Field of invention:

The present invention relates to a novel process for preparing l-{4-[2-(azepan-l- y1)ethoxy]benzy1}-2-(4-hydroxypheny1)-3-methy1-lH-indol-5-ol and its acetate, also known as bazedoxifene acetate from 2-(4-{[5-(benzy1oxy)-2-[4-(benzy1oxy)pheny1]-3-methy1-lH-indol-l- y1]methy1}phenoxy)ethy1-4-methy1benzenzene-l-sulfonate( formula 2a)

Background art:

Bazedoxifene acetate 1 – (4- [2-(azepan-1 -y1)ethoxy]benzy1} -2-(4-hydroxypheny1)-3-methy1- 1H- indol-5-ol acetate is a third generation selective estrogen receptor modulator. It is used in the prevention and treatment of post menopausal osteoporosis.

Conventional processes for preparing bazedoxifene acetate are disclosed in US patents 5998402, 6380166, European patent 0802183 and World patent application 2010118997. Miller et al (J. Med. Chem., 2001, 44, 1654-57) have also described a synthetic preparation of bazedoxifene acetate.

Scheme 1 below summarizes the method disclosed in US 5998402, EP 0802183 and in J. Med. Chem. 2001, 44, 1654-57.

Alky1ation of the indole of formula-3 with the compound of formula-4 was accomplished with sodium hydride in N,N-dimethy1 formamide. The ester of formula-5 was subsequently reduced with lithium aluminium hydride (LAH) and the primary alcohol of formula-6 thus produced was converted to the corresponding bromide of formula-7 by treatment with carbontetrabromide and tripheny1phosphine. Substitution of this bromide of formula-7 with hexamethy1eneimine yielded benzy1ated bazedoxifene of formula-8. Hydrogenation of the compound of formula-8 to bazedoxifene free base of formula-9 was followed by conversion to bazedoxifene acetate of formula-1.

The drawbacks of this process involve using LAH, a highly flammable and industrially hazardous reagent, and using CBr4 a corrosive and expensive Class 1 solvent and reagent at the bromination stage.

Scheme-1:

A second method is disclosed in US 6380166 and WO 9919293 (Shown as Scheme 2). Alky1ation of indole with the compound of formula-10 was accomplished with sodium-tert- butoxide in N,N-dimethy1 formamide yielding benzy1ated bazedoxifene directly. The remaining steps are similar to the Scheme I above.

Scheme-2

The WO 2011022596A2 application disclosed a process similar to the one described in US 6380166,wherein the alky1ation of indole with the compound of formula-10 was prepared by using sodium hydride in DMF to yield the benzy1ated bazedoxifene of formula-8 along with C- alky1ated impurity of formula-23. This impurity subsequently undergoes reaction to give debenzy1ated impurity of formula-22. The impure free base was further converted to bazedoxifene hydrochloride in methanol by treating with aqueous hydrochloric acid. However, the described process resulted in yield loss of 20 to 25%.

World Patent application 2010118997 discloses a third route of synthesis. (Shown in Scheme 3 below). N-alky1ation of indole of formula-3 with 4-chloromethy1 phenoxy acetonitrile of formula-11 was effected in the presence of sodamide and N,N-dimethy1 formamide to form {4- [5-benzy1oxy-2-(4-benzy1oxypheny1)-3-methy1indol-1 -y1-methy1phenoxy] acetonitrile of formula-12. Hydrolysis of the nitrile of formula-12 in the presence of sodium hydroxide yielded {4-[5-benzy1oxy-2-(4-benzy1oxypheny1)-3-methy1indol-l-y1-methy1phenoxy]acetic acid of formula-13. Reacting this intermediate of formula-13 with 1,1'-carbony1 di-imidazole and hexamethy1eneimine resulted in l-azepan-l-y1-2-{4-[5-benzy1oxy-2-(4-benzy1oxy pheny1)-3- methy1 indol-l-y1 methy1]-phenoxy Jethanone of formula-14. Reducing the compound of formula-14 with NaBH4/BF3 gave benzy1ated bazedoxifene of formula-8. Hydrogenation of the compound of formula-8 to bazedoxifene free base of formula-9 was followed by conversion to bazedoxifene acetate of formula-1.

These methods result in low yields and reduction of compound of formula-14 with NaBH4/BF3 etherate is a critical reaction. Handling of corrosive BF3 etherate on an industrial scale poses a major problem.

Summary of the invention:

The present invention provides an operationally simple route of synthesis for the production of bazedoxifene and its salts in high yield and purity via intermediate of formula-2, wherein X may be benzene sulfony1, tosy1 or mesy1 (methane sulfony1).

2a: X= tosy1; 2b: X= mesy1; 2c: X= benzene sulfony1

The scheme-4 below provides two alternatives of converting the intermediate 2 to bazedoxifene with equal advantage.

The present invention also provides a convenient method of preparing the intermediate of formula-2, which can also be used as intermediate in the production of other close analogs of bazedoxifene. Compound of formula-3 is condensed with compound of formula-18 to provide the key intermediate of formula-2 as shown in the scheme-4 below.
Scheme-4:

Detailed Description of the Invention:
We have surprisingly found that N-alky1ation of compound of formula-3 above using compound of formula-18 leads to pure compound of formula-2a which helps in overcoming the difficulties of the prior art. The intermediate 18 was subsequently converted to bazedoxifene of formula-9 either via compound of formula-8 or via compound of formula-19 in high yield and purity, free from the impurity 3-(4-(2-(azepan-l-y1)ethoxy)benzy1)-2-(4- hydroxy pheny1)-3-methy1-3H-indol-5-ol of formula-22 and impurity 3-(4-(2-(azepan-l- y1)ethoxy)benzy1)-5-(benzy1oxy)-2-(4-benzy1oxy pheny1)-3-methy1-3H-indol of formula-23.

According to one aspect of the present invention, the process for the synthesis of bazedoxifene acetate substantially free from impurities of formula-22 and 23, comprises of following steps:

a) 5-Benzy1oxy-2-(4-benzy1oxy pheny1)-3-methy1-lH-indole (formula-3) is reacted with 2-(4- (bromomethy1)phenoxy)ethy1-4-methy1benzenesulfonate of formula-18 in the presence of a suitable base and in a suitable solvent to afford a 2-(4-{[5-(benzy1oxy)-2-[4-(benzy1oxy)pheny1]- 3-methy1-1 H-indol-1 -y1]methy1} phenoxy)ethy1-4-methy1benzenzene-1 -sulfonate of formula-2a.

Suitable bases for this step are inorganic bases such as alkali metal hydrides, alkali metal hydroxides, alkali amides, alkoxides and carbonates. A preferred example of a suitable base is sodium hydride.

Suitable solvents for this step are aromatic hydrocarbons such as toluene and xy1ene, polar aprotic solvents such as dimethy1 sulfoxide, N,N-dimethy1 formamide, N,N-dimethy1 acetamide, acetonitrile, ethers such as tetrahydrofuran, methy1 tetrahydrofuran and mixtures there of. A preferred example of suitable solvent is N, N-dimethy1 formamide.

Suitable temperature for conducting this step is -10° to 30°C preferably -10° to5°C.
For crystallization and purification the obtained compound of formula-2a suitable solvent may be selected from alcohols, esters or mixtures there of, preferably methanol and ethy1 acetate. This step of purification helps to eliminate the process related C-alky1ated impurity of formula-24.

It is also to be noted that instead of the tosy1 derivative as in compound of formula 18, other sulfonates such as benzene sulfony1 or methane sulfony1 derivatives are equally effective.

b) The compound of formula-2a is reacted with hexamethy1eneimine in a suitable solvent to afford 5-benzy1oxy-2-(4-benzy1oxy-pheny1)-3-methy1-l-[4-(2-azepan-l-y1-ethoxy)benzy1]-lH- indole of formula-8.

The reaction is carried out in a solvent such as aromatic hydrocarbons like benzene, toluene and xy1ene or ethers like tetrahydrofuran and methy1 tetrahydrofuran, preferably toluene at a temperature between 30° and 90°C preferably at 75°C.

The compound of formula-8 is purified by formation of hydrochloride salt in a suitable solvent such as toluene or methy1-tert-buty1 ether, preferably toluene with HC1 gas or hydrochloric acid at a temperature between 30°and 90°C, preferably at 70°C.

The pure compound of formula-8 is obtained by neutralizing the salt with inorganic base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as toluene or methy1-tert- buty1 ether, preferably toluene at a temperature between 30° to 90°C, preferably at 70°C. This step improves the purity to > 99.8% by eliminating the process related impurities. The high purity of compound of formula-8 facilitates high purity of bazedoxifene without the need for further purification.
Scheme-5:

c) Deprotection of the compound of formula-8 under catalytic hydrogenation in a suitable solvent gives bazedoxifene free base of formula-9.

The reaction is carried out in a suitable solvent such as alcohols, e.g. methanol or ethanol, or a polar aprotic solvent such as ethy1 acetate or mixtures thereof, preferably ethy1 acetate at a temperature between 30° to 50°C, preferably at 40°C.

Suitable catalyst for deprotection is palladium on carbon.

The preferred salt bazedoxifene acetate is obtained as known to prior art by treatment of bazedoxifene free base of formula-9 with acetic acid in a suitable solvent such as ketone solvents, alcohols or ester solvents, preferably ketone solvents, more preferably acetone.

The reaction is carried out at a temperature range from room temperature to the reflux temperature of the solvent used.

Another aspect of the present invention is to provide an improved process for the preparation of bazedoxifene acetate of compound of formula-1, which comprises of the following steps:

a) This is carried out substantially as described above to obtain pure compound of formula-2a.

b) Deprotection of the compound 2a in a suitable solvent selected from alcohols, esters or ethers, preferably ester solvents like ethy1 acetate and a catalyst, preferably palladium on carbon at a temperature of about 30° to 60°C, preferably at 45°C, gives the compound of formula-19.

c) Reacting the compound of formula-19 with hexamethy1eneimine in a suitable solvent selected from aromatic hydrocarbons like benzene, toluene or xy1ene, preferably toluene, at a temperature of about 30° to 75°C, preferably at about 75°C gives the bazedoxifene free base of formula-9.

The bazedoxifene free base is then converted to the preferred acetate salt with acetic acid in a suitable solvent as described above.

In another embodiment of the present invention, a process for preparing 2-(4- (bromomethy1)phenoxy)ethy1-4-methy1benzenesulfonate is provided. Preparation of this novel intermediate comprises the following steps (see Scheme-6 below):

a) Reacting 4-hydroxy benzaldehyde with 2-chloro ethanol in the presence of a base like sodium hydroxide or potassium hydroxide preferably sodium hydroxide in a polar solvent like water at a temperature 35° to 105°C, preferably at a temperature of 100 to 105°C, gives the compound of formula-15.

b) Reacting the compound of formula-15 with p-toluene sulfony1 chloride in the presence of a suitable organic base such as pyridine, triethy1amine or N, N-dimethy1 amino pyridine, preferably triethy1amine in a suitable solvent such as dichloro methane or ethy1ene dichloride at a temperature of about 25° to 30°C affords the compound of formula-16.

It is also to be noted that instead of p-tosy1 chloride other sulfony1 chlorides such as methane sulfony1 chloride or benzene sulfony1 chloride may be used which work equally well giving the corresponding sulfonates.

c) Reducing the compound of formula-16 obtained with metal hydrides such as sodium borohydride or lithium aluminium hydride in a suitable solvent selected from alcohols like methanol, ethanol or 2-propanol at a temperature of about 0°to 35°C, preferably at a temperature of about 0°to 5°C, gives the compound of the formula-17.

d) Brominating the compound of formula-17 with a suitable brominating agent such as hydrobromic acid, thiony1 bromide or phosphorous tri bromide, in a suitable solvent like dichloromethane or ethy1ene dichloride at a temperature of about 0 to 40°C, preferably 25° to 30°C, affords the compound of the formula-18.
Scheme-6:

The processes described above are illustrated in the examples below. The examples do not limit the scope of the invention in any way. A person skilled in the art would be able to modify the details to achieve the objectives.

Example 1: Preparation of 2-(4-formy1 phenoxy)ethy1-4-methy1 benzene sulfonate (formula-16a)

A solution of tosy1 chloride (68.9 g, 361 mmol) in 500 ml dichloro methane was added drop wise with stirring to a solution of 4-(2-hydroxyethy1oxy)benzaldehyde of formula-15 (50 g, 301 mmol) (J.Am. Chem.Soc.,1951, 73(3), pp 906-912) in 250 ml of dichloro methane at ambient temperature followed by addition of 63 ml (451 mmol) of triethy1amine to the reaction mixture and stirred for 12 hrs. Water (300 ml) was added to reaction mixture and the layers separated. The dichloromethane layer was washed with water (250 ml) and then brine (200 ml), dried with MgSO4 and evaporated to give a crude product. This was suspended in methy1-tert-buty1 ether (150 ml) and stirred for 30 min, filtered, washed with MTBE (50 ml) and dried under vacuum to give the title compound. Yield: 82 g (85%) M.R: 102°-105°C.

H1-NMR (CDCI3): δ 9.88(s, 1H); 7.82(d, 2H); 7.79(d, 2H); 7.33(d, 2H); 6.88(d, 2H); 4.39(t, 2H); 4.22(t, 2H); 2.45(s, 3H)

Example 2: Preparation of 2-(4-formy1 phenoxy)ethy1 methane sulfonate (formula-16b)
The title compound was prepared analogous to example 1 above using methane sulfony1 chloride used in place of tosy1 chloride. M.R: 67°-69°C H1-NMR (CDCI3): δ 9.90(s, 1H); 7.84(d, 2H); 7.01(d, 2H); 4.59(t, 2H); 4.32(t, 2H); 3.1(s, 3H)

Example 3: Preparation of 2-(4-formy1 phenoxy)ethy1 benzene sulfonate (formula-16c)
The title compound was prepared analogous to example 1 above using benzene sulfony1 chloride used in place of tosy1 chloride. M.R: 92°-94°CH1-NMR (CDCI3): δ 9.88(s, 1H); 7.96-7.92(m, 2H); 7.83-7.78(m, 2H); 7.77-7.65(tt, 1H); 7.59- 7.55(m, 2H); 6.87(d, 2H); 4.42(t, 2H); 4.23(t, 2H)

Example 4: Preparation of 2-(4-hydroxymethy1)phenoxy)ethy1-4-methy1 benzene sulfonate (formula-17a) To a solution of compound 16a (75 g, 234 mmol), 13.3 g (351 mmol) of sodium boro hydride was added in 600 ml of methanol at 0°-5°C. The reaction mixture was stirred for 15 min at 0°- 5°C and for another hour at ambient temperature. Then the reaction mixture was quenched with acetic acid and concentrated under vacuum until no solvent distilled. The gummy residue was partitioned between ethy1 acetate (250 ml) and water (250 ml). The layers were separated and the aqueous layer was extracted with ethy1 acetate (150 ml). The combined organic layer was washed with water (200 ml)and then brine (200 ml), dried with MgSO4 and concentrated under vacuum to give crude product. The crude product was stirred with 200 ml of heptanes at room temperature for 30 min, filtered, the crystalline material washed with heptanes (50 ml) and dried under vacuum to afford the title compound as a white solid. Yield: 67.9 g (90%) M.R:84°-88°C

H1-NMR (CDCI3): δ 7.83(d, 2H); 7.36(d, 2H); 7.27(d, 2H); 6.90(d, 2H); 4.61(s, 2H) 4.38(t, 2H); 4.16(t, 2H); 2.45(s, 3H)

Example 5: Preparation of 2-(4-hydroxymethy1)phenoxy)ethy1 methane sulfonate (formula- 17b)

This compound was prepared analogous to example 4 above using the starting material obtained from example 2 above. M.R: 85°-88°C

HNMR (CDCI3): 7.29(d, 2H); 6.88(d, 2H); 4.62(d, 2H); 4.56(t, 2H); 4.23(t, 2H); 3.09(s, 3H) 1.67(s, 1H)

Example 6: Preparation of 2-(4-hydroxymethy1)phenoxy)ethy1 benzene sulfonate (formulaic)

This compound was prepared analogous to example 4 above using the starting material obtained from example 3 above. M.R: 61°-63°C H1-NMR (CDCI3): 7.92(d, 2H); 7.69-7.64(tt, 1H); 7.58-7.53(m, 2H); 7.21(d,2H); 6.74(d, 2H); 4.60(s, 2H); 4.37(t, 2H); 4.13(t, 2H); 1.63(s, 1H)

Example 7: Preparation of 2-(4-bromomethy1)phenoxy ethy1-4-methy1 benzene sulfonate (formula-18a)

To a solution of compound 17a (50 g, 155 mmol) from example 4 in 500 ml dichloromethane 31.5 g (116 mmol) of phosphorus tribromide was added drop wise at 0-5°C. The reaction mixture was stirred for 4 to 5 hrs at ambient temperature. The reaction mixture was decomposed in chilled water and the layers separated. The dichloromethane layer was washed with saturated sodium bicarbonate solution (250 ml), water (150 ml) and brine (150 ml) successively. The organic layer was dried over MgSO4 and evaporated to give crude product. The residual solid was suspended in 125 ml of heptanes and stirred for 30 min, filtered, washed with 50 ml heptanes and dried under vacuum to afford the title compound as a white solid. Yield: 53.7 g (90%); M.R: 79°-83°C H1-NMR (CDCI3): δ 7.79(d, 2H); 7.32(d, 2H); 7.26(d, 2H); 6.72(d, 2H); 4.47(s, 2H); 4.34(t, 2H); 4.13(t,2H); 2.45(s,3H)

Example 8: Preparation of 2-(4-bromomethy1)phenoxy ethy1 methane sulfonate (formula- 18b)

This compound was prepared analogous to example 7 above using the starting material obtained from example 5 above. M.R: 74°-76°C

H1-NMR (CDCI3): δ 7.32(d, 2H); 6.85(d, 2H); 4.55(t, 2H); 4.49(s, 2H), 4.23(t, 2H); 3.08(s, 3H)

Example 9: Preparation of 2-(4-bromomethy1)phenoxy ethy1 benzene sulfonate (formulaic)

This compound was prepared analogous to example 7 above using the starting material obtained from example 6 above. M.R: 112°-114°C

H1-NMR (CDCI3): δ 7.95-7.92(m, 2H); 7.66-7.64(tt, 1H); 7.58-7.53(m, 2H); 7.26(d, 2H); 6.72(d, 2H), 4.47(s, 2H); 4.38(t, 2H); 4.13(t, 2H)

Example 10: Preparation of 2-(4-{[5-(benzy1oxy)-2-[4-(benzy1oxy)pheny1]-3-methy1-lH- indol-l-y1]methy1}phenoxy)ethy1-4-methy1benzenzene-l-sulfonate( formula 2a)

A solution of 5-benzy1oxy-2-(4-benzy1oxypheny1)-3-methy1-lH-indole of formula 3 (25 g, 59.6 mmol) in dimethy1 formamide (DMF, 100 ml) was cooled to -10° to -5°C and treated with sodium hydride (4.8 g, 120 mmol). Reaction mixture was stirred for 30 min and then 2-(4- bromomethy1)phenoxy ethy1-4-methy1 benzene sulfonate of formula 18a (27.5 g, 71.5 mmol) in DMF (100 ml) was added and stirred for 3 hrs at -5° to 0°C. The reaction mixture was quenched with acetic acid, poured into water (200 ml) and extracted with dichloromethane (2x200 ml). The dichloromethane layer was separated and washed with water (200 ml) and brine (100 ml), dried over MgSO4 and concentrated under vacuum to afford the crude material. This was found to contain 25-30% of C-alky1 impurity of formula-24. The crude material was dissolved in 150 ml of methanol-ethy1 acetate mixture (5:2) at 50°C and stirred for 30 min at ambient temperature. A white precipitate fell out of solution almost immediately. The precipitate was filtered, washed with 50 ml methanol and dried under vacuum to give 25.8 g (60%) of 2a as a white solid. M.R: 147-149°C. Purity by HPLC: 98% (Area)

H1-NMR (CDCI3): δ 7.77(d, 2H); 7.50-7.29 (m, 12H); 7.20(d, 2H); 7.13(d, 1H); 7.06-6.93 (m, 3H); 6.89(dd, 1H); 6.80(d, 2H); 6.61(d, 2H); 5.13(s, 2H); 5.09(s, 4H); 4.30(t, 2H); 4.05(t, 2H); 2.41(s, 3H), 2.24(s, 3H)

The C-alky1 impurity of formula-24 was isolated by column chromatography using silica gel from mother liquors.

H1 NMR (CDCI3): δ 8.09(d,2H);; 7.74(d, 2H); 7.49-7.25(m, 13H); 7.07(d, 2H); 6.88(d, 2H); 6.37(d,2H); 6.29(d, 2H); 5.15(s,2H); 5.10(s, 2H); 4.23(t, 2H); 3.94(t, 2H): 3.37(q, 2H); 2.42(s, 3H); 1.66(s, 3H)

Example 11: Preparation of 2-(4-{[5-(benzy1oxy)-2-[4-(benzy1oxy)pheny1]-3-methy1-lH- indol-l-y1]methy1}phenoxy)ethy1 methane sulfonate (formula 2b)

This compound was prepared analogous to example 10 using 2-(4-bromomethy1)phenoxy ethy1 methane sulfonate from example 8 in place of 2-(4-bromomethy1)phenoxy ethy1-4-methy1 benzene sulfonate. M.R: 126°-128°C

H1-NMR (CDCl3): δ 7.4-7.31 (m, 12H); 7.20(d, 2H); 7.13(d, 1H); 7.06-6.99 (m, 3H); 6.87(dd, 1H); 6.85(d, 2H); 6.72(d, 2H); 5.13(s, 2H); 5.12(s, 2H); 5.09(s, 2H); 4.5l(t, 2H); 4.15(t, 2H); 3.05(s, 3H); 2.24(s, 3H)

Example 12: Preparation of 2-(4-{[5-(benzy1oxy)-2-[4-(benzy1oxy)pheny1]-3-methy1-lH- indol-l-y1]methy1}phenoxy)ethy1 benzene sulfonate (formula 2c)

This compound was prepared analogous to example 10 using 2-(4-bromomethy1)phenoxy ethy1 benzene sulfonate from example 9 in place of 2-(4-bromomethy1)phenoxy ethy1-4-methy1 benzene sulfonate. M.R: 105°-108°C

H1-NMR (CDCI3): δ 7.93-7.89(m, 2H); 7.62-7.59(tt, 1H); 7.54-7.31 (m, 12H); 7.23(d, 2H); 7.14(d, 1H); 7.06-6.99 (m, 3H); 6.86(dd, 1H); 6.80(d, 2H); 6.60(d, 2H); 5.13(s, 2H); 5.09(s, 4H); 4.33(t, 2H); 4.06(t, 2H); 2.24(s, 3H)

Example 13: Preparation of 5-Benzy1oxy-2-(4-benzy1oxy-pheny1)-3-methy1-l-[4-(2-azepan- l-y1-ethoxy)benzy1]-lH-indole (formula-8)

A solution of compound 2a from example 10 (18 g, 24.8 mmol) in toluene (180 ml) was treated with hexamethy1eneimine (12.3 g, 124.3 mmol) and heated to 70-75°C for 12 hrs. The reaction mixture was concentrated and taken up in fresh toluene (100 ml). Toluene layer was washed with water (100 ml) and brine (100 ml), dried (MgSO4) and concentrated under vacuum to afford a crude material. This was suspended in methanol (100 ml), stirred for 1 hr at ambient temperature, filtered, washed with methanol (50 ml) and dried to get 15.3 g (95%) of title compound. HPLC: 96%

Example 14: Preparation of 5-Benzy1oxy-2-(4-benzy1oxy-pheny1)-3-methy1-l-[4-(2-azepan- l-y1-ethoxy)benzy1]-lH-indole (formula-8)

Compound was prepared by procedure as in example 12 using starting material 2b in place of 2a.

Example 15: Preparation of 5-Benzy1oxy-2-(4-benzy1oxy-pheny1)-3-methy1-l-[4-(2-azepan- l-y1-ethoxy)benzy1]-lH-indole (formula-8)

Compound was prepared by procedure as in example 12 using starting material 2c in place of 2a.

Example 16: Purification of formula-8 via hydrochloride salt (formula-21) formation
The compound 5-Benzy1oxy-2-(4-benzy1oxy-pheny1)-3 -methy1-1 -[4-(2-azepan-1 -y1- ethoxy)benzy1]-lH-indole from example 13 (14.5 g, 22.2 mmol) was dissolved in 145 ml toluene and heated to 65-70°C. Hydrochloric acid (5.6 ml, 55.5 mmol) was added during 10 tol5 min at 65-70°C. Reaction mixture was stirred for 30 min at 65-70°C and for 30 min at 30-35°C, filtered, washed the compound with toluene (50 ml) and dried under vacuum to get 14.5g hydrochloride salt.

The hydrochloride salt (14.5 g)was suspended in toluene (145 ml) at ambient temperature and stirred for 10 min. A solution of sodium hydroxide (3.5g) in water (75 ml) was added to the reaction mixture during 10 to 15 min. Then the reaction mixture was heated to 65-70°C and stirred for 1.5 hrs. After cooling the reaction mixture to ambient temperature the organic layer was separated. Aqueous layer was extracted with toluene (50 ml). The combined organic layer was washed with water (100 ml), dried (MgSO4) and treated with activated charcoal for 30 to 45 min at 70-75°C. Charcoal was filtered through celite bed and clear filtrate was concentrated to get a solid material, which was suspended in methanol (75 ml) and stirred for 30 min at ambient temperature, filtered, washed with methanol (25 ml) and dried under vacuum to afford pure compound-8 (13.0 g, 90%) M.R: 109-111°C; HPLC: 99.9% Example 17: Preparation of bazedoxifene free base (formula-9)

The compound 8 from example 14 (17 g, 26 mmol) dissolved in 340 ml of ethy1 acetate was subjected to catalytic hydrogenation with 5.1 g of 10% Pd/C, 50%wet, at a pressure of 4 to 5 kg/cm2 at 30-35°C until completion of the reaction (6-7 hrs) as verified by TLC. The mixture was filtered and washed with ethy1 acetate (50 ml). The filtrate was distilled completely under vacuum to afford a white foamy solid. Heptanes (100 ml) was added to the solid and stirred for 30 min, filtered, washed with heptanes (25 ml) and dried under vacuum to get title compound 9 (11.9 g, 97%) M.R:170-174°C; HPLC: 99.8% with the C-alky1ated impurity below detection limits.

Example 18: Preparation of 2-(4-((5-hydroxy-2-(4-hydroxy pheny1)-3-methy1-lH-indol-l- y1)methy1)phenoxy ethy1-4-methy1 benzene sulfonate (formula-19)
Compound 2a from example 10 (17 g, 23.5 mmol) dissolved in 340 ml of ethy1 acetate was subjected to catalytic hydrogenation as in example 15 above to get title compound-19 (10.9 g, 85%)

H1 NMR (CDCI3): δ 7.7(d, 2H); 7.28(d, 2H); 7.12(d, 2H); 7.0-6.90(m, 2H); 6.84(d, 2H); 6.78(d, 2H); 6.72(dd, 1H); 6.59(d, 2H); 5.07(s, 2H); 4.29(t, 2H); 4.04(t, 2H); 2.4(s, 3H); 2.19(s, 3H)

Example 19: Preparation of bazedoxifene free base (formula-9) from compound 19
A solution of compound 19 from example 18 (10 g, 18.4 mmol) in toluene (100 ml) was treated with hexamethy1eneimine (9.1 g, 92 mmol) and heated to 70-75°C for 12 hrs. Then the reaction mixture was concentrated and taken up in fresh toluene (100 ml). Toluene layer was washed with water (100 ml) and brine (100 ml), dried (MgSO4) and concentrated to obtain a foamy solid (8.1 g, 94%). The crude material was purified by column chromatography using silica gel to get 6.9 g (80%) of title compound. M.R: 170-174°C; HPLC: 99.8% with the C-alky1ated impurity below detection limits.

Example 20: Preparation of bazedoxifene acetate (formula-1)
Bazedoxifene free base from example 17 or from example 19 (10 g, 21.2 mmol) was suspended in acetone (80 ml) and heated to 50-55°C. After getting a clear solution, a mixture of acetic acid (1.4 g, 23.3 mmol) and acetone (10 ml) was added slowly. Then the reaction mixture was allowed to cool at 20-25°C, stirred for 2 hrs, filtered the product formed, washed with acetone (20 ml) and dried under vacuum to afford the title compound in high yield and high purity (12.7 g, 95%) M.R:176-181°C HPLC: 99.9%.

We claim:

1. A process for preparation of 1-{4-[2-(azepan-1-y1)ethoxy]benzyl}-2-(4-hydroxypheny1)-3- methyl-1H-indol-5-ol, commonly known as bazedoxifene, and its acetate salt, comprising the steps

a) reacting 5-benzy1oxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (formula 3) with an ester of a sulfonic acid of 2-(4-bromomethy1)phenoxyethanol (formula 18) in presence of sodium hydride in a suitable solvent at a temperature between -10° to 10° C for adequate time to complete the reaction

X= tosy1, mesy1, benzene sulfony1.

b) quenching the reaction mixture with acetic acid and water followed by extraction with dichloromethane and isolating crude product after evaporating the solvent

c) crystallizing the crude product from a suitable polar solvent or mixture of solvents to obtain a purity of greater than 98% (area by HPLC) of the ester of the sulfonic acid of 2- (4- {[5-(benzyloxy)-2-[4-(benzyloxy)pheny1]-3-methy1- 1H-indol-1 - y1] methy1 }phenoxy)ethanol (formula 2)

X= tosy1, mesy1, benzene sulfony1.
d) treating the pure product so obtained with hexamethy1enimine in a suitable non-polar solvent at a temperature between 70° and 80° and after suitable work up isolating the crude product l-(4-(2-(azepan-l-y1)ethoxy) benzy1)-5-(benzyloxy) -2-(4-(benzyloxy) pheny1)-3-methyl-1H-indole (formula 8)

e) purifying the crude product so obtained by first forming its hydrochloride salt, crystallizing the pure hydrochloride salt, liberating the pure free base from the hydrochloride salt with an inorganic base like sodium hydroxide and isolating the product of purity greater than 99% by HPLC

f) catalytically debenzy1ating the pure product 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5- (benzyloxy)-2-(4-(benzyloxy)pheny1)-3-methyl-1H-indole (formula 8) in presence of palladium-carbon to obtain the free base of bazedoxifene

g) optionally converting the free bazedoxifene base so obtained into pharmaceutically acceptable salt such as acetae or hydrochloride.

2. A process for preparation of 1-{4-[2-(azepan-1-y1)ethoxy]benzyl}-2-(4-hydroxypheny1)-3- methyl-1H-indol-5-ol, commonly known as bazedoxifene, and its acetate salt, comprising the steps

a) reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methy1-1H-indole (formula 3) with an ester of a sulfonic acid of 2-(4-bromomethyl)phenoxyethanol (formula 18) in presence of sodium hydride in a suitable solvent at a temperature between -10° to 10° C for adequate time to complete the reaction

b) quenching the reaction mixture with acetic acid and water followed by extraction with a dichloromethane and isolating crude product after evaporating the solvent

c) crystallizing the crude product from a suitable polar solvent or a mixture of polar solvents to obtain a purity of greater than 98% (area by HPLC) of the ester of the sulfonic acid of 2-(4-{[5-(benzyloxy)- 2-[4-(benzyloxy) phenyl]-3-methyl-1H-indol-1-y1] methyl} phenoxy)ethanol (formula 2)

d) catalytically debenzy1ating the product so obtained in presence of palladium-carbon to obtain the ester of the sulfonic acid of 2-(4-((5-hydroxy-2-(4-hydroxy phenyl)-3-methyl- 1H-indol- 1-yl)methyl)phenoxy ethanol

e) reacting the product so obtained with hexamethy1enimine in a suitable non-polar solvent at a temperature between 70° and 80° and after suitable work up isolating bazedoxifene free base (formula 9) of purity greater than 99.8% by HPLC with the C-alkylated impurity below detectable limits.

3. A process according to claims la and 2a, wherein sulfonic acid is selected from the group 4- methyl benzene sulfonic acid, benzene sulfonic acid, methane sulfonic acid and ethane sulfonic acid.

4. A process according to claims la and 2a, wherein the suitablel sulfoxide, N,N-dimethy1 formamide and acetonitrile, preferably N,N-dimethyl formamide.

5. A process according to claims 1c and 2c, wherein suitable polar solvent or mixture of solvents is selected from ethy1 acetate or methanol, preferably mixture of methanol and ethyl acetate.

6. A process according to claim 1d and 2e, wherein suitable non-polar solvent is selected from aromatic hydrocarbons such as toluene or xy1ene and ethers such as tetrahydrofuran or methyl tetrahydrofuran, preferably toluene.

7. A process for the preparation of ester of the sulfonic acid of 2-(4-bromomethy1)phenoxy ethanol (formula 18) used as in claims la or 2a comprising

a) treating compound 4-(2-hydroxyethy1oxy) benzaldehyde (formula-15) with a sulfonic acid chloride in a suitable solvent like dichloromethane and an organic base like triethy1amine and after suitable work up isolate the sulfonic acid ester of 2-(4-formyl phenoxy)ethanol (formula 16)

b) treating the compound so obtained with a reducing agent like a metal hydride, preferably sodium borohydride, in a suitable solvent to obtain the sulfonic acid ester of 2- (4-hydroxymethyl)phenoxy)ethanol (formula 17)

c) reacting the product so obtained with phosphorus tribromide in dichloromethane and after suitable work up isolating the product sulfonic acid ester of 2-(4- bromomethyl)phenoxy ethanol (formula 18).

X= tosyl, mesyl, benzene sulfonyl.

9. A process according to claim 8a, wherein sulfonic acid is selected from the group 4- methy1 benzene sulfonic acid, benzene sulfonic acid, methane sulfonic acid and ethane sulfonic acid, preferably 4-methyl benzene sulfonic acid.

10. A process according to claim 8b, wherein suitable solvent is selected from alcohols such as methanol, ethanol, 2- propanol or mixtures thereof, preferably methanol.