KR101752449B1 - Manufacturing process of solifenacin or solifenacin salt, the new intermediate in the process and manufacturing process therof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition having a competitive cholinergic receptor antagonist pharmacological activity and a therapeutic agent for overactive bladder symtoms, urge urinary incontinence, urgency and urinary frequency The present invention relates to a process for efficiently producing Solifenacin and Solifenacin salts which are used in industrial processes such as pyridine and benzylchloroformate under mild reaction conditions such as room temperature, Or ethyl chloroformate, and using the same to prepare a high-yield crystalline form of solifenacin or its salt.
According to the present invention, the reaction conditions are mild, the yield and purity are high, and the cost is also low, so that it is possible to produce crystalline forms of solifenacin and its salts with high industrial efficiency.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing a crystalline form of solifenacin or a salt thereof and a novel intermediate used therefor and a process for preparing the same,

The present invention relates to a process for preparing a crystalline form of solifenacin or a salt thereof, a novel intermediate used therefor and a process for producing the same, and more particularly, to a novel intermediate by the reaction of pyridine with benzyl chloroformate or ethyl chloroformate And a method for producing solifenacin or a salt thereof, which is industrially highly efficient using the same.

Solifenacin (C ₃₀ H ₃₉ N ₃ O ₃ ) represented by the following chemical formula (1) and Solifenacin succinate salt represented by the chemical formula (2) shown below are competitive cholinergic receptor antagonists It is a competitive cholinergic receptor antagonist and is being used effectively as a treatment for overactive bladder symtoms, urge urinary incontinence, urgency and urinary frequency.

[Chemical Formula 1]

(2)

For example, in Astellas (Yamanouchi), solifenacin succinate has been developed as a drug for the treatment of hypersensitivity cystitis and is marketed under the trade name Vesicare.

(1) and (2) are all represented by the following reaction formulas (1) and (2) It can be seen that the reaction for tetrahydroisoquinoline and (R) -quinuclidin-3-ol is linked to a carbonyl group.

First, a production method according to the following reaction formula (1) is disclosed in Korean Patent No. 10-0386487 and US Patent No. 6,017,927. However, even though the reaction time for producing solifenacin of the above formula (1) takes 12 hours or more, this production method has a problem that the yield is very low and the purity is also very low There are disadvantages. Also, it is sensitive to moisture, and there is a disadvantage that it is very limited in industrial use because of the risk of explosion in mass production due to the use of sodium hydride (NaH).

[Reaction Scheme 1]

In addition, U.S. Patent No. 7,829,715 and U.S. Patent No. 7,741,489 disclose a production method as shown in the following reaction formula (2), which is an improved production method as compared with the reaction formula (1).

In this reaction scheme (2), CDI ((1,1'-carbonyldiimidazole) or 1,1'-carbonylditriazole is used to introduce a carbonyl group, (CDI) or 1,1'-carbonyldithiazole, which is a compound for the introduction of a carbonyl group, is very expensive and industrially expensive (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline and (R) -quinucridine-3 -Oryl is required to be heated to reflux for several hours at a temperature of 100 ° C or higher, and about 7 to 15% of unreacted materials remain.

[Reaction Scheme 2]

That is, as can be seen from the above reaction schemes (1) and (2), the preparation method of solifenacin is (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline and (R) In a reaction for the coupling of quinuclidin-3-ol to a carbonyl group, it is possible to use ethyl chloroformate, 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonyldithiazol The same carbonyl group derivative compound should be used, and such a derivative compound can be represented by the following formula (3).

(3)

In the above formula (3), A represents a hetero atom such as oxygen or nitrogen, R represents an alkyl or allyl group, and A-R represents a leaving group. The efficient production method of solifenacin is the key to the development of an efficient leaving group, A-R in the above formula (3).

Specific examples of the compound having the structure represented by the formula (3) to date include ethylchlorocarbonate of the following formula (4), which is disclosed in U.S. Patent No. 6,017,927 and Korean Patent Laid-open No. 10-2010-16116, (1,1'-carbonyldiimidazole) represented by the following chemical formula (5) and 1,1'-carbonyldithiol of the following chemical formula (6), which are disclosed in U.S. Patent No. 7,741,489 and U.S. Patent No. 7,829,715 (1, 1'-carbonyl-di (1,2,4-triazole)), a compound of the following formula (7), which is disclosed in Korean Patent No. 10-1298046, Korean Patent No. 10-1365849 There is a compound of the following formula (8).

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

However, the ethyl chlorocarbonate of the above formula (4) has a disadvantage in that 10% or more of unreacted material remains even after 15 hours of reaction. The 1,1'-carbonyldiimidazole and the 1, , 1'-carbonyldithiazole has a drawback that it is very expensive for industrial use. In addition, a modified imidazole salt compound having a halide salt such as iodine in 1,1'-carbonyldiimidazole in which the leaving group activity of the formula (7) is increased can be obtained by reacting 1,1'-carbonyldiimidazole with an expensive 1,1'- It is impossible to avoid the increase of the production cost of solifenacin, and the compound of the above formula (8) is also an expensive compound, which raises the manufacturing cost.

Therefore, all of the above-mentioned compounds are limited in industrial use due to the incomplete reaction or the price problem. Accordingly, there is a desperate need for the development of an industrially useful carbonyl group compound having an efficient leaving group and a method for producing the effective solifenacin using the same as the above-described formula (3).

KR 10-0386487 B1 US 6,017,927 B1 US 7,829,715 B1 US 7,741,489 B1 KR 10-2010-0016116 A KR 10-1298046 B1 KR 10-1365849 B1

Accordingly, an object of the present invention is to solve the problems of the above-mentioned conventional method of producing a crystalline form of solifenacin or its salt, which is unreliable or expensive, and which is excellent in reactivity for producing solifenacin, And an industrially efficient method for preparing an improved solifenacin or a salt thereof by using an intermediate thereof.

In order to accomplish the above object, the present invention provides a process for preparing a crystalline form of solifenacin or a salt thereof, which proposes a novel production route such as the following reaction formula (3).

[Reaction Scheme 3]

In the step of converting the solifenacin of the formula (1) into the solifenacin succinate of the formula (2), n-butanol, isobutyl alcohol, isopropyl alcohol, isopropyl Isopropyl acetate, ethyl acetate, and the like.

Wherein the solvent is a mixture of alcohols and acetates, wherein the mixing ratio is in the range of 0.1 to 2.0: 0.1 to 2.0 parts by volume, and the solifenacin is converted into the solifenacin succinate at a temperature of 50 to 80 ° C.

The compound represented by the formula (10) is a compound selected from the group consisting of ethyl chloroformate and benzyl chloroformate.

The prepared solifenacin salt was a crystalline form of solifenacin succinic acid (MCK-I), and when analyzed by infrared spectroscopy, it was found to be 2935.84, 2448.29, 1721.91, 1685.44, 1589.92, 1424.50, 1319.78, 1226.88, 1122.60, 751.93, 698.03, 620.93 cm- X-ray powder diffraction analysis showed that the 2? Diffraction angles with relative intensities of 10% or more were 3.692, 7.393, 11.087, 13.503, 14.145, 14.831, 18.126, 18.577, 19.263, 21.792, 22.338, 25.101 °, The 2? Diffraction angles of less than 10% are 11.852, 15.540, 17.662, 20.188, 20.958, 22.674, 22.997, 23.184, 23.876, 25.819, 26.127, 26.546, 27.212, 27.604, 28.597, 29.501, 29.939, 30.579, 30.756, 31.750, , 33.023, 34.967, 35.735, 36.169, 36.646, 37.652, 38.368, 40.247, 41.606, 41.894, 42.662, 43.492, 44.432, 45.604, 46.675 °.

The step of preparing the compound of formula (12) is carried out at a temperature of 0 to 30 ° C.

And a novel intermediate used in the production of solifenacin is a compound represented by the following formula (9).

[Chemical Formula 9]

(Wherein R is an ethyl group or a benzyl group, and X is chloro)

And a method for producing a novel intermediate used in the production of solifenacin is characterized by reacting a compound represented by the following formula (10) with pyridine to prepare the following formula (9).

[Chemical Formula 9]

(Wherein R is an ethyl group or a benzyl group, and X is chloro)

[Chemical formula 10]

(Wherein R is an ethyl group or a benzyl group, and X is chloro)

Industrial Applicability According to the present invention, by maximizing the activity of the leaving group by using pyridine which is industrially inexpensive in circulation, it is more milder than the conventional reaction condition, and the yield and purity are high, It becomes possible to prepare a salt.

Therefore, the present invention can be used commercially as a therapeutic agent for overactive bladder symtoms, urge urinary incontinence, urgency and urinary frequency.

Figure 1 shows IR analysis results for the crystalline form of solifenacin succinic acid (MCK-I).
2 shows the results of DSC-TGA analysis on the crystalline form of solifenacin succinic acid (MCK-I).
3 is an X-ray diffraction (XRD) analysis chart for the crystalline form of solifenacin succinic acid (MCK-I).

The present invention provides a novel intermediate for producing solifenacin or a salt thereof, which is inexpensive and has excellent yield and purity, and a process for producing high efficiency of solifenacin or a salt thereof by using the same. That is, the present invention provides a novel synthesis route of the following reaction formula (3).

[Reaction Scheme 3]

As shown in Scheme 3, the process of the present invention includes the steps of: (a) reacting a compound represented by the following formula (10) with pyridine to prepare a novel intermediate compound represented by the following formula (9) (b) reacting a novel intermediate represented by the following formula (9) with a compound represented by the following formula (11) to prepare a compound represented by the following formula (12) And reacting the compound represented by the formula (13) with a strong base to prepare a solifenacin represented by the following formula (1). (D) converting the solifenacin represented by the following formula (1) to a solifenacin succinate represented by the following formula (2).

[Chemical Formula 1]

(2)

[Chemical Formula 9]

(Wherein R is an ethyl group or a benzyl group, and X is chloro)

[Chemical formula 10]

(Wherein R is an ethyl group or a benzyl group, and X is chloro)

(11)

[Chemical Formula 12]

(Wherein R is an ethyl group or a benzyl group)

[Chemical Formula 13]

Each step will be described in detail below.

(a) reacting a compound represented by the formula (10) with pyridine to prepare a novel intermediate represented by the formula (9).

The present invention relates to novel intermediates used in the preparation of solifenacin or its salts, namely 1-phenyl-1,2,3,4-tetrahydroisoquinoline of the above formula (11) and (R) -quinoline of the formula (12) A benzyloxycarbonylpyridinium chloride salt of the above formula (9), which can be used for forming a carbamate bond by introducing a carbonyl group for coupling reaction of the pyridin-3-ol, Or an ethyloxycarbonylpyridinium chloride salt is prepared.

The compound represented by the formula (9), which is a novel intermediate, can be easily prepared by reacting the compound represented by the formula (10) with pyridine under mild conditions such as room temperature. 4). At this time, as the compound represented by the formula (10), specifically, one selected from the group consisting of ethyl chloroformate and benzyl chloroformate can be used.

[Reaction Scheme 4]

The reaction solvent used in the reaction formula (4) may be a conventional organic solvent such as an aromatic hydrocarbon solvent, a polar organic solvent or a mixed solvent thereof. Specific examples thereof include toluene, xylene, dimethylformamide, dimethyl Acetamide or a mixed solvent thereof may be used. In this case, the amount of the solvent used is not limited. For example, 5 to 15 ml of a solvent per 1 g of pyridine may be used.

 The reaction temperature is maintained at 0 to 40 ° C, preferably 20 to 40 ° C. The reaction of step (a) is completed by stirring for about 2 hours, and the resulting compound of formula (9), which is a novel intermediate, is obtained as a white solid in the reaction solution. Although this white solid can be separated and used in the next reaction by a conventional separation and purification method, even if it is used in the form of a solution without any separation and purification process, the compound of the present invention can be obtained in a high purity of 99.9% It is not necessary to separate and purify it.

The benzyloxycarbonylpyridinium chloride salt or the ethyloxycarbonylpyridinium chloride salt of the formula (9) obtained as described above is reacted with the isoquinolane compound of the formula (11) Such as a secondary alcohol of the (R) -quinuclidin-3-ol of the above formula (12) or a weak nucleophile substitution reaction. That is, the novel intermediate of the formula (9) according to the present invention shows much higher reactivity than any of the compounds of the formulas (3) to (8), so that it can be synthesized at a low cost while leaving almost no unreacted material.

(b) reacting the novel intermediate of formula (9) with the compound of formula (11) to produce the compound of formula (12).

Next, the novel intermediate of the formula (9) obtained above is reacted with 1-phenyl-1,2,3,4-tetrahydroisoquinoline of the formula (11) to obtain the (S) - (1H) -carboxylate [(S) -benzyl-1-phenyl-3,4-dihydroisoquinoline-2 (S) -ethyl-1-phenyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate [ . The reaction is shown in the following reaction formula (5).

The above reaction can be carried out at 0 to 30 ° C, and the reaction of step (b) is completed after about 2 to 3 hours of stirring.

[Reaction Scheme 5]

(c) reacting the compound represented by the formula (12) with the compound represented by the formula (13) using a strong base to prepare solifenacin represented by the following formula (1).

Next, the compound of formula (12) prepared above is reacted with the compound of formula (13) to prepare solifenacin. The reaction is as shown in the following reaction formula (6).

[Reaction Scheme 6]

The reaction scheme (6) is carried out in the presence of a base and a solvent. As the base used herein, a conventional organic base or an inorganic base can be used. Typically, an alkali metal compound can be used. Specifically, an alkali metal hydroxide, Metal C ₁ -C ₁₀ alkoxide, and the like, and most preferably potassium, tert-butoxide and sodium hydride (NaH) are used.

The base may be used in an amount of 0.2 to 3.0 equivalents, preferably 0.2 to 1.5 equivalents. The coupling reaction temperature is maintained at a heating temperature of 60 to 110 ° C, preferably at the reflux temperature of the solvent used . The reaction solvent may be an aromatic hydrocarbon solvent, a polar organic solvent, or a mixed solvent thereof. Specific examples of the reaction solvent include toluene, xylene, dimethylformamide, dicetyl acetamide or a mixed solvent thereof. This step also does not limit the amount of the solvent used.

This coupling reaction is completed within 15 hours. When the completion of the reaction is confirmed, the reaction solution is extracted, acid-treated to remove impurities, and then subjected to base treatment to extract and isolate the solifenacin as an organic layer. G.

In addition, the present invention can also produce a salt compound of solifenacin in addition to a solifenacin free base, and may further include (d) a step of converting the solifenacin to a solifenacin salt .

The salt compound of Solifenacin may include conventional pharmaceutically acceptable salts. Specifically, the acid part may be a salt. The acid addition salt is an ordinary salt used in the pharmaceutical field and is a salt of a non-toxic inorganic acid such as hydrochloric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid or nitric acid or a salt thereof such as propionic acid, succinic acid, glycolic acid, stearic acid, Citric acid, para-toluenesulfonic acid, methanesulfonic acid, and the like.

For example, succinic acid salt of solifenacin as an acid addition salt is prepared by adding succinic acid to solifenacin obtained through the above reaction formula (6), stirring at -20 to 80 ° C, more preferably 50 to 80 ° C Followed by heating and stirring. At this time, the solvent to be used may be at least one selected from the group consisting of aromatic hydrocarbons, ketones and alcohols, and preferably at least one selected from the group consisting of butanol, isobutanol, isopropanol, isopropyl acetate and ethyl acetate . In addition, alcohols and acetates may preferably be mixed in a volume ratio of 0.1 to 2.0: 0.1 to 2.0.

When the reaction solution is cooled to room temperature, the solifenacin succinic acid salt is precipitated as crystals, so that it can be easily recovered by simple filtration. In addition, the solvent may be washed with an appropriate solvent to increase the purity of the solifenacin succinate salt, or a mixed solvent of one or more selected from the aromatic hydrocarbons, ketones and alcohols used in the conversion may be used.

Infrared spectroscopic analysis of the crystal structure of the thus prepared solid phenazine succinic acid crystal form (MCK-I) showed absorption at 2935.84, 2448.29, 1721.91, 1685.44, 1589.92, 1424.50, 1319.78, 1226.88, 1122.60, 751.93, 698.03, 620.93 cm & X-ray powder diffraction analysis showed that the 2? Diffraction angles having relative intensities of 10% or more were 3.692, 7.393, 11.087, 13.503, 14.145, 14.831, 18.126, 18.577, 19.263, 21.792, 22.338, 25.101, The 2? Diffraction angles less than 10% are 11.852, 15.540, 17.662, 20.188, 20.958, 22.674, 22.997, 23.184, 23.876, 25.819, 26.127, 26.546, 27.212, 27.604, 28.597, 29.501, 29.939, 30.579, 30.756, 31.750, 32.081, 33.023 , 34.967, 35.735, 36.169, 36.646, 37.652, 38.368, 40.247, 41.606, 41.894, 42.662, 43.492, 44.432, 45.604, 46.675 °.

The crystalline form of solifenacin succinic acid may be contained as an active ingredient in a pharmaceutical composition for a competitive cholinergic receptor antagonist as described above, and specifically includes overactive bladder symtoms, urge urinary incontinence, Can be used as a therapeutic agent for urinary urgency and urinary frequency.

As in the above-mentioned method, when the crystalline form of the solifenacin or a salt thereof according to the present invention is produced, it has industrially excellent efficiency due to a novel intermediate having excellent reactivity and low cost.

Hereinafter, the present invention will be described in more detail with reference to specific examples.

[Example]

Example 1. Preparation of Solifenacin

69.6 g (880 mmol) of pyridine and 600 mL of toluene were added to a flask filled with nitrogen, and the mixture was cooled to 0 to 5 ° C and stirred. 95.5 g (880 mmol) of ethyl chloroformate was slowly added over 1 hour, stirred at the same temperature for 30 minutes, and then 122.8 g of (S) -1,2,3,4-tetrahydro-1-phenylisoquinoline Add slowly over 30 minutes and stir at 25 < 0 > C for 2 hours. After cooling to 15 ~ 20 ℃, 600 mL of purified water is added to the reaction solution and stirred at 25 ℃ for 10 min. The organic layer was washed with 600 mL of 1 N hydrochloric acid, and then washed with 200 mL of brine. Then, 7 g of magnesium sulfate was added thereto, followed by stirring for 30 minutes, followed by filtration and concentration under reduced pressure to obtain (S) -ethyl 1-phenyl- (1H) -carboxylate (165 g).

Subsequently, 1,400 mL of toluene, 150 mL of dimethylformamide and 75 g (587 mmol) of (R) -quinuclidine-3-ol were sequentially added to the obtained concentrate, and 4.7 g of sodium hydride (NaH) (118 mmol) was added slowly, and the mixture was stirred at the same temperature for 30 minutes. Then, a Dean stark trap and a reflux condenser were placed and stirred under reflux for 14 hours. Next, the reaction solution was cooled to 25 DEG C and 900 mL of 10% brine was added to separate the layers. Then, 880 mL of 1N hydrochloric acid was added thereto, followed by stirring for 10 minutes. 160 g of potassium carbonate and 1500 mL of ethyl acetate were added to the separated aqueous layer, and the mixture was stirred for 10 minutes, and the mixture was allowed to stand to separate layers. [1 H-NMR (400 MHz, CDCl 3) ppm? 1.55-2.18 (400MHz, CDCl 3) ppm? 1.55-2.18 (m / z) was obtained in a yield of 81.4% (1H, m), 2.53-3.16 (10H, m), 3.90-4.20 (1H, m), 6.17-6.55 (1H, m), 7.13-7.42

Example 2: Preparation of solifenacin succinic acid.

900 mL of n-butanol, 400 mL of isopropyl acetate and 48 g of succinic acid were sequentially added to 148 g of Solifenacin obtained in Example 1 and stirred at 65 to 70 ° C for 1 hour. Then, 1-2 g of MCK-I crystals were added between 50 and 65 ° C, the temperature was cooled to 25 ° C, and the mixture was stirred for 1 hour. The precipitated white crystals were filtered off and dried under reduced pressure at 50 DEG C for 12 hours to obtain 167 g of the desired crystal form of solifenacin succinic acid (MCK-I). The HPLC purity is 99.97%. Crystalline structure of the obtained solifenacin succinic acid crystal form (MCK-I) was confirmed by 1H NMR, DSC-TGA, FT-IR and XRD. [Purity 99.97% (HPLC); (1H, m), 2.64-2.99 (7H, m), 3.11- (3H, m) 3.58 (2H, d), 3.81-3.85 (1H, m), 4.65-4.81 (1H, d), 6.09-6.18 (1H, m), 7.18-7.37 (9H, m), Melting point; 144-146 [deg.] C]

The measurement results of FT-IR, DSX-TGA, and XRD were as shown in FIGS. 1 to 3 attached hereto. As shown in FIGS. 1 to 3, the crystalline polymorph of MCK-I was found to be 2935.84, 2448.29, 1721.91, 1685.44, 1589.92, 1424.50, 1319.78, 1226.88, 1122.60, 751.93, 698.03, 620.93 cm ^-1 X-ray powder diffraction analysis showed that the 2? Diffraction angles with relative intensity of 10% or more were 3.692, 7.393, 11.087, 13.503, 14.145, 14.831, 18.126, 18.577, 19.263, 21.792, 22.338, 25.101 °, The 2? Diffraction angles of less than 10% are 11.852, 15.540, 17.662, 20.188, 20.958, 22.674, 22.997, 23.184, 23.876, 25.819, 26.127, 26.546, 27.212, 27.604, 28.597, 29.501, 29.939, 30.579, 30.756, 31.750, , 33.023, 34.967, 35.735, 36.169, 36.646, 37.652, 38.368, 40.247, 41.606, 41.894, 42.662, 43.492, 44.432, 45.604, 46.675 °.

Example 3: Preparation of ethyloxycarbonylpyridium salt

69.6 g (880 mmol) of pyridine and 600 mL of toluene were added to a flask filled with nitrogen, and the mixture was cooled to 0 to 5 ° C and stirred. 95.5 g (880 mmol) of ethyl chloroformate was slowly added over 1 hour, and the mixture was stirred at the same temperature for 30 minutes. The precipitated crystals were filtered under nitrogen and dried under reduced pressure to obtain 98 g of ethyloxycarbonylpyridinium salt. [1 H NMR (DMSO-d 6, 300 MHz) 隆 1.55 (t, J = 7.14 Hz, 3 H); 4.69 (q, J = 7.14 Hz, 2 H); 8.18 (t, J = 6.9 Hz, 2 H); 8.62 (dd, J = 6.9, 6.24 Hz, 1 H); 9.21 (d, J = 6.24 Hz, 2H)

Example 4: Preparation of benzyloxycarbonylpyridinium salt

69.6 g (880 mmol) of pyridine and 600 mL of toluene were added to a flask filled with nitrogen, and the mixture was cooled to 0 to 5 ° C and stirred. Benzyl chloroformate (150.1 g, 880 mmol) was gradually added over 1 hour, and the mixture was stirred at the same temperature for 30 minutes. The precipitated crystals were filtered under nitrogen and dried under reduced pressure to obtain 160 g of benzyloxycarbonylpyridinium salt. 1H NMR (DMSO-d6, 300 MHz)? 5.21 (s, 1H); 7.37-7.48 (m, 5 H); 8.13 (t, J = 6.82 Hz, 2 H); 8.64 (dd, J = 6.82, 6.21 Hz, 1 H); 9.24 (d, J = 6.21 Hz, 2H)

Example 5: Preparation of solifenacin

The procedure of Example 1 was repeated except that the ethyloxycarbonylpyridium salt obtained in Example 3 was used instead of pyridine and ethyl chloroformate.

Example 6: Preparation of solifenacin

The procedure of Example 1 was repeated except that the benzyloxycarbonylpyridinium salt obtained in Example 4 was used instead of pyridine and ethyl chloroformate.

Example 7: Preparation of solifenacin succinic acid

The procedure of Example 2 was repeated except that isobutyl alcohol was used instead of n-butanol. The crystals obtained are of MCK-I crystalline form.

Example 8: Preparation of solifenacin succinic acid

The procedure of Example 2 was followed except that isobutyl alcohol was used instead of n-butanol. The crystals obtained are of MCK-I crystalline form.

Example 9: Preparation of solifenacin succinic acid

Ethyl acetate was used instead of isopropyl acetate in the same manner as in Example 2. The crystals obtained are of MCK-I crystalline form.

Example 10: Liquid chromatographic analysis (content determination)

 10 mg of the solifenacin succinic acid crystal form (MCK-I) obtained in Examples 2, 7, 8 and 9 and 10 mg of the standard product having a purity of 99.9% were accurately weighed and dissolved in 50 ml of acetonitrile to prepare a sample solution. Add 5 mL of the sample solution prepared in the 50 mL volumetric flask and use the acetonitrile as the standard solution. The content of solifenacin succinic acid crystal form (MCK-I) was calculated as the peak area by HPLC analysis according to the following analysis conditions.

  [Analysis Conditions of Liquid Chromatography (HPLC)] [

     Column: Develosil ODS-UG-5 (4.6 mm X 150 mm)

     Column temperature: 40 ° C

     Detector: UV Detector (210 nm)

     Flow rate: 1.0 mL / min

     Time: 40 minutes

     Mobile phase: Buffer / acetonitrile (700: 300 volume ratio)

     Buffer Solution: Dissolve 8.7 g of potassium dihydrogenphosphate in water to make 1 L. Add phosphoric acid to this solution to adjust the pH to 6.0.

Storage: HDPE bottle

Example 11 Stability Test of Solifenacin Succinic Acid (Content Measurement)

The solifenacin succinic acid crystal form (MCK-I) obtained in Examples 2, 7, 8, and 9 was analyzed by HPLC under the analytical conditions of Example 10, 2 months, 3 months, 6 months) under the conditions of acceleration (40 ± 2 ℃, relative humidity of 75 ± 5%) and long-term storage condition (25 ± 2 ℃, relative humidity of 60 ± 5% The changes of the contents were measured over a month.

The results are shown in Table 1 below.

Results of Stability Test of Solifenacin Succinic Acid. division
Conservation conditions
Content of active ingredient (%) 1 month 2 months 3 months 6 months Crystalline MCK-I
25 ° C, 60% RH 99.92 99.94 99.89 99.90 40 ° C, 75% RH 99.91 99.88 99.86 99.85 Amorphous
25 ° C, 60% RH 99.04 98.88 98.47 97.98 40 ° C, 75% RH 98.96 98.37 98.01 97.02

According to the above Table 1, the content of crystalline MCK-I was maintained almost at the end of 6 months under long-term storage test and accelerated test conditions at room temperature, and the total amount of impurities in each crystal during the entire test period was almost unchanged There was no. That is, the crystalline MCK-I maintains the range of 98.0 ~ 102.0%, which is the stability suitable content condition even after 6 months. Therefore, it was confirmed that the crystalline MCK-I according to the present invention exhibits excellent stability.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the scope of the present invention is not limited to the disclosed exemplary embodiments. It will also be appreciated that many modifications and variations will be apparent to those skilled in the art without departing from the scope of the invention.

Claims (9)

(a) reacting a compound represented by the following formula (10) with pyridine to prepare a compound represented by the following formula (9)
(b) reacting a compound represented by the following formula (9) with a compound represented by the following formula (11) to prepare a compound represented by the following formula (12)
(c) reacting a compound represented by the formula (12) and a compound represented by the following formula (13) using a strong base to prepare a solifenacin represented by the following formula (1)
The compound represented by the formula (10) is a compound selected from the group consisting of ethyl chloroformate and benzyl chloroformate,
Wherein the strong base is sodium hydride (NaH).
[Chemical Formula 1]

[Chemical Formula 9]

(Wherein R is an ethyl group or a benzyl group, and X is chloro)
[Chemical formula 10]

(Wherein R is an ethyl group or a benzyl group, and X is chloro)
(11)

[Chemical Formula 12]

(Wherein R is an ethyl group or a benzyl group)
[Chemical Formula 13]

The method according to claim 1,
(d) converting the solifenacin of the formula (1) to a solifenacin succinate salt of the formula (2).
(2)

3. The method of claim 2,
In step (d), at least one solvent selected from the group consisting of n-butanol, isobutyl alcohol, isopropyl alcohol, isopropyl acetate, and ethyl acetate is used as the solvent. Or a salt thereof is used.
The method of claim 3,
As the solvent, alcohols and acetates are mixed and used,
Wherein the mixing ratio is 0.1 to 2.0: 0.1 to 2.0 volume ratio.
3. The method of claim 2,
Wherein the step (d) is performed at a temperature of -20 to 80 ° C.
3. The method of claim 2,
The salt of solifenacin prepared in the step (d) was a crystalline form of solifenacin succinic acid (MCK-I). Infrared spectroscopic analysis of the salt showed 2935.84, 2448.29, 1721.91, 1685.44, 1589.92, 1424.50, 1319.78, 1226.88, 1122.60, 751.93, 698.03, having an absorption peak at 620.93 cm < -1 >
X-ray powder diffraction analysis showed that the 2? Diffraction angles having relative intensities of 10% or more were 3.692, 7.393, 11.087, 13.503, 14.145, 14.831, 18.126, 18.577, 19.263, 21.792, 22.338,
Wherein the 2? Diffraction angles having relative intensities of less than 10% are 11.852, 15.540, 17.662, 20.188, 20.958, 22.674, 22.997, 23.184, 23.876, 25.819, 26.127, 26.546, 27.212, 27.604, 28.597, 29.501, 29.939, 30.579, 30.756, Characterized in that the crystalline form of solifenacin or a salt thereof is characterized by being in the range of 32.081, 33.023, 34.967, 35.735, 36.169, 36.646, 37.652, 38.368, 40.247, 41.606, 41.894, 42.662, 43.492, 44.432, 45.604, 46.675 °. delete delete delete

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