KR20190110400A - Methods of preparingbazedoxifene by new intermediates - Google Patents

Abstract

The present invention relates to a method for manufacturing novel bazedoxifene or a pharmaceutically acceptable salt thereof. A manufacturing method according to the present invention can provide high purity and high yield of bazedoxifene, and is economical in terms of time and cost and eco-friendly due to a relatively simple manufacturing process, thereby being able to be usefully applied to mass production.

Description

 Method for preparing bazedoxifen using new intermediate {METHODS OF PREPARINGBAZEDOXIFENE BY NEW INTERMEDIATES}

The present invention relates to a method for preparing bazedoxifen with high yield and high efficiency, which is easy, economical and environmentally friendly.

Bazedock of 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol of the formula Seefenx (Bazedoxifene) is a third-generation female hormone receptor modulator (SERM). It is an active ingredient that can act as an estrogen agonist or antagonist with the same effect as estrogen, depending on the tissue of the body.

Korean Patent Publication No. 10-0480193 or Miller et al., J. Med. Chem., 2001, 44, 1654-1657, describes the preparation of bazedoxifen and its salts.

However, the existing manufacturing method of bazedoxifen is difficult to obtain starting materials for synthesis and the synthesis of intermediates, making it difficult to obtain these materials on the market, and the price is also very expensive, which causes the production cost of bazedoxifen. Among them, there is a problem of causing environmental pollution by using a metal catalyst.

Specifically, Korean Patent Publication No. 10-0480193 discloses various methods as a method for synthesizing bazedoxifen, and discloses a method for preparing bazedoxifen, as shown in Scheme 1 below.

Scheme 1

As in Scheme 1, in the case of the method for preparing bazedoxifen using the method using the hydrazine, a total of six synthesis steps are required. In addition, for the synthesis of intermediate C for the synthesis of bazedoxifen, the final product, the hydroxy group of the reactants should be protected by a protecting group (protecting group) to the reaction of Chemical Formulas (A) and (B). to be. In addition, since the hydrogenation reaction using Pd is required to remove the protecting group after the synthesis of the intermediate D, environmental pollution due to the metal catalyst may be caused, and there may be a risk of explosion due to the hydrogenation reaction.

Miller et al., J. Med. The method described in Chem., 2001, 44, 1654-1657 also does not facilitate the synthesis of intermediates, and in order to carry out the deprotection reaction, the reaction with Pd is carried out, so that bazedoxifene is prepared using conventional methods. Production is difficult to apply to mass production in terms of environmental and stability.

For the same reason as above, there is a need for a method of manufacturing bazedoxifen to solve the above problems.

Korean Patent Publication No. 10-0480193

J. Med. Chem., 2001, 44, 1654-1657

It is an object of the present invention to provide a method for preparing bazedoxifen in an easy, economical, environmentally friendly, high purity, high yield manufacturing process.

The present invention provides a new method for preparing bazedoxifen or a pharmaceutically acceptable salt thereof.

Specifically, the present invention provides a manufacturing method comprising the following steps:

(S-1) preparing a compound of Formula 2 from a compound of Formula 1;

(S-2) preparing a compound of formula 4 by reacting the compound of formula 2 with a compound of formula 3;

(S-3) preparing a compound of Formula 5 by introducing a protecting group to the hydroxyl group of the compound of Formula 4;

(S-4) preparing a compound of Chemical Formula 7 by reacting the compound of Chemical Formula 5 with the compound of Chemical Formula 6; And

(S-5) preparing a compound of Formula 8 by leaving a protecting group from the compound of Formula 7;

Method for preparing bazedoxifen or a pharmaceutically acceptable salt thereof comprising:

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

In the above formula,

R ₁ Is -pivaloyl,-(C ₃ -C ₇ cycloalkyl),-(C ₁ -C ₄ alkyl) -OR ₂ or -benzyl, wherein at least one H located on the ring in -benzyl is-(C ₁ -C ₄ alkyl), -O- (C ₁ -C ₄ alkyl) or -halogen},

R ₂ Is-(C ₁ -C ₄ alkyl) or-(C ₁ -C ₄ alkyl) -O- (C ₁ -C ₄ alkyl).

In one embodiment of the present invention, R ₁ Silver may be -pivaloyl, -cyclopentyl, -2-ethoxyethyl, -2-methoxyethoxymethyl or -4-methoxybenzyl.

Conventionally, in order to synthesize the intermediate compound of Formula 4, a protecting group was introduced to the hydroxyl group of the compound of Formula 1. However, in the present invention, without introducing a protecting group into the formula (1), by reacting the compound of the formula (4-hydrazinylphenol hydrochloride) and the compound of the formula (3 (1- (4-hydroxyphenyl) propan-1-one), The compound was obtained.

In an embodiment of the present invention, the step (S-1) is made of hydrochloride of the compound of formula 1, and then at a subzero temperature NaNO ₂ And reacted with water to prepare a compound of formula (2).

In an embodiment of the present invention, the (S-2) step may be performed in the presence of an alcohol having 1 to 4 carbon atoms. Specifically, step (S-2) may be performed in the presence of methanol, ethanol, isopropanol, 1-methoxy-2-propanol, 2-methoxy-ethanol or a mixture thereof. More specifically, the (S-2) step may be performed in the presence of methanol.

In an embodiment of the present invention, the (S-2) step may be heated in an alcohol having 1 to 4 carbon atoms to obtain a compound of formula (4). The heating may be performed at 40 to 90 ℃. The heating temperature may be carried out more specifically at 60 ℃. Specifically, step (S-2) is a compound of formula 2 and the compound of formula 3 is an alcohol solvent, such as methanol, ethanol, isopropanol, 1-methoxy-2-propanol, 2-methoxy- ethanol or their Reaction at 40 to 90 ℃ using a mixture and the like can be obtained a compound of formula (4).

In an embodiment of the present invention, in the step (S-3), a protecting group may be introduced into a hydroxyl group by reacting the compound of Formula 9 with the compound of Formula 4.

[Formula 9]

In Chemical Formula 9,

R ₁ Is the same as defined above,

X is halogen, -OMs or -OTs.

When prepared according to the production method of the present invention, it is possible to obtain a high purity bazedoxifen. In addition, in the case of the production method according to the present invention, it is possible to use a variety of catalysts (catalyst) without using a metal catalyst to deprotect the group, it is environmentally friendly.

The catalyst may be a halide, an acid or a salt, but is not limited thereto. Specifically, the catalyst is tetrabutylammonium fluoride, iodotrimethylsilane, hydrogen bromide (HBr), acetic acid, sodium hydroxide (NaOH), triethylamine (Et ₃ N), ammonium hydroxide (NH ₄ OH) may be 1 or 2 or more selected from the group consisting of.

In the present invention, the pharmaceutically acceptable salt may be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid.

Specifically, the pharmaceutically acceptable salts of the present invention mean salts commonly used in the pharmaceutical industry, for example, inorganic ions, hydrochloric acid, nitric acid, phosphoric acid, bromine, made of calcium, potassium, sodium, magnesium, and the like. Inorganic acid salts prepared with acid, iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid Organic acid salts prepared with acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid and the like; Sulfonic acid salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; Amino acid salts prepared with glycine, arginine, lysine and the like; And amine salts made of trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like, but the salts used in the present invention are not limited by these salts.

The production method of the present invention can lower the production cost of the product, it is environmentally friendly by not using a metal catalyst to remove the protecting group.

In addition, the production method of the present invention can provide a high purity and high yield of bazedoxifen.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example 1 Synthesis of Bazedoxifen

[Step 1] Synthesis of Compound of Formula 2 (4-Hydrazinylphenol hydrochloride)

5 g (45.817 mmol) of 4-aminophenol and 20 ml of concentrated hydrochloric acid were added to the reactor and cooled. NaNO ₂ at -7 ° C 3.48 g (50.399 mmol, 1.1 eq) was dissolved in 7 g of water, added dropwise for 40 minutes, and stirred at -5 to 0 ° C for 1.5 hours. SnCl ₂ at -5 ° C 19.64 g (87.502 mmol, 1.9 eq) (2H ₂ O) was added dropwise by suspension in 50 ml of 1N hydrochloric acid. Stir at 0-5 [deg.] C. for 3.5 hours, then filter at 2 [deg.] C. and wash the crystals with ethyl acetate. Drying under reduced pressure at 40 ° C. gave 4.33 g (yield 58.83%) of the title compound as a purple crystal.

¹ H NMR (400MHz, D ₂ O): δ 3.56 (5H, OH, NH overlap), 6.68 ~ 6.71 (dd, 2H), 6.88 ~ 6.90 (dd, 2H)

[Step 2] Synthesis of Compound of Chemical Formula 4 (2- (4-Hydroxyphenyl) -3-methyl-1H-indol-5-ol)

0.3 g (1.868 mmol) of 4-hydrazinylphenol hydrochloride prepared in step 1, 0.31 g (2.055 mmol, 1.1 eq) and MeOH 30 of 4-hydroxypropiophenone The ml was placed in a reactor and stirred at 60 ° C. for 5 hours. The solvent was concentrated under reduced pressure, 25 ml of ethyl acetate was added thereto, and the precipitated solid was removed by filtration. The filtrate organic layer was washed with water and extracted, and the extracted organic layer was dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to obtain 0.39 g (88% yield) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.28 (s, 3H), 5.30 (br. S, OH), 6.80-7.42 (m, 7H)

[Step 3] Synthesis of Compound of Chemical Formula 5 (2- (4-hydroxyphenyl) -3-methyl-1H-indol-5-yl pivalate)

2 g (8.35 mmol) of the compound prepared in Step 2 was dissolved in 20 ml of TFA, cooled to 0 ° C., and then 6.1 ml (41.75 mmol, 5 eq) of pivaloyl chloride was added thereto at 50 ° C. The mixture was heated and stirred for 3 hours. The reaction was cooled to 5 ° C. or lower and then the pH was neutralized with 1N NaOH solution. Extracted with water and methylene chloride (MC) and washed the organic layer with brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 2.84 g (83%) of the title compound as a pinkish white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.40-1.43 (s, 18H), 2.57 (s, 3H), 6.88-7.61 (m, 7H)

[Step 4] Compound of Formula 6 (1- (4- (2- ( azepan -One- yl ) ethoxy ) benzyl) -3-methyl-2- (4- (pivaloyloxy) phenyl) -1H-indol-5-yl pivalate ) Synthesis

1 g (2.45 mmol) of the compound prepared in step 3 and 1- (2- (4- (chloromethyl) phenyl) ethyl) azane hydrochloride (1- (2- (4- (chloromethyl) phenyl) ethyl) azepane hydrochloride) 0.8 ml (2.67 mmol, 1.1 eq) 15 ml of DMF was added to the reactor and cooled. 0.72 g (7.35 mmol, 3.0 eq) of t-BuONa was slowly added at −10 ° C. and stirred at the same temperature for 4 hours. 30 ml of ice water was slowly added dropwise to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 1.02 g (65%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.32 (s, 18H), 1.61 (m, 4H), 1.75 (m, 4H), 2.28 (s, 3H), 2.81 (m, 2H), 2.96 (t, 2H), 4.04 (t, 2H), 5.88 (s, 2H), 6.79 ~ 7.62 (m, 11H)

[Step 5] Of Bazedoxifen  synthesis

0.8 g (1.252 mmol) prepared in step 4 was dissolved with 10 ml of methanol. 0.52 g (3.75 mmol, 3.0 eq) of potassium carbonate was added thereto, followed by stirring at 45 ° C. for 3 hours. The organic layer was washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 0.49 g (83%) of bazedoxifen.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.61-1.69 (m, 8H), 2.20 (s, 3H), 2.82 (m, 2H), 2.96 (t, 2H), 4.04 (t, 2H), 5.09 ( s, 2H), 6.69 ~ 7.16 (m, 11H)

Example  2. Of Bazedoxifen  synthesis ( Example  1, in situ reaction)

1 g (2.45 mmol) of the compound prepared in Step 2 of Example 1 and 1- (2- (4- (chloromethyl) phenyl) ethyl) azane hydrochloride (1- (2- (4- (chloromethyl) 15 ml of DMF was added to 0.82 g (2.67 mmol, 1.1 eq) of (phenyl) ethyl) azepane hydrochloride and cooled. 1.13 g (12.25 mmol, 5.0 eq) of t-BuONa was slowly added at 0 ° C. and stirred at the same temperature for 2 hours. After naturally raising to room temperature, the mixture was stirred at 50 ° C. for 3 hours, and 30 ml of water was added at 0 ° C. Extraction was performed with ethyl acetate and brine, and the organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 0.55 g (48%) of bardoxifen.

¹ H NMR (400 MHz, CDCl ₃ ): same as Example 1.

Example  3. Of Bazedoxifen  synthesis

[Step 1] and [Step 2]

Same as Step 1 and Step 2 of Example 1.

[Step 3] Compound of Formula 5 (5- ( cyclopentyloxy ) -2- (4- ( cyclopentyloxy Synthesis of) phenyl) -3-methyl-1H-indole)

1.2 g (5.015 mmol) of the compound of Chemical Formula 4 prepared in Step 2 and 20 ml of DMSO were added to the reactor, and 2.08 g (15.04 mmol, 3 eq) of K ₂ CO ₃ was added thereto, followed by stirring at room temperature for 30 minutes. 1.52 g (11.04 mmol, 3.0 eq) of cyclopentyl bromide was added dropwise to the reaction, stirred at 60 ° C. for 3 hours, and then extracted with water and methylene chloride (MC). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 0.79 g (45%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.44 to 1.56 (m, 8H), 1.89 to 2.04 (m, 8H), 2.35 (s, 3H), 3.85 to 3.92 (m, 4H), 6.84 to 7.52 (m , 7H)

[Step 4] Compound of Formula 6 (1- (4- (2- ( azepan -One- yl ) ethoxy ) benzyl) -5- ( cyclopentyloxy Synthesis of) -2- (4- (cyclopentyloxy) phenyl) -3-methyl-1H-indole)

1.05 g (2.79 mmol) of the compound prepared in step 3 and 1- (2- (4- (chloromethyl) phenyl) ethyl) azane hydrochloride (1- (2- (4- (chloromethyl) phenyl) ethyl) azepane hydrochloride) 1.02 g (3.35 mmol, 1.2 eq) and 20 ml of DMF were added to the reactor and cooled. 0.67 g (6.98 mmol, 2.5 eq) of sodium tert-butoxide was added at 0 ° C., and the mixture was naturally warmed to room temperature and stirred for 3 hours. Ice water was slowly added dropwise to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 0.94 g (56%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.42-1.56 (m, 8H), 1.61-1.98 (m, 16H), 2.28 (s, 3H), 2.81 (m, 2H), 2.96 (t, 2H), 3.85 ~ 3.92 (m, 4H), 4.05 (t, 2H), 5.59 (s, 2H), 6.69 ~ 7.22 (m, 11H)

[Step 5] Of Bazedoxifen  synthesis

0.94 g (5.167 mmol, 2.8 eq) of 48% HBr and 20 ml of acetic acid were added to 1.12 g (1.845 mmol) of the compound prepared in Step 4. After stirring for 2 hours at 50 ℃ extracted with water and ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 0.66 g (61%) of bazedoxifen.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.61-1.69 (m, 8H), 2.20 (s, 3H), 2.83 (m, 2H), 2.96 (t, 2H), 4.04 (t, 2H), 5.11 ( s, 2H), 6.69 ~ 7.16 (m, 11H)

Example  4. Of Bazedoxifen  synthesis

[Step 1] and [Step 2]

Same as Step 1 and Step 2 of Example 1.

[Step 3] Compound of Formula 5 (5- (2- ethoxyethoxy ) -2- (4- (2- ethoxyethoxy Synthesis of) phenyl) -3-methyl-1H-indole)

The compound prepared in Step 2 and 25 ml of DMF were added to the reactor, and 2.6 g (18.81 mmol, 3 eq) of K ₂ CO ₃ was added thereto, and the mixture was stirred at room temperature for 30 minutes. 3.35 g (21.94 mmol, 3.5 eq) of 1-bromo-2-ethoxyethane was added dropwise to the reaction mixture, stirred at 60 ° C. for 4 hours, and extracted with water and ethyl acetate. It was. The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give 1.60 g (67%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.28-1.29 (m, 6H), 2.39 (s, 3H), 3.63 (m, 4H), 3.82 (m, 4H), 4.18-4.21 (m, 4H), 6.78 ~ 7.59 (m, 7H)

[Step 4] Compound of Formula 6 (1- (4- (2- ( azepan -One- yl ) ethoxy ) benzyl) -5- (2- ethoxyethoxy ) -2- (4- (2-ethoxyethoxy) phenyl) -3-methyl-1H-indole)

1.27 g (3.31 mmol) of the compound prepared in Step 3 and 15 ml of DMF were added to a reactor and cooled. 0.35 g (8.27 mmol, 2.5 eq) of 55% NaH was added at 0 ° C, and stirred for 30 minutes. 1.21 g (3.97 mmol, 1.2 eq) of 1- (2- (4- (chloromethyl) phenyl) ethyl) azepan hydrochloride (1- (2- (4- (chlormethyl) phenyl) ethyl) azepane hydrochloride) Dilution to 10 ml was added dropwise to the reaction solution and stirred at 0 to 5 ℃ for 3 hours. 30 ml of ice water was slowly added dropwise to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 1.18 g (58%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.18 (m, 6H), 1.58 (m, 4H), 1.72 (m, 4H), 2.33 (s, 3H), 2.77 (t, 2H) 3.10 (m, 4H ), 3.53 (m, 4H), 4.00 to 4.04 (m, 6H), 4.18 to 4.21 (m, 4H), 4.98 (s, 4H), 5.95 (s, 2H), 6.72 to 7.74 (m, 11H)

[Step 5] Of Bazedoxifen  synthesis

15 ml of methanol was added to 0.9 g (1.46 mmol) of the compound prepared in Step 4. At room temperature, 0.92 g (3.67 mmol, 2.5 eq) of Boron tribromide was added dropwise and stirred at reflux for 5 hours. The reaction was concentrated under reduced pressure and extracted with water and methylene chloride (MC). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 0.91 g (69%) of bazedoxifen.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.62-1.69 (m, 8H), 2.20 (s, 3H), 2.82 (m, 2H), 2.96 (t, 2H), 4.04 (t, 2H), 5.10 ( s, 2H), 6.69-7.36 (m, 11H)

Example  5. Of Bazedoxifen  synthesis

[Step 1] and [Step 2]

Same as Step 1 and Step 2 of Example 1.

[Step 3] Compound of Formula 5 (5-((4- methoxybenzyl ) oxy) -2- (4-((4- methoxybenzyl Synthesis of) oxy) phenyl) -3-methyl-1H-indole)

1.5 g (6.27 mmol) of the compound prepared in Step 2 was added to the reactor, and 20 ml of MeCN was added to dissolve it. 2.95 g (18.81 mmol, 3.0 eq) of 4-methoxybenzyl chloride, 2.08 g (15.05 mmol, 2.4 eq) of K ₂ CO ₃ and 0.1 g (0.1 eq) of KI were added at room temperature. Stir for 18 hours. 20 ml of water was added to the reaction mixture, extracted with ethyl acetate, and washed with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 0.66 g (22%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.27 (s, 3H), 3.91 (s, 6H), 5.24 (s, 4H), 6.95-7.89 (m, 15H)

[Step 4] Compound of Formula 6 (1- (4- (2- ( azepan -One- yl ) ethoxy Synthesis of) benzyl) -5-((4-methoxybenzyl) oxy) -2- (4-((4-methoxybenzyl) oxy) phenyl) -3-methyl-1H-indole)

1.45 g (3.02 mmol) of the compound prepared in step 3 and 1- (2- (4- (chloromethyl) phenyl) ethyl) azane hydrochloride (1- (2- (4- (chlormethyl) phenyl) ethyl) azepane hydrochloride) 1.06 g (3.48 mmol, 1.15 eq) and 20 ml of DMF were added to the reactor and cooled. 0.87 g (9.06 mmol, 3.0 eq) of sodium tert-butoxide was added at 0 to 2 ° C. and stirred at room temperature for 3 hours. Ice water was slowly added dropwise to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 0.26 g (12%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.62-1.79 (m, 8H), 2.29 (s, 3H), 2.81 (m, 2H), 3.10 (m, 2H), 3.88 (s, 6H), 4.15 ( t, 2H), 5.22 (s, 4H), 5.98 (s, 2H), 6.79 to 7.90 (m, 19H)

[Step 5] Of Bazedoxifen  synthesis

20 g of methylene chloride (MC) was added to 1.1 g (1.547 mmol) of the compound prepared in Step 4, and dissolved. 1.05 g (4.642 mmol, 3 eq) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added thereto and stirred at room temperature for 20 hours. The reaction was adjusted to pH 7 with 1N HCl solution and extracted with methylene chloride (MC). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 0.1 g (15%) of Bazedoxifen.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.61-1.69 (m, 8H), 2.20 (s, 3H), 2.82 (m, 2H), 2.96 (t, 2H), 4.04 (t, 2H), 5.09 ( s, 2H), 6.69 ~ 7.16 (m, 11H)

Example  6. Of Bazedoxifen  synthesis

[Step 1] and [Step 2]

Same as Step 1 and Step 2 of Example 1.

[Step 3] Compound of Formula 5 (5-((2- methoxyethoxy ) methoxy Synthesis of) -2- (4-((2-methoxyethoxy) methoxy) phenyl) -3-methyl-1H-indole)

1 g (4.18 mmol) of the compound prepared in Step 2, 1.67 ml (9.61 mmol, 2.3 eq) of Hnig's base (N, N-Diisopropylethylamine) and 20 ml of Dichloroethane were added to the reactor. 1.2 ml (10.45 mmol, 2.5 eq) of 2-methoxyethoxymethyl chloride was added dropwise at room temperature, followed by stirring at 80 ° C. for 20 hours. The solvent was concentrated under reduced pressure and extracted with water and methylene chloride (MC). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 0.71 g (41%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 2.37 (s, 3H), 3.35 (s, 6H), 3.67 to 3.72 (m, 8H), 5.99 (s, 4H), 6.97 to 7.82 (m, 7H)

[Step 4] Compound of Formula 6 (1- (4- (2- ( azepan -One- yl ) ethoxy ) benzyl) -5-((2- methoxyethoxy ) methoxy Synthesis of) -2- (4-((2-methoxyethoxy) methoxy) phenyl) -3-methyl-1H-indole)

1 g (2.40 mmol) of the compound prepared in step 3 and 1- (2- (4- (chloromethyl) phenyl) ethyl) azane hydrochloride (1- (2- (4- (chlormethyl) phenyl) ethyl) azepane hydrochloride) 0.84 g (2.77 mmol, 1.15 eq) and 20 ml of DMF were added to the reactor and cooled. 0.70 g (7.21 mmol, 3.0 eq) of sodium tert-butoxide was added at 0 to 2 ° C., and stirred at room temperature for 3 hours. Ice water was slowly added dropwise to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO _4δ , and filtered. The filtrate was concentrated under reduced pressure to give 0.74 g (48%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.61 (m, 4H), 1.78 (m, 4H), 2.40 (s, 3H), 2.82 (m, 2H), 3.10 (m, 4H), 3.35 (s, 6H), 3.62 (m, 8H), 4.13 (t, 2H), 5.88 (s, 2H), 6.05 (s, 4H), 6.82-7.75 (m, 11H)

[Step 5] Of Bazedoxifen  synthesis

0.9 g (1.39 mmol) of the compound prepared in Step 4 was added to the reactor, and 15 ml of methanol was added thereto. 0.44 g (5.57 mmol, 4.0 eq) of acetyl chloride was added dropwise at 0 ° C, and stirred for 3 hours at 0-2 ° C, and the solvent was concentrated under reduced pressure. The concentrate was extracted with water and ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 0.28 g (42%) of Bazedoxifen.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.61-1.69 (m, 8H), 2.19 (s, 3H), 2.81 (m, 2H), 2.96 (t, 2H), 4.04 (t, 2H), 5.09 ( s, 2H), 6.69 ~ 7.16 (m, 11H)

Claims (8)

(S-1) preparing a compound of Formula 2 from a compound of Formula 1;
(S-2) preparing a compound of formula 4 by reacting the compound of formula 2 with a compound of formula 3;
(S-3) preparing a compound of Formula 5 by introducing a protecting group to the hydroxyl group of the compound of Formula 4;
(S-4) preparing a compound of Chemical Formula 7 by reacting the compound of Chemical Formula 5 with the compound of Chemical Formula 6; And
(S-5) preparing a compound of Formula 8 by leaving a protecting group from the compound of Formula 7;
Method for preparing bazedoxifen or a pharmaceutically acceptable salt thereof comprising:
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

In the above formula,
R ₁ Is -pivaloyl,-(C ₃ -C ₇ cycloalkyl),-(C ₁ -C ₄ alkyl) -OR ₂ or -benzyl, wherein at least one H located on the ring in -benzyl is-(C ₁ -C ₄ alkyl), -O- (C ₁ -C ₄ alkyl) or -halogen,
R ₂ Is-(C ₁ -C ₄ alkyl) or-(C ₁ -C ₄ alkyl) -O- (C ₁ -C ₄ alkyl). According to claim ₁ , wherein R ₁ A process for producing silver -pivaloyl, -cyclopentyl, -2-ethoxyethyl, -2-methoxyethoxymethyl or -4-methoxybenzyl. The method according to claim 1, wherein the step (S-2) is performed in the presence of an alcohol having 1 to 4 carbon atoms. The method of claim 3, wherein the alcohol is methanol, ethanol, isopropanol, 1-methoxy-2-propanol, 2-methoxy-ethanol or mixtures thereof. The method of claim 1, wherein the step (S-2) is performed at 40 to 90 ° C. According to claim 1, wherein the step (S-3) is a method of introducing a protecting group to the hydroxyl group by reacting the compound of formula 9 to the compound of formula (4):
[Formula 9]

In the above formula,
R ₁ is the same as defined in claim 1,
X is halogen, -OMs or -OTs. The process according to claim 1, wherein the step (S-5) is performed in the presence of a catalyst. 8. The process of claim 7, wherein the catalyst is a halide, acid or salt.