JP4513535B2 - Method for producing tolterodine - Google Patents

Description

The present invention relates to a method for producing tolterodine useful as a therapeutic agent for urinary incontinence.

As a method for producing tolterodine, a method shown in the following scheme 1 is known (for example, see Patent Document 1). The lactone obtained from cinnamic acid and p-cresol is ring-opened and methylated, and then the ester group is reduced, and then demethylated through tosylation and diisopropylamination to obtain tolterodine.
This method has many steps and has a problem in economical production. Moreover, although the same method (refer patent document 2) is also known, the number of processes was large and the problem remained as an economical manufacturing method of tolterodine.
Scheme 1

On the other hand, a method of reducing lactone obtained from cinnamic acid and p-cresol to lactol shown in Scheme 2 below and then reducing in the presence of diisopropylamine is known (see Patent Document 3). Although this method has an advantage that the number of steps is small, a hydrogen pressure of 10 atm is necessary for the reduction, and the method is not always easy to implement industrially.
Scheme 2

WO 98/29402 pamphlet International Publication No. 89/06644 Pamphlet International Publication No. 03/014060 Pamphlet

An object of the present invention is to provide a method for industrially producing tolterodine in a short process.

で表される化合物を塩基で処理した後、２−（ジイソプロピルアミノ）エチル化およびそれに続くＲで示される基を脱離することにより、短工程でトルテロジンを製造しうることを見出し、本発明を完成した。

すなわち本発明は、
〔１〕式(2) The present inventors relate to a method for producing tolterodine according to the formula (2)

It was found that tolterodine can be produced in a short process by treating the compound represented by formula (2) with a base, followed by 2- (diisopropylamino) ethylation and subsequent elimination of the group represented by R. completed.

That is, the present invention
[1] Formula (2)

(Wherein R represents an alkyl group having 1 to 6 carbon atoms ) was treated with a base selected from the group consisting of n-BuLi, sec-BuLi, tert-BuLi and lithium diisopropylamide . After, formula (3)

(Wherein X represents a halogen atom, alkylsulfonyloxy or allylsulfonyloxy), and the compound represented by the formula (4)

(Wherein R is as defined above), and the group represented by R is eliminated by using hydrobromic acid or boron tribromide as a leaving agent. Formula (1)

A process for producing tolterodine or a salt thereof represented by :
[2 ] The method according to [ 1 ], wherein the base is n-BuLi or sec-BuLi,
X of the compound represented by [3] (3) A method according to chlorine atom, bromine atom, methanesulfonyloxy, toluenesulfonyloxy or benzenesulfonyloxy [1],
[ 4 ] The method according to [ 3 ], wherein X of the compound represented by the formula (3) is a chlorine atom.

According to the present invention, tolterodine or a salt thereof can be industrially produced in a short process economically.

Hereinafter, the present invention will be described in detail .
The compound represented by the formula (2) can be produced according to the following scheme with reference to the method described in Patent Document 1, but is not particularly limited.

Examples of the group represented by R include an alkyl group having 1 to 6 carbon atoms, an optionally substituted benzyl group, a trialkylsilyl group having 3 to 18 carbon atoms, or a 2-tetrahydropyranyl group. .
Examples of the alkyl group having 1 to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and the like. It is preferable from the viewpoint of economy.
Examples of the benzyl group that may have a substituent include a benzyl group, a 4-methoxybenzyl group, and a 4-nitrobenzyl group, and the benzyl group is preferable from the viewpoints of reactivity and economy.

Examples of the trialkylsilyl group having 3 to 18 carbon atoms include trimethylsilyl group, di-t-butylmethylsilyl group, and t-butyldimethylsilyl group.
Examples of the base used in the reaction for producing formula (4) from formula (2) include lithium compounds such as n-BuLi, sec-BuLi, tert-BuLi or lithium diisopropylamide, and n-BuLi or sec-BuLi. Is preferable from the viewpoint of safety and economy.
The amount of the base to be used is generally 1-2 mol, preferably 1.2-1.8 mol, per 1 mol of the compound of formula (2). If the amount of the base used is less than 1 mol, the raw material remains unreacted and the yield may be reduced. When the amount of the base used is more than 2 moles, the unreacted base remains in the reaction solution, reacting with the product to produce impurities, and there is no improvement in yield corresponding to the added base, which is not economical.

X in the formula (3) includes a halogen atom, methanesulfonyloxy, toluenesulfonyloxy, benzenesulfonyloxy and the like, and examples of the halogen atom include a chlorine atom or a bromine atom. From the viewpoint of price and reactivity, chlorine Atoms are preferred.
The amount of the compound of formula (3) to be used is generally 1-2 mol, preferably 1.2-1.8 mol, per 1 mol of the compound of formula (2). If the amount of the compound of the formula (3) used is less than 1 mol, the raw material remains unreacted and the yield may be lowered. When the amount of the compound of the formula (3) used is more than 2 mol, only the unreacted compound of the formula (3) remains in the reaction solution, and the yield is not improved corresponding to the added amount, which is not economical.

As the solvent, ether, tetrahydrofuran, dimethoxyethane, diethoxymethane, dioxane, t-butyl methyl ether, cyclopentyl methyl ether, one or more ether solvents selected from the group consisting of these solvents, or these solvents and toluene, xylene , A mixed solvent of hydrocarbon solvents such as heptane and hexane can be used.
The usage-amount of a solvent is 0.5-10L normally with respect to 1 mol of compounds of Formula (2), Preferably, it is 0.5-7L. When the amount of the solvent used is 0.5 L or less with respect to 1 mol of the compound of the formula (2), stirring may not be sufficient, and when it is 10 L or more, the reaction may be slow, which is not preferable.

The reaction temperature is generally −100 to 20 ° C., preferably −80 to 10 ° C. If the reaction temperature is −100 ° C. or lower, it is not preferable because it is difficult to implement industrially and the reaction rate is slow, and if it exceeds 20 ° C., by-products may be generated.
Although depending on the reaction temperature, the reaction time is usually 2 to 10 hours for base extraction and 1 to 5 hours for the reaction with the compound of formula (3).
After the reaction, the product can be isolated by adding water to the reaction solution and separating and concentrating the organic layer.

The method for eliminating the group represented by R can be carried out by using a general method. For example, when the group represented by R is an alkyl group having 1 to 6 carbon atoms, Green, Wuts “Protective Groups in Organic Synthesis. Edition ”(Wiley International)” can be carried out by the method described on pages 249 to 257 and pages 265 to 266.

When the group represented by R is tetrahydropyranyl, it can be carried out by the method described on page 261 of the same book, and when it is a silyl group, it can be carried out by the method of pages 273 to 276 of the same book.
When the group represented by R is a benzyl group which may be substituted, it can be carried out by the method described on pages 266 to 271 of the same document.
As the treatment method after the reaction, for example, the aqueous solution obtained by placing the reaction solution in water or extracting with aqueous hydrochloric acid is made alkaline, and then the product can be isolated by extracting and concentrating with an organic solvent. .

When the group represented by R is an alkyl group having 1 to 6 carbon atoms, examples of the leaving agent include hydrobromic acid and boron tribromide, and hydrobromic acid is preferable from the viewpoint of price and handling.
The usage-amount of hydrobromic acid is 2-10 mol amount normally with respect to 1 mol of compounds of Formula (4), Preferably it is 3-7 mol amount. If the amount of hydrobromic acid used is less than 2 mol, the raw material remains unreacted and the yield may be reduced. Even if the amount of hydrobromic acid used is more than 10 moles, the yield is not improved corresponding to the hydrobromic acid used, which is not economical.

Examples of the solvent include acetic acid and the like, but it is not always necessary to use a solvent, and hydrobromic acid can also be used as a solvent.
When acetic acid is used as a solvent, the amount is usually 200 mL to 1 L, preferably 200 mL to 500 mL, relative to 1 mol of the compound of formula (4), but the amount of acetic acid used hardly affects the reaction results.

The reaction temperature is generally 20 to 150 ° C, preferably 50 to 120 ° C.
As a treatment method after the reaction, for example, the reaction solution is poured into water to make it alkaline, and then the product can be isolated by extraction and concentration with an organic solvent.

When the group represented by R is a silyl group, fluorides such as hydrofluoric acid, potassium fluoride and tetrabutylammonium fluoride, mineral acids such as hydrochloric acid and hydrobromic acid, and hydrochloric acid is economical. This is preferable from the viewpoint of the safety of the reagent.
The amount of fluoride and acid used is usually 0.01 mol to 2 mol with respect to 1 mol of the compound of formula (4).

When the group represented by R is a 2-tetrahydropyranyl group, a mineral acid is used, and examples of the mineral acid include hydrochloric acid and the like. The use amount of the mineral acid is usually 0.001 mol to 1 mol with respect to 1 mol of the compound of the formula (4).
As the treatment method after the reaction, for example, the aqueous solution obtained by placing the reaction solution in water or extracting with aqueous hydrochloric acid is made alkaline, and then the product can be isolated by extracting and concentrating with an organic solvent. .

When the group represented by R is an optionally substituted benzyl group, reduction is performed in the same manner as when the group represented by R is an alkyl group having 1 to 6 carbon atoms or in the presence of a reduction catalyst such as palladium. A method is mentioned. Examples of the reduction catalyst include palladium carbon, palladium hydroxide carbon, palladium chloride, palladium black, and the like. Palladium carbon is preferable from the viewpoint of economy and safety of the reagent.

Tolterodine can be converted into optically active tolterodine by a method such as optical resolution with an optically active acid.

Next, the present invention will be specifically described with reference examples and examples. However, the present invention is not limited to these reference examples and examples.

Reference example
2-Benzyl-4-methylanisole
WO 89/06644 Example 4 was carried out with reference to l).
A mixture of 4-methylanisole (200 g, 1.64 mole), benzyl alcohol (40.0 g, 0.37 mole) and p-toluenesulfonic acid monohydrate (8.0 g, 0.042 mole) was added while removing water generated in the reaction. Stir at ~ 175 ° C for 2 hours. Excess 4-methylanisole was distilled off under reduced pressure (internal temperature 132 ° C / 25mmHg (3.3kPa)), the residue was dissolved in toluene (50mL), the organic layer was water (20mL), 10% caustic soda water (20mL) It was then washed with water (20 mL). After concentrating the organic layer, the residue was distilled under reduced pressure, and a component distilled at a boiling point of 120 to 138 ° C./0.7 mmHg (0.09 kPa) was obtained as a main fraction (52.75 g, 67.2%).
NMR analysis showed a 2.7: 1 mixture of 2-benzyl-4-methylanisole and 3-benzyl-4-methylanisole.
2-Benzyl-4-methylanisole ¹ H NMR (400 MHz, CDCl ₃ ); δ = 2.23 (3H, s), 3.77 (3H, s), 3.93 (2H, s), 6.76 (1H, d, J = 8 Hz), 6.87 (1H, d, J = 1.6 Hz), 6.98 (1H, dd, J = 8, 1.6 Hz), 7.10-7.30 (5H, m).
3-Benzyl-4-methylanisole ¹ H NMR (400 MHz, CDCl ₃ ); δ = 2.17 (3H, s), 3.74 (3H, s), 3.93 (2H, s), 6.62-7.45 (8H, m)

Example 1
Preparation of N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropanamine Under argon atmosphere, THF (300 ml) was mixed with 2-benzyl-4-methylanisole and 3-benzyl-4- A mixture of methylanisole (2.7: 1, 10.0 g, 47.1 mmol) was dissolved and cooled to −78 ° C.
To this solution, 13% n-butyllithium (34.8 g, 70.7 mmol) was added dropwise, and then the mixture was warmed to 0 ° C. and stirred for 6 hours. The mixture was again cooled to −78 ° C., 2- (diisopropylamino) ethyl chloride (11.6 g, 70.9 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 2 hours. After dropwise addition of water (20 ml), toluene (100 ml) was added to the organic layer and extracted twice with 10% hydrochloric acid (200 ml). The aqueous layers were combined, caustic soda (31 g) was added, and the mixture was extracted twice with toluene (300 ml, 200 ml). The organic layers were combined, washed with 5% brine, dried over anhydrous magnesium sulfate, and concentrated (14.65 g). The operation of adding xylene (120 ml) to the obtained concentrate and concentrating was repeated three times to obtain 12.5 g of a residue.
As a result of NMR analysis, N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropanamine and N, N-diisopropyl-3- (5-methoxy-2-methylphenyl)- It was an approximately 10: 1 mixture of 3-phenylpropanamine. The yield of (N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropanamine was 98.5% from 2-benzyl-4-methylanisole.
(N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropanamine ¹ H NMR (400 MHz, CDCl ₃ ); δ = 0.93 (d, J = 1.2 Hz, 6H), 0.92 (d, J = 1.2Hz, 6H), 2.09-2, 15 (m, 2H), 2.25 (s, 3H) 2.32-2.35 (m, 2H), 2.94-3.00 (m, 2H), 3.73 (s, 3H), 4.34 (t, J = 7.6Hz, 1H), 6.70 (d, J = 12Hz, 1H), 6.92 (d, J = 8Hz, 1H), 7.05 (br, 1H), 7.10-7.18 (m, 2H), 7.21-7.28 (m, 3H)

Example 2
Preparation of N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropanamine In THF (50 ml) under argon atmosphere, 2-benzyl-4-methylanisole and 3-benzyl-4- A mixture of methylanisole (2.7: 1, 10.0 g, 47.1 mmol) was dissolved and cooled to −78 ° C.
To this solution, 13.9% n-butyllithium (32.46 g, 70.5 mmol) was added dropwise, and then the mixture was heated to 0 ° C. and stirred for 4 hours. The mixture was cooled again to −78 ° C., 2- (diisopropylamino) ethyl chloride (11.6 g, 70.7 mmol) was added dropwise, the temperature was raised to 0 ° C., and the mixture was stirred for 2 hours. Water (20 ml) was added dropwise, followed by extraction twice with 10% hydrochloric acid (25 mL, 15 mL). The aqueous layers were combined, caustic soda (4.9 g) was added, and extracted twice with toluene (30 ml, 20 ml). The organic layers were combined, washed twice with 5% brine (15 mL), dried over anhydrous magnesium sulfate, and concentrated. The operation of adding xylene (100 ml) to the concentrate of the obtained reaction mixture and concentrating was repeated three times to obtain 13.7 g of a residue.
As a result of NMR analysis, N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropanamine and N, N-diisopropyl-3- (5-methoxy-2-methylphenyl)- It was an approximately 10: 1 mixture of 3-phenylpropanamine. The yield of (N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropanamine was 100% from 2-benzyl-4-methylanisole.

Example 3
Preparation of tolterodine Acetic acid (15 mL) was mixed with N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropanamine and N, N-diisopropyl-3- (5-methoxy-2-methylphenyl) ) -3-Phenylpropanamine about 10: 1 mixture (11.0 g, 32.4 mmole) was added and dissolved, 47% HBr aqueous solution (25 mL) was added, and the mixture was heated to reflux (bath temperature 120 ° C.) for 3 hours. The reaction solution was cooled to room temperature, the solvent was distilled off, water (120 mL) and toluene (110 mL) were added to the residue, and the pH was adjusted to 11 with caustic soda (2.2 g) and sodium carbonate (26 g). The aqueous layer was separated and removed, and the organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 9.04 g of racemic tolterodine (yield 85.7%).
As a result of NMR analysis, a mixture of tolterodine and N, N-diisopropyl-3- (5-hydroxy-2-methylphenyl) -3-phenylpropanamine was about 10: 1.
Tolterodine ¹ H NMR (400 MHz, CDCl ₃ ); δ = 1.06 (d, J = 6.8 Hz, 6H), 1.11 (d, J = 6.8 Hz, 6H), 2.11 (s, 3H) 2.03-2.15 (m, 1H ), 2.24−2.42 (m, 1H), 2.69−2.73 (m, 1H), 3.17−3.25 (m, 2H), 4.48 (dd, J = 3.6, 11.6Hz, 1H), 6.54 (br, 1H), 6.77 (dd, J = 2, 7.6Hz, 1H), 7.13-7.27 (m, 1H), 7.29-7.35 (m, 4H)

Example 4
Approximately 10: 1 mixture of optically active tolterodine tartrate ethanol (10 mL) and tolterodine and N, N-diisopropyl-3- (5-hydroxy-2-methylphenyl) -3-phenylpropanamine (4.0 g, 11.3 mmole) The solution in which was dissolved was heated to 40 ° C., and a solution of L-tartaric acid (2.55 g, 17.0 mmole) in ethanol (20 mL) was added dropwise. The solution was heated to reflux for 1 hour and then cooled to 0 ° C., and the precipitated crystals were filtered and washed with ethanol (3 mL) to give 2.33 g of the title compound. The yield of optically active tolterodine tartrate from tolterodine was 43.9%.
¹ H NMR (400 MHz, DMSO-d ₆ ); δ = 1.02-1.07 (m, 12H), 2.16 (s, 3H) 2.25-2.26 (m, 2H), 2.66 (br, 2H), 3.37-3.43 (m , 2H), 4.00 (s, 2H), 4.48 (t, J = 8Hz, 1H), 6.65 (d, J = 8.4Hz, 1H), 6.79 (d, J = 8.4Hz, 1H), 6.99 (s, 1H), 7.13-7.16 (m, 1H), 7.24-7.31 (m, 4H)
7.24-7.31 (m, 4H)

Claims (4)

Formula (2)

(Wherein R represents an alkyl group having 1 to 6 carbon atoms ) was treated with a base selected from the group consisting of n-BuLi, sec-BuLi, tert-BuLi and lithium diisopropylamide . After, formula (3)

(Wherein X represents a halogen atom, alkylsulfonyloxy or allylsulfonyloxy) and the compound represented by the formula (4)

(Wherein R is as defined above), and the group represented by R is eliminated by using hydrobromic acid or boron tribromide as a leaving agent. Formula (1)

A method for producing tolterodine or a salt thereof represented by: The method according to claim 1 , wherein the base is n-BuLi or sec-BuLi. X of the compound represented by the formula (3) is a chlorine atom, a bromine atom, methanesulfonyloxy, The method according to claim 1 is toluenesulfonyloxy or benzenesulfonyloxy. The method according to claim 1 , wherein X of the compound represented by formula (3) is a chlorine atom.