VISHNUKANT B (IN)
| WO2007144896A1 | 2007-12-21 |
| US20070112202A1 | 2007-05-17 | |||
| US20070100149A1 | 2007-05-03 |
We claim:
1. A process for preparing Letrozole, comprising reacting 4,4-(Hydroxy methylene) bis benzonitrile with trichloroacetonitrile. 2. The process of claim 1, wherein an acetimidate methyl ester derivative is represented by formula (I).
3. The process of claim 1, further comprising reacting acetimidate methyl ester derivative with trimethyl silyl derivative of 1,2,4- triazole to form Letrozole in an inert solvent and optionally in presence of a lewis acid
4. The process of claim 3, wherein the trimethyl silyl derivative of 1,2,4- triazole is prepared by reacting with hexamethyl disilazane and trimethyl silyl chloride.
5. The process of claim 3, wherein reaction is carried out at a temperature ranging between ambient and 40 0 C.
6. The process of claim3, wherein the lewis acid is selected from a group consisting of borontrifluoride dietherate, borontrifluoride-methanol complex and trimethylsilyl trifluoromethanesulphonate.
7. The process of claimό, wherein the preferred lewis acid is selected from a group consisting of borontrifluoride dietherate and borontrifluoride-methanol complex
8. The process of claim 3, wherein the inert solvent is selected from a group consisting of toluene, acetonitrile, ethyl acetate and dichloroethane.
9. A process of claim 3, comprising final crystallisation of Letrozole form a methylene chloride solution using hydrocarbon solvent. 10. The process of claim 8 wherein the hydrocarbon solvent used in selected from a group consisting of n-hexane, Cyclohexane and n-heptane.
11. An intermediate compound of formula (I)
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PROCESS AND INTERMEDIATE OF LETROZOLE
Field of invention: The present invention relates to a process for the preparation of Letrozole and a novel intermediate thereof.
Background of the invention:
Letrozole is a non-steroidal aromatase inhibitor used for the treatment of breast cancer and is commercially available in the market. Letrozole was developed for treatment of advanced breast cancer in post menopausal women with disease progrenion following anti-estrogen therapy, especially for first line treatment of post menopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer.
The enodosynthesis of estrogens in post menopausal women is mediated by the aromatase enzymes, which converts androstenedione and testosterone and other androgens into estradiol and estrone. Letrozole inhibits the biosyntheesis of estrogens from adrenal androgens (thus causing reduction in estrogen levels) by competitive binding to the heme portion of cytochrome P450 submit of aromatase. This binding reduces estrogens production, which significantly lowers serum estrogens. The suppression of estrogens may decrease the stimulatory effects of estrogens on tumor growth in estrogens responsive tumors Letrozole reportedly events no chemically relevant detectable effect on the synthesis of adrenal corticosteroids and aldosterone or on thyroid function.
Prior art of the invention:
US Patent No. 4,978,672 describes a process for the preparation of Letrozole by contacting 4- bromomethyl benzonitrile with 1 ,2,4-triazole to yield 4-(l-(l,2,4-triazolylmethyl) benzonitrile, which is further reacted with 4-fluorobenzonitrile to yield Letrozole.
US Patent No. 5,473,078 teaches a method of preparation of 4-[l-(l ,2,4-triazolyl)methyl] benzonitrile which is purified by column chromatography and reacted with 4- fluorobenzonitrile and potassium tert-butoxide in dimethyl formamide to yield Letrozole.
US Patent No. 5,073,574 relates to the preparation of 4-[α-(4-cyanophenyl-hydroxy methyl)- benzonitrile an intermediate useful in the preparation of Letrozole.
The foregoing processes suffer from various disadvantages like low purity of final product use of hazardous chemicals, expensive reagents rendering unsuitable for industrial manufacturing.
The processes described in US Patent No.'s 4,978,672 and 5,473,078 leads to a problem of production of considerable quantity of unwanted isomer 4-[l-(l,3,4-triazolyl)- methyl]benzonitrile. However, WO 2005/047269 describes a purification process for removing the above mentioned unwanted isomer.
Hence, there is a need for a process for the preparation of Letrozole which is free from above disadvantages.
Objects of the invention: An object of the invention is to provide a simple process for the preparation of Letrozole.
Another object of the invention is to provide a new intermediate for the preparation of Letrozole.
Summary of the invention: The present invention relates to a novel intermediate trichloroacetimidate bis-(4-cyano- phenyOmethylester of formula (I) represented below and its use in the preparation of Letrozole.
Formula (I)
The present invention provides a process for the preparations of Letrozole, which includes reacting an activated bis-(4-cyanophenyl)-methane with a triazole moiety. The activated bis- (4-cyanophenyl)-methane includes trichloroacetimidine leaving group.
The present invention provides a method, wherein the compound of formula (I) is reacted with N-silyl derivative of 1,2,4-triazole in an inert solvent and optionally in presence of leuris acid catalyst at a temperature ranging between ambient and 40 0 C to obtain Letrozole.
Detailed Description of the invention;
In accordance, the present invention provides a process for the preparation of Letrozole, the said process comprising reacting 4,4-(Hydroxy methylene) bis benzonitrile with Trichloroacetonitrile to obtain acetimidate methyl ester derivative of formula(I), which is further reacted with silyl derivative of 1,2,4-triazole and purification of the reaction mixture to yield Letrozole.
In an embodiment of the invention provides an intermediate acetimidate methyl ester derivative of formula(I)
Formula(I)
Another embodiment of the invention provides reaction of acetimidate methyl ester derivative with trimethyl silyl derivative of 1,2,4- triazole to form Letrozole in an inert solvent and optionally in presence of a lewis acid Yet another embodiment of the invention provides trimethyl silyl derivative of 1,2,4- triazole prepared by reacting with hexamethyl disilazane and trimethyl silyl chloride.
Still another embodiment of the invention provides a reaction temperature ranging between ambient and 40 0 C.
Still yet another embodiment of the invention provides use of lewis acid selected from a group consisting of borontrifluoride dietherate, borontrifluoride-methanol complex and trimethylsilyl trifluoromethanesulphonate.
Another embodiment of the invention provides preferred lewis acid selected from a group consisting of borontrifluoride dietherate and borontrifluoride-methanol complex The process of the invention provides use of inert solvent selected from a group consisting of toluene, acetonitrile, ethyl acetate and dichloroethane.
The process of the invention provides final crystallisation of Letrozole form a methylene chloride solution using hydrocarbon solvent.
The process of the invention provides hydrocarbon solvent selected from a group consisting of n-hexane, Cyclohexane and n-heptane.
An intermediate compound of formula (I).
Formula (I)
The present invention is illustrated with the following examples and should not be construed to limit the scope of the invention.
EXAMPLES
Example 1: Preparation of Trichloroacetimidate-bis-^-cyanophenyl) methyl ester of formula (L)
To a a cooled solution of 4,4-hydroxymethylene bis benzonitrile (4Og) in acetone (200ml) added Trichloroacetonitrile (36 ml) in the portions and stirred at temperature between 10 0 C - 20 0 C for a period of 10- 15 min. To this solution added 10% aqueous sodium hydroxide(60ml) to adjust the pH to around 7.00, continued stirring for further 2 to 3 hrs. HPLC monitoring of the reaction mixture showed traces of starting material .Worked up the reaction mixture by adding water (800 ml), stirred for 30 mints and filtered the precipitated solid. Washed the solid thoroughly with water till the water washing is neutral, dried the solid between 40 to 45°C under high vacuum for an overnight. Yield = 6.0.0 gms
Example 2: Preparation of N-trimethylsilyl 1,2,4-triazole.
To a suspension of 1,2,4- trizole (30 g) in ethylene dichloride (300 ml) added trimethyl silyl chloride (39.0 ml) and hexamethyl disilazone (96.0 ml) and the mixture heated around 90° for 20 h to 22 h. The solution become clear cooled the reaction mixture to room temperature to obtain silyl derivative in situ.
Example 3: Preparation of Letrozole:
To a solution of silylated derivative of example 2 added trimethylsilyl trifluoromethane sulphpnate (21.0ml) followed by product of example 1(6Og) in ethylene dichloride( 150ml). The mixture was stirred at room temperature for 24 to 30 hrs Worked up by adding water (75 ml), stirring, separating aqueous layer and organic layer. Adjusted the pH of aqueous layer between 7.00 to 8.00 below a temperature of 2O 0 C. Extracted with methylene chloride, separated methylene chloride layer concentrated Methylene chloride layer to a small volume and added n-hexane to obtain Letrozole(3.6g).
Example 4: Preparation of Letrozole
To a solution of silyl derivative of example 2 added Boron trifluoside - etherate, followed by product of example 1(6Og) in ethylene dichloride(150 ml). The mixture was stirred at room temperature for 24 to 30 hrs worded up by adding water (75.0 ml), stirring, separating aqueous layer and organic layer. Adjusted the pH of aqueous layer between 7.00 to 8.00 below a temperature of 20 0 C. Extracted with Methylene chloride, separated methylene chloride layer concentrated Methylene chloride layer to a small volume and added n-hexane to obtain Letrozole(7. Ig).
Example 5: Preparation of Letrozole
To a solution of example 2 added Boron trifluoside - Methanol, followed by product of example 1(6Og) in ethylene dichloride( 150ml). The mixture was stirred at room temperature for 24 to 30 hrs worded up by adding water (75 ml), stirring, separating aqueous layer and organic layer. Adjusted the pH of aqueous layer between 7.00 to 8.00 below a temperature of 20 0 C. Extracted with methylene chloride, separated methylene chloride layer concentrated methylene chloride layer to a small volume and added n-hexane to obtain Letrozole( 6.8g).
The schematic representation for the preparation of letrozole is enumerated as herein below:
Letrozole