Field of the invention
The present invention provides a process for the preparation of 3-(3-(trifluoromethyl) phenyl) prop-2-yn-1-ol of Formula I.

Formula I

Background of the invention

The present invention provides a process for the preparation of 3-(3-(trifluoromethyl) phenyl) prop-2-yn-1-ol which is an important intermediate for the production of pharmaceutical drugs. Particularly, it is a key intermediate for the synthesis of Cinacalcet.

The US Publication No. 2008/0319229 describes a process for the preparation of compound of Formula I by reacting 3-bromo benzotrifluoride with propargyl alcohol in the presence of copper(I)iodide, palladium(II)chloride and triphenylphosphine under nitrogen atmosphere for 17 hours. The molar ratio of palladium(II)chloride to 3-bromobenzotrifluoride used is 0.004.

While working on the present invention, the inventors have observed that the molar ratio of catalyst to 3-bromobenzotrifluoride and inert atmosphere plays a crucial role. Further, they have observed that a low molar ratio of catalyst to 3-bromo benzotrifluoride leads to incomplete reaction, longer reaction time and thereby increasing the chance of forming impurities. Thus, making the process industrially unfavourable. The inventors have surprisingly found that when the molar ratio of palladium dichloride to 3-bromobenzotrifluoride is more than 0.005 the reaction time reduces remarkably by less than half as to what is mentioned in the prior art. Additionally, carrying out the reaction under argon atmosphere aids faster reaction.

Summary of the invention

The present invention provides a process for the preparation of a compound of Formula I,

Formula I
comprising:
a) contacting a compound of Formula II with a compound of Formula III in the presence of palladium catalyst under argon atmosphere to obtain the compound of Formula I; and
b) isolating the compound of Formula I obtained from step a).

Formula II Formula III

The present invention also provides a process for the preparation of a compound of Formula I, comprising;
a) contacting a compound of Formula II with a compound of Formula III in the presence of palladium dichloride to obtain the compound of Formula I, wherein palladium dichloride and the compound of Formula II are present in a mole ratio of 0.005 or more; and
b) isolating the compound of Formula I from step a).

Formula II Formula III

Detailed description of the invention

In an aspect, the present invention provides a process for the preparation of a compound of Formula I,

Formula I
comprising:
a. contacting a compound of Formula II with a compound of Formula III in the presence of palladium catalyst under argon atmosphere to obtain the compound of Formula I; and
b. isolating the compound of Formula I obtained from step a).

Formula II Formula III
The palladium catalyst used in the step a) is selected from the group consisting of (Ph3P)4Pd, (Ph3P)2PdCl2, NaPdCl4, Pd(OAc)2, Pd(MeCN)2Cl2, PdCl2, and PdI2.

In another aspect, the present invention provides a process for the preparation of a compound of Formula I, comprising;
a. contacting a compound of Formula II with a compound of Formula III in the presence of palladium dichloride to obtain the compound of Formula I, wherein palladium dichloride and the compound of Formula II are present in a mole ratio of 0.005 or more; and
b. isolating the compound of Formula I obtained from step a).

Formula II Formula III

The compound of Formula II may be prepared by any method known in the art or may be obtained commercially. The compound of Formula III may also be obtained from a commercial source.

The step a) may be carried out at a temperature in the range of 50°C to 100°C, more preferably at 70°C to 75°C in 4 to 5 hours.

The step a) may be carried out in the presence of copper(I)iodide, triphenylphosphine and a base. The base is selected from the group consisting of triethyl amine, diisopropylethylamine, diethyl amine, pyrrolidine, potassium carbonate, sodium carbonate, cesium carbonate and piperidine.

The reaction may be carried out in the presence of organic solvent or water. An organic solvent may be selected from the group consisting of N, N dimethylformamide, N, N dimethylacetamide, N-methylpyrrolidine, dimethyl sulphoxide, dioxane, acetonitrile and tetrahydrofuran or a mixture thereof.

The molar ratio of palladium dichloride to the compound of Formula II is in the range of 0.005 to 0.1.

The compound of Formula I is isolated by any of the methods known in the art, for example, filtration, distillation, evaporation, layer separation and column separation or mixture thereof.

The compound of Formula I as obtained by the process of the present invention has a purity greater than 99%, preferably greater than 99.5% by liquid chromatography.

While the present invention has been described in terms of its specific embodiments, 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.

The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.

Example
Example 1: Process for the preparation of 3-(3-(trifluoromethyl) phenyl) prop-2-yn-1-ol
A 1-litre 4-necked round bottom flask was fitted with a mechanical stirrer, an addition funnel, thermometer sensor and take off for argon flow. 3-bromobenzotrifluoride (120 g, 0.53 moles) was dissolved in triethyl amine (180 ml) and N, N-dimethyl acetamide (60 ml) under argon atmosphere and the mixture was heated to 50°C. The copper(I)iodide (1.6g, 0.56 mmol), palladium(II) dichloride (1g, 0.84 mmol) and triphenyl phosphine (6g, 2.2mmol) were added to the mixture. The temperature of the mixture was adjusted to 70°C. Propargyl alcohol (38.4g, 0.68 mol) was slowly added to the mixture. After 5 hours, the mixture was diluted with toluene (1 litre) and filtered. The filtrate was washed with 3×300 ml 1N hydrochloric acid followed by sodium bicarbonate solution (300 ml). The toluene layer was dried with dry sodium sulphate and then concentrated under reduced pressure to afford crude compound (105 g). The crude compound (105 g) was loaded on silica gel (300 g), 5% ethyl acetate in hexane was passed through column and the title compound in hexane was collected. Solvent was evaporated and title compound was dried for 1 hour at 45°C under reduced pressure 0-5 mmHg.
Yield (%): 80
Purity (%): 100 (by liquid chromatography)

WE CLAIM:
1. A process for the preparation of a compound of Formula I,

Formula I
comprising:
a) contacting a compound of Formula II with a compound of Formula III in the presence of palladium catalyst under argon atmosphere to obtain the compound of Formula I; and
b) isolating the compound of Formula I obtained from step a).

Formula II Formula III
2. A process for the preparation of a compound of Formula I, comprising;
a) contacting a compound of Formula II with a compound of Formula III in the presence of palladium dichloride to obtain the compound of Formula I, wherein palladium dichloride and the compound of Formula II are present in a mole ratio of 0.005 or more; and
b) isolating the compound of Formula I obtained from step a).

Formula II Formula III

3. The process as claimed in claim 1, wherein the palladium catalyst is selected from the group consisting of (Ph3P)4Pd, (Ph3P)2PdCl2, NaPdCl4, Pd(OAc)2, Pd(MeCN)2Cl2, PdCl2 and PdI2.

4. The process as claimed in claim 1 and 2, wherein the process is carried out in the presence of copper(I)iodide, triphenylphosphine and a base.

5. The process as claimed in claim 4, wherein the base is selected from the group consisting of triethyl amine, diisopropylethylamine, diethyl amine, pyrrolidine, potassium carbonate, cesium carbonate and piperidine.

6. The process as claimed in claim 1 and 2, wherein the process is carried out in the presence of organic solvent or water.

7. The process as claimed in claim 6, wherein organic solvent is selected from the group consisting of N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulphoxide, dioxane, acetonitrile and tetrahydrofuran or a mixture thereof.

8. The process as claimed in claim 2, wherein the molar ratio of palladium dichloride to the compound of Formula II is in the range of 0.005 to 0.1.

9. The process as claimed in claim 1 and 2, wherein the process is carried out at a temperature in the range of 50°C to 100°C.