WO2007090464A1

WO2007090464A1 - Process for preparing letrozole

Info

Publication number: WO2007090464A1
Application number: PCT/EP2006/050743
Authority: WO
Inventors: Roberta Pizzocaro; Angelo Bedeschi
Original assignee: Solmag S.P.A.
Priority date: 2006-02-08
Filing date: 2006-02-08
Publication date: 2007-08-16

Abstract

A process for preparing letrozole by reacting p-fluorobenzonitrile with 4[1-(1,2,4- triazolyl)methyl]benzonitrile in the presence of an alkali metal alkoxide, characterised in that it comprises adding : 5 A) simultaneously separate solutions of respectively p-fluorobenzonitrile and 4[1- (1,2,4-triazolyl)methyl]benzonitrile in an aprotic dipolar solvent, or alternatively B) a unique solution of a mixture of p-fluorobenzonitrile and 4[1-(1,2,4- triazolyl)methyl]benzonitrile in an aprotic dipolar solvent, to a solution of said alkali metal alkoxide in the same dipolar aprotic solvent of (A) 10 or (B).

Description

PROCESS FOR PREPARING LETROZOLE Field of the invention

The present invention provides a process for the production of Letrozole. Background of the invention

Letrozole, which has the chemical name 4,4'-(1 H-1 ,2,4-Triazol-1 - ylmethylene)dibenzonitrile, is represented by the formula (I).

(I) Letrozole has been reported for instance in US 5,463,078 to possess antitumor activity, and aromatase inhibiting activity. Its synthesis has been reported in the same and additional patents, such as for instance US 5,352,795. Among the various possibilities, the patent claims a process wherein a compound of formula (II)

(H)

is reacted with a p-fluorobenzonitrile of formula (III),

in the presence of an alkali metal alkoxide, and in particular of potassium tert- butoxide, to afford a compound of formula (I). Typically, in the above mentioned patents, the reaction to afford compound of formula (I) is performed by: i) suspending potassium tert-butoxide in dimethylfomamide at low temperatures; ii) adding a solution of a compound of formula (II) in dimethylfomamide and maintaining the temperature below 0°C; iii) stirring the resulting solution for some short time at 0°C; iv) adding dropwise 4- fluorobenzonitrile in dimethylfomamide while maintaining the temperature below 5°C; and v) quenching the reaction mixture after a suitable short time. Alternatively, the potassium tert-butoxide solution in dimethylformamide was added to the reactants mixture when an in situ cyclization was needed to occur. Overall the step suffers of some drawbacks from the point of view of the scale-up for larger scale industrial production. In particular, the need to maintain low temperatures in several separate additions, the strict timing between the additions, and the need to add in sequence a series of reactants, make this sequence not practical for a safe scale-up. During the scale- up phases, in fact, it may be difficult to maintain the temperatures needed, and this may in turn influence the reactions and holding times, and eventually the final purity of the compound. We have found, in fact that during the scale-up phases a number of impurities are formed. Indeed, when scaled-up, the reaction resulted in a complex mixture of products, and the letrozole content was very low, accounting only for 30-40% of the products mixture observed, due to the above mentioned reasons. These impurities were in turn difficult to remove, and made the reaction work-up and purifications difficult and time and resources consuming. There was therefore the need for a better way to perform the process, that could be able to minimize the drawbacks of the above described method, and eventually to minimize the impurities formation during the reaction. In addition, according to the above mentioned US 5,352,795 patent, the compound 4[1 -(1 ,2,4-triazolyl)methyl]benzonitrile of formula (II) is in turn prepared by reacting a compound of formula (IV) with the appropriate heterocycle, like a 1 ,2,4-triazole, or a suitable salt thereof.

However, the reaction of 1 ,2,4-triazole with compound of formula (IV) in acetone was said, for instance in WO 2005/047269 A1 , to produce an isomeric mixture of 1 ,2,4- and 1 ,3,4-triazole derivatives, that then needed to be purified. It has also recently been disclosed, for instance in US 2005/0209294 A1 , that the use of DMF is beneficial in increasing the ratio toward the desired isomer. In the above mentioned US application, the 1 ,2,4-triazole is used as sodium salt, and reacted with the compound of formula (IV) above at 10-15°C. After work-up the derivative of formula (II) is isolated by crystallization from diisopropyl ether. However, this also has some drawbacks from the industrial point of view. First, it is not always optimal to use a separately prepared sodium salt, and, secondly, it is not very convenient to isolate the intermediates, and particularly from highly flammable solvents, such as diisopropyl ether. Therefore there is still the need to find a process for the preparation of compound of formula (I) that is more practical and safer from the point of view of the industrial production. Detailed description of the invention

It is therefore an object of the present invention to provide an economical, safer and industrially practical production method of Letrozole. The process for preparing letrozole according to the present invention involving the reaction of p-fluorobenzonitrile (III) with 4[1 -(1 ,2,4- triazolyl)methyl]benzonitrile (II) in the presence of an alkali metal alkoxide, which is characterised in that it comprises adding either: A) simultaneously separate solutions of respectively p-fluorobenzonitrile (III) and 4[1 -(1 ,2,4-triazolyl)methyl]benzonitrile (II) in an aprotic dipolar solvent, or alternatively

B) a unique solution of a mixture of said (II) and (III) in an aprotic dipolar solvent, to a solution of said alkali metal alkoxide in the same aprotic dipolar solvent of (A) or (B), avoids the drawbacks described above in the prior art, and allows for a safe, easy, practical, and industrially feasible process to make Letrozole. In fact, with the process according to the present invention which:

• changes the way in which the reactants are added,

• encompasses the addition of solutions of the compounds of formula (II) and (III) simultaneously, or a unique solution containing a mixture of said reactants, to a solution of the alkali metal alkoxide in the dipolar aprotic solvent at a suitable temperature, in a short time, and then passing directly the reaction mixture in water, so allowing to obtain a cleaner reaction mixture (at least 70% of chromatographic purity was observed in the crude reaction mixture), and that less impurities are formed during the reaction. This finding is also surprising in light of the way in which anionic reactions are usually performed, where generally an anion is previously formed, and subsequently reacted with a suitable alkylating agent.

In addition, this way to operate allows to run the process in a semi-batch or in a continuous way, reducing the need for operators intervention, and this finding is also part of the present invention. It was in fact found that the easier and cleaner way to perform the reaction is to maintain very short contact times and low excesses of the base and reactants in each moment during the reaction, and this also reduces the need for cooling down the reaction mixture. In addition we have found that it is possible to overcome the aforementioned drawbacks of the process for preparing the intermediate 4[1 -(1 ,2,4- triazolyl)methyl]benzonitrile of formula (II) disclosed US application 2005/0209294 A1 , which unlike the aforementioned prior art process, involves the formation of the sodium salt in situ of the compound of formula (IV). In particular the process for preparing the compound of formula (II) comprises reacting the halide of formula (IV) with a mixture of 1 ,2,4 triazole and a hydride of an alkali metal in an aprotic dipolar solvent. In addition we have surprisingly found that it is possible to use the reaction crude of intermediate (II) obtained with said process for the next step , without the need of isolating and purifying the intermediate, using the same solvent aprotic dipolar solvent into the subsequent step to transform compound (II) into compound (I), and obtaining a final compound of formula (I) above with a content < 0.1 % of the letrozole isomer (1 ,3,4 triazole), and this is also an object of the present invention. Detailed description of the invention

In the process according to the present invention the alkali metal alkoxide is preferably potassium terbutoxide, whereas the preferred aprotic dipolar solvent is dimethylformamide (DMF).

According to a preferred embodiment of the process according to the present invention the intermediate (II) and (III) are added to the solution of the alkali metal alkoxide with the modality (B), namely in an unique solution. The reaction temperature is generally maintained between -20 and +40°C.

According to a particularly preferred embodiment the process according to the present invention when run in a non continous way it comprises the following steps: i) mixing 4[1 -(1 ,2,4-triazolyl)methyl]benzonitrile (II) with p-fluoro-benzonitrile (III), in dimethylformamide at room temperature ii) adding the resulting solution in a short time to a cold (-20⁰C to 0°C) solution of tert-butoxide in dimethylformamide, maintaining the temperature in a temperature range of from -20° to 40°C, preferably from -10°C to 30°C, and most preferably between 0°C and 10°C, iii) allowing to stand the resulting mixture for a short time, preferably ranging from 1 minute to an hour, and most preferably between 5 minutes to half an hour, and iv) pouring rapidly the resulting mixture in water, let standing the resulting mixture for at least one hour, neutralizing the mixture with diluted mineral acid, and, after heating the mixture at about 40°C for at least four hours, cooling to room temperature, and v) filtering the precipitate, washing the precipitate, drying it, and vi) optionally purifying Letrozole by crystallization with a suitable solvent, wherein suitable solvents include alcohols, and water, or mixtures thereof, preferably with ethanol/water mixtures, and most preferably with 95% ethanol. When the process is run in a semi-batch or a continuous way it preferably comprises the following steps:

1 ) mixing a compound of formula (II), as defined above with a compound of formula (III), as defined above, in dimethylformamide at room temperature and then adjusting the temperature in a range between -20°C to 25 °C, preferably from -10°C to 20°C, and most preferably between -5°C to 5°C (Solution C),

2) preparing a solution of potassium tert-butoxide in dimethylformamide at a temperature comprised between -20°C to 25°C, preferably from -10°C to 20 °C, and most preferably between -5°C to 5°C (Solution D),

3) continuously mixing Solution C with Solution D, optionally under inert atmosphere, in a controlled manner at a suitable and constant flow rate, such as for instance a flow rate included between 0.01 to 1000 mL/min, preferably 0.1 to 500 mL/min, and more preferably between 1 to 50 mL/min in a suitable apparatus, such as for instance a tubing, or a piping, and the like, and

4) isolating the desired product with the modalities reported in step (iv), (v) and (vi) of the above preferred non-continuous process.

In the process for preparing the reactant of formula (II), to be used in the process according to the present invention, the alkali hydride is preferably sodium hydride, whereas the dipolar aprotic solvent is the same used in the process according to the present invention and according to a more preferred embodiment is DMF. The process for preparing the reactant of formula (II) preferably comprises the following steps : a) reacting the corresponding halogenide of formula (IV), as defined above, with a mixture of 1 ,2,4-triazole and sodium hydride in dimethylformamide, at a temperature ranging from -20°C to 40°C, preferably from -10°C to room temperature, and more preferably between -5°C to 10°C, for a time ranging from 5 minutes to a 2 hours, preferably from 10 minutes to one hour, and b) pouring the reaction mass in water, extracting compound of formula (II), as defined above, with methylene chloride, evaporating till an oily residue, and using the crude oily residue for the next step in the preparation of letrozole. The following examples are intended to illustrate the preferred method of the present invention, but are not intended to limit the scope of the invention. EXAMPLE 1-Preparation of 4-H -(1 ,2,4-triazolyl)methvπbenzonitrile (M)

1 ,2,4-triazole (43.7g) in DMF (91 ml_) was added to a suspension of sodium hydride (24g) in DMF (145 ml_), maintaining the temperature below 5°C in about one hour. The mixture was stirred at 0-5°C for about one hour, and then added to a solution of 4-bromomethyl benzonitrile (108g) (IV) in DMF (255 ml_), keeping the temperature below 5°C. The mixture was then stirred for an additional time till complete reaction. The reaction mixture was poured in cold water, and the aqueous mixture was extracted with methylene chloride. The organic solvent was evaporated in vacuo till an oily residue was obtained, with a K.F. value < 0.3%. The residue was taken up with DMF, and 4-fluoro benzonitrile (53.2g) was added. The resulting solution was divided in four portions, and each portion was then added in 5 minutes to a cold (-8°C) solution of potassium tert-butilate (29g) in DMF (150 ml_) under nitrogen, maintaining the temperature below 10°C. Each of the above mixtures was stirred for 2 minutes after the completion of the addition, and then poured into ice-water. The aqueous mixtures were combined, stirred for about one hour, and then neutralized with diluted HCI. The suspension was stirred for at about 40°C for a few hours, cooled at room temperature, filtered, and washed. The wet solid was then directly crystallized from a mixture of ethanol/water 9:1 (1000 ml_), filtered and dried to give pure Letrozole. EXAMPLE 2 -PREPARATION OF LETROZOLE 1 ,2,4-triazole (43.7g) in DMF (91 mL) was added to a suspension of sodium hydride (24g) in DMF (145 mL), maintaining the temperature below 5°C in about one hour. The mixture was stirred at 0-5°C for about one hour, and then added to a solution of 4-bromomethyl benzonitrile (108g) in DMF (255 mL), keeping the temperature below 5°C. The mixture was then stirred for an additional time till complete reaction. The reaction mixture was poured in cold water, and the aqueous mixture was extracted with methylene chloride. The organic solvent was evaporated in vacuo till an oily residue was obtained, with a K.F. value < 0.3%. The residue was taken up with DMF in inert atmosphere, and 4-fluoro benzonitrile (53.2) was added. DMF was further added to obtain a final volume of 1000 ml_, and the solution was then cooled to 0-5°C. In a second flask a 1000 ml_ solution of potassium tert-butilate (1 17.6g) in DMF under nitrogen was prepared at 0-5°C. The two cold stock solutions were passed together at the same speed, under a nitrogen pressure, through a column of 15 cm length, at a total flow rate of about 5-6 mL/min, and continuously poured in cold water. The aqueous mixture was stirred for about one hour, and then neutralized with diluted HCI. The suspension was stirred for at about 40°C for a few hours, cooled at room temperature, filtered, and washed. The wet solid was then directly crystallized from a mixture of ethanol/water 9:1 (1000 ml_), filtered and dried to give pure Letrozole.

Claims

1. A process for preparing letrozole by reacting p-fluorobenzonitrile with 4[1 - (1 ,2,4-triazolyl)methyl]benzonitrile in the presence of an alkali metal alkoxide, characterised in that it comprises adding: A) simultaneously separate solutions of respectively p-fluorobenzonitrile (III) and with 4[1 -(1 ,2,4-triazoryl)methyl]benzonitrile (II) in an aprotic dipolar solvent, or alternatively

B) a unique solution of a mixture of (II) and (III) in an aprotic dipolar solvent, to a solution of said alkali metal alkoxide in the same dipolar aprotic solvent of (A) or (B).

2. The process according to claim 1 wherein the temperature of said reaction is comprised between -20 and + 40 °C.

3. The process according to anyone of claims 1 and 2, comprising (B) adding a unique solution of a mixture of (II) and (III) in an aprotic dipolar solvent, to a solution of said alkali metal alkoxide in the same dipolar aprotic solvent of (B).

4. The process according to anyone of claims 1 -3, wherein the alkali metal alkoxide is potassium terbutoxide.

5. The process according to any one of claims 1 -4, wherein the dipolar aprotic solvent is DMF.

6. The process according to any one of claims 1 -5, wherein, when it is run in a non continous way it comprises the following steps: i) mixing 4[1 -(1 ,2,4-triazolyl)methyl]benzonitrile (II) with p-fluoro-benzonitrile

(III), in dimethylformamide at room temperature ii) adding the resulting solution in a short time to a solution of tert-butoxide in dimethylformamide at temperature comprised between -20-0°C, maintaining the temperature in a temperature range of from -20°to 40 °C, iii) allowing to stand the resulting mixture for a time ranging from 1 minute to an hour, from 5 minutes to half an hour, and then iv) pouring rapidly the resulting mixture in water, let standing the resulting mixture for at least one hour, neutralizing the mixture with diluted mineral acid, and, after heating the mixture at about 40°C for at least four hours, cooling to room temperature, and v) filtering the precipitate, washing the precipitate, drying it, and vi) optionally purifying Letrozole by crystallization with solvents selected from alcohols, water, and mixtures thereof, preferably with, and most preferably with 95% ethanol.

7. The process according to claim 6, wherein in step (iii) the temperature is maintained at from -10°C to 30 °C.

8. The process according to claim 7 wherein said temperature is comprised between 0°C and 10°C for a time comprised between 5 minutes to half an hour.

9. The process according to anyone of claims 6-8, wherein the solvent used in step (vi) is selected from ethanol/water mixtures.

10. The process according to claim 9, wherein said ethanol/water mixture is 95% ethanol.

1 1. The process according to anyone of claims 1 -5, wherein, when it is run in a semi-batch or a continuous way it comprises the following steps: 1 ) mixing 4[1 -(1 ,2,4-triazolyl)methyl]benzonitrile (II), with p-fluoro- benzonitrile (III), in dimethylformamide at room temperature and then adjusting the temperature in a range between -20°C to 25 °C (Solution

C),

2) preparing a solution of potassium tert-butoxide in dimethylformamide at a temperature comprised between -20°C to 25 °C, (Solution D),

3) continuously mixing Solution C with Solution D, optionally under inert atmosphere, in a controlled manner at a suitable and constant flow rate, such as for instance a flow rate included between 0.01 to 1000 mL/min, in an apparatus, selected from a tubing, or a piping, 4) isolating the desired product with the modalities reported in step (iv), (v) and(vi) of claim 6.

12. The process according to claim 1 1 , wherein in step (1 ) the temperature is adjusted between -10 to 20 °C.

13. The process according to claim 12, wherein said temperature is comprised between

-5°C to 5°C.

14. The process according to anyone of claims 11 -13, wherein in step (2) the temperature is comprised between -10°C to 20°C.

15. The process according to claim 14, wherein said temperature is comprised between -5°C to 5°C.

16. The process according to claim 15, wherein in step (3) the flow rate is comprised between 0.1 to 500 mL/min.

17. The process according to claim 16 wherein said flow rate is comprised between 1 to 50 mL/min.

18. The process according to anyone of claims 1 -17, wherein 4[1 -(1 ,2,4- triazolyl)methyl]benzonitrile (II) is prepared with a process comprising reacting the halide of formula (IV) with a mixture of 1 ,2,4 triazole and a hydride of an alkali metal in an aprotic dipolar solvent.

19. The process according to anyone of claims 1 -17, wherein the crude compound of formula (II) coming from the process according to claim 18 is used as the reactant.

20. The process according to anyone of claims 18-19, wherein the alkali metal hydride is sodium hydride.

21. The process according to anyone of claims 18-20, wherein the aprotic dipolar solvent is the same used in the preparation of letrozole.

22. The process according to anyone of claims 18-21 wherein the solvent is DMF.

23. The process according to anyone of claims 18-22 which comprises: a) reacting the corresponding halogenide of formula (IV), as defined above, with a mixture of 1 ,2,4-triazole and sodium hydride in dimethylformamide, at a temperature ranging from -20°C to 40°C, for a time ranging from 5 minutes to 2 hours, b) pouring the reaction mass in water, extracting compound of formula (II), as defined above, with methylene chloride, evaporating till obtaining an oily residue.

24. The process according to claim 23,whereinin step (a) the temperature is comprised between-10°C to room temperature.

25. The process according to claim 24, wherein said temperature is comprised between -5 to +10 °C.

26. The process according to anyone of claims 24 and 25 carried out for a time ranging from 10 minutes to 1 hour.