KR20090097835A - Intermediate of racemic tolterodine - Google Patents

Abstract

An intermediate of tolterodine racemate, and its manufacturing method are provided to produce a tolterodine racemate simply within a short time by using a relatively cheap and commercially usable starting material. An intermediate of tolterodine racemate is represented by the formula 4, wherein R is a p-nitrobenzenesulfonyl group or a p-toluenesulfonyl group. A manufacturing method of the tolterodine racemate comprises the steps of reducing ethyl benzoylacetate with a diol; selectively sulfonating the primary hydroxyl group of the prepared diol; substituting the prepared one with diisopropylamine; and performing Friedel-Crafts alkylation in the presence of a catalyst.

Description

Intermediate of tolterodine racemate {INTERMEDIATE OF RACEMIC TOLTERODINE}

The present invention relates to a method for preparing tolterodine (N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine) racemate, an intermediate thereof and a method for producing the same as, more particularly, muscarinic receptor antagonist to useful for the treatment of diseases caused by overactive bladder as La tolte Rodin represented by the formula (6) racemate (rac - tolte Rodin) a novel method of producing useful in a method of manufacturing the same An intermediate and a method for producing the same.

Tolterodine (N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine) is used to treat urinary urgency caused by overactive bladder (OAB). It is the first muscarinic receptor antagonist specifically designed for Life Sci ., L. Nilvebrant, 68, 2549 (2001) and Clin . Ther ., MB Chancellor, et . , et al ., 23, 753 (2001). Tolterodine is equivalent to oxybutynin, but has few side effects, especially in salivary glands, so most patients choose tolterodine for the treatment of overactive bladder. Has been reported.

There are many studies on the preparation method of tolterodine, and there are a number of patents for this. Many patents are synthesized from the coupling of p -cresol and trans -cinnamic acid, and are involved in the formation of hydrocoumarin of formula (I) as an intermediate (Gage, JR et al ., WO 98/29402; Kumar, Y. et al ., WO 03/014060; Kankan, RN et al ., WO 2005/061432; Srinivas, K. et al ., Org . Proc. Res . Dev . 9, 314 (2005); Venkataraman, S. et al , US 2006/0094904; Toplak, R., WO 2006/066931; Turchetta, S. et al ., US Patent Publication 2006/0079716). These reactions usually require stringent reaction conditions and long reaction times. In addition, some of these documents use hazardous, expensive and difficult to handle reagents such as DIBAL, lithium aluminum hydride, methyl iodide, and boron tribromide in continuous processes. There is a problem with additional reagents, solvents and time-consuming protection-deprotection strategies.

In addition, another method for preparing tolterodine is by using an asymmetric reaction using chiral auxiliaries (Anderson, PG et al ., J. Org . Chem ., 63, 8067 (1998); Hedberg, C. et al ., Adv . Synth . Catal ., 347, 662 (2005)) or using expensive metal catalysts such as rhodium (Botteghi, C. et al ., Org . Proc . Res . Dev . 6, 379 (2002); Colombo, L. et. al . Canadian Patent CA 2 502 640, 2005; Org . Lett ., Chen, G. et al , 7, 285 (2005). However, the use of such transition metal catalysts or chiral auxiliaries is not suitable for industrial scale manufacturing processes due to cost concerns. In addition, in particular, this method has a problem of using toxic carbon monoxide (CO) during the hydroformylation process.

On the other hand, the above and other methods are Pascual Coca, G. et al ., European Patent EP 1 698 615 A, 2004; Grabiak, RC et al ., WO 2004/096751; Razzetti, G. et al ., European Patent EP 1 693 361 A1, 2006, although these methods have all the problems described above.

Taken together, conventional methods of preparing tolterodine have the problem of producing under expensive, dangerous and intractable reagents and conditions. In addition, some methods have a large number of reaction steps and require a long process to require a lot of reagents, solvents and reaction time (days), or a protection-deprotection process. Therefore, the conventional methods for preparing these tolterodines are very uneconomical and have a problem that is not suitable for industrial scale.

In order to solve the problems of the prior art as described above, an object of the present invention is to provide a novel method for producing tolterodine racemate, which is a key intermediate of tolterodine, which has an excellent effect in treating diseases caused by overactive bladder. will be.

Another object of the present invention is a novel and simple tolterodine lamination that produces each intermediate in a short time through easy manipulation and purification methods using relatively inexpensive and commercially available starting materials without a protection-deprotection process. It is to provide a method for synthesizing a semi-body.

It is still another object of the present invention to provide tolterodine racemic intermediates useful for the preparation of tolterodine and methods for preparing the same.

The above object of the present invention can be achieved by the present invention described below.

In order to achieve the above object, a) reducing the ethyl benzoyl acetate of the formula (2) to phenylpropane-1,3-diol of the formula (3); b) selectively sulfonating the primary hydroxy group of phenylpropane-1,3-diol of formula (3) to produce a compound of formula (4); c) directly replacing the compound of formula 4 with diisopropylamine to produce a compound of formula 5; And d) fryingel-crafts alkylation of the compound of formula 5 in the presence of a catalyst to produce tolterodine racemate of formula 6 It provides a method for producing a sieve.

In Formula 4, R is a p -nitrobenzenesulfonyl group (p-nitrobenzenesulfonyl, Ns) or a p -toluenesulfonyl group (p-toluenesulfonyl, Ts).

[Formula 6]

The present invention also provides an intermediate of tolterodine racemate represented by the formula (4).

In addition, the present invention comprises the steps of: a) reducing the ethyl benzoyl acetate of Formula 2 to phenylpropane-1,3-diol of Formula 3; And b) selectively sulfonating the primary hydroxy group of phenylpropane-1,3-diol of formula (3) to produce a compound of formula (4). It provides a method of manufacturing.

As described above, according to the present invention, as a method for producing tolterodine in a simple, economical and practical manner, a novel manufacturing method using a readily available, non-toxic raw material, a simple process and a short reaction time are provided. do.

In addition, as a simple and cost-effective method, it can be manufactured using relatively inexpensive and commercially available materials, and the existing protection-deprotection process is eliminated, requiring a minimum reaction time for each step. Tolterodine can be prepared in one day.

The present invention is an alternative method for preparing rac -tolterodine, which overcomes the problems of the prior art. That is, the present invention provides a method for preparing the final material of Formula 6, rac -tolterodine, starting with reducing the relatively inexpensive starting material of ethylbenzoyl acetate of Formula 2.

Hereinafter, the present invention will be described in detail.

a) step: Phenylpropane -1,3- Of diol (Formula 3)  Produce

Phenylpropane-1,3-diol of formula (3) is prepared by reducing ethylbenzoyl acetate of formula (2), which is an inexpensive starting material, under a reaction solvent. In this step, a sodium borohydride (NaBH ₄ ) solution is used as the reducing agent, and the solvent used in the reaction is a lower alcohol, preferably methanol. The reduction reaction is carried out at room temperature for up to 15 minutes.

b) step: preparation of 3 -hydroxy- 3- phenylpropyl -4-nitrobenzenesulfonate (Formula 4, R = Ns)

The primary hydroxyl group of phenylpropane-1,3-diol of formula 3 obtained in step a) is selectively sulfonated to produce a compound of formula 4.

Hydrochloric acid scavenger base to act as a (scavenger) is to use triethylamine, bases are p - nitrobenzene sulfonyl chloride (p -nitrobenzenesulfonyl chloride) or p - toluene sulfonyl chloride was added (p -toluenesulfonyl chloride) It is preferable to add at the end later. In addition, the reaction temperature is carried out for a reaction time of 1 hour or less at a temperature of 0 ~ 5 ℃.

c) step: 3- ( Diisopropylamino )-One- Phenyl Preparation of -propan-1-ol (Formula 5)

3- (diisopropyl), a compound of formula 5, by subjecting the compound of formula 4 (R = Ns) to a diisopropyl amine (HN ( i Pr) ₂ ) direct substitution without solvent or in a shorter time than the prior art Prepare amino) -1-phenyl-propan-1-ol.

The step proceeds under reflux without solvent or under acetonitrile solvent in a lesser amount than diisopropylamine. Complete in less than 3 hours in acetonitrile solvents less than diisopropylamine. Pure products can easily be obtained by operation in aqueous solution.

d) step: Tolterodine  Preparation of racemate (Formula 6)

The compound of formula 4 is formulated under Friedel-Crafts alkylation under mild conditions and short reaction time to prepare rac -tolterodine of formula 6.

The catalyst of step d) may be an aqueous perchloric acid (perchloric acid, HClO ₄ ) as Lewis acid. Step d) is completed within 1 hour at room temperature.

The production method according to the present invention can be represented by the following Scheme 1.

The inventors have found that β-keto esters can be easily reduced to the corresponding diols in a methanol solvent using sodium borohydride, and ethylbenzoyl acetate, a compound of formula 2, is phenylpropane-1 as a diol of formula 3 To 3-diol. Surprisingly, this reaction is completed in 15 minutes at room temperature, showing a high yield (98%).

The primary hydroxyl group of the diol of formula 3 reacts selectively to produce a compound of formula 4. In Formula 4, R may be a p -nitrobenzenesulfonyl group or a p -toluenesulfonyl group. Since Ns functional groups are excellent leaving groups, it is more advantageous to use Ns functional groups for the alcohol reaction. This makes the next step easier. Moreover, the reaction time of the primary alcohol using NsCl is shorter than that using TsCl.

Substitution reaction using diisopropylamine for tolterodine synthesis was conventionally performed for a long reaction time in an inert atmosphere. In the present invention, however, the reaction proceeds more easily because NsCl is an excellent leaving group as mentioned above, so that the reaction can be completed within 3 hours without solvent or in acetonitrile solvent of less than diisopropylamine. have. In addition, the pure product has the advantage that it can be easily obtained by operation in an aqueous solution.

The final step is the Friedel-Crafts alkylation under very simple conditions. Typically metal Lewis acid is used to carry out the reaction, but is not used for the formula (5). Alkylation does not proceed by having two nucleophilic elements coordinating to the metal on either side. The inventors used an aqueous solution of perchloric acid (HClO ₄ ), a type of Lewis acid, which protonates amine groups, which extinguish nucleophilicity. This step is very simple for a reaction time of less than 1 hour at room temperature, no further purification is required.

The present invention also provides an intermediate of tolterodine racemate represented by the formula (4). In Formula 4, an intermediate of tolterodine racemate, wherein R is a p -nitrobenzenesulfonyl group, is more preferable. Then, by selectively reacting phenylpropane-1,3-diol of formula (3), which is a primary alcohol obtained by reducing ethylbenzoyl acetate represented by formula (2), to synthesize a novel intermediate of tolterodine racemate of formula (4) Provide a method. The reaction conditions of the method for preparing the intermediate may be carried out as in the method for preparing the tolterodine racemate.

Hereinafter, preferred examples are provided to aid the understanding of the present invention, but the following examples are merely for exemplifying the present invention, and it will be apparent to those skilled in the art that various changes and modifications can be made within the scope and spirit of the present invention. It is natural that such variations and modifications fall within the scope of the appended claims.

EXAMPLE

Example  One: Phenylpropane -1,3- Of diol (Formula III)  Produce

25.80 mL (149.93 mmol) of ethyl benzoyl acetate was dissolved in 300 mL of methanol, and 17.0159 g of sodium borohydride (449.7978 mmol) was added slowly at room temperature and mixed. The mixture was stirred for 15 minutes, the methanol was all evaporated and 50 ml of ethyl acetate was added. Then 30 ml of a super saturated brine solution was added to the mixture, followed by shaking and filtering to remove solids. After separating the layers, the aqueous layer was extracted with 50 ml of ethyl acetate as many times as necessary. All organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated using a reflux evaporator. The mixture was then further purified using shorter silica gel column chromatography in a hexane: ethyl acetate elution system (2: 1, v / v) to give 22.36 g of phenylpropane-1,3-diol, the target compound of the orange oil ( Yield 98%). ¹ H NMR data of the target compound are as follows:

¹ H NMR (300 MHz, CDCl 3): δ 7.30 (m, 5H), 4.94 (dd, J = 8.3, 6.0 Hz, 1H), 3.84 (m, 2H), 3.23 (s, 1H), 2.79 (s, 1H), 1.95 (m, 2H); ¹ H NMR (300 MHz, CDCl ₃ ) upon D ₂ O exchange: 7.31 (m, 5H), 4.94 (dd, J = 8.5, 4.1 Hz, 1H), 4.79 (br. S, 2H), 3.83 (t, J = 5.5 Hz, 1H), 1.96 (m, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ): d 144.6, 128.8, 127.8, 125.9, 74.5, 61.6, 40.7.

Example  2: 3- Hydroxy -3- Phenylpropyl -4- Of nitrobenzenesulfonate (Formula IVa)  Produce

0.6215 g (4.0837 mmol) of phenylpropane-1,3-diol obtained in Example 1 were dissolved in 8.17 mL of dichloromethane. 0.9503 g (4.2879 mmol) of 4-nitrobenzenesulfonylchloride were slowly added using a solid dropping funnel while stirring the mixture in an ice bath at 0-5 ° C. Finally 0.85 mL (6.1256 mmol) of triethylamine was added and the mixture was stirred at 0-5 ° C. for 1 h. Immediately thereafter the mixture was filtered using thin silica gel with ethyl acetate as solvent and concentrated using a reflux evaporator. Then, using silica gel column chromatography (eluent, hexane: ethyl acetate = 2: 1, v / v), 3-hydroxy-3-phenylpropyl-4-nitrobenzenesulfonate 1.1722, the target compound as a pale white solid. g (yield 85%) was obtained. ¹ H NMR data of the target compound are as follows:

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.36 (d, J = 9.0, 2H), 8.06 (d, J = 8.70, 2H), 7.28 (m, 5H), 4.76 (t, J = 6.15, 1H), 4.35 (m, 1H), 4.14 (m, 1H), 2.48 (br s, OH) 2.04 (dd, J = 6.45, 12.45, 2H); ¹³ C (75 MHz, CDCl ₃ ): 150.96, 143.51, 141.74, 129.51, 128.93, 128.27, 125.86, 124.76, 70.26, 69.20, 38.04. IR (KBr, cm ⁻¹ ): 1534 (NO 2), 1357, 1323 (NO ₂ , S═O), 1179 (S═O), 1107, 1073 (SO), 3559 (OH); HRMS m / z calcd for C ₁₅ H ₁₅ NO ₆ S 337.0620, found 337.0620.

Example  3: 3- ( Diisopropylamino )-One- Phenyl Preparation of Propan-1-ol (Formula V)

3.5011 g (10.3782 mmol) of 3-hydroxy-3-phenylpropyl-4-nitrobenzenesulfonate obtained in Example 2 was refluxed with 29.30 mL of diisopropylamine for 3 hours. The mixture was cooled to rt and washed filtered using CH ₂ Cl ₂ . The filtered material was washed several times with alternating water and brine until the salt was completely removed. All organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated using a reflux evaporator and dried under vacuum to yield 2.1021 g of the desired compound 3- (diisopropylamino) -1-phenyl-propan-1-ol as a yellow oil. Yield 86%). ¹ H NMR data of the target compound are as follows:

¹ H NMR (300 MHz, CDCl _{3 )} : δ7.32 (m, 5H), 4.90 (dd, J = 2.48, 9.91, 1H), 3.20 (m, 2H), 2.79 (m, 2H), 1.84 (m , 1H), 1.66 (m, 1H), 1.16 (d, J = 6.88, 5H), 1.06 (d, J = 6.60, 5H); ¹³ C (75 MHz, CDCl ₃ ): 145.5, 128.4, 127.0, 125.8, 47.5, 44.2, 35.3, 21.9, 18.8.

Example  4: rac - Of tolterodine (Formula VI)  Produce

2.0841 g (8.8546 mmol) of 3- (diisopropylamino) -1-phenyl-propan-1-ol obtained in Example 3 was dissolved in 3.97 mL of CH ₂ Cl _{2 and} 0.9576 g (8.8546 mmol) of p -cresol was added. After that, 5.35 ml of an aqueous 70% HClO ₄ solution was added. The mixture was stirred at rt for 3 h. Ice was added to the mixture and basified with aqueous NaOH solution. The mixture was quenched for 30 minutes. After separating the layers, the organic phase was washed three times with an aqueous NaOH solution and washed with brine and distilled water. All organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated using a reflux evaporator. Further drying in vacuo, 2.5074 g (yield 87%) of tolterodine racemate, the target compound as a sticky solid, were obtained, and the total yield was 62.33%. ¹ H NMR data of the target compound are as follows:

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.32 (d, J = 4.50, 4H), 7.23 (m, 1H), 6.83 (m, 2H), 6.53 (br s, 1H), 4.49 (dd, J = 3.90, 11.10, 1H), 3.23 (quintet, J = 6.45, 6.90, 13.35, 2H), 2.72 (m, 1H), 2.36 (m, 2H), 2.11 (s, 3H), 1.10 (dd, J = 6.60, 17.70, 12H); ¹³ C (75 MHz, CDCl ₃ ): 153.5, 144.9, 132.7, 129.6, 128.9, 128.8, 128.5, 128.0, 126.4, 118.4, 48.2, 42.2, 39.5, 33.3, 21.0, 20.2, 19.7.

Claims (1)

Intermediate of tolterodine racemate represented by the following formula (4): [Formula 4]

In Formula 4, R is a p -nitrobenzenesulfonyl group.