WO2013001511A1 - Novel salt intermediates for the synthesis of bazedoxifene acetate and process thereof - Google Patents
Novel salt intermediates for the synthesis of bazedoxifene acetate and process thereof Download PDFInfo
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- WO2013001511A1 WO2013001511A1 PCT/IB2012/053334 IB2012053334W WO2013001511A1 WO 2013001511 A1 WO2013001511 A1 WO 2013001511A1 IB 2012053334 W IB2012053334 W IB 2012053334W WO 2013001511 A1 WO2013001511 A1 WO 2013001511A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- the present invention provides novel salts of l-[ 4-(2-azepan-l-yl-ethoxy)-benzyl]-5- benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H-indole which are useful intermediates in the production of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-l-H- indol-5-ol acetic acid commonly known as apeledoxifene acetate and related compounds.
- BACKGROUND OF THE INVENTION WO2009/012734 discloses preparation of Bazedoxifene and its salts.
- the patent application discloses in situ conversion of apeledoxifene to various salts disclosed therein immediately after de-protection (debenzylation). It discloses the preparation of new crystalline salts of apeledoxifene with acids containing two and more carboxylic groups (polycarboxylic acid).
- polycarboxylic acids are fumaric, formate, succinic, oxalic, maleic, tartaric, citric, propanedioic acid, hydroxybutanoic acid.
- WO2011/022596 discloses preparation of apeledoxifene salts.
- Suitable acids employed for the preparation of the salt include but are not limited to inorganic acids such as hydrochloric acid, sulphuric acid, and phosphoric acid, and organic acids such as methanesulfonic acid, benzenesulfonic acid, propionic acid, etc. It discloses the preparation of acid addition salts of de-protected apeledoxifene as an intermediate for the subsequent production of apeledoxifene acetate substantially free of impurities and intermediates.
- novel acid addition salts of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole (Formula II).
- a process for the synthesis of novel salt intermediates comprising the steps of: i. reacting l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)- 3 -methyl- 1-H-indole (Formula I) with a suitable acid to form the acid addition salt thereof (Formula II).
- an improved process for the synthesis of apeledoxifene acetate via catalytic hydrogenation i.e. pressure hydrogenation or transfer hydrogenation and using the novel salt intermediates of Formula II comprising the steps of: i. reacting l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)- 3 -methyl- 1-H-indole (Formula I) formed in situ with a suitable acid to form the acid addition salt thereof (Formula II);
- the object of the present invention is to provide a process for the preparation of novel salt intermediates (Formula II) of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4- benzyloxy-phenyl)-3-methyl- 1-H-indole (Formula I) and their use in the preparation of apeledoxifene acetate API.
- the suitable acid used for the preparation of the acid addition salts of the compound of formula I can be either organic or inorganic.
- the preferred organic acids are maleic acid, para toluene sulfonic acid, citric acid, malonic acid, fumaric acid, succinic acid, oxalic acid while the preferred inorganic acids are sulphuric acid and hydrochloric acid.
- Suitable base for neutralization of the compound of formula III may be either organic or inorganic.
- Preferred organic are triethylamine, diisopropyl amine, pyridine and organic amines and inorganic bases are sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
- Catalytic hydrogenation of the present invention step may be carried out using hydrogen gas i.e. pressure hydrogenation or a hydrogen source i.e. transfer hydrogenation.
- a hydrogen source are ammonium formate, cyclohexene, cyclohexadiene.
- the preferred catalysts used in the present invention are Pearlman's catalyst and palladium on activated carbon (Pd/C).
- Hydrogen gas pressure for conducting the reaction may vary from about 1 kg/cm 2 to 5 kg/cm 2. Suitable temperatures for conducting de-protection are about 30°C to 55°C.
- the polar aprotic solvents of the present invention are selected from N,N- dimethylformamide, ⁇ , ⁇ -dimethyl acetamide or dimethyl sulphoxide.
- the acronym ⁇ used herein refers to 'Active Pharmaceutical Ingredient'.
- Example 1 l-r4-(2-azepan-l-yl-ethoxy)-benzyll-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) generated according to co-pending patent application 877/KOL/2011 i.e. example 3 is converted to the various acid addition salts of Formula II by the following procedures :- a.
- Example 2 Bazedoxifene acetate API (Formula V) preparation via transfer hydrogenation by Pearlman's catalyst: 10 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl- 1-H indole maleate salt (Formula II) of procedure g of example 1 was added to 150 ml of methanol. Charge 1.8 g of Pearlman's catalyst and 4.11 g of ammonium formate at 25-30°C. Heat reaction mixture to attain temperature 50-55 °C maintain for 2.5 hours. Cool to 25-30°C and filter reaction mixture. Filtrate is distilled to get concentrated mass (Formula III).
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Abstract
The present invention relates to novel salts of 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-H-indole which are useful intermediates in the production of (1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1-H- indol-5-ol acetic acid commonly known as bazedoxifene acetate and related compounds.
Description
NOVEL SALT INTERMEDIATES FOR THE SYNTHESIS OF BAZEDOXIFENE ACETATE AND PROCESS THEREOF
FIELD OF THE INVENTION
The present invention provides novel salts of l-[ 4-(2-azepan-l-yl-ethoxy)-benzyl]-5- benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H-indole which are useful intermediates in the production of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-l-H- indol-5-ol acetic acid commonly known as bazedoxifene acetate and related compounds.
BACKGROUND OF THE INVENTION WO2009/012734 discloses preparation of Bazedoxifene and its salts. The patent application discloses in situ conversion of bazedoxifene to various salts disclosed therein immediately after de-protection (debenzylation). It discloses the preparation of new crystalline salts of bazedoxifene with acids containing two and more carboxylic groups (polycarboxylic acid). Examples of polycarboxylic acids are fumaric, formate, succinic, oxalic, maleic, tartaric, citric, propanedioic acid, hydroxybutanoic acid.
WO2011/022596 discloses preparation of bazedoxifene salts. Suitable acids employed for the preparation of the salt include but are not limited to inorganic acids such as hydrochloric acid, sulphuric acid, and phosphoric acid, and organic acids such as methanesulfonic acid, benzenesulfonic acid, propionic acid, etc. It discloses the preparation of acid addition salts of de-protected bazedoxifene as an intermediate for the subsequent production of bazedoxifene acetate substantially free of impurities and intermediates.
The present inventors have found the following advantages of the present invention vis-a-vis the prior art:
• Prior art i.e. US5998502 which is the basic patent of bazedoxifene, has nine steps and results in number of impurities, which are process related. Therefore, the Bazedoxifene acetate API does not crystallize; .
• l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole salt prepared is highly pure and all process related impurities are removed completely;
• l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole is prepared as inorganic and organic salt and it can be directly taken for debenzylation without making a free base.
• Bazedoxifene acetate API thus obtained is highly pure and free from impurities.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide novel salt intermediates of l-[4-(2-azepan- l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H-indole.
It is yet another object of the present invention to provide a process for the synthesis of novel acid addition salts of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy- phenyl)-3 -methyl- 1 -H-indole.
It is a further object of the present invention to provide an improved route of synthesis for the production of Bazedoxifene acetate in high yield and purity via catalytic hydrogenation i.e. pressure hydrogenation and transfer hydrogenation using the novel salt intermediates of l-[4- (2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H-indole.
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided novel acid addition salts of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole (Formula II).
According to another aspect of the present invention there is provided a process for the synthesis of novel salt intermediates (Formula II) comprising the steps of:
i. reacting l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)- 3 -methyl- 1-H-indole (Formula I) with a suitable acid to form the acid addition salt thereof (Formula II).
According to yet another aspect of the present invention there is provided an improved process for the synthesis of bazedoxifene acetate via catalytic hydrogenation i.e. pressure hydrogenation or transfer hydrogenation and using the novel salt intermediates of Formula II comprising the steps of: i. reacting l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)- 3 -methyl- 1-H-indole (Formula I) formed in situ with a suitable acid to form the acid addition salt thereof (Formula II);
ii. catalytically hydrogenating the acid addition salt of l-[4-(2-azepan-l-yl-ethoxy)- benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H-indole (Formula II) of the present invention by transfer hydrogenation or pressure hydrogenation to yield the compound of Formula III;
iii. neutralizing the compound of Formula III with a suitable base or mixture thereof to yield the bazedoxifene free base (Compound of Formula IV)
iv. converting the compound of Formula IV to the Bazedoxifene acetate API (Formula V), optionally by seeding with a few crystals of bazedoxifene acetate.
DETAILED DESCRIPTION OF THE INVENTION
The object of the present invention is to provide a process for the preparation of novel salt intermediates (Formula II) of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4- benzyloxy-phenyl)-3-methyl- 1-H-indole (Formula I) and their use in the preparation of bazedoxifene acetate API.
HA in the reaction scheme represents the 'acid'
Pd/C in the reaction scheme represents 'catalytic hydrogenation'
Reaction scheme:
Formula V
The preparation of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy- phenyl)-3 -methyl- 1-H-indole is well known in the art and is also disclosed in co-pending patent application 877/KOL/2011. The present invention involves the conversion of l-[4-(2- azepan- 1 -yl-ethoxy)-benzyl] -5-benzyloxy-2-(4-benzyloxy-phenyl)-3 -methyl- 1 -H-indole (Formula I) without isolation (other than that which occurs in the prior art process) i.e. in situ conversion to produce the acid addition salts of the present invention.
According to an aspect of the present invention there is provided novel acid addition salts of
1- [4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole (Formula II). According to yet another aspect of the present invention there is provided a process for the synthesis of novel acid addition salts of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2- (4-benzyloxy-phenyl)-3-methyl-l-H-indole (Formula II) which comprises the step of:
Treating the compound of Formula I formed in situ with a suitable acid to provide the acid addition salt (Formula II).
The suitable acid used for the preparation of the acid addition salts of the compound of formula I can be either organic or inorganic. The preferred organic acids are maleic acid, para toluene sulfonic acid, citric acid, malonic acid, fumaric acid, succinic acid, oxalic acid while the preferred inorganic acids are sulphuric acid and hydrochloric acid.
According to yet another aspect there is provided a process for preparing bazedoxifene acetate API from the acid addition salt of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-
2- (4-benzyloxy-phenyl)-3-methyl-l-H-indole (Formula II) of the present invention by deprotection (debenzylation) i.e. catalytic hydrogenation of the acid addition salt of l-[4-(2- azepan- 1 -yl-ethoxy)-benzyl] -5-benzyloxy-2-(4-benzyloxy-phenyl)-3 -methyl- 1 -H-indole (Formula II) by transfer hydrogenation or pressure hydrogenation to yield the compound of Formula III followed by neutralizing the compound of Formula III with a suitable base or mixture thereof to yield the bazedoxifene free base (Compound of Formula IV); converting the compound of Formula IV to the Bazedoxifene acetate API (Formula V), optionally by seeding with a few crystals of bazedoxifene acetate.
Suitable base for neutralization of the compound of formula III may be either organic or inorganic. Preferred organic are triethylamine, diisopropyl amine, pyridine and organic
amines and inorganic bases are sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
Catalytic hydrogenation of the present invention step may be carried out using hydrogen gas i.e. pressure hydrogenation or a hydrogen source i.e. transfer hydrogenation. Examples of a hydrogen source are ammonium formate, cyclohexene, cyclohexadiene. The preferred catalysts used in the present invention are Pearlman's catalyst and palladium on activated carbon (Pd/C). Hydrogen gas pressure for conducting the reaction may vary from about 1 kg/cm 2 to 5 kg/cm 2. Suitable temperatures for conducting de-protection are about 30°C to 55°C.
The polar aprotic solvents of the present invention are selected from N,N- dimethylformamide, Ν,Ν-dimethyl acetamide or dimethyl sulphoxide. The acronym ΆΡΓ used herein refers to 'Active Pharmaceutical Ingredient'.
According to yet another aspect of the present invention there are provided acid addition salt intermediates of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)- 3-methyl-l-H-indole (Formula II) i.e.
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole maleic acid;
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole para-toluene sulfonic acid;
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole citric acid;
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole malonic acid;
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole succinic acid;
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole oxalic acid;
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole fumaric acid salt;
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole sulphuric acid; and
l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H- indole hydrochloric acid. The following examples further illustrate certain specific aspects and embodiments of the invention in detail and are not intended to limit the scope of the invention.
EXAMPLES
Example 1: l-r4-(2-azepan-l-yl-ethoxy)-benzyll-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) generated according to co-pending patent application 877/KOL/2011 i.e. example 3 is converted to the various acid addition salts of Formula II by the following procedures :- a. Preparation of l-r4-(2-azepan-l-yl-ethoxy)-benzyll-5-benzyloxy-2-(4-benzyloxy-phenyl)- 3-methyl-l-H indole para toluene sulfonic acid salt (Formula II): To 1 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in 20 ml of Toluene at 25-30°C. Add 0.48 g of para toluene sulfonic acid at 25-30°C. Stir reaction mixture for 30 min and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l-yl-ethoxy)- benzyl]-5-benzyloxy-2(4-benzyloxy-phenyl)-3-methyl-l-H indole para toluene sulfonic acid salt (Formula II) = 1.12 g Yield = 86%.
13CMR (DMSO-d6,400 MHz) δ (ppm) = 9.39, 20.74, 22.60, 25.88, 46.05, 54.33, 54.94, 62.25, 69.32, 69.82, 102.14, 107.59, 111.13, 111.85, 114.55, 114.84, 123.81, 125.48,
127.28, 127.54, 127.58, 127.78, 127.90, 128.19, 128.32, 128.44, 128.57, 128.75, 131.32, 131.41, 131.47, 136.86, 137.75, 137.79, 138.11, 144.92, 152.59, 156.42, 158.10.
Preparation of 1 - T4-(2-azepan- 1 - yl-ethox y)-benz yll -5 -benz yloxy-2-(4-benzylox v- phenyl)-3 -methyl- 1-H indole citric acid salt (Formula II):
To 1 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in 20 ml of Toluene at 25-30°C add 1.6 g of citric acid at 25-30°C. Stir reaction mixture for 30 min and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5- benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H indole citric acid salt (Formula II) = 1.22 g. Yield = 93%.
13CMR (DMSO-d6,400MHz) δ (ppm) = 9.39, 23.15, 26.01, 43.61, 46.04, 54.32, 54.98 62.68, 69.32, 69.79, 71.75 102.10, 107.58, 111.12, 111.85, 114.54, 114.83, 123.81, 127.30, 127.55, 127.58, 127.80, 127.91, 128.17, 128.33, 128.45, 128.73, 128.86, 131.24, 131.41, 136.86, 137.75, 137.78, 152.58, 156.55, 158.09, 171.28, 175.93.
Preparation of 1 - T4-(2-azepan- 1 -yl-ethox v)-benz yll -5 -benz yloxy-2-(4-benzylox v- phenyl)-3 -methyl- 1-H indole Hydrochloric acid salt (Formula II):
To 3 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in 30 ml of Toluene at 25-30°C add 5 ml of Ethyl acetate.HCl (5%) at 25-30°C. Stir reaction mixture for 1 hour and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l -yl-ethox y)- benzyl] -5-benzyloxy-2-(4-benzyloxy-phenyl)-3 -methyl- 1 -H-indole Hydrochloric acid salt (Formula II) = 2.52 g. Yield = 80%.
13CMPv (DMSO-d6,400MHz) δ (ppm) = 9.40, 22.66, 25.99, 46.07, 54.04, 54.72, 62.38, 69.33, 69.83, 102.14, 107.59, 111.13, 111.86, 114.55, 114.84, 123.81, 127.30, 127.55, 127.79, 127.90, 128.32, 128.44, 128.76, 131.26, 131.40, 131.49, 136.87, 137.76, 137.80, 152.61, 156.43, 158.10.
Preparation of 1 - T4-(2-azepan- 1 - yl-ethox y)-benzyll -5 -benzyloxy-2-(4-benzylox v- phenyl)-3 -methyl- 1-H indole malonic acid salt (Formula II):
To 3 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in 30 ml of Toluene at 25-30°C add 0.72 g of malonic acid at 25-30°C. Stir reaction mixture for 1 hour and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5- benzyloxy-2(4-benzyloxy-phenyl)-3 -methyl- 1-H-indole malonic acid salt (Formula II) = 2.68 g Yield = 77%.
13CMR (DMSO-d6,400MHz) δ (ppm) = 9.39, 22.86, 26.00, 40.53, 46.05, 54.26, 54.90, 62.46, 69.33, 69.82, 102.12, 107.60, 111.13, 111.86, 114.54, 114.83, 123.82, 127.31, 127.55, 127.58, 127.79, 127.91, 128.16128.32, 128.44, 128.76, 128.86, 131.29, 131.41, 131.47, 136.87, 137.76, 137.79, 152.60, 156.50, 158.10, 170.02.
Preparation of 1 - T4-(2-azepan- 1 -yl-ethox v)-benz yll -5 -benz yloxy-2-(4-benzylox v- phenyl)-3 -methyl- 1-H indole succinic acid salt (Formula II):
To 3 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in 30 ml of Toluene at 25-30°C add 0.81 g of succinic acid at 25-30°C. Stir reaction mixture for 1 hour and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5- benzyloxy-2(4-benzyloxy-phenyl)-3 -methyl- 1-H-indole succinic acid salt (Formula II) = 2.8 g Yield = 78%
13CMPv (DMSO-d6,400MHz) δ (ppm) = 9.36, 20.98, 25.4926.33, 29.39, 46.10, 54.56, 55.35, 64.44, 69.31, 69.84, 102.11, 107.58, 111.08, 111.83, 114.38, 114.78, 123.84, 125.25, 127.23, 127.52, 127.74, 127.87, 128.14, 128.30, 128.41, 128.76, 128.85, 130.73, 131.39, 131.51, 136.84, 137.75, 137.80, 152.62, 157.04, 158.09, 174.00. Preparation of 1 - T4-(2-azepan- 1 -yl-ethox y)-benzyll -5 -benzyl oxy-2-(4-benzyl ox y- phenyl)-3 -methyl- 1-H indole sulfuric acid salt (Formula II):
To 3 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in 30 ml of Toluene at 25-30°C add 0.67 g of sulfuric acid at 25-30°C. Stir reaction mixture for 1 hour and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5- benzyloxy-2(4-benzyloxy-phenyl)-3 -methyl- 1-H indole sulfuric acid salt (Formula II) = 2.45 g Yield = 71%
13CMR (DMSO-d6,400MHz) δ (ppm) = 9.39, 24.67, 26.15, 46.07, 54.58, 55.32, 63.84, 69.31, 69.82, 102.10, 107.57, 111.12, 111.83, 114.45, 114.81, 123.82, 127.25, 127.54,
127.78, 127.90, 128.17, 128.32, 128.43, 128.75, 130.91, 131.40, 131.48, 136.86, 137.75,
137.79, 152.60, 156.85, 158.09.
Preparation of 1 - T4-(2-azepan- 1 - yl-ethox y)-benz yll -5 -benz yloxy-2-(4-benzylox v- phenyl)-3 -methyl- 1-H indole maleic acid salt (Formula II):
To 221 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in 2.45 litre of Toluene at 25-30°C add 850 ml of Acetone and 49.30 g of maleic acid at 25-30°C. Stir reaction mixture for 30 min and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l- yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H indole maleic acid salt (Formula II) = 175.12 g Yield = 67%
13CMR (DMSO-d6,400MHz) δ (ppm) = 9.40, 22.66, 25.96, 46.02, 48.57, 54.29, 54.89, 62.26, 69.31, 69.76, 102.06, 107.58, 111.14, 111.85, 114.56, 114.82, 123.80, 127.31, 127.56, 127.60, 127.81, 127.93, 128.33, 128.46, 128.72, 128.87, 131.35, 131.42, 135.95, 136.85, 137.74, 137.76, 152.57, 156.44, 158.09, 167.17.
Preparation of 1 - T4-(2-azepan- 1 - yl-ethox v)-benz yll -5 -benz yloxy-2-(4-benzylox v- phenyl)-3 -methyl- 1-H indole oxalic acid salt (Formula II):
1 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in toluene at 25-30°C. Add 0.48 g of oxalic acid
at 25-30°C. Stir reaction mixture for 30 min. and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4- benzyloxy-phenyl)-3-methyl-l-H indole oxalic acid salt (Formula II) = 0.53g Yield = 47% i. Preparation of 1 - T4-(2-azepan- 1 -yl-ethoxy)-benzyll -5 -benzyl oxy-2-(4-benzyl ox y- phenyl)-3 -methyl- 1-H indole fumaric acid salt (Formula II):
1 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-l-H indole (Formula I) dissolved in 20 ml of Toluene at 25-30°C. Add 0.30 g of fumaric acid at 25-30°C. Stir reaction mixture for 30 min and filter. Wash by Toluene and dry the product at 55°C. Dried weight of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5- benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H-indole fumaric acid salt (Formula II) = 0.57 g Yield = 48%
Example 2: Bazedoxifene acetate API (Formula V) preparation via transfer hydrogenation by Pearlman's catalyst: 10 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl- 1-H indole maleate salt (Formula II) of procedure g of example 1 was added to 150 ml of methanol. Charge 1.8 g of Pearlman's catalyst and 4.11 g of ammonium formate at 25-30°C. Heat reaction mixture to attain temperature 50-55 °C maintain for 2.5 hours. Cool to 25-30°C and filter reaction mixture. Filtrate is distilled to get concentrated mass (Formula III). To concentrated mass add 150 ml ethyl acetate, 15 ml of triethyl amine and 200 ml of 8% aqueous sodium bicarbonate at 25-30°C. Stir and separate the layers. Wash ethyl acetate layer by 100 ml of water and distill to get solid (Formula IV). Add 65 ml of ethyl acetate, 9 ml of ethanol, 1.67 g of acetic acid and 0.36 g of ascorbic acid at 25-30°C, heat reaction mixture to reflux and maintain for 1 hour Cool to 25-30°C and maintain at 25-30°C for 1 hour filter and wash by ethyl acetate. Dry the product at 40-45°C.
Dried weight of the compound of Bazedoxifene acetate API (Formula V) = 3.80 g Yield = 57%
Example 3: Bazedoxifene acetate API (Formula V) preparation via transfer hydrogenation by 10% Pd/C:
5 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl- 1-H indole maleate salt (Formula II) of procedure g of example 1 was added to 75 ml of methanol. Charge 1 g of Pd/C catalyst and 2.05 g of ammonium formate at 25-30°C. Heat reaction mixture to attain reflux and maintain for 3 hours. Cool to 25-30°C and filter reaction mixture. Filtrate is distilled to get concentrated mass (Formula III). To concentrated mass add 100ml ethyl acetate, 5 ml of triethyl amine and 50 ml of 8% aqueous sodium bicarbonate at 25-30°C. Stir and separate the layers. Wash ethyl acetate layer by 10 ml x 2 of water and distill to get foam containing the compound of Formula IV. Add 18 ml of ethyl acetate, 3.5 ml of ethanol, 0.8 g of acetic acid and 0.12 g of ascorbic acid at 25-30°C. Add few seed crystals of bazdoxifene acetate and heat reaction mixture to reflux. Wash product by ethyl acetate and dried at 40-45°C. Dried weight of the compound of Formula V = 2.14 g Yield = 67 % Example 4: Bazedoxifene acetate API (Formula V) preparation via transfer hydrogenation by 10% Pd/C:
10 g of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl- 1-H indole maleate salt (Formula II) of procedure (g) of example 1 was added to 100 ml of methanol. Charge 1 g of 10% Pd/C catalyst and 2.05 g of ammonium formate at 25-30°C. Stir reaction mixture at 25-30°C for 7 hours and filter reaction mixture. Filtrate is distilled to get concentrated mass (Formula III). To concentrated mass add 150 ml ethyl acetate, 10 ml of triethyl amine and 200 ml of 8% aqueous sodium bicarbonate at 25-30°C. Stir and separate the layers. Wash ethyl acetate layer by 50 ml of water. Ethyl acetate layer distilled to get solids (Formula IV). Add 58 ml of ethanol, 0.81 g of acetic acid and heat to attain 50-55°C for 1 hour. Cool reaction mixture to 25-30°C and maintain for 1 hour and filter. Wash product by ethanol 5 ml x 2 by and dry at 40-45°C.
Dried weight of the compound of Formula V = 3.25 g Yield = 49 %
Claims
1. Novel acid addition salts of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy- 2-(4-benzyloxy-phenyl)-3-methyl-l-H-indole (Formula II):
•- Dtrfn.sk> \\ A
wherein 'HA' represents the 'acid'.
A process for the synthesis of novel salt intermediates of Formula II comprising the step of: i. reacting l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4- benzyloxy-phenyl)-3-methyl-l-H-indole (Formula I) formed in situ with a suitable acid to form the acid addition salt thereof (Formula II).
An improved process for the synthesis of bazedoxifene acetate via catalytic hydrogenation using the novel acid addition salt intermediates of Formula II, comprising the steps of: i. reacting l-[4-(2-azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4- benzyloxy-phenyl)-3-methyl-l-H-indole (Formula I) formed in situ with a suitable acid to form the acid addition salt thereof (Formula II)
Fmssa !ii ***
iii. neutralizing the compound of Formula III with a suitable base or mixture thereof to yield the bazedoxifene free base (Compound of Formula IV)
Formula IV
iv. converting the compound of Formula IV to the Bazedoxifene acetate API (Formula V)
CHjCOOH optionally by seeding with a few crystals of bazedoxifene acetate.
4. The process according to claim 3 wherein the catalytic hydrogenation is either by pressure hydrogenation or transfer hydrogenation.
5. The process according to claim 2 or claim 4 wherein the suitable acid selected can either be an organic or inorganic acid.
6. The process according to claim 5 wherein the suitable organic acid is selected from maleic acid, para toluene sulfonic acid, citric acid, malonic acid, fumaric acid, succinic acid, oxalic acid.
7. The process according to claim 2 or claim 4 wherein the inorganic acid is selected from sulphuric acid or hydrochloric acid.
8. The process according to any one of the claims 3 to 7 wherein the suitable base selected is either an organic or inorganic base.
9. The process according to claim 8 wherein the organic base is selected from triethylamine, diisopropyl amine, pyridine or organic amines.
10. The process according to claim 8 wherein the inorganic base is selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
11. The process according to any of the claims 3 to 10 wherein the polar aprotic solvent is selected from N, N-dimethylformamide, N, N-dimethyl acetamide or dimethyl sulphoxide.
12. The process according to claim 4 wherein the catalyst used is selected from Pearlman's catalyst or palladium on activated carbon (Pd/C).
13. The process according to claim 4 or claim 12 wherein the hydrogen source for transfer hydrogenation is ammonium formate, cyclohexene or cyclohexadiene.
14. The process according to claim 4 or claim 12 wherein the hydrogen gas pressure for pressure hydrogenation varies from 0.5 to 5 kg/cm .
15. The process according to claim 14 wherein the pressure varies from 3 to 5 kg/cm2.
16. The process according to claims 3 to 15 wherein the catalytic hydrogenation is carried out at a temperature of 30°C to 55 °C.
17. Novel acid addition salt intermediates of l-[4-(2-azepan-l-yl-ethoxy)-benzyl]- 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-H-indole: i. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole maleic acid; ii. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole para-toluene sulfonic acid; iii. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole citric acid; iv. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole malonic acid; v. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole succinic acid; vi. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole oxalic acid; vii. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole fumaric acid salt; viii. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole sulphuric acid; and
ix. l-[4-(2-azepan-l-yl-ethoxy)-benzyl] -5 -benzyl oxy-2-(4-benzyl oxy- phenyl)-3-methyl-l-H-indole hydrochloric acid.
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| IN876/KOL/2011 | 2011-06-30 | ||
| IN876KO2011 | 2011-06-30 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370796A (en) * | 2014-11-21 | 2015-02-25 | 扬子江药业集团有限公司 | Preparation method of bazedoxifene acetate polycrystalline type B |
| KR101806782B1 (en) | 2015-09-07 | 2018-01-10 | 주식회사 경보제약 | Method for the preparation of high purity Bazedoxifene Acetate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998502A (en) | 1994-01-12 | 1999-12-07 | Domino Uk Limited | Ink jet inks |
| WO2009012734A2 (en) | 2007-07-25 | 2009-01-29 | Zentiva A.S. | New salts of bazedoxifene |
| WO2010118997A1 (en) * | 2009-04-13 | 2010-10-21 | Sandoz Ag | Processes for the synthesis of bazedoxifene acetate and intermediates thereof |
| WO2011022596A2 (en) | 2009-08-21 | 2011-02-24 | Dr. Reddy's Laboratories Ltd. | Preparation of bazedoxifene and its salts |
-
2012
- 2012-06-29 WO PCT/IB2012/053334 patent/WO2013001511A1/en not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998502A (en) | 1994-01-12 | 1999-12-07 | Domino Uk Limited | Ink jet inks |
| WO2009012734A2 (en) | 2007-07-25 | 2009-01-29 | Zentiva A.S. | New salts of bazedoxifene |
| WO2010118997A1 (en) * | 2009-04-13 | 2010-10-21 | Sandoz Ag | Processes for the synthesis of bazedoxifene acetate and intermediates thereof |
| WO2011022596A2 (en) | 2009-08-21 | 2011-02-24 | Dr. Reddy's Laboratories Ltd. | Preparation of bazedoxifene and its salts |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370796A (en) * | 2014-11-21 | 2015-02-25 | 扬子江药业集团有限公司 | Preparation method of bazedoxifene acetate polycrystalline type B |
| CN104370796B (en) * | 2014-11-21 | 2016-09-14 | 扬子江药业集团有限公司 | A kind of preparation method of bazedoxifene acetate polymorph b |
| KR101806782B1 (en) | 2015-09-07 | 2018-01-10 | 주식회사 경보제약 | Method for the preparation of high purity Bazedoxifene Acetate |
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