Description

A PROCESS FOR PREPARING INTERMEDIATE OF

DONEPEZIL

Technical Field

[1] The present invention relates to a method for preparing a compound represented by the following Formula 1. [2] <Formula 1>

[3]

[4]

Background Art

[5] The compound 2-[(E)- l-(l-benzyl-4-piperidyl)methylidene] -

5,6-dimethoxy-l-indanone uses herein is an intermediate of donepezil that has been widely known as a therapeutic agent for treating dementia, and is disclosed in European Patent Publication No. 0296560.

[6]

[7] A method for preparing a compound of Formula 1 as disclosed in the known literature may be described in brief, as represented by the following Schemes 1, 2 and 3.

[8] <Scheme 1>

[9]

(2) (3) (1)

[10]

[11] According to the Scheme 1, a target compound represented by Formula 1 may be obtained by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3, but this reaction has a problem that lithium diisopropylamide (LDA) that may not be used for the commercial purpose

should be used as a base. The lithium diisopropylamide has a disadvantage that this compound is generally obtained through the reaction of diisopropylamine and n-butyl lithium at around -8O ⁰ C in a solvent such as tetrahydrofuran and used directly, but very carefully handled at a low temperature since the compound is very sensitive to moisture.

[12] <Scheme 2> [13]

(2) (4) (5)

(5) (3) (1)

[14] [15] An alternative method that does not use lithium diisopropylamide that may not used for the commercial purpose is introduced in Scheme 2. According to the Scheme 2, this method is carried out by first preparing a bromo compound represented by Formula 4 and preparing a phosphonate compound represented by Formula 5 so as to react a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3, but this reaction has a disadvantage that the two reaction steps are further employed and its yield is low.

[16] <Scheme 3> [17]

(2) (6) (7)

(8) (9) (10)

[18] [19] Another alternative method that does not use lithium diisopropylamide that may not used for the commercial purpose is also introduced in Scheme 3, and an intermediate of donepezil that is not identical that of the present invention may be obtained in this method. According to the Scheme 3, a compound having a benzoyl group compound represented by Formula 7 is prepared by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound that is represented by Formula 6 but different from the Formula 3 under a basic condition, as in sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide and sodium hydride, that is more easily used for the commercial purpose than the lithium diisopropylamide, and performing a reduction reaction on them. Next, a final target compound represented by Formula 10 is obtained by removing a benzoyl group to prepare a compound in the form of HCl salt and introducing a benzyl group. However, this reaction has a disadvantage that the two reaction steps are further employed.

[20] [21] Therefore, the present inventors have ardent attempts to develop a synthetic method that is suitable for mass-producing an intermediate of donepezil as a more easy and simple method. As a result, the present inventors have found that a target compound represented by Formula 1 was obtained by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3 in the Scheme 1 whose reaction steps are simplest in the art. In this case, lithium diisopropylamide (LDA) that may not be used commercially was used as a base in this reaction, but the optimum condition for this reaction was established using a base, such as sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide, that may

be used more easily for the commercial purpose instead of the lithium diiso- propylamide, thereby improving the production yield. Therefore, the present invention was completed on the basis of the above facts. [22]

Disclosure of Invention

Technical Problem [23] Accordingly, the present invention is designed to solve such drawbacks of the prior art, and therefore an object of the present invention is to provide a method for preparing capable of preparing an intermediate,

2- [(E)- 1 - ( 1 -benzyl-4-piperidyl)methylidene] -5 ,6-dimethoxy- 1 -indanone, of donepezil in more safe manner and higher yield than the known conventional methods. [24]

Technical Solution [25] According to an aspect of the present invention, there is provided a method for preparing a compound represented by the following formula 1. Here, the compound of the following formula 1 is prepared by reacting a 1 -indanone compound represented by

Formula 2 with an aldehyde compound represented by Formula 3 under a basic condition as in sodium alkoxide. [26] <Formula 1>

[27]

[28]

[29] <Formula 2>

[30]

[31]

[32] <Formula 3>

[33]

[34]

[35] Hereinafter, the method according to the present invention will be described in detail in the following Scheme 4.

[36] European Patent Publication No. 0296560 disclosed a method for preparing a compound of the following formula 1 by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3 in the following Scheme 4.

[37] Lithium diisopropylamide has been used as a base in the reaction of the compound of Formula 2 with the compound of Formula 3 in the prior art, but sodium alkoxide that is easily used for the commercial purpose is used as a base in the method according to the present invention since the lithium diisopropylamide has problems that it is difficult to be used for the commercial purpose due to the high instability, and its yield is very low.

[38]

[39] <Scheme 4>

[40]

(2) (3) (1)

[41]

[42] A reaction solvent, that may be used in the present invention, includes lower alcohols such as methanol, ethanol, isopropanol, and t-butanol, ethers such as tetrahydrofuran, 1,4-dioxane and diisopropyl ether, and polar solvents such as dimethylformamide, dimethylsulfoxide and nitromethane, or combinations thereof.

[43] In this case, a base that is easily used for the commercial purpose is used to adjust the reaction condition to a basic condition, and includes inorganic basic compounds such as sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide, and the other conventional basic compounds may be also used herein. An amount of the used basic compound ranges from 0.8 to 1.5 equivalent weight, based on the total amount of the compound represented by Formula 2.

[44] In this case, the reaction temperature is preferably maintained to a temperature range from -4O ⁰ C to 8O ⁰ C, and more preferably from -2O ⁰ C to 3O ⁰ C.

[45]

[46] As seen from the Scheme 1, lithium diisopropylamide (LDA) that may not be used for the commercial purpose was used in the reaction for preparing a target compound represented by Formula 1 by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3 in the prior art.

[47]

[48] The method according to the present invention may be useful to mass-produce an intermediate of donepezil by establishing a condition where the reaction of the present invention is completed using a base, such as sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide, that may be more easily used for the commercial purpose and enhancing its yield.

[49]

[50] Comparing the yields in the main reaction steps of the present invention with the yield of the conventional methods, in the case of the method disclosed in European Patent Publication No. 0296560, the target compound, in the form of HCl salt, is obtained at a yield of 62% in Example 3 according to Process C in which lithium diisopropylamide that may not be used for commercial purpose is used as base (Scheme 1). Secondly, the target compound, in the form of HCl salt, is obtained in a low yield of 27% in Example 2 according to Process B except for two reaction steps (Scheme 2), and thirdly, the target compounds are obtained respectively in yields of 71%, 85% (except for the hydrogenation reaction) and 72% in the reactions of Example 178, Example 179 and Example 180, but the total yield is low with 43.5% (Scheme 3). On the contrary, the target compound is obtained in a significantly increased yield of 93% in the method according to the present invention.

[51]

[52] Also, all the final products are obtained in the form of HCl salt in the reaction

(Example 3 and Example 2)of obtaining target compounds represented by Formula 1 in the Schemes 1 and 2 (there is no Example where the target compound is obtained in the form of free base but the target compound represented by Formula 1 is used as a free base in the next hydrogenated reduction reaction of Example 4; the target compound represented by Formula 1 does not easily proceed into the hydrogenated reduction reaction and has difficulty to finish the reduction reaction when the target compound is in the form of HCl salt, and therefore the target compound needs to be handled to remove the HCl salt at any costs), but the target compound represented by Formula 1 may be obtained in the form of free base in the method of the present

invention, which may be advantageously directly used in the next reaction.

[53]

[54] When the method of the present invention is carried out as described above, a production yield of a desired intermediate of donepezil, which is a target compound represented by Formula 1 synthesized from the compound represented by the Formula 2, is in a range of about 93%, which indicates that the method of the present invention shows a significantly high yield of the target compound, compared to the recently published methods.

[55]

Advantageous Effects

[56] The method according to the present invention may be useful to prepare a compound represented by Formula 1 using a base, such as sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide, that is easily used for the commercial purpose instead of lithium diisopropylamide that may not be used for the commercial purpose.

[57] Also, the method according to the present invention may be useful to enhance the production yield of the compound of Formula 1, and mass-produce the compound of Formula 1.

[58]

Best Mode for Carrying Out the Invention

[59] Hereinafter, preferable embodiments according to the present invention will be described in detail. However, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the invention, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the invention as apparent to those skilled in the art. Therefore, it should be understood that the present invention might be not defined within the scope of which is described in detailed description but within the scope of which is defined in the claims and their equivalents.

[60]

[61] Example 1: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -

5,6-dimethoxy-l-indanone compound

[62] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 6.75 g of sodium methoxide was added dropwise at 0 to 1O ⁰ C under nitrogen current. The resulting mixture was stirred at 0 to 1O ⁰ C for 15 minutes, and slowly warmed to a temperature of 20 to 25 ⁰ C and stirred for 3 hours. 160 ml of dichloromethane and 100

ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O ⁰ C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.53 g of a target compound (yield: 93.0%).

[63] m.p. 175-177 ⁰ C;

[64] m/e 377.5 (parent ion);

[65] ¹ U NMR (CDCl ) δl.62~1.83 (m, 4H), 2.08-2.26 (m, 2H), 2.27-2.42 (m, IH),

2.92-3.03 (m, 2H), 3.55-3.67 (m, 4H), 3.92 (s, 3H), 3.97 (s, 3H), 6.65 (d, IH), 6.89 (s, IH), 7.28 (s, IH), 7.30-7.39 (m, 5H)

[66]

[67] Example 2: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -

5,6-dimethoxy-l-indanone compound

[68] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 8.50 g of sodium methoxide was added dropwise at 0 to 1O ⁰ C under nitrogen current. The resulting mixture was stirred at 0 to 1O ⁰ C for 15 minutes, and slowly warmed to a temperature of 20 to 25 ⁰ C and stirred for 3 hours. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O ⁰ C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 33.86 g of a target compound (yield: 86.2%).

[69]

[70] Example 3: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -

5,6-dimethoxy-l-indanone compound

[71] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 14.01 g of potassium t-butoxide was added dropwise at 0 to 1O ⁰ C under nitrogen current. The resulting mixture was stirred at 0 to 1O ⁰ C for 15 minutes, and slowly warmed to a temperature of 20 to 25 ⁰ C and stirred for 1 hour. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O ⁰ C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum

condition to obtain 35.15 g of a target compound (yield: 89. f [72] [73] Example 4: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -

5,6-dimethoxy-l-indanone compound

[74] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of t-butanol, and 14.01 g of potassium t-butoxide was added drop wise at 0 to 1O ⁰ C under nitrogen current. The resulting mixture was stirred at 0 to 1O ⁰ C for 15 minutes, and slowly warmed to a temperature of 20 to 25 ⁰ C and stirred for 1 hour. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O ⁰ C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.2 g of a target compound (yield: 92.2%).

[75]

[76]

[77] Example 5: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -

5,6-dimethoxy-l-indanone compound

[78] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of isopropanol, and 6.75 g of sodium methoxide was added drop wise at 0 to 1O ⁰ C under nitrogen current. The resulting mixture was stirred at 0 to 1O ⁰ C for 15 minutes, and slowly warmed to a temperature of 20 to 25 ⁰ C and stirred for 3 hours. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O ⁰ C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.33 g of a target compound (yield: 92.5%).

[79]

[80] Example 6: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -

5,6-dimethoxy-l-indanone compound

[81] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of ethanol, and 6.75 g of sodium methoxide was added drop wise at 0 to 1O ⁰ C under nitrogen current. The resulting mixture was stirred at 0 to 1O ⁰ C for 15 minutes, and slowly warmed to a temperature of 20 to 25 ⁰ C and stirred for 3 hours. 160 ml of dichloromethane and 100

ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O ⁰ C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 33.78 g of a target compound (yield: 86.0%).