represented by the following general formula (I).

In the above formula (V), R is a phenyl group substituted with an alkyl group of C ₁ to C ₄ , a phenyl group or an alkyl group of C ₁ to C ₃ . The compound represented by the formula (V) is 2- (3-methanesulfonyloxy-1-phenyl-propyl) -4-methylphenol or 2- (3-p-toluenesulfonyloxy-. 1-phenyl-propyl) -4-methylphenol. A process for producing tolterodine racemate. The method for producing tolterodine racemate according to claim 1, wherein the alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide. The solvent used in the reaction of the second step is tetrahydrofuran, diisopropyl ether, ethers such as dioxane, nitriles such as acetonitrile, dichloromethane, chloroform, 1,2-dichloro A method for producing tolterodine racemates, which is selected from chlorinated hydrocarbons such as ethane, amides such as dimethylacetamide and dimethylformamide. The method for producing tolterodine racemate according to claim 4, wherein the solvent is acetonitrile. The method of claim 1, wherein the third step is performed under a mixed solvent of water-soluble solvent and water selected from the group consisting of tetrahydrofuran, acetonitrile, ethanol, and methanol.