FIELD OF THE INVENTION
The present invention relates to a simple and cost effective process for the preparation of highly pure a-ethyl-4-hydroxydesoxybenzoin of Formula-I,
(Formula Removed)
a key intermediate in the preparation of tamoxifen, which is useful in the treatment of harmone dependent tumors such as breast cancer.
BACKGROUND OF THE INVENTION
Tamoxifen of formula II is a well known non-steroidal antiestrogen, useful in the treatment of hormone-dependent tumors such as breast cancer. Tamoxifen is the Z or trans isomer of l,2-diphenyl-l-4-(2-dimethylamino-ethoxy)phenyl)-l-butene.
(Formula Removed)
Tamoxifen therapy has been one of the greatest success stories in the
pharmacological management of breast cancer and it remains the treatment of choice for most clinicians.
Tamoxifen was first disclosed in US Patent 4,536,516. There are several processes reported in this patent for the preparation of tamoxifen and its salts. In one of the process, a-ethyl-4-hydroxydesoxybenzoin of formula-I is prepared by demethylation of a-ethyl-4-methoxydesoxybenzoin of formula-III,
(Formula Removed)

using pyridine hydrochloride at a high temperature (above 160°C), which was further converted to tamoxifen in subsequent steps. The major drawback of this process is that the demethylation reaction is carried out at reflux temperature in the absence of solvent. In the exemplified process, yields are also not mentioned. As the reaction is a solid phase reaction and carried out at a very high temperature, it leads to decomposition and hence yields are very low. Further pyridine is reported to be carcinogenic, gastrointestinal or liver toxicant, neurotoxicant, respiratory toxicant, skin and sense organ toxicant and is not advised to be used in the preparation of useful medicaments.
US Patent.5,047,431 describes the process for the preparation of a-ethyl-4-hydroxydlesoxybenzoin comprising the Friedel-Crafts reaction of methoxybenzene with phenylacetyl chloride to afford l-(4'-methoxyphenyl)-2-phenylethan-l-one, which on reacting with ethyl bromide in dimethylformamide in the presence of
sodium hydride yields l-(4'-methoxyphenyl)-2-phenyl-n-butan-l-one. An ether cleavage of the resultant compound with pyridine hydrochloride leads to the formation of a-ethyl-4-hydroxydesoxybenzoin.
Other known processes for the preparation of tamoxifen and intermediates thereof include stereoselective syntheses of tamoxifen described in J. Chem. Soc., (Perkin Trans 1) 1987, 1101 and J. Org. Chem. 1990,55,6184 involving expensive catalysts.
So, in the light of the above description, it is clear that only a few processes are described in the prior art for the preparation of a-ethyl-4-hydroxydesoxybenzoin. Most of the prior art processes are involving expensive and harmful reagents, stringent reaction conditions which are not suitable for large-scale production. Further targe amount of unwanted impurities are also formed during reaction which leads to low yields and increases cost of production.
It is therefore, an object of the present invention to provide an efficient and industrial friendly method for the preparation of a-ethyl-4-hydroxydesoxybenzoin, in high yield and high purity avoiding using any toxic and expensive reagents and stringent reaction conditions.
A further object of present invention is to provide a simple and efficient one step process for the preparation of pure a-ethyl-4-hydroxydesoxybenzoin from 2-phenyl butyric acid, which is viable on industrial scale and leads to the formation of highly pure of tamoxifen.
A further object of present invention is to provide a simple and efficient process for the preparation of highly pure α-ethyl-4-methoxydesoxybenzoin leading to the formation of tamoxifen in exceptionally high purity and yield.
SUMMARY OF THE INVENTION
The present invention describes an industrially advantageous, simple and efficient process for the preparation of highly pure a-ethyl-4-hydroxydesoxybenzoin,
chemically known as l-(4'-hydroxyphenyl)-2-phenyl-n-butan-l-one of formula-I,
(Formula Removed)

by demelhylation of α-ethyl-4-methoxydesoxybenzoin of formula-III,
(Formula Removed)

using hydrobromic acid in acetic acid at temperature 30-120°C.
More particularly, one aspect of the present invention describes an improved one step process for the preparation of a-ethyl-4-hydroxydesoxybenzoin from 2-phenylbutyric acid, a key intermediate in the preparation of tamoxifen and pharmaceutically acceptable salts thereof.
Another aspect of the present invention deals with a process for the preparation of highly pure a-ethyl-4-methoxydesoxybenzoin leading to the formation of tamoxifen in exceptionally high purity and yield.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention describes a simple and efficient process for the preparation of a-ethyl-4-hydroxydesoxybenzoin of formula-I,
(Formula Removed)
a key intermediate in the preparation of tamoxifen.
More particularly, the process involves demethylation of a-ethyl-4-methoxydesoxybenzoin of formula-III,
(Formula Removed)

using hyclrobromic acid in acetic acid to afford a compound of formula-I.
According to the detailed embodiment of the present invention, a-ethyl-4-methoxydesoxybenzoin of formula-Ill is reacted with hydrobromic acid in the presence of acetic acid. Specifically, the reaction is conducted at temperature 110-120°C and it takes about 15-22 hours for completion of reaction. The progress of reaction is monitored by thin layer chromatography (TLC) as well as by high performance liquid chromatography (HPLC). After completion of reaction, the reaction mixture is cooled to 70-80°C and the mixture of 48 % hydrobromic acid and acetic acid is distilled out completely under reduced pressure. To remove the traces of hydrobromic acid and acetic acid, water is added to reaction mass at 70-80°C followed; by distillation. Thereafter, water is again added to the reaction mass and cooled to ambient temperature. The reaction mixture is filtered and compound of formula-l is isolated in high yield with 98% purity which can optionally purified to attain purity of more than 99%.
Another embodiment of the present invention describes an improved one step process for the preparation of a-ethyl-4-hydroxydesoxybenzoin of formula-I from 2-phenylbutyric acid of formula-IV,
(Formula Removed)
where intermediates are not isolated and is easily reproducible and amenable to large-scale production.
According to the detailed embodiment of the present invention, 2-phenylbutyric acid of formula-IV is treated with thionyl chloride at ambient temperature and the reaction mixture is refluxed to a temperature of 68-77°C for a period of about 2-4 hours.
Thereafter, thionyl chloride is distilled out completely, to afford 2-phenylbutyryl chloride of formula-V.


(Formula Removed)
To the resulting 2-phenylbutyryl chloride, suitable solvent is added at ambient temperature and the reaction mixture is cooled to temperature -35 to -25°C. To the reaction mass, aluminium chloride is added followed by addition of anisole at temperature -35 to -25°C and stirred for a period of 1-1.5 hours while maintaining the temperature -35 to -25°C. The suitable solvent may be selected from halogenated solvents and preferably methylene dichloride is used.
The progress of reaction is monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mass is quenched with dilute hydrochloric acid at 0° to 10°C. The layers are separated and organic layer is distilled out completely to afford α-ethyl-4-methoxydesoxybenzoin of formula-Ill.
(Formula Removed)
To the compound of formula-Ill, acetic acid is added at ambient temperature followed by addition of hydrobromic acid. The reaction mass is then slowly heated to
temperature at 110-120°C. Generally it takes about 15-24 hours for completion of reaction and preferably 18-22 hours are required. After completion of reaction, the reaction mass is cooled to 70-80°C and the solvent is distilled out completely under reduced pressure. Thereafter, water is added and distilled out completely to remove traces of hydrobromic acid and acetic acid. To the reaction mixture, water is again added and the reaction mass is cooled to 25-35°C and stirred at this temperature for 1 -2 hours. The reaction mass is filtered to afford a compound of formula-I in high yield and with 98% purity. The above compound is optionally purified to get product with purity greater than 99%. The purification is carried out by acid base treatment.
In another embodiment of the present invention, α-ethyl-4-hydroxydesoxybenzoin can be used without further purification to yield tamoxifen and its pharmaceutically acceptable salts, preferably citrate, by the methods given in prior art such as in US Patent 4,536,516.
Another embodiment of the present invention describes a process where intermediates such as α-ethyl-4-methoxydesoxybenzoin of formula-Ill can be optionally isolated and purified using a suitable solvent preferably hexane.
Major advantages realized in the present invention are high productivity and product purity. The process is simple, cost effective and avoids the use of toxic reagents and stringent reaction conditions. Further the process is industrial and environment friendly.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1
Preparation of a-ethyl-4-hvdroxydesoxybenzoin
To α-ethyl-4-methoxydesoxybenzoin (25 gm), acetic acid (125 ml) and 48% hydrobromic acid (125 ml) were added. The temperature of reaction mass was slowly raised to 110-115°C and retluxed for about 20 hours. After completion of reaction (monitored by TLC), the reaction mass was cooled to 80°C and the solvent was distilled out completely under reduced pressure to precipitate the product. To the precipitated product, water (25 ml) was added and distilled out completely under reduced pressure. Again water (25 ml) was added and reaction mass was cooled to ambient temperature. The precipitated product was filtered, washed with water, and dried to isolate 20.2 gm of a-ethyl-4-hydroxydesoxybenzoin having relative purity of 98.27 % (HPLC).
Example 2
Preparation of a-ethyI-4-hydroxydesoxybenzoin
Thionyl chloride (400 ml) was added to 2-phenylbutyric acid (100 gm) at ambient temperature and the reaction mixture was refluxed at 68-77°C for 3.0 hours. After completion of reaction, thionyl chloride was distilled out completely. To the resultant oil, methylene dichloride (660 ml) was added at ambient temperature, and the reaction mixture was cooled to -35 to -25°C. To the reaction mass, aluminium chloride (110 gm) was added at same temperature and stirred for 15 mints. To the above mass anisole (71.5 gm) was added and reaction mass was stirred for a period of 1-1.5 hours while maintaining the temperature at - 35 to -25°C. After completion of reaction (monitored by TLC), the reaction mass was added to dilute hydrochloric acid solution (prepared by adding 448.8ml of hydrochloric acid and 1100 ml of water) at 0° to 10°C. The layers were separated and the aqueous layer was extracted with
methylerae dichloride (220 ml). The combined methylene dichloride layer was washed twice with 10% sodium bicarbonate solution and concentrated in vacuum. To the above reaction mixture, acetic acid (785 ml) and 48% hydrobromic acid (785 ml) were added. The temperature of reaction mass was slowly raised to 110-115°C and refluxed for about 22 hours and after completion of reaction, it was lowered to 80°C. The solvent was distilled out completely under reduced pressure and to the resulting precipitated product; water (160 ml) was added and distilled out completely under reduced pressure. Again water (160 ml) was added and reaction mass was cooled to 25-35°C and stirred for 2 hours. The precipitated product was filtered, washed with water and dried under vacuum to obtain 112 gm of α-ethyl-4-hydroxydesoxybenzoin.
Example 3
Preparation of a-ethyl-4-hvdroxydesoxybenzoin
Thionyl chloride (400 ml) was added to 2-phenylbutyric acid (100 gm) at ambient temperature and the reaction mixture was refluxed to a temperature of 68-77°C for 3.0 hours. After completion of reaction, thionyl chloride was distilled out completely. To the resultant oil, methylene dichloride (660 ml) was added at ambient temperature, and the reaction mixture was cooled to -35 to -25°C. To the reaction mass, aluminium chloride (104 gm) was added at same temperature and stirred for 15 minutes. To the above mass anisole (72 gm) was added and reaction mass was stirred for 1-1.5 hours at - 35 to -25"C. After completion of reaction, the reaction mass was added to dilute hydrochloric acid solution (440.6 ml of hydrochloric acid and 1080 ml of water) at 0° to 10°C. The temperature of reaction mixture was raised to 25-30°C and the layers were separated. The aqueous layer was extracted with methylene dichloride (220 ml). The combined dichloride layer was washed twice with 10% sodium bicarbonate solution and concentrated in vacuum. To the above reaction mixture, acetic acid (785 ml) and hydrobromic acid (785 ml) was added. The temperature of reaction mass was slowly raised to 110-120°C and refluxed for about 22 hours. After completion of

reaction, the reaction mass was cooled to 80°C and the solvent was distilled out completely. To the resulting product, water (100 ml) was added and distilled out completely. Again water (100 ml) was added and reaction mass was cooled to 25-35°C and stirred for 2 hours. The precipitated product was filtered and wet product was added to water (600ml) and pH was adjusted to 12.0 with 10% sodium hydroxide solution. The reaction mass was carbonized and the filtered solution was treated with hydrochloric acid till pH 1.0-1.5. The reaction mixture was filtered, washed with water and dried at 50-60°C to obtain 104 gm of the α-ethyl-4-hydroxydesoxybenzoin having relative purity of 99.32 % by HPLC.

WE CLAIM

I. A process for the preparation of a-ethyl-4-hydroxydesoxybenzoin, namely, l-(4' hydr0xyphenyl)-2-phenyl-n-butan-l-one of formula-I,
Formula-I
(Formula Removed)
comprises demethylation of a-ethyl-4-methoxydesoxybenzoin of formula-III,
(Formula Removed)
using hydrobromic acid in acetic acid at temperature 30~120°C.

2. The process according to claim 1, wherein reaction mixture is refluxed at 110-
120°C for about 15-22 hours.

2. The process according to claim 1, wherein after completion of reaction, solvent is
distilled out completely.
4. The process according to claim 3, wherein after complete distillation of solvent,
product is washed with water and isolated.
5. A process for the preparation of a-ethyl-4-hydroxydesoxybenzoin, namely, l-(4'-

Formula-I
(Formula Removed)
which comprises,
reacting 2-phenylbutyric acid with thionyl chloride to prepare acid chloride,
reacting the acid chloride with anisole in the presence of aluminium chloride in
suitable solvent at temperature below -20°C,
distilling off the solvent,
refluxing the resulting residue with hydrobromic acid in acetic acid for a
sufficient time required to complete demethylation,
distilling off the solvent and
isolating the compound of formula-I.
6. The process according to claim 5, wherein suitable solvent is selected from hologenated solvents and preferably methylene dichloride.
7. The process according to claim 5, wherein the reaction mixture is refluxed for 15-
22 hours.
8. The process according to claim 5, wherein after complete distillation of solvent,
product is washed with water and isolated.