Indian Patents. 279266:PROCESS FOR THE PREPARATION OF 5-BENZYLOXY-2- (4-BENZYLOXYPHENYL) -3- METHYL-1H-INDOLE

Title of Invention	PROCESS FOR THE PREPARATION OF 5-BENZYLOXY-2- (4-BENZYLOXYPHENYL) -3- METHYL-1H-INDOLE
Abstract	Present invention is related to a process for the preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3- methyl-1H-Indole (formula-1, a useful intermediate for the synthesis of bazedoxifene) using 4-benzyloxy propiophenone and 4-benzyloxy phenyl hydrazine hydrochloride.

Full Text	Field of Invention: The present invention relates to a novel process for preparing 5-benzyloxy-2-(4-benzyloxyphenyl)-3- methyl-1H-Indole which is used for the production of bazedoxifene. Back Ground of the Invention : Bazedoxifene is a third generation selective estrogen receptor modulator. It is used in the prevention and treatment of postmenopausal osteoporosis (Miller et al., EP0802183). Conventional processes for preparing 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole are disclosed in patents US 5998402, EP 0802183, World application WO- 2008098527 and Journal of Medicinal Chemistry, 2001, volume 44, page no. 1654- 1657. The process disclosed in US 5998402 may be summarized as following reaction Scheme-1. In the above process according to the reaction 2-bromo-4'-benzyloxy propiophenone is reacted with 4- benzyloxy aniline hydrochloride in dimethyl formamide. The process has the following disadvantages: use of bromine calls for special safety measures and equipment to handle, the process involves isolation of bromo intermediate and results in only 33-54% overall yield. Hence process is not economical. The process disclosed in World application WO-2008098527 may be summarized as following reaction Scheme-2. The process is essentially similar to the scheme -1. In the above process, the intermediate N-(4- benzyloxyphenyl)-a-amino-4-benzyloxy propiophenone is isolated and treated with excess of the aniline reagent to complete the cyclisation step. Reaction is carried out in an organic solvent and in the presence of an inorganic or an organic base from a group including sodium carbonate, potassium carbonate, triethylamine or diisopropylamine. The process (Scheme-2) has the following disadvantages. Large excess of 4-benzyloxy aniline hydrochloride is required though later recovered through isolation from mother liquors. The overall yield is 65-70% only. The second step of the reaction is conducted in a pressure vessel at a temperature of 100- 120°C. Hence the above process suffers from avoidable reaction conditions of reagent quantity, temperature and pressure. Thus there is a need for a simple, less cumbersome and better yielding process for manufacture of 5- benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-IH-indole of formula-1, the key intermediate in the manufacture of bazedoxifene. Summary of the Invention : The present invention reveals a novel method for the preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)- 3-methyl-lH-indole, based on Fischer indole synthesis. Detailed description of invention: Surprisingly we found that the starting material 4-benzyloxy propiophenone (formula-2) reacts with 4- benzyloxy phenyl hydrazine hydrochloride (formula-3) in the presence of a Lewis or Bronsted acid in an organic solvent preferably a polar organic solvent as outlined in Scheme-3 below yielding the required indole compound in a single step. Suitable acid for use in this reaction includes Lewis acids such as ZnCl2, ZnBr2, BF3, FeCla, AICI3, SnCl4 and Bronsted acids such as acetic acid, hydrochloric acid, sulphuric acid, polyphosphoric acid, polyphosphate ester, p-toluene sulfonic acid, methane sulfonic acid but preferably acetic acid. A suitable solvent used in the reaction includes a solvent or mixtures of solvents like C1-C4 alcohols or toluene, acetonitrile or mixtures thereof but preferably ethanol. The temperature for conducting reaction can range from about 0 -140 C, preferably 75 - 80 C. The product is isolated by filtration, the yield being 93-95% with high purity (>99%), which can be used without further purification in the next step. The simple and new process of the present invention is industrially well suited, reproducible and commercially viable. Examples: The invention is described in more detail in the following examples and do not limit the invention in any way. The reagents and solvents mentioned in examples are for illustration purpose only and may be replaced by other reagents and solvents known to those skilled in the art. Preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (formula-1): Example-1: 4-Benzyloxy phenyl hydrazine hydrochloride (1.0 g, 4 mmol), 4-benzyloxy propiophenone (0.06 g, 4 mmol) were suspended in 15 ml of ethanol and mixture was refluxed for 12 hrs at a temperature of 75- 800C. Then the mixture was cooled to 10-15°C within 1 hr. The white product was filtered and washed with chilled ethanol (3 ml). The title compound 5-benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-lH-indole (formula-1) melting at 152-153°C and purity by HPLC 99.5% was obtained in a yield of 1.4 g (83.6%). Example-2 : 4-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and acetic acid (0.1 ml, 1.7 mmol) were suspended in 140 ml of ethanol and the mixture was refluxed for 12 hrs at the temperature of 75-800C. During said period the product precipitates. After cooling the mixture at 10-15'^C the crystallized product was isolated by filtration and washed with chilled ethanol (30 ml) and water (50 ml). 5-Benzyloxy-2-(4-benzyloxy)-3-methyl-lH-indole melting at 152- 153°C was obtained in a yield of 15.7 g (94%). 1H-NMR (DMSO) 6 10.65 (s, IH); 7.55 (d, 2H); 7.50(d, 4H); 7.30-7.45(m, 6H); 7.21(d, IH); 7.10(d, IH); 7.10(d, IH); 6.91(dd, IH); 5.16(s, 2H); 5.1 l(s, 2H); 2.33(s, 3H) Example-3 : 4-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and aluminium chloride (0.1 gm, 0.75 mmol) were suspended in 140 ml of ethanol and the mixture was refluxed for 12 hrs at a temperature of 75-80'^C. During this period the product precipitates. After cooling the mixture tolO-15'^C the crystallized product was isolated by filtration and washed with chilled ethanol (30 ml) and water (50 ml). 5-Benzyloxy-2-(4-benzyloxy)-3-methyl-lH-indole melting at 152- 153°C was obtained in a yield of 15.0 g (90%). Example-4 : 4-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and acetic acid (0.1 ml, 1.7 mmol) were suspended in 140 ml of toluene and the mixture was refluxed for 12 hrs at the temperature of 105-110'^C. During this period the product precipitates. After cooling the mixture to 10-15°C the crystallized product was isolated by filtration and washed with toluene (30 ml) and water (50 ml). 5-Benzyloxy-2-(4-benzyloxy)-3-methyl-lH-indole melting at 149-150°C was obtained in a yield of 10.0 g (60%). Example-5 : 4-Benzyloxy phenyl hydrazine hydrochloride (1.0 g, 4 mmol), 4-benzyloxy propiophenone (0.96 g, 4 mmol) and acetic acid (10^1, 0.17 mmol) were suspended in 15 ml of acetonitrile and mixture was refluxed for 12hrs at a temperature of 81-82'C. Then mixture was cooled to 10-15'^C within 1 hr. The white product was filtered and washed with chilled acetonitrile (3 ml). 5-Benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-lH-indole (1) melfing at 149-150°C was obtained in a yield of 1.0 g (60%). We Claim : 1. A process for the preparation of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-1H-indole (formula-1); which comprises reacting 4-benzyloxy propiophenone of formula-2 with 4-benzyloxy phenyl hydrazine or its hydrochloride of formula-3 in an organic solvent and at a temperature from 0C 140 0C in presence an acid catalyst. 2. The process according to claim 1, the reaction is carried out in an organic solvent selected from the group of C1-C4 alcohols, toluene and acetonitrile or mixtures thereof. 3. The process according to claim 1, the acid catalyst used includes Bronsted acids such as acetic acid, hydrochloric acid, sulphuric acid, polyphosphoric acid, polyphosphate ester, p-toluene sulfonic acid, methane sulfonic acid and the like or Lewis acids such as ZnCl2, ZnBr2, BF3, FeCl3, AICl3, SnCl4 and the like. 4. The process according to any of the claims 1 to 3, the reaction is carried out at 00 C-1400 C, preferably at 750C- 800 C. 5. The process according to claim 2, the preferred solvent is ethanol. 6. The process according to claim 3, the preferred acid catalyst is acetic acid. 7. The process according to claim 4, the reaction is carried out at reflux temperature of the solvent used.

Full Text

Field of Invention:

The present invention relates to a novel process for preparing 5-benzyloxy-2-(4-benzyloxyphenyl)-3- methyl-1H-Indole which is used for the production of bazedoxifene.

Back Ground of the Invention :
Bazedoxifene is a third generation selective estrogen receptor modulator. It is used in the prevention and treatment of postmenopausal osteoporosis (Miller et al., EP0802183). Conventional processes for preparing 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole are disclosed in patents US 5998402, EP 0802183, World application WO- 2008098527 and Journal of Medicinal Chemistry, 2001, volume 44, page no. 1654- 1657.

The process disclosed in US 5998402 may be summarized as following reaction Scheme-1.

In the above process according to the reaction 2-bromo-4'-benzyloxy propiophenone is reacted with 4- benzyloxy aniline hydrochloride in dimethyl formamide. The process has the following disadvantages: use of bromine calls for special safety measures and equipment to handle, the process involves isolation of bromo intermediate and results in only 33-54% overall yield. Hence process is not economical.

The process disclosed in World application WO-2008098527 may be summarized as following reaction Scheme-2.

The process is essentially similar to the scheme -1. In the above process, the intermediate N-(4- benzyloxyphenyl)-a-amino-4-benzyloxy propiophenone is isolated and treated with excess of the aniline reagent to complete the cyclisation step. Reaction is carried out in an organic solvent and in the presence of an inorganic or an organic base from a group including sodium carbonate, potassium carbonate, triethylamine or diisopropylamine.

The process (Scheme-2) has the following disadvantages. Large excess of 4-benzyloxy aniline hydrochloride is required though later recovered through isolation from mother liquors. The overall yield is 65-70% only. The second step of the reaction is conducted in a pressure vessel at a temperature of 100- 120°C. Hence the above process suffers from avoidable reaction conditions of reagent quantity, temperature and pressure.

Thus there is a need for a simple, less cumbersome and better yielding process for manufacture of 5- benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-IH-indole of formula-1, the key intermediate in the manufacture of bazedoxifene.

Summary of the Invention :
The present invention reveals a novel method for the preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)- 3-methyl-lH-indole, based on Fischer indole synthesis.

Detailed description of invention:
Surprisingly we found that the starting material 4-benzyloxy propiophenone (formula-2) reacts with 4- benzyloxy phenyl hydrazine hydrochloride (formula-3) in the presence of a Lewis or Bronsted acid in an organic solvent preferably a polar organic solvent as outlined in Scheme-3 below yielding the required indole compound in a single step.

Suitable acid for use in this reaction includes Lewis acids such as ZnCl2, ZnBr2, BF3, FeCla, AICI3, SnCl4 and Bronsted acids such as acetic acid, hydrochloric acid, sulphuric acid, polyphosphoric acid, polyphosphate ester, p-toluene sulfonic acid, methane sulfonic acid but preferably acetic acid.

A suitable solvent used in the reaction includes a solvent or mixtures of solvents like C1-C4 alcohols or toluene, acetonitrile or mixtures thereof but preferably ethanol.

The temperature for conducting reaction can range from about 0 -140 C, preferably 75 - 80 C.

The product is isolated by filtration, the yield being 93-95% with high purity (>99%), which can be used without further purification in the next step.

The simple and new process of the present invention is industrially well suited, reproducible and commercially viable.

Examples:
The invention is described in more detail in the following examples and do not limit the invention in any way. The reagents and solvents mentioned in examples are for illustration purpose only and may be replaced by other reagents and solvents known to those skilled in the art.

Preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (formula-1):
Example-1:
4-Benzyloxy phenyl hydrazine hydrochloride (1.0 g, 4 mmol), 4-benzyloxy propiophenone (0.06 g, 4 mmol) were suspended in 15 ml of ethanol and mixture was refluxed for 12 hrs at a temperature of 75- 800C. Then the mixture was cooled to 10-15°C within 1 hr. The white product was filtered and washed with chilled ethanol (3 ml). The title compound 5-benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-lH-indole (formula-1) melting at 152-153°C and purity by HPLC 99.5% was obtained in a yield of 1.4 g (83.6%).

Example-2 :
4-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and acetic acid (0.1 ml, 1.7 mmol) were suspended in 140 ml of ethanol and the mixture was refluxed for 12 hrs at the temperature of 75-800C. During said period the product precipitates. After cooling the mixture at 10-15'^C the crystallized product was isolated by filtration and washed with chilled ethanol (30 ml) and water (50 ml). 5-Benzyloxy-2-(4-benzyloxy)-3-methyl-lH-indole melting at 152- 153°C was obtained in a yield of 15.7 g (94%).
1H-NMR (DMSO) 6 10.65 (s, IH); 7.55 (d, 2H); 7.50(d, 4H); 7.30-7.45(m, 6H); 7.21(d, IH); 7.10(d, IH); 7.10(d, IH); 6.91(dd, IH); 5.16(s, 2H); 5.1 l(s, 2H); 2.33(s, 3H)

Example-3 :
4-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and aluminium chloride (0.1 gm, 0.75 mmol) were suspended in 140 ml of ethanol and the mixture was refluxed for 12 hrs at a temperature of 75-80'^C. During this period the product precipitates. After cooling the mixture tolO-15'^C the crystallized product was isolated by filtration and washed with chilled ethanol (30 ml) and water (50 ml). 5-Benzyloxy-2-(4-benzyloxy)-3-methyl-lH-indole melting at 152- 153°C was obtained in a yield of 15.0 g (90%).

Example-4 :
4-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and acetic acid (0.1 ml, 1.7 mmol) were suspended in 140 ml of toluene and the mixture was refluxed for 12 hrs at the temperature of 105-110'^C. During this period the product precipitates. After cooling the mixture to 10-15°C the crystallized product was isolated by filtration and washed with toluene (30 ml) and water (50 ml). 5-Benzyloxy-2-(4-benzyloxy)-3-methyl-lH-indole melting at 149-150°C was obtained in a yield of 10.0 g (60%).

Example-5 :
4-Benzyloxy phenyl hydrazine hydrochloride (1.0 g, 4 mmol), 4-benzyloxy propiophenone (0.96 g, 4 mmol) and acetic acid (10^1, 0.17 mmol) were suspended in 15 ml of acetonitrile and mixture was refluxed for 12hrs at a temperature of 81-82'C. Then mixture was cooled to 10-15'^C within 1 hr. The white product was filtered and washed with chilled acetonitrile (3 ml). 5-Benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-lH-indole (1) melfing at 149-150°C was obtained in a yield of 1.0 g (60%).

We Claim :

1. A process for the preparation of 5-benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-1H-indole (formula-1);

which comprises reacting 4-benzyloxy propiophenone of formula-2 with 4-benzyloxy phenyl

hydrazine or its hydrochloride of formula-3 in an organic solvent and at a temperature from 0C 140 0C in presence an acid catalyst.

2. The process according to claim 1, the reaction is carried out in an organic solvent selected from the group of C1-C4 alcohols, toluene and acetonitrile or mixtures thereof.

3. The process according to claim 1, the acid catalyst used includes Bronsted acids such as acetic acid, hydrochloric acid, sulphuric acid, polyphosphoric acid, polyphosphate ester, p-toluene sulfonic acid, methane sulfonic acid and the like or Lewis acids such as ZnCl2, ZnBr2, BF3, FeCl3, AICl3, SnCl4 and the like.

4. The process according to any of the claims 1 to 3, the reaction is carried out at 00 C-1400 C, preferably at 750C- 800 C.

5. The process according to claim 2, the preferred solvent is ethanol.

6. The process according to claim 3, the preferred acid catalyst is acetic acid.

7. The process according to claim 4, the reaction is carried out at reflux temperature of the solvent used.

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Patent Number

279266

Indian Patent Application Number

2612/CHE/2010

PG Journal Number

03/2017

Publication Date

20-Jan-2017

Grant Date

17-Jan-2017

Date of Filing

07-Sep-2010

Name of Patentee

DIVI'S LABORATORIES LTD.,

Applicant Address

7-1-77/E/1/303; DIVI TOWERS; DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016.

Inventors:

#	Inventor's Name	Inventor's Address
1	MURALI KRISHNA PRASAD DIVI	7-1-77/E/1/303, DIVI TOWERS; DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016.
2	BOLINENI NAGESWARA RAO	7-1-77/E/1/303, DIVI TOWERS; DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016.
3	DANDU VENKATA SURESH	7-1-77/E/1/303, DIVI TOWERS; DHARAM KARAN ROAD, AMEERPET, HYDERABAD - 500 016.

PCT International Classification Number

C07D 209/04 ; A61K 31/404

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA